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.

Table 2 Plant-derived compounds affecting inflammatory bowel disease by modulating nitric oxide pathways

Ref.	Phytochemical	type of animal	Model of IBD	Route of administration	Duration of treatment	Numbers of animals in intervention group and control group	Outcomes
[71]	Naringenin (25, 50, 100 mg/kg per day)	Rat	Acetic acid (AA)	Transrectal	7 d before colitis induction	n = 6	Disease activity index (DAI) ↓, total glutathione sulphadryls (T-GSH) ↑, non-protein sulphadryls ↑, DNA, RNA and total protein content ↑, nitrit oxide (NO) ↓, catalase (CAT) ↑, superoxide dismutase (SOD) ↑, tumor necrosis factor (TNF)-α ↓, interleukin (IL)-1β ↓, IL-6 ↓
[82]	Eupatilin (ethanol extract of aerial parts of Artemisiae herba, EIE) and quercetin-3-β-D-glucuronopyranoside from Rumex aquaticus (EIQ) (EIE, 100 mg/kg & EIQ, 30 mg/kg)	Rat	2,4,6-trinitrobenzene sulfonic acid (TNBS)	Oral	48, 24 and 1 h prior to the TNBS instillation and again 24 h later	n = 6	DAI ↓, myeloperoxidase (MPO) ↓, NO ↓, TNF-α ↓, total glutathione sulphadryls (GSH) ↑, malondialdehyde (MDA) ↓
[74]	Naringin (20, 40, or 80 mg/kg)	Rat	AA	Oral	12 d (8 d before colitis induction and 4 d after)	n = 6	DAI ↓, spleen weight ↓, white blood cell (WBC) ↑, red blood cell (RBC) ↑, hemoglobin (Hb) ↑ & platelet ↑, lactate dehydrogenase (LDH) ↓, alkaline phosphatase (ALP) ↓, SOD ↑, GSH ↑, Colon lipid peroxidation (LPO) ↓, NO ↓, MPO ↓, xanthine oxidase activity ↓, protein carbonyl content ↓, the number of unwinded double strand DNA ↓
[222]	Oligonol (0.5 and 5 mg/kg/d)	Mice	Dextran sulfate sodium (DSS)	Oral	7 d before colitis induction	n = 5	DAI ↓, IkBα phosphorylation & degradation ↓, p65 phosphorylation & nuclear translocation ↓, cyclooxygenase (COX-2) ↓, iNOS ↓, expression of antioxidant enzymes ↑, colon carcinogenesis ↓, the incidence and the multiplicity of colonic adenoma ↓
[223]	Algal meroterpene11hydroxy11Omethylamentadione (1, 10 & 20 mg/ kg)	Mice	DSS	Oral	7 d after colitis induction		DAI ↓, MPO ↓, TNF-α ↓, IL-1β ↓, IL-10 ↓, COX-2 ↓, iNOS ↓
[224]	Fraxinellone	Mice	DSS and lipopolysacchari-de (LPS)	intraperitoneal	9 d	n = 10	DAI ↓, MPO ↓, alkaline phosphatase (ALP) ↓, glutathione ↑, IL-1β ↓, IL-6 ↓, IL-18 ↓, TNF-α ↓, inhibition of cluster of differentiation molecule 11B (CD11B).+ macrophage infiltration, ICAM1 ↓, vascular cell adhesion molecule 1 ↓, iNOS ↓, COX-2 ↓, NO ↓, NF-κB signaling ↓ & NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome ↑
[79]	Isoquercitrin (1 and 10 mg/kg/d)	Rat	DSS	Oral	14 d (DSS induced the second half)	n = 8	Colon shortening ↓, COX-2 ↓, iNOS ↓, tissue healing did not encompass rectum
[225]	Oridonin (5.0 and 7.5 mg/kg)	Mice	TNBS	ntraperitoneal	7 d	n = 3-9	DAI ↓, TNF-α ↓, interferon (INF) ↓, IL-17A ↓, iNOS ↓, COX-2 ↓, in vitro lymphocyte proliferation ↓, NF-κB p65 expression & activity ↓
[68]	Cardamonin (20, 50, and 100 mg/kg)	Mice	DSS	Oral	2 d before DSS treatment & 7 d after	n = 10	NO ↓, TNF-α ↓, IL-6 ↓, toll like receptor (TLR)-4 ↓, myeloid differentiation factor (MDF) 88 ↓, IL-1 receptor-associated kinase-1 ↓, IκBα ↓, IκBK-α/β ↓, mitogen-activated protein kinase (MAPK) ↓, c-Jun NH2-terminal kinase ↓, nuclear translocation of NF-κB p65 ↓

IBD: Inflammatory bowel disease.

Table 3 Synthetic compounds affecting inflammatory bowel disease by modulation of nitric oxide pathways

Ref.	Type of animal	Model of IBD	Intervention	Duration of treatment	Numbers of animals in intervention group and control group	Outcomes
[226]	Rat	Dextran sulfate sodium (DSS)	Dinitrate-barbiturate (rectally twice daily)	5 d	n = 12	Matrix metalloproteinase (MMP)-9 activity ↓, disease activity ↓, colonic injury ↓
[227]	Rats	Lipopolysaccharide (LPS)	Ursodeoxycholate (gavage)	4 d	n = 4	Circulating nitrite/nitrate ↓, intestinal epithelial inducible nitric oxide synthase (iNOS) activity ↓, colonic injury ↓
[177]	Rat	Acetic acid (AA)	N-Acetylcysteine (NAC) (100 mg/kg for 7 d, 20 mg/kg for 2 d) (intraperitoneal, intracolonic)	2 d, 7 d	-	100 mg/kg NAC → tissue myeloperoxidase ↓, glutathione ↓, NO ↓, colonic injury ↓ 20 mg/kg NAC→ no protective effects
[229]	Rat	2,4,6-trinitrobenzene sulfonic acid (TNBS), AA	NG-nitro-L arginine methyl ester (L-NAME)	accompanied by TNBS or 7 d before AA	n = 55	TNBS-treated rats→ tissue injury ↓, lesion area ↓, colonic weight ↓, myeloperoxidase activity ↓, nitric oxide synthase (NOS) activity ↓ 24 hours after AA+ capsaicin pretreated rats→ tissue injury ↓, lesion area ↓, colonic weight ↓, NOS activity ↓ TNBS + L-NAME treated rats→ mean arterial blood pressure was higher than in TNB treated rats
[228]	Mice	Dinitrobenzene sulfonic acid (DNBS)	Trichinella spiralis antigens (helminth ags), (rectal submucosal)	5 d before DNBS induction	n = 6-8	Macroscopically and histologically colitis ↓, mortality rate↓, MPO activity↓, IL-1β production↓, inducible nitric oxide synthase (iNOS) expression ↓, IL-13 ↑, transforming growth factor beta (TGF)-β ↑, TH2 dominancy
[170]	Human mixed mono- nuclear cells (MMCs) co-cultured with HT-29 cells from UC patients	IFN-γ and LPS	Budesonide or prednisolone (corticosteroids)	Incubation or Pre-treatment	-	Nitrite content ↓, iNOS expression ↓
[191]	Rat	TNBS	Arginine-Glycine-Aspartic acid (RGD)-functionalized silk fibroin nanoparticles (SFN) (intrarectal, 1 mg/rat)	7 d	n = 10	Adhesion of integrins of the cell surface to the extra- cellular matrix of connective tissue ↓→ leukocyte recruitment to the inflamed intestinal tissue ↓→ iNOS expression ↓
[179]	Mice	DSS	Pravastatin, an 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, (intraperitoneal, 1 mg/kg)	10 d	n = 4-9	Cachexia ↓, hematochezia ↓, intestinal epithelial permeability ↓ with no effect on serum cholesterol, colonic injury ↓, expression of mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) ↓, mucosal endothelial nitric-oxide synthase (eNOS) mRNA degradation ↓, eNOS expression ↑, protective effects of pravastatin in DSS-induced colitis were not found in eNOS-deficient mice
[153]	Mice	Pathogen Citrobacter rodentium as an infection model and DSS as an injury model	Antennapedia-linked Apolipoprotein E-mimetic peptide COG112, (intraperitoneal)	Concurrent with induction of colitis, during induction plus recovery, or only during the recovery phase of disease	n = 4	C. rodentium treated mice→ improving the clinical parameters of survival, body weight loss, colon weight, histologic injury, expression of iNOS & the CXC chemokine keratinocytes (KC) & macrophage inflammatory protein (MIP)-2, more effective in iNOS-deficient mice, DSS treated mice→ body weight loss ↓, colon length ↓, histologic injury ↓, iNOS ↓, KC ↓, TNF-α ↓, IFN-γ ↓, IL-17 mRNA expression↓, nuclear translocation of NF-κB ↓, IKB kinase (IKK) activity ↓
[192]	Mice	DSS	3,3-Diindolylmethane (oral)	7 d, commencing at the same time DSS exposure began	n = 5	Number of iNOS- & COX-2-producing cells ↓
[147]	Rat	DSS	Glutamine (oral)	7 d with DSS	n = 13	Cytokine-induced iNOS expression↓, nuclear translocation of NF-κB p65 subunit ↓, cellular heat shock proteins (HSP)25 & HSP70 in a dose-dependent manner ↑
[180]	Rat	TNBS	Lactulose (oral)	2 wk before TNBS adminstration	n = 10	MPO activity ↓, colonic TNF-α ↓, leukotriene B4↓, iNOS expression ↓, levels of Lactobacilli and Bifidobacteria species in colonic contents ↑
[229]	Rat	Iodoacetamide	NG-nitro - L-NAME (oral)	21 d	n = 9-16	lesion area ↓, NOS activity ↓
[200]	Mice	DSS	GL-V9, a synthesized flavonoid derivative (intragastric)	From day 1 to day 10	-	Inflammatory cells infiltration↓, myeloperoxida-se (MPO) activity ↓, iNOS activity ↓, ROS & MDA generation ↓, SOD ↓, GSH reservoir ↑, pro-inflammatory cytokines production in serum & colon ↓; pro-inflammatory cytokines ↓, ROS production ↓, antioxidant defenses ↑ in mouse macrophage RAW264.7 cells by promoting thioredoxin-1 expression
[159]	Mice	DSS	Glucosamine oligomers (Chitooligosaccharid-es) (oral)	5 d	n = 8	Number of positive areas of iNOS & nuclear factor (NF)-κB staining in the colonic epithelium ↓
[27]	Mice	DSS	Nitrite (1 mmol/L) or nitrate (10 mmol/L) (oral)	7 d	n = 27-29	Nitrite (1 mM) → DAI score↓, colon length ↑, iNOS expression ↓, histopathology ↓, DSS-induced decrease in colonic mucus thickness↓, goblet cell abundance ↑. Nitrate (10 mM)→ DAI-score ↓
[176]	Rats, mice	TNBS and DSS	Doxycycline (oral)	5 d after the first DSS colitis induction	n = 10-21	Macrophages → IL-8 production ↓ by intestinal epithelial cells & NO production ↓. TNBS-colitic rats (5, 10 and 25 mg/kg) → DAI score ↓, colonic tissue damage ↓, mRNA expression of IL-6, TNF, IL-17, intercellular adhesion molecule 1 (ICAM1), iNOS & MCP-1 ↓, partial restoration of the mRNA levels of markers of intestinal barrier function (ZO-1, occludin & mucin (MUC)-3
[173]	Ulcerative Colitis (UC) and Crohn's Disease (CD) patients	-	Corticosteroids (Sulfasalazine and Azathioprine) (intravenous)	-	(1) UC treated with high dose corticosteroids (6 patients, 10 blocks); (2) UC patients who had never received corticosteroids (10 patients, 16 blocks); (3) CD treated with high dose corticosteroids (12 patients, 24 blocks); (4) Non-inflammatory, non-neoplastic controls (4 patients, 6 blocks)	Immunostaining with an antibody raised against the C terminal end of iNOS for NOS→ diffuse in UC & patchy in CD in epithelial cells & was most intense near areas of inflammation, Non-inflamed epithelium showed no immunoreactivity, treatment with corticosteroids made no difference to the amount of NOS
[162]	Rat	TNBS	Telmisartan (angiotensin II receptor antagonist) (oral, 10 mg/kg)	10 d before TNBS and until day 4 of TNBS	n = 8	DAI score ↓, colon weight/length ratio ↓, macroscopic damage ↓, histopathological findings ↓. Inflammation ↓, leukocyte migration ↓, TNF-α ↓, prostaglandin E2 (PGE2) ↓, MPO activity ↓, restoration of IL-10 mRNA and protein expression of NF-κB p65↓, mRNA expression of COX-2 and iNOS ↓, peroxisome proliferator-activated receptor (PPAR)-γ ↑, oxidative stress ↓ [lipid peroxidation (LPO) ↓, NO ↓, GSH ↑, TAC ↑, SOD ↑, glutathione peroxidase activity↑], apoptosis ↓ (mRNA, protein expression and activity of caspase-3 ↓, cytochrome C and Bax mRNA ↓, Bcl-2 ↓)

IBD: Inflammatory bowel disease.