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

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.