Hepatic fibrosis is a common pathological process that occurs in the development of various chronic liver diseases into cirrhosis and liver cancer,characterized by excessive deposition of the extracellular matrix.In t...Hepatic fibrosis is a common pathological process that occurs in the development of various chronic liver diseases into cirrhosis and liver cancer,characterized by excessive deposition of the extracellular matrix.In the past,hepatic fibrosis was thought to be a static and irreversible pathological process.In recent years,with the rapid development of molecular biology and the continuous in-depth study of the liver at the microscopic level,more and more evidence has shown that hepatic fibrosis is a dynamic and reversible process.Therefore,it is particularly important to find an effective,simple,and inexpensive method for its prevention and treatment.Traditional Chinese medicine(TCM)occupies an important position in the treatment of hepatic fibrosis due to its advantages of low adverse reactions,low cost,and multi-target effectiveness.A large number of research results have shown that TCM monomers,single herbal extracts,and TCM formulas play important roles in the prevention and treatment of hepatic fibrosis.Oxidative stress(OS)is one of the key factors in the occurrence and development of hepatic fibrosis.Therefore,this article reviews the progress in the understanding of the mechanisms of TCM monomers,single herbal extracts,and TCM formulas in preventing and treating hepatic fibrosis by inhibiting OS in recent years,in order to provide a reference and basis for drug therapy of hepatic fibrosis.展开更多
Background: Liver diseases including chronic hepatitis, steatosis, fibrosis, cirrhosis and liver cancer are now a public health problem. In 2002, cirrhosis accounted for 27.63% of hepatobiliary diseases in Burkina Fas...Background: Liver diseases including chronic hepatitis, steatosis, fibrosis, cirrhosis and liver cancer are now a public health problem. In 2002, cirrhosis accounted for 27.63% of hepatobiliary diseases in Burkina Faso. In Africa and more particularly in Burkina Faso, the majority of the population (about 80%) uses medicinal plants for their primary health care. Calotropis procera (Ait.) R.Br (Apocynaceae) is a medicinal plant used in Burkina Faso in the treatment of liver problems. This work aims to evaluate the anti-fibrotic properties of Calotropis procera roots barks. Methods: The anti-fibrotic activity of the ethanolic extract of Calotropis procera roots barks was evaluated using diethylnitrosamine (DEN) to induce liver fibrosis in male Wistar rats. Serum biomarkers, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), Total protein, Albumin, Υ-Glutamyl transferase (GGT) were evaluated and the activities of antioxidant enzymes (Superoxide dismutase and catalase) as well as the level of malonedialdehyde (MDA) and that of nitric oxide (NO) were determined in the liver homogenate. Results: The treatment of rats suffering from hepatic fibrosis with the ethanolic extract leads to a significant restoration of the biomarkers of the hepatic function in particular, AST, ALP, GGT, Albumin. The extract also causes a reduction in oxidative stress in the liver through a significant increase in the activity rate of the antioxidant enzymes Superoxide dismutase (SOD) and catalase accompanied by a significant drop in the rate of MDA and NO suggesting the anti-oxidant effect of extract. Conclusion: The results of the study show that the ethanolic extract of the roots barks of Calotropis procera has anti-fibrotic properties.展开更多
Objective:To study the mechanism of action of Xiayuxue Tang in treating hepatic fibrosis by combining GEO data mining,network pharmacology,and molecular docking technology,and provide new research directions for the t...Objective:To study the mechanism of action of Xiayuxue Tang in treating hepatic fibrosis by combining GEO data mining,network pharmacology,and molecular docking technology,and provide new research directions for the treatment of hepatic fibrosis.Method:Utilizing multiple databases,we aim to identify the relevant targets of various components in Xiayuxue Tang and their associations with hepatic fibrosis.After pinpointing the key targets through interaction analysis,we will construct both the compound-target network and the protein interaction network for Xiayuxue Tang.Conclusively,we will conduct GO and KEGG enrichment analyses on these key targets,followed by molecular docking verification.Result:Through mining the GEO database,171 related targets were identified.When combined with other databases,a total of 2,343 hepatic fibrosis-related targets were obtained.Xiayuxue Tang comprises 82 related components,which include 26 active components from rhubarb,1 from ground beetle worm,46 from peach kernels,with a total of 314 predicted targets.The GO enrichment analysis revealed 748 biological processes,32 cellular components,and 73 molecular functions,while the KEGG enrichment analysis identified 222 pathways.Molecular docking verification confirmed that effective compounds can bind stably to key proteins,exhibiting strong binding activity.This underscores the potential efficacy of Xiayuxue Tang in addressing hepatic fibrosis.Conclusion:Xiayuxue Tang exerts regulatory effects on hepatic fibrosis through different targets and pathways,suggesting that the herbal compound has the characteristics of multiple pathways and targets.展开更多
AIM To investigate the value of the gamma-glutamyltraspeptidase(GGT)-to-platelet(PLT) ratio(GPR) in the diagnosis of hepatic fibrosis in patients with chronic hepatitis B(CHB). METHODS We included 390 untreated CHB pa...AIM To investigate the value of the gamma-glutamyltraspeptidase(GGT)-to-platelet(PLT) ratio(GPR) in the diagnosis of hepatic fibrosis in patients with chronic hepatitis B(CHB). METHODS We included 390 untreated CHB patients in this study. The GPR, aspartate aminotransferase(AST)-to-PLT ratio index(APRI), and fibrosis-4(FIB-4) of all patients were analysed to determine if these parameter were correlated with age, gender, medical history, liver function [total bilirubin(TBil), alanine aminotransferase(ALT), and AST], GGT, PLT count, or hepatic fibrosis stage. The GPR, APRI, and FIB-4, as well as the combination of the GPR and APRI or the GPR and FIB-4 were assessed in different cirrhosis stages using receiver operating characteristic(ROC) curve analysis to evaluate their value in diagnosing hepatic fibrosis in CHB patients. RESULTS The GPR, APRI, and FIB-4 were not correlated withCHB patients' age, gender, or disease duration(P > 0.05), but all of these parameters were positively correlated with serum ALT, AST, GGT, and PLT count(P < 0.01). Additionally, the GPR, APRI, and FIB-4 were positively correlated with hepatic fibrosis(P < 0.01); the areas under the ROC curve for the GPR in F1, F2, F3, and F4 stages were 0.723, 0.741, 0.826, and 0.833, respectively, which were significantly higher than the respective values for the FIB-4 and APRI(F1: 0.581, 0.612; F2: 0.706, 0.711; F3: 0.73, 0.751; and F4: 0.799, 0.778). The respective diagnostic cut-off points for each stage were 0.402, 0.448, 0.548, and 0.833, respectively. The diagnostic sensitivity and specificity were, respectively, 88.8% and 87.5% in F1, 72.7% and 89.7% in F2, 81.3% and 98.6% in F3, and 80% and 97.4% in F4 when the GPR and APRI were connected in parallel; 86.6% and 90.2%, 78.4% and 96%, 78.6% and 97.4%, and 73.2% and 97.9%, respectively, when the GPR and APRI were connected in series; 80.2% and 89%, 65% and 89%, 70.3% and 98.5%, and 78.8% and 96.8%, respectively, when the GPR and FIB-4 were connected in parallel; and 83.6% and 87.9%, 76.8% and 96.6%, 72.7% and 98%, and 74.4% and 97.7%, respectively, when the GPR and FIB-4 were connected in series.CONCLUSION The GPR, as a serum diagnostic index of liver fibrosis, is more accurate, sensitive, and easy to use than the FIB-4 and APRI, and the GPR can significantly improve the sensitivity and specificity of hepatic fibrosis diagnosis in CHB when combined with the FIB-4 or APRI.展开更多
Congenital hepatic fibrosis(CHF) is an autosomal recessive inherited malformation defined pathologically by a variable degree of periportal fibrosis and irregularly shaped proliferating bile ducts.It is one of the fib...Congenital hepatic fibrosis(CHF) is an autosomal recessive inherited malformation defined pathologically by a variable degree of periportal fibrosis and irregularly shaped proliferating bile ducts.It is one of the fibropolycystic diseases,which also include Caroli disease,autosomal dominant polycystic kidney disease,and autosomal recessive polycystic kidney disease. Clinically it is characterized by hepatic fibrosis,portal hypertension,and renal cystic disease.CHF is known to occur in association with a range of both inherited and non-inherited disorders,with multiorgan involvement,as a result of ductal plate malformation.Because of the similarities in the clinical picture,it is necessary to differentiate CHF from idiopathic portal hypertension and early liver cirrhosis,for which a liver biopsy is essential. Radiological tests are important for recognizing involvement of other organ systems.With regards to our experience at Hacettepe University,a total of 26 patients have been diagnosed and followed-up between 1974 and 2009 with a diagnosis of CHF.Presentation with Caroli syndrome was the most common diagnosis,with all such patients presenting with symptoms of recurrentcholangitis and symptoms related to portal hypertension. Although portal fibrosis is known to contribute to the ensuing portal hypertension,it is our belief that portal vein cavernous transformation also plays an important role in its pathogenesis.In all patients with CHF portal vein morphology should be evaluated by all means since portal vein involvement results in more severe and complicated portal hypertension.Other associations include the Joubert and Bardet-Biedl syndromes.展开更多
AIM:To investigate the effects of blueberry on hepatic fibrosis and NF-E2-related factor 2(Nrf2) transcription factor in rats.METHODS:Forty-five male Sprague-Dawley rats were randomly divided into control group(A);CCl...AIM:To investigate the effects of blueberry on hepatic fibrosis and NF-E2-related factor 2(Nrf2) transcription factor in rats.METHODS:Forty-five male Sprague-Dawley rats were randomly divided into control group(A);CCl4-induced hepatic fibrosis group(B);blueberry prevention group(C);Dan-shao-hua-xian capsule(DSHX) prevention group(D);and blueberry + DSHX prevention group(E).Liver fibrosis was induced in rats by subcutaneous injection of CCl4 and a high-lipid/low-protein diet for 8 wk(except the control group).The level of hyaluronic acid(HA) and alanine aminotransferase(ALT) in serum was examined.The activity of superoxide dismutase(SOD),glutathione-S-transferase(GST) and malondialdehyde(MDA) in liver homogenates was determined.The degree of hepatic fibrosis was evaluated by hematoxylin and eosin and Masson staining.Expression of Nrf2 and NADPH quinone oxidoreductase 1(Nqo1) was detected by real-time reversed transcribed-polymerase chain reaction,immunohistochemical techniques,and western blotting.RESULTS:Compared with group B,liver indices,levels of serum HA and ALT of groups C,D and E were reduced(liver indices:0.038 ± 0.008,0.036 ± 0.007,0.036 ± 0.005 vs 0.054 ± 0.009,P<0.05;HA:502.33 ± 110.57 ng/mL,524.25 ± 255.42 ng/mL,499.25 ± 198.10 ng/mL vs 828.50 ± 237.83 ng/mL,P<0.05;ALT:149.44 ± 16.51 U/L,136.88 ± 10.07 U/L,127.38 ± 11.03 U/L vs 203.25 ± 31.62 U/L,P<0.05),and SOD level was significantly higher,but MDA level was lower,in liver homogenates(SOD:1.36 ± 0.09 U/mg,1.42 ± 0.13 U/mg,1.50 ± 0.15 U/mg vs 1.08 ± 0.19 U/mg,P<0.05;MDA:0.294 ± 0.026 nmol/mg,0.285 ± 0.025 nmol/mg,0.284 ± 0.028 nmol/mg vs 0.335 ± 0.056 nmol/mg,P<0.05).Meanwhile,the stage of hepatic fibrosis was significantly weakened(P<0.05).Compared with group A,the activity of GST liver homogenates and expression levels of Nrf2 and Nqo1 in group B were elevated(P<0.05).The expression level of Nrf2 and Nqo1 in groups C,D,and E were increased as compared with group B,but the difference was not significant.CONCLUSION:Blueberry has preventive and protective effects on CCl4-induced hepatic fibrosis by reducing hepatocyte injury and lipid peroxidation.However,these effects may not be related to the activation of Nrf2 during long-term of CCl4.展开更多
AIM:To explore the anti-fibrotic effect of Haobie Yangyin Ruanjian Decoction(HYRD)on CCl4-induced hepatic fibrosis in rats and its modulation on the transforming growth factor(TGF)β-Smad signaling pathway.METHODS:Fif...AIM:To explore the anti-fibrotic effect of Haobie Yangyin Ruanjian Decoction(HYRD)on CCl4-induced hepatic fibrosis in rats and its modulation on the transforming growth factor(TGF)β-Smad signaling pathway.METHODS:Fifty-six healthy Wistar rats were randomly divided into five groups:normal control group(n=6),CCl4-induced hepatic fibrosis group(n=14) and three treatment groups(the treated rats received HYRD via oral administration at daily dosages of 8.2,2.5 and 0.82 g/kg,respectively)of HYRD(n=12,respectively).Experimental hepatic fibrosis was induced by subcutaneous injection of carbon tetrachloride solution(CCl4 dissolved in peanut oil,4:6,V/V)with 0.5 mL/100 g body weight for the first time,and then 0.3 mL/100 g body weight twice a week for 8 wk.In the former 2 wk,rats were raised by feedstuffⅠ(80% corn meal,20%lard,0.5%cholesterol).After 2 wk,they were raised by feedstuffⅡ(corn meal and 0.5% cholesterol).Except for the control group,30%alcohol solution was given orally to each rat every other day from the beginning,1 mL for each rat.Liver function parameters and hepatic hydroxyproline content were detected by chromatometry.Serum levels of hyaluronic acid(HA),typeⅣcollagen(CIV),typeⅢprecollagen(PCⅢ)and laminin(LN)were assayed with radioimmunoassay.Deposition of collagen was observed with hematoxylin-eosin staining and collagen staining.Gene expression of TGFβ1 and Smad3 were detected with real-time reverse transcriptase-polymerase chain reaction and Western blotting,respectively.RESULTS:The serum levels of alanine transaminase and aspartate transaminase were increased in the model group compared with the control group(P<0.01),and they were decreased in the three treatment groups compared with the model group.The serum levels of total protein and albumin were decreased in the model group and increased in the three treatment groups.The hepatic hydroxyproline content and serum levels of PCⅢ,HA,LN and CIV were markedly increased in the model group compared with the control group,and decreased in the treatment groups.The gene expression of TGFβ1 and Smad3 was enhanced in the model group compared with the control group,and HYRD could down regulate their expression.CONCLUSION:HYRD can inhibit hepatic fibrosis induced by CCl4 in rats,which is probably associated with its down-regulation on fibrogenic signal transduction of TGFβ-Smad pathway.展开更多
AIM To investigate the protective effects of Foeniculum vulgare root bark(FVRB), a traditional Uyghur medicine, against carbon tetrachloride(CCl4)-induced hepatic fibrosis in mice. METHODS Mice were randomly divided i...AIM To investigate the protective effects of Foeniculum vulgare root bark(FVRB), a traditional Uyghur medicine, against carbon tetrachloride(CCl4)-induced hepatic fibrosis in mice. METHODS Mice were randomly divided into eight groups(n = 20 each). Except for the normal control group, mice in the rest groups were intraperitoneally injected(i.p.) with 0.1% CCl4-olive oil mixture at 10 m L/kg twice a week to induce liver fibrosis. After 4 wk, mice were treated concurrently with the 70% ethanol extract of FVRB(88, 176, 352 and 704 mg/kg, respectively) daily by oral gavage for 4 wk to evaluate its protective effects. Serum aspartate aminotransferase(AST), alanine aminotransferase(ALT), triglyceride(TG), hexadecenoic acid(HA), laminin(LN), glutathione(GSH), superoxide dismutase(SOD), and malondialdehyde(MDA) in liver tissues were measured. Hematoxylin-eosin(H and E) staining and Masson trichrome(MT) staining were performed to assess histopathological changes in the liver. The expression of transforming growth factor β1(TGF-β1), matrix metalloprotein 9(MMP-9) and metallopeptidase inhibitor 1(TIMP-1) was detected by immunohistochemical analysis. Additionally, TGF-β1 and alpha-smooth muscle actin(α-SMA) protein expression was measured by Western blot.RESULTS A significant reduction in serum levels of AST, ALT, TG, HA and LN was observed in the FVRB-treated groups, suggesting that FVRB displayed hepatoprotective effects. Also, the depletion of GSH, SOD, and MDA accumulation in liver tissues was suppressed by FVRB. The expression of TGF-β1, MMP-9 and TIMP-1 determined by immunohistochemistry was markedly reduced in a dose-dependent manner by FVRB treatment. Furthermore, protective effects of FVRB against CCl4-induced liver injury were confirmed by histopathological studies. Protein expression of TGF-β1 and α-SMA detected by Western blot was decreased by FVRB treatment.CONCLUSION Our results indicate that FVRB may be a promising agent against hepatic fibrosis and its possible mechanisms are inhibiting lipid peroxidation and reducing collagen formation in liver tissue of liver fibrosis mice.展开更多
Hepatic stellate cells(HSCs)are essential drivers of fibrogenesis.Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis.18beta-glycyrrhetinic acid(18b-GA)is a natural compound that exi...Hepatic stellate cells(HSCs)are essential drivers of fibrogenesis.Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis.18beta-glycyrrhetinic acid(18b-GA)is a natural compound that exists widely in herbal medicines,such as Glycyrrhiza uralensis Fisch,which is used for treating multiple liver diseases,especially in Asia.In the present study,we demonstrated that 18b-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs.18b-GA inhibited the expression of a-smooth muscle actin and collagen type Ⅰ alpha-1.Using a chemoproteomic approach derived from activity-based protein profiling,together with cellular thermal shift assay and surface plasmon resonance,we found that 18b-GA covalently targeted peroxiredoxin 1(PRDX1)and peroxiredoxin 2(PRDX2)proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities.18b-GA induced the elevation of reactive oxygen species(ROS),resulting in the apoptosis of activated HSCs.PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs.Collectively,our findings revealed the target proteins and molecular mechanisms of 18b-GA in ameliorating hepatic fibrosis,highlighting the future development of 18b-GA as a novel therapeutic drug for hepatic fibrosis.展开更多
Objective The present study was designed to examine whether the renin-angiotensin system would be implicated in the development of hepatic fibrosis induced by CCI4. The effects of enalapril on the ex-pression of plate...Objective The present study was designed to examine whether the renin-angiotensin system would be implicated in the development of hepatic fibrosis induced by CCI4. The effects of enalapril on the ex-pression of platelet derived growth factor receptor (PDGFR) in liver tissue were also investigated. Methods 50 Sprague-Dawley rats were randomly divided into S groups (control group, model group, and 3 enalapril treated groups). Except rats of the model group, all rats received subcutanous injection of 40% CC14 (every 3d for 6 weeks). Rats of enalapril treated groups were given enalapril (10mg/kg, 5mg/kg, 2.5mg/kg per day, orally)for 6 weeks before they were killed. Serum levels of hyaluronic acid (HA) and laminin (LW) were de-termined by radioimmunoassay techniques. Van Gieson collagen staining was used to evaluate the extracellular matrix of the liver. The expressions of PDGFR and a-smooth muscle actin (a-SMA) were confirmed by im-munohistochemical methods. Results Compared with those in the model gr oup, it was found in enalapril treated groups: (1) serum levels of collagen type 1V and LN were significantly reduced (P< 0. 01); (2) the pro-gression of fibrosis was delayed (P < 0. 01); (3) the expressions of PDGFR and a-SMA were decreased. Conclusion The renin-angiotensin system was involved in the development of hepatic fibrosis induced by Cd4. Angiotensin-converting enzyme (ACE) inhibitor and enalapril could slow down the rate of hepatic fibrosis. This effect might be due to the ability of this drug in suppressing the expression of PDGFR of liver tissue.展开更多
BACKGROUND Congenital hepatic fibrosis(CHF)is a rare autosomal recessive disorder characterized by variable degrees of periportal fibrosis and malformation of bile ducts.CHF is generally accompanied by a variety of co...BACKGROUND Congenital hepatic fibrosis(CHF)is a rare autosomal recessive disorder characterized by variable degrees of periportal fibrosis and malformation of bile ducts.CHF is generally accompanied by a variety of conditions or syndromes with other organ involvement.CASE SUMMARY We report a 5-year-4-month-old Chinese boy with congenital hypothyroidism(CH)diagnosed with CHF.The patient was diagnosed with CH by a newborn screening test and has since been taking levothyroxine.He has developed normally without neurocognitive deficits.Abnormal liver function was observed in the patient at the age of 4 years and 11 mo,and elevated levels of liver function indices were persistent for 5 mo.Radiological imaging indicated hepatosplenomegaly without narrowing of the portal vein but dilated splenic vein.A liver biopsy confirmed the pathological features of CHF.Genetic testing revealed two novel homozygous mutations,namely,c.2141-3T>C variant in PKHD1 related to CHF and c.2921G>A(p.R974H)in DUOX2 related to CH.The patient was treated with compound glycyrrhizin tablet,ursodeoxycholic acid,and levothyroxine after diagnosis.The patient achieved a favorable clinical outcome during a follow-up period of over 2 years.CONCLUSION Herein,we report the first case of a Chinese boy with comorbidity of CHF and CH,carrying both PKHD1 gene and DUOX2 gene novel mutations.Liver biopsy and genetic testing should be considered for the diagnosis of coexistent liver disease in CH patients with unexplained abnormal liver function.展开更多
Congenital hepatic fibrosis is part of many different malformation syndromes, of which oculo-encephalohepato-renal syndrome is the most common. These syndromes largely overlap, and so accurate classification of indivi...Congenital hepatic fibrosis is part of many different malformation syndromes, of which oculo-encephalohepato-renal syndrome is the most common. These syndromes largely overlap, and so accurate classification of individual patients may be difficult. We present herein three syndromic siblings who were products of a consanguineous marriage. We investigated in detail at least six organ systems in these patients, namely the liver, brain, eye, kidneys, skeleton, and gonads. The common features observed in these three cases were congenital hepatic fibrosis, retinitis pigmentosa, truncal obesity, rotatory nystagmus, mental retardation, advanced myopia, and high-arched palate. The clinical dysmorphology in these patients was distinct and lacked the major features of the known syndromes associated with congenital hepatic fibrosis. Although some features of these presented cases are similar to those found in Bardet-Biedl syndrome(BBS), the absence of some major criteria of BBS(polydactyly, renal abnormality, and hypogonadism) suggests that this may be a new syndrome. All three patients remain under follow-up in the departments of Gastroenterology, Ophthalmology, and Neurology at Hacettepe University.展开更多
Hepatic sinusoidal endothelial cell is a highly differentiated cell in hepatic sinusoid,and plays an important role in the occurrence and development of hepatic fibrosis.The dysfunction of hepatic sinusoidal endotheli...Hepatic sinusoidal endothelial cell is a highly differentiated cell in hepatic sinusoid,and plays an important role in the occurrence and development of hepatic fibrosis.The dysfunction of hepatic sinusoidal endothelial cells is considered to be the key cause of a variety of liver diseases.At present,the researches on hepatic fibrosis at home and abroad are mainly focused on inhibiting the activation of hepatic stellate cells and accelerating the hydrolysis of extracellular matrix.However,there are few studies on the important role of the structure and function of hepatic sinusoidal endothelial cells in hepatic fibrosis.This paper reviews the research progress on the effect of hepatic sinusoidal endothelial cells on hepatic fibrosis and its regulatory mechanism in recent years.This paper summarizes the results of the research on the structural characteristics of hepatic sinusoidal endothelial cells,secretion of fibrosis-related cytokines and regulation of hepatic stellate cells activation in the development of hepatic fibrosis.展开更多
Objective Toinvestigate the diagnostic value of hepatic fibrosis parameter model and elastic modulus of liver and spleen in hepatic fibrosis of chronic hepatitis b.Methods 77 patients with hepatic fibrosis of chronic ...Objective Toinvestigate the diagnostic value of hepatic fibrosis parameter model and elastic modulus of liver and spleen in hepatic fibrosis of chronic hepatitis b.Methods 77 patients with hepatic fibrosis of chronic hepatitis in the infection clinic were recruited from July 2016 to December 2018.According to the classification of hepatic fibrosis,23 patients were classified as S1,20 as S2,18 as S3 and 16 as S4.The serum indexes of liver function in all patients were tested,FIB-4,APRI and GPR model indexes were calculated.SWE values of liver and spleen were evaluated,and the correlation between FIB-4,APRI,GPR and SWE was analyzed.Results The SWE values of liver and spleen in the study group were significantly higher than those in the normal group(P<0.01),and the differences in serum GGT,PLT,AST and portal vein velocity between the two groups were statistically significant(P<0.01).GGT and PLT were correlated with SWE values of liver and spleen,which were statistically significant(P<0.01).The model indexes of fib-4,APRI and GPR in the study group were all higher than those in the normal group,with statistically significant differences(P<0.01).Pearson correlation analysis showed that liver SWE value and spleen SWE value were positively correlated with fib-4,APRI and GPR,and the differences were significant(P<0.01),with a higher correlation with GPR.Conclusion GGT,PLT and GPR are positively correlated with SWE of liver and spleen,and combined detection can improve the early diagnosis accuracy of liver fibrosis.展开更多
Hepatic fibrosis(HF)is the common pathological basis of all chronic liver diseases,and is a necessary stage for the development of chronic liver disease into cirrhosis.The pathogenesis of liver fibrosis is very compli...Hepatic fibrosis(HF)is the common pathological basis of all chronic liver diseases,and is a necessary stage for the development of chronic liver disease into cirrhosis.The pathogenesis of liver fibrosis is very complicated.Different cells and cytokines play a major role in the pathogenesis of liver fibrosis.This article focuses on the development mechanism of liver fibrosis,different cells and cytokines(macrophages,natural killer cells,natural killer T cells,tumor necrosis factor,IL-22,transforming growth factor-β,connective tissue growth factor,vascular endothelial growth factor)Its impact on the development of liver fibrosis is reviewed.展开更多
Hepatic fibrosis is a necessary stage in the development of chronic liver disease to cirrhosis.Western medicine drug treatment takes etiological treatment,symptomatic treatment and anti-fibrosis treatment as the main ...Hepatic fibrosis is a necessary stage in the development of chronic liver disease to cirrhosis.Western medicine drug treatment takes etiological treatment,symptomatic treatment and anti-fibrosis treatment as the main means and aims to protect the liver and improve hepatic function while there are many adverse reactions after long-term administration.However,Dai medicine mainly focuses on balancing the four towers and five aggregates,and regulating the"three plates".Hence it has slight side effects and is safe and effective.Therefore,this paper reviewed the current status of Dai and Western medicine in the treatment of hepatic fibrosis,in order to provide reference for clinical medication.展开更多
Hepatic fibrosis/cirrhosis is a significant health burden worldwide,resulting in liver failure or hepatocellular carcinoma(HCC)and accounting for many deaths each year.The pathogenesis of hepatic fibrosis/cirrhosis is...Hepatic fibrosis/cirrhosis is a significant health burden worldwide,resulting in liver failure or hepatocellular carcinoma(HCC)and accounting for many deaths each year.The pathogenesis of hepatic fibrosis/cirrhosis is very complex,which makes treatment challenging.Endogenous mesenchymal stromal cells(MsCs)have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis.Paradoxically,exogenous MsCs have also been used in clinical trials for liver cirrhosis,and their effectiveness has been observed in most completed clinical trials.There are still many issues to be resolved to promote the use of MsCs in the clinic in the future.In this review,we will examine the controversial role of MsCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis.We also investigated the clinical trials involving MsCs in liver cirrhosis,summarized the parameters that need to be standardized,and discussed how to promote the use of MsCs from a clinical perspective.展开更多
The mesencephalic astrocyte-derived neurotrophic factor(MANF)has been recently identified as a neurotrophic factor,but its role in hepatic fibrosis is unknown.Here,we found that MANF was upregulated in the fibrotic li...The mesencephalic astrocyte-derived neurotrophic factor(MANF)has been recently identified as a neurotrophic factor,but its role in hepatic fibrosis is unknown.Here,we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl4.MANF deficiency in either hepatocytes or hepatic mono-macrophages,particularly in hepatic mono-macrophages,clearly exacerbated hepatic fibrosis.Myeloid-specific MANF knockout increased the population of hepatic Ly6C^(high)macrophages and promoted HSCs activation.Furthermore,MANF-sufficient macrophages(from WT mice)transfusion ameliorated CCl4-induced hepatic fibrosis in myeloid cells-specific MANF knockout(MKO)mice.Mechanistically,MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation.Pharmacologically,systemic administration of recombinant human MANF significantly alleviated CCl_(4)-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout(HKO)mice.This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a“brake”on the upstream of NF-κB pathway,which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.展开更多
Liver cirrhosis is a leading cause of death from liver‐related diseases accompanied by a variety of complications;however,hepatic fibrosis,an inevitable stage of cirrhosis,is possible to be reversed and cured.Hepatic...Liver cirrhosis is a leading cause of death from liver‐related diseases accompanied by a variety of complications;however,hepatic fibrosis,an inevitable stage of cirrhosis,is possible to be reversed and cured.Hepatic stellate cells(HSCs)are the primary cells that secrete extracellular matrix in the liver and play a dominant role in the pathogenesis of hepatic fibrosis.Effective therapeutic approaches for reversing hepatic fibrosis aim at inhibiting the activation of HSCs and inducing their inactivation or death.This review highlights the mechanism by which traditional Chinese medicine(TCM)regulates the activity of HSCs and exerts antifibrotic effects,providing insights and prospects for the treatment of hepatic fibrosis with TCM.展开更多
Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron-and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfor...Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron-and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfordii, shows effective anti-fibrotic and anti-inflammatory activities in multiple hepatic diseases. However, the exact molecular mechanisms of action and the direct protein targets of celastrol in the treatment of liver fibrosis remain largely elusive. Here, we discover that celastrol exerts anti-fibrotic effects via promoting the production of reactive oxygen species(ROS) and inducing ferroptosis in activated hepatic stellate cells(HSCs). By using activity-based protein profiling(ABPP) in combination with bio-orthogonal click chemistry reaction and cellular thermal shift assay(CETSA), we show that celastrol directly binds to peroxiredoxins(PRDXs), including PRDX1, PRDX2, PRDX4 and PRDX6,through the active cysteine sites, and inhibits their anti-oxidant activities. Celastrol also targets to heme oxygenase 1(HO-1) and upregulates its expression in activated-HSCs. Knockdown of PRDX1, PRDX2,PRDX4, PRDX6 or HO-1 in HSCs, to varying extent, elevated cellular ROS levels and induced ferroptosis. Taken together, our findings reveal the direct protein targets and molecular mechanisms via which celastrol ameliorates hepatic fibrosis, thus supporting the further development of celastrol as a promising therapeutic agent for liver fibrosis.展开更多
文摘Hepatic fibrosis is a common pathological process that occurs in the development of various chronic liver diseases into cirrhosis and liver cancer,characterized by excessive deposition of the extracellular matrix.In the past,hepatic fibrosis was thought to be a static and irreversible pathological process.In recent years,with the rapid development of molecular biology and the continuous in-depth study of the liver at the microscopic level,more and more evidence has shown that hepatic fibrosis is a dynamic and reversible process.Therefore,it is particularly important to find an effective,simple,and inexpensive method for its prevention and treatment.Traditional Chinese medicine(TCM)occupies an important position in the treatment of hepatic fibrosis due to its advantages of low adverse reactions,low cost,and multi-target effectiveness.A large number of research results have shown that TCM monomers,single herbal extracts,and TCM formulas play important roles in the prevention and treatment of hepatic fibrosis.Oxidative stress(OS)is one of the key factors in the occurrence and development of hepatic fibrosis.Therefore,this article reviews the progress in the understanding of the mechanisms of TCM monomers,single herbal extracts,and TCM formulas in preventing and treating hepatic fibrosis by inhibiting OS in recent years,in order to provide a reference and basis for drug therapy of hepatic fibrosis.
文摘Background: Liver diseases including chronic hepatitis, steatosis, fibrosis, cirrhosis and liver cancer are now a public health problem. In 2002, cirrhosis accounted for 27.63% of hepatobiliary diseases in Burkina Faso. In Africa and more particularly in Burkina Faso, the majority of the population (about 80%) uses medicinal plants for their primary health care. Calotropis procera (Ait.) R.Br (Apocynaceae) is a medicinal plant used in Burkina Faso in the treatment of liver problems. This work aims to evaluate the anti-fibrotic properties of Calotropis procera roots barks. Methods: The anti-fibrotic activity of the ethanolic extract of Calotropis procera roots barks was evaluated using diethylnitrosamine (DEN) to induce liver fibrosis in male Wistar rats. Serum biomarkers, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), Total protein, Albumin, Υ-Glutamyl transferase (GGT) were evaluated and the activities of antioxidant enzymes (Superoxide dismutase and catalase) as well as the level of malonedialdehyde (MDA) and that of nitric oxide (NO) were determined in the liver homogenate. Results: The treatment of rats suffering from hepatic fibrosis with the ethanolic extract leads to a significant restoration of the biomarkers of the hepatic function in particular, AST, ALP, GGT, Albumin. The extract also causes a reduction in oxidative stress in the liver through a significant increase in the activity rate of the antioxidant enzymes Superoxide dismutase (SOD) and catalase accompanied by a significant drop in the rate of MDA and NO suggesting the anti-oxidant effect of extract. Conclusion: The results of the study show that the ethanolic extract of the roots barks of Calotropis procera has anti-fibrotic properties.
基金funded by the National Natural Science Foundation of China(Grant Nos.82204755,81960751,and 81660705)the Guangxi Young and Middle-aged Teachers’Research Ability Improvement Project(Grant No.2022KY1667)+4 种基金the Guangxi Zhuangyao Pharmaceutical Key Laboratory(Grant Nos.GXZYZZ2019-1,GXZYZZ2020-07)the Guangxi Natural Science Foundation Youth Project(Grant No.2020GXNSFBA297094)the Guangxi University of Traditional Chinese Medicine School-level Project Youth Fund(Grant No.2022QN008)Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine Research Project(2022MS008,2022QJ001)Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine,Autonomous Region-level Innovation and Entrepreneurship Training Program for College Students(S202213643016).
文摘Objective:To study the mechanism of action of Xiayuxue Tang in treating hepatic fibrosis by combining GEO data mining,network pharmacology,and molecular docking technology,and provide new research directions for the treatment of hepatic fibrosis.Method:Utilizing multiple databases,we aim to identify the relevant targets of various components in Xiayuxue Tang and their associations with hepatic fibrosis.After pinpointing the key targets through interaction analysis,we will construct both the compound-target network and the protein interaction network for Xiayuxue Tang.Conclusively,we will conduct GO and KEGG enrichment analyses on these key targets,followed by molecular docking verification.Result:Through mining the GEO database,171 related targets were identified.When combined with other databases,a total of 2,343 hepatic fibrosis-related targets were obtained.Xiayuxue Tang comprises 82 related components,which include 26 active components from rhubarb,1 from ground beetle worm,46 from peach kernels,with a total of 314 predicted targets.The GO enrichment analysis revealed 748 biological processes,32 cellular components,and 73 molecular functions,while the KEGG enrichment analysis identified 222 pathways.Molecular docking verification confirmed that effective compounds can bind stably to key proteins,exhibiting strong binding activity.This underscores the potential efficacy of Xiayuxue Tang in addressing hepatic fibrosis.Conclusion:Xiayuxue Tang exerts regulatory effects on hepatic fibrosis through different targets and pathways,suggesting that the herbal compound has the characteristics of multiple pathways and targets.
基金Supported by National Natural Science Foundation of China,No.81460301 and No.81760363Key Project of Natural Science Foundation of Ningxia,No.NZ15134
文摘AIM To investigate the value of the gamma-glutamyltraspeptidase(GGT)-to-platelet(PLT) ratio(GPR) in the diagnosis of hepatic fibrosis in patients with chronic hepatitis B(CHB). METHODS We included 390 untreated CHB patients in this study. The GPR, aspartate aminotransferase(AST)-to-PLT ratio index(APRI), and fibrosis-4(FIB-4) of all patients were analysed to determine if these parameter were correlated with age, gender, medical history, liver function [total bilirubin(TBil), alanine aminotransferase(ALT), and AST], GGT, PLT count, or hepatic fibrosis stage. The GPR, APRI, and FIB-4, as well as the combination of the GPR and APRI or the GPR and FIB-4 were assessed in different cirrhosis stages using receiver operating characteristic(ROC) curve analysis to evaluate their value in diagnosing hepatic fibrosis in CHB patients. RESULTS The GPR, APRI, and FIB-4 were not correlated withCHB patients' age, gender, or disease duration(P > 0.05), but all of these parameters were positively correlated with serum ALT, AST, GGT, and PLT count(P < 0.01). Additionally, the GPR, APRI, and FIB-4 were positively correlated with hepatic fibrosis(P < 0.01); the areas under the ROC curve for the GPR in F1, F2, F3, and F4 stages were 0.723, 0.741, 0.826, and 0.833, respectively, which were significantly higher than the respective values for the FIB-4 and APRI(F1: 0.581, 0.612; F2: 0.706, 0.711; F3: 0.73, 0.751; and F4: 0.799, 0.778). The respective diagnostic cut-off points for each stage were 0.402, 0.448, 0.548, and 0.833, respectively. The diagnostic sensitivity and specificity were, respectively, 88.8% and 87.5% in F1, 72.7% and 89.7% in F2, 81.3% and 98.6% in F3, and 80% and 97.4% in F4 when the GPR and APRI were connected in parallel; 86.6% and 90.2%, 78.4% and 96%, 78.6% and 97.4%, and 73.2% and 97.9%, respectively, when the GPR and APRI were connected in series; 80.2% and 89%, 65% and 89%, 70.3% and 98.5%, and 78.8% and 96.8%, respectively, when the GPR and FIB-4 were connected in parallel; and 83.6% and 87.9%, 76.8% and 96.6%, 72.7% and 98%, and 74.4% and 97.7%, respectively, when the GPR and FIB-4 were connected in series.CONCLUSION The GPR, as a serum diagnostic index of liver fibrosis, is more accurate, sensitive, and easy to use than the FIB-4 and APRI, and the GPR can significantly improve the sensitivity and specificity of hepatic fibrosis diagnosis in CHB when combined with the FIB-4 or APRI.
文摘Congenital hepatic fibrosis(CHF) is an autosomal recessive inherited malformation defined pathologically by a variable degree of periportal fibrosis and irregularly shaped proliferating bile ducts.It is one of the fibropolycystic diseases,which also include Caroli disease,autosomal dominant polycystic kidney disease,and autosomal recessive polycystic kidney disease. Clinically it is characterized by hepatic fibrosis,portal hypertension,and renal cystic disease.CHF is known to occur in association with a range of both inherited and non-inherited disorders,with multiorgan involvement,as a result of ductal plate malformation.Because of the similarities in the clinical picture,it is necessary to differentiate CHF from idiopathic portal hypertension and early liver cirrhosis,for which a liver biopsy is essential. Radiological tests are important for recognizing involvement of other organ systems.With regards to our experience at Hacettepe University,a total of 26 patients have been diagnosed and followed-up between 1974 and 2009 with a diagnosis of CHF.Presentation with Caroli syndrome was the most common diagnosis,with all such patients presenting with symptoms of recurrentcholangitis and symptoms related to portal hypertension. Although portal fibrosis is known to contribute to the ensuing portal hypertension,it is our belief that portal vein cavernous transformation also plays an important role in its pathogenesis.In all patients with CHF portal vein morphology should be evaluated by all means since portal vein involvement results in more severe and complicated portal hypertension.Other associations include the Joubert and Bardet-Biedl syndromes.
基金Supported by A grant from Foundation of High Level Talented Specialists of Guizhou Province,China,No. TZJF-200850a grant from Foundation of the Program for Tackling Key Problems of Guizhou Science and Technology Department,China,No. 2010GZ97666
文摘AIM:To investigate the effects of blueberry on hepatic fibrosis and NF-E2-related factor 2(Nrf2) transcription factor in rats.METHODS:Forty-five male Sprague-Dawley rats were randomly divided into control group(A);CCl4-induced hepatic fibrosis group(B);blueberry prevention group(C);Dan-shao-hua-xian capsule(DSHX) prevention group(D);and blueberry + DSHX prevention group(E).Liver fibrosis was induced in rats by subcutaneous injection of CCl4 and a high-lipid/low-protein diet for 8 wk(except the control group).The level of hyaluronic acid(HA) and alanine aminotransferase(ALT) in serum was examined.The activity of superoxide dismutase(SOD),glutathione-S-transferase(GST) and malondialdehyde(MDA) in liver homogenates was determined.The degree of hepatic fibrosis was evaluated by hematoxylin and eosin and Masson staining.Expression of Nrf2 and NADPH quinone oxidoreductase 1(Nqo1) was detected by real-time reversed transcribed-polymerase chain reaction,immunohistochemical techniques,and western blotting.RESULTS:Compared with group B,liver indices,levels of serum HA and ALT of groups C,D and E were reduced(liver indices:0.038 ± 0.008,0.036 ± 0.007,0.036 ± 0.005 vs 0.054 ± 0.009,P<0.05;HA:502.33 ± 110.57 ng/mL,524.25 ± 255.42 ng/mL,499.25 ± 198.10 ng/mL vs 828.50 ± 237.83 ng/mL,P<0.05;ALT:149.44 ± 16.51 U/L,136.88 ± 10.07 U/L,127.38 ± 11.03 U/L vs 203.25 ± 31.62 U/L,P<0.05),and SOD level was significantly higher,but MDA level was lower,in liver homogenates(SOD:1.36 ± 0.09 U/mg,1.42 ± 0.13 U/mg,1.50 ± 0.15 U/mg vs 1.08 ± 0.19 U/mg,P<0.05;MDA:0.294 ± 0.026 nmol/mg,0.285 ± 0.025 nmol/mg,0.284 ± 0.028 nmol/mg vs 0.335 ± 0.056 nmol/mg,P<0.05).Meanwhile,the stage of hepatic fibrosis was significantly weakened(P<0.05).Compared with group A,the activity of GST liver homogenates and expression levels of Nrf2 and Nqo1 in group B were elevated(P<0.05).The expression level of Nrf2 and Nqo1 in groups C,D,and E were increased as compared with group B,but the difference was not significant.CONCLUSION:Blueberry has preventive and protective effects on CCl4-induced hepatic fibrosis by reducing hepatocyte injury and lipid peroxidation.However,these effects may not be related to the activation of Nrf2 during long-term of CCl4.
基金Supported by The Major Project of Applied Basic Research Plan of the Scientific and Technological Department of Tianjin,No.06YFJZJC02900
文摘AIM:To explore the anti-fibrotic effect of Haobie Yangyin Ruanjian Decoction(HYRD)on CCl4-induced hepatic fibrosis in rats and its modulation on the transforming growth factor(TGF)β-Smad signaling pathway.METHODS:Fifty-six healthy Wistar rats were randomly divided into five groups:normal control group(n=6),CCl4-induced hepatic fibrosis group(n=14) and three treatment groups(the treated rats received HYRD via oral administration at daily dosages of 8.2,2.5 and 0.82 g/kg,respectively)of HYRD(n=12,respectively).Experimental hepatic fibrosis was induced by subcutaneous injection of carbon tetrachloride solution(CCl4 dissolved in peanut oil,4:6,V/V)with 0.5 mL/100 g body weight for the first time,and then 0.3 mL/100 g body weight twice a week for 8 wk.In the former 2 wk,rats were raised by feedstuffⅠ(80% corn meal,20%lard,0.5%cholesterol).After 2 wk,they were raised by feedstuffⅡ(corn meal and 0.5% cholesterol).Except for the control group,30%alcohol solution was given orally to each rat every other day from the beginning,1 mL for each rat.Liver function parameters and hepatic hydroxyproline content were detected by chromatometry.Serum levels of hyaluronic acid(HA),typeⅣcollagen(CIV),typeⅢprecollagen(PCⅢ)and laminin(LN)were assayed with radioimmunoassay.Deposition of collagen was observed with hematoxylin-eosin staining and collagen staining.Gene expression of TGFβ1 and Smad3 were detected with real-time reverse transcriptase-polymerase chain reaction and Western blotting,respectively.RESULTS:The serum levels of alanine transaminase and aspartate transaminase were increased in the model group compared with the control group(P<0.01),and they were decreased in the three treatment groups compared with the model group.The serum levels of total protein and albumin were decreased in the model group and increased in the three treatment groups.The hepatic hydroxyproline content and serum levels of PCⅢ,HA,LN and CIV were markedly increased in the model group compared with the control group,and decreased in the treatment groups.The gene expression of TGFβ1 and Smad3 was enhanced in the model group compared with the control group,and HYRD could down regulate their expression.CONCLUSION:HYRD can inhibit hepatic fibrosis induced by CCl4 in rats,which is probably associated with its down-regulation on fibrogenic signal transduction of TGFβ-Smad pathway.
基金Supported by National Key Technology R&D Program,No.2012BAI30B02
文摘AIM To investigate the protective effects of Foeniculum vulgare root bark(FVRB), a traditional Uyghur medicine, against carbon tetrachloride(CCl4)-induced hepatic fibrosis in mice. METHODS Mice were randomly divided into eight groups(n = 20 each). Except for the normal control group, mice in the rest groups were intraperitoneally injected(i.p.) with 0.1% CCl4-olive oil mixture at 10 m L/kg twice a week to induce liver fibrosis. After 4 wk, mice were treated concurrently with the 70% ethanol extract of FVRB(88, 176, 352 and 704 mg/kg, respectively) daily by oral gavage for 4 wk to evaluate its protective effects. Serum aspartate aminotransferase(AST), alanine aminotransferase(ALT), triglyceride(TG), hexadecenoic acid(HA), laminin(LN), glutathione(GSH), superoxide dismutase(SOD), and malondialdehyde(MDA) in liver tissues were measured. Hematoxylin-eosin(H and E) staining and Masson trichrome(MT) staining were performed to assess histopathological changes in the liver. The expression of transforming growth factor β1(TGF-β1), matrix metalloprotein 9(MMP-9) and metallopeptidase inhibitor 1(TIMP-1) was detected by immunohistochemical analysis. Additionally, TGF-β1 and alpha-smooth muscle actin(α-SMA) protein expression was measured by Western blot.RESULTS A significant reduction in serum levels of AST, ALT, TG, HA and LN was observed in the FVRB-treated groups, suggesting that FVRB displayed hepatoprotective effects. Also, the depletion of GSH, SOD, and MDA accumulation in liver tissues was suppressed by FVRB. The expression of TGF-β1, MMP-9 and TIMP-1 determined by immunohistochemistry was markedly reduced in a dose-dependent manner by FVRB treatment. Furthermore, protective effects of FVRB against CCl4-induced liver injury were confirmed by histopathological studies. Protein expression of TGF-β1 and α-SMA detected by Western blot was decreased by FVRB treatment.CONCLUSION Our results indicate that FVRB may be a promising agent against hepatic fibrosis and its possible mechanisms are inhibiting lipid peroxidation and reducing collagen formation in liver tissue of liver fibrosis mice.
基金the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine,China(Grant No.:ZYYCXTD-C-202002)the National Key Research and Development Program of China,China(Grant No.:2020YFA0908000)+1 种基金the National Natural Science Foundation of China,China(Grant Nos.:81803389,81903588,32101219,81702580,82074098,81903866,and 81803456)the Fundamental Research Funds for the Central Public Welfare Research Institutes,China(Grant Nos.:ZZ14-YQ-050,ZZ14-YQ-059,ZZ15-ND-10,ZZ15-YQ-063,ZZ14-ND-010,and ZZ14-FL-002).
文摘Hepatic stellate cells(HSCs)are essential drivers of fibrogenesis.Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis.18beta-glycyrrhetinic acid(18b-GA)is a natural compound that exists widely in herbal medicines,such as Glycyrrhiza uralensis Fisch,which is used for treating multiple liver diseases,especially in Asia.In the present study,we demonstrated that 18b-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs.18b-GA inhibited the expression of a-smooth muscle actin and collagen type Ⅰ alpha-1.Using a chemoproteomic approach derived from activity-based protein profiling,together with cellular thermal shift assay and surface plasmon resonance,we found that 18b-GA covalently targeted peroxiredoxin 1(PRDX1)and peroxiredoxin 2(PRDX2)proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities.18b-GA induced the elevation of reactive oxygen species(ROS),resulting in the apoptosis of activated HSCs.PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs.Collectively,our findings revealed the target proteins and molecular mechanisms of 18b-GA in ameliorating hepatic fibrosis,highlighting the future development of 18b-GA as a novel therapeutic drug for hepatic fibrosis.
基金grant from Shanghai Science and Technology Commission (99XD14006)
文摘Objective The present study was designed to examine whether the renin-angiotensin system would be implicated in the development of hepatic fibrosis induced by CCI4. The effects of enalapril on the ex-pression of platelet derived growth factor receptor (PDGFR) in liver tissue were also investigated. Methods 50 Sprague-Dawley rats were randomly divided into S groups (control group, model group, and 3 enalapril treated groups). Except rats of the model group, all rats received subcutanous injection of 40% CC14 (every 3d for 6 weeks). Rats of enalapril treated groups were given enalapril (10mg/kg, 5mg/kg, 2.5mg/kg per day, orally)for 6 weeks before they were killed. Serum levels of hyaluronic acid (HA) and laminin (LW) were de-termined by radioimmunoassay techniques. Van Gieson collagen staining was used to evaluate the extracellular matrix of the liver. The expressions of PDGFR and a-smooth muscle actin (a-SMA) were confirmed by im-munohistochemical methods. Results Compared with those in the model gr oup, it was found in enalapril treated groups: (1) serum levels of collagen type 1V and LN were significantly reduced (P< 0. 01); (2) the pro-gression of fibrosis was delayed (P < 0. 01); (3) the expressions of PDGFR and a-SMA were decreased. Conclusion The renin-angiotensin system was involved in the development of hepatic fibrosis induced by Cd4. Angiotensin-converting enzyme (ACE) inhibitor and enalapril could slow down the rate of hepatic fibrosis. This effect might be due to the ability of this drug in suppressing the expression of PDGFR of liver tissue.
基金Supported by National Natural Science Foundation of China,No.81870373Shanghai Hospital Development Center New Frontier Technology Joint Research Project,No.SHDC12017115and 2019 Shanghai“Innovative Action Plan of Science and Technology”Animal Research Project Guide,No.19140904301.
文摘BACKGROUND Congenital hepatic fibrosis(CHF)is a rare autosomal recessive disorder characterized by variable degrees of periportal fibrosis and malformation of bile ducts.CHF is generally accompanied by a variety of conditions or syndromes with other organ involvement.CASE SUMMARY We report a 5-year-4-month-old Chinese boy with congenital hypothyroidism(CH)diagnosed with CHF.The patient was diagnosed with CH by a newborn screening test and has since been taking levothyroxine.He has developed normally without neurocognitive deficits.Abnormal liver function was observed in the patient at the age of 4 years and 11 mo,and elevated levels of liver function indices were persistent for 5 mo.Radiological imaging indicated hepatosplenomegaly without narrowing of the portal vein but dilated splenic vein.A liver biopsy confirmed the pathological features of CHF.Genetic testing revealed two novel homozygous mutations,namely,c.2141-3T>C variant in PKHD1 related to CHF and c.2921G>A(p.R974H)in DUOX2 related to CH.The patient was treated with compound glycyrrhizin tablet,ursodeoxycholic acid,and levothyroxine after diagnosis.The patient achieved a favorable clinical outcome during a follow-up period of over 2 years.CONCLUSION Herein,we report the first case of a Chinese boy with comorbidity of CHF and CH,carrying both PKHD1 gene and DUOX2 gene novel mutations.Liver biopsy and genetic testing should be considered for the diagnosis of coexistent liver disease in CH patients with unexplained abnormal liver function.
文摘Congenital hepatic fibrosis is part of many different malformation syndromes, of which oculo-encephalohepato-renal syndrome is the most common. These syndromes largely overlap, and so accurate classification of individual patients may be difficult. We present herein three syndromic siblings who were products of a consanguineous marriage. We investigated in detail at least six organ systems in these patients, namely the liver, brain, eye, kidneys, skeleton, and gonads. The common features observed in these three cases were congenital hepatic fibrosis, retinitis pigmentosa, truncal obesity, rotatory nystagmus, mental retardation, advanced myopia, and high-arched palate. The clinical dysmorphology in these patients was distinct and lacked the major features of the known syndromes associated with congenital hepatic fibrosis. Although some features of these presented cases are similar to those found in Bardet-Biedl syndrome(BBS), the absence of some major criteria of BBS(polydactyly, renal abnormality, and hypogonadism) suggests that this may be a new syndrome. All three patients remain under follow-up in the departments of Gastroenterology, Ophthalmology, and Neurology at Hacettepe University.
基金National Natural Science Foundation of China(81960761,81960751,81902764).
文摘Hepatic sinusoidal endothelial cell is a highly differentiated cell in hepatic sinusoid,and plays an important role in the occurrence and development of hepatic fibrosis.The dysfunction of hepatic sinusoidal endothelial cells is considered to be the key cause of a variety of liver diseases.At present,the researches on hepatic fibrosis at home and abroad are mainly focused on inhibiting the activation of hepatic stellate cells and accelerating the hydrolysis of extracellular matrix.However,there are few studies on the important role of the structure and function of hepatic sinusoidal endothelial cells in hepatic fibrosis.This paper reviews the research progress on the effect of hepatic sinusoidal endothelial cells on hepatic fibrosis and its regulatory mechanism in recent years.This paper summarizes the results of the research on the structural characteristics of hepatic sinusoidal endothelial cells,secretion of fibrosis-related cytokines and regulation of hepatic stellate cells activation in the development of hepatic fibrosis.
基金Youth project of national natural science foundation of China(No.81603578,81503536))General project of Jiangsu provincial natural science foundation(No.BK20181235)
文摘Objective Toinvestigate the diagnostic value of hepatic fibrosis parameter model and elastic modulus of liver and spleen in hepatic fibrosis of chronic hepatitis b.Methods 77 patients with hepatic fibrosis of chronic hepatitis in the infection clinic were recruited from July 2016 to December 2018.According to the classification of hepatic fibrosis,23 patients were classified as S1,20 as S2,18 as S3 and 16 as S4.The serum indexes of liver function in all patients were tested,FIB-4,APRI and GPR model indexes were calculated.SWE values of liver and spleen were evaluated,and the correlation between FIB-4,APRI,GPR and SWE was analyzed.Results The SWE values of liver and spleen in the study group were significantly higher than those in the normal group(P<0.01),and the differences in serum GGT,PLT,AST and portal vein velocity between the two groups were statistically significant(P<0.01).GGT and PLT were correlated with SWE values of liver and spleen,which were statistically significant(P<0.01).The model indexes of fib-4,APRI and GPR in the study group were all higher than those in the normal group,with statistically significant differences(P<0.01).Pearson correlation analysis showed that liver SWE value and spleen SWE value were positively correlated with fib-4,APRI and GPR,and the differences were significant(P<0.01),with a higher correlation with GPR.Conclusion GGT,PLT and GPR are positively correlated with SWE of liver and spleen,and combined detection can improve the early diagnosis accuracy of liver fibrosis.
基金General program of national natural science foundation of China(No.81774236)Innovation research team project of science and technology department,Guangxi Zhuang autonomous region(No.2018GXNSFGA281002)Graduate education innovation project of Guangxi Zhuang autonomous region(No.YCSY201900117)。
文摘Hepatic fibrosis(HF)is the common pathological basis of all chronic liver diseases,and is a necessary stage for the development of chronic liver disease into cirrhosis.The pathogenesis of liver fibrosis is very complicated.Different cells and cytokines play a major role in the pathogenesis of liver fibrosis.This article focuses on the development mechanism of liver fibrosis,different cells and cytokines(macrophages,natural killer cells,natural killer T cells,tumor necrosis factor,IL-22,transforming growth factor-β,connective tissue growth factor,vascular endothelial growth factor)Its impact on the development of liver fibrosis is reviewed.
基金Supported by National Natural Science Foundation of China(82160867)。
文摘Hepatic fibrosis is a necessary stage in the development of chronic liver disease to cirrhosis.Western medicine drug treatment takes etiological treatment,symptomatic treatment and anti-fibrosis treatment as the main means and aims to protect the liver and improve hepatic function while there are many adverse reactions after long-term administration.However,Dai medicine mainly focuses on balancing the four towers and five aggregates,and regulating the"three plates".Hence it has slight side effects and is safe and effective.Therefore,this paper reviewed the current status of Dai and Western medicine in the treatment of hepatic fibrosis,in order to provide reference for clinical medication.
文摘Hepatic fibrosis/cirrhosis is a significant health burden worldwide,resulting in liver failure or hepatocellular carcinoma(HCC)and accounting for many deaths each year.The pathogenesis of hepatic fibrosis/cirrhosis is very complex,which makes treatment challenging.Endogenous mesenchymal stromal cells(MsCs)have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis.Paradoxically,exogenous MsCs have also been used in clinical trials for liver cirrhosis,and their effectiveness has been observed in most completed clinical trials.There are still many issues to be resolved to promote the use of MsCs in the clinic in the future.In this review,we will examine the controversial role of MsCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis.We also investigated the clinical trials involving MsCs in liver cirrhosis,summarized the parameters that need to be standardized,and discussed how to promote the use of MsCs from a clinical perspective.
基金supported by the National Natural Science Foundation of China(81973336)the Joint Fund of the National Natural Science Foundation of China(U21A20345)。
文摘The mesencephalic astrocyte-derived neurotrophic factor(MANF)has been recently identified as a neurotrophic factor,but its role in hepatic fibrosis is unknown.Here,we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl4.MANF deficiency in either hepatocytes or hepatic mono-macrophages,particularly in hepatic mono-macrophages,clearly exacerbated hepatic fibrosis.Myeloid-specific MANF knockout increased the population of hepatic Ly6C^(high)macrophages and promoted HSCs activation.Furthermore,MANF-sufficient macrophages(from WT mice)transfusion ameliorated CCl4-induced hepatic fibrosis in myeloid cells-specific MANF knockout(MKO)mice.Mechanistically,MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation.Pharmacologically,systemic administration of recombinant human MANF significantly alleviated CCl_(4)-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout(HKO)mice.This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a“brake”on the upstream of NF-κB pathway,which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.
基金Major Project of Shanghai Municipal S and T Commission,Grant/Award Number:19401972300Shandong Province Key R&D Program(Major Science and Technology Innovation Project),Grant/Award Number:2021CXGC010509+2 种基金Shanghai Key Laboratory of Traditional Chinese Clinical Medicine,Key Disciplines of Liver and Gall Bladder Diseases,Key Laboratory of Chronic Deficiency Liver Disease of the State Administration of Traditional Chinese Medicine of the People's Republic of China,Grant/Award Number:20DZ2272200Shanghai Key Specialty of Traditional Chinese Clinical Medicine,Grant/Award Number:shslczdzk01201Outstanding TCM reserve talents of Shanghai University of Traditional Chinese Medicine(2020)。
文摘Liver cirrhosis is a leading cause of death from liver‐related diseases accompanied by a variety of complications;however,hepatic fibrosis,an inevitable stage of cirrhosis,is possible to be reversed and cured.Hepatic stellate cells(HSCs)are the primary cells that secrete extracellular matrix in the liver and play a dominant role in the pathogenesis of hepatic fibrosis.Effective therapeutic approaches for reversing hepatic fibrosis aim at inhibiting the activation of HSCs and inducing their inactivation or death.This review highlights the mechanism by which traditional Chinese medicine(TCM)regulates the activity of HSCs and exerts antifibrotic effects,providing insights and prospects for the treatment of hepatic fibrosis with TCM.
基金supported by the National Key Research and Development Program of China (2020YFA0908000)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202002,China)+1 种基金the National Natural Science Foundation of China(81903588,81803456,82074098 and 81841001,China)the Fundamental Research Funds for the Central Public Welfare Research Institutes (ZXKT18003 and ZZ15-YQ-063,China)。
文摘Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron-and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfordii, shows effective anti-fibrotic and anti-inflammatory activities in multiple hepatic diseases. However, the exact molecular mechanisms of action and the direct protein targets of celastrol in the treatment of liver fibrosis remain largely elusive. Here, we discover that celastrol exerts anti-fibrotic effects via promoting the production of reactive oxygen species(ROS) and inducing ferroptosis in activated hepatic stellate cells(HSCs). By using activity-based protein profiling(ABPP) in combination with bio-orthogonal click chemistry reaction and cellular thermal shift assay(CETSA), we show that celastrol directly binds to peroxiredoxins(PRDXs), including PRDX1, PRDX2, PRDX4 and PRDX6,through the active cysteine sites, and inhibits their anti-oxidant activities. Celastrol also targets to heme oxygenase 1(HO-1) and upregulates its expression in activated-HSCs. Knockdown of PRDX1, PRDX2,PRDX4, PRDX6 or HO-1 in HSCs, to varying extent, elevated cellular ROS levels and induced ferroptosis. Taken together, our findings reveal the direct protein targets and molecular mechanisms via which celastrol ameliorates hepatic fibrosis, thus supporting the further development of celastrol as a promising therapeutic agent for liver fibrosis.