Multifocal fibrosis is a rare condition occurring at any age and characterized by chronic inflammation, soft tissue proliferation and subsequent fibrosis of various vascular connective tissues. Following diagnosis in ...Multifocal fibrosis is a rare condition occurring at any age and characterized by chronic inflammation, soft tissue proliferation and subsequent fibrosis of various vascular connective tissues. Following diagnosis in a 43-year accountant with multiple vascular lesions, the patients was treated successfully with azathioprine and steroids over a period of 3 years. Fatigue and sweating, serologic sign of inflammation and radiological imaging studies normalized completely. Twenty four months after termination of therapy, there were no clinical or serologic signs of relapse.展开更多
Twelve new diterpenoids,euphorwallnoids A-L(1-12),comprising five rhamnofolanes(1-5),five tiglianes(6-10),and two daphnanes(11 and 12),along with six known analogues(13-18),were isolated from the whole plants of Eupho...Twelve new diterpenoids,euphorwallnoids A-L(1-12),comprising five rhamnofolanes(1-5),five tiglianes(6-10),and two daphnanes(11 and 12),along with six known analogues(13-18),were isolated from the whole plants of Euphorbia wallichii(E.wallichii).Their structures were determined using spectroscopic analysis,computational methods,chemical derivatization,and single-crystal X-ray diffraction.Euphorwallnoid A(1)features an unusual 5/7/6/5-tetracyclic scaffold,whereas 2-5 represent a rare subclass of 4-deoxygenated rhamnofolanes and 6-8 constitute 13-deoxygenated tiglianes.Notably,compound 1 demonstrated promising anti-liver fibrosis activity by significantly inhibiting the expression of fibronectin(FN),α-smooth muscle actin(α-SMA),and collagen I in transforming growth factorβ1(TGF-β1)-stimulated LX-2 cells at micromolar concentrations.展开更多
Artificial intelligence(AI)is revolutionizing medical imaging,particularly in chronic liver diseases assessment.AI technologies,including machine learning and deep learning,are increasingly integrated with multiparame...Artificial intelligence(AI)is revolutionizing medical imaging,particularly in chronic liver diseases assessment.AI technologies,including machine learning and deep learning,are increasingly integrated with multiparametric ultrasound(US)techniques to provide more accurate,objective,and non-invasive evaluations of liver fibrosis and steatosis.Analyzing large datasets from US images,AI enhances diagnostic precision,enabling better quantification of liver stiffness and fat content,which are essential for diagnosing and staging liver fibrosis and steatosis.Combining advanced US modalities,such as elastography and doppler imaging with AI,has demonstrated improved sensitivity in identifying different stages of liver disease and distinguishing various degrees of steatotic liver.These advancements also contribute to greater reproducibility and reduced operator dependency,addressing some of the limitations of traditional methods.The clinical implications of AI in liver disease are vast,ranging from early detection to predicting disease progression and evaluating treatment response.Despite these promising developments,challenges such as the need for large-scale datasets,algorithm transparency,and clinical validation remain.The aim of this review is to explore the current applications and future potential of AI in liver fibrosis and steatosis assessment using multiparametric US,highlighting the technological advances and clinical relevance of this emerging field.展开更多
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
Objective:To investigate the antifibrotic effects of curcumin in a transverse aortic constriction(TAC)mouse model and elucidate its molecular mechanisms.Methods:Male C57BL/6 mice underwent TAC and received vehicle,low...Objective:To investigate the antifibrotic effects of curcumin in a transverse aortic constriction(TAC)mouse model and elucidate its molecular mechanisms.Methods:Male C57BL/6 mice underwent TAC and received vehicle,low-dose curcumin(50 mg/kg),high-dose curcumin(200 mg/kg),high-dose curcumin plus a scrambled control antagomir,or high-dose curcumin plus anti-miR-29b treatments.Cardiac function was assessed by echocardiography.Fibrosis was evaluated by histology,collagen volume fraction,and hydroxyproline content.Expression of miR-29b,HDAC4,and fibrosis-related markers(Col1a1,Col3a1,TGF-β1)was measured by quantitative RT-PCR and Western blotting assays.Myocardial procollagen type I carboxy-terminal propeptide was determined by ELISA,and HDAC4-specific enzymatic activity was assayed using a fluorogenic kit.Results:Curcumin improved cardiac function,reduced fibrosis,restored miR-29b expression,and suppressed HDAC4 expression and activity in a dose-dependent manner.Furthermore,curcumin decreased myocardial procollagen type I carboxy-terminal propeptide levels,confirming reduced collagen synthesis.Anti-miR-29b administration partially abrogated the antifibrotic and cardioprotective effects of curcumin.Conclusions:Curcumin attenuates pressure overload-induced cardiac fibrosis and dysfunction in a TAC mouse model via modulation of the miR-29b/HDAC4 axis and suppression of collagen synthesis.展开更多
In recent years,different drugs therapies for treatment pulmonary fibrosis(PF) have gained much attention due to development of drug delivery technology and urgent clinical needs.PF treatment existed a variety of curr...In recent years,different drugs therapies for treatment pulmonary fibrosis(PF) have gained much attention due to development of drug delivery technology and urgent clinical needs.PF treatment existed a variety of currently clinical problem but PF could be treated with different drugs potentially though drug delivery technology.This review systematically expounds its basic theory,various drug delivery technologies,and future development directions.In the introduction,the relationship between the pathological mechanism of PF and drug delivery,the basic principles of the drug delivery system and the biological barriers faced by pulmonary drug delivery are analyzed.This review details delivery of small molecule drug,macromolecular drug and cells,including chemical synthesis and natural small molecule drug delivery,as well as RNA and cell-based delivery.Finally,the challenges and perspectives of these drugs to treat PF delivery technologies are discussed and key aspects in the development of PF drugs are considered.We hoped that this review can provide comprehensive and in-depth theoretical reference and technical support for the drug treatment of PF.展开更多
Pulmonary fibrosis(PF)is a progressive,fatal fibrotic disease caused by respiratory conditions.The condition can ultimately lead to severe organ failure and mortality,and is associated with multiple risk factors.Growi...Pulmonary fibrosis(PF)is a progressive,fatal fibrotic disease caused by respiratory conditions.The condition can ultimately lead to severe organ failure and mortality,and is associated with multiple risk factors.Growing evidence highlights the immune system’s role in PF,with various immune components participating in inflammatory and fibrotic processes.Different immune cells,including neutrophils,lymphocytes,and macrophages,demonstrate distinct effects on PF progression and development.Furthermore,key immune system cytokines,including the interleukin(IL)family,tumor necrosis factor(TNF)-α,interferon(IFN)-γ,transforming growth factor(TGF)-β,and connective tissue growth factor(CTGF),contribute to PF initiation and progression through independent mechanisms and mutual regulation.Currently,limited effective treatments exist for PF,with several treatments causing severe adverse reactions.Natural products,characterized by multi-target effects,holistic regulation,and low toxicity,have emerged as a research focus.This review compiles the mechanisms,therapeutic potential,and active components of various natural products.These compounds can ameliorate pulmonary inflammation,epithelial-mesenchymal transition,and collagen deposition through diverse immune mechanisms,acting at specific stages or throughout the fibrotic process,thereby supporting PF management.This review examines current scientific understanding of natural products’immunological effects in PF,which is crucial for developing future anti-PF therapeutics.展开更多
Progressive skin fibrosis ultimately results in irreversible contractures,causing both joint dysfunction and cosmetic deformity.The key pathological features of skin fibrosis include persistent inflammation and abnorm...Progressive skin fibrosis ultimately results in irreversible contractures,causing both joint dysfunction and cosmetic deformity.The key pathological features of skin fibrosis include persistent inflammation and abnormal accumulation of the extracellular matrix(ECM),with epithelialmesenchymal transition(EMT)playing a critical role in disease progression.However,current therapeutic strategies for cutaneous fibrosis are largely palliative and often require repeated interventions,with limited efficacy.Celastrol(Cel)exerts anti-inflammatory and anti-fibrotic effects in skin tissue,but its clinical application is limited by poor bioavailability and a narrow therapeutic window.Tetrahedral framework nucleic acid(tFNA),a novel nanocarrier system,exhibits multiple advantages,including enhanced cellular uptake,improved cell viability,and intrinsic anti-fibrotic and anti-inflammatory properties.Therefore,this study applied tFNA-Cel complex(TCC)as an advanced nanotherapeutic agent,designed to exert a synergistic anti-fibrotic effect.In this study,an in vitro model of skin fibrosis was established using human keratinocyte(HaCaT)cells treated with 5 ng mL^(-1) transforming growth factor beta(TGF-β)for 24 h.The results showed that TCC significantly inhibited EMT progression by reducingα-smooth muscle actin(α-SMA)levels and increasing E-cadherin level.Compared to tFNA or Cel alone,TCC exhibited superior anti-fibrotic effects in the fibrosis model,as evidenced by modulation of SMAD family member 2(SMAD2)signaling and collagen I expression.Furthermore,the TCC group showed lower levels of nuclear factorκB p65(NF-κB p65),BCL-2-associated X protein(Bax),and reactive oxygen species(ROS)compared to the Cel or tFNA groups.These findings highlight TCC as a promising treatment for skin fibrosis,with its synergistic anti-fibrotic effects providing new therapeutic avenues.展开更多
The activation of pancreatic stellate cells(PSCs)and the secretion of inflammatory factors play critical roles in the development of pancreatic fibrosis.While gambogic acid(GA),a flavonoid with anti-tumor properties,h...The activation of pancreatic stellate cells(PSCs)and the secretion of inflammatory factors play critical roles in the development of pancreatic fibrosis.While gambogic acid(GA),a flavonoid with anti-tumor properties,has been studied,its role in this process remains unclear.This study demonstrated that GA promoted YAP1 degradation and reduced its nuclear localization,thereby inhibiting PSC activation and the progression of pancreatic fibrosis.GA inhibited PSC proliferation,decreasedα-smooth muscle actin(α-SMA)expression,and reduced lipid droplets in LTC14 and primary mouse PSCs(mPSCs).Additionally,GA suppressed the expression of inflammatory factors[nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),nuclear factor erythroid 2-related factor 2(NRF2),interleukin-6(IL-6),tumor necrosis factorα(TNF-α),and nuclear factorκB(NF-κB)]in PSCs and counteracted the transforming growth factor(TGF)-β-induced increase in these proteins.GA also reduced collagenΙand tissue inhibitor of metalloproteinase-1(TΙMP1)expression,thereby attenuating fibrosis.Mechanistically,GA decreased YAP1 expression and nuclear translocation and reversed TGF-β-induced YAP1 upregulation.YAP1 overexpression abrogated GA’s inhibitory effects on PSC activation and inflammation.Furthermore,GA activated the Hippo pathway,increased phosphorylated(p)-LATS1 and p-YAP levels,and promoted ubiquitin-mediated YAP1 degradation.In vivo studies confirmed that GA inhibited dibutyltin dichloride(DBTC)-induced pancreatic fibrosis via suppressing YAP1 and NF-κB in BALB/c mice.In conclusion,GA activates the Hippo pathway and promotes YAP1 translocation to the cytoplasm,leading to its degradation and subsequent inhibition of PSC activation and fibrosis.These findings highlight the critical role of ubiquitin-mediated YAP1 degradation in regulating PSC activity and offer novel insights into the therapeutic potential of GA for treating pancreatic fibrosis.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
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
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
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
T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue ...T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin.Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0,10,and 100 nanograms per gram body weight per day(ng/(g·day)),respectively.Morphological,pathological,and ultrastructural alterations in cardiac tissue were meticulously examined.Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites.The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected.The results showed that exposure to T-2 toxin elicited myocardial tissue disorders,interstitial hemorrhage,capillary dilation,and fibrotic damage.Mitochondria were markedly impaired,including swelling,fusion,matrix degradation,and membrane damage.Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiacmetabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway.T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress.In conclusion,the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway.This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.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
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
文摘Multifocal fibrosis is a rare condition occurring at any age and characterized by chronic inflammation, soft tissue proliferation and subsequent fibrosis of various vascular connective tissues. Following diagnosis in a 43-year accountant with multiple vascular lesions, the patients was treated successfully with azathioprine and steroids over a period of 3 years. Fatigue and sweating, serologic sign of inflammation and radiological imaging studies normalized completely. Twenty four months after termination of therapy, there were no clinical or serologic signs of relapse.
基金supported by the National Natural Science Foundation of China(Nos.82404454,22407144,82304322)the China Postdoctoral Science Foundation(No.2024M753800)+1 种基金the Postdoctoral Fellowship Program of CPSF(No.GZC20242113)the Open Program of Shenzhen Bay Laboratory(No.SZBL2021080601007)。
文摘Twelve new diterpenoids,euphorwallnoids A-L(1-12),comprising five rhamnofolanes(1-5),five tiglianes(6-10),and two daphnanes(11 and 12),along with six known analogues(13-18),were isolated from the whole plants of Euphorbia wallichii(E.wallichii).Their structures were determined using spectroscopic analysis,computational methods,chemical derivatization,and single-crystal X-ray diffraction.Euphorwallnoid A(1)features an unusual 5/7/6/5-tetracyclic scaffold,whereas 2-5 represent a rare subclass of 4-deoxygenated rhamnofolanes and 6-8 constitute 13-deoxygenated tiglianes.Notably,compound 1 demonstrated promising anti-liver fibrosis activity by significantly inhibiting the expression of fibronectin(FN),α-smooth muscle actin(α-SMA),and collagen I in transforming growth factorβ1(TGF-β1)-stimulated LX-2 cells at micromolar concentrations.
文摘Artificial intelligence(AI)is revolutionizing medical imaging,particularly in chronic liver diseases assessment.AI technologies,including machine learning and deep learning,are increasingly integrated with multiparametric ultrasound(US)techniques to provide more accurate,objective,and non-invasive evaluations of liver fibrosis and steatosis.Analyzing large datasets from US images,AI enhances diagnostic precision,enabling better quantification of liver stiffness and fat content,which are essential for diagnosing and staging liver fibrosis and steatosis.Combining advanced US modalities,such as elastography and doppler imaging with AI,has demonstrated improved sensitivity in identifying different stages of liver disease and distinguishing various degrees of steatotic liver.These advancements also contribute to greater reproducibility and reduced operator dependency,addressing some of the limitations of traditional methods.The clinical implications of AI in liver disease are vast,ranging from early detection to predicting disease progression and evaluating treatment response.Despite these promising developments,challenges such as the need for large-scale datasets,algorithm transparency,and clinical validation remain.The aim of this review is to explore the current applications and future potential of AI in liver fibrosis and steatosis assessment using multiparametric US,highlighting the technological advances and clinical relevance of this emerging field.
文摘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supported by China International Medical Foundation(Z-2019-42-1908-4)Natural Science Basic Research Program of Shaanxi Province(2019JM-440).
文摘Objective:To investigate the antifibrotic effects of curcumin in a transverse aortic constriction(TAC)mouse model and elucidate its molecular mechanisms.Methods:Male C57BL/6 mice underwent TAC and received vehicle,low-dose curcumin(50 mg/kg),high-dose curcumin(200 mg/kg),high-dose curcumin plus a scrambled control antagomir,or high-dose curcumin plus anti-miR-29b treatments.Cardiac function was assessed by echocardiography.Fibrosis was evaluated by histology,collagen volume fraction,and hydroxyproline content.Expression of miR-29b,HDAC4,and fibrosis-related markers(Col1a1,Col3a1,TGF-β1)was measured by quantitative RT-PCR and Western blotting assays.Myocardial procollagen type I carboxy-terminal propeptide was determined by ELISA,and HDAC4-specific enzymatic activity was assayed using a fluorogenic kit.Results:Curcumin improved cardiac function,reduced fibrosis,restored miR-29b expression,and suppressed HDAC4 expression and activity in a dose-dependent manner.Furthermore,curcumin decreased myocardial procollagen type I carboxy-terminal propeptide levels,confirming reduced collagen synthesis.Anti-miR-29b administration partially abrogated the antifibrotic and cardioprotective effects of curcumin.Conclusions:Curcumin attenuates pressure overload-induced cardiac fibrosis and dysfunction in a TAC mouse model via modulation of the miR-29b/HDAC4 axis and suppression of collagen synthesis.
基金funded by the National Natural Science Foundation of China (No.NSFC82400096)Science and Technology Department of Sichuan Province (No.2025ZNSFSC1538)Xihua University Internal Talent Introduction Project with Scientific Research Funding (No.ZX20250087)。
文摘In recent years,different drugs therapies for treatment pulmonary fibrosis(PF) have gained much attention due to development of drug delivery technology and urgent clinical needs.PF treatment existed a variety of currently clinical problem but PF could be treated with different drugs potentially though drug delivery technology.This review systematically expounds its basic theory,various drug delivery technologies,and future development directions.In the introduction,the relationship between the pathological mechanism of PF and drug delivery,the basic principles of the drug delivery system and the biological barriers faced by pulmonary drug delivery are analyzed.This review details delivery of small molecule drug,macromolecular drug and cells,including chemical synthesis and natural small molecule drug delivery,as well as RNA and cell-based delivery.Finally,the challenges and perspectives of these drugs to treat PF delivery technologies are discussed and key aspects in the development of PF drugs are considered.We hoped that this review can provide comprehensive and in-depth theoretical reference and technical support for the drug treatment of PF.
基金supported by the National Natural Science Foundation of China(No.82260820)the Natural Science Foundation of Jilin Province,Jilin,China(No.YDZJ202201ZYTS155).
文摘Pulmonary fibrosis(PF)is a progressive,fatal fibrotic disease caused by respiratory conditions.The condition can ultimately lead to severe organ failure and mortality,and is associated with multiple risk factors.Growing evidence highlights the immune system’s role in PF,with various immune components participating in inflammatory and fibrotic processes.Different immune cells,including neutrophils,lymphocytes,and macrophages,demonstrate distinct effects on PF progression and development.Furthermore,key immune system cytokines,including the interleukin(IL)family,tumor necrosis factor(TNF)-α,interferon(IFN)-γ,transforming growth factor(TGF)-β,and connective tissue growth factor(CTGF),contribute to PF initiation and progression through independent mechanisms and mutual regulation.Currently,limited effective treatments exist for PF,with several treatments causing severe adverse reactions.Natural products,characterized by multi-target effects,holistic regulation,and low toxicity,have emerged as a research focus.This review compiles the mechanisms,therapeutic potential,and active components of various natural products.These compounds can ameliorate pulmonary inflammation,epithelial-mesenchymal transition,and collagen deposition through diverse immune mechanisms,acting at specific stages or throughout the fibrotic process,thereby supporting PF management.This review examines current scientific understanding of natural products’immunological effects in PF,which is crucial for developing future anti-PF therapeutics.
基金supported by the National Natural Science Foundation of China(82101077)Sichuan Science and Technology Program(2023NSFSC1516)+2 种基金West China School/Hospital of Stomatology Sichuan University(RCDWJS2023-5)Fundamental Research Funds for the Central UniversitiesResearch and Develop Program,West China School/Hospital of Stomatology Sichuan University。
文摘Progressive skin fibrosis ultimately results in irreversible contractures,causing both joint dysfunction and cosmetic deformity.The key pathological features of skin fibrosis include persistent inflammation and abnormal accumulation of the extracellular matrix(ECM),with epithelialmesenchymal transition(EMT)playing a critical role in disease progression.However,current therapeutic strategies for cutaneous fibrosis are largely palliative and often require repeated interventions,with limited efficacy.Celastrol(Cel)exerts anti-inflammatory and anti-fibrotic effects in skin tissue,but its clinical application is limited by poor bioavailability and a narrow therapeutic window.Tetrahedral framework nucleic acid(tFNA),a novel nanocarrier system,exhibits multiple advantages,including enhanced cellular uptake,improved cell viability,and intrinsic anti-fibrotic and anti-inflammatory properties.Therefore,this study applied tFNA-Cel complex(TCC)as an advanced nanotherapeutic agent,designed to exert a synergistic anti-fibrotic effect.In this study,an in vitro model of skin fibrosis was established using human keratinocyte(HaCaT)cells treated with 5 ng mL^(-1) transforming growth factor beta(TGF-β)for 24 h.The results showed that TCC significantly inhibited EMT progression by reducingα-smooth muscle actin(α-SMA)levels and increasing E-cadherin level.Compared to tFNA or Cel alone,TCC exhibited superior anti-fibrotic effects in the fibrosis model,as evidenced by modulation of SMAD family member 2(SMAD2)signaling and collagen I expression.Furthermore,the TCC group showed lower levels of nuclear factorκB p65(NF-κB p65),BCL-2-associated X protein(Bax),and reactive oxygen species(ROS)compared to the Cel or tFNA groups.These findings highlight TCC as a promising treatment for skin fibrosis,with its synergistic anti-fibrotic effects providing new therapeutic avenues.
基金supported by the Fundamental Research Funds for the Central Universities (No. 2632024TD07).
文摘The activation of pancreatic stellate cells(PSCs)and the secretion of inflammatory factors play critical roles in the development of pancreatic fibrosis.While gambogic acid(GA),a flavonoid with anti-tumor properties,has been studied,its role in this process remains unclear.This study demonstrated that GA promoted YAP1 degradation and reduced its nuclear localization,thereby inhibiting PSC activation and the progression of pancreatic fibrosis.GA inhibited PSC proliferation,decreasedα-smooth muscle actin(α-SMA)expression,and reduced lipid droplets in LTC14 and primary mouse PSCs(mPSCs).Additionally,GA suppressed the expression of inflammatory factors[nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),nuclear factor erythroid 2-related factor 2(NRF2),interleukin-6(IL-6),tumor necrosis factorα(TNF-α),and nuclear factorκB(NF-κB)]in PSCs and counteracted the transforming growth factor(TGF)-β-induced increase in these proteins.GA also reduced collagenΙand tissue inhibitor of metalloproteinase-1(TΙMP1)expression,thereby attenuating fibrosis.Mechanistically,GA decreased YAP1 expression and nuclear translocation and reversed TGF-β-induced YAP1 upregulation.YAP1 overexpression abrogated GA’s inhibitory effects on PSC activation and inflammation.Furthermore,GA activated the Hippo pathway,increased phosphorylated(p)-LATS1 and p-YAP levels,and promoted ubiquitin-mediated YAP1 degradation.In vivo studies confirmed that GA inhibited dibutyltin dichloride(DBTC)-induced pancreatic fibrosis via suppressing YAP1 and NF-κB in BALB/c mice.In conclusion,GA activates the Hippo pathway and promotes YAP1 translocation to the cytoplasm,leading to its degradation and subsequent inhibition of PSC activation and fibrosis.These findings highlight the critical role of ubiquitin-mediated YAP1 degradation in regulating PSC activity and offer novel insights into the therapeutic potential of GA for treating pancreatic fibrosis.
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.
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 the National Natural Science Foundation of China(No.81872567).
文摘T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin.Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0,10,and 100 nanograms per gram body weight per day(ng/(g·day)),respectively.Morphological,pathological,and ultrastructural alterations in cardiac tissue were meticulously examined.Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites.The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected.The results showed that exposure to T-2 toxin elicited myocardial tissue disorders,interstitial hemorrhage,capillary dilation,and fibrotic damage.Mitochondria were markedly impaired,including swelling,fusion,matrix degradation,and membrane damage.Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiacmetabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway.T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress.In conclusion,the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway.This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.
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.
