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
Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that extends beyond joint inflammation,affecting pulmonary and metabolic pathways.Interstitial lung disease(ILD)is one of its most serious extra-articul...Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that extends beyond joint inflammation,affecting pulmonary and metabolic pathways.Interstitial lung disease(ILD)is one of its most serious extra-articular complications,while type 2 diabetes mellitus(T2DM)frequently coexists with RA and may exacerbate inflammatory and fibrotic processes.This editorial discusses the study by Sutton et al,the largest population-based analysis to date exploring the link between T2DM and ILD in patients with RA,and reflects on its mechanistic and clinical implications.In a nationwide cohort of more than 120000 hospitalized RA patients,Sutton et al demonstrated that the coexistence of T2DM nearly doubles the odds of developing ILD(odds ratio=2.02;95%confidence interval:1.84-2.22),with additional increases in pulmonary hypertension,pneumothorax,and length of stay.These findings reinforce the concept of a metabolic-pulmonary-autoimmune axis,in which chronic inflammation promotes insulin resistance and metabolic dysfunction,while hyperglycaemia and advanced glycation end-products amplify oxidative stress and fibrogenesis.This reciprocal interaction may induce a self-perpetuating cycle of“metaflammation”,fibrosis,and organ damage.Conclusion:Recognizing diabetes as a silent amplifier of RA-associated ILD redefines the interface between rheumatology,pulmonology,and endocrinology.Early detection and integrated management of metabolic and pulmonary comorbidities should be prioritized,while future studies must determine whether optimizing glycemic control can attenuate pulmonary fibrosis and improve longterm outcomes.展开更多
Fibrosis is characterized as an aberrant reparative process involving the direct replacement of damaged or deceased cells with connective tissue,leading to progressive architectural remodeling across various tissues a...Fibrosis is characterized as an aberrant reparative process involving the direct replacement of damaged or deceased cells with connective tissue,leading to progressive architectural remodeling across various tissues and organs.This condition imposes a substantial burden,resulting in considerable morbidity and mortality.Ginseng(Panax ginseng C.A.Meyer),renowned for its medicinal properties,has been incorporated as a key component in Chinese patent medicines to mitigate fibrotic diseases.Ginsenosides,the primary bioactive compounds in ginseng,have garnered significant attention.Over the past five years,extensive research has explored the pharmaceutical potential of ginsenosides in diverse organ fibrosis conditions,including liver,myocardial,renal,and pulmonary fibrosis.Studies have elucidated that ginsenosides demonstrate potential effects on inflammatory responses stemming from parenchymal cell damage,myofibroblast activation leading to extracellular matrix(ECM)production,and myofibroblast apoptosis or inactivation.Additionally,potential downstream targets and pathways associated with these pathological processes have been identified as being influenced by ginsenosides.This review presents a comprehensive overview of the efficacious treatments utilizing ginsenosides for various tissue fibrosis types and their potential antifibrotic mechanisms.Furthermore,it offers a reference for the development of novel candidate drugs for future organ fibrosis therapies.展开更多
Oral submucous fibrosis(OSF),characterized by excessive deposition of extracellular matrix(ECM)that causes oral mucosal tissue sclerosis,and even cancer transformation,is a chronic,progressive fibrosis disease.However...Oral submucous fibrosis(OSF),characterized by excessive deposition of extracellular matrix(ECM)that causes oral mucosal tissue sclerosis,and even cancer transformation,is a chronic,progressive fibrosis disease.However,despite some advancements in recent years,no targeted antifibrotic strategies for OSF have been approved;likely because the complicated mechanisms that initiate and drive fibrosis remain to be determined.In this review,we briefly introduce the epidemiology and etiology of OSF.Then,we highlight how cell-intrinsic changes in significant structural cells can drive fibrotic response by regulating biological behaviors,secretion function,and activation of ECM-producing myofibroblasts.In addition,we also discuss the role of innate and adaptive immune cells and how they contribute to the pathogenesis of OSF.Finally,we summarize strategies to interrupt key mechanisms that cause OSF,including modulation of the ECM,inhibition of inflammation,improvement of vascular disturbance.This review will provide potential routes for developing novel anti-OSF therapeutics.展开更多
Silicosis,a major persistent occupational disease in China,is a progressive and irreversible pulmonary fibrosis disease with unclear pathogenesis.Cellular senescence,a state of stable cell cycle arrest that is recogni...Silicosis,a major persistent occupational disease in China,is a progressive and irreversible pulmonary fibrosis disease with unclear pathogenesis.Cellular senescence,a state of stable cell cycle arrest that is recognized as a key underlying factor in age-related fibroproliferative disorders,plays an important role in chronic lung diseases,particularly pulmonary fibrosis.We previously reported that SiO2-stimulated mice and alveolar type II epithelial cells develop cellular senescence,which is involved in silicosis formation in alveolar type II epithelial cells[1].Cellular senescence may play an important role in silicosis development;however,the exact underlying mechanisms are not fully understood.展开更多
Cardiac injury initiates repair mechanisms and results in cardiac remodeling and fi-brosis,which appears to be a leading cause of cardiovascular diseases.Cardiac fi-brosis is characterized by the accumulation of extra...Cardiac injury initiates repair mechanisms and results in cardiac remodeling and fi-brosis,which appears to be a leading cause of cardiovascular diseases.Cardiac fi-brosis is characterized by the accumulation of extracellular matrix proteins,mainly collagen in the cardiac interstitium.Many experimental studies have demonstrated that fibrotic injury in the heart is reversible;therefore,it is vital to understand differ-ent molecular mechanisms that are involved in the initiation,progression,and resolu-tion of cardiac fibrosis to enable the development of antifibrotic agents.Of the many experimental models,one of the recent models that has gained renewed interest is isoproterenol(ISP)-induced cardiac fibrosis.ISP is a synthetic catecholamine,sympa-thomimetic,and nonselectiveβ-adrenergic receptor agonist.The overstimulated and sustained activation ofβ-adrenergic receptors has been reported to induce biochemi-cal and physiological alterations and ultimately result in cardiac remodeling.ISP has been used for decades to induce acute myocardial infarction.However,the use of low doses and chronic administration of ISP have been shown to induce cardiac fibrosis;this practice has increased in recent years.Intraperitoneal or subcutaneous ISP has been widely used in preclinical studies to induce cardiac remodeling manifested by fibrosis and hypertrophy.The induced oxidative stress with subsequent perturbations in cellular signaling cascades through triggering the release of free radicals is consid-ered the initiating mechanism of myocardial fibrosis.ISP is consistently used to induce fibrosis in laboratory animals and in cardiomyocytes isolated from animals.In recent years,numerous phytochemicals and synthetic molecules have been evaluated in ISP-induced cardiac fibrosis.The present review exclusively provides a comprehensive summary of the pathological biochemical,histological,and molecular mechanisms of ISP in inducing cardiac fibrosis and hypertrophy.It also summarizes the application of this experimental model in the therapeutic evaluation of natural as well as syn-thetic compounds to demonstrate their potential in mitigating myocardial fibrosis and hypertrophy.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
Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central ...Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.展开更多
Fibrosis is marked by the excessive accumulation of extracellular matrix(ECM)components,leading to tissue scarring and progressive loss of organ function.Myofibroblasts,which emerge during tissue repair,are specialize...Fibrosis is marked by the excessive accumulation of extracellular matrix(ECM)components,leading to tissue scarring and progressive loss of organ function.Myofibroblasts,which emerge during tissue repair,are specialized contractile cells exhibiting features of both fibroblasts and smooth muscle cells.Their expression ofα-smooth muscle actin facilitates contractile activity,while their persistent activation and overproduction of ECM components contribute significantly to pathological wound contraction and fibrotic progression.Beyond ECM production,myofibroblasts play a significant role in the tumor microenvironment(TME)of various solid tumors.The TME is a complex network of immune cells,blood vessels,ECM components,and stromal cells like fibroblasts and myofibroblasts that surrounds and interacts with cancer cells,thereby influencing tumor growth,progression,and therapy responsiveness.Through these interactions,myofibroblasts modulate inflammation,angiogenesis,and tissue remodeling.Maintaining myofibroblast homeostasis is therefore crucial,as its disruption can drive the onset of chronic fibrotic conditions and malignancies.This review explores preclinical and clinical developments in targeting myofibroblasts in fibrotic and TME across various disease models,including hypertrophic scar,idiopathic pulmonary fibrosis,oral submucous fibrosis,cardiac fibrosis,and the desmoplastic stroma of pancreatic and breast cancers.展开更多
BACKGROUND Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis,but their validation is limited because of insufficient data.AIM To investigate the diagnostic performanc...BACKGROUND Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis,but their validation is limited because of insufficient data.AIM To investigate the diagnostic performance of three fibrosis noninvasive tests[FibroTest,vibration-controlled transient elastography(VCTE),and the fibrosis-4 index(FIB-4)and two activity biomarkers(alanine aminotransferase(ALT)and ActiTest].METHODS This study enrolled 103 patients for whom liver biopsy,hepatic elastography results,and laboratory markers were available.Diagnostic performance was assessed with receiver operating characteristic(ROC)curves,the Obuchowski measure(OM),and the Bayesian latent class model.RESULTS FibroTest and VCTE outperformed FIB-4 in cases of significant fibrosis(≥F2),with areas under the ROC curve of 0.83[95%confidence interval(CI):0.73-0.90],0.86(95%CI:0.77-0.92),and 0.71(95%CI:0.60-0.80),respectively.The mean(standard error)OM values were 0.92(0.01),0.93(0.01),and 0.88(0.02)for FibroTest,VCTE,and FIB-4,respectively;FibroTest and VCTE performed comparably,and both were superior to FIB-4(P=0.03 and P=0.005).The areas under the ROC curve values for activity biomarkers were 0.86(95%CI:0.76-0.92)for ActiTest and 0.84(95%CI:0.73-0.90)for ALT(P=0.06).The OM values for ActiTest and ALT were 0.92(0.02)and 0.90(0.02),respectively(P=0.005).CONCLUSION FibroTest and VCTE outperformed FIB-4 according to the OM.FibroTest-ActiTest facilitated the evaluation of both fibrosis and activity.展开更多
Individuals with congenital absence of the vas deferens(CAVD)may transmit cystic fibrosis(CF)-causing variants of the cystic fibrosis transmembrane conductance regulator(CFTR)gene to their offspring through assisted r...Individuals with congenital absence of the vas deferens(CAVD)may transmit cystic fibrosis(CF)-causing variants of the cystic fibrosis transmembrane conductance regulator(CFTR)gene to their offspring through assisted reproductive technology(ART).We aimed to delineate the spectrum and estimate the prevalence of CF-causing variants in Chinese individuals with CAVD through a cohort analysis and meta-analysis.CFTR was sequenced in 145 Chineseindividuals with CAVD.CFTR variants were classified as CF-causing or non-CF-causing variants regarding clinical significance.A comprehensive genotype analysis was performed in Chinese individuals with CAVD,incorporating previous studies and our study cohort.The prevalence of CF-causing variants was estimated through meta-analysis.In our cohort,56 differentCFTR variants were identified in 108(74.5%)patients.Twenty variants were categorized as CF-causing and were detected in 28(19.3%)patients.A comprehensive genotype analysis of 867 patients identified 174 differentCFTR variants.Sixty-four were classified as CF-causing variants,56.3%of which had not been previously reported in Chinese patients with CF.Meta-analysis showed that 14.8%(95%confidence interval[CI]:11.0%-18.9%)CAVD cases harbored one CF-causing variant,and 68.6%(95%CI:65.1%-72.0%)CAVD cases carried at least one CFTR variant.Our study underscores the urgent need for extensiveCFTR screening,including sequencing of whole exons and flanking regions and detection of large rearrangements and deep intronic CF-causing variants,in Chinese individuals with CAVDbefore undergoing ART.The established CF-causing variants spectrum may aid in the development of genetic counseling strategies and preimplantation diagnosis to prevent the birth of a child with CF.展开更多
Fibrosis is a necessary process in the progression of chronic disease to cirrhosis or even cancer,which is a serious disease threatening human health.Recent studies have shown that the early treatment of fibrosis is t...Fibrosis is a necessary process in the progression of chronic disease to cirrhosis or even cancer,which is a serious disease threatening human health.Recent studies have shown that the early treatment of fibrosis is turning point and particularly important.Therefore,how to reverse fibrosis has become the focus and research hotspot in recent years.So far,the considerable progress has been made in the development of effective anti-fibrosis drugs and targeted drug delivery.Moreover,the existing research results will lay the foundation for more breakthrough delivery systems to achieve better anti-fibrosis effects.Herein,this review summaries anti-fibrosis delivery systems focused on three major organ fibrotic diseases such as liver,pulmonary,and renal fibrosis accompanied by the elaboration of relevant pathological mechanisms,which will provide inspiration and guidance for the design of fibrosis drugs and therapeutic systems in the future.展开更多
Arrhythmogenic right ventricular cardiomyopathy(ARVC)is a progressive disease characterized by adipose and fibrous replacement of the myocardium.While elevated testosterone levels have been implicated in the pathologi...Arrhythmogenic right ventricular cardiomyopathy(ARVC)is a progressive disease characterized by adipose and fibrous replacement of the myocardium.While elevated testosterone levels have been implicated in the pathological process of ARVC,its exact contribution to cardiac fibrosis in ARVC remains unclear.In this study,we analyzed the potential contribution of gender-based differences on the distribution of the low-voltage area in an ARVC cohort undergoing an electrophysiological study,which was indicated by feature selection.Additionally,we established engineered cardiac spheroid models in vitro using patient-specific induced pluripotent stem cell(iPSC)-derived cardiomyocytes(iPSC-CMs)and iPSC-derived cardiac fibroblasts(icFBs).We elucidated the pathogenicity of abnormal splicing in the plakophilin-2(PKP2)gene caused by an intronic mutation.Additionally,pathogenic validation of the desmoglein-2(DSG2)point mutation further confirms the reliability of the models.Moreover,testosterone exacerbated the DNA damage in the mutated cardiomyocytes and further activated myofibroblasts in a chain reaction.In conclusion,we designed and constructed an in vitro three-dimensionally-engineered cardiac spheroid model of ARVC based on clinical findings and provided direct evidence of the fibrotic role of testosterone in ARVC.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 The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed th...BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed that nuclear receptor subfamily 4 group A member 1(NR4A1)may serve as a novel pathogenic element in DKD;however,the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.AIM To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.METHODS Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD.Typically,45 mmol/L glucose[high glucose(HG)]was used to activate HK-2 cells to mimic the DKD model in vitro.HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.RESULTS NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells.Concurrently,NOD-like receptor protein 3(NLRP3)and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathways were triggered,and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro.These alterations were significantly reversed via NR4A1 silencing.CONCLUSION Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.展开更多
Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an imp...Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.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
BACKGROUND Neonatal screening(NS)is a public health policy to identify genetic pathologies such as cystic fibrosis(CF),sickle cell disease,and other diseases.Sickle cell disea-se is the comprehensive term for a group ...BACKGROUND Neonatal screening(NS)is a public health policy to identify genetic pathologies such as cystic fibrosis(CF),sickle cell disease,and other diseases.Sickle cell disea-se is the comprehensive term for a group of hemoglobinopathies characterized by the presence of hemoglobin S.CF is an autosomal recessive multisystemic disease with pathophysiology involving deleterious mutations in the transmembrane re-gulatory gene that encodes a protein that regulates the activity of chloride and sodium channels in the cell surface epithelium.NS is crucial for early diagnosis and management,which ensures a better quality of life.AIM To report a case of the coexistence of sickle cell anemia(SCA)and CF and perform an integrative literature review.METHODS This is an observational study and a review of the literature focusing on two rare genetic pathologies identified simultaneously in NS from the perspective of a clinical case.The authors identified only 5 cases of SCA associated with CF.No clinical trials or review articles were identified considering the rarity of the coexistence of these two pathologies.RESULTS Herein,the authors reported the case of a girl who after undergoing NS on day 8 of life was diagnosed with SCA with an alteration in the dosage of immunoreactive trypsin.The diagnosis of CF was confirmed by the Coulometry Sweat Test.The rarity of the co-occurrence of these two severe genetic pathologies(CF and SCA)is a challenge for medical science.CONCLUSION This study adds to the few case reports present in the literature that highlight the identification of two severe diseases via NS.展开更多
[Objectives]To investigate the anti-hepatic fibrosis mechanism of lavandulyl flavonoid Kurarinol A(KA)from Sophora flavescens through the TGF/Smad signaling pathway.[Methods]A hepatic fibrosis model was established by...[Objectives]To investigate the anti-hepatic fibrosis mechanism of lavandulyl flavonoid Kurarinol A(KA)from Sophora flavescens through the TGF/Smad signaling pathway.[Methods]A hepatic fibrosis model was established by TGF-β1-induced activation of human hepatic stellate cells LX-2.Western blot and RT-qPCR techniques were employed to study the anti-fibrotic mechanism of KA through the TGF/Smad signaling pathway.[Results]KA exerted anti-hepatic fibrosis effects by significantly reducing the gene expression levels of TGF-β1,Smad2,Smad3,and Smad4,as well as markedly decreasing the protein expression levels of TGF-β1,p-Smad2/3/Smad2/3,and Smad4.[Conclusions]KA demonstrates significant anti-hepatic fibrosis activity and alleviates liver fibrosis through the TGF/Smad signaling pathway.展开更多
HOX transcription factors and their cofactors,MEINOX,are critical regulators of positional identity and cellular plasticity.While their functions are essential during embryonic development,they also play key roles in ...HOX transcription factors and their cofactors,MEINOX,are critical regulators of positional identity and cellular plasticity.While their functions are essential during embryonic development,they also play key roles in maintaining adult tissue homeostasis.Dysregulation of HOX and MEINOX has been implicated in the pathogenesis of various diseases,including fibrosis and cancer.This review explores the contributions of HOX and MEINOX to dedifferentiation and cellular reprogramming,processes that drive fibrotic disease onset and cancer progression.It also addresses their role in extracellular matrix remodeling in these conditions.Particular attention is given to their involvement in epithelialmesenchymal transition,where altered HOX and MEINOX expression promotes phenotypic plasticity,cancer invasiveness,and fibrotic tissue remodeling.By integrating these perspectives,this review underscores the significance of HOXMEINOX dysregulation and altered positional identity in disease progression.Targeting this dysregulation may offer innovative strategies to modulate epithelial-mesenchymal transition and extracellular matrix dynamics,presenting new therapeutic opportunities for combating fibrosis and cancer.展开更多
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Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that extends beyond joint inflammation,affecting pulmonary and metabolic pathways.Interstitial lung disease(ILD)is one of its most serious extra-articular complications,while type 2 diabetes mellitus(T2DM)frequently coexists with RA and may exacerbate inflammatory and fibrotic processes.This editorial discusses the study by Sutton et al,the largest population-based analysis to date exploring the link between T2DM and ILD in patients with RA,and reflects on its mechanistic and clinical implications.In a nationwide cohort of more than 120000 hospitalized RA patients,Sutton et al demonstrated that the coexistence of T2DM nearly doubles the odds of developing ILD(odds ratio=2.02;95%confidence interval:1.84-2.22),with additional increases in pulmonary hypertension,pneumothorax,and length of stay.These findings reinforce the concept of a metabolic-pulmonary-autoimmune axis,in which chronic inflammation promotes insulin resistance and metabolic dysfunction,while hyperglycaemia and advanced glycation end-products amplify oxidative stress and fibrogenesis.This reciprocal interaction may induce a self-perpetuating cycle of“metaflammation”,fibrosis,and organ damage.Conclusion:Recognizing diabetes as a silent amplifier of RA-associated ILD redefines the interface between rheumatology,pulmonology,and endocrinology.Early detection and integrated management of metabolic and pulmonary comorbidities should be prioritized,while future studies must determine whether optimizing glycemic control can attenuate pulmonary fibrosis and improve longterm outcomes.
基金the National Natural Science Foundation of China(Nos.82374103、82174036)the Fundamental Research Funds for the Central Universities(No.2632024TD03).
文摘Fibrosis is characterized as an aberrant reparative process involving the direct replacement of damaged or deceased cells with connective tissue,leading to progressive architectural remodeling across various tissues and organs.This condition imposes a substantial burden,resulting in considerable morbidity and mortality.Ginseng(Panax ginseng C.A.Meyer),renowned for its medicinal properties,has been incorporated as a key component in Chinese patent medicines to mitigate fibrotic diseases.Ginsenosides,the primary bioactive compounds in ginseng,have garnered significant attention.Over the past five years,extensive research has explored the pharmaceutical potential of ginsenosides in diverse organ fibrosis conditions,including liver,myocardial,renal,and pulmonary fibrosis.Studies have elucidated that ginsenosides demonstrate potential effects on inflammatory responses stemming from parenchymal cell damage,myofibroblast activation leading to extracellular matrix(ECM)production,and myofibroblast apoptosis or inactivation.Additionally,potential downstream targets and pathways associated with these pathological processes have been identified as being influenced by ginsenosides.This review presents a comprehensive overview of the efficacious treatments utilizing ginsenosides for various tissue fibrosis types and their potential antifibrotic mechanisms.Furthermore,it offers a reference for the development of novel candidate drugs for future organ fibrosis therapies.
基金study was supported by the National Key Research and Development Program of China(2022YFC2402900)National Natural Science Foundation of China(82470989,52103327)+3 种基金The Joint Funds of the Hunan Provincial Natural Science Foundation(2023JJ60509)The Science and Technology Talent Support Project of the Hunan Provincial Science Popularization Special Project(2023TJ-Z08)Hunan Provincial Innovation Foundation for Postgraduate(2023ZZTS0218)The Postgraduate Inde-pendent Exploration Innovation Fund of the Central South University(2023ZZTS0987)。
文摘Oral submucous fibrosis(OSF),characterized by excessive deposition of extracellular matrix(ECM)that causes oral mucosal tissue sclerosis,and even cancer transformation,is a chronic,progressive fibrosis disease.However,despite some advancements in recent years,no targeted antifibrotic strategies for OSF have been approved;likely because the complicated mechanisms that initiate and drive fibrosis remain to be determined.In this review,we briefly introduce the epidemiology and etiology of OSF.Then,we highlight how cell-intrinsic changes in significant structural cells can drive fibrotic response by regulating biological behaviors,secretion function,and activation of ECM-producing myofibroblasts.In addition,we also discuss the role of innate and adaptive immune cells and how they contribute to the pathogenesis of OSF.Finally,we summarize strategies to interrupt key mechanisms that cause OSF,including modulation of the ECM,inhibition of inflammation,improvement of vascular disturbance.This review will provide potential routes for developing novel anti-OSF therapeutics.
文摘Silicosis,a major persistent occupational disease in China,is a progressive and irreversible pulmonary fibrosis disease with unclear pathogenesis.Cellular senescence,a state of stable cell cycle arrest that is recognized as a key underlying factor in age-related fibroproliferative disorders,plays an important role in chronic lung diseases,particularly pulmonary fibrosis.We previously reported that SiO2-stimulated mice and alveolar type II epithelial cells develop cellular senescence,which is involved in silicosis formation in alveolar type II epithelial cells[1].Cellular senescence may play an important role in silicosis development;however,the exact underlying mechanisms are not fully understood.
基金United Arab Emirates University,Grant/Award Number:12R104 and 12R121。
文摘Cardiac injury initiates repair mechanisms and results in cardiac remodeling and fi-brosis,which appears to be a leading cause of cardiovascular diseases.Cardiac fi-brosis is characterized by the accumulation of extracellular matrix proteins,mainly collagen in the cardiac interstitium.Many experimental studies have demonstrated that fibrotic injury in the heart is reversible;therefore,it is vital to understand differ-ent molecular mechanisms that are involved in the initiation,progression,and resolu-tion of cardiac fibrosis to enable the development of antifibrotic agents.Of the many experimental models,one of the recent models that has gained renewed interest is isoproterenol(ISP)-induced cardiac fibrosis.ISP is a synthetic catecholamine,sympa-thomimetic,and nonselectiveβ-adrenergic receptor agonist.The overstimulated and sustained activation ofβ-adrenergic receptors has been reported to induce biochemi-cal and physiological alterations and ultimately result in cardiac remodeling.ISP has been used for decades to induce acute myocardial infarction.However,the use of low doses and chronic administration of ISP have been shown to induce cardiac fibrosis;this practice has increased in recent years.Intraperitoneal or subcutaneous ISP has been widely used in preclinical studies to induce cardiac remodeling manifested by fibrosis and hypertrophy.The induced oxidative stress with subsequent perturbations in cellular signaling cascades through triggering the release of free radicals is consid-ered the initiating mechanism of myocardial fibrosis.ISP is consistently used to induce fibrosis in laboratory animals and in cardiomyocytes isolated from animals.In recent years,numerous phytochemicals and synthetic molecules have been evaluated in ISP-induced cardiac fibrosis.The present review exclusively provides a comprehensive summary of the pathological biochemical,histological,and molecular mechanisms of ISP in inducing cardiac fibrosis and hypertrophy.It also summarizes the application of this experimental model in the therapeutic evaluation of natural as well as syn-thetic compounds to demonstrate their potential in mitigating myocardial fibrosis and hypertrophy.
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].
基金supported by grants from National Key R&D Program of China,No.2023YFC2506100(to JZ)the National Natural Science Foundation of China,No.82171062(to JZ).
文摘Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.
文摘Fibrosis is marked by the excessive accumulation of extracellular matrix(ECM)components,leading to tissue scarring and progressive loss of organ function.Myofibroblasts,which emerge during tissue repair,are specialized contractile cells exhibiting features of both fibroblasts and smooth muscle cells.Their expression ofα-smooth muscle actin facilitates contractile activity,while their persistent activation and overproduction of ECM components contribute significantly to pathological wound contraction and fibrotic progression.Beyond ECM production,myofibroblasts play a significant role in the tumor microenvironment(TME)of various solid tumors.The TME is a complex network of immune cells,blood vessels,ECM components,and stromal cells like fibroblasts and myofibroblasts that surrounds and interacts with cancer cells,thereby influencing tumor growth,progression,and therapy responsiveness.Through these interactions,myofibroblasts modulate inflammation,angiogenesis,and tissue remodeling.Maintaining myofibroblast homeostasis is therefore crucial,as its disruption can drive the onset of chronic fibrotic conditions and malignancies.This review explores preclinical and clinical developments in targeting myofibroblasts in fibrotic and TME across various disease models,including hypertrophic scar,idiopathic pulmonary fibrosis,oral submucous fibrosis,cardiac fibrosis,and the desmoplastic stroma of pancreatic and breast cancers.
文摘BACKGROUND Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis,but their validation is limited because of insufficient data.AIM To investigate the diagnostic performance of three fibrosis noninvasive tests[FibroTest,vibration-controlled transient elastography(VCTE),and the fibrosis-4 index(FIB-4)and two activity biomarkers(alanine aminotransferase(ALT)and ActiTest].METHODS This study enrolled 103 patients for whom liver biopsy,hepatic elastography results,and laboratory markers were available.Diagnostic performance was assessed with receiver operating characteristic(ROC)curves,the Obuchowski measure(OM),and the Bayesian latent class model.RESULTS FibroTest and VCTE outperformed FIB-4 in cases of significant fibrosis(≥F2),with areas under the ROC curve of 0.83[95%confidence interval(CI):0.73-0.90],0.86(95%CI:0.77-0.92),and 0.71(95%CI:0.60-0.80),respectively.The mean(standard error)OM values were 0.92(0.01),0.93(0.01),and 0.88(0.02)for FibroTest,VCTE,and FIB-4,respectively;FibroTest and VCTE performed comparably,and both were superior to FIB-4(P=0.03 and P=0.005).The areas under the ROC curve values for activity biomarkers were 0.86(95%CI:0.76-0.92)for ActiTest and 0.84(95%CI:0.73-0.90)for ALT(P=0.06).The OM values for ActiTest and ALT were 0.92(0.02)and 0.90(0.02),respectively(P=0.005).CONCLUSION FibroTest and VCTE outperformed FIB-4 according to the OM.FibroTest-ActiTest facilitated the evaluation of both fibrosis and activity.
基金supported by the National Natural Science Foundation of China(grant No.82171588)the Fundamental Research Funds for the Central Institutes(grant No.2023GJZD01).
文摘Individuals with congenital absence of the vas deferens(CAVD)may transmit cystic fibrosis(CF)-causing variants of the cystic fibrosis transmembrane conductance regulator(CFTR)gene to their offspring through assisted reproductive technology(ART).We aimed to delineate the spectrum and estimate the prevalence of CF-causing variants in Chinese individuals with CAVD through a cohort analysis and meta-analysis.CFTR was sequenced in 145 Chineseindividuals with CAVD.CFTR variants were classified as CF-causing or non-CF-causing variants regarding clinical significance.A comprehensive genotype analysis was performed in Chinese individuals with CAVD,incorporating previous studies and our study cohort.The prevalence of CF-causing variants was estimated through meta-analysis.In our cohort,56 differentCFTR variants were identified in 108(74.5%)patients.Twenty variants were categorized as CF-causing and were detected in 28(19.3%)patients.A comprehensive genotype analysis of 867 patients identified 174 differentCFTR variants.Sixty-four were classified as CF-causing variants,56.3%of which had not been previously reported in Chinese patients with CF.Meta-analysis showed that 14.8%(95%confidence interval[CI]:11.0%-18.9%)CAVD cases harbored one CF-causing variant,and 68.6%(95%CI:65.1%-72.0%)CAVD cases carried at least one CFTR variant.Our study underscores the urgent need for extensiveCFTR screening,including sequencing of whole exons and flanking regions and detection of large rearrangements and deep intronic CF-causing variants,in Chinese individuals with CAVDbefore undergoing ART.The established CF-causing variants spectrum may aid in the development of genetic counseling strategies and preimplantation diagnosis to prevent the birth of a child with CF.
基金financially supported by the National Science and Technology Major Project(2017YFA0205400)the National Natural Science Foundation of China(81773667,81573369)+2 种基金NSFC Projects of International Cooperation and Exchanges(81811540416)the“111”Project from the Ministry of Education of Chinathe State Administration of Foreign Experts Affairs of China(D17010).
文摘Fibrosis is a necessary process in the progression of chronic disease to cirrhosis or even cancer,which is a serious disease threatening human health.Recent studies have shown that the early treatment of fibrosis is turning point and particularly important.Therefore,how to reverse fibrosis has become the focus and research hotspot in recent years.So far,the considerable progress has been made in the development of effective anti-fibrosis drugs and targeted drug delivery.Moreover,the existing research results will lay the foundation for more breakthrough delivery systems to achieve better anti-fibrosis effects.Herein,this review summaries anti-fibrosis delivery systems focused on three major organ fibrotic diseases such as liver,pulmonary,and renal fibrosis accompanied by the elaboration of relevant pathological mechanisms,which will provide inspiration and guidance for the design of fibrosis drugs and therapeutic systems in the future.
基金supported by the National Natural Science Foundation of China(Nos.82370322 to CC,82200352 to FZ,82300352 to YZ,22275034 to HX,and 82070343 to MLC)the Natural Science Foundation of Jiangsu Province of China(Nos.BK20220710 to FZ and BK20230733 to YZ)Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.JX13414086 to HYC).
文摘Arrhythmogenic right ventricular cardiomyopathy(ARVC)is a progressive disease characterized by adipose and fibrous replacement of the myocardium.While elevated testosterone levels have been implicated in the pathological process of ARVC,its exact contribution to cardiac fibrosis in ARVC remains unclear.In this study,we analyzed the potential contribution of gender-based differences on the distribution of the low-voltage area in an ARVC cohort undergoing an electrophysiological study,which was indicated by feature selection.Additionally,we established engineered cardiac spheroid models in vitro using patient-specific induced pluripotent stem cell(iPSC)-derived cardiomyocytes(iPSC-CMs)and iPSC-derived cardiac fibroblasts(icFBs).We elucidated the pathogenicity of abnormal splicing in the plakophilin-2(PKP2)gene caused by an intronic mutation.Additionally,pathogenic validation of the desmoglein-2(DSG2)point mutation further confirms the reliability of the models.Moreover,testosterone exacerbated the DNA damage in the mutated cardiomyocytes and further activated myofibroblasts in a chain reaction.In conclusion,we designed and constructed an in vitro three-dimensionally-engineered cardiac spheroid model of ARVC based on clinical findings and provided direct evidence of the fibrotic role of testosterone in ARVC.
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 Research Fund for Academician Lin He New Medicine,No.JYHL2022FMS02.
文摘BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed that nuclear receptor subfamily 4 group A member 1(NR4A1)may serve as a novel pathogenic element in DKD;however,the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.AIM To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.METHODS Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD.Typically,45 mmol/L glucose[high glucose(HG)]was used to activate HK-2 cells to mimic the DKD model in vitro.HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.RESULTS NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells.Concurrently,NOD-like receptor protein 3(NLRP3)and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathways were triggered,and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro.These alterations were significantly reversed via NR4A1 silencing.CONCLUSION Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.
基金supported by the National Natural Science Foundation of China(82270386,82070252,and 8207025)the Zhejiang Provincial Medical and Health Science and Technology Plan(2023RC020)the Zhejiang Provincial Natural Science Foundation(LR21H020001).
文摘Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.
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.
文摘BACKGROUND Neonatal screening(NS)is a public health policy to identify genetic pathologies such as cystic fibrosis(CF),sickle cell disease,and other diseases.Sickle cell disea-se is the comprehensive term for a group of hemoglobinopathies characterized by the presence of hemoglobin S.CF is an autosomal recessive multisystemic disease with pathophysiology involving deleterious mutations in the transmembrane re-gulatory gene that encodes a protein that regulates the activity of chloride and sodium channels in the cell surface epithelium.NS is crucial for early diagnosis and management,which ensures a better quality of life.AIM To report a case of the coexistence of sickle cell anemia(SCA)and CF and perform an integrative literature review.METHODS This is an observational study and a review of the literature focusing on two rare genetic pathologies identified simultaneously in NS from the perspective of a clinical case.The authors identified only 5 cases of SCA associated with CF.No clinical trials or review articles were identified considering the rarity of the coexistence of these two pathologies.RESULTS Herein,the authors reported the case of a girl who after undergoing NS on day 8 of life was diagnosed with SCA with an alteration in the dosage of immunoreactive trypsin.The diagnosis of CF was confirmed by the Coulometry Sweat Test.The rarity of the co-occurrence of these two severe genetic pathologies(CF and SCA)is a challenge for medical science.CONCLUSION This study adds to the few case reports present in the literature that highlight the identification of two severe diseases via NS.
基金Supported by Guizhou Provincial Science and Technology Project(2024-023ZK2024-047,2024-015)+3 种基金the Innovation and Entrepreneurship Training Program for Undergraduates from China(202310660082,S2024106601432X)University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province(2023-035)Administration of Traditional Chinese Medicine of Guizhou Province(QZYY-2024-134)Science Foundation of the Health Commission of Guizhou Province(gzwkj2025-538).
文摘[Objectives]To investigate the anti-hepatic fibrosis mechanism of lavandulyl flavonoid Kurarinol A(KA)from Sophora flavescens through the TGF/Smad signaling pathway.[Methods]A hepatic fibrosis model was established by TGF-β1-induced activation of human hepatic stellate cells LX-2.Western blot and RT-qPCR techniques were employed to study the anti-fibrotic mechanism of KA through the TGF/Smad signaling pathway.[Results]KA exerted anti-hepatic fibrosis effects by significantly reducing the gene expression levels of TGF-β1,Smad2,Smad3,and Smad4,as well as markedly decreasing the protein expression levels of TGF-β1,p-Smad2/3/Smad2/3,and Smad4.[Conclusions]KA demonstrates significant anti-hepatic fibrosis activity and alleviates liver fibrosis through the TGF/Smad signaling pathway.
文摘HOX transcription factors and their cofactors,MEINOX,are critical regulators of positional identity and cellular plasticity.While their functions are essential during embryonic development,they also play key roles in maintaining adult tissue homeostasis.Dysregulation of HOX and MEINOX has been implicated in the pathogenesis of various diseases,including fibrosis and cancer.This review explores the contributions of HOX and MEINOX to dedifferentiation and cellular reprogramming,processes that drive fibrotic disease onset and cancer progression.It also addresses their role in extracellular matrix remodeling in these conditions.Particular attention is given to their involvement in epithelialmesenchymal transition,where altered HOX and MEINOX expression promotes phenotypic plasticity,cancer invasiveness,and fibrotic tissue remodeling.By integrating these perspectives,this review underscores the significance of HOXMEINOX dysregulation and altered positional identity in disease progression.Targeting this dysregulation may offer innovative strategies to modulate epithelial-mesenchymal transition and extracellular matrix dynamics,presenting new therapeutic opportunities for combating fibrosis and cancer.
