Fibroblasts are the most abundant cellular components of connective tissue. They possess phenotypical heterogenicity and may be present in the form of smooth muscle cells or myofibroblasts(MFs). MFs are spindle-shaped...Fibroblasts are the most abundant cellular components of connective tissue. They possess phenotypical heterogenicity and may be present in the form of smooth muscle cells or myofibroblasts(MFs). MFs are spindle-shaped cells with stress fibres and welldeveloped fibronexus,and they display α-smooth muscle actin immunohistochemically and smoothmuscle myofilaments ultrastructurally. MFs play a crucial role in physiological and pathological processes. Derived from various sources,they play pivotal roles not only by synthesizing and producing extracellular matrix components,such as other connective tissue cells,but also are involved in force production. In the tissue remodelling phase of wound closure,integrinmediated interactions between MFs and type I collagen result in scar tissue formation. The tumour stroma in oral cancer actively recruits various cell types into the tumour mass,where they act as different sources of MFs. This article reviews the importance of MFs and its role in pathological processes such as wound healing,odontogenic cysts and tumours,salivary gland tumours,oral preneoplasia,and oral squamous cell carcinoma. Research oriented on blocking the transdifferentiation of fibroblasts into MFs can facilitate the development of noninvasive therapeutic strategies for the treatment of fibrosis and/or cancer.展开更多
In order to investigate the roles of Wnt signal pathway in transformation of cardiac valvular myofibroblasts to the osteoblast-like phenotype, the primary cultured porcine aortic valve myofibroblasts were incubated wi...In order to investigate the roles of Wnt signal pathway in transformation of cardiac valvular myofibroblasts to the osteoblast-like phenotype, the primary cultured porcine aortic valve myofibroblasts were incubated with oxidized low density lipoprotein（ox-LDL, 50 mg/L）, and divided into four groups according to the ox-LDL treatment time： control group, ox-LDL 24-h group, ox-LDL 48-h group, and ox-LDL 72-h group. Wnt signal pathway blocker Dickkopf-1（DDK-1, 100 μg/L） was added in ox-LDL 72-h group. The expression of α-smooth muscle actin（α-SMA）, bone morphogenetic protein 2（BMP2）, alkaline phosphatase（ALP）, and osteogenic transcription factor Cbfa-1 was detected by Western blotting, and that of β-catenin, a key mediator of Wnt signal pathway by immunocytochemical staining method. The Wnt/β-catenin was observed and the transformation of myofibroblasts to the osteoblast-like phenotype was examined. The expression of α-SMA, BMP2, ALP and Cbfa-1 proteins in the control group was weaker than in the ox-LDL-treated groups. In ox-LDL-treated groups, the protein expression of α-SMA, BMP2, ALP, and Cbfa-1 was significantly increased in a time-dependent manner as compared with the control group, and there was significant difference among the three ox-LDL-treated groups（P〈0.05 for all）; β-catenin protein was also up-regulated in the ox-LDL-treated groups in a time-dependent manner as compared with the control group（P〈0.05）, and its transfer from cytoplasm to nucleus and accumulation in the nucleus were increased in the same fashion（P〈0.05）. After addition of DKK-1, the expression of α-SMA, bone-related proteins and β-catenin protein was significantly reduced as compared with ox-LDL 72-h group（P〈0.05）. The Wnt/ β-catenin signaling pathway may play an important role in transformation of valvular myofibroblasts to the osteoblast-like phenotype.展开更多
AIM:To test the effect of a standardized red wine polyphenolic extract(RWPE)on the phenotype of human liver myofibroblasts in culture.METHODS:Human myofibroblasts grown from liver explants were used in this study.Cell...AIM:To test the effect of a standardized red wine polyphenolic extract(RWPE)on the phenotype of human liver myofibroblasts in culture.METHODS:Human myofibroblasts grown from liver explants were used in this study.Cell proliferation was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide(MTT)assay.Signaling events were analyzed by western blot with phosphospecific antibodies.Matrix-metalloproteinase activity was measured with gel zymography.RESULTS:We found that cell proliferation was dose-dependently decreased by up to 90%by RWPE while cell viability was not affected.Exposure to RWPE also greatly decreased the phosphorylation of ERK1/ERK2 and Akt in response to stimulation by the mitogenic factor platelet-derived growth factor BB(PDGF-BB).Finally,RWPE affected extracellular matrix remodeling by decreasing the secretion by myofibroblasts of matrix-metalloproteinase-2 and of tissue inhibitor of matrix-metalloproteinases-1.CONCLUSION:Altogether,RWPE decreases the activation state of liver myofibroblasts.The identification of the active compounds in RWPE could offer new therapeutic strategies against liver fibrosis.展开更多
Quantification of nitric oxide (NO) from cultured cells is a valuable tool for studying cell signaling. Detection of NO in biological fluids can be difficult however, due to its transient half-life and low physiologic...Quantification of nitric oxide (NO) from cultured cells is a valuable tool for studying cell signaling. Detection of NO in biological fluids can be difficult however, due to its transient half-life and low physiological concentrations. In this study, we have refined an existing amperometric method to determine relative levels of accumulated nitrogen oxides (NOX) in cell culture and have used this method to reproducibly quantify NO from cultured pulmonary myofibroblasts. Basal levels of NO produced by pulmonary myofibroblasts ranged from 0.6 nM to 20 nM and varied due to the growth conditions of the cells, i.e. higher NO concentrations were observed in differentiated cells. The constitutive eNOS isoform is primarily responsible for the observed NO accumulation in these cells since transcript levels of eNOS are 10-fold higher than the inducible iNOS form while nNOS was undetectable. Treatment of myofibroblasts with the inhibitors L-NNA and L-NAME resulted in a concentration dependent decrease in measured NOx. Overall, the improved assay presented here should be applicable to measuring NOX levels from many different cell types and under a wide variety of conditions.展开更多
Idiopathic pulmonary fibrosis(IPF)is a complex interstitial lung disease in which myofibroblasts are the primary effector cells.FK506-binding protein(FKBP10),a procollagen chaperone,is upregulated in IPF and primarily...Idiopathic pulmonary fibrosis(IPF)is a complex interstitial lung disease in which myofibroblasts are the primary effector cells.FK506-binding protein(FKBP10),a procollagen chaperone,is upregulated in IPF and primarily localizes to myofibroblasts.Exosomes have garnered significant attention as novel drug delivery vehicles,particularly when engineered.However,myofibroblasts remain underexplored in terms of engineered exosome-based therapies and associated drug targets.In this study,RDYH58,a peptide that targets myofibroblasts,was conjugated to the exosomal membrane protein Lamp2b to produce RDYH58-linked exosomes(RDYH58-exo).In vitro and in vivo experiments demonstrated that compared to unmodified exosomes(unm-exo),RDYH58-exo preferentially localized to myofibroblasts.A small interfering RNA targeting FKBP10(siFKBP10)was loaded into exosomes using ultrasonic microfluidics method,and the antifibrotic effects of RDYH58-exo carrying siFKBP10(RDYH58-siFKBP10)were assessed both in vitro and in vivo.The results demonstrated that RDYH58-siFKBP10 effectively silenced FKBP10 gene expression,significantly inhibiting fibroblast activation and extracellular matrix deposition,with superior antifibrotic efficacy compared to unmodified exosome vectors(unm-siFKBP10).RNA-seq analysis confirmed the pivotal regulatory role of FKBP10,providing critical evidence for the development of targeted therapeutic strategies.The RDYH58-siFKBP10 delivery system developed in this study demonstrates remarkable clinical translation potential.展开更多
In heart disease, transforming growth factor-β1 （TGF-β1） converts fibroblasts into myofibroblasts, which synthesize and se- crete fibrillar type I and III collagens. The purpose of the present study was to investi...In heart disease, transforming growth factor-β1 （TGF-β1） converts fibroblasts into myofibroblasts, which synthesize and se- crete fibrillar type I and III collagens. The purpose of the present study was to investigate how hydrogen sulfide （HzS） sup- presses TGF-~l-induced differentiation of human cardiac fibroblasts to myofibroblasts. Human cardiac fibroblasts were se- rum-starved in fibroblast medium for 16 h before exposure to TGF-β1 （10 ng mL-1） for 24 h with or without sodium hydrosul- fide （NariS, 100 μmol L-1, 30 min pretreatment） treatment. NariS, an exogenous HzS donor, potently inhibited the prolifera- tion and migration of TGF-β1-induced human cardiac fibroblasts and regulated their cell cycle progression. Furthermore, NariS treatment led to suppression of fibroblast differentiation into myofibroblasts, and reduced the levels of collagen, TGF-β1, and activated Smad3 in TGF-β1-induced human cardiac fibroblasts in vitro. We therefore conclude that H2S sup- presses TGF-β1-stimulated conversion of fibroblasts to myofibroblasts by inhibiting the TGF-β1/Smad3 signaling pathway, as well as by inhibiting the proliferation, migration, and cell cycle progression of human cardiac myofibroblasts. These effects of H2S may play significant roles in cardiac remodeling associated with heart failure.展开更多
Previous studies have demonstrated the important role of angiotension II(AngII)in promoting proliferation of myofibroblasts(myoFbs)and myocardial fibrosis.However,the underlying mechanisms and the role of oxygen free ...Previous studies have demonstrated the important role of angiotension II(AngII)in promoting proliferation of myofibroblasts(myoFbs)and myocardial fibrosis.However,the underlying mechanisms and the role of oxygen free radicals in the proliferation of myofibroblasts induced by AngII are unclear.The present study was designed to shed light on this issue through exploration of AngII signaling pathways via in vitro experiments.Primary cultures of neonatal rat myoFbs were divided into five groups which were treated with AngII(10^(-8) to 10^(-6) M),AngII with the antioxidant N-acetyl-L-cysteine(NAC),or normal culture medium.We observed the proliferation of myoFbs as induced by AngII at different concentrations with MTT.Reactive oxygen species(ROS)levels in myoFbs were detected by monitoring the fluorescence of 2',7'-dichlorofluorescein.The contents and levels of oxygen free radicals(OH·)in the three groups were detected by spectrophotometer,immunocytochemical staining,and confocal fluorescence.Western blot and image analysis were used to measure membrane translocation and expression of phospho-protein kinase Ca.MyoFbs incubated with AngII(10^(-8) to 10^(-6) M)for 24 h increased their rate of proliferation,the content of OH·,and expression of ROS(P<0.01 vs.control group),whereas these parameters decreased in the presence of NAC.Immunocytochemistry,confocal fluorescence staining and image analysis showed that AngII could promote the translocation and expression of p-PKCα in membrane,and the antioxidant NAC blocked this increase(P<0.01).Western blot results also showed that NAC could inhibit the expression of p-PKCα.展开更多
Fibrosis can occur in almost all tissues and organs and affects normal physiological function,which may have serious consequences,such as organ failure.However,there are currently no effective,broad-spectmm drugs suit...Fibrosis can occur in almost all tissues and organs and affects normal physiological function,which may have serious consequences,such as organ failure.However,there are currently no effective,broad-spectmm drugs suitable for clinical application.Revealing the process of fibrosis is an important prerequisite for the development of new therapeutic targets and drugs.Studies have shown that the limiting of myofibroblast activation or the promoting of their elimination can ameliorate fibrosis.However,it has not been reported whether a direct decrease in cell contraction can inhibit fibrosis in vivo.Here,we have shown that(-)-blebbistatin(Ble),a non-muscle myosin II inhibitor,displayed significant inhibition of liver fibrosis in different chronic injury mouse models in vivo.We found that Ble reduced the stiffness of fibrotic tissues from the early stage,which reduced the extent of myofibroblast activation induced by a stiffer extracellular matrix(ECM).Moreover,Ble also reduced the activation of myofibroblasts induced by TGF-β1,which is the most potent pro-fibrotic cytokine.Mechanistically,Ble reduced mechanical contraction,which inhibited the assembly of stress fibers,decreased the F/G-actin ratio,and led to the exnucleation of YAPJ and MRTF-A.Finally,we verified its broad-spectrum antifibrotic effect in multiple models of organ fibrosis.Our results highlighted the important role of mechanical contraction in myofibroblast activation and maintenance,rather than just a characteristic of activation,suggesting that it may be a potential target to explore broad-spectrum drugs for the treatment of fibrotic diseases.展开更多
AIM:To investigate the clinical features and prognosis of patients with orbital inflammatory myofibroblastic tumor(IMT).METHODS:This retrospective study collected clinical data from 22 patients diagnosed with orbital ...AIM:To investigate the clinical features and prognosis of patients with orbital inflammatory myofibroblastic tumor(IMT).METHODS:This retrospective study collected clinical data from 22 patients diagnosed with orbital IMT based on histopathological examination.The patients were followed up to assess their prognosis.Clinical data from patients,including age,gender,course of disease,past medical history,primary symptoms,ophthalmologic examination findings,general condition,as well as imaging,laboratory,histopathological,and immunohistochemical results from digital records were collected.Orbital magnetic resonance imaging(MRI)and(or)computed tomography(CT)scans were performed to assess bone destruction of the mass,invasion of surrounding tissues,and any inflammatory changes in periorbital areas.RESULTS:The mean age of patients with orbital IMT was 28.24±3.30y,with a male-to-female ratio of 1.2:1.Main clinical manifestations were proptosis,blurred vision,palpable mass,and pain.Bone destruction and surrounding tissue invasion occurred in 72.73%and 54.55%of cases,respectively.Inflammatory changes in the periorbital site were observed in 77.27%of the patients.Hematoxylin and eosin staining showed proliferation of fibroblasts and myofibroblasts,accompanied by infiltration of lymphocytes and plasma cells.Immunohistochemical staining revealed that smooth muscle actin(SMA)and vimentin were positive in 100%of cases,while anaplastic lymphoma kinase(ALK)showed positivity in 47.37%.The recurrence rate of orbital IMT was 27.27%,and sarcomatous degeneration could occur.There were no significant correlations between recurrence and factors such as age,gender,laterality,duration of the disease,periorbital tissue invasion,bone destruction,periorbital inflammation,tumor size,fever,leukocytosis,or treatment(P>0.05).However,lymphadenopathy and a Ki-67 index of 10%or higher may be risk factors for recurrence(P=0.046;P=0.023).CONCLUSION:Orbital IMT is a locally invasive disease that may recur or lead to sarcomatoid degeneration,primarily affecting young and middle-aged patients.The presence of lymphadenopathy and a Ki-67 index of 10%or higher may signify a poor prognosis.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
Hepatic fibrosis is a pathological process characterized by an imbalance between the deposition and degradation of extracellular matrix components.This process is initiated by chronic liver injuries resulting from vir...Hepatic fibrosis is a pathological process characterized by an imbalance between the deposition and degradation of extracellular matrix components.This process is initiated by chronic liver injuries resulting from viral infections,alcoholic liver disease,non-alcoholic fatty liver disease,and autoimmune-mediated hepatic damage.If left untreated,hepatic fibrosis can progress to life-threatening conditions such as cirrhosis and hepatocellular carcinoma.Central to the development of fibrosis is the transdifferentiation of quiescent hepatic stellate cells(HSCs)into proliferative and fibrogenic myofibroblast-like activated HSCs(aHSCs),which play a crucial role in extracellular matrix accumulation and fibrotic tissue formation.Beyond resmetirom,a recently Food and Drug Administrationapproved medication for liver fibrosis and nonalcoholic steatohepatitis,there are currently no other established pharmacological treatments available to slow down the progression of these conditions.Moreover,activation of HSCs and formation of hepatic fibrosis have been considered irreversible.Recent studies reported transforming growth factor beta as one of the key regulators of HSCs activation and pathogenesis of hepatic fibrosis.It has been also reported that the features of aHSCs can be reversed to those of quiescent HSCs by modulating transforming growth factor beta mediated pathways.The potential of extracellular vesicles(EVs)as cell free therapeutics to treat hepatic fibrosis has been suggested earlier.However,detailed knowledge of the mechanisms involved in the alleviation of hepatic fibrosis using EVs from mesenchymal stem cells is still lacking.Hence,this review aims to describe the pathogenesis of hepatic fibrosis from the cellular and molecular point of views and shed light on the potential of EVs from mesenchymal stem cells in reversing the properties of aHSCs to their quiescent state.展开更多
Myofibroblastic sarcoma(MS)is a rare malignant soft tissue tumor characterized by myofibroblasts.It most commonly arises in the head and neck region,especially the tongue,with rare occurrences in the limbs.MS exhibits...Myofibroblastic sarcoma(MS)is a rare malignant soft tissue tumor characterized by myofibroblasts.It most commonly arises in the head and neck region,especially the tongue,with rare occurrences in the limbs.MS exhibits varying histopathology,ranging from low-to high-grade,with diverse subtypes showing different clinical behaviors and prognoses.This article reports the first case of high-grade MS in the hand,adding to the limited documentation of this rare condition.Here,we present the case of a 30-year-old healthy female with a year-long history of progressive shortening,mobility loss,and weakness in the first finger of the left hand.Left-hand imaging revealed a lytic,cottony tumor involving the entire first metacarpal.Following surgical resection,which included metatarsal grafting and joint reconstruction,a diagnosis of high-grade MS was confirmed based on histological manifestations and immunohistochemical staining,which was further classified as grade 2 according to the French Federation of Cancer Centers Sarcoma Group system.Postoperative radiotherapy was administered and the patient experienced a successful recovery without graft osteonecrosis.The patient regained 90%mobility and strength,without shortening,after surgical resection and radiotherapy.Six months post-surgery,the patient reported full hand functionality.MS is a rare tumor that infrequently affects bones and is often misdiagnosed owing to its controversial characteristics.The initial treatment should focus on complete resection with negative margins,followed by reconstructive surgery to preserve function.Further case studies are needed to establish standardized surgical treatment protocols.展开更多
Fibrosis is marked by the excessive accumulation of extracellular matrix(ECM)components,leading to tissue scarring and progressive loss of organ function.Myofibroblasts,which emerge during tissue repair,are specialize...Fibrosis is marked by the excessive accumulation of extracellular matrix(ECM)components,leading to tissue scarring and progressive loss of organ function.Myofibroblasts,which emerge during tissue repair,are specialized contractile cells exhibiting features of both fibroblasts and smooth muscle cells.Their expression ofα-smooth muscle actin facilitates contractile activity,while their persistent activation and overproduction of ECM components contribute significantly to pathological wound contraction and fibrotic progression.Beyond ECM production,myofibroblasts play a significant role in the tumor microenvironment(TME)of various solid tumors.The TME is a complex network of immune cells,blood vessels,ECM components,and stromal cells like fibroblasts and myofibroblasts that surrounds and interacts with cancer cells,thereby influencing tumor growth,progression,and therapy responsiveness.Through these interactions,myofibroblasts modulate inflammation,angiogenesis,and tissue remodeling.Maintaining myofibroblast homeostasis is therefore crucial,as its disruption can drive the onset of chronic fibrotic conditions and malignancies.This review explores preclinical and clinical developments in targeting myofibroblasts in fibrotic and TME across various disease models,including hypertrophic scar,idiopathic pulmonary fibrosis,oral submucous fibrosis,cardiac fibrosis,and the desmoplastic stroma of pancreatic and breast cancers.展开更多
Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in s...Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelialand endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic proc-ess, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.展开更多
肾脏纤维化是各种原因引起的慢性肾脏病的重要标志[1]。肌成纤维细胞增殖和细胞外基质积聚是肾脏纤维化的特征性改变。目前认为,肾脏纤维化程度能可靠地反映肾脏病的预后。近几十年来,肌成纤维细胞的来源颇具争议。传统观点认为肌成纤...肾脏纤维化是各种原因引起的慢性肾脏病的重要标志[1]。肌成纤维细胞增殖和细胞外基质积聚是肾脏纤维化的特征性改变。目前认为,肾脏纤维化程度能可靠地反映肾脏病的预后。近几十年来,肌成纤维细胞的来源颇具争议。传统观点认为肌成纤维细胞起源于固有的成纤维细胞,但是,循环中的纤维细胞、肾小管上皮细胞转分化（epithelial to myofibroblast transformation,EMT）和内皮细胞向间充质细胞的分化均被认为是其可能的来源。展开更多
AIM： To investigate the effects of transforming growth factor β1 （TGF-β1） on the differentiation of colonic lamina propria fibroblasts （CLPF） into myofibroblasts in vitro.METHODS： Primary CLPF cultures were in...AIM： To investigate the effects of transforming growth factor β1 （TGF-β1） on the differentiation of colonic lamina propria fibroblasts （CLPF） into myofibroblasts in vitro.METHODS： Primary CLPF cultures were incubated with TGF-β1 and analyzed for production of m-smooth muscle actin （α-SMA）, fibronectin （FN） and FN isoforms. Migration assays were performed in a modified 48-well Boyden chamber. Levels of total and phosphorylated focal adhesion kinase （FAK） in CLPF were analyzed after induction of migration.did not change α-SMA levels, while TGF-β1 treatment for 6 d significantly increased α-SIVlA production. Short term incubation （6 h） with TGF-β1 enhanced CLPF migration, while long term treatment （6 d） of CLPF with TGF-β1 reduced migration to 15%-37% compared to untreated cells. FN and FN isoform mRNA expression were increased after short term incubation with TGF-β1 （2 d） in contrast to long term incubation with TGF-β1 for 6 d. After induction of migration, TGF-β1-preincubated CLPF showed higher amounts of FN and its isoforms and lower levels of total and phosphorylated FAK than untreated cells.CONCLUSION： Long term incubation of CLPF with TGF-β1 induced differentiation into myofibroblasts with enhanced α-SMA, reduced migratory potential and FAK phosphorylation, and increased FN production. In contrast, short term contact （6 h） of fibroblasts with TGF-β1 induced a dose-dependent increase of cell migration and FAK phosphorylation without induction of α-SMA production.展开更多
Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and PSC the targets of t...Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells.Persistent liver injury,associated with chronic AILD,leads to un-resolving inflammation,cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts.Liver cirrhosis,and the resultant loss of normal liver function,inevitably ensues.Patients with cirrhosis have higher risks or morbidity and mortality,and that in the decompensated phase,complications of portal hypertension and/or liver dysfunction lead to rapid deterioration.Accurate diagnosis and monitoring of cirrhosis is,therefore of upmost importance.Liver biopsy is currently the gold standard technique,but highly promising non-invasive methodology is under development.Liver transplantation(LT) is an effective therapeutic option for the management of endstage liver disease secondary to AIH,PBC and PSC.LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy;in addition,LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.展开更多
AIM： To investigate the effects of troglitazone （TGZ）, an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-y （PPAR-y）, for liver tissue repair, and the development of ductular reaction...AIM： To investigate the effects of troglitazone （TGZ）, an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-y （PPAR-y）, for liver tissue repair, and the development of ductular reaction, following common bile duct ligation （BDL） in rats. METHODS： Rats were supplemented with TGZ （0.2% w/w in the pelleted food） for i wk before BDL or sham operation. Animals were killed at 1, 2, or 4 wk after surgery. RESULTS： The development of liver fibrosis was reduced in rats receiving TGZ, as indicated by significant decreases of procollagen type I gene expression and liver hydroxyproline levels. Accumulation of a-smooth-muscle actin （SMA）-expressing cells surrounding newly formed bile ducts following BDL, as well as total hepatic levels of SMA were partially inhibited by TGZ treatment, indicating the presence of a reduced number and/or activation of hepatic stellate cells （HSC） and myofibroblasts. Development of the ductular reaction was inhibited by TGZ, as indicated by histochemical evaluation and hepatic activity of γ-glutamyltransferase （GGT）. CONCLUSION： Treatment with thiazolidinedione reduces ductular proliferation and fibrosis in a model of chronic cholestasis, and suggests that limiting cholangiocyte proliferation may contribute to the lower development of scarring in this system.展开更多
Background: Upon liver injury, quiescent hepatic stellate cells(q HSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells(MFBs). The q HSCs in the normal liver are le...Background: Upon liver injury, quiescent hepatic stellate cells(q HSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells(MFBs). The q HSCs in the normal liver are less fibrogenic, migratory, and also have less proliferative potential. However, activated HSCs(a HSCs) are more fibrogenic and have a high migratory and proliferative MFBs phenotype. HSCs activation is a highly energetic process that needs abundant intracellular energy in the form of adenosine triphosphate(ATP) for the synthesis of extracellular matrix(ECM) in the injured liver to substantiate the injury. Data sources: The articles were collected through Pub Med and EMBASE using search terms "mitochondria and hepatic stellate cells", "mitochondria and HSCs", "mitochondria and hepatic fibrosis", "mitochondria and liver diseases", and "mitochondria and chronic liver disease", and relevant publications published before September 31, 2020 were included in this review. Results: Mitochondria homeostasis is affected during HSCs activation. Mitochondria in a HSCs are highly energetic and are in a high metabolically active state exhibiting increased activity such as glycolysis and respiration. a HSCs have high glycolytic enzymes expression and glycolytic activity induced by Hedgehog(Hh) signaling from injured hepatocytes. Increased glycolysis and aerobic glycolysis(Warburg effect) endproducts in a HSCs consequently activate the ECM-related gene expressions. Increased Hh signaling from injured hepatocytes downregulates peroxisome proliferator-activated receptor-γ expression and decreases lipogenesis in a HSCs. Glutaminolysis and tricarboxylic acid cycle liberate ATPs that fuel HSCs to proliferate and produce ECM during their activation. Conclusions: Available studies suggest that mitochondria functions can increase in parallel with HSCs activation. Therefore, mitochondrial modulators should be tested in an elaborate manner to control or prevent the HSCs activation during liver injury to subsequently regress hepatic fibrosis.展开更多
To investigate interleukin (IL)-26 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and the function of IL-26. METHODSHuman colonic subepithelial myofibroblasts (SEMFs) were isolated...To investigate interleukin (IL)-26 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and the function of IL-26. METHODSHuman colonic subepithelial myofibroblasts (SEMFs) were isolated from colon tissue surgically resected. The expression of IL-26 protein and its receptor complex was analyzed by immunohistochemistry. The gene expression induced by IL-26 was evaluated by real-time polymerase chain reaction. Intracellular signaling pathways were evaluated by immunoblotting and specific small interfering (si) RNA transfection. RESULTSThe mRNA and protein expression of IL-26 were significantly enhanced in the inflamed mucosa of patients with IBD. IL-26 receptor complex was expressed in colonic SEMFs in vivo and in vitro. IL-26 stimulated the mRNA expression of IL-6 and IL-8 in colonic SEMFs. The inhibitors of mitogen-activated protein kinases and phosphoinositide 3-kinase, and siRNAs for signal transducers and activator of transcription 1/3, nuclear factor-kappa B and activator protein-1 significantly reduced the mRNA expression of IL-6 and IL-8 induced by IL-26. CONCLUSIONThese results suggest that IL-26 plays a role in the pathophysiology of IBD through induction of inflammatory mediators.展开更多
文摘Fibroblasts are the most abundant cellular components of connective tissue. They possess phenotypical heterogenicity and may be present in the form of smooth muscle cells or myofibroblasts(MFs). MFs are spindle-shaped cells with stress fibres and welldeveloped fibronexus,and they display α-smooth muscle actin immunohistochemically and smoothmuscle myofilaments ultrastructurally. MFs play a crucial role in physiological and pathological processes. Derived from various sources,they play pivotal roles not only by synthesizing and producing extracellular matrix components,such as other connective tissue cells,but also are involved in force production. In the tissue remodelling phase of wound closure,integrinmediated interactions between MFs and type I collagen result in scar tissue formation. The tumour stroma in oral cancer actively recruits various cell types into the tumour mass,where they act as different sources of MFs. This article reviews the importance of MFs and its role in pathological processes such as wound healing,odontogenic cysts and tumours,salivary gland tumours,oral preneoplasia,and oral squamous cell carcinoma. Research oriented on blocking the transdifferentiation of fibroblasts into MFs can facilitate the development of noninvasive therapeutic strategies for the treatment of fibrosis and/or cancer.
基金supported by grants from the National Nature Science Foundation of China(No.81070190)the Foundation of Natural Sciences of Hubei Province of China(No.2014CFB962)
文摘In order to investigate the roles of Wnt signal pathway in transformation of cardiac valvular myofibroblasts to the osteoblast-like phenotype, the primary cultured porcine aortic valve myofibroblasts were incubated with oxidized low density lipoprotein（ox-LDL, 50 mg/L）, and divided into four groups according to the ox-LDL treatment time： control group, ox-LDL 24-h group, ox-LDL 48-h group, and ox-LDL 72-h group. Wnt signal pathway blocker Dickkopf-1（DDK-1, 100 μg/L） was added in ox-LDL 72-h group. The expression of α-smooth muscle actin（α-SMA）, bone morphogenetic protein 2（BMP2）, alkaline phosphatase（ALP）, and osteogenic transcription factor Cbfa-1 was detected by Western blotting, and that of β-catenin, a key mediator of Wnt signal pathway by immunocytochemical staining method. The Wnt/β-catenin was observed and the transformation of myofibroblasts to the osteoblast-like phenotype was examined. The expression of α-SMA, BMP2, ALP and Cbfa-1 proteins in the control group was weaker than in the ox-LDL-treated groups. In ox-LDL-treated groups, the protein expression of α-SMA, BMP2, ALP, and Cbfa-1 was significantly increased in a time-dependent manner as compared with the control group, and there was significant difference among the three ox-LDL-treated groups（P〈0.05 for all）; β-catenin protein was also up-regulated in the ox-LDL-treated groups in a time-dependent manner as compared with the control group（P〈0.05）, and its transfer from cytoplasm to nucleus and accumulation in the nucleus were increased in the same fashion（P〈0.05）. After addition of DKK-1, the expression of α-SMA, bone-related proteins and β-catenin protein was significantly reduced as compared with ox-LDL 72-h group（P〈0.05）. The Wnt/ β-catenin signaling pathway may play an important role in transformation of valvular myofibroblasts to the osteoblast-like phenotype.
文摘AIM:To test the effect of a standardized red wine polyphenolic extract(RWPE)on the phenotype of human liver myofibroblasts in culture.METHODS:Human myofibroblasts grown from liver explants were used in this study.Cell proliferation was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide(MTT)assay.Signaling events were analyzed by western blot with phosphospecific antibodies.Matrix-metalloproteinase activity was measured with gel zymography.RESULTS:We found that cell proliferation was dose-dependently decreased by up to 90%by RWPE while cell viability was not affected.Exposure to RWPE also greatly decreased the phosphorylation of ERK1/ERK2 and Akt in response to stimulation by the mitogenic factor platelet-derived growth factor BB(PDGF-BB).Finally,RWPE affected extracellular matrix remodeling by decreasing the secretion by myofibroblasts of matrix-metalloproteinase-2 and of tissue inhibitor of matrix-metalloproteinases-1.CONCLUSION:Altogether,RWPE decreases the activation state of liver myofibroblasts.The identification of the active compounds in RWPE could offer new therapeutic strategies against liver fibrosis.
文摘Quantification of nitric oxide (NO) from cultured cells is a valuable tool for studying cell signaling. Detection of NO in biological fluids can be difficult however, due to its transient half-life and low physiological concentrations. In this study, we have refined an existing amperometric method to determine relative levels of accumulated nitrogen oxides (NOX) in cell culture and have used this method to reproducibly quantify NO from cultured pulmonary myofibroblasts. Basal levels of NO produced by pulmonary myofibroblasts ranged from 0.6 nM to 20 nM and varied due to the growth conditions of the cells, i.e. higher NO concentrations were observed in differentiated cells. The constitutive eNOS isoform is primarily responsible for the observed NO accumulation in these cells since transcript levels of eNOS are 10-fold higher than the inducible iNOS form while nNOS was undetectable. Treatment of myofibroblasts with the inhibitors L-NNA and L-NAME resulted in a concentration dependent decrease in measured NOx. Overall, the improved assay presented here should be applicable to measuring NOX levels from many different cell types and under a wide variety of conditions.
基金funded by National Natural Science Foundation of China(Nos.82404552,82273969,and 82473967)Natural Science Foundation of Shandong Province(No.ZR2021MH395,China)+5 种基金Yantai University Doctoral Program(No.SM20B35,China)Development of engineered exosomes for nucleic acid drug delivery in the treatment of pulmonary fibrosis(No.SK22KH114,China)Research on the development of multiple methods to increase exosome production(No.SK22KH304,China)Science Fund of Shandong Laboratory of Advanced Materials and Green Manufacturing at Yantai(No.AMGM2024A07,China)Taishan Scholar Project of Shandong Province(No.tsqn202211112,China)Shandong Laboratory Program(No.SYS202205,China).
文摘Idiopathic pulmonary fibrosis(IPF)is a complex interstitial lung disease in which myofibroblasts are the primary effector cells.FK506-binding protein(FKBP10),a procollagen chaperone,is upregulated in IPF and primarily localizes to myofibroblasts.Exosomes have garnered significant attention as novel drug delivery vehicles,particularly when engineered.However,myofibroblasts remain underexplored in terms of engineered exosome-based therapies and associated drug targets.In this study,RDYH58,a peptide that targets myofibroblasts,was conjugated to the exosomal membrane protein Lamp2b to produce RDYH58-linked exosomes(RDYH58-exo).In vitro and in vivo experiments demonstrated that compared to unmodified exosomes(unm-exo),RDYH58-exo preferentially localized to myofibroblasts.A small interfering RNA targeting FKBP10(siFKBP10)was loaded into exosomes using ultrasonic microfluidics method,and the antifibrotic effects of RDYH58-exo carrying siFKBP10(RDYH58-siFKBP10)were assessed both in vitro and in vivo.The results demonstrated that RDYH58-siFKBP10 effectively silenced FKBP10 gene expression,significantly inhibiting fibroblast activation and extracellular matrix deposition,with superior antifibrotic efficacy compared to unmodified exosome vectors(unm-siFKBP10).RNA-seq analysis confirmed the pivotal regulatory role of FKBP10,providing critical evidence for the development of targeted therapeutic strategies.The RDYH58-siFKBP10 delivery system developed in this study demonstrates remarkable clinical translation potential.
基金supported by the State Key Program of National Natural Science of China(81230007)
文摘In heart disease, transforming growth factor-β1 （TGF-β1） converts fibroblasts into myofibroblasts, which synthesize and se- crete fibrillar type I and III collagens. The purpose of the present study was to investigate how hydrogen sulfide （HzS） sup- presses TGF-~l-induced differentiation of human cardiac fibroblasts to myofibroblasts. Human cardiac fibroblasts were se- rum-starved in fibroblast medium for 16 h before exposure to TGF-β1 （10 ng mL-1） for 24 h with or without sodium hydrosul- fide （NariS, 100 μmol L-1, 30 min pretreatment） treatment. NariS, an exogenous HzS donor, potently inhibited the prolifera- tion and migration of TGF-β1-induced human cardiac fibroblasts and regulated their cell cycle progression. Furthermore, NariS treatment led to suppression of fibroblast differentiation into myofibroblasts, and reduced the levels of collagen, TGF-β1, and activated Smad3 in TGF-β1-induced human cardiac fibroblasts in vitro. We therefore conclude that H2S sup- presses TGF-β1-stimulated conversion of fibroblasts to myofibroblasts by inhibiting the TGF-β1/Smad3 signaling pathway, as well as by inhibiting the proliferation, migration, and cell cycle progression of human cardiac myofibroblasts. These effects of H2S may play significant roles in cardiac remodeling associated with heart failure.
基金This study was supported by the National Basic Research Program(also called 973 Program No.2007CB512006)the National Natural Science Foundation of China(No.30873066/C180102).
文摘Previous studies have demonstrated the important role of angiotension II(AngII)in promoting proliferation of myofibroblasts(myoFbs)and myocardial fibrosis.However,the underlying mechanisms and the role of oxygen free radicals in the proliferation of myofibroblasts induced by AngII are unclear.The present study was designed to shed light on this issue through exploration of AngII signaling pathways via in vitro experiments.Primary cultures of neonatal rat myoFbs were divided into five groups which were treated with AngII(10^(-8) to 10^(-6) M),AngII with the antioxidant N-acetyl-L-cysteine(NAC),or normal culture medium.We observed the proliferation of myoFbs as induced by AngII at different concentrations with MTT.Reactive oxygen species(ROS)levels in myoFbs were detected by monitoring the fluorescence of 2',7'-dichlorofluorescein.The contents and levels of oxygen free radicals(OH·)in the three groups were detected by spectrophotometer,immunocytochemical staining,and confocal fluorescence.Western blot and image analysis were used to measure membrane translocation and expression of phospho-protein kinase Ca.MyoFbs incubated with AngII(10^(-8) to 10^(-6) M)for 24 h increased their rate of proliferation,the content of OH·,and expression of ROS(P<0.01 vs.control group),whereas these parameters decreased in the presence of NAC.Immunocytochemistry,confocal fluorescence staining and image analysis showed that AngII could promote the translocation and expression of p-PKCα in membrane,and the antioxidant NAC blocked this increase(P<0.01).Western blot results also showed that NAC could inhibit the expression of p-PKCα.
基金the Institute of Zoology,Chinese Academy of Sciences for their technical assistance.This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030400 to W.L.)the National Key Research and Development Program(2018YFC1004500 to Y.Z.and 2017YFA0103803 to Q.Z.)+3 种基金the National Natural Science Foundation of China(31621004 to Q.Z.and W.L.)CAS Project for Young Scientists in Basic Research(YSBR-012 to W.L.)the China Postdoctoral Science Foundation(2019M650841 to Z.H.)the National Natural Science Foundation of China(31900510 to Y.L.).
文摘Fibrosis can occur in almost all tissues and organs and affects normal physiological function,which may have serious consequences,such as organ failure.However,there are currently no effective,broad-spectmm drugs suitable for clinical application.Revealing the process of fibrosis is an important prerequisite for the development of new therapeutic targets and drugs.Studies have shown that the limiting of myofibroblast activation or the promoting of their elimination can ameliorate fibrosis.However,it has not been reported whether a direct decrease in cell contraction can inhibit fibrosis in vivo.Here,we have shown that(-)-blebbistatin(Ble),a non-muscle myosin II inhibitor,displayed significant inhibition of liver fibrosis in different chronic injury mouse models in vivo.We found that Ble reduced the stiffness of fibrotic tissues from the early stage,which reduced the extent of myofibroblast activation induced by a stiffer extracellular matrix(ECM).Moreover,Ble also reduced the activation of myofibroblasts induced by TGF-β1,which is the most potent pro-fibrotic cytokine.Mechanistically,Ble reduced mechanical contraction,which inhibited the assembly of stress fibers,decreased the F/G-actin ratio,and led to the exnucleation of YAPJ and MRTF-A.Finally,we verified its broad-spectrum antifibrotic effect in multiple models of organ fibrosis.Our results highlighted the important role of mechanical contraction in myofibroblast activation and maintenance,rather than just a characteristic of activation,suggesting that it may be a potential target to explore broad-spectrum drugs for the treatment of fibrotic diseases.
基金Supported by the National Key R&D Program of China(No.2023YFC2410203)Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support(No.ZLRK202503).
文摘AIM:To investigate the clinical features and prognosis of patients with orbital inflammatory myofibroblastic tumor(IMT).METHODS:This retrospective study collected clinical data from 22 patients diagnosed with orbital IMT based on histopathological examination.The patients were followed up to assess their prognosis.Clinical data from patients,including age,gender,course of disease,past medical history,primary symptoms,ophthalmologic examination findings,general condition,as well as imaging,laboratory,histopathological,and immunohistochemical results from digital records were collected.Orbital magnetic resonance imaging(MRI)and(or)computed tomography(CT)scans were performed to assess bone destruction of the mass,invasion of surrounding tissues,and any inflammatory changes in periorbital areas.RESULTS:The mean age of patients with orbital IMT was 28.24±3.30y,with a male-to-female ratio of 1.2:1.Main clinical manifestations were proptosis,blurred vision,palpable mass,and pain.Bone destruction and surrounding tissue invasion occurred in 72.73%and 54.55%of cases,respectively.Inflammatory changes in the periorbital site were observed in 77.27%of the patients.Hematoxylin and eosin staining showed proliferation of fibroblasts and myofibroblasts,accompanied by infiltration of lymphocytes and plasma cells.Immunohistochemical staining revealed that smooth muscle actin(SMA)and vimentin were positive in 100%of cases,while anaplastic lymphoma kinase(ALK)showed positivity in 47.37%.The recurrence rate of orbital IMT was 27.27%,and sarcomatous degeneration could occur.There were no significant correlations between recurrence and factors such as age,gender,laterality,duration of the disease,periorbital tissue invasion,bone destruction,periorbital inflammation,tumor size,fever,leukocytosis,or treatment(P>0.05).However,lymphadenopathy and a Ki-67 index of 10%or higher may be risk factors for recurrence(P=0.046;P=0.023).CONCLUSION:Orbital IMT is a locally invasive disease that may recur or lead to sarcomatoid degeneration,primarily affecting young and middle-aged patients.The presence of lymphadenopathy and a Ki-67 index of 10%or higher may signify a poor prognosis.
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Hepatic fibrosis is a pathological process characterized by an imbalance between the deposition and degradation of extracellular matrix components.This process is initiated by chronic liver injuries resulting from viral infections,alcoholic liver disease,non-alcoholic fatty liver disease,and autoimmune-mediated hepatic damage.If left untreated,hepatic fibrosis can progress to life-threatening conditions such as cirrhosis and hepatocellular carcinoma.Central to the development of fibrosis is the transdifferentiation of quiescent hepatic stellate cells(HSCs)into proliferative and fibrogenic myofibroblast-like activated HSCs(aHSCs),which play a crucial role in extracellular matrix accumulation and fibrotic tissue formation.Beyond resmetirom,a recently Food and Drug Administrationapproved medication for liver fibrosis and nonalcoholic steatohepatitis,there are currently no other established pharmacological treatments available to slow down the progression of these conditions.Moreover,activation of HSCs and formation of hepatic fibrosis have been considered irreversible.Recent studies reported transforming growth factor beta as one of the key regulators of HSCs activation and pathogenesis of hepatic fibrosis.It has been also reported that the features of aHSCs can be reversed to those of quiescent HSCs by modulating transforming growth factor beta mediated pathways.The potential of extracellular vesicles(EVs)as cell free therapeutics to treat hepatic fibrosis has been suggested earlier.However,detailed knowledge of the mechanisms involved in the alleviation of hepatic fibrosis using EVs from mesenchymal stem cells is still lacking.Hence,this review aims to describe the pathogenesis of hepatic fibrosis from the cellular and molecular point of views and shed light on the potential of EVs from mesenchymal stem cells in reversing the properties of aHSCs to their quiescent state.
文摘Myofibroblastic sarcoma(MS)is a rare malignant soft tissue tumor characterized by myofibroblasts.It most commonly arises in the head and neck region,especially the tongue,with rare occurrences in the limbs.MS exhibits varying histopathology,ranging from low-to high-grade,with diverse subtypes showing different clinical behaviors and prognoses.This article reports the first case of high-grade MS in the hand,adding to the limited documentation of this rare condition.Here,we present the case of a 30-year-old healthy female with a year-long history of progressive shortening,mobility loss,and weakness in the first finger of the left hand.Left-hand imaging revealed a lytic,cottony tumor involving the entire first metacarpal.Following surgical resection,which included metatarsal grafting and joint reconstruction,a diagnosis of high-grade MS was confirmed based on histological manifestations and immunohistochemical staining,which was further classified as grade 2 according to the French Federation of Cancer Centers Sarcoma Group system.Postoperative radiotherapy was administered and the patient experienced a successful recovery without graft osteonecrosis.The patient regained 90%mobility and strength,without shortening,after surgical resection and radiotherapy.Six months post-surgery,the patient reported full hand functionality.MS is a rare tumor that infrequently affects bones and is often misdiagnosed owing to its controversial characteristics.The initial treatment should focus on complete resection with negative margins,followed by reconstructive surgery to preserve function.Further case studies are needed to establish standardized surgical treatment protocols.
文摘Fibrosis is marked by the excessive accumulation of extracellular matrix(ECM)components,leading to tissue scarring and progressive loss of organ function.Myofibroblasts,which emerge during tissue repair,are specialized contractile cells exhibiting features of both fibroblasts and smooth muscle cells.Their expression ofα-smooth muscle actin facilitates contractile activity,while their persistent activation and overproduction of ECM components contribute significantly to pathological wound contraction and fibrotic progression.Beyond ECM production,myofibroblasts play a significant role in the tumor microenvironment(TME)of various solid tumors.The TME is a complex network of immune cells,blood vessels,ECM components,and stromal cells like fibroblasts and myofibroblasts that surrounds and interacts with cancer cells,thereby influencing tumor growth,progression,and therapy responsiveness.Through these interactions,myofibroblasts modulate inflammation,angiogenesis,and tissue remodeling.Maintaining myofibroblast homeostasis is therefore crucial,as its disruption can drive the onset of chronic fibrotic conditions and malignancies.This review explores preclinical and clinical developments in targeting myofibroblasts in fibrotic and TME across various disease models,including hypertrophic scar,idiopathic pulmonary fibrosis,oral submucous fibrosis,cardiac fibrosis,and the desmoplastic stroma of pancreatic and breast cancers.
文摘Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelialand endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic proc-ess, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.
文摘肾脏纤维化是各种原因引起的慢性肾脏病的重要标志[1]。肌成纤维细胞增殖和细胞外基质积聚是肾脏纤维化的特征性改变。目前认为,肾脏纤维化程度能可靠地反映肾脏病的预后。近几十年来,肌成纤维细胞的来源颇具争议。传统观点认为肌成纤维细胞起源于固有的成纤维细胞,但是,循环中的纤维细胞、肾小管上皮细胞转分化（epithelial to myofibroblast transformation,EMT）和内皮细胞向间充质细胞的分化均被认为是其可能的来源。
文摘AIM： To investigate the effects of transforming growth factor β1 （TGF-β1） on the differentiation of colonic lamina propria fibroblasts （CLPF） into myofibroblasts in vitro.METHODS： Primary CLPF cultures were incubated with TGF-β1 and analyzed for production of m-smooth muscle actin （α-SMA）, fibronectin （FN） and FN isoforms. Migration assays were performed in a modified 48-well Boyden chamber. Levels of total and phosphorylated focal adhesion kinase （FAK） in CLPF were analyzed after induction of migration.did not change α-SMA levels, while TGF-β1 treatment for 6 d significantly increased α-SIVlA production. Short term incubation （6 h） with TGF-β1 enhanced CLPF migration, while long term treatment （6 d） of CLPF with TGF-β1 reduced migration to 15%-37% compared to untreated cells. FN and FN isoform mRNA expression were increased after short term incubation with TGF-β1 （2 d） in contrast to long term incubation with TGF-β1 for 6 d. After induction of migration, TGF-β1-preincubated CLPF showed higher amounts of FN and its isoforms and lower levels of total and phosphorylated FAK than untreated cells.CONCLUSION： Long term incubation of CLPF with TGF-β1 induced differentiation into myofibroblasts with enhanced α-SMA, reduced migratory potential and FAK phosphorylation, and increased FN production. In contrast, short term contact （6 h） of fibroblasts with TGF-β1 induced a dose-dependent increase of cell migration and FAK phosphorylation without induction of α-SMA production.
文摘Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells.Persistent liver injury,associated with chronic AILD,leads to un-resolving inflammation,cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts.Liver cirrhosis,and the resultant loss of normal liver function,inevitably ensues.Patients with cirrhosis have higher risks or morbidity and mortality,and that in the decompensated phase,complications of portal hypertension and/or liver dysfunction lead to rapid deterioration.Accurate diagnosis and monitoring of cirrhosis is,therefore of upmost importance.Liver biopsy is currently the gold standard technique,but highly promising non-invasive methodology is under development.Liver transplantation(LT) is an effective therapeutic option for the management of endstage liver disease secondary to AIH,PBC and PSC.LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy;in addition,LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.
基金Supported by the Italian MIUR Grant, No. MM_06315722,by the University of Florenceby the Italian Liver Foundation. Eva Efsen was Supported in Part by the Tode Travel Grant, the Direktφr Madsen's GrantFhv. Direktφr Nielsen's Grant (Denmark)
文摘AIM： To investigate the effects of troglitazone （TGZ）, an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-y （PPAR-y）, for liver tissue repair, and the development of ductular reaction, following common bile duct ligation （BDL） in rats. METHODS： Rats were supplemented with TGZ （0.2% w/w in the pelleted food） for i wk before BDL or sham operation. Animals were killed at 1, 2, or 4 wk after surgery. RESULTS： The development of liver fibrosis was reduced in rats receiving TGZ, as indicated by significant decreases of procollagen type I gene expression and liver hydroxyproline levels. Accumulation of a-smooth-muscle actin （SMA）-expressing cells surrounding newly formed bile ducts following BDL, as well as total hepatic levels of SMA were partially inhibited by TGZ treatment, indicating the presence of a reduced number and/or activation of hepatic stellate cells （HSC） and myofibroblasts. Development of the ductular reaction was inhibited by TGZ, as indicated by histochemical evaluation and hepatic activity of γ-glutamyltransferase （GGT）. CONCLUSION： Treatment with thiazolidinedione reduces ductular proliferation and fibrosis in a model of chronic cholestasis, and suggests that limiting cholangiocyte proliferation may contribute to the lower development of scarring in this system.
文摘Background: Upon liver injury, quiescent hepatic stellate cells(q HSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells(MFBs). The q HSCs in the normal liver are less fibrogenic, migratory, and also have less proliferative potential. However, activated HSCs(a HSCs) are more fibrogenic and have a high migratory and proliferative MFBs phenotype. HSCs activation is a highly energetic process that needs abundant intracellular energy in the form of adenosine triphosphate(ATP) for the synthesis of extracellular matrix(ECM) in the injured liver to substantiate the injury. Data sources: The articles were collected through Pub Med and EMBASE using search terms "mitochondria and hepatic stellate cells", "mitochondria and HSCs", "mitochondria and hepatic fibrosis", "mitochondria and liver diseases", and "mitochondria and chronic liver disease", and relevant publications published before September 31, 2020 were included in this review. Results: Mitochondria homeostasis is affected during HSCs activation. Mitochondria in a HSCs are highly energetic and are in a high metabolically active state exhibiting increased activity such as glycolysis and respiration. a HSCs have high glycolytic enzymes expression and glycolytic activity induced by Hedgehog(Hh) signaling from injured hepatocytes. Increased glycolysis and aerobic glycolysis(Warburg effect) endproducts in a HSCs consequently activate the ECM-related gene expressions. Increased Hh signaling from injured hepatocytes downregulates peroxisome proliferator-activated receptor-γ expression and decreases lipogenesis in a HSCs. Glutaminolysis and tricarboxylic acid cycle liberate ATPs that fuel HSCs to proliferate and produce ECM during their activation. Conclusions: Available studies suggest that mitochondria functions can increase in parallel with HSCs activation. Therefore, mitochondrial modulators should be tested in an elaborate manner to control or prevent the HSCs activation during liver injury to subsequently regress hepatic fibrosis.
文摘To investigate interleukin (IL)-26 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and the function of IL-26. METHODSHuman colonic subepithelial myofibroblasts (SEMFs) were isolated from colon tissue surgically resected. The expression of IL-26 protein and its receptor complex was analyzed by immunohistochemistry. The gene expression induced by IL-26 was evaluated by real-time polymerase chain reaction. Intracellular signaling pathways were evaluated by immunoblotting and specific small interfering (si) RNA transfection. RESULTSThe mRNA and protein expression of IL-26 were significantly enhanced in the inflamed mucosa of patients with IBD. IL-26 receptor complex was expressed in colonic SEMFs in vivo and in vitro. IL-26 stimulated the mRNA expression of IL-6 and IL-8 in colonic SEMFs. The inhibitors of mitogen-activated protein kinases and phosphoinositide 3-kinase, and siRNAs for signal transducers and activator of transcription 1/3, nuclear factor-kappa B and activator protein-1 significantly reduced the mRNA expression of IL-6 and IL-8 induced by IL-26. CONCLUSIONThese results suggest that IL-26 plays a role in the pathophysiology of IBD through induction of inflammatory mediators.
