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Objective To investigate the effect of liver CD8 + T lymphocytes on co-cultured hepatic stellate cells (HSCs) after the application of Fuzheng Huayu prescription in a moues model of acute liver injury, as well as the mechanism of action of Fuzheng Huayu prescription in preventing liver fibrosis. Methods A total of 18 specific pathogen-free male C57BL/6NCrl Vr mice were randomly divided into normal group, model group, and Fuzheng Huayu prescription group, with 6 mice in each group. The mice in the Fuzheng Huayu prescription group were given Fuzheng Huayu prescription for 5 days in advance. At 12 hours before the experiment, 10% CCl 4 was injected intraperitoneally at a dose of 2 mL/kg body weight. Blood was collected from the main abdominal vein, and the serum was separated to measure the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Part of the liver was used for pathological observation. After the mice were pretreated with medication in vivo, flow cytometry was used for the sorting of mouse liver CD8 + T lymphocytes, which were then co-cultured with the mouse HSC cell line (JS 1) in a 96-well plate at a ratio of 2∶ 1, and after co-culture for 24 and 48 hours, qPCR was used to measure the changes in the mRNA expression of Col.I and α-SMA. An analysis of variance was used for comparison of normally distributed continuous data between multiple groups, and the SNK- q test or the least significant difference t -test was used for further comparison between two groups. Results The model group had significantly higher activities of ALT and AST than the normal group (both P < 0.000 1), and compared with the model group, the Fuzheng Huayu prescription group had a significantly lower degree of increase in ALT activity ( P < 0.001). HE staining showed that the Fuzheng Huayu prescription group had a significantly lower degree of hepatocyte degeneration and necrosis compared with the model group. Compared with the normal group, the total lymphocytes, CD45, CD4 - CD8 + T and CD8 + CD28 - T in the model group increased significantly, while the proportion of the above lymphocytes in the Fuzheng Huayu formula group decreased significantly compared with the model group ( P < 0.001). CD8 + T lymphocytes isolated from the liver of mice in each group were co-cultured with JS 1 for 48 hours, and compared with the control group (JS 1 cultured alone) and the normal group, the model group had a significant increase in the mRNA expression of α-SMA (both P < 0.01) and significantly higher mRNA expression of Col.I than the control group and the normal group (normal mouse liver CD8 + T lymphocytes co-cultured with JS 1) (both P < 0.001). The Fuzheng Huayu prescription group had significantly lower mRNA expression levels of α-SMA and Col.I than the model group (both P < 0.01). Conclusion Fuzheng Huayu prescription can indirectly inhibit activated HSCs by altering the functional phenotype of CD8 + T lymphocytes in mouse liver.
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ObjectiveTo investigate the efficacy and safety of Fuzheng Huayu tablets (FZHY) combined with entecavir (ETV) in the treatment of chronic hepatitis B (CHB) liver fibrosis. MethodsA total of 52 patients with CHB liver fibrosis with an Ishak stage of ≥F3 who were treated in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine and Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from April 2011 to January 2013 were enrolled and divided into FZHY combined with ETV group (combination group) and placebo combined with ETV group (control group), with 26 patients in each group, and the course of treatment was 48 weeks for both groups. Liver biopsy was performed before and after these treatment; clinical outcome was determined based on the reversal rate of Ishak stage for liver fibrosis and the improvement rate of histological activity index (HAI) for inflammation grade, and safety was evaluated based on electrocardiographic findings. Three datasets (full analysis set, per-protocol set, and safety dataset) were identified for analysis; the t-test or the Wilcoxon test was used for comparison of continuous data between two groups, and the CMH chi-square test, the chi-square test, or the Fisher’s exact test was used for comparison of categorical data between groups. ResultsOf all 52 patients, 46 underwent the two liver biopsies before and after treatment, with 22 in the combination group and 24 in the control group. At week 48 of treatment, there was a significant difference in the proportion of patients with Ishak stage reduced by ≥1 stage between the combination group and the control group (81.8% vs 54.2%, χ2=5.297, P=0.021). There was also a significant difference in the improvement rate of HAI grade between the combination group and the control group were (59.1% vs 25.0%, χ2=6.822, P=0.009). There were no significant differences between the two groups in the incidence rates of adverse events and serious adverse events, the safety analysis of vital signs, and laboratory safety indicators (all P＞0.05). ConclusionFZHY combined with ETV has significant advantages over ETV alone in improving liver fibrosis and inflammation, and antiviral therapy combined with anti-fibrosis therapy can bring better hepatic histological improvement for CHB patients. FZHY combined with ETV has good safety in the treatment of patients with CHB liver fibrosis.
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Portal vein thrombosis refers to the formation of a thrombus in the trunk of the portal vein and /or its branches due to various causes, and is one of the common complications of cirrhosis. Synthesizing the existing evidence, this paper summaries the cirrhosis with portal vein thrombosis in terms of epidemiology, etiology, pathophysiology, risk factors, definition and classification, clinical manifestations and complications, diagnosis and screening, treatment, follow-up and prognosis, prospects and problems.
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Objective@#To determine whether the anti-hepatic fibrosis effect of Fuzheng-Huayu formula is related to suppress autophagy in mice.@*Methods@#C57 mice were randomly divided into normal group (N group) and model group. The model group was induced by intraperitoneal injection of carbon tetrachloride to induce liver fibrosis in mice, and the normal group was injected with equal volume of olive oil. After 1 week, the model group was randomly divided into model (M) group, rapamycin (Rapa) group, rapamycin plus chloroquine (Rapa+CQ) group, rapamycin plus salvianolic acid B (Rapa+Sal B) group, rapamycin plus Fuzheng -Huayu formula (Rapa+FZ) group. Each drug group was administered corresponding drugs by gavage on a daily basis, and N group and M group were given the equal amount of drinking water by gavage. After 5 weeks, the mice were sacrificed, and HE and Sirius red staining were used to observe the inflammation and collagen deposition on liver tissue in each group. The hydroxyproline content was determined by alkaline hydrolysis method. Western blotting was used to detect changes in the expression of autophagy in liver tissue and microtubule-associated protein 1 light chain 3II/I (LC3II/I), p62, α-smooth muscle actin (ɑ-SMA) and type I collagen expression. Immunofluorescence staining was used to observe the immunofluorescence localization of ɑ-SMA and LC3B in liver tissues of each group. ). A t-test was used to compare the two independent samples. LSD or Dunnett’s T3 test were used to compare the mean of multiple samples.@*Results@#There was no significant difference in N and M groups in terms of body weight. The body weight of the mice in each drug group decreased significantly (F = 14.041, P < 0.001). The liver/spleen /body weight ratios of each drug group and M group were significantly higher than the N group (F = 26.992, 6.589, P < 0.001). The expression of p62 protein in the liver tissue of mice in each drug group was lower than M group, and the difference between Rapa group and Rapa+Sal B group (F = 3.085, P = 0.039, 0.003) was statistically significant, while that of Rapa + Sal B group was lower. Compared with group M, the expression of LC3B II in Rapa group was significantly higher (F = 7.514, P = 0.01). Immunofluorescence staining showed that LC3B and α-SMA CO-stained cells were absent in the liver of mice in N group, and co-stained cells were found in the liver of mice in M group. The co-stained cells in the liver of mice in each drug group were significantly higher than M group, and the co-stained cells in Rapa+FZ group were fewer. Compared with the N group, the collagen deposition of M group and each drug group was significantly increased; the collagen deposition of each drug group was lower than that of the M group. There was no statistically significant difference between each drug group. Compared with N group (77.75 + 48.79), hydroxyproline in liver tissue of mice in M group was significantly increased (293.48 + 84.43) (F = 3.015, P = 0.005), and the content of hydroxyproline in liver tissue of mice in each drug group was lower than M group, but the difference was not statistically significant (F = 0.750, P = 0.573). Compared with the N group, the expressions of α-SMA and type I collagen in the M group were significantly increased (F = 27.718, 18.893, P < 0.01). The expression of α-SMA in Rapa group and Rapa+Sal B group was similar to M group, while Rapa + CQ group and Rapa + FZ group were significantly lower than Rapa group and M group (P < 0.01). The expression of type I collagen in Rapa + CQ group was significantly higher than Rapa group (P = 0.017), while the expression of type I collagen in Rapa + FZ group was significantly lower than M group (P = 0.013).@*Conclusion@#Autophagy of hepatic stellate cells was observed in carbon tetrachloride-induced liver fibrosis model. Rapamycin can promote autophagy in hepatocytes and hepatic stellate cells. Fuzheng-Huayu formula and Salvianolic Acid B might antagonize the effect of rapamycin on autophagy.
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Liver fibrosis has a complex pathogenesis, and at present, the research mainly focuses on hepatic stellate cells (HSC). Many stimulating factors and regulatory pathways have been found to promote the activation of HSC. This article reviews the recent research findings on several major cytokines and peroxisome proliferator-activated receptor γ and research hotspots in recent years, including the association of microRNAs, long non-coding RNA, and exosomes with HSC activation. This article also introduces potential targets for the treatment of liver fibrosis and new markers for noninvasive diagnosis of liver diseases and proposes that chemical drugs or traditional Chinese medicine compounds which act on the targets of HSC activation can be formulated, in order to make a breakthrough in the therapeutics of liver fibrosis.
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Liver fibrosis has a complex pathogenesis, and at present, the research mainly focuses on hepatic stellate cells (HSC). Many stimulating factors and regulatory pathways have been found to promote the activation of HSC. This article reviews the recent research findings on several major cytokines and peroxisome proliferator-activated receptor γ and research hotspots in recent years, including the association of microRNAs, long non-coding RNA, and exosomes with HSC activation. This article also introduces potential targets for the treatment of liver fibrosis and new markers for noninvasive diagnosis of liver diseases and proposes that chemical drugs or traditional Chinese medicine compounds which act on the targets of HSC activation can be formulated, in order to make a breakthrough in the therapeutics of liver fibrosis.
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Objective@#To investigate the effect of Fuzheng Huayu capsules on the survival rate of patients with liver cirrhosis.@*Methods@#A retrospective analysis was performed for the clinical data of the patients with various types of liver cirrhosis who were hospitalized in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from January 1, 2006 to December 31, 2008. The data collected for these patients included their basic information, diagnosis and treatment, and results of laboratory examination. The Kaplan-Meier method was used to analyze the effect of Fuzheng Huayu capsules on the survival rate of patients with liver cancer. The starting point of observation was the first day of the patient’s admission and the ending point of follow-up observation was the date of death or the end of follow-up April 1, 2014. The cut-off value was obtained if the patient did not experience any outcome event (death) at the end of follow-up. With reference to the outcome, the time when the outcome occurred, and the cut-off value, the life-table method was used to calculate survival rates and survival curves were plotted. The Kaplan-Meier product-limit method was used to calculate the arithmetic mean of survival time and median survival time, and the log-rank test was used to compare the survival data.@*Results@#A total of 430 patients with liver cirrhosis were enrolled, among whom 191 died and 239 survived or were censored. The average constituent ratio of death was 55.6% and the average constituent ratio of survival was 44.4%. The life-table method showed that the half-, 1-, 2-, and 5-year survival rates were 70%, 64%, 58%, and 48%, respectively. The median survival time was 112.1 weeks for the patients who did not take Fuzheng Huayu capsules and 351.6 weeks for those who did, and there was a significant difference in survival rate between the two groups (P = 0.000). Among 313 patients who had an etiology of hepatitis B, 164 did not take Fuzheng Huayu capsules and had a median survival time of 195.9 weeks and a 5-year survival rate of 44%, and 149 took Fuzheng Huayu capsules and had a median survival time of 336.9 weeks and a 5-year survival rate of 59%; there was a significant difference in survival rate between the two groups (P = 0.038). Among 117 patients who did not have hepatitis B, 68 did not take Fuzheng Huayu capsules and had a median survival time of 78.1 weeks and a 5-year survival rate of 32%, and 49 took Fuzheng Huayu capsules and had a median survival time of 277.4 weeks and a 5-year survival rate of 53%; there was a significant difference in survival rate between the two groups (P = 0.013). Among 92 patients with compensated liver cirrhosis, 47 did not take Fuzheng Huayu capsules and had a 5-year survival rate of 65%, and 45 took Fuzheng Huayu capsules and had a 5-year survival rate of 82%; both groups of patients had a median survival of 440 weeks; there was a significant difference in survival rate between the two groups (P = 0.027). Among 338 patients with decompensated liver cirrhosis, 185 did not take Fuzheng Huayu capsules and had a median survival time of 60.3 weeks and a 5-year survival rate of 33%, and 153 took Fuzheng Huayu capsules and had a median survival time of 267.7 weeks and a 5-year survival rate of 51%; there was a significant difference in survival rate between the two groups (P = 0.001).@*Conclusion@#Fuzheng Huayu capsules can improve the prognosis of patients with liver cirrhosis and increase their survival rates and have good long-term efficacy.
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In recent years, many studies have been conducted on liver fibrosis. This article introduces the latest advances in the pathogenesis, diagnosis, and treatment of liver fibrosis. There is still a long way to go for the research on anti-fibrosis therapy, and this difficult problem will finally be solved with the help of further studies.
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China has become one of the leading counties in the world to treat hepatic fibrosis with Chinese patent drugs.The therapeutic effect of traditional Chinese medicine (TCM) should be evalvated from the aspects of short-term therapeutic effect,long-term therapeutic effect,and effect of relief of symptoms.This article introduces the results of our exploration of the application of liver stiffness measurement to evaluate therapeutic effect,five-year survival rate to assess]ong-term therapeutic effect,and a TCM syndrome scale to evaluate effect of relief of symptoms,suggesting that the Chinese patent drug Fuzheng Huayu capsules/tablets have a marked clinical effect in the treatment of hepatic fibrosis.It is recommended to use serological diagnostic models,conduct prospective studies with long-term follow-up,and analyze the samples and data accumulated over a long period of time,in order to perfect the methods for evaluating the outcome of hepatic fibrosis.
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Autophagy is a highly conservative cellular process in eukaryotes that plays an important role in nutrition and energy metabolism in the liver. It can promote the autophagy of hepatocytes and protect the hepatocytes against the adverse external stimulation, but excessive autophagy can cause autophagic cell death of hepatocytes. Hepatic stellate cells (HSC) play an important role in the development and progression of liver fibrosis. Autophagy can provide energy for their activation, but may also lead to their death. This article introduces the relationship of autophagy with hepatocytes/HSC and the mitogen-activated protein kinase pathway, and points out that in-depth studies on the relationship between autophagy and pathway regulation during liver fibrosis can provide new targets for developing antifibrotic drugs.
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Vitamin D is mainly produced in the liver, and chronic liver injury caused by various reasons will affect the metabolism of vitamin D, lead to vitamin D deficiency, and accelerate disease progression. Recent studies have confirmed that in patients with liver cirrhosis, the degree of vitamin D deficiency is closely associated with the severity and complications of liver cirrhosis. This article introduces the role of vitamin D and vitamin D receptor in the evaluation and treatment of liver cirrhosis and points out that vitamin D helps to evaluate the severity of liver cirrhosis and may become a new point and an important drug for the treatment of liver cirrhosis.
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<p><b>OBJECTIVE</b>To investigate the effects of salvianolic acid B (Sal B) on endothelin-1 (ET1)-induced contraction and cytoskeleton reorganization of rat hepatic stellate cells (HSCs).</p><p><b>METHODS</b>HSCs were collected from Sprague-Dawley rats by in situ perfusion with pronase E and isolated by density-gradient centrifugation with Nycodenz. Cells were treated with ET-1, with or without Sal B or Y-27632 (a specific inhibitor of rho-associated protein kinases) pretreatment. HSC contraction was evaluated by collagen gel contraction assay. Cytoskeletal reorganization in response to ET-1 was evaluated by detecting changes in phosphorylation of myosin light chain 2 (MLC2) using glycerol-urea PAGE and the Odyssey Infrared Imaging System. Changes in actin stress fiber polymerization were detected by FITC-labeled phalloidin. Differences between the various cell treatment/pretreatment groups were statistically analyzed.</p><p><b>RESULTS</b>Compared to the untreated control cells, the lattice area of ET-1-treated cells showed significant shrinkage (76.89% ± 3.84% vs. 37.10% ± 5.10%; P less than 0.01). Pretreatment with 105 M Sal B or 105 M Y-27632 significantly reduced ET-1-induced contraction (67.01% ± 4.14% and 77.28% ± 2.00%, respectively; bothP less than 0.01 vs. the ET-1-treated cells). The untreated control cells showed a basal MLC2 phosphorylation of (0.35 ± 0.05) mol PO4/mol MLC2. In contrast, ET-1 treatment elicited a rapid and sustained MLC2 phosphorylation, which was (0.87 ± 0.04) mol PO₄/mol MLC2 at 5 min post-treatment and with the maximal level of (0.96 ± 0.04) mol PO₄/mol MLC2 detected at 30 min post-treatment. The Sal B pretreatment led to a significant decrease in ET-1-induced MLC2 phosphorylation (by 63.1%) and an obvious disassembly of actin stress fibers.</p><p><b>CONCLUSION</b>Sal B effectively inhibits ET-1-induced rat HSC contraction, through its suppressive effects on MLC2 phosphorylation and promotion of the disassembly of actin stress fibers.</p>
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Animals , Male , Rats , Actins , Metabolism , Benzofurans , Pharmacology , Cardiac Myosins , Metabolism , Cell Shape , Cells, Cultured , Cytoskeleton , Endothelin-1 , Pharmacology , Hepatic Stellate Cells , Cell Biology , Myosin Light Chains , Metabolism , Phosphorylation , Rats, Sprague-DawleyABSTRACT
<p><b>OBJECTIVE</b>To evaluate the efficacy of Fuzhenghuayu capsule for the prevention of oesophageal variceal bleeding in patients with liver cirrhosis.</p><p><b>METHODS</b>A multicentre randomized placebo-controlled trial was conducted. A total of 181 liver cirrhosis patients were enrolled in the study and randomly assigned to different groups according to the level of oesophageal variceal bleeding. Patients with light oesophageal varices received Fuzhenghuayu capsule or a placebo. Patients with medium to heavy oesophageal varices received either Fuzhenghuayu capsule alone, Fuzhenghuayu capsule plus propranolol, or propranolol plus a placebo. Patients with a history of oesophageal variceal bleeding received either Fuzhenghuayu capsule plus propranolol, propranolol alone, or a placebo. For all patients, the treatment lasted 2 years. The primary end point of the study was oesophageal variceal bleeding. The secondary end points were liver cancer, death by any cause, and liver transplantation. Risk of bleeding and survival were statistically assessed.</p><p><b>RESULTS</b>The median follow-up time was 50 months. The patients with small oesophageal varices who were treated with Fuzhenghuayu capsule showed a significantly higher cumulative probability of bleeding than their counterparts treated with the placebo (3.4% vs. 23.7%, x² = 4.829, P =0.028). The patients with medium to heavy oesophageal varices and no history of oesophageal variceal bleeding who were treated with Fuzhenghuayu capsule plus propranolol showed a remarkably higher cumulative probability of bleeding than their counterparts treated with propranolol alone (15.2% vs. 43.6%, x² =6.166, P =0.013). There were no significant differences between the patients treated with Fuzhenghuayu capsule alone and those treated with propranolol alone (P =0.147) or the patients treated with Fuzhenghuayu capsule plus propranolol and those treated with Fuzhenghuayu capsule alone (P =0.147). The patients with history of oesophageal variceal bleeding who were treated with Fuzhenghuayu capsule showed significantly higher cumulative probability of bleeding and median time of bleeding than their counterparts treated with propranolol alone (44.0% vs. 24.2% and 40.00 ± 17.92 months vs. 7.00 ± 2.35 months; x² = 4.433, P =0.035). There were no significant differences in the cumulative probability of liver cancer and survival among all of the groups.</p><p><b>CONCLUSION</b>Fuzhenghuayu capsule can decrease the cumulative probability of bleeding in cirrhotic patients with light oesophageal varices. For cirrhosis patients with a history of oesophageal variceal bleeding, the combination of Fuzhenghuayu capsule plus propranolol can decrease the cumulative probability of bleeding with median or heavy varices.</p>
Subject(s)
Adult , Female , Humans , Male , Middle Aged , Double-Blind Method , Drugs, Chinese Herbal , Therapeutic Uses , Esophageal and Gastric Varices , Gastrointestinal Hemorrhage , Liver Cirrhosis , Drug Therapy , Phytotherapy , Prospective Studies , Treatment OutcomeABSTRACT
Traditional Chinese medicine (TCM) is commonly used in treating liver diseases worldwide, especially in China. The advantages of using TCM for treatment of liver diseases include: protecting hepatocytes, inhibiting hepatic inflammation and antifibrosis in the liver. In this article, we introduce TCM herbal preparations from the Chinese materia medica (such as Fuzheng Huayu) that are typically used for the treatment of liver diseases. Literature surrounding the mechanisms of TCM therapy for treatment of liver diseases is presented and discussed. We propose that side effects of herbal compounds are often under-appreciated, and that more care should be taken in the prescription of potentially hepatotoxic medicines. Further, to deepen the understanding of TCM mechanisms, new techniques and methodologies must be developed. Future studies will lead to the enhancement of clinical outcomes of TCM. As complementary and alternative therapies, TCMs will play an expanding role in the future of liver disease treatment.
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To investigate the effects of salvianolic acid B (SA-B) on extracellular signal-regulated kinase (ERK) signal transduction pathway activated by transforming growth factor-β1 (TGF-β1) in rat hepatic stellate cells (HSCs).
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To evaluate the effects of Xiayuxue Decoction, a compound traditional Chinese medicine, on liver angiogenesis in rats with carbon tetrachloride (CCl(4))-induced liver fibrosis.
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Objective The therapeutic effect of epigallocatechin-3-gallate (EGCG) on the collageninduced arthritis model (CIA) was observed and its immunological mechanism was analyzed. Methods EGCG was administered to CIA mice and PBS was admitted as negative control. The severity of CIA was evaluated by clinical scores and histopathological assessment (H-E staining). Immunological mechanisms inv-suppressive effect on IL-17 secretion of CD4+T cells (EGCG group: 0.41%; PBS group: 4.05% ) and inhibitive activity of C Ⅱ -reactive splenocytes proliferation. There was statistical significant difference between IKB expression and down-regulate phosphorylated IKB expression in lymph node cells of CIA mice.Conclusion EGCG can significantly ameliorate the severity of CIA. The therapeutic mechanisms may be related to inhibition of C Ⅱ -reactive splenocyte proliferation and IL-17 secretion and via inhibiting the activity of NF-κB by inducing the expression of IKB and by suppressing the expression of phosphorylated IKB in CIA mice.
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To observe the effects of Salviae miltiorrhizae and its component, salvianolic acid B (SA-B), on the microcirculation of liver in mice with portal hypertension induced by endothelin-1 (ET-1).
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Objective To investigate the effect of DSG biologic information infrared liver disease therapy instrument(BILT liver disease therapy instrument)on liver microcirculations in mice.Methods Liver fibrosis was induced in 40 SPF mice which were randomized into 4 groups:without irradiation group,coht light irradiation group,infrared light irradiation group and BILT group(10 in each group).Twenty healthy mice were taken as the control.Liver blood flow of each group was observed by laser-Doppler flow instrument,and blood flow rate of liver microcirculation in each group was observed by intravital microscopy.Pathological examination and serum biochemistry were also performed.Results In fibrosis mice,the liver blood flow in average of BIUF group Was higher than that of without irradiation group(P=0.004),while comparing with without irradiation group there were no significant differences in liver blood flows of the cold light irradiation group and infrared light irradiation group(P=0.713 and 0.465).Red blood cell velocity of microvessels in average of the healthy group(without irradiation)wag higher than that in the without irradiation group offibrosis mice(P=0.001),and it in the BILT group(fibrosis mice)Was also higher than those in other groups of fibrosis mice(P=0.004,0.020 and 0.030).For fibrosis mice,the average AST in BILT group was lower than that in the without irradiation group(P=0.027),and the difference in hydroxyproline(Hyp)levels between the groups was not of statistical significance(P=0.433).Conclusion BILT liver disease therapy instrument can improve the liver microcir-culation,reduce AST level and improve liver pathological state in mouse with fibrosis.
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To study the effects of Cordyceps mycelia extract (CME) on portal hypertension in rats with dimethylnitrosamine (DMN) induced liver cirrhosis and probe into the mechanism of the action.