The authors regret that an error has been identified in Fig.5 of this original article.Specifically,the representative image of BDL group was incorrectly selected during figure assembly.The corrected version of Fig.5 ...The authors regret that an error has been identified in Fig.5 of this original article.Specifically,the representative image of BDL group was incorrectly selected during figure assembly.The corrected version of Fig.5 is shown below.This correction does not affect the overall results,interpretations,and conclusions of the study.展开更多
Background and aims:Hepatocellular carcinoma(HCC)is a malignant tumor with a high mortality rate,but there are still no effective treatments.The aim of this study was to investigate the anticancer potential of the com...Background and aims:Hepatocellular carcinoma(HCC)is a malignant tumor with a high mortality rate,but there are still no effective treatments.The aim of this study was to investigate the anticancer potential of the combined use of brefeldin A(BFA)and tunicamycin(TM)in HepG2 cells,as well as the underlying mechanisms.Methods:HepG2 cells were treated with different concentrations of BFA(0.1e2.5 mg/L)and TM(1 e5 mg/L)for 24 h.DMSO(0.1%,v/v)was used as a vehicle control.Cell viability and cell migration were measured using MTT assay and scratch wound assay,respectively.Apoptosis was detected using flow cytometry and acridine orange(AO)staining.The protein and mRNA levels of various factors involved in apoptosis(poly(ADP-ribose)polymerase-1(PARP-1),caspase-12,caspase-3,and stearoyl-CoA desaturase 1)and endoplasmic reticulum(ER)stress(binding immunoglobulin protein(BiP),protein kinase R-like endoplasmic reticulum kinase(PERK),p-PERK,phosphorylation of eukaryotic translation initiation factor 2alpha(p-eIF2a),activating transcription factor(ATF)4,and C/EBP homologous protein(CHOP))were measured using Western blotting and qRT-PCR,respectively.Results:Both BFA and TM alone significantly reduced the viability of HepG2 cells in a dose-dependent way.The co-incubation with TM(1 mg/L)further significantly reduced the viability of HepG2 cells treated with BFA(0.25 mg/L)alone(P<0.05).BFA significantly increased the protein and mRNA levels of caspase-3 and PARP-1(P<0.05)compared to control and DMSO-treated cells,indicating that BFA induced apoptosis in HepG2 cells by increasing the expression of caspase-3 and PARP-1.The induction of apoptosis by BFA could be further significantly enhanced by co-incubation with TM.In addition,BFA significantly increased the mRNA levels of BiP,PERK and ATF4(P<0.05)compared to control and DMSOtreated cells.After co-incubation of BFA and TM,the protein levels of BiP,p-PERK,p-eIF2a and CHOP were significantly increased,indicating that TM could enhance BFA-induced ER stress in HepG2 cells through the PERK-eIF2a-ATF4-CHOP pathway.Conclusions:BFA could induce apoptosis and ER stress,and TM could enhance the ability of BFA to induce apoptosis and ER stress in HepG2 cells through the PERK-eIF2ɑ-ATF4-CHOP pathway.The findings highlight the therapeutic potential of the combined use of BFA and TM in treating HCC.展开更多
Background and aims:Metabolic dysfunction-associated fatty liver disease(MAFLD)is a common chronic condition that can lead to cancer due to its complex pathogenesis.Therapeutic agents targeting AMPactivated protein ki...Background and aims:Metabolic dysfunction-associated fatty liver disease(MAFLD)is a common chronic condition that can lead to cancer due to its complex pathogenesis.Therapeutic agents targeting AMPactivated protein kinase(AMPK)activation have been suggested as potential treatments for metabolic disorders such as metabolic dysfunction-associated steatohepatitis(MASH).Rhizoma Atractylodis Macrocephalae(RAM)has been clinically used to treat obesity-related health problems,but its therapeutic effects on MAFLD and the underlying mechanism remain unclear.Therefore,this study was conducted to evaluate the function and underlying mechanism of RAM in the treatment of MAFLD.Methods:The effect of RAM decoction on MAFLD was evaluated using a high-fat diet(HFD)-induced MAFLD mouse model.In vitro studies were conducted using a palmitic acid/oleic acid-induced lipid accumulation model in the alpha mouse liver 12 cells and RAM-containing serum.The underlying mechanisms were elucidated through a combination of network pharmacology analysis,immunohistochemistry,western blotting,and polymerase chain reaction analysis.Results:Administration of RAM decoction significantly reduced body weight gain in MAFLD mice without changing food intake.The weights of the liver and inguinal adipose tissues were also reduced after RAM treatment.Additionally,RAM administration decreased serum levels of alanine aminotransferase,aspartate transaminase,total cholesterol,triglyceride,low-density lipoprotein cholesterol,and glucose,while reducing lipid droplet accumulation in the liver tissues of MAFLD mice.The underlying mechanisms included the activation of the phosphorylation of AMPK and acetyl-CoA carboxylase(ACC),and inhibition of the expression of sterol regulatory element binding protein 1(SREBP1).However,RAM did not alter the protein expression levels of peroxisome proliferator-activated receptor a and carnitine palmitoyltransferase-1a.Furthermore,the RAM-induced upregulation of phosphorylated AMPK,phosphorylated ACC,and SREBP1 expression,as well as the downregulation of fatty acid synthase expression,were reversed by using an AMPK inhibitor.Conclusions:Through a combination of network pharmacology and experimental validation,we demonstrated that RAM may exert therapeutic effects on MAFLD by inhibiting lipid synthesis and activating phosphorylated AMPK pathways.展开更多
Dear Editor,Metabolic dysfunction-associated steatotic liver disease(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD),has emerged as the most prevalent chronic liver condition globally,affecting nearl...Dear Editor,Metabolic dysfunction-associated steatotic liver disease(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD),has emerged as the most prevalent chronic liver condition globally,affecting nearly 100 million individuals in the United States alone.1 The recent reclassification of NAFLD to MASLD and non-alcoholic steatohepatitis(NASH)to metabolic dysfunctionassociated steatohepatitis(MASH)reflects a paradigm shift in understanding the metabolic underpinnings of this disease.展开更多
Dear Editor,Liver diseases,as a significant global health issue,are characterized by complex and diverse pathogenic mechanisms.In recent years,the rapid development of biotechnology,particularly advancements in single...Dear Editor,Liver diseases,as a significant global health issue,are characterized by complex and diverse pathogenic mechanisms.In recent years,the rapid development of biotechnology,particularly advancements in single-cell omics,genomics,and metabolomics,has led to significant improvements in the early diagnosis,treatment,and regeneration research of liver diseases.展开更多
Dear Editor,The liver is a vital organ that plays a crucial role in metabolism,detoxification,and immune defense.However,modern lifestyles characterized by an unhealthy diet,lack of exercise,excessive alcohol consumpt...Dear Editor,The liver is a vital organ that plays a crucial role in metabolism,detoxification,and immune defense.However,modern lifestyles characterized by an unhealthy diet,lack of exercise,excessive alcohol consumption,and hepatitis viral infections are significant threats to liver health of the Chinese population.In response,China initiated the National Protect Liver Day in 2001,which is observed annually on March 18.展开更多
Background and aims:Clinical data regarding patients with chronic hepatitis B(CHB)after Omicron BA.5 infection are currently limited.This study aimed to assess the clinical characteristics of patients with CHB and Omi...Background and aims:Clinical data regarding patients with chronic hepatitis B(CHB)after Omicron BA.5 infection are currently limited.This study aimed to assess the clinical characteristics of patients with CHB and Omicron BA.5 infection in South China.Methods:This retrospective study was conducted from January to March 2023 in a cohort of 485 healthy individuals and 553 patients with CHB.Clinical features,encompassing COVID-19-related symptoms,levels of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)antibodies,vaccination status,liver functions,and virological markers of hepatitis B virus(HBV)infection were measured.Results:COVID-19-related symptom patterns were similar in both groups,except for fever,which was notably less prevalent(85.4%vs.90.4%,P?0.047)among patients with CHB who experienced a significantly shorter duration of fever(median 2.2(25the75th percentile,1.0e3.0)days vs.2.3(1.0e3.0)days,P=0.048)and a shorter time for symptom relief(9.2(5.0e14.0)vs.11.1(5.0e14.0)days,P=0.015).The levels of SARS-CoV-2 antibodies were comparable between the two groups but increased after booster vaccinations.In patients with CHB,globulin(GLB)and hepatitis B envelope antibody levels were significantly increased after Omicron BA.5 infection,regardless of nucleos(t)ide analog regimens comparing entecavir(ETV)with tenofovir(TFV).Patients with CHB treated with TFV had significantly higher levels of SARS-CoV-2 antibodies than those treated with ETV(1065.1(346.9e1188.5)COI vs.765.5(24.5e1119.1)COI,P=0.025).Conclusions:No significant exacerbation of COVID-19 symptoms was observed in conjunction with the efficacy of COVID-19 booster vaccinations.There were no notable alterations in liver functions except for GLB.HBV reactivation,as evidenced by increased HBV DNA,was observed among patients with CHB after Omicron BA.5 infection.These changes were not affected by ETV versus TFV administration;however,TFV resulted in a significant increase in SARS-CoV-2 antibody levels.Further studies are required to improve care and therapeutics for patients with CHB who contracted COVID-19.展开更多
Background and aims:Primary sclerosing cholangitis(PSC)is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options.The mechanisms underlying the development and progr...Background and aims:Primary sclerosing cholangitis(PSC)is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options.The mechanisms underlying the development and progression of PSCs remain unclear.Liver X receptor beta(LXR-β)is recognized to modulate lipid metabolism and immune response,but its specific involvement in the PSC has not been elucidated.Here,we explored the role and mechanism of LXR-βin PSC induced by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine(DDC).Methods:CRISPR-Cas9 technology was applied to generate Abcb4(coding MDR2,next named as Mdr2),Nr1h2(coding LXR-β,next named as Lxrβ),and Rag2(coding RAG2)knockout mice.DDC was used to induce PSC.Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis.Flow cytometry was used to observe immune cell subsets.Results:We observed a declining trend in hepatic Lxrβin the PSC model.Unexpectedly,Lxrβknockout failed to modulate DDC-induced PSC pathogenesis.Concomitantly,assessment of the influence of Rag2 deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the Rag2^(−/−)DDC mice.However,Lxrβdepletion intensified DDC-induced PSC in the Rag2^(−/−)mice,with more abundant infiltrative inflammatory cells and more severe liver fibrosis.Compared with Rag2^(−/−)DDC mice,Lxrβ^(−/−)Rag2^(−/−)DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes.Flow cytometry showed that LXR-βdeficiency resulted in a diminished population of hepatic innate immune cells.Conclusion:This study indicated innate immune cell LXR-βdeficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-βmay regulate the function of innate immunity in the fibrotic advancement of PSC.展开更多
Extracellular vesicles(EVs)are membrane-bound entities secreted by each cell,categorized as,exosomes,microvesicles or apoptotic bodies based on their size and biogenesis.They serve as promising vectors for drug delive...Extracellular vesicles(EVs)are membrane-bound entities secreted by each cell,categorized as,exosomes,microvesicles or apoptotic bodies based on their size and biogenesis.They serve as promising vectors for drug delivery due to their capacity to carry diverse molecular signatures reflective of their cell of origin.EV research has significantly advanced since their serendipitous discovery,with recent studies focusing on their roles in various diseases and their potential for targeted therapy.In liver diseases,EVs are particularly promising for precision medicine,providing diagnostic and therapeutic potential in conditions such as metabolic dysfunction-associated steatotic liver disease and metabolic dysfunctionassociated steatohepatitis,hepatocellular carcinoma,alcoholic liver disease,liver fibrosis,and acute liver failure.Despite challenges in isolation and characterization,engineered EVs have shown efficacy in delivering therapeutic agents with improved targeting and reduced side effects.As research progresses,EVs hold great promise to revolutionize precision medicine in liver diseases,offering targeted,efficient,and versatile therapeutic options.In this review,we summarize various techniques for loading EVs with therapeutic cargo including both passive and active methods,and the potential of bioengineered EVs loaded with various molecules,such as miRNAs,proteins,and anti-inflammatory drugs in ameliorating clinical pathologies of liver diseases.展开更多
The prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has rapidly increased world-wide to 30%,with increasing of type 2 diabetes(T2D)and obesity in last two decades.The spectrum of MASLD cov...The prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has rapidly increased world-wide to 30%,with increasing of type 2 diabetes(T2D)and obesity in last two decades.The spectrum of MASLD covers from simple hepatic steatosis to the progressive metabolic dysfunctionassociated steatohepatitis(MASH)with or without fibrosis,cirrhosis and hepatocellular carcinoma.The MASLD symptoms include dyslipidemia,hyperglycemia,insulin resistance and obesity,the liver manifestations of metabolic syndrome.Treatment option for MASH fibrosis is limited.Since the discovery of bile acids as the endogenous ligands of farnesoid X receptor(FXR)in early 1990,bile acid and FXR based-drug therapies have been developed and tested in clinical trials for cholestatic liver diseases and MASH fibrosis.However,many of these drugs have unwanted side-effects and moderate efficacy in improving fibrosis.The US Food and Drug Administration has not approved any of bile acid-and FXRbased drugs for MASH fibrosis.Drug therapies alternative to bile acid derivatives for MASH have been in clinical trials.Recently,resmetirom,a liver-specific-and thyroid hormone receptor beta-selective agonist has been approved for MASH fibrosis.Glucagon-like peptide-1 receptor agonists also are in clinical trials for MASH.This review covers recent development of novel drug therapies for MASH fibrosis,T2D and obesity.展开更多
Liver,as a predominant digestive and metabolic organ,orchestrates systemic homeostasis.Intricate functions and reactions are facilitated by heterogeneous liver cells across spatial compartments,developmental stages,an...Liver,as a predominant digestive and metabolic organ,orchestrates systemic homeostasis.Intricate functions and reactions are facilitated by heterogeneous liver cells across spatial compartments,developmental stages,and ages.Such spatiotemporal dynamics remain crucial characteristics in liver biology and pathology,leading to challenges in conducting liver studies but also inspiring novel solutions.展开更多
Non-coding RNAs(ncRNAs),encompassing microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),have emerged as critical regulators of gene expression and cellular function.In alcohol-associated liver...Non-coding RNAs(ncRNAs),encompassing microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),have emerged as critical regulators of gene expression and cellular function.In alcohol-associated liver disease(ALD),chronic alcohol consumption disrupts the expression and function of ncRNAs in the liver and circulation,contributing to the disease's pathogenesis and progression.Dysregulated ncRNAs influence key pathways involved in hepatocyte injury,lipid metabolism,inflammation,and hepatic stellate cell(HSC)activation,thereby exacerbating steatosis,inflammation,and fibrosis.Furthermore,extracellular vesicles play a pivotal role in mediating ncRNA-driven intercellular communication,amplifying liver damage and fibrosis.This review provides a comprehensive overview of the multifaceted roles of ncRNAs in ALD,with a focus on their mechanistic contributions to disease development and progression.Additionally,we discuss the potential of ncRNAs as diagnostic biomarkers and therapeutic targets,emphasizing their translational relevance in addressing the burden of ALD.展开更多
Declaration of competing interest statement was not included in the published version.The appropriate declaration of competing interest statement,provided by the authors,is included below.Declaration of competing inte...Declaration of competing interest statement was not included in the published version.The appropriate declaration of competing interest statement,provided by the authors,is included below.Declaration of competing interest:The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jiahua Jin,Liqin Ding,and Biye Wang are employed by the Shanghai Zhonghua Pharmaceutical Co.,Ltd.展开更多
Background and aims:Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors(ICIs)to increased allograft rejection risk after liver transplantation(LT),a lack of comparative studies to d...Background and aims:Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors(ICIs)to increased allograft rejection risk after liver transplantation(LT),a lack of comparative studies to definitively establish the correlation between ICI exposure and adverse short-term outcomes after LT exists.This study aimed to analyze the impact of preoperative ICI exposure on short-term post-LT prognosis and allograft rejection risk.Methods:This retrospective cohort study included 121 recipients who underwent LT for hepatocellular carcinoma(HCC)between June 2019 and March 2023.The recipients were categorized into ICI(n=35)and non-ICI(n^(+)86)exposure groups based on pretransplant ICI exposure.Demographics,clinical characteristics,and short-term outcomes were compared between the cohorts.Kaplan-Meier analysis evaluated the impact of ICI exposure on graft survival.Univariate and multivariate logistic regression models assessed the impact of patient characteristics on allograft rejection.Results:Recipients with or without ICI exposure exhibited comparable demographic baseline charac-teristics.The incidences of early allograft dysfunction and biliary and vascular complications were similar between both groups.Post-transplant infection incidence was 37.1%and 20.9%in the ICI and non-ICI groups,respectively(P=0.064).Allograft rejection rates were significantly higher in the ICI group than in the non-ICI group(22.9%vs.5.8%,P=0.015).The ICI group exhibited a higher 90-day post-transplant mortality rate than that of the non-ICI group(14.3%vs.2.3%,P=0.034).Logistic regression analyses demonstrated that allograft rejection independently correlated with 90-day post-transplant mortality,with ICI exposure being an independent risk factor for allograft rejection.In recipients with ICI exposure,a shorter interval between ICIs and LT(washout period)was significantly associated with a higher allograft rejection risk,with the optimal washout period identified as 21 days for predicting 90-day rejection-free survival(P=0.0001).Moreover,in recipients with allograft rejection,the peripheral CD4^(+)/CD8^(+)T cell ratio was much lower in the ICI group than in the non-ICI group.Conclusions:Pretransplant ICI exposure was an independent risk factor for allograft rejection and was significantly associated with 90-day post-transplant mortality after LT for HCC.A-21-day washout period was significantly associated with allograft rejection.Future multicenter studies with larger cohorts and prospective designs are essential to validate these findings,confirm causality,and establish standardized clinical guidelines for ICI use before transplantation.展开更多
Hepatocellular carcinoma(HCC),commonly known as primary liver cancer,is a leading cause of cancerrelated mortality worldwide,primarily attributed to changing lifestyles and dietary habits.HCC arises from liver cirrhos...Hepatocellular carcinoma(HCC),commonly known as primary liver cancer,is a leading cause of cancerrelated mortality worldwide,primarily attributed to changing lifestyles and dietary habits.HCC arises from liver cirrhosis,hepatic fibrosis,or hepatitis B virus infection,and is caused by disruptions in protein and lipid metabolism.These metabolic alterations,recognized as a hallmark of cancer,are pivotal in the progression of chronic liver disease to HCC.Due to its asymptomatic nature in early stages,HCC is often diagnosed at advanced stages when treatment options are limited.Despite being a potentially curative option,liver transplantation remains hindered by high costs and donor scarcity,further compounded by suboptimal long-term success rates.This review examines the critical metabolites that play a part in developing HCC,focusing on their roles as possible biomarkers for disease progression and therapeutic targets.Additionally,the influence of the gut microbiome on HCC development is discussed,highlighting its interplay with metabolic pathways.Understanding the roles of metabolites and the gut microbiome in HCC progression underscores the importance of their potential use in early detection and the development of targeted therapies,offering new avenues for improving patient outcomes.展开更多
Lactic acidosis is a hallmark of the tumor microenvironment(TME)and a critical impediment to the efficacy of transarterial chemoembolization(TACE)in hepatocellular carcinoma(HCC).Incomplete embolization preserves viab...Lactic acidosis is a hallmark of the tumor microenvironment(TME)and a critical impediment to the efficacy of transarterial chemoembolization(TACE)in hepatocellular carcinoma(HCC).Incomplete embolization preserves viable tumor cells that amplify hypoxia-driven glycolysis,generating a lactic acid-rich milieu that drives treatment resistance,skews immune populations toward immunosuppressive phenotypes,and impairs cytotoxic T lymphocyte function.In this review,we elucidate the pathways through which lactic acidosis compromises TACE efficacy and propose novel strategies for its mitigation.We examine emerging approaches,including systemic or intra-arterial alkalization,targeted inhibition of lactate production and export,and calcium carbonate nanoparticles,and evaluate their respective merits and limitations.Finally,we propose a combination regimen of calcium carbonate nanoparticles,lactate-targeting agents,and TACE to achieve precise drug delivery,synergistic lactic acid depletion,and enhanced antitumor immunity.These integrated strategies have the potential to convert immunologically“cold”HCC lesions into“hot”ones,thereby improving TACE outcomes and disease control.展开更多
Background and aims:Hepatocellular carcinoma(HCC)is a leading cause of cancer-related mortality worldwide,and its etiology involves a complex interplay of genetic and environmental factors.Despite advancements in our ...Background and aims:Hepatocellular carcinoma(HCC)is a leading cause of cancer-related mortality worldwide,and its etiology involves a complex interplay of genetic and environmental factors.Despite advancements in our understanding of HCC biology and the development of novel therapeutic strategies,the molecularmechanisms underlying its onset,progression,and resistance to therapy remain largely vague.This study aimed to investigate the role ofmechanosensitive ion channel-related genes(MICRGs)in HCC,focusing on their potential as prognostic biomarkers and their involvement in immunemodulation and drug resistance.Methods:A comprehensive analysis was conducted using The Cancer Genome Atlas database to identify MICRGs that are upregulated in HCC.Gene expression profiling,bioinformatics tools,and functional experiments were employed to elucidate the role of these channels.In addition,proteineprotein interaction(PPI)network analyses and enrichment analyses were performed to explore the biological significance of these genes.An immune cell infiltration analysis was also conducted to understand MICRG-related immune landscape.Single-cell RNA sequencing(scRNA-seq)data were utilized to identify MICRGs in different cell types within the HCC tissue.Deep-learning neural network analysis across patient cohorts was conducted to identify genes associated with sorafenib resistance.Knockdown experiments,cell viability assays,and apoptosis assays on HCC cell lines were performed to examine the role of Piezo-type mechanosensitive ion channel component 1(PIEZO1)in sorafenib resistance.Results:The analysis identified a subset of MICRGs,including PIEZO1,thatwere significantly upregulated in HCC and associated with poor prognosis.The PPI network analysis revealed complex interactions among these genes.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses proposed the involvement of these genes in calcium signaling pathways.Immune cell infiltration analysis demonstrated distinct associations between MICRGs and various immune subpopulations,highlighting their potential roles in immune modulation.scRNA-seq data indicated the upregulation of MICRGs in various cell types in HCC tissues,particularly in endothelial cells and tumor-associated macrophages.Deeplearning neural network analysis across different patient cohorts identified PIEZO1 as a crucial regulator of sorafenib resistance in HCC,which was further validated by functional assays on HCC cell lines.Conclusions:This study provides evidence that MICRGs,particularly PIEZO1,take on crucial roles in HCC progression and drug resistance.The upregulation of PIEZO1 in HCC cells is associated with poor prognosis and resistance to sorafenib.These findings indicate that PIEZO1 could serve as a potential therapeutic target for overcoming drug resistance and a prognostic biomarker in HCC.Future studies should focus on validating these findings in larger patient cohorts and exploring the functional implications of targeting PIEZO1 in preclinical models.展开更多
Females experience adverse drug reactions at approximately twice the rate of males,contributing to drug-related morbidity and mortality in the United States.This disparity has been strongly associated with sex-based d...Females experience adverse drug reactions at approximately twice the rate of males,contributing to drug-related morbidity and mortality in the United States.This disparity has been strongly associated with sex-based differences in pharmacokinetics.Hepatic drug-metabolizing enzymes and transporters,key regulators of pharmacokinetics,exhibit notable sex-based differences in expression and/or activity.However,findings on the sex-specific impacts of these enzymes and transporters are often scattered,highlighting the need for a comprehensive and up-to-date overview of knowledge in this area.This review compiles and analyzes existing data on sex differences in the expression and activity of clinically relevant hepatic drug-metabolizing enzymes and transporters across species,such as cytochrome P450s,UDP-glucuronosyltransferase,carboxylesterases,P-glycoprotein,breast cancer resistance protein,multidrug resistance-associated protein,organic anion-transporting polypeptides and organic cation transporters.It also summarizes how these differences influence clinical pharmacokinetics,adverse drug reactions,and drug dosing regimens.Furthermore,we explore potential underlying mechanisms,including the influence of sex hormones,sex chromosomes and lifestyle-related factors.Lastly,we discuss clinical implications and future directions in the field,highlighting the urgent need for more human-centered research to clarify the sex-specific impact on drug metabolism and transport in human.Such effort will support the development of sex-informed pharmacotherapy strategies that ultimately reduce adverse drug reactions and improve therapeutic outcomes for patients.展开更多
Both cold stress and ischemia-reperfusion injury significantly contribute to poor prognosis after liver transplantation(LT).However,limited animal models incorporating both stimuli hinder the advancement of transplant...Both cold stress and ischemia-reperfusion injury significantly contribute to poor prognosis after liver transplantation(LT).However,limited animal models incorporating both stimuli hinder the advancement of transplant-related research.Here,a simplified and reproducible isolated perfused liver model is established to simulate the stresses experienced by livers maximally during transplantation.We provide a detailed protocol for a straightforward technique that requires 20e30 min for harvesting,24e48 h for static cold storage(SCS),and 2 h for normothermic machine perfusion(NMP)to induce LT-like stresses in the liver.Hepatic injury from SCS and NMP(LT-like stresses)is evaluated using three types of parameters.The pH values and hepatic enzyme levels of cold preservation solutions and perfusate serve as dynamic indicators of hepatic injury.Bile production and portal venous resistance directly reflect liver function,whereas pathological analysis visually illustrates the location and extent of injury.This animal model eliminates the influence of hemodynamic and immune factors,yielding highly reproducible results,and is strongly recommended as a standardized animal model for inducing LT-like stresses.展开更多
Background and aims:Early and accurate diagnosis of the coexistence of Wilson’s disease(WD)and chronic hepatitis B(CHB)presents a significant challenge for clinicians.The objective of this study was to retrospectivel...Background and aims:Early and accurate diagnosis of the coexistence of Wilson’s disease(WD)and chronic hepatitis B(CHB)presents a significant challenge for clinicians.The objective of this study was to retrospectively analyse the characteristics of such patients to improve clinical practice and provide a reference for clinical management.Methods:From January 2011 to December 2022,35 patients with concurrent CHB and WD(CHB+WD group)were identified.A total of 127 patients with CHB(CHB group)and 168 patients with WD(WD group)were included in the control group between January 2016 and December 2021.Propensity score matching(PSM)was performed to balance the baseline values between groups.The KaplaneMeier(KeM)survival analysis and log-rank test were performed to compare the prognoses.Results:In the cohort of 35 patients with concurrent CHB and WD,74.3%of patients(26 patients)faced a substantial delay of up to 10 years(range:0e40 years)in WD diagnosis following their CHB diagnosis.Twenty-three(65.7%)patients had cirrhosis at the time of WD diagnosis,and 26(74.3%)patients experienced liver failure.The levels of serum copper and uric acid were lower in patients in the CHB+WD group than in those in the CHB group.Patients in the CHB+WD group presented higher alanine transaminase and total bile acid levels compared to those in the WD group.KeM survival analysis indicated that patients with CHB and WD had poorer outcomes than those with CHB alone;however,the outcomes were similar to those of individuals with WD alone.The optimal cut-point of serum ceruloplasmin(CP)in identifying WD in CHB patients was 0.10 g/L before PSM and after PSM.Conclusions:The present study emphasizes the importance of clinicians being vigilant for concurrent CHB and WD diagnoses,as delays in WD diagnosis may adversely affect patient outcomes.CHB patients with serum CP below 0.10 g/L are highly recommended to screen for WD.展开更多
文摘The authors regret that an error has been identified in Fig.5 of this original article.Specifically,the representative image of BDL group was incorrectly selected during figure assembly.The corrected version of Fig.5 is shown below.This correction does not affect the overall results,interpretations,and conclusions of the study.
基金supported by the National Natural Science Foundation of China(No.30972445)the Natural Science Foundation of Shanxi Province of China(No.202203021211231).
文摘Background and aims:Hepatocellular carcinoma(HCC)is a malignant tumor with a high mortality rate,but there are still no effective treatments.The aim of this study was to investigate the anticancer potential of the combined use of brefeldin A(BFA)and tunicamycin(TM)in HepG2 cells,as well as the underlying mechanisms.Methods:HepG2 cells were treated with different concentrations of BFA(0.1e2.5 mg/L)and TM(1 e5 mg/L)for 24 h.DMSO(0.1%,v/v)was used as a vehicle control.Cell viability and cell migration were measured using MTT assay and scratch wound assay,respectively.Apoptosis was detected using flow cytometry and acridine orange(AO)staining.The protein and mRNA levels of various factors involved in apoptosis(poly(ADP-ribose)polymerase-1(PARP-1),caspase-12,caspase-3,and stearoyl-CoA desaturase 1)and endoplasmic reticulum(ER)stress(binding immunoglobulin protein(BiP),protein kinase R-like endoplasmic reticulum kinase(PERK),p-PERK,phosphorylation of eukaryotic translation initiation factor 2alpha(p-eIF2a),activating transcription factor(ATF)4,and C/EBP homologous protein(CHOP))were measured using Western blotting and qRT-PCR,respectively.Results:Both BFA and TM alone significantly reduced the viability of HepG2 cells in a dose-dependent way.The co-incubation with TM(1 mg/L)further significantly reduced the viability of HepG2 cells treated with BFA(0.25 mg/L)alone(P<0.05).BFA significantly increased the protein and mRNA levels of caspase-3 and PARP-1(P<0.05)compared to control and DMSO-treated cells,indicating that BFA induced apoptosis in HepG2 cells by increasing the expression of caspase-3 and PARP-1.The induction of apoptosis by BFA could be further significantly enhanced by co-incubation with TM.In addition,BFA significantly increased the mRNA levels of BiP,PERK and ATF4(P<0.05)compared to control and DMSOtreated cells.After co-incubation of BFA and TM,the protein levels of BiP,p-PERK,p-eIF2a and CHOP were significantly increased,indicating that TM could enhance BFA-induced ER stress in HepG2 cells through the PERK-eIF2a-ATF4-CHOP pathway.Conclusions:BFA could induce apoptosis and ER stress,and TM could enhance the ability of BFA to induce apoptosis and ER stress in HepG2 cells through the PERK-eIF2ɑ-ATF4-CHOP pathway.The findings highlight the therapeutic potential of the combined use of BFA and TM in treating HCC.
基金supported by the National Natural Science Foundation of China(No.82370582 to Xiaoni Kong)The YangFan project from the Science and Technology Commission of Shanghai Municipality(No.22YF1449600 to Jiacheng Lin)State Administration of Traditional Chinese Medicine High-level Key Disciplines Program(No.ZYYZDXK-2023060)。
文摘Background and aims:Metabolic dysfunction-associated fatty liver disease(MAFLD)is a common chronic condition that can lead to cancer due to its complex pathogenesis.Therapeutic agents targeting AMPactivated protein kinase(AMPK)activation have been suggested as potential treatments for metabolic disorders such as metabolic dysfunction-associated steatohepatitis(MASH).Rhizoma Atractylodis Macrocephalae(RAM)has been clinically used to treat obesity-related health problems,but its therapeutic effects on MAFLD and the underlying mechanism remain unclear.Therefore,this study was conducted to evaluate the function and underlying mechanism of RAM in the treatment of MAFLD.Methods:The effect of RAM decoction on MAFLD was evaluated using a high-fat diet(HFD)-induced MAFLD mouse model.In vitro studies were conducted using a palmitic acid/oleic acid-induced lipid accumulation model in the alpha mouse liver 12 cells and RAM-containing serum.The underlying mechanisms were elucidated through a combination of network pharmacology analysis,immunohistochemistry,western blotting,and polymerase chain reaction analysis.Results:Administration of RAM decoction significantly reduced body weight gain in MAFLD mice without changing food intake.The weights of the liver and inguinal adipose tissues were also reduced after RAM treatment.Additionally,RAM administration decreased serum levels of alanine aminotransferase,aspartate transaminase,total cholesterol,triglyceride,low-density lipoprotein cholesterol,and glucose,while reducing lipid droplet accumulation in the liver tissues of MAFLD mice.The underlying mechanisms included the activation of the phosphorylation of AMPK and acetyl-CoA carboxylase(ACC),and inhibition of the expression of sterol regulatory element binding protein 1(SREBP1).However,RAM did not alter the protein expression levels of peroxisome proliferator-activated receptor a and carnitine palmitoyltransferase-1a.Furthermore,the RAM-induced upregulation of phosphorylated AMPK,phosphorylated ACC,and SREBP1 expression,as well as the downregulation of fatty acid synthase expression,were reversed by using an AMPK inhibitor.Conclusions:Through a combination of network pharmacology and experimental validation,we demonstrated that RAM may exert therapeutic effects on MAFLD by inhibiting lipid synthesis and activating phosphorylated AMPK pathways.
基金supported by Howard University Center for Women,Gender and Global Leadership(HUCWGGL)Summer Research grant 2022 to Dr.Padmamalini Baskaran.
文摘Dear Editor,Metabolic dysfunction-associated steatotic liver disease(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD),has emerged as the most prevalent chronic liver condition globally,affecting nearly 100 million individuals in the United States alone.1 The recent reclassification of NAFLD to MASLD and non-alcoholic steatohepatitis(NASH)to metabolic dysfunctionassociated steatohepatitis(MASH)reflects a paradigm shift in understanding the metabolic underpinnings of this disease.
基金supported in part by the National Natural Science Foundation of China(No.82270697 to Yun-Wen Zheng)the Science and Technology Planning Project of Guangdong Province of China(No.2021B1212040016 to Yun-Wen Zheng)+3 种基金the Guangdong Basic and Applied Basic Research Foundation(No.2023A1515012574 to Yun-Wen Zheng)the Jiangsu Provincial Med〓〓ical Key Discipline Cultivation Unit(No.JSDW202229 to Yun-Wen Zheng)Haihe Laboratory of Cell Ecosystem Innovation Fund(No.HH24KYZX0008 to Yun-Wen Zheng)the Student Research Project of Jiangsu University(No.23A189 to Xiang-Long Huang).
文摘Dear Editor,Liver diseases,as a significant global health issue,are characterized by complex and diverse pathogenic mechanisms.In recent years,the rapid development of biotechnology,particularly advancements in single-cell omics,genomics,and metabolomics,has led to significant improvements in the early diagnosis,treatment,and regeneration research of liver diseases.
基金supported by Noncommunicable Chronic Disease-National Science and Technology Major Project of China(No.2023ZD0508700).
文摘Dear Editor,The liver is a vital organ that plays a crucial role in metabolism,detoxification,and immune defense.However,modern lifestyles characterized by an unhealthy diet,lack of exercise,excessive alcohol consumption,and hepatitis viral infections are significant threats to liver health of the Chinese population.In response,China initiated the National Protect Liver Day in 2001,which is observed annually on March 18.
文摘Background and aims:Clinical data regarding patients with chronic hepatitis B(CHB)after Omicron BA.5 infection are currently limited.This study aimed to assess the clinical characteristics of patients with CHB and Omicron BA.5 infection in South China.Methods:This retrospective study was conducted from January to March 2023 in a cohort of 485 healthy individuals and 553 patients with CHB.Clinical features,encompassing COVID-19-related symptoms,levels of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)antibodies,vaccination status,liver functions,and virological markers of hepatitis B virus(HBV)infection were measured.Results:COVID-19-related symptom patterns were similar in both groups,except for fever,which was notably less prevalent(85.4%vs.90.4%,P?0.047)among patients with CHB who experienced a significantly shorter duration of fever(median 2.2(25the75th percentile,1.0e3.0)days vs.2.3(1.0e3.0)days,P=0.048)and a shorter time for symptom relief(9.2(5.0e14.0)vs.11.1(5.0e14.0)days,P=0.015).The levels of SARS-CoV-2 antibodies were comparable between the two groups but increased after booster vaccinations.In patients with CHB,globulin(GLB)and hepatitis B envelope antibody levels were significantly increased after Omicron BA.5 infection,regardless of nucleos(t)ide analog regimens comparing entecavir(ETV)with tenofovir(TFV).Patients with CHB treated with TFV had significantly higher levels of SARS-CoV-2 antibodies than those treated with ETV(1065.1(346.9e1188.5)COI vs.765.5(24.5e1119.1)COI,P=0.025).Conclusions:No significant exacerbation of COVID-19 symptoms was observed in conjunction with the efficacy of COVID-19 booster vaccinations.There were no notable alterations in liver functions except for GLB.HBV reactivation,as evidenced by increased HBV DNA,was observed among patients with CHB after Omicron BA.5 infection.These changes were not affected by ETV versus TFV administration;however,TFV resulted in a significant increase in SARS-CoV-2 antibody levels.Further studies are required to improve care and therapeutics for patients with CHB who contracted COVID-19.
基金supported by the National Natural Science Foundation of China(No.82370555 to Jun Xu,and No.82370537 and No.82341228 to Yulan Liu)the Capital Health Research and Development of Special(No.CFH2024-1-4081 to Yulan Liu,and No.CFH2024-4-4089 to Jun Xu)+1 种基金the Beijing Municipal Natural Science Foundation(No.7232196 to Yulan Liu)Peking University People's Hospital Scientific Research Development Funds(No.RDJP2023-22 to Jun Xu and No.RDGS2024-02 to Shan Cao).
文摘Background and aims:Primary sclerosing cholangitis(PSC)is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options.The mechanisms underlying the development and progression of PSCs remain unclear.Liver X receptor beta(LXR-β)is recognized to modulate lipid metabolism and immune response,but its specific involvement in the PSC has not been elucidated.Here,we explored the role and mechanism of LXR-βin PSC induced by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine(DDC).Methods:CRISPR-Cas9 technology was applied to generate Abcb4(coding MDR2,next named as Mdr2),Nr1h2(coding LXR-β,next named as Lxrβ),and Rag2(coding RAG2)knockout mice.DDC was used to induce PSC.Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis.Flow cytometry was used to observe immune cell subsets.Results:We observed a declining trend in hepatic Lxrβin the PSC model.Unexpectedly,Lxrβknockout failed to modulate DDC-induced PSC pathogenesis.Concomitantly,assessment of the influence of Rag2 deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the Rag2^(−/−)DDC mice.However,Lxrβdepletion intensified DDC-induced PSC in the Rag2^(−/−)mice,with more abundant infiltrative inflammatory cells and more severe liver fibrosis.Compared with Rag2^(−/−)DDC mice,Lxrβ^(−/−)Rag2^(−/−)DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes.Flow cytometry showed that LXR-βdeficiency resulted in a diminished population of hepatic innate immune cells.Conclusion:This study indicated innate immune cell LXR-βdeficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-βmay regulate the function of innate immunity in the fibrotic advancement of PSC.
文摘Extracellular vesicles(EVs)are membrane-bound entities secreted by each cell,categorized as,exosomes,microvesicles or apoptotic bodies based on their size and biogenesis.They serve as promising vectors for drug delivery due to their capacity to carry diverse molecular signatures reflective of their cell of origin.EV research has significantly advanced since their serendipitous discovery,with recent studies focusing on their roles in various diseases and their potential for targeted therapy.In liver diseases,EVs are particularly promising for precision medicine,providing diagnostic and therapeutic potential in conditions such as metabolic dysfunction-associated steatotic liver disease and metabolic dysfunctionassociated steatohepatitis,hepatocellular carcinoma,alcoholic liver disease,liver fibrosis,and acute liver failure.Despite challenges in isolation and characterization,engineered EVs have shown efficacy in delivering therapeutic agents with improved targeting and reduced side effects.As research progresses,EVs hold great promise to revolutionize precision medicine in liver diseases,offering targeted,efficient,and versatile therapeutic options.In this review,we summarize various techniques for loading EVs with therapeutic cargo including both passive and active methods,and the potential of bioengineered EVs loaded with various molecules,such as miRNAs,proteins,and anti-inflammatory drugs in ameliorating clinical pathologies of liver diseases.
基金supported by National Institutes of Health(NIH)grants DK44442 and DK58379.
文摘The prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has rapidly increased world-wide to 30%,with increasing of type 2 diabetes(T2D)and obesity in last two decades.The spectrum of MASLD covers from simple hepatic steatosis to the progressive metabolic dysfunctionassociated steatohepatitis(MASH)with or without fibrosis,cirrhosis and hepatocellular carcinoma.The MASLD symptoms include dyslipidemia,hyperglycemia,insulin resistance and obesity,the liver manifestations of metabolic syndrome.Treatment option for MASH fibrosis is limited.Since the discovery of bile acids as the endogenous ligands of farnesoid X receptor(FXR)in early 1990,bile acid and FXR based-drug therapies have been developed and tested in clinical trials for cholestatic liver diseases and MASH fibrosis.However,many of these drugs have unwanted side-effects and moderate efficacy in improving fibrosis.The US Food and Drug Administration has not approved any of bile acid-and FXRbased drugs for MASH fibrosis.Drug therapies alternative to bile acid derivatives for MASH have been in clinical trials.Recently,resmetirom,a liver-specific-and thyroid hormone receptor beta-selective agonist has been approved for MASH fibrosis.Glucagon-like peptide-1 receptor agonists also are in clinical trials for MASH.This review covers recent development of novel drug therapies for MASH fibrosis,T2D and obesity.
基金funded by National Natural Science Foundation of China(82300730)Changzhou Science and Technology Bureau of China(CJ20241116).
文摘Liver,as a predominant digestive and metabolic organ,orchestrates systemic homeostasis.Intricate functions and reactions are facilitated by heterogeneous liver cells across spatial compartments,developmental stages,and ages.Such spatiotemporal dynamics remain crucial characteristics in liver biology and pathology,leading to challenges in conducting liver studies but also inspiring novel solutions.
基金supported by the National Key Research and Development Program of China(No.2022YFC2304800 to Ge Zeng)NIH K99AA031067,the CSCTR Early Career Development Award,and Indiana Clinical and Translational Sciences Institute grant UM1TR004402(in part to Jing Ma)+3 种基金the National Institutes of Health(NIH R01AA030993 to Zhihong Yang)the American Liver Foundation Postdoctoral Award(in part to Themis Thoudam)NIH grant R01AA030312,Department of Veterans Affairs Merit Awards 1I01CX000361 and I01BX006202the Indiana University School of Medicine Dean's Scholar Award(in part to Suthat Liangpunsakul)。
文摘Non-coding RNAs(ncRNAs),encompassing microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),have emerged as critical regulators of gene expression and cellular function.In alcohol-associated liver disease(ALD),chronic alcohol consumption disrupts the expression and function of ncRNAs in the liver and circulation,contributing to the disease's pathogenesis and progression.Dysregulated ncRNAs influence key pathways involved in hepatocyte injury,lipid metabolism,inflammation,and hepatic stellate cell(HSC)activation,thereby exacerbating steatosis,inflammation,and fibrosis.Furthermore,extracellular vesicles play a pivotal role in mediating ncRNA-driven intercellular communication,amplifying liver damage and fibrosis.This review provides a comprehensive overview of the multifaceted roles of ncRNAs in ALD,with a focus on their mechanistic contributions to disease development and progression.Additionally,we discuss the potential of ncRNAs as diagnostic biomarkers and therapeutic targets,emphasizing their translational relevance in addressing the burden of ALD.
文摘Declaration of competing interest statement was not included in the published version.The appropriate declaration of competing interest statement,provided by the authors,is included below.Declaration of competing interest:The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jiahua Jin,Liqin Ding,and Biye Wang are employed by the Shanghai Zhonghua Pharmaceutical Co.,Ltd.
基金supported by the National Natural Science Foundation of China(No.82472903,82203747,82173229,and 82173195)Guangzhou Key Laboratory of Precise Diagnosis and Treatment of Biliary Tract Cancer(No.202201020375)+4 种基金China Postdoctoral Science Foundation(No.2022TQ0388 and 2023M734036)Science and Technology Program of Guangzhou(No.202102010326 and 2023A03J0700)Sun Yat-sen University Clinical Research 5010 Program(No.2018008)Sun Yat-sen Me〓〓morial Hospital Clinical Research 5010 Program(No.SYS-5010-202305)Sun Yat-sen Pilot Scientific Research Fund(SYSQH-II-2024-05).
文摘Background and aims:Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors(ICIs)to increased allograft rejection risk after liver transplantation(LT),a lack of comparative studies to definitively establish the correlation between ICI exposure and adverse short-term outcomes after LT exists.This study aimed to analyze the impact of preoperative ICI exposure on short-term post-LT prognosis and allograft rejection risk.Methods:This retrospective cohort study included 121 recipients who underwent LT for hepatocellular carcinoma(HCC)between June 2019 and March 2023.The recipients were categorized into ICI(n=35)and non-ICI(n^(+)86)exposure groups based on pretransplant ICI exposure.Demographics,clinical characteristics,and short-term outcomes were compared between the cohorts.Kaplan-Meier analysis evaluated the impact of ICI exposure on graft survival.Univariate and multivariate logistic regression models assessed the impact of patient characteristics on allograft rejection.Results:Recipients with or without ICI exposure exhibited comparable demographic baseline charac-teristics.The incidences of early allograft dysfunction and biliary and vascular complications were similar between both groups.Post-transplant infection incidence was 37.1%and 20.9%in the ICI and non-ICI groups,respectively(P=0.064).Allograft rejection rates were significantly higher in the ICI group than in the non-ICI group(22.9%vs.5.8%,P=0.015).The ICI group exhibited a higher 90-day post-transplant mortality rate than that of the non-ICI group(14.3%vs.2.3%,P=0.034).Logistic regression analyses demonstrated that allograft rejection independently correlated with 90-day post-transplant mortality,with ICI exposure being an independent risk factor for allograft rejection.In recipients with ICI exposure,a shorter interval between ICIs and LT(washout period)was significantly associated with a higher allograft rejection risk,with the optimal washout period identified as 21 days for predicting 90-day rejection-free survival(P=0.0001).Moreover,in recipients with allograft rejection,the peripheral CD4^(+)/CD8^(+)T cell ratio was much lower in the ICI group than in the non-ICI group.Conclusions:Pretransplant ICI exposure was an independent risk factor for allograft rejection and was significantly associated with 90-day post-transplant mortality after LT for HCC.A-21-day washout period was significantly associated with allograft rejection.Future multicenter studies with larger cohorts and prospective designs are essential to validate these findings,confirm causality,and establish standardized clinical guidelines for ICI use before transplantation.
基金the Department of Science and Technology,Science and Engineering Research Board(DST-SERB),Government of India for direct financial assistance Grant No.EEQ/2020/000017 in the form of a Junior Research Fellow(JRF)DST-SERB for offering further financial assistance from Strat-up Research Grant(SRG)Grant no.SRG/2021/002312instrumental support from Empowerment and Equity Opportunities for Excellence in Science(EEQ)Grant No.EEQ/2022/000218.
文摘Hepatocellular carcinoma(HCC),commonly known as primary liver cancer,is a leading cause of cancerrelated mortality worldwide,primarily attributed to changing lifestyles and dietary habits.HCC arises from liver cirrhosis,hepatic fibrosis,or hepatitis B virus infection,and is caused by disruptions in protein and lipid metabolism.These metabolic alterations,recognized as a hallmark of cancer,are pivotal in the progression of chronic liver disease to HCC.Due to its asymptomatic nature in early stages,HCC is often diagnosed at advanced stages when treatment options are limited.Despite being a potentially curative option,liver transplantation remains hindered by high costs and donor scarcity,further compounded by suboptimal long-term success rates.This review examines the critical metabolites that play a part in developing HCC,focusing on their roles as possible biomarkers for disease progression and therapeutic targets.Additionally,the influence of the gut microbiome on HCC development is discussed,highlighting its interplay with metabolic pathways.Understanding the roles of metabolites and the gut microbiome in HCC progression underscores the importance of their potential use in early detection and the development of targeted therapies,offering new avenues for improving patient outcomes.
基金funded by Yunnan Province Science and Technology Talents and Platform Plan Project(No.202305AF150067)The scientific and technological innovation team building program of Yunnan Provincial Education Department(No.K1322149)+2 种基金Yunnan Province Talent Support Program(No.CZ0096-901264)Noncommunicable Chronic DiseasesNational Science and Technology Major Project(No.2025ZD0551500,2023ZD0501500)Start-up fund of Southeast University&the China Hepatitis Prevention and Treatment Foundation Wang Baoen Liver Fibrosis Research Fund(No.2025055).
文摘Lactic acidosis is a hallmark of the tumor microenvironment(TME)and a critical impediment to the efficacy of transarterial chemoembolization(TACE)in hepatocellular carcinoma(HCC).Incomplete embolization preserves viable tumor cells that amplify hypoxia-driven glycolysis,generating a lactic acid-rich milieu that drives treatment resistance,skews immune populations toward immunosuppressive phenotypes,and impairs cytotoxic T lymphocyte function.In this review,we elucidate the pathways through which lactic acidosis compromises TACE efficacy and propose novel strategies for its mitigation.We examine emerging approaches,including systemic or intra-arterial alkalization,targeted inhibition of lactate production and export,and calcium carbonate nanoparticles,and evaluate their respective merits and limitations.Finally,we propose a combination regimen of calcium carbonate nanoparticles,lactate-targeting agents,and TACE to achieve precise drug delivery,synergistic lactic acid depletion,and enhanced antitumor immunity.These integrated strategies have the potential to convert immunologically“cold”HCC lesions into“hot”ones,thereby improving TACE outcomes and disease control.
基金supported by the Natural Science Foundation of Guangdong Province,China(No.2023A1515012686 and No.2024A1515012988)Natural Science Foundation of China(No.82470904)+1 种基金Science and Technology Program of Guangzhou,China(No.202102010289)Fostering Fund of The Third Affiliated Hospital of Sun Yat-Sen University for NSFC Program(No.2022GZRPYMS01).
文摘Background and aims:Hepatocellular carcinoma(HCC)is a leading cause of cancer-related mortality worldwide,and its etiology involves a complex interplay of genetic and environmental factors.Despite advancements in our understanding of HCC biology and the development of novel therapeutic strategies,the molecularmechanisms underlying its onset,progression,and resistance to therapy remain largely vague.This study aimed to investigate the role ofmechanosensitive ion channel-related genes(MICRGs)in HCC,focusing on their potential as prognostic biomarkers and their involvement in immunemodulation and drug resistance.Methods:A comprehensive analysis was conducted using The Cancer Genome Atlas database to identify MICRGs that are upregulated in HCC.Gene expression profiling,bioinformatics tools,and functional experiments were employed to elucidate the role of these channels.In addition,proteineprotein interaction(PPI)network analyses and enrichment analyses were performed to explore the biological significance of these genes.An immune cell infiltration analysis was also conducted to understand MICRG-related immune landscape.Single-cell RNA sequencing(scRNA-seq)data were utilized to identify MICRGs in different cell types within the HCC tissue.Deep-learning neural network analysis across patient cohorts was conducted to identify genes associated with sorafenib resistance.Knockdown experiments,cell viability assays,and apoptosis assays on HCC cell lines were performed to examine the role of Piezo-type mechanosensitive ion channel component 1(PIEZO1)in sorafenib resistance.Results:The analysis identified a subset of MICRGs,including PIEZO1,thatwere significantly upregulated in HCC and associated with poor prognosis.The PPI network analysis revealed complex interactions among these genes.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses proposed the involvement of these genes in calcium signaling pathways.Immune cell infiltration analysis demonstrated distinct associations between MICRGs and various immune subpopulations,highlighting their potential roles in immune modulation.scRNA-seq data indicated the upregulation of MICRGs in various cell types in HCC tissues,particularly in endothelial cells and tumor-associated macrophages.Deeplearning neural network analysis across different patient cohorts identified PIEZO1 as a crucial regulator of sorafenib resistance in HCC,which was further validated by functional assays on HCC cell lines.Conclusions:This study provides evidence that MICRGs,particularly PIEZO1,take on crucial roles in HCC progression and drug resistance.The upregulation of PIEZO1 in HCC cells is associated with poor prognosis and resistance to sorafenib.These findings indicate that PIEZO1 could serve as a potential therapeutic target for overcoming drug resistance and a prognostic biomarker in HCC.Future studies should focus on validating these findings in larger patient cohorts and exploring the functional implications of targeting PIEZO1 in preclinical models.
文摘Females experience adverse drug reactions at approximately twice the rate of males,contributing to drug-related morbidity and mortality in the United States.This disparity has been strongly associated with sex-based differences in pharmacokinetics.Hepatic drug-metabolizing enzymes and transporters,key regulators of pharmacokinetics,exhibit notable sex-based differences in expression and/or activity.However,findings on the sex-specific impacts of these enzymes and transporters are often scattered,highlighting the need for a comprehensive and up-to-date overview of knowledge in this area.This review compiles and analyzes existing data on sex differences in the expression and activity of clinically relevant hepatic drug-metabolizing enzymes and transporters across species,such as cytochrome P450s,UDP-glucuronosyltransferase,carboxylesterases,P-glycoprotein,breast cancer resistance protein,multidrug resistance-associated protein,organic anion-transporting polypeptides and organic cation transporters.It also summarizes how these differences influence clinical pharmacokinetics,adverse drug reactions,and drug dosing regimens.Furthermore,we explore potential underlying mechanisms,including the influence of sex hormones,sex chromosomes and lifestyle-related factors.Lastly,we discuss clinical implications and future directions in the field,highlighting the urgent need for more human-centered research to clarify the sex-specific impact on drug metabolism and transport in human.Such effort will support the development of sex-informed pharmacotherapy strategies that ultimately reduce adverse drug reactions and improve therapeutic outcomes for patients.
基金supported by the National Natural Science Foundation of China(No.82400773,82400745,82370646)Young Talent Support Program of Henan Association for Science and Technology(No.2025HYTP083).
文摘Both cold stress and ischemia-reperfusion injury significantly contribute to poor prognosis after liver transplantation(LT).However,limited animal models incorporating both stimuli hinder the advancement of transplant-related research.Here,a simplified and reproducible isolated perfused liver model is established to simulate the stresses experienced by livers maximally during transplantation.We provide a detailed protocol for a straightforward technique that requires 20e30 min for harvesting,24e48 h for static cold storage(SCS),and 2 h for normothermic machine perfusion(NMP)to induce LT-like stresses in the liver.Hepatic injury from SCS and NMP(LT-like stresses)is evaluated using three types of parameters.The pH values and hepatic enzyme levels of cold preservation solutions and perfusate serve as dynamic indicators of hepatic injury.Bile production and portal venous resistance directly reflect liver function,whereas pathological analysis visually illustrates the location and extent of injury.This animal model eliminates the influence of hemodynamic and immune factors,yielding highly reproducible results,and is strongly recommended as a standardized animal model for inducing LT-like stresses.
基金supported by the Guangdong Key Field R&D plan(No.2019B020228001)5010 Project of Sun Yat-sen University(No.2018024)Guangdong Rural Science and Technology Program(No.KTPYJ2022012).
文摘Background and aims:Early and accurate diagnosis of the coexistence of Wilson’s disease(WD)and chronic hepatitis B(CHB)presents a significant challenge for clinicians.The objective of this study was to retrospectively analyse the characteristics of such patients to improve clinical practice and provide a reference for clinical management.Methods:From January 2011 to December 2022,35 patients with concurrent CHB and WD(CHB+WD group)were identified.A total of 127 patients with CHB(CHB group)and 168 patients with WD(WD group)were included in the control group between January 2016 and December 2021.Propensity score matching(PSM)was performed to balance the baseline values between groups.The KaplaneMeier(KeM)survival analysis and log-rank test were performed to compare the prognoses.Results:In the cohort of 35 patients with concurrent CHB and WD,74.3%of patients(26 patients)faced a substantial delay of up to 10 years(range:0e40 years)in WD diagnosis following their CHB diagnosis.Twenty-three(65.7%)patients had cirrhosis at the time of WD diagnosis,and 26(74.3%)patients experienced liver failure.The levels of serum copper and uric acid were lower in patients in the CHB+WD group than in those in the CHB group.Patients in the CHB+WD group presented higher alanine transaminase and total bile acid levels compared to those in the WD group.KeM survival analysis indicated that patients with CHB and WD had poorer outcomes than those with CHB alone;however,the outcomes were similar to those of individuals with WD alone.The optimal cut-point of serum ceruloplasmin(CP)in identifying WD in CHB patients was 0.10 g/L before PSM and after PSM.Conclusions:The present study emphasizes the importance of clinicians being vigilant for concurrent CHB and WD diagnoses,as delays in WD diagnosis may adversely affect patient outcomes.CHB patients with serum CP below 0.10 g/L are highly recommended to screen for WD.
