Liver fibrosis is a pathological condition characterized by replacement of normal liver tissue with scar tissue,and also the leading cause of liver-related death worldwide.During the treatment of liver fibrosis,in add...Liver fibrosis is a pathological condition characterized by replacement of normal liver tissue with scar tissue,and also the leading cause of liver-related death worldwide.During the treatment of liver fibrosis,in addition to antiviral therapy or removal of inducers,there remains a lack of specific and effective treatment strategies.For thousands of years,Chinese herbal medicines(CHMs)have been widely used to treat liver fibrosis in clinical setting.CHMs are effective for liver fibrosis,though its mechanisms of action are unclear.In recent years,many studies have attempted to determine the possible mechanisms of action of CHMs in treating liver fibrosis.There have been substantial improvements in the experimental investigation of CHMs which have greatly promoted the understanding of anti-liver fibrosis mechanisms.In this review,the role of CHMs in the treatment of liver fibrosis is described,based on studies over the past decade,which has addressed the various mechanisms and signaling pathways that mediate therapeutic efficacy.Among them,inhibition of stellate cell activation is identified as the most common mechanism.This article provides insights into the research direction of CHMs,in order to expand its clinical application range and improve its effectiveness.展开更多
The rapid formation of a glial/fibrotic scar is one of the main factors hampering axon growth after spinal cord injury. The bidirectional Eph B2/ephrin-B2 signaling of the fibroblast-astrocyte contact-dependent intera...The rapid formation of a glial/fibrotic scar is one of the main factors hampering axon growth after spinal cord injury. The bidirectional Eph B2/ephrin-B2 signaling of the fibroblast-astrocyte contact-dependent interaction is a trigger for glial/fibrotic scar formation. In the present study, a new in vitro model was produced by coculture of fibroblasts and astrocytes wounded by scratching to mimic glial/fibrotic scar-like structures using an improved slide system. After treatment with RNAi to downregulate Eph B2, changes in glial/fibrotic scar formation and the growth of VSC4.1 motoneuron axons were examined. Following RNAi treatment, fibroblasts and astrocytes dispersed without forming a glial/fibrotic scar-like structure. Furthermore, the expression levels of neurocan, NG2 and collagen I in the coculture were reduced, and the growth of VSC4.1 motoneuron axons was enhanced. These findings suggest that suppression of Eph B2 expression by RNAi attenuates the formation of a glial/fibrotic scar and promotes axon growth. This study was approved by the Laboratory Animal Ethics Committee of Jiangsu Province, China(approval No. 2019-0506-002) on May 6, 2019.展开更多
In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly unders...In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly understood. M2 macrophages regulate fibrotic scar formation after injury to the heart, lung, kidney, and central nervous system. However, it remains to be clarified whether and how M2 macrophages regulate fibrotic scar formation after cerebral ischemia injury. In this study, we found that, in a rat model of cerebral ischemia induced by middle cerebral artery occlusion/reperfusion, fibrosis and macrophage infiltration were apparent in the ischemic core in the early stage of injury(within 14 days of injury). The number of infiltrated macrophages was positively correlated with fibronectin expression. Depletion of circulating monocyte-derived macrophages attenuated fibrotic scar formation. Interleukin 4(IL4) expression was strongly enhanced in the ischemic cerebral tissues, and IL4-induced M2 macrophage polarization promoted fibrotic scar formation in the ischemic core. In addition, macrophage-conditioned medium directly promoted fibroblast proliferation and the production of extracellular matrix proteins in vitro. Further pharmacological and genetic analyses showed that sonic hedgehog secreted by M2 macrophages promoted fibrogenesis in vitro and in vivo, and that this process was mediated by secretion of the key fibrosis-associated regulatory proteins transforming growth factor beta 1 and matrix metalloproteinase 9. Furthermore, IL4-afforded functional restoration on angiogenesis, cell apoptosis, and infarct volume in the ischemic core of cerebral ischemia rats were markedly impaired by treatment with an sonic hedgehog signaling inhibitor, paralleling the extent of fibrosis. Taken together, our findings show that IL4/sonic hedgehog/transforming growth factor beta 1 signaling targeting macrophages regulates the formation of fibrotic scar and is a potential therapeutic target for ischemic stroke.展开更多
AIM: To investigate tumor necrosis factor-α (TNF-α), syndecan 1 and basic fibroblast growth factor (bFGF) balance in Crohn's disease (CD) strictures. METHODS: Our study was performed on 24 surgical specimens of ...AIM: To investigate tumor necrosis factor-α (TNF-α), syndecan 1 and basic fibroblast growth factor (bFGF) balance in Crohn's disease (CD) strictures. METHODS: Our study was performed on 24 surgical specimens of CD fibrotic stenosis. Ten histological normal surgical samples were retrieved for both the large and small bowel from patients with benign conditions and healthy tissue represented control collection. Sex and age in controls did not differ from CD group. Three endoscopic biopsy specimens taken after informed consent in subjects with normal colon were also used as negative controls. TNF-α, syndecan 1 and bFGF were detected by both reverse transcriptase reverse transcriptase polymerase chain reaction after mRNA extraction (results expressed as fold-change) and immunohistochemistry.RESULTS: TNF-α did not show any significant difference between CD and control specimens (1.54 ± 1.19; P > 0.05). Very high levels of bFGF were observed in CD (11.76 ± 4.65; P < 0.001) unlike syndecan 1 which showed a moderate increase (5.53 ± 2.18; P < 0.005). analysis of variance (ANOVA) plus Student-NeumannKeuls showed: bFGF > syndecan 1 > TNF-α = control. Immunoreactivity for bFGF was observed in epithelial, stromal, endothelial cells and even in the muscular layer, whilst in normal tissue it was almost unexpressed. Syndecan 1 and TNF-α staining was confined to mucosal epithelial and stromal cells, while in controls syndecan 1 was found in its normal site, i.e. , basolateral area of the crypts and TNF-α very poorly expressed. CONCLUSION: Fibrotic stenosis of CD may be the final result of an irreversible transformation of different cells into fibrogenic phenotype no longer inhibited by posttranscriptional regulation.展开更多
AIM： Hydrodynamics based transfection （HBT）, the injection of a large volume of naked plasmid DNA in a short time is a relatively simple, efficient and safe method for in vivo transfection of liver cells. Though us...AIM： Hydrodynamics based transfection （HBT）, the injection of a large volume of naked plasmid DNA in a short time is a relatively simple, efficient and safe method for in vivo transfection of liver cells. Though used for quite some time, the mechanism of gene transfection has not yet been elucidated. METHODS： A lucJferase encoding plasmid was injected using the hydrodynamics based procedure into normal and thioacetamide-induced fibrotic Sprague Dawley rats. Scanning and transmission electron microscopy images were taken. The consequence of a dual injection of Ringer solution and luciferase pDNA was followed. Halofuginone, an anti collagen type I inhibitor was used to reduce ECM load in fibrotic rats prior to the hydrodynamic injection. RESULTS： Large endothelial gaps formed as soon as 10＇ following hydrodynamic injection; these gradually returned to normal 10 d post injection. Hydrodynamic administration of Ringer 10 or 30 m prior to moderate injection of plasmid did not result in efficient transfection suggesting that endothelial gaps by themselves are not sufficient for gene expression. Gene transfection following hydrodynamic injection in thioacetamide induced fibrotic rats was diminished coinciding with the level of fibrosis. Halofuginone, a specific collagen type I inhibitor, alleviated this effect. CONCLUSION： The hydrodynamic pressure formed following HBT results in the formation of large endothelial gaps. These gaps, though important in the transfer of DNA molecules from the blood to the space of Disse are not enough to provide the appropriate conditions for hepatocyte transfection. Hydrodynamics based injection is applicable in fibrotic rats provided that ECM load is reduced.展开更多
BACKGROUND Fibrotic hypersensitivity pneumonitis(FHP)is an allergic and diffuse pneumonia caused by repeated inhalation of antigenic substances,and sometimes developed in people working in specific environments.While ...BACKGROUND Fibrotic hypersensitivity pneumonitis(FHP)is an allergic and diffuse pneumonia caused by repeated inhalation of antigenic substances,and sometimes developed in people working in specific environments.While novel antigens and exposures continued to be described,physicians should maintain a high suspicion of potential exposures.A detailed assessment of the patient's occupational exposures as well as living environment is necessary and complete allergen avoidance is the first and most important step in the management of FHP once the allergens are determined.CASE SUMMARY A 35-year-old female was admitted to the hospital with a cough and breathing difficulties for more than one year.She was a nonsmoker and a manufacturer of halogen dishes,which are characteristic Chinese foods,for 15 years without any protection.High resolution computed tomography of the chest demonstrated an interstitial pneumonia pattern.Pulmonary function examination showed restricted ventilation dysfunction and a significant reduction in dispersion ability.Cell differentiation in bronchoalveolar lavage fluid demonstrated lymphocytosis(70.4%)with an increased lymphocyte CD4/CD8 ratio(0.94).Transbronchial lung biopsy combined with lung puncture pathology showed diffuse uniform alveolar interval thickening,chronic inflammatory cell infiltration,a proliferation of tissue in the bronchial wall fiber and alveolar epithelial follicle degeneration,resulting in fibrosis.CONCLUSION Exposure to spices used for the production of halogen dishes may cause FHP.展开更多
AIM: To compare the outcome of an Ex-Press implant and subscleral trabeculectomy(SST) in the management of glaucoma after previous trabeculectomy on a fibrotic bleb.METHODS: This randomized prospective study included ...AIM: To compare the outcome of an Ex-Press implant and subscleral trabeculectomy(SST) in the management of glaucoma after previous trabeculectomy on a fibrotic bleb.METHODS: This randomized prospective study included 28 eyes from 28 patients(age range: 42-55 y) with primary open angle glaucoma(POAG) presented with elevated intraocular pressure(IOP) with fibrotic bleb despite previous SST for more than 4 mo. The eyes enrolled in the study were divided into two groups: group I(subjected to Ex-Press implant surgery) and group II [subjected to SST with mitomycin C(MMC)]. The follow-up continued one year after surgery to evaluate IOP, visual acuity(VA), visual field(VF), and postoperative complications. RESULTS: A significant decrease in IOP was found in both groups with a higher reduction in Ex-Press implant surgery with the mean IOP of 14.50 mm Hg(P=0.001), while the SST group recorded the mean IOP of 16.50 mm Hg(P=0.001) after one year. However, the difference between the two groups in terms of the decrease in IOP was insignificant. Fewer postoperative complications were recorded in the Ex-Press implant surgery and more cases requiring further anti-glaucomatous medications were seen in the SST group. Both groups showed stability in terms of VA and VF.CONCLUSION: Ex-Press implant surgery and SST with MMC are two surgical alternatives for controlling IOP in late failure that occurs more than 4 mo after previous SST with a fibrotic bleb. However, Ex-Press shunt is a safer surgery with fewer complications.展开更多
Background: Complete hypopharyngo-oesophageal occlusion is a rare complication of head and neck radiotherapy and a range of other conditions. Absolute dysphagia is accompanied by aspiration and dependence on gastrosto...Background: Complete hypopharyngo-oesophageal occlusion is a rare complication of head and neck radiotherapy and a range of other conditions. Absolute dysphagia is accompanied by aspiration and dependence on gastrostomy feeding. The condition presents a substantial management challenge. Surgical approaches to re-establish pharyngo-oesophageal continuity are varied, highly invasive and are associated with unpredictable outcomes. Minimally invasive techniques employing endoscopic and radiological techniques are emerging. This report describes a multidisciplinary approach which translates two interventional radiology techniques used in the management of central venous occlusions and biliary strictures to the management of three cases of complete hypopharyngo-oesophageal occlusion. Methods: Three cases with different underlying aetiologies had treatment initiated between 2009 and 2011. Antegrade pharyngoscopic access to the occlusions was accompanied by retrograde endoscopic access via a small gastrostomy. Luminal continuity was re-established by the interventional radiology technique of “sharp recanalisation” followed by passage of a wide bore nasogastric tube which was maintained in situ for 4-6 months, a duration of treatment analogous to that applied in the radiological management of fibrotic biliary strictures. After treatment a radiological contrast swallows examination was performed to gauge the calibre of the re-established lumen, assess functionality and to rule out aspiration. Results: Pharyngo-oesophageal continuity was re-established in all three cases on the first attempt. No complications occurred as a result of the procedures. In two cases, the excellent swallowing function was re-established, although one of these required prolonged post-treatment adjuvant interventions. In one case no swallowing function resulted, despite apparently successful re-establishment of luminal continuity. Conclusions: Complete fibrotic occlusion of the hypopharyngo-oesophageal lumen is rare and presents a substantial management challenge. A minimally invasive treatment combining antegrade radiological and retrograde endoscopic approaches resulted in successful re-establishment of luminal continuity in three cases of complete fibrotic occlusion of the hypopharyngo-oesophageal lumen. However variable responses to treatment suggest that both the underlying aetiology and the chronicity of the occlusion may influence the likelihood of a successful functional outcome. Until definitive management guidelines are established, we suggest that such cases are managed only by motivated multidisciplinary teams keen to develop their expertise in this area.展开更多
Fibrosis is a pathological process characterized by chronic inflammation and excessive ECM deposition,leading to tissue scarring and organ dysfunction.(1)Fibrotic tissue accumulation results from persistent injuries t...Fibrosis is a pathological process characterized by chronic inflammation and excessive ECM deposition,leading to tissue scarring and organ dysfunction.(1)Fibrotic tissue accumulation results from persistent injuries triggered by factors such as epigenetic alterations,infections,hypertension,myocardial infarction,autoimmune inflammation,and metabolic disorders.(2.3)Although fibrosis shares similarities with normal wound healing,dysregulated or repeated tissue repair can result in rreversible scarring,ultimately leading to organ failure.(4)The inflammatory response and the activation of myofibroblasts-fibroblasts that secrete collagen and express α-SMA are essential for stimulating the repair response and triggering fibrosis in many organs.Normal tissue repair can become an irreversible fibrotic response if the tissue damage is extensive,repetitive,or if the wound-healing process becomes dysregulated,(5)This irreversible fibrotic response leads to several adverse outcomes,including irreversible scarring,disruption of tissue architecture,organ dysfunction,and ultimately,organ failure and death.(6)Chronic liver diseases,kidney disorders,interstitial lung disease,and heart failure are representative examples.(7.8)The incidence of pulmonary fibrosis has risen globally,particularly following the COVID-19 pandemic.展开更多
Progranulin(PGRN),a multifunctional growth factor-like protein expressed by a variety of cell types,serves an important function in the physiologic and pathologic processes of fibrotic diseases,including wound healing...Progranulin(PGRN),a multifunctional growth factor-like protein expressed by a variety of cell types,serves an important function in the physiologic and pathologic processes of fibrotic diseases,including wound healing and the inflammatory response.PGRN was discovered to inhibit proinflammation effect by competing with tumor necrosis factor-alpha(TNF-a)binding to TNF receptors.Notably,excessive tissue repair in the development of inflammation causes tissue fibrosis.Previous investigations have indicated the significance of PGRN in regulating inflammatory responses.Recently,multiple studies have shown that PGRN was linked to fibrogenesis,and was considered to monitor the formation of fibrosis in multiple organs,including liver,cardiovascular,lung and skin.This paper is a comprehensive review summarizing our current knowledge of PGRN,from its discovery to the role in fibrosis.This is followed by an in-depth look at the characteristics of PGRN,consisting of its structure,basic function and intracellular signaling.Finally,we will discuss the potential of PGRN in the diagnosis and treatment of fibrosis.展开更多
Idiopathic pulmonary fibrosis(IPF)is characterized by accumulation of myofibroblasts(MYFs)and extracellular matrix components,which leads to severe distortion and scarring of the gas exchange units of the lung,the alv...Idiopathic pulmonary fibrosis(IPF)is characterized by accumulation of myofibroblasts(MYFs)and extracellular matrix components,which leads to severe distortion and scarring of the gas exchange units of the lung,the alveoli,and ultimately respiratory failure.Fibrosis-associated MYFs are therefore widely regarded as the culprits that compromise the architectural makeup of the lung in fibrotic disease.During the past decade,the cellular source of MYFs has been intensely investigated.The rationale for such studies is that identifying the origin of these cells might help identify novel therapeutic targets and candidates to treat IPF patients.Recent advances in basic and translational research employing lineage tracing and multi-omics approaches have helped address the identity of MYF precursors,highlight the underlying heterogeneity,and to a less extent investigate MYF fate during fibrosis resolution.In this review,we discuss the current understanding of such important aspects of MYF biology as well as recent developments in the treatment of IPF.展开更多
Background:Immunoglobulin G4-related disease(IgG4-RD)is a recently recognized immune-mediated disorder that can affect almost any organ in the human body.IgG4-RD can be categorized into proliferative and fibrotic subt...Background:Immunoglobulin G4-related disease(IgG4-RD)is a recently recognized immune-mediated disorder that can affect almost any organ in the human body.IgG4-RD can be categorized into proliferative and fibrotic subtypes based on patients’clinicopathological characteristics.This study aimed to compare the clinical manifestations,laboratory findings,and treatment outcomes of IgG4-RD among different subtypes.Methods:We prospectively enrolled 622 patients with newly diagnosed IgG4-RD at Peking Union Medical College Hospital from March 2011 to August 2021.The patients were divided into three groups according to their clinicopathological characteristics:proliferative,fibrotic,and mixed subtypes.We compared demographic features,clinical manifestations,organ involvement,laboratory tests,and treatment agents across three subtypes.We then assessed the differences in treatment outcomes among 448 patients receiving glucocorticoids alone or in combination with immunosuppressants.Moreover,risk factors of relapse were revealed by applying the univariate and multivariate Cox regression analysis.Results:We classified the 622 patients into three groups consisting of 470 proliferative patients,55 fibrotic patients,and 97 mixed patients,respectively.We found that gender distribution,age,disease duration,and frequency of allergy history were significantly different among subgroups.In terms of organ involvement,submandibular and lacrimal glands were frequently involved in the proliferative subtype,while retroperitoneum was the most commonly involved site in both fibrotic subtype and mixed subtype.The comparison of laboratory tests revealed that eosinophils(P=0.010),total IgE(P=0.006),high-sensitivity C-reactive protein(P<0.001),erythrocyte sedimentation rate(P<0.001),complement C4(P<0.001),IgG(P=0.001),IgG1(P<0.001),IgG4(P<0.001),and IgA(P<0.001),at baseline were significantly different among three subtypes.Compared with proliferative and mixed subtypes,the fibrotic subtype showed the lowest rate of relapse(log-rank P=0.014).Conclusions:Our study revealed the differences in demographic characteristics,clinical manifestations,organ involvement,laboratory tests,treatment agents,and outcomes across proliferative,fibrotic,and mixed subtypes in the retrospective cohort study.Given significant differences in relapse-free survival among the three subtypes,treatment regimens,and follow-up frequency should be considered separately according to different subtypes.Trial Registration:ClinicalTrials.gov,NCT01670695.展开更多
Thrombospondin 4(THBS4;TSP4),a crucial component of the extracellular matrix(ECM),serves as an important regulator of tissue homeostasis and various pathophysiological processes.As a member of the evolutionarily conse...Thrombospondin 4(THBS4;TSP4),a crucial component of the extracellular matrix(ECM),serves as an important regulator of tissue homeostasis and various pathophysiological processes.As a member of the evolutionarily conserved thrombospondin family,THBS4 is a multidomain adhesive glycoprotein characterized by six distinct structural domains that mediate its diverse biological functions.Through dynamic interactions with various ECM components,THBS4 plays pivotal roles in cell adhesion,proliferation,inflammation regulation,and tissue remodeling,establishing it as a key modulator of microenvironmental organization.The transcription and translation of THBS4 gene,as well as the activity of the THBS4 protein,are tightly regulated by multiple signaling pathways and extracellular cues.Positive regulators of THBS4 include transforming growth factorβ(TGF-β),interferonγ(IFNγ),granulocyte-macrophage colony-stimulating factor(GM-CSF),bone morphogenetic proteins(BMP12/13),and other regulatory factors(such as B4GALNT1,ITGA2/ITGB1,PDGFRβ,etc.),which upregulate THBS4 at the mRNA and/or protein level.Conversely,oxidized low-density lipoprotein(OXLDL)acts as a potent negative regulator of THBS4.This intricate regulatory network ensures precise spatial and temporal control of THBS4 expression in response to diverse physiological and pathological stimuli.Functionally,THBS4 acts as a critical signaling hub,influencing multiple downstream pathways essential for cellular behavior and tissue homeostasis.The best-characterized pathways include:(1)the PI3K/AKT/mTOR axis,which THBS4 modulates through both direct and indirect interactions with integrins and growth factor receptors;(2)Wnt/β-catenin signaling,where THBS4 functions as either an activator or inhibitor depending on the cellular context;(3)the suppression of DBET/TRIM69,contributing to its diverse regulatory roles.These signaling connections position THBS4 as a master regulator of cellular responses to microenvironmental changes.Substantial evidence links aberrant THBS4 expression to a range of pathological conditions,including neoplastic diseases,cardiovascular disorders,fibrotic conditions,neurodegenerative diseases,musculoskeletal disorders,and atopic dermatitis.In cancer biology,THBS4 exhibits context-dependent roles,functioning either as a tumor suppressor or promoter depending on the tumor type and microenvironment.In the cardiovascular system,THBS4 contributes to both adaptive remodeling and maladaptive fibrotic responses.Its involvement in fibrotic diseases arises from its ability to regulate ECM deposition and turnover.The diagnostic and therapeutic potential of THBS4 is particularly promising in oncology and cardiovascular medicine.As a biomarker,THBS4 expression patterns correlate significantly with disease progression and patient outcomes.Therapeutically,targeting THBS4-mediated pathways offers novel opportunities for precision medicine approaches,including anti-fibrotic therapies,modulation of the tumor microenvironment,and enhancement of tissue repair.This comprehensive review systematically explores three key aspects of THBS4 research:(1)the fundamental biological functions of THBS4 in ECM organization;(2)its mechanistic involvement in various disease pathologies;(3)its emerging potential as both a diagnostic biomarker and therapeutic target.By integrating recent insights from molecular studies,animal models,and clinical investigations,this review provides a framework for understanding the multifaceted roles of THBS4 in health and disease.The synthesis of current knowledge highlights critical research gaps and future directions for exploring THBS4-targeted interventions across multiple disease contexts.Given its unique position at the intersection of ECM biology and cellular signaling,THBS4 represents a promising frontier for the development of novel diagnostic tools and therapeutic strategies in precision medicine.展开更多
The fibrotic response plays an important role in the performance and longevity of implantable devices. Thus, development of effective anti-inflammatory and anti-fibrosis biomaterial implants has become an urgent task....The fibrotic response plays an important role in the performance and longevity of implantable devices. Thus, development of effective anti-inflammatory and anti-fibrosis biomaterial implants has become an urgent task. In this work, we developed a novel supramolecular polymer hydrogel through the copolymerization of N-acryloyl glycinamide(NAGA) and carboxybetaine acrylamide(CBAA) in the absence of any chemical crosslinker, which the mechanical properties being tunable through changing the monomer concentration and the monomer ratio over a broad scope. The hydrogel possessed the superior mechanical performances: high tensile strength(～1.13 MPa), large stretchability(～1200%), and excellent compressive strength(～9 MPa) at high monomer concentration and NAGA/CBAA ratio. Introduction of CBAA could promote the self-healability, thermoplasticity of suparmolecular polymer hydrogels at lower temperatures, meanwhile dramatically improving anti-fouling property.Histological analysis and in vitro cytotoxicity assays testified the excellent biocompatibility of the hydrogel. This high strength supramolecular polymer hydrogel with integrated multiple functions holds promising potentials as a scaffold biomaterial for treating degenerated soft supporting tissues.展开更多
Annexin A1,a well-known endogenous anti-inflammatory mediator,plays a critical role in a variety of pathological processes.Fibrosis is described by a failure of tissue regeneration and contributes to the development o...Annexin A1,a well-known endogenous anti-inflammatory mediator,plays a critical role in a variety of pathological processes.Fibrosis is described by a failure of tissue regeneration and contributes to the development of many diseases.Accumulating evidence supports that Annexin A1 participates in the progression of tissue fibrosis.However,the fundamental mechanisms by which Annexin A1 regulates fibrosis remain elusive,and even the functions of Annexin A1 in fibrotic diseases are still paradoxical.This review focuses on the roles of Annexin A1 in the development of fibrosis of lung,liver,heart,and other tissues,with emphasis on the therapy potential of Annexin A1 in fibrosis,and presents future research interests and directions in fibrotic diseases.展开更多
apamvcin was first isolated from a strain of Sreptomyces hygroscopicus in the early 1970s froma soil sample taken on Easter Island. Because the antiproliferative effects of rapamycin on yeast cell, as well as B and T ...apamvcin was first isolated from a strain of Sreptomyces hygroscopicus in the early 1970s froma soil sample taken on Easter Island. Because the antiproliferative effects of rapamycin on yeast cell, as well as B and T lymphocytes, it was first identified as an antimicrobial agent with potent immunosuppressive activity and has been used in antirejection therapy.展开更多
Background and Aims:Occlusive portal vein thrombosis(PVT)often causes portal hypertension-related complications in cirrhotic patients.Transjugular intrahepatic portosystemic shunt(TIPS)is an effective treatment for th...Background and Aims:Occlusive portal vein thrombosis(PVT)often causes portal hypertension-related complications in cirrhotic patients.Transjugular intrahepatic portosystemic shunt(TIPS)is an effective treatment for this difficult problem.However,the factors influencing TIPS success and overall survival in patients with occlusive PVT are unknown.This study investigated the factors influencing TIPS success and overall survival in cirrhotic patients with occlusive PVT.Methods:Cirrhotic patients with occlusive PVT were selected from a prospective database of consecutive patients treated with TIPS in Xijing Hospital between January 2015 and May 2021.Baseline characteristics,TIPS success rate,complications,and survival were collected,and the factors associated with the TIPS success rate and transplant-free survival were analyzed.Results:A total of 155 cirrhotic patients with occlusive PVT were enrolled.TIPS succeeded in 126(81.29%)cases.The 1-year survival rate was 74%.Compared with those without,patients with portal fibrotic cord had a lower TIPS success rate(39.02%vs.96.49%,p<0.001),shorter median overall survival(300 vs.1,730 days,p<0.001)and more operation-related complications(12.20%vs.1.75%,p<0.01).Logistic regression analysis found that portal fibrotic cord(odds ratio 0.024)was a risk factor for TIPS failure.Univariate and multivariate analysis showed that portal fibrotic cord was an independent predictor of death(hazard ratio 2.111;95%CI:1.094-4.071,p=0.026).Conclusions:Portal fibrotic cord increased the TIPS failure rate and is a risk factor for poor prognosis in cirrhotic patients.展开更多
Purpose Skin cutaneous melanoma(SKCM)is a malignant tumor responsible for over 75%of skin cancer deaths,the relationship between fibrosis and cancer has been increasingly appreciated.The aim of this study is to invest...Purpose Skin cutaneous melanoma(SKCM)is a malignant tumor responsible for over 75%of skin cancer deaths,the relationship between fibrosis and cancer has been increasingly appreciated.The aim of this study is to investigate the fibrotic gene signature(FGS)in melanoma and construct a prognostic model based on FGS.Methods SKCM-related datasets were obtained from the Gene Expression Omnibus(GEO)database and The Cancer Genome Atlas(TCGA)database.By weighted gene co-expression network analysis(WGCNA)of the TCGA-SKCM cohort and GSE65904 cohort,core modules and central genes highly associated with fibrotic features were identified and intersecting genes were defined as fibrotic gene signature(FGS).The least absolute shrinkage and selection operator(LASSO)regression analysis and the Akaike information criterion(AIC)method were conducted to construct a prognostic model based on the FGS gene set.The fibrotic gene signature enrichment score(FGES)and fibrotic gene signature risk score(FGRS)were used to analyze immune infiltration.For FGRS,the correlation between clinical characteristics and the expression of immune checkpoint genes between different risk groups was also analyzed in depth.Results A total of 301 genes were defined as FGS,and a robust eight-gene prediction model was constructed based on FGS,these 8 genes are SV2A,HEYL,OLFML2A,PROX1,ACOX2,PRRX1,PHACTR1 and LHX6.On the basis of the model,a nomogram consisting of FGRS could accurately predict prognosis.In addition,patients in the high-risk group showed immunosuppression,while patients in the low-risk group may benefit more from immunotherapy.However,there was no significant difference between the immune infiltration of different FGES groups.Conclusion In this study,taken together,we developed a fibrotic gene signature in melanoma,and construct an eight-gene prognostic model based on the FGS to provide a reference for prognosis estimation and treatment selection for melanoma patients.展开更多
AIM: To determine the association between the neutrophil to lymphocyte(N/L) ratio and the degree of liver fibrosis in patients with chronic hepatitis B(CHB) infection. METHODS: Between December 2011 and February 2013,...AIM: To determine the association between the neutrophil to lymphocyte(N/L) ratio and the degree of liver fibrosis in patients with chronic hepatitis B(CHB) infection. METHODS: Between December 2011 and February 2013, 129 consecutive CHB patients who were admitted to the study hospitals for histological evaluation of chronic hepatitis B-related liver fibrosis were included in this retrospective study. The patients were divided into two groups based on the fibrosis score: individuals with a fibrosis score of F0 or F1 were included in the "no/minimal liver fibrosis" group, whereas patients with a fibrosis score of F2, F3, or F4 were included in the "advanced liver fibrosis" group. The Statistical Package for Social Sciences 18.0 for Windows was used to analyze the data. A P value of < 0.05 was accepted as statistically significant.RESULTS: Three experienced and blinded pathologists evaluated the fibrotic status and inflammatory activity of 129 liver biopsy samples from the CHB patients. Following histopathological examination, the "no/minimal fibrosis" group included 79 individuals, while the "advanced fibrosis" group included 50 individuals. Mean(N/L) ratio levels were notably lower in patients with advanced fibrosis when compared with patients with no/minimal fibrosis. The mean value of the aspartate aminotransferase-platelet ratio index was markedly higher in cases with advanced fibrosis compared to those with no/minimal fibrosis.CONCLUSION: Reduced levels of the peripheral blood N/L ratio were found to give high sensitivity, specificity and predictive values in CHB patients with significant fibrosis. The prominent finding of our research suggests that the N/L ratio can be used as a novel noninvasive marker of fibrosis in patients with CHB.展开更多
AIM： To assess the correlation between the fibrotic area （FA） as calculated by a digital image analysis （DIA）, and to compare the diagnostic accuracy of FibroScan to the other existing Liver fibrosis （LF） marke...AIM： To assess the correlation between the fibrotic area （FA） as calculated by a digital image analysis （DIA）, and to compare the diagnostic accuracy of FibroScan to the other existing Liver fibrosis （LF） markers using the receiver operating curve analysis.METHODS： We recruited 30 patients who underwent a liver resection for three different etiologies including normal liver, hepatitis B, and hepatitis C. Liver stiffness was measured by using a FibroScan. The FA was then calculated by DIA to evaluate LF in order to avoid any sampling bias. RESULTS： The FA negatively correlated with Prothrombin time （PT）, platelet count, lecithin-cholesterol acyltransferase （LCAT）, and pre-albumin （ALB）. On the other hand, the findings of FibroScan correlated with similar markers. The FA positively correlated with FibroScan, serum hyaluronate level, and type Ⅳ collagen level, and aspartate transaminase to platelet ratio index （APRI）. The area under the receiver operating curve for FibroScan was higher than that for the other markers, even though the statistical significance was minimal. CONCLUSION： Our findings suggest that FibroScan can initially be used to assess LF as an alternative to a liver biopsy （LB） and serum diagnosis, because it is a safe method with comparable diagnostic accuracy regarding the existing LF markers.展开更多
基金Liaoning Provincial Local Professional Technology Innovation Platform Construction Project(2016007013)Liaoning Provincial Natural Science Foundation(2014021007)+2 种基金Outstanding Scientiffc Fund of Shengjing Hospital(2011-02)345 Talent Project of Shengjing Hospital(2020-01)The Mechanism of Immune Tolerance Mediated by Myeloid-Derived Suppressor Cells inhibiting T Cell Immune Responses via PD-L1 in Chronic Hepatits B(2022-12).
文摘Liver fibrosis is a pathological condition characterized by replacement of normal liver tissue with scar tissue,and also the leading cause of liver-related death worldwide.During the treatment of liver fibrosis,in addition to antiviral therapy or removal of inducers,there remains a lack of specific and effective treatment strategies.For thousands of years,Chinese herbal medicines(CHMs)have been widely used to treat liver fibrosis in clinical setting.CHMs are effective for liver fibrosis,though its mechanisms of action are unclear.In recent years,many studies have attempted to determine the possible mechanisms of action of CHMs in treating liver fibrosis.There have been substantial improvements in the experimental investigation of CHMs which have greatly promoted the understanding of anti-liver fibrosis mechanisms.In this review,the role of CHMs in the treatment of liver fibrosis is described,based on studies over the past decade,which has addressed the various mechanisms and signaling pathways that mediate therapeutic efficacy.Among them,inhibition of stellate cell activation is identified as the most common mechanism.This article provides insights into the research direction of CHMs,in order to expand its clinical application range and improve its effectiveness.
基金supported by the Priority Academic Program Development of Jiangsu Higher Education Institutes of China(PAPD)the Science and Technology Plan Project of Nantong of China,No.JC2020026(to JW)the National Science Research of Jiangsu Higher Education Institutions of China,No.19KJB310012(to RYY)。
文摘The rapid formation of a glial/fibrotic scar is one of the main factors hampering axon growth after spinal cord injury. The bidirectional Eph B2/ephrin-B2 signaling of the fibroblast-astrocyte contact-dependent interaction is a trigger for glial/fibrotic scar formation. In the present study, a new in vitro model was produced by coculture of fibroblasts and astrocytes wounded by scratching to mimic glial/fibrotic scar-like structures using an improved slide system. After treatment with RNAi to downregulate Eph B2, changes in glial/fibrotic scar formation and the growth of VSC4.1 motoneuron axons were examined. Following RNAi treatment, fibroblasts and astrocytes dispersed without forming a glial/fibrotic scar-like structure. Furthermore, the expression levels of neurocan, NG2 and collagen I in the coculture were reduced, and the growth of VSC4.1 motoneuron axons was enhanced. These findings suggest that suppression of Eph B2 expression by RNAi attenuates the formation of a glial/fibrotic scar and promotes axon growth. This study was approved by the Laboratory Animal Ethics Committee of Jiangsu Province, China(approval No. 2019-0506-002) on May 6, 2019.
基金supported by the National Natural Science Foundation of China,Nos.82171456 (to QY),81971229 (to QY)the Natural Science Foundation of Chongqing,No.cstc2021jcyj-msxmX0263 (to QY)the Postgraduate Research and Innovation Project of Chongqing,Nos.CYB20151 (to QY),CYS19182 (to YC)。
文摘In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly understood. M2 macrophages regulate fibrotic scar formation after injury to the heart, lung, kidney, and central nervous system. However, it remains to be clarified whether and how M2 macrophages regulate fibrotic scar formation after cerebral ischemia injury. In this study, we found that, in a rat model of cerebral ischemia induced by middle cerebral artery occlusion/reperfusion, fibrosis and macrophage infiltration were apparent in the ischemic core in the early stage of injury(within 14 days of injury). The number of infiltrated macrophages was positively correlated with fibronectin expression. Depletion of circulating monocyte-derived macrophages attenuated fibrotic scar formation. Interleukin 4(IL4) expression was strongly enhanced in the ischemic cerebral tissues, and IL4-induced M2 macrophage polarization promoted fibrotic scar formation in the ischemic core. In addition, macrophage-conditioned medium directly promoted fibroblast proliferation and the production of extracellular matrix proteins in vitro. Further pharmacological and genetic analyses showed that sonic hedgehog secreted by M2 macrophages promoted fibrogenesis in vitro and in vivo, and that this process was mediated by secretion of the key fibrosis-associated regulatory proteins transforming growth factor beta 1 and matrix metalloproteinase 9. Furthermore, IL4-afforded functional restoration on angiogenesis, cell apoptosis, and infarct volume in the ischemic core of cerebral ischemia rats were markedly impaired by treatment with an sonic hedgehog signaling inhibitor, paralleling the extent of fibrosis. Taken together, our findings show that IL4/sonic hedgehog/transforming growth factor beta 1 signaling targeting macrophages regulates the formation of fibrotic scar and is a potential therapeutic target for ischemic stroke.
文摘AIM: To investigate tumor necrosis factor-α (TNF-α), syndecan 1 and basic fibroblast growth factor (bFGF) balance in Crohn's disease (CD) strictures. METHODS: Our study was performed on 24 surgical specimens of CD fibrotic stenosis. Ten histological normal surgical samples were retrieved for both the large and small bowel from patients with benign conditions and healthy tissue represented control collection. Sex and age in controls did not differ from CD group. Three endoscopic biopsy specimens taken after informed consent in subjects with normal colon were also used as negative controls. TNF-α, syndecan 1 and bFGF were detected by both reverse transcriptase reverse transcriptase polymerase chain reaction after mRNA extraction (results expressed as fold-change) and immunohistochemistry.RESULTS: TNF-α did not show any significant difference between CD and control specimens (1.54 ± 1.19; P > 0.05). Very high levels of bFGF were observed in CD (11.76 ± 4.65; P < 0.001) unlike syndecan 1 which showed a moderate increase (5.53 ± 2.18; P < 0.005). analysis of variance (ANOVA) plus Student-NeumannKeuls showed: bFGF > syndecan 1 > TNF-α = control. Immunoreactivity for bFGF was observed in epithelial, stromal, endothelial cells and even in the muscular layer, whilst in normal tissue it was almost unexpressed. Syndecan 1 and TNF-α staining was confined to mucosal epithelial and stromal cells, while in controls syndecan 1 was found in its normal site, i.e. , basolateral area of the crypts and TNF-α very poorly expressed. CONCLUSION: Fibrotic stenosis of CD may be the final result of an irreversible transformation of different cells into fibrogenic phenotype no longer inhibited by posttranscriptional regulation.
基金Supported by the Israel Science Foundation, No. 537/01, the C. Rosenblantt Cancer Research Fund and the Rappaport Institute Fund
文摘AIM： Hydrodynamics based transfection （HBT）, the injection of a large volume of naked plasmid DNA in a short time is a relatively simple, efficient and safe method for in vivo transfection of liver cells. Though used for quite some time, the mechanism of gene transfection has not yet been elucidated. METHODS： A lucJferase encoding plasmid was injected using the hydrodynamics based procedure into normal and thioacetamide-induced fibrotic Sprague Dawley rats. Scanning and transmission electron microscopy images were taken. The consequence of a dual injection of Ringer solution and luciferase pDNA was followed. Halofuginone, an anti collagen type I inhibitor was used to reduce ECM load in fibrotic rats prior to the hydrodynamic injection. RESULTS： Large endothelial gaps formed as soon as 10＇ following hydrodynamic injection; these gradually returned to normal 10 d post injection. Hydrodynamic administration of Ringer 10 or 30 m prior to moderate injection of plasmid did not result in efficient transfection suggesting that endothelial gaps by themselves are not sufficient for gene expression. Gene transfection following hydrodynamic injection in thioacetamide induced fibrotic rats was diminished coinciding with the level of fibrosis. Halofuginone, a specific collagen type I inhibitor, alleviated this effect. CONCLUSION： The hydrodynamic pressure formed following HBT results in the formation of large endothelial gaps. These gaps, though important in the transfer of DNA molecules from the blood to the space of Disse are not enough to provide the appropriate conditions for hepatocyte transfection. Hydrodynamics based injection is applicable in fibrotic rats provided that ECM load is reduced.
文摘BACKGROUND Fibrotic hypersensitivity pneumonitis(FHP)is an allergic and diffuse pneumonia caused by repeated inhalation of antigenic substances,and sometimes developed in people working in specific environments.While novel antigens and exposures continued to be described,physicians should maintain a high suspicion of potential exposures.A detailed assessment of the patient's occupational exposures as well as living environment is necessary and complete allergen avoidance is the first and most important step in the management of FHP once the allergens are determined.CASE SUMMARY A 35-year-old female was admitted to the hospital with a cough and breathing difficulties for more than one year.She was a nonsmoker and a manufacturer of halogen dishes,which are characteristic Chinese foods,for 15 years without any protection.High resolution computed tomography of the chest demonstrated an interstitial pneumonia pattern.Pulmonary function examination showed restricted ventilation dysfunction and a significant reduction in dispersion ability.Cell differentiation in bronchoalveolar lavage fluid demonstrated lymphocytosis(70.4%)with an increased lymphocyte CD4/CD8 ratio(0.94).Transbronchial lung biopsy combined with lung puncture pathology showed diffuse uniform alveolar interval thickening,chronic inflammatory cell infiltration,a proliferation of tissue in the bronchial wall fiber and alveolar epithelial follicle degeneration,resulting in fibrosis.CONCLUSION Exposure to spices used for the production of halogen dishes may cause FHP.
文摘AIM: To compare the outcome of an Ex-Press implant and subscleral trabeculectomy(SST) in the management of glaucoma after previous trabeculectomy on a fibrotic bleb.METHODS: This randomized prospective study included 28 eyes from 28 patients(age range: 42-55 y) with primary open angle glaucoma(POAG) presented with elevated intraocular pressure(IOP) with fibrotic bleb despite previous SST for more than 4 mo. The eyes enrolled in the study were divided into two groups: group I(subjected to Ex-Press implant surgery) and group II [subjected to SST with mitomycin C(MMC)]. The follow-up continued one year after surgery to evaluate IOP, visual acuity(VA), visual field(VF), and postoperative complications. RESULTS: A significant decrease in IOP was found in both groups with a higher reduction in Ex-Press implant surgery with the mean IOP of 14.50 mm Hg(P=0.001), while the SST group recorded the mean IOP of 16.50 mm Hg(P=0.001) after one year. However, the difference between the two groups in terms of the decrease in IOP was insignificant. Fewer postoperative complications were recorded in the Ex-Press implant surgery and more cases requiring further anti-glaucomatous medications were seen in the SST group. Both groups showed stability in terms of VA and VF.CONCLUSION: Ex-Press implant surgery and SST with MMC are two surgical alternatives for controlling IOP in late failure that occurs more than 4 mo after previous SST with a fibrotic bleb. However, Ex-Press shunt is a safer surgery with fewer complications.
文摘Background: Complete hypopharyngo-oesophageal occlusion is a rare complication of head and neck radiotherapy and a range of other conditions. Absolute dysphagia is accompanied by aspiration and dependence on gastrostomy feeding. The condition presents a substantial management challenge. Surgical approaches to re-establish pharyngo-oesophageal continuity are varied, highly invasive and are associated with unpredictable outcomes. Minimally invasive techniques employing endoscopic and radiological techniques are emerging. This report describes a multidisciplinary approach which translates two interventional radiology techniques used in the management of central venous occlusions and biliary strictures to the management of three cases of complete hypopharyngo-oesophageal occlusion. Methods: Three cases with different underlying aetiologies had treatment initiated between 2009 and 2011. Antegrade pharyngoscopic access to the occlusions was accompanied by retrograde endoscopic access via a small gastrostomy. Luminal continuity was re-established by the interventional radiology technique of “sharp recanalisation” followed by passage of a wide bore nasogastric tube which was maintained in situ for 4-6 months, a duration of treatment analogous to that applied in the radiological management of fibrotic biliary strictures. After treatment a radiological contrast swallows examination was performed to gauge the calibre of the re-established lumen, assess functionality and to rule out aspiration. Results: Pharyngo-oesophageal continuity was re-established in all three cases on the first attempt. No complications occurred as a result of the procedures. In two cases, the excellent swallowing function was re-established, although one of these required prolonged post-treatment adjuvant interventions. In one case no swallowing function resulted, despite apparently successful re-establishment of luminal continuity. Conclusions: Complete fibrotic occlusion of the hypopharyngo-oesophageal lumen is rare and presents a substantial management challenge. A minimally invasive treatment combining antegrade radiological and retrograde endoscopic approaches resulted in successful re-establishment of luminal continuity in three cases of complete fibrotic occlusion of the hypopharyngo-oesophageal lumen. However variable responses to treatment suggest that both the underlying aetiology and the chronicity of the occlusion may influence the likelihood of a successful functional outcome. Until definitive management guidelines are established, we suggest that such cases are managed only by motivated multidisciplinary teams keen to develop their expertise in this area.
基金Supported by the National Natural Science Foundation of China(No.82004254)。
文摘Fibrosis is a pathological process characterized by chronic inflammation and excessive ECM deposition,leading to tissue scarring and organ dysfunction.(1)Fibrotic tissue accumulation results from persistent injuries triggered by factors such as epigenetic alterations,infections,hypertension,myocardial infarction,autoimmune inflammation,and metabolic disorders.(2.3)Although fibrosis shares similarities with normal wound healing,dysregulated or repeated tissue repair can result in rreversible scarring,ultimately leading to organ failure.(4)The inflammatory response and the activation of myofibroblasts-fibroblasts that secrete collagen and express α-SMA are essential for stimulating the repair response and triggering fibrosis in many organs.Normal tissue repair can become an irreversible fibrotic response if the tissue damage is extensive,repetitive,or if the wound-healing process becomes dysregulated,(5)This irreversible fibrotic response leads to several adverse outcomes,including irreversible scarring,disruption of tissue architecture,organ dysfunction,and ultimately,organ failure and death.(6)Chronic liver diseases,kidney disorders,interstitial lung disease,and heart failure are representative examples.(7.8)The incidence of pulmonary fibrosis has risen globally,particularly following the COVID-19 pandemic.
基金supported by the National Natural Science Foundation of China(Nos.81274172,81473267,81973637 and 82373933)The National Traditional Chinese Medicine Inheritance and Innovation“Hundreds and Thousands”Talent Project:Young Qihuang Scholar Support Project of the State Administration of Traditional Chinese Medicine in 2020(China).
文摘Progranulin(PGRN),a multifunctional growth factor-like protein expressed by a variety of cell types,serves an important function in the physiologic and pathologic processes of fibrotic diseases,including wound healing and the inflammatory response.PGRN was discovered to inhibit proinflammation effect by competing with tumor necrosis factor-alpha(TNF-a)binding to TNF receptors.Notably,excessive tissue repair in the development of inflammation causes tissue fibrosis.Previous investigations have indicated the significance of PGRN in regulating inflammatory responses.Recently,multiple studies have shown that PGRN was linked to fibrogenesis,and was considered to monitor the formation of fibrosis in multiple organs,including liver,cardiovascular,lung and skin.This paper is a comprehensive review summarizing our current knowledge of PGRN,from its discovery to the role in fibrosis.This is followed by an in-depth look at the characteristics of PGRN,consisting of its structure,basic function and intracellular signaling.Finally,we will discuss the potential of PGRN in the diagnosis and treatment of fibrosis.
基金B was supported by grants from the German Research Foundation(DFGNos.BE 4443/1-1,BE 4443/4-1,BE4443/6-1,KFO309284237345 P7 and CRC1213268555672 projects A02 and A04)+3 种基金German Center for Lung Research(DZL),and Excellence Cluster CardioPulmonary Institute(CPINo.EXC2026390649896)XC acknowledges the support of the Natural Science Foundation of Zhejiang Grant(No.LQ24H210001)EEA was supported by the DFG(Nos.EL 931/5-1,EL 931/4-1,KFO309284237345 P7 and SFB CRC1213268555672 project A04),Institute for Lung Health(ILH),CPI,and DZL.
文摘Idiopathic pulmonary fibrosis(IPF)is characterized by accumulation of myofibroblasts(MYFs)and extracellular matrix components,which leads to severe distortion and scarring of the gas exchange units of the lung,the alveoli,and ultimately respiratory failure.Fibrosis-associated MYFs are therefore widely regarded as the culprits that compromise the architectural makeup of the lung in fibrotic disease.During the past decade,the cellular source of MYFs has been intensely investigated.The rationale for such studies is that identifying the origin of these cells might help identify novel therapeutic targets and candidates to treat IPF patients.Recent advances in basic and translational research employing lineage tracing and multi-omics approaches have helped address the identity of MYF precursors,highlight the underlying heterogeneity,and to a less extent investigate MYF fate during fibrosis resolution.In this review,we discuss the current understanding of such important aspects of MYF biology as well as recent developments in the treatment of IPF.
基金supported by the National Key Research and Development Program of China(No.2022YFC2703104)the National Natural Science Foundation of China(Nos.82071839,82271848)+2 种基金CAMS Innovation Fund for Medical Sciences(Nos.CIFMS 2021-1-I2M-003,2022-I2M-C&T-B-005)National High Level Hospital Clinical Research Funding(Nos.2022-PUMCH-A-041,2022-PUMCH-C-006,2022-PUMCH-B-013)Open Research Fund of State Key Laboratory of Environmental Chemistry and Ecotoxicology(No.KF2021-15)
文摘Background:Immunoglobulin G4-related disease(IgG4-RD)is a recently recognized immune-mediated disorder that can affect almost any organ in the human body.IgG4-RD can be categorized into proliferative and fibrotic subtypes based on patients’clinicopathological characteristics.This study aimed to compare the clinical manifestations,laboratory findings,and treatment outcomes of IgG4-RD among different subtypes.Methods:We prospectively enrolled 622 patients with newly diagnosed IgG4-RD at Peking Union Medical College Hospital from March 2011 to August 2021.The patients were divided into three groups according to their clinicopathological characteristics:proliferative,fibrotic,and mixed subtypes.We compared demographic features,clinical manifestations,organ involvement,laboratory tests,and treatment agents across three subtypes.We then assessed the differences in treatment outcomes among 448 patients receiving glucocorticoids alone or in combination with immunosuppressants.Moreover,risk factors of relapse were revealed by applying the univariate and multivariate Cox regression analysis.Results:We classified the 622 patients into three groups consisting of 470 proliferative patients,55 fibrotic patients,and 97 mixed patients,respectively.We found that gender distribution,age,disease duration,and frequency of allergy history were significantly different among subgroups.In terms of organ involvement,submandibular and lacrimal glands were frequently involved in the proliferative subtype,while retroperitoneum was the most commonly involved site in both fibrotic subtype and mixed subtype.The comparison of laboratory tests revealed that eosinophils(P=0.010),total IgE(P=0.006),high-sensitivity C-reactive protein(P<0.001),erythrocyte sedimentation rate(P<0.001),complement C4(P<0.001),IgG(P=0.001),IgG1(P<0.001),IgG4(P<0.001),and IgA(P<0.001),at baseline were significantly different among three subtypes.Compared with proliferative and mixed subtypes,the fibrotic subtype showed the lowest rate of relapse(log-rank P=0.014).Conclusions:Our study revealed the differences in demographic characteristics,clinical manifestations,organ involvement,laboratory tests,treatment agents,and outcomes across proliferative,fibrotic,and mixed subtypes in the retrospective cohort study.Given significant differences in relapse-free survival among the three subtypes,treatment regimens,and follow-up frequency should be considered separately according to different subtypes.Trial Registration:ClinicalTrials.gov,NCT01670695.
文摘Thrombospondin 4(THBS4;TSP4),a crucial component of the extracellular matrix(ECM),serves as an important regulator of tissue homeostasis and various pathophysiological processes.As a member of the evolutionarily conserved thrombospondin family,THBS4 is a multidomain adhesive glycoprotein characterized by six distinct structural domains that mediate its diverse biological functions.Through dynamic interactions with various ECM components,THBS4 plays pivotal roles in cell adhesion,proliferation,inflammation regulation,and tissue remodeling,establishing it as a key modulator of microenvironmental organization.The transcription and translation of THBS4 gene,as well as the activity of the THBS4 protein,are tightly regulated by multiple signaling pathways and extracellular cues.Positive regulators of THBS4 include transforming growth factorβ(TGF-β),interferonγ(IFNγ),granulocyte-macrophage colony-stimulating factor(GM-CSF),bone morphogenetic proteins(BMP12/13),and other regulatory factors(such as B4GALNT1,ITGA2/ITGB1,PDGFRβ,etc.),which upregulate THBS4 at the mRNA and/or protein level.Conversely,oxidized low-density lipoprotein(OXLDL)acts as a potent negative regulator of THBS4.This intricate regulatory network ensures precise spatial and temporal control of THBS4 expression in response to diverse physiological and pathological stimuli.Functionally,THBS4 acts as a critical signaling hub,influencing multiple downstream pathways essential for cellular behavior and tissue homeostasis.The best-characterized pathways include:(1)the PI3K/AKT/mTOR axis,which THBS4 modulates through both direct and indirect interactions with integrins and growth factor receptors;(2)Wnt/β-catenin signaling,where THBS4 functions as either an activator or inhibitor depending on the cellular context;(3)the suppression of DBET/TRIM69,contributing to its diverse regulatory roles.These signaling connections position THBS4 as a master regulator of cellular responses to microenvironmental changes.Substantial evidence links aberrant THBS4 expression to a range of pathological conditions,including neoplastic diseases,cardiovascular disorders,fibrotic conditions,neurodegenerative diseases,musculoskeletal disorders,and atopic dermatitis.In cancer biology,THBS4 exhibits context-dependent roles,functioning either as a tumor suppressor or promoter depending on the tumor type and microenvironment.In the cardiovascular system,THBS4 contributes to both adaptive remodeling and maladaptive fibrotic responses.Its involvement in fibrotic diseases arises from its ability to regulate ECM deposition and turnover.The diagnostic and therapeutic potential of THBS4 is particularly promising in oncology and cardiovascular medicine.As a biomarker,THBS4 expression patterns correlate significantly with disease progression and patient outcomes.Therapeutically,targeting THBS4-mediated pathways offers novel opportunities for precision medicine approaches,including anti-fibrotic therapies,modulation of the tumor microenvironment,and enhancement of tissue repair.This comprehensive review systematically explores three key aspects of THBS4 research:(1)the fundamental biological functions of THBS4 in ECM organization;(2)its mechanistic involvement in various disease pathologies;(3)its emerging potential as both a diagnostic biomarker and therapeutic target.By integrating recent insights from molecular studies,animal models,and clinical investigations,this review provides a framework for understanding the multifaceted roles of THBS4 in health and disease.The synthesis of current knowledge highlights critical research gaps and future directions for exploring THBS4-targeted interventions across multiple disease contexts.Given its unique position at the intersection of ECM biology and cellular signaling,THBS4 represents a promising frontier for the development of novel diagnostic tools and therapeutic strategies in precision medicine.
基金supported by the National Natural Science Foundation of China(Grant Nos.51325305,51733006)
文摘The fibrotic response plays an important role in the performance and longevity of implantable devices. Thus, development of effective anti-inflammatory and anti-fibrosis biomaterial implants has become an urgent task. In this work, we developed a novel supramolecular polymer hydrogel through the copolymerization of N-acryloyl glycinamide(NAGA) and carboxybetaine acrylamide(CBAA) in the absence of any chemical crosslinker, which the mechanical properties being tunable through changing the monomer concentration and the monomer ratio over a broad scope. The hydrogel possessed the superior mechanical performances: high tensile strength(～1.13 MPa), large stretchability(～1200%), and excellent compressive strength(～9 MPa) at high monomer concentration and NAGA/CBAA ratio. Introduction of CBAA could promote the self-healability, thermoplasticity of suparmolecular polymer hydrogels at lower temperatures, meanwhile dramatically improving anti-fouling property.Histological analysis and in vitro cytotoxicity assays testified the excellent biocompatibility of the hydrogel. This high strength supramolecular polymer hydrogel with integrated multiple functions holds promising potentials as a scaffold biomaterial for treating degenerated soft supporting tissues.
基金This work was supported by the National Natural Science Foundation of China(No.81770176)the Special Support Plan for Zhejiang Province High-level Talents(No.2019R52011)+1 种基金the Zhejiang Provincial Natural Science Foundation of China(No.LD22H310004)the Scientific Research Foundation of Zhejiang Sci-Tech University(No.21042100-Y).
文摘Annexin A1,a well-known endogenous anti-inflammatory mediator,plays a critical role in a variety of pathological processes.Fibrosis is described by a failure of tissue regeneration and contributes to the development of many diseases.Accumulating evidence supports that Annexin A1 participates in the progression of tissue fibrosis.However,the fundamental mechanisms by which Annexin A1 regulates fibrosis remain elusive,and even the functions of Annexin A1 in fibrotic diseases are still paradoxical.This review focuses on the roles of Annexin A1 in the development of fibrosis of lung,liver,heart,and other tissues,with emphasis on the therapy potential of Annexin A1 in fibrosis,and presents future research interests and directions in fibrotic diseases.
基金This work was supported by grants from National Natural Science Foundation of China （No. 30971312） and the Key Project of Beijing Municipal Education Commission Sci-Tech Development Program （No. KZ201110025028）.
文摘apamvcin was first isolated from a strain of Sreptomyces hygroscopicus in the early 1970s froma soil sample taken on Easter Island. Because the antiproliferative effects of rapamycin on yeast cell, as well as B and T lymphocytes, it was first identified as an antimicrobial agent with potent immunosuppressive activity and has been used in antirejection therapy.
文摘Background and Aims:Occlusive portal vein thrombosis(PVT)often causes portal hypertension-related complications in cirrhotic patients.Transjugular intrahepatic portosystemic shunt(TIPS)is an effective treatment for this difficult problem.However,the factors influencing TIPS success and overall survival in patients with occlusive PVT are unknown.This study investigated the factors influencing TIPS success and overall survival in cirrhotic patients with occlusive PVT.Methods:Cirrhotic patients with occlusive PVT were selected from a prospective database of consecutive patients treated with TIPS in Xijing Hospital between January 2015 and May 2021.Baseline characteristics,TIPS success rate,complications,and survival were collected,and the factors associated with the TIPS success rate and transplant-free survival were analyzed.Results:A total of 155 cirrhotic patients with occlusive PVT were enrolled.TIPS succeeded in 126(81.29%)cases.The 1-year survival rate was 74%.Compared with those without,patients with portal fibrotic cord had a lower TIPS success rate(39.02%vs.96.49%,p<0.001),shorter median overall survival(300 vs.1,730 days,p<0.001)and more operation-related complications(12.20%vs.1.75%,p<0.01).Logistic regression analysis found that portal fibrotic cord(odds ratio 0.024)was a risk factor for TIPS failure.Univariate and multivariate analysis showed that portal fibrotic cord was an independent predictor of death(hazard ratio 2.111;95%CI:1.094-4.071,p=0.026).Conclusions:Portal fibrotic cord increased the TIPS failure rate and is a risk factor for poor prognosis in cirrhotic patients.
基金supported by National Natural Science Foundation of China grants(No.8197102109).
文摘Purpose Skin cutaneous melanoma(SKCM)is a malignant tumor responsible for over 75%of skin cancer deaths,the relationship between fibrosis and cancer has been increasingly appreciated.The aim of this study is to investigate the fibrotic gene signature(FGS)in melanoma and construct a prognostic model based on FGS.Methods SKCM-related datasets were obtained from the Gene Expression Omnibus(GEO)database and The Cancer Genome Atlas(TCGA)database.By weighted gene co-expression network analysis(WGCNA)of the TCGA-SKCM cohort and GSE65904 cohort,core modules and central genes highly associated with fibrotic features were identified and intersecting genes were defined as fibrotic gene signature(FGS).The least absolute shrinkage and selection operator(LASSO)regression analysis and the Akaike information criterion(AIC)method were conducted to construct a prognostic model based on the FGS gene set.The fibrotic gene signature enrichment score(FGES)and fibrotic gene signature risk score(FGRS)were used to analyze immune infiltration.For FGRS,the correlation between clinical characteristics and the expression of immune checkpoint genes between different risk groups was also analyzed in depth.Results A total of 301 genes were defined as FGS,and a robust eight-gene prediction model was constructed based on FGS,these 8 genes are SV2A,HEYL,OLFML2A,PROX1,ACOX2,PRRX1,PHACTR1 and LHX6.On the basis of the model,a nomogram consisting of FGRS could accurately predict prognosis.In addition,patients in the high-risk group showed immunosuppression,while patients in the low-risk group may benefit more from immunotherapy.However,there was no significant difference between the immune infiltration of different FGES groups.Conclusion In this study,taken together,we developed a fibrotic gene signature in melanoma,and construct an eight-gene prognostic model based on the FGS to provide a reference for prognosis estimation and treatment selection for melanoma patients.
文摘AIM: To determine the association between the neutrophil to lymphocyte(N/L) ratio and the degree of liver fibrosis in patients with chronic hepatitis B(CHB) infection. METHODS: Between December 2011 and February 2013, 129 consecutive CHB patients who were admitted to the study hospitals for histological evaluation of chronic hepatitis B-related liver fibrosis were included in this retrospective study. The patients were divided into two groups based on the fibrosis score: individuals with a fibrosis score of F0 or F1 were included in the "no/minimal liver fibrosis" group, whereas patients with a fibrosis score of F2, F3, or F4 were included in the "advanced liver fibrosis" group. The Statistical Package for Social Sciences 18.0 for Windows was used to analyze the data. A P value of < 0.05 was accepted as statistically significant.RESULTS: Three experienced and blinded pathologists evaluated the fibrotic status and inflammatory activity of 129 liver biopsy samples from the CHB patients. Following histopathological examination, the "no/minimal fibrosis" group included 79 individuals, while the "advanced fibrosis" group included 50 individuals. Mean(N/L) ratio levels were notably lower in patients with advanced fibrosis when compared with patients with no/minimal fibrosis. The mean value of the aspartate aminotransferase-platelet ratio index was markedly higher in cases with advanced fibrosis compared to those with no/minimal fibrosis.CONCLUSION: Reduced levels of the peripheral blood N/L ratio were found to give high sensitivity, specificity and predictive values in CHB patients with significant fibrosis. The prominent finding of our research suggests that the N/L ratio can be used as a novel noninvasive marker of fibrosis in patients with CHB.
基金Supported by the Grants-in-Aid from the Society for the Promotion of Science, Sapporo Medical University for T. Mizuguchi, and Grants-in-Aid from the Ministry of Education, Culture, Sports Science and Technology, Japan. No. 18591519 for T. Mizuguchi, No. 17591420 for T. Katsuramaki, and No. 15390403 for K. Hirata
文摘AIM： To assess the correlation between the fibrotic area （FA） as calculated by a digital image analysis （DIA）, and to compare the diagnostic accuracy of FibroScan to the other existing Liver fibrosis （LF） markers using the receiver operating curve analysis.METHODS： We recruited 30 patients who underwent a liver resection for three different etiologies including normal liver, hepatitis B, and hepatitis C. Liver stiffness was measured by using a FibroScan. The FA was then calculated by DIA to evaluate LF in order to avoid any sampling bias. RESULTS： The FA negatively correlated with Prothrombin time （PT）, platelet count, lecithin-cholesterol acyltransferase （LCAT）, and pre-albumin （ALB）. On the other hand, the findings of FibroScan correlated with similar markers. The FA positively correlated with FibroScan, serum hyaluronate level, and type Ⅳ collagen level, and aspartate transaminase to platelet ratio index （APRI）. The area under the receiver operating curve for FibroScan was higher than that for the other markers, even though the statistical significance was minimal. CONCLUSION： Our findings suggest that FibroScan can initially be used to assess LF as an alternative to a liver biopsy （LB） and serum diagnosis, because it is a safe method with comparable diagnostic accuracy regarding the existing LF markers.
