Abstract. Metallothioneins (MTs) are a family of cysteine-rich low molecular-weight proteins that can act as reactive oxygen species scavengers. Although it is known that the induction of MT expression suppresses various inflammatory disorders, the role of MTs in intestinal inflammation remains unclear. In this study, we investigated the effects of dextran sulfate sodium (DSS) administration in mice with targeted deletions of the MT-I/II genes. Acute colitis was induced by 2% DSS in male MT-I/II double knockout (MT-null) and C57BL/6 (wild-type) mice. The disease activity index (DAI) was determined on a daily basis for each animal, and consisted of a calculated score based on changes in body weight, stool consistency and intestinal bleeding. Histology, colon length, myeloperoxidase (MPO) activity and colonic mRNA expression and the concentration of inflammatory cytokines were evaluated by real-time-PCR and enzyme-linked immunosorbent assay (ELISA). The localization of MTs and macrophages was determined by immunohistological and immunofluorescence staining. To investigate the role of MTs in macrophages, peritoneal macrophages were isolated and their responses to lipopolysaccharide were measured. Following DSS administration, the DAI score increased in a time-dependent manner and was significantly enhanced in the MT-I/II knockout mice. Colonic MPO activity levels and inflammatory cytokines [tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-17] production increased following DSS administration, and these increases were significantly enhanced in the MT-I/II knockout mice compared with the wild-type mice. MT-positive cells were detected in the lamina propria and submucosal layer by immunohistochemical and immunofluorescence staining, and were mainly co-localized in F4/80-positive macrophages. The production of inflammatory cytokines (TNF-α, IFN-γ and IL-17) from isolated peritoneal macrophages increased following lipopolysaccharide stimulation, and these increases were significantly enhanced in the macrophages obtained from the MT-I/II knockout mice. These data indicate that MTs play an important role in the prevention of colonic mucosal inflammation in a mouse model of DSS-induced colitis, thus suggesting that endogenous MTs play a protective role against intestinal inflammation. IntroductionInflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease are known as refractory and recurrent diseases of the gastrointestinal tract. Although the features of IBDs suggest a number of possible causes, including genetic, infectious and immunological factors, the precise pathogenesis of IBDs remains unknown (1-3). Recent evidence suggests that oxidative stress caused by reactive oxygen species (ROS) is an important factor involved in the onset and development of intestinal inflammation. Furthermore, it has also been demonstrated that disruptions in the antioxidant defense system are involved in the pathophysiology of IBDs (4,5). Therefore, it is important to investigate the oxidative s...

BackgroundHelicobacter pylori (Hp) infection increases the risk of gastric cancer. Therefore, eradication is a global goal, which requires continuous monitoring of therapeutic regimens and effectiveness. Clarithromycin resistance is an important contributor to eradication failure, and metronidazole is recommended as second‐line treatment in such cases. Here, we retrospectively evaluated the clarithromycin and metronidazole resistance rates and treatment effectiveness in patients with Hp using tailored therapies according to clarithromycin susceptibility testing.MethodsData on drug susceptibility were obtained for 5249 Japanese Hp patients between July 2005 and August 2018. Clarithromycin/metronidazole resistance rates were analyzed according to year, gender, and age with Fisher's exact test. The relationship between clarithromycin resistance and Hp therapy outcomes was assessed for 1300 patients. Treatment regimens included a clarithromycin‐ or metronidazole‐containing 7‐day triple therapy with one of several proton pump inhibitors and vonoprazan.ResultsClarithromycin resistance increased annually and was higher in women and younger patients (<30 years). Rates of metronidazole resistance were stable but decreased with age. Hp treatment regimens using PPIs had eradication rates of 88% and 45% among clarithromycin‐sensitive and clarithromycin‐resistant cases, respectively, while regimens including vonoprazan had eradication rates of around 90% regardless of clarithromycin susceptibility. In particular, triple therapy with vonoprazan, amoxicillin, and metronidazole achieved 98% eradication.ConclusionClarithromycin‐containing triple therapy even using vonoprazan did not achieve satisfactory eradication rates even in the clarithromycin‐sensitive group. To avoid antibiotic misuse in population with low metronidazole resistance, 7‐day vonoprazan, amoxicillin, and metronidazole triple therapy might be a strong candidate as a first‐line eradication therapy.

BTB and CNC homologue 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1). This study hypothesized that Bach1 plays an important role in the indomethacin-induced apoptosis in the case of small-intestinal mucosal injury. Eight-week-old male C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice were included in this study. Mucosal injuries induced by subcutaneously administering indomethacin were evaluated macroscopically, histologically and biochemically. Indomethacin-induced injuries were improved in Bach1-deficient mice. Immunohistochemistry showed an increase in the number of HO-1-positive cells, which were mainly F4/80 positive macrophages, in Bach1-deficient mice. Indomethacin administration increased the expression of HO-1 mRNA and protein in the small intestine in Bach1-deficient mice. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining showed that the extent of apoptosis was suppressed in Bach1-deficent mice. In conclusion, deficiency of the Bach1 gene inhibited apoptosis and thus suppressed mucosal injury, indicating that Bach1 is a novel therapeutic target for indomethacin-induced intestinal injury.