BACKGROUND Noninvasive methods have been developed to detect fibrosis in many liver diseases due to the limits of liver biopsy.However,previous studies have focused primarily on chronic viral hepatitis and nonalcoholi...BACKGROUND Noninvasive methods have been developed to detect fibrosis in many liver diseases due to the limits of liver biopsy.However,previous studies have focused primarily on chronic viral hepatitis and nonalcoholic fatty liver disease.The diagnostic value of transient elastography for autoimmune liver diseases(AILDs)is worth studying.AIM To compare the diagnostic accuracy of imaging techniques with serum biomarkers of fibrosis in AILD.METHODS The PubMed,Cochrane Library and EMBASE databases were searched.Studies evaluating the efficacy of noninvasive methods in the diagnosis of AILDs[autoimmune hepatitis(AIH),primary biliary cholangitis(PBC)and primary sclerosing cholangitis(PSC)]were included.The summary area under the receiver operating characteristic curve(AUROC),diagnostic odds ratio,sensitivity and specificity were used to assess the accuracy of these noninvasive methods for staging fibrosis.RESULTS A total of 60 articles were included in this study,and the number of patients with AIH,PBC and PSC was 1594,3126 and 501,respectively.The summary AUROC of transient elastography in the diagnosis of significant fibrosis,advanced fibrosis and cirrhosis in patients with AIH were 0.84,0.88 and 0.90,respectively,while those in patients with PBC were 0.93,0.93 and 0.91,respectively.The AUROC of cirrhosis for patients with PSC was 0.95.However,other noninvasive indices(aspartate aminotransferase to platelet ratio index,aspartate aminotransferase/alanine aminotransferase ratio,fibrosis-4 index)had corresponding AUROCs less than 0.80.CONCLUSION Transient elastography exerts better diagnostic accuracy in AILD patients,especially in PBC patients.The appropriate cutoff values for staging advanced fibrosis and cirrhosis ranged from 9.6 to 10.7 and 14.4 to 16.9 KPa for PBC patients.展开更多
The prevalence of non-alcoholic fatty liver disease(NAFLD) is rising exponentially worldwide. The spectrum of NAFLD includes non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver cirrhosis, and even hepatoce...The prevalence of non-alcoholic fatty liver disease(NAFLD) is rising exponentially worldwide. The spectrum of NAFLD includes non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver cirrhosis, and even hepatocellular carcinoma. Evidence shows that microbial metabolites play pivotal roles in the onset and progression of NAFLD. In this review, we discuss how microbederived metabolites, such as short-chain fatty acids, endogenous ethanol, bile acids and so forth, contribute to the pathogenesis of NAFLD.展开更多
BACKGROUND Serum amyloid A(SAA)is an acute phase protein mainly synthesized by the liver.SAA induces inflammatory phenotype and promotes cell proliferation in activated hepatic stellate cells,the major scar forming ce...BACKGROUND Serum amyloid A(SAA)is an acute phase protein mainly synthesized by the liver.SAA induces inflammatory phenotype and promotes cell proliferation in activated hepatic stellate cells,the major scar forming cells in the liver.However,few studies have reported on the serum levels of SAA in human liver disease and its clinical significance in various liver diseases.AIM To investigate the serum levels of SAA in patients with different liver diseases and analyze the factors associated with the alteration of SAA levels in chronic hepatitis B(CHB)patients.METHODS Two hundred and seventy-eight patients with different liver diseases and 117 healthy controls were included in this study.The patients included 205 with CHB,22 with active autoimmune liver disease(AILD),21 with nonalcoholic steatohepatitis(NASH),14 with drug-induced liver injury(DILI),and 16 with pyogenic liver abscess.Serum levels of SAA and other clinical parameters were collected for the analysis of the factors associated with SAA level.Mann-Whitney U test was used to compare the serum SAA levels of patients with various liver diseases with those of healthy controls.Bonferroni test was applied for post hoc comparisons to control the probability of type 1 error(alpha=0.05/6=0.008).For statistical tests of other variables,P<0.05 was considered statistically significant.Statistically significant factors determined by single factor analysis were further analyzed by binary multivariate logistic regression analysis.RESULTS All patients with active liver diseases had higher serum SAA levels than healthy controls and the inactive CHB patients,with the highest SAA level found in patients with pyogenic liver abscess(398.4±246.8 mg/L).Patients with active AILD(19.73±24.81 mg/L)or DILI(8.036±5.685 mg/L)showed higher SAA levels than those with active CHB(6.621±6.776 mg/L)and NASH(6.624±4.891 mg/L).Single(P<0.001)and multivariate logistic regression analyses(P=0.039)for the CHB patients suggested that patients with active CHB were associated with an SAA serum level higher than 6.4 mg/L.Serum levels of SAA and CRP(C-reactive protein)were positively correlated in patients with CHB(P<0.001),pyogenic liver abscess(P=0.045),and active AILD(P=0.02).Serum levels of SAA(0.80-871.0 mg/L)had a broader fluctuation range than CRP(0.30-271.3 mg/L).CONCLUSION Serum level of SAA is a sensitive biomarker for inflammatory activity of pyogenic liver abscess.It may also be a weak marker reflecting milder inflammatory status in the liver of patients with CHB and other active liver diseases.展开更多
BACKGROUND Rebleeding after recovery from esophagogastric variceal bleeding(EGVB)is a severe complication that is associated with high rates of both incidence and mortality.Despite its clinical importance,recognized p...BACKGROUND Rebleeding after recovery from esophagogastric variceal bleeding(EGVB)is a severe complication that is associated with high rates of both incidence and mortality.Despite its clinical importance,recognized prognostic models that can effectively predict esophagogastric variceal rebleeding in patients with liver cirrhosis are lacking.AIM To construct and externally validate a reliable prognostic model for predicting the occurrence of esophagogastric variceal rebleeding.METHODS This study included 477 EGVB patients across 2 cohorts:The derivation cohort(n=322)and the validation cohort(n=155).The primary outcome was rebleeding events within 1 year.The least absolute shrinkage and selection operator was applied for predictor selection,and multivariate Cox regression analysis was used to construct the prognostic model.Internal validation was performed with bootstrap resampling.We assessed the discrimination,calibration and accuracy of the model,and performed patient risk stratification.RESULTS Six predictors,including albumin and aspartate aminotransferase concentrations,white blood cell count,and the presence of ascites,portal vein thrombosis,and bleeding signs,were selected for the rebleeding event prediction following endoscopic treatment(REPET)model.In predicting rebleeding within 1 year,the REPET model ex-hibited a concordance index of 0.775 and a Brier score of 0.143 in the derivation cohort,alongside 0.862 and 0.127 in the validation cohort.Furthermore,the REPET model revealed a significant difference in rebleeding rates(P<0.01)between low-risk patients and intermediate-to high-risk patients in both cohorts.CONCLUSION We constructed and validated a new prognostic model for variceal rebleeding with excellent predictive per-formance,which will improve the clinical management of rebleeding in EGVB patients.展开更多
Intrahepatic arterioportal fistula(IAPF)can be caused by many secondary factors.We report four cases of portal hypertension that were eventually determined to be caused by congenital hepatic arterioportal fistula.The ...Intrahepatic arterioportal fistula(IAPF)can be caused by many secondary factors.We report four cases of portal hypertension that were eventually determined to be caused by congenital hepatic arterioportal fistula.The clinical manifestations included ascites,variceal hemorrhage and hepatic encephalopathy.Computed tomography scans from all of the patients revealed the early enhancement of the portal branches in the hepatic arterial phase.All patients were diagnosed using digital subtraction angiography(DSA).DSA before embolization revealed an arteriovenous fistula with immediate filling of the portal venous radicles.All four patients were treated with interventional embolization.The four patients remained in good condition throughout follow-up and at the time of publication.IAPF is frequently misdiagnosed due to its rarity;therefore,clinicians should consider IAPF as a potential cause of non-cirrhotic portal hypertension.展开更多
Background: Nonalcoholic fatty liver disease(NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver(NAFL) and nonalcoholic steatohepatitis(NASH). However, there is no re...Background: Nonalcoholic fatty liver disease(NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver(NAFL) and nonalcoholic steatohepatitis(NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. Methods: Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin staining and Masson’s trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflammation, hepatocellular necroptosis, fibrosis, and NAFLD activity score(NAS) was analyzed. Results: Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidylcholine(PC)(P-22:0/18:1), sphingomyelin(SM)(d14:0/18:0), SM(d14:0/24:0), SM(d14:0/22:0), phosphatidylethanolamine(PE)(18:0/22:5), PC(O-22:2/12:0), and PC(26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC(14:0/18:2), PE(18:0/22:5) and PC(26:1/11:0)] or plasmalogens [PC(O-22:0/0:0), PC(O-18:0/0:0), PC(O-16:0/0:0)], which were significantly altered in NASH patients. In addition, PC(14:0/18:2), phosphatidic acid(18:2/24:4) were positively correlated with NAS;whereas PC(18:0/0:0) was correlated positively with fibrosis score. Conclusions: The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization of NAFLD. The correlations between lipid moieties and NAS and fibrosis scores indicate that these lipid biomarkers may be used to predict the severity of the disease.展开更多
BACKGROUND Chronic hepatitis B virus(HBV)infection is a leading cause of liver morbidity and mortality worldwide.Liver fibrosis resulting from viral infection-associated inflammation and direct liver damage plays an i...BACKGROUND Chronic hepatitis B virus(HBV)infection is a leading cause of liver morbidity and mortality worldwide.Liver fibrosis resulting from viral infection-associated inflammation and direct liver damage plays an important role in disease management and prognostication.The mechanisms underlying the contribution of the liver microenvironment to fibrosis in HBV patients are not fully understood.There is an absence of effective clinical treatments for liver fibrosis progression;thus,establishing a suitable in vitro microenvironment in order to design novel therapeutics and identify molecular biomarkers to stratify patients is urgently required.AIM To examine a subset of pre-selected microenvironment factors of chronic HBV patients that may underlie fibrosis,with a focus on fibroblast activation.METHODS We examined the gene expression of key microenvironment factors in liver samples from patients with more advanced fibrosis compared with those with less severe fibrosis.We also used the human stellate cell line LX-2 in the in vitro study.Using different recombinant cytokines and growth factors or their combination,we studied how these factors interacted with LX-2 cells and pinpointed the crosstalk between the aforementioned factors and screened the most important factors.RESULTS Of the secreted factors examined,transforming growth factor(TGF)-β1,interleukin(IL)-1βand tumor necrosis factor(TNF)-αwere increased in patients with advanced fibrosis.We found that besides TGF-β1,IL-1βcan also induce a profibrotic cascade by stimulating the expression of connective tissue growth factor and platelet-derived growth factor(PDGF)in LX-2 cells.Furthermore,the proinflammatory response can be elicited in LX-2 cells following treatment with IL-1βand TNF-α,suggesting that stellate cells can respond to proinflammatory stimuli.By combining IL-1βand TGF-β1,we observed not only fibroblast activation as shown byαlpha-smooth muscle actin and PDGF induction,but also the inflammatory response as shown by increased expression of IL-1β.CONCLUSION Collectively,our data from HBV patients and in vitro studies demonstrate that the hepatic microenvironment plays an important role in mediating the crosstalk between profibrotic and proinflammatory responses and modulating fibrosis in chronic HBV patients.For the establishment of a suitable in vitro microenvironment for HBV-induced liver fibrosis,not only TGF-β1 but also IL-1βshould be considered as a necessary environmental factor.展开更多
Emerging evidence supports that the gut microbiome,reconsidered as a new organ in the human body,can not only affect the local gut,but also communicate with the brain via multiple pathways related to neuroendocrine,im...Emerging evidence supports that the gut microbiome,reconsidered as a new organ in the human body,can not only affect the local gut,but also communicate with the brain via multiple pathways related to neuroendocrine,immune,and neural pathways,thereby proposing the new concept of the microbiome-gut-brain(MGB)axis.Recently,the role of short-chain fatty acids(SCFAs),which are the main anaerobic fermented metabolites of the gut microbiota in the MGB axis,has garnered significant attention.SCFAs are involved in a broad range of central neurological diseases,including neurodegenerative diseases,cerebral vascular diseases,epilepsy,neuroimmune inflammatory diseases,and mood disorders.However,the underlying mechanism of SCFA-related distant organ crosstalk is yet to be elucidated.Herein,we summarize current knowledge regarding interactions between SCFAs and the MGB axis,as well as their protective effects against central neurological diseases.展开更多
Pancreatic carcinoma(PC)has one of the highest rates of cancer-related death worldwide.Except for surgery,adjuvant chemotherapy,chemoradiotherapy,and immunotherapy have shown various efficacies depending on the stage ...Pancreatic carcinoma(PC)has one of the highest rates of cancer-related death worldwide.Except for surgery,adjuvant chemotherapy,chemoradiotherapy,and immunotherapy have shown various efficacies depending on the stage of the patient.We read the review“Current and emerging therapeutic strategies in pancreatic cancer:Challenges and opportunities”and offer some opinions that may improve its precision and completeness.This review presents a map of appropriate therapies for PC at different stages.Based on the clinical trial outcomes mentioned in the review,we evaluated the potential therapeutic options for PC and helped explain the contradictory efficacy between different programmed cell death protein 1/programmed cell death ligand 1 clinical trials,which may have resulted from the unique features of PC.Although R0 resection and adjuvant chemotherapy are still the gold standards for PC,new modalities,with or without clinical validation,are needed to establish more specific and precise treatments for PC.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD),also called non-alcoholic fatty liver disease,is the most epidemic chronic liver disease worldwide.Metabolic dysfunction-associated steatohepatitis(MASH)...Metabolic dysfunction-associated steatotic liver disease(MASLD),also called non-alcoholic fatty liver disease,is the most epidemic chronic liver disease worldwide.Metabolic dysfunction-associated steatohepatitis(MASH)is the critical stage of MASLD,and early diagnosis and treatment of MASH are crucial for reducing the incidence of intrahepatic and extrahepatic complications.So far,pharmacotherapeutics for the treatment of MASH are still a major challenge,because of the complexity of the pathogenesis and heterogeneity of MASH.Many agents under investigation have shown impressive therapeutic effects by targeting different key pathways,including the attenuation of steatohepatitis or fibrosis or both.It is notable that thyroid hormone receptor-βagonist,resmetirom has become the first officially approved drug for treating MASH with fibrosis.Other agents such as peroxisome proliferator-activated receptor agonists,glucagon-like peptide-1 analogs,and fibroblast growth factor 21 analogs are awaiting approval.This review focuses on the current status of drug therapy for MASH and summarizes the latest results of new medications that have completed phase 2 or 3 clinical trials,and presents the future directions and difficulties of new drug research for MASH.展开更多
The clinical data of a patient with acute-on-chronic liver failure were analyzed retrospectively. The patient has suffered from hepatitis B for 30 years. His liver function deteriorated, yielding Child-Pugh grade C an...The clinical data of a patient with acute-on-chronic liver failure were analyzed retrospectively. The patient has suffered from hepatitis B for 30 years. His liver function deteriorated, yielding Child-Pugh grade C and reaching a model for end-stage liver disease score of 33 points within a short period; this condition was complicated with highly active variceal bleeding and coagulation system failure （PT 〉 100 s）. The patient also presented hepatocellular carcinoma. Comprehensive treatments included effective inhibition of hepatitis B virus replication and intensive care support. Piggyback orthotopic liver transplantation was performed as the final treatment. The patient recovered uneventfully and was discharged after surgery.展开更多
We conducted a comprehensive review of existing prediction models pertaining to the efficacy of immune-checkpoint inhibitor(ICI)and the occurrence of immune-related adverse events(irAEs).The predictive potential of ne...We conducted a comprehensive review of existing prediction models pertaining to the efficacy of immune-checkpoint inhibitor(ICI)and the occurrence of immune-related adverse events(irAEs).The predictive potential of neutrophil-to-lymphocyte ratio(NLR)and platelet-to-lymphocyte ratio(PLR)in determining ICI effectiveness has been extensively investigated,while limited research has been conducted on predicting irAEs.Furthermore,the combined model incor-porating NLR and PLR,either with each other or in conjunction with additional markers such as carcinoembryonic antigen,exhibits superior predictive capabilities compared to individual markers alone.NLR and PLR are promising markers for clinical applications.Forthcoming models ought to incorporate established efficacious models and newly identified ones,thereby constituting a multifactor composite model.Furthermore,efforts should be made to explore effective clinical application approaches that enhance the predictive accuracy and efficiency.展开更多
Protein tyrosine phosphatase nonreceptor type 2(PTPN2)is a promising target for sensitizing solid tumors to immune checkpoint blockades.However,the highly polar active sites of PTPN2 hinder drug discovery efforts.Leve...Protein tyrosine phosphatase nonreceptor type 2(PTPN2)is a promising target for sensitizing solid tumors to immune checkpoint blockades.However,the highly polar active sites of PTPN2 hinder drug discovery efforts.Leveraging small interfering RNA(siRNA)technology,we developed a novel glutathione-responsive nano-platform HPssPT(HA/PEIss@siPtpn2)to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma(HCC).HPssPT showed potent transfection and favorable safety profiles.PTPN2 deficiency induced by HPssPT amplified the interferon g signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1,resulting in enhanced antigen presentation and T cell activation.The nanoplatform was also able to promote the M1-like polarization of macrophages in vitro.The unique tropism of HPssPT towards tumor-associated macrophages,facilitated by hyaluronic acid coating and CD44 receptor targeting,allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages,thereby synergistically reshaping tumor microenvironment to an immunostimulatory state.In HCC,colorectal cancer,and melanoma animal models,HPssPT monotherapy provoked robust antitumor immunity,thereby sensitizing tumors to PD-1 blockade,which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.展开更多
Background and Aims:Pyrrolizidine alkaloids(PAs),widely distributed in plants,are known to induce liver failure.Hepatic platelet accumulation has been reported during the progression of PA-induced liver injury(PA-ILI)...Background and Aims:Pyrrolizidine alkaloids(PAs),widely distributed in plants,are known to induce liver failure.Hepatic platelet accumulation has been reported during the progression of PA-induced liver injury(PA-ILI).This study aimed to investigate the mechanisms underlying platelet accumulation in PA-ILI.Methods:Cases of PA-ILI,non-PA-ILI,and control subjects were collected from patients hospitalized at Zhongshan Hospital,Fudan University(Shanghai,China)between 2012 and 2019.A mouse model of PA-ILI was established using monocrotaline administration.Liver RNA sequencing was performed,and gene interactions were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins online database.Low-molecular-weight heparin and recombinant a disintegrin and metalloproteinase with a thrombospondin type I motif member 13(ADAMTS13)were applied.The necrotic liver area,hepatic platelet accumulation,and von Willebrand factor(VWF)deposition were examined using hematoxylin and eosin staining and immunofluorescence assay.Results:Hepatic platelet accumulation,necrotic area expansion,and increased VWF expression were observed in both PA-ILI patients and mice.The Search Tool for the Retrieval of Interacting Genes/Proteins database indicated that ADAMTS13 regulates VWF expression and was differentially expressed in the livers of PA-ILI mice.Plasma and hepatic ADAMTS13 levels were significantly downregulated in both PA-ILI patients and mice.Systemic administration of recombinant ADAMTS13 decreased hepatic platelet accumulation,downregulated VWF expression,and mitigated mouse hepatic necrosis.Conclusions:Hepatic platelet accumulation in PA-ILI was confirmed in both patients and mice.Deficiency of ADAMTS13 plays a critical role in platelet accumulation in PA-ILI,suggesting that ADAMTS13 could be a potential therapeutic target for this condition.展开更多
Hepatitis C virus(HCV)infection remains a major public health concern,with 56.8 million people chronically infected worldwide and 1.5 million new infections yearly.1 As a leading cause of liver-related mortality,chron...Hepatitis C virus(HCV)infection remains a major public health concern,with 56.8 million people chronically infected worldwide and 1.5 million new infections yearly.1 As a leading cause of liver-related mortality,chronic HCV infection is associated with 19%of hepatocellular carcinoma and 21%of cirrhosis cases.2 The advent of direct-acting antiviral agents(DAA)in recent decades,which target viral replication proteins and inhibit various steps in the HCV life cycle,has shown remarkable progress in achieving a cure for hepatitis C.DAA regimens block replication complex formation,reduce virion assembly and release,accelerate viral RNA degradation,and are associated with the restoration of liver function and improvement in histology.Pangenotypic DAA regimens,with DAA combinations targeting different and complementary stages of the HCV cycle,have been recommended by current practice guidelines3 and can be initiated without knowledge of the HCV genotype and subtype.As the global prevalence of chronic HCV infections has decreased by seven million since 2015,the World Health Organization has set the goals of a 90%reduction in new infections,an 80%reduction in diagnosed patients,and a 65%reduction in HCV-related mortality by 2030.To accomplish this,expanded access,active HCV screening,and linkage to care are required.展开更多
Immunotherapy for cardiovascular diseases(CVDs)holds great promise for precision management by modulating localized immune-inflammatory responses.The interplay between focal cardiovascular pathology and panvascular di...Immunotherapy for cardiovascular diseases(CVDs)holds great promise for precision management by modulating localized immune-inflammatory responses.The interplay between focal cardiovascular pathology and panvascular disease,necessitates highly integrated therapeutic strategies.Nano-technology-based theranostic platforms address this challenge by enabling both regulation and real-time imaging of immune cell activity within cardiovascular lesions.These functional nanotherapy systems not only halt disease progression at pathological sites but also reduce secondary cardiovascular events driven by shared inflammatory mechanisms.Additionally,nanoplatform-based dynamic visualization of immune cell responses facilitates adaptive,personalized interventions.This review introduces the role of immune cells in CVDs.It summarizes recent advances in nanomaterial-based immunomodulation strategies,including mechanisms of immune regulation,enhanced imaging,and therapeutic applications in atherosclerosis,myocardial infarction,ischemic stroke,abdominal aortic aneurysm,and myocarditis.Collectively,this integrated nanotheranostic paradigm establishes a robust foundation for the next generation of cardiovascular precision medicine.展开更多
Background:The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma(HCC)remains poor.Although serine-and arginine-rich splicing factor(SRSF)family members play crucial roles in tumo...Background:The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma(HCC)remains poor.Although serine-and arginine-rich splicing factor(SRSF)family members play crucial roles in tumors,their impact on tumor immunology remains unclear.This study aimed to elucidate the role of SRSF10 in HCC immunotherapy.Methods:To identify the key genes associated with immunotherapy resistance,we conducted single-nuclear RNA sequencing,multiplex immunofluorescence,and The Cancer Genome Atlas and Gene Expression Omnibus database analyses.We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems,flow cytometry,various tumor-bearing mouse models,and patient-derived organotypic tumor spheroids.Results:SRSF10 was upregulated in various tumors and associated with poor prognosis.Moreover,SRSF10 positively regulated lactate production,and SRSF10/glycolysis/histone H3 lysine 18 lactylation(H3K18la)formed a positive feedback loop in tumor cells.Increased lactate levels promoted M2 macrophage polarization,thereby inhibiting CD8^(+)T cell activity.Mechanistically,SRSF10 interacted with the 3′-untranslated region of MYB,enhancing MYB RNA stability,and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1(GLUT1),hexokinase 1(HK1),lactate dehydrogenase A(LDHA),resulting in elevated intracellular and extracellular lactate levels.Lactate accumulation induced histone lactylation,which further upregulated SRSF10 expression.Additionally,lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages,thereby activating transcription and enhancing pro-tumor macrophage activity.M2 macrophages,in turn,inhibited the enrichment of CD8^(+)T cells and the proportion of interferon-γ+CD8^(+)T cells in the tumor microenvironment(TME),thus creating an immunosuppressive TME.Clinically,SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors.Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1(PD-1)monoclonal antibodies(mAbs)in both murine and human preclinical models.Conclusions:The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance.Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.展开更多
基金Natural Science and Technology Major Project of Fujian Province,No.2021D033Natural Science Foundation of Shanghai,No.20ZR1410900+1 种基金Medical Innovation Project of Fujian Province,No.2022CXB020National Science and Technology Major Project,No.2017ZX 10203202-003-002.
文摘BACKGROUND Noninvasive methods have been developed to detect fibrosis in many liver diseases due to the limits of liver biopsy.However,previous studies have focused primarily on chronic viral hepatitis and nonalcoholic fatty liver disease.The diagnostic value of transient elastography for autoimmune liver diseases(AILDs)is worth studying.AIM To compare the diagnostic accuracy of imaging techniques with serum biomarkers of fibrosis in AILD.METHODS The PubMed,Cochrane Library and EMBASE databases were searched.Studies evaluating the efficacy of noninvasive methods in the diagnosis of AILDs[autoimmune hepatitis(AIH),primary biliary cholangitis(PBC)and primary sclerosing cholangitis(PSC)]were included.The summary area under the receiver operating characteristic curve(AUROC),diagnostic odds ratio,sensitivity and specificity were used to assess the accuracy of these noninvasive methods for staging fibrosis.RESULTS A total of 60 articles were included in this study,and the number of patients with AIH,PBC and PSC was 1594,3126 and 501,respectively.The summary AUROC of transient elastography in the diagnosis of significant fibrosis,advanced fibrosis and cirrhosis in patients with AIH were 0.84,0.88 and 0.90,respectively,while those in patients with PBC were 0.93,0.93 and 0.91,respectively.The AUROC of cirrhosis for patients with PSC was 0.95.However,other noninvasive indices(aspartate aminotransferase to platelet ratio index,aspartate aminotransferase/alanine aminotransferase ratio,fibrosis-4 index)had corresponding AUROCs less than 0.80.CONCLUSION Transient elastography exerts better diagnostic accuracy in AILD patients,especially in PBC patients.The appropriate cutoff values for staging advanced fibrosis and cirrhosis ranged from 9.6 to 10.7 and 14.4 to 16.9 KPa for PBC patients.
基金Supported by National Key Research and Development Plan ‘Precision Medicine Research’,No.2017YFSF090203the National Natural Science Foundation of China,No.81470840,No.81873565,and No.81800510Shanghai Sailing Program,No.18YF1415900
文摘The prevalence of non-alcoholic fatty liver disease(NAFLD) is rising exponentially worldwide. The spectrum of NAFLD includes non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver cirrhosis, and even hepatocellular carcinoma. Evidence shows that microbial metabolites play pivotal roles in the onset and progression of NAFLD. In this review, we discuss how microbederived metabolites, such as short-chain fatty acids, endogenous ethanol, bile acids and so forth, contribute to the pathogenesis of NAFLD.
基金the National Natural Science Foundation of China,No.91129705,No.81070340,and No.30570825Science and Technology Commission of Shanghai Municipality,Shanghai Pujiang Talent Program,No.09PJ1402600
文摘BACKGROUND Serum amyloid A(SAA)is an acute phase protein mainly synthesized by the liver.SAA induces inflammatory phenotype and promotes cell proliferation in activated hepatic stellate cells,the major scar forming cells in the liver.However,few studies have reported on the serum levels of SAA in human liver disease and its clinical significance in various liver diseases.AIM To investigate the serum levels of SAA in patients with different liver diseases and analyze the factors associated with the alteration of SAA levels in chronic hepatitis B(CHB)patients.METHODS Two hundred and seventy-eight patients with different liver diseases and 117 healthy controls were included in this study.The patients included 205 with CHB,22 with active autoimmune liver disease(AILD),21 with nonalcoholic steatohepatitis(NASH),14 with drug-induced liver injury(DILI),and 16 with pyogenic liver abscess.Serum levels of SAA and other clinical parameters were collected for the analysis of the factors associated with SAA level.Mann-Whitney U test was used to compare the serum SAA levels of patients with various liver diseases with those of healthy controls.Bonferroni test was applied for post hoc comparisons to control the probability of type 1 error(alpha=0.05/6=0.008).For statistical tests of other variables,P<0.05 was considered statistically significant.Statistically significant factors determined by single factor analysis were further analyzed by binary multivariate logistic regression analysis.RESULTS All patients with active liver diseases had higher serum SAA levels than healthy controls and the inactive CHB patients,with the highest SAA level found in patients with pyogenic liver abscess(398.4±246.8 mg/L).Patients with active AILD(19.73±24.81 mg/L)or DILI(8.036±5.685 mg/L)showed higher SAA levels than those with active CHB(6.621±6.776 mg/L)and NASH(6.624±4.891 mg/L).Single(P<0.001)and multivariate logistic regression analyses(P=0.039)for the CHB patients suggested that patients with active CHB were associated with an SAA serum level higher than 6.4 mg/L.Serum levels of SAA and CRP(C-reactive protein)were positively correlated in patients with CHB(P<0.001),pyogenic liver abscess(P=0.045),and active AILD(P=0.02).Serum levels of SAA(0.80-871.0 mg/L)had a broader fluctuation range than CRP(0.30-271.3 mg/L).CONCLUSION Serum level of SAA is a sensitive biomarker for inflammatory activity of pyogenic liver abscess.It may also be a weak marker reflecting milder inflammatory status in the liver of patients with CHB and other active liver diseases.
基金Supported by National Natural Science Foundation of China,No.81874390 and No.81573948Shanghai Natural Science Foundation,No.21ZR1464100+1 种基金Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission,No.22S11901700the Shanghai Key Specialty of Traditional Chinese Clinical Medicine,No.shslczdzk01201.
文摘BACKGROUND Rebleeding after recovery from esophagogastric variceal bleeding(EGVB)is a severe complication that is associated with high rates of both incidence and mortality.Despite its clinical importance,recognized prognostic models that can effectively predict esophagogastric variceal rebleeding in patients with liver cirrhosis are lacking.AIM To construct and externally validate a reliable prognostic model for predicting the occurrence of esophagogastric variceal rebleeding.METHODS This study included 477 EGVB patients across 2 cohorts:The derivation cohort(n=322)and the validation cohort(n=155).The primary outcome was rebleeding events within 1 year.The least absolute shrinkage and selection operator was applied for predictor selection,and multivariate Cox regression analysis was used to construct the prognostic model.Internal validation was performed with bootstrap resampling.We assessed the discrimination,calibration and accuracy of the model,and performed patient risk stratification.RESULTS Six predictors,including albumin and aspartate aminotransferase concentrations,white blood cell count,and the presence of ascites,portal vein thrombosis,and bleeding signs,were selected for the rebleeding event prediction following endoscopic treatment(REPET)model.In predicting rebleeding within 1 year,the REPET model ex-hibited a concordance index of 0.775 and a Brier score of 0.143 in the derivation cohort,alongside 0.862 and 0.127 in the validation cohort.Furthermore,the REPET model revealed a significant difference in rebleeding rates(P<0.01)between low-risk patients and intermediate-to high-risk patients in both cohorts.CONCLUSION We constructed and validated a new prognostic model for variceal rebleeding with excellent predictive per-formance,which will improve the clinical management of rebleeding in EGVB patients.
基金Supported by National Nature Science Foundation of China No.81000968,No.81101540,No.81101637,No.81172273,No.81272388,No.81301820 and No.81472673Doctoral Fund of Ministry of Education of China No.20120071110058The National Clinical Key Special Subject of China
文摘Intrahepatic arterioportal fistula(IAPF)can be caused by many secondary factors.We report four cases of portal hypertension that were eventually determined to be caused by congenital hepatic arterioportal fistula.The clinical manifestations included ascites,variceal hemorrhage and hepatic encephalopathy.Computed tomography scans from all of the patients revealed the early enhancement of the portal branches in the hepatic arterial phase.All patients were diagnosed using digital subtraction angiography(DSA).DSA before embolization revealed an arteriovenous fistula with immediate filling of the portal venous radicles.All four patients were treated with interventional embolization.The four patients remained in good condition throughout follow-up and at the time of publication.IAPF is frequently misdiagnosed due to its rarity;therefore,clinicians should consider IAPF as a potential cause of non-cirrhotic portal hypertension.
基金supported by grants from the Ministry of Science&Technology of China(2016YFE0107400)the National Natural Science Foundation of China(81272436,81572356,81871997,81500665 and 82070588)+1 种基金High Level Creative Talents from Department of Public Health in Zhejiang Province(S2032102600032)Project of New Century 551 Talent Nurturing in Wenzhou。
文摘Background: Nonalcoholic fatty liver disease(NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver(NAFL) and nonalcoholic steatohepatitis(NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. Methods: Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin staining and Masson’s trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflammation, hepatocellular necroptosis, fibrosis, and NAFLD activity score(NAS) was analyzed. Results: Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidylcholine(PC)(P-22:0/18:1), sphingomyelin(SM)(d14:0/18:0), SM(d14:0/24:0), SM(d14:0/22:0), phosphatidylethanolamine(PE)(18:0/22:5), PC(O-22:2/12:0), and PC(26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC(14:0/18:2), PE(18:0/22:5) and PC(26:1/11:0)] or plasmalogens [PC(O-22:0/0:0), PC(O-18:0/0:0), PC(O-16:0/0:0)], which were significantly altered in NASH patients. In addition, PC(14:0/18:2), phosphatidic acid(18:2/24:4) were positively correlated with NAS;whereas PC(18:0/0:0) was correlated positively with fibrosis score. Conclusions: The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization of NAFLD. The correlations between lipid moieties and NAS and fibrosis scores indicate that these lipid biomarkers may be used to predict the severity of the disease.
基金National Natural Science Foundation for the Youth of China,No.81500460,No.81700550.
文摘BACKGROUND Chronic hepatitis B virus(HBV)infection is a leading cause of liver morbidity and mortality worldwide.Liver fibrosis resulting from viral infection-associated inflammation and direct liver damage plays an important role in disease management and prognostication.The mechanisms underlying the contribution of the liver microenvironment to fibrosis in HBV patients are not fully understood.There is an absence of effective clinical treatments for liver fibrosis progression;thus,establishing a suitable in vitro microenvironment in order to design novel therapeutics and identify molecular biomarkers to stratify patients is urgently required.AIM To examine a subset of pre-selected microenvironment factors of chronic HBV patients that may underlie fibrosis,with a focus on fibroblast activation.METHODS We examined the gene expression of key microenvironment factors in liver samples from patients with more advanced fibrosis compared with those with less severe fibrosis.We also used the human stellate cell line LX-2 in the in vitro study.Using different recombinant cytokines and growth factors or their combination,we studied how these factors interacted with LX-2 cells and pinpointed the crosstalk between the aforementioned factors and screened the most important factors.RESULTS Of the secreted factors examined,transforming growth factor(TGF)-β1,interleukin(IL)-1βand tumor necrosis factor(TNF)-αwere increased in patients with advanced fibrosis.We found that besides TGF-β1,IL-1βcan also induce a profibrotic cascade by stimulating the expression of connective tissue growth factor and platelet-derived growth factor(PDGF)in LX-2 cells.Furthermore,the proinflammatory response can be elicited in LX-2 cells following treatment with IL-1βand TNF-α,suggesting that stellate cells can respond to proinflammatory stimuli.By combining IL-1βand TGF-β1,we observed not only fibroblast activation as shown byαlpha-smooth muscle actin and PDGF induction,but also the inflammatory response as shown by increased expression of IL-1β.CONCLUSION Collectively,our data from HBV patients and in vitro studies demonstrate that the hepatic microenvironment plays an important role in mediating the crosstalk between profibrotic and proinflammatory responses and modulating fibrosis in chronic HBV patients.For the establishment of a suitable in vitro microenvironment for HBV-induced liver fibrosis,not only TGF-β1 but also IL-1βshould be considered as a necessary environmental factor.
基金Supported by the National Natural Science Foundation of China,No.81800510Shanghai Sailing Program,No.18YF1415900.
文摘Emerging evidence supports that the gut microbiome,reconsidered as a new organ in the human body,can not only affect the local gut,but also communicate with the brain via multiple pathways related to neuroendocrine,immune,and neural pathways,thereby proposing the new concept of the microbiome-gut-brain(MGB)axis.Recently,the role of short-chain fatty acids(SCFAs),which are the main anaerobic fermented metabolites of the gut microbiota in the MGB axis,has garnered significant attention.SCFAs are involved in a broad range of central neurological diseases,including neurodegenerative diseases,cerebral vascular diseases,epilepsy,neuroimmune inflammatory diseases,and mood disorders.However,the underlying mechanism of SCFA-related distant organ crosstalk is yet to be elucidated.Herein,we summarize current knowledge regarding interactions between SCFAs and the MGB axis,as well as their protective effects against central neurological diseases.
文摘Pancreatic carcinoma(PC)has one of the highest rates of cancer-related death worldwide.Except for surgery,adjuvant chemotherapy,chemoradiotherapy,and immunotherapy have shown various efficacies depending on the stage of the patient.We read the review“Current and emerging therapeutic strategies in pancreatic cancer:Challenges and opportunities”and offer some opinions that may improve its precision and completeness.This review presents a map of appropriate therapies for PC at different stages.Based on the clinical trial outcomes mentioned in the review,we evaluated the potential therapeutic options for PC and helped explain the contradictory efficacy between different programmed cell death protein 1/programmed cell death ligand 1 clinical trials,which may have resulted from the unique features of PC.Although R0 resection and adjuvant chemotherapy are still the gold standards for PC,new modalities,with or without clinical validation,are needed to establish more specific and precise treatments for PC.
基金supported by grants from the National Science and Technology Major Project of China(No.2023ZD0508700)the National Natural Science Foundation of China(No.82170593).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD),also called non-alcoholic fatty liver disease,is the most epidemic chronic liver disease worldwide.Metabolic dysfunction-associated steatohepatitis(MASH)is the critical stage of MASLD,and early diagnosis and treatment of MASH are crucial for reducing the incidence of intrahepatic and extrahepatic complications.So far,pharmacotherapeutics for the treatment of MASH are still a major challenge,because of the complexity of the pathogenesis and heterogeneity of MASH.Many agents under investigation have shown impressive therapeutic effects by targeting different key pathways,including the attenuation of steatohepatitis or fibrosis or both.It is notable that thyroid hormone receptor-βagonist,resmetirom has become the first officially approved drug for treating MASH with fibrosis.Other agents such as peroxisome proliferator-activated receptor agonists,glucagon-like peptide-1 analogs,and fibroblast growth factor 21 analogs are awaiting approval.This review focuses on the current status of drug therapy for MASH and summarizes the latest results of new medications that have completed phase 2 or 3 clinical trials,and presents the future directions and difficulties of new drug research for MASH.
文摘The clinical data of a patient with acute-on-chronic liver failure were analyzed retrospectively. The patient has suffered from hepatitis B for 30 years. His liver function deteriorated, yielding Child-Pugh grade C and reaching a model for end-stage liver disease score of 33 points within a short period; this condition was complicated with highly active variceal bleeding and coagulation system failure （PT 〉 100 s）. The patient also presented hepatocellular carcinoma. Comprehensive treatments included effective inhibition of hepatitis B virus replication and intensive care support. Piggyback orthotopic liver transplantation was performed as the final treatment. The patient recovered uneventfully and was discharged after surgery.
文摘We conducted a comprehensive review of existing prediction models pertaining to the efficacy of immune-checkpoint inhibitor(ICI)and the occurrence of immune-related adverse events(irAEs).The predictive potential of neutrophil-to-lymphocyte ratio(NLR)and platelet-to-lymphocyte ratio(PLR)in determining ICI effectiveness has been extensively investigated,while limited research has been conducted on predicting irAEs.Furthermore,the combined model incor-porating NLR and PLR,either with each other or in conjunction with additional markers such as carcinoembryonic antigen,exhibits superior predictive capabilities compared to individual markers alone.NLR and PLR are promising markers for clinical applications.Forthcoming models ought to incorporate established efficacious models and newly identified ones,thereby constituting a multifactor composite model.Furthermore,efforts should be made to explore effective clinical application approaches that enhance the predictive accuracy and efficiency.
基金supported by the Natural Science Foundation of Shanghai Science and Technology Innovation Plan(No.22ZR1414100)Oriental Youth Talent Program(to T.Sun,China)+5 种基金Key Special Project of the Ministry of Science and Technology(2023YFC2510000,China)National Natural Science Foundation of China(No.81872808,81972234,82103252,82121002,82173122,and 82273027)Open Grant from the Pingyuan Lab(2023PY-OP-0106,China)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)ZJLab,Shanghai Science and Technology Committee(Nos.20Y11908100,and 22ZR1411800)Shanghai Sailing Program(No.21YF1407400).
文摘Protein tyrosine phosphatase nonreceptor type 2(PTPN2)is a promising target for sensitizing solid tumors to immune checkpoint blockades.However,the highly polar active sites of PTPN2 hinder drug discovery efforts.Leveraging small interfering RNA(siRNA)technology,we developed a novel glutathione-responsive nano-platform HPssPT(HA/PEIss@siPtpn2)to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma(HCC).HPssPT showed potent transfection and favorable safety profiles.PTPN2 deficiency induced by HPssPT amplified the interferon g signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1,resulting in enhanced antigen presentation and T cell activation.The nanoplatform was also able to promote the M1-like polarization of macrophages in vitro.The unique tropism of HPssPT towards tumor-associated macrophages,facilitated by hyaluronic acid coating and CD44 receptor targeting,allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages,thereby synergistically reshaping tumor microenvironment to an immunostimulatory state.In HCC,colorectal cancer,and melanoma animal models,HPssPT monotherapy provoked robust antitumor immunity,thereby sensitizing tumors to PD-1 blockade,which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.
基金funded by the Shanghai Science and Technology Commission(21Y11921800)Zhongshan Hospital,Fudan University(2019ZSGG12 and 2020ZSLC24).
文摘Background and Aims:Pyrrolizidine alkaloids(PAs),widely distributed in plants,are known to induce liver failure.Hepatic platelet accumulation has been reported during the progression of PA-induced liver injury(PA-ILI).This study aimed to investigate the mechanisms underlying platelet accumulation in PA-ILI.Methods:Cases of PA-ILI,non-PA-ILI,and control subjects were collected from patients hospitalized at Zhongshan Hospital,Fudan University(Shanghai,China)between 2012 and 2019.A mouse model of PA-ILI was established using monocrotaline administration.Liver RNA sequencing was performed,and gene interactions were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins online database.Low-molecular-weight heparin and recombinant a disintegrin and metalloproteinase with a thrombospondin type I motif member 13(ADAMTS13)were applied.The necrotic liver area,hepatic platelet accumulation,and von Willebrand factor(VWF)deposition were examined using hematoxylin and eosin staining and immunofluorescence assay.Results:Hepatic platelet accumulation,necrotic area expansion,and increased VWF expression were observed in both PA-ILI patients and mice.The Search Tool for the Retrieval of Interacting Genes/Proteins database indicated that ADAMTS13 regulates VWF expression and was differentially expressed in the livers of PA-ILI mice.Plasma and hepatic ADAMTS13 levels were significantly downregulated in both PA-ILI patients and mice.Systemic administration of recombinant ADAMTS13 decreased hepatic platelet accumulation,downregulated VWF expression,and mitigated mouse hepatic necrosis.Conclusions:Hepatic platelet accumulation in PA-ILI was confirmed in both patients and mice.Deficiency of ADAMTS13 plays a critical role in platelet accumulation in PA-ILI,suggesting that ADAMTS13 could be a potential therapeutic target for this condition.
基金supported by the National Natural Science Foundation of China(Nos.91129705,81070340,81971921)the Shanghai Pujiang Talent Program(09PJ1402600)the Shanghai Science and Technology Innovation Action Plan(24142202800).
文摘Hepatitis C virus(HCV)infection remains a major public health concern,with 56.8 million people chronically infected worldwide and 1.5 million new infections yearly.1 As a leading cause of liver-related mortality,chronic HCV infection is associated with 19%of hepatocellular carcinoma and 21%of cirrhosis cases.2 The advent of direct-acting antiviral agents(DAA)in recent decades,which target viral replication proteins and inhibit various steps in the HCV life cycle,has shown remarkable progress in achieving a cure for hepatitis C.DAA regimens block replication complex formation,reduce virion assembly and release,accelerate viral RNA degradation,and are associated with the restoration of liver function and improvement in histology.Pangenotypic DAA regimens,with DAA combinations targeting different and complementary stages of the HCV cycle,have been recommended by current practice guidelines3 and can be initiated without knowledge of the HCV genotype and subtype.As the global prevalence of chronic HCV infections has decreased by seven million since 2015,the World Health Organization has set the goals of a 90%reduction in new infections,an 80%reduction in diagnosed patients,and a 65%reduction in HCV-related mortality by 2030.To accomplish this,expanded access,active HCV screening,and linkage to care are required.
基金supported by the National Natural Science Foundation of China(32371477,82090051,82301104,and 82300345)the National Key Research and Development Program of China(2021YFA1201000,2023YFC2605000)+2 种基金the National Natural Science Foundation of China Key Project(82430067,32030060)the Natural Science Foundation of Jiangsu Province(BK20230160)the Fundamental Research Funds for the Central Universities,Peking Union Medical College(3332025033).
文摘Immunotherapy for cardiovascular diseases(CVDs)holds great promise for precision management by modulating localized immune-inflammatory responses.The interplay between focal cardiovascular pathology and panvascular disease,necessitates highly integrated therapeutic strategies.Nano-technology-based theranostic platforms address this challenge by enabling both regulation and real-time imaging of immune cell activity within cardiovascular lesions.These functional nanotherapy systems not only halt disease progression at pathological sites but also reduce secondary cardiovascular events driven by shared inflammatory mechanisms.Additionally,nanoplatform-based dynamic visualization of immune cell responses facilitates adaptive,personalized interventions.This review introduces the role of immune cells in CVDs.It summarizes recent advances in nanomaterial-based immunomodulation strategies,including mechanisms of immune regulation,enhanced imaging,and therapeutic applications in atherosclerosis,myocardial infarction,ischemic stroke,abdominal aortic aneurysm,and myocarditis.Collectively,this integrated nanotheranostic paradigm establishes a robust foundation for the next generation of cardiovascular precision medicine.
基金supported by the National Natural Science Foundation of China(No.82372946 and No.82072670)the 12 Leading Project of the Science and Technology Committee of Shanghai Municipality(No.21Y21900100)the Project of Shanghai Municipal Health Commission(No.202140269).
文摘Background:The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma(HCC)remains poor.Although serine-and arginine-rich splicing factor(SRSF)family members play crucial roles in tumors,their impact on tumor immunology remains unclear.This study aimed to elucidate the role of SRSF10 in HCC immunotherapy.Methods:To identify the key genes associated with immunotherapy resistance,we conducted single-nuclear RNA sequencing,multiplex immunofluorescence,and The Cancer Genome Atlas and Gene Expression Omnibus database analyses.We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems,flow cytometry,various tumor-bearing mouse models,and patient-derived organotypic tumor spheroids.Results:SRSF10 was upregulated in various tumors and associated with poor prognosis.Moreover,SRSF10 positively regulated lactate production,and SRSF10/glycolysis/histone H3 lysine 18 lactylation(H3K18la)formed a positive feedback loop in tumor cells.Increased lactate levels promoted M2 macrophage polarization,thereby inhibiting CD8^(+)T cell activity.Mechanistically,SRSF10 interacted with the 3′-untranslated region of MYB,enhancing MYB RNA stability,and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1(GLUT1),hexokinase 1(HK1),lactate dehydrogenase A(LDHA),resulting in elevated intracellular and extracellular lactate levels.Lactate accumulation induced histone lactylation,which further upregulated SRSF10 expression.Additionally,lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages,thereby activating transcription and enhancing pro-tumor macrophage activity.M2 macrophages,in turn,inhibited the enrichment of CD8^(+)T cells and the proportion of interferon-γ+CD8^(+)T cells in the tumor microenvironment(TME),thus creating an immunosuppressive TME.Clinically,SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors.Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1(PD-1)monoclonal antibodies(mAbs)in both murine and human preclinical models.Conclusions:The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance.Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.
