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
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
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
Post-translational modifications(PTMs)regulate the activity and functionality of RELA,but their role in the pathogenesis of liver fibrosis is unclear.This study was performed to understand the regulation mechanism of ...Post-translational modifications(PTMs)regulate the activity and functionality of RELA,but their role in the pathogenesis of liver fibrosis is unclear.This study was performed to understand the regulation mechanism of acetylation of RELA on liver inflammation and fibrosis in a model animal of innate glucose intolerance,largemouth bass,and to provide a potential target and biomarker for liver fibrosis therapy.We found that the acetylation of total proteins and RELA was significantly reduced in fibrotic livers of largemouth bass induced by a high-carbohydrate and high-fat diet(HCHFD)and CCL4 challenge.Furthermore,quantitative acetylome data showed that the K119 site of RELA was deacetylated in fibrotic livers compared to healthy controls.Subsequently,we reveal a new mechanism that SIRT7 deacetylates RELA at the K119 site in largemouth bass.RELA K119 deacetylation enhances RELA transcriptional activity by increasing its DNA-binding activity,and facilitates nuclear translocation of RELA,resulting in the overwhelming release of proinflammatory factors,and subsequently enhancing liver inflammation and fibrosis.Pharmacological inhibition of SIRT7 using a specific inhibitor restores the decreased acetylation of RELA in vivo and in vitro,and reduces the transcriptional activity,nuclear localization of RELA and the expression of its target genes,which ultimately attenuates liver inflammation and fibrosis.These findings uncover a novel mechanism underlying liver fibrosis involving SIRT7-mediated deacetylation of RELA to activate the proinflammatory gene program,and thus provide important insights and biomarkers into the effective strategies for limiting liver inflammation and fibrosis.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
Objective This study aimed to investigate the therapeutic effects and underlying mechanisms of the combination of Yinchenhao decoction(YCHD)and praziquantel(PZQ)in a Schistosoma japonicum(S.japonicum)-induced mouse mo...Objective This study aimed to investigate the therapeutic effects and underlying mechanisms of the combination of Yinchenhao decoction(YCHD)and praziquantel(PZQ)in a Schistosoma japonicum(S.japonicum)-induced mouse model of schistosomiasis.Methods Six-week-old male BALB/c mice were randomly divided into five groups:control group,infected group,infected-PZQ group(I-PZQ),infected-YCHD group(I-YCHD),and infected-PZQ+YCHD group(I-PZQ+YCHD).The mice were infected with S.japonicum cercariae in infected group,I-PZQ group,I-YCHD group,and I-PZQ+YCHD group(n=6 per group)and maintained for 63 days.From day 43 to day 63 postinfection,the mice received PZQ(150 mg/kg,intragastric gavage),YCHD(10 mL/kg,intragastric gavage),or a combination of both.The control and infected groups received equal amounts of sterile double-distilled water for the same period.At the end of the experiment,the mice were anesthetized with pentobarbital sodium and sacrificed.Serum alanine transaminase(ALT)and aspartate transaminase(AST)levels were measured.Network pharmacology analysis was used to predict the targets of YCHD in the treatment of schistosomiasis.Histopathological analysis,Western blotting,immunofluorescence,quantitative polymerase chain reaction and flow cytometry were employed to evaluate liver pathology and molecular changes.Results Compared with the other groups,the I-PZQ+YCHD group presented significantly decreased serum ALT and AST levels(P<0.001).The I-PZQ+YCHD group exhibited improved pathological changes in the liver,as evidenced by reduced area of single granuloma(P<0.01),granuloma area(P<0.01),and Ishak score of liver fibrosis(P<0.01).Network pharmacology analysis suggested that YCHD may alleviate schistosomiasis-related liver injury through the modulation of the endoplasmic reticulum stress(ERS)pathway.Western blot analysis revealed that ERS-related markers,including glucose-regulated protein 78(GRP78),inositol-requiring enzyme 1 alpha(IRE1α),X-box binding protein 1(XBP-1),and C/EBP homologous protein(CHOP),were significantly downregulated in the I-PZQ+YCHD group(P<0.05).Furthermore,the I-PZQ+YCHD group presented reduced hepatocyte apoptosis(P<0.05),diminished hepatic macrophage infiltration(P<0.05)and downregulated expression of proinflammatory cytokines(TNF-α,IL-1βand IL-6)(P<0.05).Conclusion YCHD combined with PZQ reduced schistosomiasis-associated hepatic granulomatous inflammation and fibrosis by inhibiting hepatic apoptosis and ERS.展开更多
Two novel skeleton sesquiterpenoids(1 and 6),along with four new iphionane-type sesquiterpenes(2−5)and six new cyperane-type sesquiterpenes(7−11),were isolated from the whole plant of Artemisia hedinii(A.hedinii).The ...Two novel skeleton sesquiterpenoids(1 and 6),along with four new iphionane-type sesquiterpenes(2−5)and six new cyperane-type sesquiterpenes(7−11),were isolated from the whole plant of Artemisia hedinii(A.hedinii).The two novel skeleton compounds(1 and 6)were derived from the decarbonization of iphionane and cyperane-type sesquiterpenes,respectively.Their structures were elucidated through a comprehensive analysis of spectroscopic data,including high-resolution electrospray ionization mass spectrometry(HR-ESI-MS)and 1D and 2D nuclear magnetic resonance(NMR)spectra.The absolute configurations were determined using electronic circular dichroism(ECD)spectra,single-crystal X-ray crystallographic analyses,time-dependent density functional theory(TDDFT)ECD calculation,density functional theory(DFT)NMR calculations,and biomimetic syntheses.The biomimetic syntheses of the two novel skeletons(1 and 6)were inspired by potential biogenetic pathways,utilizing a predominant eudesmane-type sesquiterpene(A)in A.hedinii as the substrate.All compounds were evaluated in LX-2 cells for their anti-hepatic fibrosis activity.Compounds 2,8,and 10 exhibited significant activity in downregulating the expression ofα-smooth muscle actin(α-SMA),a protein involved in hepatic fibrosis.展开更多
BACKGROUND Liver fibrosis and cirrhosis are global medical challenges that require safe and effective treatments.In the past two decades,there has been a surge in research on stem cell therapy for liver fibrosis and c...BACKGROUND Liver fibrosis and cirrhosis are global medical challenges that require safe and effective treatments.In the past two decades,there has been a surge in research on stem cell therapy for liver fibrosis and cirrhosis.This study aimed to conduct a comprehensive analysis of the research hotspots and trends in this field through bibliometrics.sters was conducted.RESULTS As of September 20,2024,a total of 1935 documents were retrieved dating from 2004 to 2024,with 1186 strongly relevant publications obtained after screening.China,the United States,and Japan were the major contributors in this field.Cairo University,Zhejiang University and Yamaguchi University were the major institution in this field.The journal Stem Cell Research&Therapy published the most papers.There were 686 authors,with Shuji Terai,Isao Sakaida,Soon Koo Baik,and Lanjuan Li publishing the most papers.The research focused on alcoholic cirrhosis and nonalcoholic fatty liver disease.The emerging areas of interest were extracellular vesicles,exosomes,and their enriched microRNAs.The field is experiencing rapid growth due to the changing research trends and increasing literature.CONCLUSION These findings provide a thorough overview of stem cell therapy in the field of liver fibrosis and cirrhosis.展开更多
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(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.
基金supported by National Natural Sci-ence Foundation of China(32273141,32202954,32172981)Beijing Natural Science Foundation(6232038).
文摘Post-translational modifications(PTMs)regulate the activity and functionality of RELA,but their role in the pathogenesis of liver fibrosis is unclear.This study was performed to understand the regulation mechanism of acetylation of RELA on liver inflammation and fibrosis in a model animal of innate glucose intolerance,largemouth bass,and to provide a potential target and biomarker for liver fibrosis therapy.We found that the acetylation of total proteins and RELA was significantly reduced in fibrotic livers of largemouth bass induced by a high-carbohydrate and high-fat diet(HCHFD)and CCL4 challenge.Furthermore,quantitative acetylome data showed that the K119 site of RELA was deacetylated in fibrotic livers compared to healthy controls.Subsequently,we reveal a new mechanism that SIRT7 deacetylates RELA at the K119 site in largemouth bass.RELA K119 deacetylation enhances RELA transcriptional activity by increasing its DNA-binding activity,and facilitates nuclear translocation of RELA,resulting in the overwhelming release of proinflammatory factors,and subsequently enhancing liver inflammation and fibrosis.Pharmacological inhibition of SIRT7 using a specific inhibitor restores the decreased acetylation of RELA in vivo and in vitro,and reduces the transcriptional activity,nuclear localization of RELA and the expression of its target genes,which ultimately attenuates liver inflammation and fibrosis.These findings uncover a novel mechanism underlying liver fibrosis involving SIRT7-mediated deacetylation of RELA to activate the proinflammatory gene program,and thus provide important insights and biomarkers into the effective strategies for limiting liver inflammation and fibrosis.
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.
基金supported by the National Natural Science Foundation of China(No.81802036 and No.81876182).
文摘Objective This study aimed to investigate the therapeutic effects and underlying mechanisms of the combination of Yinchenhao decoction(YCHD)and praziquantel(PZQ)in a Schistosoma japonicum(S.japonicum)-induced mouse model of schistosomiasis.Methods Six-week-old male BALB/c mice were randomly divided into five groups:control group,infected group,infected-PZQ group(I-PZQ),infected-YCHD group(I-YCHD),and infected-PZQ+YCHD group(I-PZQ+YCHD).The mice were infected with S.japonicum cercariae in infected group,I-PZQ group,I-YCHD group,and I-PZQ+YCHD group(n=6 per group)and maintained for 63 days.From day 43 to day 63 postinfection,the mice received PZQ(150 mg/kg,intragastric gavage),YCHD(10 mL/kg,intragastric gavage),or a combination of both.The control and infected groups received equal amounts of sterile double-distilled water for the same period.At the end of the experiment,the mice were anesthetized with pentobarbital sodium and sacrificed.Serum alanine transaminase(ALT)and aspartate transaminase(AST)levels were measured.Network pharmacology analysis was used to predict the targets of YCHD in the treatment of schistosomiasis.Histopathological analysis,Western blotting,immunofluorescence,quantitative polymerase chain reaction and flow cytometry were employed to evaluate liver pathology and molecular changes.Results Compared with the other groups,the I-PZQ+YCHD group presented significantly decreased serum ALT and AST levels(P<0.001).The I-PZQ+YCHD group exhibited improved pathological changes in the liver,as evidenced by reduced area of single granuloma(P<0.01),granuloma area(P<0.01),and Ishak score of liver fibrosis(P<0.01).Network pharmacology analysis suggested that YCHD may alleviate schistosomiasis-related liver injury through the modulation of the endoplasmic reticulum stress(ERS)pathway.Western blot analysis revealed that ERS-related markers,including glucose-regulated protein 78(GRP78),inositol-requiring enzyme 1 alpha(IRE1α),X-box binding protein 1(XBP-1),and C/EBP homologous protein(CHOP),were significantly downregulated in the I-PZQ+YCHD group(P<0.05).Furthermore,the I-PZQ+YCHD group presented reduced hepatocyte apoptosis(P<0.05),diminished hepatic macrophage infiltration(P<0.05)and downregulated expression of proinflammatory cytokines(TNF-α,IL-1βand IL-6)(P<0.05).Conclusion YCHD combined with PZQ reduced schistosomiasis-associated hepatic granulomatous inflammation and fibrosis by inhibiting hepatic apoptosis and ERS.
基金supported from the National Natural Science Foundation of China(No.21920102003)the Key-Area Research and Development Program of Guangdong Province(No.2020B0303070002)the National Key R&D Program“Strategic Scientific and Technological Innovation Cooperation”Key Project(No.2022YFE0203600).
文摘Two novel skeleton sesquiterpenoids(1 and 6),along with four new iphionane-type sesquiterpenes(2−5)and six new cyperane-type sesquiterpenes(7−11),were isolated from the whole plant of Artemisia hedinii(A.hedinii).The two novel skeleton compounds(1 and 6)were derived from the decarbonization of iphionane and cyperane-type sesquiterpenes,respectively.Their structures were elucidated through a comprehensive analysis of spectroscopic data,including high-resolution electrospray ionization mass spectrometry(HR-ESI-MS)and 1D and 2D nuclear magnetic resonance(NMR)spectra.The absolute configurations were determined using electronic circular dichroism(ECD)spectra,single-crystal X-ray crystallographic analyses,time-dependent density functional theory(TDDFT)ECD calculation,density functional theory(DFT)NMR calculations,and biomimetic syntheses.The biomimetic syntheses of the two novel skeletons(1 and 6)were inspired by potential biogenetic pathways,utilizing a predominant eudesmane-type sesquiterpene(A)in A.hedinii as the substrate.All compounds were evaluated in LX-2 cells for their anti-hepatic fibrosis activity.Compounds 2,8,and 10 exhibited significant activity in downregulating the expression ofα-smooth muscle actin(α-SMA),a protein involved in hepatic fibrosis.
基金Supported by the School-Level Project Fund of Chongqing Medical and Pharmaceutical College,No.Ygzrc2023109the Science and Technology Research Program of Chongqing Municipal Education Commission,No.KJQN202302822+1 种基金the Special Fund for Agro-Scientific Research in The Public Interest,No.201303040-05the Special Project for Fundamental Work of Science and Technology,No.2013FY110600-03.
文摘BACKGROUND Liver fibrosis and cirrhosis are global medical challenges that require safe and effective treatments.In the past two decades,there has been a surge in research on stem cell therapy for liver fibrosis and cirrhosis.This study aimed to conduct a comprehensive analysis of the research hotspots and trends in this field through bibliometrics.sters was conducted.RESULTS As of September 20,2024,a total of 1935 documents were retrieved dating from 2004 to 2024,with 1186 strongly relevant publications obtained after screening.China,the United States,and Japan were the major contributors in this field.Cairo University,Zhejiang University and Yamaguchi University were the major institution in this field.The journal Stem Cell Research&Therapy published the most papers.There were 686 authors,with Shuji Terai,Isao Sakaida,Soon Koo Baik,and Lanjuan Li publishing the most papers.The research focused on alcoholic cirrhosis and nonalcoholic fatty liver disease.The emerging areas of interest were extracellular vesicles,exosomes,and their enriched microRNAs.The field is experiencing rapid growth due to the changing research trends and increasing literature.CONCLUSION These findings provide a thorough overview of stem cell therapy in the field of liver fibrosis and cirrhosis.
