Twelve new diterpenoids,euphorwallnoids A-L(1-12),comprising five rhamnofolanes(1-5),five tiglianes(6-10),and two daphnanes(11 and 12),along with six known analogues(13-18),were isolated from the whole plants of Eupho...Twelve new diterpenoids,euphorwallnoids A-L(1-12),comprising five rhamnofolanes(1-5),five tiglianes(6-10),and two daphnanes(11 and 12),along with six known analogues(13-18),were isolated from the whole plants of Euphorbia wallichii(E.wallichii).Their structures were determined using spectroscopic analysis,computational methods,chemical derivatization,and single-crystal X-ray diffraction.Euphorwallnoid A(1)features an unusual 5/7/6/5-tetracyclic scaffold,whereas 2-5 represent a rare subclass of 4-deoxygenated rhamnofolanes and 6-8 constitute 13-deoxygenated tiglianes.Notably,compound 1 demonstrated promising anti-liver fibrosis activity by significantly inhibiting the expression of fibronectin(FN),α-smooth muscle actin(α-SMA),and collagen I in transforming growth factorβ1(TGF-β1)-stimulated LX-2 cells at micromolar concentrations.展开更多
Artificial intelligence(AI)is revolutionizing medical imaging,particularly in chronic liver diseases assessment.AI technologies,including machine learning and deep learning,are increasingly integrated with multiparame...Artificial intelligence(AI)is revolutionizing medical imaging,particularly in chronic liver diseases assessment.AI technologies,including machine learning and deep learning,are increasingly integrated with multiparametric ultrasound(US)techniques to provide more accurate,objective,and non-invasive evaluations of liver fibrosis and steatosis.Analyzing large datasets from US images,AI enhances diagnostic precision,enabling better quantification of liver stiffness and fat content,which are essential for diagnosing and staging liver fibrosis and steatosis.Combining advanced US modalities,such as elastography and doppler imaging with AI,has demonstrated improved sensitivity in identifying different stages of liver disease and distinguishing various degrees of steatotic liver.These advancements also contribute to greater reproducibility and reduced operator dependency,addressing some of the limitations of traditional methods.The clinical implications of AI in liver disease are vast,ranging from early detection to predicting disease progression and evaluating treatment response.Despite these promising developments,challenges such as the need for large-scale datasets,algorithm transparency,and clinical validation remain.The aim of this review is to explore the current applications and future potential of AI in liver fibrosis and steatosis assessment using multiparametric US,highlighting the technological advances and clinical relevance of this emerging field.展开更多
Traditional Chinese medicine(TCM)has shown remarkable potential for treating liver fibrosis.In this study,to identify novel TCMs with antifibrotic properties,we used a technique called high-throughput sequencing-based...Traditional Chinese medicine(TCM)has shown remarkable potential for treating liver fibrosis.In this study,to identify novel TCMs with antifibrotic properties,we used a technique called high-throughput sequencing-based high-throughput screening(HTS2),which is based on RNA-mediated oligonucleotide annealing,selection,and ligation followed by sequencing.This technology achieved parallel and quantitative analysis of gene expression in response to thousands of drug treatments[1].展开更多
This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid acc...This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid accumulation,apoptosis,and inflammatory responses exacerbated by gut barrier dysfunction.The study explored the therapeutic potential of elafibranor,a dual peroxisome proliferatoractivated receptor alpha/delta agonist.In clinical trials,elafibranor has shown promise for the treatment of other liver conditions;however,its effects on ALD remain unclear.The authors’findings indicate that elafibranor significantly reduced liver fibrosis and enhanced gut barrier integrity in patients with ALD.These positive effects of elafibranor are mediated through multiple pathways.Elafibranor promotes lipid metabolism,reduces oxidative stress,and inhibits inflammatory responses by restoring gut barrier function.Specifically,it improves hepatocyte function by enhancing autophagic and antioxidant capacity,and it mitigates inflammation by suppressing the lipopolysaccharide/toll-like receptor 4/nuclear factor kappa B signaling pathway.These findings indicate that elafibranor has promising clinical applications.In addition,the study highlights elafibranor’s potential as a therapeutic agent for liver diseases,particularly ALD.This article underscores the importance of understanding the mechanistic pathways underlying ALD and suggests directions for future research aimed at elucidating the benefits and limitations of elafibranor.展开更多
Liver fibrosis is a common outcome of various chronic hepatic insults,characterized by excessive extracellular matrix(ECM)deposition.The precise mechanisms,however,remain largely undefined.This study identified an ele...Liver fibrosis is a common outcome of various chronic hepatic insults,characterized by excessive extracellular matrix(ECM)deposition.The precise mechanisms,however,remain largely undefined.This study identified an elevated expression of platelet-activating factor acetylhydrolase 1B3(Pafah1b3)in liver tissues from both carbon tetrachloride(CCl_(4))-treated mice and patients with cirrhosis.Deletion of Pafah1b3 significantly attenuated CCl_(4)-induced fibrosis,hepatic stellate cell(HSC)activation,and activation of transforming growth factor-β(TGF-β)signaling.Mechanistically,PAFAH1B3 binds to mothers against decapentaplegic homolog 7(SMAD7),disrupting SMAD7's interaction with TGF-βreceptor 1(TβR1),which subsequently decreases TbR1 ubiquitination and degradation.Pharmacological inhibition using 3-IN-P11,a specific Pafah1b3 inhibitor,conferred protective effects against CCl_(4)-induced fibrosis in mice.Furthermore,Pafah1b3 deficiency reduced hepatic inflammation.Overall,these results establish a pivotal role for Pafah1b3 in modulating TGF-βsignaling and driving HSC activation.展开更多
BACKGROUND This review evaluated the diagnostic effectiveness of various ultrasound(US)methods compared to liver biopsy.AIM To determine the diagnostic accuracy of US techniques in assessing liver fibrosis and steatos...BACKGROUND This review evaluated the diagnostic effectiveness of various ultrasound(US)methods compared to liver biopsy.AIM To determine the diagnostic accuracy of US techniques in assessing liver fibrosis and steatosis in adults,using the area under the receiver operating characteristic curve(AUROC)as the standard measure.METHODS The review included original retrospective or prospective studies published in the last three years in peer-reviewed medical journals,that reported AUROC values.Studies were identified through PubMed searches on January 3 and April 30,2024.Quality was assessed using the QUADAS-2 tool.Results were tabulated according to the diagnostic method and the type of liver pathology.RESULTS The review included 52 studies.For liver fibrosis detection,2D-shear wave elastography(SWE)AUROCs ranged from 0.54 to 0.994,showing better accuracy for advanced stages.Modifications,including 2D-SWE with propagation map guidance and supersonic imagine achieved AUROCs of 0.84 to nearly 1.0.point SWE and classical SWE had AUROCs of 0.741-0.99,and 0.507-0.995,respectively.Transient elastography(TE),visual TE,vibration-controlled TE(VCTE),and FibroTouch reported AUROCs close to 1.0.For steatosis,VCTE with controlled attenuation parameter showed AUROCs up to 0.89(for≥S1),acoustic radiation force impulse ranged from 0.762 to 0.784,US attenuation parameter from 0.88 to 0.93,and normalized local variance measurement from 0.583 to 0.875.Most studies had a low risk of bias across all or most domains,but evidence was limited by variability in study quality and small sample sizes.Innovative SWE variants were evaluated in a single study.CONCLUSION Modern US techniques can serve as effective noninvasive diagnostic tools for liver fibrosis and steatosis,with the potential to reduce the reliance on biopsies.展开更多
BACKGROUND The Streptococcus salivarius(S.salivarius)group,which produces the enzyme urease has been identified as a potential contributor to ammonia production in the gut.Researchers have reported that patients with ...BACKGROUND The Streptococcus salivarius(S.salivarius)group,which produces the enzyme urease has been identified as a potential contributor to ammonia production in the gut.Researchers have reported that patients with minimal HE had an increased abundance of the S.salivarius group,which is a specific change in the gut microbiota that distinguishes them from healthy individuals.The correlation between the aggregation of specific bacterial species and fibrosis progression in chronic liver disease(CLD)is yet to be fully elucidated.AIM To quantify S.salivarius using digital PCR(dPCR)as a liver fibrosis marker of CLD.METHODS This study retrospectively analysed 52 patients with CLD.To quantify S.salivarius in patients with CLD using dPCR,we evaluated the specificity and sensitivity of S.salivarius bacterial load using dPCR for a type strain.Next,we evaluated the clinical usefulness of dPCR for S.salivarius load quantification for detecting liver fibrosis in patients with CLD.The liver fibrosis stage was categorized into mild and advanced fibrosis based on pathological findings.RESULTS The dPCR assay revealed that S.salivarius was highly positive for the tnpA gene.The lower limit of quantification for dPCR using the tnpA gene with a 1μL template comprising 1.28×102 CFU/mL was 4.3 copies.After considering the detection range in dPCR,we adjusted the extracted DNA concentration to 5.0×10-4 ng/μL from 200 mg stool samples.The median bacterial loads of S.salivarius in stool sample from patients with mild and advanced fibrosis were 1.9 and 7.4 copies/μL,respectively.The quantification of S.salivarius load was observed more frequently in patients with advanced fibrosis than in those with mild fibrosis(P=0.032).CONCLUSION Quantifying of S.salivarius load using digital PCR is a useful biomarker for liver fibrosis in patients with CLD.展开更多
BACKGROUND In metabolic dysfunction-associated steatotic liver disease(MASLD)the identi-fication of patients at high risk of evolution to metabolic dysfunction-associated steatohepatitis(MASH)is challenging.AIM To inv...BACKGROUND In metabolic dysfunction-associated steatotic liver disease(MASLD)the identi-fication of patients at high risk of evolution to metabolic dysfunction-associated steatohepatitis(MASH)is challenging.AIM To investigate the performance of different ultrasound(US)-based techniques for the non-invasive assessment of liver fibrosis,steatosis,and inflammation in these patients.METHODS We collected data from consecutive patients who underwent liver biopsy for suspected MASLD between January 2019 and December 2021.Two-dimensional shear-wave elastography,sound speed plane-wave US,attenuation plane-wave US,viscosity plane-wave US(Vi.PLUS)using Aixplorer MACH 30 system,and transient elastography and controlled attenuation parameter from FibroScan were measured before biopsy.RESULTS A total of 120 participants were enrolled.Both transient elastography and two-dimensional shear-wave elasto-graphy showed good performance for the diagnosis of advanced fibrosis[area under the receiver operating charac-teristic curve(AUROC)=0.93 and 0.90,respectively].The diagnostic performance of Vi.PLUS for the presence of both ballooning grade≥1 and lobular inflammation≥1 was good with an AUROC of 0.72.A score based on Vi.PLUS,aspartate aminotransferase,and sound speed plane-wave US[viscosity-aspartate aminotransferase-speed of sound MASH ultrasound score(VAS-MASH-US score)]had a good accuracy for the diagnosis of MASH(AUROC=0.75).VAS-MASH-US score>0.6 showed a good sensitivity for MASH diagnosis(79.0%).According to decision curve analysis,the application of the VAS-MASH-US score would lead to a more accurate selection of patients who are candidates to undergo liver biopsy and would reduce the need for invasive procedures for patients at low risk of MASH.CONCLUSION Multiparametric US allows the non-invasive assessment of steatosis,inflammation,and fibrosis in patients with MASLD.Liver viscosity improved the capability of non-invasively identifying patients with MASH.展开更多
Chronic liver disease results in a response resembling"wound healing",also known as fibrosis,resulting in the progressive accumulation of connective tissue.Excessive fibrogenesis that results in the disrupti...Chronic liver disease results in a response resembling"wound healing",also known as fibrosis,resulting in the progressive accumulation of connective tissue.Excessive fibrogenesis that results in the disruption of intercellular connections,interactions,and extracellular matrix composition are features of the fibrotic pro-cess mediated by various cell types and chemical mediators such as transforming growth factor-β.Redox-sensitive processes are major contributors to controlling this inflammatory and pro-fibrogenic cytokine's production and synthesis.Other essential hepatic fibrogenesis activities,such as the activation of stellate cells,the expression of metalloproteinases and their inhibitors can also be linked to ge-neration of reactive oxygen species and lipid peroxidation products,which are implicated in development and progression of fibrosis.The herb Silybum maria-num,also known as milk thistle,is widely studied for its potential to treat liver illnesses.Silymarin contains 50%to 70%silybin,which has the highest level of biological activity.In comparison,silybin seems to be relatively safer and the avai-lable evidence on its potential mechanisms of action is encouraging.The aim of this article is to analyze the increasing evidences linking biochemical oxidative events to excessive fibrogenesis and silybin's inhibitory mechanisms that aid in the reversal of fibrosis and fibrotic lesions.展开更多
Background:The emerging incidence of pathogenic liver conditions is turning into a major concern for global health.Induction of pyroptosis in hepatocytes instigates cel-lular disintegration,which in turn liberates sub...Background:The emerging incidence of pathogenic liver conditions is turning into a major concern for global health.Induction of pyroptosis in hepatocytes instigates cel-lular disintegration,which in turn liberates substantial quantities of pro-inflammatory intracellular substances,thereby accelerating the advancement of liver fibrosis.Consequently,directing therapeutic efforts towards inhibiting pyroptosis could po-tentially serve as an innovative approach in managing inflammation related chronic hepatic disorders.Methods:GSDMD-NT^(ki/wt)mice and Alb-cre^(ki/wt)mice were generated using CRISPR/Cas9 technology.After crossing the two strains together,we induced conditional cell death by doxycycline to construct a mouse model of liver fibrosis.We analyzed differ-entially expressed genes by RNA sequencing and explored their biological functions.The efficacy of obeticholic acid(OCA)in the treatment of liver fibrosis was assessed.Results:Doxycycline-treated GSDMD-NT^(ki/wt)×Alb-cre^(ki/wt)mice showed severe liver damage,vacuolation of hepatocytes,increased collagen fibers,and accumulation of lipid droplets.The expression of liver fibrosis related genes was greatly increased in the doxycycline-treated mouse liver compared with untreated mouse liver.RNA-sequencing showed that upregulated differentially expressed genes were involved in inflammatory responses,cell activation,and metabolic processes.Treatment with OCA alleviated the liver fibrosis,with reduced ALT and AST levels seen in the GSDMD-NT^(ki/wt)×Alb-cre^(ki/wt)mice.Conclusions:We successfully constructed a novel mouse model for liver fibrosis.This GSDMD-NT-induced fibrosis may be mediated by abnormal lipid metabolism.Our re-sults demonstrated that we successfully constructed a mouse model of liver fibrosis,and GSDMD-NT induced fibrosis by mediating lipid metabolism.展开更多
Liver diseases are among the most insidious and life-threatening conditions due to their progressive nature and late symptom onset.Cirrhosis and hepatocellular carcinoma account for most liver-related deaths,often fol...Liver diseases are among the most insidious and life-threatening conditions due to their progressive nature and late symptom onset.Cirrhosis and hepatocellular carcinoma account for most liver-related deaths,often following the progression from fibrosis.Fibrosis creates a hostile microenvironment,characterized by portal hypertension,vascular capillarization,intrahepatic vasoconstriction,and extracellular matrix deposition,which severely limits drug efficacy.Advances in pharmaceutical science have prompted efforts to develop liver-targeted drug delivery systems to prevent or reduce the progression of fibrosis,a central feature of many liver diseases.Fibrosis often reduces the in vivo efficacy of both approved and experimental drugs,underscoring the need for improved delivery strategies focused on stability,controlled release,and precise targeting.Nanoparticle(NP)-based systems show promise,either by delivering therapeutic agents,or in some cases,by contributing directly to the therapeutic effects.This review summarizes the main types of NPs explored for liver disease treatment,especially those aiming to reverse fibrosis or prevent its progression,a critical therapeutic target in chronic liver diseases.Additionally,it examines gene delivery and ultrasoundguided microbubble strategies,which can be combined with NPs to improve cellspecific targeting and boost therapeutic effects.Together,these approaches have the potential to address current therapeutic challenges and accelerate the development of liver-targeted treatments for clinical application.展开更多
BACKGROUND Hepatitis C virus(HCV)infection process of progression encompasses multiple stages,commencing with inflammation and culminating in hepatocellular cancer.Numerous invasive and non-invasive procedures exist f...BACKGROUND Hepatitis C virus(HCV)infection process of progression encompasses multiple stages,commencing with inflammation and culminating in hepatocellular cancer.Numerous invasive and non-invasive procedures exist for diagnosing chronic HCV infection.Though beneficial,invasive procedures can cause morbidity and inadequate representation of the overall degree of fibrosis.Due to these reasons,non-invasive liver fibrosis biomarkers are becoming more prevalent to diagnose and track liver fibrosis without a liver biopsy.These biomarkers can detect liver fibrosis early,improving treatment and preventing cirrhosis and liver failure.Micro ribonucleic acid(MiRNA)dysregulation causes and worsens several diseases including liver disease.MiRNAs can facilitate the diagnosis of liver fibrosis and serve as a predictive tool to enhance patient care by minimizing invasive procedures and enabling more efficient and prompt therapy.AIM To investigate the diagnostic effectiveness of several miRNAs(miRNA-122,miRNA-21,miRNA-199a,miRNA-155)in assessing the liver fibrosis severity in untreated HCV patients from the Indian Punjab population.We seek to identify the intricate diagnostic relationship of miRNAs with the extent of fibrosis among individuals with HCV.METHODS We considered 100 persons determined as HCV infected by a quantitative Real-Time Polymerase Chain Reaction examination.We employed statistical as well as probabilistic tools to ascertain the diagnostic validity of miRNAs for determining the liver fibrosis stages.We employed Bayesian Networks,to introduce a unique diagnostic paradigm for miRNAs that can be adopted as benchmark to evaluate the liver fibrosis severity in HCV cases.RESULTS We found that miRNAs(miR-122,miR-155 and miR-21)showed significant upregulation when compared with control and according to severity of fibrosis(P≤0.05).The area under the curve for miR-122,miR-155,miR-21 and miR-199a in HCV group in relation to Liver Stiffness Measurement was calculated as 0.889,0.933,0.912 and 0.035 respectively.MiR-199a was downregulated according to degree of fibrosis.CONCLUSION Depending on the diagnostic accuracy,we have concluded that miR-122,miR-155 and miR-21 are reliable markers to detect fibrosis in Hepatitis C patients.展开更多
BACKGROUND The albumin-bilirubin(ALBI)score was developed as a prognostic tool for pa-tients with hepatocellular carcinoma.However,its new role as an indicator of liver fibrosis in chronic hepatitis C virus(HCV)patien...BACKGROUND The albumin-bilirubin(ALBI)score was developed as a prognostic tool for pa-tients with hepatocellular carcinoma.However,its new role as an indicator of liver fibrosis in chronic hepatitis C virus(HCV)patients is under investigation.AIM To investigate the ALBI score as a non-invasive means of assessing the extent of liver fibrosis in chronic HCV patients.METHODS We evaluated hospital records of 231 eligible chronic HCV patients from King Fahad Specialist Hospital in Buraydah,Saudi Arabia.Demographic/clinical data,liver function tests,non-invasive tests for liver fibrosis,and ALBI score/grades were evaluated before and two years after direct-acting antivirals(DAA)treatment.RESULTS The median ALBI score improved from-2.51 to-2.62 after DAA treatment(P<0.05).Additionally,the ALBI score improved irrespective of the level of fibrosis,with improvement more evident in patients with advanced fibrosis(-2.26 to-2.41,P<0.05).The ALBI score showed significant positive correlation with non-invasive tests for liver fibrosis(aspartate aminotransferase/alanine aminotransferase ratio,aspartate aminotransferase to platelet ratio index,and fibrosis-4 index)at baseline and after DAA treatment(P<0.05).Moreover,the receiver operating characteristic curve demonstrated ALBI score’s ability to predict advanced fibrosis(F3,F4)[area under the curve=0.76,(95%confidence interval:0.70-0.81),P<0.001,best cut-off value=-2.38(sensitivity 60%and specificity 83%)].CONCLUSION The ALBI score appears to be a useful non-invasive marker for assessing liver fibrosis in chronic HCV patients and may serve as a valuable tool for monitoring hepatic function during and after DAA treatment.展开更多
Liver fibrosis,a hallmark pathological endpoint of chronic aging-related liver diseases,remains a clinical challenge with limited therapeutic options.In healthy liver,myeloid cells constitute<5%of total hepatic imm...Liver fibrosis,a hallmark pathological endpoint of chronic aging-related liver diseases,remains a clinical challenge with limited therapeutic options.In healthy liver,myeloid cells constitute<5%of total hepatic immune cells,primarily comprising tissue-resident Kupffer cells.However,during aging or chronic injury,bone marrow-derived myeloid cell recruitment increases by two-to threefold in murine fibrotic models,reaching 15%-20% of intrahepatic immune populations.These infiltrating myeloid subsets exhibit functional plasticity,dynamically differentiating into pro-inflammatory mac-rophages or fibrosis-promoting Kupffer-like cells,contingent upon chemokine gradi-ents(e.g.,CCL2/CCR2 axis)and damage-associated molecular patterns(DAMPs).This review systematically examines the regulatory mechanisms of myeloid cells in liver fibrogenesis,with particular emphasis on their developmental origins,hepatic recruit-ment dynamics,functional heterogeneity,and pathogenic contributions to fibrosis.Furthermore,signaling pathways involving myeloid cells in liver fibrosis and therapeu-tic approaches modulating their differentiation and recruitment are discussed in this review.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)requires accurate liver fibrosis assessment for management.While liver biopsy remains the gold standard,its invasiveness drives demand for non-invasive bi...Metabolic dysfunction-associated steatotic liver disease(MASLD)requires accurate liver fibrosis assessment for management.While liver biopsy remains the gold standard,its invasiveness drives demand for non-invasive biomarkers.This review evaluates blood biomarkers for MASLD fibrosis staging.Established scores(fibrosis-4,non-alcoholic fatty liver disease fibrosis score)offer accessible screening but exhibit variable performance influenced by age,obesity,and comorbidities.Patented panels(e.g.,enhanced liver fibrosis test,FibroMeter)improve accuracy by integrating extracellular matrix or metabolic markers,though context-specific thresholds are essential.Emerging biomarkers like propeptide of type 3 collagen,Mac-2 binding protein glycosylation isomer,epigenetic markers(proliferator-activated receptor-γmethylation),and angiopoietin-like proteins a family of eight glycoproteins show promise but require large-scale validation.Genetic risk scores and multi-omics approaches face generalizability challenges.Integration strategies,such as combining serum biomarkers with liver stiffness measurement via Agile scores,enhance diagnostic precision and reduce indeterminate classifications.Current tools aid risk stratification,but no single biomarker replicates biopsy-level precision.Future efforts must prioritize MASLD-specific diagnostic frameworks,standardized protocols,and multi-modal integration to enhance clinical utility and address MASLD’s growing burden.展开更多
Alcohol-associated liver disease(ALD)is a major global health concern,contributing to liver injury,morbidity,and mortality.Elafibranor(EFN),a dual peroxisome proliferator-activated receptorα/δagonist,has shown promi...Alcohol-associated liver disease(ALD)is a major global health concern,contributing to liver injury,morbidity,and mortality.Elafibranor(EFN),a dual peroxisome proliferator-activated receptorα/δagonist,has shown promise as a therapeutic candidate in preclinical studies.EFN reduces liver fibrosis by inhibiting lipid accumulation,apoptosis,and inflammatory pathways(LPS/TLR4/NF-κB),while enhancing autophagy and antioxidant responses.It also improves intestinal barrier function and modulates gut microbiota,reducing endotoxin-producing bacteria and increasing beneficial species.By strengthening the intestinal barrier and suppressing pro-inflammatory mediators like tumor necrosis factor-alpha and interleukin-6,EFN mitigates hepatic stellate cell activation and fibrogenic signaling.Macrophages play a central role in ALD progression,and EFN’s ability to modulate macrophage activity further highlights its anti-inflammatory properties.This review emphasizes EFN’s dual-targeted approach,addressing both hepatic and intestinal dysfunctions,distinguishing it from conventional ALD treatments.While preclinical results are promising,EFN remains under clinical investigation,with ongoing trials evaluating its safety and efficacy.Future research should focus on elucidating EFN’s molecular mechanisms and advancing its clinical application to establish its therapeutic potential in human populations.EFN represents a novel,comprehensive strategy for ALD management,targeting both liver and gut pathologies.展开更多
This study employs combined network pharmacology and molecular docking approaches to investigate the potential mechanisms by which Erigeron breviscapus polyphenols inhibit liver fibrosis.Active compounds were identifi...This study employs combined network pharmacology and molecular docking approaches to investigate the potential mechanisms by which Erigeron breviscapus polyphenols inhibit liver fibrosis.Active compounds were identified through literature mining,with targets predicted using TCMSP,PubChem,SwissTarget,and SwissADME databases.Liver fibrosis-related targets were retrieved from GeneCards,OMIM,and TTD.Following rigorous screening,12 bioactive polyphenolic compounds and 117 corresponding targets were identified,intersecting with 8,375 liver fibrosis targets to yield 67 common targets.Protein-protein interaction analysis revealed 80 key targets(e.g.,EGFR,ESR1,PTGS2).GO and KEGG analyses indicated enrichment in 352 biological terms and 50 pathways,including chemical carcinogenesis receptor activation and steroid hormone biosynthesis.Molecular docking confirmed effective binding affinity between the top four compounds(by degree value)and their respective targets.In summary,the results of this study indicate that Erigeron breviscapus can inhibit the development of liver fibrosis and related diseases through multiple components,targets,and pathways.This study provides a solid theoretical basis for the research of Erigeron breviscapus in the field of anti liver fibrosis.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is now the leading cause of chronic liver disease in children,affecting up to 38%with obesity of children.With the global shift from non-alcoholic fatty l...Metabolic dysfunction-associated steatotic liver disease(MASLD)is now the leading cause of chronic liver disease in children,affecting up to 38%with obesity of children.With the global shift from non-alcoholic fatty liver disease(NAFLD)to MASLD using affirmative criteria(hepatic steatosis plus≥1 cardiometabolic risk factor)and approximately 99%concordance in pediatrics,the development of non-invasive fibrosis tools is accelerating.Yao et al report a machine-learning“chronic MASLD with fibrosis(CH-MASLD-Fib)”score for advanced fibrosis with area under the receiver operating characteristic curve(AUROC)of 0.92.While timely,we urge caution.First,high accuracy from a single-center cohort signals overfitting:Complex models can learn cohort-specific noise and fail to generalize.Consistent with this,established pediatric scores(NAFLD fibrosis score,fibrosis-4,pediatric NAFLD fibrosis score)perform modestly(AUROC:Approximately 0.6-0.7),and aspartate aminotransferase-to-platelet ratio index is variable,raising concern that CH-MASLD-Fib’s result reflects a statistical artifact.Second,MASLD epidemiology varies by ethnicity(highest in Hispanic,lower in Black children);a model derived in a mono-ethnic Chinese cohort may misclassify other populations.Third,clinical utility and cost-effectiveness are unproven;dependence on specialized assays(e.g.,bile acids,cholinesterase)would limit access and increase cost.We recommend external validation in multi-ethnic cohorts,head-to-head comparisons with simple serum indices and elastography,and formal economic analyses.Until then,clinical judgment anchored in readily available markers and judicious,targeted liver biopsy remains paramount.展开更多
Background Changes in macrophage function are crucial contributors to hepatic inflammation and fibrosis.However,the role of macrophages in the development of liver fibrosis in dairy cows with ketosis remains unclear.T...Background Changes in macrophage function are crucial contributors to hepatic inflammation and fibrosis.However,the role of macrophages in the development of liver fibrosis in dairy cows with ketosis remains unclear.This study integrated proteomics and cytokine array approach to identify the multifactorial and multicellular interaction effects driving liver fibrosis in dairy cows with ketosis and analyze the mechanism by which the proinflammatory shift in macrophages contributes to liver fibrosis.Results Histopathological analysis revealed liver injury,including severe steatosis,infiltration of inflammatory cells,an increase in lipid deposition,and a decrease in glycogen expression in ketotic cows.Moreover,the number of mitochondria considerably increased in hepatocytes.The activation of the dynamin-related protein 1/mitochondrial fission factor(DRP1/MFF)pathway induced excessive mitochondrial fission,and the inhibition of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1(Nrf2/HO-1)pathway led to the accumulation of intracellular reactive oxygen species(ROS).Proteomic analysis revealed the activation of extracellular matrix(ECM)-related functions and the NF-κB pathway in the liver,whereas cytokine array analysis revealed that the cytokine network was dysregulated.The accumulation of ROS triggered NF-κB nuclear translocation,inducing a proinflammatory shift in macrophages and liver inflammation.M1 polarization of macrophages promotes the release of proinflammatory mediators,which stimulated hepatic stellate cells(HSCs)activation,leading to ECM deposition,ultimately contributing to liver fibrosis.Conclusions To summarize,our study revealed the multifactorial and multicellular interaction effects driving liver fibrosis.Our results preliminarily showed that increased mitochondrial fission and inhibition of the Nrf2/HO-1 pathway are key factors in activating macrophages,which can lead to liver fibrosis in dairy cows with ketosis.展开更多
BACKGROUND Core-fucosylated low-molecular-weight kininogen(LMWK-Fc)levels are significantly elevated in patients with liver fibrosis and cirrhosis.AIM To assess the value of LMWK-Fc as a diagnostic biomarker for liver...BACKGROUND Core-fucosylated low-molecular-weight kininogen(LMWK-Fc)levels are significantly elevated in patients with liver fibrosis and cirrhosis.AIM To assess the value of LMWK-Fc as a diagnostic biomarker for liver fibrosis.METHODS Our study included 132 healthy people and 132 patients with liver fibrosis.The LMWK-Fc level was measured based on the principle of chemiluminescence.Fibrosis stage and inflammatory activity were assessed by liver biopsy.Comparative analysis between groups and receiver operating characteristic curve analysis were performed.RESULTS LMWK-Fc had an area under the curve of 0.871,which indicates a good level of performance in distinguishing between patients with and without fibrosis.Furthermore,the LMWK-Fc level had a certain correlation with the liver stiffness value,which reached 0.5789.CONCLUSION LMWK-Fc could be used as a non-invasive marker of liver fibrosis.Further studies are needed to evaluate the usefulness of this marker.展开更多
基金supported by the National Natural Science Foundation of China (Nos.82404454,22407144,and 82304322)the China Postdoctoral Science Foundation (No.2024M753800)+1 种基金the Postdoctoral Fellowship Program of CPSF (No.GZC20242113)the Open Program of Shenzhen Bay Laboratory(No.SZBL2021080601007)
文摘Twelve new diterpenoids,euphorwallnoids A-L(1-12),comprising five rhamnofolanes(1-5),five tiglianes(6-10),and two daphnanes(11 and 12),along with six known analogues(13-18),were isolated from the whole plants of Euphorbia wallichii(E.wallichii).Their structures were determined using spectroscopic analysis,computational methods,chemical derivatization,and single-crystal X-ray diffraction.Euphorwallnoid A(1)features an unusual 5/7/6/5-tetracyclic scaffold,whereas 2-5 represent a rare subclass of 4-deoxygenated rhamnofolanes and 6-8 constitute 13-deoxygenated tiglianes.Notably,compound 1 demonstrated promising anti-liver fibrosis activity by significantly inhibiting the expression of fibronectin(FN),α-smooth muscle actin(α-SMA),and collagen I in transforming growth factorβ1(TGF-β1)-stimulated LX-2 cells at micromolar concentrations.
文摘Artificial intelligence(AI)is revolutionizing medical imaging,particularly in chronic liver diseases assessment.AI technologies,including machine learning and deep learning,are increasingly integrated with multiparametric ultrasound(US)techniques to provide more accurate,objective,and non-invasive evaluations of liver fibrosis and steatosis.Analyzing large datasets from US images,AI enhances diagnostic precision,enabling better quantification of liver stiffness and fat content,which are essential for diagnosing and staging liver fibrosis and steatosis.Combining advanced US modalities,such as elastography and doppler imaging with AI,has demonstrated improved sensitivity in identifying different stages of liver disease and distinguishing various degrees of steatotic liver.These advancements also contribute to greater reproducibility and reduced operator dependency,addressing some of the limitations of traditional methods.The clinical implications of AI in liver disease are vast,ranging from early detection to predicting disease progression and evaluating treatment response.Despite these promising developments,challenges such as the need for large-scale datasets,algorithm transparency,and clinical validation remain.The aim of this review is to explore the current applications and future potential of AI in liver fibrosis and steatosis assessment using multiparametric US,highlighting the technological advances and clinical relevance of this emerging field.
文摘Traditional Chinese medicine(TCM)has shown remarkable potential for treating liver fibrosis.In this study,to identify novel TCMs with antifibrotic properties,we used a technique called high-throughput sequencing-based high-throughput screening(HTS2),which is based on RNA-mediated oligonucleotide annealing,selection,and ligation followed by sequencing.This technology achieved parallel and quantitative analysis of gene expression in response to thousands of drug treatments[1].
文摘This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid accumulation,apoptosis,and inflammatory responses exacerbated by gut barrier dysfunction.The study explored the therapeutic potential of elafibranor,a dual peroxisome proliferatoractivated receptor alpha/delta agonist.In clinical trials,elafibranor has shown promise for the treatment of other liver conditions;however,its effects on ALD remain unclear.The authors’findings indicate that elafibranor significantly reduced liver fibrosis and enhanced gut barrier integrity in patients with ALD.These positive effects of elafibranor are mediated through multiple pathways.Elafibranor promotes lipid metabolism,reduces oxidative stress,and inhibits inflammatory responses by restoring gut barrier function.Specifically,it improves hepatocyte function by enhancing autophagic and antioxidant capacity,and it mitigates inflammation by suppressing the lipopolysaccharide/toll-like receptor 4/nuclear factor kappa B signaling pathway.These findings indicate that elafibranor has promising clinical applications.In addition,the study highlights elafibranor’s potential as a therapeutic agent for liver diseases,particularly ALD.This article underscores the importance of understanding the mechanistic pathways underlying ALD and suggests directions for future research aimed at elucidating the benefits and limitations of elafibranor.
基金supported by the National Natural Science Foundation of China(Grant No.:81873576)Wenzhou Municipal Science and Technology Bureau,China(Grant No.:Y20220023).
文摘Liver fibrosis is a common outcome of various chronic hepatic insults,characterized by excessive extracellular matrix(ECM)deposition.The precise mechanisms,however,remain largely undefined.This study identified an elevated expression of platelet-activating factor acetylhydrolase 1B3(Pafah1b3)in liver tissues from both carbon tetrachloride(CCl_(4))-treated mice and patients with cirrhosis.Deletion of Pafah1b3 significantly attenuated CCl_(4)-induced fibrosis,hepatic stellate cell(HSC)activation,and activation of transforming growth factor-β(TGF-β)signaling.Mechanistically,PAFAH1B3 binds to mothers against decapentaplegic homolog 7(SMAD7),disrupting SMAD7's interaction with TGF-βreceptor 1(TβR1),which subsequently decreases TbR1 ubiquitination and degradation.Pharmacological inhibition using 3-IN-P11,a specific Pafah1b3 inhibitor,conferred protective effects against CCl_(4)-induced fibrosis in mice.Furthermore,Pafah1b3 deficiency reduced hepatic inflammation.Overall,these results establish a pivotal role for Pafah1b3 in modulating TGF-βsignaling and driving HSC activation.
基金Supported by Wroclaw Medical University’s Grant,No.SUBZ.C270.24.078.
文摘BACKGROUND This review evaluated the diagnostic effectiveness of various ultrasound(US)methods compared to liver biopsy.AIM To determine the diagnostic accuracy of US techniques in assessing liver fibrosis and steatosis in adults,using the area under the receiver operating characteristic curve(AUROC)as the standard measure.METHODS The review included original retrospective or prospective studies published in the last three years in peer-reviewed medical journals,that reported AUROC values.Studies were identified through PubMed searches on January 3 and April 30,2024.Quality was assessed using the QUADAS-2 tool.Results were tabulated according to the diagnostic method and the type of liver pathology.RESULTS The review included 52 studies.For liver fibrosis detection,2D-shear wave elastography(SWE)AUROCs ranged from 0.54 to 0.994,showing better accuracy for advanced stages.Modifications,including 2D-SWE with propagation map guidance and supersonic imagine achieved AUROCs of 0.84 to nearly 1.0.point SWE and classical SWE had AUROCs of 0.741-0.99,and 0.507-0.995,respectively.Transient elastography(TE),visual TE,vibration-controlled TE(VCTE),and FibroTouch reported AUROCs close to 1.0.For steatosis,VCTE with controlled attenuation parameter showed AUROCs up to 0.89(for≥S1),acoustic radiation force impulse ranged from 0.762 to 0.784,US attenuation parameter from 0.88 to 0.93,and normalized local variance measurement from 0.583 to 0.875.Most studies had a low risk of bias across all or most domains,but evidence was limited by variability in study quality and small sample sizes.Innovative SWE variants were evaluated in a single study.CONCLUSION Modern US techniques can serve as effective noninvasive diagnostic tools for liver fibrosis and steatosis,with the potential to reduce the reliance on biopsies.
文摘BACKGROUND The Streptococcus salivarius(S.salivarius)group,which produces the enzyme urease has been identified as a potential contributor to ammonia production in the gut.Researchers have reported that patients with minimal HE had an increased abundance of the S.salivarius group,which is a specific change in the gut microbiota that distinguishes them from healthy individuals.The correlation between the aggregation of specific bacterial species and fibrosis progression in chronic liver disease(CLD)is yet to be fully elucidated.AIM To quantify S.salivarius using digital PCR(dPCR)as a liver fibrosis marker of CLD.METHODS This study retrospectively analysed 52 patients with CLD.To quantify S.salivarius in patients with CLD using dPCR,we evaluated the specificity and sensitivity of S.salivarius bacterial load using dPCR for a type strain.Next,we evaluated the clinical usefulness of dPCR for S.salivarius load quantification for detecting liver fibrosis in patients with CLD.The liver fibrosis stage was categorized into mild and advanced fibrosis based on pathological findings.RESULTS The dPCR assay revealed that S.salivarius was highly positive for the tnpA gene.The lower limit of quantification for dPCR using the tnpA gene with a 1μL template comprising 1.28×102 CFU/mL was 4.3 copies.After considering the detection range in dPCR,we adjusted the extracted DNA concentration to 5.0×10-4 ng/μL from 200 mg stool samples.The median bacterial loads of S.salivarius in stool sample from patients with mild and advanced fibrosis were 1.9 and 7.4 copies/μL,respectively.The quantification of S.salivarius load was observed more frequently in patients with advanced fibrosis than in those with mild fibrosis(P=0.032).CONCLUSION Quantifying of S.salivarius load using digital PCR is a useful biomarker for liver fibrosis in patients with CLD.
文摘BACKGROUND In metabolic dysfunction-associated steatotic liver disease(MASLD)the identi-fication of patients at high risk of evolution to metabolic dysfunction-associated steatohepatitis(MASH)is challenging.AIM To investigate the performance of different ultrasound(US)-based techniques for the non-invasive assessment of liver fibrosis,steatosis,and inflammation in these patients.METHODS We collected data from consecutive patients who underwent liver biopsy for suspected MASLD between January 2019 and December 2021.Two-dimensional shear-wave elastography,sound speed plane-wave US,attenuation plane-wave US,viscosity plane-wave US(Vi.PLUS)using Aixplorer MACH 30 system,and transient elastography and controlled attenuation parameter from FibroScan were measured before biopsy.RESULTS A total of 120 participants were enrolled.Both transient elastography and two-dimensional shear-wave elasto-graphy showed good performance for the diagnosis of advanced fibrosis[area under the receiver operating charac-teristic curve(AUROC)=0.93 and 0.90,respectively].The diagnostic performance of Vi.PLUS for the presence of both ballooning grade≥1 and lobular inflammation≥1 was good with an AUROC of 0.72.A score based on Vi.PLUS,aspartate aminotransferase,and sound speed plane-wave US[viscosity-aspartate aminotransferase-speed of sound MASH ultrasound score(VAS-MASH-US score)]had a good accuracy for the diagnosis of MASH(AUROC=0.75).VAS-MASH-US score>0.6 showed a good sensitivity for MASH diagnosis(79.0%).According to decision curve analysis,the application of the VAS-MASH-US score would lead to a more accurate selection of patients who are candidates to undergo liver biopsy and would reduce the need for invasive procedures for patients at low risk of MASH.CONCLUSION Multiparametric US allows the non-invasive assessment of steatosis,inflammation,and fibrosis in patients with MASLD.Liver viscosity improved the capability of non-invasively identifying patients with MASH.
文摘Chronic liver disease results in a response resembling"wound healing",also known as fibrosis,resulting in the progressive accumulation of connective tissue.Excessive fibrogenesis that results in the disruption of intercellular connections,interactions,and extracellular matrix composition are features of the fibrotic pro-cess mediated by various cell types and chemical mediators such as transforming growth factor-β.Redox-sensitive processes are major contributors to controlling this inflammatory and pro-fibrogenic cytokine's production and synthesis.Other essential hepatic fibrogenesis activities,such as the activation of stellate cells,the expression of metalloproteinases and their inhibitors can also be linked to ge-neration of reactive oxygen species and lipid peroxidation products,which are implicated in development and progression of fibrosis.The herb Silybum maria-num,also known as milk thistle,is widely studied for its potential to treat liver illnesses.Silymarin contains 50%to 70%silybin,which has the highest level of biological activity.In comparison,silybin seems to be relatively safer and the avai-lable evidence on its potential mechanisms of action is encouraging.The aim of this article is to analyze the increasing evidences linking biochemical oxidative events to excessive fibrogenesis and silybin's inhibitory mechanisms that aid in the reversal of fibrosis and fibrotic lesions.
基金National Natural Science Foundation of China,Grant/Award Number:82174292Key Project of Jiangsu Provincial Administration of Traditional Chinese Medicine,Grant/Award Number:ZD202312+2 种基金Natural Science Foundation of Laboratory Medicine School in Chengdu Medical College,Grant/Award Number:JYZK202203Sichuan Province Science and Technology Program,Grant/Award Number:2024NSFSC0577 and 2021YFG0316Technology innovation group project of Foshan 2019,Grant/Award Number:FS0AA-KJ919-4402-0027。
文摘Background:The emerging incidence of pathogenic liver conditions is turning into a major concern for global health.Induction of pyroptosis in hepatocytes instigates cel-lular disintegration,which in turn liberates substantial quantities of pro-inflammatory intracellular substances,thereby accelerating the advancement of liver fibrosis.Consequently,directing therapeutic efforts towards inhibiting pyroptosis could po-tentially serve as an innovative approach in managing inflammation related chronic hepatic disorders.Methods:GSDMD-NT^(ki/wt)mice and Alb-cre^(ki/wt)mice were generated using CRISPR/Cas9 technology.After crossing the two strains together,we induced conditional cell death by doxycycline to construct a mouse model of liver fibrosis.We analyzed differ-entially expressed genes by RNA sequencing and explored their biological functions.The efficacy of obeticholic acid(OCA)in the treatment of liver fibrosis was assessed.Results:Doxycycline-treated GSDMD-NT^(ki/wt)×Alb-cre^(ki/wt)mice showed severe liver damage,vacuolation of hepatocytes,increased collagen fibers,and accumulation of lipid droplets.The expression of liver fibrosis related genes was greatly increased in the doxycycline-treated mouse liver compared with untreated mouse liver.RNA-sequencing showed that upregulated differentially expressed genes were involved in inflammatory responses,cell activation,and metabolic processes.Treatment with OCA alleviated the liver fibrosis,with reduced ALT and AST levels seen in the GSDMD-NT^(ki/wt)×Alb-cre^(ki/wt)mice.Conclusions:We successfully constructed a novel mouse model for liver fibrosis.This GSDMD-NT-induced fibrosis may be mediated by abnormal lipid metabolism.Our re-sults demonstrated that we successfully constructed a mouse model of liver fibrosis,and GSDMD-NT induced fibrosis by mediating lipid metabolism.
文摘Liver diseases are among the most insidious and life-threatening conditions due to their progressive nature and late symptom onset.Cirrhosis and hepatocellular carcinoma account for most liver-related deaths,often following the progression from fibrosis.Fibrosis creates a hostile microenvironment,characterized by portal hypertension,vascular capillarization,intrahepatic vasoconstriction,and extracellular matrix deposition,which severely limits drug efficacy.Advances in pharmaceutical science have prompted efforts to develop liver-targeted drug delivery systems to prevent or reduce the progression of fibrosis,a central feature of many liver diseases.Fibrosis often reduces the in vivo efficacy of both approved and experimental drugs,underscoring the need for improved delivery strategies focused on stability,controlled release,and precise targeting.Nanoparticle(NP)-based systems show promise,either by delivering therapeutic agents,or in some cases,by contributing directly to the therapeutic effects.This review summarizes the main types of NPs explored for liver disease treatment,especially those aiming to reverse fibrosis or prevent its progression,a critical therapeutic target in chronic liver diseases.Additionally,it examines gene delivery and ultrasoundguided microbubble strategies,which can be combined with NPs to improve cellspecific targeting and boost therapeutic effects.Together,these approaches have the potential to address current therapeutic challenges and accelerate the development of liver-targeted treatments for clinical application.
文摘BACKGROUND Hepatitis C virus(HCV)infection process of progression encompasses multiple stages,commencing with inflammation and culminating in hepatocellular cancer.Numerous invasive and non-invasive procedures exist for diagnosing chronic HCV infection.Though beneficial,invasive procedures can cause morbidity and inadequate representation of the overall degree of fibrosis.Due to these reasons,non-invasive liver fibrosis biomarkers are becoming more prevalent to diagnose and track liver fibrosis without a liver biopsy.These biomarkers can detect liver fibrosis early,improving treatment and preventing cirrhosis and liver failure.Micro ribonucleic acid(MiRNA)dysregulation causes and worsens several diseases including liver disease.MiRNAs can facilitate the diagnosis of liver fibrosis and serve as a predictive tool to enhance patient care by minimizing invasive procedures and enabling more efficient and prompt therapy.AIM To investigate the diagnostic effectiveness of several miRNAs(miRNA-122,miRNA-21,miRNA-199a,miRNA-155)in assessing the liver fibrosis severity in untreated HCV patients from the Indian Punjab population.We seek to identify the intricate diagnostic relationship of miRNAs with the extent of fibrosis among individuals with HCV.METHODS We considered 100 persons determined as HCV infected by a quantitative Real-Time Polymerase Chain Reaction examination.We employed statistical as well as probabilistic tools to ascertain the diagnostic validity of miRNAs for determining the liver fibrosis stages.We employed Bayesian Networks,to introduce a unique diagnostic paradigm for miRNAs that can be adopted as benchmark to evaluate the liver fibrosis severity in HCV cases.RESULTS We found that miRNAs(miR-122,miR-155 and miR-21)showed significant upregulation when compared with control and according to severity of fibrosis(P≤0.05).The area under the curve for miR-122,miR-155,miR-21 and miR-199a in HCV group in relation to Liver Stiffness Measurement was calculated as 0.889,0.933,0.912 and 0.035 respectively.MiR-199a was downregulated according to degree of fibrosis.CONCLUSION Depending on the diagnostic accuracy,we have concluded that miR-122,miR-155 and miR-21 are reliable markers to detect fibrosis in Hepatitis C patients.
文摘BACKGROUND The albumin-bilirubin(ALBI)score was developed as a prognostic tool for pa-tients with hepatocellular carcinoma.However,its new role as an indicator of liver fibrosis in chronic hepatitis C virus(HCV)patients is under investigation.AIM To investigate the ALBI score as a non-invasive means of assessing the extent of liver fibrosis in chronic HCV patients.METHODS We evaluated hospital records of 231 eligible chronic HCV patients from King Fahad Specialist Hospital in Buraydah,Saudi Arabia.Demographic/clinical data,liver function tests,non-invasive tests for liver fibrosis,and ALBI score/grades were evaluated before and two years after direct-acting antivirals(DAA)treatment.RESULTS The median ALBI score improved from-2.51 to-2.62 after DAA treatment(P<0.05).Additionally,the ALBI score improved irrespective of the level of fibrosis,with improvement more evident in patients with advanced fibrosis(-2.26 to-2.41,P<0.05).The ALBI score showed significant positive correlation with non-invasive tests for liver fibrosis(aspartate aminotransferase/alanine aminotransferase ratio,aspartate aminotransferase to platelet ratio index,and fibrosis-4 index)at baseline and after DAA treatment(P<0.05).Moreover,the receiver operating characteristic curve demonstrated ALBI score’s ability to predict advanced fibrosis(F3,F4)[area under the curve=0.76,(95%confidence interval:0.70-0.81),P<0.001,best cut-off value=-2.38(sensitivity 60%and specificity 83%)].CONCLUSION The ALBI score appears to be a useful non-invasive marker for assessing liver fibrosis in chronic HCV patients and may serve as a valuable tool for monitoring hepatic function during and after DAA treatment.
基金National Key Research and Development Program of China,Grant/Award Number:2021YFA0804903National Natural Science Foundation of China,Grant/Award Number:882171545 and 91949125The Start-up Fund for Distinguished Research Fellows,the International Institute of Health Medicine,Zhejiang University,Grant/Award Number:Q22005。
文摘Liver fibrosis,a hallmark pathological endpoint of chronic aging-related liver diseases,remains a clinical challenge with limited therapeutic options.In healthy liver,myeloid cells constitute<5%of total hepatic immune cells,primarily comprising tissue-resident Kupffer cells.However,during aging or chronic injury,bone marrow-derived myeloid cell recruitment increases by two-to threefold in murine fibrotic models,reaching 15%-20% of intrahepatic immune populations.These infiltrating myeloid subsets exhibit functional plasticity,dynamically differentiating into pro-inflammatory mac-rophages or fibrosis-promoting Kupffer-like cells,contingent upon chemokine gradi-ents(e.g.,CCL2/CCR2 axis)and damage-associated molecular patterns(DAMPs).This review systematically examines the regulatory mechanisms of myeloid cells in liver fibrogenesis,with particular emphasis on their developmental origins,hepatic recruit-ment dynamics,functional heterogeneity,and pathogenic contributions to fibrosis.Furthermore,signaling pathways involving myeloid cells in liver fibrosis and therapeu-tic approaches modulating their differentiation and recruitment are discussed in this review.
基金Supported by the National Natural Science Foundation of China,No.82402719Sichuan Science and Technology Program,No.2025ZNSFSC1553.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)requires accurate liver fibrosis assessment for management.While liver biopsy remains the gold standard,its invasiveness drives demand for non-invasive biomarkers.This review evaluates blood biomarkers for MASLD fibrosis staging.Established scores(fibrosis-4,non-alcoholic fatty liver disease fibrosis score)offer accessible screening but exhibit variable performance influenced by age,obesity,and comorbidities.Patented panels(e.g.,enhanced liver fibrosis test,FibroMeter)improve accuracy by integrating extracellular matrix or metabolic markers,though context-specific thresholds are essential.Emerging biomarkers like propeptide of type 3 collagen,Mac-2 binding protein glycosylation isomer,epigenetic markers(proliferator-activated receptor-γmethylation),and angiopoietin-like proteins a family of eight glycoproteins show promise but require large-scale validation.Genetic risk scores and multi-omics approaches face generalizability challenges.Integration strategies,such as combining serum biomarkers with liver stiffness measurement via Agile scores,enhance diagnostic precision and reduce indeterminate classifications.Current tools aid risk stratification,but no single biomarker replicates biopsy-level precision.Future efforts must prioritize MASLD-specific diagnostic frameworks,standardized protocols,and multi-modal integration to enhance clinical utility and address MASLD’s growing burden.
文摘Alcohol-associated liver disease(ALD)is a major global health concern,contributing to liver injury,morbidity,and mortality.Elafibranor(EFN),a dual peroxisome proliferator-activated receptorα/δagonist,has shown promise as a therapeutic candidate in preclinical studies.EFN reduces liver fibrosis by inhibiting lipid accumulation,apoptosis,and inflammatory pathways(LPS/TLR4/NF-κB),while enhancing autophagy and antioxidant responses.It also improves intestinal barrier function and modulates gut microbiota,reducing endotoxin-producing bacteria and increasing beneficial species.By strengthening the intestinal barrier and suppressing pro-inflammatory mediators like tumor necrosis factor-alpha and interleukin-6,EFN mitigates hepatic stellate cell activation and fibrogenic signaling.Macrophages play a central role in ALD progression,and EFN’s ability to modulate macrophage activity further highlights its anti-inflammatory properties.This review emphasizes EFN’s dual-targeted approach,addressing both hepatic and intestinal dysfunctions,distinguishing it from conventional ALD treatments.While preclinical results are promising,EFN remains under clinical investigation,with ongoing trials evaluating its safety and efficacy.Future research should focus on elucidating EFN’s molecular mechanisms and advancing its clinical application to establish its therapeutic potential in human populations.EFN represents a novel,comprehensive strategy for ALD management,targeting both liver and gut pathologies.
基金supported by the Liaoning Provincial Department of Education(No.LJ212510163023)Liaoning Provincial Natural Science Foundation(No.2024-MSLH-443).
文摘This study employs combined network pharmacology and molecular docking approaches to investigate the potential mechanisms by which Erigeron breviscapus polyphenols inhibit liver fibrosis.Active compounds were identified through literature mining,with targets predicted using TCMSP,PubChem,SwissTarget,and SwissADME databases.Liver fibrosis-related targets were retrieved from GeneCards,OMIM,and TTD.Following rigorous screening,12 bioactive polyphenolic compounds and 117 corresponding targets were identified,intersecting with 8,375 liver fibrosis targets to yield 67 common targets.Protein-protein interaction analysis revealed 80 key targets(e.g.,EGFR,ESR1,PTGS2).GO and KEGG analyses indicated enrichment in 352 biological terms and 50 pathways,including chemical carcinogenesis receptor activation and steroid hormone biosynthesis.Molecular docking confirmed effective binding affinity between the top four compounds(by degree value)and their respective targets.In summary,the results of this study indicate that Erigeron breviscapus can inhibit the development of liver fibrosis and related diseases through multiple components,targets,and pathways.This study provides a solid theoretical basis for the research of Erigeron breviscapus in the field of anti liver fibrosis.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is now the leading cause of chronic liver disease in children,affecting up to 38%with obesity of children.With the global shift from non-alcoholic fatty liver disease(NAFLD)to MASLD using affirmative criteria(hepatic steatosis plus≥1 cardiometabolic risk factor)and approximately 99%concordance in pediatrics,the development of non-invasive fibrosis tools is accelerating.Yao et al report a machine-learning“chronic MASLD with fibrosis(CH-MASLD-Fib)”score for advanced fibrosis with area under the receiver operating characteristic curve(AUROC)of 0.92.While timely,we urge caution.First,high accuracy from a single-center cohort signals overfitting:Complex models can learn cohort-specific noise and fail to generalize.Consistent with this,established pediatric scores(NAFLD fibrosis score,fibrosis-4,pediatric NAFLD fibrosis score)perform modestly(AUROC:Approximately 0.6-0.7),and aspartate aminotransferase-to-platelet ratio index is variable,raising concern that CH-MASLD-Fib’s result reflects a statistical artifact.Second,MASLD epidemiology varies by ethnicity(highest in Hispanic,lower in Black children);a model derived in a mono-ethnic Chinese cohort may misclassify other populations.Third,clinical utility and cost-effectiveness are unproven;dependence on specialized assays(e.g.,bile acids,cholinesterase)would limit access and increase cost.We recommend external validation in multi-ethnic cohorts,head-to-head comparisons with simple serum indices and elastography,and formal economic analyses.Until then,clinical judgment anchored in readily available markers and judicious,targeted liver biopsy remains paramount.
基金supported by the National Natural Science Foundation of China(32125038 and 32402957)China National Postdoctoral Program for Innovative Talents(BX20240417)+1 种基金China Postdoctoral Science Foundation funded project(2024M753563)National Key Research and Development Program of China(2023YFD1801100).
文摘Background Changes in macrophage function are crucial contributors to hepatic inflammation and fibrosis.However,the role of macrophages in the development of liver fibrosis in dairy cows with ketosis remains unclear.This study integrated proteomics and cytokine array approach to identify the multifactorial and multicellular interaction effects driving liver fibrosis in dairy cows with ketosis and analyze the mechanism by which the proinflammatory shift in macrophages contributes to liver fibrosis.Results Histopathological analysis revealed liver injury,including severe steatosis,infiltration of inflammatory cells,an increase in lipid deposition,and a decrease in glycogen expression in ketotic cows.Moreover,the number of mitochondria considerably increased in hepatocytes.The activation of the dynamin-related protein 1/mitochondrial fission factor(DRP1/MFF)pathway induced excessive mitochondrial fission,and the inhibition of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1(Nrf2/HO-1)pathway led to the accumulation of intracellular reactive oxygen species(ROS).Proteomic analysis revealed the activation of extracellular matrix(ECM)-related functions and the NF-κB pathway in the liver,whereas cytokine array analysis revealed that the cytokine network was dysregulated.The accumulation of ROS triggered NF-κB nuclear translocation,inducing a proinflammatory shift in macrophages and liver inflammation.M1 polarization of macrophages promotes the release of proinflammatory mediators,which stimulated hepatic stellate cells(HSCs)activation,leading to ECM deposition,ultimately contributing to liver fibrosis.Conclusions To summarize,our study revealed the multifactorial and multicellular interaction effects driving liver fibrosis.Our results preliminarily showed that increased mitochondrial fission and inhibition of the Nrf2/HO-1 pathway are key factors in activating macrophages,which can lead to liver fibrosis in dairy cows with ketosis.
文摘BACKGROUND Core-fucosylated low-molecular-weight kininogen(LMWK-Fc)levels are significantly elevated in patients with liver fibrosis and cirrhosis.AIM To assess the value of LMWK-Fc as a diagnostic biomarker for liver fibrosis.METHODS Our study included 132 healthy people and 132 patients with liver fibrosis.The LMWK-Fc level was measured based on the principle of chemiluminescence.Fibrosis stage and inflammatory activity were assessed by liver biopsy.Comparative analysis between groups and receiver operating characteristic curve analysis were performed.RESULTS LMWK-Fc had an area under the curve of 0.871,which indicates a good level of performance in distinguishing between patients with and without fibrosis.Furthermore,the LMWK-Fc level had a certain correlation with the liver stiffness value,which reached 0.5789.CONCLUSION LMWK-Fc could be used as a non-invasive marker of liver fibrosis.Further studies are needed to evaluate the usefulness of this marker.
