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Autophagy is a reparative life-sustaining process. Dysfunctions of autophagy play an important role in the progression of chronic liver diseases. The role of autophagy in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) is still controversial. This study aimed to analyse the roles and molecular mechanisms of autophagy in NAFLD. In hepatic L02 and liver cancer cells (HuH-7), nonalcoholic fatty liver (NAFL) cell model was induced by free fatty acids (FFA). The cytotoxic effect was measured by MTS assay. Lipid droplets were detected by immunofluorescence assay and flow cytometry. The autophagy-related genes were measured by Western blot analysis. The autophagy inhibitor 3-methyladenine (3-MA) was used to block the autophagy. FFA induced a significant increase in the intracellular content of lipid droplets, and the accumulation of fatty droplets was dose-dependent in L02 and HuH-7 cells. FFA (800 µM) had no cytotoxic effect on L02 and HuH-7 cells. The levels of LC3-II/LC3-I and BECN1 were increased, but the level of p62 was decreased in the NAFL cell models. The expression of these genes was dose-dependent in the NAFL cell models. Intracellular lipid accumulation was associated with the upregulation of LC3-II/LC3-I and BECN1 and the deregulation of p62 in the NAFL cell models. The autophagy inhibitor 3-MA suppressed the FFA-induced autophagy in the NAFL cell models. Furthermore, 3-MA treatment significantly alleviated the accumulation of lipid droplets in L02 and HuH-7 cells. Our results suggest that autophagy has a significant effect on lipid accumulation in the NAFL cell models. Inhibition of autophagy impairs FFA-induced excessive lipid accumulation in hepatocellular carcinoma and hepatic cells. [ABSTRACT FROM AUTHOR]

COVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10−10, allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10−9, AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10−8, AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19. Chaolong Wang and colleagues report a large genome-wide association study for COVID-19 severity in Chinese individuals. By meta-analysis with European data, they identify 3 loci associated with severe disease that suggest key roles for the adaptive immune system and the ABO blood group system in development of severe COVID-19. [ABSTRACT FROM AUTHOR]

Purpose: We designed a network meta-analysis that investigated relatively different interventions that included the effects of metformin, oral contraceptives, and lifestyle modification on the metabolic parameters of patients with polycystic ovary syndrome. In addition, we searched for eligible interventions that improved the metabolism of glucose and lipids. Methods: We searched the PubMed, EMBASE, and Cochrane Central databases from inception to May 2018. Publication types that were categorized as randomized controlled trials met our inclusion criteria. The main outcome included the homeostasis model assessment of insulin resistance, total cholesterol, low-density lipoprotein cholesterol, and total triglycerides. We performed both a pairwise meta-analysis and a network meta-analysis to evaluate the mean difference value and 95% credibility intervals, and we calculated the surface cumulative rank curve. Results: There were a total of 12 kinds of interventions: metformin, 2 mg cyproterone acetate plus 0.05 mg ethinylestradiol (EE/CA), 0.15 mg desogestrel plus 0.03 mg ethinylestradiol (EE/DSG), and 3 mg drospirenone plus 0.03 mg ethinylestradiol (EE/DRSP), lifestyle, exercise, diet, metformin + lifestyle, metformin + diet, EE/CA + lifestyle, metformin + EE/CA, and EE/DRSP + lifestyle from the 20 eligible RCTs that were included in this study. Our meta-analysis results showed that metformin + lifestyle (MD = −2.04, 95% CrI = −3.64 to −0.41), EE/CA + lifestyle (MD = −2.23, 95% CrI = −4.11 to −0.35), and EE/DRSP + lifestyle (MD = −2.59, 95% CrI = −4.66 to −0.50) resulted in lower in the levels of total cholesterol. Women treated with metformin + lifestyle (MD = −1.82, 95% CrI = −2.88 to −0.79), EE/CA + lifestyle (MD = −2.25, 95% CrI = −3.58 to −1.08), or EE/DRSP + lifestyle (MD = −2.29, 95% CrI = −3.69 to −1.07) exhibited significantly lower low-density lipoprotein cholesterol when compared with the placebo group. There was no significant difference between any of the interventions compared with a placebo in the levels of homeostasis model assessment of insulin resistance and total triglycerides. The surface cumulative rank curve revealed that metformin + lifestyle might be the best intervention with respect to the improvement of the homeostasis model of assessment insulin resistance and EE/DRSP + lifestyle appeared to be the best intervention for the reduction of total cholesterol and low-density lipoprotein cholesterol. Moreover, the metformin + diet intervention was more effective in reducing the level of total triglycerides. Conclusions: For overweight polycystic ovary syndrome patients, our evidence revealed that EE/CA and EE/SRSP combined with metformin or lifestyle changes can reduce the adverse effects on glucose and lipid metabolism of the use of oral contraceptive agents alone. Conventional PCOS treatments, such as metformin, EE/CA, and EE/DRSP, combined with lifestyle control can be particularly effective in improving the homeostasis model assessment of insulin resistance and lipid metabolism. [ABSTRACT FROM AUTHOR]

Benzo(a)pyrene (BaP) is a widespread environmental contaminant that has been associated with neurotoxicity in mammals. It has strong toxic effects on the developing central nervous system. Cerebellum is associated with locomotor activity and anxiety behavior, but there is very little research about the toxic effects of BaP in cerebellum. The present study aims to investigate the global influence of BaP subacute exposure on the metabolome of rat cerebellum. Male neonatal rats (postnatal day 5) were divided into two groups: control group and BaP-treated group (2 mg/kg/day for 7 weeks). Open field test and transmission electron microscopy were performed to analyze neurobehavior and ultramicrostructure alteration. Gas chromatography-mass spectrometry (GC-MS) was used to analyze metabolites of the cerebellum in both groups. The results revealed that postnatal exposure to BaP promoted pathological changes in the cerebellum and increased locomotor and anxiety activities in early adulthood. Twenty differential significant metabolites were identified by multivariate statistical analysis. Further metabolic pathway impact analysis and network analysis suggested that the primary metabolic pathways affected included pathway involved in energy metabolism, methionine and cysteine metabolism, and glutathione metabolism. These findings suggest that BaP-induced cerebellum injury may be correlated with metabolic changes and provide an area to target to reduce the negative effects of BaP. [ABSTRACT FROM AUTHOR]