The pathologic relevance of metabolic criteria in patients with biopsy-proven nonalcoholic fatty liver disease and metabolic dysfunction associated fatty liver disease:A multicenter cross-sectional study in China

Background:This study aimed to assess the association between metabolic syndrome(Met S)and severity of nonalcoholic fatty liver disease(NAFLD),and to discuss the pathological relevance of the diagnostic criteria in metabolic(dysfunction)associated fatty liver disease(MAFLD).Methods:This was a multicenter,cross-sectional study.Patients with NAFLD confirmed by liver biopsy were enrolled between July 2016 and December 2018 from 14 centers across the mainland of China.Anthropometric and metabolic parameters were collected to assess the pathological relevance.Results:Of 246 enrolled patients with NAFLD,150(61.0%)had the comorbidity of Met S.With the increase of metabolic components,the proportions of nonalcoholic steatohepatitis(NASH)and significant fibrosis were notably increased.The comorbid three metabolic components significantly increased the proportion of NASH,and further increase of metabolic components did not increase the proportion of NASH.However,the increase of metabolic components was parallel to the increase of the proportion of liver fibrosis.Among the 246 patients,239(97.2%)met the diagnostic criteria of MAFLD.Although non-MAFLD patients had less NASH,they present with similar proportion of significant fibrosis and cirrhosis.In the diagnostic criteria of MAFLD,BMI≥23 kg/m2 was related to NASH(Mantel-Haenszel Common Estimate OR:2.975;95%CI:1.037–8.538;P=0.043),and T2 DM was related to significant fibrosis(Mantel-Haenszel Common Estimate OR:2.531;95%CI:1.388–4.613;P=0.002).The homeostasis model assessment of insulin resistance(HOMA-IR)≥2.5 was the most significant factor for NASH(OR:4.100;95%CI:1.772–9.487;P=0.001)and significant factor for liver fibrosis(OR:2.947;95%CI:1.398–6.210;P=0.004)after the adjustments of the BMI and diabetes.Conclusions:Metabolic dysregulations are important risk factors in NAFLD progression.The insulin resistance status may play a predominant role in the progression in MAFLD patients.

Essential phospholipids for nonalcoholic fatty liver disease associated with metabolic syndrome: A systematic review and network meta-analysis

BACKGROUND Essential phospholipids(EPL)are used for the supportive treatment of nonalcoholic fatty liver disease(NAFLD),but data are mostly from small-scale studies.AIM To evaluate the efficacy of EPL treatment in adult patients with NAFLD and type 2 diabetes and/or obesity.METHODS The MEDLINE,PubMed,Embase,and Cochrane databases were searched up to March 2019 for clinical trials and comparative observational studies.Eligible studies were those published in English or Chinese that enrolled adult patients(≥18 years)with NAFLD and type 2 diabetes mellitus and/or obesity receiving EPL as monotherapy or as add-on therapy to existing therapy,and that included at least one of the efficacy outcomes of interest.A variety of studies were identified;thus,direct,indirect and cohort meta-analyses were performed.Mean difference(MD)and 95%confidence interval(CI)were calculated for continuous variables,and relative risk with 95%CI for disease response and recovery.A random-effects model was used to address between-study heterogeneity.RESULTS Ten studies met the inclusion criteria(n=22-324).EPL treatment duration ranged from 4 to 72 wk.In the direct meta-analysis(four randomized controlled trials),compared with antidiabetic therapy alone,EPL plus antidiabetic therapy was associated with a significantly greater reduction in[alanine aminotransferase(ALT);MD:11.28 U/L(95%CI:-17.33,-5.23),P=0.0003],triglyceride[MD:-49.33 mg/dL(95%CI:-66.43,-32.23),P<0.0001]and total cholesterol levels[MD:-29.74 mg/dL(95%CI:-38.02,-21.45),P<0.0001].There was also a significant increase in the rate of overall improvement[relative risk 1.50(95%CI:1.26-1.79),P<0.0001],and risk of no disease(P=0.0091),and a reduction in moderate disease(P=0.0187);there were no significant differences in severe disease,mild disease,or significant improvement.In the cohort meta-analysis of three non-randomized clinical trials,the MD in ALT levels was-16.71 U/L(95%CI:-24.94,-8.49)and 23%of patients had improved disease.In the cohort meta-analysis of five randomized trials,MD in ALT levels was–28.53 U/L(95%CI:-35.42,-21.65),and 87%(95%CI:81%,93%)and 58%(95%CI:46%,70%)of patients showed clinical improvement and significant clinical improvement.CONCLUSION This analysis provides evidence for a benefit of EPL in patients with NAFLD and diabetes and/or obesity.Further large-scale trials are warranted.

Determination of serum biomarkers in osteoarthritis patients：a previous interventional imaging study revisited

To evaluate in an interventional trial on knee osteoarthritis（OA） the level and change of two serum biomarkers and their correlation with imaging parameters.The previously reported interventional OA study（ClinicalTrials.gov：NCT00536302） identified a positive effect of collagen hydrolysate（CH） on cartilage morphology in patients with knee OA using delayed gadolinium enhanced magnetic resonance imaging（dGEMRIC）.It was the objective in this research project to evaluate in an interventional clinical trial on knee OA the level and change of two serum biomarkers and their correlation with imaging parameters.In blood samples of study participants,we determined the concentration of procollagen type II N-terminal propeptide（PIIANP） and aggrecan chondroitin sulfate 846 epitope（CS846） at baseline（BL） and at the follow-up（FU） visits at 24 and 48 weeks.We measured the level and change of biomarker concentrations in both study groups,and the correlation of those changes with changes in dGEMRIC.For the biomarker PIIANP,we observed a significantly greater increase in the CH group（29.9%vs.1.2%at week 24,P =0.001）.For CS846,the mean concentration was lower among the CH treated participants at 24 weeks（78%vs.96%,P= 0.045）.Consistent correlations of changes in biomarkers PIIANP and CS846 with changes of the dGEMRIC score could not be observed.In this study,different changes per treatment group,CH and placebo were seen for dGEMRIC and PIIANP BL to 24 weeks FU,but only weak correlations between changes in dGEMRIC and biochemical markers.

Antidiabetic profiling of veramycins,polyketides accessible by biosynthesis,chemical synthesis and precursor-directed modification

Seven new polyketides,termed veramycins,were isolated from a Streptomyces sp.from the Sanofi microbial strain collection along with their known congeners NFAT-133 and TM-123.Veramycin A,anα-pyrone congener of TM-123 and NFAT-133 showed an increased baseline deoxy-glucose uptake in the absence of insulin in a modified L6 rat skeletal muscle cell line(L6 GLUT4 AS160-like cells).In addition,both compounds slightly increased the sensitivity to insulin in this cell line.Total syntheses of NFAT-133,TM-123 and veramycin A were accomplished starting from a central building block,which bears the three contiguous stereogenic centers of this polyketide family.Our approach enables an efficient,selective and flexible access to all possible isomers of the stereotriad for further exploration of this series as a potential anti-diabetic lead structure as exemplified by the synthesis of an NFAT-133 epimer.Finally,the corresponding biosynthetic gene cluster(BGC)was identified by genome sequencing and gene inactivation.Based on feeding experiments,a biosynthetic pathway was proposed,which enabled access to new veramycin A analogs by precursor-directed biosynthesis.