The amazing potential of fungi: 50 ways we can exploit fungi industrially

REVIEW The amazing po en ial o ungi: 50 ways we can exploi ungi indus ially Ke in D. Hyde 1,2,3,4,5,9 ·Jianchu Xu 1,10,21 ·Syl ie Rapio 22 ·Rajesh Jeewon 18 ·Saisamo n Lumyong 9,13 · Allen G ace T. Niego 2,3,20 ·P anami D. Abeywick ama 2,3,7 ·Jani h V. S. Alu hmuhandi am 2,3,7 · Rashika S. B ahamanage 2,3,7 ·Si ap apa B ooks 3 ·Amo n a Chaiyasen 28 ·K. W. Thilini Che hana 2,3,7 · Pu a ak Chomnun i 2,3 ·Cla a Chepki ui 12 ·Boon iya Chuankid 2,3 ·Nimali I. de Sil a 1,2,4,13 · Mingkwan Doilom 1,4,13 ·C aig Faulds 6 ·Eleni Gen ekaki 3 ·Venka Gopalan 14 ·Pa ana Kakumyan 2,3 · Dulanjalee Ha ishchand a 2,3,7 ·H idya Hemachand an 24 ·Sinang Hongsanan 26,27 ·Anu uddha Ka una a hna 2,17 · Saman ha C. Ka una a hna 1 ·Seh oon Khan 10 ·Ja u ong Kumla 13,9 ·Ru ishika S. Jayawa dena 2,3 · Jian-Kui Liu 11 ·Ningguo Liu 2,3 ·Tha sanee Luangha n 1,21,22,29 ·Allan Pa ick G. Macabeo 12,23 · Diana S. Ma asinghe 2,3 ·Dan Meeks 19 ·Pe e E. Mo ime 1,10 ·Pe e Muelle 19 ·Sadia Nadi 10,15,21 · Ka aba N. Na a aja 16 ·Su eepo n Non achaiyapoom 3 ·Meghan O’B ien 19 ·Wa sana Penkh ue 9,13 · Chayana d Phukhamsakda 2,3 ·Uma Shaanke Ramanan 16,25 ·Achala R. Ra hnayaka 2,3 ·Resu eccion B. Sadaba 29 · Bi he Sanda go 12 ·Binu C. Sama akoon 2,3 ·Danushka S. Tennakoon 2,3 ·Ramamoo hy Si a 24 · Wasan S ip om 9,13 ·T. S. Su yana ayanan 30 ·Kanapo n Suja i 9,13 ·Naka in Suwanna ach 9,13 · Thi ipone Suwunwong 3,8 ·Benja ong Thongbai 12 ·Na i sada Thongklang 2 ·Deping Wei 1,2,3,17 · S. Nuwan hika Wijesinghe 2,3 ·Jake Winiski 19 ·Jiye Yan 7 ·E andi Yasan hika 2,3 ·Ma c S adle 12 Recei ed: 5 Ap il 2019 / Accep ed: 20 May 2019 / Published online: 3 July 2019 ©The Au ho (s) 2019 Abs ac Fungi a e an unde s udied, bio echnologically aluable g oup o o ganisms. Due o he immense ange o habi a s ha ungi inhabi , and he consequen need o compe e agains a di e se a ay o o he ungi, bac e ia, and animals, ungi ha e de eloped nume ous su i al mechanisms. The unique a ibu es o ungi hus he ald g ea p omise o hei applica ion in bio echnology and indus y. Mo eo e , ungi can be g own wi h ela i e ease, making p oduc ion a scale iable. The sea ch o ungal biodi e si y, and he cons uc ion o a li ing ungi collec ion, bo h ha e inc edible economic po en ial in loca ing o ganisms wi h no el indus ial uses ha will lead o no el p oduc s. This manusc ip e iews i y ways in which ungi can po en ially be u ilized as bio echnology. We p o ide no es and examples o each po en ial exploi a ion and gi e examples om ou own wo k and he wo k o o he no able esea che s. We also p o ide a low cha ha can be used o con ince unding bodies o he impo ance o ungi o bio echnological esea ch and as po en ial p oduc s. Fungi ha e p o ided he wo ld wi h penicillin, lo as a in, and o he globally signi ican medicines, and hey emain an un apped esou ce wi h eno mous indus ial po en ial. Keywo ds Biocon ol · Biodi e si y · Bio echnology · Food · Fungi · Mush ooms Table o con en s F om basic o applied esea ch, p o o ypes and p oduc s con ibu ion by Bi he Sanda go, Ma c S adle S a egies agains human disease 1. An ibac e ial an ibio ics con ibu ion by Cla a Chepki ui, Benja ong Thong- bai, Ma c S adle , 2. An imyco ics con ibu ion by Benja ong Thongbai, Ma c S adle 3. Bio ilm inhibi o s con ibu ion by Benja ong Thongbai, Ma c S adle &Jianchu Xu [email p o ec ed] Ex ended au ho in o ma ion a ailable on he las page o he a icle 123 Fungal Di e si y (2019) 97:1–136 h ps://doi.o g/10.1007/s13225-019-00430-9 4. An i-cance agen s con ibu ion by Chayana d Phukhamsakda, Ma c S adle 5. An i-diabe es con ibu ion by Achala R. Ra hnayaka, Ma c S adle 6. Imp o ing ne e unc ioning con ibu ion by Benja ong Thongbai, Ma c S adle 7. Fungi in T adi ional Chinese Medicine con ibu ion by Tha sanee Luangha n, Ma c S adle 8. Ca dio ascula disease con ol by ungi con ibu ion by Anu uddha Ka una a hna, Ma c S adle 9. An i i al agen s con ibu ion by Allan Pa ick G. Macabeo, Ma c S adle 10. Immunosupp essi e and immunomodula o y agen s om ungi con ibu ion by Cla a Chepki ui, Ma c S adle S a egies agains plan disease 11. Biocon ol o plan disease using endophy es con ibu ion by Nimali I. de Sil a, Si ap apa B ooks 12. Biocon ol o insec s using ungi con ibu ion by Allen G ace T. Niego 13. Biocon ol o nema odes and ungal nema izides con ibu ion by Diana S. Ma asinghe, Cla a Chepki ui 14. Biocon ol o weeds and he bicides om ungi con ibu ion by P anami D. Abeywick ama, Jiye Yan 15. Fungal an agonis s used in pos -ha es disease con ol con ibu ion by Binu C. Sama akoon 16. Bio con ol o us s and smu s by an agonis ic ungi con ibu ion by Rashika S. B ahmanage Enhancing c ops and o es y 17. Bio e ilize s con ibu ion by Mingkwan Doilom 18. A buscula myco hizae as bio e ilize s con ibu ion by Amo n a Chaiyasen, Saisamo n Lumyong 19. Applica ion o ec omyco hizal ungi in o es y con ibu ion by Ja u ong Kumla, Saisamo n Lumyong 20. Use o o chid myco hizae and endophy es in bio echnology con ibu ion by Nimali I. de Sil a, Su eepo n Non achaiyapoom 21. G ow h p omo ing ho mones om ungi con ibu ion by Saisamo n Lumyong 22. Mi iga ing abio ic s ess in plan s: he endophy e me hod con ibu ion by Ka aba N. Na a aja, Uma Shaanke Ramanan Food and be e ages om ungi 23. G owing mush ooms in compos con ibu ion by Na i sada Thongklang 24. G owing mush ooms in bags con ibu ion by Saman ha Ka una a hna 25. G owing mush ooms in he ield con ibu ion by Pe e E. Mo ime , Saman ha C. Ka una a hna 26. Mode n mush oom p oduc ion: an au oma ed ac o y p ocess con ibu ion by Jianchu Xu 27. New edible mush ooms con ibu ion by Saman ha Ka una a hna 28. Aga icus sub u escens con ibu ion by Na i sada Thongklang 29. Using ungi o enhance ood alue con ibu ion by Danushka S. Tennakoon 30. Food colou ing om ilamen ous ungi con ibu ion by Wasan S ip om and Saisamo n Lumyong 31. Food la ou ing con ibu ion by S. Nuwan hika Wijesinghe 32. Wha is mush oom s ock? P oduc s, p ocess and la ou s con ibu ion by Deping Wei 33. Fungi in making ea con ibu ion by Ningguo Liu, Jack JK Lui 34. Wine, bee and spi i s con ibu ion by Sinang Hongsanan 35. Func ional oods and nu aceu icals con ibu ion by Boon iya Chuankid 36. Ha es ing he un apped p obio ic po en ial o ungi con ibu ion by Eleni Gen ekaki, Achala R. Ra hnayaka Sa ing he plane 37. Ag icul u al was e disposal con ibu ion by Pu a ak Chomnun i, C aig Faulds 38. Myco emedia ion: Fungi o he escue con ibu ion by Dulanjalee Ha ishchand a, Jiye Yan 39. Myco umiga ion using Muscodo con ibu ion by Naka in Suwanna ach, Saisamo n Lumyong 40. Biomass o bio uel: unmasking he po en ial o lesse -known ungi con ibu ion by Venka Gopalan, T.S. Su yana ayanan 41. Packed-bed bio eac o o mycoma e ial p oduc ion con ibu ion by Pe e Muelle , Dan Meeks, Meghan O’B ien, Jake Winiski 2 Fungal Di e si y (2019) 97:1–136 123 42. Fungal deg ada ion o plas ics: A hidden easu e o g een en i onmen con ibu ion by Seh oon Khan, Sadia Nadi 43. Polycyclic a oma ic hyd oca bon deg ada ion by basidiomyce es con ibu ion by Allen G ace T. Niego, Resu eccion B. Sadaba 44. Can ungi help modi y he sus ainable soil enhance biocha ? con ibu ion by Thi ipone Suwunwong, C aig Faulds Commodi ies 45. Fungi and cosme ics con ibu ion by E andi Yasan hika 46. Aga wood con ibu ion by S. Nuwan hika Wijesinghe 47. Fungal enzymes con ibu ion by Pa ana Kakumyan 48. P ese a i es con ibu ion by Benja ong Thongbai 49. O ganic acids con ibu ion by Jani h V.S. Alu hmuhandi am 50. Tex ile dyes con ibu ion by Ru ishika S. Jayawa dena The u u e Func ional genomics and he sea ch o no el an i- in ec i es con ibu ion by K.W. Thilini Che hana, Jiye Yan and Bi he Sanda go F om basic o applied esea ch, p o o ypes and p oduc s Fungi ha e bo h good and bad ace s (Poin ing and Hyde 2001). They a e essen ial o nu ien cycling because o hei abili y o deg ade cellulose and lignin (Poin ing e al. 2001). On he o he hand, hey cause se ious human, ani- mal and plan diseases and ha e nume ous nega i e aspec s on human li e (Hyde e al. 2018a). Fungi a e, howe e , also ela i ely unde s udied, bu a e an essen ial, ascina ing and bio echnologically use ul g oup o o ganisms wi h an inc edible bio echnological po en ial o indus ial exploi a ion. In his pape , we de ail 50 ways in which we can po en ially exploi ungi. We p o ide no es and examples o all po en ial exploi a ions and gi e examples om ou own wo k and he wo k o o he s. We also p o- ide a low cha ha can be used o con ince unding bodies jus how impo an ungi a e and hei po en ial o bio echnological esea ch and po en ial p oduc s. While se e al o ou chap e s a e dealing wi h ma ke ed p oduc s ha e en include blockbus e pha maceu icals, such as he be a-lac am an ibio ics, he s a ins and cyclos- po ine, o he s a e dedica ed o newly upcoming a eas ha s ill emain o be explo ed. O he chap e s ea ela i ely small ma ke segmen s ha may expand in he u u e. Fo example, he consume s a ound he wo ld now inc easingly p e e na u al compounds o e syn he ic chemicals and e en in he indus ial sec o s ha p oduce commodi y chemicals, he e is now an inc eased in e es in de elop- men o sus ainable bio echnological p ocesses, in o de o ob ain new na u al p oduc s ha can e en ually eplace adi ional syn he ics. As compa ed o o he biological sou ces, in pa icula plan s, ungi ha e he g ea ad an age ha hey can be g own in la ge bio eac o s a an indus ial scale, and sui able p ocesses o hei cos -e icien e - men a ion ha e been a ailable o many decades, e.g. o p oduc ion o ce ain o ganic acids, enzymes and an ibi- o ics. As exempli ied by he ecen s udies o he Thai mycobio a, mode n polyphasic axonomic app oaches a e cons an ly e ealing a ple ho a o new and undesc ibed species e en in he ai ly well-known gene a o ungi like Aga icus (Hyde e al. 2018b). E en he majo i y o he known species in he ungal kingdom a e i ually un ap- ped wi h ega d o po en ial applica ions, also because hey we e ne e cul u ed and s udied o hei g ow h cha ac- e is ics and physiology. New me hods and p o ocols ha e o be de eloped o his pu pose, and his implies ha subs an ial basic esea ch mus be ca ied ou be o e he exploi a ion o he no el o ganisms can be en isaged. Al hough ungi ha e so many po en ial uses, esea ch on hei po en ial applica ions is in gene al poo ly unded and much o he esea ch ha is being ca ied ou in academia is undamen al, e en in a eas ha belong o he ields o bio echnology and applied mycology. Fo example, sc eening ungi o p oduc ion o an ibio ics by an ago- nis ic cul u e es ing has o en been epo ed, bu is unli- kely o lead o indus ial p ojec s. O en, i will ake o e a decade e en o b ing a gi en p ojec based on a no el ungal me aboli e in o he p eclinics, and e en his is only possible by join , in e disciplina y e o s o biologis s, bio echnologis s, pha macis s and chemis s. Mo eo e , he Big Pha ma indus y has ecen ly downsized hei capaci- ies o in-house esea ch, meaning ha he academic sec o (some imes suppo ed by smalle companies o o ganisa ions like he Bill and Melinda Ga es Founda ion and he Wellcome T us ) has become mo e and mo e in ol ed in he p eclinical e alua ion o new compounds. In es ing in basic esea ch may seem, a i s sigh , a cos ly a ai . Howe e , he e a e nume ous examples o he Fungal Di e si y (2019) 97:1–136 3 123 pas demons a ing why in es ing in basic esea ch pays o in he long un, and e en mo e easons, why i is oday mo e impo an han e e o enew an in e es in basic esea ch on ungi. Bu how o con ince unde s, in pa - icula om he p i a e sec o , o in es in o esea che s doing basic esea ch on ungi? The e a e, no doub , a eas o esea ch, which a e o u mos impo ance o he en i e wo ld, ye a e conside ed alueless o he pha maceu ical indus y. One o hese is he sea ch o no el an i-in ec i es, as he wo ld is unning ou o an ibio ics (Hes e kamp 2017; WHO epo 2017). I has long been seen as a edious p ocess o ob ain no el an ibio ics om li ing o ganisms. Howe e , he ocus in he pas has been on he same bac e ial and ungal gene a, such as S ep omyces in he Ac inobac e ia and common soil moulds like Aspe gillus and Penicillium in he ilamen ous ungi (Ka wehl and S adle 2017). Since almos no no el ca bon skele ons ha e been disco e ed om hese common soil mic obes in he pas 20 yea s, i makes much mo e sense o s udy he nume ous species ha a e cons an ly being disco e ed and shown o belong o new phylogene ic g oups. In ou e iew, we p esen ungi, in pa icula Basid- iomyco a, as a s ill unde explo ed, highly p omising sou ce o an i-in ec i es, immunosupp essan s, and o he pha - maceu icals (see Badalyan e al. 2019; Sanda go e al. 2019a) ha is nowhe e nea d ied up. We gi e examples on ecen de elopmen s o u ning ungal na u al p oduc s in o comme cial d ugs and gi e an o e iew o he cu en s a e o applied esea ch in his ield. In he pas , ungal na u al p oduc s ha e also led o some blockbus e s and a ious de elopmen al candida e com- pounds o he ag ochemical indus y (Bills and Gloe 2016). Howe e , he uncon olled usage o such ungal pes icides has led o he de elopmen o mo e and mo e esis ances agains hese ag ochemicals (Lucas e al. 2015). A mo e con olled app oach o c op p o ec ion is he e o e ad isable. Mo e basic esea ch is needed o unde s and na u al p ocesses, and he eby allow o he sea ch o na u al con ol agen s. In he en ies dealing wi h “S a e- gies agains plan disease”, we show he g ea po en ial o ungi as biocon ol agen s. We gi e examples o how ungal biocon ol agen s can help sa e he Ag o sec o emendous amoun s o money, i companies a e gi en he oppo uni y o p oduce cos e icien biocon ol agen s. In a likewise manne , he pa on “Enhancing c ops and o - es y” deals wi h he cu en esea ch on ec omyco hiza and hei po en ial applica ion as na u al bio e ilize s. Wi h he new end o a mo e sus ainable, heal h-o i- en ed li ing, and cons an epo s o haza dous chemicals ound in ood and cosme ics, he demand o mo e eco- logical, mo e “na u al” al e na i es is high. This is again, whe e ungi can s ep in. In he en ies on “Food and be e ages om ungi” and “Commodi ies”, we p esen examples o how basic esea ch on ungi has made i s way in o he ood and be e age, bu also he ex ile and la ou indus y. Finally, in he pa on “Sa ing he plane ” we illus a e he g ea po en ial o ungi owa ds a mo e sus- ainable li ing and how ungi can assis o cope wi h some po en ial u u e challenges ha a e h ea ening human ci ilisa ion. A diag am illus a ing all po en ial bene icial uses o ungi ha a e ea ed he ein is gi en in Fig 1. S a egies agains human disease The scien i ic communi y ecen ly celeb a ed he 90 h anni e sa y o Si Alexande Fleming’s disco e y o penicillin, which ma ked he s a ing poin o he e a o an ibio ic chemo he apy. As ou lined by Ka wehl and S adle (2017), among he nume ous an ibio ics ha we e disco e ed o e he nex 50 yea s, ela i ely ew compound classes we e de i ed om ungi. The la e include he cephalospo ins (New on and Ab aham 1955), which belong o he same class as he penicillins, i.e. he be a glucan an ibio ics, as well as usidic acid (God edsen e al. 1962) and pleu omu ilin (No ak and Shlaes 2010; Sanda go e al. 2019a). Thei chemical s uc u es (1–4) 1 a e depic ed in Fig. 2. Mos o he comme cial an ibio ics a e ac ually de i ed om S ep omyces species and o he ac inobac e- ia, o e en om o he p oka yo es. Fo de ails o he his o y o esea ch on an ibio ics, we e e o he e iew by Moh e al. (2017), as his does no all wi hin he scope o he cu en pape . As we canno co e he en i e ield in his pape , we will gi e a b ie o e iew on an ibac e ials, an imyco ics and bio ilm inhibi o s and illus a e hei usages wi h some examples o ma ke ed d ugs as well as o he compounds ha ha e ecen ly been disco e ed. 1. An ibac e ial an ibio ics The e m “an ibio ics” is used in he li e a u e wi h di - e en de ini ions. The indus y mainly use i o an ibac- e ial agen s, bu he de ini ion ha we p e e he e, which was adap ed om he o iginal one coined by Waksman (1947), i.e., an an ibio ic is “a chemical subs ance, p o- duced by mic o-o ganisms (including ungi), which has he capaci y o inhibi he g ow h o and e en o des oy bac- e ia and o he mic o-o ganisms”. The na u al unc ions o an ibio ics can easily be explained, esul ing om he high compe i ion be ween ungi, bac e ia and o he o ganisms in 1 All chemical s uc u es o ungal seconda y me aboli es p esen ed in his pape ha e been nume ed consecu i ely in bold ypese in bo h, he igu es and he co esponding ex . 4 Fungal Di e si y (2019) 97:1–136 123 subs a es such as soil, dung and plan deb is. I a gi en o ganism has acqui ed he abili y o p oduce a ce ain seconda y me aboli e by which i can kill he compe ing o ganisms ha dwell in he same habi a , i is conside ed o possess a selec i e ad an age ha ul ima ely inc eases i s i ness (Shea e 1995). The e o e i should come as no su p ise ha one la ge expe imen al s udy concluded ha he majo i y o ilamen ous ungi a e able o p oduce an ibio ic compounds (Bills e al. 2009). Bills and Gloe (2016) summa ized nume ous impo an ac s conce ning he cu en s a e o he a in esea ch on ungal seconda y me aboli es and concen a ed hea ily on he biochemical and gene ic backg ound o hei biosyn hesis. We a e cu en ly li ing in he “pos -an ibio ic” e a, whe e bo h, he numbe s and pe cen ages o mul i- esis an bac e ial and ungal pa hogens agains he es ablished Fig. 1 Diag am showing he po en ial use o ungi in bio echnology. The cycle s a s wi h basic biodi e si y esea ch, which in u n leads o cul u es placed in he cen al cul u e collec ion. The cul u es a e hen used o applied esea ch, which in u n leads o p oduc s in he o m o he i ems discussed in he en ies o his pape Fungal Di e si y (2019) 97:1–136 5 123 an ibio ics a e d as ically inc easing, while he numbe o new he apeu ic agen s and de elopmen al candida es has dec eased (Coope and Shlaes 2011). The easons o his de elopmen a e mani old, bu he phenomenon is p i- ma ily due o he ac ha he majo i y o pha maceu ical companies ha e los in e es in Resea ch and De elopmen on na u al p oduc s and/o gi en up hei ac i i ies in he an i-in ec i es sec o . Expe s a ound he wo ld a e now gi ing wa nings abou he se ious consequences ha he lack o an ibio ics—in pa icula agains he mul i- esis an G am nega i e human pa hogenic bac e ia—can ha e (F iedman e al. 2016). A e wo decades o neglec , e o s o bo h he p i a e and he academic sec o on he disco e y o new an ibio ics ha e subs an ially inc eased. The pipeline o an ibac e ial an ibio ics (Hes e kamp 2017) shows ha he e a e s ill some compounds unde de elopmen , bu he majo i y o hose ha e been op i- mised om old compounds wi h known modes o ac ion, e. g. by chemical modi ica ions. The e o e, i is likely ha he esis an pa hogens will easily ind a way o cope wi h he new p oduc s, once hey ha e eached he ma ke . The a o emen ioned mu ilins, which a e de i ed om e men- a ion o he basidiomyce e Cli opilus passecke ianus and subsequen semisyn hesis, he e o e ep esen he “newes ” compound class ha has been egis e ed as an an ibac e ial d ug. A de i a i e, e apamulin (5), was launched o use as a opical an ibio ic agains skin in ec ions, and se e al u he de i a i es a e unde going clinical ials as sys- emic an ibio ics. In gene al, basidiomyce e cul u es a e much mo e di icul o handle wi h espec o la ge scale p oduc ion o seconda y me aboli es, since hey g ow a he slowly and o en ha e low yields. Fo he p oduc ion o pleu omu ilin, howe e , Bailey e al. (2016) managed o inc ease he yields subs an ially a e he ans e o he biosyn he ic genes in o a as g owing he e ologous Aspe gillus hos , which can mo e easily be handled in he p oduc ion p ocess. This accomplishmen can gi e ise o some hope ha in he u u e, mo e o he hi he o neglec- ed, unique biologically ac i e me aboli es o basid- iomyce es can be made accessible o p eclinical de elopmen . 2. An imyco ics and ungicides Whe eas mul i- esis an bac e ial pa hogens a e e y high on he agenda o bo h he p ess and unding agencies, ela i ely li le a en ion is p esen ly being paid o he ac ha he numbe o esis an pa hogenic ungi is also on he ise. This opic was ea ed by Hyde e al. (2018a), we e e o i o he mos impo an an h ea ening human pa ho- genic ungal o ganisms. In ac , he e a e only a hand ul o e icien compound classes on he ma ke ha a e used in an imyco ic chemo he apy, including g iseo ul in (6), which was al eady disco e ed by G o e e al. (1952; Fig. 3). The newes class o an imyco ics ha we e laun- ched o he ma ke a e he echinocandins (e.g., pneumo- candin B 0 (7) (Denning 2002). The biosyn hesis o hese highly complex lipopep ides elies on PKS-NRPS hyb id gene clus e s (Chen e al. 2013). They a e being p oduced bio echnologically by la ge scale e men a ion using di - e en ungi ha a e no phylogene ically ela ed and sub- sequen semisyn hesis. The knowledge abou he molecula mechanisms o hei biosyn hesis may in he u u e lead o he concise manipula ion o he p oduc ion p ocess ha can be di ec ed owa ds new na u al de i a i es. In e es ingly, a compa a i e genomics s udy by Yue e al. (2015) has e ealed a he high homologies among he biosyn hesis gene clus e s o he p oduce o ganisms ha belong o h ee di e en classes o Ascomyco a, namely Do hideomyce es, Eu o iomyce es, and Leo iomyce es. Possibly, his has O NH N S O O O OH OH O O ON SNH O NH 2 O OHO OH H OH O O COOH H O H OH O O OH Pleu omu ilin (4) Fusidic acid (3) Cephalospo in C (2) Penicillin V (1) O H OH O O S N Re apamulin ( 5 ) Fig. 2 Chemical s uc u es o ungal me aboli es ha we e de eloped o an ibac e ial d ugs 6 Fungal Di e si y (2019) 97:1–136 123 been due o ho izon al gene ans e du ing he e olu ion- a y his o y o hese o ganisms. Recen e o s aimed a he disco e y o no el an i ungal agen s ha e esul ed in a numbe o de elopmen al p o- jec s, such as en uma ungin (8) om Ho monema spp. (Pela ´ez e al. 2000). This compound class may soon yield he i s pha maceu ical d ug o use in humans ha o ig- ina ed om a ungal endophy e, o e 15 yea s a e hei i s disco e y. E en he biosyn hesis genes encoding o hese unique i e penoids (Fig. 3) has only ecen ly been iden i ied (Kuhne e al. 2018). The sea ch o no el an imyco ics and ungicides has also esul ed in he edisco e y o “old” compounds ha may become mo e in e es ing in he u u e because hey ha e o iginally been ound in a sc eening o ag ochemical ungicides and we e ne e e alua ed o hei e ec s on human ungal pa hogens o hei mode o ac ion. While he s obilu ins, which a e a e y comme cially success ul an i ungal agen s in ag icul u e (Sau e e al. 1999), ha e been ound ine icien o oo oxic o applica ion in humans, many o he me aboli es wi h p onounced an i- ungal e ec s we e appa en ly ne e es ed on hei e i- cacy agains human pa hogens. A ecen example o such edisco e ies is a olon (9), which is ac ually a co- me aboli e o s obilu ins p oduced by he in asi e basid- iomyce e Fa olaschia caloce a (Chepki ui e al. 2016) and was o iginally isola ed by Anke e al. (1995). Like he spo o h iolodes (10) om he xyla ialean ungus Hypoxy- lon mon iculosum (Su up e al. 2014; Fig. 3; now classi ied in he new genus Hypomon agnella as H. mon iculosa; c . Lambe e al. 2019), his me aboli e shows e y s ong an i ungal e ec s ha a e no accompanied by p ominen cy o oxici y. 3. Bio ilm inhibi o s Scien is s a e explo ing di e en a enues o comba in ec ious diseases caused by bo h bac e ial and ungal pa hogens, o which he inhibi ion o bio ilm o ma ion is one o he mos p omising leads. Ab aham and Es ela (2016) epo ed ha ungal me aboli es a e becoming inc easingly explo ed o hei po en ial o inhibi he o - ma ion o bio ilms, e.g. by in e e ing wi h quo um sensing, and some compounds ha e al eady been disco e ed ha can e en des oy p e- o med bio ilms. A ecen example is cop inuslac one (11) (de Ca alho e al. 2016; Fig 3), a small molecule de i ed om he edible mush oom Cop i- nus coma us, which ac s agains Pseudomonas ae uginosa bio ilms. O he examples include oussoellenic acid (12) om a Roussoella sp. (Phukhamsakda e al. 2018), which is ac i e agains bio ilm o ma ion in S aphylococcus au eus, as well as mic opo enic acid A (13) om a Kenyan basidiomyce e (Chepki ui e al. 2018; Fig. 4), which can no only inhibi bio ilm o ma ion in bo h S aphlococcus au eus and he human pa hogenic yeas , Candida albicans, bu e en des oys p e- o med bio ilm in C. albicans a a he low concen a ions. These compounds do no ha e p ominen an imic obial ac i i ies and he e o e hei applica ion is unlikely o aise esis ance. The bio ilm inhibi o s a e e y p omising candida es o use in O NH OH OH NH O OH N O NH O NH O OH N O NH O OH OH OH OH OH NH 2 O HH O O Cl O O O O Pneumocandin B0 (7) O OH H H H O O OH OH O O O Fa olon (9) G iseo ul in (6) OHO H O OH O AcO O OH OH OH OH En uma ungin (8) O O O O H H Spo oh ioide (10) Fig. 3 Chemical s uc u es o ungal me aboli es wi h an i ungal ac i i y agains human pa hogens Fungal Di e si y (2019) 97:1–136 7 123 combina ion he apy wi h an ibio ics. In se e al s udies, bio ilm inhibi o s we e shown o enhance he ac i i y o he an ibio ics by inc easing hei abili y o pene a e he bio ilms. These examples illus a e ha ungi a e unde -explo ed wi h espec o no el an ibio ics and o he he apeu ic agen s, and ha i is ce ainly wo hwhile o expend mo e e o in his a ea o esea ch wi h an emphasis on hi he o neglec ed species om egions and habi a s ha ha e no ye been s udied sys ema ically. Fungi ha e much o o e in e ms o no el chemis y: due o he ad en o e olu- iona y echniques in genomics, ansc ip omics, bioin o - ma ics, analy ical chemis y and bio echnological p ocess de elopmen , we can now explo e he chemical di e si y o he mycobio a much mo e concisely han e e be o e. E idence is also accumula ing ha no el phylogene ic lineages o hi he o neglec ed axonomic and ecological g oups o ungi can now much mo e easily be ecognized and subjec ed o he exploi a ion o hei seconda y me a- bolome. Howe e , mo e public unding is needed o assu e ha he subs an ial know-how ha has been acqui ed o e many decades does no become o go en, and ha he nex gene a ion o esea che s will also s ill be able o wo k on no el, hi he o unexplo ed ungal g oups, a he han only on model o ganisms. 4. An i-cance agen s Cance is he second leading cause o mo ali y a e ca - dio ascula disease, wi h an es ima ed 9.6 million cance - ela ed dea hs in 2018 (GBD 2015). Cance is a mul i ac- o ial disease cha ac e ized by he loss o g ow h ac o s ha con ol he p oli e a ion and di ision o cells. These abno mal malignan cells can e ade he umou supp esso ac o s o he human immune sys em, hen de elop o umou s and des oy adjacen issues (Saeidnia and Abdollahi 2014). The e a e se e al ea men s o cance , adminis e ed acco ding o de elopmen al s a e o he dis- ease. Chemo he apy, adia ion he apy, su ge y and immuno he apy a e all impo an elemen s o cance ea men . Howe e , while many cy o oxic agen s a e known o Science (which could in p inciple se e as chemo he apeu ic agen s), only ew o hem speci ically a ge umou cells and a e less oxic o egula , heal hy human issue (Pe elli e al. 2012; Cai e al. 2013; Zuga- zagoi ia e al. 2016). Ta ge ed he apy, usually he conju- ga ed elemen o cance ea men s, deli e s d ugs o genes o p o eins ha a e speci ic o cance cells o he en i onmen al issues ha p omo es he g ow h o cance (Padma 2015). Fungi a e an impo ance sou ce o na u al p oduc disco e y, albei mos an icance d ugs a e e ie ed om plan s and bac e ia. In his en y, we desc ibe se e al p omising na u al p oduc s de i ed om ungi and highligh some o he chie compounds ha a e cu en ly in he clinical and p eclinical de elopmen al s age (Fig. 5). I o ul en (14) is a semi-syn he ic de i a i e o illudin S (15), a na u al oxin isola ed om Omphalo us illudens (Jack O’Lan e n mush oom; c . Chin e al. 2006; Mo as- saghi e al. 2006). I o ul en in e e es wi h DNA eplica- ion-complexes and cell di ision in DNA syn hesis. The abno mal cells in S-phase lead o apop o ic cell dea h (Walse and Heins ein 1973; Jaspe s e al. 2002). The an i- umou ac i i ies o i o ul en ha e been e alua ed in phase I and II clinical ials wi h p omising esul s agains a a ie y o cance s, including hose in he b ain and cen al ne ous sys em, b eas , blood, colon, sa coma, p os a e, lungs, o a ian and panc eas (Alexand e e al. 2004; Miyamo o e al. 2018; Topka e al. 2018). Sanda go e al. (2019a) ha e ecen ly desc ibed he s a e o he a , including some exci ing new illudin conjuga es ha show supe io in i o ac i i ies han i u ul en and a e p esen ly unde ea ly p eclinical de elopmen . Aphidicolin (16) is a e acyclic di e pene wi h an i i al and an imi o ic p ope ies. The compound was o iginally isola ed om “Cephalospo ium aphidicola”(cu en ly alid name: Akan homyces musca ius) and la e also epo ed om Nig ospo a sphae ica (Bucknall e al. 1973; S a a a and Loschia o 1974). Aphidicolin compe es o he speci ic binding si e on DNA polyme ase α,δ, and ε enzymes. I s mechanism o ac ion and e icacy ha e been in ensi ely es ed in clinical ials (C ose o e al. 2013; Ayob e al. 2017), bu so a i has no become a ma ke ed d ug. O he an icance lead compounds de i ed om ungi include lep osins F (17) and C (18) isola ed om Lep- oshae ia sp., which showed an i umo ac i i y in mouse emb yos (Yanagiha a e al. 2005; Pejin e al. 2013); β- glucans, he polysaccha ides ha a e na u ally ound on he cell walls o ungi (Chan e al. 2009; Bashi and Choi 2017); as well as palma umycin (Powis e al. 2006) and spi op eussione A (Chen e al. 2009). The la e Fig. 4 Chemical s uc u es o ungal me aboli es wi h bio ilm inhibi ion ac i i ies 8 Fungal Di e si y (2019) 97:1–136 123 compounds, howe e , ha e only demons a ed hese ac i i ies in i o, and i is no clea whe he hey will e en ually each he la e explo a o y s age o p eclinical de elopmen . 5. An i-diabe es Diabe es melli us, also known simply as diabe es, is a ch onic me abolic diso de (De Sil a e al. 2012). People who su e om diabe es canno p oduce o e ec i ely use insulin in he body. Due o his insulin imbalance, hey ha e high amoun s o glucose in hei blood. The e a e wo common ypes o diabe es, i.e. ype 1 diabe es (insulin dependen diabe es melli us) and ype 2 diabe es (nonin- sulin-dependen diabe es melli us). Pa ien s wi h ype 1 diabe es canno p oduce insulin, due o he lack o unc ions o he insulin-sec e ing be a cells in he panc eas (Meie e al. 2005). They mus ake insulin con inuously e e y day o s ay ali e. Type 1 diabe es mos ly a ec s child en and adolescen pa ien s, and i ep esen s 5–10% o o al diabe es cases wo ldwide. Pa ien s wi h ype 2 diabe es canno p oduce su icien insulin o canno e ec i ely me abolize i . This o m o he diso de commonly a ec s elde ly people and accoun s o 90–95% o all diabe es cases (Hameed e al. 2015). People wo ldwide su e om diabe es melli us and 7% o he wo ld’s adul popula ion is a ec ed by he disease (Phi- lippe and Raccah 2009). In 2017, he la ges numbe o diabe ic pa ien s, a ound 114 million, was eco ded in China. Roughly 73 million diabe ic pa ien s we e eco ded in India, and 30 million we e eco ded in he Uni ed S a es. (h ps://www.s a is a.com/s a is ics/281082/coun ies-wi h- highes -numbe -o diabe ics/). The e a e many nega i e consequences o pa ien s i diabe es emains un ea ed, such as blindness, kidney ailu e, dep ession, ca dio ascula diseases, cance and e en dea h (Ge s ein e al. 2011; Hansen e al. 2012; Huang e al. 2018). Re inopa hy (damage o he e ina, leading o blindness) and neu opa hy (damage o he ne ous sys em) a e some o he mos se e e complica ions ha ha e been a ibu ed o diabe es (De Sil a e al. 2012; Sobngwi e al. 2012). Many Basidiomyco a, such as Aga icus bispo us,Cy- clocybe aege i a, C. cylind acea and T emella uci o mis a e used as medicine o he ea men o p ophylaxis o ype 2 diabe es. These mush ooms help pa ien s a oid high le els o glucose because hey con ain he leas amoun o diges ible ca bohyd a es in he die (Pouche e e al. 2006). Bioac i e me aboli es, which a e isola ed om medical mush ooms and hei cul u ed mycelia, ac as biological an ihype glycemic agen s in diabe es ea men (Table 1) (De Sil a e al. 2012). Ex ac s o Inocu is le is (Hy- menochae aceae) ha e been epo ed o possess u ili y as a emedy o diabe es because hey inc ease insulin esis- ance, insulin sensi i i y and glucose up ake in issues and hence help o con ol blood glucose le els (Ehsani a d OH OH H H H OH OH Aphidicolin (16) NH NH N N H O O S 4 OH Lep osin F (17) OH O OH OH O OH OH Illudin S (15) I o ul en (14) NH N N H O O S 2 OH NH N N H O OH O S 2 OH Lep osin C ( 18 ) Fig. 5 Chemical s uc u es o p omising na u al p oduc s de i ed om ungi wi h an icance ac i i y Fungal Di e si y (2019) 97:1–136 9 123 lowe ing p ope ies a e mainly caused by he s uc u al simila i y wi h choles e ol (Gil-Ramı ´ ez e al. 2016). Fu - he , he biological ac i i y o β-glucans and chi in may be due o hei binding abili ies o choles e ol ecep o s (Gil- Ramı ´ ez e al. 2016). F ancia e al. (1999) eco ded 16 species o edible mush ooms wi h biological ac i i ies agains ca dio ascu- la disease. Species o he gene a Au icula ia (Fan e al. 1989), Ganode ma (Kabi e al. 1988), G i ola (Kubo and Namba 1997), Pleu o us (Bobeck e al. 1991) and T emella (Cheung 1996) ha e been epo ed o con ain choles e ol- lowe ing compounds. Ophioco dyceps sinensis has also been shown o educe o al choles e ol le els, which has been a ibu ed o he ac ha i con ains polysaccha ide “CS-F30” composed o galac ose, glucose and mannose (Kiho e al. 1996). Fo ins ance, low densi y lipop o ein choles e ol le els we e epo ed o be educed by Au icu- la ia au icula-judae (Fan e al. 1989) and T emella uci- o mis (Cheung 1996), and iglyce ide le els we e epo ed o be educed by G i ola ondosa (Kubo and Namba 1997), Len inula edodes (Kabi and Kimu a 1989) and Ophioco dyceps sinensis (Kiho e al. 1996). 9. An i i al agen s Heal h and mo ali y-debili a ing diseases caused by i u- ses con inue o cause se ious global epidemics, especially in cases whe e accines and an i i al chemo he apies a e insu icien o no a ailable. The cu en s a e o i us- ela ed pandemics is also signi ican ly limi ing d ug e i- cacy by he eme gence o d ug- esis an s ains. Hence, he e is an u gen need o iden i y and de elop na u al p oduc -inspi ed d ug leads ha could help con ol i al in ec ions. A ple ho a o po en ially ac i e na u al p oduc s ha e been isola ed om ungi and sc eened o an i i al ac i i y, e en hough none o hem has eached he ma ke ye . This en y ocuses on na u al p oduc s exhibi ing po en ac i i y on selec ed human pa hogenic i uses, such as he human immunode iciency i us (HIV), in luenza i us, he pes simplex i us (HSV), hepa i is i us and o he human pa hogenic i uses such as en e o i us-71, and espi a o y syncy ial i us (RSV). Human Immunode iciency Vi us (HIV) inhibi o y na u al p oduc s om ungi A comp ehensi e e iew o he li e a u e iden i ies h ee main a ge s o an i-HIV d ug disco e y: i us en y, e e se ansc ip ion and in eg a ion. The en y o HIV in ol es in e ac ions wi h p o eins and is a a ge o he disco e y o new i al en y blocke s. Examples o a ew disco e ies a e p o ided. A bis-indolyl quinone, hinnuliquinone (25) (Fig. 9) om an unknown ungus isola ed om Que cus cocci e a, inhibi ed wild- ype and clinically- esis an HIV-1 p o ease. HIV-1 p o- ease is a key enzyme in ol ed in he eplica ion and NH O OH O OH NH Hinnuliquinone (25) O O OH MeO OH OH OH OMe O In eg as a in A (27) OH O N O OH H O S achybosin D (26) OH H N H O O OH O O O OH OH OH O Vani a acin A (29) S achy lin (28) OH OH OH O O OOH OH Cy ospo aquinone B (31) OH OH OH O O H H 4-hyd oxypleu og isein (30) O OH O O OH OH Rhoda in (32) Fig. 9 Chemical s uc u es o ungal me aboli es ha we e epo ed o possess an i i al ac i i ies 16 Fungal Di e si y (2019) 97:1–136 123 ma u a ion o he HIV-1 i us (Singh e al. 2004). Al e - oxins I–III and V, oxidized pe ylenes om Al e na ia enuissima, inhibi ed HIV-1 eplica ion a mic omola concen a ions (Bashyal e al. 2014). The dime ic e ahy- d oxan hone, penicillixan hone A om Aspe gillus umi- ga us displayed s ong an i-HIV ac i i y by inhibi ing CCR5- opic HIV-1 SF162 and CXCR4- opic HIV NL4-3 (Tan e al. 2017). A ma ine-de i ed A. nige p oduced mal o min C, which exhibi ed a e y s ong an i-HIV-1 ac i i y (Zhou e al. 2015a). An endophy ic Aspe gillus sp. CPCC 400735 p oduced h ee phenalone and cy ochalasin de i a i es also showing an i-HIV ac i i y (Pang e al. 2017). Concen icolide om “Daldinia concen ica” ( ax- onomy doub ul since his species does no occu in China acco ding o he wo ld monog aph by S adle e al. 2014) inhibi ed HIV-1 by induc ion o cy opa hic e ec s (Fang and Liu 2009). No el sesqui e penoids om Pa aconio- hy ium b asiliense showed mode a e an i-HIV-1 eplica- ion in C8166 cells (Liu e al. 2010b). The pupukeanane sesqui e penoid chlo opupukeannolide A om Pes alo- iopsis ici showed signi ican an i-HIV-1 ac i i y (Liu e al. 2010c). The cy ochalasan pe coniasin J and he me o e - penoid pe iconone B om Pe iconia sp. displayed mod- e a e an i-HIV ac i i y (Liu e al. 2016,2017b). The a nesyla ed isoindolinones s achybo ysams A–C and he phenylspi od imane de i a i es s achbo ysin A and G om S achybo ys cha a um displayed mode a e an i-HIV ac i i y (Zhao e al. 2017a,b). The h ee consecu i e unc ions con olled by HIV e e se ansc ip ase a e: RNA e e se ansc ip ion o DNA, deg ada ion o RNA empla e by RNase H, and duplica ion o he emaining DNA s and. Inhibi ion o hese p ocesses is impo an o he disco e y o an i-HIV d ugs. S achybosin D (26) (Fig. 9), a phenylspi od imane me aboli e om a sponge-de i ed isola e o S achybo ys cha a um, showed inhibi o y e ec s on HIV-1 eplica ion by a ge ing e e se ansc ip ase. I was able o inhibi NNRTIs- esis an s ains and wild- ype HIV-1 (Ma e al. 2013). In eg ase is he only p o ein encoded by HIV-1, aside om he enzymes p o ease and e e se ansc ip ase. Singh e al. (1998,2002a,b,2003a,b,c) desc ibed se e al compounds wi h inhibi o y ac i i y agains in eg ase om a ious ungal species. Acco dingly, equise in and pho- mase in om Fusa ium he e ospo um and Phoma sp., espec i ely Singh e al. 1998); in eg acins (In eg as a in A (27)) om Cy onaema sp. (Singh e al. 2002a); in eg as- a ins ( om an uniden i ied ungus; c . Singh e al. 2002b); epiphiobolins C and K om “Neosa o ya”; i.e., Aspe - gillus sp.; 8-O-me hylan h agallol om Cylind oca pon ian ho hele; hispidin and ca eic acid om Inono us ama icis; 3-hyd oxy e phenyllin om Aspe gillus can- didus (Singh e al. 2003a); naph ho-γ-py ones om Fusa ium sp. (Singh e al. 2003b); and xan ho i idica ins om Penicillium ch ysogenum (Singh e al. 2003c) all showed low mic omola inhibi ion agains he clea age eac ion o HIV in eg ase. Funalenone om Penicillium sp. FKI-1463 also had he same e ec (Shiomi e al. 2005). In luenza i us inhibi o y na u al p oduc s om ungi The H1N1 and H3N2 i uses a e among he a ge s o na u al p oduc s o ungal o igin wi h an i-in luenza ac i i y. The e penoid s achy lin (28), isola ed om a ma ine-de i ed isola e o S achybo ys showed modes ac i i y agains he in luenza A i us (H1N1) wi h an IC 50 o 3 910 −3 µM (Minagawa e al. 2002). The γ-py one isoas el oxin om Aspe gillus och aceope ali o mis showed low mic omola ac i i y (IC 50 =0.23 µM) agains bo h in luenza i uses (Wang e al. 2016). Ano he Aspe gillus sp., s ain p oduced he γ-py one de i a i e as el oxin E wi h IC 50 alues o 6.2 and 3.5 µM agains H1N1 and H3N2, espec i ely (Tian e al. 2016). 3β-Hy- d oxys e ol om Pes alo iopsis sp. (Sun e al. 2014) and che mesinone om Nig ospo a sp. (Zhang e al. 2016b) also had mode a e inhibi o y e ec s. Au eoni ol, a me aboli e o Gliocladium spp. inhibi ed in luenza A and B i us eplica ion wi h an EC 50 o 100 nM agains H3N2 ia supp ession o in luenza hemagglu ina ion, while signi i- can ly impai ing i al adso p ion (Sac amen o e al. 2015). He pes Simplex i us (HSV) inhibi o y na u al p od- uc s om ungi The impo an human pa hogenic i uses HSV-1 and HSV-2 we e also subjec o sceening p og ams o ungal me aboli e lib a ies, e en hough up o da e no d ug could be disco e ed ha would ma ch he ac i i y o he ma ke s anda d. Coccoquinone, an an h aquinone om Aspe gil- lus e sicolo , demons a ed an IC 50 o 3 µM agains HSV- 1 (Huang e al. 2017a,b). Fi e lipopep ides om he ma ine-de i ed ungus Scy alidium sp. showed mode a e an i-HSV-1 and an i-HSV-2 ac i i ies in a dose- and ime- dependen pa e n (Rowley e al. 2003). The diphenyl e he glycoside co dyol C om Co dyceps sp. BCC 186 exhib- i ed signi ican an i-HSV-1 ac i i y wi h an IC 50 alue o 1.3 μg/ml (Bunyapaiboons i e al. 2011). Hepa i is i us inhibi o y na u al p oduc s om ungi One no el icyclic polyke ide de i ed om a collec ion o ungal-de i ed compounds, ani a acin A (29), was epo ed o inhibi i al en y p ocess wi h an IC 50 alue o 0.6 µM and good selec i i y. I was obse ed o di ec ly in e ac wi h he HBV en y ecep o co ela ed o hepa i is D i us and impai ed i al bile acid anspo pa hway. This compound also inhibi ed all HBV geno ypes (A–D) (Kaneko e al. 2015). The an h aquinone me aboli e, 2′R-1- hyd oxyiso hodop ilonme in, showed be e an i-hepa i is B i us ac i i y as compa ed o he posi i e d ug con ol, Fungal Di e si y (2019) 97:1–136 17 123 lami udine (Jin e al. 2018). The epipoly hiodioxopipe - azine de i a i e, 11′-deoxy e icillin A, showed an i i al ac i i y by dec easing HBV-X eplica ion h ough inhibi- ion o Ak ac i i y o deple ion o he au ophagic genes, LC3 and p62 (Wu e al. 2015a). Sanda go e al. (2018) and Na mani e al. (2019) ha e ecen ly disco e ed addi ional an i-HCV agen s like 4-hyd oxypleu og isein (30) om he nema ode apping basidiomyce e Hohenbuehelia g isea and cy ospo aquinone B (31) om an I anian phy- opa hogen belonging o he genus Cy ospo a. Recen ly Sanda go e al. (2019b) epo ed he me o e penoid ho- da in (32) om cul u es o he a e basidiomyce e Rhodo- us palma us and also ound signi ican an i-HCV ac i i ies o his compound, which ea u es a new ca bon skele on. In iew o he ac ha newly a ising i al diseases a e s eadily being epo ed and hey can sp ead mo e easily due o g lobaliza ion e ec s, he sea ch o no el an i i al agen s is as o ecen ly gaining impo ance. Some o he na u al p oduc s poin ed ou in his en y may po en ially ind hei way o an i i al d ug de elopmen in he u u e. Howe e , he disco e y o new chemical de i a i es wi h nanomola ac i i y and high selec i i y indices is s ill wa an ed. 10. Immunosupp essi e and immunomodula o y agen s om ungi Immunosupp ession is a o m o he apy ha p e en s he immune sys em o pa ien s om ac ing agains ansplan ed issues and o gans; wi hou he a ailabili y o immunosupp essi e d ugs, he p og esses made in mode n medicine, in pa icula ega ding kidney, hea and li e ansplan s, would be un hinkable. Fu he mo e, immuno- supp essan s a e used o con ol se e e mani es a ions o alle gic and au oimmune ela ed diseases. Many o hese d ugs speci ically add ess ce ain biochemical pa hways ha a e c ucial o he unc ioning o human de ense agains alien o ganisms, such as pa hogens, by selec i ely inhibi ing he immunocompe en lymphocy es o signal ansduc ion cascades ha egula e he ansc ip ion o cy okines. Fo his eason, pa ien s ea ed wi h immuno- supp essan s o en ha e o be hospi alized and ea ed in pa allel wi h an ibio ics o p e en in ec ion. Some o he mos impo an immunosupp essi e d ugs a e na u al p oduc s ha a e being p oduced bio echno- logically by e men a ion o bac e ia and ungi. While ac olimus and si olimus a e de i ed om ac inobac e ia and will acco dingly no be ea ed he e, cyclospo ine (35) and mycophenola e mo e il (33) a e ungal me aboli es, and he p esen en y is he e o e dedica ed o hese impo an molecules (Fig. 10). Mycophenolic acid (34) (Fig. 10) was he i s an ibio ic disco e ed and isola ed in c ys alline o m om ungi, con a y o wha is w i en elsewhe e in he li e a u e, whe e he penicillins a e o en ega ded as he oldes na - u al an ibio ics. Biogene ically, his compound is a me o e penoid, p oduced by Penicillium species, including P. b e icompac um and P. oque o ii, and i s biosyn hesis has ecen ly been elucida ed in he la e species (Del-Cid e al. 2016). Fo a ious easons, he compound ne e made N N O O NH ON NH O NH O N O O N N O N O NH OH O O Cyclospo in A (35) O OOH OOH O Mycophenolic acid (34) O OOH OO O N O Mycophenola e mo e il (33) Fig. 10 Chemical s uc u es o immunosupp essi e d ugs de i ed om ungal e men a ion 18 Fungal Di e si y (2019) 97:1–136 123 i in o clinical de elopmen as an an ibac e ial o an i ungal agen (Ben ley 2000; Bills and Gloe 2016). Ul ima ely, i s u ili y as an immunosupp essan became e iden , and i is now he ac i e p inciple o se e al ma ke ed d ugs, such as My o ic ® and CellCep ® . The compound selec i ely inhibi s inosine monophospha e dehyd ogenase (IMPDH), an enzyme ha is c ucial o he biosyn hesis o guanosine nucleo ides in mammalian cells. As his enzyme is mo e essen ial in he T- and B-lymphocy es han in o he cell ypes, and i s iso o m in he lymphocy es is mo e sensi i e o mycophenolic acid, he d ug has a mo e po en cy os a ic e ec on lymphocy es han on o he cell ypes, and he eby supp esses he immune sys em (Allison and Eugui 2000). Ano he seconda y bene icial e ec o mycophenolı ´c acid is he deple ion o e ahyd obiop e in, which is a co- ac o o he inducible ni ic oxide syn hase (iNOS). Conse- quen ly, he adminis a ion o mycophenolic acid p e en s damage o issues media ed by pe oxyni i e. The d ug is mainly being used o p e en o gan ejec ion ollowing ansplan s, as well as in he he apy o pso iasis (Epine e e al. 1987) and o he immunological diso de s. Cyclospo ine A (35) (Fig. 10) was i s disco e ed as a mildy ac i e an i ungal an ibio ic by D ey uss e al. (1996), who also ga e he i s hin s as o i s immunomodula o y ac i i y. The compound is a non ibosomally biosyn hesized pep ide de i ed om e men a ion o he ascomyce e Tolypocladium in la um, and i s biosyn he ic gene clus e was ecen ly elucida ed by Bushley e al. (2013). A e yea s o in ensi e esea ch, i was ound ha his cyclopep ide has a highly speci ic biochemical mode o ac ion as i selec i ely binds o cyclophilin A. This p o ein is an inhibi o o calcineu in, which is esponsible o ac i a ion o ansc ip ion o he cy okine, in e leukine 2. I in e leukine 2 is deple ed, he immune esponse o he human body will be supp essed and ejec ion o ansplan s can be p e en ed (G een e al. 1981; Wiesinge and Bo el 1980). The e o e, cyclospo ine A has become he ac i e ing edien o blockbus e d ugs, such as Sandimmune ® , Neo al ® and Res asis ® ). In addi ion o o gan ansplan s, such immunosupp essan s can be e y use ul in he he apy o o he diseases, including alle gies and neu odegene a- ion. An example o he la e indica ion is he syn he ic d ug, ingolimod (Gilenya ® ;21 in Fig. 6), which is desc ibed u he abo e in chap e 6. In his con ex , i is wo hwhile o no e ha many ungal me aboli es a e highly use ul in he apy because hey show he opposi e ac i i ies in biological sys ems, i.e., hey boos he immune sys em and he e o e inc ease he esis ance agains pa hogens o e en help o p e en cance . S iking examples o such molecules a e he β-glucanes and p o- ein–polysaccha ide complexes ha a e being ea ed elsewhe e he ein. S a egies agains plan disease Fungi a e impo an agen s in comba ing a ious ungal pes s and plan diseases ound in g eenhouses, he ield, and e en pos -ha es . Fungi also ha e he po en ial o be used agains ce ain animal pa asi es, such as nema odes. In his sec ion, we discuss how ungi a e being used o con ol plan disease, pes s, nema odes, and he bicides, as well as hei possible u u e applica ions. 11. Biocon ol o plan disease using endophy es Fungal pa hogens a e he chie agen o plan disease, e ec ing se e e ag icul u al losses wo ldwide (Hyde e al. 2014; Punja and Raj 2003; S ange and Sco 2005; Ho - bach e al. 2011). Ag ochemicals play a signi ican ole in plan disease managemen and ensu e sus ainable and p oduc i e ag icul u e sys ems. Howe e , he in ensi e use o chemicals (de e mined by equen and high dose o pes icides) has ad e se e ec s on human heal h, ecosys em unc ioning, and ag icul u al sus ainabili y (Ande son e al. 2004; Vinale e al. 2008; Su yana ayanan e al. 2016). Biocon ol is a s a egy used o con ol plan pa hogens, esul ing in minimal impac o he en i onmen (De Waa d e al. 1993; Vinale e al. 2008). Endophy es eside asymp oma ically wi hin a plan o a leas pa o hei li e cycle (Ca ol 1998; Huang e al. 2009; Sun e al. 2011; Clay e al. 2016). Fungal endophy es can be b oadly classi ied in o wo g oups, he cla icipi a- ceous (C) and he non-cla icipi aceous (NC). These endophy es a e classi ied based on e olu iona y ela ed- ness, axonomy, hos plan ange and ecological unc ion (Hyde and Soy ong 2008; Rod iguez e al. 2009; O’Hanlon e al. 2012; San angelo e al. 2015). Cla icipi aceous endophy es, including A kinsonella,Balansia,Balansiop- sis,Echinodo his,EpichloS ˇ,My iogenospo a and Pa a- epichloS ˇspecies a e commonly associa ed wi h g asses in he amily Poaceae and ely on hei hos h oughou hei li e cycle as mu ualis species (Rod iguez e al. 2009; Pu ahong and Hyde 2011; O’Hanlon e al. 2012; De Sil a e al. 2016). Non-cla icipi aceous endophy es, such as Fusa ium sp., Colle o ichum sp., Phomopsis sp. and Xy- la ia sp. a e ound in mos e es ial plan s, and migh no inhabi he hos plan s o hei en i e li e cycle (Rod iguez e al. 2009; Delaye e al. 2013; De Sil a e al. 2016; Jayawa dena e al. 2016). Endophy es a e neu al o bene icial o hei plan hos s (Backman and Siko a 2008). They boos hos plan g ow h, i ness, s ess ole ance, and al e in e ac ions wi h pes s and pa hogens (Oono e al. 2015; Clay e al. 2016). Endophy es also p o ide p o ec ion agains he bi o y (O’Hanlon e al. 2012; San angelo e al. 2015). Mo e Fungal Di e si y (2019) 97:1–136 19 123 impo an ly, endophy es ha e po en ial as an unexplo ed sou ce o candida e s ains o po en ial biocon ol appli- ca ions (Ek-Ramos e al. 2013; Oono e al. 2015). Fo example, endophy ic Ampelomyces species pa asi ize powde y mildews (Busby e al. 2016). Since powde y mildews a e bio ophs, hei an agonis s ac mainly h ough an ibiosis and mycopa asi ism (Busby e al. 2016). Biocon ol s a egies u ilize an agonis ic mechanisms o dis up he li e cycle o pa hogens (c . Fig. 11), leading o he p e en ion o in ec ion, educ ion in coloniza ion o hos issues, educ ions in spo ula ion, and a ec ing he pa hogen’s abili y o su i e (Punja and Raj 2003; Busby e al. 2016). The hype pa asi ic an agonism may be medi- a ed by ac o s such as include he as p oduc ion o ly ic enzymes and/o an ibio ics, while o he biocon ol agen s may induce he hos plan ’s de ense o jus compe e wi h he pa hogen o nu ien s and ecological niches (Yan e al. 2015; Busby e al. 2016; Lecom e e al. 2016; Schlegel e al. 2016). Mejı ´a e al. (2008) s udied endophy es wi hin he heal- hy lea es o Theob oma cacao, as well as hei an agonism agains he pa hogenic Basidiomyco a species Monilioph- ho a pe niciosa (wi ches b oom), Monilioph ho a o e i ( os y pod o ) and he oomyce e Phy oph ho a palmi o a (black pod o ). The esul s showed ha wo endophy es, iden ied as Colle o ichum gloeospo ioides and Clonos- achys osea, espec i ely, dec eased pod loss due o black pod o , and educed spo ula ing lesions in cacao pods caused by Monilioph ho a o e i. Endophy ic ungi om a ious hos plan s ha e been shown o be e ec i e biocon ol agen s, including Al- e na ia sp. and Cladospo ium sp., isola ed om whea (Huang e al. 2016), and Al e na ia al e na a, isola ed om g ape ine lea es (Zhang e al. 2017b). The use o an ag- onis ic endophy es as biocon ol agen s, such as T icho- de ma and Chae omium, p esen an a ac i e op ion o managemen o ce ain plan diseases. I is impo an o sc een po en ial endophy es h ough in- i o expe imen s ollowing ield expe imen s unde di e en en i onmen condi ions. In u u e esea ch using molecula echnologies (e.g., me agenomics), ecological dynamics a e essen ial o de eloping comme cial biocon ol agen s, as hese con- ibu e o sus ainable ag icul u e. I is c i ical o no e ha he species isola ed as endophy es om a ce ain hos plan may be pa hogenic o o he plan s. Mo eo e , a ca e ul isk assessmen ha excludes he possibili y o he o e p o- duc ion o myco oxins is a manda o y p e equisi e o egis a ions o new biocon ol agen s, ega dless o whe- he he p oduce o ganisms a e endophy es. 12. Biocon ol o insec s using ungi The loss in p oduc i i y due o c op damage om insec s ep esen s a se ious h ea o he ag icul u al sec o . The global c op loss due o insec s con ibu ed o losses o almos $470 billion each yea (Culliney 2014), wi h he global expendi u es on pes icides being in he ange o $56 billion in 2012. S ikingly, o he $56 billion, only $2–3 billion was spen on biopes icides (Ma one 2014). In he USA, insec icides con ibu ed o almos 14% o all pes i- cide expendi u es (Saba wal e al. 2018). The mos common s a egy o con olling insec in a- sions is he use o syn he ic chemical pes icides, such as Chlo py i os, Acepha e and Bi en h in (Dai e al. 2019a). Howe e , insec icidal esis ance has become an undeniable phenomenon, and has led o he disas ous collapse o he pes con ol in many coun ies (Naqqash e al. 2016). The e a e also o he conce ns a ising ega ding he use o hese syn he ic chemicals, namely wi h ood sa e y, ad e se e ec s o non- a ge o ganisms—especially hose Endophy es we e isola ed om heal hy lea es and pods o Theob oma cacao plan Dual cul u e assays An agonis ic ac i i y o endophy es agains h ee pa hogens; Monilioph ho a pe niciosa, M. o e i and Phy oph ho a palmi o a Used 3 me hods – an ibiosis, compe i ion o subs a e and mycopa asi ism G eenhouse expe imen Spo e suspension o endophy es we e inocula ed o cacao lea es and he pe cen o ungal coloniza ion pe lea assessed pla ing on cul u e media Field ials Spo e suspension was sp ayed o cocoa pods and measu e he pe cen age o each pod had been colonized by he inocula ed ungus Fig. 11 Me hodology used o assess biocon ol ac i i y o endophy es agains pa hogens in cocoa plan s 20 Fungal Di e si y (2019) 97:1–136 123 bene icial an agonis s o insec s—and he en i onmen al impac associa ed wi h he use o ha m ul chemical com- pounds (Sandhu e al. 2017). The d awbacks o con en- ional insec icides spu ed he sea ch o po en and eco- iendly biocon ol agen s. Biological con ol agen s o e mo e ad an ages han hei chemical coun e pa s, since hey a e sa e o o he non- a ge o ganisms and in ec only speci ic species, wi h long- e m esul s on a ge pes s (Sanda and Sunusi 2016). In pa icula , he en omopa hogenic ungi, ha e he capaci y o educe o e adica e insec popula ions. Mos ungi used o he con ol o insec pes s a e ascomyce es, which a e usually ound in he soil and can cause na u al ou b eaks on hei own when en i onmen al condi ions a e a o able. Some ungal s ains ha e been de eloped in o comme cial p oduc s because o hei abili y o be mass p oduced (e.g. Beau e ia bassiana, Lecanicillium mus- ca ium, Me a hizium anisopliae). These can in ec a wide ange o insec hos s. (c . Fig. 12). Speci ic ungal s ains in comme cial p oduc s a ge insec g oups such as Coleop- e a, Dip e a, Hemip e a, Hymenop e a, Lepidop e a and O hop e a (Dauda e al. 2018). Some en omopa hogenic ungi can also exis as plan endophy es in a a ie y o hos s. They can exhibi dual unc ions, ac ing agains insec s and plan pa hogens, hus gi ing p o ec ion o plan hos s. Mo eo e , hey can ha e addi ional oles in endophy ism, plan disease an agonism, g ow h p omo ion and hizosphe e coloniza ion (Yun e al. 2017; Jabe and Ownley 2018). Gene ally, he i s mode o ac ion o en omopa hogenic ungi is o p oduce s icky spo es o insu e adhesion o he body o he hos . The non-speci ic adhesion mechanism o he conidia is due o hei hyd ophobic p ope ies, which has p o ein in e ac ions wi h he hyd ophobic exoskele on o he suscep ible hos . The spo es ge mina e quickly and ini ia e pene a ion o he insec exoskele on. The ungal cells mul iply in he hemocoel o he hos ’s body, inc easing he u go p essu e and e en ually killing he insec . The en omopa hogen g ows in he hos ’s cada e o op imize spo e p oduc ion and dispe sal unde a o able en i onmen al condi ions (Roy e al. 2006). High numbe s o spo es a e equi ed o insu e in ec ion, wi h a minimum o 1910 8 o 1910 9 conidia/ml (Inglis e al. 2012). En omopa hogenic ungi also p oduce seconda y me aboli es ha can ac as oxins wi h insec icidal e ec s. P oli e a ing p o oplas s p oduce hese compounds o weaken he hos ’s de ense mechanisms, causing apid dea h (Hussain e al. 2014). The en omopa hogens ha p oduce oxins a e mo e e ec i e a killing he insec hos s as compa ed wi h hose s ains ha do no p oduce such me aboli es (Ke shaw e al. 1999). The e a e a a ie y o ac i e compounds p oduced by en omopa hogenic ungi ha exhibi insec icidal p ope ies, as lis ed in Table 4. Beau e icin (36 in Fig. 13) is a well-known ac i e com- pound p oduced by en omopa hogenic ungi. I plays a key Fig. 12 En omopa hogens in ec ing insec hos s. aAc odon ium c a e i o me, bCo dyceps mili a is, cOphioco dyceps nu ans Fungal Di e si y (2019) 97:1–136 21 123 ole in he i ulence o ungi ha in ec a h opods (Rohl s and Chu chill 2011). I is a cyclic hexadepsipep ide, con- aining h ee D-hyd oxyiso ale yl and h ee N-me hylphenylalanyl esidues in al e na ing sequence, and belongs o he ennia in an ibio ic amily. I is s uc- u ally simila o ennia ins; howe e , i di e s in he na u e o i s N-me hylamino acid (Wang and Xu 2012). I was i s isola ed om Beau e ia bassiana (Hamill e al. 1969) and la e om Fusa ium species (Liuzzi e al. 2017). Beau- e icin has a s ong insec icidal unc ion agains a b oad spec um o insec s. Since he a ge insec s a e mo ing o ganisms, he en omopa hogenic ungi p oducing beau- e icin a e mo e e ec i e insec icidal agen s han he di ec use o he compound. Beau e icin was i s disco - e ed o ha e insec icidal ac i i y by Hamill e al. (1969). O he s udies p o ed he e icacy o beau e icin in killing o he insec s, such as Callipho a e y h ocephala,Lygus spp. (Leland e al. 2005), Aedes aegyp ii (G o e and Pople 1980), Spodop e a ugipe da and Schizaphis g aminum (Ganassi e al. 2002); howe e , i can also be oxic o bees, hus posing a h ea o o he bene icial insec s when applied in he ield. Bassianolide (37) a cyclic depsipep ide om Lecani- cilium lecanii, exhibi s mode a e cy o oxici y and an immunosupp essi e e ec o insec hos s. I can cause signi ican maximum mo ali y o Plu ella xylos ella a 0.5 mg/ml concen a ions (Keppanan e al. 2018). As in o he g oups o ungal cyclopep ides, se e al a ian s i bassianolies a e known (Ma suda e al. 2004). Des uxins (38–40), he cyclic hexadepsipep ide myco oxins a e p oduced by Me a hizium anisopliae. They can kill a a ie y o insec pes s. The pu i ied des uxins can cause oxic e ec s on he la al de elopmen al s age o mosqui oes (Aedes aegyp ii) wi h high mo ali y a es (Ra ind an e al. 2016). The s udy o Dong e al. (2016) also e ealed posi i e co ela ions be ween des uxin p o- duc ion and blas ospo e o ma ion, and he p oduce s ain has he po en ial o be de eloped in o a mycoinsec icide. Ennia ins (41–44) a e only p oduced by Fusa ium species. They ac as ionopho es ha bind wi h ammonium in he anspo o ions in he lipid bilaye memb ane o he cell. This ionopho ic p ope y o ennia ins leads o he oxic ac ion in he cell h ough he dis u bance o he no mal physiological concen a ion. Thei bes s udied de i a i e, Ennia in B was p e iously shown o exhibi insec icidal ac i i y agains blow ly (Callipho a e y h o- cephala) and mosqui o la ae (Aedes aegyp i) (G o e and Pople 1980). The success ul applica ion o en omopa hogenic ungal s ains elies on se e al ac o s, such as le el o i ulence, p oduc ion e iciency and le el o sa e y o humans and o he non- a ge species. Vi ulence depends on a complex o ac o s, such as spo e hyd ophobici y, which is in ol ed in he conidial adhesion, ge mina ion pola i y o he spo es whe ein unidi ec ional spo es a e mo e i ulen han mul i- Table 4 Some insec icidal compounds p oduced by en omopa hogenic ungi En omopa hogen Insec icidal compounds Re e ences Beau e ia bassiana Bassiac idin Bassianin Bassianolide Beau e icins (36) Beau e olides Ma suda e al. (2004), Quesada-Mo aga e al. (2004), Ohshi o e al. (2006), Heneghan e al. (2011), Fisch e al. (2011), Su ¨ssmu h e al. (2011) Beau e ia enella Beau e olides, Beau e icins (36) Bassianolide (37) Ohshi o e al. (2006), Nama ame e al. (1999), Su ¨ssmu h e al. (2011) Lecanicillium lecanii Hel olic acid Kildgaa d e al. (2014), Liang e al. (2016) Fusa ium spp.;“Paecilomyces”(Isa ia) umoso oseus, Paecilomyces (Isa ia) enuipes Beau e icins (36) Isa ia sp. Beau e olides B iggs and A kins (1966), Isogai e al. (1978), Elswo h and G o e (1980), G o e (1980) Me a hizium anisopliae Des uxins (38–40) Wang e al. (2012), Yoshida e al. (2014) 22 Fungal Di e si y (2019) 97:1–136 123 di ec ional ones, p esence o hyd oly ic enzymes o b each he hos ’s de ense wall, and sensi i i y o abio ic ac o s like empe a u e and humidi y. Mo eo e , en o- mopa hogenic ungi should only be conside ed o com- me cializa ion i hey demons a e high p oduc ion e iciency, whe ein he s ains ha e minimum equi emen s o g ow h and can be g own and mass p oduced in solid subs a e (Hussain e al. 2014), hus educing p oduc ion cos s. Ce ain echniques should be conside ed in o de o inc ease he e ec i eness o mycoinsec icides. Since insec la ae usually embed hemsel es in o plan issues o soil and do no eed on c ops (Hall 1998), hey do no ypically s ay in a speci ic loca ion and he e o e a e e y di icul o a ge . Sp ay applica ion can be ine icien a his s age and deposi ing mycoinsec ides o e a ield o c op may no be e ec i e. The e o e, g anula o mula ions which coa d y spo es on o b an o g ains, o he d ying and agmen a ion o mycelium o hold spo es in s a ch, can bo h be e ec i e me hods o ea insec s in he ield (Hall 1998). Adding he g anula subs ances o mycoinsec icides inc eases he accu acy and e iciency o he sp ay. Se e al ac ics ha e been iden i ied by Lacey and Kaya (2007) o inc ease he e ec i eness o mycoinsec icides. P e en i e applica ions could be ine icien because he esidues a e no long-las ing, and he e o e hey should be applied only when he a ge pes is seen. Mycoinsec icides should be applied be o e he pes popula ion eaches peak numbe s, and he e o e ea ly applica ion is essen ial. Timing is also impo an : iden i ying he li e cycle o he hos , which has a highe p obabili y o being in con ac wi h he spo es, could also inc ease he e ec i eness o he mycoinsec icide. Fo example, Beau e ia bassiana is mo e e icien in in ec ing ac i e nymphs han winged adul s. Mo eo e , mycoinsec icides should no be applied du ing N O O O O NO O O O N O O O N O Bassianolide (37) NH O N N O NHO O O H O O N H NH O N N O NHO O O H O R O N H Des uxin A (39) Des uxin B, R= CH-(CH (38) 3 ) 2 Des uxin E, R= (40) O O NN OO N O O O O O O Ennia in A (41) O NN OO N O O O O O O Ennia in A1 (42) O NN OO N O O O R O O O Ennia in B, R=CH (43) 3 Ennia in B1, R=-CH (44) 2 CH 3 O N O N O O O N O O O O Beau e icin ( 36 ) Fig. 13 Chemical s uc u es o insec icidal compounds om ungi Fungal Di e si y (2019) 97:1–136 23 123 d ough s because he en i onmen al condi ions a e no a o able o he ge mina ion o he spo es. App oxima ely 750 ungal species ha e been iden i ied as insec pa hogens; howe e , in 1998 only 12 species we e u ilized as mycoinsec icides in insec sp ays (W aigh and Ca u he s 1998). By 2007 he numbe o mycoinsec icides had inc eased o abou 110 comme cially a ailable p od- uc s in he ma ke (de Fa ia and W aigh 2007). The numbe has con inued o inc ease, wi h almos 2700 a h opod pes icides in oduced wo ldwide (Cock e al. 2010), in which abou 230 species o biological con ol agen s ha e been ma ke ed and a ailable o comme cial use ( an Len e en 2012). The demand and comme cial applica ion o mic obial pes icides ha e inc eased emendously. O 82 mic obial biopes icides egis e ed in B azil, nea ly 46% a e mycoinsec icides (Masca in e al. 2018). Fungal biopes icides con ibu ed o a la ge po ion o his inc eased demand and popula i y in pes manage- men in he pas wo decades (Ja onski and Masca in 2017). Se e al p oduc s ha e al eady disappea ed om he in e - na ional ma ke place because hey we e no comme ically success ul, bu a subs an ial numbe o ungal species ha e been exploi ed (Kabaluk e al. 2010; Lacey e al. 2015) (Fig. 12). De Fa ia and W aigh (2007) and Masca in e al. (2018) lis ed ep esen a i es o mycoinsec icides de i ed om Beau e ia, Isa ia, Lecanicillium, and Me a hizium species ound in he ma ke . Mos de eloped mycoinsec icdes we e made o Eu opean and Ame ican ma ke s, whe eas only a ew we e aimed a he A ican and Asian ma ke s (Table 5). The e ha e been con inual obs acles and challenges o he de elopmen and comme cializa ion o ungal biolog- ical con ol agen s o use in con olling insec popula ions, anging om gaps in unde s anding he basic biological knowledge o hei po en ial socio-economic impac . P oblems ega ding he e ec i eness o insec icides a e linked o economic p oduc ion. The inc ease in pes - e- sis ance o chemical o mulas has led o d as ic en i on- men al p oblems. New chemical insec icides a e no being de eloped quickly enough, and he e o e he e is oom o mic obial insec icides, which a e g owing a he apid pace o 10–25% pe yea (S a nes e al. 1993), wi hin he ma - ke . Enhancing he i ulence o po en ial ungal species is essen ial o mycoinsec icides o de elop and each hei ma ke po en ial. The u u e o mycoinsec icides is p omising, wi h con- inued esea ch o inc ease pa hogenic i ulence o en o- mopa hogenic ungi in o de o achie e comme cial success wi h gene ic and physiological enginee ing. Fu - he s udies should be conduc ed o de e mine he ungal ai s esponsible o he e ec i eness o mycoinsec icides, enhancemen o hei i ulence, and de elopmen o eco- iendly and e ec i e pes managemen s a egies. 13. Biocon ol o nema odes and ungal nema icides Plan -pa asi ic nema odes a e pa asi es which cause se e e damage o many economically impo an c ops such as oma oes, po a oes and whea . Fo example, a ound US $80 billion o yield losses a e caused annually by damage om plan oo –kno nema odes, such as M. ja anica and M. incogni a (Li e al. 2007). Nema icidal chemicals ha we e once a he e ec i e, such as me hyl b omide, ha e ul i- ma ely been banned because hey a e b oad-spec um biocides ha kill all li e in he soil and con ibu e o he deple ion o he ozone laye , he eby causing g a e p ob- lems o he en i onmen . The e o e, in ecen yea s he e ha e been g ea e o s in bo h academia and indus y o ind ecologically iable al e na i es. Nema ophagous ungi a e capable o con olling plan pa asi ic nema odes h ough an agonis ic beha iou (Zaki and Siddiqui 1996). The e a e mo e han 700 species o nema ophagous ungi, which a e ound in ungal axa including Muco omyco a, Basidiomyco a, Ascomyco a and Chy idiomyco a (Li e al. 2005; Degenkolb and Vilcinskas 2016). These nema ophagous ungi a e ca ego ized in o ou g oups acco ding o hei mode o pa asi ism: nema- ode- apping (o he wise known as p edacious); nema ode egg and emale pa asi es; endopa asi ic; and oxin-p o- ducing ungi (Li e al. 2005; Degenkolb and Vilcinskas 2016). Nema ode– apping ungi o m speci ic apping s uc u es on hypha, such as adhesi e knobs, cons ic ing ings and adhesi e ne wo ks; hese h ee apping de ices can be ca ego ized u he in o se en ypes: simple adhe- si e b anches, uns alked adhesi e knobs, s alked adhesi e knobs, non-cons ic ing ings, cons ic ing ings, wo dimensional ne wo ks and h ee-dimensional ne wo ks (Rubne 1996). The cons ic ing ing ap is he mos sophis ica ed mo phological adap a ion, which can be ound in ungi ha a e no accommoda ed in he genus D echsle ella (Ba al e al. 2018). When a nema ode en e s he ing, he h ee cells swell, o ming h ee sphae ical s uc u es ha ap and immobilize he nema ode (Jansson and Lopez-Llo ca 2004). Endopa asi ic ungi a ack nema odes o ally o by pene a ion o spo es o zoospo es h ough he cu icles o he nema ode hos (Moosa i e al. 2011). A e in ec ion, he hyphae de elop inside he nema ode and diges s i s con en . Fo example, he spo es o Ca ena ia anguillulae a e inges ed by seden a y nema odes such as He e ode a spp. The spo es ge mina e in he esophagus and he mycelia hen diges he nema odes; 10–12 h a e he in ec ion, zoospo angia de elop o elease new zoospo es 24 Fungal Di e si y (2019) 97:1–136 123 Table 5 Rep esen a i e mycoinsec icides in he ma ke (de Fa ia and W aigh 2007; Masca in e al. 2018) Fungal species Ma ke ed ade name Coun y egis e ed Pes s a ge ed Manu ac u e Me a hizium anisopliae A izium B azil Mahana a imb iola a, No ozulia (Zulia) en e iana TecniCon ol BioMe ha GR Plus B azil M. imb iola a, No ozulia sp., Deois sp. Bio ech Bioninsec B azil M. imb iola a, N. en e iana, D. la opic a Koppe do B asil GR-INN B azil M. imb iola a, N. en e iana, D. la opic a Ag i alle Me amax Lı ´quido B azil M. imb iola a Bio Soja Me ap emium B azil M. imb iola a, N. en e iana, D. la opic a Biop emium Me a i o B azil M. imb iola a, N. en e iana Fi oag o Con ole Biolo ´gico Me a hizium JCO WP B azil M. imb iola a, N. en e iana, D. la opic a JCO Me a hizium Oligos B azil M. imb iola a, N. en e iana, D. la opic a Oligos Bio ecnologia Me a hizium P obio B azil M. imb iola a, N. en e iana, D. la opic a P obio Me haCon ol B azil M. imb iola a, N. en e iana, D. la opic a Simbiose Me hamax EC B azil M. imb iola a No ozymes Me ie B azil N. en e iana Ballag o Opala B azil M. imb iola a, N. en e iana Lab. Biocon ole Fa oupilha Real Me a hizium Kenya, Sou h A ica, E hiopia, Ghana Mealybugs, h ips, whi e lies Real IPM (Kenya) Me a hizium b unneum Me 52 EC USA Whi e lies, h ips, wee ils No ozymes Biologicals (USA) Me 52 G anula USA, Eu ope Wee ils, h ips No ozymes Biologicals (USA) Bio1020 Ne he lands Wee ils No ozymes Biologicals F ance Beau e ia bassiana Ad al Colombia Aphids Bio-C op (Colombia) Ag i alle AUIN B azil Bemisia abaci,Cosmopoli es so didus, Dalbulus maidis, Te anychus u icae Ag i alle Ball e ´ ia B azil B. abaci Ballag o Bassico e SC Colombia Whi e lies Co e Bio echnology (Colombia) Beau eCon ol B azil B. abaci, D. maidis, T. u icae Simbiose Beau e ia JCO B azil B. abaci, C. so didus, D. maidis, T. u icae JCO BioExpe Colombia Whi e lies, h ips Li e Sys ems Technology (Colombia) Bio e ia WP B azil B. abaci, C. so didus, D. maidis, T. u icae Bioene gia do B asil SA Bo emax EC B azil H. hampei, Diapho ina ci i, Hedypa hes be ulinus No ozymes Bo e il WP B azil B. abaci, Hypo henemus hampei, Gonip e us scu ella us, T. u icae Koppe do B asil B oadband Sou h A ica Whi e lies, h ips BASF Sou h A ica Cade e SC Colombia Whi e lies, h ips Myc os In e nacional (Colombia) Ecobass B azil B. abaci, C. so didus, D. maidis, T. u icae Toyobo do B asil Fungal Di e si y (2019) 97:1–136 25 123 in i o applica ion o Pichia anomala has educed c own o disease in banana (Lassois e al. 2008). Saccha omyces boula dii can induce phy oalexin o ma ion on so ghum and soybean (S anga lin e al. 2010). Saccha omyces ce e isiae inhibi ed he ac i i y o Bo y is cine ea (in g apes) by p oducing ola ile compounds (Pa a a i e al. 2015). In i o applica ion o Me schnikowia pulche ima agains pos -ha es o o g apes (Ble e e al. 2006, Pa - a a i e al. 2015) was also no ably success ul. O he Ascomyco a:Au eobasidium pullulans has been used o con ol bunch o in able g apes caused by Bo y is cine ea (Pa a a i e al. 2015). In addi ion, pos -ha es o o able g apes caused by Monilinia laxa (Schena e al. 2003) we e also con olled success ully by his ungus. Penicillium equen ans has been shown o e ec i ely inhibi he g ow h o Monilinia sp., which causes b own o in peaches (Guija o e al. 2007). Basidiomyco a:C yp ococcus magnus can inhibi he mycelial g ow h o Colle o ichum gloeospo ioides in i o, and con olled pos -ha es an h acnose in papaya (de Capde ille e al. 2007). An aqueous ex ac s om he basidiomes o Len inula edodes has con olled he g ow h o Puccinia econdi a . sp. i ici (Fio i-Tu ida e al. 2007). In addi ion, he in i o applica ion o Pycnopo us san- guineus has con olled he angula lea spo in beans caused by Pseudoce cospo a g iseola (Viecelli e al. 2009). Aqueous ex ac s o he basidiomes o Aga icus sub- u escens ha e also shown an an agonism agains Puccinia econdi a . sp. i ici. (Fio i-Tu ida e al. 2007). Howe e , hese basidiomyce es and hei ex ac s ha e no been p o en o be e ec i e in ield ials, and he de elopmen o me hods o e ec i e mass p oduc ion o a ain a o - able cos s o goods will cons i u e a se ious p oblem. 16. Biocon ol o us s and smu s by an agonis ic ungi Rus ungi (U edinales) a e one o he la ges g oups in he Basidiomyco a, comp ising abou 5000–6000 species ound on a wide ange o hos s, including e ns, gym- nospe ms, and mono- and dico yledonous angiospe ms (Alexopoulos e al. 1996). Diseases such as co ee lea us , Hemileia as a ix, whea s em us , Puccinia g aminis, Melampso a lea us s o Salicaceae (Populus and Salix) and C ona ium s em us s o ha d pines a e causing eno mous losses and o en making i necessa y o eplace suscep ible c ops en i ely wi h non-hos species (Li le ield 1981). Smu s p ima ily a ec g asses iz co n (maize), whea , suga cane, ba ley, oa s, o age g asses and so ghum (Feldb u ¨gge e al. 2013). A smu is cha ac e ized by spo es ha accumula e in soo -like masses called so i, which a e o med wi hin blis e s in seeds, lea es, s ems, lowe pa s, and bulbs (Lau ie e al. 2012). The so i usually b eak up in o a black powde ha is eadily dispe sed by he wind. Many smu ungi en e emb yos o seedling plan s, hen de elop sys emically, and appea ex e nally only when he plan s a e nea ing ma u i y (Liu e al. 2017a). Cu en ly, he mos widely used con ol me hod o suga cane smu disease is he b eeding o esis an cul i a s (Shen 2002; Wada 2003; C o e al. 2008; Lwin e al. 2012; Shen e al. 2014). Howe e , i s de elopmen is cons ained by long b eeding p ocesses, high cos s, and he a ailabili y o smu - esis an pa en al lines. Disease a ibu ed o smu ungi could also be con olled by soaking seed canes wi h chemical ungicides (Olu olaji 1993; Bhuiyan e al. 2012). Ano he app oach is using plan o ungal ex ac s ha inhibi smu pa hogen ge mina ion and g ow h (Lal e al. 2009). A la ge numbe o ungi ha e been iden i ied as hype pa asi es o us and smu ungi, which a e being used as biocon ol agen s wo ldwide (Gowdu and Balasub a- manian 1988; K anz 1981; Feldb u ¨gge e al. 2013). Va ious s udies suppo he abili y o ce ain ungi o con ol he g ow h o smu s and us s. The mechanisms h ough which biocon ol agen s ac a e an ibiosis, sec e- ion o me aboli es ha a e oxic, ly ic enzymes, pa asi ism and compe i ion o nu ien s. Figu e 3shows he di e en mechanisms o an agonis ic ungal species ac ion. Bio- logical app oaches a e gaining popula i y, including he use o mic obial an agonis s (Ecke and Ogawa 1988). Cla- dospo ium species co-exis wi h us so i, and some a e belie ed o be in a iably hype pa asi es o U edinales (Mo icca e al. 1999). Cladospo ium u edinicola is a common nec o ophic hype pa asi e ha can des oy us hyphae and causes coagula ion and disin eg a ion o he cell cy oplasm o Puccinia ces i (Spegazzini 1912), Puc- cinia (Ellis 1976), C ona ium que cuum (Mo gan-Jones and McKemy 1990), Puccinia iolae (T aquai e al. 1984) and Puccinia ho iana (S i as a a e al. 1985). Mo eo e , C. u edinophilum was also epo ed o colonize and des oy U edo cyclo auma p opagules in Pa aguay (Spegazzini 1912). S eyae (1930) also desc ibed C. hemileiae as an e ec i e hype pa asi e o co ee us ungus, Hemileia as a ix, in Zai e (Democ a ic Republic o Congo). Powell (1971) epo ed ha C. gallicola in galls o C ona ium comand ae on Pinus con o a a . la i olia is pa asi ic on aeciospo es. Hyphae o C. gallicola pene a e in o he aeciospo es o pine gall us , Endoc ona ium ha knessii (Su on 1973). Tsuneda and Hi a suka (1979) in es iga ed C. gallicola and ound ha i pa asi ized E. ha knessii by bo h simple con ac —disin eg a ing he cell walls o he spo es—and by ac ual pene a ion o he spo e walls, wi h o wi hou he o ma ion o app esso ia, causing he coagula ion and disappea ance o he hos cy oplasm. 32 Fungal Di e si y (2019) 97:1–136 123 Hulea (1939) and Rayss (1943) documen ed a simila phenomenon whe e C. aecidiicola, a common hype pa a- si e o us s in Eu ope and in he Medi e anean a ea, pa asi ized E. ha knessii on Pinus spp. in Cali o nia (Byle e al. 1972). Keene (1954) s a ed ha his hype pa asi e also d as ically pa asi ized aecia o Puccinia conspicua in A izona and u ediniospo es o Melampso a medusae unde s o age condi ions (Sha ma and Hea he 1980). Mo eo e , S i as a a e al. (1985) also documen ed ha Puccinia ho iana was o en egula ed by Cladospo ium sphae os- pe mum and C. enuissimum. They we e also de ec ed om aeciospo es o he wo-needle pine s em us C ona ium laccidum (Mo icca e al. 1999). O he g oups o ungi aside om Cladospo ium we e also epo ed o ac as biocon ol agen s. The en omopa hogenic and mycopa a- si ic ungus Lecanicillium lecanii is also known o a ack co ee lea us , Hemileia as a ix (Jackson e al. 1997). No many comme cial bio ungicides o us and smu s based on an agonis ic ungi a e cu en ly a ailable. Mah- mud and Hossain (2016) showed ha he BAU-bio ungi- cide (2%) (T ichode ma based p epa a ion) signi ican ly a ec ed he mycelial g ow h o Us ilaginoidea i ens in an in- i o es , bu his obse a ion emains o be con i med in g eenhouse and ield ials. K anz (1981) documen ed mo e han 80 species o ungi om o e 50 gene a epo ed as hype pa asi es o us s. Howe e , his numbe migh be an o e es ima e due o some axa being synonyms. E en hough his la ge numbe o an agonis ic ungi on us s and smu s has been epo ed, ew comme cially, imp o ed bio ungicides a e a ailable o p ac ical applica ion. As in o he applica ions o bio- con ol agen s (see he abo e chap e s), p oduc o mula- ion is he mos c i ical s ep o he en i e de elopmen p ocess (Janisiewicz and Je e s 1997). The nex ew yea s will likely see he inc eased applica ion o biocon ol agen s in ag icul u e, wi h pa icula emphasis on he use o mix u es o an agonis s on he same plan o gan. This app oach may lead o a wide spec um o ac i i y o he biological ea men o an inc ease in ei he he e icacy o consis ency o he biological ea men . Fu he mo e, col- labo a i e wo k o academic, ede al and p i a e sec o scien is s is necessa y o de elop mo e e ec i e and con- sis en bio ungicides. Enhancing c ops and o es y In his sec ion, we epo on he ways in which ungi a e being used o may be used in he u u e in enhancing plan de elopmen wi hin ag icul u e, o es y and ho icul u e. 17. Bio e ilize s Bio e ilize s a e p oduced om o ganic ma e o ag o- indus ial was es, which ac as subs a e o p opaga ion o inoculum o selec ed mic oo ganisms (Kaewchai e al. 2009). The e a e wo app oaches o de eloping po en ial bio e ilzie s: ei he he applica ion o a single supe io species wi h mul i unc ions, o g oups o mic oo ganisms (conso ia) bene icial o plan s (Vassile e al. 2015). Bio e ilize s ha e been used in ag icul u e, ho icul u e, landscape es o a ion, and soil emedia ion since he la e 1980s (Ha and T e o s 2005). The long- e m use o bio e ilize s is economical and also eco- iendly o plan , animal and human heal h, and bio e ilize s a e enewable and low-cos esou ces which a e accessible o ma ginal and small a me s (Dubey and Maheshwa i 2008; Pal e al. 2015). Thus, he use o bio e ilize s is ecommended o e chemical e ilize s. De ails ega ding bio e ilize s such as e m, ole, ypes and ad an ages ha e been desc ibed by Kaewchai e al. (2009), Pal e al. (2015), Vassile e al. (2015) and I elima e al. (2018). Se e al s udies ha e applied ungal inocula as bio e - ilize s in g eenhouse and/o ield ials (G ige a e al. 2007; Rahi e al. 2009; Goe en e al. 2016; Zhang e al. 2016a; Wang e al. 2018c). Myco hizal ungi a e widely used in ag icul u e, as hey o m oo symbio ic ela ion- ships and p o ide many bene i s o plan s, such as imp o ed plan g ow h and de elopmen , inc eased nu i- en up ake and enhanced plan ole ance o disease (Whipps 2004; Liu and Chen 2007; El-Shaikh and Mohammed 2009; Smi h e al. 2010; He na ´ndez-Mon iel e al. 2013; Goe en e al. 2016; Janous ˇko a ´e al. 2017). S ains o he gene a, such as Al e na ia,Aspe gillus,Chae omium, Fusa ium,Penicillium,Se endipi a (Pi i o mospo a), Phoma, and T ichode ma ha e been epo ed as plan g ow h p omo ing ungi (Soy ong e al. 2001; Muhammad e al. 2009; Salas-Ma ina e al. 2011; Va ma e al. 2012; Bi as e al. 2015; Mu ali and Am u hesh 2015; Zhang e al. 2016a; Zhou e al. 2018). Examples o he use o ungal inocula ea men s on plan s a e p o ided in Table 8. These po en ial plan g ow h-p omo ing ungi can be u he esea ched and de eloped as po en ungal bio e ilize s. Nume ous comme cial ungal bio e ilize p oduc s ha e been manu ac u ed globally and a e a ailable on he ma ke oday. The e a e a ious o mula ion ypes, such as g anules, we able powde , pelle s and liquids, which comp ise one o mul iple ungal inocula. Aspe gillus, Chae omium,Penicillium and T ichode ma species ha e been used in bio e ilize p oduc s. Fo example, Ke omium ® has been de eloped and imp o ed om s ains o Chae omium spp. in pelle and powde o m. The p o- duc was used in g eenhouse and ield ials o oma o, Fungal Di e si y (2019) 97:1–136 33 123 co n, ice, peppe , ci us, du ian, bi d o pa adise and ca na ion plan s in Thailand (Soy ong e al. 2001). Plan s ea ed wi h Ke omium ® showed be e plan g ow h and highe yield han non- ea ed con ol plan s. In addi ion, Ke omium ® had he abili y o con ol Phy oph ho a sp., causing ci us oo o in he ield. O he examples o ungal bio e ilize p oduc s a e gi en in Table 8. Bio e ilize s inc ease he up ake o nu ien s om he soil o a mosphe e, and p oduce bioac i e compounds, enzymes and ho mones which s imula e plan g ow h and enhance oo g ow h (Chi e al. 2010; Abdel-Fa ah e al. 2013; Pal e al. 2015). Fungal bio e ilize s a e able o solubilize and mobilize una ailable o ganic and ino ganic o ms o phospho us in o soluble o ms, making hem a ailable o plan s. Fo example, Aspe gillus nige was mixed wi h Bacillus mega e ium o o m phospha e solu- bilizing mic oo ganisms. These mic oo ganisms we e applied as bio e ilize s in India (Pal e al. 2015). A bus- cula myco hizae ha e been used as phospha e mobilizing bio e ilize s (Zhang e al. 2018). Bio e ilize s play an impo an ole in he ecycling o plan nu ien s and in enhancing he a e o compos deg ada ion (Pal e al. 2015). Some bio e ilize s ac as an agonis s and supp ess he incidence o soil bo ne plan pa hogens while helping in he biocon ol o plan diseases (Thame e al. 2011; Pal e al. 2015). Table 8 Examples o he use o ungal (and oomyce e) inocula ea ed on plan s Fungal inoculum T ea ed plan Resul Re e ences A buscula myco hiza Zea mays Ac i e du ing he ep oduc i e g ow h s ages and may bene i high p oduc i i y o maize c ops by acili a ing P up ake G ige a e al. (2007) A buscula myco hiza Ci ullus lana us Reduced eplan p oblems h ough e ec i e modi ica ion o he soil mic obo a s uc u e, and by inc easing he soil enzyme ac i i ies Zhao e al. (2010) A buscula myco hiza (Rhizophagus cla us and Cla oideoglomus e unica um) Woody plan seedlings o a ious plan s - Inc eased oo coloniza ion o all woody plan seedlings - Inc eased plan heigh and s em diame e o L. di a ica a, C. obus um and C. issilis - Inc eased shoo biomass g ow h o L. di a ica a,C. obus um,G. ga dne iana and C. issilis - Inc eased shoo phospho us o C. obus um,S. e ebin hi olius and G. ga dne iana Goe en e al. (2016) Aspe gillus nige (CS-1) Whea P omo ed plan g ow h by inc easing he esh and d y mass o whea pe plan in po expe imen s Wang e al. (2018c) Discosia sp. (HKUCC 6626) Zea mays,Pisum sa i um,Cice a ie inum Inc eased oo leng h, shoo leng h and d y ma e in he es plan s o e he uninocula ed con ol unde he con olled en i onmen Rahi e al. (2009) Endophy ic s ains o Fusa ium icinc um (RSF-4L) and Al e na ia al e na a (RSF-6L) Rice plan s Enhanced g ow h a ibu es, including inc eased oo -shoo leng hs, chlo ophyll con en s, and biomass Khan e al. (2015a) Penicillium sp., T ichode ma sp., (Py hium sp. (Oomyce e) Pea l mille seeds - Penicillium sp. a 5% (w/w) concen a ion eco ded highes seed ge mina ion o 92% and 1701.9 seedling igo -Penicillium sp. a 5% (w/w) and Py hium sp. a 10% (w/ w) showed maximum disease p o ec ion o 67% and 61% espec i ely agains downy mildew disease o pea l mille -Penicillium sp. and T ichode ma sp. eco ded highes disease p o ec ion o 71% and 66%, espec i ely unde g eenhouse condi ions Mu ali e al. (2012) Pu pu eocillium lilacinum Toma o seeds Inc eased o he pe cen age o oma o seed ge mina ion om 71 o 85% a e 48 h Ca ello e al. (2015) T ichode ma longib achia um Whea seeds Inc eased whea seedling heigh and oo leng h, compa ed o he NaCl s ess ea men Zhang e al. (2016a) 34 Fungal Di e si y (2019) 97:1–136 123 Fungal de i ed s imulan s, o elici o s, a e ungi o ungal compounds ha enhance he p oduc ion o sec- onda y me aboli es, o elici g ow h o immune esponse in a a ge plan species upon applica ion. Plan esponses include he up egula ion o genes in ol ed in plan de ense, as well as he inc eased p oduc ion o an imic obial com- pounds, lignin, seconda y me aboli es, and ce ain p o eins (Vassile e al. 2015). Po en ial uses o such elici o s include he enhanced p oduc ion o comme cially aluable compounds/me aboli es, o he a i icial enhancemen o plan de enses when pa hogens a e de ec ed (Radman e al. 2003). A no el app oach o he use o elici o s is o inco po a e hem wi h immobilized s imulan s, such as wi h a buscula myco hizal inoculum. Addi ionally, plan - de i ed elici o s, which enhance he g ow h and de elop- men o bene icial ungi such as a buscula myco hizae, also show p omise in ad ancing his ield o s udy (Akiyama e al. 2005; Besse e e al. 2006). Elici o s ha e a high po en ial o enhancing plan p oduc i i y and imp o ing plan de enses agains pa hogens, and gi en ha elici o s can be used in combina ion wi h o he ypes o bio e ilize s, hey hold much po en ial o wide scale applica ion in he u u e. Fungal bio e ilize s a e applied on a e y small scale in ag icul u e as compa ed o chemical e ilize s due o hei limi ed shel li e and slowe a e o e ec . Oli ian e al. (2004) epo ed using s e ilized pea as solid suppo o Fusa ium oxyspo um inocula ion, s o ing his admix u e a oom empe a u e wi hou loss o ac i i y. G ow h and o mula ions based on ecycling ag o-indus ial was es can be expec ed o employ ni ogen- ixing and o he mic oo - ganisms wi h di e en cha ac e is ics, such as biocon ol, P-solubiliza ion, lignocelluloly ic ac i i y. Fo example, combina ions be ween T ichode ma spp. and P-solubilizing ungi can be cul u ed based on ag oindus ial-was es, leading o mine aliza ion o he ma ix/subs a e by he combined enzyme ac ions. We could apply immobiliza ion o ungal cells oge he wi h enhanced bio echnology and in combina ion wi h elici o s. Immobilized cell echnolo- gies pe mi he use o wo and mo e mic oo ganisms, which esul in highly e ec i e syne gies bene i ing all he o ganisms in ol ed, including he plan s (Vassile e al. 2015). In o de o e ec i ely implemen he use and gain he ull bene i s o bio e ilize s, an in eg a ed app oach engaging a a ie y o mechanisms should be conside ed. Such an app oach could be ailo ed o sui speci ic indus y needs and a ge de ined ou comes, such as imp o ed g ow h, up egula ion o key me aboli es, o enhanced plan de enses. 18. A buscula myco hizae as bio e ilize s Ec omyco hizal associa ion desc ibes a s uc u e ha esul s om a mu ualis ic symbiosis be ween he oo s o highe plan s and oo -inhabi ing ungi. Wi hin his sym- bio ic ela ionship, he ole o he ungi is o help he hos plan s ake up wa e and nu ien s, ecei ing plan -de i ed ca bohyd a es om pho osyn hesis in e u n. Abou 6000 plan species in 145 gene a and 26 amilies (app oxima ely 5600 angiospe ms and 285 gymnospe ms) ha e been es i- ma ed o possess ec omyco hizal symbio ic ungal pa - ne s (B und e 2009; Tede soo e al. 2010). Ec omyco hizal associa ion helps bo h he ungi and hei hos plan s o o e come en i onmen al s esses caused by low nu ien s, d ough , disease, ex eme empe a u es and hea y me al con amina ion (Smi h and Read 2008; Cou y e al. 2010; Kip e e al. 2012; Heilmann-Clausen e al. 2014). Mo eo e , ec omyco hizae can imp o e soil s uc u e and nu ien s; p o ec he plan s agains oo pa hogens; p omo e plan g ow h by p oducing phy oho - mones; and inc ease he pho osyn he ic a e o he plan s (Spli allo e al. 2009; Ramachela and The on 2010; Maki a e al. 2012). Ec omyco hizae a e domina ed by membe s o he Basidiomyco a, some Ascomyco a, and, a ely, Muco omyco a (Taylo and Alexande 2005; Rinaldi e al. 2008; Tede soo e al. 2010). Gene ally, ec omyco hizae p oduce ep oduc i e ui ing bodies appea ing abo e- o below-g ound ha a e essen ial o he ood webs o o es ecosys ems and hei spo e dispe sal (Rinaldi e al. 2008; Wilson e al. 2011). Plan seedling egene a ion and es o a ion a e o pi o al in e es o o es y, bu he su i al o seedlings is o en poo bo h in nu se ies and na u al plan a ion a eas, espe- cially in mine spoils, pollu ed a eas, and o he eeless a eas. The e o e, he main pu pose o he applica ion o ec omyco hizae is o imp o e he su i al and g ow h o seedlings. The po en ial ad an ages o ec omyco hizal associa ion in nu se ies a e no only he posi i e g ow h esponses o he seedlings, bu also a educ ion o e il- iza ion cos s in an en i onmen ally iendly manne . The ole o ec omyco hizae in o es es ablishmen and eco e y has been well-es ablished. Nume ous s udies on he ec omyco hizae inocula ion o seedlings ha e shown inc eases in plan g ow h and p oduc i i y, he iabili y o seedlings, and seedling es ablishmen on a o es es o a- ion p og ams (Tes e e al. 2009; Dalong e al. 2011; B ea ley e al. 2016; Velmala e al. 2018). Ec omyco - hizae a e pa icula ly impo an o he g ow h o eco- nomically impo an ees, including species o beech (Fagus), dip e oca ps (Dip e oca pus and Sho ea), euca- lyp us (Eucalyp us), oak (Que cus and Cas anopsis), pine Fungal Di e si y (2019) 97:1–136 35 123 (Pinus) and sp uce (Picea) (Tennakoon e al. 2005; Flyk e al. 2008; Dalong e al. 2011; Kayama and Yamanaka 2016). Cenocococum,Pisoli hus,Lacca ia, Rhizopogon, Russula, Scle ode ma and Thelepho a species ha e been shown o inc ease he a e o su i al and g ow h o eucalyp us, pine and oak seedlings in bo h plan a ion and e o es a ion p og ams (Fig. 16) (Chen e al. 2006; Jha e al. 2008; C am and Dum oese 2012; Kip e e al. 2012; Zong e al. 2015). Gene ally, h ee main ypes o ec omyco hizal inocu- lan s—soil, ui ing body/spo e and ege a i e mycelium— ha e been used in nu se ies. Fo es soil was used as a sou ce o indigenous ec omyco hizal ungi in an inocula ion expe imen mixed wi h plan ing subs a es (Kaewg ajang e al. 2013; Dulme e al. 2014; Res ep-Liano e al. 2014; Li ne-Luzon e al. 2017). This me hod is s ill used in many pa s o he wo ld, pa icula ly in de eloping coun ies. Howe e , he use o o es soil inoculan s has he majo disad an age ha he ec omyco hizal composi ion is unknown. Mo eo e , i equi es la ge amoun s o soil and hence isks in oducing plan pa hogens and weeds exi s. F ui ing bodies/spo es o a ious ec omyco hizae a e easily ob ained om na u al o es s and can be easily applied o plan seedlings as inoculan s. The a ie y o applica ion me hods include mixing wi h sand, clay, o e miculi e ca ie be o e being added o plan ing subs a e o soil, sus- pension in wa e and d enching o i iga ing, sp aying, and encapsula ion o coa ing on o seeds. Ec omyco hizae ha a e “gas e omyce es” (pu ball ungi) wi h conspicuous basidomes a e be e sou ces han he gilled ungi i la ge numbe s o spo es a e equi ed, as hey a e easie o collec and use. Fo ins ance, species o he gene a Pisoli hus,Rhi- zopogon and Scle ode ma p oduce a la ge quan i y o spo es, and he app oxima e spo e concen a ion in a seedling inocula ion may ange om 10 5 –10 7 spo es/ml (Chen e al. 2006; B uns e al. 2009; Rai and Va ma 2011; Aggangan e al. 2013). Mos p e ious s udies esul ed in accep - able le els o ec omyco hizal associa ion, imp o ed seed- ling g ow h o pines in he nu se y, and imp o ed ou plan ing success ollowing inocula ion wi h Pisoli hus and Rhizo- pogon spo es (B uns e al. 2009; Dalong e al. 2011). The e a e o cou se limi a ions o ui ing body/spo e inoculan s: only hose ec omyco hizal species able o p oduce la ge numbe s o ui ing bodies and spo es can be used, and he e may be a conce n abou he compa ibili y and e iciency o ec omyco hizae o he plan species o be cul i a ed. As an al e na i e, ege a i e mycelial inocu- lan s ob ained om pu e cul u es o ec omyco hizae may be p epa ed om a pu e cul u e using di e en me hods, e. g. using mycelial suspensions and subs a e ca ie s such as o es li e , ce eal g ains, pea moss, e miculi e, and algina e-beads (de Oli ei a e al. 2006; Rossi e al. 2007; Lee e al. 2008a,b; Res ep-Liano e al. 2014; Kayama and Yamanaka 2016; Kumla e al. 2016). This inoculan ype Fig. 16 A buscula myco hizae inoculum p oduc ion. aPo cul u e o so ghum and maize, bon- a m inoculum p oduc ion using lea li e compos and ag icul u al was es; cIn i o p oduc ion wi h oo o gan cul u e; dnewly p oduced Funneli o mis mosseae spo es a ached o Ri T-DNA ans o med ca o oo s 36 Fungal Di e si y (2019) 97:1–136 123 has p o en o be he mos sui able me hod because o hei e iciency in p omo ing plan g ow h by selec ed ungal isola es. Howe e , op imal condi ions, including nu i ion, empe a u e and subs a e ca ie , mus always be es ab- lished empi ically o la ge-scale p oduc ion. Se e al comme cial ec omyco hizal p oduc s ha e been de eloped. Fo ins ance, he comme cial mycelial inocu- lan s o MycoRhiz ® , Ec omyco hiza Spawn ® , Somycel PV and Mycobead ® a e a ailable. BioG ow Blend ® , MycoApply ® -Ec o, Ec o i ® and Myco T ee ® Ec o-In- jec able a e comme cially a ailable p oduc s wi h ec o- myco hizae spo es. The comme cial p oduc s p oduced by mixing endomyco hizae and ec omyco hizae spo es a e MycoApply ® -Endo/Ec o, BioO ganic TM Myco hizal Landscape Inoculan and Mycoke ® P o ARBOR·WP. In o de o apply ec omyco hizae in o es y, i is necessa y o selec ec omyco hizal isola es o high compa ibili y and e iciency in he coloniza ion o he a ge plan species. Inoculan ypes, as well as inocula ion p o ocols and skills in nu se y p ac ices, lead o he success o an inocula ion p og am unde he p ope en i onmen al condi ions in he plan a ion si e. The po en ial o a buscula myco hizae o inc ease c op yields has been known o decades, bu he e a e ew published s udies demons a ing he e ec i eness o he la ge-scale inocula ion o globally impo an c ops, espe- cially in he opics whe e popula ion g ow h is high (Ro- d iguez and Sande s 2015). The e o e, esea che s need o s udy la ge-scale a buscula myco hizae applica ion o c ops in he opics whe e phospha e bioa ailabili y is low and he applica ion o a buscula myco hizae has he s onges po en ial o inc ease ood p oduc ion and educe he need o apply phospha e e ilize s (Ceballos e al. 2013). Manu ac u e s should ensu e hei a buscula myc- o hizae p oduc s a e ee om o he mic oo ganisms and ensu e p oduc quali y and su icien weigh o cheap anspo . Fa me s should ha e easy access o a buscula myco hizae p oduc s, co ec ly apply hem o he c ops, and know how o p oduce on- a m a buscula myco hizae inoculum o sus ainable ag icul u e. 19. Applica ion o ec omyco hizal ungi in o es y Ec omyco hizal associa ion desc ibes a s uc u e ha esul s om a mu ualis ic symbiosis be ween he oo s o highe plan s and oo -inhabi ing ungi. Wi hin his sym- bio ic ela ionship, he ole o he ungi is o help he hos plan s ake up wa e and nu ien s, ecei ing plan -de i ed ca bohyd a es om pho osyn hesis in e u n. Abou 6000 plan species in 145 gene a and 26 amilies (app oxima ely 5600 angiospe ms and 285 gymnospe ms) ha e been es i- ma ed o possess ec omyco hizal symbio ic ungal pa ne s (B und e 2009; Tede soo e al. 2010). Ec omy- co hizal associa ion helps bo h he ungi and hei hos plan s o o e come en i onmen al s esses caused by low nu ien s, d ough , disease, ex eme empe a u es and hea y me al con amina ion (Smi h and Read 2008; Cou y e al. 2010; Kip e e al. 2012; Heilmann-Clausen e al. 2014). Mo eo e , ec omyco hizae can imp o e soil s uc u e and nu ien s; p o ec he plan s agains oo pa hogens; p omo e plan g ow h by p oducing phy oho - mones; and inc ease he pho osyn he ic a e o he plan s (Spli allo e al. 2009; Ramachela and The on 2010; Maki a e al. 2012). Ec omyco hizae a e domina ed by membe s o he Basidiomyco a, some Ascomyco a, and, a ely, Muco omyco a (Taylo and Alexande 2005; Rinaldi e al. 2008; Tede soo e al. 2010). Gene ally, ec omyco hizae p oduce ep oduc i e ui ing bodies appea ing abo e- o below-g ound ha a e essen ial o he ood webs o o es ecosys ems and hei spo e dispe sal (Rinaldi e al. 2008; Wilson e al. 2011). Plan seedling egene a ion and es o a ion a e o pi o al in e es o o es y, bu he su i al o seedlings is o en poo bo h in nu se ies and na u al plan a ion a eas, espe- cially in mine spoils, pollu ed a eas, and o he eeless a eas. The e o e, he main pu pose o he applica ion o ec omyco hizae is o imp o e he su i al and g ow h o seedlings. The po en ial ad an ages o ec omyco hizal associa ion in nu se ies a e no only he posi i e g ow h esponses o he seedlings, bu also a educ ion o e il- iza ion cos s in an en i onmen ally iendly manne . The ole o ec omyco hizae in o es es ablishmen and eco e y has been well-es ablished. Nume ous s udies on he ec omyco hizae inocula ion o seedlings ha e shown inc eases in plan g ow h and p oduc i i y, he iabili y o seedlings, and seedling es ablishmen on a o es es o a- ion p og ams (Tes e e al. 2009; Dalong e al. 2011; B ea ley e al. 2016; Velmala e al. 2018). Ec omyco - hizae a e pa icula ly impo an o he g ow h o eco- nomically impo an ees, including species o beech (Fagus), dip e oca ps (Dip e oca pus and Sho ea), euca- lyp us (Eucalyp us), oak (Que cus and Cas anopsis), pine (Pinus) and sp uce (Picea) (Tennakoon e al. 2005; Flyk e al. 2008; Dalong e al. 2011; Kayama and Yamanaka 2016). Cenocococum,Pisoli hus,Lacca ia, Rhizopogon, Russula, Scle ode ma and Thelepho a species ha e been shown o inc ease he a e o su i al and g ow h o eucalyp us, pine and oak seedlings in bo h plan a ion and e o es a ion p og ams (Fig. 17) (Chen e al. 2006; Jha e al. 2008; C am and Dum oese 2012; Kip e e al. 2012; Zong e al. 2015). Gene ally, h ee main ypes o ec omyco hizal inocu- lan s—soil, ui ing body/spo e and ege a i e mycelium— ha e been used in nu se ies (Fig. 18a). Fo es soil was used as a sou ce o indigenous ec omyco hizal ungi in an Fungal Di e si y (2019) 97:1–136 37 123 inocula ion expe imen mixed wi h plan ing subs a es (Kaewg ajang e al. 2013; Dulme e al. 2014; Res ep- Liano e al. 2014; Li ne-Luzon e al. 2017). This me hod is s ill used in many pa s o he wo ld, pa icula ly in de eloping coun ies. Howe e , he use o o es soil inoculan s has he majo disad an age ha he ec omyco hizal composi ion is unknown. Mo eo e , i equi es la ge amoun s o soil and hence isks in oducing plan pa hogens and weeds exi s. F ui ing bodies/spo es o a ious ec omyco hizae a e easily ob ained om na u al o es s and can be easily applied o plan seedlings as inoculan s. The a ie y o applica ion me hods include mixing wi h sand, clay, o e miculi e ca ie be o e being added o plan ing subs a e o soil, suspension in wa e and d enching o i iga ing, sp aying, and encapsula ion o coa ing on o seeds. Ec omyco hizae ha a e “gas- e omyce es” (pu ball ungi) wi h conspicuous basidomes a e be e sou ces han he gilled ungi i la ge numbe s o spo es a e equi ed, as hey a e easie o collec and use. Fo ins ance, species o he gene a Pisoli hus,Rhizopogon and Scle ode ma p oduce a la ge quan i y o spo es, and he app oxima e spo e concen a ion in a seedling inocu- la ion may ange om 10 5 –10 7 spo es/ml (Chen e al. 2006; B uns e al. 2009; Rai and Va ma 2011; Aggangan e al. 2013). Mos p e ious s udies esul ed in accep - able le els o ec omyco hizal associa ion, imp o ed seedling g ow h o pines in he nu se y, and imp o ed ou plan ing success ollowing inocula ion wi h Pisoli hus and Rhizopogon spo es (B uns e al. 2009; Dalong e al. 2011). The e a e o cou se limi a ions o ui ing body/spo e inoculan s: only hose ec omyco hizal species able o p oduce la ge numbe s o ui ing bodies and spo es can be used, and he e may be a conce n abou he compa ibili y and e iciency o ec omyco hizae o he plan species o be cul i a ed. As an al e na i e, ege a i e mycelial inocu- lan s ob ained om pu e cul u es o ec omyco hizae may be p epa ed om a pu e cul u e using di e en me hods, e. Fig. 17 Applica ion o Pisoli hus albus in eucalyp us (Eucalyp us camaldulensis) seedlings a e 3 mon hs o inocula ion (a). T1 Pisoli hus inocula ion expe imen . T2 Nu ien solu ion expe imen . T3 Uninocula ed expe imen . Ec omyco hizal oo ip o Pisoli hus albus (b). C oss sec ion o ec omyco hizal oo ip o E.camaldulensis showed man le shea h (M) and Ha ig ne (a owed). Scale ba B=1 mm, C =20 μm Fig. 18 Inoculan ypes o ec omyco hizae (Pisoli hus o ien alis). aSoil inoculan , bspo e suspension inoculan , c,d ege a i e mycelial inoculan s 38 Fungal Di e si y (2019) 97:1–136 123 g. using mycelial suspensions and subs a e ca ie s such as o es li e , ce eal g ains, pea moss, e miculi e, and algina e-beads (de Oli ei a e al. 2006; Rossi e al. 2007; Lee e al. 2008a,b; Res ep-Liano e al. 2014; Kayama and Yamanaka 2016; Kumla e al. 2016). This inoculan ype has p o en o be he mos sui able me hod because o hei e iciency in p omo ing plan g ow h by selec ed ungal isola es. Howe e , op imal condi ions, including nu i ion, empe a u e and subs a e ca ie , mus always be es ab- lished empi ically o la ge-scale p oduc ion. Se e al comme cial ec omyco hizal p oduc s ha e been de eloped In o de o apply ec omyco hizae in o es y, i is necessa y o selec ec omyco hizal isola es o high compa ibili y and e iciency in he coloniza ion o he a ge plan species. Inoculan ypes, as well as inocula ion p o ocols and skills in nu se y p ac ices, lead o he success o an inocula ion p og am unde he p ope en i onmen al condi ions in he plan a ion si e. 20. Use o o chid myco hizae and endophy es in bio echnology O chidaceae is one o he la ges amilies o lowe ing plan s wi h o e 700 gene a and 25,000 species (Dea naley 2007; Sa hiyadash e al. 2012). O chids a e ound in a wide ange o habi a s and may g ow au o ophically o he e o ophically (Sa hiyadash e al. 2012; Tan e al. 2014; Fochi e al. 2017). O chids a e economically e y impo - an and hei sales ep esen a ound 8% o he wo ld lo icul u e ade. The economically mos impo an gene a a e Cymbidium,Dend obium, and Phalaenopsis (Dea na- ley 2007, 2016; Chugh e al. 2009; Emsa-a e al. 2018). Some o chids, such as Gas odia (G iesbach 2002; Dea - naley 2007), Dend obium o icinale and D. nobile a e used as na u al medicines (Li e al. 2009). Fu he mo e, he economically mos impo an o chid p oduc s a e he la- ou s de i ed om some species o he genus Vanilla, which a e g own a a la ge scale and used in ood and d inks (Dea naley 2007; Gonzalez-Cha ez e al. 2018). Mos o chids ely on myco hizal ungi o su i al, as hey a e essen ial o seed ge mina ion and ea ly plan g ow h (Sa hiyadash e al. 2012; Fochi e al. 2017). Di - e en ungal symbio ic myco hizae ha e been eco ded om o chids (Table 9). O chid associa ed non-myco hizal endophy ic ungi ha e been in es iga ed ia heal hy plan o gans including lea es, oo s and s ems (Ma e al. 2015a), whe eas myco hizal ungi a e gene ally isola ed om oo issues (Tan e al. 2014; Ma e al. 2015a,b). Non-myco - hizal endophy ic ungi ep esen o e 110 gene a, including So da iomyce es (Neonec ia,T ichode ma,Ni- g ospo a,Pes alo iopsis) and Do hideomyce es (Ce - cospo a,Lasiodiplodia,Phyllos ic a) (Ma e al. 2015a,b). Da k sep a e endophy es isola ed om Dend obium and Lep odon idium sp. enhanced seedling de elopmen o Dend obium nobile by o ming pelo on-like s uc u es in he co ical cells o he o chid (Hou and Guo 2009;Ma e al. 2015a,b). Fusa ium species p omo ed seed ge mi- na ion o Cyp ipedium and Pla an he a o chids (Ma e al. 2015a,b). The endophy e Umbelopsis nana isola ed om Cymbidium spp., p omo ed g ow h o Cymbidium hyb i- dum (Ma e al. 2015a,b). Many epiphy ic and e es ial o chids p oduce minu e seeds wi h minimal nu ien ese es, and lack nu ien s o seed ge mina ion and de elopmen in he ea ly g ow h s age (Came on e al. 2006, Sa hiyadash e al. 2012; Tan e al. 2014). A e ge mina ion, o chid seeds p oduce a p o oco m (a p eseedling s age/ ea ly s age o he plan ) ha lacks chlo ophyll (Leake 2004; Sa hiyadash e al. 2012; Fochi e al. 2017). P o oco ms g ow in comple e dependence on ungal symbion s o nu ien s and o ganic ca bon supply (Came on e al. 2006; Dea naley 2007). O chid seedlings de elop pho osyn he ic lea es la e and hen ma u e oo s a e colonized by myco hizal ungi (Came on e al. 2006; Smi h and Read 2008; Fochi e al. 2017). The p o oco m and ma u e oo s cells a e colonized by in acellula ungal coils (pelo ons) (Fig. 19) (Dea naley 2007; Dea naley e al. 2016; Fochi e al. 2017). O chid myco hizal associa ions a e use ul in he lo i- cul u e ade, as hey s imula e seed ge mina ion and Table 9 Fungal symbion s associa ed wi h di e en o chid species Fungal symbion s (Basidiomyco a) O chid species Locali y Re e ences Rhizoc onia Gas ochilus acaulis,Ne ilia p ainiana and Polys chya conc e a India Sen hilkuma (2003) Sa hiyadash e al. (2012) Ce a obasidium Zeuxine s a euma ica India Kuma and Kaushik (2004) Tulasnella Ame o chis o undi olia Dac ylo hiza majalis Neuwiedia e a i olia Wo ldwide Zelme e al. (1996) K is iansen e al. (2001) K is iansen e al. (2004) Fungal Di e si y (2019) 97:1–136 39 123 p opaga e o chids (Tan e al. 2014). A b ie me hodology o he inocula ion o myco hizal ungus (Tulasnella sp.) o o chids acco ding o Non achaiyapoom e al. (2010) and Tan e al. (2014) is ep esen ed in a low cha (Fig. 20). A Tulasnella sp. isola ed om oo s o Dend obium nobile acili a es signi ican ly highe seed ge mina ion o D.o - icinale han ha o he con ol (wi hou inocula ion o Tulasnella sp.) (Tan e al. 2014). In addi ion, Tulasnella sp. Fig. 19 a,bMycelial coils (pelo ons, seen as b own a eas) in he oo sec ion o Cymbidium lowianum collec ed om he o chid nu se y a Queen Si iki Bo anical Ga den in Chiang Mai, Thailand, in No embe 2008 Seed ge mina ion and p o oco m de elopmen a e assessed. Small sec ions o oo a e placed on he po a o dex ose aga (PDA), and hyphal ips o ungi a e ans e ed o esh PDA. PDA aga plugs wi h ungi a e inocula ed o oa meal aga wi h n y lon clo hes. Axenic seeds a e sown on o plan issue cul u e media. A e 60 days, seedlings a e ans e ed o esh media. Iden i ica ion o pelo ons om o chid oo s – using mic oscope Su ace s e iliza ion o oo - 70% ( / ) e hanol, 2.5% ( / ) 2 mon hs old seedlings and aga plugs wi h ungi a e g own on PDA. Seedlings a e ans e ed o s e ile cylind ical glass bo le a e 10 d Axenic o chid seeds a e sown on he su ace o nylon clo hes and placed in issue cul u e chambe . F esh weigh and d y weigh a e assessed a e 7 weeks. B A Fig. 20 Scheme illus a ing he me hodology o o chid seed p opaga ion using myco hizal ungi (in- i o condi ions) (Non achaiyapoom e al. 2010; Tan e al. 2014). aE ec o myco hizal ungi on ge mina ion o o chid seeds. bE ec o myco hizal ungi on g ow h o o chid seedlings 40 Fungal Di e si y (2019) 97:1–136 123 p omo es seed de elopmen up o s age 5 (Table 10), while he con ol wi hou he ungus de eloped only o s age 2 (Table 10) (Tan e al. 2014). Howe e , ungi isola ed om o chid plan oo s do no always exhibi unc ional sym- bio ic associa ions wi h he o chid plan (Dea naley 2007). Mic oscopic obse a ions o o chid oo sec ions migh be use ul o con i m he p esence o in acellula ungal mycelium (Non achaiyapoom e al. 2010; Emsa-a e al. 2018). Fu he mo e, i is impo an o e alua e seedling g ow h o myco hizal inocula ed o chids unde na u al condi ions (Tan e al. 2014). O chid myco hizal ungi a e also impo an o con- olling disease in lo icul u e ade (Yode e al. 2000; Emsa-a e al. 2018). Inocula ion o o chid myco hizal ungi may enhance plan immuni y agains pa hogenic diseases (Wu e al. 2011; Emsa-a e al. 2018). Fo example, so o disease is one o he mos de as a ing diseases caused by Dickeya spp., which kills o chids o causes spo s/sca s on lea es and lowe s (Liau e al. 2003; Emsa-a e al. 2018). One ecen s udy showed ha so o de elopmen in myco hizal ungi inocula ed o chids was signi ican ly educed compa ed o ha o non-myco hizal ungi inocula ed o chids in g eenhouse condi ions. Pha- laenopsis is a popula po ed plan species ha was used o he s udy by Emsa-a e al. (2018). A b ie o e iew o he me hodology o inocula ion o myco hizal ungi (Tulas- nella deliquescens) oPhalaenopsis o con ol pa hogenic Dickeya is p esen ed in Fig. 21. Se e al comme cial p oduc s con aining myco hizal inoculan s exis . These inoculan s a e a ailable o sale in liquid and powde o m o easy and e ec i e usage. Mos o hese p oduc s a e o ganic e ilize s inocula ed wi h myco hizae spo es and wi h i amins, mine als, and nu ien s o help bols e he e ili y and biological ac i i y o he soil (see Table 11). Myco hizal ungi a e use ul in o chid conse a ion (Tan e al. 2014). O chids a e a highly di e se plan amily and many species may ace ex inc ion h ea s (Rei e e al. 2016) because o habi a loss and o e - exploi a ion o a ac i e species (Dea naley 2007). Wi h his decline o o chid di e si y, i is now an u gen equi emen o encou age esea ch on he ein oduc ion o endange ed species o na u al habi a s (Rei e e al. 2016). 21. G ow h p omo ing ho mones om ungi Fungi li e in di e se habi a s and ha e adap ed o eco- logical niches, including plan sys ems. Plan s and ungi ha e es ablished complex mu ualis ic ela ionships, and wild plan s a e almos always colonized by endophy ic, pa asi ic and myco hizal ungi (Rod iguez e al. 2009; Pa ka and Naq i 2017). Fungi p oduce a a ie y o bioac i e compounds ha play an impo an ole in he physiological ac i i ies o he hos plan , in luencing he g ow h o he hos s. This can e en lead o an inc eased ole ance o abio ic and bio ic s esses o he plan s (Pineda e al. 2010). Many s udies ha e shown ha ungi enhance plan g ow h h ough he solubiliza ion o insoluble min- e als in soil and sec e ion o plan g ow h egula o s (Bilal e al. 2018; Chanclud and Mo el 2016;Ju ´nio e al. 2017; Khan e al. 2012). G ow h p omo ion by plan g ow h egula o s o phy oho mones p oduc ion, a e signal mole- cules ac ing as chemical messenge s and play a unda- men al ole in plan s. Plan g ow h ho mones p oduced by symbio ic ungi may g ea ly in luence p ocesses including Plan le s o Phalaenopsis sp. and Tulasnella deliquescens, ungal myco hizal isola es we e selec ed o he expe imen . Fungal inoculum p epa a ion - coconu dus was soaked in ap wa e o e nigh and d ied. PDA pieces con aining he ungal mycelium we e placed on coconu dus . Plan le s o Phalaenopsis we e asep ically placed on coconu dus and incuba ed a 25oC o 30 days. Randomly selec ed oo samples we e checked he p esence o pelo ons. Plan le s we e po ed o small plas ic po s con aining sphagnum moss. Bac e ial suspension was applied and checked o de elopmen so o a eas on lea es. Fig. 21 Scheme illus a ing he me hodology o he inocula ion o myco hizal ungi, Tulasnella deliquescens o he o chid Phalaenop- sis o con ol pa hogenic bac e ia (Emsa-a e al. 2018) Table 10 Di e en s ages o o chid seed ge mina ion (Tan e al. 2014) S age Desc ip ion 0 No ge mina ion, iable emb yo 1 Enla ged emb yo, p oduc ion o hizoid(s) (=ge mina ion) 2 Con inued emb yo enla gemen , up u e o es a, u he p oduc ion o hizoids 3 Appea ance o p o ome is em 4 Eme gence o i s lea 5 Elonga ion o i s lea Fungal Di e si y (2019) 97:1–136 41 123 24. G owing mush ooms in bags Wood-inhabi ing mush ooms can be cul i a ed in any ype o lignocellulosic ma e ial, such as s aw, sawdus o ice hulls (Vic o and Ola omiwa 2013). Pa hmashini e al. (2008) showed ha he cul i a ion o he oys e mush oom (Pleu o us os ea us) on a ious sawdus ypes p oduces di e en ui ing yields. Sawdus is he mos commonly used ma e ial o he cul i a ion o oys e mush ooms and is he p e e ed medium o comme cial p oduc ion (Oei 2005). Maximum biological e iciency o oys e mush oom cul i a ion is gained om g ow h on he sawdus o ubbe ees (Pa hmashini e al. 2008). I has also been shown ha so wood sawdus such as coconu , cashew, mango and ubbe a e mo e sui able han ha dwood sawdus (Cus odio and C is ophe 2004). The a ailabili y o aw ma e ials such as sawdus , ice s aw, suga cane was es a e key ac o s in he choice o ag icul u al was e o g owing mush ooms (Pa hmashini e al. 2008). The mos commonly and easily cul i a ed mush ooms in Sou h Eas Asian coun ies a e oys e mush ooms (Pleu o us), ea mush- ooms (Au icula ia), and s aw mush ooms (Vol a iella), Len inula edodes (shii ake), as well as Len inus (e.g. Len inus squa osulus), Ganode ma, Mac olepio a and “Ag ocybe” (i.e., Cyclocybe) spp. (Kwon and Tha i ha - goon 2004). Di e en ypes o sawdus a e used as he g owing medium in opical a eas, depending on he cha ac e is ics o he a ea and he ees a ailable. Rubbe ee sawdus is he mos popula (Kwon and Tha i ha goon 2004; Klomk- lung e al. 2012; Nguyen 2004), ollowed by Acacia au iculi o mis (Tapingkae 2005), Mangi e a indica (Tong and Rajend a 1992) and Tama indus indica. Fo e e y 1 kg saw dus bag, addi ions a e made o 10 g o calcium ca - bona e, 50 g o iceb an, 10 g o pumice, 10 ml o molasses, 10 g o lou and 10 g o b ewe ’s was e. These componen s a e hen mixed wi h wa e o ob ain a wa e con en o 65–70%. Each 800 g o subs a e is hen igh ly packed in a 25.8 cm polyp opylene bag and capped wi h a plas ic ing o bo le neck, lea ing space o la e inocula e wi h mycelium (Kwon and Tha i ha goon 2004; S ame s 2000; Klomklung e al. 2012; Yamamaka 1997). Each sawdus bag is sealed wi h a co on wool plug, co e ed wi h newspape , and ied wi h a ubbe band. The sawdus bags a e s e ilized a 121 °C o 15 min o a 90–100 °C o 3 h. A e he empe a u e d ops o 25 °C, he bags a e inocula ed wi h spawn (Fig. 25c) ha comp ises 10% o he weigh o he sawdus bag. Sawdus bags a e kep a oom empe a u e (25 °C) a 70–80% humidi y o p oduce ui ing bodies (Klomklung e al. 2012). When new wild mush ooms a e in oduced o he ma - ke , i is impo an o conduc ui ing es s. Depending on he ype o mush oom, a choice can be made be ween compos o sawdus media. As a ule o humb, o wood- inhabi ing mush ooms (e.g. Len inula,Au icula ia)i is be e o use sawdus media in bags (Fig. 25a, b), while o soil-inhabi ing mush ooms (e.g. Aga icus,Mac olepio a)i is be e o use s aw compos . Fo wood-inhabi ing mush ooms, p o ocols adap ed om Klomklung e al. (2012) a e ollowed. The su ace o sawdus g owing bags is inocula ed wi h spawn. The bags a e kep in a da k incuba ion oom a he op imum em- pe a u e and ela i e humidi y o he pa icula mush oom. Bags a e opened when he mycelium has comple ely col- onized he subs a e. The su ace o he subs a e is sc aped sligh ly wi h a s e ile easpoon o emo e he hin whi ish Fig. 25 aAu icula ia hailandica g owing on sawdus subs a e bags; bAu icula ia co nea whi e a ie y g owing on sawdus subs a e bags; cmush oom spawn bo les 48 Fungal Di e si y (2019) 97:1–136 123 mycelia. The subs a e bags a e hen placed on a shel and co e ed wi h black clo h o allow app op ia e en ila ion. They a e main ained in a g owing house a 80–85% ela i e humidi y, and sp ayed daily wi h wa e un il pin heads appea and e en ually de elop in o ui ing bodies. The ui ing bodies a e manually ha es ed, coun ed and weighed (Klomklung e al. 2012). 25. G owing mush ooms in he ield Wi h he inc ease in consume awa eness and subsequen demand o cul i a ed mush ooms, he e now exis s a need o al e na i e, cos -e ec i e s a egies o mush oom cul- i a ion. The global mush oom indus y is o ecas o g ow om a alue o abou $35 billion USD in 2015 o nea ly $60 billion USD in 2021, hus cla i ying he need o a di e se ange o p oduc ion s yles in o de o de elop he indus y in a sus ainable manne (Resea ch and Ma ke s 2018). Al e na i es o mo e adi ional high- olume p o- duc ion echniques include he inocula ion o logs, cul i- a ion in o es unde s o ies, and use o managed o es s, as well as ield-g own mush ooms. Field-g own mush ooms o e an e ec i e use o space, allowing o he p oduc ion o mush ooms in ag icul u al ields, alongside c ops, o be ween c opping cycles (Fig. 26). O e ing addi ional income o a me s, his p ac ice has become popula wi h u al de elopmen p o- g ams (Zhang e al. 2014a,b; B um and B um 2017). Addi ionally, ield cul i a ion allows o imp o ed soil sys ems in ag icul u al ields due he inc eased a es o nu ien cycling and p o ision o o ganic ma e in o he soils (Phan and Saba a nam 2012; Zhang e al. 2012). In his sec ion, we ou line some o he basic p inciples and conside a ions o ield cul i a ion while lis ing some Table 12 Examples o mush oom species sui able o ield cul i a ion, including soil cha ac e is ics, subs a es, and clima ic equi emen s o he lis ed species Species Soil ype Soil pH Subs a e Tempe a u e (°C) Humidi y (%) Re e ences Cop inus coma us Sandy 7 Co onseed meal 16–22 85–95 Chen (2000) Dic yopho a indusia a Loam 6.5–7 Bamboo li e , s aw, sawdus 22–30 60–65 Chen (2000) a Ganode ma sp. Sandy 4.2– 5.3 Sawdus 23–34 80–90 Mayzumi e al. (1997), Cha and Yoo (1997) Len inula edodes Clay loam 4.5–6 Sawdus , whea / ice b an 5–20 80–90 a Mo chella spp. Sandy loam 7–7.5 Sawdus , whea b an, humus 20 50–70 Liu e al. (2018a) a Oudemansiella adica a Clay loam 6.5– 7.2 Wood chips/co n cobs 20–30 60–80 Hao e al. (2016) Phlebopus po en osus Clay loam, humus 4–6 Sawdus 27–37 55–80 Ji e al. (2011), Kumla e al. (2011,2015) a Polypo us umbella us Sandy loam, humus 5.5–7 Lea es, humus, 18–24 60–80 Banda a e al. (2015) a S opha ia ugosoannula a Humus ich sandy 5–6 Wood chips/ ice s aw 22–28 70–75 a Vol a iella ol acea Clay 7.5–8 Rice s aw 22–40 90 a a Rows include unpublished indings/da a Fig. 26 Field p epa a ion o cul i a ion o S opha ia ugosoannula a in Honghe Coun y, China Fungal Di e si y (2019) 97:1–136 49 123 o he key species ha can be success ully cul i a ed in a ield en i onmen (Table 12). We will limi ou discussion o he cul i a ion o mush ooms in ag icul u al ields and soils, no he b oade p ac ices o ou doo cul i a ion using bags o inocula ed logs. The e a e a ange o mush ooms ha can be cul i a ed ou doo s, and app op ia e species can be selec ed acco ding o local g owing condi ions (Table 12). Fo example, Co- p inus coma us o S opha ia ugosoannula a can be g own du ing he au umn and win e mon hs when em- pe a u es a e milde , and Vol a iella ol acea should be g own du ing he wa me summe mon hs. Conside a ion o soil pH, ex u e and heal h is also c i ical. The pH and ex u e will pa ially de e mine which species o mush oom will be g own, and also he deg ee o i iga ion equi ed o main ain desi ed soil wa e le els (Table 12). Soil heal h is c ucial o he inal p oduc , as many species o ungi can hype accumula e hea y me als (Cocchi e al. 2006;Tu - kekul e al. 2004). A e he selec ion o an app op ia e g owing a ea, a ew basic s eps a e equi ed o he p epa a ion o he ield and subsequen cul i a ion. A e ligh illing o he ield, compos is applied, ollowed by he applica ion o he ungal ma e ial (spawn o colonized bags), his is hen co e ed in compos and a inal laye o soil o e ha (a mulch o s aw o shade clo h could u he p o ec agains desicca ion and d ying ou ) (Fig. 26). The e a e a wide ange o applica ions o he ield cul i a ion o mush ooms, bu mos ela e o he in ensi i- ca ion o land use sys ems, gene a ion o addi ional sou ces o income, and appeal o low income g oups ha canno a o d he cos s o es ablishing g ow houses. This me hod o p oduc ion has become popula in many pa s o Asia whe e clima es a e sui able and smallholde a me s need al e na i e sou ces o income. Fo example, in Cambodia, a me s ha e adop ed he p ac ice o sp eading spawn p oduced om Len inus o Vol a iella species o e ice s aw was e in he paddies (wi h supplemen ed wa e ing). This p o ides an addi ional ha es o mush ooms om he paddies du ing he o season. Ano he p og am un in Honghe Coun y, Yunnan P o ince, China, assis s local a me s wi h he cul i a ion o S opha ia ugosoannula a in hei ields; his is a seasonal mush oom c op p oduced mos ly in au umn and sp ing when he empe a u es a e sui able (Fig. 27, Table 12). The na u e o g owing mush ooms ou doo s means ha he mush oom c op is subjec o ambien en i onmen al condi ions, wi h no clima e con ols in place, o example, empe a u e and humidi y luc ua e wi h no eal mecha- nisms in place o con ol hese pa ame e s. In addi ion o clima ic a iabili y, ou doo cul i a ion exposes he mush ooms o non-s e ile condi ions, allowing easy access o seconda y in ec ion by slime molds, p eda o y ungi, and insec s (Table 12). Field cul i a ion o mush ooms is applicable o a wide ange o habi a s and condi ions, depending on he desi ed species o be g own. By o e ing no el and exci ing al e na i es o plan -based ag icul u e, and p o iding addi ional income o a me s, ield cul i a ion o mush- ooms is becoming popula in p og ams aimed a imp o - ing he li elihoods o smallholde a me s and o inco po a ion in o p ojec s looking o di e si y he ag i- cul u al ou pu o a uni o land. Howe e , g owing mush ooms ou doo s is no wi hou challenges and equi es ca e ul species selec ion and aining o p ac i ione s be o e any such p og ams can commence. 26. Mode n mush oom p oduc ion: an au oma ed ac o y p ocess Limi ed ha es s du ing unp oduc i e seasons and he isk o mush oom poisoning p e en wild mush ooms om en e ing he ood ma ke alue chain in a majo way. Domes ica ion and indus y p oduc ion has he e o e Fig. 27 S opha ia ugosoannula a eme ging om soil subs a e mix and ma u e c op shown. Shade clo h is pulled back o e eal ha es 50 Fungal Di e si y (2019) 97:1–136 123 become essen ial o inco po a ing mush ooms in o die a y di e si y and nu i ional secu i y. The global p oduc ion has inc eased om 30.2 million ons in 2010 o 48 million in 2017 (FAO). As a leading p oduce , China inc eased om 22.6 million ons in 2010 o 38.4 million in 2017, accoun ing o 75% o global p oduc ion (CIRI 2017). O he 16,000 known mush oom species (Hawkswo h 2012), abou 7000 species ha e a ying deg ees o edibili y, mo e han 3000 species a e majo edible mush ooms, and 700 a e ega ded as sa e medicinal mush ooms (Chang and Wasse 2017). Global demand o mush ooms has apidly inc eased and hus la ge-scale g owe s ha e been es ablished, wi h yea - ound ma ke ing domina ing comme cial mush oom p oduc ion. In China, he e a e six g oups o mush ooms each wi h a p oduc ion capaci y o o e one million ons pe yea (Zhang e al. 2015): 8.2 million ons o Au icu- la ia species; 7.7 million ons o Len inula edodes (Shi- i ake mush oom); 5.9 million ons o Pleu o us species; 3.4 million ons o Aga icus bispo us; 2.6 million ons o Flammulina spp.; and 1.4 million ons o Pleu o us e yngii. The g ow h o he comme cial mush oom indus y depends on p oduc i i y, e iciency, and compe i i eness wi hin he en i e ma ke alue chain. Mos o he mo e ecen ly domes ica ed species can ecycle was e subs a es Fig. 28 Di e en mush oom species cul i a ed wo ldwide. a,bHy- menopellis sp., c,ePleu o us sp. (Oys e mush ooms), Ganode ma sp. (Lingzhi). Pho o c edi : T. Luangha n Fig. 29 Equipmen o manu ac u e s o mush oom cul i a ion. aSubs a e media mixe , bmush oom bag illing machine, c anspo e and con eyo s ca y ou subs a e bags, ds eam s e iliza ion machine, einocula ion, au o- anspo a ion, gincuba ion. Pho o c edi : F. Huang Fungal Di e si y (2019) 97:1–136 51 123 and he e o e sui smallholde s in ag oecosys ems (Dai e al. 2010b) (Fig. 28). In he las decade, he e ha e been ema kable ad ances in mush oom g owing echnology. No only ha e s ains been imp o ed, bu he whole mush oom p oduc ion p o- cess has changed om manual o au oma ed sys ems. The mixing o subs a es, illing o bags, g owing o liquid spawn, inocula ion o bags, mo ing o bags, empe a u e and humidi y con ol, and packing a e all au oma ed p o- cesses (Fig. 29). Reliable subs a e sou ces and machine y a e wo o he ac o s ha de e mine he scale o ope a ion and p oduc- i i y. Subs a es can be ha es ed om nea by o es s h ough sus ainable o es managemen , om ecycled ag icul u al esidue, suga cane ac o ies, li es ock eed and was e, and he mulbe y indus y (Fig. 29) (Zhou e al. 2012). Al hough mush ooms can be cul i a ed using di - e en me hods, such as sawdus bags, bo les, shel es, and logs (see p eceding chap e s) he e is an inc easing demand o he es ablishmen o mode n mush oom acili ies, which p o ides a ange o 1*10 million bags annually wi h well-equipped enclosed cooling and s e ilized build- ings. This enables p ope g owing condi ions o be main- ained. The mos sui able condi ions o mush oom p oduc ion mus be es ablish and a e empe a u e, humid- i y, uni o m en ila ion, subs a e mois u e le els and o ligh o p omo e he o ma ion o ui bodies. Fo example, blue ligh -emi ing diodes impac he quali y o Len inus sajo -caju (Huang e al. 2017a). Howe e , main aining and unning such g owing houses equi es high olumes o elec ici y and wa e , making he p oduc ion p ocess cos ly and ha ing a la ge impac on he elease o g eenhouse gases. Fu u e ends should ocus on he use o enewable ene gy sou ces. The de elopmen o new echnologies, such as pho o- ol aics o hea ing and cooling, a i icial in elligen and echnology o con olling he en i onmen o op imize empe a u es and mois u e and e en ligh o mula by LED, will maximize he p oduc ion season, enhance he p o- duc i i y and quali y o mush ooms, and educe ene gy cos s (Fig. 30). A i icial in elligence o au oma ion includes subs a e bag illing, inocula ion, cul i a ion, scanning and picking up con amina ed bags, and obo s o packing and anspo a ion. Bo h small- and la ge-scale p oduc ion lines should emb ace in eg a ed sys ems, o example inco po a ing he use o ecycled ma e ials, such as ag icul u al was e, o making use o a sus ainable supply Fig. 30 Mush oom indus y zone wi h con olled en i onmen o u al employmen and u al de elopmen 52 Fungal Di e si y (2019) 97:1–136 123 o woody subs a es om managed plan a ions, coupled wi h he in eg a ion o enewable ene gies. Edible mush ooms ha e been cul i a ed o many cen- u ies, and i is expec ed ha hei p oduc ion will inc ease u he due o ma ke demand. The imp o emen and de elopmen o mode n echnologies, such as compu e - ized con ol sys ems o con ol en i onmen al pa ame e s, au oma ed ha es ing, echniques o he p oduc ion o mush ooms in a non-compos ed subs a e, and new me h- ods o subs a e s e iliza ion and spawn p epa a ion, will inc ease he p oduc i i y o mush ooms (Sa ´nchez 2004). Howe e , he mode n au oma ed ac o y p ocesses o mush oom p oduc ion equi e a signi ican ini ial in es - men o ixed asse s. Typically, his la ge capi al ou lay o ixed asse s equi es a eco e y pe iod o a leas 5 yea s (Li and Hu 2014). I is un easonable o a me s in low- and middle-income coun ies o own au oma ed equipmen , since he up on capi al in es men equi ed o hese i ems is economically unsus ainable, e en in he long e m (Higgins e al. 2017). A mo e iable, long- e m solu ion is he g an ing o unds o a me s ia ei he public o p i- a ely unded o ganiza ions (Zied and Pa do-Gime ´nez 2017). 27. New edible mush ooms Due o hei culina y, nu i ional, and heal h bene i s, he global ma ke o mush ooms con inues o g ow, om US $34.1 billion in 2015 o US$69.3 billion by he end o 2024 (Val e de e al. 2015; Bal 2018). Mush ooms also show po en ial o use in was e managemen , as discussed else- whe e. Howe e , mush ooms ha e li e cycles e y di e - en om hose o g een plan s. The choice o mush oom species o cul i a ion depends bo h on he g ow h media a ailable and on ma ke conside a ions (Bee z and G ee 1999; Rosmiza e al. 2016;Sa ´nchez 2004). Oys e mush- ooms, which g ow on many subs a es, a e easies (Pa il e al. 1989). Shii ake mush ooms ha e al eady ga ne ed conside able consume demand (Teng 2008). To da e, only wo myco hizal mush ooms, mo els (Mo chella spp.) and u les (Tube spp.), ha e been comme cially cul i a ed (Selosse e al. 2017). Se e al new species o wild edible mush ooms ha e been success ully domes ica ed o e he las ew yea s, especially in opical a eas (Klomklung e al. 2012; Thongklang e al. 2014a,b,2016; Rizal e al. 2016; Ban- da a e al. 2017) (Fig. 31A). Luangha n e al. (2017), Thongbai e al. (2017) and Klomklung e al. (2012) ha e shown ha i is possible o domes ica e local s ains o Pleu o us gigan eus ha can g ow a empe a u es Fig. 31 AAu icula ia hailandica;BHyb id om Thai and F ench s ains o Aga icus sub u escens;CWhi e Au icula ia co nea; DLepis a so dida;EAga icus locculosipes;FAga icus sub ilipes; GF ui ing bodies o Mac olepio a dolichaula s ain MFLUCC-13- 0579. adi e en s ages o ui ing body de elopmen , bpileus wi h annulus, csquamules on pileus, dand ebud s ages o ui ing bodies; ma u e ui ing bodies. a =25 cm, b =10 cm, c, d, e, =5cm Fungal Di e si y (2019) 97:1–136 53 123 consis en wi h Thai a m p oduc ion. A new hyb id de eloped om Thai and F ench s ains o Aga icus sub- u escens was de eloped success ully be ween INRA, F ance and Mae Fah Luang Uni e si y, which uc i ies in opical clima es (Thongklang e al. 2014b, Fig. 31B). Fo he i s ime, a new whi e s ain o Au icula ia co nea was success ully domes ica ed a he Kunming Ins i u e o Bo any, Chinese Academy o Sciences (Fig. 31C). In Thailand, s ains o Au icula ia hailandica (Fig. 35), Lepis a so dida (Fig. 31D), Aga icus locculosipes (Fig. 31E), A. sub ilipes (Fig. 31F) and Mac olepio a dolichaula (Fig. 31G) ha e success ully been cul i a ed. Mush ooms a e no only used in adi ional medicines, bu a e known o con ain a ious bioac i e componen s which can be used in cosme ics (Kwon and Tha i ha goon 2004; Hyde e al. 2010) and in medicine (De Sil a 2013; Wisi- assameewong e al. 2012b). People in mos pa s o he wo ld enjoy ea ing mush ooms, and he e o e he e is eno mous po en ial o in oducing new opical mush- ooms o he global ma ke . The numbe o ungi wo ldwide is es ima ed o be be ween 2.2 o 3.8 million, bu only 120,000 species ha e been desc ibed, so i appea s ha abou 92% o ungi ha e ye o be desc ibed (Hawkswo h and Lu ¨cking 2017). O e he pas 5 yea s, nume ous new ungi ha e been desc ibed, especially wi hin opical a eas (A iyawansa e al. 2015; Liu e al. 2015; Li e al. 2016; Hyde e al. 2016; Tibp omma e al. 2017,2018; Hyde e al. 2017; Wanasinghe e al. 2018). One ecen pape published by Hyde e al. (2018a,b,c) showed ha up o 96% o ungi in no he n Thailand may be new o science. On he o he hand, he S a e o he Wo ld’s Fungi epo 2018 (Willis 2018) s a es ha abou 350 species o edible ungi a e collec ed and ea en wo ldwide annually, bu his igu e should be highe . To add ess his knowledge gap, he Cen e o Excellence in Fungal Resea ch in Mae Fah Luang Uni e si y and he Soil Biology g oup o he Kunming Ins i u e o Bo any a e wo king on upda ing he global lis o edible and medicinal ungi. The e a e many easons o being op imis ic abou he u u e o wild edible ungi: hey help main ain he heal h o o es s and a e a aluable sou ce o nu i ion and income. 28. Aga icus sub u escens Aga icus sub u escens is an impo an medicinal mush- oom (Wisi assameewong e al. 2012a; De Sil a e al. 2013), which belongs o sec ion A enses (subgenus Fla oaga icus)o Aga icus. The main synonyms o A. sub u escens a e A. blazei sensu Heinemann (misapplied), A. b asiliensis (illegi ima e), and A. u o egulis. This spe- cies has a b oad clima ic and geog aphical dis ibu ion ange in Asia, Eu ope, Oceania and A ica (Thongklang e al. 2016). Aga icus sub u escens was disco e ed in Ame ica in he la e nine een h cen u y and la e in Sao Paolo, B azil; i was called Piedade mush oom. One mush oom (named A.blazei Mu ill) was in oduced in Asia in 1965 by T. Fu omo o, who sen i o Japan o medicinal in es iga ion bu u ned ou o be conspeci ic wi h A. sub u escens (Ke igan 2005). The common name o A.sub u escens is he almond mush oom. In addi ion, o he common names a e Himema su ake in Japan, Cogu- melo do Sol in B azil, and Royal Sun Aga icus in se e al o he coun ies (Wisi assameewong e al. 2012a,b). The main cha ac e s o A. sub u escens a e a eddish-b own cap co e ed wi h silk-like ib es, a wo-laye ed and loccose annulus, he odou o almond, yellow s aining, and a pos- i i e Scha ¨ e ’s eac ion (Thongklang e al. 2014b). Aga icus sub u escens has been comme cially cul i a ed in B azil, Japan, China, Ko ea and Taiwan (Ke igan 2005; G ego i e al. 2008). In B azil, he mush oom is a pa ic- ula ly impo an expo mush oom wi h a highe p ice han o he comme cial mush ooms (Souza Dias e al. 2004). Bu on mush oom compos is no mally used o cul i a e A.sub u escens comme cial s ains. O he o ms o ag i- cul u al was e a e also used as al e na i e subs a es o g ow his mush oom. Gonza ´lez Ma u e e al. (2011) p o- duced A.sub u escens based on spen oys e mush oom subs a e mixed wi h sun lowe seed hulls, e micompos and supplemen s. Wild s ains o A. sub u escens ha e been s udied o cul i a ion. Zied e al. (2011) epo ed he success o whea s aw wi h chicken manu e and black pea ?soil (4:1) as casing o cul i a e a B azilian/F ench A.sub u escens s ain and hei hyb ids. Thongklang e al. (2014b) isola ed a wild Thai A.sub u escens s ain and success ully cul i a ed i in whea s aw/ho se manu e based compos a 25 °C and 95% humidi y (Fig. 26a). Thongklang e al. (2014b) epo ed ha samples om B azil, F ance and Thailand a e in e e ile. Hyb id s ains o Thai 9B azilian and Thai 9F ench showed highe yields han Thai pa en al s ains. The mush oom is bo h nu i ious and medicinal. Zied e al. (2017) e alua ed he chemical composi ion o A. sub- u escens, and epo ed ha he s ipe o he mush oom con- ained 69.56% o o al ca bohyd a es, 63.89% o a ailable ca bohyd a es, and an ene gy alue o 363.97 kcal 100 g −1 DM). The pilei comp ised 33.96% p o ein, 7.75% ni ogen, 8.24 and 2.44% ash and c ude a . Medicinal bene i s ha e also been epo ed o his mush oom, o example in cance ca e, as an i umo agen s, and in choles e ol educ ion (Wisi assameewong e al. 2012a,b; De Sil a e al. 2013; S adle and Ho meis e 2015). Aga icus sub u escens p o- duces se e al bioac i e compounds, such as lec in, iboglu- can, glucomannan, aga i ine and blazien, all o which we e shown o educe umo g ow h. In addi ion, spi o i e - penoids o he blazeispi ol ype a e p oduced in mycelial cul u es o his mush oom (Hi o ani e al. 54 Fungal Di e si y (2019) 97:1–136 123 1999,2000,2001,2002). Ex ac s we e ound o be highly selec i e an agonis s o Li e X ecep o s (LXR) alpha (G o he e al. 2011). Thongklang e al. (2017) epo ed ha Thai–B azilian and Thai–F ench hyb id s ains p oduce highe yields o blazeispi ol A in cul u e han hei Thai pa en al s ain. Howe e , blazeispi ols ha e ne e been ound in he basidiomes o A. sub u escens (Thongklang e al. 2017). This is impo an , as i s ains could be ound wi h blazeispi ols in he basidiomes, hen ea ing he mush- oom would ha e impo an medicinal bene i s. Mush ooms ha e been used as ood and heal h p oduc s o millions yea s o hei pe cei ed medicinal p ope ies. Aga icus sub u escens is widely cul i a ed in B azil (Souza Dias e al. 2004; Mendonc¸a e al. 2005), and he mush oom is expo ed om B azil o a ious coun ies such as Aus alia, Boli ia, Ge many, Ko ea, India, Japan, Sou h A ica, Thai- land, and he USA (Mendonc¸a e al. 2005). The mush oom no mally equi es compos o cul i a ion (Thaw hong e al. 2014). Aga icus sub u escens is consumed wo ldwide in esh, d ied and powde o m om mycelium/ ui ing bod- ies. F esh mush ooms ha e been consumed as ood because o hei po en ial medicinal p ope y and pleasan almond la ou . Mo eo e , d ied o powde ed mycelium/ ui ing bodies a e used as nu ien supplemen s. In Japan, 100,000– 300,000 kg o d ied almond mush ooms is p oduced e e y yea (Takaku e al. 2001). The mush ooms ha e been used as complemen a y and al e na i e medicine o cance ca e. P i a e companies such as King Aga icus 100, Sen-Sei-Ro Gold, and ABMK sell p oduc s om A. sub u escens, and hese p oduc s a e cu en ly being used by a ound 500,000 people o cance ea men and p ophylaxis (Hyodo e al. 2005). 29. Using ungi o enhance ood alue Fo housands o yea s, human socie ies ha e been u ilizing ungi as ood sou ces (Chang 1980; Moon and Lo 2014; Siddiq e al. 2018). In pa icula , edible mush ooms a e ideal o ege a ians, because hey a e excellen sou ces o p o ein ( ypically 20–30% c ude p o eins as a pe cen age o d y ma e ), ha e a low- a con en , a e ee o choles e ol, and con ain mos o he amino acids essen ial o human and animal nu i ion (Kau e al. 2018). Fungal axa a e u ilized in he ood indus y aking ad an age o hei me abolism and me aboli es (Gilbe and Robinson 1957; Moo e and Chiu 2001; Ad io and Demain 2003; Gho ai e al. 2009). In pa icula , ungal species a e used in he p oduc ion o e men ed oods and be e ages in many adi ional and indigenous cul u es a ound he wo ld (Abe e al. 2008; Dupon e al. 2016). Fo ins ance, he yeas Saccha omyces ce e isae is he oldes and bes known ungal species used o wine and b ead making, in d ug p oduc ion, as bio- con ol agen s, in enzyme bio echnology, as well as o esea ch and de elopmen (Gho ai e al. 2009; Sha ma e al. 2018). A b ie desc ip ion o some o he mos impo an e men ed ood indus ies is p o ided below. Mold- ipened cheese Cheese is a solid o semi-solid p o ein ood p oduc man- u ac u ed om milk. Fungal species a e impo an o he manu ac u e and ipening o wo ypes o cheese, he Camembe and Blue- eined a ie ies (Fox e al. 2017). The name “blue- eined cheese” de i es om he blue– g een mold g owing h oughou he p oduc (Ma ı ´n and Co on 2016). The e a e a ious kinds o blue- eined cheese p oduc s, iz. Roque o , Go gonzola, S il on, Danish Blue, and Blue Cheshi e. Mos Blue cheese is p oduced om unpas eu ized milk, and Penicillium oque o i is added o he cheese p io o s o age a con olled empe a u e and humidi y. Penicillium oque o i g ows h oughou he cheese and p oduces p o eoly ic and lipoly ic enzymes ( iz. p o eases, lipase and be a-ke oacid deca boxylase) and me hyl ke ones, pa icula ly 2-hep anone, as he majo la ou and odou compounds (Kinsella e al. 1976; Dupon e al. 2016; Ropa s e al. 2017). Penicillium oque o i g ows a a low oxygen ension and low pH alues, while ha ing he abili y o use bo h pen oses and hexoses as subs a e. These cha ac e is ics make he ungus ideally sui ed o he indus ial Roque o - ype cheese p oduc ion (Babel 1953; Kinsella e al. 1976, Ga cı ´a-Es ada and Ma ı ´n2016). Camembe cheese is a he di e en om blue- eined cheese, as i cha ac e ized by a whi e mold g ow h on he su ace and a so ex u e. Penicillium can- didum and P.camembe i a e used o he camembe cheese p oduc ion (Bou dichon e al. 2012). Fe men ed p oduc s Soy sauce (Shoyu) and Miso Soy sauce is one o wo ld’s oldes la o ing edien s; made om e men ed soybeans/whea . I is a da k b own liquid ha is s able a ambien empe a u e and does no equi e e ige a ion du ing s o age due o i s low wa e ac i i y and high sal con en . Soy sauce has been used in cooking o o e 1000 yea s, in pa icula in China, Japan, Ko ea and o he Asian coun ies (Luh 1995; Hong e al. 2015; Liu 2017). The soy sauce p oduc ion p ocess com- p ises h ee majo s eps, which a e Koji p oduc ion, b ine e men a ion and e ining. In he i s s ep, soaked, cooked, mashed soy beans a e mixed wi h an equal amoun o oas ed, ligh ly c ushed whea , and inocula ed wi h 0.1– 0.2% s a e mold (Aspe gillus o yzae o A.sojae)in wooden ays. The e men ed mix u e (Koji) hen unde - goes b ine e men a ion using he lac ic acid bac e ium, Pediococcus halophiIus, and yeas s including Zygosac- cha omyces ouxii and Candida species (Liu 2017). The inal s ep o soy sauce e men a ion ( e ining), includes p essing, il a ion, pas eu iza ion and packaging. The Fungal Di e si y (2019) 97:1–136 55 123 e men ed soybean pas e is called miso, has a simila a oma and la o o soy sauce. Indonesian empeh Tempeh is a mould- e men ed p oduc p epa ed om e men ed soy beans and is consumed mos ly in Indonesia (Babu e al. 2009). Tempeh possesses some unique cha - ac e is ics, including i s la o , sliceable mea -like ex u e, and nu i ional p ope ies (As u i e al. 2000; Nou and Kie s 2005). Rhizopus oligospo us is he dominan ungal species used in he soy bean e men a ion p ocess. Ini ially, husk- ee, soaked and p essed soybeans a e inocula ed wi h R. oligospo us and e men ed o 1–2 days. Du ing he e men a ion p ocess, he whi e mycelia o R. oligospo us in ade and co e he subs a e mass o bind he soy bean (Shu le and Aoyagi 1979; S eink aus 1995; Nou and Kie s 2005; Babu e al. 2009; Shah and Pa el 2017). Tempeh p o ides many heal h bene i s, in pa icula o hea diseases, s okes, os eopo osis, cance and diges i e diso de s, loss o excess weigh ), as i con ains essen ial a y acids, nume ous i amins, ibe and mine als. Quo n Quo n is made om myco-p o eins, which a e p oduced by a e men a ion p ocess using he ilamen ous ungus Fusa ium enena um (Finnigan e al. 2017; Kozubal e al. 2019). Quo n mycop o ein s ains we e p e iously misiden i ied as Fusa ium g aminea um, bu we e la e ound o ep esen F. enena um (Wheelock 1993; T inci 1994; Wiebe 2004; Finnigan e al. 2017). Wi h a low a con en and being ee o choles e ol, quo n p o ides an al e na i e p o ein op ion ha is mea - ee and nu i ious (Ga odia e al. 2017). In addi ion, i is high in die a y ib e, which has been ound o lowe blood choles e ol (Denny e al. 2008; Rux on and McMillan 2010; Ga odia e al. 2017; Kozubal e al. 2019). The p oduc ion p ocess o Quo n is simila o ha o bee , equi ing less whea and wa e o p oduc ion, as well as esul ing in lowe ca bon emissions, compa ed wi h mea sou ced p o eins (Finnigan 2011). Du ing he p oduc ion p ocess, mycop o ein is mixed wi h ege able la o ings and a small amoun o egg albumen. To ob ain i s cha ac e is ic ex u e, a se ies o s eaming, chilling and eezing p ocesses a e used o ob ain he mea -like ex u e o Quo n p oduc s (Wiebe 2004; Finnigan 2011). Ini ially, Quo n p oduc s o igina ed in he UK, bu cu en ly a e a ailable wo ldwide (Apos olidis and McLeay 2016). Renne Renne is used by ood companies o he milk clo ing p ocess wi hin cheese p oduc ion (Ogel 2018). Cal enne was adi ionally used o cheese-making wo ldwide (Thaku e al. 1990; Mamo and Balasub amanian 2018). Subsequen ly, he global inc ease in cheese p oduc ion, along wi h a dec ease in animal enne p oduc ion, aised he p ice o adi ional enne . The e o e, ood esea che s ied o ind al e na i es o he milk clo ing p ocess wi hin cheese p oduc ion (Moschopoulou 2017; Ogel 2018). As a consequence, mic obial enne was p oduced using Rhi- zomuco miehei and R. pusilus (Thaku e al. 1990; Sil ei a e al. 2005; De Lima e al. 2008). Mic obial enne is cheape han he enne p oduced by animals, and he bes op ion o ege a ians. O he han hose e men ed ood p oduc s, he e a e many comme cial ood indus ies in he wo ld. Some ood p oduc s which use ungal species a e lis ed in Table 13. 30. Food colou ing om ilamen ous ungi Syn he ic colo an s a e widely used in ood p oduc ion o enhance he appea ance o ood colo s. Al hough syn he ic colo an s a e s able and inexpensi e, he demand o hese p oduc s has dec eased due o hei po en ial o pe cei ed ha m ul e ec s on human heal h (Ba eman e al. 2004). Today, many syn he ic colo an s ha e been eplaced wi h sa e na u al colo an s. Pigmen s om plan s a e o en used as ood colo an s (Shamina e al. 2007; Amba i e al. 2014; Leong e al. 2018; Upadhyay 2018). Al hough hese pig- men s can gene a e a ious colo s, p oduc ion p ocesses a e limi ed due o plan g ow h needs. Filamen ous ungi can be g own in e men e s, and a e also being in es iga ed as impo an sou ces o pigmen s (Table 14, Fig. 32). Some examples a e gi en below. Red mold ice, also known as ed yeas ice, is an Asian adi ional e men a ion p oduc o s eamed ice e men ed wi h ilamen ous ungi belonging o he genus Monascus (Fig. 33). Red mold ice has been widely used in Eas Asian coun ies wi h a e y long his o y as bo h ood colo ing and medicine. The ed colou om ed mold ice is used in a a ie y o Chinese, Ko ean and Japanese oods, such as e men ed bean cu d, p ese ed d y ish, po k s ew, oas duck, and oas po k (Chen e al. 2015). Red mold ice is also used as subs a e o he p oduc ion o “Hong Qu glu inous ice wine,” which gi es i a b igh - ed colou and ine swee la o (Liu e al. 2018b; Pa k e al. 2016). A e he op imiza ion o bio echnological p oduc ion p ocesses, some species can easily p oduce pigmen s a a la ge scale in bio eac o s, elying on ela i ely sho e - men a ion imes, and esul ing in accep able cos s-o - goods. Fo example, he op imiza ion o ed pigmen p o- duc ion in a subme ged cul u e by Monascus ube in complex cul u e media esul ed in he de elopmen o a medium con aining 10 g/l glucose, 5 g/l co n s eep liquo and 7.6 g/l monosodium glu ama e, gene a ing he highes amoun o ed pigmen a 20.7 U (Hamano and Kilikian 2006). 56 Fungal Di e si y (2019) 97:1–136 123 Red mold ice also gene a es o ange pigmen . Pigmen p oduc ion is pa ially associa ed wi h cell g ow h and a dissol ed oxygen concen a ion o be ween 0.894 and 1.388 mg O 2 /l a 30 °C. Limi ing condi ions o dissol ed oxygen dec eases he p oduc ion o o ange pigmen s (Vend uscolo e al. 2017). An induced mu a ion o M. pu pu eus led o p oduc ion o yellow pigmen s, which can be added o Chinese esh noodles, p o iding a yellow shade wi h no discolo a ion (Yongsmi h e al. 2013). Klinsupa e al. (2016) in es iga ed using in aspeci ic p o oplas s o a yellow mu an o Monascus spp. wi h a whi e p o o oph, and a s ain wi h high yellow pigmen p oduc ion was p oduced. Ano he mu an s ain o M. ube 10910, gene a ed h ough UV mu agenesis, imp o ed he p oduc ion o ex acellula hyd ophilic yel- low pigmen en old (Wu e al. 2015b). Un o una ely, he myco oxin ci inin is o en ound in ed mold ice, and has a nega i e impac on heal h. This myco oxin has been in es iga ed as neph o oxic and hep- a o oxic o human cells (Bilg ami e al. 1988). The egu- la ion o ci inin concen a ion in comme cial ed mold ice occu s in many coun ies, such as Commission Regula ion (EU), Taiwan, US FAD, and Japan (Le Bloc’h e al. 2015; Eu opean Commission 2014). The e o e, he p oduc ion o ed mold ice wi h low ci inin is impo an o inc easing i s alue and sa e y. Pengnoi e al. (2017) e alua ed he e ec s o a ious pu ple ice a ie ies on he p oduc ion o ci inin and ed pigmen s by M. pu pu eus CMU002U (UV-mu an s ain). The lowes alue o ci inin concen a ion (132 ppb) was ound in he Na a ie y, which passed he s anda ds o Japan, Taiwan, and he Eu opean Union. The highes ed pigmen yield was ob ained om he e men ed Doi Muse a ie y. These esul s demons a e ha e - men ed pu ple ice has a high po en ial o be de eloped as a sa e ood colo an . Table 13 Fungal species used in he ood and be e age indus ies Applica ion P oduc Fungal species Be e ages Bee , Rum, Wine Saccha omyces ce e isae Sake Aspe gillus o yzae Cheeses Roque o , Blue cheese Penicillium oque o i Camembe , B ie, so ipened Penicillium camembe i O ien al ood e men a ions Ang-kak Monascus pu pu eus Doenjang Aspe gillus o yzae Hamana o Aspe gillus o yzae Miso Aspe gillus o yzae,A.sojae On jom Neu ospo a in e media Renne Rhizomuco miehei Rhizomuco pusilus Shoyu (soy sauce) Aspe gillus o yzae,A.sojae Tempeh (Indonesian) Rhizopus oligospo us Quo n Fusa ium enena um Table 14 Examples o pigmen s p oduced by ilamen ous ungi Colo Pigmen s Fungal p oduce s Re e ences Blue Sanguinone A Mycena sanguinolen a Pe e s and Spi elle (2007) G een Xylindein Chlo ocibo ia ae uginosa Saikawa e al. (2000) O ange Monasco ub in Rub opunc a in Monascus sp. Vend uscolo e al. (2017) β-Ca o ene Muco ci cinelloides Neu ospo a in e media To es e al. (2016) Red Rub opunc amine Monasco ub amine Monascus sp. Hamano and Kilikian (2006), Dikshi and Tallap agada (2013) Lycopene Blakeslea ispo a Feo ilo a e al. (2006) Yellow Anka la in Monascin Monascus sp. Yongsmi h e al. (2013), Klinsupa e al. (2016) Fungal Di e si y (2019) 97:1–136 57 123 essel. The liquids dis illed a e cooled in a condense and o en be e-boiled o ensu e hei pu i y (Fo bes 1970; Lembeck 1983; Bi ch and Lindley 1985; Thomas and Shipman 2016). The aw ma e ials esul in a a ie y o la ou s and a omas in he spi i s, bu he aging p ocesses and pe iods a e also impo an (Ch is oph and Baue - Ch is oph 2007; Rosso e al. 2009; Robe 2010). The a ie y o spi i s is showed in Table 17; howe e , he e a e many sub-ca ego ies wi hin each ype o spi i as well. The b ewed alcoholic be e age indus y has g own apidly o e ecen decades, and i is inc easingly p o- ducing compe i i e p oduc s heigh ened by consume equi emen s wo ldwide. C ea ing unique expe iences o bee consume s is one o he mos impo an goals o alcoholic be e age manu ac o ies. B ewe s ha e es ab- lished nume ous new echniques and p ocesses o imp o ing he la ou s, colou s, and nu ien s in wines, bee s, and spi i s. Nume ous new ma e ials and p ocesses in b ewing ha can a ec la ou s and a omas a e being de eloped, and he e will likely be hund eds o di e en kinds o alcoholic be e ages in he u u e. The de elop- men o bio echnology and new disco e ies will be he mos impo an ools o each he goals o u u e b ewing. 35. Func ional oods and nu aceu icals The a e age age o he global popula ion is inc easing, and socie y is becoming mo e awa e o he po en ial side e ec s o p esc ip ion medicines, and he e o e a e seeking al e na i e he apeu ics (Eko 2014; Rowe e al. 2016; WHO 2004a,b,2015). Va ious new nu i ional concep s, such as unc ional oods and nu aceu icals ha e been de eloped o e ecen decades. By de ini ion, unc ional oods a e con en ional o e e yday oods consumed as pa o he no mal daily die , a ge ing he enhancemen o he well-being and quali y o li e and hus educing he isk o Fig. 36 Global ma ke sha e o bee consump ion in 2016 by egions ( ep duced wi h kind pe mission om Ki in Holdings Company, Limi ed) Table 16 The majo di e ences be ween ales and lage s Bee s ypes B ewing p ocess Types o yeas (Saccha omyces) Fe men a ion empe a u e B ewing imes Colou Example Ale Top- e men ing S. ce e isiae Wa m (15.5 o 25.5 °C) 7 days B own o da k Goose Island Bou bon Coun y S ou Samuel Smi h’s Taddy Po e Sie a Ne ada Th ee Floyds Da k Lo d Lage s Bo om- e men ing S. pas o ianus Cool (7.2 o 12.8 °C) Se e al mon hs Bligh gold o yellow Ca lsbe g Co ona Dunkel Heineken Ki in Mille Pilsne U quell Schwa zbie Singha Tsing ao 64 Fungal Di e si y (2019) 97:1–136 123 disease (El Sohaimy 2012). The e m “nu aceu icals” is de ined as ood cons i uen s ha p o ide medical o heal h bene i s, including he p e en ion and ea men o disease (Kal a 2003). Nu aceu icals can be ood in he o m o ex ac s, single, pu e na u al compounds, o nu ien s ha ha e been u ned in o a pha maceu ical o mula ion (e.g. pills o able s), and hey can be applied as die a y sup- plemen s o as pa o a speci ic die (Gia asis 2014;Reis e al. 2017). The e o e, he ole o unc ional oods is mainly ela ed o educing he isk o disease, while nu aceu icals a e usually consumed o p omo e well-being h ough he p e en ion o ea men o diseases and diso - de s (Bagchi e al. 2014). Fungi, and especially edible mush ooms, a e well known o hei nu i ional alue and heal h-p omo ing p ope ies. Mush ooms a e ideal die a y supplemen s because hey a e ela i ely ich in p o eins, con ain almos no a , and possess a a ie y o ibe s and i amins (Val- e de e al. 2015). Many s udies ha e been conduc ed o p o e he bene i s o unc ional oods and nu aceu icals de i ed om ungi in a ious pa hological complica ions, such as diabe es, a he oscle osis, ca dio ascula diseases, cance , in ec ion, enal, and gas oin es inal and neu o- logical diso de s (Banik e al. 2015). Polysaccha ides such as be a-glucanes a e one o he mos widely s udied and ecognized g oups o bioac i e molecules de i ed om mush ooms. Fo ins ance, he glucanes om Len inula edodes (shii ake, Fig. 37) we e success ully used as a pa ial eplacemen o whea lou in baked oods o p oduce a low calo ie, ibe - ich, unc ional ood (Guillamo ´n e al. 2010). Among all s udied mush ooms species, L. edodes is also known o ha e an ibac e ial ac i i ies agains bo h G am-posi i e and G am-nega i e bac e ia (Al es e al. 2012a,b). In ano he s udy, he be a glucane len inan (65, Fig. 38)o L. edodes was added o noodles as a pa ial whea lou eplacemen , and i was claimed ha hei an i-oxidan and hypocholes e olemic e ec s in i o would imp o e he quali y o he noodles (Kalac ˇ2013). Ex ac s om Ganode ma glucans, on he o he hand, ha e been epo ed o ac as ee adical sca enge s, he eby p e- en ing lipid pe oxida ion, and o s imula e in e e on syn hesis in human blood cells a e consump ion (Koza ski e al. 2011). In o he s udies, glucans om a ious edible mush ooms including Aga icus bispo us,Au icula ia au icula-judae, and he Asian “Flammulina elu ipes”(Enoki ake: cu en name: F. ili o mis; c . Wang e al. 2018a), we e shown o possess no able an ioxidan capaci ies and ee adical sca enging po en ial in i o, and hence we e p oposed as na u al an ioxidan s in ood applica ions. O he snack oods en iched wi h a powde om ex ac s o he Ches nu Mush oom (Cyclocybe aege i a) as a pa ial s a ch eplacemen exhibi ed a low glycemic esponse a e con- sump ion, which was co ela ed o he die a y ibe con en (B ennan e al. 2012). Aga icus sub u escens (synonyms: A. blazei; A. b asiliensis) is ano he mush oom which has been sugges ed as a sa e immunos imulan and o ame- lio a ing obesi y o diabe es (Yamanaka e al. 2013). Las ly, Japanese esea che s managed o p oduce a unc- ional cheese-like ood con aining Schizophyllum com- mune. The inal p oduc con ains a be a-glucan, which was claimed o ha e a signi ican an i h ombo ic unc ion (Okamu a-Ma sui e al. 2001). The e m “mush oom nu aceu icals” was coined by Chang and Buswell (1996) o desc ibe hose compounds ha ha e conside able po en ial as die a y supplemen s and a e used o he enhancemen o heal h and p e en ion o Table 17 Di e ences o majo ypes o spi i s Spi i s Raw ma e ials Mashing Fe men a ion Dis illing Aging Mos % ABV B andy G apes and ui s e c. ✓✓ ✓(dis illed wine) In oak 40% (80 p oo ) Gin Vodka?junipe be ies ✓✓ ✓ 940–47% (80–94 p oo ) Liqueu Spi i s?suga ? la o ( ui , c eam, he bs, spices, lowe s o nu s) ✓✓ ✓ 9/✓15–55% Rum Suga cane o Molasses ✓✓ ✓ 9(ligh um) ✔in oak ba els (o he ums) 40% (80 p oo ), up o 75% (150 p oo ) Tequila Juices om blue Aga e plan ✓✓ ✓(dis illed Aga e) 9(whi e/sil e equila) ✓in oak ba els (gold equila-blended) 40–50% (80–100 p oo ) Vodka G ains, ye, co n, whea , po a oes e c. ✓✓ ✓ 940–50% (80–100 p oo ) Whisky G ains (co n, ye, whea , ba ley, e c.) ✓✓ ✓(dis illed bee ) ✓in cha ed oak, o used whiskey o wine ba els 40–50% (80–100 p oo ) Summa ized om G aham (h ps://www. hesp uceea s.com/quick-guide- o-dis illed-spi i s-760713) Fungal Di e si y (2019) 97:1–136 65 123 Fig. 37 Len inula edodes (shii ake) ONH OH N NH N O OH OH OH OH Ganode iol A (62), Ganode ma sp. (Sa o e al. 1986) Hispidin (63), Phellinus lin eus (Shao e al. 2015) OH O O OH OH O O OH MeO O He icenone A (64), He icium e inaceus (Thongbai e al. 2015) O OH OH OH OH O OH OH OH OO OH O OH O OH OH H OO OH O OH OH O O O OH OH OH OH O O OH OH OH OH n len inan (65), Len inula edodes (Eaele e al.2015) Didanosine (61), Sy he ic compound (based on he Co yceps spp compound) (Alapi EM and Fische J 2006) Fig. 38 Examples o biologically ac i e compounds om ungi used in unc ional oods and nu aceu icals. 61: Syn he ic compound inspi ed om co dycepin (Alapi and Fische 2006); 62: T i e penoid om Ganode ma sp. (Sa o e al. 1986); 63: Main ac i e p inciple o “Phellinus” (i.e. T opicopo us)lin eus (Shao e al. 2015); 64: Blazeispi ols ( i e penoid om cul u es o Aga icus sub u escens (Thongklang e al. 2017); 65: Len inan, a be a-glucane om Len inula edodes (Ina e al. 2013) 66 Fungal Di e si y (2019) 97:1–136 123 a ious human diseases (Tao iq e al. 2016). The impo an edible mush ooms wi h ema kable nu aceu icals p ope - ies include he species o Au icula ia,G i ola,He icium, Lac a ius,Pisoli hus,Pleu o us and T emella. Some s ud- ies sugges mush ooms as inhibi o s o myco oxin p o- duc ion (Re e be i e al. 2005). The bioac i e glycop o ein (SX- ac ion) ex ac ed om G i ola ondosa, o mai ake mush ooms, ha e been in es iga ed in animal and clinical ials. I is pa icula ly encou aging ha he glycemic con ol o se e al diabe ic pa ien s unde o al medica ions was signi ican ly imp o ed wi h a SX- ac ion egimen ha may p ima ily a ge o ac on he insulin signal ansduc- ion pa hway, o e coming insulin esis ance (IR and IRS-1) (Konno e al. 2013). O he o mula ions exis on he ma - ke , such as a new p oduc o demen ia, pa icula ly Alz- heime ’s disease, based on a p op ie a y s anda dized ex ac ha con ains he icenones (e.g. 64) and amyloban (bo h om H. e inaceus) (Thongbai e al. 2015). The popula culina y oys e mush oom Pleu o us os ea us and o he species o his genus syn hesize bioac i e pleu an, which is ano he po en ial candida e o he de elopmen o nu aceu icals (Gia asis and Biliade is 2006; Zhang e al. 2001). Some examples o biologically ac i e compounds om ungi used in unc ional oods and nu aceu icals a e gi en in Fig. 38. Today, i is e y easy o ind unc ional oods and nu aceu icals de i ed om mush ooms in he ma ke . Many o hese p oduc s can e en be pu chased ia he In e ne . Howe e , i mus be kep in mind ha hese s udies do o en no ely on s anda dized ma e ial and ha he “heal h claims” de i ed om hem a e o en no sub- s an ially jus i ied, e.g. because he s udies we e conduc ed wi h oden s o e en only in i o (cell-based o enzyme based assays), and we e ne e alida ed by ea men on humans in a simila manne as he clinical ials ha a e manda o y in de elopmen o e hical d ugs. Se ious dis- eases should he e o e no be ea ed be sel -medica ion and pa ien s should by all means seek ad ice om a medical doc o . Among he a ious side e ec s epo ed o pa ien s ha ha e used such p epa a ions om TCM mush ooms as sel -medica ions, pancy openia (i.e. a dec ease in he numbe o all blood cells) has ecen ly been equen ly eco ded (Yoon e al. 2011; Jung e al. 2013). E en hough he symp oms disappea ed a e he con- sump ion o he mush oom p oduc s opped, hese cases should gi e a wa ning o e e ybody who uses mush oom nu aceu icals no o o e dose hem. 36. Ha es ing he un apped p obio ic po en ial o ungi Gas oin es inal diso de s and diseases cons i u e a majo cause o mo bidi y and mo ali y wo ldwide (Kaplan 2015; Ki k e al. 2015; Pee y e al. 2015). Diseases o he gas- oin es inal ac may o may no be con agious. In he case o non-communicable gas oin es inal ac diseases, he e is no ansmissible o ganism in ol ed. These include in lamma o y bowel disease, i i able bowel synd ome, colon cance , C ohn’s disease and coli is. In he case o communicable gas oin es inal ac diseases, he ae iolog- ical agen is an in ec ious o ganism. Su e e s may exhibi one o se e al o a b oad a ay o gas oin es inal ac dis u bances and pe u ba ions, including la ulence, abdominal pain, omi ing, nausea, gas oin es inal ac bleeding, cons ipa ion, and dia hoea (Wadswo h e al. 2011). Se e al gas oin es inal ac diso de s a e becoming inc easingly di icul o ea due o ambiguous o e all symp oma ology o inc eased esis ance o pa hogens o adminis e ed pha maceu ical d ugs, mainly an ibio ics (P es inaci e al. 2015). Gi en hese issues, he e is a c i ical need o he apeu ics ha will complemen / eplace exis ing s a egies. In ha ligh , p obio ics p esen an a ac i e op ion. The Food and Ag icul u e O ganiza ion o he Uni ed Na ions and he Wo ld Heal h O ganiza ion along wi h he In e na ional Scien i ic Associa ion o P obio ics and P ebio ics de ine p obio ics as “li e mic oo ganisms, which when adminis e ed in adequa e amoun s, con e a heal h bene i on he hos ” (FAO/WHO 2001; Hill e al. 2014). P obio ics can be deli e ed as die a y supplemen s (e.g. capsules, able s, and powde ) o ood ing edien s (e.g. yogu s and ke i s) (Szajewska e al. 2016). The heal h bene i s o p obio ics include s eng hening o he gu mucosal ba ie ollowed by gu pa hogen coloniza ion esis ance, eplenishing o bene icial gu mic obes a e dia he ic episodes, and enhancing o e all heal h o he diges i e ac (Hill e al. 2014). P obio ics ha e been used o a limi ed ex en o he ea men /p e en ion o gas- oen e i is, in lamma o y bowel disease, i i able bowel synd ome, colo ec al cance , and coli is (B own and Valie e 2004; Hill e al. 2014). Mos p obio ics cu en ly in use a e limi ed o bac e ial s ains wi h membe s o he gene a Bacillus, Bi idobac- e ium, En e ococcus, Lac obacillus, P opionibac e ium and S ep ococcus being he mos common (Ouwehand e al. 2002; B own and Valie e 2004; Szajewska e al. 2016). A no able excep ion is he yeas Saccha omyces boula dii, which was ini ially isola ed o comba chole a- associa ed dia hoea, and is now being used o ea dia - hoea o a ying ae iology (McFa land and Be nasconi 1993). The heal h bene i s o S. boula dii ha e been well- documen ed in se e al andomized clinical ials (Table 18). None heless, he p obio ic po en ial o a ious o he ungal species is also well known. Fo ins ance, membe s o he gene a Kluy e omyces and Ya owia a e Fungal Di e si y (2019) 97:1–136 67 123 p omising candida es due o hei s ong ac i i y agains bac e ial pa hogens and hei abili y o ole a e he inhos- pi able en i onmen o he gu (Kumu a e al. 2004; Chen e al. 2010). Howe e , his a enue o esea ch emains la gely unexplo ed (Huseyin e al. 2017). A la gely un apped sou ce o po en ial ungal p obio ics is he human gu mycobiome, he collec ion o ungi esiding in he gu . Membe s o he gene a Candida and Saccha omyces a e consis en ly p e alen ac oss s udies, bu Cladospo ium, Malassezia and Penicillium seem o be also abundan depending on he popula ion unde s udy (Ho mann e al. 2013; Rod iguez e al. 2015; Nash e al. 2017). Fu u e esea ch should ocus on iden i ying and p ecisely cha ac e izing app op ia e ungal p obio ic s ains. Ou comes o each p obio ic ungal s ain should be de e mined explici ly and op imal doses de ined acco ding o age g oup and disease s a e. Resea ch e o s should also expand o examine he use o ungal p obio ics in he aquacul u e and animal husband y indus ies. Sa ing he plane Was e is a common and majo global p oblem. An h o- pogenic ac i i ies esul in he gene a ion o millions o ons o plas ic was e each yea . Ex ensi e ag icul u al p ac ices ha e also con ibu ed o he gene a ion o eno - mous quan i ies o was e, which a e being disposed o in non-cos -e ec i e and en i onmen ally un iendly ways. The e a e a ious ways in which ungi can help dec ease was e and educe pollu ion. The e is he e o e an u gen need o ap in o he powe o ungal o ganisms and de ise sma s a egies ega ding how hey can educe he nega- i e e ec s ha pollu an s ha e on he en i onmen . The sec ion below ou lines how ungi con ibu e o he heal h o ou plane and ha e he abili y o cu b a numbe o en i- onmen al p oblems, mos no ably pollu ion. Examples a e gi en as o how ag icul u al was e (which was p e iously disposed o o bu n , esul ing in ai pollu ion) can be con e ed in o use ul subs a es on which o g ow edible mush ooms a an indus ial scale. Mycologis s ha e also conduc ed esea ch on esilien ungal mic oo ganisms and explo ed hei abili y o deg ade plas ics, ex ile e luen s, and hyd oca bons, all o which a e pollu ing ou en i on- men a an ala ming a e. 37. Ag icul u al was e disposal Ag icul u al was e, he esidue om plan ing un il ha es , gene ally con ains a mix u e o plan was e, animal/insec was e, and oxic esidues om he chemicals used as pes- icides, insec icides, and he bicides. Asia is one o he wo ld’s mos ag icul u e-in ensi e a eas: om 2010 o 2016, 46.9% o emissions in Asia came om c op esidue, compa ed o 28.2% and 16.2% om Ame ica and Eu ope, espec i ely. Acco ding o he FAOSTAT 2 emissions da abase, 90.6% o ice p oduced wi hin Asia gene a ed mo e han a hund ed million ons o esidual ma e ial. This ag icul u al was e accoun ed o o e 50% o he ni ous oxide gene a ed om he decomposi ion o c op esidue on cul i a ed soils, one o he main con ibu o s o he g eenhouse gas e ec and a cause o global wa ming. In he Sac amen o Valley o Cali o nia, ice and whea s aw a e also majo con ibu o s o gene a ed ag icul u al was e, wi h 1.5 ons o ice s aw was e p oduced annually (Zhang e al. 2002). In Thailand, he main c ops a e suga cane, ce eal, ice, cassa a and oil palm, and hese con ibu e 80% o he o al solid was e gene a ed om c op cul i a ion. A numbe o p ocesses ha e been de eloped o p o- posed o ag icul u al was e managemen (such as com- pos ing, which is a sus ainable p ocess), while he common p ac ice o bu ning he ice s aw, husk, s alks, co n cobs, s ubble and g asses is conside ed a cheap and easy means o he disposal o excess esidues (Obi e al. 2016; Walia e al. 1999). Un o una ely, bu ning ag icul u al was e gene a es many poisonous and ha m ul oxides and hyd o- ca bona es in o he a mosphe e (Shaban and Omaima Table 18 Fungal p obio ics and hei heal h bene i s Fungi Heal h bene i s Re e ences Saccha omyces boula dii Conside able educ ion o du a ion o dia hoea-RCT Szajewska e al. (2016) and e e ences he ein Risk educ ion o an ibio ic-associa ed dia hoea-RCT Risk educ ion o dia hoea associa ed wi h Clos idium di icile in child en-RCT Reduc ion o dia hoea associa ed wi h Helicobac e pylo i in ec ion- RCT Amelio a ion o abdominal pain in IBS su e e s-RCT Saccha omyces ce e isiae Abso p ion o myco oxins Moslehi-Jenabian e al. (2010) RCT andomized clinical ials 2 h p://www. ao.o g/ aos a /en/?#da a/GA. 68 Fungal Di e si y (2019) 97:1–136 123 2010), which in u n inc eases ai pollu ion and causes espi a o y p oblems, which hen impac he economy h ough highe medical cos s and employee absences. The e o e, he e is an inc easing demand o sus ainable p ocesses ha u ilize ag icul u al was e in mo e eco- iendly ways. Biological p ocesses a e conside ed bo h na u al and sus ainable, and a e also impo an in ca bon ecycling. Fungi a e some o he mos e ec i e decompose s in an ecosys em and a e ex emely e icien in he deg ada ion o plan -based ag icul u al was e such as ice s aw, whea s aw, maize s o es and suga cane esidue (Dinis e al. 2009). Mush oom cul i a ion using ag icul u al was e, e.g. whea , ice, paddy s aw, ice b an, co ee s aw, ea lea es, co on s aw sawdus , p o ide p o i able ag i-business oppo uni ies o small a me s and o e s an eco- iendly al e na i e o disposing o was e, which is no mally bu n (Zhang e al. 2002). Va ious comme cial mush ooms a e cul i a ed wo ldwide, and ag icul u al esidues a e used as cheap and enewable subs a es, and a selec ion is gi en in Table 19. Ag icul u al was e consis s o la ge quan i ies o ligno- cellulosic was e, and is composed o app oxima ely 60– 70% e men able suga s and 20–30% a oma ic compounds. Lignocellulosic was e is a enewable and impo an sou ce o biomass/e hanol p oduc ion (Kim and Dale 2004). Whea s aw, co n s o e , suga cane bagasse, and ice s aw a e he mos common subs a es o bio uel p oduc- ion, and ilamen ous ungi a e key componen s o he e men a ion p ocess. Pichia s ipi es (s ain NRRL Y-7124) is used in he e men a ion p ocess o p oduce e hanol om whea s aw and ice s aw (Moni uzzaman 1995), and Fusa ium oxyspo um, Neu ospo a c assa, and Paecilomyces sp. a e ypically used o e men cellulose di ec ly o e hanol (Szczod ak and Fiedu ek 1996). The e o e, a ious ungi ha e he po en ial o p oduce lignocellulosic enzymes and play impo an oles in eco- ag icul u al was e p ac ice. Whi e- o ungi can also be used o p e- ea he ag icul u al was e o enhance he enzyma ic saccha i ica ion p ocess due o he selec i e emo al o lignin (Miyauchi e al. 2018; Rouches e al. 2018; Zhou e al. 2015b,2018). The sc eening o he sec e ed enzymes om ungi can also be used o enhance he saccha i ica ion o ag icul u al was e by comme cial enzyme cock ails, and his app oach has led o he dis- co e y o new ac i i ies such as ly ic polysaccha ide oxi- dases which open up he lignocellulose s uc u es o acili a e u he access o celluloly ic enzymes (Be in e al. 2012; Cou u ie e al. (2012,2018). Al e na i ely, ungi can be used o ans o m compounds in ag icul u al was e in o highe alue comme cial molecules such as anillin (Tai a e al. 2018) and cannolo (Odino e al. 2017). In mos coun ies, some was e, such as ce eal esidue, is uni e sal, whe eas o he o ms o ag icul u al was e a e mo e egion-speci ic. In he F ench egion o P o ence, o example, la ende is g own on a la ge scale o he p o- duc ion o essen ial oils. Globally, hese oils a e among hose mos commonly used o indus ial pu poses, including in pe umes, pha maceu icals and cosme ics. Table 19 Ag icul u al was e use as subs a e o mush oom cul i a ion Fungal axa Ag icul u al was e Re e ences Aga icus bispo us Bu on mush oom Whea s aw Kam han and Tiwa i (2017) Ganode ma sp. Chinese mush oom Sawdus Shashi ha e al. (2016) Len inula edodes Shii ake mush oom B ac s o pineapple c own, suga cane bagasse, suga cane lea es, whea s aw, co n- cobs, oak-wood sawdus Salmones e al. (1999) Philippoussis e al. (2007) Pleu o us e yngii King oys e mush oom Supplemen a ion o whea b an wi h wood chips. Ba ley s aw and suga bee pulp wi h ice b an Jeznabadi e al. (2016) Pleu o us djamo Pink oys e mush oom Supplemen a ion o whea b an wi h suga cane bagasse Hasan e al. (2015) Pleu o us os ea us Oys e mush oom Paddy s aw, ice s aw whea s aw, da e-palm lea es emp y ui bunch, oli e cake, oma o u , banana lea es, pine needles, suga cane bagasse Alananbeh e al. (2014) Ananbeh and Almomany (2005,2008) Ali e al. (2010) Ma lina e al. (2015) Rezania e al. (2017) Yang e al. (2013a) Fungal Di e si y (2019) 97:1–136 69 123 A e s eam dis illa ion, he esidual s aw is conside ed o be ag icul u al was e, hough i can also be used as a sou ce o e pene de i a i es (e.g. τ-cadinol, β-ca yophyllene), lac ones (e.g. couma in, he nia in), and phenolic com- pounds o indus ial in e es , including osma inic acid ( h ough ungal ea men s) (Lesage-Meessen e al. 2018). Fungal-de i ed enzymes ep esen o e 60% o he wo ld ma ke in indus ial enzymes. La ende esidues, like mos ag icul u al was e esidues, a e bo h sui able ca alys s o he sec e ion o a wide panel o lignocellulose-ac ing enzymes, such as cellulases, laccases and xylanases, and he e o e can p o ide a local and cheap sou ce o deg ada i e and ans o ming bioca alys s. E en plan pa hogens like Phyllos ic a capi alensis p oduce a abinase, cellulase, laccase, pec inase and xylanase, especially when cul i a ed on la ende esidues. The ini ial g ow h o P. capi alensis on la ende was e was highe in compa ison o i s g ow h on o he ag icul u al was e ma e ials, such as miscan hus, ice s aw, ice husk, so ghum, and whea s aw, sugges ing u he s imula ion o g ow h by a com- pound emaining wi hin he la ende esidue (Wikee e al. 2017). This opens up u he a enues o in es iga e he p esence o mic obial g ow h enhance s wi hin ag icul u al was e o u iliza ion in bio echnology. The e o e, he aims o his p esen e iew a e o e eal he capaci y o ungi o ag icul u al was e managemen and o explo e he a ie ies o ungi and hei lignocelluloly ic p oduc ion, aking ull ad an age o a ious ag icul u al was e p oduc s as subs a e. 38. Myco emedia ion: Fungi o he escue Man-made ac i i ies ha e esul ed in ex eme en i on- men al pollu ion, and he e o e en i onmen ally iendly emedia ion echniques a e mo e necessa y han e e be o e (Rhodes 2013). Fungi, he mos igo ous decompose s ound in na u e, a e a po en ial solu ion o his p oblem (Singh 2006). Bio emedia ion wi h ungi, known as myco emedia ion, is an inno a i e bio echnological app oach which uses li e ungi o clean up con amina ion h ough o al mine aliza ion using enzymes, o h ough he o al emo al o he con aminan ia abso p ion (S ame s 2005). Pollu an s eleased in o he en i onmen due o man- made ac i i ies pose a signi ican h ea o he sus ainabili y o he en i onmen and o human heal h. The bu ning o wood and ossil uels, as well as coal mining and oil d illing all elease ecalci an pollu an s such as polycyclic a o- ma ic hyd oca bons (PAH), which a e no easy o emo e once hey ha e been eleased. In addi ion, pes icides ha leak in o na u al wa e ways and indus ial e luen s con- aining hea y me als, ha ha e been eleased in o he en i onmen wi hou p ope ea men can be e ec i ely emo ed i ungi a e u ilized as a emedia ion ool. The ege a i e pa o he ungi, called mycelium, has he abili y o exude powe ul ex acellula enzymes and acids ha a e able o decompose many o ganic subs a es, including lignin and cellulose (Poin ing e al. 2001; Buche e al. 2004). Wi h a simple sc eening p ocedu e, he mos sui able ungal species o he a ge pollu an can be iden i ied (Ma suba a e al. 2006). Many species o ungi, such as Aspe gillus nige , A. e eus, Cladospo ium oxys- po um, Fusa ium en icosum, Rhizopus o yzae, T icho- de ma ha zianum as well as he model whi e o ungus, Phane ochae e ch ysospo ium, ha e been es ed o hei abili y o deg ade pes icides (Bhale ao and Pu anik 2007; Leo ´n-San ies eban e al. 2016). Polychlo ina ed biphenyls, which a e highly oxic chemicals p e iously used in many indus ies and one o he mo e pe sis en o ganopollu an s, can be deg aded by non-ligninoly ic enzymes om ungi such as Fusa ium solani, Penicillium ch ysogenum and Scedospo ium apiospe mum (Tigini e al. 2009). Di e en species o basidomyce e whi e o ungi a e bes sui ed o myco emedia ion, as hei ex acellula lignin modi ying enzymes ha e low subs a e speci ici y (Lang e al. 1995). No only do hey a ge lignin, bu hey also a e capable o a ge ing many o ganic pollu an s ha a e simila in s uc u e o lignin, like DDT, lindane, chlo odane and PCBs (A isoy 1998; Poin ing 2001; Man- su e al. 2017). Enzymes like lignin pe oxidases (LiP), manganese pe oxidases (MnP) and laccases (LAC) sec e- ed by whi e o ungi a e excellen a deg ading o ganopollu an s held oge he by hyd oca bon bonds (Ku ¨es 2015). Whi e o ungi such as Len inus subnudus, Phlebia acan hocys is and Pleu o us os ea us, and many o he s ha e been success ully used sepa a ely as well as in mix u es o ea si es con amina ed wi h pes icides and he bicides (Kamei e al. 2011; Nyakundi e al. 2011; Xiao e al. 2011). Since whi e o ungi g ow by hyphal ex en- sion, hey can be e each he pollu an s in con amina ed si es, unlike o he o ganisms wi h a low colonizing capaci y (Reddy and Ma hew 2001). Fu he mo e, he lig- nin deg ading enzymes used by whi e o ungi a e ex a- cellula (No o ny ´e al. 2004). These ungi can ole a e high concen a ions o he pollu an , as he pollu an does no need o be in e nalized in o de o s a he deg ada ion p ocess. Lama and Whi e (2001) ecommend a ou -s ep s a - egy o he p ac ical implemen a ion o ungi o he myco emedia ion o con amina ed si es. The s eps include labo a o y scale expe imen s o es ablish p epa a ion me hods; on-si e pilo es ing o unde s and sound echnical and enginee ing echniques; and he p oduc ion o inocu- lum o i ied wi h nu ien s o ensu e g ow h and inally ull-scale applica ion (Fig. 39). Because o hei ole ance o ex eme pH condi ions, empe a u es, and nu ien a ailabili y, ungal species such 70 Fungal Di e si y (2019) 97:1–136 123 as Aspe gillus sp. and S e igma omyces halophilus ha e been es ed o hei abili y o abso b hea y me als om con amina ed si es (Bano e al. 2018). The cell walls o hese ungi ha e excellen me al binding capabili ies, and can abso b con aminan s which hen can be physically emo ed by ha es ing he ungus (Bald ian 2003). The u iliza ion o he biosu ac an s o ungal species has been a success o he emo al o hea y me als such as Fe, Zn and Pb (Igi i e al. 2018). Fo example, an anionic biosu ac an om Candida sphae ica was es ed on cleaning soil col- lec ed om an au omo i e ba e y indus y, and he hea y me al emo al success a e was 95%, 90% and 79% o Fe, Zn and Pb, espec i ely (Luna e al. 2016). The ex ile indus y is one o he p ima y con ibu o s o en i onmen al pollu ion. Un ea ed ex ile e luen s, ine - iciency in he dyeing p ocess, and he poo handling o spen dye s u e luen s a e he main causes o su ounding na u al wa e and land con amina ion, bo h o which ad e sely a ec plan , human and animal li e. Tex ile dyes, such as azo dyes (acid ed) o an h aquinonic dyes (basic blue) a e highly oxic and mu agenic in na u e (Delclos e al. 1984). Biological ea men o hese ha m ul pollu- an s h ough mic obial decolou iza ion and deg ada ion ha e a ac ed a en ion as he con en ional ea men me hods p oduce haza dous by-p oduc s and a e no e y cos e ec i e. T ichode ma ha zianum (Singh and Singh 2011) has been success ully bench es ed o he decon- amina ion o a ious ex ile dyes. Apa om he abso bance p ocess, enzyma ic deg a- da ion o was e is ano he easible app oach ha can be used o he emo al o slow-deg ading was e. Va ious ypes o cellulose-based u ban solid was e a e p ima ily disposed o ia incine a ion. One s udy conduc ed by Espinosa-Valdema e al. (2011) used Pleu o us os ea us (Oys e mush oom) o educe he mass and olume o used disposable diape s ia cellulose deg ading enzymes sec e- ed by he ungi, which simul aneously p oduced a pa ho- gen- ee, high-p o ein ood sou ce in he o m o a mush oom ui ing body ha could be used o human consump ion o as a ood supplemen o animals. Fig. 39 The p ocess o myco emedia ion Fungal Di e si y (2019) 97:1–136 71 123 O he con en ional s a egies o he decon amina ion o pollu ed si es, such as he use o chemicals o h ough incine a ion, a e compa a i ely less e ec i e han myco emedia ion. The washing and ex ac ing used in he chemical me hod only shi s he con aminan om one place o ano he (Valen ı ´n e al. 2013); likewise, incine - a ion can be highly ene gy in ensi e, no cos e ec i e, and has he po en ial o cause ha m h ough he o ma ion o dioxides (Shibamo o e al. 2007). The e a e ongoing s udies o es whe he edible mush- ooms could be used i s o myco emedia ion and hen o human consump ion. In one s udy, o example, Pleu o us pulmona ius was success ully es ed o cleaning c ude oil (Olusola and Anslem 2010); in ano he s udy, Aga icus bispo us and Lac a ius pipe a us we e success ully used o he bioso p ion o Cd 2? unde labo a o y condi ions (Nagy e al. 2013). Howe e , hese myco emedia ion p o- cesses emain imp ac ical due o he ac ha he abso p- ion o pollu an s, such as hea y me als migh ende he edible pa o he mush ooms highly con amina ed (Kul- sh esh ha e al. 2014). Howe e , i means o u ilizing mush ooms wi h an i-mu agenic and an i-geno oxic abili- ies could be de eloped (Mendez-Espinoza e al. 2013), hen i would be possible o simul aneously educe he oxici y o he pollu an s, clean he lands deemed un i o ag icul u e, and p oduce c ops o animal eed. Some ungi no being able o g ow in he p esence o he na u al mic obio a o he con amina ed si e and he need o ha e p ecise unde s anding he nu ien equi emen s o he ungus o i o h i e in he con amina ed si e migh be some small se backs o his echnology. In compa ison o he al e na i e me hods, hese p oblems a e negligible. And hey can be eadily sol ed wi h imp o ed in-si u and ex- si u ails. The lack o mo e comp ehensi e in o ma ion abou deg ada ion mechanisms and he enzymes in ol ed in he pollu an deg ada ion by di e en ungal species hinde s he possible use o hem in myco emedia ion in a mo e speci ic manne . Mo e in dep h s udies should be done o ecognize he oxida i e enzymes, o ganic acids and chela o s exc e ed by ungi du ing he mine aliza ion and deg ada ion p ocess. Ano he way o inc ease e iciency o myco emedia ion is using la ge scale s udies o e i y he esul s o he bench scale s udies ha would p o ide insigh s in o e icien use o he exis ing species o ungi and iden i ying new species sui able o bio emedia ion. Mo e esilien ungal species adap ed o ha sh en i on- men al condi ions should be es ed o hei adap abili y as bio emedia e s as hey a e mo e physiologically ac i e. Fo example in some a eas o he wo ld, he soil is high in sal concen a ion due o ine icien d ainage and his makes he ecosys ems in hese a eas e y simple and agile. To make hese a eas mo e ag icul u ally easible, halophilic o halo ole an ungi can be used use o clean up he soil o he excessi e sal . Up un il now mos o he s udies done ega ding halophilic ungi only ocus on he cha ac e iza- ion. Fungi such as Aspe gillus penicillioides,Gymnascella ma ismo ui,Cladospo ium cladospo ioides and Penicil- lium wes lingii a e well cha ac e ized as halophilic bu hei po en ial use as soil myco emedia o s should be done wi h mo e ocused s udies speci ically designed o check hei sal emedia ion abili y (Zhang and Wei 2017). By s udying he genes ela ed o enzyme deg ada ion, mine aliza ion, abso bance and adap abili y o ex eme en i onmen al condi ions, ansgenic ungi can be p o- duced wi h supe io myco emedia ion capabili ies. How- e e , since he emedia ion capaci y o na u ally occu ing ungi is s ill e y much unde s udied, isola ing and sc eening sui able ungi om hei na u al habi a s should ca ied ou in o de o eclaim pollu ed si es and o sus ain a be e en i onmen o u u e gene a ions. 39. Myco umiga ion using he genus Muscodo Myco umiga ion is he use o an imic obial ola iles p o- duced by ungi o he con ol o o he o ganisms (S inson e al. 2003). The p o o ypes o he myco umigan agen s belong o s ains o he genus Muscodo , on which mos o he ac i i ies in esea ch and de elopmen in his a ea ha e so a been ocused. Muscodo species a e endophy es ha belong o he o de Xyla iales (Ez a e al. 2004; Gonza ´lez e al. 2009; Kudalka e al. 2012; Suwanna ach e al. 2013a; Wijayawa dene e al. 2018; Chen e al. 2019), bu he axonomic and phylogene ic posi ion o he genus emains unse led (Da anagama e al. 2018; Wend e al. 2018). Muscodo cul u es do no spo ula e, hei sexual s a e is as ye unknown, and hei mos salien common ea u e is hei abili y o p oduce ola ile o ganic com- pounds. All s ains o his genus can inhibi and kill o he ungi, including human and plan pa hogenic species, as well as bac e ia and insec s, h ough he p oduc ion o a mix u e o ola ile o ganic compounds. These mix u es a e p ima ily composed o a ious small molecula weigh alcohols, o ganic acids, es e s, ke ones, and se e al a o- ma ic hyd oca bons as de e mined by gas ch oma og aphy- mass spec ome y. The mix u e o VOCs p oduced om Muscodo species has been epo ed o be an imic obial ola iles ( o a selec ion see compounds 66–72 in Fig. 40; o o iginal li e a u e see, A mosuka o e al. 2005; Kudalka e al. 2012; Me cie and Jime ´nez 2004; Mi chell e al. 2008; Ramin e al. 2005; Si i-Udom e al. 2017; Suwanna ach e al. 2013a,2015a,2017; Wo apong e al. 2001; Zhang e al. 2010b). S udies by Alpha e al. (2015) and Hu chings e al. (2017) sugges ed ha VOC p oduced by Muscodo may ac in he bac e ial DNA damage h ough inducing DNA alkyla ion and DNA me hyla ion 72 Fungal Di e si y (2019) 97:1–136 123 p ocesses; howe e , he ac i e ing edien s ye emain o be iden i ied. I such biological ac i i ies would also be obse ed in euka yo es, including mammalian cells, his migh cons i u e a u u e challenge o he egis a ion o p oduc s based on he espec i e s ains because o hei mu agenic po en ial. The mos ad anced p ojec o his kind has ocused on Muscodo albus (s ain 620), o iginally isola ed om Cinnamomum zeylanicum. This s ain was shown o be an e ec i e bio umigan capable o con olling lemon decay caused by Penicillium digi a um; lemon sou o caused by Geo ichum ci i-au an ii; apple decay caused by Penicil- lium expansum and Bo y is cine ea; as well as peach b own o caused by Monilinia uc icola (Me cie and Jime ´nez 2004; Me cie and Smilanick 2005). The s ain also can con ol g ain smu ungi (Goa es and Me cie 2009) and ac as an insec icide agains po a o ube mo hs (Lacey and Ne en 2006). Ano he s ain, Muscodo su hepensis (Fig. 41a), isola ed om Cinnamomum bejol- gho a in Thailand, has po en ial applica ion as a bio umi- gan o con olling blue mold (Penicillium digi a um) decay o he ange ine ui (Fig. 42a) (Suwanna ach e al. 2015a,b). Muscodo inoculum also has he po en ial o eplace me hyl b omide (a oxic chemical umigan and pes icide) umiga ion in con olling soil-bo ne plan diseases. Mus- codo albus (s ain MFC2), isola ed om My is ica ag ans, has he po en ial o con ol kale oo o disease caused by Py hium ul imum (Wo apong and S obel 2009). Muscodo albus (s ain 620) and M. oseus (isola ed om G e illea p e idi olia) showed he abili y o con ol disease se e i y caused by a a ie y o ungal and oomyce e plan pa hogens, e.g. Aphanomyces cochlioides, Rhizoc onia solani,Py hium ul imum and Ve icillium dahliae (S inson e al. 2003; Me cie and Jime ´nez 2009). Muscodo oseus also has nema icidal and nema os a ic applica ion agains ou plan -pa asi ic nema ode species (Meloidogyne chi - woodi,M. hapla,Pa a ichodo us allius, and P.pene ans) ound on economically impo an ege able c ops (Riga e al. 2008). Muscodo cinnamomi (Fig. 41b) comple ely con olled damping-o symp oms on plan seedlings and Rhizoc onia- oo o in oma o plan s, (Fig. 42c) (Suwan- na ach e al. 2012,2015b). Muscodo he eae isola ed om ubbe ees (He ea b asiliensis) is e ec i e a con olling whi e oo o disease in ubbe ees caused by Rigido- po us mic opo us (Si i-Udom e al. 2017). The applica ion o Muscodo in he con ol o soil-bo ne disease migh be o conce n due o he phy o oxic ac i i y which depends on he mix u e o ola ile o ganic com- pounds and ype o plan (Suwanna ach e al. 2012; Si i- Udom e al. 2017). Suwanna ach e al. (2017) sugges ed ha M.cinnamomi could be used in umiga ion wi h an ac i e cul u e o a biological con ol agen o educe he numbe o mic oo ganisms p esen on eggshell su aces O O 3-Me hylbu yl ace a e (66) OH 2-Me hylbu an-1-ol (67) OH 3-Me hylbu an-1-ol (68) O 2-Me hyl u an (69) O Te ahyd o u an (70) O 2-Bu anone (71) OH O 2-Me hylp opanoic cid (72) Fig. 40 Bioac i e compounds epo ed om Muscodo species Fig. 41 Colonies o Muscodo su hepensis (a) and M. cinnamomi (b) on po a o dex ose aga a 25°C a e 12 days. Scale ba =1cm Fungal Di e si y (2019) 97:1–136 73 123 manu ac u ing p ocess and biodeg adabili y a he p o- duc ’s end-o -li e s age, i was ound ha op imum pe - o mance occu ed a he c i ical au omo i e oad noise equency o 1000 Hz. Subsequen ly, es ing was pe - o med wi h panels p oduced wi hin he bulk bin eac o pa adigm wi h h ee subs a e blends (Table 20), acco ding o ASTM C423 using an IBM HVAL wi h a No sonics NE840 eal ime analyse . The highes sound abso p ion was ound wi h he aspen sha ing blend, which boas ed an NRC a ing o 0.9, hus demons a ing a Class A abso p ion coe icien and sugges ing po en ial applica ion o manu- ac u e o low VOC, biodeg adable, acous ic panels. S a e- o - he-a acous ic panels a e p oduced wi h polyu e hane oam, wi h mine al wool and ibe glass p o iding low- VOC op ions, bu he e is a g owing in e es in de elop- men o na u al al e na i es due o human heal h and p o- duc end-o -li e conce ns (Kaamin 2017). A c i ical p ope y o acous ic panels o indoo applica ions is i e a ing. Jones e al. (2017) epo ed meaning ully lowe CO2 and CO elease, along wi h educed smoke densi y, o mycelium- ice hull composi es, as compa ed o XPS by cone calo ime e . Addi ionally, i e pe o mance can be imp o ed by amendmen wi h glass ines (Jones e al. 2018). Cons uc ed loa ing we land panels ep esen ano he applica ion oppo uni y o he mechanical and end-o -li e p ope ies o mycelium composi es. Cons uc ed loa ing we lands a e p ima ily u ilized o imp o e we land wa e o was ewa e quali y, hough hey a e also used o a a ie y o o he objec i es, including habi a c ea ion, sho eline p o ec ion, and landscape imp o emen . Floa ing we lands a e ypically cons uc ed om a a ie y o ma e ials, including non-biodeg adable ma e ials such as ex uded polys y ene, PVC pipes, and high-densi y polye hylene (Pa line i e al. 2017). In his conside a ion, mycelium composi e panels may p o ide a biodeg adable op ion wi h he equi ed mechanical and hyd ophobic p ope ies (Ha- nee e al. 2017). This applica ion is being es ed by he G een Fu u es Resea ch and Design Lab a he Uni e si y o Washing on (Sea le, WA, USA), wi h mycelium com- posi e panels cu en ly in ield deploymen . 42. Fungal deg ada ion o plas ics: A hidden easu e o a g eene en i onmen In he mode n plas ic e a, p ima y plas ic p oduc ion has inc eased o 335 million onnes pe yea , wi h Asia accoun ing o 50% o he o al wo ldwide p oduc ion (Plas icsEu ope 2017). Acco ding o a ecen es ima e, om 1950 o 2015 abou 9150 million onnes o p ima y plas ics we e p oduced, esul ing in he accumula ion o abou 6945 million onnes o plas ic was e on he su ace o he ea h. O he o al was e gene a ed, only a small pe - cen age was ecycled (9%) and incine a ed (12%), while 79% amassed in land ills and o he e es ial and ma ine en i onmen s (Geye e al. 2017). The majo i y o pe oleum-based plas ics, such as polye hylene (PE), poly(e hylene e eph hala e) (PET), polys y enes (PS), polyu e hanes (PUs), and poly inyl chlo ide (PVC), a e esis an o biodeg ada ion, and he e o e pe sis in he en i onmen wi h a ious conse- quences (Wei and Zimme mann 2017). Biodeg adable plas ics a e conside ed eco- iendly al e na i es o pe o- leum-based non-biodeg adable polyme s. Howe e , limi ed in o ma ion is a ailable ega ding he exac mechanisms unde lying he biodeg ada ion p ocess, he ime scale o biodeg ada ion, and he op imal en i onmen al condi ions equi ed o hei biodeg ada ion (Yang e al. 2014a). Thus, he ca eless disposal and deg ada ion o bo h biodeg adable and syn he ic plas ics esul in he accumula ion o was e in e es ial land ills and ma ine en i onmen s, and pose a se ious h ea o su ounding ecosys ems (And ady 2015). None heless, nume ous s udies ha e epo ed ha plas ics a e ulne able o mic obial a ack (Ba a e al. 2003; K asowska e al. 2012; Ma hu and P asad 2012; Za a e al. 2013,2014; Res epo-Flo ´ ez e al. 2014; Khan e al. 2017). The conse a ional and ecological oles o ungi a e no only limi ed o ene gy o elemen al cycling, bu can also be used in he biodeg ada ion o a ious ypes o plas ics. Nume ous s udies ha e men ioned ungi as he p edomi- nan mic oo ganisms esponsible o he biodeg ada ion o bo h bio- and syn he ic- plas ics (Ba a e al. 2003; Khan e al. 2017). Acco ding o he indings o one su ey, he majo i y o plas ic deg ading ungi belong o he gene a Aspe gillus, Fusa ium, Paecilomyces and Penicillium (Kim and Rhee 2003). The mechanical o ces exe ed by he ungi du ing g ow h, hyphal pene a ion in o he plas ic laye , as well as he simul aneous sec e ion o a ious enzymes and adicals, a e all cha ac e ized as he ungal deg ada ion o plas ics (Moo e e al. 2000). The mecha- nism o ungal deg ada ion begins wi h he a achmen o hyphal ilamen s o he su ace o a plas ic subs a e. The hyphal ips hen ex end, using mechanical o ce o sec e e enzymes and adicles ha allow he pene a ion o he ungus in o he subs a e (see Fig. 45). The nex s ep is he abso p ion o small molecules, polyme s, adicles, o a oms h ough he po ous ips o he hyphae, ollowed by hei anspo a ion h ough he unde lying plasma memb ane (Moo e e al. 2000; Khan e al. 2017). The enzymes a e known o hyd olyze he polyme ic subs a e and in u n p o ide nu ien s, which acili a es he g ow h o ungi o o he mic oo ganisms (San e e e al. 1994; Lucas e al. 2008; Bane jee e al. 80 Fungal Di e si y (2019) 97:1–136 123 2014). The a ious ungal species and he associa ed enzymes epo ed o deg ade a ious ypes o plas ics a e lis ed in Table 21. Mos o he enzymes known o he deg ada ion o plan polyme s a e able o depolyme ize syn he ic polyme s, such as PE and PU, by hyd olyzing he es e bonds p esen in he polyme backbone. The su ace a ea o polyme s exposed o ungal enzyme a ack has an ad ancing e ec on biodeg ada ion. The e o e, plas ic pa icles in he ange o 0.5 o 0.25 mm a e mos sui able o enzyme biodeg ada ion. Al hough pu i ied enzymes a e known o b eakdown he C–C bond in poly inyl chlo ide (PVC), he use o mic oo ganisms is a o ed o he biodeg ada ion o polyme s. Mo eo e , he mixed cul i a ion o se e al s ains is known o ha e a g ea e impac on biodeg ada ion e iciencies han he use o single s ains (Wei and Zim- me mann 2017). The o e all p ocess o plas ic biodeg ada ion is depen- den on he p esence o op imal en i onmen al condi ions o acili a e he g ow h o ungi and maximize he ac i i ies o he enzymes o depolyme ize he polyme ic ma e ials. The biodeg ada ion p ocess is also a ec ed by he physio- chemical p ope ies o he plas ics, such as su ace opology, molecula weigh , hyd ophobici y, and he deg ee o c ys allini y (Manzu e al. 2004; B ueckne e al. 2008; Jenkins and Ha ison 2008; Ronk is e al. 2009; Res epo-Flo ´ ez e al. 2014; Wei and Zimme mann 2017). Highe deg ees o c ys allini y s ongly educed he biodeg ada ion o speci ic plas ics. Alipha ic ca bon chains a e mo e easily biodeg adable han a oma ic polyme s. The hyd ophobici y o plas ics makes he su ace wa e epel- lan , educing he success o he a achmen , g ow h, and p opaga ion o ungal hyphae, and he eby educing he deg ee o plas ic biodeg ada ion. Simila ly, abio ic ac o s such as en i onmen al empe a u e; a ailabili y o oxygen; exposu e o ligh o UV; and a ailabili y o adicles in he en i onmen all a ec he mechanisms o plas ic biodeg ada ion (Wei and Zimme mann 2017). The di e si y, zonal dis ibu ion, and niche pa i ioning o ungal s ains in he en i onmen also a ec he biodeg ada ion p ocess. Fu he mo e, he amoun and ype o enzymes sec e ed by he ungal s ain o diges he polyme also s ongly a ec he biodeg ada ion p ocess (Fig. 10). The sec e ion o speci ic ypes o enzymes o a ious ypes o enzymes by ungi o deg ade polyme s Fig. 45 Fungal deg ada ion o polyes e polyu e hane (PEU) ilms. aPEU ilm no exposed o ungal deg ada ion (con ol); b– dPEU ilms exposed o di e en Aspe gillus spp. on mal ex ac aga medium incuba ed o 28 days in da k a 30 °C. The ex en o biodeg ada ion di e ed o each s ain. Fungal hyphal g ow h is obse ed on he PEU su ace and some po ions o he PEU ilms a e deg aded due o ungal ac i i ies Fungal Di e si y (2019) 97:1–136 81 123 Fig. 46 Polyes e polyu e hane (PEU) ilms wi h ungal g ow h and signs o biodeg ada ion on he su ace. aPEU ilm no exposed o Aspe gillus species; b ungal g ow h on he su ace o PEU; c,dPEU ilms a e he washing o ungal hyphae om he su ace o he ilms Table 21 Lis o ungal species wi h hei enzymes esponsible o biodeg ada ion and ypes o plas ics used Fungal s ain Enzyme Plas ic ype Re e ences Aspe gillus la us Glucosidases PCL Tokiwa e al. (2009) Aspe gillus nige Ca alase, p o ease PCL Tokiwa e al. (2009) Aspe gillus e eus Es e ase, u e hane hyd olase PU Boubendi (1993) Aspe gillus ubingensis Es e ase, lipase PU Khan e al. (2017) Bipola is (Cochliobolus) sp. Laccase PVC Suma hi e al. (2016) Chae omium globosum Es e ase, u e hane hyd olase PU Boubendi (1993) Cu ula ia senegalensis Polyu e hanase PU C abbe e al. (1994) Fusa ium sp. Cu inase PCL Shimao (2001) Pes alo iopsis mic ospo a Se ine hyd olase PU Russell e al. (2011) Phane ochae e ch ysospo ium Manganese pe oxidase PE Shimao (2001) Tala omyces uniculosus ( o me ly Penicillium uniculosum) Glucosidases PHB Tokiwa e al. (2009) Tala omyces pinophilus ( o me ly Penicillium pinophilum) PHB-depolyme as PHB Panagio idou e al. (2014) T ichode ma sp. U ease, p o ease, es e ase and laccase PU Lo edo-T e in ˜o e al. (2011) Disclaime : Some o he ungal species in he able a e pa hogenic and i is ou o ques ion o use hem in bio echnological p ocesses PCL polycap olac one, PE polye hylene, PHB polyhyd oxybu y a e, PU polyu e hane, PVC poly inyl chlo ide 82 Fungal Di e si y (2019) 97:1–136 123 a y om one species o ano he , o e en wi hin he same species (Doi 1990; Howa d 2012). Cu en ly, mo e han 100 ungal species a e known o deg ade di e en ypes o plas ics, and many mo e a e s ill in he p ocess o being isola ed and iden i ied (Howa d 2012). Mos o he ungal s ains disco e ed we e s udied o hei enzyme biodeg ada ion abili ies a he labo a o y scale. No e o s ha e ye been made o de elop la ge scale o indus ial scale bio eac o s o speci ic ypes o plas ic deg ading ungi. The e o e, his esea ch is o g ea impo ance o indus ial de elopmen , as well as o u u e esea ch pu poses. Collabo a ions be ween chemis s, biol- ogis s, enginee s and physicis s could esul in he de el- opmen o a la ge-scale bio eac o o plas ic biodeg ada ion u ilizing ungi. A p esen , such p ocesses a e oo expensi e o be applied a la ge scale, and col- lec ing and bu ning plas ics unde high hea emains mo e economical. Howe e , once such bio eac o s a e success- ully de eloped, new indus ies will eme ge o bo h he deg ada ion o a ious plas ics as well as o he u iliza ion o he deg aded compounds in he manu ac u ing o new p oduc s. The e is a need o p ope ly collec disposed plas ics and de elop sophis ica ed la ge-scale bio eac o s in which ungi could be used o deg ade a ious ypes o plas ics sepa a ely in con olled condi ions using mode n bio echnological echniques. A en ion should be gi en o esea ch and de elopmen on immobilized enzyme ech- nologies wi h ega d o ungal-deg ada ion o plas ics h ough enzymes. Mo e knowledge is needed conce ning he connec ion be ween speci ic-plas ic ypes and speci ic ungal species, o de e mine he ac ual ood web o a ious ungi. In eg a ion o low-cos and easily deg adable bio- plas ics in ma ke s a ound he globe is impo an . The mechanisms o ungal deg ada ion o plas ics need o be cla i ied using iso opic ma king o plas ics. The s uc u e and ac i e si es o biodeg ading enzymes o a ious ungi need o be de e mined, and me hods o inc ease he ca - aly ic deg ada ion o polyme s need o be de eloped. 43. Polycyclic a oma ic hyd oca bon deg ada ion by basidiomyce es Polycyclic a oma ic hyd oca bons a e ubiqui ous con am- inan s widely dis ibu ed in he en i onmen , wi h sus- pec ed ca cinogenic and mu agenic e ec s. The clean-up o polycyclic a oma ic hyd oca bon con amina ed si es is o g ea impo ance o p o ec ing human heal h. Polycyclic a oma ic hyd oca bons a e o ganic compounds composed o wo o mo e used benzene ings which a e o med du ing he combus ion o o ganic molecules and hei subsequen ecombina ion (Ha i ash and Kaushik 2009). Low molecula weigh polycyclic a oma ic hyd oca - bons a e composed o 2–3 a oma ic ings. They a e commonly ound in pe ogenic sou ces (e.g. gasoline, ke osene) and can be in oduced o he aqua ic en i onmen h ough oil spillage and discha ge om ships, anke s, mo o boa s, e c. Con amina ion can also come om municipal and u ban uno (Viei a e al. 2018). Polycyclic a oma ic hyd oca bons o high molecula weigh , com- posed o 4–6 a oma ic ings (e.g. py ene and benzo[a] py ene), a e o en eleased in o he en i onmen h ough py ogenic sou ces (Souza e al. 2015). Such polycyclic a oma ic hyd oca bons a e conside ed p io i y pollu an s because hey a e ecalci an in he soil, due o hei high a ini y and low wa e solubili y (Ro he mich e al. 2002). The biodeg ada ion o polycyclic a oma ic hyd oca bon (Fig. 46) con aminan s is a complex p ocess which is highly dependen on he numbe o con aminan s, na u al condi ions (e.g. empe a u e, humidi y and clima e), and p esence o o ganisms consuming he a ailable hyd oca - bons. Polycyclic a oma ic hyd oca bons end o bind o soil componen s, hus becoming di icul o emo e and deg ade (Pandey e al. 2016). Hyd oca bons di e in hei suscep ibili y o mic obial a ack, in which some o he high molecula weigh polycyclic a oma ic hyd oca bons may only be pa ially deg aded o no deg aded a all (A las and B agg 2009). Fungi can u n hyd oca bon con aminan s in o an ene gy sou ce. In he hyd oca bon con amina ed en i onmen , hose ungi capable o deg ading hyd oca bon ha e be e chance o su i ing by u ilizing his ca bon sou ce o g ow h (Fe nandez-Luqueno e al. 2010). Some ungi, and in pa icula basidiomyce es, a e e icien deg ade s o high molecula weigh polycyclic a oma ic hyd oca bons. In his way, ungi a e unlike bac e ia, which a e be e equipped o deg ading smalle molecules (Peng e al. 2008). The biodeg ada ion o polycyclic a oma ic hyd oca - bons can be enhanced h ough ex acellula oxida ion. Whi e o ungi a e he mos e icien p oduce s o oxida- i e ex acellula enzymes. Whi e- o ungi a e wood deg ading basidiomyce es which p oduce special oxidases o enzymes ha help in he deg ada ion o lignin and o he plan polyme s. These enzymes can also deg ade a a ie y o chemicals, including en i onmen al pollu an s (C aw- o d 2006) such as polycyclic a oma ic hyd oca bon. Success ul polycyclic a oma ic hyd oca bon biodeg a- da ion is b ough abou by di e en ca abolic ac i i ies, such as me abolic capabili ies, he induc ion o speci ic enzymes, and he p esence o a ou able o ganisms cap- able o deg ada ion (Al-Hawash e al. 2018) unde a ou able condi ions. The deg ada ion o polycyclic a oma ic hyd oca bons can be a ec ed by condi ions such as empe a u e, oxygen, pH, and nu ien a ailabili y. Tempe a u es can a ec he physical and chemical composi ion o polycyclic a oma ic hyd oca bons: a low empe a u es, he deg ada ion a e is Fungal Di e si y (2019) 97:1–136 83 123 slow due o he dec eased enzyma ic ac i i ies (Bish e al. 2015). Polycyclic a oma ic hyd oca bon deg ada ion can ac ually occu a a wide ange o empe a u es acco ding o medium: he maximum deg ada ion was documen ed o be in he ange o 30 o 40 °C in soil en i onmen s, 20 o 30 ° C in ma ine en i onmen s, and 15 o 20 °C in esh wa e en i onmen s (Al-Hawash e al. 2018). Oxygen concen- a ion is also impo an in he biodeg ada ion p ocess. Biodeg ada ion can be a i s bes in highly oxygena ed en i onmen s. Though he deg ada ion o polycyclic a o- ma ic hyd oca bons can also occu a negligible a es unde anae obic en i onmen s (Ha i ash and Kaushik 2009), he p ocess is no as apid as unde ae obic condi ions (G - ishchenko e al. 2000). The pH alue should also be aken in o accoun in he success ul deg ada ion o polycyclic a oma ic hyd oca bons, as i egula es he passage o small molecules and ions in he biological memb ane and a ec s he ca aly ic eac ion balance. In gene al, ungi would p e e nea ly neu al pH o maximize hei deg ada ion ac i i y, al hough hey can also ole a e acidic condi ions (Bonomo e al. 2001). Nu ien s can also become a limi ing ac o in he p ocess o biodeg ada ion. The concen a ion as well as he a io o ce ain nu ien s such as ca bon, ni ogen, i on and phospho ous can a ec he g ow h and spo ula ion o hyd oca bon-deg ading ungi (Za a and Co e ´s-Espinosa 2015). The chemical composi ion o polycyclic a oma ic hyd oca bons is ye ano he ac o ha can g ea ly a ec he success o polycyclic a oma ic hyd oca bon deg ada ion. The highe he molecula weigh , he mo e ecalci an polycyclic a oma ic hyd oca bons a e in he en i onmen , hus aking much longe o be deg aded (Fedo ak and Wes lake 1981). Basidiomyce es use a a ie y o mechanisms o com- ple ely deg ade o ganic compounds such as hyd oca bons. In gene al, bo h oxida i e and educ i e eac ions a e equi ed o he comple e me abolism o hyd oca bon compounds. The i s s ep in deg ada ion occu s a he in a-cellula le el in he o m o oxida ion and he in e- g a ion o oxygen wi h he aid o he enzyma ic ca alys s pe oxidases and oxygena es (Al-Hawash e al. 2018). Basidiomyce es sec e e hese enzymes o ca alyse bo h he di ec and indi ec oxida ion o chemicals. The enzymes, which a e oxido educ ases, aid in he de oxi ica ion o oxic o ganic compounds h ough biochemical eac ions, which in u n ans o m polycyclic a oma ic hyd oca bons s ep by s ep in o in e media es o he cen al in e media y me a- bolisms (such as he ica boxylic acid cycle). The ac ion o oxido educ ases ende s he con aminan s and xenobio ics in o ha mless compounds ha can be easily deg aded u - he (ITRC 2002). Fo ins ance, he ligninoly ic ungus, Pleu o us os ea us, can deg ade phenan h ene in o less ha m ul compounds, including 2,2′-diphenic acid (Fig. 47). Whi e- o basidiomyce es p oduced non-speci ic ex a- cellula ligninoly ic enzymes consis ing o h ee g oups: lignin pe oxidase (LiP), manganese-dependen pe oxidases (MnP), and laccase (Ho ich e e al. 2001), all o which a e essen ial o he ans o ma ion and mine aliza ion o o ganic pollu an s (Wang e al. 2009) such as polycyclic a oma ic hyd oca bons. The gene a Ganode ma (Ag awal e al. 2018), A milla ia (Hadiba a a and K is an i 2013), Cop inus (Li e al. 2009), Ma asmiellus (Viei a e al. 2018), Pleu o us (Hadiba a a and Teh 2014; Li e al. 2009), Pycnopo us (Munusamy e al. 2008) and Phane ochae e (Wang e al. 2009) we e able o deg ade polycyclic a o- ma ic hyd oca bon moie ies such as an h acene, py ene, phenan h ene and benzo[a]py ene (Table 22). Many ungal species, and in pa icula whi e- o basid- iomyce es, ha e demons a ed he abili y o deg ade poly- cyclic a oma ic hyd oca bons unde labo a o y condi ions; howe e , hese p ocesses equi e u he in es iga ion in he ield, and o da e a limi ed numbe o s udies ha e es ed he e icacy o hese ungi in he deg ada ion o polycyclic a oma ic hyd oca bons wi hin ypical en i on- men al condi ions. The placemen o ungi in o he en i- onmen equi es u he s udies o e alua e hei impac on o he o ganisms. In ensi e s udies should also be con- duc ed in o analy ical chemis y and gene ic enginee ing ools which could help in success ul bio emedia ion o inc ease ungal e iciency in deg ading hyd oca bons and o he ecalci an con aminan s. Fu he mo e, h ough he op imiza ion o adso p ion, bioa ailabili y and mass ans e o polycyclic a oma ic hyd oca bons, scien is s could enhance he a e o bio emedia ion. This could p o- ide one e ec i e means o mi iga ing en i onmen al pollu ion. 44. Can ungi help modi y he sus ainable soil enhance biocha ? Biocha has achie ed popula i y as a sus ainable soil enhance . Biocha is de i ed om biomass such as lea es, o es y and ag icul u al esidue, and animal manu e (Spokas 2010; Shackley e al. 2012). This biomass is con e ed in o a highly po ous, ca bonaceous p oduc h ough a con olled py olysis p ocess, namely he mo- chemical decomposi ion in he absence o oxygen (p e- en ing combus ion). In his way, i is di e en om cha coal. While cha coal p oduces ene gy, biocha is used in ca bon seques a ion, en i onmen al managemen , and soil amendmen s (Lehmann and Joseph 2009; Wa nock e al. 2007). Biocha is added o poo ly pe o ming o con amina ed soil as a means o inc easing he ecalci ance o o ganic soil ma e in a sus ainable manne . Due o i s polycon- densed a oma ic s uc u es, he added biocha can emain 84 Fungal Di e si y (2019) 97:1–136 123 in he soil o cen u ies o millennia, hus con ibu ing highe le els o a oma ic compounds o he soil o e long pe iods o ime. Impo an physicochemical p ope ies o he e alua ion o biocha u ilized in soil ha e been de ined: pH, ola ile compounds con en , ash con en , bulk densi y, wa e -holding capaci y, po e diame e and olume, and speci ic su ace a ea (Sohi e al. 2010). The o igin o he biomass o eeds ock and he py olysis condi ions, he e- o e, a e he key ac o s go e ning he physicochemical p ope ies o biocha . Wi hin he py olysis p ocess, em- pe a u es be ween 400 and 500 °C p oduce highe amoun s o biocha (Gaun and Lehmann 2008; Qamb ani e al. 2017). While py olysis occu s mo e apidly a high em- pe a u es, a slowed py olysis p ocess can p oduce a sub- s an ially highe quan i y o biocha p oduc . The yields o ash- ee biocha we e posi i ely co ela ed wi h he cellu- lose, hemicellulose and lignin con en s o eeds ock; he biomass samples possessing highe lignin con en p oduced highe amoun s o biocha , and he samples o high ash con en hampe ed biocha p oduc ion (Sun e al. 2017). When inco po a ed in o soils, biocha exhibi s a na u al oxida ion h ough he o ma ion o unc ional g oups. These g oups a e dependen on he empe a u e employed o p oduce he biocha . Thus, biocha s a e edox ac i e and as such con ibu e o he educ i e ans o ma ion o o ganic con aminan s in soil by acili a ing elec on ans- e om bulk chemical elec on dono s (e.g. phenolic moie ies a ising om he lignin in he o iginal biomass) o he ecei ing o ganic compounds (e.g. quinone–hyd o- quinone moie ies) and edox-ac i e me als (e.g. i on, manganese, coppe ), e e sibly dona ing and ecei ing up o 2 mmol elec ons pe g am o biocha (Klu ¨p el e al. 2014). Biocha -media ed mic obial elec on shu ling has also been conside ed as an impo an p ocess in soil O OH OH OH OSO 3 OH OH O O COOH COOH PHENANTHRENE s ep 1. OXIDATION (CYTOCHROME P450 MONOXYGENASE) PHENANTHRENE 9,10-OXIDE S ep 2. HYDROLYSIS (EPOXIDE HYDROLYSIS) ans-9,10- PHENANTHRENE DIHYDRODIOL 9-O-(HYDROXY- aNs-9,10- DIHYDROPHENANTRYL) SULFATE s ep 3. CONJUGATION WITH SULFATE 9,10-DIHYDROPHENANTHRENE S ep4 S ep 5B 9,10-PHENANTHRENEQUINONE 2, 2'-DIPHENIC ACID CO 2 S ep 5A LIGNINOLYTIC RING CLEAVAGE ENZYMESS S ep6 Fig. 47 P oposed pa hway o he deg ada ion o phenan h ene by he ligninoly ic ungus Pleu o us os ea us (Bezalel e al. 1996; Aus e al. 2003; Gup e e al. 2016) Fungal Di e si y (2019) 97:1–136 85 123 emedia ion and o he biogeochemical eac ions (Yu e al. 2016), leading o an inc ease in mic obial g ow h while educing Fe(III) mine als in he soil (Kapple e al. 2014). The e ec s o biocha on soil e ili y ha e been demons a ed h ough he pH inc ease o he acid ound in soils (Van Zwie en e al. 2010), and he bene i s in high nu ien le els and e en ion h ough he ions abso p ion (Liang e al. 2006). Howe e , biocha has also been shown o bo h s abilize and change soil biological communi y composi ion and abundance, depending on he biomass sou ce and he empe a u e used in he py olysis eac ion (Kim e al. 2012; Lo enz and Lai 2014). Such changes may a ec soil s uc u e and nu ien cycles (Gaskin e al. 2010; Rillig and Mummey 2006; S eine e al. 2008), he eby indi ec ly a ec ing plan g ow h (Wa nock e al. 2007). Rhizosphe e bac e ia and ungi may also di ec ly p omo e he g ow h o plan s (Compan e al. 2010). Soil ungi (e.g. sap o ophs, pa hogens and myco hizae) espond di e - en ly o biocha applica ions. Sap o ophic ungi ha e he po en ial o modi y biocha in he soil h ough he colo- niza ion o he po es p esen in he s uc u e, and his can lead o decomposi ion (A kinson e al. 2010; Lipczynska- Kochany 2018). Ce ain a buscula myco hizae a e able o inc ease hei oo coloniza ion si es in he p esence o biocha , enhancing he a ailabili y o phospha e o he plan , and he eby nega ing he need o add a i icial e ilize s. Fungal ex acellula enzymes a e he agen s o bo h coloniza ion and decomposi ion, and a e becoming inc easingly common ools o examining soil mic obial esponse in clima e change expe imen s (Weedon e al. 2011). Sap o ophic ungi a e conside ed o be e icien Table 22 Deg ada ion o polycyclic a oma ic hyd oca bons by enzymes om basidiomyce es Enzyme Basidiomyce e s ain Polycyclic a oma ic hyd oca bon moi ies Pe cen age o deg ada ion (%) Re e ences Laccase “Ganode ma lucidum” a Phenan h ene 99.65 Ag awal e al. (2018) Py ene 99.58 Pycnopo us sanguineus Phenan h ene 90.00 Munusamy e al. (2008) Py ene 96.00 An h acene 37.00 A milla ia sp. Py ene 63.00 Hadiba a a and K is an i (2013) Pleu o us e yngii An h acene 99.90 Li e al. (2009) Benzo[a]py ene 87.50 Aga icus bispo us An h acene 89.80 Benzo[a]py ene 48.60 Pleu o us os ea us An h acene 38.00 Benzo[a]py ene 31.00 Cop inus coma us An h acene 9.80 Benzo[a]py ene 9.30 Lignin pe oxidase “Ganode ma lucidum” Phenan h ene 99.65 Ag awal e al. (2018) Py ene 99.58 Phane ochae e ch ysospo ium Phenan h ene 72.77 Wang e al. (2009) Py ene 51.16 Benzo[a]py ene 25.50 Ma asmiellus sp. Py ene 100.00 Viei a e al. (2018) Manganese pe oxidase “Ganode ma lucidum” Phenan h ene 99.65 Ag awal e al. (2018) Py ene 99.58 Phane ochae e ch ysospo ium Phenan h ene 72.77 Wang e al. (2009) Py ene 51.16 Benzo[a]py ene 25.50 a The axonomy o “Ganode ma lucidum” gi en in he pape by Ag awal e al. (2018) is doub ul since his species has ne e been sa ely eco ded om India 86 Fungal Di e si y (2019) 97:1–136 123 deg ade s o lignocellulosic biomass due o he wide spec um o ex acellula enzymes hey p oduce. Thei p oduc ion and ac i i ies a e s ongly a ec ed by empe - a u e, mois u e and pH. Many s udies ha e been pe o med on he in luence o empe a u e and mois u e on he mic obial ecosys em o soils and he concomi an e ec on global enzyme pool composi ion and size (Schimel e al. 2007; Sowe by e al. 2005). Enzyme pool size is con olled by he a e a which enzymes a e p oduced by mic obes ela i e o he a e a which hey a e deg aded by he en i onmen . The p oduc ion o hese ex acellula enzymes incu s a cos o he mic oo ganism in e ms o ene gy and nu ien s, and so mic obes p oduce ce ain enzymes a ge ing speci ic compounds ich in ca bon, ni ogen o phospho ous. Mois u e le els in luence he di usion o subs a es, he hyd a ion s a e o he indi idual enzymes, and he a e o wa e eac i i y. Due o he chemical na u e o biocha , i may be pos- sible o use ungi di ec ly a ached o he biosou ced ma e ial o o use ungi in solid-s a e e men a ion condi- ions o p e ea he biocha p io o soil addi ion (a ype o compos ing). Figu e 48 p o ides a scanning elec on mic oscopy (SEM) image o ield-aged biocha bu ied in ag icul u al soil in which hyphal agmen s o ungi we e ixed on he biocha su ace. I is also possible, h ough a mo e bio echnologically sophis ica ed app oach, o ha ness he powe o hese sec e ed enzymes o modi y he physicochemical p ope ies o he exposed hyd oxyl and ca bonyl g oups on he su ace o he biocha . This will make hem mo e unc ionally ac i e as a soil amendmen o he s imula ion o he exis ing mic obial communi ies. The s uc u e o biocha is simila o lignin, and so he edox- esponsi e enzymes, such as laccases and heme- pe oxidases p oduced by Basidiomyce es, Ascomyce es and so - o ungi such as Chae omium globosum,Phialo- pho a malo um, and P. mu abilis a e designed o modi y hese s uc u es, and o gene a e hyd oxyl adicals (Gao e al. 2018). These ungi also con ol he a ailabili y o me al ions in he sys em, ei he h ough hei inco po a ion in o he p o ein s uc u e as co- ac o s, o chela ed in o ganic acids. While his ex acellula p ocess is designed o aid he ungus in he lignin deg ada ion p ocess, hese enzymes and chela o s could also be a way o con ol he elease o cap i a ion o me als in soils. A modi ied bio- cha , wi h inc eased su ace-ac i e g oups, would enhance he soil e en u he , mos no ably he ac i i y o he na - u al soil mic obiome, including myco hizal ungi. This in u n would u he imp o e he wa e dynamics, nu ien cycling, and supp ession o c op diseases, he eby enhancing he p oduc i i y o he soil and he c ops ha a e cul i a ed in i , while a he same ime con ibu ing o ca bon seques a ion and educed ai con amina ion in u al a eas o he wo ld. Commodi ies Fungi ha e been exploi ed bo h indus ially and comme - cially in many ways especially when aluable commodi ies a e in ol ed. These o ganisms o e unique ad an ages in bio echnology as hey can be easily cul u ed, ep oduce quickly and ha e sho li e cycles. In his sec ion we Fig. 48 The scanning elec on mic og aphs o ield-aged biocha bu ied in ag icul u al soil, showing he ou e su ace o biocha soil in e ace (Quilliam e al. 2013; wi h pe mission), wi h he a ow indica ing an example o po e blockage (a); spa ial he e ogenei y and spa si y o in e nal mic obial colonisa ion (b); in e nal colonisa ion by hyphal and single-celled mic obes (a ows) (c,d) Fungal Di e si y (2019) 97:1–136 87 123 discuss some o he many non- ood commodi ies de i ed om ungi. 45. Fungi and cosme ics Fungi a e used as ing edien s in nume ous cosme ic p od- uc s, including in some o he e y expensi e b ands. The bene icial claims a e all-encompassing, bu many ha e ye o be p o en. As he uses o ungi in cosme ics was e iewed by Hyde e al. (2010), which includinges, skin whi ene s, mois u ize s, an i-aging, shampoos and many o he s we e e iewed by Hyde e al. (2010), we b ie ly summa ize he opic he e. The demand o cosme ic p oduc s has apidly inc eased, and; hence cosme ics has ha e become a wo ldwide indus y (Hyde e al. 2010). Cosme ics a e mainly classi ied as cosmeceu icals, applied ex e nally o he skin, such as c eams, lo ions o oin men s, and nu icosme ics, which a e consumed as die a y sup- plemen s (Hyde e al. 2010). Apa om makeup, cosme- ceu icals a e ca ego ized as an i-aging, an i-w inklinge, skin e i alizinga ion, skin whi ening, an i-oxidan and mois u izing p oduc s. To a oid any ca cinogenic e ec s, he e has been a ecen end owa ds na u al cosme ics, such as ungi-based p oduc s (Hyde e al. 2010; Imho e al. 2011; Mohd-Nasi and Mohd-Se apa 2018). Fu - he mo e, he po en ial o ungi o be u ilized as “bio ac- o ies” o p oduce nanopa icles in he cosme ic indus y is cu en ly being explo ed (El Enshasy e al. 2018). Ascomyco a and Basidiomyco a a e ex ensi ely used in he cosme ic indus y (Hyde e al. 2010). Seconda y me aboli es ex ac ed om he mycelia o ui ing bodies and ing edien s om ungal e men a ion a e used as cos- me ic ing edien s. Aspe gillus species (Hyde e al. 2010) and Rhizopus species (Muco omyco a) a e used in he p oduc ion o lac ic acid, which is a main ing edien in bo h an i-aging and skin whi ening cosme ics. Lac ic acid is mainly used o hyd a e and make he skin smoo h. Addi- ionally, in peeling lo ions, lac ic acid is con ained in highe concen a ions and helps o emo e he ou e laye o he skin (Zhang e al. 2007). Fungi a e u ilized in he p oduc ion o an i-oxidan s, a y acids and polysaccha ides in an i-aging p oduc s, such as he chi in-glucan complexes o Aspe gillus nige and some mush oom species (Syny - sya e al. 2009; Vyso skaya e al. 2009). Eicosapen aenoic acid is a a e omega a y acid used in an i-aging p oduc s. I is ex ac ed om Mo ie ella species (Wang e al. 2007). Mo ie ella and Rhizopus species p oduce γ-linolenic acid. This compound is used as an an i- in lamma o y agen and acili a es heal hy skin (K is ˇ o ı ´- ko a ´e al. 1991). Spo o ichum p uinosum is used o p oduce melanocy ic enzymes h ough a subme ged ae o- bic e men a ion p ocess. Melanocy ic enzyme is used in some skin whi ening cosme ics o ac i a e he depigmen a ion o he skin (Moho c ˇic ˇe al. 2007). To ea neu ode ma i is and scle ode ma i is, an ex ac ob ained om T emella sp. is used. Ex ac s o Ophioco dyceps sinensis and T emella uci o mis a e u ilized o inc ease he mois u ising e ec in ce ain cosme ic p oduc s (Hyde e al. 2010) (Fig. 49). 46. Aga wood Aga wood is an economically aluable esinous hea wood p oduc de i ed om wounded ees o he amily Thy- malaeaceae (No iyan i e al. 2010; Subasinghe e al. 2012; Peng e al. 2015a; Chowdhu y e al. 2016; Chen e al. 2018b). Aga wood incenses a e used o ag ance in soaps and shampoos and ha e a pleasan a oma and gene al pe ume and a e an elemen o impo an eligious i uals in Ayu edic, Tibe an and adi ional Eas Asian medicine (Subasinghe e al. 2012; Rhind 2013; Chowdhu y e al. 2016; Lee and Mohamed 2016;Lo ´pez-Sampson and Page 2018) and as a oma ic ood ing edien s (Liu e al. 2013; Tan e al. 2019). India as well as he Sou heas Asian coun ies a e he main manu ac u es o aga wood p oduc s, while China, India, he Middle Eas and Japan a e he p ima y consume coun ies. Species o Aquila ia (Adams e al. 2014; Mohamed e al. 2014; Sel an e al. 2014: Az en e al. 2019), Gy inops, Ae oxylon and Gonys ylus a e used o he p oduc ion o aga wood (Subasinghe e al. 2012; Mohamed e al. 2014; Mohamed and Rasool 2016). Cu - en ly, aga wood p oducing Aquila ia species a e cul i- a ed om he home ga den le el o la ge scale plan a ions in Sou heas Asia, India and sou he n China (Lee and Mohamed 2016; Az en e al. 2019). Na u ally, aga wood o ma ion occu s h ough wounds. The in ec ed issues p oduce oleo esin which is con e ed o odo i e ous a oma ic aga wood esin (Peng e al. 2015a; Chowdhu y e al. 2016). When mic obial pa hogens en e Fig. 49 The King’s Co dy Se um con ains Co dyceps mili a is ex ac . The ex ac is claimed o acili a e an i-w inkle e ec s and add mois u e and an ioxidan s o he skin. I is p oduced in he Cen e o Excellence in Fungal Resea ch in Mae Fah Lung Uni e si y, Chiang Rai, Thailand 88 Fungal Di e si y (2019) 97:1–136 123 he wound, he de ense mechanism o he ees is igge ed (Mohamed e al. 2014; Chowdhu y e al. 2016; Az en e al. 2019). Sesqui e penes and 2-(2-phenyle hyl) ch omone de i a i es a e he key ac i e compounds in aga wood (Chen e al. 2011; Nae 2011; Mohamed e al. 2014;Li e al. 2019; Tan e al. 2019). Aga wood causal agen s a e di ided in o chemical, physical, and biological agen s. Fungi a e he biological agen s (No iyan i e al. 2010; Chhipa e al. 2017). Depending on he s ess, he ee o ms ei he physical o chemical de ense mechanisms (Mohamed and Rasool 2016; Chhipa e al. 2017). The de ense subs ances p o- duced ac as biochemical o biological de ense agen s (Mohamed and Rasool 2016). The wounded o in ec ed ee s em u ns da k b ownish o black (Fig. 50, Adams e al. 2014). A e in ec ion aga wood esin is sec e ed by he ee and deposi ed a ound he wound o numbe o yea s. Resinous aga wood o m pe umed compounds and is a a e na u al mechanism which is poo ly unde s ood (Sen e al. 2015). Vola ile compounds e en ually esul in aga wood (Tan e al. 2019). O he han na u al aga wood o ma ion, a i icial aga wood inducing me hods ha e been de eloped. Biological inocula such as mic obes and ungi a e key agen s o non-con en ional a i icial aga wood o ma ion (Az en e al. 2019). Resea ch has been ca ied ou o de e mine which ungi a e esponsible o aga wood p oduc ion and some o he isola ed axa a e lis ed in Table 23. Howe e , he ole o indi idual ungi needs ex ensi e esea ch o es ablish which species a e impo an in he p ocess. 47. Fungal enzymes Enzymes a e bioca alys s ha a e in ol ed in ca alysis eac ions wi hou needing ex eme condi ions, such as e y high empe a u es, high p essu es o co osi e en i on- men s, all o which a e o en equi ed in chemical p o- cesses. Enzymes o en o e a compe i i e ad an age when compa ed o chemical ca alys s. The enzyma ic app oach is en i onmen ally iendly, as i equi es mild condi ions and does no no mally esul in he p oduc ion o oxic by- p oduc s (Chapla e al. 2012). Enzymes a e used o ca alyze eac ions in p oduc ion p ocesses o se e al sec o s including indus ial biocon e sion (bioca alys ), en i on- men al bio emedia ion, ag icul u al sec o s and also bio- ans o ma ions o nume ous compounds such as la onoids (Das and Rosazza 2006; Wohlgemu h 2010; Choi e al. 2015). The e a e se e al sou ces o enzymes including animals, plan s and mic oo ganisms (bac e ia, ungi and p o is s). Mic obial enzymes ha e gene ally been used because o hei easie isola ion in high amoun s, low- cos p oduc ion, s abili y a a ious ex eme condi ions, and hei co-compounds, which a e also mo e con ollable and less ha m ul. Mic obial enzymes sec e ed in o he media a e highly eliable o indus ial p ocesses and applica ions. Mic obes isola ed om di e en sou ces e en among species and s ains o he same genus may p oduce a ying le els o enzymes o di e ing p ope ies. Fungal enzymes ha e a ac ed a en ion o se e al applica ions because ungi can g ow on low cos ma e ials and sec e e la ge amoun s o enzymes in o he cul u e medium, which eases downs eam p ocessing (Ani ha and Palani elu 2013). Se e al ungal enzymes a e a ailable comme cially including amylases, cellulases, lipases, phy ases, p o eases, and xylanases (Saxena e al. 2005; S ilakshmi e al. 2015). The posi i e en i onmen al impac o he p oduc ion p ocesses is o gene al in e es and he use o enzyma ic eac ions ins ead o o ganic sol en s o chemical eac ions is highly alued. Figu e 51 and Table 24 show examples o impo an ungal enzymes and he enzyme sou ces ha a e used in many applica ions, bu only a ew ungal s ains mee he c i e ia o comme cial p oduc ion. Mos applica ions o enzymes in he ood indus y ha e ocused on hyd oly ic eac ions (Akoh e al. 2008; Choi e al. 2015). Glycoside hyd olases and β-galac osidase a e Fig. 50 Ba ks o Gy inops walla Gae n. (Thymelaeaceae) in Sba agmuwa Uni e si y p emises, S i Lanka 2018 aHeal hy ba k, b,cdamaged ba k (Pho o c edi : H.A.T. Chin haka) Fungal Di e si y (2019) 97:1–136 89 123 g ade uma ic acid is adminis e ed in he managemen o pso iasis in humans (Balak 2015) and has shown o sig- ni ican ly educe me hane emission by ca le, when added as a supplemen in ca le eed (Roa Engel e al. 2008). I also has applica ions in ood and be e age indus y as an acidulan and la o enhancing agen . Fuma ic acid can Table 25 O ganic acids p oduced by ungi and di e si y o hei applica ions O ganic acids O ganisms Applica ions Chemical o mula Molecula s uc u e Ci ic acid Aspe gillus awamo i Aspe gillus la us Aspe gillus onsecaeus Aspe gillus nidulans Aspe gillus nige Aspe gillus phoenicis Aspe gillus sai oi Aspe gillus wen ii Ya owia lipoly ica Cosme ics Food and be e ages Me al cleaning Pha maceu icals Toile ies C 6 H 8 O 7 OH OH O OH OH O OH Fuma ic acid Rhizopus a hizus Rhizopus o mosa Rhizopus nig icans Rhizopus o yzae Bio-polyme s Ca le eed Food and be e ages Pha maceu icals C 4 H 4 O 4 O OH OH O Gluconic acid Aspe gillus nige De i a iza ion eac ions Food and be e ages C 6 H 12 O 7 OH OH OH OH OH OOH I aconic acid Aspe gillus e eus Saccha omyces ce e isiae Us ilago maydis Coa ings De e gen s Polyme s (poly-MMA) Rubbe indus y Supe -abso ben s C 5 H 6 O 4 OH O O OH Lac ic acid Recombinan yeas s ains Rhizopus o yzae Biodeg adable polyme s Cosme ics Food indus y O al hygiene p oduc s Bio-polyme s De i a iza ion eac ions C 3 H 6 O 3 OH OH O Succinic acid Rhizopus sp. C 4 H 6 O 4 OOH OOH 96 Fungal Di e si y (2019) 97:1–136 123 unde go de i a iza ion eac ions o p oduce malic acid and L-aspa ic acid (Goldbe g e al. 2006; Roa Engel e al. 2008). Bio-based uma ic acid is p oduced by he e - men a ion o di e en subs a es such as glucose by Rhi- zopus a hizus, R. nig icans, and R. o yzae, molasses by R. a hizus and cassa a bagasse by R. o mosa (Table 25) (Roa Engel e al. 2008; Xu e al. 2012). Gluconic acid Since he chemical s uc u e o gluconic acid combines bo h, ca boxylic and alcohol unc ional g oups, i can unde go a ious de i a iza ion eac ions including in a molecula es e i ica ion. Gluconic acid has applica ions in he ood and be e age indus y as a senso y p ope y enhance , acidi y egula o and p ese a i e o pickled ood and p ocessed mea p oduc s (Cane e-Rod iguez e al. 2016). Gluconic acid is p oduced by su ace o subme ged e men a ion p ocedu es wi h a ious ypes o inpu ma e ials such as s a ch, lignocellulosic biomass, suga - cane molasses, whey, was e pape , igs, banana mus and g ape mus as ca bon sou ce using Aspe gillus nige s ains (Table 25) (Cane e-Rod iguez e al. 2016). Du ing he e men a ion p ocess, glucose in he medium is con e ed ex acellula ly by he enzyma ic eac ion o glucose oxi- dase by A. nige (Magnuson and Lasu e 2004). I aconic acid I aconic acid has applica ions in de e gen s, coa ings and in he ubbe indus y. Poly(ac ylamide-co-i aconic acid) a supe abso ben polyme which is used o abso b aqueous solu ions is also de i ed om i aconic acid (Choi e al. 2015). The mos on demand indus ial scale applica ion is he con e sion o i aconic acid o me hyl me hac yla e (MMA) and he p oduc ion o poly MMA, commonly known as Plexiglass (Becke e al. 2015; Choi e al. 2015). The acid is gene ally p oduced ia e men a ion o glucose using Aspe gillus e eus. Fu he mo e, Us ilago maydis and Saccha omyces ce e isiae a e also capable o p o- ducing i aconic acid by glucose e men a ion (Table 25) (Becke e al. 2015). Lac ic acid Lac ic acid is widely used in ood indus y in yoghu and cheese p oduc ion, cosme ic indus y in skin ca e p oduc s, and o al hygiene p oduc s (Ma inez e al. 2013). One o he mos impo an uses o lac ic acid is he man- u ac u ing o polylac ic acid which has applica ions in he ex ile indus y and ood packaging u ensils (Saue e al. 2008; Bozell and Pe e sen 2010; Ma inez e al. 2013). Lac ic acid is mos ly p oduced by e men a ion wi h lac ic acid bac e ia (Saue e al. 2008); howe e , he exploi a ion o Rhizopus o yzae has shown p omising ou comes by p oducing highe i e s o lac ic acid o 280 g/ L as anhyd ous calcium lac a e wi h 0.92 g/g p oduc i i y o glucose inpu unde ed-ba ch cul u es (Yamane and Tanaka 2013). Xylose, a pen ose suga de i ed om lig- nocellulosic biomass hyd olysis, can also be u ilized as an inpu ca bon sou ce o lac ic acid biosyn hesis. Xylose e men a ion is ca ied ou by employing ecombinan yeas s ains (Saue e al. 2010) and R. o yzae, g own in mine al medium (Magnuson and Lasu e 2004; Maas e al. 2006) (Table 25). The ex acellula elease o amylases by ungi is an added ad an age o he e men a ion p ocess in hyd olyzing s a ch om a ious inpu sou ces, especially by he species o Rhizopus (Ma inez e al. 2013). Fig. 53 Schema ic ep esen a ion o gene al o ganic acid p oduc ion p ocedu e using ungi Fungal Di e si y (2019) 97:1–136 97 123 Succinic acid Succinic acid ac s as a building block componen o he syn hesis o aluable chemicals, such as 1,4-bu anediol, e ahyd o u an, γ-bu y olac one, N-me hylpy olidone, and e en in he syn hesis o bio-based polyme s such as polybu ylene succina e and polyes e polyols, which may e en ually eplace con en ional pe ol-de i ed polyme s in he u u e (Choi e al. 2015). An imp o ed e men a ion p ocess o Rhizopus species was pa en ed by DuPon o inc ease he TCA cycle based ca boxylic acid p oduc ion by limi ing he dissol ed oxygen le els in e men e s be ween 30 and 80%. Du ing his e men a ion p ocess uma ic acid, succinic acid and L-malic acid a e p oduced (Ling and Ng 1989). In a ecen s udy 209.7 g/L succinic acid i e was ob ained unde ed ba ch e men a ion con- di ions using Ya owia lipoly ica ed wi h c ude glyce ol as he ca bon sou ce (Li e al. 2018). Comme cial scale p oduc ion o o ganic acids is highly dependen on s ain pe o mance. Since mos o he wild ype s ains do no p oduce comme cially accep - able yields, e men a ion condi ions need o be modi ied acco ding o he equi emen and s ain (Xu e al. 2012). To mee indus ial scale equi emen s, he wild ype s ains a e being gene ically modi ied o subjec ed o classical mu a- genesis wi h he goal o inc ease p oduc ion. Recen ly, i was epo ed ha he dele ion o he mi ochond ial uma ase gene and in oduc ion o succina e/ uma a e anspo e inc eased uma ic acid p oduc ion in Saccha- omyces ce e isiae (Yin e al. 2015). A high yielding uma ic acid p oducing Rhizopus o yzae RUR709 s ain was de eloped by UV and γ- ay mu agenesis and inally p oduced 32.1 g/L uma ic acid—a concen a ion 1.9- old highe han he wild ype s ain (Huang e al. 2010). Glu- cose oxidase de icien mu an s o Aspe gillus ca bona ius ha e shown inc eased ci ic acid p oduc ion by educing by-p oduc (gluconic acid) o ma ion h ough an inc ease o he ca bon lux owa ds he educ i e ica boxylic acid pa hway (Yang e al. 2014b). These me abolic enginee ing echniques ha e led o he indus ial scale p oduc ion o na u al p oduc s by modi y- ing na u al biosyn he ic pa hways o inc ease p oduc i i y o syn hesize no el de i a i es o mee he global demand o o ganic acids. 50. Tex ile dyes Fungi a e impo an as na u al dye p oduce s in ex ile indus ies (Mapa i e al. 2010; Chadni e al. 2017). The ex ile indus y is he la ges consume o o ganic pigmen s and syn he ic dyes (Mapa i e al. 2010). Tons o dyes a e los as e luen s and can esul in en i onmen al pollu ion and se ious human heal h p oblems, especially i hei elease is no p ope ly ea ed. Colou as ness o washing and c ocking a e essen ial quali ies o any dye/ ab ic combina ion. Fungal species ha a e used in ex ile dyeing a e lis ed in Table 26. He na ´ndez e al. (2018a) epo ed ha wood o ing ungi can be used in ex ile dyeing. Sucia mih (2002) s udied he e ec o colou ing pH and mo dan on ungal dyes quali y using woolen ya n (Fig. 54). In hei s udy, h ee isola es o Aspe gillus, h ee isola es o Penicillium, wo isola es o Paecilomyces, one isola e o Monascus pu pu eus and one isola e o T ichode ma ha zianum we e used wi h wo di e en mo dan s (alum and FeSO 4 )by h ee di e en dying pH (3, 6, and 9). The esul s indica ed ha low pH alue exhibi ed a s ong colou as well as he mo dan FeSO 4 p oduced almos da ke colou . When used in manu ac u ed p oduc s, conce ns ela ed o he p esence o oxic me aboli es in pigmen s and dyes p oduced by ungi a e commonly aised. In his ega d, he co ec iden i ica ion o ungal s ains and he implemen- a ion o oxici y es s a e key ac o s o ensu e a sa e en i onmen o wo ke s and ha mless p oduc s o end use s (He na ´ndez e al. 2018a). Rega ding he b oad spec um o he ungal pigmen s, ungi including edible and non-edible mush ooms a e a esou ce o na u al dyes. The u u e Func ional genomics and he sea ch o no el an i-in ec i es Func ional genomics is he app oach used o s udy unc- ions and in e ac ions o genes and hei p oduc s in a speci ic con ex (Liu e al. 2010a; Buza and McCa hy 2013). This equi es sequencing o he en i e genome. Sequencing echniques ha e come a long way, since he elease o he i s whole ungal genome o Saccha omyces ce e isiae (Go eau e al. 1996). Today he combining o newly a ising echniques like PacBio wi h Illumina o p o ide ully closed genomes has led o nume ous ungal genome da abases, such as he ungal genome ini ia i e (Haas e al. 2011), comp ising o e 100 ungal genomes, o FungiDB (S ajich e al. 2012) and Ensembl Fungi (Ke sey e al. 2010) wi h o e 1000 ungal genomes. Ou o many examples ha a ge a ious p oduc ca ego ies, we will he e only gi e some examples on wha is easible now o he seconda y me aboli e biosyn hesis due o he employ- men o —OMICS and bioin o ma ics ools and syn he ic bio echnology. The genomes o he Fungi con ain many genes and gene clus e s ha encode o po en ially bene icial p oduc s, including indus ially impo an enzymes as well as sec- onda y me aboli es. Also he bioin o ma ics ools o he 98 Fungal Di e si y (2019) 97:1–136 123 Table 26 Examples o pigmen s p oduced by ungi Fungal p oduce Pigmen name/colou Applica ion Re e ences Ac os alagmus sp. B own and eddish b own A alla e al. (2011) Aga icus xan hode mus Yellow Hanson (2008) Al e na ia al e na a Dyeing o wool and silk Sha ma e al. (2012) B own and eddish b own A alla e al. (2011) Amani a musca ia Be ains(O ange- ed Li and Obe lies (2005) Aspe gillus nige B own and eddish b own A alla e al. (2011) Aspe gillus sp. Yellow Dyeing o co on, silk and silk co on Anchana de i (2014), Kuma e al. (2017), Sa ka e al. (2017) Bole ales (Gomphidiaceae and Suillaceae) Yellow pul inic acid de i a i es Knigh and Pa enden (1976) Bispo omyces sp. B own and eddish b own A alla e al. (2011) Chlo ocibo ia ae uginosa Xylindein/G een Colou as dyeing o co on, polyamide, polyes e and wool Webe e al. (2014), Hinsch and Robinson (2016) Co ina ius cinnaba inus (Eu opean oads ool) Fallacinol/ Da k o ange Gill (1994) Co ina ius iolaceus S iking deep iole colou Von Nussbaum e al. (1998) Co ina ius sp. Dime ic an h aquinone de i a i e/ B igh yellow Velis ˇek and Cejpek (2011) Cunninghamella sp. B own and eddish b own A alla e al. (2011) Cu ula ia luna a Dyeing o wool and silk Sha ma e al. (2012) De mocybe sanguinea An h aquinone compounds as aglycones Hynninen e al. (2000), Ra ¨isa ¨nen e al. (2000) De mocybe sp. Dime ic an h aquinone de i a i e/ B igh yellow Velis ˇek and Cejpek (2011) Fusa ium oxyspo um An h aquinone/Pu ple Dyeing o wool Nagia and El-Mohamedy (2007), He na ´ndez e al. (2018a) Gymnopilus sp. Yellow-b own s y ylpy one pigmen s bis-no yangonin and hispidin Gill (1994) Hymenochae aceae (Inono us,Onnia and Phellinus) Yellow pigmen hispolon Lee and Yun (2006) Hypholoma sp. Yellow-b own s y ylpy one pigmen s bis-no yangonin and hispidin Gill (1994) Hyg ocybe sp. (wi chs’ ha ) Musca la in/yellow Li and Obe lies (2005) Penicillium ch ysogenum B own and eddish b own A alla e al. (2011) Penicillium i alicum B own and eddish b own A alla e al. (2011) Penicillium miniolu eum Dyeing o web blue goa nappa skin Gup a and Agga wal (2016) Penicillium mu cianum Yellow Dyeing o wool He na ´ndez e al. (2018a,b) Penicillium oxalicum B own and eddish b own A alla e al. (2011) Penicillium egulosum B own and eddish b own A alla e al. (2011) Penicillium sp. Dyeing o co on and silk Sa ka e al. (2017) Pholio a sp. Yellow-b own s y ylpy one pigmen s bis-no yangonin and hispidin Gill (1994) Phyma o ichum sp. B own and eddish b own A alla e al. (2011) es ed Scy alidium cuboideum D aconin ed Colou as dyeing o co on, polyamide, polyes e and wool Colou as en Webe e al. (2014), Hinsch and Robinson (2016) Scy alidium ganode moph ho um Yellow Colou as dyeing o co on, polyamide, polyes e and wool Webe e al. (2014), Hinsch and Robinson (2016) Fungal Di e si y (2019) 97:1–136 99 123 anno a ion o genomes ha e signi ican ly imp o ed and oday, nex o he long es ablished an iSMASH (Blin e al. 2017), ungi-speci ic algo i hms o iden i ying biosyn- he ic gene clus e s, like he FunGeneClus e S (Ves h e al. 2016) exis . These ools ha e enabled esea che s o he e ologously exp ess such gene clus e s in well-known hos s, such as Aspe gillus nige (Boecke e al. 2018). This s a egy can be used no only o acili a e an easie p o- duc ion o a known me aboli e a indus ial scale, bu also o exp ess p e iously silen gene clus e s, which we e ound while analysing he genome—a echnique o en e e ed o as ‘genome mining’, o e ing a whole new sou ce o he disco e y o no el an i-in ec i es. He e ol- ogous exp ession o speci ic gene clus e s in a di e en hos now also allows o he elucida ion o biosyn heses o known an ibio ics/na u al p oduc s. One o he i s ungal biosyn hesis s udied in such manne , was his o he myco oxin icho hecene (Tokai e al. 2007). O e he Fig. 54 aColou a ia ion on woolen ya n dyed wi h Pu pu eocillium lilacinum dye wi h di e en mo dan s and dyeing pH. bColou a ia ion on woolen ya n dyed wi h Penicillium sp. dye wi h di e en mo dan s and dyeing pH (Fe =FeSO 4 ·7H 2 O, A =alum and K =pH con ol) (cou esy o Sucia mih) Table 26 con inued Fungal p oduce Pigmen name/colou Applica ion Re e ences Suillus g e illei Con ains a leas 11 yellow, o ange and ed pigmen s Besl and B esinsky (1997) Tala omyces aus alis Red Dyeing o wool He na ´ndez e al. (2018a,b) Tala omyces sp. O ange Mo ales-Oye ides e al. (2017), He na ´ndez e al. (2018a) Tala omyces e uculosus Red Adequa e colou one o co on ab ic wi hou any cy o oxic e ec Chadni e al. (2017) The momyces sp. Yellow Dyeing o silk (Poo niammal e al. 2013) T ichode ma spi ale Yellow He na ´ndez e al. (2018a) T ichode ma i ens Dyeing o wool and silk and ha e an i ungal p ope ies Sha ma e al. (2012) T ichode ma sp. Dyeing o co on, silk and silk co on Anchana de i (2014) T icholoma sp. Dime ic an h aquinone de i a i e/ B igh yellow Velis ˇek and Cejpek (2011) Xyla ia polymo pha Blackish b own Kuma e al. (2017) 100 Fungal Di e si y (2019) 97:1–136 123 yea s, many o he s udies on Ascomyco a ha e ollowed, bu as o ecen ly e en he Basidiomyco a ha e been a - ge ed o elucida ion o he biosyn hesis o hei seconda y me aboli es (Lin e al. 2019). Mos ecen ly, he biosyn- hesis o he an i ungal s obilu ins (see en y on an imy- co ics and ungicides), has been elucida ed, h ough exp ession in Aspe gillus o yzae (No iani e al. 2018). In he u u e, modi ying he biosyn hesis o a ungal me aboli e in o de o enhance i s p oduc ion a comme cial scale o o achie e adjus ed, be e bioa ailable d ugs, may well become he no m. S udies on he egula ion o sec- onda y me aboli e biosyn hesis (B akhage and Sch oeckh 2010) ha e also been de eloped in model o ganisms and a e now a ailable o b oad applica ions ac oss he ungal kingdom. This may soon lead o he disco e y o o ally no el classes o me aboli es, using genome mining, which was al eady demons a ed o enzymes (e.g. Dilokpimol e al. 2018). Figu e 55 illus a es he p oduc ion and iso- la ion p ocedu e o a bioac i e me aboli e om a basidi- myce e cul u e, which was ob ained in e y high yields in a ela i ely sho ime, owing o he ac ha mode n bio- p ocess echnology and me hods o sys ems biology we e employed. Acknowledgemen s This wo k was suppo ed by he S a egic P i- o i y Resea ch P og am o he Chinese Academy o Sciences, G an No. XDB31000000. Na i sada Thongklang would like o hank Thailand esea ch und g an s “S udy o sap obic Aga icales in Thailand o ind new indus ial mush oom p oduc s” (G an No. DBG6180015) and Mae Fah Luang Uni e si y g an “Op imal condi ions o domes ica ion and biological ac i i ies o selec ed species o Ganode ma” (G an No. 621C1535). K.D. Hyde and Na i sada Thongklang would like o hanks o Thailand esea ch und g an s “Domes ica ion and bioac i e e alua ion o Thai Hymenopel- lis,Oudemansiella,Xe ula and Vol a iella species (basidiomyce es)” (G an No. DBG6180033). K.D. Hyde hanks he inancial suppo om he Visi ing P o esso g an a Chiang Mai Uni e si y, Thailand and KIB. The au ho s acknowledge he con ibu ion o M.M. Vas- an hakuma i, K.M. Manasa and P. Rajani, in a ious s ages o p epa a ion o he manusc ip . Saman ha C. Ka una a hna hanks CAS P esiden ’s In e na ional Fellowship Ini ia i e (PIFI) o unding his pos doc o al esea ch (Numbe 2018PC0006), and he Na ional Sci- ence Founda ion. Associa e P o esso R Jeewon hanks Uni e si y o Mau i ius o suppo . Binu C. Sama akoon o e s he since e g a i- ude o he “Na ional Resea ch Council o Thailand” (NRCT G an No. 256108A3070006) o he inancial suppo . Pe e E Mo ime would like o hank he Na ional Science Founda ion o China and he Chinese Academy o Sciences o inancial suppo unde he ol- lowing G an s: 41761144055, 41771063, Y4ZK111B01. M. Doilom would like o hank Chiang Mai Uni e si y, he 5 h ba ch o Pos - doc o al O ien a ion T aining Pe sonnel in Yunnan P o ince and he 64 h ba ch o China Pos doc o al Science Founda ion. T.S. Su ya- na ayanan hanks he Uni ed S a es-India Educa ional Founda ion (USIEF), New Delhi and he Fulb igh Schola P og am (USA) o he awa d o a Fulb igh -Neh u Senio Resea che g an o conduc esea ch in he Depa men o Chemis y and Biochemis y, The Ohio S a e Uni e si y, USA. Thanks o Resea ch and Resea che s o Indus ies G an (PHD57I0015) o inancial suppo o Boon iya Chuankid. Bi he Sanda go is g a e ul o he Deu sche Fo schungs- gemeinscha (DFG) o a PhD g an . Cla a Chepki ui is indeb ed o a PhD s ipend om he Ge man Academic Exchange Se ice (DAAD) and he Kenya Na ional Council o Science and Technology (NACOSTI). Ke in D Hyde would also like o hank he Na ional Resea ch Council o Thailand g an s Thailands’ Fungal Di e si y, Sol ing P oblems and C ea ing Bio echnological P oduc s (G an No. 61201321016). This wo k is pa ly suppo ed by he Depa men o Fig. 55 S ages o he p oduc ion and isola on o a biologically ac i e me aboli e om he cul u es o a basidiomyce e (Omphalo us nidi o mis).aSubme ged cul i a ion in shake lasks. bS i ed ank e men a ion in a pa allel 1.5 L Bio eac o sys ems. C. Bench-Scale 10 L s i ed ank. D. Column ch oma og aphy o ac iona ion and compound eco e y using he polyme ic adso ben XAD. E. Elu ed ac ions om compound pu i ica ion. F. C ys als o pu e compound. Images by Te esa B iem and Lillibe h Cha e a-Mun ˜oz, HZI, B aunschweig, Ge many Fungal Di e si y (2019) 97:1–136 101 123 Bio echnology, Go e nmen o India, New Delhi (Chemical Ecology o he No h Eas Region (NER) o India: A collabo a i e p og amme Linking NER and Bangalo e Resea che s; DBT-NER/Ag i/24/2013) and Indian Council o Ag icul u al Resea ch (ICAR-CAAST-P ojec F.No./NAHEP/CAAST/2018-19), Go e nmen o India, New Delhi. Open Access This a icle is dis ibu ed unde he e ms o he C ea i e Commons A ibu ion 4.0 In e na ional License (h p://c ea i ecommons.o g/licenses/by/4.0/), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons license, and indica e i changes we e made. Re e ences Abdel-Fa ah GM, Ib ahim AH, Al-Am i SM, Shoke AE (2013) Syne gis ic e ec o a buscula myco hizal ungi and spe mine on amelio a ion o salini y s ess o whea (“‘T i icum aes i um L.” c . 9). Aus J C op Sci 7:1525 Abdelaziz ME, Kim D, Ali S, Fedo o NV, Al-Babili S (2017) The endophy ic ungus Pi i o mospo a indica enhances A abidopsis haliana g ow h and modula es Na ? /K ? homeos asis unde sal s ess condi ions. Plan Sci 263:107–115 Abe M, Takaoka N, Idemo o Y, Takagi C e al (2008) Cha ac e is ic ungi obse ed in he e men a ion p ocess o Pue ea. In J Food Mic obiol 124:199–203 Ab aham WR, Es ela AB (2016) Fungal me aboli es o he con ol o bio ilm in ec ions. Ag icul u e 6:37 Adams SJ, Manoha a T, K ishnamu hy K, Kuma TS (2014) His ochemical s udies on ungal-induced aga wood. Indian J Plan Sci 5:102–110 Adekunle AE, Guo C, Liu CZ (2016) Lignin-enhanced laccase p oduc ion om T ame es e sicolo . Was e Biomass Valo i 8:1061–1066 Ad io JL, Demain AL (2003) Fungal bio echnology. In Mic obiol 6:191–199 Aggangan NS, Pollisco MA, B uzon JB, Gilbe o JS (2013) G ow h o Sho ea con o a Vid. inocula ed wi h eucalyp us ec omyco hiza ungi in he nu se y and in a logged-o e dip e oca p o es in Su igao, Philippines. Am J Plan Sci 4:896–904 Ag awal N, Ve ma P, Shahi SK (2018) Deg ada ion o polycyclic a oma ic hyd oca bons (phenan h ene and py ene) by he ligninoly ic ungi Ganode ma lucidum isola ed om he ha d- wood s ump. Bio esou Biop ocess 5:11 Ahmed ME, Rahman A (2014) De ec ion o he pe ec condi ion o p oduce he annase om Aspe gillus nige a di e en medium. J Babylon Uni Pu e Appl Sci 22:1363–1371 Aka in MY (2013) Cha ac e iza ion o a β-glucosidase om an edible mush oom, Lycope don py i o me. In J Food P op 16:1565– 1577 Akihisa T, Uchiyama E, Kikuchi T, Tokuda H e al (2009) An i- umo -p omo ing e ec s o 25-me hoxypo icoic acid A and o he i e pene acids om Po ia cocos. J Na P od 72:1786–1792 Akiyama K, Ma suzaki K, Hayashi H (2005) Plan sesqui e penes induce hyphal b anching in a buscula myco hizal ungi. Na u e 435:824–827 Akoh CC, Chang SW, Lee GC, Shaw JF (2008) Bioca alysis o he p oduc ion o indus ial p oduc s and unc ional oods om ice. J Ag ic Food Chem 56:10445–10451 Al-Hawash AB, Alkoo anee JT, Abbood HA, Zhang J e al (2018) Isola ion and cha ac e iza ion o wo c ude oil-deg ading ungi s ains om Rumaila oil ield, I aq. Bio echnol Rep 17:104–109 Al-Hazmi AS, Schmi DP, Sasse JN (1982) The e ec o A h obo ys conoides on Meloidogyne incogni a popula ion densi ies in co n as in luenced by empe a u e, ungus inoculum densi y, and ime o ungus in oduc ion in he soil. J Nema ol 14:168 Alananbeh KM, Bouqellah NA, Al Ka NS (2014) Cul i a ion o oys e mush oom Pleu o us os ea us on da e-palm lea es mixed wi h o he ag o-was es in Saudi A abia. Saudi J Biol Sci 21:616– 625 Alapi EM, Fische J (2006) Table o selec ed analogue classes. In: Fische J, Ganellin CR (eds) Analogue-based d ug disco e y. Wiley-VCH, Weinheim, pp 441–552 Albe mann S, El e T, Teubne A, K ischke W, Hi h T, Tudzynski B (2013) Cha ac e iza ion o no el mu an s wi h an al e ed gibbe ellin spec um in compa ison o di e en wild- ype s ains o Fusa ium ujiku oi. Appl Mic obiol Bio echnol 97(17):7779– 7790 Albe s AW, Chen J, Ku on G, Hun V e al (1980) Me inolin: a highly po en compe i i e inhibi o o hyd oxyme hylglu a yl- coenzyme A educ ase and a choles e ol-lowe ing agen . P oc Na l Acad Sci USA 77:3957–3961 Alexand e J, Raymond E, Kaci MO, B ain EC e al (2004) Phase I and pha macokine ic s udy o i o ul en adminis e ed weekly o biweekly in ad anced solid umo pa ien s. Clin Cance Res 10:3377–3385 Alexopoulos CJ, Mims CW, Blackwell M (1996) In oduc o y mycology, 4 h edn. Wiley, New Yo k Ali MR, Hoque MS, Ahmed KU, Rahman MH (2010) E ec o whea b an supplemen s wi h suga cane bagasse on he yield and p oxima e composi ion o Pleu o us os ea us. Bangladesh J Mush oom 4:21–26 Allison AC, Eugui EM (2000) Mycophenola e mo e il and i s mechanisms o ac ion. Immunopha macology 47:85–118 Almeida JR, Be ilsson M, Go wa-G auslund MF, Go sich S, Lide ´nG (2009) Me abolic e ec s o u aldehydes and impac s on bio echnological p ocesses. Appl Mic obiol Bio echnol 82:625–638 Alpha CJ, Campos M, Jacobs-Wagne C, S obel SA (2015) Myco umiga ion by he ola ile o ganic compound-p oducing ungus Muscodo albus induces bac e ial cell dea h h ough DNA damage. Appl En i on Mic obiol 81:1147–1156 Al es MJ, Fe ei a IC, Dias JF, Teixei a V, Ma ins A, Pin ado M (2012a) A e iew on an imic obial ac i i y o mush oom (Basidiomyce es) ex ac s and isola ed compounds. Plan a Med 78:1707–1718 Al es MJ, Fe ei a IC, Ma ins A, Pin ado M (2012b) An imic obial ac i i y o wild mush oom ex ac s agains clinical isola es esis an o di e en an ibio ics. J Appl Mic obiol 113:466–475 Amba i RR, Phang SM, Ra i S, Aswa hana ayana RG (2014) As axan hin: sou ces, ex ac ion, s abili y, biological ac i i ies and i s comme cial applica ions—a e iew. Ma D ugs 12:128– 152 Ananbeh KM, Almomany AR (2005) P oduc ion o oys e mush oom Pleu o us os ea us on oli e cake ag o was e. Di asa Ag ic Sci 32:64–70 Ananbeh KM, Almomany AR (2008) P oduc ion o Oys e mush oom (Pleu o us os ea us) on oma o u ag o–was e. Di asa Ag ic Sci 35:133–138 Anchana De i A (2014) Ex ac ion o na u al dyes om ungus—an al e na e o ex ile dyeing. J Na Sci Res 4:1–7 Ande son PK, Cunningham AA, Pa el NG, Mo ales FJ e al (2004) Eme ging in ec ious diseases o plan s: pa hogen pollu ion, clima e change and ag o echnology d i e s. T ends Ecol E ol 19:535–544 102 Fungal Di e si y (2019) 97:1–136 123 And ady AL (2015) Pe sis ence o plas ic li e in he oceans. In: Be gmann M, Gu ow L, Klages M (eds) Ma ine an h opogenic li e . Sp inge , Cham, pp 57–72 Ani ha TS, Palani elu P (2013) Pu i ica ion and cha ac e iza ion o an ex acellula ke a inoly ic p o ease om a new isola e o Aspe gillus pa asi icus. P o ein Exp Pu i 88:214–220 Anke H, S adle M, Maye A, S e ne O (1995) Seconda y me aboli es wi h nema icidal and an imic obial ac i i y om nema ophaous ungi and Ascomyce es. Can J Bo 73:932–939 Ao T, Deb CR, Kh uomo N (2016) Wild edible mush ooms o Nagaland, India: a po en ial ood esou ce. J Exp Biol Ag ic Sci 4:59–65 Apos olidis C, McLeay F (2016) I ’s no ege a ian, i ’s mea - ee! Mea ea e s, mea educe s and ege a ians and he case o Quo n in he UK. Soc Bus 6:267–290 A i Y, Che e D, Hen issa B, Be in JG e al (2013) Cha ac e - iza ion o sal -adap ed sec e ed lignocelluloly ic enzymes om he mang o e ungus Pes alo iopsis sp. Na Commun 4:1810 A isoy M (1998) Biodeg ada ion o chlo ina ed o ganic compounds by whi e- o ungi. Bull En i on Con am Toxicol 60:872–876 A iyawansa HA, Hyde KD, Jayasi i SC, Buyck B e al (2015) Fungal di e si y no es 111–252 axonomic and phylogene ic con ibu- ions o ungal axa. Fungal Di e s 75:1–248 A ms ong DW, B own LA (1994) Alipha ic, a oma ic, and lac one compounds. Biop ocess p oduc ion o la o , ag ance, and colo ing edien s. Wiley, Hoboken, pp 41–94 A o a DK (2003) Handbook o ungal bio echnology, 2nd edn. Ma cel Dekke Inc., New Yo k, p 573 A o a DS, Chande M, Gill PK (2002) In ol emen o lignin pe oxidase manganese pe oxidase and laccase in deg ada ion and selec i e ligninolysis o whea s aw. In Biode e Biodeg 15:115–120 Ash a i S, Helaly S, Sch oe s HJ, S adle M e al (2017a) Ijuhya i ellina sp. no ., a no el sou ce o chae oglobosin A, is a des uc i e pa asi e o he ce eal cys nema ode He e ode a ilipje i. PLoS ONE 12:e0180032 Ash a i S, S adle M, Dababa AA, Riche - Poeggele KR e al (2017b) Monocillium gamsii sp. no . and Monocillium bulbil- losum: wo nema ode-associa ed ungi pa asi ising he eggs o He e ode a ilipje i. MycoKeys 27:21 Ash a i S, Knapp DG, Blaudez D, Chalo M e al (2018) Inhabi ing plan oo s, nema odes, and u les—Polyphilus, a new helo- ialean genus wi h wo globally dis ibu ed species. Mycologia 110:286–299 Asmelash F, Bekele T, Bi hane E (2016) The po en ial ole o a buscula myco hizal ungi in he es o a ion o deg aded lands. F on Mic obiol 7:1095 As u i M, Meliala A, Dalais FS, Wahlq is ML (2000) Tempe, a nu i ious and heal hy ood om Indonesia. Asia Pac J Clin Nu 9:322–325 A alla MM, El-kh isy EAM, Yousse YA, Mohamed AA (2011) P oduc ion o ex ile eddish b own dyes by ungi. Mal J Mic ob 7:33–40 A kinson CJ, Fi zge ald JD, Hipps NA (2010) Po en ial mechanisms o achie ing ag icul u al bene i s om biocha applica ion o empe a e soils: a e iew. Plan Soil 337:1–18 A las R, B agg J (2009) Bio emedia ion o ma ine oil spills: when and when no — he Exxon Valdez expe ience. Mic ob Bio echnol 2:213–221 A mosuka o I, Cas illo U, Hess WM, Sea s J, S obel G (2005) Isola ion and cha ac e iza ion o Muscodo albus I-41.3 s, a ola ile an ibio ic p oducing ungus. Plan Sci 169:854–861 Auld BA (1993) Vege able oil suspension emulsions educe dew dependence o a mycohe bicide. C op P o 12:477–479 Auld BA (1997) Biohe bicides in biological con ol o weeds. Theo y and p ac ical applica ion. Aus alian Cen e o In e na ional Ag icul u al Resea ch, Canbe a, pp 129–134 Aus SD, Swane PR, S ahl JD (2003) De oxi ica ion and me abolism o chemicals by whi e- o ungi. In: Zhu JJPC, Asu SD, Lemley- Gan AT (eds) Pes icide decon amian ion and de oxi ica ion. Ox o d Uni e si y P ess, Washing on, DC, pp 3–14 Ayob FW, Sima ani K, Zainal Abidin N, Mohamad J (2017) Fi s epo on a no el Nig ospo a sphae ica isola ed om Ca ha- an hus oseus plan wi h an ica cinogenic p ope ies. Mic ob Bio echnol 10:926–932 Az en PD, Lee SY, Emang D, Mohamed R (2019) His o y and pe spec i es o induc ion echnology o aga wood p oduc ion om cul i a ed Aquila ia in Asia: a e iew. J Fo Res 30:1–11 Babel FJ (1953) The ole o ungi in cheese ipening. Econ Bo 7:27– 42 Babu PD, Bhakya aj R, Vidhyalakshmi R (2009) A low cos nu i ious ood “ empeh”—a e iew. Wo ld J Dai y Food Sci 4:22–27 Backman PA, Siko a RA (2008) Endophy es: an eme ging ool o biological con ol. Biol Con ol 46:1–3 Badalyan SM, Ba khuda yan A, Rapio S (2019) Recen p og ess in esea ch on he pha macological po en ial o mush ooms and p ospec s o hei clinical applica ion. In: Ag awal DC, Dhanseka an M (eds) Medicinal mush ooms: ecen p og ess in esea ch and de elopmen . Publishe Sp inge Na u e Singapo e, pp 1–70. h ps://doi.o g/10.1007/978-981-13-6382-5_1 Bagchi D, Ghosh D, Konishi T (2014) Clinical aspec s o unc ional oods and nu aceu icals, 1s edn. CRC P ess, Boca Ra on, pp 51–76 Bagga J, P amanik SK, Pandey V (2015) P oduc ion and pu i ica ion o annase om Aspe gillus aculea us using plan de i ed aw annin. In J Sci Eng Technol 4:50–55 Bai R, Zhang CC, Yin X, Wei J, Gao JM (2015) S ia oids A-F, cya hane di e penoids wi h neu o ophic ac i i y om cul u es o he ungus Cya hus s ia us. J Na P od 78:783–788 Bailey KL, Boye chko SM, Langle T (2010) Social and economic d i e s shaping he u u e o biological con ol: a Canadian pe spec i e on he ac o s a ec ing he de elopmen and use o mic obial biopes icides. Biol Con ol 52:221–229 Bailey KL, Pi WM, Falk S, De by J (2011) The e ec s o Phoma mac os oma on non- a ge plan and a ge weed species. Biol Con ol 58:379–386 Bailey KL, Falk S, De by JA e al (2013) The e ec o e ilize s on he e icacy o he biohe bicide, Phoma mac os oma, o con ol dandelions in u g ass. Biol Con ol 65:147–151 Bailey AM, Albe i F, Kila u S, Collins CM e al (2016) Iden i ica ion and manipula ion o he pleu omu ilin gene clus e om Cli opilus passecke ianus o inc eased apid an ibio ic p oduc- ion. Sci Rep 6:25202 Bajaj R, Huang Y, Geb ech is os S, Mikolajczyk B e al (2018) T ansc ip ional esponses o soybean oo s o coloniza ion wi h he oo endophy ic ungus Pi i o mospo a indica e eals al e ed phenylp opanoid and seconda y me abolism. Sci Rep 8(1):10227 Bakshi M, She ame i I, Meichsne D, Thu ¨ ich J e al (2017) Pi i o mospo a indica ep og ams gene exp ession in A abidop- sis phospha e me abolism mu an s bu does no compensa e o phospha e limi a ion. F on Mic obiol 8:1262 Bal C (2018) Bene i s and uses o mush oom. J Bac e iol Mycol 6:155–156 Balak DMW (2015) Fuma ic acid es e s in he managemen o pso iasis. Pso iasis 5:9–23 Balak ishnan B, Ka ki S, Chiu SH, Kim HJ e al (2013) Gene ic localiza ion and in i o cha ac e iza ion o a Monascus azaphilone pigmen biosyn he ic gene clus e . Appl Mic obiol Bio echnol 97:6337–6345 Fungal Di e si y (2019) 97:1–136 103 123 Bald ian P (2003) In e ac ions o hea y me als wi h whi e- o ungi. Enzyme Mic ob 32(1):78–91 Banda a AR, Rapio S, Bha DJ, Kakumyan P e al (2015) Polypo us umbella us, an edible–medicinal cul i a ed mush oom wi h mul iple de eloped heal h-ca e p oduc s as ood, medicine and cosme ics: a e iew. C yp ogamie Mycol 36(1):3–42 Banda a AR, Ka una a hna SC, Mo ime PE, Hyde KD e al (2017) Fi s success ul domes ica ion and de e mina ion o nu i ional and an ioxidan p ope ies o he ed ea mush oom Au icula ia hailandica (Au icula iales, Basidiomyco a). Mycol P og 16(11– 12):1029–1039 Bane jee A, Cha e jee K, Mad as G (2014) Enzyma ic deg ada ion o polyme s: a b ie e iew. J Ma e Sci Technol 30:567–573 Banik SP, Khowala S, Pal C, Mukhe jee S (2015) P o eomic app oaches o iden i y no el he apeu ics and nu aceu icals om ilamen ous ungi. In: Bagchi D, Swa oop A, Bagchi M (eds) Genomics, p o eomics and me abolomics in nu aceu icals and unc ional oods, 2nd edn. Wiley, New Yo k, pp 265–295 Bano A, Hussain J, Akba A, Mehmood K e al (2018) Bioso p ion o hea y me als by obliga e halophilic ungi. Chemosphe e 199:218–222 Banu AR, De i MK, Gnanap abhal GR, P adeep BV e al (2010) P oduc ion and cha ac e iza ion o pec inase enzyme om Penicillium ch ysogenum. Indian J Sci Technol 3:377–381 Ba al HO, Webe E, Gams W, Hagedo n G, Liu B, Liu X, Ma son G, Ma ano a ´L, S adle M, Weiß M (2018) Recommenda ions abou gene ic names o be p o ec ed o supp essed in he O biliaceae (O biliomyce es). Mycol P og 17:5–31 Ba oni TJ (2017) Mush ooms o he No heas e n Uni ed S a es and Eas e n Canada. Timbe P ess, Po land Ba a SR, Ennos AR, G eenhalgh M, Robson GD e al (2003) Fungi a e he p edominan mic o-o ganisms esponsible o deg ada- ion o soil-bu ied polyes e polyu e hane o e a ange o soil wa e holding capaci ies. J Appl Mic obiol 95:78–85 Ba y D, Williams G, Chan C (2015) Au oma ed analysis o ilamen ous mic obial mo phology wi h AnaMo . Bio echnol P og 31:849–852 Bashi KM, Choi JS (2017) Clinical and physiological pe spec i es o β-glucans: he pas , p esen , and u u e. In J Mol Sci 18:1906 Bashyal B, Wellensiek B, Ramak ishnan R, Fae h SH, Ahmad N, Guna ilaka AA (2014) Al e oxins wi h po en an i-HIV ac i i y om Al e na ia enuissima QUE1Se, a ungal endophy e o Que cus emo yi. Bioo g Med Chem 22:6112–6116 Ba eman B, Wa ne JO, Hu chinson E, Dean T e al (2004) The e ec s o a double blind, placebo con olled, a i icial ood colou ings and benzoa e p ese a i e challenge on hype ac i i y in a gene al popula ion sample o p eschool child en. A ch Dis Child 89:506–511 Ba a A, Saxena RK (2005) Po en ial annase p oduce s om he gene a Aspe gillus and Penicillium. P ocess Biochem 40:1553– 1557 Becke J, Lange A, Faba ius J, Wi mann C (2015) Top alue pla o m chemicals: bio-based p oduc ion o o ganic acids. Cu Opin Bio echnol 36:168–175 Bee z AE, G ee L (1999) Mush oom cul i a ion and ma ke ing. ATTRA, Melbou ne Bei J, Chen Z, Fu J, Jiang Z e al (2009) S uc u e-based agmen shu ling o wo ungal phy ases o combina ion o desi able p ope ies. J Bio echnol 139:186–193 Belma es R, Con e as-Esqui el JC, Rod iguez-He e a R, Co onel AR e al (2004) Mic obial p oduc ion o annase: an enzyme wi h po en ial use in ood indus y. Lebensm Wiss Technol 37:857–864 Benjamins R, Sche es B (2008) Auxin: he looping s a in plan de elopmen . Annu Re Plan Biol 59:443–465 Benocci T, Aguila -Pon es MV, Zhou M, Seibo h B, V ies RP (2017) Regula o s o plan biomass deg ada ion in ascomyce ous ungi. Bio echnol Bio uels 10:152 Ben ley R (2000) Mycophenolic acid: a one hund ed yea odyssey om an ibio ic o immunosupp essan . Chem Re 100:380–3826 Be in JG, Na a o D, Cou u ie M, Oli e ´C e al (2012) Explo ing he na u al ungal biodi e si y o opical and empe a e o es s owa d imp o emen o biomass con e sion. Appl En i on Mic obiol 78(18):6483–6490 Besl H, B esinsky A (1997) Chemosys ema ics o Suillaceae and Gomphidiaceae (subo de Suillineae). Plan Sys E ol 206:223– 242 Besse e A, Puech-Pages V, Kie e P, Gomez-Roldan V e al (2006) S igolac ones s imula e a buscula myco hizal ungi by ac i- a ing mi ochond ia. PLoS Biol 4:e226 Beye DM (2003) Basic p ocedu es o Aga icus mush oom g owing. Pennsyl ania S a e Uni e si y, Uni e si y Pa k, pp 1–16 Bezalel L, Hada Y, Fu PP, F eeman JP e al (1996) Ini ialoxida ion p oduc s in he me abolism o py ene, an h acene, luo ene, and dibenzo hiophene by he whi e o ungus Pleu o us os ea us. Appl En i on Mic obiol 62:2554–2559 Bhale ao TS, Pu anik P (2007) Biodeg ada ion o o ganochlo ine pes icide, endosul an, by a ungal soil isola e, Aspe gillus nige . In Biode e io Biodeg ad 59:315–321 Bha MK (2000) Cellulases and ela ed enzymes in bio echnology. Bio echnol Ad 18:355–383 Bhuiyan SA, C o BJ, James RS, Cox MC (2012) Labo a o y and ield e alua ion o ungicides o he managemen o suga cane smu caused by Spo iso ium sci amineum in seedcane. Aus alas Plan Pa hol 41:591–599 Bilal L, Asa S, Hamayun M, Gul H (2018) Plan g ow h p omo ing endophy ic ungi Aspe gillus umiga us TS1 and Fusa ium p oli e a um BRL1 p oduce gibbe ellins and egula es plan endogenous ho mones. Symbiosis 76:117–127 Bilg ami KS, Sinha SP, Jeswal P (1988) Neph o oxic and hepa o oxic e ec s o ci inin in mice (Mus musculus). P oc Na l Acad Sci India B 54(1):35–37 Bills GF, Gloe JB (2016) Biologically ac i e seconda y me aboli es om he Fungi. Mic obiol Spec 4:VE-0001-2014 Bills GF, Ma ı ´n J, Collado J, Pla as G e al (2009) Measu ing he dis ibu ion and di e si y o an ibiosis and seconda y me aboli es in he ilamen ous ungi. SIM News 59:133–147 Bi ch GG, Lindley MG (1985) Alcoholic be e ages. Else ie , London Bish S, Pandey P, Bha ga a B, Sha ma S e al (2015) Bio emedia ion o polya oma ic hyd oca bons (PAHs) using hizosphe e ech- nology. B az J Mic obiol 46:7–21 Bi as V, McCa ney N, Li N, Deme s J (2015) Fusa ium oxyspo um ola iles enhance plan g ow h ia a ec ing auxin anspo and signaling. F on Mic obiol 6:1248 Bi ze J, Henkel T, Niki o o AI, Rihne MO, Hende son KA (2017a) A 90-day o al oxici y s udy o glycolipids om Dac yopinax spa hula ia in Beagle dogs. Food Chem Toxicol 109:544–551 Bi ze J, Henkel T, Niki o o AI, Rihne MO, Leuschne J (2017b) A 90-day o al oxici y s udy o glycolipids om Dac yopinax spa hula ia in CD ® a s. Food Chem Toxicol 109:569–584 Bi ze J, Henkel T, Niki o o AI, Rihne MO, Thomas JA (2017c) Pha macokine ics, exc e ion balance, and issue dis ibu ion o [14C]-labeled glycolipids and long chain a y acids om Dac yopinax spa hula ia in a s. Food Chem Toxicol 109:552– 568 Bi ze J, Henkel T, Niki o o AI, Rihne MO, He be h MT (2018) De elopmen al and ep oduc ion oxici y s udies o glycolipids om Dac yopinax spa hula ia. Food Chem Toxicol 120:430– 438 Biz A, Finkle ATJ, Pi ol LO, Medina BS e al (2016) P oduc ion o pec inases by solid-s a e e men a ion o a mix u e o ci us 104 Fungal Di e si y (2019) 97:1–136 123 was e and suga cane bagasse in a pilo -scale packed-bed bio eac o . Biochem Eng J 111:54–62 Bjawa AA (2014) Sus ainable weed managemen in conse a ion ag icul u e. C op P o 65:105–113 Ble e G, G ieco F, Cozzi G, Log ieco A, Viscon i A (2006) Isola ion o epiphy ic yeas s wi h po en ial o biocon ol o Aspe gillus ca bona ius and A. nige on g ape. In J Food Mic obiol 108:204–209 Blin K, Wol T, Che e e MG, Lu X e al (2017) an iSMASH 40-imp o emen s in chemis y p edic ion and gene clus e bounda y iden i ica ion. Nucl Acids Res 45(W1):W36–W41 Blomq is J (2011) Dekke a b uxellensis—a compe i i e yeas o e hanol p oduc ion om con en ional and non-con en ional subs a es. Doc o al hesis, Facul y o Na u al Resou ces and Ag icul u al Sciences Depa men o Mic obiology. Swedish Uni e si y o Ag icul u al Sciences, Uppsala Bluemke W, Sch ade J (2001) In eg a ed biop ocess o enhanced p oduc ion o na u al la o s and ag ances by Ce a ocys is monili o mis. Biomol Eng 17:137–142 Boa E (2004) Wild edible ungi: a global o e iew o hei use and impo ance o people (non-wood o es p oduc s). Food & Ag icul u e O ganiza ion o he Uni ed Na ions, Rome Bobeck P, Gin e E, Ju co ico a M, Kuniak L (1991) Choles e ol- lowe ing e ec o he mush oom Pleu o us os ea us in he ed- i a y hype choles e olemic a s. Ann Nu Me ab 35:191–195 Boecke S, G a ¨ z S, Ke wa D, Adam L e al (2018) Aspe gillus nige is a supe io exp ession hos o he p oduc ion o bioac i e ungal cyclodepsipep ides. Fungal Biol Bio echnol 5:7 Bonomo L, Sola i E, Scopelli i R, Flo iani C (2001) The π complexa ion o alkali and alkaline ea h ions by he use o m meso-Oc aalkylpo phy inogen and a oma ic hyd oca bons. Chem Eu J 7:1322–1332 Bonugli-San os RC, Du an LR, Sil a M, Se e LD (2010) P oduc- ion o laccase manganese pe oxidase and lignin pe oxidase by B azilian ma ine-de i ed ungi. Enzyme Mic ob Technol 46:32– 37 Boubendi A (1993) Pu i ica ion and biochemical e alua ion o polyu e hane deg ading enzymes o ungal o igin. Diss Abs In 53:4632 Bou dichon F, Casa egola S, Fa okh C, F is ad JC e al (2012) Food e men a ions: mic oo ganisms wi h echnological bene icial use. In J Food Mic obiol 154:87–97 Boye chko SM, Pede sen E, Punja ZK, Reddy MS (1999) Fo mula- ions o biopes icides. In: Hall FR, Ba y JW (eds) Bio pes icides: use and deli e y. Me hods in bio echnology, ol 5. Humana P ess, To owa, pp 487–508 Boye e CD, Temple on GE, Smi h RJ J (1979) Con ol o winged wa e p im ose (Jussiaea decu ens) and No he n join e ch (Aeschynomene i ginica) wi h ungal pa hogens. Weed Sci 27:497–501 Bozell JJ, Pe e sen GR (2010) Technology de elopmen o he p oduc ion o biobased p oduc s om bio e ine y ca bohyd a es- he US Depa men o Ene gy’s “Top10” e isi ed. G een Chem 12:539–554 B akhage AA, Sch oeckh V (2010) Fungal seconda y me aboli es— s a egies o ac i a e silen gene clus e s. Fungal Gene Biol 48:15–22 B ea ley FQ, Sane P, Uchida A, Bu slem DFRP e al (2016) Tes ing he impo ance o a common ec omyco hizal ne wo k o dip e oca p seedling g ow h and su i al in opical o es s o Bo neo. Plan Ecol Di e s 9:563–576 B ennan MA, De byshi e E, Tiwa i BK, B ennan CS (2012) En ichmen o ex uded snack p oduc s wi h cop oduc s om ches nu mush oom (Ag ocybe aege i a) p oduc ion: in e ac ions be ween die a y ibe , physicochemical cha ac e is ics, and glycemic load. J Ag ic Food Chem 60:4396–4401 B iggs RS, A kins E (1966) S udies in c yp ococcal e e . I. Re- sponses o in ac o ganisms and o a soluble agen de i ed om c yp ococci. Yale J Biol Med 38:431–448 B own AC, Valie e A (2004) P obio ics and medical nu i ion he apy. Nu Clin Ca e 7:56 B own AG, Smale TC, King TJ, Hasenkamp R, Thompson RH (1976) C ys al and molecula s uc u e o compac in, a new an i ungal me aboli e om Penicillium b e icompac um. J Chem Soc 11:1165–1170 B own MS, Faus JR, Golds ein JL (1978) Induc ion o 3-hyd oxy-3- me hylglu a yl coenzyme A educ ase ac i i y in human ib ob- las s incuba ed wi h compac in (ML-236B), a compe i i e inhibi o o he educ ase. J Biol Chem 253:1121–1128 B ueckne T, Ebe l A, Heumann S, Rabe M, Guebi z GM (2008) Enzyma ic and chemical hyd olysis o poly(e hylene e eph ha- la e) ab ics. J Polym Sci A 46:6435–6443 B ugge R, Nunes CS, Hug D, Vogel K e al (2004) Cha ac e is ics o ungal phy ases om Aspe gillus umiga us and Sa o ya umiga e. Appl Mic obiol Bio echnol 63:383–389 B um AN, B um AA (2017) Mush oom cul i a ion as an al e na i e o u al de elopmen in sou h B azil. J Nu Food Sci 7:57 B und e MC (2009) Myco hizal associa ions and o he means o nu i ion o ascula plan s: unde s anding he global di e si y o hos plan s by esol ing con lic ing in o ma ion and de eloping eliable means o diagnosis. Plan Soil 320:37–77 B uns TD, Peay KG, Boyn on P, G ubisha LC e al (2009) Inoculum po en ial o Rhizopogon spo es inc eases wi h ime o e he i s 4-y o a 99-y spo e bu ial expe imen . New Phy ol 181:463– 470 Buche VVC, Poin ing SB, Hyde KD, Reddy CA (2004) P oduc ion o wood decay enzymes, loss o mass, and lignin solubiliza ion in wood by di e se opical esh wa e ungi. Mic ob Ecol 48:331–337 Bucknall RA, Moo es H, Simms R, Hesp B (1973) An i i al e ec s o aphidicolin, a new an ibio ic p oduced by Cephalospo ium aphidicola. An imic ob Agen s Chemo he 4:294–298 Budi S, San oso E, Wahyudi A (2010) Iden i ica ion o po en ial ypes o ungi on es ablishmen aga wood s em o Aquila ia spp. Ju nal Sil ikul u T opika 1:1–5 Bunyapaiboons i T, Yoip omma a S, S isanoh U, Choowong W e al (2011) Isa io ins G-J om cul u es o he Lepidop e a pa ho- genic ungus Isa ia enuipes. Phy ochem Le 4:283–286 Busby PE, Ridou M, Newcombe G (2016) Fungal endophy es: modi ie s o plan disease. Plan Mol Biol 90:645–655 Bushley KE, Raja R, Jaiswal P, Cumbie JS e al (2013) The genome o Tolypocladium in la um: e olu ion, o ganiza ion, and exp es- sion o he cyclospo in biosyn he ic gene clus e . PLoS Gene 9: e1003496 Buza T, Mcca hy FM (2013) Func ional genomics: applica ions o p oduc ion ag icul u e. CAB Re 8:1–21 Byle JW, Cobb FW, Pa men e JR (1972) Occu ence and signi - icance o ungi inhabi ing galls caused by Pe ide mium ha k- nessii. Can J Bo 50:1275–1282 CPL Business Consul an s (2010) The 2010 wo ldwide biopes icides ma ke summa y. CAB In e na ional, Walling o d Cai J, Ma H, Huang F, Zhu D, Bi J, Ke Y, Zhang T (2013) Co ela ion o be acizumab-induced hype ension and ou comes o me a- s a ic colo ec al cance pa ien s ea ed wi h be acizumab: a sys ema ic e iew and me a-analysis. Wo ld J Su g Oncol 11:306 Cambell I (1996) Wild yeas in b ewing and dis illing. In: P ies FG, Campbell I (eds) B ewing mic obiology, 2nd edn. Chapman & Hall, London, pp 193–208 Came on DD, Leake JR, Read DJ (2006) Mu ualis ic myco hiza in o chids: e idence om plan – ungus ca bon and ni ogen Fungal Di e si y (2019) 97:1–136 105 123 Gue ini L, Angeloni G, Baldi F, Pa en i A (2017) The mal e ec s o pump-o e s du ing ed wine e men a ion. Appl The m Eng 112:621–626 Guija o B, Melga ejo P, To es R, Lama ca N e al (2007) E ec s o di e en biological o mula ions o Penicillium equen ans on b own o o peaches. Biol Con ol 42:86–96 Guillamo ´n E, Ga cı ´a-La uen e A, Lozano M, Ros agno MA, Villa es A, Ma ı ´nez JA (2010) Edible mush ooms: ole in he p e en ion o ca dio ascula diseases. Fi o e apia 81:715–723 Guo YX, Qin JZ, Chen JZ, Yang YC (2011) S udy on he p oduc ion o Ag icus bispo us seasoning by enzyme me hod. J Shanxi Uni Sci Technol 29:53–57 In Chinese Gup a S, Agga wal S (2016) Dyeing we blue goa nappa skin wi h a mic obial colo an ob ained om Penicillium miniolu eum. J Clean P od 127:585–590 Gup a C, P akash D, Gup a S (2015) Bio echnological app oach o mic obial based pe umes and la o s. J Mic obiol Exp 2:34–41 Gup e A, T ipa hi A, Pa el H, Rudakiya D, Gup e S (2016) Bio emedia ion o polycyclic a oma ic hyd oca bon (PAHs): a pe spec i e. Open Bio echnol J 10:363–378 Gup a S, Summuna B, Gup a M, Annepu SK (2018) Edible mush ooms: cul i a ion, bioac i e molecules, and heal h bene- i s. In: Me ´ illon JM, Ramawa K (eds) Bioac i e molecules in ood. Sp inge , Be lin, pp 1–33 Gu ¨lse C, Peks¸en A (2003) Using ea was e as a new casing ma e ial in mush oom Aga icus bispo us (L.) Sing. cul i a ion. Bio esou Technol 88:153–156 Gu ¨n he M, Zibek S, Rupp S (2017) Fungal glycolipids as biosu - ac an s. Cu Bio echnol 6:205–218 Gu ¨ enc¸ A, Kapucu N, Mehme og ˘lu U ¨(2002) The p oduc ion o isoamyl ace a e using immobilized lipases in a sol en - ee sys em. P ocess Biochem 38:379–386 Haas BJ, Zeng Q, Pea son MD, Cuomo CA, Wo man JR (2011) App oaches o ungal genome anno a ion. Mycology 2:118–141 Hadiba a a T, K is an i RA (2013) Biodeg ada ion and me aboli e ans o ma ion o py ene by basidiomyce es ungal isola e A milla ia sp. F022 36: 461. Biop ocess Biosys Eng 36:461– 468 Hadiba a a T, Teh ZC (2014) Op imiza ion o py ene deg ada ion by whi e- o ungus Pleu o us pulmona ius F043 and cha ac e iza- ion o i s me aboli es. Biop ocess Biosys Eng 37:1679–1684 Hagedo n S, Kaphamme B (1994) Mic obial bioca alysis in he gene a ion o la o and ag ance chemicals. Annu Re Mic obiol 48:773–800 Hai jema CH, Gilmo e SP, Henske JK, Solomon KV e al (2017) A pa s lis o ungal cellulosomes e ealed by compa a i e genomics. Na Mic obiol 2:17087 Hall FR (1998) Biopes icides: use and deli e y. Humana P ess, To owa, pp 233–270 Hamano PS, Kilikian BV (2006) P oduc ion o ed pigmen s by Monascus ube in cul u e media con aining co n s eep liquo . B az J Chem Eng 23:443–449 Hameed I, Masoodi SR, Mi SA, Nabi M e al (2015) Type 2 diabe es melli us: om a me abolic diso de o an in lamma o y condi- ion. Wo ld J Diabe es 6:598–612 Hameed A, Hussain SA, Yang J, Ijaz MU e al (2017) An ioxidan s po en ial o he ilamen ous ungi (Muco ci cinelloides). Nu ien s 9:1101 Hamill RL, Higgens CE, Boaz HE, Go man M (1969) The s uc u e o beau e icin, a new depsipep ide an ibio ic oxic o A emia salina. Te ahed on Le 10:4255–4258 Han SY, Hong ZY, Xie YH, Zhao Y, Xu X (2017) The apeu ic e ec o Chinese he bal medicines o pos s oke eco e y: a adi ional and ne wo k me a-analysis. Medicine 96:1–13 Hanee M, Cese acciu L, Canale C, Ilke B e al (2017) Ad anced ma e ials om ungal mycelium: ab ica ion and uning o physical p ope ies. Sci Rep 7:41292 Hansen MB, Jensen ML, Ca s ensen B (2012) Causes o dea h among diabe ic pa ien s in Denma k. Diabe ologia 55:294–302 Hanson JR (2008) Fungal me aboli es de i ed om amino acids. In: Hanson JR (ed) The chemis y o Fungi. The Royal Socie y o Chemis y, Camb idge, pp 32–46 Hao YJ, Zhao Q, Wang SX, Yang ZL (2016) Wha is he adica e Oudemansiella cul i a ed in China? Phy o axa 286:1–12 Hapua achchi KK, Wen TC, Jeewon R, Wu XL, Kang JC (2014) Mycosphe e essays 7. Ganode ma lucidum—a e he bene icial an i-cance p ope ies subs an ia ed? Mycosphe e 7:305–332 Hapua achchi KK, Ka una a hna SC, Phengsin ham P, Kakumyan P, Hyde KD, Wen TC (2018) Amau ode ma (Ganode ma aceae, Polypo ales)—bioac i e compounds, bene icial p ope ies and wo new eco ds om Laos. Asian J Mycol 1:121–136 Hapua achchi KK, Ka una a hna SC, McKenzie EHC, Wu XL, Kakumyan P, Hyde KD, Wen TC (2019) High pheno ypic plas ici y o Ganode ma sinense (Ganode ma aceae, Polypo- ales) in China. Asian J Mycol 2:1–47 Ha i ash AK, Kaushik CP (2009) Biodeg ada ion aspec s o poly- cyclic a oma ic hyd oca bons (PAHs): a e iew. J Haza d Ma e 169:1–15 Ha MM, T e o s JT (2005) Mic obe managemen : applica ion o myco hizal ungi in sus ainable ag icul u e. F on Ecol En i on 3:533–539 Hasan HA (2002) Gibbe ellin and auxin-indole p oduc ion by plan oo - ungi and hei biosyn hesis unde salini y-calcium in e ac- ion. Ac a Mic obiol Immunol Hung 49:105–118 Hasan S, Ay es PG (1990) The con ol o weeds h ough ungi: p inciples and p ospec s. New Phy ol 115:201–222 Hasan MT, Kha un MHA, Sajib MAM, Rahman MM e al (2015) E ec o whea b an supplemen wi h suga cane bagasse on g ow h, yield and p oxima e composi ion o pink oys e mush- oom Pleu o us djamo . Am J Food Sci Technol 3:150–157 Hawkswo h DL (2012) Global species numbe s o ungi: a e opical s udies and molecula app oaches con ibu ing o a mo e obus es ima e. Biodi e s Conse 21:2425–2433 Hawkswo h DL, Lu ¨cking R (2017) Fungal di e si y e isi ed: 2.2 o 3.8 million species. Mic obiol Spec um 5:1–17 He W, Zhao W, Yang R (2019) E ec s o whea glu en modi ied by deamida ion-hea ing wi h h ee di e en acids on he mic os uc- u e o model oil-in-wa e emulsion and heological–physical p ope y o ice c eam. Food Hyd ocoll 87:679–690 Hecque L, Sancelme M, Bol e J, Demuynck C (1996) Biosyn hesis o 4-hyd oxy-2,5-dime hyl-3(2H)- u anone by Zygosaccha omyces ouxii. J Ag ic Food Chem 44:1357–1360 Hedden P, Sponsel V (2015) A cen u y o gibbe ellin esea ch. J Plan G ow h Regul 34:740–760 Heilmann-Clausen J, Ba on ES, Boddy L, Dahlbe g A e al (2014) A ungal pe spec i e on conse a ion biology. Conse Biol 29:61– 68 Helaly SE, Ash a i S, Teponno RB, Be necke S e al (2018a) Nema icidal cyclic lipodepsipep ides and a xan hocillin de i a- i e om a phaeospha iaceous ungus pa asi izing eggs o he plan pa asi ic nema ode He e ode a ilipje i. J Na P od 81:2228–2234 Helaly SE, Thongbai B, S adle M (2018b) Di e si y o biologically ac i e seconda y me aboli es om endophy ic and sap o ophic ungi o he ascomyce e o de Xyla iales. Na P od Rep 35:992– 1014 Heneghan MN, Yakasai A, Williams K, Kadi KA e al (2011) The p og amming ole o ans-ac ing enoyl educ ases du ing he biosyn hesis o highly educed ungal polyke ides. Chem Sci 2:972–980 112 Fungal Di e si y (2019) 97:1–136 123 He na ´ndez VA, Galleguillos F, Thibau R, Mu ¨lle A (2018a) Fungal dyes o ex ile applica ions: es ing o indus ial condi ions o wool ab ic dyeing. J Tex ile Ins . h ps://doi.o g/10.1080/ 00405000.2018.1460037 He na ´ndez VA, Galleguillos FA, Sag edo N, Machuca A ´(2018b) A no e on he dyeing o wool ab ics using na u al dyes ex ac ed om o en wood-inhabi ing ungi. Coa ings 8:77–83 He na ´ndez-Mon iel LG, Rueda-Puen e EO, Co doba-Ma son MV, Holguı ´n-Pen ˜a JR, Zulue a-Rod ı ´guez R (2013) Mu ualis ic in e ac ion o izobac e ia wi h a buscula myco hizal ungi and i s an agonis ic e ec on Fusa ium oxyspo um in Ca ica papaya seedlings. C op P o 47:61–66 Hes e kamp T (2017) An ibio ics clinical de elopmen and pipeline. In How o o e come he an ibio ic c isis— ac s, challenges, echnologies & u u e pe spec i e (S adle , M, De sch P, eds.). Cu Top Mic obiol Immunol 398:447–474 Hibbe DS, Vilgalys R (1993) Phylogene ic ela ionships o Len inus (Basidiomyco ina) in e ed om molecula and mo phological cha ac e s. Sys Bo 18:409–433 Hicks W (2011) Wal e Hicks wine lis 2011, p 92 Higgins C, Ma go H, Wa nquis S, Obeyseka e E, Meh a K (2017) Mush oom cul i a ion in he de eloping wo ld: a compa ison o cul i a ion echnologies. In: Global Humani a ian Technology Con e ence (GHTC), pp 1–7 Hill C, Gua ne F, Reid G, Gibson GR e al (2014) The In e na ional Scien i ic Associa ion o P obio ics and P ebio ics consensus s a emen on he scope and app op ia e use o he e m p obio ic. Na Re Gas oen e ol Hepa ol 11:506–514 Himmel ME, Ding SY, Johnson DK, Adney WS e al (2007) Biomass ecalci ance: enginee ing plan s and enzymes o bio uels p oduc ion. Science 315:804–807 Hinsch E, Robinson S (2016) Mechanical colou eading o wood- s aining ungal pigmen ex ile dyes: an al e na i e me hod o de e mining colou as ness. Coa ings 6:1–12 Hi o ani M, Hi o ani S, Takayanagi H, Yoshikawa T (1999) Blazeispi ol A, an unp eceden ed skele on om he cul u ed mycelia o he ungus Aga icus blazei. Te ahed on Le 40:329– 332 Hi o ani M, Hi o ani S, Yoshikawa T (2000) Blazeispi ol X and Y, wo no el ca bon skele al s e ols om he cul u ed mycelia o he ungus Aga icus blazei. Te ahed on Le 41:5107–5110 Hi o ani M, Hi o ani S, Yoshikawa T (2001) Blazeispi ol D and Z, as he ac ual in e media es o blazeispi ol A biosyn hesis om he cul u ed mycelia o he ungus Aga icus blazei. Te ahed on Le 42:5261–5264 Hi o ani M, Sai K, Hi o ani S, Yoshikawa T (2002) Blazeispi ols B, C, E and F, des-A-e gos ane- ype compounds, om he cul u ed mycelia o he ungus Aga icus blazei. Phy ochemis y 59:571– 577 Ho mann C, Dolli e S, G unbe g S, Chen J e al (2013) A chaea and ungi o he human gu mic obiome: co ela ions wi h die and bac e ial esiden s. PLoS ONE 8:1–12 Ho mann T, K au wu s D, Schiebe le P (2018) Cu en s a us and u u e pe spec i es in la o esea ch: highligh s o he 11 h Wa bu g Symposium on la o chemis y & biology. J Ag ic Food Chem 66:2197–2203 Ho ich e M, Lundell T, Ha akka A (2011) Con e sion o milled pine wood by manganese pe oxidase om Phlebia adia a. Appl En i on Mic obiol 67:4588–4593 Holland RJ, Williams KL, Khan A (1999) In ec ion o Meloidogyne ja anica by Paecilomyces lilacinus. Nema ology 1:131–139 Hong SB, Kim DH, Samson RA (2015) Aspe gillus associa ed wi h Meju, a e men ed soybean s a ing ma e ial o adi ional soy sauce and soybean pas e in Ko ea. Mycobiology 43:218–224 Ho bach R, Quesada ARN, Knogge W, Deising HB (2011) When and how o kill a plan cell: in ec ion s a egies o plan pa hogenic ungi. J Plan Physiol 5:722–732 Ho nsey IS (2003) A his o y o bee and b ewing. The Royal Socie y o Chemis y, Camb idge Ho nsey IS (2012) Alcohol and i s ole in he e olu ion o human socie y. Royal Socie y o Chemis y, London Ho a MAC, Filho JAF, Mu ad NF, de Oli ei a SE e al (2018) Ne wo k o p o eins, enzymes and genes linked o biomass deg ada ion sha ed by T ichode ma species. Sci Rep 8:1–11 Hosseini F, Mosaddeghi MR, Dex e AR (2017) E ec o he ungus Pi i o mospo a indica on physiological cha ac e is ics and oo mo phology o whea unde combined d ough and mechanical s esses. Plan Physiol Biochem 118:107–120 Hou XQ, Guo SX (2009) In e ac ion be ween a da k sep a e endophy ic isola e om Dend obium sp. and oo s o D. nobile seedlings. J In eg Plan Biol 51:374–381 Hou CW, Jeng KC, Chen YS (2010) Enhancemen o e men a ion p ocess in Pu-e h ea by ea-lea ex ac . J Food Sci 75:44–48 Howa d GT (2012) Polyu e hane biodeg ada ion. In: Singh SN (ed) Mic obial deg ada ion o xenobio ics. Sp inge , Be lin, pp 371– 394 Hua MDS, Kuma RS, Shyu LF, Cheng YB e al (2017) Me abolomic compounds iden i ied in Pi i o mospo a indica- colonized Chinese cabbage oo s delinea e symbio ic unc ions o he in e ac ion. Sci Rep 7:1–14 Huang WY, Cai YZ, Su eswa an S, Hyde KD, Co ke H, Sun M (2009) Molecula phylogene ic iden i ica ion o endophy ic ungi isola ed om h ee A emisia species. Fungal Di e s 36:69–88 Huang L, Wei PL, Zang R, Xu ZN, Cen PL (2010) High- h oughpu sc eening o high-yield colonies o Rhizopus o yzae o enhanced p oduc ion o uma ic acid. Ann Mic obiol 60:287– 292 Huang R, Li GQ, Zhang J, Yang L e al (2011) Con ol o pos ha es Bo y is ui o o s awbe y by ola ile o ganic compounds o Candida in e media. Phy opa hology 101:859–869 Huang Y, Kuang Z, Wang W, Cao L (2016) Explo ing po en ial bac e ial and ungal biocon ol agen s ansmi ed om seeds o sp ou s o whea . Biol Con ol 98:27–33 Huang MY, Lin KH, Lu CC, Chen LR e al (2017a) The in ensi y o blue ligh -emi ing diodes in luences he an ioxidan p ope ies and suga con en o oys e mush ooms (Len inus sajo -caju). Sci Ho 218:8–13 Huang Z, Nong X, Wang J, Zhang X e al (2017b) An i-HSV-1, an ioxidan and an i ouling phenolic compounds om he deep- sea-de i ed ungus Aspe gillus e sicolo SCSIO 41502. Bioo g Med Chem Le 27:787–789 Huang H, Wang SL, Nguyen V, Kuo YH (2018) Isola ion and iden i ica ion o po en an idiabe ic compounds om An odia cinnamomea—an edible Taiwanese mush oom. Molecules 23:1– 12 Hulea A (1939) Con ibu ions a `la connaissance des champignons commensaux des U e ´dine ´es. Bulle in de la Sec ion Scien i ique de l’Acade ´mie de Roumanie 22:1–19 Huseyin CE, O’Toole PW, Co e PD, Scanlan PD (2017) Fo go en ungi- he gu mycobiome in human heal h and disease. FEMS Mic obiol Re 41:479–511 Hussain A, Rizwan-ul-Haq M, Al-Ayedh H, Al-Jab M (2014) Mycoinsec icides: po en ial and u u e pe spec i e. Recen Pa Food Nu Ag ic 6:45–53 Hu chings ML, Alpha-Cobb CJ, Hille DA, Be o J, S obel SA (2017) Myco umiga ion h ough p oduc ion o he ola ile DNA me hyla ing agen N-me hyl-N-ni osoisobu y amide by ungi in he genus Muscodo . J Biol Chem 292:7358–7371 Hyde KD, Soy ong K (2008) The ungal endophy e dilemma. Fungal Di e s 33:163–173 Fungal Di e si y (2019) 97:1–136 113 123 Hyde KD, Bahkali AH, Moslem MA (2010) Fungi—an unusual sou ce o cosme ics. Fungal Di e s 43:1–9 Hyde KD, Nilsson RH, Alias SA, A iyawansa HA e al (2014) One s op shop: backbones ees o impo an py opa hogenic gene a: I. Fungal Di e s 67:21–125 Hyde KD, Hongsanan S, Jeewon R, Bha DJ e al (2016) Fungal di e si y no es 367–490: axonomic and phylogene ic con ibu- ions o ungal axa. Fungal Di e s 80:1–270 Hyde KD, No phanphoun C, Ab eu VP, Bazzicalupo A e al (2017) Fungal di e si y no es 603–708: axonomic and phylogene ic no es on gene a and species. Fungal Di e s 87:1–235 Hyde KD, Al-Ha mi AM, Ande sen B, Boekhou T, Buzina W, Dawson TL, Eas wood DC, Jones EG, de Hoog S, Kang Y, Longco e JE (2018a) The wo ld’s en mos ea ed ungi. Fungal Di e s 93:161–194 Hyde KD, Chaiwan N, No phanphoun C, Boonmee S e al (2018b) Mycosphe e no es 169-224. Mycosphe e 9:271–430 Hyde KD, No phanphoun C, Chen J, Dissanayake AJ e al (2018c) Thailand’s amazing di e si y: up o 96% o ungi in no he n Thailand may be no el. Fungal Di e s 93:215–239 Hynninen PH, Ra ¨isa ¨nen R, Elo aa a P, Nokelainen E (2000) P epa a i e isola ion o an h aquinones om he ungus De mo- cybe sanguinea using enzyma ic hyd olysis by he endogenous ß-glucosidase. Z Na u o sch 55:600–610 Hyodo I, Amano N, Eguchi K, Na abayashi M e al (2005) Na ionwide su ey on complemen a y and al e na i e medicine in cance pa ien s in Japan. J Clin Oncol 23:2645–2654 Ib ahim AA (1994) E ec o cadusa os, Paecilomyces lilacinus and Nemou on ep oduc ion and damage po en ial o Meloidogyne ja anica. Pak J Nema ol 12:141–147 Igi i BE, Okoduwa SIR, Idoko GO, Akabuogu EP e al (2018) Toxici y and bio emedia ion o hea y me als con amina ed ecosys em om Tanne y was ewa e : a e iew. J Toxicol 2018:1–16 Ilmbe ge N, Meske D, Jue gensen J, Schul e M e al (2012) Me agenomic cellulases highly ole an owa ds he p esence o ionic liquids-linking he mos abili y and halo ole ance. Appl Mic obiol Bio echnol 95:135–146 Imho JF, Labes A, Wiese J (2011) Bio-mining he mic obial easu es o he ocean: new na u al p oduc s. Bio echnol Ad 29:468–482 Ina K, Ka aoka T, Ando T (2013) The use o len inan o ea ing gas ic cance . An icance Agen s Med Chem 13:681–688 Inglis DG, Enke li J, Goe el M (2012) Labo a o y echniques used o en omopa hogenic ungi. Hypoc eales. In: Lacey L (ed) Manual o echniques in in e eb a e pa hology, 2nd edn. Academic P ess, Bos on, pp 189–253 In e s a e Technology and Regula o y Council (ITRC) (2002) A sys ema ic app oach o in si u bio emedia ion in g ound wa e including decisions ees on in si u bio emedia ion o ni a es, ca bon e achlo ide and pe chlo a e. h ps://clu-in.o g/con /i c/ sysisb/. Accessed 3 Ma 2019 Islam MR, Tud yn G, Bucinell R, Schadle L, Picu C (2018) Mechanical beha io o mycelium-based pa icula e composi es. J Ma e Sci 53:16371–16382 Isogai A, Kanaoka M, Ma suda H, Ho i Y, Suzuki A (1978) S uc u e o a new cyclodepsipep ide, Beau e ilide A om Beau e ia bassiana. Ag ic Biol Chem 42:1797–1798 I elima JU, Bang WJ, Onyimba IA, Egbe e OJ (2018) A e iew: bio e ilize - a key playe in enhancing soil e ili y and c op p oduc i i y. J Mic obiol Bio echnol Rep 2:22–28 Jabe LR, Ownley BH (2018) Can we use en omopa hogenic ungi as endophy es o dual biological con ol o insec pes s and plan pa hogens? Biol Con ol 116:36–45 Jackson AJ, Wal e s DR, Ma shall G (1997) An agonis ic in e ac ions be ween he olia pa hogen Bo y is abae and isola es o Penicillium b e icompac um and Cladospo ium cladospo ioides on aba beans. Biol Con ol 8:97–106 Jah omi MF, Liang JB, Ho YW, Mohamad R, Goh YM, Shok yazdan P (2012) Lo as a in p oduc ion by Aspe gillus e eus using ag o-biomass as subs a e in solid s a e e men a ion. J Biomed Bio echnol 2012:1–11 Jai el N, Ma imu hu P (2010) Op imiza ion o lo as a in p oduc ion in solid s a e e men a ion by Aspe gillus e eus. In J Eng Sci 2:2730–2733 Jalaluddin M (1977) A use ul pa hological condi ion o wood. Econ Bo 31:222–224 Janisiewicz WJ, Je e s SN (1997) E icacy o comme cial o mula- ion o wo bio ungicides o con ol o blue mold and g ay mold o apples in cold s o age. C op P o 16:629–633 Janous ˇko a ´M, K ak K, Vosa ´ ka M, Pu ¨schel D, S ˇ o cho a ´H (2017) Inocula ion e ec s on oo -colonizing a buscula myco hizal ungal communi ies sp ead beyond di ec ly inocula ed plan s. PLoS ONE 12:e0181525 Jansson HB, Jeyap akash A, Zucke man BM (1985) Con ol o oo - kno nema odes on oma o by endopa asi ic ungus Me ia coniospo a. J Nema ol 17:327–329 Jansson HB, Lopez-Llo ca LV (2004) Con ol o nema odes by ungi. In: A o a DK (ed) Fungal bio echnology in ag icul u al, ood, and en i onmen al applica ions, mycology se ies, ol 21. CRC P ess, Boca Ra on, pp 205–215 Ja onski ST, Masca in GM (2017) Mass p oduc ion o ungal en omopa hogens. In: Lacey LA (ed) Mic obial con ol o insec s and mi e pes s, ol 9. Academic P ess, Ams e dam, pp 141–155 Jaspe s NG, Raams A, Kelne MJ, Ng JM e al (2002) An i- umou compounds illudin S and I o ul en induce DNA lesions igno ed by global epai and exclusi ely p ocessed by ansc ip ion-and eplica ion-coupled epai pa hways. DNA Repai 1:1027–1038 Jayawa dena RS, Hyde KD, Damm U, Cai L e al (2016) No es on cu en ly accep ed species o Colle o ichum. Mycosphe e 7:1192–1260 Jenkins MJ, Ha ison KL (2008) The e ec o c ys alline mo phology on he deg ada ion o polycap olac one in a solu ion o phospha e bu e and lipase. Polym Ad Technol 19:1901–1906 Jeon S, Bose S, Hu J, Jun K, Kim YK, Cho KS, Koo BS (2011) A modi ied o mula ion o Chinese adi ional medicine imp o es memo y impai men and educes Aβle el in he Tg-APPswe/ PS1dE9 mouse model o Alzheime ’s disease. J E hnopha macol 137:783–789 Jeong SC, Jeong YT, Yang BK, Islam R e al (2010) Whi e bu on mush oom (Aga icus bispo us) lowe s blood glucose and choles e ol le els in diabe ic and hype choles e olemic a s. Nu Res 30:49–56 Jeschke R, Iinuma K, Ha de A, Schindle M, Mu akami T (2005) In luence o he cyclooc adepsipep ides PF1022A and PF1022E as na u al p oduc s on he design o semi–syn he ic an helmin ics such as emodepside. Pa asi ol Res 97(1):S11–S16 Jeznabadi EK, Ja a pou M, Eghbalsaied S (2016) King oys e mush oom p oduc ion using a ious sou ces o ag icul u al was es in I an. In J Recycl O g Was e Ag ic 5:17–24 Jha BN, Sha ma GD, Shukla AK (2008) E ec o ec omyco hizal de elopmen on g ow h in pine seedling. J Plan Sci 3:77–84 Ji KP, Cao Y, Zhang CX, He MX e al (2011) Cul i a ion o Phlebopus po en osus in sou he n China. Mycol P o 10:293– 300 Jiang YF, Chang TJ, Liu Y, Zhang M e al (2017) O e iew o Ganode ma sinense polysaccha ide–an adjunc i e d ug used du ing concu en chemo/ adia ion he apy o cance ea men in China. Biomed Pha maco he 96:865–870 Jime ´nez DJ, Chaib De Ma es M, Salles JF (2018) Tempo al exp ession dynamics o plan biomass-deg ading enzymes by a 114 Fungal Di e si y (2019) 97:1–136 123 syn he ic bac e ial conso ium g owing on suga cane bagasse. F on Mic obiol 9:299 Jin X, Cus is D (2011) Mic oencapsula ing ae ial conidia o T ichode ma ha zianum h ough sp ay d ying a ele a ed empe a u es. Biol Con ol 56:202–208 Jin Y, Qin S, Gao H, Zhu G e al (2018) An an i-HBV an h aquinone om acidu ic ungus Penicillium sp. OUCMDZ-4736 unde low pH s ess. Ex emophiles 22:39–45 Jogaiah S, Abdel ahman M, T an LSP, I o SI (2018) Di e en mechanisms o T ichode ma i ens-media ed esis ance in oma o agains Fusa ium wil in ol e he jasmonic and salicylic acid pa hways. Mol Plan Pa hol 19:870–882 Jogawa A, Vadasse y J, Ve ma N, Oelmu ¨lle R e al (2016) PiHOG1, a s ess egula o MAP kinase om he oo endophy e ungus Pi i o mospo a indica, con e s salini y s ess ole ance in ice plan s. Sci Rep 6:36765 Johjima T, I oh N, Kabu o M, Tokimu a F e al (1999) Di ec in e ac ion o lignin and lignin pe oxidase om Phane ochae e ch ysospo ium. PNAS 96:1989–1994 Jones N (2013) Food uelled wi h ungi. Na u e 504:199 Jones M, Bha T, Wang C, Moinuddin K, John S (2017) The mal deg ada ion and i e p ope ies o ungal mycelium and mycelium- biomass composi e ma e ials. Sci Rep 8:1–10 Jones M, Bha T, Huynh T, Kanda e E e al (2018) Was e-de i ed low-cos mycelium composi e cons uc ion ma e ials wi h imp o ed i e sa e y. Fi e Ma e 9:71–80 Julien MH, G i i hs MW (1998) Biological con ol o weeds, a wo ld ca alogue o agen s and hei a ge weeds, 4 h edn. CAB In e na ional, Walling o d, p p223 Jung JH, Lee HW, Lee YJ, Lee HR, Um TH, Pa k JY, Yi SY (2015) Fou cases o acqui ed aplas ic anemia a ec ing an en i e amily a e inges ing Ganode malucidum. Ko ean J Medicine 88:94– 100 Jus o A, Hibbe DS (2011) Phylogene ic classi ica ion o T ame es (Basidiomyco a, Polypo ales) based on a i e-ma ke da ase . Taxon 60:1567–1583 Kabaluk JT, S i ce AM, Goe el MS, Woo SG (eds) (2010) The use and egula ion o mic obial pes icides in ep esen a i e ju isdic- ions wo ldwide. IOBC Global, S . Paul Kabi Y, Kimu a S (1989) Die a y mush ooms educe blood p eassu e in spon aneously hype ensi e a s (SHR). J Nu Sci Vi aminol 35:91–94 Kabi Y, Kimu a S, Tamu a T (1988) Die a y e ec o Ganode ma lucidum mush oom on blood p essu e and lipid le els in spon aneously hype ensi e a s (SHR). J Nu Sci Vi aminol 34:433–438 Kaewchai S, Soy ong K, Hyde KD (2009) Myco ungicides and ungal bio e ilize s. Fungal Di e s 38:25–50 Kaewg ajang T, Sangwani U, Kodama M, Yamo a M (2013) Ec omyco hizal ungal communi ies o Dip e oca pus ala us seedlings in oduced by soil inocula om a na u al o es and a plan a ion. J Fo Res 9:260–267 Kalac ˇP (2013) A e iew o chemical composi ion and nu i ional alue o wild-g owing and cul i a ed mush ooms. J Sci Food Ag ic 93:209–218 Kal a EK (2003) Nu aceu ical-de ini ion and in oduc ion. AAPS Pha m Sci 5:27–28 Kamei I, Takagi K, Kondo R (2011) Deg ada ion o endosul an and endosul an sul a e by whi e- o ungus T ame es hi su a. J Wood Sci 57:317–322 Kam han R, Tiwa i I (2017) Ag icul u al was es – Po en ial subs a es o mush oom cul i a ion. Eu Exp Biol 7:31 Kaneko M, Wa ashi K, Kamisuki S, Ma sunaga H e al (2015) A no el icyclic polyke ide, ani a acin A, speci ically inhibi s he en y o hepa i is B and D i uses by a ge ing sodium au ochola e co- anspo ing polypep ide. J Vi ol 89:11945– 11953 Kaplan GG (2015) The global bu den o IBD: om 2015 o 2025. Na Re Gas oen e ol Hepa ol 12:720–727 Kapple A, Wues ne ML, Ruecke A, Ha e J e al (2014) Biocha as an elec on shu le be ween bac e ia and Fe(III) mine als. En i on Sci Technol Le 1:339–344 Ka wehl S, S adle M (2017) Exploi a ion o ungal biodi e si y o disco e y o no el an ibio ics he an ibio ic c isis— ac s, challenges, echnologies & u u e pe spec i e. Cu Top Mic o- biol Immunol 398:303–338 Ka hi esan K, Mani annan S (2006) α-Amylase p oduc ion by Penicillium ellu anum isola ed om mang o e hizosphe e soil. A J Bio echnol 5:829–832 Kau G, Kalia A, Sodhi HS (2018) Selenium bio o i ica ion o Pleu o us species and i s e ec on yield, phy ochemical p o iles, and p o ein chemis y o ui ing bodies. J Food Biochem 42:12467 Kayama M, Yamanaka T (2016) G ow h cha ac e is ics o ec omy- co hizal seedlings o Que cus glauca, Que cus salicina, Que - cus my sinae olia, and Cas anopsis cuspida e plan ed in calca eous soil. Fo es s 7:266 Kazan K, Lyons R (2014) In e en ion o phy oho mone pa hways by pa hogen e ec o s. Plan Cell 26:2285–2309 Keene PD (1954) Cladospo ium aecidiicola Thuem. and Tube colina pe sicina (Di m). Sacc. associa ed wi h Puccinia conspicua (A h.) Mains on Helenium hoopesii A. G ay in A izona. Plan Dis Rep 38:691–694 Ke ialew Y, Ayalew A (2008) Pos ha es biological con ol o an h acnose (Colle o ichum gloeospo ioides) on mango (Man- gi e a indica). Pos ha es Biol Technol 50:8–11 Kend ick B (1992) The i h kingdom. Hacke Publishing, Indianapolis Ken JM (1994) Plan p o ec ion B—no es and eadings: weeds. Cha les S u Uni e si y, Sydney Olympic Pa k Keppanan R, Si ape umal S, Ramos Aguila LC, Hussain M e al (2018) Isola ion and cha ac e iza ion o Me a hizium anisopliae TK29 and i s mycoinsec icide e ec s agains sub e anean e mi e Cop o e mes o mosanus. Mic ob Pa hog 123:52–59 Ke igan RW (2005) Aga icus sub u escens, a cul i a ed edible and medicinal mush oom, and i s synonyms. Mycologia 97:12–24 Ke sey PJ, Lawson D, Bi ney E, De wen PS e al (2010) Ensembl genomes: ex ending Ensembl ac oss he axonomic space. Nucleic Acids Res 38:D563–D569 Ke shaw MJ, Moo house ER, Ba eman R, Reynolds SE, Cha nley AK (1999) The ole o des uxins in he pa hogenici y o Me a hiz- ium anisopliae o h ee species o insec . J In e Pa hol 74:213–223 Kesha a z B, Khalesi M (2016) T ichode ma eesei, a supe io cellulase sou ce o indus ial applica ions. Bio uels 7:713–721 Khan AL, Hamayun M, Kang SM, Kim YH e al (2012) Endophy ic ungal associa ion ia gibbe ellins and indole ace ic acid can imp o e plan g ow h unde abio ic s ess: an example o Paecilomyces o mosus LHL10. BMC Mic obiol 12:1–14 Khan AL, Hussain J, Al-Ha asi A, Al-Rawahi A, Lee IJ (2015a) Endophy ic ungi: esou ce o gibbe ellins and c op abio ic s ess esis ance. C i Re Bio echnol 35:62–74 Khan AR, Ullah I, Waqas M, Shahzad R e al (2015b) Plan g ow h- p omo ing po en ial o endophy ic ungi isola ed om Solanum nig um lea es. Wo ld J Mic obiol Bio echnol 31:1461–1466 Khan S, Nadi S, Shah ZU, Shah AA e al (2017) Biodeg ada ion o polyes e polyu e hane by Aspe gillus ubingensis. En i on Pollu 225:469–480 Kiho T, Yamane A, Hui J, Usui S, Ukai S (1996) Polysaccha ides in ungi. XXXVI Hypoglycemic ac i i y o a polysaccha ide (CS- F30) om he cul u al mycelium o Co dyceps sinensis and i s Fungal Di e si y (2019) 97:1–136 115 123 e ec on glucoseme abolism in mouse li e . Biol Pha m Bull 19:294–296 Kildgaa d S, Mansson M, Dosen I, Kli gaa d A e al (2014) Accu a e de eplica ion o bioac i e seconda y me aboli es om ma ine- de i ed ungi by UHPLC-DAD-QTOFMS and a MS/HRMS lib a y. Ma D ugs 12:3681–3705 Kim AY (2005) Applica ion o bio echnology o he p oduc ion o na u al la o and ag ance chemicals. In: ACS symposium se ies. Ox o d Uni e si y P ess, pp 60–75 Kim JD (2007) Pu i ica ion and cha ac e iza ion o a ke a inase om a ea he -deg ading ungus, Aspe gillus la us S ain K-03. Mycobiology 35:219–225 Kim DY, Rhee YH (2003) Biodeg ada ion o mic obial and syn he ic polyes e s by ungi. Appl Mic obiol Bio echnol 61:300–308 Kim S, Dale BE (2004) Global po en ial bioe hanol p oduc ion om was ed c ops and c op esidues. Biomass Bioene g 26:361–375 Kim KH, Kim JY, Cho TS, Choi JW (2012) In luence o py olysis empe a u e on physicochemical p ope ies o biocha ob ained om he as py olysis o pi ch pine (Pinus igida). Bio esou Technol 118:158–162 Kim YW, Kim KH, Choi HJ, Lee DS (2005) An i-diabe ic ac i i y o β-glucans and hei enzyma ically hyd olyzed oligosaccha ides om Aga icus blazei. Bio echnol Le 27:483–487 Kinsella JE, Hwang DH, Dwi edi B (1976) Enzymes o Penicillium oque o i in ol ed in he biosyn hesis o cheese la o . C i Re Food Sci Nu 8:191–228 Kip e T, Wohlgemu h T, an de Heiden MGA, Ghazoul J, Egli S (2012) G ow h esponse o d ough -s essed Pinus syl es is seedlings o single- and mul i-species inocula ion wi h ec omy- co hizal ungi. PLoS ONE 7:e35275 Ki k O, Bo che TV, Fuglsang CC (2002) Indus ial enzyme applica ions. Cu Opin Bio echnol 13:345–351 Ki k MD, Pi es SM, Black RE, Caipo M (2015) Wo ld Heal h O ganiza ion es ima es o he global and egional disease bu den o 22 oodbo ne bac e ial, p o ozoal, and i al diseases, 2010: a da a syn hesis. PLoS Med 12(12):e1001921 Klinsupa W, Phansi i S, Thongp adis P, Yongsmi h B, Po hi a ana C (2016) Enhancemen o yellow pigmen p oduc ion by in aspeci ic p o oplas usion o Monascus spp. yellow mu an (ade-) and whi e mu an (p o o oph). J Bio echnol 217:62–71 Kloa eg B, Qua ano RS (1988) S uc u e o he cell walls o ma ine algae and ecophysiological unc ions o he ma ix polysaccha- ides. Oceanog Ma Biol Annu Re 26:259–315 Klomklung N, Ka una a hna SC, Chukea i o e E, Hyde KD (2012) Domes ica ion o wild s ain o Pleu o us gigan eus. Sydowia 60:39–53 Klu ¨p el L, Keiluwei M, Klebe M, Sande M (2014) Redox p ope ies o plan biomass-de i ed black ca bon (Biocha ). En i on Sci Technol 48:5601–5611 Knigh DW, Pa enden G (1976) Syn hesis o he pul inic acid pigmen s o lichen and ungi. J Chem Soc Chem Com 639:660– 661 Ko HG, Pa k SH, Kim SH, Pa k HG, Pa k WM (2005) De ec ion and eco e y o hyd oly ic enzymes om spen compos o ou mush oom species. Folia Mic obiol 50:103–106 Konno S, Alexande B, Zade J, Choudhu y M (2013) Possible hypoglycemic ac ion o SX- ac ion a ge ing insulin signal ansduc ion pa hway. In J Gen Med 6:181 Koza ski M, Klaus A, Niksic M, Jako lje ic D e al (2011) An ioxida i e and immunomodula ing ac i i ies o polysaccha- ide ex ac s o he medicinal mush ooms Aga icus bispo us, Aga icus b asiliensis, Ganode ma lucidum, and Phellinus lin eus. Food Chem 129:1667–1675 Kozubal MA, Macu RE, A niel YC, Sus ainable Biop oduc s, Inc. (2019) Filamen ous ungal bioma s, me hods o hei p oduc ion and me hods o hei use. US pa en applica ion 16/118:370 K anz J (1981) Hype pa asi ism o bio ophic ungi. In: Blakeman JP (ed) Mic obial ecology o he phylloplane. Academic P ess, London, pp 327–352 K asowska K, Janik H, G adys A, Ru kowska M (2012) Deg ada ion o polyu e hanes in compos unde na u al condi ions. J Appl Polym Sci 125:4252–4260 K ings U, Be ge RG (1998) Bio echnological p oduc ion o la o s and ag ances. Appl Mic obiol Bio echnol 49:1–8 K is iansen KA, Taylo DL, Kjolle R, Rasmussen HN, Rosendahl S (2001) Iden i ica ion o myco hizal ungi om single pelo ons o Dac ylo hiza majalis (O chidaceae) using single-s and con- o ma ion polymo phism and mi ochond ial ibosomal la ge subuni DNA sequences. Mol Ecol 10(8):2089–2093 K is iansen KA, F eudens ein JV, Rasmussen FN, Rasmussen HN (2004) Molecula iden i ica ion o myco hizal ungi in Neuwie- dia e a i olia (O chidaceae). Mol Phylogene E ol 33:251–258 K is ˇ o ı ´ko a ´L, Rosenbe g M, Vlno a A, S ˇajbido J, C ˇe ı ´k M (1991) Selec ion o Rhizopus s ains o l (?)-lac ic acid andγ-linolenic acid p oduc ion. Folia Mic obiol 36:451–455 K oge us K, Magalha ˜es F, Vidg en V, Gibson B (2017) No el b ewing yeas hyb ids: c ea ion and applica ion. Appl Mic obiol Bio echnol 101:65–78 K u ¨gene S, K ings U, Zo n H, Be ge RG (2010) A dioxygenase o Pleu o us sapidus ans o ms (?)- alencene egio-speci ically o (?)-noo ka one ia a s e eo-speci ic allylic hyd ope oxida ion. Bio esou Technol 101:457–462 K u ¨ge D, K eisel H (2003) P oposing Mo ganella subgen. Apiop- e don subgen. no . o he pu ball Lycope don py i o me. Myco axon 86:169–177 Kuanyshe N, Adamo GM, Po o D, B andua di P (2017) The spoilage yeas Zygosaccha omyces bailii: Foe o iend? Yeas 34:359–370 Kubo K, Namba H (1997) An i-hype liposis e ec o Mai ake ui body (G i ola ondosa). Biol Pha m Bull 20:781–785 Kubo T, Te abayashi S, Takeda S, Sasaki H e al (2006) Indoo cul i a ion and cul u al cha ac e is ics o Wol ipo ia cocos scle o ia using mush oom cul u e bo les. Biol Pha m Bull 29:1191–1196 Kudalka P, S obel G, Hassan S, Gea y B, Sea s J (2012) Muscodo su u a, a no el endophy ic ungus wi h ola ile an ibio ic ac i i ies. Mycoscience 53:319–325 Kuhne E, Li Y, Lan N, Yue Q e al (2018) En uma ungin syn hase ep esen s a no el lineage o ungal i e pene cyclases. En i- onm Mic obiol 1:12. h ps://doi.o g/10.1111/1462-2920.14333 Kulsh esh ha S, Ma hu N, Bha naga P (2014) Mush oom as a p oduc and hei ole in myco emedia ion. AMB Exp ess 4:29 Kuma R, Kaushik P (2004) Isola ion o a cellulose p oducing myco hizal ungus Rhizoc onia solani om Zeuxine s a eu- ma ica (Linn.) Schl . J O chid Soc India 18:11108 Kuma U, Be line J, Adak T, Ra h PC e al (2017) Non- a ge e ec o con inuous applica ion o chlo py i os on soil mic obes, nema odes and i s pe sis ence unde sub-humid opical ice- ice c opping sys em. Eco oxicol En i on Sa 135:225–235 Kumla J, Danell E, Bussaban B, Lumyong S (2011) Sui able g ow h condi ions and nu i ion ac o s on in i o cul u e o Phlebopus po en osus (Bole ales). Chiang Mai J Sci 38:156–159 Kumla J, Danell E, Lumyong S (2015) Imp o emen o yield o a opical black bole e, Phlebopus po en osus, cul i a ion in no he n Thailand. Mycoscience 56:114–117 Kumla J, Suwanna ach N, Lumyong S (2016) Cha ac e iza ion o Pisoli hus o ien alis in cul u e and in i o myco hiza ion wi h Eucalyp us camaldulensis and Pinus kesiya. Mycosphe e 7:1415–1424 Kumu a H, Tanoue Y, Tsukaha a M, Tanaka T e al (2004) Sc eening o dai y yeas s ains o p obio ic applica ions. J Dai y Sci 87:4050–4056 116 Fungal Di e si y (2019) 97:1–136 123 Kupco a ´K, S e ano a I, Pla co a Z, Hosek J e al (2018) An imic obial, cy o oxic, an i-In lamma o y, and an ioxidan ac i i y o culina y p ocessed shii ake medicinal mush oom (Len inus edodes, Aga icomyce es) and i s majo sul u senso y- ac i e compound-Len hionine. In J Med Mush ooms 20:165– 175 Ku zman CP, Fell JW, Boekhou T (2011) The yeas s, a axonomic s udy, 5 h edn. Else ie , Bu ling on Kwon H, Tha i ha goon S (2004) Mush oom g owing o a li ing wo ldwide: mush oom g owing in No he n Thailand. In: Gush R (ed) Mush oom g owe s’ handbook 1: oys e mush oom cul i a ion. Mush Wo ld-Heinea Inc, Seoul Ku ¨es U (2015) Fungal enzymes o en i onmen al managemen . Cu Opin Bio echnol 33:268–278 Lacey LA, Kaya HK (2007) Field manual o echniques in in e eb a e pa hology. Applica ion and e alua ion o pa hogens o con ol o insec s and o he in e eb a e pes s, 2nd edn. Sp inge , Do d ech , p 484 Lacey LA, Ne en LG (2006) The po en ial o he ungus, Muscodo albus, as a mic obial con ol agen o po a o ube mo h (Lepidop e a: Gelechiidae) in s o ed po a oes. J In e eb Pa hol 91:195–198 Lacey LA, G zywacz D, Shapi o-Ilan DI, F u os R, B ownb idge M, Goe el MS (2015) Insec pa hogens as biological con ol agen s: back o he u u e. J In e Pa hol 132:1–41 Lai LST, Pan CC, Tzeng BK (2003) The in luence o medium design on lo as a in p oduc ion and pelle o ma ion wi h a high- p oducing mu an o Aspe gillus e eus in subme ged cul u es. P ocess Biochem 38:1317–1326 Lal RJ, Sinha OK, Bha naga S, Lal S, Awas hi SK (2009) Biological con ol o suga cane smu (Spo iso ium sci amineum) h ough bo anicals and T ichode ma i ide. Suga Tech 11:381–386 Lale G, Jogdand VV, Gad e RV (2006) Mo phological mu an s o Gibbe ella ujiku oi o enhanced p oduc ion o gibbe ellic acid. J Appl Mic obiol 100:65–72 Lama RT, Whi e RB (2001) Myco emedia ion: comme cial s a us and ecen de elopmen s. In: Maga VS e al (eds) P oceedings o he six h in e na ional symposium on in si u and on-si e bio emedia ion, San Diego, CA, ol 6, pp 263–278 Lambe C, Wend L, Hladki AI, S adle M, Si EB (2019) Hypomon agnella (Hypoxylaceae): a new genus seg ega ed om Hypoxylon by a polyphasic axonomic app oach. Mycol P og 18:187–201 Lang E, E’Ue G, Kleebe g I, Ma ens R, Zad azil F (1995) In e ac ion o whi e o ungi and soil mic oo ganisms leading o biodeg ada ion o soil pollu an s. In: Van Den B ink WJ, Bosman R, A end F (eds) Con amina ed soil ’95. Soil & en i onmen , ol 5. Sp inge , Do d ech Lange L, Pilgaa d B, He bes F-A, Busk PK, Gleason F, Pede sen AG (2018) O igin o ungal biomass deg ading enzymes: e olu ion, di e si y and unc ion o enzymes o ea ly lineage ungi. Fungal Biol Re 33:82–97 La gen DL, B adshaw DE, Wood WF (1990) The candy-like odo o Nolanea uc u ag ans. Mycologia 82:786–787 La sson E, Jeppson M (2008) Phylogene ic ela ionships among species and gene a o Lycope daceae based on ITS and LSU sequence da a om No h Eu opean axa. Mycol Res 112:4–22 Lassois L, de Bellai e LDL, Jijakli MH (2008) Biological con ol o c own o o bananas wi h Pichia anomala s ain K and Candida oleophila s ain O. Biol Con ol 45:410–418 Lau ie JD, Ali S, Linning R, Mannhaup G e al (2012) Genome compa ison o ba ley and maize smu ungi e eals a ge ed loss o RNA silencing componen s and species-speci ic p esence o ansposable elemen s. Plan Cell 24:1733–1745 Le Bloc’h J, Pauquai T, Bou ges C (2015) Au ho ised EU heal h claim o ed yeas ice. In: Sadle M (ed) Foods, nu ien s and ood ing edien s wi h au ho ised EU heal h claims, ol 2. Else ie , Ams e dam, pp 139–142 Le Jeune C, Lollie M, Demuy e C, E ny C e al (2007) Cha ac e iza ion o na u al hyb ids o Saccha omyces ce e isiae and Saccha omyces bayanus a . u a um. FEMS Yeas Res 7:540–549 Leake JR (2004) Myco-he e o oph/epipa asi ic plan in e ac ions wi h ec omyco hizal and a buscula myco hizal ungi. Cu Opin Plan Biol 7:422–428 Lecom e C, Alabou e e C, Edel-He mann V, Robe F, S einbe g C (2016) Biological con ol o o namen al plan diseases caused by Fusa ium oxyspo um: a e iew. Biol Con ol 101:17–30 Lee G, A epally GM (2012) An icoagula ion echniques in aphe esis: om hepa in o ci a e and beyond. J Clin Aphe esis 27:117–125 Lee SY, Mohamed R (2016) The o igin and domes ica ion o Aquila ia, an impo an aga wood-p oducing genus. In: Mohamed R (ed) Aga wood. Sp inge , Singapo e, pp 1–20 Lee IK, Yun BS (2006) Hispidin analogs om he mush oom Inono us xe an icus and hei ee adical sca enging ac i i y. Bioo g Med Chem Le 16:2376–2379 Lee KH, Wi SG, Singh AP, Kim YS (2004) Mic omo phological cha ac e is ics o decayed wood and laccase p oduced by he b own- o ungus Coniopho a pu eana. J Wood Sci 50:281–284 Lee JS, Baik HS, Pa k SS (2006) Pu i ica ion and cha ac e iza ion o wo no el ib inoly ic p o eases om mush oom Fomi ella axinea. J Mic obiol Bio echnol 16:264–271 Lee SS, Pa ahayah M, Chong WS, Lapey ie F (2008a) Success ul ec omyco hizal inocula ion o wo dip e oca p species wi h a locally isola ed ungus in Peninsula Malaysia. J T op Fo Sci 20:237–247 Lee SW, Lee EH, Eom AH (2008b) E ec s o o ganic a ming on communi ies o a buscula myco hizal ungi. Mycobiology 36:19–23 Lee SO, Kim HY, Choi GJ, Lee HB e al (2009a) Myco umiga ion wi h Oxypo us la ema gina us EF069 o con ol o pos ha es apple decay and Rhizoc onia oo o on mo h o chid. J Appl Mic obiol 106:1213–1219 Lee SS, Chang YS, No aswa i MNR (2009b) U iliza ion o mac o- ungi by some indigenous communi ies o ood and medicine in Peninsula Malaysia. Fo Ecol Manag 257:2062–2065 Lee KH, Mo is-Na schke SL, Yang X, Huang R e al (2012) Recen p og ess o esea ch on medicinal mush ooms, oods, and o he he bal p oduc s used in adi ional Chinese medicine. J T ad Complemen Med 2:1–12 Lehmann J, Joseph S (2009) Biocha o en i onmen al managemen : an in oduc ion. In: Lehmann J, Joseph S (eds) Biocha o en i onmen al managemen : science and echnology. Ea hscan, London, pp 1–12 Leland JE, Mullins DE, Vaughan LJ, Wa en HL (2005) E ec s o media composi ion on subme ged cul u e spo es o he en o- mopa hogenic ungus, Me a hizium anisopliae a . ac idum Pa 2: E ec s o media osmolali y on cell wall cha ac e is ics, ca bohyd a e concen a ions, d ying s abili y, and pa hogenici y. Biocon ol Sci Technol 15:379–392 Lembeck H (1983) G ossman’s guide o wines, bee s, & spi i s, 7 h edn. Cha les Sc ibne ’s Sons, New Yo k Leong HY, Show PL, Lim MH, Ooi CW, Ling TC (2018) Na u al ed pigmen s om plan s and hei heal h bene i s: a e iew. Food Re In 34:463–482 Lesage-Meessen L, Dela e M, Haon M, Thibaul JF e al (1996) A wo-s ep biocon e sion p ocess o anillin p oduc ion om e ulic acid combining Aspe gillus nige and Pycnopo us cinnaba inus. J Bio echnol 50:107–113 Lesage-Meessen L, Bou M, Ginies C, Che e D, Na a o D e al (2018) La ende - and la andin-dis illed s aws: an un apped eeds ock wi h g ea po en ial o he p oduc ion o high-added Fungal Di e si y (2019) 97:1–136 117 123 [Document text truncated for crawler view.]