Peroxisome proliferator-activated receptor α,a potential therapeutic target for alcoholic liver disease

Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α(PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease.

Serum N-glycan markers for diagnosing liver fibrosis induced by hepatitis B virus

BACKGROUND Hepatitis B virus (HBV) infection is the primary cause of hepatitis with chronic HBV infection,which may develop into liver fibrosis,cirrhosis and hepatocellular carcinoma.Detection of early-stage fibrosis related to HBV infection is of great clinical significance to block the progression of liver lesion.Direct liver biopsy is regarded as the gold standard to detect and assess fibrosis;however,this method is invasive and prone to clinical sampling error.In order to address these issues,we attempted to find more convenient and effective serum markers for detecting HBV-induced early-stage liver fibrosis.AIM To investigate serum N-glycan profiling related to HBV-induced liver fibrosis and verify multiparameter diagnostic models related to serum N-glycan changes.METHODS N-glycan profiles from the sera of 432 HBV-infected patients with liver fibrosis were analyzed.Significant changed N-glycan levels (peaks)(P <0.05) in differentfibrosis stages were selected in the modeling group,and multiparameter diagnostic models were established based on changed N-glycan levels by logistic regression analysis.The receiver operating characteristic (ROC) curve analysis was performed to evaluate diagnostic efficacy of N-glycans models.These models were then compared with the aspartate aminotransferase to platelet ratio index (APRI),fibrosis index based on the four factors (FIB-4),glutamyltranspeptidase platelet albumin index (S index),GlycoCirrho-test,and GlycoFibro-test.Furthermore,we combined multiparameter diagnostic models with alanine aminotransferase (ALT) and platelet (PLT) tests and compared their diagnostic power.In addition,the diagnostic accuracy of N-glycan models was also verified in the validation group of patients.RESULTS Multiparameter diagnostic models constructed based on N-glycan peak 1,3,4and 8 could distinguish between different stages of liver fibrosis.The area under ROC curves (AUROCs) of Model A and Model B were 0.890 and 0.752,respectively differentiating fibrosis F0-F1 from F2-F4,and F0-F2 from F3-F4,and surpassing other serum panels.However,AUROC (0.747) in Model C used for the diagnosis of F4 from F0-F3 was lower than AUROC (0.795) in FIB-4.In combination with ALT and PLT,the multiparameter models showed better diagnostic power (AUROC=0.912,0.829,0.885,respectively) when compared with other models.In the validation group,the AUROCs of the three combined models (0.929,0.858,and 0.867,respectively) were still satisfactory.We also applied the combined models to distinguish adjacent fibrosis stages of 432patients (F0-F1/F2/F3/F4),and the AUROCs were 0.917,0.720 and 0.785.CONCLUSION Multiparameter models based on serum N-glycans are effective supplementary markers to distinguish between adjacent fibrosis stages of patients caused by HBV,especially in combination with ALT and PLT.

Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis:A systematic review of in vivo studies

Although multiple drugs are accessible for recovering liver function in patients,none are considered efficient.Liver transplantation is the mainstay therapy for end-stage liver fibrosis.However,the worldwide shortage of healthy liver donors,organ rejection,complex surgery,and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases.Mesenchymal stem cell(MSC)therapy is an emerging alternative method for treating patients with liver fibrosis.However,many aspects of this therapy remain unclear,such as the efficiency compared to conventional treatment,the ideal MSC sources,and the most effective way to use it.Because bone marrow(BM)is the largest source for MSCs,this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors.We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy.Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases.In contrast,the cotreatment presented a more efficient way.Nevertheless,BM-MSCs are lacking as a therapy for liver fibrosis;thus,this paper also reviews factors that affect BM-MSC efficiency,such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis.Ultimately,our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis.It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy,focusing on the preclinical in vivo experiments,and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.

Tricistronic hepatitis C virus subgenomic replicon expressing double transgenes

AIM:To construct a tricistronic hepatitis C virus(HCV)replicon with double internal ribosome entry sites(IRESes)of only 22 nucleotides for each,substituting the encephalomyocarditis virus(EMCV)IRESes,which are most often used as the translation initiation element to form HCV replicons.METHODS:The alternative 22-nucleotide IRES,RNA-binding motif protein 3 IRES(Rbm3 IRES),was used to form a tricistronic HCV replicon,to facilitate constructing HCV-harboring stable cell lines andsuccessive antiviral screening using a luciferase marker.Briefly,two sequential Rbm3 IRESes were inserted into bicistronic p UC19-HCV plasmid,consequently forming a tricistronic HCV replicon(p HCV-rep-Neo R-h Rluc),initiating the translation of humanized Renilla luciferase and HCV non-structural gene,along with HCV authentic IRES initiating the translation of neomycin resistance gene.The s H7 cell lines,in which the novel replicon RNA stably replicated,were constructed by neomycin and luciferase activity screening.The intracellular HCV replicon RNA,expression of inserted foreign genes and HCV non-structural gene,as well as response to anti-HCV agents,were measured in s H7 cells and cells transiently transfected with tricistronic replicon RNA.RESULTS:The intracellular HCV replicon RNA and expression of inserted foreign genes and HCV nonstructural gene in s H7 cells and cells transiently transfected with tricistronic replicon RNA were comparable to those in cells stably or transiently transfected with traditional bicistronic HCV replicons.The average relative light unit in p HCV-rep-Neo R-h Rluc group was approximately 2-fold of those in the p UC19-HCV-h RLuc and Tri-JFH1 groups(1.049×108±2.747×107 vs 5.368×107±1.016×107,P<0.05;1.049×108±2.747×107 vs 5.243×107±1.194×107,P<0.05),suggesting that the translation initiation efficiency of the first Rbm3 IRES in the two sequential IRESes was stronger than the HCV authentic IRES and EMCV IRES.The fold changes of 72 h/4 h relative light units in the p HCV-rep-Neo R-h Rluc and p UC19-HCV-h RLuc groups were similar(159.619±9.083 vs163.536±24.031,P=0.7707),and were both higher than the fold change in the Tri-JFH1 group 159.619±9.083 vs 140.811±9.882,P<0.05;163.536±24.031 vs 140.811±9.882,P<0.05),suggesting that the replication potency of the Rbm3 IRES tricistronic replicon matched the replication of bicistronic replicon and exceeded the potency of EMCV IRES replicon.Replication of tricistronic replicons was suppressed by ribavirin,simvastatin,atorvastatin,telaprevir and boceprevir.Interferon-alpha 2b could not block replication of the novel replicon RNA in s H7 cells.After interferon stimulation,Mx A m RNA and protein levels were lower in s H7 than in parental cells.CONCLUSION:Tricistronic HCV replicon with double Rbm3 IRESes could be applied to evaluate the replication inhibition efficacy of anti-HCV agents.

Adverse Effect of Nonalcoholic Fatty Liver Disease on the Therapeutic Response in Patients with Chronic Hepatitis B

Background and Aims:The impact of nonalcoholic fatty liver disease(NAFLD)on the treatment outcome of chronic hepatitis B(CHB)is undefined and deserves an in-depth investigation.Methods:Histologically-proven CHB receiving first-line antiviral regimens as initial therapy was enrolled and grouped by the concurrence of NAFLD,and followed up at six monthly intervals.Therapeutic response related data were recorded and compared at multiple time points.Kaplan-Meier and Cox regression analyses were utilized to estimate the impact of NAFLD on complete virological response(CVR).Results:We enrolled 267 patients(CHB:164;CHB with NAFLD:103)with comparable follow-up durations.They were also comparable in baseline HBV DNA levels and HBeAg positivity.Patients with concomitant NAFLD showed less significant decline in HBV DNA,qHBsAg,pgRNA,and liver enzyme levels over time;moreover,their cumulative incidences of CVR were significantly lower and that of low-level viremia(LLV)were significantly higher at 6,12,18,24 months.First CVR of CHB was delayed with the presence NAFLD(11.0 vs.7.0 months,p<0.001)and further prolonged with higher grade of liver steatosis(Grade 2–3 vs.1:13.0 vs.9.0 months).On multivariate analysis,HBeAg positivity(HR:0.650,p=0.036),grade of steatosis(G2[HR:0.447,p=0.004];G3[HR:0.085,p=0.002])and HBV DNA(log10 IU/mL)(HR:0.687,p<0.001)were significantly associated with delayed CVR,whereas grade of necroinflammation(HR:1.758,p<0.001)accelerated the CVR.Conclusions:In CHB patients receiving initial antiviral therapy,NAFLD was associated with higher levels of HBV DNA,pgRNA,and liver enzymes,and higher incidence of LLV and delayed CVR.