Abstract
Ulcerative colitis (UC) is a chronic relapsing disease without satisfactory treatments, in which intestinal inflammation and disrupted intestinal epithelial barrier are two main pathogeneses triggering UC. Berberrubine (BB) is deemed as one of the major active metabolite of berberine (BBR), a naturally-occurring isoquinoline alkaloid with appreciable anti-UC effect. This study aimed to comparatively investigate the therapeutic effects of BB and BBR on dextran sodium sulfate (DSS)-induced mouse colitis model, and explore the potential underlying mechanism. Results revealed that BB (20 mg/kg) produced a comparable therapeutic effect as BBR (50 mg/kg) and positive control sulfasalazine (200 mg/kg) by significantly reducing the disease activity index (DAI) with prolonged colon length and increased bodyweight as compared with the DSS group. BB treatment was shown to significantly ameliorate the DSS-induced colonic pathological alternations and decreased histological scores. In addition, BB markedly attenuated colonic inflammation by alleviating inflammatory cell infiltration and inhibiting myeloperoxidase (MPO) and cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-4 and IL-10) productions in DSS mice. Furthermore, BB treatment substantially upregulated the expression of tight junction (TJ) proteins (zonula occludens-1, zonula occludens-2, claudin-1, occludin) and mRNA expression of mucins (mucin-1 and mucin-2), and decreased the Bax/Bcl-2 ratio. In summary, BB exerted similar effect to its analogue BBR and positive control in attenuating DSS-induced UC with much lower dosage and similar mechanism. The protective effect observed may be intimately associated with maintaining the integrity of the intestinal mucosal barrier and mitigating intestinal inflammation, which were mediated at least partially, via favorable modulation of TJ proteins and mucins and inhibition of inflammatory mediators productions in the colonic tissue. This is the first report to demonstrate that BB possesses pronounced anti-UC effect similar to BBR and sulfasalazine with much smaller dosage. BB might have the potential to be further developed into a promising therapeutic option in the treatment of UC.
Highlights
Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is clinically characterized by acute abdominal pain, weight loss, diarrhea, even hematochezia which severely lower the quality of life [1]
BB mitigated the clinical symptoms in dextran sodium sulfate (DSS)-induced colitis mice
The increased IL-10 in DSS mice in the present work was consistent with our preceding investigation [48] and other previous reports [49]. These results showed that suppression of inflammatory response in the colonic tissue of mice might contribute to the ameliorative effect of BB against DSS-induced colitis, which paralleled the histological evidence of protection
Summary
Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is clinically characterized by acute abdominal pain, weight loss, diarrhea, even hematochezia which severely lower the quality of life [1]. There are different drugs for UC treatment, including 5-aminosalicylic acid, steroid hormone, immunosuppressive agents and anti-tumor necrosis factorα (anti-TNF-α) agent. The frequency and severity of side effects, inconvenient dosing regimen, and partially prohibitive price limit their clinical application [2]. It is of great significance to seek effective alternative for the treatment of UC. The increased pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL-1β, extend the inflammatory cascade and eventually lead to intestinal/colonic tissue damage in UC induced by DSS [4]. The onset of UC is accompanied by obvious diffused intestinal inflammation which is closely associated with the increased permeability of intestinal epithelial barrier [5, 6]
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