Despite significant advances in therapies in past decades, the mortality rate of septic cardiomyopathy remains high. The aim of this study is to explore the therapeutic effects of combined treatment using melatonin and irisin in a mouse model of lipopolysaccharide (LPS)-mediated septic cardiomyopathy. Our data found that melatonin and irisin could further attenuate LPS-induced myocardial depression.Molecular investigation illustrated that melatonin and irisin cotreatment sustained cardiomyocyte viability and improved mitochondrial function under LPS stress.Pathway analysis demonstrated that macrophage-stimulating 1 (Mst1), which was significantly activated by LPS, was drastically inhibited by melatonin/irisin cotreatment. Mechanically, Mst1 activated c-Jun N-terminal kinase (JNK) pathway and the latter induced oxidative stress, adenosine triphosphate metabolism disorder, mitochondrial membrane potential reduction, and cardiomyocyte death activation.Melatonin and irisin cotreatment effectively inhibited the Mst1-JNK pathway and, thus, promoted cardiomyocyte survival and mitochondrial homeostasis. Interestingly, Mst1 overexpression abolished the beneficial effects of melatonin and irisin in vivo and in vitro. Altogether, our results confirmed that melatonin and irisin combination treatment could protect heart against sepsis-induced myocardial depression via modulating the Mst1-JNK pathways.
Background and Aims To clarify high‐risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI. Approach and Results Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high‐risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3‐fold in patients with significant inflammation compared to none or mild inflammation (p < 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR‐6) with a concordance index of 0.824 (95% CI, 0.798–0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort. Conclusions Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR‐6 model provides an easy‐to‐use approach to assess the outcome of chronic DILI.
OBJECTIVE To examine the associations of circulating 25-hydroxyvitamin D (25[OH]D) concentrations with cardiovascular disease (CVD) and all-cause mortality in individuals with prediabetes and diabetes from the large population-based UK Biobank cohort study. RESEARCH DESIGN AND METHODS A total of 67,789 individuals diagnosed with prediabetes and 24,311 with diabetes who had no CVD or cancer at baseline were included in the current study. Serum 25(OH)D concentrations were measured at baseline. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for cardiovascular outcomes and mortality after 10–14 years. RESULTS After multivariable adjustment, higher serum 25(OH)D levels were significantly and nonlinearly associated with lower risk of cardiovascular outcomes and all-cause mortality among participants with prediabetes and diabetes (all P nonlinearity < 0.05). Compared with those in the lowest category of 25(OH)D levels (<25 nmol/L), participants with prediabetes in the highest category of 25(OH)D levels (≥75 nmol/L) had a significant association with lower risk of cardiovascular events (HR 0.78; 95% CI 0.71–0.86), coronary heart disease (CHD) (HR 0.79; 95% CI 0.71–0.89), heart failure (HR 0.66; 95% CI 0.54–0.81), stroke (HR 0.75; 95% CI 0.61–0.93), CVD mortality (HR 0.43; 95% CI 0.32–0.59), and all-cause mortality (HR 0.66; 95% CI 0.58–0.75). Likewise, these associations with cardiovascular events, CHD, heart failure, CVD mortality, and all-cause mortality were observed among participants with diabetes, except for stroke. CONCLUSIONS These findings highlight the importance of monitoring and correcting vitamin D deficiency in the prevention of CVD and mortality among adults with prediabetes and diabetes.
Background The mechanism of how intermittent fasting (IF) improves metabolism is not fully understood. Our study aimed to explore the effect of IF on lipid metabolism in obese mice, specifically on the intestinal flora. Material/Methods Diet-induced obese (DIO) mice were subjected to ad libitum (AL) feeding or IF (alternate-day fasting) for 30 days. We examined the lipid metabolism, fat distribution, gene expression of lipid metabolism, and intestinal flora in the mice. Results Despite having access to the same high-fat diet as the AL-fed groups, IF mice displayed pronounced weight loss, and their lipid metabolism significantly improved, mainly reflected in lower serum lipid levels and ameliorated liver steatosis. IF also reduced metabolic endotoxemia in DIO mice. The 16S ribosomal deoxyribonucleic acid gene amplicon sequencing suggested that IF did not change the community richness but had a tendency to increase community diversity in the intestinal flora. In addition, IF significantly reduced the ratio of Firmicutes to Bacteroidetes and increased the relative abundance of Allobaculum in the intestinal flora. Conclusions IF can improve fat metabolism, reduce fat accumulation, promote white fat conversion to beige, and improve gut microbiota.
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