Review
Copyright ©The Author(s) 2020.
World J Gastroenterol. Jun 28, 2020; 26(24): 3365-3400
Published online Jun 28, 2020. doi: 10.3748/wjg.v26.i24.3365
Table 3 Synthetic compounds affecting inflammatory bowel disease by modulation of nitric oxide pathways
Ref.Type of animalModel of IBDInterventionDuration of treatmentNumbers of animals in intervention group and control groupOutcomes
[226]RatDextran sulfate sodium (DSS)Dinitrate-barbiturate (rectally twice daily)5 dn = 12Matrix metalloproteinase (MMP)-9 activity ↓, disease activity ↓, colonic injury ↓
[227]RatsLipopolysaccharide (LPS)Ursodeoxycholate (gavage)4 dn = 4Circulating nitrite/nitrate ↓, intestinal epithelial inducible nitric oxide synthase (iNOS) activity ↓, colonic injury ↓
[177]RatAcetic 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]Rat2,4,6-trinitrobenzene sulfonic acid (TNBS), AANG-nitro-L arginine methyl ester (L-NAME)accompanied by TNBS or 7 d before AAn = 55TNBS-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]MiceDinitrobenzene sulfonic acid (DNBS)Trichinella spiralis antigens (helminth ags), (rectal submucosal)5 d before DNBS inductionn = 6-8Macroscopically 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 patientsIFN-γ and LPSBudesonide or prednisolone (corticosteroids)Incubation or Pre-treatment-Nitrite content ↓, iNOS expression ↓
[191]RatTNBSArginine-Glycine-Aspartic acid (RGD)-functionalized silk fibroin nanoparticles (SFN) (intrarectal, 1 mg/rat)7 dn = 10Adhesion of integrins of the cell surface to the extra- cellular matrix of connective tissue ↓→ leukocyte recruitment to the inflamed intestinal tissue ↓→ iNOS expression ↓
[179]MiceDSSPravastatin, an 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, (intraperitoneal, 1 mg/kg)10 dn = 4-9Cachexia ↓, 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]MicePathogen Citrobacter rodentium as an infection model and DSS as an injury modelAntennapedia-linked Apolipoprotein E-mimetic peptide COG112, (intraperitoneal)Concurrent with induction of colitis, during induction plus recovery, or only during the recovery phase of diseasen = 4C. 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]MiceDSS3,3-Diindolylmethane (oral)7 d, commencing at the same time DSS exposure begann = 5Number of iNOS- & COX-2-producing cells ↓
[147]RatDSSGlutamine (oral)7 d with DSSn = 13Cytokine-induced iNOS expression↓, nuclear translocation of NF-κB p65 subunit ↓, cellular heat shock proteins (HSP)25 & HSP70 in a dose-dependent manner ↑
[180]RatTNBSLactulose (oral)2 wk before TNBS adminstrationn = 10MPO activity ↓, colonic TNF-α ↓, leukotriene B4↓, iNOS expression ↓, levels of Lactobacilli and Bifidobacteria species in colonic contents ↑
[229]RatIodoacetamideNG-nitro - L-NAME (oral)21 dn = 9-16lesion area ↓, NOS activity ↓
[200]MiceDSSGL-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]MiceDSSGlucosamine oligomers (Chitooligosaccharid-es) (oral)5 dn = 8Number of positive areas of iNOS & nuclear factor (NF)-κB staining in the colonic epithelium ↓
[27]MiceDSSNitrite (1 mmol/L) or nitrate (10 mmol/L) (oral)7 dn = 27-29Nitrite (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, miceTNBS and DSSDoxycycline (oral)5 d after the first DSS colitis inductionn = 10-21Macrophages → 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]RatTNBSTelmisartan (angiotensin II receptor antagonist) (oral, 10 mg/kg)10 d before TNBS and until day 4 of TNBSn = 8DAI 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 ↓)