Recent Trends in Pharmacological Activity of Alkaloids in Animal Colitis: Potential Use for ...

25 Pages·2017·2.29 MB·English

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Evidence-Based Complementary and Alternative Medicine
Volume 2017, Article ID 8528210, 24 pages
https://doi.org/10.1155/2017/8528210
Review Article
Recent Trends in Pharmacological Activity of Alkaloids in
Animal Colitis: Potential Use for Inflammatory Bowel Disease
AnaCristinaAlvesdeAlmeida,1FelipeMeirade-Faria,1
RicardoJoséDunder,2LuisPauloBognoniManzo,1
AlbaReginaMonteiroSouza-Brito,1andAndersonLuiz-Ferreira3
1InstituteofBiology,DepartmentofStructuralandFunctionalBiology,UniversityofCampinas,Campinas,SP,Brazil
2FacultyofMedicalSciences,DepartmentofPharmacology,UniversityofCampinas,Campinas,SP,Brazil
3InstituteofBiotechnology,DepartmentofBiologicalSciences,FederalUniversityofGoia´s,Catala˜o,GO,Brazil
CorrespondenceshouldbeaddressedtoAnaCristinaAlvesdeAlmeida;[email protected]
Received6September2016;Revised30October2016;Accepted24November2016;Published9January2017
AcademicEditor:CaiganDu
Copyright©2017AnaCristinaAlvesdeAlmeidaetal. This is an open access article distributed under the Creative Commons
AttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkis
properlycited.
Inflammatory bowel disease (IBD) is a chronic and disrupted inflammation of the gastrointestinal tract. IBD have two main
conditions,Crohn’sdiseaseandulcerativecolitis,andhavebeenextensivelyinvestigatedinrecentyears.Antibioticsderivedfrom
salicylates,steroids,immunosuppressors,andanti-TNFtherapyarepartofthetherapeuticarsenalforIBD.However,veryoften
patientsstoprespondingtotreatmentsoverthetime.Inthiscontext,searchingforalternativeagentsiscrucialforIBDclinical
management. Natural products derived from medicinal plants are an interesting therapeutic alternative, since several studies
haveproveneffectivetreatmentsinanimalmodelsofintestinalinflammation.Severalnaturallyoccurringcompoundsarepotent
antioxidants,bothasfreeradicalscavengersandasmodulatorsofantioxidantenzymesexpressionandactivity.Anumberofnatural
compoundshavealsobeenprovedtoinhibitthereleaseofproinflammatorycytokines,decreasingtheactivationofnuclearfactor
𝜅B(NF-𝜅B),whichisimportanttotheinflammatoryresponseinIBD.Thealkaloidsaresubstancesofaverydiverseclassofplant
secondary metabolites; an extensive list of biological activities has been attributed to alkaloids, such as being anticholinergic,
antitumor,diuretic,antiviral,antihypertensive,antiulcer,analgesic,andanti-inflammatory.Inthepresentwork,studiesonthe
pharmacologicalactivityofalkaloidsinexperimentalmodelsofIBDwerereviewed.
1.Introduction IBDiscomplexandinvolvesenvironmentalfactors,genetic
factors,andanexacerbatedimmuneresponsetocommensal
Inflammatoryboweldisease(IBD)isachronicinflammatory bacteria[4–6].
disorderinthegastrointestinaltractandprimarilyincludes IBD was initially recognized as a health problem of
twoforms,ulcerativecolitis(UC)andCrohn’sdisease(CD) developedcountries;however,inarecentreview,Molodecky
[1]. UC is characterized by an inflammatory response with andcollaborators[7]havealsoreportedincreasingincidence
edema,ulcerationandbleeding,andmorphologicalchanges andprevalenceofIBDindevelopingcountries,probablydue
along with the intestine mucosae, involving infiltration of tochangesinlifestylesofthesepopulations[8].
polymorphonuclear cells (PMN), abscesses formation in The therapy of IBD presents lack of effectiveness, high
mucosal crypts, and glands distortion. These changes are costs, and numerous side effects [9, 10]. Although anti-
concentratedinthemucosaandrestrictedtothecolonand TNF𝛼therapyrevolutionizedIBDclinicalmanagement,the
rectum[2].CDcanaffectanyportionofthegastrointestinal number of reports showing loss of response in patients
tract, disturbing mainly the submucosa, but may be trans- have been increasing. Moreover, almost one-third of IBD
muralandexceedtheserosa,creatingfistulas[3].Etiologyof cases have not improved after anti-TNF𝛼 therapy [11].
2 Evidence-BasedComplementaryandAlternativeMedicine
Thus, the search for new alternative for the IBD therapy is have also been presented in different experimental models
stillsinequanon. or pathological conditions [31–35]. Based on the chemical
Foracentury,naturalproductshavebeeninthevanguard diversityofalkaloidsandtheirbiologicalactivitiespreviously
ofdrugdiscoveryresearch,but,aftertheadventofautomated reported, these compounds emerge as potential agents for
highthroughputscreening(HTS)programs,theuseofnat- intestinalinflammatorydisorders.
uralproductsindrugdiscoveryinpharmaceuticalindustry
declined [12]. However, natural products still continue to
3.AlkaloidsandExperimentalColitis
contribute to the drug development for cancer, infectious
(bacterial, fungal, parasitic, and viral), immunological, car-
This search was carried out on PubMed, Scopus, and Web
diovascular,neurological,inflammatory,andrelateddiseases
of Science database, using the terms “Inflammatory Bowel
[13, 14]. There is an increase in the number of IBD patients
Disease”OR“experimentalcolitis”OR“ulcerativecolitis”OR
usingcomplementaryherbaltherapiesandmanyexperimen-
“Crohn’sDisease”OR“Colitis”AND“Alkaloid”.Publications
talstudiesandclinicaltrialspresentbeneficialeffectofvegetal
overthelastdecadewereconsidered.
extracts,fractions,orcompounds[15].
In this work, we made a review in the studies on the
3.1. Nicotine: Dual Role on IBD. Nicotine is studied as the
effects of alkaloids, a class of plant compounds with sev-
maincompoundresponsibleforcigarettesmokingproperties
eralbiologicalactivitiesreported,inexperimentalintestinal
onintestinalmucosa[36].Smokinghasanoppositeeffectin
inflammatoryinjury.
thetwoformsofIBD:whilesmokingincreasesthenumber
andtheriskofdevelopingrelapsesinCD,inUC,surprisingly,
the episodes of active disease are decreased [37, 38]. The
2.Alkaloids
effectofnicotineonintestinalinflammationhasbeenwidely
studiedinexperimentalassays[39–42]andclinicaltrials[43–
The definition of the term alkaloid is not simple, but, in
45]andthereareseveralreviewsontheeffectsofnicotinein
general,alkaloidsareagroupofnaturalnitrogen-containing
relationtoIBD[46–49].
basic compounds with low molecular weight, synthetized
fromaminoacidsandbiologicallyactive[16].Alkaloidsare
a diverse group of compounds found in bacteria, fungi, 3.2.PlantExtractsandHerbalFormulation. Thesearchshows
plants, and animals [17]. There are three types of alkaloids: some studies with plant extracts or herbal formulations,
true alkaloids, protoalkaloids, and pseudoalkaloids. True richinalkaloids,usedintraditionalChineseandAyurvedic
alkaloids have a heterocyclic ring with nitrogen, while, in medicine as Amaranthus roxburghianus, Hangeshashinto,
the protoalkaloids, the N atom derived from amino acids FructusMumepill,Sangrovit,andSophoraalopecuroides.
is not part of heterocyclic ring. Pseudoalkaloids are not OursearchonalkaloidandIBDhasledtoseveralplant
originatedfromaminoacids,includingterpene-like,purine- extractsorherbalformulationscommonlyusedintraditional
like,andsteroid-likealkaloids.Themajorgroupsofalkaloids Chinese and Ayurvedic medicine, such as Hangeshashinto
aresummarizedin Figure1. (HST), Sophora alopecuroides, Fructus Mume pill (FMP),
Thefirstalkaloidsformedicinalusewereisolatedatthe Sangrovitand,andAmaranthusroxburghianus.
beginning of 19th century, by Derosne (opium salt, nar- Kawashimaandcolleagues[50]evaluatedacombination
cotine) and Sertu¨rner (principium somniferum, morphine). of oriental medicinal plants, HST, in TNBS-induced colitis.
The chemical identification of morphine was carried in WistarratstreatedwithHSTfor5dayspresenteddecreased
1923, by Robinson and Gulland [18, 19]. So far, there are colondamage(macroscopiclesionscore,ulcerativearea,and
morethan20000alkaloidsidentifiedandanumberofthem colonweight),reduceddiarrhea,andincreasedbodyweight.
have been placed an important role in clinical practice Theauthorsalsoevaluatedtheeffectofmainconstituentsof
[20]. They present numerous biological activities such as HST, berberine (BE), baicalin (BA), glycyrrhizin (GL), and
being emetic, anticholinergic, antitumor, diuretic, sympa- ginsenosides (GS) in the experimental TNBS colitis. These
thomimetic, antiviral, antihypertensive, analgesic, antide- componentsweregivenalone,incombination(BA+BEand
pressant, muscle relaxant, anti-inflammatory,antimicrobial, GL + GS), or in a total mixture (BA + BE + GL + GS).
and antiulcer [21, 22]. The alkaloids have proton-accepting The compoundsgiven alone and the combinationBA + BE
nitrogen atom and one or more proton-donating amine did not prevent colon injury, while GL + GS and the total
hydrogenatoms,whichformhydrogenbondswithproteins, mixtureamelioratedtheintestinalinflammation.Theauthors
enzymes, and receptors. Furthermore, they, generally, have concludedthatneitherberberinenorbaicalinisresponsible
functionalgroupssuchasphenolichydroxyl.Thelatermight forHSTanticolitiseffect;thus,HSTwassuggestedtoprevent
explaintheexceptionalbioactivityofthealkaloids[17]. or diminish the colitic phenotype due to the synergistic
Several studies have been demonstrating the anti- combinationofitscomponents.
inflammatory activity of alkaloids, involving inhibition or EffectsoftotalalkaloidsofSophoraalopecuroides(TASA)
regulation of important inflammation mediators such as wereevaluatedinTNBS-inducedcolitisinrats,byChenand
NF-𝜅B, COX-2, and iNOS [23–29]. Souto et al. reviewed Deng[51].TASAamelioratedhistologicaldamage,increased
publishedstudiestoevaluatetheanti-inflammatoryactivity SODactivity,anddecreasedMDAlevels,aswellasNOand
of alkaloids and reported 40 of these compounds with MPO activity. In a study from Zhou and colleagues [52],
significant activity [30]. Antioxidant activity of alkaloids employingthesameexperimentalmodel,theoraltreatment
Evidence-BasedComplementaryandAlternativeMedicine 3
True alkaloids
Precursor: L-ornithine Precursor: nicotinic acid
Pyrrolidine Tropane Pyrrolizidine Pyridine
N N
H
N N
H
Precursor: L-lysine
Piperidine Quinolizidine Indolizidine
N N
N
Precursor: L-tryptophan
Indole Quinoline pyrroloindole
N
N N N
H
Precursor: anthranilic acid
Quinazoline Quinoline Acridone
H
N
N
N N
O
Precursor: L-tyrosine or L-phenylalanine Precursor: L-histidine
Isoquinoline Imidazole Manzamine
N
N O
H N
N N N
H N
(a)
Figure1:Continued.
4 Evidence-BasedComplementaryandAlternativeMedicine
Protoalkaloids
Precursor: L-tyrosine Precursor: L-tryptophan
Phenylethylamine Terpenoid indole
H NH
N
H
N
H
H
H
O
O
H
O
(b)
Pseudoalkaloids
Precursor: acetate Precursor: pyruvic acid
Piperidine Sesquiterpene Ephedra
O
O
O O
O O O O H N
H
O H H
O O
H
O
O O O
N
O O
N O
Precursor: adenine/ guanine Precursor: geraniol
Purine Terpenoid
H
H O
N
N H
N
O
N N H
H
(c)
Figure1:Mainalkaloidsgroups:TrueAlkaloids(a),Protolakaloids(b)andPseudoalkaloids(c),precursors,andskeletonstructures.Adapted
fromAniszewski,2007[18].ChemicalstructuresweregettinginPubChemdatabase.
with TASA decreased damage scores, maybe due to the TASA treatment on DSS-induced chronic intestine injury.
upregulationofCD4+CD25+regulatoryTcells(Tregs)and Chronically,TASAexhibitedprotectiveeffectsonDSScolitis
anti-inflammatorycytokineIL-10. inhibiting secretory immunoglobulin A and haptoglobin
The effect of TASA on DSS-induced intestinal inflam- release; likewise, the intercellular adhesion molecule 1
mation in mice has also been investigated. In this model, (ICAM-1)geneexpressionandp65recruitmenttotheICAM-
TASAinhibitedacuteinflammationinthegutbyinhibiting 1 gene promoter were also found inhibited, suggesting that
the secretion of IL-1𝛽 and promoting the release of anti- TASA might protect the intestine from injury by inhibiting
inflammatory cytokine IL-4 [53]. Zhao et al. [54] assayed NF-𝜅Bactivation.
Evidence-BasedComplementaryandAlternativeMedicine 5
FMPisacombinationoftenChineseherbsthathasbeen the downregulation of MUC-2 mRNA expression in the
used for a long time in traditional Chinese medicine for colon.InLPS-stimulatedCMT93cells,AFCpreventedupreg-
the treatment of diarrhea and dysentery; indeed, the State ulation of of ICAM-1, TNF-𝛼, and IL-6 mRNA expression
Food and Drug Administration of China approved its use andthereleaseofTNF-𝛼andIL-6.Inaddition,ACFhasalso
forthemanagementofgastrointestinaldisorders.Theeffect preventedthedownregulationofofMUC-2andZO-1expres-
ofFMPwasevaluatedonTNBS-inducedcolitisinSprague- sioninLPS-stimulatedCMT93cells.Stylopine,coptisine,and
Dawleyrats.Remarkableresultsincludereducedulcerarea, protropinewereidentifiedasmajorcompoundsinAFC.
colon weight/length ratio, diarrhea, colonic MPO activity,
INF-𝛾levels,gram−/gram+bacteriarelation,andincreased
IL-4 levels [55]. The authors suggested that these effects 3.3. Isolated Alkaloids. We found 32 alkaloids with activity
may be related to the alkaloids aconitine and berberine. assessedinexperimentalmodelsthatinducedthedisruptof
In another study, Zhang and colleagues [56] reported the the epithelial barrier (DSS, acetic acid, or mustard oil) or
synergistic activity of three alkaloids from FMP: berberine, thatinvolvedhapten-inducedhypersensitivereactionsinthe
hypaconitine,andskimmianineonTNBS-inducedcolitisin intestinalinflammation(TNBS),mainlyinmice.
rats.Berberineamelioratedintestinalinjuryanddiminished In accordance with structural forms, the cited alkaloids
TNF-𝛼 levels and NF-𝜅B expression in colon but had no are classified in diterpenoid alkaloids (14-O-acetylneoline,
effect on abdominal pain (in acetic acid-induced writhing) 14-O-veratroylpseudaconine,andhypaconitine),indolealka-
norgastrointestinaltransit.Althoughhypaconitineandskim- loids(fumigaclavineCandisatin),indolonaphthyridinealka-
mianinedidnotexhibitanti-inflammatoryactivityonTNBS- loids (nigakinone), indoloquinazoline alkaloids (tryptan-
induced colitis, the treatment with the combination of the thin), isoquinoline alkaloids (berberine, boldine, cavidine,
three alkaloids ameliorated the colonic injury. The authors coptisinederivatives,EM012,papaverine,sanguinarine,sino-
suggest that berberine exerted mainly anti-inflammatory menine, tetrahydrocoptisine, and tetrandrine), phenan-
activity, while hypaconitine possesses analgesic effect and throindolizidine alkaloids (NK-007 and W-8), piperidine
skimmianineantidiarrhealproperties. alkaloids (piperine), purine alkaloids (caffeine), quinoline
Vrublovaandcolleagues[57]assayedtheSangrovit(rich alkaloids (skimmianine), and quinolizidine alkaloids (mat-
in isoquinoline alkaloids) feeding supplementation in DSS- rine, oxymatrine, sophocarpine, and sophoridine). The
inducedcolitisinWistarrats.Sangrovitisusedasappetizer effectsofthesealkaloidsonexperimentalcolitisaresumma-
supplementinlivestockfeed.Sangrovitamelioratedhistolog- rizedinTable1.Berberine,sinomenine,andpiperineeffects
icaldamagescore,decreasingCOX-2expressionandcolonic on experimental colitis were assessed in two or more
MPOactivity.Thealkaloidssanguinarine,dihydrosanguinar- manuscripts,asdetailedhereafter.
ine, chelerythrine, and dihydrochelerythrine were found in Berberine has been the wieldiest studied alkaloid with
the colon of Sangrovit-treated animals, suggesting a direct pharmacologicalactivityinintestinalinflammatorymodels.
effectofthesecompoundsinthecolonicmucosae. It is one of the main substances of Berberis sp. [95]. It
Iablokov and colleagues [58] evaluated the effects of is also isolated from Hydrastis, Coptis, and Phellodendron
potatoes glycoalkaloids on IL-10 knockout mice (genetic species[96].Theeffectofberberineincolitiswasevaluated
predisposition to develop colitis) and DSS treated mice. in DSS and TNBS-induced colitis in mice and rats. This
Their data show increased INF-𝛾 levels in ileum of IL-10 alkaloidamelioratescoloninjuryandinhibitstheincreaseof
knockout mice and increased intestinal permeability and inflammatorymediatorsandoxidativedamage,asdescribed
INF-𝛾, IL-17, and TNF-𝛼 levels in DSS colitis mice. As inTable1.
a consequence, deleterious effects of glycoalkaloids were Thetreatmentwithberberinewasusedasreferencedrug
reported.Theauthorsattributedsuch effects,mainly,tothe for Berberis vulgaris fruit extract (BFE) treatment during
compounds𝛼-chaconineand𝛼-solanine.Theglycoalkaloids the evaluation of its effects on acetic acid-induced colitis
concentration can raise in about threefold in fried potatoes [65]. Both oral BFE and enema treatment were effective in
whichhasbeenshowntoaggravateintestinalinflammation. diminishingthemacroscopicandhistopathologicaldamage.
Nirmal and collaborators [59] analyzed the effect of AsBFEisnearlydisprovedofberberinealkaloid,theauthors
Amaranthusroxburghianusrootextractincombinationwith attributed the effect to other components, such as antho-
piperineonacidacetic-inducedcolonicinjuryinmice.The cyanins.Kawashimaandcollaborators[50]reportednosig-
treatmentwithA.roxburghianusdecreasedhistopathological nificanteffectofberberine(3.75or6.5mg⋅kg−1)treatmentin
damage, MPOactivity,andMDAlevelsandmajorlevelsof TNBS-inducedcolitis.Thisresultisprobablyduetothedoses
reduced GSH compared to control (5% acetic acid). Inter- used,whiletheprotectiveeffectofberberineinexperimental
estingly,thecombinationwithpiperineimprovedtheeffects colitiswasobservedwithdosesof10–100mg⋅kg−1[64,66,67,
oftheextract,similarlytothoseobservedforprednisolone- 69].
treatedanimalswhilepiperineitselfhadnoeffect. The addition of berberine (20mg⋅kg−1) to 5-ASA treat-
Inarecentpublication,Bribiandcolleagues[60]reported ment (200mg⋅kg−1) decreased disease severity of colitis
theprotectiveeffectoftotalalkaloidsofFumariacapreolata induced by DSS in mice. 5-ASA in combination with
(AFC) on DNBS-induced colitis in mice. AFC treatment berberine decreased the disease activity index (DAI) and
decreased the body weight loss, colon weight/length ratio, histological injury, inhibited COX-2, TNF-𝛼, IL-12b, and
andmicroscopicscore.AFCinhibitedtheincreaseofTNF-𝛼, IL-23 expression in colon tissue, and inhibited NF-𝜅B and
IL-1𝛽,Il-6,IL-12,iNOS,ICAM-1,andMMP-9andprevented JAK activation. Moreover, the combination of 5-ASA and
6 Evidence-BasedComplementaryandAlternativeMedicine
e
c
eferen [61] [62] [62]
R
Results ↓bodyweightloss↓DAI↓colonlengthshortening ↓bodyweightloss↓clinicalscore↓piloerectionandmobilityscore↓faecalconsistencescore↓macroscopicdamagescore↓colonlengthdecrease↓histologicalinjury↓𝛾INF-secretion ↑inflammation(bodyweightloss)
s.
el
d
o
m
s
oliti
c
al
nt el
e d
ffectsinexperim xperimentalmo C57BL/6JmiceDSS C57BL/6miceTNBS C57BL/6miceTNBS
e E
s
d
oi
al
k
al
of
y
r
a
m
m
u
S
1:
e
l
b p.
a s
T s
ali
d
y
r
o
C
p.,
s
s
pti
o
C
n
i
redR O O O H O H
e
ne unt
Substance(class)andsource±()-8-Acetonyldihydrocoptisi(Isoquinoline)Derivativeofcoptisine,encoOO NO 14-O-Acetylneoline(Diterpenoid)AconitumlaciniatumH OH OAc N OHH OO 14-O-Veratroylpseudaconine(Diterpenoid)AconitumlaciniatumOH O OVr NOHHO OO
Evidence-BasedComplementaryandAlternativeMedicine 7
e
c
eferen [63] [64] [56]
R
Results↑bodyweight↓macroscopicdamagescore↓histologicaldamagescore↓MPOactivityandIL-8production ↓bodyweightlossandmacroscopicdamagescore↓MPOactivity,iNOS,MDA,and4-HNElevels↓𝛽𝛼IL-1,TNF-,andIL-6levels↑IL-10andGSHlevels,SOD,andCATactivity ↓colonindexandulcerativearea↓𝛼TNF-levelsincolontissue↓𝜅NF-Bexpressionincolontissue=TLR4expressionincolontissue=LBPlevelincolontissue↓LBPlevelinLPStreatedcells(HT29cells)=PGElevelinLPS2treatedcells(HT29cells)↓𝛼TNF-levelinLPStreatedcells(HT29cells)
1:Continued. Experimentalmodel Sprague-DawleyratsTNBS C3H/NeHmiceC3H/HeJmiceTNBS Sprague-DawleyratsTNBS
e
l
b
a
T
e
s
onica,muren
pa
a
jn
so
optindr
Cde
nsis,hello
eP
hinm,
cu
optisuifoli O
Cq
a
m,a
rce oliuhoni O
ou uifMa
ands B.aqnsis, +N
Substance(class) Berberine(Isoquinoline)Berberisvulgaris,Hydrastiscanade O O
8 Evidence-BasedComplementaryandAlternativeMedicine
e
c
eferen [65] [66] [67]
R
Results↓lesionscoreandulcerativearea↓colonweight/lengthratio↓histopathologicaldamage↓colitisindexandulcerindex ↓bodyweightloss↓inflammationscore↓MPOactivity↓𝛼𝛾TNF-,INF-,IL-17,andKClevels↓𝛼TNF-levelsincolonicmacrophages↓𝜅IBdegradation,ERK1/2,andp38activationincolonicmacrophagesandepithelialcells ↓bodyweightloss↓spleenweight↑thymusweight↓bloodhemoglobinlevelsreduction↓colonicMPOactivityandMDAlevels↓𝛾INF-andIL-12inspleniclymphocyteproduction↑IL-10andIL-4inspleniclymphocyteproduction
el
d
Continued. perimentalmo WistarratsAceticacid C57BL/6miceDSS BALB/cmiceDSS
x
1: E
e
l
b
a
T
e
a,ens
nicmur
o
pa
an
ptisjndro
oe
Cd
nsis,hello
eP
hinm,
cu
optisuifoli O
Cq
a
m,a
rce oliuhoni O
ou uifMa
ands B.aqnsis, +N
Substance(class) Berberine(Isoquinoline)Berberisvulgaris,Hydrastiscanade O O
Evidence-BasedComplementaryandAlternativeMedicine 9
e
c
eferen [68] [69]
R
Results↓bodyweightloss↓colonlengthdecrease↓lymphocytesinfiltration↓𝛾INF-andIL-17secretion(acutephase)DopamineD1andD2-likereceptorsantagonism↓𝛾𝛼INF-,TNF-,andIL-6secretioninspleniclymphocytesandperitonealmacrophages↓𝛼TNF-,IL-6,IL-12,𝛽andTGF-secretioninbonemarrowdendriticcells(BMDC)↑𝛽IL-1secretioninBMDCcells ↓bodyweightloss↓stoolconsistenceandbleedingscores↓DAIandhistologicalinjuryscore↓colonlengthdecrease↑occludin,IL-4,IL-10,andFoxp3expression↓IL-17,IL-6,IL-23,𝛼𝛾TNF-,T-bet,ROR-texpression,andSTAT3activation↓Th17cellsinfiltration
el
d
o e e
m c c
Continued. perimental C57BL/6miDSS C57BL/6miDSS
x
1: E
e
l
b
a
T
e
a,ens
nicmur
o
pa
an
ptisjndro
oe
Cd
nsis,hello
eP
hinm,
cu
optisuifoli O
Cq
a
m,a
rce oliuhoni O
ou uifMa
ands B.aqnsis, +N
Substance(class) Berberine(Isoquinoline)Berberisvulgaris,Hydrastiscanade O O
10 Evidence-BasedComplementaryandAlternativeMedicine
e
c
eferen [70] [71] [72]
R
Results↓DAIandhistologicaldamage↑↓colonlengthandspleenweight↓MPOactivityandMDAcontentincolon↑SODandCATactivitiesincolon↓𝛼TNF-,IL-6,IL-17,+𝜅CD68,andNF-BexpressionandpSTAT3activationincolon↑𝜅𝛼IB-expressionincolon↓𝜅NF-BexpressioninnucleusofLPS-treatedRAW264.7cells↓bodyweightloss↓clinicalandhistologicalscores↓tissueF4/80,CD4andC11bpositivecellsandbacterianumber↓𝛼𝛾TNF-,INF-andIL-17blevels↑IL-10andIL-4levels↓AMCaseandCHI3L1expression↓Aktactivation↓bodyweightlossandmortality↓DAI↓macroscopicalandhistologicalscores↓colonweight/lengthratio↓𝜅𝛼NF-B,TNF-,andIL-6expressionincolon↓𝛼TNF-andIL-6serumlevels↓MPOactivityandMDAlevelsincolon↑SODactivityandGSHlevelsincolon
el
d
Continued. perimentalmo Balb/cmiceDSS C57BL/6miceDSS KunmingmiceAceticacid
x
1: E
e
l
b
a
T
a
n
a
p
u
c
a
ni
ulli
a
P
s,
si
n
e
ri
a
u
g
a
r
a
p
x
e
Il
a,
ce H N nat
ur O H mi
o u
s c
d a
n a s
Substance(class)a Boldine(Isoquinoline)Peumusboldus O O OH Caffeine(Purine)Coffeaarabica,ColO NN NNO Cavidine(Isoquinoline)Corydalisimpatien O O HN O O