title: Zhikang Capsule ameliorates dextran sodium sulfate-induced colitis by inhibition of inflammation, apoptosis, oxidative stress and MyD88-dependent TLR4 signaling pathway.
abstract: BACKGROUND
  Zhikang Capsule (ZKC) is a traditional Chinese medicine (TCM) modified from classic formulas Qi-Li-San (an ancient formula dating to Qing Dynasty) and Fu-Jin-Sheng-Ji-San (written into The Golden Mirror of Medicine). ZKC contains 14 kinds of materials and has been widely used for the clinical therapy of inflammatory bowel diseases (IBD) for a long time. However, the therapeutic mechanisms of ZKC are still unclear.
  
  
  OBJECTIVE
  To determine the protective effect of ZKC on dextran sodium sulfate (DSS)-induced colitis and explore the underlying mechanisms.
  
  
  METHODS
  C57BL/6 mice were fed with 3% DSS in drinking water for one week to induce experimental colitis. They were randomly assigned to six groups according to the treatment conditions. The histological changes of colon tissues were observed by hematoxylin and eosin (H&E) staining. The serum concentration of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-12) and anti-inflammatory mediators (IL-4 and IL-10) was detected by enzyme-linked immune sorbent assays (ELISAs). The production of MPO, SOD, MDA, NO, and caspase-3 was assessed by biochemical assay kits. The expression of iNOS, ICAM-1, and NF-ΚB was evaluated by immunohistochemistry staining. The levels of TLR4, MyD88, and TRAF6 were determined by western blot.
  
  
  RESULTS
  Histologic analysis exhibited that ZKC alleviated the inflammation, loss of goblet cells, and submucosal edema induced by DSS. ZKC significantly suppressed the pro-inflammatory cytokines and promoted the anti-inflammatory mediators. The antioxidation of ZKC was indicated by increased activity of SOD and reduced production of MDA, NO, and iNOS in ZKC-treated mice. Furthermore, ZKC repressed the colonic expression of caspase-3 and the activity of the MyD88-dependent TLR4 signaling pathway.
  
  
  CONCLUSIONS
  This research demonstrated the protective effect of ZKC on DSS-induced colitis. For the first time, we identified four therapeutic mechanisms of ZKC, including effective inhibition of the inflammatory responses, significant alleviation of intestinal epithelium apoptosis, considerable prevention of oxidative stress, and selective down-regulation of the MyD88-dependent TLR4 signaling pathway. With high therapeutic effects and low toxic effects, ZKC exhibits great superiority over western medicines in IBD treatment.
authors.affiliation: Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277Jiefang Road, Wuhan 430022, PR China. Electronic address: LiangFei2016@126.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Fei
authors.affiliation: Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277Jiefang Road, Wuhan 430022, PR China. Electronic address: xuzou2016@126.com.
authors.forename: Keshu
authors.initials: K
authors.lastname: Xu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003092:Colitis / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000097:blood; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015415:Biomarkers; D016207:Cytokines; D004365:Drugs, Chinese Herbal; C090509:Icam1 protein, mouse; D018836:Inflammation Mediators; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C000617393:zhikang capsule; D018799:Intercellular Adhesion Molecule-1; D008315:Malondialdehyde; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase
keywords: Aloe emodin (PubChem CID: 10207); Apoptosis; Berberine (PubChem CID: 2353); Chrysophanol (PubChem CID: 10208); Dencichine (PubChem CID: 2360); Emodin (PubChem CID: 3220); Glycyrrhizic acid (PubChem CID: 14982); Imperatorin (PubChem CID: 10212); Inflammation; Inflammatory bowel disease; Isoimperatorin (PubChem CID: 68081); Oxidative stress; Physcion (PubChem CID: 10639); Rhein (PubChem CID: 10168); Toll-like receptor 4