Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways

Table 1 Medicinal plants affecting inflammatory bowel disease via modulating nitric oxide pathways

Ref.	Plant	Plant part/ ingredients	Type of animal/cells	Model of IBD	Route of administra-tion	Duration of treatment	Numbers of animals in intervention group and control group	Outcomes
[199]	Terminalia catappa	Stem bark	Rat	2,4,6-trinitrobenzene sulfonic acid (TNBS)	Oral	Two days before colitis induction	n = 6	Disease activity index (DAI) ↓, myeloperoxida-se (MPO) ↓, glutathione content ↑, tumor necrosis factor (TNF)-α ↓, interleukin (IL)-6 ↓, IL-23 ↓, cytokine-induced neutrophil chemoattractan-t 1 ↓, mucin (MUC)-2 ↑, MUC-3 ↑, villin ↑
[200]	Veronica polita	Whole plant	Mice	Dextran sulfate sodium (DSS)	Oral	7 d	n = 10	DAI ↓, malondialdehy-de (MDA) ↓, nitric acid (NO) ↓, TNF-α ↓, IL-1β ↓, IL-6 ↓, inducible nitric oxide synthase (iNOS) ↓, cyclooxygenase (COX-2) ↓, nuclear factor (NF)-κB ↓, phosphoryla-tion of Junas kinase/signal transducer and activator of transcription (JAK2/STAT-3) ↓
[32]	Lavandula stoechas/ Lavandula dentate	Aerial parts	Rat	TNBS	Intrarectal	7 d	n =10	DAI ↓, MPO ↓, reduced glutathione (GSH) content ↓, iNOS ↓, IL-1β ↓, IL-6 ↓, monocyte chemoattrac-tant protein 1 (MCP-1) ↓, intercellular adhesion molecule 1 (ICAM1) ↓, IL-17 ↓, MUC-3 ↑, trefoil factor 3 gene (TFF)-3 ↑
[201]	Ziziphora clinopoides	Aerial parts	Mice	DSS	Oral	7 d before colitis induction	n = 6	Colon lipid peroxidation (LPO) ↓, total thiol molecules (TTM) ↑, total antioxidant capacity (TAC) ↑, NO ↑, TNF-α ↓, superoxide dismutase (SOD) ↑, catalase (CAT) ↑
[202]	Lavandula intermedia (cultivar Okanagan)	Essential oil	Mice	Citrobacter rodentium	Oral	5-10 d	-	Mortality and morbidity ↓, cecal damage ↓, damage of distal colon↔, iNOS ↓, IFN-γ ↓, IL-22 ↓, macrophage inflammatory protein (MIP)-2α ↓
[203]	Pisum sativum (Green Pea)	Powdered fruit	Mice	DSS	Oral	9 wk	n = 7	DAI ↓, MCP-1 ↓, COX-2 ↓, IL-6 ↓, IFN-γ ↓, IL-17 ↓, iNOS ↓, MUC-2 secretion ↑, TFF-3 ↑, kruppel-like factor 4 ↑, sam-pointed domain Ets transcription factor-1 ↑, activating transcription factor 6 (ATF)-6 ↓
[33]	Cannabis sativa	Cannabidiol	Mice	Dinitrobenzene sulfonic acid (DNBS)	Intracolonic	6 d	-	DAI ↓, iNOS ↓, nitrite production ↓, IL-1β↓, IL-10 ↑, anandamide & 2-arachydonylgly-cerol ↓, reactive oxygen species (ROS) formation ↓
[204]	Cannabis sativa	Cannabigerol	Mice	DNBS	Intracolonic	Preventive protocol: 6 d/ curative protocol: 2 d	-	Pre-treatment→DAI ↓, Fluorescein isothiocyanate (FITC)-conjugated dextran in the serum ↓, nitrite ↓ treatment→ MPO ↓, SOD ↑, iNOS ↓, IL-1β ↓, interferon (INF)-γ ↓, IL-10 ↑
[34]	Olea europaea (olive)	Leaves	Rat	Acetic acid (AA)	Oral	3 d	n = 6	DAI ↓, TNF-α ↓, NO ↓, IL-1β ↓, IL-6 ↓, iNOS ↓, IL-2 ↓
[83]	Crude canola (rapeseed) oil	Phenolic compound 4-vinyl-2,6-dimethoxyphen-ol (canolol)	Mice	DSS	Oral	7 d	-	DAI ↓, COX-2 ↓, free 8-hydroxy-2' deoxyguanosin-e (OHdG) in the plasma ↓, IL-12 ↓, TNF-α ↓, NO ↓
[37]	Retama monosperma	Aerial parts/ flavonoids	Rat	TNBS	Oral	48, 24 and 1 h prior to the induction of colitis & 24 h later	n = 10-11	DAI ↓, COX-2 ↓, iNOS ↓, p38 mitogen-activated protein kinase (MAPK) ↓
[38]	Hibiscus rosa sinensis	Leaves/ alkaloid, flavonoids, steroid and phenols	Mice and rat	AA	Oral	7 d before colitis induction	n = 6	DAI ↓, spleen enlargement ↓, white blood cell (WBC) count ↑, red blood cell (RBC) count ↑, hemoglobin (Hb) ↑, hematocrit ↑, platelet count ↑, SOD ↑, GSH ↑, LPO ↓, MPO ↓, nitrite/nitrate levels ↓, TNF-α ↓
[205]	Changtai granule	Traditional Chinese empirical formula comprised of Phellodendro Chinense, Sanguisorba officinalis , Euphorbia humifusa and polygonum hydropiper	Rat	TNBS	Oral	7 d	-	DAI ↓, MPO ↓, COX-2 ↓, iNOS ↓, Th1 cytokine response ↓, translocation of NF-κB in lamina propria mononuclear cells ↓
[206]	Syringa vulgaris	Verbascoside/ phenylpropano-id glycosides	Rat	DNBS	Oral	3 d	n = 10	DAI ↓, TNF-α ↓, IL-1β ↓, iNOS ↓, NO ↓, poly(ADP ribose) ↓, IκB-α levels in colon ↑, pro-matrix metalloproteina-se (MMP)-2 ↑, MMP-9 ↑
[39]	Curcuma longa	Curcumin	Rat	TNBS	Oral	3 d before induction of IBD & was continued for 5 d after	n = 8	DAI ↓, TNF-α ↓, MPO ↓, NO ↓, colonic hydroxyproline & ceruloplasmin levels ↓, expression of MMP-1, MMP-3 and tissue inhibitors of metalloproteina-ses 1 (TIMP)-1 ↓
[39]	Ginkgo biloba	Root	Rat	TNBS	Oral	3 d before induction of IBD & was continued for 5 d after	n = 8	DAI ↓, TNF-α ↓, MPO ↓, NO ↓, colonic hydroxyproline and ceruloplasmin levels ↓, expression of MMP-1, MMP-3 and TIMP-1 ↓
[207]	Cordyceps militaris Grown on Germinated Soybeans (GSC)	Mycelia	Mice	DSS	Oral	2 or 9 d before colitis induction	n ≥ 15	DAI ↓, MMP-3 ↓, MMP-9 ↓, TNF-α ↓, iNOS ↓, p53 ↓
[208]	Ficus bengalensis	Stem bark	Rat	TNBS	Oral	21 d	n = 6	DAI ↓, colon mucosal damage index ↓, MPO ↓, MDA ↓, NO ↓, SOD ↑
[46]	Vaccinium corymbosum (blueberry)	Fruits/phenolic acids and flavonoids	Mice	DSS	Oral	14 d	n = 6	DAI ↓, COX-2 ↓, IL-1β ↓, p65 NF-κB ↓, IFN-γ ↓, iNOS ↓, MDA ↓, CAT ↑, SOD ↑, prostaglandin E2 (PGE2) ↑
[209]	Hericium erinaceus (Lion's Mane Medicinal Mushroom)	Mycelia	Mice	DSS	Oral	7 d	-	DAI ↓, MPO ↓, TNF-α ↓, IL-1β ↓, IL-6 ↓, NO ↓, MDA ↓, SOD ↓ in serum
[40]	Panax notoginseng	Root/saponin	Mice	AOM and DSS	Oral	15 d	n = 3	DAI ↓, COX-2 ↓, iNOS ↓
[75]	Citrus nobiletin	Nobiletin	Rat	TNBS	Intragastric	7 d (1 d after colitis induction)	-	MPO ↓, iNOS ↓, COX-2 ↓, myosin light-chain kinase (MLCK) ↓, NF-kB ↓, protein kinase B (Akt) phosphoryla-tion ↓, trans epithelial electrical resistance ↓, inhibition of the Akt–NF‐κB–MLCK pathway
[66]	Vaccinium corymbosum (Portuguese blueberries)	Anthocyanin-rich fraction	Rat	TNBS	Intragastric	8 d	n = 8	DAI ↓, iNOS ↓, COX-2 ↓
[41]	Malus sylvestris (apple)	Fruit	Rat	AA	Oral	6 d	n = 5-6	iNOS expression ↓, COX-2 expression ↓, Copper Zinc (CuZn) SOD expression ↑ protein expression of iNOS ↓ in ulcerated area, COX-2↔ & 8-OHdG ↔
[210]	Scutellariae baicalensis	Oroxyloside	Mice	DSS	Intragastrically	10 d	n = 8	DAI ↓, MPO ↓, iNOS ↓, pro-inflammatory, cytokines in serum & colon ↓, peroxisome proliferator-activated receptor (PPAR)c ↑ →NF-κB ↓
[211]	Rheum tanguticum	Polysaccharide	Rat	TNBS	Intrarectal	5 d	n = 12	DAI ↓, NF-κB p65 ↓, TNF-α ↓, COX-1↔, COX-2 ↓, PGE2 ↑, iNOS ↓
[212]	Hypericum perforatum (St. John's Wort)	Hypericum perforatum extract	Rat	TNBS	Intraperitoneal	3 and 7 d treatments	-	DAI ↓, CAT ↓, GSH ↑, tissue NO ↓, MPO, glutathione reductase (GR), MDA, GSH-Px ↔
[42]	Allium sativum (garlic)	Diallyl sulfide (DAS) and diallyl disulfide (DADS)	Mice	DNBS + DAS DADS	Oral	2 d after first day of treatment	n = 10	In vivo→ DAI ↓ In vitro→ DADS→ IL-6 ↓, hydrogen sulfide ↑ DAS→ nitrite ↓, STAT-1 ↓, hydrogen sulfide ↑
[213]	Avena sativa (oat)	β-glucan	Mice	DSS	Intragastric	14 d	n = 20	DAI, TNF-α, IL-1β, IL-6, iNOS, NO, MDA, MPO ↓
[31]	Eryngium duriaei subsp. Juresianum; Laserpitium eliasii subsp. Thalictrifolium; Lavandula luisieri, Thapsia villosa	Essential oils (EO)	Primary human chondrocyte & C2BBe1	IL-1β or a cytokine mixture (IFN-γ, IL-1β TNF-α)	-	EO added 30 min before cytokine stimulation	-	EO of L. luisieri→ iNOS ↓, p-IκB-α ↓ in both cell models EO of E. duriaei subsp. juresianum→ iNOS ↓, p-IκB-α ↓ in human chondrocytes EO of L. eliasii subsp. thalictrifolium & O. maritimus → iNOS ↓ in C2BBe1 cells EO of T. villosa → inactive in both cell types
[214]	Rhizophora apiculate	Whole plant	Mice	AA	Intraperitoneal	7 d	n = 6	SOD ↑, GSH ↑, LPO ↓, NO ↓, MPO ↓, lactate dehydrogenase (LDH) ↓, iNOS ↓, COX-2 ↓, translocation of NF-κBp65 & p50 subunits ↓
[215]	Polygonum multiflorum	2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucoside (THSG)	Mice	AA+ mitomycin C	Oral	7 d and 24 d	n = 12	THSG (60 mg/kg) →DAI ↓, MPO ↓, MDA ↓, NO level ↓, iNOS ↓, SOD ↑ THSG (120 mg/kg) & 24th day of mitomycin C→ > positive control, 5-aminosalicylic acid (5-ASA)
[94]	Oryza sativa L. (black rice )	Anthocyanin and rosmarinic acid	Mice	DSS	Oral	8 d	n = 8	Macroscopic damage ↓, microscopic damage ↓, body weight loss ↓, iNOS ↓- COX-2 ↓, IL-6 ↓, IL-1β ↓, TNF-α ↓
[67]	Dioscorea alata	Anthocyanidin-es	Mice	TNBS	Rectal	7 d	n = 10	Macroscopic damage ↓, microscopic damage↓, body weight loss ↓, tight junction proteins ↑, MPO ↓, iNOS ↓, TNF-α ↓, IFN-γ ↓
[216]	Patrinia scabiosaefolia	Root	Mice	DSS	Oral	7 d	n = 8	Macroscopic damage ↓, microscopic damage↓, IL-6 ↓, IL-1β ↓, TNF-α ↓, iNOS ↓
[217]	Morinda citrifolia (noni)	Fruit juice/ flavonoids	Mice	DSS	Oral	9 d	n = 8	Microscopic damage ↓, IL-6 ↓, INF-γ ↓, NO ↓, MPO ↓
[201]	Ziziphora clinopoides (kahlioti)	Aerial parts	Mice	DSS	Oral	7 d	n = 6	TNF-α ↓, TAC ↑, TTM ↑, LPO ↓, NO ↓
[44][43]	Camellia sinensis (Black tea)	Theaflavin-3,30-digallate	Mice	TNBS	Oral	18 d	-	Macroscopic damage ↓, microscopic damage ↓, iNOS ↓, MPO ↓, TNF-α↓, IFN-γ ↓, IL-12 p40 ↓, NFκB ↓
		Thearubigin	Mice	TNBS	Oral	18 d	-	Macroscopic damage ↓, microscopic damage ↓, iNOS ↓, O2- ↓, MPO ↓, IFN-γ ↓, IL-12 ↓, IL-4 ↓, NFκB ↓
[218]	Picrasma quassiodes	Dried branches/ alkaloids	Mice	TNBS	Gastric lavage	7 d	n = 10	Macroscopic damage, microscopic damage, body weight loss, MPO, TNF-α, IL-8, COX-2, iNOS↓
[95]	Aronia berries	Berry extract/ polyphenols	Mice	DSS	Oral	10 d	-	Macroscopic damage, microscopic damage, body weight loss, TNF-α, IL-6, PGE2, NO, MAPK ↓
[199]	Terminalia catappa	Stem/phenolic compound	Rat	TNBS	Oral	9 d	-	Macroscopic damage ↓, microscopic damage ↓, NO ↓, IL-1β ↓, MUC2 ↑, MUC3 ↑
[45]	Glycyrrhiza glabra (liquorice)	Glabridin	Mice	DSS	Oral	7 d	-	Macroscopic damage, microscopic damage, body weight loss, iNOS, MPO, COX-2, TNF-α, IL-6↓
[219]	Punica granatum (pomegranate)	Extract/ phenolic compounds	Rat	DSS	Oral	30 d	n = 8	Macroscopic damage ↓, Bifidobacteria and Lactobacilli ↑, lipid peroxidation ↓, iNOS ↓- COX-2 ↓, P53 ↑, cluster of differentiation molecule (CD) 40 ↓, IL-1β ↓, IL-4 ↓
[220]	Physalis peruviana	Calyx/flavonoi-ds, terpenoids & glycosides	Rat	TNBS	Intraperitoneal	3 d in protective protocol and 15 d in therapeutic protocol	-	Macroscopic damage ↓, microscopic damage ↓, COX-2 ↓, iNOS ↓, MPO ↓, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) ↓, IL-1β ↓, IL-6 ↓, IL-10 ↓, MUC2 ↑
[221]	Perilla frutecens	Whole plant	Mice	DSS	Oral	14 d (starting from 7 d before induction of colitis)	n = 6	NF-кB ↓, COX-2 ↓, iNOS ↓, cyclin D1 ↓, STAT-3 activation ↓, nuclear factor erythroid 2–related factor (Nrf)2 ↑, heme oxygenase-1 (HO-1) ↑, interferon regulatory factor 3 (IRF3) ↓ PE (10 mg/mL) in CCD841CoN human normal colon epithelial cells→ TNF-α ↓, iNOS ↓, P-IкB α ↓, P-STAT-3 ↓, C-X-C Motif Chemokine Receptor 2 (CXCR)2 ↓

IBD: Inflammatory bowel disease.