Non-alcoholic fatty liver disease (NAFLD) is an emerging liver disease worldwide. In subset of patients, NAFLD progresses to its advanced form, nonalcoholic steatohepatitis (NASH), which is accompanied with inflammation and fibrosis. Saturated free fatty acid-induced hepatocyte apoptosis is a feature of NASH. Death signaling in NASH does not always result in apoptosis, but can alternatively lead to the survival of cells presenting signs of pro-inflammatory and pro-fibrotic signals. With the current lack of established treatments for NASH, it is important to understand the molecular mechanisms responsible for disease development and progression. This review focuses on the latest findings in hepatocyte death signaling and discusses possible targets for intervention, including caspases, death receptor and c-Jun N-terminal kinase 1 signaling, oxidative stress, and endoplasmic reticulum stress, as well as epigenomic factors.

A high serum level of saturated free fatty acids (FFAs) is associated with the development of nonalcoholic fatty liver disease (NAFLD). X-box binding protein-1 (XBP-1) is activated by FFA treatment upon splicing. XBP-1 is a transcription factor induced by the endoplasmic reticulum (ER) stress sensor endoribonuclease inositol-requiring enzyme 1 alpha (IRE1α). However, the role of XBP-1 in NAFLD remains relatively unexplored. Toyocamycin was recently reported to attenuate the activation of XBP-1, possibly by inducing a conformational change in IRE1α. In this study, we examined the effect of toyocamycin on hepatocyte lipoapoptosis and steatosis. We also explored the effects of toyocamycin in a mouse model of NAFLD. Huh-7 cells and isolated rat primary hepatocytes were treated with palmitic acid (PA), which is a saturated FFA, in the presence or absence of toyocamycin. In addition, male C57BL/6J mice were fed a diet rich in saturated fat, fructose, and cholesterol (FFC) for 4 months, after which the effect of toyocamycin was assessed. Toyocamycin attenuated FFA-induced steatosis. It also significantly reduced PA-induced hepatocyte lipoapoptosis. In addition, toyocamycin reduced the expression of cytosine-cytosine-adenosine-adenosine-thymidine enhancer-binding protein homologous protein (CHOP), which is a key player in ER stress-mediated apoptosis, as well as its downstream cell death modulator, death receptor 5. In the in vivo study, toyocamycin ameliorated the liver injury caused by FFC-induced NAFLD. It also reduced hepatic steatosis and the expression of lipogenic genes. The data we obtained suggest that toyocamycin attenuates hepatocyte lipogenesis and ameliorates NAFLD in vivo and may therefore be beneficial in the treatment of NAFLD in humans.

Stable suppression of gastric acid secretion is a crucial factor in Helicobacter pylori eradication. Vonoprazan is a potassium-competitive acid blocker recently approved for use in Japan. As vonoprazan has a long duration of action and causes rapid and strong inhibition of gastric acid secretion, it has gained clinical attention for treating erosive oesophagitis, peptic ulcers, and H. pylori infection. In this review, we discuss the recent knowledge regarding the safety and efficacy of vonoprazan, focusing on its use in H. pylori eradication. The latest literature and our clinical experience have shown that vonoprazan-based therapies have satisfactory eradication rates. Additionally, vonoprazan-based therapies are associated with similar rates of adverse events as standard triple therapies with conventional proton-pump inhibitors.

Background: Per oral endoscopic myotomy (POEM) has been reported to be a new therapeutic option for esophageal achalasia. The possibility that POEM could reduce the risk of developing esophageal squamous cell carcinoma was evaluated. Methods: This was a single-centre, retrospective study. Fifteen consecutive patients with esophageal achalasia who underwent POEM in our institution between August 2010 and January 2012 were enrolled. Ultra-high magnification with endocytoscopy was performed, and both histopathological and immunohistochemical evaluations for Ki-67 and p53 were assessed before and 3 months after POEM. Results: POEM was successfully performed and effectively released the dysphagia symptom in all patients without severe complications. Subjective symptoms (mean Ekcardt score, before 7.4 vs. after 0.5, p<0.05) and manometric pressure studies (mean lower esophageal sphincter pressure), before 82.7 vs. after 22.9 mmHg, p<0.05) showed substantial improvement following POEM. The average numbers of esophageal epithelial nuclei before and after POEM on endocytoscopic images were 128.0 and 78.0, respectively (p<0.05). The mean Ki-67-positive ratio was 26.0 (median 25.4, range, 10.3-33.2) before and 20.7 (median 20.0, 13.1-29.9; p=0.07) after POEM, and the mean p53-positive ratio was 2.35 (median 2.61, 0.32-4.23) before and 0.97 (median 1.49, 0.32-1.56; p<0.05) after POEM. A significant positive correlation was seen between the number of nuclei and the Ki-67-positive ratio (p<0.05). Conclusions: POEM appears to be an effective and less invasive treatment of choice against achalasia and may reduce the risk of esophageal carcinogenesis. Endocytoscopy can be useful for the assessment of esophageal cellular proliferation.