Golden be y ui modula es in lamma ion in LPS-s imula ed RAW 264.7
mac ophages and he DSS-induced acu e coli is model
Jenny Cas o
a,b
, Guille mo Lopez-Lluch
c
, Juan Ca los Rod íguez
d
, Rocío de la Pue a
e
,
Lía Ba ios
, Rub´
en Salas
a
, Luis F anco
a,*
a
Biological E alua ion o P omising Subs ances G oup, Uni e sidad de Ca agena, Ca agena, Colombia
b
Facul y o Chemis y and Pha macy, Uni e sidad del A l´
an ico, Ba anquilla 081007, Colombia
c
Cen o Andaluz de Biología del Desa ollo, Uni e sidad Pablo de Ola ide, Se illa, Spain
d
Depa amen o de Fisiología, Ana omía y Biología Celula , Uni e sidad Pablo de Ola ide, Se illa, Spain
e
Depa men o Pha macology, Facul ad de Fa macia, Uni e sidad de Se illa, Se illa, Spain
His opa hology Resea ch G oup, Uni e sidad de Ca agena, Ca agena, Colombia
ARTICLE INFO
Keywo ds:
Physalis pe u iana L
Golden be y
Die a y supplemen s
RAW 264.7
In lamma o y bowel disease
Dex an sodium sulpha e-induced acu e coli is
ABSTRACT
Physalis pe u iana L. (golden be y) ui is a ac i e o i s many heal h bene i s, associa ed wi h he p esence o
an i-in lamma o y and an ioxidan compounds. High ui consump ion has been associa ed wi h a lowe isk o
de eloping ch onic non-communicable diseases. This wo k e alua ed he an i-in lamma o y po en ial o en
ui s cul i a ed in Colombia, de e mining hei capaci y o inhibi ⋅NO p oduc ion in LPS-ac i a ed RAW 264.7
mac ophages. The mos ac i e ex ac s we e e alua ed o hei e ec on he p oduc ion o IL-1β, IL-6, TNF-
α
,
and PGE2. Golden be y was he mos ac i e ex ac , so i s immunomodula o y e ec was e alua ed in a model o
DSS-induced coli is in BALB/c mice. Die a y supplemen a ion wi h golden be y a enua es he pa hological
symp oms o coli is. This e ec may be associa ed wi h he inhibi ion o neu ophil in il a ion and impac s on
he p oduc ion o IL-6, IL-1β, IL-10, TNF-
α
, and ROS. Ou esul s sugges ha consis en ly consuming golden
be ies could bene i in es inal in lamma ion.
1. In oduc ion
Subop imal nu i ion anks i s among li es yle- ela ed NCD isk
ac o s wo ldwide and has been iden i ied as he mos impo an p e-
en able NCD isk ac o . In ecen decades, as pa o globaliza ion,
wes e n li es yles ha include unheal hy die a y pa e ns ha e been
adop ed wo ldwide; his end is known as he “nu i ion ansi ion” and
is cha ac e ized by he eplacemen o a die adi ionally ich in ui s
and ege ables wi h a die high in calo ies om simple ca bohyd a es
and animal a s. This has inc eased he incidence o NCDs wo ldwide
(As up, Dye be g, Selleck, & S ende , 2008; Beaglehole & Yach, 2003;
Kimoko i & Millen, 2016). Al hough he associa ion be ween in lam-
ma ion and ch onic diseases is widely ecognized, he causali y and
ex en o which in lamma ion con ibu es o and ac s as a isk ac o o
disease de elopmen emain un esol ed (Minihane e al., 2015). Non-
communicable diseases a e non-in ec ious and long-las ing (mo e han
h ee o six mon hs); mos o which can only be ea ed bu no cu ed,
and usually de elop slowly and asymp oma ically bu esul in de as-
a ing complica ions, leading o p ema u e dea h and poo quali y o li e
(Mee oo, 2008; Sen hilkuma & Kim, 2013). These diseases a e he
leading cause o mo ali y globally. I is es ima ed ha 70 % o all dea hs
wo ldwide a e a ibu able o noncommunicable diseases (Hol ,
Ka iani, She h, & an D iel, 2018; Ruby, Knigh , Pe el, Blanche , &
Robe s, 2015). These diseases ha e adi ionally been high in de el-
oped coun ies due o unheal hy die s and physical inac i i y (Wagne &
B a h, 2012). Howe e , a apid inc ease in hese diseases has been
obse ed in low- and middle-income coun ies, wi h signi ican ad e se
social, economic, and heal h e ec s (Alwan e al., 2010). In ecogni ion
o he impac o a heal hy die on p e en ing he onse o NCDs, he
Wo ld Heal h O ganiza ion (WHO) has issued expe die a y ecom-
menda ions o educe he isk o NCDs, including consuming a signi i-
can amoun o ege ables and ui s (Kimoko i & Millen, 2016). F ui s
a e a ood g oup o g ea impo ance in human nu i ion because hey
a e a signi ican sou ce o i amins, mine als, and die a y ibe (Pala ox-
* Co esponding au ho a : Biological E alua ion o P omising Subs ances G oup, Facul ad de Ciencias Fa mac´
eu icas, Uni e sidad de Ca agena, Za agocilla
Campus, Calle 50 No. 24–120, Ca agena 130014, Colombia.
E-mail add ess: [email p o ec ed] (L. F anco).
Con en s lis s a ailable a ScienceDi ec
Jou nal o Func ional Foods
jou nal homepage: www.else ie .com/loca e/j
h ps://doi.o g/10.1016/j.j .2025.106665
Recei ed 28 Decembe 2023; Recei ed in e ised o m 12 Decembe 2024; Accep ed 2 Janua y 2025
Jou nal o Func ional Foods 125 (2025) 106665
A ailable online 8 Janua y 2025
1756-4646/© 2025 The Au ho s. Published by Else ie L d. This is an open access a icle unde he CC BY-NC license ( h p://c ea i ecommons.o g/licenses/by-
nc/4.0/ ).
Ca los, Ayala-Za ala, & Gonz´
alez-Aguila , 2011). High die a y ui
consump ion has been associa ed wi h a lowe isk o ch onic and
degene a i e diseases, while low ui consump ion is among he op en
isk ac o s mos implica ed in o e all mo ali y (Li e al., 2016; Sla in &
Lloyd, 2012). This ela ionship is suppo ed by s udies showing ha
egula consump ion o ui s in he die can modula e ch onic in lam-
ma ion, which has been ecognized as a pa hophysiological mechanism
unde lying he onse o many NCDs (Joseph, Edi isinghe, & Bu on-
F eeman, 2016).
F ui s g own in Colombia such as yellow pi aya (Hyloce eus mega-
lan hus), banana passion (Passi lo a cumbalensis), pu ple passion (Passi-
lo a edulis), golden be y (Physalis pe u iana), ama illo (Solanum
be aceum), lulo (Solanum qui oense), sou sop (Annona mu ica a), kalipa i
sapo a (Manilka a zapo a), sapo e (Pou e ia sapo a), and sou gua a
(Psidium ied ichs halianum), and a e commonly consumed in Colombia
and a e widely used o ea a ious ch onic non-communicable diseases
(Mejia e al., 2020). Among hese s ands ou he cape goosebe y
(Physalis pe u iana), which is app ecia ed na ionally and in e na ionally
no only o i s a ac i e colo and la o bu also o i s mul iple
bene icial heal h p ope ies, being used by a ious cul u es o ea
diges i e diso de s such as indiges ion and hea bu n, as well as o
s eng hen he immune sys em and p e en espi a o y diseases
(Ca illo-Pe domo, Alle , C uz-Quin ana, Giampie i, & Al a ez-Sua ez,
2015; F anco, Ma iz, Calle, Pinz´
on, & Ospina, 2007; Na a o-Hoyos
e al., 2022; Pin o e al., 2009). This has a oused g ea in e es in he
scien i ic communi y, leading o mul iple s udies ha ha e iden i ied
bioac i e compounds in his ui , such as β-ca o ene, lycopene, lu ein,
que ce in, u in, pe u iosas, campes e ol, β-si os e ol, s igmas e ol,
a enas e ol, lupeol, linalool, and se e al wi hanolides (Kasali e al.,
2021; Mie -Gi aldo, Díaz-Ba e a, Delgado-Mu cia, Vale o-Valdi ieso,
& C´
aez-Ramí ez, 2017). These compounds ha e an ioxidan and an i-
in lamma o y p ope ies ha could con ibu e o he p e en ion and
ea men o diseases in ol ing ch onic in lamma ion, such as ca dio-
ascula , espi a o y, and neu odegene a i e diseases, cance , diabe es
melli us, and in lamma o y bowel disease (Pan, Lai, & Ho, 2010).
This wo k e alua ed he in i o an i-in lamma o y po en ial o en
e hanolic ex ac s o ui s g own in Colombia, de e mining hei ca-
paci y o inhibi ni ic oxide (⋅NO) p oduc ion in LPS-ac i a ed RAW
264.7 mac ophages. In addi ion, he e ec s o he ac i e ex ac s on he
p oduc ion o IL-1β, IL-6, TNF-
α
, and PGE-2 in LPS-ac i a ed RAW 264.7
mac ophages we e de e mined, as i was hypo hesized ha he ui
inhibi ing he highes numbe o in lamma o y media o s could ha e an
immunomodula o y e ec when egula ly included in he die . To
co obo a e his hypo hesis, he golden be y ex ac , which p o ed o
be he mos ac i e, was e alua ed in he dex an sul a e sodium (DSS)-
induced IBD model in BALB/c mice, which simula es he p olonged and
exace ba ed ch onic in lamma o y p ocess ha cha ac e izes he in-
lamma o y bowel disease.
2. Ma e ials and me hods
2.1. Reagen s
Penicillin-s ep omycin, ypan blue, lipopolysaccha ide om
Esche ichia coli (LPS), sodium ni i e, N-[1,1-naph hyl] e hylenediamine
dihyd ochlo ide, sul anilamide, TEMED, 2
′
,7
′
-dichlo o luo escein diac-
e a e (DCFH-DA), phospha e bu e saline (PBS) able s, O-Dianisidine,
e hylenediamine e aace ic acid (EDTA), hyd ogen pe oxide (H
2
O
2
),
indome hacin, dexame hasone, o ecoxib, hema oxylin and eosin, we e
pu chased om Sigma Ald ich (S Louis, MO). E hanol, dime hyl sul -
oxide (DMSO), Dulbecco’s Modi ied Eagle Medium (DMEM), and Fe al
Bo ine Se um (FBS) we e ob ained om The mo Fishe Scien i ic
(Pi sbu gh, PA). Ac ylamide/bisac ylamide, T is HCL, B ad o d assay,
p ecision plus p o ein s anda ds dual colo , T is/Glycine/SDS bu e ,
T is/Glycine bu e , Blo ing-g ade blocke we e ob ained om Bio-Rad.
B omide o 3[4,5-dime hyl hiazol-2-yl]-2,5-diphenyl e azolium (MTT),
hexadecyl- ime hylammonium b omide (HTAB), we e ob ained om
Calbiochem® (San Diego, CA). Mac ophages RAW 264.7 we e acqui ed
om he Ame ican Type Cul u e Collec ion (Manassas, VA). Phospho ic
acid was ob ained om JT Bake (Phillipsbu g, NJ). ELISA ki s om
eBiosciences. Wes e n HRP subs a e was ob ained om Millipo e and T-
PER issue p o ein ex ac ion eagen om The mo Scien i ic.
2.2. F ui samples and de e mina ion o physicochemical pa ame e s
F ui s included in his s udy we e ob ained om Fusagasuga (Cun-
dinama ca) and Tu bana (Boli a ) and in ol ed yellow pi aya (Hylo-
ce eus megalan hus), banana passion (Passi lo a cumbalensis), pu ple
passion (Passi lo a edulis), golden be y (Physalis pe u iana), ama illo
(Solanum be aceum), lulo (Solanum qui oense), sou sop (Annona mu -
ica a), kalipa i sapo a (Manilka a zapo a), sapo e (Pou e ia sapo a) and
sou gua a (Psidium ied ichs halianum). Taxonomic iden i ica ion was
ca ied ou a he He ba ium o he Uni e sidad de An ioquia, Medellín,
Colombia; one specimen o each species was kep a ha ins i u ion.
2.3. P epa a ion o ex ac s
F ui s (1000 g each) we e washed wi h ap wa e , cu in o small
pieces, homogenized in a p o essional blende (Ninja BN751), ozen a
−80 ◦C and lyophilized (Labconco F eeZone 2.5, Kansas Ci y, MO, USA).
The powde was ex ac ed in co e ed con aine s o 3 days wi h h ee
olumes o e hanol (96 %) a oom empe a u e, equen ly shaking; his
p ocedu e was epea ed un il exhaus ed. The ex ac was il e ed and
concen a ed in a o a y e apo a o (Buchi R100, Swi ze land) a a
con olled empe a u e (38–40 ◦C) and educed p essu e o emo e
e hanol. In o ma ion on he ui s chosen o he s udy and yields a e
p esen ed in Table 1.
2.4. Cell cul u e expe imen s
Mu ine mac ophage cell line RAW 264.7 (ATCC® TIB-71™ Rock-
ille, MD, USA) was main ained in DMEM supplemen ed wi h 10 %
hea -inac i a ed e al bo ine se um (FBS) in a humidi ied a mosphe e o
5 % CO
2
a 37 ◦C. Fo he in i o assays, he ex ac s we e dissol ed in
DMSO, ensu ing ha he inal concen a ion o DMSO in he cul u e
medium was less han 1 %.
Table 1
In o ma ion on ui s included in he s udy.
F ui s Pa used Ex ac yields
(%)
Vouche
numbe
Yellow pi aya
Hyloce eus megalan hus
pulps and
seed
30,08 199,083
Banana passion
Passi lo a cumbalensis
pulps 81.41 199,085
Pu ple passion
Passi lo a edulis
pulps 84,44 199,081
Golden be y
Physalis pe u iana
Whole ui 44,70 199,086
Tama illo
Solanum be aceum
pulps 42,87 199,080
Lulo
Solanum qui oense
Pulps and
seed
60,0 199,084
Sou sop
Annona mu ica a
pulps 57,91 201,951
Kalipa i sapo a
Manilka a zapo a
pulps 49,95 201,955
Sapo e
Pou e ia sapo a
pulps 36,21 201,953
Sou gua a
Psidium
ied ichs halianum
pulps 52,66 201,952
Ex ac yields: (g o ex ac s ob ained/ g o eeze-d ied ui )*100.
J. Cas o e al.
Jou nal o Func ional Foods 125 (2025) 106665
2
2.4.1. Assessmen o cell iabili y
The oxici y o ui ex ac s on RAW 264.7 mac ophages was
assessed by he colo ime ic MTT me hod (Scudie o e al., 1988). RAW
264.7 mac ophages we e seeded in s e ile 96-well pla es (2 ×10
4
cells/
well) and incuba ed a 37 ◦C o 48 h. The medium was emo ed, and he
cells we e washed wi h PBS and ea ed o 30 min wi h di e en con-
cen a ions o ui ex ac s (2000–500
μ
g/mL) dissol ed in he medium,
a e which hey we e ac i a ed wi h LPS (1
μ
g/mL) and incuba ed again
o 24 h a 37 ◦C, cells we e washed wi h PBS, and 100
μ
L o MTT so-
lu ion (0.25 mg/mL) was added o each well o he pla e. The pla es
we e incuba ed a 37 ◦C o 4 h in a CO
2
incuba o . Finally, he supe -
na an was emo ed, 100
μ
L o DMSO was added o dissol e he o -
mazan c ys als, and he abso bance was de e mined a 550 nm on a
Mul iskan EX mic opla e eade (The mo Scien i ic, Wal ham, MA,
USA). In each ial, a g oup o cells no exposed o he ex ac s was
included as a nega i e con ol, and a g oup exposed o T i on X-100 (20
%) as a maximally oxic con ol. Viabili y was calcula ed as a pe cen -
age, conside ing he nega i e con ol as 100 % iabili y. The concen-
a ions used o e alua e he ui ex ac s we e de ined in e ms o hei
solubili y in DMSO (2000
μ
g/mL was he maximum concen a ion a
which all ui ex ac s could be solubilized in DMSO).
2.4.2. De e mina ion o ni ic oxide (NO)
To de e mine he e ec o ui ex ac s on he elease o ni ic oxide,
RAW 264.7 mac ophages we e seeded in s e ile 96-well pla es (2 ×10
4
cells/well) and incuba ed a 37 ◦C o 48 h. The medium was emo ed,
and he cells we e washed wi h PBS and ea ed o 30 min wi h he ui
ex ac s (2000, 1000 and 500
μ
g/mL), a e which hey we e ac i a ed
wi h LPS (1
μ
g/mL) and incuba ed again o 24 h a 37 ◦C. A e his
ime, 70
μ
L o he supe na an s we e emo ed, and NO eleased as i s
end p oduc (ni i e) was measu ed by he G iess me hod (G een e al.,
1982). Supe na an s we e mixed wi h equal olumes o G iess eagen
(1 % sul anilamide in 3 % phospho ic acid and 0.1 % naph hyl e hyl-
enediamine dihyd ochlo ide), and he mix u e was incuba ed a oom
empe a u e o 5 min. The abso bance was measu ed a 550 nm wi h a
Mul iskan EX mic opla e eade (The mo Scien i ic, Wal ham, MA,
USA). Ni i e concen a ion was de e mined using a s anda d cu e
p epa ed wi h sodium ni i e (1–200
μ
M) dissol ed in PBS. The con-
cen a ions o he ex ac s unde s udy we e selec ed based on he
iabili y assessmen esul s obse ed in he MTT assay (Table S1). A
con ol g oup o uns imula ed LPS, a g oup ea ed wi h LPS alone, and a
g oup ea ed wi h 1400 W, used as a posi i e con ol o inhibi ion o
ni ic oxide p oduc ion, we e included in each ial.
2.4.3. Cy okine and p os aglandin E2 (PGE2) p oduc ion
RAW 264.7 mac ophages we e seeded in 24-well pla es (2 ×10
5
cells/well) and incuba ed o 48 h. Cells we e p e ea ed wi h he ui
ex ac s (2000, 1000, and 500
μ
g/mL) o 30 min and incuba ed o 24 h
wi h LPS (1
μ
g/mL). A e incuba ion, he medium was collec ed.
Quan i ica ion o TNF-
α
, IL-6, and IL-1β sec e ed in o he cul u e me-
dium was pe o med wi h comme cial enzyme-linked immunoso ben
assay (ELISA) ki s pu chased om eBioscience, ollowing he manu ac-
u e ’s p o ocol. PGE2 p oduc ion was measu ed wi h a comme cial
compe i i e ELISA ki (Enzo®), ollowing he manu ac u e ’s in-
s uc ions. A non-s imula ed LPS con ol g oup and a g oup ea ed wi h
LPS alone we e included in each assay.
2.4.4. Wes e n blo analysis
B ie ly, RAW 264.7 mac ophages p e iously ea ed wi h a ious
concen a ions o he ui ex ac s we e collec ed and dissol ed in RIPA
lysis bu e supplemen ed wi h a cock ail o p o ease and phospha ase
inhibi o s. P o ein concen a ion was de e mined by B ad o d assay
(Bio-Rad). The exac amoun o p o ein samples (80
μ
g) was sepa a ed
on a 10 % sodium dodecyl sul a e-polyac ylamide gel and elec ically
ans e ed o ni ocellulose memb anes. The memb anes we e hen
blocked wi h 5 % (w/ ) milk powde and washed in TBST bu e ,
incuba ed wi h a speci ic p ima y an ibody o wo hou s a oom
empe a u e, and hen incuba ed wi h a ho se adish pe oxidase-
conjuga ed seconda y an ibody o one hou a oom empe a u e.
Immuno eac i e bands we e de ec ed by being exposed o X- ay ilm,
and hei densi ies we e quan i ied using Ca es eam Molecula Imaging
So wa e. Wes e n blo da a we e quan i ied o de e mine di e ences
be ween ea men g oups.
2.5. In i o animal expe imen s
2.5.1. Animals
Six- o eigh -week-old BALB/c emale mice we e ob ained om he
Ins i u o Nacional de Salud (Bogo ´
a, Colombia). Animals we e housed in
il e ed-capped polyca bona e cages and kep in a con olled en i on-
men (22 ±3 ◦C, 65–75 % humidi y, unde a 12 h ligh /da kness cycle)
wi h access o ood and wa e ad libi um. All he expe imen s we e
designed and conduc ed in acco dance wi h local and in e na ional
egula ions (EU Di ec i e 2010/63/EU) and app o ed by he Commi ee
o E hics in Resea ch o he Uni e si y o Ca agena (Minu es No. 74 o
June 5 h, 2014). Fo he in i o assay, he golden be y ex ac was
dissol ed in e hanol (96 %) o inco po a ion in o he animal eed; his
sol en was inally emo ed du ing he eed p epa a ion p ocess.
2.5.2. Acu e oxici y s udy
The acu e o al oxici y s udy was pe o med ollowing he p o ocol o
Cas o, Ocampo, & F anco, 2015 (Cas o e al., 2015) wi h modi ica-
ions. B ie ly, BALB/c mice (n =6) as ed o e nigh wi h wa e ad libi-
um, and he golden be y ex ac was adminis e ed o ally a 2000 mg/
kg. Mo ali y and gene al beha io al changes we e obse ed o h ee
days. Fo his ological analysis, li e and kidney samples we e p ese ed
in bu e ed o malin, s ained wi h hema oxylin and eosin, and analyzed
by a blinded pa hologis employing ligh mic oscopy (Olympus BX41,
Tokyo, Japan).
2.5.3. Die s and ch onic oxici y s udy
Six- o eigh -week-old BALB/c mice (n =6) we e ed chow supple-
men ed wi h golden be y ex ac (0.15 % o 0.3 %) o 30 days. These
pe cen ages we e selec ed based on he acu e oxici y s udy and
conside ing ha he amoun o ex ac used may be easonably
achie able in a human popula ion. Fo 30 days, gene al beha io al
changes associa ed wi h ale ness, such as passi i y, i i abili y, and
ne ousness, o changes ela ed o mo o ac i i y, such as mobili y,
ac ile esponse, and esponse o pain, we e moni o ed, and li e and
kidney samples we e p ese ed in bu e ed o malin and s ained wi h
hema oxylin and eosin o his ological analysis by a blinded pa hologis .
2.5.4. Dex an sul a e sodium (DSS)-induced acu e coli is
Coli is was induced by employing he me hod desc ibed by Kim,
Shajib, Manocha, & Khan, 2012, wi h some modi ica ions (Kim e al.,
2012). B ie ly, mice we e andomly di ided in o i e g oups (n =7):
con ol g oup, DSS alone, DSS +GB ( ood supplemen ed wi h 0.15 and
0.3 % o golden be y ex ac ), and GB alone. All s udy g oups o animals
we e ed o 30 days wi h comme cial mouse ood (Roden LabDie
5010). The con ol and DSS g oups ecei ed he non-supplemen ed die ,
while he DSS +GB and GB g oups ecei ed he die supplemen ed wi h
GB ex ac . Fo he las nine days, he DSS g oups we e exposed o 3 %
DSS in d inking wa e ad libi um. Du ing he induc ion o coli is wi h
DSS, mice we e weighed daily, and ec al bleeding and dia hea we e
assessed. An o e dose o anes hesia will painlessly eu hanize hose an-
imals ha mee he e mina ion c i e ia de ined in he p ojec . The
disease ac i i y index (DAI) was de e mined acco ding o he pa ame e s
desc ibed by Li e al., 2014 (Li e al., 2014). On day 30 o he es , he
mice we e sac i iced, and he colon was emo ed, cleaned, weighed, and
leng h measu ed. A sample o colon issue was p ese ed in bu e ed
o malin and s ained wi h hema oxylin and eosin o pe iodic acid-Schi
(PAS) o his opa hological analysis by a blinded pa hologis . The es o
J. Cas o e al.
Jou nal o Func ional Foods 125 (2025) 106665
3
he colon was kep o de e mine ROS le el, MPO ac i i y, and cy okine
le els.
2.5.5. Measu emen o issue cy okine le el
Colonic issue was homogenized in Tissue P o ein Ex ac ion Re-
agen (T-PER) wi h a p o ease inhibi o cock ail (Roche) a 4 ◦C using
he TissueRup o ® (Qiagen, Haan, Ge many). The samples we e
cen i uged a 12.000 pm a 4 ◦C, and IL-1β, IL-6, IL-10, and TNF-
α
le els we e de e mined in he supe na an s using a comme cial enzyme-
linked immunoso ben assay (ELISA) ki s (eBioscience), ollowing he
manu ac u e ’s p o ocol. Resul s we e exp essed as picog ams o cy o-
kine pe millig am o p o ein (pg/mg), quan i ied by he B ad o d
me hod using a s anda d comme cial ki (Bio ad 500–0206).
2.5.6. Measu emen o issue ROS le el
ROS le els in he colon o mice we e de e mined using he echnique
desc ibed by (Song e al., 2008). Colon biopsies we e ozen in liquid
ni ogen and igo ously homogenized in 0.1 M phospha e bu e (pH
7.4), and hei homogena e was incuba ed wi h DCF-DA (20
μ
M) o 30
min. Fluo escence in ensi y was measu ed in a Fluo oskan Ascen 96-
well pla e eade (The mo Scien i ic, Wal ham, MA, USA) a an exci a-
ion wa eleng h o 485 nm and an emission wa eleng h o 538 nm.
2.5.7. MPO ac i i y
Enzyme ac i i y was de e mined acco ding o he echnique
desc ibed by Cas o, Ri e a, & F anco, 2019 (Cas o e al., 2019), wi h
modi ica ions. B ie ly, colon issue was homogenized in phospha e
bu e (pH: 7.4) a 4 ◦C using TissueRup o ® (Qiagen, Haan, Ge many).
The samples we e cen i uged a 10.000 pm a 4 ◦C; he pelle ob ained
was suspended in a solu ion o 0.5 % HTAB and 0.3 % EDTA in phos-
pha e bu e (pH 6.0). The homogena e ob ained was subjec ed o wo
apid eeze- haw cycles, sonica ed o 10 s, and inally cen i uged o
10 min a 10.000 pm a 4 ◦C. The eco e ed supe na an was used o
assess MPO ac i i y; 50
μ
L o he supe na an was mixed wi h 50
μ
L o O-
Dianisidine (0.067 %), 50
μ
L o 0.5 % HTAB solu ion, and 50
μ
L o
hyd ogen pe oxide (H
2
O
2
0.003 %). OD
450
was de e mined using a
Mul iskan Go mic opla e eade (The mo Scien i ic, Wal ham, MA,
USA). Resul s we e exp essed as uni s o MPO pe millig am o p o ein;
one uni o ac i i y is de ined as he amoun o enzyme capable o
deg ading 1
μ
mol o hyd ogen pe oxide in one minu e a 25 ◦C.
2.6. S a is ical analysis
Resul s a e exp essed as he mean ±s anda d e o o he mean
(SEM) o wo (in i o assay) o h ee (in i o assay) independen ex-
pe imen s. Da a we e analyzed by one-way analysis o a iance
(ANOVA) ollowed by Dunne ’s pos hoc es . Values o p <0.05 we e
conside ed signi ican .
3. Resul s
3.1. E ec o ui ex ac s on NO, IL-1β, IL-6, TNF-
α
and PGE-2
p oduc ion in LPS-ac i a ed RAW 264.7 mac ophages
The esul s o he e alua ion o he e ec o e hanolic ex ac s on NO
p oduc ion in RAW 264.7 mac ophages s imula ed wi h LPS (1
μ
g/mL)
e eal ha he ex ac s o pu ple passion, yellow pi aya, ama illo, and
golden be y we e he mos ac i e (Fig. 1). Fig. 2 shows he e ec o
ac i e ex ac s on he p oduc ion o IL-6, IL-1β, TNF-
α
, and PGE-2 in
RAW 264.7 mac ophages s imula ed wi h LPS (1
μ
g/mL) o 24 h. I can
be obse ed ha excep o he pu ple passion ex ac , all he o he s
signi ican ly dec eased IL-6 and IL-1β p oduc ion, wi h he golden be y
ex ac being he mos ac i e (Fig. 2A–B). A he same ime, TNF-
α
and
PGE2 we e signi ican ly inhibi ed by all he ex ac s es ed; again, he
golden be y ex ac showed high inhibi o y ac i i y o hese media o s
(Fig. 2C–D). These esul s allowed us o iden i y he golden be y ex ac
as ha ing he bes an i-in lamma o y po en ial. The e o e, we decided o
e alua e i s e ec on he NF-kB ansc ip ion ac o and i s immuno-
modula o y e ec in he DSS-induced IBD model in mice.
3.2. Inhibi ion o NF-kB-dependen LPS ac i a ion
As shown in Fig. 3, he le el o IκB
α
p o ein in he cy oplasm
dec eased by LPS ea men , indica ing he deg ada ion o IκB
α
, while in
Fig. 1. E ec o he ex ac s on NO p oduc ion in RAW 264.7 mac ophages s imula ed wi h LPS (1
μ
g/mL) o 24 h. 1400 W (10
μ
M) was used as a posi i e con ol.
Resul s ep esen he mean ±s anda d e o o he mean. (*p <0.01, **p <0.001 and ****p <0.00001 s a is ically signi ican compa ed o he LPS- ea ed g oup).
J. Cas o e al.
Jou nal o Func ional Foods 125 (2025) 106665
4
he golden be y ex ac - ea ed g oups, he le els o IκB p o ein in he
cy oplasm we e main ained, showing a p o ec i e e ec o NF-κB ac i-
a ion in a concen a ion-dependen manne . In addi ion, we examined
he e ec o golden be y ex ac on NF-κB ac i a ion, de e mining NF-
κB p65. As can be seen, s imula ion wi h LPS caused ansloca ion o p65
om he cy osol o he nucleus, while ea men wi h golden be y
Fig. 2. E ec o pu ple passion, yellow pi aya, ama illo, and golden be y ex ac s on IL-6, IL-1β, TNF-
α
and PGE-2 p oduc ion in RAW 264.7 mac ophages
s imula ed wi h LPS (1
μ
g/mL) o 24 h. 1400 W (10
μ
M), Dexame hasone (20
μ
M), and Ro ecoxib (10
μ
M) we e used as posi i e con ol. Resul s ep esen he mean
±s anda d e o o he mean. (*p <0.01, **p <0.001, ***p <0.0001 and ****p <0.00001 s a is ically signi ican compa ed o he LPS- ea ed g oup). (Fo
in e p e a ion o he e e ences o colo in his igu e legend, he eade is e e ed o he web e sion o his a icle.)
Fig. 3. Inhibi ion o nuclea ansc ip ion ac o NF-κB by golden be y ex ac s in RAW 264.7 mac ophages s imula ed wi h LPS (1
μ
g/mL) o 24 h. The da a shown
a e ep esen a i e o h ee independen expe imen s.
J. Cas o e al.
Jou nal o Func ional Foods 125 (2025) 106665
5
ex ac s educed his ansloca ion (Fig. 3).
3.3. An i-in lamma o y e ec o golden be ies in mice wi h in lamma o y
bowel disease
Conside ing he an i-in lamma o y backg ound o golden be y and
he esul s ob ained in his s udy, whe e golden be y ex ac showed he
bes an i-in lamma o y po en ial by signi ican ly inhibi ing he p o-
duc ion o NO, IL 6, IL-1β, TNF
α
, and PGE2 in LPS s imula ed mac o-
phages, we con inue o e alua e he immunomodula o y e ec o a die
supplemen ed wi h golden be y ex ac in mice wi h DSS-induced in-
lamma o y bowel disease. Ini ially, an acu e oxici y s udy was pe -
o med, which showed ha he adminis a ion o a dose o 2000 mg/kg
o he gold be y ex ac did no p oduce signs o oxici y du ing he 72 h
a e adminis a ion, and he his ological analysis did no show al e -
a ions a hepa ic o enal le el. Simila ly, no oxici y signs we e de ec ed
in he ch onic oxici y s udy, whe e animals we e ed a die supple-
men ed wi h golden be y ex ac (0.15 % and 0.3 %) o 30 days and
checked daily. In addi ion, he his opa hological analysis showed ha
he die supplemen ed wi h golden be y ex ac (0.15 % and 0.3 %) did
no p oduce li e o kidney damage Fig. S1.
In lamma o y bowel disease is cha ac e ized by weigh loss, so his
pa ame e was conside ed an impo an ma ke o he disease. The an-
imals we e weighed daily du ing he 30-day es pe iod. Animals
consuming he golden be y ex ac -supplied die we e obse ed o ha e
a lowe weigh loss han he disease con ol g oup (DSS) (Fig. 4A). In
addi ion, he disease ac i i y index was de e mined, co esponding o a
sco e calcula ed based on weigh a ia ion, ecal consis ency, and blood
in he eces. Cohe en ly, he DSS g oup ob ained he highes sco e
(Fig. 4B). On day 30 o he ial, animals we e sac i iced. A mac oscopic
analysis o he colon was pe o med, measu ing i s leng h and calcu-
la ing he weigh /leng h a io indica i e o in es inal mucosa damage.
As expec ed, he heal hy con ol had a no mal appea ance, and he
leng h o he colon issue was g ea e han ha o he dex an sul a e
sodium (DSS)-induced coli is g oup. G oups gi en he eed supple-
men ed wi h golden be y ex ac (0.15 and 0.3 %) had a g ea e colonic
leng h han hose gi en only DSS (Fig. 4 C and D). Rega ding he esul s
o he weigh /leng h a io, an inc ease in his a io was obse ed in he
g oup wi h dex an sul a e sodium (DSS)-induced coli is due o he
hickening and sho ening o he issue as a consequence o damage o
he in es inal mucosa and submucosa caused by his agen ; while in he
g oups ea ed wi h he golden be y ex ac , he index was lowe ,
indica ing an imp o emen in he in es inal in lamma o y p ocess
(Fig. 4E).
The indings o he his ological s udy a e consis en wi h he esul s
o he mac oscopic analysis. The heal hy g oup and he g oup ha only
ecei ed he 0.30 % supplemen ed die we e in no mal condi ion and
wi hou cellula al e a ions. In con as , he IBD-induced g oups showed
ulce a ion, edema, ib osis, in lamma ion, neu ophil in il a ion, and
inc eased hickness o he submucosal and muscula laye s. Howe e ,
es o a ion o colon issue wi h dec eased neu ophil in il a ion was
obse ed in g oups ea ed wi h ood supplemen ed wi h golden be y
ex ac (0.15 % and 0.30 %) (Fig. 5A). In lamma o y bowel disease may
be accompanied by a dec ease in goble cells, which con ibu e signi i-
can ly o he p ope unc ioning o he in es ine by p oducing an imi-
c obial p o eins, cy okines, and mucus (Choi e al., 2022; Gus a sson &
Johansson, 2022). PAS s aining allows he iden i ica ion o goble cells
by s aining he mucin g anules o hese cells pu plish ed (Zugibe, 1970).
E alua ion o PAS-s ained issue shows ha he g oup ea ed wi h he
ood supplemen ed wi h golden be y ex ac (0.15 % and 0.30 %) has a
lowe goble cell deple ion han he DSS g oup. On he o he hand, he
g oup ha only ecei ed 0.3 % supplemen ed eed did no show sig-
ni ican di e ences om he heal hy g oup, indica ing ha he ex ac is
no esponsible o he deple ion o goble cells (Fig. 5B).
A dec ease in MPO enzyme ac i i y was obse ed, indica ing a
dec ease in neu ophil in il a ion in o colonic issue, which was
accompanied by a educ ion o le els o he eac i e oxygen species
(ROS) (Fig. 6 A and B). Fu he mo e, signi ican inhibi ion o le els o
he p oin lamma o y cy okines IL-1β and IL-6 was obse ed in he
colonic issue o he g oups wi h die a y supplemen a ion wi h a golden
be y ex ac (Fig. 6 C and F), as well as a downwa d end in he le els
o TNF-
α
and ising end in he le els o he an i-in lamma o y cy okine
IL-10 (Fig. 6 D and E). The simul aneous e ec o golden be y ex ac on
all hese media o s cons i u es an immunomodula o y e ec wi h a
Fig. 4. Golden be y die a y supplemen a ion a enua es pa hological symp oms o dex an sul a e sodium (DSS) induced acu e coli is. BALB/c mice we e ed wi h
golden be y (0.15 y 0.30 %) o 30 days and exposed o 3 % DSS in d inking wa e du ing he las 10 days. A: Body weigh changes ollowing he DSS coli is
induc ion. B: Disease ac i i y index. C and D: Mac oscopic analysis (measu ing he leng h o he colon). E: Weigh /leng h a io o he colon. The esul s ep esen he
mean ±SEM. [n =10]. (*p < 0,01 and ****p < 0.00001 s a is ically signi ican compa ed wi h DSS g oup).
J. Cas o e al.
Jou nal o Func ional Foods 125 (2025) 106665
6
signi ican impac on colonic issue es o a ion in mice wi h DSS-
induced in lamma o y bowel disease.
4. Discussion
In ecen yea s, ui s ha e a ac ed inc easing in e es among e-
sea che s. This in e es is ela ed o he ac ha ui s may po en ially
p e en and ea some ch onic diseases (Li e al., 2016; Sla in & Lloyd,
2012). Expe imen al s udies ha e shown ha modula ing he in lam-
ma o y esponse h ough ui in ake p oduces posi i e heal h ou comes
(Pan e al., 2010; Zhu, Du, & Xu, 2018).
Ni ic oxide was selec ed as an in lamma o y bioma ke o pe o m
he ini ial sc eening o he an i-in lamma o y po en ial o he en ui
ex ac s o be e alua ed. Al hough ⋅NO is no one o he common in-
lamma o y bioma ke s, i is an impo an in lamma o y media o , as
inhibi ion o iNOS ac i i y o down- egula ion o iNOS exp ession is
desi able o educe he ex en o he in lamma o y esponse (Zhu e al.,
2018). Mo eo e , i can be easily quan i ied a a meage cos , making i a
sui able me hod o sc eening plan species o me aboli es wi h an i-
in lamma o y ac i i y. The e o e, we e alua ed he in i o an i-
in lamma o y po en ial o he en ui ex ac s by assessing hei abil-
i y o inhibi he p oduc ion o in lamma o y media o ni ic oxide in
LPS-ac i a ed RAW 264.7 mac ophages, which allowed us o ini ially
iden i y ha pu ple passion, yellow pi aya, ama illo, and golden be y
ex ac s we e he mos ac i e.
To u he in es iga e he an i-in lamma o y po en ial o he ou
Fig. 5. Rep esen a i e images o he his ological s udy (A) Hema oxylin and eosin s aining (B) Pe iodic acid-Schi [PAS] s aining.
Fig. 6. E ec o die a y supplemen a ion wi h golden be y ex ac on myelope oxidase enzyme [MPO] ac i i y, eac i e oxygen species (ROS) p oduc ion, and he
IL-1β, TNF-
α
, IL-10, and -IL-6 le els in he colonic issue. Resul s ep esen mean ±s anda d e o o he mean [SEM] [n =10]. (**p <0.001, ***p <0.0001 and
****p <0.00001 s a is ically signi ican compa ed o he DSS g oup).
J. Cas o e al.
Jou nal o Func ional Foods 125 (2025) 106665
7
ac i e ex ac s, clinically impo an in lamma o y bioma ke s ha could
be a ec ed by egula ui consump ion and exe e ec s on in lam-
ma o y p ocesses cha ac e is ic o ch onic non-communicable diseases
we e selec ed. Human clinical s udies in di e en popula ions and age
g oups show an associa ion be ween ui in ake and educed le els o
common in lamma o y bioma ke s, such as CRP, IL-1β, IL-6, TNF-
α
o
PGE-2 (Calde e al., 2011; Calde e al., 2017; Wu & Schauss, 2012; Zhu
e al., 2018). On he o he hand, he e is an associa ion be ween he
de elopmen and p og ession o ch onic non-communicable diseases
such as neu ological diso de s, cance , diabe es, obesi y, and in lam-
ma o y bowel disease, wi h inc eased le els o he in lamma o y bio-
ma ke s MCP-1, CRP, TNF-
α
, IL-6, IL-1β, NO, and PGE2 (Pan e al.,
2010). Excep o CRP, hese in lamma o y bioma ke s a e mainly
sec e ed by mac ophages, so iden i ying subs ances ha can inhibi he
p oduc ion o hese in lamma o y media o s in hese cells is a good
s a ing poin o he p e en ion and ea men o many ch onic dis-
eases. In his ega d, we subsequen ly de e mined he e ec o he ou
ac i e ex ac s on he in lamma o y bioma ke s IL-1β, IL-6, TNF-
α
, and
PGE-2. Iden i ying he golden be y ex ac as he mos ac i e co e-
sponds wi h esul s p esen ed in o he s udies in which golden be y
ex ac s ha e shown immunomodula o y e ec s on he exp ession o
in lamma o y bioma ke s in human ce ical cance cells (HeLa), mu ine
ib oblas s (L929) and li e (Mie -Gi aldo e al., 2017; Pino-de la Fuen e
e al., 2020).
The an i-in lamma o y ac i i y ha some ui s may be due o
bioac i e subs ances p esen in hese oods, such as phenolic com-
pounds, saponins, alkaloids, polyunsa u a ed a y acids, and e pe-
noids, among o he s; hese compounds can inhibi pa hways ela ed o
in lamma ion (Ade egha, 2018; Calde e al., 2017; P asad, Sung, &
Agga wal, 2012; Szos ak, Cybulska, Kłosiewicz-La oszek, & Szos ak-
Węgie ek, 2013; Zhu e al., 2018) Modula ing he in lamma o y
esponse by ui phy ochemicals has been linked o inhibi ing se e al
ansc ip ion ac o s, including NF-κB (Iddi e al., 2020; O eissi e al.,
2019). The nuclea ansc ip ion ac o (NF-κB) is an essen ial molecula
egula o o inna e and adap i e immune sys ems and is ubiqui ous in
he cy oplasm. The p esence o exogenous s imuli such as bac e ial in-
ec ions and gu mic o lo a can s imula e he TLR4 ecep o , which in
u n ac i a es a phospho yla ion cascade leading o he ac i a ion o
TAK1, which binds o he IKK complex ia ubiqui in chains, allowing i
o phospho yla e and ac i a e IKKβ. The IKK complex phospho yla es
he IκB
α
p o ein ha ac s as an inhibi o o NF-κB, which unde goes
p o eoly ic deg ada ion by he p o easome, allowing NF-κB o ans-
loca e o he nucleus. Classical NF-kB is a he e odime consis ing o a
p50 and a p65 subuni . T ansac i a o domains a he C- e minal end o
p65 make i a po en ac i a o o gene exp ession om kB si es. Once in
he nucleus, i binds o p omo e s ha induce he coo dina ed exp es-
sion o many genes encoding cy okines, chemokines, enzymes and
adhesion molecules in ol ed in he ampli ica ion and main enance o
he in lamma o y esponse (Guo e al., 2024; Kawasaki & Kawai, 2014;
Ma e al., 2024; Scho elius & Baldwin J , 1999). Thus, inhibi ion o he
ansc ip ion ac o NF-κB is o en conside ed a aluable s a egy o
ea ing in lamma o y diso de s. This pa hway ep esen s an impo an
and a ac i e he apeu ic a ge o compounds ha selec i ely in e -
e e wi h i (Niu e al., 2015; Yoon & Baek, 2005). To de e mine whe he
he inhibi o y e ec o golden be y ex ac on he p oduc ion o NO, IL-
6, IL-1β, TNF-
α
, and PGE2 was ela ed o he inhibi ion o he an-
sc ip ion ac o NF-κB, we e alua ed he p o ec i e e ec s o his ex ac
on he deg ada ion o IκB
α
in LPS-s imula ed mac ophages.
As he esul s show, golden be y ex ac p e en s he deg ada ion o
IκB
α
in a concen a ion-dependen manne . I main ains he le els o his
p o ein in he cy oplasm, consequen ly a oiding he phospho yla ion
and ansloca ion o he nucleus o he NF-κB ac o . This dec eases he
p oduc ion o p oin lamma o y media o s (Fig. S2). These esul s a e in
ag eemen wi h a p e ious s udy in which compounds isola ed om
golden be ies we e shown o signi ican ly inhibi NF-κB ansc ip ion
ac o ac i i y in HEK 293 / NF-kB-Luc cells (Chang, Sang-Nge n,
Pezzu o, & Ma, 2016).
A model o in lamma o y bowel disease was selec ed o de e mine in
i o he an i-in lamma o y po en ial o golden be y ex ac . Among he
a ious ch onic diseases wi h in lamma ion, his pa hology is cha ac-
e ized by de eloping a se e e in lamma o y esponse, which has been
well s udied and desc ibed du ing he las decades (Ga a aglia e al.,
2024; Yue e al., 2024). In an a emp o unde s and he pa hogenesis o
IBD and p og ess in he sea ch o new ea men s, a ious animal
models ha e been de eloped o simula e his disease. The dex an sul-
a e sodium (DSS) model is one o he mos widely used; i is a ep o-
ducible model ha mo phologically and symp oma ically esembles
ulce a i e coli is, one o he mos common o ms o in lamma o y bowel
disease. I is by a he mos popula mu ine model o in lamma o y
bowel disease because i is easy o de elop due o i s wide a ailabili y
and low cos (F edin e al., 2008; Ka sandegwaza, Ho snell, & Smi h,
2022; Kiesle , Fuss, & S obe , 2015).
The impo ance o die in p e en ing and de eloping IBD lies in he
ac ha die no only di ec ly a ec s in es inal in lamma ion by egu-
la ing in lamma o y media o s bu can also in luence epigene ic modi-
ica ions and in es inal mic obio a (Spoo en e al., 2013); mo eo e ,
some ood p oduc s, including ui s, can egula e he immune sys em
esponse and modi y in es inal in lamma ion (Be ns ein, 2017; Sal-
a i aba e al., 2017). The ui o he species Physalis pe u iana L.,
commonly known as golden be y o cape goosebe y, is used in adi-
ional medicine o educe blood suga le els, p e en ca a ac o ma ion,
and ea in es inal p oblems such as ulce s and dia hea (Rod íguez-
Eche e y, 2010) in addi ion many s udies a e also ound in he li e a-
u e on he a ious ac i i ies o his ui , including epo s o an i-
in lamma o y ac i i y (Chang e al., 2016; Hassan, Se ag, Qadi , &
Ramadan, 2017; Mie -Gi aldo e al., 2017). Howe e , no epo s ela e
he e ec o ui consump ion o he an i-in lamma o y e ec s o IBD.
An app oach o his is he wo k done by Moya e al., whe e hey elab-
o a ed on an ex ac ob ained by in i o diges ion ha simula es he
o al, gas ic, and in es inal phases o human diges ion and e alua ed he
e ec on he exp ession o in lamma o y ma ke s in an in i o in lam-
ma ion model o Caco-2 in es inal epi helium-like cells (Moya, Mi ada,
Ri e a, & A edondo, 2024). Gi en he an i-in lamma o y backg ound
o gold be y ex ac and he complex ole o nu i ion in he e iology o
in lamma o y bowel disease (IBD) (Gen schew & Fe guson, 2012; Hou,
Ab aham, & El-Se ag, 2011), we e alua ed he immunomodula o y e -
ec o a die supplemen ed wi h golden be y ex ac in mice wi h DSS-
induced in lamma o y bowel disease in BALB/c mice, wi h his s udy he
i s epo ha demons a es his ac i i y. These esul s sugges ha
egula consump ion o he ui o a unc ional ood based on i could
bene i in es inal in lamma ion. They es ablish a s a ing poin o u u e
s udies in animal models explo ing he e ec on he in es inal mic o-
bio a and o he signaling pa hways in ol ed in he in lamma o y
esponse, such as in lammasome ac i a ion and he MAPK pa hway, as
well as in clinical s udies in pa ien s wi h IBD, in ending o imp o e hei
quali y o li e.
5. Conclusion
Die a y supplemen a ion wi h golden be y (Physalis pe u iana) ui
ex ac showed an immunomodula o y e ec in he DSS-induced in-
lamma o y bowel disease model in BALB/c mice, a enua es he pa h-
ological symp oms o DSS-induced acu e coli is, dec easing he
in il a ion o polymo phonuclea neu ophils in o he issue and eac-
i e oxygen species, and modula ing he le els o impo an media o s o
he in lamma o y p ocess. Ou esul s sugges ha consis en con-
sump ion o a unc ional ood based on golden be ies in he die could
bene i in es inal in lamma ion. Fu he s udies a e equi ed o iden i y
he componen s esponsible o he ac i i y, i s impac on he mic o-
bio a, and he immunomodula o y e ec s i could ha e a he sys emic
le el.
Supplemen a y da a o his a icle can be ound online a h ps://doi.
J. Cas o e al.
Jou nal o Func ional Foods 125 (2025) 106665
8
o g/10.1016/j.j .2025.106665.
E hics s a emen
The animal expe imen s complied wi h he ARRIVE guidelines and
we e ca ied ou in acco dance wi h he ecommenda ions o he Eu-
opean Union ega ding animal expe imen a ion (Di ec i e o he Eu-
opean Council 2010/63/EU). The p o ocol was app o ed by he
Commi ee o E hics in Resea ch o he Uni e si y o Ca agena (Minu es
No. 74 o June 5 h, 2014). All e o s we e made o minimize animal
su e ing.
CRediT au ho ship con ibu ion s a emen
Jenny Cas o: W i ing – o iginal d a , Visualiza ion, Me hodology,
In es iga ion. Guille mo Lopez-Lluch: W i ing – e iew & edi ing,
Supe ision, Me hodology. Juan Ca los Rod íguez: W i ing – e iew &
edi ing, Valida ion, Me hodology. Rocío de la Pue a: W i ing – e iew
& edi ing, Supe ision, Resou ces. Lía Ba ios: Me hodology, In es i-
ga ion. Rub´
en Salas: W i ing – e iew & edi ing, Me hodology, In es-
iga ion, Funding acquisi ion. Luis F anco: W i ing – e iew & edi ing,
Valida ion, Supe ision, P ojec adminis a ion, Me hodology, Funding
acquisi ion, Fo mal analysis, Concep ualiza ion.
Decla a ion o compe ing in e es
The au ho s decla e ha hey ha e no known compe ing inancial
in e es s o pe sonal ela ionships ha could ha e appea ed o in luence
he wo k epo ed in his pape .
Da a a ailabili y
Da a will be made a ailable on eques .
Acknowledgmen s
This wo k was suppo ed by Colombia’s Minis y o Science Tech-
nology and Inno a ion (Minciencias- g an 689-2014) and he Uni-
e sidad de Ca agena (g an 025 -2019). The au ho s also hank
Danei a Ca o, Nely Mejia, Yu i Palacio, Jaime Salgado, and Daniela
Ama ís o collabo a ing du ing expe imen s. G aphical abs ac c ea ed
wi h BioRende .com.
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