Plasma metabolome identifies potential biomarkers of gastric precancerous lesions and gastric cancer risk.

OBJECTIVES: Currently, metabolic biomarkers with great practicability of gastric cancer (GC) and gastric precancerous lesions (GPL) are scarce. Thus, we are devoted to determining the plasma metabolic profiles of patients with GPL or GC and validate candidate biomarkers for disease diagnosis. METHODS: In this hospital-based case-control study, 68 plasma samples from 27 non-atrophic gastritis (NAG, control), 31 GPL, and 10 GC patients were collected for targeted metabolomics analysis. Univariate and multivariate analyses were used for selecting the differential metabolites. A receiver operating characteristic curve combined with binary logistic regression analysis was performed to test the diagnostic performance of the differential metabolites. Dietary data were obtained using a semiquantitative food frequency questionnaire. RESULTS: Distinct metabolomic profiles were noted for NAG, GPL, and GC. Compared to the NAG patients, the levels of 5 metabolites in the GPL group and 4 metabolites in the GC group were found to significantly elevate. Compared with the model involving 9 traditional risk factors (AUC: 0.89, 95%CI: 0.78-1.00), Trimethylamine N-oxide, the most significant metabolite (P = 2.00 × 10-5, FDR = 0.003, FC > 2, VIP > 2), showed a good diagnostic performance for the patients with GC (AUC: 0.90, 95%CI: 0.78-1.00), and its diagnostic performance has been further improved with the integration of Rhamnose (AUC: 0.96, 95%CI: 0.89-1.00). CONCLUSION: In our study, 9 defined metabolites might serve as meaningful biomarkers for identifying the high-risk population of GPL and GC, possibly enhancing the prevention and control of GPL and GC.

Leonurine exerts a protective effect in dextran sodium sulfate-induced experimental inflammatory bowel disease mice model.

Inflammatory bowel disease (IBD) is a common chronic inflammatory gastrointestinal disease. The therapeutic strategies of IBD are limited. IBD mouse models were established by administering 4% dextran sodium sulfate (DSS), which were further treated with Leonurine (7.5, 15, 30 mg/kg). The disease phenotypes, cell apoptosis, inflammation factors and oxidative stress related chemicals were evaluated. In addition, the potential related mechanism was also explored. Consequently, Leonurine ameliorated IBD-associated disease phenotypes and increase colon lengths and inhibited intestinal cell apoptosis in DSS-induced IBD mice. In addition, Leonurine reduced the expression of inflammation factors and oxidative stress level in DSS-induced IBD mice. Finally, Leonurine inhibited TLR4/NF-κB signaling pathway and activated of Nrf2/HO-1 signaling pathway. Leonurine can ameliorate IBD-induced apoptosis, inflammation response and oxidative stress via the activation of Nrf2/HO-1 signaling pathway and suppression of TLR4/ NF-κB pathway.

Mononuclear myeloid-derived suppressor cells expansion is associated with progression of liver failure in patients with acute decompensation of cirrhosis.

Patients with acute decompensation (AD) of cirrhosis have different clinical courses. Immune dysfunction affects disease outcomes. The profile of myeloid-derived suppressor cells (MDSCs), polymorphonuclear- (PMN-MDSCs) and mononuclear- (M-MDSCs) subsets in AD and their associations with different clinical courses are still unclear. This study included 36 healthy controls (HC), 20 patients with compensated cirrhosis (CC) and 107 patients with AD. Based on the condition at enrollment and 90 days of follow-up, the patients with AD were divided into AD-acute-on-chronic liver failure (AD-ACLF), stable decompensated cirrhosis (SDC), unstable decompensated cirrhosis (UDC) and pre-acute-on-chronic liver failure (Pre-ACLF) groups. The percentages of MDSCs, PMN-MDSCs, and M-MDSCs in the peripheral blood of patients with AD were significantly higher than those in HC and CC. Lactate levels, Child-Pugh score, and MDSCs were risk factors for the occurrence of AD. A positive correlation exists between MDSCs and indices of systemic inflammation and liver failure. In the AD cohort, the percentages of M-MDSCs in the Pre-ACLF and AD-ACLF groups were significantly higher than those in the UDC and SDC groups. The percentages of MDSCs and PMN-MDSCs in the AD groups increased; however, the difference was not statistically significant. MDSCs and M-MDSCs positively correlated with the incidence of liver failure. Sex, alcoholic etiology, bacterial infection, and M-MDSCs were independent risk factors for liver failure in patients with AD. Our data indicate that M-MDSCs expansion, rather than PMN-MDSCs expansion, might predict poor prognosis in patients with AD. Reducing the suppressive activity and number of MDSCs and M-MDSCs are promising strategies for immunotherapy in patients with AD.

Melatonin alleviates lipopolysaccharide-induced hepatic SREBP-1c activation and lipid accumulation in mice.

A link between endotoxemia and nonalcoholic fatty liver disease (NAFLD) has been demonstrated in human and rodent animals. Nevertheless, the molecular mechanisms of endotoxin-evoked NAFLD remain poorly understood. We hypothesize that reactive oxygen species (ROS) mediate lipopolysaccharide (LPS)-evoked hepatic lipid accumulation. Melatonin is an antioxidant. In the present study, we investigated the effects of melatonin on LPS-induced hepatic lipid accumulation. We showed that a single dose of LPS significantly increased hepatic triglyceride (TG) contents and caused hepatic lipid accumulation in mice. Further analysis found that hepatic sterol regulatory element-binding protein (SREBP)-1c was activated in LPS-treated mice. In agreement with hepatic SREBP-1c activation, fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), two SREBP-1c target genes, were significantly upregulated in liver of mice injected with LPS. Melatonin significantly attenuated LPS-induced SREBP-1c activation and the expression of SREBP-1c target genes. In addition, melatonin reduced serum and hepatic triglyceride (TG) content and prevented LPS-induced hepatic lipid accumulation. Taken together, these results suggest that ROS might be, at least partially, mediated in LPS-induced SREBP-1c activation and hepatic lipid accumulation. Melatonin may be useful as pharmacological agents to protect against endotoxin-evoked NAFLD.

Low vitamin D status is associated with advanced liver fibrosis in patients with nonalcoholic fatty liver disease.

Several studies explored the association between vitamin D status and nonalcoholic fatty liver disease with contradictory results. We aimed to investigate the association between vitamin D status, inflammatory cytokines and liver fibrosis in nonalcoholic fatty liver disease patients. Two hundred nineteen nonalcoholic fatty liver disease patients and 166 age- and gender- matched healthy controls were recruited for this study. Serum 25(OH)D was measured by radioimmunoassay. Serum interleukin-8 and transforming growth factor-ß1 were measured using ELISA. Serum 25(OH)D was only marginally decreased in nonalcoholic fatty liver disease patients. Interestingly, serum 25(OH)D was markedly reduced in nonalcoholic fatty liver disease patients with advanced liver fibrosis compared to nonalcoholic fatty liver disease patients with indeterminate liver fibrosis and no advanced fibrosis. Logistic regression analysis showed that there was an inverse association between serum 25(OH)D and severity of liver fibrosis in nonalcoholic fatty liver disease patients. Further analysis showed that serum interleukin-8 was elevated in nonalcoholic fatty liver disease patients, the highest interleukin-8 in patients with advanced fibrosis. An inverse correlation between serum 25(OH)D and interleukin-8 was observed in nonalcoholic fatty liver disease patients with and without liver fibrosis. Although serum transforming growth factor-ß1 was slightly elevated in nonalcoholic fatty liver disease patients, serum transforming growth factor-ß1 was reduced in nonalcoholic fatty liver disease patients with advanced fibrosis. Unexpectedly, a positive correlation between serum 25(OH)D and transforming growth factor-ß1 was observed in nonalcoholic fatty liver disease patients with advanced fibrosis. In conclusion, low vitamin D status is associated with advanced liver fibrosis in nonalcoholic fatty liver disease patients. Interleukin-8 may be an important mediator for hepatic fibrosis in nonalcoholic fatty liver disease patients with low vitamin D status.