INTRODUCTIONIt has been reported that renin-angiotensin systemexists in tissue and aldosterone can be synthesizedin extra-adrenal tissue including heart,bloodvessels and brain.Recent studies have broughtrich evidences...INTRODUCTIONIt has been reported that renin-angiotensin systemexists in tissue and aldosterone can be synthesizedin extra-adrenal tissue including heart,bloodvessels and brain.Recent studies have broughtrich evidences in favour of aldosterone as a strongstimulator of fibrogenesis and mitogenesis.展开更多
AIM： To investigate the location alteration of Smad2 and Smad4 mRNAs in the liver during and after fibrogenesis in rats. METHODS： Eighty male Wistar rats weighing approximately 200 g each were used. The rat models o...AIM： To investigate the location alteration of Smad2 and Smad4 mRNAs in the liver during and after fibrogenesis in rats. METHODS： Eighty male Wistar rats weighing approximately 200 g each were used. The rat models of experimental hepatic fibrosis were established by injection with carbon tetrachloride （CCh）, normal rats and rats were injected with olive oil and served as control groups. In situ hybridization（ISH） was used to detect the Smad2 and Smad4 mRNA in liver. RESULTS： In situ hybridization showed Smad2 and Smad4 mRNA expressions in the cytoplasm of hepatic stellate cells （HSC）, fibroblasts and myofibroblasts around the central vein and hepatic sinus during and after fibrogenesis. Expression of Smad2, 4 mRNA was higher than that in normal and control rats. CONCLUSION： In the process of and after hepatic fibrosis formation, HSC, fibroblasts and myofibroblasts are the major cells that express Smad2 and Smad4. The more serious the hepatic fibrosis is in the injured liver, the higher the level of Smad2 and Smad4 gene expression is during and after fibrogenesis respectively.展开更多
Fibrogenesis in inflammatory bowel diseases is a complex phenomenon aimed at mucosal repair. However, it may provoke intestinal fibrosis with the development of strictures which require surgery. Therefore, fibrogenesi...Fibrogenesis in inflammatory bowel diseases is a complex phenomenon aimed at mucosal repair. However, it may provoke intestinal fibrosis with the development of strictures which require surgery. Therefore, fibrogenesis may be considered as a 'two-faced' process when related to chronic intestinal inflammation. Many types of cells may be converted into the fibrogenic phenotype at different levels of the intestinal wall. A complex interaction of cytokines, adhesion molecules and growth factors is involved in the process. We report an overview of recent advances in molecular mechanisms of stricturizing Crohn’s disease(CD) including the potential role of trasforming growth factor beta, protein kinase C and Ras, Raf and ERK proteins. Fibrotic growth factors such as vascular endothelial growth factor and platelet-derived growth factor, as well as the Endothelial-to-Mesenchymal Transition induced by transforming growth factor-β, are considered. Finally, our experience, focused on tumor necrosis factor α(the main cytokine of inflammatory bowel diseases) and the link between syndecan 1(a heparan sulphate adhesion molecule) and basic fibroblast growth factor(a strong stimulator of collagen synthesis) is described. We hypothesize a possible molecular pattern for mucosal healing as well as how its deregulation could be involved in fibrotic complications of CD. A final clinical point is the importance of performing an accurate evaluation of the presence of fibrotic strictures before starting anti-tumor necrosis α treatment, which could worsen the lesions.展开更多
identify aldosterone synthase gene CYP11B2 mRNA expression in normal and fibrotic liver in rats and evaluate the curative effect of antisterone Methods 160 Wistar rats weighing about 250?g were divided into 4 grou...identify aldosterone synthase gene CYP11B2 mRNA expression in normal and fibrotic liver in rats and evaluate the curative effect of antisterone Methods 160 Wistar rats weighing about 250?g were divided into 4 groups In the model group (n=40), the rats were injected with 40% CCl 4 (0 25?ml/100?g) subcutaneously three times a week In the antisterone group (n=40), the rats were injected with 40% CCl 4 (0 25?ml/100?g) subcutaneously three times a week Antisterone equivalent to 20?mg·kg 1 ·d 1 was given intragastrically (ig) In the malotilate group (n=40), the rats were injected with 40% CCl 4 (0 25?ml/100?g) subcutaneously three times a week Malotilate equivalent to 50?mg·kg 1 ·d 1 was given ig In the control group (n=40), the rats were injected with olive oil only After 2,4,6,8 and 10 weeks, animals were sacrificed, and morphological examination was carried out The area of collagen was examined with an Image Analyse System Expression of the aldosterone synthase gene, CYP11B2 mRNA, in fibrotic and normal liver was detected by means of reverse transcriptase polymerase chain reaction (RT PCR) and in situ hybridization Results In situ hybridization and RT PCR showed that the expression of CYP11B2 mRNA, which localized in the endoplasm of hepatic stellate cells (HSCs), was up regulated when fibrogenesis occurred Histological observation indicated that the grade of fibrosis and the area of collagen in the antisterone group were less than those in model group before 6 weeks ( P <0 05) There was no significant difference between the antisterone and malotilate groups ( P >0 05) After that, however, the grade of fibrosis and the area of collagen in the antisterone group were higher than those in the malotilate group ( P <0 05) There was no significant difference between the antisterone and model groups ( P >0 05) Conclusions The expression of CYP11B2 mRNA is up regulated in fibrotic liver Antisterone can have a partial fibrogenesis inhibiting effect in the early stages展开更多
Intestinal fibrosis is a frequent complication of inflammatory bowel diseases(IBD),and can lead to stricture formation and intestinal obstruction.Clinically apparent stenosis occurs in more than 30%of patients with Cr...Intestinal fibrosis is a frequent complication of inflammatory bowel diseases(IBD),and can lead to stricture formation and intestinal obstruction.Clinically apparent stenosis occurs in more than 30%of patients with Crohn's disease(CD)and about 5%~10%of patients with ulcerative colitis(UC)[l-2],and its management represents an important and frequent challenge in clinical practice.Despite its tremendous clinical impact the tools we currently have to address this challenge are limited(l)Anti-inflammatory therapies are only a temporizing measure to relieve obstruction and re-obstruction is frequent,necessitating endoscopic balloon dilation or surgical intervention(35)No specific anti-fibrotic therapy exists at present,and therefore it is critical to understand the mechanisms of intestinal fibrogenesis to develop targeted therapeutic approaches.展开更多
There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis.Recent data indicate that the termination of fibrogenic processes...There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis.Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis.Therefore,efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis.Activation of hepatic stellate cells(HSCs)remains a central event in fibrosis,complemented by other sources of matrix-producing cells,including portal fibroblasts,fibrocytes and bone marrow-derived myofibroblasts.These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury.Defining the interaction of different cell types,revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets.Moreover,the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies.This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies.The pathogenesis of liver fibrosis associated with alcoholic liver disease,non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.展开更多
Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoh...Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.展开更多
The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as ...The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as a major determinant of liver fat content.Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver:from simple steatosis to steatohepatitis and progressive fibrosis.Furthermore,the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis,and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis,and possibly chronic hepatitis B virus hepatitis,hereditary hemochromatosis and primary sclerosing cholangitis.All in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.Remarkably,the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation,suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes,directly promoting fibrogenesis.Therefore,PNPLA3 is a key player in liver disease progression.Assessment of the I148M polymorphism will possibly inform clinical practice in the future,whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.展开更多
In addition to complications relating to the liver, patients with cirrhosis and portal hypertension develop extrahepatic functional disturbances of multiple organ systems. This can be considered a multiple organ failu...In addition to complications relating to the liver, patients with cirrhosis and portal hypertension develop extrahepatic functional disturbances of multiple organ systems. This can be considered a multiple organ failure that involves the heart, lungs, kidneys, the immune systems, and other organ systems. Progressive fibrosis of the liver and subsequent metabolic impairment leads to a systemic and splanchnic arteriolar vasodilatation. This affects both the haemodynamic and functional homeostasis of many organs and largely determines the course of the disease. With the progression of the disease, the circulation becomes hyperdynamic with cardiac, pulmonary as well as renal consequences for dysfunction and reduced survival. Infections and a changed cardiac function known as cirrhotic cardiomyopathy may be involved in further aggravation of other complications such as renal failure precipitatingthe hepatorenal syndrome.Patients with end-stage liver disease and related complications as for example the hepatopulmonary syndrome can only radically be treated by liver transplantation.As a bridge to this treatment,knowledge on the mechanisms of the pathophysiology of complications is essential for the choice of vasoactive drugs,antibiotics,drugs with specific effects on fibrogenesis and inflammation,and drugs that target specific receptors.展开更多
Recent data indicate that hepatic angiogenesis, regardless of the etiology, takes place in chronic liver diseases(CLDs) that are characterized by inflammat ion and progre s s ive f ibros is. B e c aus e ant iangiogeni...Recent data indicate that hepatic angiogenesis, regardless of the etiology, takes place in chronic liver diseases(CLDs) that are characterized by inflammat ion and progre s s ive f ibros is. B e c aus e ant iangiogenic therapy has been found to be efficient in the prevention of fibrosis in experimental models of CLDs, it is suggested that blocking angiogenesis could be a promising therapeutic option in patients with advanced fibrosis. Consequently, efforts are being directed to revealing the mechanisms involved in angiogenesis during the progression of liver fibrosis. Literature evidences indicate that hepatic angiogenesis and fibrosis are closely related in both clinical andexperimental conditions. Hypoxia is a major inducer of angiogenesis together with inflammation and hepatic stellate cells. These profibrogenic cells stand at the intersection between inflammation, angiogenesis and fibrosis and play also a pivotal role in angiogenesis. This review mainly focuses to give a clear view on the relevant features that communicate angiogenesis with progression of fibrosis in CLDs towards the-end point of cirrhosis that may be translated into future therapies. The pathogenesis of hepatic angiogenesis associated with portal hypertension, viral hepatitis, non-alcoholic fatty liver disease and alcoholic liver disease are also discussed to emphasize the various mechanisms involved in angiogenesis during liver fibrogenesis.展开更多
AIM： TO explore the relationship among interferon-γ （IFN-γ） activity, fibrogenesis, T cell immune responses and hepatic inflammatory activity. METHODS： Peripheral blood samples from a total of 43 hepatitis B cir...AIM： TO explore the relationship among interferon-γ （IFN-γ） activity, fibrogenesis, T cell immune responses and hepatic inflammatory activity. METHODS： Peripheral blood samples from a total of 43 hepatitis B cirrhotic patients （LC） and 19 healthy controls （NC） were collected to measure their serum levels of IFN-γ, interleukin-2 （IL-2）, soluble interleukin-2 receptor （sIL-2R）, interleukin-10 （IL-10） and three serological markers of fibrosis including hyaluronic acid （HA）, procollagen type III peptide （PIIIP）, and type iV collagen were measured using a double antibody sandwich ELISA. Also, serum total bilirubin （TB） and alanine aminotransferase （ALT） were measured by routine measures. RESULTS： The concentrations of serological markers of fibrosis in patients with active cirrhosis （ALC） were significantly higher than those in stationary liver cirrhosis （SLC） or NC groups. The levels of serological markers in HBeAg-positive patients were significantly higher than those in HBeAg-negative patients. In SLC and ALC patients, a negative linear correlation was found between IFN-γ levels and the serological markers of fibrosis. IFN-γ and IL-2 levels in the ALC group were significantly higher than those in the SLC and NC groups, but the statistical difference was not significant between the latter two. In contrast, IL-10 levels in the SLC group were significantly higher than that in the NC group, but no significant difference was found between SLC and ALC groups. The sIL-2R level was elevated gradually in all these groups, and the differences were significant. Positive linear correlations were seen between IFN-γ activity and ALT levels （r = 0.339, P 〈 0.05）, and IL-2 activity and TB levels （r = 0.517, P 〈 0.05）. sIL-2R expression was positively correlated with both ALT and TB levels （r = 0.324, 0.455, P 〈 0.05）, whereas there was no statistically significant correlation between IL-10 expression and serum ALT and TB levels （r = -0.102, -0.093, P 〉 0.05）. Finally, there was a positive correlation between IFN-γ and IL-2 levels. CONCLUSION： T cell immune responses are correlated with fibrosis and hepatic inflammatory activity and may play an important role in liver cirrhosis.展开更多
AIM To investigate the relationship between levels of iron metabolism markers and hepatitis B virus(HBV)-related chronic liver diseases.METHODS This case-control study with 318 participants included 78 cases of chroni...AIM To investigate the relationship between levels of iron metabolism markers and hepatitis B virus(HBV)-related chronic liver diseases.METHODS This case-control study with 318 participants included 78 cases of chronic hepatitis B, 85 cases of HBV-related liver cirrhosis, 77 cases of HBV-related hepatocellular carcinoma, and 78 healthy controls. Markers of iron metabolism were detected in participants. Hematological and biochemical parameters and HBV-DNA were assessed. Child-Pugh grade and Barcelona Clinic Liver Cancer stage were determined for each hepatocellular carcinoma patient. Perls' staining was performed on liver sections. The SPSS program was used for all statistical analyses, and statistical significance was considered if a P-value < 0.05.RESULTS Significantly higher serum ferritin and lower serum hepcidin levels were detected in all groups of HBV-infected patients compared with healthy controls. Serum iron, total iron binding capacity, and serum transferrin levels were significantly lower in patients with cirrhosis and hepatocellular carcinoma, whereas the hepcidin level was higher than that in chronic hepatitis B patients. Correlation analysis indicated that serum hepcidin was negatively correlated with HBV-DNA load(P < 0.01). Serum ferritin and transferrin saturation levels increased proportionally to the extent of liver cirrhosis and poorer Child-Pugh scores(P < 0.05). The decreased serum iron and transferrin saturation levels were significantly correlated with a smaller hepatocellular carcinoma tumor burden according to Barcelona Clinic Liver Cancer staging. Liver histology showed a clearly increasing trend in iron deposition in the liver tissues with increased fibrosis, which became prominent at stages 3(severe liver fibrosis) and 4(cirrhosis). CONCLUSION Iron metabolism disorders occur in patients with HBVrelated liver diseases. The serum markers of iron metabolism disorders vary in different stages of HBV-related liver diseases.展开更多
BACKGROUND Studies show that the antifibrotic mechanism of taurine may involve its inhibition of the activation and proliferation of hepatic stellate cells(HSCs). Since the molecular mechanism of taurine-mediated anti...BACKGROUND Studies show that the antifibrotic mechanism of taurine may involve its inhibition of the activation and proliferation of hepatic stellate cells(HSCs). Since the molecular mechanism of taurine-mediated antifibrotic activity has not been fully unveiled and is little studied, it is imperative to use "omics" methods to systematically investigate the molecular mechanism by which taurine inhibits liver fibrosis.AIM To establish a network including transcriptomic and protein-protein interaction data to elucidate the molecular mechanism of taurine-induced HSC apoptosis.METHODS We used microarrays, bioinformatics, protein-protein interaction(PPI) network,and sub-modules to investigate taurine-induced changes in gene expression in human HSCs(LX-2). Subsequently, all of the differentially expressed genes(DEGs) were subjected to gene ontology function and Kyoto encyclopedia of genes and genomes pathway enrichment analysis. Furthermore, the interactions of DEGs were explored in a human PPI network, and sub-modules of the DEGs interaction network were analyzed using Cytoscape software.RESULTS A total of 635 DEGs were identified in taurine-treated HSCs when compared with the controls. Of these, 304 genes were statistically significantly up-regulated, and 331 down-regulated. Most of these DEGs were mainly located on the membrane and extracellular region, and are involved in the biological processes of signal transduction, cell proliferation, positive regulation of extracellular regulated protein kinases 1(ERK1) and ERK2 cascade, extrinsic apoptotic signaling pathway and so on. Fifteen significantly enriched pathways with DEGs were identified, including mitogen-activated protein kinase(MAPK) signaling pathway, peroxisome proliferators-activated receptor signaling pathway,estrogen signaling pathway, Th1 and Th2 cell differentiation, cyclic adenosine monophosphate signaling pathway and so on. By integrating the transcriptomics and human PPI data, nine critical genes, including MMP2, MMP9, MMP21,TIMP3, KLF10, CX3CR1, TGFB1, VEGFB, and EGF, were identified in the PPI network analysis.CONCLUSION Taurine promotes the apoptosis of HSCs via up-regulating TGFB1 and then activating the p38 MAPK-JNK-Caspase9/8/3 pathway. These findings enhance the understanding of the molecular mechanism of taurine-induced HSC apoptosis and provide references for liver disorder therapy.展开更多
Hepatitis C virus(HCV) infection is associated with increased thrombotic risk. Several mechanisms are involved including direct endothelial damage by the HCV virus, with activation of tissue factor, altered fibrinolys...Hepatitis C virus(HCV) infection is associated with increased thrombotic risk. Several mechanisms are involved including direct endothelial damage by the HCV virus, with activation of tissue factor, altered fibrinolysis and increased platelet aggregation and activation. In advanced stages, chronic HCV infection may evolve to liver cirrhosis, a condition in which alterations in the portal microcirculation may also ultimately lead to thrombin activation, platelet aggregation, and clot formation. Therefore in advanced HCV liver disease there is an increased prevalence of thrombotic phenomena in portal vein radicles. Increased thrombin formation may activate hepatic stellate cells and promote liver fibrosis. In addition, ischemic changes derived from vascular occlusion by microthrombi favor the so called parenchymal extinction, a process that promotes collapse of hepatocytes and the formation of gross fibrous tracts. These reasons may explain why advanced HCV infection may evolve more rapidly to end-stage liver disease than other forms of cirrhosis.展开更多
AIM: To investigate over-expression of Osteopontin (OPN) pathway expression and mechanisms of action in human alcoholic liver disease (ALD), in vivo and in vitro acute alcohol models.
AIM:The transforming growth factor-beta(TGF-β)/Smad signaling pathway system plays a prominent role in the control of cell growth and extracellular matrix formation in the progression of liver fibrogenesis.Smad prote...AIM:The transforming growth factor-beta(TGF-β)/Smad signaling pathway system plays a prominent role in the control of cell growth and extracellular matrix formation in the progression of liver fibrogenesis.Smad proteins can either positively or negatively regulate TGF-βresponses.In this study,the therapeutic effects of Chinese traditional compound decoction,JinSanE,and the changes of TGF-β/Smad signaling pathway system in carbon tetrachloride(CCl4)-induced rat experimental liver fibrosis were examined.METHODS:Seventy-two healthy Wistar rats were assigned to groups including normal control group,CCl4 model group,JinSanE treatment group I and JinSanE treatment group II.Each group contained 18 rats.All groups,except the normal control group,received CCl4 subcutaneous injection for 8 wk.Rats in JinSanE groups I and II were orally treated with JinSanE daily at the 1st and 5th wk,respectively,after exposure to CCl4.The expression of TGF-β1 and TGF-β1 type II receptor(TRII)mRNA in the liver was determined by reverse transcription polymerase chain reaction,and the expression of TGF-β1,Smad3 and Smad7 by immunohistochemistry.The liver histopathology was also examined by HE staining and observed under electron microscope.The activities of several serum fibrosis-associated enzymes,alanine aminotransferase(ALT),aspartate aminotransferase(AST),the levels of serum hyaluronic acid(HA)were assayed.RESULTS:Hepatic fibrosis caused by CCl4 was significantly inhibited in the JinSanE-treated groups.The degrees of necrosis/degeneration and fibrosis scores were significantly lower in the JinSanE-treated groups than in the model control group.The expression of TGF-β1,TRII and Smad3 was significantly higher in the model group than that in the JinSanE-treated groups,and the active/total TGF-β1 ratio in the JinSanE groups was suppressed.Expression of TRII mRNA and Smad3 proteins snowed a distribution pattern similar to that of TGF-β1 with a direct correlation in terms of the degree of hepatic fibrosis.The amount of positive staining Smad7 cells was significantly less in the model group than in the JinSanE-treated groups and the normal group.The contents of ALT,AST and HA were significantly lower in the JinSanE-treated groups than those in the model group.CONCLUSION:Traditional Chinese medicine,JinSanE,prevents the progression of hepatic damage and fibrosis through the inhibition of TGF-β1,TRII and Smad3 signal proteins,and increases expression of Smad7 signal protein in vivo.展开更多
Transforming growth factor-beta(TGF-β)is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression.Among different ligands of the TGF-βfamily,TGF-β1 mod...Transforming growth factor-beta(TGF-β)is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression.Among different ligands of the TGF-βfamily,TGF-β1 modulates most of its biological outcomes.Despite the abundant expression of TGF-β1 in the liver,steatosis to hepatocellular carcinoma(HCC)progression triggers elevated TGF-β1 levels,contributing to poor prognosis and survival.Additionally,elevated TGF-β1 levels in the tumor microenvironment create an immunosuppressive stage via various mechanisms.TGF-β1 has a prime role as a diagnostic and prognostic biomarker in HCC.Moreover,TGF-β1 is widely studied as a therapeutic target either as monotherapy or combined with immune checkpoint inhibitors.This review provides clinical relevance and up-to-date information regarding the potential of TGF-β1 in diagnosis,prognosis,and therapy against HCC.展开更多
Background: Triclosan [5-chloro-2-(2,4-dichlorophenoxy) phenol, TCS], a common antimicrobial additive in many personal care and health care products, is frequently detected in human blood and urine. Therefore, it has ...Background: Triclosan [5-chloro-2-(2,4-dichlorophenoxy) phenol, TCS], a common antimicrobial additive in many personal care and health care products, is frequently detected in human blood and urine. Therefore, it has been considered an emerging and potentially toxic pollutant in recent years. Long-term exposure to TCS has been suggested to exert endocrine disruption effects, and promote liver fibrogenesis and tumorigenesis. This study was aimed at clarifying the underlying cellular and molecular mechanisms of hepatotoxicity effect of TCS at the initiation stage.Methods: C57BL/6 mice were exposed to different dosages of TCS for 2 weeks and the organ toxicity was evaluated by various measurements including complete blood count, histological analysis and TCS quantification. Single cell RNA sequencing(scRNA-seq) was then carried out on TCS-or mock-treated mice livers to delineate the TCS-induced hepatotoxicity. The acquired single-cell transcriptomic data were analyzed from different aspects including differential gene expression, transcription factor(TF) regulatory network, pseudotime trajectory, and cellular communication, to systematically dissect the cellular and molecular events after TCS exposure. To verify the TCS-induced liver fibrosis,the expression levels of key fibrogenic proteins were examined by Western blotting, immunofluorescence, Masson’s trichrome and Sirius red stainings. In addition, normal hepatocyte cell MIHA and hepatic stellate cell LX-2 were used as in vitro cell models to experimentally validate the effects of TCS by immunological, proteomic and metabolomic technologies.Results: We established a relatively short term TCS exposure murine model and found the TCS mainly accumulated in the liver. The scRNA-seq performed on the livers of the TCS-treated and control groups profiled the gene expressions of > 76,000 cells belonging to 13 major cell types. Among these types, hepatocytes and hepatic stellate cells(HSCs)were significantly increased in TCS-treated group. We found that TCS promoted fibrosis-associated proliferation of hepatocytes, in which Gata2 and Mef2c are the key driving TFs. Our data also suggested that TCS induced the proliferation and activation of HSCs, which was experimentally verified in both liver tissue and cell model. In addition,other changes including the dysfunction and capillarization of endothelial cells, an increase of fibrotic characteristics in B plasma cells, and M2 phenotype-skewing of macrophage cells, were also deduced from the scRNA-seq analysis, and these changes are likely to contribute to the progression of liver fibrosis. Lastly, the key differential ligand-receptor pairs involved in cellular communications were identified and we confirmed the role of GAS6_AXL interactionmediated cellular communication in promoting liver fibrosis.Conclusions: TCS modulates the cellular activities and fates of several specific cell types(including hepatocytes, HSCs,endothelial cells, B cells, Kupffer cells and liver capsular macrophages) in the liver, and regulates the ligand-receptor interactions between these cells, thereby promoting the proliferation and activation of HSCs, leading to liver fibrosis.Overall, we provide the first comprehensive single-cell atlas of mice livers in response to TCS and delineate the key cellular and molecular processes involved in TCS-induced hepatotoxicity and fibrosis.展开更多
To evaluate prospectively 4 selected serum fibrosis markers （tenascin, hyaluronan, collagen Ⅵ, TIMP-1） before, during and 12 mo after IFN treatment of children with chronic hepatitis B. METHODS： Forty-seven consec...To evaluate prospectively 4 selected serum fibrosis markers （tenascin, hyaluronan, collagen Ⅵ, TIMP-1） before, during and 12 mo after IFN treatment of children with chronic hepatitis B. METHODS： Forty-seven consecutive patients with chronic hepatitis B （range 4-16 years, mean 8 years） underwent IFN treatment （3 MU tiw for 20 wk）. Fibrosis stage and inflammation grade were assessed in a blinded fashion before and 12 mo after end of treatment. Serum fibrosis markers were determined using automated assays.RESULTS： IFN treatment improved histological inflammation but did not change fibrosis in the whole group or in subgroups. Only hyaluronan correlated significantly with histological fibrosis（r = 0.3383, P = 0.022）. Basal fibrosis markers did not differ between responders （42.5%） and nonresponders（57.5%）. During IFN treatment only serum tenascin decreased significantly in the whole group and in nonresponders. When pretreatment values were compared to values 12 mo after therapy, TIMP-1 increased in all patients and in nonresponders, and hyaluronan decreased in all patients and in responders.CONCLUSION： Tenascin reflects hepatic fibrogenesis and inflammation which decreases during IFN treatment of children with chronic hepatitis B. TIMP-1 correlates with nonresponse and hyaluronan with histological fibrosis.展开更多
BACKGROUND Matrix metalloproteinases(MMPs)participate in the degradation of extracellular matrix compounds,maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver.However,there are few s...BACKGROUND Matrix metalloproteinases(MMPs)participate in the degradation of extracellular matrix compounds,maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver.However,there are few studies on the regulation of liver MMPs in fibrosis progression in humans.AIM To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C(CHC).METHODS A prospective,cross-sectional,multicenter study was conducted.CHC patients were categorized in fibrosis grades through FibroTest®and/or FibroScan®.Serum MMP-2,-7,and-9 were determined by western blot and multiplex suspension array assays.Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests.The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated.Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test,whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays.RESULTS Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects.MMP-7 distinguished early and advanced stages,with a correlation of 0.32(P<0.001),and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4(area under the receiver operating characteristic,0.705;95%confidence interval:0.605-0.805;P<0.001).Collagenolytic activity was detected at F0 and F1,whereas gelatinase activity was not detected at any fibrosis stage.Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2(P<0.001).CONCLUSION High concentrations of inactive MMPs were present in the serum of CHC patients,reflecting the impossibility to restrain liver fibrosis progression.MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.展开更多
基金the National Natural Science Foundation of China,No.39870331.
文摘INTRODUCTIONIt has been reported that renin-angiotensin systemexists in tissue and aldosterone can be synthesizedin extra-adrenal tissue including heart,bloodvessels and brain.Recent studies have broughtrich evidences in favour of aldosterone as a strongstimulator of fibrogenesis and mitogenesis.
基金Supported by the Research Foundation of Department of Education of Heilongjiang Province, No.10551131
文摘AIM： To investigate the location alteration of Smad2 and Smad4 mRNAs in the liver during and after fibrogenesis in rats. METHODS： Eighty male Wistar rats weighing approximately 200 g each were used. The rat models of experimental hepatic fibrosis were established by injection with carbon tetrachloride （CCh）, normal rats and rats were injected with olive oil and served as control groups. In situ hybridization（ISH） was used to detect the Smad2 and Smad4 mRNA in liver. RESULTS： In situ hybridization showed Smad2 and Smad4 mRNA expressions in the cytoplasm of hepatic stellate cells （HSC）, fibroblasts and myofibroblasts around the central vein and hepatic sinus during and after fibrogenesis. Expression of Smad2, 4 mRNA was higher than that in normal and control rats. CONCLUSION： In the process of and after hepatic fibrosis formation, HSC, fibroblasts and myofibroblasts are the major cells that express Smad2 and Smad4. The more serious the hepatic fibrosis is in the injured liver, the higher the level of Smad2 and Smad4 gene expression is during and after fibrogenesis respectively.
文摘Fibrogenesis in inflammatory bowel diseases is a complex phenomenon aimed at mucosal repair. However, it may provoke intestinal fibrosis with the development of strictures which require surgery. Therefore, fibrogenesis may be considered as a 'two-faced' process when related to chronic intestinal inflammation. Many types of cells may be converted into the fibrogenic phenotype at different levels of the intestinal wall. A complex interaction of cytokines, adhesion molecules and growth factors is involved in the process. We report an overview of recent advances in molecular mechanisms of stricturizing Crohn’s disease(CD) including the potential role of trasforming growth factor beta, protein kinase C and Ras, Raf and ERK proteins. Fibrotic growth factors such as vascular endothelial growth factor and platelet-derived growth factor, as well as the Endothelial-to-Mesenchymal Transition induced by transforming growth factor-β, are considered. Finally, our experience, focused on tumor necrosis factor α(the main cytokine of inflammatory bowel diseases) and the link between syndecan 1(a heparan sulphate adhesion molecule) and basic fibroblast growth factor(a strong stimulator of collagen synthesis) is described. We hypothesize a possible molecular pattern for mucosal healing as well as how its deregulation could be involved in fibrotic complications of CD. A final clinical point is the importance of performing an accurate evaluation of the presence of fibrotic strictures before starting anti-tumor necrosis α treatment, which could worsen the lesions.
基金theNationalNaturalScienceFoundationofChina (No 39870 331)
文摘identify aldosterone synthase gene CYP11B2 mRNA expression in normal and fibrotic liver in rats and evaluate the curative effect of antisterone Methods 160 Wistar rats weighing about 250?g were divided into 4 groups In the model group (n=40), the rats were injected with 40% CCl 4 (0 25?ml/100?g) subcutaneously three times a week In the antisterone group (n=40), the rats were injected with 40% CCl 4 (0 25?ml/100?g) subcutaneously three times a week Antisterone equivalent to 20?mg·kg 1 ·d 1 was given intragastrically (ig) In the malotilate group (n=40), the rats were injected with 40% CCl 4 (0 25?ml/100?g) subcutaneously three times a week Malotilate equivalent to 50?mg·kg 1 ·d 1 was given ig In the control group (n=40), the rats were injected with olive oil only After 2,4,6,8 and 10 weeks, animals were sacrificed, and morphological examination was carried out The area of collagen was examined with an Image Analyse System Expression of the aldosterone synthase gene, CYP11B2 mRNA, in fibrotic and normal liver was detected by means of reverse transcriptase polymerase chain reaction (RT PCR) and in situ hybridization Results In situ hybridization and RT PCR showed that the expression of CYP11B2 mRNA, which localized in the endoplasm of hepatic stellate cells (HSCs), was up regulated when fibrogenesis occurred Histological observation indicated that the grade of fibrosis and the area of collagen in the antisterone group were less than those in model group before 6 weeks ( P <0 05) There was no significant difference between the antisterone and malotilate groups ( P >0 05) After that, however, the grade of fibrosis and the area of collagen in the antisterone group were higher than those in the malotilate group ( P <0 05) There was no significant difference between the antisterone and model groups ( P >0 05) Conclusions The expression of CYP11B2 mRNA is up regulated in fibrotic liver Antisterone can have a partial fibrogenesis inhibiting effect in the early stages
文摘Intestinal fibrosis is a frequent complication of inflammatory bowel diseases(IBD),and can lead to stricture formation and intestinal obstruction.Clinically apparent stenosis occurs in more than 30%of patients with Crohn's disease(CD)and about 5%~10%of patients with ulcerative colitis(UC)[l-2],and its management represents an important and frequent challenge in clinical practice.Despite its tremendous clinical impact the tools we currently have to address this challenge are limited(l)Anti-inflammatory therapies are only a temporizing measure to relieve obstruction and re-obstruction is frequent,necessitating endoscopic balloon dilation or surgical intervention(35)No specific anti-fibrotic therapy exists at present,and therefore it is critical to understand the mechanisms of intestinal fibrogenesis to develop targeted therapeutic approaches.
文摘There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis.Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis.Therefore,efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis.Activation of hepatic stellate cells(HSCs)remains a central event in fibrosis,complemented by other sources of matrix-producing cells,including portal fibroblasts,fibrocytes and bone marrow-derived myofibroblasts.These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury.Defining the interaction of different cell types,revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets.Moreover,the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies.This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies.The pathogenesis of liver fibrosis associated with alcoholic liver disease,non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.
文摘Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.
基金Supported by Associazione Malattie Metaboliche del Fegato ONLUS(Non-profit organization for the Study and Care of Metabolic Liver Diseases)Centro Studi Malattie Metaboliche del Fegato,Universitàdegli Studi di Milano
文摘The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as a major determinant of liver fat content.Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver:from simple steatosis to steatohepatitis and progressive fibrosis.Furthermore,the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis,and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis,and possibly chronic hepatitis B virus hepatitis,hereditary hemochromatosis and primary sclerosing cholangitis.All in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.Remarkably,the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation,suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes,directly promoting fibrogenesis.Therefore,PNPLA3 is a key player in liver disease progression.Assessment of the I148M polymorphism will possibly inform clinical practice in the future,whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.
基金Supported by Novo Nordisk Foundation and the University of Copenhagen
文摘In addition to complications relating to the liver, patients with cirrhosis and portal hypertension develop extrahepatic functional disturbances of multiple organ systems. This can be considered a multiple organ failure that involves the heart, lungs, kidneys, the immune systems, and other organ systems. Progressive fibrosis of the liver and subsequent metabolic impairment leads to a systemic and splanchnic arteriolar vasodilatation. This affects both the haemodynamic and functional homeostasis of many organs and largely determines the course of the disease. With the progression of the disease, the circulation becomes hyperdynamic with cardiac, pulmonary as well as renal consequences for dysfunction and reduced survival. Infections and a changed cardiac function known as cirrhotic cardiomyopathy may be involved in further aggravation of other complications such as renal failure precipitatingthe hepatorenal syndrome.Patients with end-stage liver disease and related complications as for example the hepatopulmonary syndrome can only radically be treated by liver transplantation.As a bridge to this treatment,knowledge on the mechanisms of the pathophysiology of complications is essential for the choice of vasoactive drugs,antibiotics,drugs with specific effects on fibrogenesis and inflammation,and drugs that target specific receptors.
文摘Recent data indicate that hepatic angiogenesis, regardless of the etiology, takes place in chronic liver diseases(CLDs) that are characterized by inflammat ion and progre s s ive f ibros is. B e c aus e ant iangiogenic therapy has been found to be efficient in the prevention of fibrosis in experimental models of CLDs, it is suggested that blocking angiogenesis could be a promising therapeutic option in patients with advanced fibrosis. Consequently, efforts are being directed to revealing the mechanisms involved in angiogenesis during the progression of liver fibrosis. Literature evidences indicate that hepatic angiogenesis and fibrosis are closely related in both clinical andexperimental conditions. Hypoxia is a major inducer of angiogenesis together with inflammation and hepatic stellate cells. These profibrogenic cells stand at the intersection between inflammation, angiogenesis and fibrosis and play also a pivotal role in angiogenesis. This review mainly focuses to give a clear view on the relevant features that communicate angiogenesis with progression of fibrosis in CLDs towards the-end point of cirrhosis that may be translated into future therapies. The pathogenesis of hepatic angiogenesis associated with portal hypertension, viral hepatitis, non-alcoholic fatty liver disease and alcoholic liver disease are also discussed to emphasize the various mechanisms involved in angiogenesis during liver fibrogenesis.
基金Supported by Shanghai Leading Academic Discipline Project,No. Y0205
文摘AIM： TO explore the relationship among interferon-γ （IFN-γ） activity, fibrogenesis, T cell immune responses and hepatic inflammatory activity. METHODS： Peripheral blood samples from a total of 43 hepatitis B cirrhotic patients （LC） and 19 healthy controls （NC） were collected to measure their serum levels of IFN-γ, interleukin-2 （IL-2）, soluble interleukin-2 receptor （sIL-2R）, interleukin-10 （IL-10） and three serological markers of fibrosis including hyaluronic acid （HA）, procollagen type III peptide （PIIIP）, and type iV collagen were measured using a double antibody sandwich ELISA. Also, serum total bilirubin （TB） and alanine aminotransferase （ALT） were measured by routine measures. RESULTS： The concentrations of serological markers of fibrosis in patients with active cirrhosis （ALC） were significantly higher than those in stationary liver cirrhosis （SLC） or NC groups. The levels of serological markers in HBeAg-positive patients were significantly higher than those in HBeAg-negative patients. In SLC and ALC patients, a negative linear correlation was found between IFN-γ levels and the serological markers of fibrosis. IFN-γ and IL-2 levels in the ALC group were significantly higher than those in the SLC and NC groups, but the statistical difference was not significant between the latter two. In contrast, IL-10 levels in the SLC group were significantly higher than that in the NC group, but no significant difference was found between SLC and ALC groups. The sIL-2R level was elevated gradually in all these groups, and the differences were significant. Positive linear correlations were seen between IFN-γ activity and ALT levels （r = 0.339, P 〈 0.05）, and IL-2 activity and TB levels （r = 0.517, P 〈 0.05）. sIL-2R expression was positively correlated with both ALT and TB levels （r = 0.324, 0.455, P 〈 0.05）, whereas there was no statistically significant correlation between IL-10 expression and serum ALT and TB levels （r = -0.102, -0.093, P 〉 0.05）. Finally, there was a positive correlation between IFN-γ and IL-2 levels. CONCLUSION： T cell immune responses are correlated with fibrosis and hepatic inflammatory activity and may play an important role in liver cirrhosis.
基金Supported by the National Science and Technology Major Project,No.2014ZX10002002 and No.2017ZX10202202the National Key Research Plan "Precision Medicine Research" Key Project,No.2017YFC0908103+1 种基金the National Natural Science Foundation of China,No.81700534Program for JLU Science and Technology Innovative Research Team,No.2017TD-08
文摘AIM To investigate the relationship between levels of iron metabolism markers and hepatitis B virus(HBV)-related chronic liver diseases.METHODS This case-control study with 318 participants included 78 cases of chronic hepatitis B, 85 cases of HBV-related liver cirrhosis, 77 cases of HBV-related hepatocellular carcinoma, and 78 healthy controls. Markers of iron metabolism were detected in participants. Hematological and biochemical parameters and HBV-DNA were assessed. Child-Pugh grade and Barcelona Clinic Liver Cancer stage were determined for each hepatocellular carcinoma patient. Perls' staining was performed on liver sections. The SPSS program was used for all statistical analyses, and statistical significance was considered if a P-value < 0.05.RESULTS Significantly higher serum ferritin and lower serum hepcidin levels were detected in all groups of HBV-infected patients compared with healthy controls. Serum iron, total iron binding capacity, and serum transferrin levels were significantly lower in patients with cirrhosis and hepatocellular carcinoma, whereas the hepcidin level was higher than that in chronic hepatitis B patients. Correlation analysis indicated that serum hepcidin was negatively correlated with HBV-DNA load(P < 0.01). Serum ferritin and transferrin saturation levels increased proportionally to the extent of liver cirrhosis and poorer Child-Pugh scores(P < 0.05). The decreased serum iron and transferrin saturation levels were significantly correlated with a smaller hepatocellular carcinoma tumor burden according to Barcelona Clinic Liver Cancer staging. Liver histology showed a clearly increasing trend in iron deposition in the liver tissues with increased fibrosis, which became prominent at stages 3(severe liver fibrosis) and 4(cirrhosis). CONCLUSION Iron metabolism disorders occur in patients with HBVrelated liver diseases. The serum markers of iron metabolism disorders vary in different stages of HBV-related liver diseases.
基金the National Natural Science Foundation of China,No.81360595 and No.81860790Guangxi Natural Science Foundation Program,No.KJT13066+2 种基金the Bagui Scholars Foundation Program of Guangxithe Special-term Experts Foundation Program of Guangxithe Project of Guangxi Young Teacher Fundamental Ability Promotion,No.2017KY0298
文摘BACKGROUND Studies show that the antifibrotic mechanism of taurine may involve its inhibition of the activation and proliferation of hepatic stellate cells(HSCs). Since the molecular mechanism of taurine-mediated antifibrotic activity has not been fully unveiled and is little studied, it is imperative to use "omics" methods to systematically investigate the molecular mechanism by which taurine inhibits liver fibrosis.AIM To establish a network including transcriptomic and protein-protein interaction data to elucidate the molecular mechanism of taurine-induced HSC apoptosis.METHODS We used microarrays, bioinformatics, protein-protein interaction(PPI) network,and sub-modules to investigate taurine-induced changes in gene expression in human HSCs(LX-2). Subsequently, all of the differentially expressed genes(DEGs) were subjected to gene ontology function and Kyoto encyclopedia of genes and genomes pathway enrichment analysis. Furthermore, the interactions of DEGs were explored in a human PPI network, and sub-modules of the DEGs interaction network were analyzed using Cytoscape software.RESULTS A total of 635 DEGs were identified in taurine-treated HSCs when compared with the controls. Of these, 304 genes were statistically significantly up-regulated, and 331 down-regulated. Most of these DEGs were mainly located on the membrane and extracellular region, and are involved in the biological processes of signal transduction, cell proliferation, positive regulation of extracellular regulated protein kinases 1(ERK1) and ERK2 cascade, extrinsic apoptotic signaling pathway and so on. Fifteen significantly enriched pathways with DEGs were identified, including mitogen-activated protein kinase(MAPK) signaling pathway, peroxisome proliferators-activated receptor signaling pathway,estrogen signaling pathway, Th1 and Th2 cell differentiation, cyclic adenosine monophosphate signaling pathway and so on. By integrating the transcriptomics and human PPI data, nine critical genes, including MMP2, MMP9, MMP21,TIMP3, KLF10, CX3CR1, TGFB1, VEGFB, and EGF, were identified in the PPI network analysis.CONCLUSION Taurine promotes the apoptosis of HSCs via up-regulating TGFB1 and then activating the p38 MAPK-JNK-Caspase9/8/3 pathway. These findings enhance the understanding of the molecular mechanism of taurine-induced HSC apoptosis and provide references for liver disorder therapy.
文摘Hepatitis C virus(HCV) infection is associated with increased thrombotic risk. Several mechanisms are involved including direct endothelial damage by the HCV virus, with activation of tissue factor, altered fibrinolysis and increased platelet aggregation and activation. In advanced stages, chronic HCV infection may evolve to liver cirrhosis, a condition in which alterations in the portal microcirculation may also ultimately lead to thrombin activation, platelet aggregation, and clot formation. Therefore in advanced HCV liver disease there is an increased prevalence of thrombotic phenomena in portal vein radicles. Increased thrombin formation may activate hepatic stellate cells and promote liver fibrosis. In addition, ischemic changes derived from vascular occlusion by microthrombi favor the so called parenchymal extinction, a process that promotes collapse of hepatocytes and the formation of gross fibrous tracts. These reasons may explain why advanced HCV infection may evolve more rapidly to end-stage liver disease than other forms of cirrhosis.
基金Supported by Philanthropic Anonymous Sourcethe University of Sydney Bridging Support Grant,in part for Honours ProjectSupported by the National Health and Medical Research Council,No.NHMRC Practitioner Research Fellowship for PH support
文摘AIM: To investigate over-expression of Osteopontin (OPN) pathway expression and mechanisms of action in human alcoholic liver disease (ALD), in vivo and in vitro acute alcohol models.
基金Supported by the Basic Research Program of Hubei Province Education Bureau,No.2003X113.
文摘AIM:The transforming growth factor-beta(TGF-β)/Smad signaling pathway system plays a prominent role in the control of cell growth and extracellular matrix formation in the progression of liver fibrogenesis.Smad proteins can either positively or negatively regulate TGF-βresponses.In this study,the therapeutic effects of Chinese traditional compound decoction,JinSanE,and the changes of TGF-β/Smad signaling pathway system in carbon tetrachloride(CCl4)-induced rat experimental liver fibrosis were examined.METHODS:Seventy-two healthy Wistar rats were assigned to groups including normal control group,CCl4 model group,JinSanE treatment group I and JinSanE treatment group II.Each group contained 18 rats.All groups,except the normal control group,received CCl4 subcutaneous injection for 8 wk.Rats in JinSanE groups I and II were orally treated with JinSanE daily at the 1st and 5th wk,respectively,after exposure to CCl4.The expression of TGF-β1 and TGF-β1 type II receptor(TRII)mRNA in the liver was determined by reverse transcription polymerase chain reaction,and the expression of TGF-β1,Smad3 and Smad7 by immunohistochemistry.The liver histopathology was also examined by HE staining and observed under electron microscope.The activities of several serum fibrosis-associated enzymes,alanine aminotransferase(ALT),aspartate aminotransferase(AST),the levels of serum hyaluronic acid(HA)were assayed.RESULTS:Hepatic fibrosis caused by CCl4 was significantly inhibited in the JinSanE-treated groups.The degrees of necrosis/degeneration and fibrosis scores were significantly lower in the JinSanE-treated groups than in the model control group.The expression of TGF-β1,TRII and Smad3 was significantly higher in the model group than that in the JinSanE-treated groups,and the active/total TGF-β1 ratio in the JinSanE groups was suppressed.Expression of TRII mRNA and Smad3 proteins snowed a distribution pattern similar to that of TGF-β1 with a direct correlation in terms of the degree of hepatic fibrosis.The amount of positive staining Smad7 cells was significantly less in the model group than in the JinSanE-treated groups and the normal group.The contents of ALT,AST and HA were significantly lower in the JinSanE-treated groups than those in the model group.CONCLUSION:Traditional Chinese medicine,JinSanE,prevents the progression of hepatic damage and fibrosis through the inhibition of TGF-β1,TRII and Smad3 signal proteins,and increases expression of Smad7 signal protein in vivo.
基金Supported by the Amrita Vishwa Vidyapeetham SEED grant (K-PHAR-22-662)
文摘Transforming growth factor-beta(TGF-β)is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression.Among different ligands of the TGF-βfamily,TGF-β1 modulates most of its biological outcomes.Despite the abundant expression of TGF-β1 in the liver,steatosis to hepatocellular carcinoma(HCC)progression triggers elevated TGF-β1 levels,contributing to poor prognosis and survival.Additionally,elevated TGF-β1 levels in the tumor microenvironment create an immunosuppressive stage via various mechanisms.TGF-β1 has a prime role as a diagnostic and prognostic biomarker in HCC.Moreover,TGF-β1 is widely studied as a therapeutic target either as monotherapy or combined with immune checkpoint inhibitors.This review provides clinical relevance and up-to-date information regarding the potential of TGF-β1 in diagnosis,prognosis,and therapy against HCC.
基金supported by the National Key Research and Development Program of China(2020YFA0908000 and 2022YFC2303600)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202002)+12 种基金the National Natural Science Foundation of China(82141001,82274182,82173914,82074098,81903588 and 82003814)the Science and Technology Foundation of Shenzhen(JCYJ20210324115800001)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)the Fundamental Research Funds for the Central Public Welfare Research Institutes(ZXKT18003)the Fundamental Research Funds for the Central public welfare research institutes(ZZ14-YQ-050)the National Key R&D Program of China Key projects for international cooperation on science,technology and innovation(2020YFE0205100)the Shenzhen Governmental Sustainable Development Fund(KCXFZ20201221173612034)the Shenzhen Governmental Sustainable Development Fund(KCXFZ20201221173612034)the Shenzhen key Laboratory of Kidney Diseases(ZDSYS201504301616234)the Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties(SZGSP001)the Shenzhen Key Laboratory of Kidney Diseases(ZDSYS201504301616234)the Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties(SZGSP001)partially supported by a Grant from the Sanming Project of Medicine in Shenzhen(SZSM201612034).
文摘Background: Triclosan [5-chloro-2-(2,4-dichlorophenoxy) phenol, TCS], a common antimicrobial additive in many personal care and health care products, is frequently detected in human blood and urine. Therefore, it has been considered an emerging and potentially toxic pollutant in recent years. Long-term exposure to TCS has been suggested to exert endocrine disruption effects, and promote liver fibrogenesis and tumorigenesis. This study was aimed at clarifying the underlying cellular and molecular mechanisms of hepatotoxicity effect of TCS at the initiation stage.Methods: C57BL/6 mice were exposed to different dosages of TCS for 2 weeks and the organ toxicity was evaluated by various measurements including complete blood count, histological analysis and TCS quantification. Single cell RNA sequencing(scRNA-seq) was then carried out on TCS-or mock-treated mice livers to delineate the TCS-induced hepatotoxicity. The acquired single-cell transcriptomic data were analyzed from different aspects including differential gene expression, transcription factor(TF) regulatory network, pseudotime trajectory, and cellular communication, to systematically dissect the cellular and molecular events after TCS exposure. To verify the TCS-induced liver fibrosis,the expression levels of key fibrogenic proteins were examined by Western blotting, immunofluorescence, Masson’s trichrome and Sirius red stainings. In addition, normal hepatocyte cell MIHA and hepatic stellate cell LX-2 were used as in vitro cell models to experimentally validate the effects of TCS by immunological, proteomic and metabolomic technologies.Results: We established a relatively short term TCS exposure murine model and found the TCS mainly accumulated in the liver. The scRNA-seq performed on the livers of the TCS-treated and control groups profiled the gene expressions of > 76,000 cells belonging to 13 major cell types. Among these types, hepatocytes and hepatic stellate cells(HSCs)were significantly increased in TCS-treated group. We found that TCS promoted fibrosis-associated proliferation of hepatocytes, in which Gata2 and Mef2c are the key driving TFs. Our data also suggested that TCS induced the proliferation and activation of HSCs, which was experimentally verified in both liver tissue and cell model. In addition,other changes including the dysfunction and capillarization of endothelial cells, an increase of fibrotic characteristics in B plasma cells, and M2 phenotype-skewing of macrophage cells, were also deduced from the scRNA-seq analysis, and these changes are likely to contribute to the progression of liver fibrosis. Lastly, the key differential ligand-receptor pairs involved in cellular communications were identified and we confirmed the role of GAS6_AXL interactionmediated cellular communication in promoting liver fibrosis.Conclusions: TCS modulates the cellular activities and fates of several specific cell types(including hepatocytes, HSCs,endothelial cells, B cells, Kupffer cells and liver capsular macrophages) in the liver, and regulates the ligand-receptor interactions between these cells, thereby promoting the proliferation and activation of HSCs, leading to liver fibrosis.Overall, we provide the first comprehensive single-cell atlas of mice livers in response to TCS and delineate the key cellular and molecular processes involved in TCS-induced hepatotoxicity and fibrosis.
基金Supported by the Interdisciplinary Center for Clinical Research(IZKF) of the University of Erlangen-Nuernberg, Germany
文摘To evaluate prospectively 4 selected serum fibrosis markers （tenascin, hyaluronan, collagen Ⅵ, TIMP-1） before, during and 12 mo after IFN treatment of children with chronic hepatitis B. METHODS： Forty-seven consecutive patients with chronic hepatitis B （range 4-16 years, mean 8 years） underwent IFN treatment （3 MU tiw for 20 wk）. Fibrosis stage and inflammation grade were assessed in a blinded fashion before and 12 mo after end of treatment. Serum fibrosis markers were determined using automated assays.RESULTS： IFN treatment improved histological inflammation but did not change fibrosis in the whole group or in subgroups. Only hyaluronan correlated significantly with histological fibrosis（r = 0.3383, P = 0.022）. Basal fibrosis markers did not differ between responders （42.5%） and nonresponders（57.5%）. During IFN treatment only serum tenascin decreased significantly in the whole group and in nonresponders. When pretreatment values were compared to values 12 mo after therapy, TIMP-1 increased in all patients and in nonresponders, and hyaluronan decreased in all patients and in responders.CONCLUSION： Tenascin reflects hepatic fibrogenesis and inflammation which decreases during IFN treatment of children with chronic hepatitis B. TIMP-1 correlates with nonresponse and hyaluronan with histological fibrosis.
基金the National Council for Science and Technology,No.SALUD-2016-272579 and No.PAPIIT-UNAM TA200515.
文摘BACKGROUND Matrix metalloproteinases(MMPs)participate in the degradation of extracellular matrix compounds,maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver.However,there are few studies on the regulation of liver MMPs in fibrosis progression in humans.AIM To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C(CHC).METHODS A prospective,cross-sectional,multicenter study was conducted.CHC patients were categorized in fibrosis grades through FibroTest®and/or FibroScan®.Serum MMP-2,-7,and-9 were determined by western blot and multiplex suspension array assays.Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests.The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated.Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test,whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays.RESULTS Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects.MMP-7 distinguished early and advanced stages,with a correlation of 0.32(P<0.001),and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4(area under the receiver operating characteristic,0.705;95%confidence interval:0.605-0.805;P<0.001).Collagenolytic activity was detected at F0 and F1,whereas gelatinase activity was not detected at any fibrosis stage.Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2(P<0.001).CONCLUSION High concentrations of inactive MMPs were present in the serum of CHC patients,reflecting the impossibility to restrain liver fibrosis progression.MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.
