Green and sustainable valorization of bioactive phenolic compounds from pinus by-products

molecules Re iew G een and Sus ainable Valo iza ion o Bioac i e Phenolic Compounds om Pinus By-P oduc s Ped o Fe ei a-San os , Elisa Zanuso , Zla ina Genishe a, C is ina M. R. Rocha and JoséA. Teixei a * CEB—Cen e o Biological Enginee ing, Uni e si y o Minho, Campus de Gual a , 4710-057 B aga, Po ugal; [email p o ec ed] (P.F.-S.); [email p o ec ed] (E.Z.); [email p o ec ed] (Z.G.); [email p o ec ed] (C.M.R.R.) *Co espondence: [email p o ec ed]; Tel.: +253-604-406 Academic Edi o : Vassiliki O eopoulou Recei ed: 2 June 2020; Accep ed: 23 June 2020; Published: 25 June 2020   Abs ac : In Eu ope, pine o es s a e one o he mos ex ended o es s o ma ions, making pine esidues and by-p oduc s an impo an sou ce o compounds wi h high indus ial in e es as well as o bioene gy p oduc ion. Mo eo e , he alo iza ion o lumbe indus y esidues is desi able om a ci cula economy pe spec i e. Di e en ex ac ion me hods and sol en s ha e been used, esul ing in ex ac s wi h di e en cons i uen s and consequen ly wi h di e en bioac i i ies. Recen ly, eme ging and g een echnologies as ul asounds, mic owa es, supe c i ical luids, p essu ized liquids, and elec ic ields ha e appea ed as p omising ools o bioac i e compounds ex ac ion in alignmen wi h he G een Chemis y p inciples. Pine ex ac s ha e a ac ed he esea che s’ a en ion because o he posi i e biop ope ies, such as an i-in lamma o y, an imic obial, an i-neu odegene a i e, an i umo al, ca diop o ec i e, e c., and po en ial indus ial applica ions as unc ional oods, ood addi i es as p ese a i es, nu aceu icals, pha maceu icals, and cosme ics. Phenolic compounds a e esponsible o many o hese bioac i i ies. Howe e , he e is no much in o ma ion in he li e a u e abou he indi idual phenolic compounds o ex ac s om he pine species. The p esen e iew is abou he eu iliza ion o esidues and by-p oduc s om he pine species, using eco iendly echnologies o ob ain added- alue bioac i e compounds o indus ial applica ions. Keywo ds: pine; by-p oduc s; bio e ine y; g een p ocess; polyphenols; biological ac i i y; adi ional applica ions; high alue-added p oduc s 1. In oduc ion Ag o o es y indus ies a e an impo an pa o he manu ac u ing indus y, and hei g ow h can help o achie e he objec i es o Eu opean Union (EU) indus ial policy, ac ing in di e en s a egic a eas, such as inc easing ene gy e iciency, deploying enewable sou ces, ci cula economy, bioeconomy, and na u al ca bon sinks [ 1 , 2 ]. Mo eo e , he de elopmen o hese indus ies should also be in line wi h he 17 sus ainable de elopmen goals by 2030 dic a ed by he Uni ed Na ions; in pa icula , he ag oindus y can di ec ly impac on a leas 4 o hese goals ela ed o he use o clean ene gy, indus y inno a ion, esponsible consump ion, and clima e ac ion [3]. Nowadays, 5 billion ons o biomass esidues om ag o o es y and ood indus ies a e es ima ed wo ldwide and ep esen an emission o 3.3 billion onnes o ca bon dioxide each yea [ 4 , 5 ]. In he EU, he o al annual biowas e is es ima ed a a ound 100 million onnes, gene a ing a nega i e ecological impac [6]. One o he s a egies o he educ ion o gene a ed en i onmen al impac is he euse o indus ial biowas es o ob ain new na u al ing edien s. Concomi an ly, he g owing in e es in he de elopmen Molecules 2020,25, 2931; doi:10.3390/molecules25122931 www.mdpi.com/jou nal/molecules Molecules 2020,25, 2931 2 o 29 o e ec i e/in ensi ied p ocesses and applica ion o g een echnologies o ob ain sus ainable, ecological, sa e and high-quali y p oduc s has become a eali y [ 7 , 8 ]. This idea is in close associa ion wi h he p inciples go e ning he concep o g een chemis y, which a e mainly aimed a educing was es and p omo ing a mo e e icien use o ene gy and esou ces [9]. The dec ease in he use o “non- ecyclable” ossil de i a i es and he inc ease in he use o biowas es and by-p oduc s is in he sigh s o he EU and he wo ld, con ibu ing o he educ ion o he nega i e impac o p ocesses in he en i onmen and he igh agains clima e changes [2]. In his sense, he use o di e en plan by-p oduc s as sou ces o ma e ials, bio uels, ene gy, and bioac i e compounds has come o be explo ed ollowing he concep o bio e ine y, con ibu ing o a ci cula economy [6]. The p esen e iew ocuses on he app ecia ion o di e en g een ex ac ion s a egies ela ed o he eco e y o high added- alue compounds (such as polyphenols) om pine by-p oduc s, hei po en ial bioac i i ies, and possible indus ial applica ions. 2. Bio e ine y and Lignocellulosic By-P oduc s Resou ces deple ion, was e accumula ion, and clima e change a e a combina ion o o ces d i ing he need o he sus ainable p ac ices we a e acing nowadays. Addi ionally, u baniza ion and popula ion g ow h a e causing he global ene gy demand o be in con inuous ise. Wi h he ene gy demand inc easing, he necessi y o de achmen om ossil uels and he ansi ion o enewable esou ces is manda o y o educe he en i onmen al p oblems. Ene gy esou ces such as biomass, wind, and sola ene gy can mee he ene gy equi emen s i la ge-scale echnologies a e well de eloped [ 10 ]. In his sense, bio e ine y is analogous o ossil uel e ine y. The bio e ine y e m da es back o 1980. Since hen, se e al de ini ions ha e been conside ed. These de ini ions a e based on he ype o eeds ock used, ype o p ocesses, and ype o p oduc s ob ained [ 11 ]. In gene al, he bio e ine y concep is he syne gy o echnologies ha con e biomass in o hei building blocks o p oduce a a ie y o bio uels, chemicals, and high added- alue compounds. He eo , he de elopmen o a sus ainable p ocess in ol es no only he use o biomass bu also implies educing he use o ha m ul chemicals, ansi ion o g eene p ocesses, e icien use o ene gy, and elimina ion o was es (Figu e 1) [9]. Figu e 1. Pine alo iza ion unde bio e ine y concep . Molecules 2020,25, 2931 3 o 29 E hanol is a well-known bio uel p oduc o he second gene a ion bio e ine y. Second gene a ion o lignocellulosic bio e ine y usually begins wi h he p e ea men o he biomass in o de o inc ease he diges ibili y o cellulose, o solubilize he hemicellulose, and o eloca e he lignin [ 12 ]. P e ea men s can be mechanical, chemical, physicochemical, o biological [ 13 ]. A e wa d, o libe a e he e men able suga s (i.e., monosaccha ide uni s) om he p e ea ed biomass, acid o enzyma ic hyd olysis p ocesses a e applied [ 14 ]. Then, he e men a ion o he ob ained suga s o ob ain e hanol can be ca ied ou using mic oo ganisms as yeas o bac e ia [ 15 , 16 ], whe e, in an in eg a ed bio e ine y, e hanol can also be conside ed as a p ecu so o chemicals, hyd oca bon uels, and a oma ic compounds [ 17 ]. Hence, he esea ch and de elopmen o sus ainable p ocesses a e g owing no only o bio uels bu also o he high added- alue compounds han can allow an economically iable p ocess (Figu e 1). Cu en ly, lignocellulosic biomass has been la gely s udied as a po en ial subs a e in e men a ion p ocesses, and mainly o bio uel p oduc ion. Ne e heless, inno a i e and new eme ging echnologies a e being s udied o inc ease he ob ainmen o high- alue compounds o in e es , pa icula ly bioac i e ones. The eco e y o hese o high- alue compounds is linked o he bio e ine y concep and he g een chemis y p inciples. Lignocellulosic biomass (in which pine by-p oduc s may be included) is mos ly conside ed as a esidue om c ops as s aw, suga cane bagasse, co n s o e , and wood was e. Cellulose is he majo componen o he lignocellulosic ma e ials, ollowed by hemicellulose and lignin. Cellulose is he wo ld’s mos abundan biopolyme made up o glucose uni s. Applica ions o cellulose ex ac ed om lignocellulosics include he manu ac u e o cellulosic ibe and nanoc ys alline cellulose in a wide ange o indus ies such as au omo i e, ex ile, and medicine due o he s eng h on i s s uc u e, a ailabili y, modi iable su ace, enewabili y, and low cos [ 18 , 19 ]. Hemicellulose is he second mos abundan polysaccha ide in lignocellulosic biomass mainly composed by monome ic uni s as xylose, mannose, a abinose, glucose, galac ose, and acids such as u anic acid [ 20 ]. Hemicellulose and speci ic a ge p oduc s om hemicellulose a e used in a a ie y o a eas as ood, medicine, and chemicals due o he biocompa ibili y and bioac i i y p ope ies hey show [ 20 ]. Pine sawdus has been used o p oduce le ulinic, o mic, and ace ic acid and u u al o m hemicellulose ex ac ed by s eam explosion [ 21 ]. In addi ion, pinewood (Pinus elda ica) p e ea ed wi h dilu e sodium hyd oxide was used o p oduce e hanol om he p e ea ed solid whe e he solubilized hemicellulose ac ion was used o p oduce biogas [ 22 ]. The hi d main componen o lignocellulosic ma e ials is lignin, which is an amo phous phenolic polyme ha p o ides mechanical s eng h and igidi y o plan s [ 23 ]. In he bio e ine y p ocess, lignin canno be used as a subs a e o e men a ion as i con ains no suga s. The e o e, a wide a ea o esea ch is on lignin alo iza ion. Lignin is mainly used o gene a e hea and elec ici y due o he high hea ing alue al hough o he applica ions a e possible, including he use as a p ecu so o ca bon ibe syn hesis, esins, and low molecula weigh a oma ic and phenolic compounds [ 24 , 25 ]. Nowadays, he mode n polyme indus y om na u al sou ces o a oma ic compounds is limi ed due o he high p ices o he inal p oduc . He e, lignin plays an impo an ole, since phenolic compounds can be ob ained om lignin decons uc ion [26]. His o ically, wood has been a majo ene gy sou ce o human beings. Fo es biomass is he mos abundan eeds ock on ea h, ep esen ing 89.3% o he o al biomass [ 27 ]. In Eu ope, o es a ea is one o he mos impo an enewable esou ces, ep esen ing nea 5% o he wo ld’s o es and co e ing 43% o i s land, comp ising close o 182 million hec a es o o es . Fo es is also conside ed as a esou ce o imp o ing li e quali y and job gene a ion [ 28 ]. Wood biomass can be densi ied in o solid uels, as pelle s, o con e ed in o hea , elec ici y, bio uels, and o he biop oduc s h ough a a ie y o chemical, he mochemical, and biochemical p ocesses [ 29 ]. On he o he hand, he lumbe indus y gene a es a conside able amoun o was e ha includes lea es, ba ks, sawdus , chips, cones, esins, and b anches. These esidues a e no usually well alued and a e h own ou , bu ned, o used o animal bedding, al hough hey can be a p o i able sou ce o high added- alue compounds [ 30 ]. The ein, wood biomass esidues inc ease hei o e all alue due o he me aboli es ha a e p esen in lowe abundance compa ed wi h cellulose, hemicellulose, and lignin. These ex ac i e compounds combine alkaloids, waxes, phenolics, pec ins, esins, and essen ial oils [ 31 ], and hey a e o g ea impo ance Molecules 2020,25, 2931 4 o 29 conside ing he wide indus y applica ions, mo e p ecisely, in ood and pha maceu ical indus ies due o he an ioxidan , an imic obial, an i-in lamma o y, and an i umo al e ec s hey show [32]. 3. Pine as Feeds ocks This wo k is mainly ocused on he alo iza ion o he Pinus species (and i s by-p oduc s), which a e e e g een ees o esinous coni e s g oup om he Pinaceae amily. In he EU, he e a e mo e han 14 di e en species, ep esen ing one o he la ges o es occupa ions. Table 1desc ibes he main Pinus species dis ibu ed in he Eu opean coun ies acco ding o he “Eu opean o es gene ic esou ces p og am (EUFORGEN)” [33]. In Po ugal, pine o es s a e he hi d o es o ma ion a e eucalyp us and co k oaks, wi h an a ea o app oxima ely 1 million hec a es, ep esen ing an impo an pa o he o al o es , abou 23% [34]. Table 1. Pinus ees species implemen ed in Eu opean coun ies, as well as i s geog aphical dis ibu ion. La in Name Common Name Geog aphical Dis ibu ion Pinus syl es is Sco s pine All coun ies o Eu opa and Asia Pinus nig a Eu opean black pine Moun ain a eas o Eu ope, Uni ed S a es, and Asia Mino Pinus b u ia B u ia pine Eas e n Coas o he Medi e anean (Tu key, G eece, I aly) Pinus pinas e Ma i ime pine Wes e n Medi e anean Sea, Cen al and Sou he n Eu ope, and No h A ica Pinus halepensis Aleppo pine Coas al a eas o he Wes e n Medi e anean egion, Sou he n F ance and I aly, and No h A ica Pinus cemb a Swiss s one pine Con inen al Alps and egions o he Ca pa hian Moun ains Pinus uncina a Moun ain pine Moun ains o Wes e n Eu ope, No he n Eu ope, and Medi e anean Pinus pinea S one pine Medi e anean Basin, ex ending om Po ugal o Sy ia Pinus s obus Whi e pine Eas e n No h Ame ica and Ca pa hian Moun ains in Czech Republic and Sou he n Poland Pinus mugo Moun ain pine Moun ains o Cen al and Eas e n Eu ope Pinus held eichii Bosnian pine Sou he n and Wes e n pa o he Balkans, nea he Medi e anean basin Pinuscon o a Lodgepole pine Wes e n No h Ame ica, Eu ope, and New Zealand Pinus peuce Macedonian pine Moun ain a eas o he Balkan Peninsula Pinus adia a Mon e ey pine Cen al Coas o Cali o nia, Aus alia, New Zealand, Mexico, A gen ina, Chile, U uguay, Kenya, Spain, and Sou h A ica The chemical composi ion o pine and i s cons i uen s (wood, ba k, lea es, cones, seeds, and esin) a ies depending on he Pinus ee and also on many o he ac o s, such as geno ypic, ecological, and seasonal, among o he s [ 35 ]. The me hodology used o he de e mina ion o chemical composi ion o plan esou ces is also a ac o o conside , since di e en me hods lead o di e en esul s [36]. The gene al chemical/nu i ional composi ion o pine by-p oduc s has been desc ibed by se e al au ho s (wood [ 37 – 42 ], ba k [ 43 – 47 ], needles [ 48 , 49 ], cones [ 41 , 50 ], seeds (nu s) [ 51 – 53 ], and esin o oleo esin [54,55]) and is summa ized in Figu e 2. Molecules 2020,25, 2931 5 o 29 Figu e 2. Gene al chemical/nu i ional composi ion o pine by-p oduc s. Pine Applica ions A p esen , ag o o es y esidues and by-p oduc s a e mainly used as combus ion eeds ock o bio uels p oduc ion [ 56 ]. The mos impo an biomasses a e ob ained om lumbe indus y (ba k and sawdus ) o o es ac i i ies, he esidues om a ms and ag o-business, he o ganic ac ion o municipal solid was es, and he plan s delibe a ely g own o ene ge ic pu poses. In his sense, i is impo an o educe and gi e a “second li e” o hese esidues, mo ing o “ze o was e”. The Pinus plan is e y impo an economically, as i is conside ed good eeds ock o he bioeconomy (Figu e 1) [ 57 ]. In i s na u al en i onmen , i has an impo an p o ec i e unc ion, such as imp o ing wa e in il a ion, p e en ing soil e osion on d y slopes, and se ing as a windb eak [ 33 ]. T ees a e also used as o namen al plan s in u ban and indus ial con ex s. O he uses include Ch is mas ees and uelwood. In e es ingly, in a s udy by Ehn and co-wo ke s [ 58 ], i has been ound ha pine o es a oma ( o i s con en in ola ile compounds, e penes) can limi clima e change, p e en ing he global wa ming. The main indus ial ac i i ies a e ela ed o he usage o pine wood and wooden p oduc s, including sawmills, wood panels, cellulose pulp and pape p oduc ion, wood uels, ca pen y, packing, and wood u ni u e [ 33 ]. These eeds ock, hei componen s, and hei by-p oduc s a e conside ed a good sou ce o wood bio e ine ies, ans o ming he lignocellulosic ac ions in o bio uels, chemical p oduc s, and composi e ma e ials, as p e iously men ioned [57]. Pine ba k, he by-p oduc ob ained in la ge quan i ies ha is p oduced when wood is ans o med, is almos exclusi ely used as uel, being also subjec ed o compos ing o illing subs a e in nu se ies, u ilized o co e in public ga dens, o simply h own away on landscapes [ 44 , 59 ]. Nowadays, his by-p oduc has been used as low-cos and g een al e na i es was e-based bioso ben s o he emo al o a wide ange o wa e pollu an s [60]. The pine lea es (needles) a e no mally used in ag icul u e o en ich he soil, and he seeds a e used o human consump ion because hey a e highly nu i ious and much app ecia ed by consume s in cooked/p epa ed dishes ( ood indus y) o simply as edible pine nu s. The esins, a p oduc esul ing om he exploi a ion o hese species, a e mo e egula ly used as a sealan , glue, a nish, and also as a sol en and pain hinne ( u pen ine oil) [55,57,61]. Molecules 2020,25, 2931 6 o 29 In addi ion o he “ adi ional” uses o hese by-p oduc s, i is impo an o ake ad an age o hese bio- esou ces o c ea e high alue-added p oduc s. Cu en ly, he ag o o es y by-p oduc s ha e been inc easingly exploi ed o isola e biocompounds wi h high indus ial in e es . S udies using na u al ma ices as a po en ial sou ce o bioac i e compounds ha e been published in ecen decades [ 7 , 62 – 67 ]. Fo ins ance, in a new e iew pape [ 68 ], he au ho s epo ha in addi ion o ui s and ege ables, ee ba ks a e ich in phenolic compounds wi h excellen biological p ope ies (such as an ioxidan , immunos imula o y, an icance , an ibac e ial, an i-in lamma o y, an imu agenic, e c.) and may used o ob ain unc ional ing edien s. Pine ba k is one o he mos sough a e sou ces o an ioxidan biocompounds o na u al o igin. The ex ac s ob ained om his by-p oduc a e mos ly composed o phenolic compounds wi h high biological ac i i y [ 46 , 59 , 62 , 69 – 72 ]. Nowadays, he e a e nume ous s udies epo ing he applicabili y o pine bioac i e ex ac s in a ious a eas, such as heal h ca e, ood, ag ochemical, and o he s [ 73 – 75 ]. One o he mos p omising applica ions o hese ex ac s is in he p ese a ion and en ichmen o oods, hus eplacing syn he ic an ioxidan s, as well as a nu aceu ical, cosmeceu ical, o pha maceu ical. The pine wood/sawdus ex ac i es, ich in phenolic an ioxidan compounds, ha e a po en ial o ood and pha maceu ical applica ions, such as p ese a i es o nu aceu icals [40,76]. Pine a s, a by-p oduc o pine wood and ba k, a e known o con ain icyclic di e penoid esin acids, icyclic di e pene hyd oca bons, alkylphenan h enes, and a y acids. This wa e - esis an by-p oduc has a wide ange o applica ions, o example, as a mul ipu pose adhesi e, sealan , and in medicine [77,78]. Knowing he chemical composi ion and physicochemical p ope ies, pine seeds o nu s appea o ha e a posi i e e ec on human heal h [ 52 , 53 ]. The seed lipids, ich in linoleic acid, ha e a bene icial e ec on blood p essu e and choles e ol. The a y acid composi ion and he ela i ely high polyphenol con en p esen high p o ec ion agains oxida i e s ess. In his sense, pine seeds can po en ially be used in he ood indus y and o he non- ood indus ies, such as pha maceu ical and cosme ics [ 79 – 81 ]. Oleo esins a e widely used in he syn hesis o pe umed compounds o cosme ics, essences as addi i es o ood and be e ages, ood p o ec ion (an imic obial), bioinsec icides (high epellen ac i i y), apping g een chemicals, bio uels, and ca bon seques a ion om mul ipu pose ees [54,55,57,61]. In e es ingly, his sea ch o unc ional ex ac s, new na u al molecules, and he c ea ion o new high alue-added p oduc s has inc eased he use/s udy o ag o o es y by-p oduc s and esidues, including pine ba k, sawdus , lea es, seeds, and esin. This makes i possible o po en ially b ing hese “was es” back o he ma ke . 4. Ex ac ion P ocesses o Phenolic Compounds Reco e y The eco e y o bioac i e and unc ional pu i ied biomolecules o ex ac s om plan ma e ials is an impo an s ep o enable he euse o na u al esou ces o subsequen applica ion in pha maceu ical and cosme ic p oduc s, ood en ichmen and p ese a i es, die a y supplemen s, and nu aceu icals. The ex ac ion p ocess o na u al ex ac s depends on se e al ac o s, including he applied ex ac ion echnique, he pa ame e s associa ed wi h he echnique (such as empe a u e, ime, and he ex ac ion sol en ), and he aw ma e ials composi ion [ 63 ]. I is known ha he phenolic compounds a e me aboli es p esen in he cell acuoles [ 82 ]. The e o e, i is also impo an o p omo e he opening o po es o e en he up u e o he cell wall o acili a e he elease o he compounds in o he ex ac ion medium. In his sense, i is impo an o s udy all a iables o he p ocess in o de o maximize he po en ial o he ex ac ion me hod, de eloping a highly e icien p ocess [ 8 ]. On he o he hand, all a iables in he p ocess ha e o make i possible o ob ain a sa e and high quali y inal p oduc (eco-ex ac ), in addi ion o maximizing he ex ac ion o he compounds o in e es . Figu e 3illus a es he main p inciples o an e icien ex ac ion p ocess, ollowing he concep o g een ex ac ion. Molecules 2020,25, 2931 7 o 29 Figu e 3. P inciples o e icien p ocess o ob aining na u al ex ac s. Adap ed om Chema e al. [ 8 ]. 4.1. Ex ac ion Sol en s The educ ion use o haza dous sol en s is also conside ed one o he p io i ies o he EU policy o he 2010 o 2050 pe iod [ 7 ]. Nowadays, ex ac ion using con en ional o ganic sol en s is he mos commonly used p ocedu e o p epa e ex ac s om plan ma e ials due o hei ease o use, e iciency, and wide applicabili y. The e iciency o he ex ac ion me hods depends on he choice o he sol en , since sol en s wi h di e en pola i ies a e needed o he isola ion o compounds wi h di e en chemical cons i u ion. In addi ion, i is di icul o de ine a single me hod o he e icien ex ac ion o all compounds, since he pola i ies o he molecules o be ex ac ed a y [63]. A sui able sol en has o be able o ob ain sa e and high-quali y ex ac s and o p ese e he biological e ec s o he ex ac ed compounds wi hou exhibi ing oxici y when consumed. Fu he mo e, i should be ecyclable and eusable, p e en ing nega i e en i onmen al e ec s. O he pa ame e s, such as lammabili y, explosi eness, ola ili y, mass ans e , and (in)abili y o dissocia e he complex ex ac should be conside ed [ 65 ]. The ex ac ion yield depends no only on he sol en used bu also on se e al o he ac o s such as sample/sol en a io, empe a u e, ex ac ion ime, s i ing, and aw ma e ial composi ion [83]. Con en ional sol en s om “non-na u al”/pe oleum esou ces, such as me hanol, e hanol, ace one, e hyl ace a e, dichlo ome hane, hexane, e c. and hei aqueous solu ions ha e been used o he ex ac ion o bioac i e compounds om plan ma e ials. Se e al s udies ha e been done demons a ing he impo ance o hese sol en s in he eco e y o na u al molecules and ac i e ex ac s om di e en plan s and by-p oduc s [ 65 , 84 – 86 ], including he lignocellulosic by-p oduc s [ 87 ]. Resea che s also s udied he in luence o hese di e en sol en s in ob aining an ioxidan phenolic compounds om pine by-p oduc s, and depending on he sol en used, he ex ac ed ac ion (ex ac composi ion) is di e en [ 59 , 85 , 88 ]. Fo example, in a wo k by Venka esan and collabo a o s [ 85 ], he impac o di e en ex ac ion sol en s (such as e hanol, me hanol, isop opanol, ace oni ile, and ace one) was analyzed o ob ain phenolic ex ac s wi h an ioxidan ac i i y om Pinus densi lo a ba k. Thei esul s showed ha low concen a ions o e hanol and ace oni ile a e a o able o he ex ac ion o phenolics wi h high an ioxidan ac i i y. In ano he s udy, using Pinus ni u i, me hanol was mo e e icien han o he sol en s such as e hanol, hexane, and e hyl ace a e, showing an enhanced ex ac ion a e o phenolic and la onoid compounds wi h highe biological ac i i ies [88]. I is known ha wa e is an e icien sol en o he ex ac ion o a ious compounds, due o i s p ope ies and hanks o he ac ha wa e is easily a ailable, sa e, non- oxic, non- lammable, and en i onmen ally iendly [ 8 ]. In his sense, i is conside ed he cleanes /g eenes sol en (apa om Molecules 2020,25, 2931 8 o 29 he use o no sol en , which is he g eenes ), acco ding o he p inciples o g een chemis y [ 64 , 89 ]. Howe e , i is no sui able o he ex ac ion o less pola subs ances. O he possible en i onmen al iendly sol en s’ op ion is o eplace pe oleum-based sol en s by “bio-sol en s”. Fo ins ance, “bioe hanol” can be p oduced om bio esou ces, by e men a ion. This second-gene a ion sol en could be made cos -compe i i e by he de elopmen o bio e ine y-based p ocesses o he in eg al use o lignocellulosic biomass, subs i u ing e hanol ob ained om pe oleum de i a i es [90]. As al e na i es o con en ional sol en s, he use o g een sol en s such as ionic liquids (ILs) and na u al deep eu ec ic sol en s (NADES) is eme ging, in o de o make he ex ac ion p ocess eco- iendly and mo e e ec i e [ 91 ]. In gene al, ILs and NADES a e de i ed om cheap, abundan , low oxic, and biodeg adable na u al componen s [ 6 , 7 ]. NADES can be de ined as “mix u es o pu e na u ally occu ing compounds ha p esen an eu ec ic poin empe a u e below an ideal liquid mix u e” [ 6 , 92 ]. ILs a e liquid mol en sal s a empe a u es below 100 ◦ C composed by ca ions and o ganic o ino ganic anions wi h exclusi e and adjus ed physicochemical p ope ies [93]. Howe e , a lack o in o ma ion on he biological ac i i y and oxici y o he ob ained ex ac s limi s he use and indus ial applica ions o ILs and NADES [ 7 ], leading o hese sol en s no being egula ed by he Fede al D ug Adminis a ion (FDA) [ 94 ]. Fu he mo e, al hough hey can be uned o enhanced a ini y owa d he compound o in e es , hei sepa a ion om he inal mix u e may be hinde ed by he high boiling poin cha ac e is ic o hese sol en s. Mu ado and collabo a o s [ 95 ] summa ize he main chemical cons i uen s o hese ILs and NADES and men ion some wo ks whe e hey a e applied in he ex ac ion o an ioxidan compounds, such as phenolic compounds and ca o enoids, among o he s. Speci ically, ILs and NADES ha e been applied o he phenolic compounds and o he an ioxidan compounds ex ac ion om lignocellulosic biomass and ag i- ood was es [4,6,93,96–98]. In he case o pine plan s as eeds ock, he p ocess o ex ac ing bioac i e compounds wi h added alue (such as phenolics) using hese g een sol en s is no widely explo ed. In a ecen s udy, ILs we e combined wi h enzymes and mic owa e echnology o p omo e cell wall dis up ion o he ex ac ion o essen ial oil and p ocyanidins om pine cones o Pinus ko aiensis [ 99 ]. Howe e , he e a e no epo s using ILs and NADES as al e na i e sol en s o ex ac ion o bioac i e molecules o o he pa s o pine plan , despi e he ad an age hey showed o ob aining unc ional compounds in o he lignocellulosic esidues. 4.2. Ex ac ion Technologies Con en ionalme hodso ex ac ion,suchas hesolid–liquidme hod,hyd odis illa ion,mace a ion, and Soxhle equi e he use o la ge amoun s o wa e o o ganic sol en s, agi a ion, long ex ac ion ime, high empe a u es, and ene gy consump ion, as well as he gene a ion o a conside able quan i y o was es [8,100,101]. The need o ob aining g eene , sus ainable, and iable p ocesses has led scien is s and indus ies o de elop new p ocesses in ull co espondence wi h he g een ex ac ion concep [ 102 , 103 ]. In his con ex , he sea ch o al e na i e ex ac ion echnologies wi h en i onmen al and economic ad an ages, aking in o accoun he cha ac e is ics o he inal p oduc s has eme ged [ 104 ]. As a esul , echniques such as ul asound-assis ed ex ac ion (UAE), mic owa e-assis ed ex ac ion (MAE), supe c i ical luid ex ac ion (SFE), p essu ized liquid ex ac ion (PLE), and ohmic hea ing (OH) elec o echnology ha e been de eloped, op imized, and applied o imp o e he ex ac ion p ocess o an ioxidan phenolic compounds om plan esou ces, such as pine by-p oduc s (Table 2). In he ollowing sub-sec ions, a b ie in oduc ion o hese ex ac ion echnologies and some examples o hei applica ion in ob aining phenolic compounds om pine by-p oduc s will be p esen ed. Molecules 2020,25, 2931 9 o 29 4.2.1. Ul asound-Assis ed Ex ac ion Ul asound p oduces high-in ensi y sound wa es ( ypically highe han 20 kHz) [ 104 ]. The ope a ion mechanism o UAE is based in p essu e a ia ions ha o m mic obubbles esul ing in mic o u bulence and a high collision o pa icles. The collapse o mic opa icles caused by ul asound wa es can p omo e highe pene a ion o he sol en in o he cellula ma e ial causing he cell walls dis up ion and inc easing he elease o in acellula compounds in o he ex ac ion medium [ 105 , 106 ]. UAE is an al e na i e echnology wi h ad an ages compa ed o con en ional echniques, since less p ocessing ime, low sol en usage, and lowe ex ac ion empe a u es a e equi ed, p ese ing hea -sensi i e compounds. In addi ion, i leads o an inc ease in ex ac ion yield, equi ing less ene gy in he p ocess [ 106 ]. Due o i s ad an ages, ul asound echnology is men ioned as an eco- iendly and cheap p ocess and can be easily implemen ed o ex ac phenolic compounds om plan s and plan by-p oduc s [76,107–110]. In he las decade, UAE has been used o ob ain ex ac s ich in phenolic compounds om pine by-p oduc s. In a s udy o Liazid and co-wo ke s [ 111 ], UAE was used o ob ain phenolic ex ac s om seeds o wo pine species (Pinus ma i ima and Pinus d’Alpes). The esul s o his wo k showed ha he applica ion o ul asound wa es, using wa e as a sol en a 75 ◦ C du ing 20 min, doubled he eco e y o phenolic compounds compa ed o a con en ional mace a ion echnique, inc easing he an ioxidan ac i i y o hese ex ac s. Using he ba k o he Pinus adia a as a aw ma e ial, Asp é and collabo a o s [ 112 ] e i ied ha he syne ge ic e ec o ul asounds (35 kHz/85 W) wi h ace one 70% ( / ) allows he o ma ion o po es in he ma ix cells, p omo ing he apid up u e o he cell wall, acili a ing he ex ac ion o phenolic compounds, and d as ically educing he ex ac ion ime ( om 180 min o con en ional ex ac ion in a wa e ba h o Soxhle , o 6 min when using UAE). In ano he s udy, au ho s used ul asound echnology in combina ion wi h me hanol 70% ( / ) as a sol en o ex ac phenolic compounds, such as la onoids om lea es (needles) o ou di e en pine species (Pinus peuce,P. nig a,P. mugo and P. syl es is) [ 113 ]. UAE p o ed o be a po en ial ool o he sus ainable eco e y o phenolic compounds om pine lea es, wi hou using empe a u e in he p ocess. Recen ly, Meullemies e and co-wo ke s [ 76 ] epo ed ha he UAE, in addi ion o inc easing he ex ac ion o phenolic compounds om ma i ime pine wood (sawdus was e) by 40% compa ed o con en ional ex ac ion echniques (solid–liquid), also allowed educing he ime o he p ocess. On he o he hand, hey also epo ed ha UAE is a scalable echnique and can be applied indus ially o ob ain bio- unc ional ex ac s. 4.2.2. Mic owa e Assis ed Ex ac ion MAE is a hea ing p ocess using elec omagne ic wa es o equency be ween 300 MHz and 300 GHz ha in e ac wi h samples o ex ac analy es om a ma ix o a sol en . The mic owa e i adia ion inc eases he in e nal p essu e o he plan cells by hea ing he cells om he inside, leading o cell dis up ion and eleasing he compounds o in e es . Some o he ad an ages o MAE a e a lowe ime o ex ac ion compa ed wi h o he ex ac ion p ocesses, he possibili y o mul iple ex ac ions, low sol en olume, an a ainmen o high empe a u es, and mo e e ec i e, uni o m and selec i e hea ing [ 107 , 114 ]. To ha e be e ex ac ion yields, i is impo an o conside he capabili y o he sol en o abso b mic owa es, as i can be a d awback when he sol en lacks he capaci y o ene gy abso p ion. Fu he mo e, he hickness o he sample o be hea ed may also be a d awback, pa icula ly in he scalabili y o he ex ac ion p ocess, as he abili y o mic owa es o pene a e a sample is limi ed. Liazid e al. [ 111 ] s udied he ex ac ion o phenolic compounds om Pinus pinas e seeds using wa e as sol en and demons a ed ha MAE p oduces ex ac s wi h g ea polyphenols con en , since i can achie e high empe a u es, which is a decisi e ac o in phenolic compounds ex ac ion, as mos o hese p ocesses a e empe a u e dependen . In his wo k, he polyphenolic ex ac s ob ained a 75 ◦ C demons a ed high an ioxidan ac i i y. In ano he wo k, he ex ac ion ime o ob ain phenolic compounds om Pinus adia a ba k was educed by 98.3% using MAE compa ed wi h he Soxhle Molecules 2020,25, 2931 16 o 29 depends on he pa icle size [ 76 ]. The pa icle size has a di ec e ec on he amoun o he polyphenol ex ac ed. The smalle he pa icle size is, he mo e ex ac s a e ob ained (bes esul s we e egis e ed o size 0.4 mm). Howe e , he e is no impac on he na u e o he ex ac and on he ypes o he compounds ex ac ed [ 115 ]. The e is a lowe limi o he pa icle size beyond which he quan i y o ex ac ed polyphenols dec eased. I was egis e ed ha e y ine pa icles s ayed in suspension a he su ace o he sol en and he e o e we e no subjec ed o p ope ex ac ion [76]. The ex ac ion o polyphenols would also depend on he solid/liquid a io. Meullemies e e al. [ 76 ] ound he op imum a io o be abou 6 g o d y ma e ial/100 mL; when concen a ions we e highe han 7.5 g o d y ma e ial/100 mL, he ma i ime pine wood abso bed all a ailable liquid. Eigh een phenolic compounds we e iden i ied in he ex ac s o P. pinas e by Fe ei a-San os and co-wo ke s [ 45 , 59 ]. In one o he s udies, he au ho s ied o unde s and he ac ion o he ype o sol en (wa e and e hanol) and me hod o ex ac ion (con en ional o ohmic hea ing) o e he chemical p o ile o he ex ac s. Ex ac s made wi h he di e en sol en s we e ound o be s a is ically di e en in e ms o con en o phenolic compounds [ 59 ]. The an ioxidan ac i i y o he ex ac s we e always highe in he hyd oe hanolic ex ac s compa ing wi h he aqueous ex ac s. Mo eo e , signi ican co ela ions we e ound be ween o al phenolic con en and an ioxidan ac i i ies o he ob ained ex ac s [ 59 ]. In a second s udy, om he same au ho , pine ba k ex ac s made wi h di e en concen a ions o e hanol ( om 0% o 90%) we e e alua ed o hei bioac i i ies (an ioxidan , an imic obial, and an idiabe ic) and in i o cell iabili y (in no mal and cance cell lines). The s udy demons a ed ha he pine ba k ex ac s ha e high po en ial an ioxidan , an idiabe ic, and an imic obial ac i i ies, especially when made wi h 50% and 70% o e hanol [ 45 ]. Mo eo e , he au ho s concluded ha pine ba k ex ac s ac selec i ely on cance cells, as hese a e nega i ely selec ed and he non- umo cells a e no . In gene al, bo h s udies [ 45 , 59 ] showed ha he compounds wi h he highes concen a ions in all samples we e ellagic acid and axi olin. The concen a ions o ellagic acid accoun ed o be ween 9.0% and 50% o he o al phenolic compounds, while axi olin accoun ed o be ween 15% and 42% o he o al phenolic compounds. Indi idual concen a ions o phenolic compounds such as ca echin, axi olin, que ce in, ca eic acid, o-couma ic acid, e ulic acid, and ellagic acid in he ex ac s made wi h 50% e hanol we e almos wice as high as in he co esponden ex ac s ob ained wi h wa e . The e a e no many s udies showing he iden i ica ion and e en less s udies showing he quan i ica ion o polyphenols in ex ac s om Pine species. The ex ac s a e ob ained mos ly om he pine ba k, and ewe a e ob ained om needles (Table 3). The chemical composi ion o he ex ac s depends on he ype o pine used (species, loca ion), on he pa o he plan , on he me hod o ex ac ion, and on he sol en . Fo example, he main g oup o polyphenols compounds ound in he P. syl es is is he g oup o s ilbenes [ 151 ], while in P. pinas e , he main g oup o compounds a e he la onoids [59]. Table 3. Indi idual phenolic compounds ound in pine by-p oduc s and hei epo ed bioac i i ies. Name Chemical Fo mula Concen a ion Range (mg/g) Bioac i i ies Re e ence NEEDLES Epica echin C15H14O61.5 an ioxidan [152,153] p-Couma ic Acid C9H8O32.3 an ioxidan , an i-in lamma o y, hepa op o ec i e and enop o ec i e, an i-neu odegene a i e, an i-choles e olemic, imp o e insulin esis ance, an i- y osinase, an imic obial [152,154–156] Molecules 2020,25, 2931 17 o 29 Table 3. Con . Name Chemical Fo mula Concen a ion Range (mg/g) Bioac i i ies Re e ence SEEDS P o oca echuic Acid C7H6O40.5 an i- y osinase, an imic obial, and an i-in lamma o y ac i i ies [156,157] Ca echin C15H14O60.5 hepa op o ec i e ac i i y [145,157] Epigalloca echin Galla e C22H18O11 0.5 an imic obial, an ioxidan , pho op o ec i e [145,157] Vanillic Acid C8H8O40.9 an i-in lamma o y, neu op o ec i e [157,158] Sy ingic Acid C9H10O51.0 ca diop o ec i e, an ioxidan , an imic obial, an i-in lamma o y, neu o and hepa op o ec i e ac i i ies [157,159] Epica echin C15H14O61.3 an ioxidan [157] Taxi olin C15H14O71.7 an ioxidan , an icance , an i-in lamma o y [157] Cinnamic Acid C9H8O20.1 an i- y osinase, an imic obial, and an i-in lamma o y [156,157] E iodic yol C15H12O63.8 an i-in lamma o y [157,160] m-Couma ic Acid C9H8O3 aces no ound [157] BARK Gallic Acid C7H6O5 aces–5.5 an i-in lamma o y, an ihype lipidemic, an ioxidan , an i umo , an ihype glycemic, and an i-neu odegene a i e, ca diop o ec i e [59,154,155,159, 161] Galloca echin C15H14O70.07–0.95 inhibi o o melanin biosyn hesis [45,59,162] Epica echin C15H14O60.06–1.9 an ioxidan [71,161] Epica echin Galla e C22H18O10 0.3–0.9 an ioxidan [161] Ca echin C15H14O60.095–7.7 an ioxidan , an icance , ca diop o ec i e, an i ungal [45,59,71,161,162] Vanillic Acid C8H8O40.02–0.07 neu op o ec i e, an i-in lamma o y [45,59,158] Ca eic Acid C9H8O40.03–0.2 an ioxidan , pho op o ec i e [45,59,163] Rosmani ic Acid C18H16O80.4–0.8 an ioxidan , an idiabe ic, an ibac e ial, an i i al [59,164,165] Ca echin Galla e C22H18O10 0.002–1.5 an ioxidan , an icance [71,166] Taxi olin C15H12O70.01–4.7 an ioxidan , an icance , an i-in lamma o y [45,59,148,167] 3,4 Dihyd oxy-Benzoic Acid C9H10O40.08–0.8 neu op o ec i e, an ioxidan , nema icidal ac i i y [45,59,168] Ellagic acid C14H6O80.4–4.0 an i-in lamma o y, an ioxidan [45,59,169] Na ingin C27H32O17 0.8–2.0 no ound [45,59] Apigenin C15H10O50.3–0.5 an icance , an ioxidan , an i-in lamma o y [45,59,170] Res e a ol C14H12O30.03–0.4 an ioxidan , an i-cance , ca diop o ec i e, an i-in lamma o y [45,59,159,171] Fe ulic acid C10H10O40.06–0.5 an ioxidan , pho op o ec i e [45,59,163] p-couma ic acid C9H8O3n.q. an ioxidan , an i-in lamma o y, hepa op o ec i e and enop o ec i e, an i-neu odegene a i e, an i-choles e olemic, imp o e insulin esis ance, an i- y osinase, an imic obial [59,154–156] Molecules 2020,25, 2931 18 o 29 Table 3. Con . Name Chemical Fo mula Concen a ion Range (mg/g) Bioac i i ies Re e ence Que ce in C15H10O70.06–1.1 in lamma o y, an imic obial, an icance [45,59] P ocyanidin A2 C30H24O12 n.q. an ioxidan [148] P ocyanidin B1 C30H26O12 n.q. an ioxidan , neu op o ec i e, an i-p oli e a i e ac i i y [148] P ocyanidin B2 C30H26O12 n.q. an ioxidan , an i-in lamma o y, ca diop o ec i e, neu op o ec i e, an i-p oli e a i e ac i i y [148] n.q.–no quan i ied. As one can see om Table 3, he main polyphenol compounds ound in ex ac s om pine needles a e p-couma ic acid and epica echin, in pine seeds e iodic yol and axi olin, and in pine ba k ca echin, gallic acid, and axi olin. In he ollowing ex , we summa ize he bioac i i ies o he indi idual compound ound in he ex ac s o pine species. Howe e , we wan o d aw he a en ion o he eade o he idea ha , in e ms o exp essing biological ac i i ies, he polyphenols ac as g oup o compounds a he han indi idual compounds, and syne gis ic and/o an agonis o simply di e en e ec s may be ound. The p-couma ic acid oge he wi h e ulic and ca eic acids a e he mos common hyd oxycinnamic acids in pine-based ex ac s. The hyd oxyla ion o p-couma ic acid esul s in he o ma ion o e ulic acid, while he oxyme hyla ion o p-couma ic acid p oduces ca eic acid, espec i ely. These phenolic acids a e used as p ecu so s in he syn hesis o lignins and o he phenolics [ 136 ]. Tao iq e al. [ 156 ] conduc ed a s udy on indi idual compounds as possible ing edien s in cosmeceu ical o mula ions. The au ho s concluded ha p-couma ic, p o oca echuic, and cinnamic acids displayed an i- y osinase, an imic obial, and an i-in lamma o y ac i i ies, showing hei po en ial o he cosmeceu ical indus y. Ca eic acid and, a a highe deg ee, e ulic acid p o ed o p o ec he skin agains UVB-induced e y hema. Besides as an ioxidan s, hese wo hyd oxycinnamic acids can be used as pho op o ec o s in skin cosme ics [163]. The p o oca echuic, anillic, and sy ingic acids a e he h ee commonly ound hyd oxybenzoic acids [ 136 ]. This ee hyd oxybenzoic acids we e also ound in pine ex ac s (Table 3). Vanillic acid demons a ed an i-in lamma o y ac i i y wi h neu op o ec i e ac i i y and was ound o be a p omising candida e o p e en ing and/o delaying he onse and p og ession o ischemic inju y and ascula demen ia [ 158 ]. In o he cases, he use o a mix u e o phenolic compounds a he han he indi idual compounds exhibi s s onge ac i i ies. Fo example, he combined use o sy ingic acid, es e a ol, and gallic acid, in a s, e ealed an ioxidan and ca diop o ec i e ac i i ies [ 159 ]. Res e a ol also showed an an icance e ec when examined in lung, p os a e, b eas , skin, and gas oin es inal cance s [ 172 ]. Res e a ol is he mos known cons i uen o wines and g apes, bu i was also ound in pine ba k ex ac s (Table 3). I was also p o en ha es e a ol has an i-in lamma o y capaci y, especially in he skele al muscle, bu i is less ac i e in li e [ 171 ]. Mo eo e , gallic and p-couma ic acids we e conside ed as p omising adju an agen s agains he p og ession o neu odegene a ion in he b ain by diabe es [ 155 ]. Rosma inic acid is known o ha e a numbe o po en ially bene icial biological e ec s and is an acid es e o ca eic acid and 3(3,4-dihyd oxyphenyl)lac ic acid. The use o osma inic acid in gela in edible ilm showed long- e m an ibac e ial ac i i y. Rosma inic acid edible ilms may ha e p omising applica ion in he ields o ood and pha maceu ical packaging, as hey showed a good an ibac e ial ac i i y e en a e 3 mon hs o s o age [ 173 ]. Rosma inic acid was ound in ex ac s o pine ba k in concen a ions be ween 0.4 and 0.8 mg/g [ 59 ]. This acid was ound o be he p edominan compound o Sal ia species. S ong co ela ions be ween he osma inic acid con en s and bioac i i es o Sal ia samples we e es ablished [ 165 ]. Mo eo e , his acid demons a ed po en an i i al p ope ies [ 164 ]. 3,4 dihyd oxybenzoic acid is uni e sal in he Angiospe m plan s, as i Molecules 2020,25, 2931 19 o 29 is cons i uen o lignin. I is a s ong an ioxidan , as well as a neu op o ec i e agains A β -induced neu onal damage [ 168 ]. This acid can be used in o mula ions o phy onema ode con ol, as i showed nema icidal ac i i y agains ju eniles o M. incogni a [174]. As we can see om he Table 3, in di e en pine ex ac s, many ca echin compounds wi h diphenylp opane (C 6 –C 3 –C 6 –) skele ons we e ound. Epigalloca echin, epigalloca echin galla e, and epica echin a e he main cons i uen s o he lea es o Camellia sinensis ( he ea plan ), while ca echin galla e is a mino polyphenolic cons i uen in g een ea: 1.28% (by weigh ) o he o al ca echin con en in g een ea [ 166 ]. These ca echins a e esponsible o he as ingen and bi e as e o he g een ea [ 153 ]. Ca echin is he main phenolic compound p esen in P.pinas e ba k ex ac ollowed by epica echin and epica echin galla e [ 161 ]. Galloca echin was ound also in No way sp uce and con i med o be a s ong inhibi o o melanin biosyn hesis; howe e , he e is li le in o ma ion on he biological ac i i ies o his compound [ 162 ]. All hese ca echins ha e s ong an ioxidan s and an icance ac i i ies agains di e en ypes o cance [ 166 ]. Ca echins ha e ecei ed conside able a en ion as p omising candida es o de elopmen o he apeu ic agen s. Taxi olin, as an indi idual compound, is ex ensi ely s udied. I was ound in he pine ex ac s o seeds and ba k; in ba k, i is p esen in much highe concen a ions han in seeds [ 45 , 59 , 157 ]. Fo ins ance, his compound was eco e ed om P.nig a ba k [ 120 ] wi h a maximum ex ac ion eco e y o 34%. Taxi olin was de ec ed as he majo compound in o he needle lea ed ees such as he Japanese la ch, La ix kaemp e i [ 175 ]. I s main bioac i i ies a e an ioxidan , an icance , and an i-in lamma o y [ 148 , 167 ]. Que ce in is a axi olin- ela ed la onoid ound in onions, and i showed an i-in lamma o y, an imic obial, and an icance p ope ies ( in i o and in i o ) [ 176 ]. Que ce in- ich ex ac s om onion skin can be used in unc ional b ead p oduc ion [176]. Acco ding o Lan o and co-wo ke s [ 157 ], e iodic yol was one o he main compounds ound in ex ac s o Sibe ian pine ba k. E iodic yol, as axi olin, can be ind in ci us ui s. I has showed an ioxidan and an i-in lamma o y ac i i ies. Recen indings indica ed ha e iodic yol migh be a new p e en a i e agen o ps eoa h i is [ 177 ]. Ano he p omising he apeu ic agen o he ea men o os eoa h i is is ellagic acid [ 169 ]. I is ound in high concen a ions in he e hanolic ex ac s o P. pinas e [59], which is also a cons i uen in he ui peel o be ies and nu s [169]. Apigenin is ound abundan ly in he bs, ui s, and ege ables (peppe min , g ape ui , pa sley). I has po en an ioxidan , an i-in lamma o y, and an icance p ope ies [ 170 ]. Gascon e al. [ 148 ] ound h ee p ocyanidin compounds in pine ba k ex ac s: A2, B1, and B2. The ac i i ies o p ocyanidins depend on hei s uc u e, especially on hei deg ee o polyme iza ion. P ocyanidin B2 is one o he mos ac i e molecules wi hin he p ocyanidins, as well as he mos s udied. I is also ound in cocoa and g ape seeds. The h ee compounds ha e an ioxidan ac i i y; B- ype p ocyanidins ha e also neu op o ec i e ac i i y. The iches se o bioac i i ies agglome a es o he p ocyanidins B2, bu as we men ioned, his is also he mos s udied one. The e a e se e al pine ba k comme cial ex ac s: Oligopin ® , Pycnogenol ® , and Fla angenol ® . Pycnogenol ® is he mos known and mos s udied one. I s ex ac ion in ol es s anda dized consecu i e s eps using wa e and e hanol as sol en s. I is a polyphenol- ich ex ac p epa ed om P. pinas e (F ench ma i ime pine). The main cons i uen s a e p ocyanidins (85%), la onoids (ca echin, axi olin), as well as some phenolic acids in mino amoun s (gallic, ca eic, and e ulic acid) [ 149 ]. This ex ac p o ed o ha e excellen an ioxidan p ope ies ha can p omo e a ious heal h p ope ies such as ca diop o ec i e, an icance , an ihype ensi e, and an i-in lamma o y [ 118 , 150 ]. In ano he s udy, he clinical e iciency o Pycnogenol ® in he managemen , ea men , and con ol o ch onic enous insu iciency and enous mic oangiopa hy was p o en [ 178 ]. This ex ac showed also an i-diabe ic p ope y, as he supplemen a ion o Pycnogenol ® o con en ional diabe es ea men lowe ed glucose le els and imp o ed endo helial unc ion [ 179 ]. Oligopin ® is ano he ex ac ob ained om he pine ee P. pinas e om a speci ic loca ion in F ance (Landes o Gascony). I s p oduc ion includes wo ex ac ion s eps and one pu i ica ion s ep. This me hodology ensu e ha he ob ained ex ac has Molecules 2020,25, 2931 20 o 29 a speci ic and cons an composi ion. The main compounds ound in Oligopin ® a e la onoids (ca echin and axi olin) and acids ( e ulic, gallic, ca eic, p-couma ic, and p o oca echic) [180]. As a inal ema k, he indi idual polyphenol compounds ound in he ex ac s o pine ba k ha e di e se bioac i i ies ha align wi h he men ioned p e iously bioac i i ies o he hole ex ac s such as an ioxidan , an icance , ca diop o ec i e, an idiabe ic, an i-in lamma o y, e c. Pine ex ac s ha e ac i e ing edien s ha a e use ul o he ood indus y as supplemen s o na u al pigmen s, o ood p ese a ion and as ac i e ood packaging. In he cosme ic o mula ions, hey can be used o p o ec ing he skin agains oxygen eac i e species, o med by pollu ion, s ess, o ul a iole eac ion. 6. Conclusions and Fu u e Pe spec i es Pine esidues and by-p oduc s a e an impo an sou ce o biocompounds wi h high indus ial in e es . They can be eco e ed using he bio e ine y concep , hus con ibu ing o he ci cula economy. Mo e en i onmen ally iendly echniques ha e been explo ed o a oid he la ge amoun s o (o ganic) sol en s, ene gy consump ion, and was e gene a ion ypical o con en ional sol en ex ac ion p ocesses. Al hough eplacing con en ional echnologies by non-con en ional ones has eme ged, imp o emen s a e necessa y in e ms o deep knowledge o he ex ac ion p ocesses and scaling up. UAE, MAE, SFE, PLE, and OH a e some o hese eme ging p omising echnologies o bioac i e compounds ex ac ion in alignmen wi h he G een Chemis y p inciples. Rega ding he ex ac ion s ep, he selec ion o he mos app op ia e echniques di e s acco ding o he ype o compounds a ge ed o eco e y and inal aimed unc ionali y/applica ion. Howe e , he e is no a uni e sal ex ac ion me hod sui able o he ex ac ion o all pine phenolics. The di e en pine species ha e di e en indi idual phenolic composi ion. Fo example, he main phenolic compound ound in ex ac s o Po uguese pine is he axi olin, whe eas i was no ound in Macedonian pine species. Depending on he inal pu pose o he ex ac ion, an indi idual s udy mus be ca ied on o une he bes ex ac ion p ocedu e. In e es ingly, all ex ac s om pine, ega dless he sol en , he me hod, pine species, and he plan pa used, ha e high amoun s o polyphenols. Howe e , he e a e di e ences in he concen a ions and ype o he indi idual compounds as well as in he s eng h o he bioac i i ies. The e a e no many s udies showing iden i ica ion and e en less s udies showing quan i ica ion o he indi idual polyphenols in ex ac s om pine species. Pine ex ac s ha e a numbe o desc ibed bioac i i ies ha may be bene icial o he human heal h. As a consequence, pine ex ac s ha e high po en ial as cons i uen s in o mula ion o he ood, cosmeceu ical, and pha maceu ical indus ies. The possible eu iliza ion o he pine esidues is ye limi ed, compa ed o i s po en ial. In his con ex , mo e s udies a e needed o ind and de elop new p oduc s and uses esul ing om pine esidues and by-p oduc s. Funding: Thiswo kwas undedby hePo ugueseFounda ion o ScienceandTechnology(FCT)unde hescopeo he s a egic unding o UIDB/04469/2020 uni and BioTecNo e ope a ion (NORTE-01-0145-FEDER-000004) unded by he Eu opean Regional De elopmen Fund unde he scope o No e2020 - P og ama Ope acional Regional do No e and by p og am INTERREG V-B Sudoe (REDVALUE, SOE1/P1/E0123). Zla ina Genishe a is suppo ed by he p ojec OH2O (POCI-01-0145-FEDER-029145) unded by FCT and Fundo Eu opeu de Desen ol imen o Regional (FEDER) unde he scope o P og ama Ope acional de Compe i idade e In e nacionalizaçao (POCI)-COMPETE 2020 and Po ugal 2020. Elisa Zanuso is ecipien o a PhD ellowship suppo ed by he Mexican Science and Technology Council (CONACYT ID 639021/495314). Ped o San os is ecipien o a PhD ellowship suppo ed by a doc o al ad anced aining (call NORTE-69-2015-15), unded by he Eu opean Social Fund unde he scope o No e2020 - P og ama Ope acional Regional do No e (NORTE-08-5369-FSE-000036). Con lic s o In e es : The au ho s decla e no con lic o in e es . Molecules 2020,25, 2931 21 o 29 Re e ences 1. Eu opean Commission. Going Clima e-Neu al by 2050: A S a egic Long-Te m Vision o a P ospe ous, Mode n, Compe i i e and Clima e-Neu al EU Economy. 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