Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies

Nonalcoholic fatty liver disease(NAFLD),a leading chronic disease worldwide,affects approximately a quarter of the global population.Nonalcoholic steatohepatitis(NASH)is an advanced form of NAFLD and is more likely to progress to liver fibrosis than simple steatosis.NASH is also identified as the most rapidly growing cause of hepatocellular carcinoma.Although in the past decade,several phase II/III clinical trials have shown promising results in the use of novel drugs targeting lipid synthase,farnesoid X receptor signaling,peroxisome proliferatoractivated receptor signaling,hepatocellular injury,and inflammatory signaling,proven pharmaceutical agents to treat NASH are still lacking.Thus,continuous exploration of the mechanism underlying the pathogenesis of NAFLD and the identification of novel therapeutic targets remain urgent tasks in the field.In the current review,we summarize studies reported in recent years that not only provide new insights into the mechanisms of NAFLD development but also explore the possibility of treating NAFLD by targeting newly identified signaling pathways.We also discuss evidence focusing on the intrahepatic targets involved in the pathogenesis of NAFLD as well as extrahepatic targets affecting liver metabolism and function.

Cucurbitacins mitigate vascular neointimal hyperplasia by suppressing cyclin A2 expression and inhibiting VSMC proliferation

Background:Restenosis frequently occurs after percutaneous angioplasty in patients with vascular occlusion and seriously threatens their health.Substantial evidence has revealed that preventing vascular smooth muscle cell proliferation using a drug-eluting stent is an effective approach to improve restenosis.Cucurbitacins have been demonstrated to exert an anti-proliferation effect in various tumors and a hypoten-sive effect.This study aims to investigate the role of cucurbitacins extracted from Cucumis melo L.(CuECs)and cucurbitacin B(CuB)on restenosis.Methods:C57BL/6 mice were subjected to left carotid artery ligation and subcu-taneously injected with CuECs or CuB for 4 weeks.Hematoxylin-Eosin,immuno-fluorescence and immunohistochemistry staining were used to evaluate the effect of CuECs and CuB on neointimal hyperplasia.Western blot,real-time PCR,flow cytometry analysis,EdU staining and cellular immunofluorescence assay were em-ployed to measure the effects of CuECs and CuB on cell proliferation and the cell cycle in vitro.The potential interactions of CuECs with cyclin A2 were performed by molecular docking.Results:The results demonstrated that both CuECs and CuB exhibited significant inhibitory effects on neointimal hyperplasia and proliferation of vascular smooth muscle cells.Furthermore,CuECs and CuB mediated cell cycle arrest at the S phase.Autodocking analysis demonstrated that CuB,CuD,CuE and CuI had high binding en-ergy for cyclin A2.Our study also showed that CuECs and CuB dramatically inhibited FBS-induced cyclin A2 expression.Moreover,the expression of cyclin A2 in CuEC-and CuB-treated neointima was downregulated.Conclusions:CuECs,especially CuB,exert an anti-proliferation effect in VSMCs and may be potential drugs to prevent restenosis.

The role of FMO3 in metabolic diseases

Flavin containing monooxygenase 3(FMO3)is a member of the flavin monooxygenase family,which can oxidize the precursor Trimethylamine(TMA)provided from food to produce Trimethylamine N-oxide(TMAO).The autosomal recessive inherited disease caused by partial functional loss of Fmo3 gene,which leads to excessive excretion of TMA in body fluids and emits fishy odor,is called Fish Odor Syndrome or Trimethylaminuria.This disease has been documented for 3,000 years ago and was first reported in the case report in 1970.FMO3 mainly exists in the liver and can participate in the TMA-TMAO metabolic balance in intestinal microorganisms,liver,and kidneys,closely related to insulin resistance,diabetes,cholesterol metabolism,and cardiovascular disease.Due to its wide range of catalytic substrates and low susceptibility to metabolite accumulation,its role in drug metabolism,new drug development,and discovery of new drug targets are increasingly valued.This review will summarize the research progress on the metabolic process and localization of FMO3,congenital genetic defects,metabolic diseases,and its related possible mechanisms.

Ethical review of off-label drugs during the COVID-19 pandemic

High-quality scientific research is very important in attempting to effectively control the coronavirus disease 2019(COVID-19)pandemic and ensure people’s health and safety.Chloroquine(CQ)and hydroxychloroquine(HCQ)have received much attention.This article comprehensively investigates the ethical review of off-label CQ and HCQ research during the COVID-19 pandemic with regard to strictly abiding by review standards,improving review efficiency,ensuring the rights and interests of subjects and that ethics committees conduct independent reviews,and achieving full ethics supervision of research conducted during an emergency.Research must be both rigorous and prudent to ensure the best outcome,with the maximization of benefits as the core principle.Standardization of the application,implementation and ethical review processes are needed to prevent unnecessary risk.

Melatonin decreases GSDME mediated mesothelial cell pyroptosis and prevents peritoneal fibrosis and ultrafiltration failure

Peritoneal fibrosis together with increased capillaries is the primary cause of peritoneal dialysis failure.Mesothelial cell loss is an initiating event for peritoneal fibrosis.We find that the elevated glucose concentrations in peritoneal dialysate drive mesothelial cell pyroptosis in a manner dependent on caspase-3 and Gasdermin E,driving downstream inflammatory responses,including the activation of macrophages.Moreover,pyroptosis is associated with elevated vascular endothelial growth factor A and C,two key factors in vascular angiogenesis and lymphatic vessel formation.GSDME deficiency mice are protected from high glucose induced peritoneal fibrosis and ultrafiltration failure.Application of melatonin abrogates mesothelial cell pyroptosis through a MT1R-mediated action,and successfully reduces peritoneal fibrosis and angiogenesis in an animal model while preserving dialysis efficacy.Mechanistically,melatonin treatment maintains mitochondrial integrity in mesothelial cells,meanwhile activating m TOR signaling through an increase in the glycolysis product dihydroxyacetone phosphate.These effects together with quenching free radicals by melatonin help mesothelial cells maintain a relatively stable internal environment in the face of high-glucose stress.Thus,Melatonin treatment holds some promise in preserving mesothelium integrity and in decreasing angiogenesis to protect peritoneum function in patients undergoing peritoneal dialysis.

Intestinal Microbiota and Kidney Diseases

Kidney diseases are common and the incidence rate is increasing. Gut microbiota is involved in metabolic and immune regulation of the host. Genetic, alimentary and environmental disease factors may change gut flora and increase opportunistic and pathogenic bacteria, contributing to immune or non-immune mediated kidney diseases including IgA nephropathy and diabetic nephropathy. Additionally, bacterial metabolites may be a source of uremic toxins. Thus, identification of diversity, composition, and metabolic and immunologic features of gut bacteria in chronic kidney diseases may help understand pathogenetic mechanism and develop therapy for diseases.

The Human MSI2 Gene is Associated with Schizophrenia in the Chinese Han Population

It has been suggested that altered neurogenesis may be involved in the etiology of schizophrenia,so genes impacting on neurogenesis could be potential candidates for schizophrenia.A member of the Musashi family,the human MSI2 gene plays a substantial role in stem-cell maintenance,asymmetric division,and differentiation during neurogenesis.Our previous genome-wide association study（GWAS）implied an association of MSI2 with schizophrenia in a Han Chinese population.To further explore this association,three single-nucleotide polymorphisms（SNPs）,rs9892791,rs11657292,and rs1822381,were selected for a replication study involving 921 schizophrenia cases and 1244 controls.After rigorous Bonferroni correction,two of the SNPs（rs9892791 and rs11657292） displayed significant differences in allele and genotype distribution frequencies between the case and control groups.When our GWAS and replication samples were combined,the three MSI2 SNPs were all strongly associated with schizophrenia（rs9892791：allelic P = 1.07E-5;rs11657292：allelic P = 1.95E-12;rs1822381：allelic P = 1.44E-4）.These results indicate that the human MSI2 gene might be a susceptibility gene forschizophrenia and encourage future research on the functional relationship between this gene and schizophrenia.

Correlation between serum miR-154-5p and urinary albumin excretion rates in patients with type 2 diabetes mellitus:a cross-sectional cohort study

This study aimed to investigate the correlation between serum miR-154-5p and urinary albumin to creatinine ratio(UACR)in patients with type 2 diabetes mellitus(T2DM)and the association with biomarkers of inflammation and fibrosis in diabetic kidney disease(DKD).A total of 390 patients with T2DM were divided into three groups:normal albuminuria(UACR<30 mg/g,n=136,NA),microalbuminuria(UACR at 30-300 mg/g,n=132,MA),and clinical albuminuria(UACR>300 mg/g,n=122,CA).Circulating miR-154-5p,inflammatory(C-reactive protein(CRP);erythrocyte sedimentation rate(ESR);and tumor necrosis factor-a(TNF-α)and fibrotic markers(vascular endothelial growth factor(VEGF);transforming growth factor-β1(TGF-β1);and fibronectin(FN),and other biochemical indicators were assessed via real-time PCR,enzyme-linked immunosorbent assay,and chemiluminescence assay in patients with T2DM and 138 control subjects(NC).UACR,miR-154-5p,glycated hemoglobin(HbA1c),serum creatinine(sCr),blood urea nitrogen(BUN),ESR,CRP,VEGF,TNF-α,TGF-β1,and FN were significantly higher and the estimated glomerular filtration rate(eGFR)was significantly lower in NA,MA,and CA groups than in NC subjects(P<0.05).Elevated levels of UACR and miR-154-5p were directly correlated with HbA1c,sCr,BUN,ESR,CRP,VEGF,TNF-α,TGF-β1,and FN and negatively correlated with eGFR(P<0.05).miR-154-5p,HbA1c,sCr,BUN,eGFR,ESR,CRP,VEGF,TNF-α,TGF-β1,and FN were important factors affecting UACR.These findings indicated that elevated serum miR-154-5p is significantly correlated with high UACR in patients with T2DM and may offer a novel reference for the early diagnosis of DKD.

Association of MSI2 Gene Polymorphism with Age-at-Onset of Schizophrenia in a Chinese Population

Dear Editor,Schizophrenia is one of the most complicated and challenging mental disorders psychiatrists and mental health caregivers confront.It is a heavy burden for the patients and usually occurs during adulthood.With a peak age-atonset of 18–25 years,schizophrenia results in the loss of productivity,poses a considerable burden on the relatives,and causes high medical and social costs.In the general population worldwide,the life risk for schizophrenia is

Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue

Among the four prostaglandin E2 receptors,EP3 receptor is the one most abundantly expressed in white adipose tissue(WAT).The mouse EP3 gene gives rise to three isoforms,namely EP3α,EP3β,and EP3γ,which differ only at their C-terminal tails.To date,functions of EP3 receptor and its isoforms in WAT remain incompletely characterized.In this study,we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice.Genetic ablation of three EP3 receptor isoforms(EP3^(−/−)mice)or EP3αand EP3γisoforms with EP3βintact(EP3βmice)led to an obese phenotype with increased food intake,decreased motor activity,reduced insulin sensitivity,and elevated serum triglycerides.Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγpathway,increased adipogenesis may contribute to obesity in EP3^(−/−)and EP3βmice.Moreover,both EP3^(−/−)and EP3βmice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway.Taken together,our findings suggest that EP3 receptor and itsαandγisoforms are involved in both adipogenesis and lipolysis and influence food intake,serum lipid levels,and insulin sensitivity.