Functions of ULK1 in autophagy and non-autophagy pathways and its implications in human physiology and disease

ULK1(unc-51 like autophagy activating kinase 1),a mammalian serine/threonine kinase,is a key component of autophagy initiation complex and helps to induce all types of autophagy.Canonical autophagy is a process in which,through the interactions of a series of autophagy-related proteins,damaged organelles or misfolded proteins are engulfed by autophagosomes and then merged with lysosomes to be degraded.Thus,canonical autophagy is an important constituent part of the cellular“quality control.”Besides,accumulating evidence indicates that ULK1 exerts autophagy-independent effects in a cell-specific manner.For example,ULK1 facilitates neurite elongation through the regulation of endoplasmic reticulum(ER)–Golgi trafficking in neurons,stimulates phosphopentose pathway to help NADPH(nicotinamide adenine dinucleotide phosphate hydrogen)production,and acts as a duplex regulator in type I IFN(type I interferon)induced innate immune response.Considering the importance and diversity of ULK1 in various biological processes,this review aims to present a comprehensive overview of autophagy and non-autophagy related functions of ULK1 in a variety of human physiological,pathological,and disease processes.

Molecular mechanisms of gender disparity in hepatitis B virus-associated hepatocellular carcinoma

Chronic hepatitis B virus(HBV)infection is one of the most common causes of hepatocellular carcinoma(HCC),a malignant tumor with high mortality worldwide.One remarkable clinical feature of HBVrelated HCC is that its incidence is higher in males and postmenopausal females compared to other females.Increasing evidence indicates that HBV-associated HCC may involve gender disparity and that it may be a type of hormone-responsive malignant tumor.Sex hormones,such as androgen and estrogen,have been shown to play very different roles in the progression of an HBV infection and in the development of HBVrelated HCC.Through binding to their specific cellular receptors and affecting the corresponding signaling pathways,sex hormones can regulate the transactivation of HBx,cause the chronic release of inflammatory cytokines in the hepatocellular microenvironment,and participate in epigenetic and genetic alternations in hepatocytes.All of these functions may be related to the initiation and progression of HBV-associated HCC.A thorough investigation of the molecular mechanisms underlying the gender-related disparity in HBV-related HCC should provide a new perspective for better understanding its pathogenesis and exploring more effective methods for the prevention and treatment of this disease.

Effects of Incretin-based Therapies on Weight-related Indicators among Patients with Type 2 Diabetes: A Network Meta-analysis

Objective To evaluate the effects of incretin-based therapies on body weight as the primary outcome,as well as on body mass index(BMI)and waist circumference(WC)as secondary outcomes.Methods Databases including Medline,Embase,the Cochrane Library,and clinicaltrials.gov(www.clinicaltrials.gov)were searched for randomized controlled trials(RCTs).Standard pairwise meta-analysis and network meta-analysis(NMA)were both carried out.The risk of bias(ROB)tool recommended by the Cochrane handbook was used to assess the quality of studies.Subgroup analysis,sensitivity analysis,meta-regression,and quality evaluation based on the Grading of Recommendations Assessment,Development,and Evaluation(GRADE)were also performed.Results A total of 292 trials were included in this study.Compared with placebo,dipeptidyl-peptidase IV inhibitors(DPP-4 Is)increased weight slightly by 0.31 kg[95%confidence interval(CI):0.05,0.58]and had negligible effects on BMI and WC.Compared with placebo,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)lowered weight,BMI,and WC by-1.34 kg(95%CI:-1.60,-1.09),-1.10 kg/m2(95%CI:-1.42,-0.78),and-1.28 cm(95%CI:-1.69,-0.86),respectively.Conclusion GLP-1 RAs were more effective than DPP-4 Is in lowering the three indicators.Overall,the effects of GLP-1 RAs on weight,BMI,and WC were favorable.

Peri-operative use of sorafenib in liver transplantation:A time-to-event meta-analysis

AIM:To evaluate whether the application of sorafenib during the peri-operative period of liver transplantation improves prognosis in liver cancer patients.METHODS:We searched Pub Med,EMBASE and MEDLINE for eligible articles.A total of 4 studieswere found that fulfilled the previously agreed-upon standards.We then performed a systematic review and meta-analysis on the enrolled trials that met the inclusion criteria.RESULTS:Out of the 104 studies identified in the database,82 were not clinical experiments,and 18 did not fit the inclusion standards.Among the remaining 4 articles,only 1 was related to the preoperative use of sorafenib,whereas the other 3 were related to its postoperative use.As the heterogeneity among the 4 studies was high,with an I2 of 86%,a randomized effect model was applied to pool the data.The application of sorafenib before liver transplantation had a hazard ratio(HR) of 3.29 with a 95% confidence interval(CI) of 0.33-32.56.The use of sorafenib after liver transplantation had an HR of 1.44(95%CI:0.27-7.71).The overall pooled HR was 1.68(95%CI:0.41-6.91).CONCLUSION:The results showed that the use of sorafenib during the peri-operative period of liver transplantation did not improve patient survival significantly.In fact,sorafenib could even lead to a worse prognosis,as its use may increase the hazard of poor survival.

TIMP-1 Promotes Expression of MCP-1 and Macrophage Migration by Inducing Fli-1 in Experimental Liver Fibrosis

Background and Aims:Tissue inhibitor of metalloproteinase-1(TIMP-1)plays a role in the excessive generation of extracellular matrix in liver fibrosis.This study aimed to explore the pathways through which TIMP-1 controls monocyte chemoattractant protein-1(MCP-1)expression and promotes hepatic macrophage recruitment.Methods:Liver fibrosis was triggered through carbon tetrachloride,and an adenoassociated virus containing small interfering RNA targeting TIMP-1(siRNA-TIMP-1)was administered to both rats and mice.We assessed the extent of fibrosis and macrophage recruitment.The molecular mechanisms regulating macrophage recruitment by TIMP-1 were investigated through transwell migration assays,luciferase reporter assays,the use of pharmacological modulators,and an analysis of extracellular vesicles(EVs).Results:siRNA-TIMP-1 alleviated carbon tetrachloride-induced liver fibrosis,reducing macrophage migration and MCP-1 expression.Co-culturing macrophages with hepatic stellate cells(HSCs)post-TIMP-1 downregulation inhibited macrophage migration.In siRNATIMP-1-treated HSCs,microRNA-145(miRNA-145)expression increased,while the expression of Friend leukemia virus integration-1(Fli-1)and MCP-1 was inhibited.Downregulation of Fli-1 led to decreased MCP-1 expression,whereas Fli-1 overexpression increased MCP-1 expression within HSCs.Transfection with miRNA-145 mimics reduced the expression of both Fli-1 and MCP-1,while miRNA-145 inhibitors elevated the expression of both Fli-1 and MCP-1 in HSCs.miRNA-145 bound directly to the 3'-UTR of Fli-1,and mi RNA-145-EN-riched EVs secreted by HSCs after TIMP-1 downregulation influenced macrophage recruitment.Conclusions:TIMP-1 induces Fli-1 expression through miRNA-145,subsequently increasing MCP-1 expression and macrophage recruitment.MiRNA-145-enriched EVs from HSCs can transmit biological information and magnify the function of TIMP-1.

Comparative effectiveness and safety of 32 pharmacological interventions recommended by guidelines for coronavirus disease 2019:a systematic review and network meta-analysis combining 66 trials

Background:The global pandemic coronavirus disease 2019(COVID-19)has become a major public health problem and presents an unprecedented challenge.However,no specific drugs were currently proven.This study aimed to evaluate the comparative efficacy and safety of pharmacological interventions in patients with COVID-19.Methods:Medline,Embase,the Cochrane Library,and clinicaltrials.gov were searched for randomized controlled trials(RCTs)in patients infected with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)/SARS-CoV.Random-effects network metaanalysis within the Bayesian framework was performed,followed by the Grading of Recommendations Assessment,Development,and Evaluation system assessing the quality of evidence.The primary outcome of interest includes mortality,cure,viral negative conversion,and overall adverse events(OAEs).Odds ratio(OR)with 95%confidence interval(CI)was calculated as the measure of effect size.Results:Sixty-six RCTs with 19,095 patients were included,involving standard of care(SOC),eight different antiviral agents,six different antibiotics,high and low dose chloroquine(CQ_HD,CQ_LD),traditional Chinese medicine(TCM),corticosteroids(COR),and other treatments.Compared with SOC,a significant reduction of mortality was observed for TCM(OR=0.34,95%CI:0.20–0.56,moderate quality)and COR(OR=0.84,95%CI:0.75–0.96,low quality)with improved cure rate(OR=2.16,95%CI:1.60–2.91,low quality for TCM;OR=1.17,95%CI:1.05–1.30,low quality for COR).However,an increased risk of mortality was found for CQ_HD vs.SOC(OR=3.20,95%CI:1.18–8.73,low quality).TCM was associated with decreased risk of OAE(OR=0.52,95%CI:0.38–0.70,very low quality)but CQ_HD(OR=2.51,95%CI:1.20–5.24)and interferons(IFN)(OR=2.69,95%CI:1.02–7.08)vs.SOC with very low quality were associated with an increased risk.Conclusions:COR and TCM may reduce mortality and increase cure rate with no increased risk of OAEs compared with standard care.CQ_HD might increase the risk of mortality.CQ,IFN,and other antiviral agents could increase the risk of OAEs.The current evidence is generally uncertain with low-quality and further high-quality trials are needed.

“Treat-all”Strategy for Patients with Chronic Hepatitis B Virus Infection in China:Are We There Yet?

Chronic hepatitis B remains the primary cause of liver-related events in China.The World Health Organization set a goal to eliminate viral hepatitis as a public health threat by 2030.However,achieving this goal appears challenging due to the current low rates of diagnosis and treatment.The“Treat-all”strategy,which proposes treating all patients with detectable hepatitis B virus(HBV)DNA or even all patients with positive HBsAg,has been suggested to simplify anti-HBV treatment.In 2022,the Chinese Society of Hepatology and the Chinese Society of Infectious Diseases updated the guidelines for the prevention and treatment of chronic hepatitis B in China,expanding antiviral indications and simplifying the treatment algorithm.According to this latest guideline,nearly 95%of patients with detectable HBV DNA are eligible for antiviral treatment.This review aimed to provide a detailed interpretation of the treatment indications outlined in the Chinese Guidelines for the Prevention and Treatment of Chronic Hepatitis B(version 2022)and to identify gaps in achieving the“Treat-all”strategy in China.

Baseline Hepatitis B Virus DNA Level is a Promising Factor for Predicting the 3^rd Month Virological Response to Entecavir Therapy： A Study of Strict Defined Hepatitis B virus Induced Cirrhosis

Background： Cirrhosis is a common complication of chronic hepatitis B. It remains unclear if viral and biochemical parameters at baseline affect virological response to entecavir and therefore warrant investigation. In the present study, we aimed to eval uate the efficacy of entecavir therapy by monitoring virological response at the end of the 3^rd month of treatment and try to figure out whether baseline factors could help predict it in a cohort of hepatitis B virus （HBV） compensated cirrhosis patients and to determine the cut-off value of a predicting parameter.Methods： A total of 91 nucleos（t）ide-naive patients with HBV induced cirrhosis （compensatory stage） were enrolled in a prospective cohort. HBV DNA and alanine aminotransferase （ALT） were tested at baseline and monitored every 3-6 months after starting therapy. Results： Of all 91 patients, the median follow-up time was 12 （9-24） months. Overall, 64 patients （70.3%） achieved virological response in the 3^rd month. Univariate analysis showed that the 3^rd month virological response can be predicted by baseline HBV DNA levels （P 〈 0.001, odds ratio [OR]： 2.13, 95% confidence interval [CI]： 1.44-3.15）, ALT value （P = 0.023, OR： 1.01, 95% CI： 1.00 1.01 ） and hepatitis B e antigen （HBeAg） negativity （P = 0.016, OR： 0.30, 95% CI： 0.11-0.80）. Multiple regression analysis showed baseline H BV DNA level was the only parameter related to full virological response. Higher baseline HBV DNA strata indicated a higher probability that HBV DNA remains detectable at the 3^rd month （P = 0.001）. Area under receiver operating characteristic curve for determining the 3^rd month virological response by baseline HBV DNA was 77.6% （95% CI： 66.7-85.2%）, with a best cut-offvalue of 5.8 log10. Conclusions： Baseline HBV DNA, HBeAg negativity, and ALT were independent factors contributing to virological response at the 3^rt month. Further, multiple regression showed that HBV DNA level was the only parameter predicting full virological response as early as the 3^rd month, in this cirrhosis cohort.

Regression of liver fibrosis: evidence and challenges

It has been reported that liver fibrosis could be reversed after eliminating liver injuries.This article systematically summarizes the evidence of fibrosis regression based on histology,liver stiffness,and serum biomarkers,and discusses several clinically relevant challenges.Evidence from liver biopsy has been regarded as the gold standard in the assessment of fibrosis regression.Semiquantitative staging and grading systems are traditionally and routinely used to define regression.Recently,the predominantly regressive,indeterminate,and predominantly progressive score was proposed,based on the regressive features from“hepatic repair complex”,to provide additional information regarding the quality of fibrosis.For non-invasive assessment,although liver stiffness and serum biomarkers could be applied to reflect the dynamic changes of liver fibrosis,other confounding factors such as liver inflammation have to be considered.In conclusion,both histology and non-invasive methods can provide evidence regarding fibrosis regression.The predictive value of fibrosis regression in long-term prognosis warrants further investigation.

Hepatic Arterioportal Fistulas: A Retrospective Analysis of 97 Cases

Background and Aims:Hepatic arterioportal fistulas(HAPFs)are abnormal shunts or aberrant functional con-nections between the portal venous and the hepatic arte-rial systems.Detection of HAPFs has increased with the ad-vances in diagnostic techniques.Presence of HAPFs over a prolonged period can aggravate liver cirrhosis and further deteriorate liver function.However,the underlying causes of HAPFs and the treatment outcomes are now well character-ized.This study aimed to summarize the clinical character-istics of patients with HAPFs,and to compare the outcomes of different treatment modalities.Methods:Data of 97 pa-tients with HAPFs who were admitted to the Second Xiang-ya Hospital between January 2010 and January 2020 were retrospectively reviewed.Demographic information,clinical manifestations,underlying causes,treatment options,and short-term outcomes were analyzed.Results:The main cause of HAPF in our cohort was hepatocellular carcinoma(78/97,80.41%),followed by cirrhosis(10/97,10.31%).The main clinical manifestations were abdominal distention and abdominal pain.Treatment methods included transcath-eter arterial embolization(n=63,64.9%),surgery(n=13,13.4%),and liver transplantation(n=2,2.1%);nineteen(19.6%)patients received conservative treatment.Among patients who underwent transcatheter arterial embolization,polyvinyl alcohol,lipiodol combined with gelatin sponge,and spring steel ring showed comparable efficacy.Conclusions:Hepatocellular carcinoma and cirrhosis are common causes of HAPFs.Transcatheter arterial embolization is a safe and effective method for the treatment of HAPFs,and polyvinyl alcohol,lipiodol combined with gelatin sponge,and spring steel ring showed comparable efficacy in our cohort.

Negative association of time in range and urinary albumin excretion rate in patients with type 2 diabetes mellitus:a retrospective study of inpatients

Background:Time in range(TIR)refers to the time an individual spends within their target glucose range,which now has been popularized as an important metric to classify glycemic management and also recognized as an important outcome of current diabetes therapies.This study aimed to investigate the association between TIR and the severity of the urinary albumin excretion rate(UAER)in patients with type 2 diabetes mellitus(T2DM).Methods:We retrospectively analyzed the data of 1014 inpatients with T2DM at the Department of Endocrinology and Metabolism of Peking University International Hospital,China.TIR was defined as the percentage of blood glucose within the target range of 3.90-10.00 mmol/L.Urine samples for assessment of UAER were collected for 3 consecutive days from the start of hospitalization.Results:The TIR values for patients with normal urine levels of albumin,microalbuminuria,and macroalbuminuria were 70%±20%,50%±20%,and 30%±20%,respectively(allP<0.001).The patients were stratified according to quartiles of TIR as follows:quartile(Q)1,<55%;Q2,55%-72%;Q3,73%-83%;and Q4,>83%.The incidences of microalbuminuria in Q1,Q2,Q3,and Q4 were 41.1%,21.6%,7.1%,and 5.5%(allP<0.001),respectively.The respective incidences of macroalbuminuria were 24.2%,1.1%,1.4%,and 0%(allP<0.001).In multinomial logistic regression analyses,TIR was significantly correlated with microalbuminuria(odds ratio[OR]0.58,95%confidence interval[CI]:0.52-0.65,P<0.001)and macroalbuminuria(OR 0.26,95%CI:0.18-0.38,P<0.001)after adjusting for age,sex,body mass index,diabetes duration,systolic blood pressure,and levels of triglycerides,glycosylated hemoglobin A1c,and creatinine.Conclusion:The proportion of blood glucose in TIR is closely related to the severity of UAER in patients with T2DM.

Impact of National Centralized Drug Procurement Policy on Antiviral Utilization and Expenditure for Hepatitis B in China

Background and Aims:The National Centralized Drug Procurement(NCDP)policy was launched in China's Mainland in April 2019,with entecavir(ETV)and tenofovir disoproxil fumarate(TDF)being included in the procurement list.We conducted the current study to investigate the impact of the NCDP policy on the utilization and expenditures of antiviral therapy for chronic hepatitis B(CHB)in China.Methods:Procurement records,including monthly purchase volume,expenditure,and price of nucleos(t)ide analogs(NAs),were derived from the National Healthcare Security Administration from April 2018 to March 2021.The changes in volumes and expenditures of the first-line NAs and bid-winning products were calculated.The effects of price,volume,and structure related to drug expenditure were calculated by the Addis and Magrini(AM)Index System Analysis.Results:The purchase volume of NAs significantly increased from 134.3 to 318.3 million DDDs,whereas the expenditure sharply decreased from 1,623.41 to 490.43 million renminbi(RMB)or 241.94 to 73.09 million US dollars(USD).The proportions of firstline NAs rose from 72.51%(ETV:69.00%,TDF:3.51%)to 94.97%(ETV:77.42%,TDF:17.55%).AM analysis showed that the NCDP policy decreased the expenditure of all NAs(S=0.91)but increased that of the first-line NAs in the bidwinning list(S=1.13).Assuming the population size of CHB patients remains stable and a compliance rate of≥75%,the proportion of CHB patients receiving first-line antiviral therapy would increase from 6.36–8.48%to 11.56–15.41%.Conclusions:The implementation of the NCDP policy significantly increased the utilization of first-line NAs for CHB patients at a lower expenditure.The findings provided evidence for optimizing antiviral therapy strategy and allocating medical resources in China.

Compensation for Neurodegeneration by Hippocampal Neurogenesis in Alzheimer’s Disease: Where is the way?

Neurodegeneration,a defining hallmark of Alzheimer's disease(AD),features the progressive loss of neuronal structure and functions.Therapeutic approaches to AD show limited efficiency in halting the neurodegeneration to date.Given the lack of neuronal renewability in most subareas of the adult brain,symptomatic drugs or treatments cannot repopulate neurons and rewire the degenerated neuronal circuits in AD.

Overexpression of Hepcidin Alleviates Steatohepatitis and Fibrosis in a Diet-induced Nonalcoholic Steatohepatitis

Background and Aims:Iron overload can contribute to the progression of nonalcoholic fatty liver disease(NAFLD)to nonalcoholic steatohepatitis(NASH).Hepcidin(Hamp),which is primarily synthesized in hepatocytes,is a key reg-ulator of iron metabolism.However,the role of Hamp in NASH remains unclear.Therefore,we aimed to elucidate the role of Hamp in the pathophysiology of NASH.Methods:Male mice were fed a choline-deficient L-amino acid-defined(CDAA)diet for 16 weeks to establish the mouse NASH model.A choline-supplemented amino acid-defined(CSAA)diet was used as the control diet.Recombinant adeno-asso-ciated virus genome 2 serotype 8 vector expressing Hamp(rAAV2/8-Hamp)or its negative control(rAAV2/8-NC)was administered intravenously at week 8 of either the CDAA or CSAA diet.Results:rAAV2/8-Hamp treatment markedly decreased liver weight and improved hepatic steatosis in the CDAA-fed mice,accompanied by changes in lipogenesis-related genes and adiponectin expression.Compared with the control group,rAAV2/8-Hamp therapy attenuated liver damage,with mice exhibiting reduced histological NAFLD inflammation and fibrosis,as well as lower levels of liver enzymes.Moreover,α-smooth muscle actin-positive acti-vated hepatic stellate cells(HSCs)and CD68-postive mac-rophages increased in number in the CDAA-fed mice,which was reversed by rAAV2/8-Hamp treatment.Consistent with the in vivo findings,overexpression of Hamp increased adi-ponectin expression in hepatocytes and Hamp treatment inhibited HSC activation.Conclusions:Overexpression of Hamp using rAAV2/8-Hamp robustly attenuated liver stea-tohepatitis,inflammation,and fibrosis in an animal model of NASH,suggesting a potential therapeutic role for Hamp.

Detection of Hepatitis B Virus M204V Mutation Quantitatively via Real-time PCR

Background and Aims:Drug-resistant DNA mutations of the hepatitis B virus(HBV)affect treatment response in chronic hepatitis B patients.We have established a new,sensitive,specific,accurate and convenient real-time PCR method to detect HBV mutations quantitatively.Methods:Blood samples were collected from patients showing viral breakthrough,primary nonresponse,or poor response during treatment,and mutations were detected via direct sequencing to assess our method.A plasmid containing the M204V mutation was synthesized and standard curves plotted.Results:The determination coefficient for linear correlation between Ct and log plasmid copy numbers was 0.996,where Ct value was−3.723log(DNA concentration)+48.647.Coefficients of variation indicated good reproducibility.Correctness was within tolerable bias.Limit of detection was 103 copies/mL.Specificity,accuracy,positive predictive value and negative predictive value were 92.86%,100%,96.88%,100%and 94.74%,respectively.Conclusions:These results show that our method can be used to detect HBV M204V mutations with the advantages of sensitivity,specificity and efficiency,providing a new choice for monitoring drug resistance.

Chinese guidelines for the application of colon cancer staging recognition systems based on artificial intelligence platforms (2021)

The incidence and mortality of colon cancer in China are increasing each year.At present,treatment selection for colon cancer patients mainly depends on imaging results,which require a large number of radiologists to interpret.In China,there is a shortage and uneven distribution of experienced radiologists,which leads to delays and bias in the evaluation of imaging data.Based on these considerations,the Colorectal Surgery Group of the Surgery Branch of the Chinese Medical Association in collaboration with experts at Beihang University has independently developed an artificial intelligence(AI)-based recognition system for the preoperative determination of colon cancer stage to partially replace the work of and relieve the pressure on radiologists.These guidelines aim to standardize the use of AI-based recognition systems in the preoperative staging of colon cancer and guide their clinical application.