Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets

Yadav, Vipul; Varum, Felipe; Bravo, Roberto; Furrer, Esther; Bojic, Daniela; Basit, Abdul W.

doi:10.1016/j.trsl.2016.04.009

Cited by 147 publications

(101 citation statements)

References 243 publications

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“…Although the precise etiology of IBD remains unknown [1] , it is mainly caused by ulcerative colitis and Crohn's disease [2] . Crohn's disease causes inflammation that extends through the entire bowel wall, whereas ulcerative colitis affects the colon and/or the large intestine [3] .…”

Section: Introductionmentioning

confidence: 99%

Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function

et al. 2017

Acta Pharmacol Sin

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Geniposide is an iridoid glycosides purified from the fruit of Gardenia jasminoides Ellis, which is known to have antiinflammatory, antioxidative and anti-tumor activities. The present study aimed to investigate the effects of geniposide on experimental rat colitis and to reveal the related mechanisms. Experimental rat colitis was induced by rectal administration of a TNBS solution. The rats were treated with geniposide (25, 50 mg·kg, ig) or with sulfasalazine (SASP, 100 mg·kg, ig) as positive control for 14 consecutive days. A Caco-2 cell monolayer exposed to lipopolysaccharides (LPS) was used as an epithelial barrier dysfunction model. Transepithelial electrical resistance (TER) was measured to evaluate intestinal barrier function. In rats with TNBS-induced colitis, administration of geniposide or SASP significantly increased the TNBS-decreased body weight and ameliorated TNBS-induced experimental colitis and related symptoms. Geniposide or SASP suppressed inflammatory cytokine (TNF-α, IL-1β, and IL-6) release and neutrophil infiltration (myeloperoxidase activity) in the colon. In Caco-2 cells, geniposide (25-100 μg/mL) ameliorated LPS-induced endothelial barrier dysfunction via dose-dependently increasing transepithelial electrical resistance (TER). The results from both in vivo and in vitro studies revealed that geniposide down-regulated NF-κB, COX-2, iNOS and MLCK protein expression, up-regulated the expression of tight junction proteins (occludin and ZO-1), and facilitated AMPK phosphorylation. Both AMPK siRNA transfection and AMPK overexpression abrogated the geniposide-reduced MLCK protein expression, suggesting that geniposide ameliorated barrier dysfunction via AMPKmediated inhibition of the MLCK pathway. In conclusion, geniposide ameliorated TNBS-induced experimental rat colitis by both reducing inflammation and modulating the disrupted epithelial barrier function via activating the AMPK signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function

et al. 2017

Acta Pharmacol Sin

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“…Therefore, the identification of genetic factors associated with IBD will aid in the development of novel therapeutic targets [37]. Genome-wide association studies (GWAS) have found more than 200 genetic risk loci for IBD [38, 39].…”

Section: Discussionmentioning

confidence: 99%

Glutathione S-Transferase T1 Null Genotype is Associated with Susceptibility to Inflammatory Bowel Disease

Qian¹,

Song

et al. 2017

Cell Physiol Biochem

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Background: The published literature contains conflicting results regarding the impact of the glutathione S-transferase T1 (GSTT1) null genotype on the susceptibility to inflammatory bowel disease. Therefore, we conducted a meta-analysis of observational studies to assess the association. Methods: We searched four online databases for eligible studies. The odds ratio (OR) with 95% CI was used to assess the gene-disease association. We also performed subgroup analyses by type of inflammatory bowel disease and ethnicity. Results: There were 16 individual studies from 11 publications included in the analysis. There were 3366 cases with inflammatory bowel disease and 6013 controls. The meta-analysis of all 16 studies showed the GSTT1 null genotype was associated with increased susceptibility to inflammatory bowel disease (OR = 1.98, 95%CI 1.39-2.84, P < 0.001). The subgroup analysis by ethnicity further identified an association between the GSTT1 null genotype and inflammatory bowel disease in Caucasians, Asians, and Africans. The GSTT1 null genotype was associated with both ulcerative colitis (OR = 1.96, P = 0.004) and Crohn’s disease (OR = 2.01, P = 0.022). The GSTT1 null genotype was still significantly associated with ulcerative colitis (OR = 1.63, P < 0.0001) and Crohn’s disease (OR = 1.40, P = 0.023) after adjusting for study heterogeneity. Conclusion: The GSTT1 null genotype is significantly associated with an increased susceptibility to inflammatory bowel disease and is a risk factor for both ulcerative colitis and Crohn’s disease.

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“…Among these pro-inflammatory mediators, the pro-inflammatory cytokines, particularly tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6, IL-12 and IL-23 are believed to play crucial roles in the pathogenesis of IBD [7–9]. Therefore,the regulation of these cytokines has been proposed as a strategy to treat IBD [10]. In this regard, anti-inflammatory drugs, aminosalicylates and corticosteroids, and immunosuppressive agents, are considered as the first-line therapies for IBD patients [11].…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory effect of Chang-An-Shuan on TNBS-induced experimental colitis in rats

Liu

et al. 2017

BMC Complement Altern Med

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BackgroundInflammatory bowel disease (IBD), denominated by Crohn’s disease and ulcerative colitis, is often associated with abdominal pain, diarrhea and bloody stool. The standard protocols for treating colitis conditions are not satisfactory; thus, complementary and alternative medicines have been increasingly accepted by IBD sufferers worldwide. In this study, we aimed to elucidate the anti-inflammatory effect of Chang-An-Shuan (CAS), a 6-herb Chinese medicinal formula, on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats and the underlying mechanisms.MethodsSprague-Dawley rats were administered with rectal gavage of 2.5% TNBS in 50% ethanol for the induction of experimental colitis which is considered as a model for Crohn’s disease. Upon the TNBS induction, rats were given CAS at 0.5 g/kg/day or 5 g/kg/day for 10 days. The application of salicylazosulfapyridine (0.5 g/kg/day) was served as a positive reference drug for the colitis condition. The efficacy and mechanistic action of CAS were evaluated by means of histopathological and biochemical approaches such as histological staining, real-time polymerase chain reaction, Western blotting analysis and enzyme-linked immunosorbent assay.ResultsOral administration of CAS at 5 g/kg/day, but not 0.5 g/kg/day, significantly ameliorated the severity of TNBS-induced colitis as evidenced by the reduced loss of body weight, alleviated diarrhea and decreased bloody stool. While lowering the disease activity index, the administration of CAS lessened mucosal lesions thus mucosal integrity of the colitis rats was notably improved. Further, the CAS treatment also significantly suppressed the mRNA and protein levels of pro-inflammatory cytokines, namely interleukin-1β and tumor necrosis factor-α while enhancing the level of anti-inflammatory cytokine IL-10 in the TNBS-treated rats. Importantly, the ameliorative effect of CAS was related to an inhibition of the nuclear factor-κB (NF-κB) signaling pathway by downregulating the expression levels of NF-κBp-65, p-38 and p-AKT.ConclusionsWe suggest that CAS is a potential alternative remedial approach for treating IBD conditions, and the anti-inflammatory effect of CAS is associated with the down-regulation of the NF-κB signaling pathway and the balanced production of pro- and anti-inflammatory cytokines.

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Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets

Cited by 147 publications

References 243 publications

Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function

Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function

Glutathione S-Transferase T1 Null Genotype is Associated with Susceptibility to Inflammatory Bowel Disease

Anti-inflammatory effect of Chang-An-Shuan on TNBS-induced experimental colitis in rats

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