Berberrubine attenuates mucosal lesions and inflammation in dextran sodium sulfate-induced colitis in mice

PLoS One. 2018 Mar 14;13(3):e0194069. doi: 10.1371/journal.pone.0194069. eCollection 2018.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Berberine / analogs & derivatives*
  • Berberine / pharmacology
  • Colitis / chemically induced
  • Colitis / drug therapy*
  • Colitis / metabolism
  • Colon / drug effects
  • Colon / metabolism
  • Cytokines / metabolism
  • Dextran Sulfate / adverse effects
  • Disease Models, Animal
  • Inflammation / chemically induced
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Peroxidase / metabolism
  • Tight Junction Proteins / metabolism
  • Tight Junctions / metabolism

Substances

  • Cytokines
  • Tight Junction Proteins
  • Berberine
  • berberrubine
  • Dextran Sulfate
  • Peroxidase

Grants and funding

This work was supported by: 1. Hongkong, Macao and Taiwan Science & Technology Cooperation Program of China (2014DFH30010), http://www.most.gov.cn/, (Zi-Ren Su: study design); 2. Science and Technology Planning Project of Guangdong Province, China (2013B090600007), http://www.gdstc.gov.cn/, (Zi-Ren Su: study design); 3. Science and Technology Planning Project of Guangdong Province, China (2013B090600026), http://www.gdstc.gov.cn/, (Hui-Fang Zeng: study design); 4. Guangdong International Cooperation Project (2013508102016), http://www.gdstc.gov.cn/, (Zi-Ren Su: study design); 5. Shenzhen Science and Technology Plan Project (ZDSYS201606081515458), http://www.szsti.gov.cn/, (Jian-Ping Chen: study design); 6. Shenzhen Science and Technology Plan Project (JCYJ20140408153331810), http://www.szsti.gov.cn/, (Jian-Ping Chen: study design); 7. Natural Science Foundation of Guangdong Province (2015A030310247), http://www.gdstc.gov.cn/, (Jian-Ping Chen: study design).