title: Hydrogen-rich water protects against inﬂammatory bowel disease in mice by inhibiting endoplasmic reticulum stress and promoting heme oxygenase-1 expression.
abstract: OBJECTIVE
  To investigate the therapeutic effect of hydrogen-rich water (HRW) on inﬂammatory bowel disease (IBD) and to explore the potential mechanisms involved.
  
  
  METHODS
  Male mice were randomly divided into the following four groups: control group, in which the mice received equivalent volumes of normal saline (NS) intraperitoneally (ip); dextran sulfate sodium (DSS) group, in which the mice received NS ip (5 mL/kg body weight, twice per day at 8 am and 5 pm) for 7 consecutive days after IBD modeling; DSS + HRW group, in which the mice received HRW (in the same volume as the NS treatment) for 7 consecutive days after IBD modeling; and DSS + HRW + ZnPP group, in which the mice received HRW (in the same volume as the NS treatment) and ZnPP [a heme oxygenase-1 (HO-1) inhibitor, 25 mg/kg] for 7 consecutive days after IBD modeling. IBD was induced by feeding DSS to the mice, and blood and colon tissues were collected on the 7thd after IBD modeling to determine clinical symptoms, colonic inﬂammation and the potential mechanisms involved.
  
  
  RESULTS
  The DSS + HRW group exhibited significantly attenuated weight loss and a lower extent of disease activity index compared with the DSS group on the 7thd (P< 0.05). HRW exerted protective effects against colon shortening and colonic wall thickening in contrast to the DSS group (P< 0.05). The histological study demonstrated milder inflammation in the DSS + HRW group, which was similar to normal inflammatory levels, and the macroscopic and microcosmic damage scores were lower in this group than in the DSS group (P< 0.05). The oxidative stress parameters, including MDA and MPO in the colon, were significantly decreased in the DSS + HRW group compared with the DSS group (P< 0.05). Simultaneously, the protective indicators, superoxide dismutase and glutathione, were markedly increased with the use of HRW. Inflammatory factors were assessed, and the results showed that the DSS + HRW group exhibited significantly reduced levels of TNF-α, IL-6 and IL-1β compared with the DSS group (P< 0.05). In addition, the pivotal proteins involved in endoplasmic reticulum (ER) stress, including p-eIF2α, ATF4, XBP1s and CHOP, were dramatically reduced after HRW treatment in contrast to the control group (P< 0.05). Furthermore, HRW treatment markedly up-regulated HO-1 expression, and the use of ZnPP obviously reversed the protective role of HRW. In the DSS + HRW + ZnPP group, colon shortening and colonic wall thickening were significantly aggravated, and the macroscopic damage scores were similar to those of the DSS + HRW group (P< 0.05). The histological study also showed more serious colonic damage that was similar to the DSS group.
  
  
  CONCLUSIONS
  HRW has a significant therapeutic potential in IBD by inhibiting inflammatory factors, oxidative stress and ER stress and by up-regulating HO-1 expression.
authors.affiliation: Nai-Ying Shen, Jian-Bin Bi, Jing-Yao Zhang, Si-Min Zhang, Jing-Xian Gu, Kai Qu, Chang Liu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
authors.forename: Nai-Ying
authors.initials: NY
authors.lastname: Shen
authors.affiliation: Nai-Ying Shen, Jian-Bin Bi, Jing-Yao Zhang, Si-Min Zhang, Jing-Xian Gu, Kai Qu, Chang Liu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
authors.forename: Jian-Bin
authors.initials: JB
authors.lastname: Bi
authors.affiliation: Nai-Ying Shen, Jian-Bin Bi, Jing-Yao Zhang, Si-Min Zhang, Jing-Xian Gu, Kai Qu, Chang Liu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
authors.forename: Jing-Yao
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: Nai-Ying Shen, Jian-Bin Bi, Jing-Yao Zhang, Si-Min Zhang, Jing-Xian Gu, Kai Qu, Chang Liu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
authors.forename: Si-Min
authors.initials: SM
authors.lastname: Zhang
authors.affiliation: Nai-Ying Shen, Jian-Bin Bi, Jing-Yao Zhang, Si-Min Zhang, Jing-Xian Gu, Kai Qu, Chang Liu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
authors.forename: Jing-Xian
authors.initials: JX
authors.lastname: Gu
authors.affiliation: Nai-Ying Shen, Jian-Bin Bi, Jing-Yao Zhang, Si-Min Zhang, Jing-Xian Gu, Kai Qu, Chang Liu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Qu
authors.affiliation: Nai-Ying Shen, Jian-Bin Bi, Jing-Yao Zhang, Si-Min Zhang, Jing-Xian Gu, Kai Qu, Chang Liu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D003106:Colon / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000097:blood*; D006859:Hydrogen / Q000737:chemistry*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D011897:Random Allocation; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014867:Water / Q000737:chemistry*; D000071717:X-Box Binding Protein 1 / Q000378:metabolism
chemical_list: C081452:Atf4 protein, mouse; C497250:Ddit3 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D053583:Interleukin-1beta; D015850:Interleukin-6; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D014867:Water; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D006859:Hydrogen; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Endoplasmic reticulum stress; Heme oxygenase-1; Hydrogen; Inﬂammatory bowel disease; Oxidative stress