Aldehyde dehydrogenase 2 suppresses cirrhosis and alcohol-induced hepatocellular carcinoma via the inhibition of acetaldehyde-derived DNA damage and multiple oncogenic signaling pathways

Objective:Hepatocellular carcinoma(HCC)is the most common primary liver cancer,the fifth most common cancer and the third most common global cause of cancer related deaths.Chronic alcohol consumption is a well-known risk factor for HCC.Acetaldehyde,a main metabolite of ethanol oxidation.

New Algorithm Rules Out Acute-on-chronic Liver Failure Development within 28 Days from Acute Decompensation of Cirrhosis

Background and Aims:Approximately 10%of patients with acute decompensated(AD)cirrhosis develop acute-on-chronic liver failure(ACLF)within 28 days.Such cases have high mortality and are difficult to predict.Therefore,we aimed to establish and validate an algorithm to identify these patients on hospitalization.Methods:Hospitalized patients with AD who developed ACLF within 28 days were considered pre-ACLF.Organ dysfunction was defined accord-ing to the chronic liver failure-sequential organ failure as-sessment(CLIF-SOFA)criteria,and proven bacterial infec-tion was taken to indicate immune system dysfunction.A retrospective multicenter cohort and prospective one were used to derive and to validate the potential algorithm,re-spectively.A miss rate of<5%was acceptable for the calcu-lating algorithm to rule out pre-ACLF.Results:In the deri-vation cohort(n=673),46 patients developed ACLF within 28 days.Serum total bilirubin,creatinine,international normalized ratio,and present proven bacterial infection at admission were associated with the development of ACLF.AD patients with≥2 organ dysfunctions had a higher risk for pre-ACLF patients[odds ratio=16.58195%confidence interval:(4.271-64.363),p<0.001].In the derivation co-hort,67.5%of patients(454/673)had≤1 organ dysfunction and two patients(0.4%)were pre-ACLF,with a miss rate of 4.3%(missed/total,2/46).In the validation cohort,65.9%of patients(914/1388)had≤1 organ dysfunction,and four(0.3%)of them were pre-ACLF,with a miss rate of 3.4%(missed/total,4/117).Conclusions:AD patients with≤1 organ dysfunction had a significantly lower risk of developing ACLF within 28 days of admission and could be safely ruled out with a pre-ACLF miss rate of<5%.

Copper homeostasis dysregulation promoting cell damage and the association with liver diseases

Copper plays an important role in many metabolic activities in the human body.Copper level in the human body is in a state of dynamic equilibrium.Recent research on copper metabolism has revealed that copper dyshomeostasis can cause cell damage and induce or aggravate some diseases by affecting oxidative stress,proteasome,cuprotosis,and angiogenesis.The liver plays a central role in copper metabolism in the human body.Research conducted in recent years has unraveled the relationship between copper homeostasis and liver diseases.In this paper,we review the available evidence of the mechanism by which copper dyshomeostasis promotes cell damage and the development of liver diseases,and identify the future research priorities.

Investigation on the short-term outcome and prognostic impact of predisposition,and precipitants in inpatients with chronic liver disease from Chinese AcuTe on CHronic LIver FailurE(CATCH-LIFE)cohorts

Aim:The study aimed to investigate the short-term outcomes of hospitalized patients with chronic liver disease(CLDs)and assess the prognostic impact of predisposition and precipitants,which currently remains unclear.Methods:The study included 3970 hospitalized patients with CLDs from two prospective longitudinal multicenter studies(NCT02457637 and NCT03641872)conducted in highly endemic hepatitis B virus(HBV)areas.Competing risk analysis was used to evaluate the effect of predispositions,including the etiology and severity of CLDs and precipitants;on sequential 28,90,and 365-day liver transplantation(LT)-free mortality.Results:Among all enrolled patients,76.8%of adverse outcomes(including death and LT)within one year occurred within 90 days.Compared with alcoholic etiology,the association of HBV etiology with poorer outcomes was remarkably on the 28th day(hazard ratio[HR],1.81;95%confidence interval[CI],1.07-3.06;p=0.026);however,and dimin-ished or became insignificant at 90 days and 365 days.Cirrhosis increased the adjusted risk for 365-day(HR,1.50;CI,1.13-1.99;p=0.004)LT-free mortality when compared with noncirrhosis.In patients with cirrhosis,prior decompensation(PD)independently increased the adjusted risk of 365-day LT-free mortality by 1.25-fold(p=0.021);however,it did not increase the risk for 90-day mortality.Neither the category nor the number of precipitants influenced the adjusted risk of 28 or 90-day LT-free mortality.Conclusions:The 90-day outcome should be considered a significant endpoint for evaluating the short-term prognosis of hospitalized patients with CLD.Predisposing factors,other than etiology,mainly affected the delayed(365-day)outcome.Timely effective therapy for CLD etiology,especially antiviral treatments for HBV,and post-discharge long-term surveillance monitoring in cirrhotic patients undergoing PD are suggested to enhance disease management and reduce mortality.

nterferon alpha （IFNα）-induced TRIM22 interrupts HCV ＇eplication by ubiquitinating NS5A

TRIM22, a tripartite-motif （TRIM） protein, is upregulated upon interferon alpha （IFNa） administration to hepatitis C virus （HCV）-infected patients. However, the physiological role of TRIM22 upregulation remains unclear. Here, we describe a potential antiviral function of TRI M22＇s targeting of the HCV NSSA protein. NS5A is important for HCV replication and for resistance to I FNa therapy. During the first 24 h following the initiation of I FNa treatment, upregulation of TRIM22 in the peripheral blood mononuclear cells （PBMCs） of HCV patients correlated with a decrease in viral titer. This phenomenon was confirmed in the hepatocyte-derived cell line Huh-7, which is highly permissive for HCV infection. TRIM22 over-expression inhibited HCV replication, and Small interfering RNA （siRNA）-mediated knockdown of TRIM22 diminished IFNα-induced anti-HCV function. Furthermore, we determined that TRIM22 ubiquitinates NS5A in a concentration-dependent manner. In summary, our results suggest that TRIM22 upregulation is associated with HCV decline during IFNα treatment and Dlavs an important role in controlling HCV replication in vitro.

Inhibition of the Neddylation Pathway Suppresses Enterovirus Replication

Dear Editor,Human enteroviruses(HEVs)comprise polioviruses,coxsackieviruses,echoviruses,rhinoviruses,and the enterovirus subgroups and belong to the genus Enterovirus in the family Picornaviridae(Baggen et al.2018).The HEV genome was thought to contain a single open reading frame(ORF)encoding one polyprotein,which was post-translationally processed into structural capsid proteins(VP1-4)and non-structural accessory proteins(2A,2B,2C,3A,3B,3C,3D)(Baggen et al.2018).Recently,we and others,have identified an additional upstream ORF(Guo et al.2019a;Lulla et al.2019)(ORF2/uORF).