Comparative analysis of clinical diagnosis and treatment guidelines for drug-induced liver injury at home and abroad / 中华肝脏病杂志

Drug-induced liver injury influencing factors are complex and have diverse clinical manifestations. Simple and reliable diagnostic methods are still deficient, and further classification of toxicological mechanisms is required. There are numerous pertinent discrepancies between domestic and international guidelines aimed at drug-induced liver injury diagnosis and treatment, with partial to no consensus on the content. The American Gastroenterological Association's 2021 Clinical Guidelines, the Asia-Pacific Association for the Study of the Liver's 2021 Consensus Guidelines, the Council for International Organizations of Medical Sciences' 2020 International Consensus, the European Society's Hepatology Committee's 2019 Clinical Practice Guidelines, and the 2015 Chinese Medical Association Guidelines are five influential clinical guidelines on drug-induced liver injury at home and abroad. The epidemiology, risk factors, diagnosis and evaluation, treatment management, and other contents, particularly traditional Chinese medicine, were compared and analyzed using other relevant consensus opinions or guidelines in order to improve understanding and provide a reference for clinical diagnosis and treatment of drug-induced liver injury.

Efficacy of Fuzheng Huayu Tablets for Treating Pulmonary Inflammation in COVID-19 Patients / 中国实验方剂学杂志

ObjectiveTo observe the efficacy and safety of Fuzheng Huayu tablets （FHT） for treating pulmonary inflammation in patients with coronavirus disease 2019 （COVID-19）. MethodA total of 70（4 cases were lost to follow-up, and 66 cases were finally completed） COVID-19 patients were recruited from February 1 to April 15 in 2020. They were assigned to a control group （35 patients） and a FHT group （31 patients）. The patients in the control group received routine treatment alone and those in the FHT group received FHT in addition to routine treatment. The primary outcome was the ratio of patients showing improvement in chest computed tomographic manifestations after 14 days. The secondary outcome measures included remission rate or progression rate of critical illness， clinical remission rate of respiratory symptoms， routine blood examination， C-reactive protein （CPR） level， procalcitonin （PCT） level， and blood oxygen saturation （SPO2）. The safety was assessed based on liver and kidney functions and adverse events. ResultAfter the 14-day treatment， the ratio of patients showing improvement in the FHT group （100%） was higher than that in the control group （77.1%） （χ2=8.063，P<0.01）. The ratio of disease stages after treatment showed no significant difference between two groups. In the FHT group， the symptoms including cough， dyspnea， and fatigue were alleviated after treatment （P<0.01）. In the control group， the symptoms including fever， cough， and dyspnea were alleviated （P<0.01）， while the fatigue was not relieved after treatment. No significant difference was observed in the clinical symptoms between the two groups after treatment. After treatment， the FHT group showed decreased white blood cell （WBC） count and neutrophil-to-lymphocyte ratio （NLR） （P<0.01）， elevated platelet （PLT） level （P<0.05）， lowered CRP level （P<0.05）， and no significant difference in lymphocyte （LYM）， hemoglobin （Hb）， SPO2 or PCT level. The control group showed decreased NLR （P<0.05） and WBC count （P<0.01）， elevated PCT level （P<0.05）， and no significant change in LYM， Hb， PLT， SPO2 or CRP level after treatment. Furthermore， the FHT group had higher PLT level than the control group （P<0.05） after treatment， and other indicators had no significant differences between the two groups. The liver and kidney functions had no significant difference between the two groups after treatment. ConclusionFHT can safely promote the absorption of acute pulmonary inflammation in COVID-19 patients.

Active Components Formulation Developed from Fuzheng Huayu Recipe for Anti-Liver Fibrosis / 中国结合医学杂志

OBJECTIVE@#To screen the active components from Fuzheng Huayu Recipe (FZHY) and redesign a new recipe composed of the active components, and validate the effect of active components formulation from FZHY against liver fibrosis.@*METHODS@#Thirty-two components from FZHY were evaluated for their activities against liver fibrosis respectively, with 6 kinds of cell models in vitro, including oxidative stressed hepatocyte in L-02, hypoxia injured/proliferative hepatic sinusoidal endothelial cells in SK-HEP-1 and human hepatic sinusoidal endothelial cells (HHSEC), and activated hepatic stellate cell in LX-2. The comprehensive activity of each component against liver fibrosis was scored according to the role of original herbs in FZHY and cell functions in fibrogenesis. Totally 7 active components were selected and combined with equal proportion to form a novel active components formulation (ACF). The efficacy of ACF on liver fibrosis were evaluated on activation of LX-2 and proliferation of HHSEC in vitro and in liver fibrosis model mice induced by dimethylnitrosamine (DMN). Totally 72 mice were divided into 6 groups using a random number table, including normal, high-dose ACF control (20 µ mol/L × 7 components/kg body weight), model, low-, medium-, high-dose ACF groups (5, 10, 20 µ mol/L × 7 components/kg body weight, respectively). Hematoxylin eosin and Sirius red stainings were used to observe inflammation and fibrosis change of liver tissue; scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were utilized to observe the effect of ACF on ultrastructure of hepatic sinusoids.@*RESULTS@#Fifteen components from FZHY showed higher scores for their activity on against liver fibrosis. Among them, 7 components including tanshinone II A, salvianolic acid B, cordycepin, amygdalin, quercetin, protopanaxatriol, and schizandrin B were recombined with equal proportions to form ACF. ACF at 1,2, 4 µ mol/L showed strong inhibitory effects on activation of LX-2 and proliferation of HHSEC in vitro (all P<0.01). Compared with the model group, ACF attenuated liver collagen deposition, improved sinusoidal capillarization in a dose-dependent manner (all P<0.05).@*CONCLUSION@#ACF exerts a satisfactory effect against experimental liver fibrosis and attenuates sinusoidal capillarization, which warrant a further research and development for herbal components formulation on liver fibrosis.

Treatment of HBV Cirrhosis with Fuzheng Huayu Tablet () and Entecavir: Design of a Randomized, Double-Blind, Parallel and Multicenter Clinical Trial / 中国结合医学杂志

BACKGROUND@#Antiviral therapy can lead to regression of fibrosis in chronic hepatitis B (CHB), but it has a limited effect on cirrhosis. Chinese medicines (CMs), particularly Fuzheng Huayu Tablet (, FZHY), have an antifibrotic effect in patients with CHB.@*OBJECTIVE@#To observe the safety and efficacy of adjunctive FZHY in patients with hepatitis B virus (HBV) cirrhosis, this study was designed as a randomized, placebo-controlled, double-blind, parallel assignment, multicenter trial at 20 centers in China. The total 700 naive patients will be enrolled with compensate cirrhosis due to HBV, and randomly assigned into 2 groups, receiving entecavir (0.5 mg, daily) and FZHY placebo (1.6 g, 3 times a day), or entecavir (0.5 mg, daily) and FZHY (1.6 g, 3 times a day), respectively. The primary endpoint was histological improvement at week 48. The secondary outcome is the decline values of liver fibrosis using the noninvasive methods from baseline to week 48 in each arm of the study. Adverse events such as stomach upset, headache, fatigue, dizziness, nausea will be strictly recorded.@*DISCUSSION@#Through this study, we hope to generate a solid evidence for the therapeutic strategy of HBV cirrhosis with a combination of anti-viral such as ETV and anti-fibrotic herbal product such as FZHY. Protocol version: Version 1.3, Date: 2014.12.4.@*TRIAL REGISTRATION NUMBER@#NCT02241590.

Research ideas and method on screening active components of traditional Chinese medicine against hepatotoxicity with mitochondria as target / 中国中药杂志

Liver is the main place of drug metabolism. Mitochondria of hepatocytes are important targets of drug-induced liver injury. Mitochondrial autophagy could maintain the healthy operation of mitochondria in cells and the stable proliferation of cells. Therefore, the use of mitochondrial autophagy to remove damaged mitochondria is an important strategy of anti-drug-induced liver injury. Active ingredients that could enhance mitochondrial autophagy are contained in many traditional Chinese medicines, which could regulate the mitochondrial autophagy to alleviate relevant diseases. However, there are only a few reports on how to accurately and efficiently identify and evaluate such components targeting mitochondria from traditional Chinese medicine. Liquid chromatography-mass spectro-metry(LC-MS) combined with serum pharmacology in vivo can be used to accurately and efficiently find active ingredients of traditional Chinese medicine acting on mitochondrial targets. This paper reviewed the research ideas and methods of traditional Chinese medicine ingredients for increasing the hepatotoxicity of mitochondrial autophagy, in order to provide new ideas and methods for the study of active ingredients of traditional Chinese medicine targeting mitochondria.

Clinical metabolomics research on Xiaozhang Tie with the umbilical compress therapy for cirrhotic ascites / 药学学报

We used metabolomics technology to identify and understand the biomarkers and therapeutic mechanisms of umbilical compress therapy based on Xiaozhang Tie (XT) to provide scientific evidence for its clinical application. A total of 10 patients with cirrhotic ascites and gastrointestinal motility disorders who were hospitalized in the Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from November 2017 to June 2018 were divided into a placebo group (4 cases) or an XT group (5 cases), and 10 healthy volunteers were included as controls. This clinical trial was approved according to the Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (2017-528-11-01). The patients in the XT group were given umbilical compress therapy with Xiaozhang Tie, and patients in the placebo group were administered a plaster patch in which the drug content was less than 5%, receiving one patch per day for three consecutive days. Non-targeted metabolomics technology and UPLC-Q/Orbitrap-MS/MS analysis technology were utilized to investigate the fluctuations in endogenous metabolic profiles in the patient's urine prior to and after administration of XT. By analyzing and comparing the urine metabolic profiles of patients with cirrhotic ascites to those of healthy volunteers, a total of 31 biomarkers were identified, 14 of which were significantly decreased by the intervention with Xiaozhang Tie (P <0.05). Pathway enrichment analysis revealed that phenylalanine metabolism and tryptophan metabolism are key pathways affected by XT treatment. The results suggest that XT can alleviate cirrhotic ascites by modulating abnormalities in amino acid metabolism.

Fuzheng Huayu recipe, a traditional Chinese compound herbal medicine, attenuates renal interstitial fibrosis via targeting the miR-21/PTEN/AKT axis / 中西医结合学报

OBJECTIVE@#MicroRNAs (miRNAs) may be viable targets for treating renal interstitial fibrosis (RIF). Fuzheng Huayu recipe (FZHY), a traditional Chinese compound herbal medicine, is often used in China to treat fibrosis. This study sought to assess the mechanisms through which FZHY influences miRNAs to treat RIF.@*METHODS@#RIF was induced in rats by mercury chloride and treated with FZHY. Hydroxyproline content, Masson's staining and type I collagen expression were used to evaluate renal collagen deposition. Renal miRNA profiles were evaluated using a miRNA microarray. Those miRNAs that were differentially expressed following FZHY treatment were identified and subjected to bioinformatic analyses. The miR-21 target gene phosphatase and tensin homolog (PTEN) expression and AKT phosphorylation in kidney tissues were assessed via Western blotting. In addition, HK-2 human proximal tubule epithelial cells were treated using angiotensin II (Ang-II) to induce epithelial-to-mesenchymal transition (EMT), followed by FZHY exposure. miR-21 and PTEN expressions were evaluated via quantitative reverse transcription-polymerase chain reaction (qRT-PCR), while E-cadherin and α-smooth muscle actin (α-SMA) expressions were assessed by immunofluorescent staining and qRT-PCR. Western blotting was used to assess PTEN and AKT phosphorylation.@*RESULTS@#FZHY significantly decreased kidney collagen deposition, hydroxyproline content and type I collagen level. The miRNA microarray identified 20 miRNAs that were differentially expressed in response to FZHY treatment. Subsequent bioinformatic analyses found that miR-21 was the key fibrosis-related miRNA regulated by FZHY. FZHY also decreased PTEN expression and AKT phosphorylation in fibrotic kidneys. Results from in vitro tests also suggested that FZHY promoted E-cadherin upregulation and inhibited α-SMA expression in Ang-II-treated HK-2 cells, effectively reversing Ang-II-mediated EMT. We also determined that FZHY reduced miR-21 expression, increased PTEN expression and decreased AKT phosphorylation in these cells.@*CONCLUSION@#miR-21 is the key fibrosis-related miRNA regulated by FZHY. The ability of FZHY to modulate miR-21/PTEN/AKT signaling may be a viable approach for treating RIF.

Salvianolate Reduces Glucose Metabolism Disorders in Dimethylnitrosamine-Induced Cirrhotic Rats / 中国结合医学杂志

<p><b>OBJECTIVE</b>To evaluate the preventive effect of salvianolate (Sal B) on glucose metabolism disorders of dimethylnitrosamine (DMN)-induced cirrhotic rats.</p><p><b>METHODS</b>Fifty-five Wistar rats were randomly divided into a control group (n=10) and a cirrhotic group (n=45) according to a random number table. Liver cirrhosis was induced by intraperitoneal administration of DMN. The cirrhotic rats were divided into model, Sal B and metformin groups (n=15), respectively. Rats in the model group were given saline, two treatment groups were given Sal B (50 mg/kg), metformin (150 mg/kg) respectively for 28 consecutive days, while rats in the control group were injected 0.9% saline with same volume of vehicle. Body weight was measured everyday. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp. Organ index, glucose tolerance test (OGTT), and fasting plasma glucose (FPG), fasting insulin (FINS), hepatic glycogen, hydroxyproline (HYP) and liver function were detected at the end of the treatment. Area under the curve (AUC) for OGTT was calculated. Liver and pancreas histology were determined by histopathological examination with hematoxylin and eosin staining (HE), Sirius Red staining and Masson's trichrome staining, respectively. Hepatic expression of α-smooth muscle actin (α-SMA) and collagen (Col I) were evaluated by immunohistochemical staining.</p><p><b>RESULTS</b>Compared with the model group, Sal B significantly increased body and liver weight, liver-body ratio, glucose infusion rate (GIR), FPG, FINS levels and hepatic glycogen at the end of administration (P<0.05 or P<0.01). Meanwhile, Sal B significantly decreased AUC for OGTT, spleen weight, spleen-body ratio, aminotransferase and HYP level (P<0.05 or P<0.01). Sal B was also effective in alleviating necrosis of liver tissue, suppressing fibrosis progression and inhibiting the expression of α-SMA and Col I in liver. Compared with the metformin group, Sal B had advantages in ameliorating FPG, hepatic glycogen, spleen weight, organ index, liver function and cirrhosis (P<0.05). Metformin increased insulin sensitivity more potently than Sal B (P<0.05).</p><p><b>CONCLUSIONS</b>Sal B could improve glucose metabolism in cirrhotic rats by protecting hepatic glycogen reserve, increasing insulin sensitivity, and alleviating pancreatic morphology abnormalities. Sal B was clinically potential in preventing glucose metabolism anomalies accompanied with cirrhosis.</p>

Fuzheng Huayu Formula () prevents rat renal interstitial fibrosis induced by HgClvia antioxidative stress and down-regulation of nuclear factor-kappa B activity / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate the mechanism of action of Fuzheng Huayu Formula (, FZHY) against renal interstitial fibrosis (RIF) relating to oxidative injury and nuclear factor-kappa B (NF-κB) activity.</p><p><b>METHODS</b>Thirty-two Sprague-Dawley rats were randomly divided into 3 groups: normal group, model group and FZHY treatment group. The RIF model was induced by oral administration of HgClat a dose of 8 mg/kg body weight once a day for 9 weeks. Meanwhile, rats in FZHY treatment group orally took FZHY at a dose of 4.0 g/kg rat weight for 9 weeks. The content of hydroxyproline (Hyp) and collagen deposition in kidney were observed. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), the content of glutathione (GSH) and malondialdehyde (MDA) of kidney were tested. The expressions of inhibitor-κappa B (IκB), phospho-IκB (p-IκB), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-2 (MMP-2) and α-smooth muscle actin (α-SMA) were analyzed by Western blot. α-SMA expression was also observed by immunofluorescent staining. MMP-2 activity was measured by gelatin zymography. NF-κB activation was determined by electrophoretic mobility shift assay.</p><p><b>RESULTS</b>Renal interstitial fibrosis was induced by HgCl, demonstrated by remarkably increased Hyp contents and excessive collagen deposition in kidney (P<0.01). FZHY significantly inhibited renal interstitial collagen deposition and reduced Hyp content of the HgCl-treated rats (P<0.01). GSH content decreased obviously, and MDA content increased signifificantly in HgCl-treated rats compared with that of normal rats (P<0.01). FZHY significantly increased GSH content and decreased MDA content in the model rats (P<0.01). The expression α-SMA was increased in model rats compared with that of normal rats, FZHY signifificantly decreased its expression (P<0.01). The expressions of p-IκB and TNF-α and MMP-2, MMP-2 activity, and NF-κB activation were increased in model group compared with that in normal group (P<0.01), FZHY signifificantly decreased NF-κB activation, MMP-2 activity and p-IκB and TNF-α expressions (P<0.01).</p><p><b>CONCLUSIONS</b>FZHY could protect kidney from oxidative injury intoxicated by HgCl, and antagonized oxidative stress-stimulated NF-κB activity through inhibition of IκB phosphorylation in the interstitial fibrotic kidney, these effects importantly contributed to FZHY action mechanism against renal interstitial fifibrosis.</p>

Evaluation of cryptotanshinone inhibition of angiogenesis in human hepatic sinusoidal endothelial cells / 药学学报

To investigate the effects of cryptotanshinone (an active ingredient of Salvia Miltiorrhiza) inhibition of angiogenesis, the toxicity of cryptotanshinone was assayed in human hepatic sinusoidal endothelial cells (HHSEC) by CCK8 method. Max dose without toxicity is 10 μmol·L-1. The proliferation of HHSEC were induced by the endothelial cell growth supplement (ECGS), with 2.5 μmol·L-1 sorafenib as the positive control. Cell proliferation was analyzed by EdU assay. Cell viability was analyzed by CCK8 method. The expression of vWF was analyzed by immunofluorescence method. Fluorescence probe method was used to detect the intracellular nitric oxide (NO) levels. Tube formation of HHSEC and transgenic zebrafish were also observed to evaluate the effects of cryptotanshinone against angiogenesis. Compared with normal control, there is a proliferation of HHSEC induced by ECGS. The expression of vWF and the NO levels increased significantly. Cryptotanshinone inhibited the proliferation, down regulated the expression of vWF and the NO levels. Further, cryptotanshinone inhibited the tube formation of HHSEC and reduced the number of fu nctional vessels in transgenic zebrafish. The results suggest that cryptotanshinone could inhibit angiogenesis by regulating the HHSEC cell function.

Effect of Fuzheng Huayu capsule on serum metabolomics in rats with liver fibrosis induced by dimethylnitrosamine / 中国中药杂志

To investigate the effect of Fuzheng Huayu capsule(FHC) on serum metabolomics in rats with liver fibrosis induced by dimethylnitrosamine(DMN). The metabolic profiles of rat serum of normal group, model group, and FHC group were established by liquid chromatography-mass spectrometry technology. Furthermore, the levels of endogenous metabolites such as amino acids and bile acids were measured in each group. The results showed that there were significant differences in the serum metabolic fingerprints between the FHC group and the model group. Moreover, 5 potential lysophosphatidylcholines biomarkers were identified by using principal component analysis(PCA) and partial least squares discriminant analysis (PLS-DA). Quantitative analysis of amino acids and bile acids in serum of rats showed that 14 kinds of amino acids and 5 kinds of bile acids returned to normal levels after four weeks of FHC treatment. In conclusion, the anti-hepatic fibrosis mechanisms of FHC may be related to the metabolic process of lysophosphatidylcholines, amino acids and bile acids.

Effect of schisantherin A inhibit liver sinusoid endothelial cell function and action against liver fibrosis relating to angiogenesis / 中国中药杂志

To investigate the effect of schisantherin A on liver sinusoid endothelial cell function and angiogenesis. Different dosages (0-40 μmol•L⁻¹) of schisantherin A were incubated 24 h with SK-HEP-1 cells, and the toxicity of SK-HEP-1 cells was assayed by MTT method. The proliferation of SK-HEP-1 cells were induced by the vascular endothelial growth factor (VEGF), with receptor tyrosine kinase inhibitor sorafenib as the control, at the same time, set up the control group, 2, 20 μmol•L⁻¹ schisantherin A were incubated with SK-HEP-1 cells, cell proliferation was analyzed by EdU DNA cell proliferation kit. Fluorescence probe method was used to assay the intracellular NO levels and NOS activity. Tube formation was observed using cell migration and a matrigel tube formation assay. Rat aortic ring assay was performed to observe the sprouting vessels from aortic ring. The fluorescence vessels, the number of functional blood vessels, and intersegmental vessel changes of transgenic zebrafish were also observed. Compared with control group, the proliferation of SK-HEP-1 cells induced by VEGF increased and and the level of NO and NOS activity induced; compared with model group, 2, 20 μmol•L⁻¹ schisantherin A and sorafenib inhibited the proliferation of SK-Hep-1 cells induced by VEGF, and reduced the level of NO and NOS activity. At the dosage of 20 μmol•L⁻¹, schisantherin A attenuated the migration and tube formation of SK-HEP-1 cells induced by VEGF, and also inhibition the formation of rat aortic rings and intersegmental vessel changes of transgenic zebrafish, and significantly reduce the number of vessels in zebrafish. Schisantherin A has potential effects on function of endothelial cell proliferation and angiogenesis.

Effect of Fuzheng Huayu recipe on CYP450 isozymes in normal and liver fibrosis rats / 中国中药杂志

To study the effect of Fuzheng Huayu recipe (FZHY) on five types of isozymes of cytochrome P450 (CYP450) of normal and liver fibrosis rats by using the cocktail probe method. Dimethylnitrosamine ( DMN) was injected to induce the liver fibrosis model. After the tail vein injection with Cocktail probe solutions prepared with five CYP450s probe substrates (phenacetin-CYP1A2, omeprazole-CYP2C9, tolbutamide-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A4), the plasma concentrations of the five probe substrates were determined by LC-MS/MS, and the pharmacokinetic parameters were calculated by PK solutions 2. After the oral administration with FZHY, normal rats given phenacetin, omeprazole, tolbutamide and dextromethorphan showed increase in AUC(0-t) and decrease in CL to varying degrees, indicating that FZHY obviously inhibited the activities of CYP1A2, CYP2C9, CYP2C19 and CYP2D6 in normal rats, but with no obvious effect on the activity of CYP3A4. After the oral administration with FZHY, liver fibrosis rats treated with CYP2C9 showed the significant increase in AUC(0-t) and significant decrease in Vd, hut with no obvious changes in the pharmacokinetic parameters of other four types of prove substances, suggesting that FZHY could significantly inhibit the activity of CYP2C9 in rats but had no effect on the activities of CYP1A2, CYP2C19, CYP2D6 and CYP3A4. The changes in the activity of CYP450 isozymes in liver fibrosis rats may be the reason for FZHY's different effects on CYP450 isozymes in normal and liver fibrosis rats.

Effects of cordyceps acid and cordycepin on the inflammatory and fibrogenic response of hepatic stellate cells / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the effects of cordyceps acid and cordycepin on the inflammatory phenotype and fibrogenic property of hepatic stellate cells (HSCs).</p><p><b>METHODS</b>An immortalized mouse HSC line (JS1) was stimulated with lippolysaccharide (LPS; 100 ng/ml) to induce an inflammatory response with or without co-administration of cordyceps acid or cordycepin in various concentrations (10, 50, or 200 mumol/L). Effects of the treatments on the chemokine monocyte chemotactic protein-1 (MCP-1) mRNA expression in the cells and the protein secretion in the cell culture supernatants were determined by reverse transcription and real-time quantitative PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. In addition, JS1 cells were treated with transforming growth factor-b1 (TGFb1; 10 ng/ml) to induce a fibrogenic response with or without co-administration of cordyceps acid or cordycepin in various concentrations (10, 50, or 200 mumol/L). Effects on the expression of fibrogenic proteins including collagen type I and a-smooth muscle actin (a-SMA), were investigated by Western blot.</p><p><b>RESULTS</b>High-concentration (200 mumol/L) treatments of both cordyceps acid and cordycepin significantly inhibited the LPS-induced up-regulation of MCP-1 transcription and secretion (mRNA: 2.07 +/- 0.29 vs. 3.35 +/- 0.26, t = 15.90 and 1.15 +/- 0.23 vs. 4.17 +/- 0.61, t = 8.93; protein: 1.88 +/- 0.06 vs. 2.33 +/- 0.06, t = 10.39 and 1.47 +/- 0.25 vs. 1.97 +/- 0.04, t = 4.60; all P less than 0.05). All concentrations of cordyceps acid and cordycepin inhibited the TGFb1-induced up-regulation of collagen type I and a-SMA protein expression. However, the effects were more robust with the 200 mumol/L concentrations (P less than 0.05).</p><p><b>CONCLUSION</b>Cordyceps acid and cordycepin ameliorate the LPS-induced inflammatory phenotype and TGFb1-induced fibrogenic response of cultured HSCs. These effects may contribute significantly to the drugs' therapeutic mechanisms to inhibit and resolve liver fibrosis.</p>

Protective effect of Tanreqing injection on acute hepatic injury induced by CCl4 in rats / 中国中药杂志

<p><b>OBJECTIVE</b>To observe the protective effect of Tanreqing injection(TRQ) on carbon tetrachloride-induced acute hepatic injury in rats.</p><p><b>METHOD</b>Rats were randomly divided into the normal group and the model group, and injected subcutaneously with 100% CCl4 5 mL x kg(-1) to establish the single CCl4 infection model, in order to observe the changes in rat liver injury after 3 h and 6 h. Subsequently, the multiple CCl4 infection liver injury model was reproduced by subcutaneously injecting 100% CCl4 (5 mL x kg(-1)), 50% CCl4 olive oil solution (2 mL x kg(-1)) and then 20% CCl4 olive oil solution (2 mL x kg(-1)). At 6 h after the first CCl4 injection, the rats were divided into six groups: the model group, the control group, the diammonium glycyrrhizinate-treated group, and TRQ high, middle and low dose groups. They were injected through caudal veins, while a normal control group was set up. Their weight and liver-body ratio were observed. Hepatic inflammation was observed with HE staining. Assay kits were adopted to detect ALT, AST, T. Bil, D. Bil, CHE, TBA, gamma-GT and Alb.</p><p><b>RESULT</b>According to the single injection model, serum AST and T. Bil of model rats were obviously increased at 6 h after single subcutaneous injection of CCl4, with disordered lobular structure in liver tissues, notable swollen liver cells and remarkable liver injury. According to the results of the multiple injection pharmacological experiment, compared with the normal group, the model group had higher serum ALT, AST, and gamma-GT activities (P < 0. 05), TBA and T. Bil contents (P < 0.05) and lower CHE activity (P < 0.05). HE staining showed disorganized lobular structure in liver tissues and notable ballooning degeneration in liver cells. Compared with the model group, TRQ high and middle dose groups and the diammonium glycyrrhizinate-treated group showed significant charges in serum liver function and inflammation in liver cells. Specifically, TRQ high and middle dose groups were superior to the diammonium glycyrrhizinate-treated group.</p><p><b>CONCLUSION</b>Tanreqing injection has significant protective effect on CCl4-induced acute hepatic injury in rats.</p>

Effects of Danggui Buxue Decoction () on lipid peroxidation and MMP-2/9 activities of fibrotic liver in rats / 中国结合医学杂志

<p><b>OBJECTIVE</b>To explore the mechanism of Danggui Buxue Decoction (, DBD) on the liver fifibrosis related to hepatic lipid peroxidation and matrix metalloproteinases (MMP) -2/9 activities.</p><p><b>METHODS</b>The liver fifibrosis in 28 rats was induced by an injection of carbon tetrachloride (CCl(4)) and fed with high lipid and low protein diet for 6 weeks, the model rats were randomly divided into the model group and DBD treated group, 14 in each group, and another 10 rats as the normal group were observed as well. Rats in the DBD group were administered with DBD at the dose of 6 g/kg body weight for 6 weeks since CCl(4) intoxication. The hepatic inflammation and fibrosis were examined with HE and Sirius red stain. The liver function including serum alanine aminotransamine (ALT), aspartate transamine (AST), albumin (Alb) and total bilirubin (TBIL), liver triglyceride (TG) and malondialdehyde (MDA) contents, superoxide dismutase (SOD) activity were assayed. Hepatic hydroxyproline (Hyp) content was detected with Jamall's method. The alpha-SMA expression was analyzed by immunohistochemistry and the Western blot. Liver MMP-2 mRNA was analyzed with Real-time PCR, and MMP-2/9 activities were measured with gelatin zymography and in situ zymography.</p><p><b>RESULTS</b>Compared with the normal group, the levels of ALT, AST and TBIL, the content of Hyp, TG and MDA were remarkably increased, the Alb content and SOD activity were signifificantly decreased in the model group (P<0.05), and higher levels of MMP-2 mRNA and MMP-2/9 activities (P<0.01), the hepatic fatty degeneration and collagen accumulation and fifibrosis at liver were observed. Compared with the model control, DBD group showed slighter hepatic fatty degeneration and collagen deposition, and had lower levels of ALT, AST and TBIL activities, lower contents of MDA, TG and Hyp, but higher SOD level and Alb content (P<0.05), and DBD also down-regulated MMP-2 mRNA expression and decreased MMP-2/9 activities in the fifibrotic livers (P<0.01).</p><p><b>CONCLUSION</b>The action of DBD against liver fibrosis is related to prevent lipid peroxidation and inhibit MMP-2/9 activities in the fibrotic livers.</p>

Effects of Fuzheng Huayu recipe on MMP-2 activity and type IV collagen expression at fibrotic lung / 中国中药杂志

<p><b>OBJECTIVE</b>To study the mechanism of Fuzheng Huayu (FZHY) recipe against pulmonary fibrosis relating to MMP-2 activity and type IV collagen expression at lung tissue.</p><p><b>METHOD</b>The pulmonary fibrosis model was induced by intratracheal instillation with bleomycin once in rats. The models were divided into 3 groups: model control, FZHY recipe treated, and methylprednisolone (Solu-Medrol) treated group, each group was of 14 model rats. Normal control group with 10 rats was intoxicated with the same amount of saline. From the second day of intoxication, FZHY recipe treated group orally took FZHY recipe at the dosage of 4.6 g x kg(-1) rat wt, methylprednisolone treated group received intraperitoneal injection with 15 mg x kg(-1) rat wt of methylprednisolone, while model and normal controls took the same volume of saline, 1 time each day and lasting for 4 weeks. Lung and body weights were weighed and the lung/body ratio was calculated. Collagens deposition was check with Masson stain, and lung hydroxyproline (Hyp) content was assayed with Jamall's method. Protein expressions of MMP-2/9 and type IV collagen at lung tissue were analyzed with Western blot and of MMP-2/9 activities by gelatin zymography.</p><p><b>RESULT</b>Compared to normal rats, the model control rats had a high lung/body ratio, remarkable collagen deposition, increased Hyp content and the expressions of type IV collagen, MMP-2 and MMP-9 protein at lung tissue, increased MMP-2 activity, in particular active MMP-2 activity, but decreased MMP-9 activity. Compared to model control, FZHY recipe and methylprednisolone obviously attenuated pulmonary collagen deposition, decreased lung/body ratio and Hyp content, downregulated MMP-2 protein expression and activity, in particular active MMP-2 activity, and FZHU recipe had some better actions than methylprednisolone on lung/body ratio, type IV collagen expression and active MMP-2 activity. But both drug groups had no influence on MMP-9 protein expression and activity.</p><p><b>CONCLUSION</b>FZHY recipe has a good action against experimental pulmonary fibrosis and its mechanisms are associated with the inhibition of MMP-2 protein and activity, and with the inhibition of over expression of type IV collagen at lung tissue.</p>

The value of serum markers in evaluating liver fibrotic changes / 中华肝脏病杂志

<p><b>OBJECTIVE</b>Serum fibrotic markers were investigated for diagnosing and prognosing liver fibrosis in chronic hepatitis B.</p><p><b>METHODS</b>Liver biopsy data of 93 patients before and after treatment were gathered from an experiment group (Fuzhenghuayu capsule, 36 cases) and a control group (Heluoshugan capsule, 57 cases) from multiple medical centers, using randomized and double blind strategies to evaluate the effectiveness of Fuzhenghuayu capsules against liver fibrosis. The patients were divided into 2 groups according to the treatment efficacy: an effectual group and a non-effectual group. The hepatic inflammation, liver function and serum fibrotic markers of the patients of the two groups were analyzed.</p><p><b>RESULTS</b>We found that (1) Liver fibrosis improved with hepatic inflammation improvement. (2) After the drug treatment, the serum HA and PIIIP levels of the effectual group decreased obviously (t = 3.34, t =3.17, P < 0.01), and the decreased degree was higher than that of the non-effectual group, but there were no changes for LN and IV-C levels. (3) Alb contents increased (t = 3.24, P < 0.01) and activities of GGT and AST and PT decreased significantly in the effectual group, but there was no change in the non-effectual group.</p><p><b>CONCLUSION</b>The serum GGT and AST activities, PT, Alb, HA and PIIIP contents in the chronic hepatitis B patients are good markers for evaluating the degree of liver fibrosis and the effectiveness of the drug action, but the values of LN and IV-C in the evaluation need to be studied more.</p>

Dynamic characteristics of SARA during liver fibrogenesis in rats / 中华肝脏病杂志

<p><b>OBJECTIVES</b>To investigate the dynamic characteristics of Smad anchor for receptor activation (SARA) expression during liver fibrogenesis in rats and the relationship between SARA and liver fibrosis.</p><p><b>METHODS</b>Liver fibrosis was induced in 74 rats by intraperitoneal injection of dimethylnitrosamine (DMN) with a dosage of 10 microl/kg body weight, once a day, 3 days per week for 4 weeks. The model rats were randomly divided into 9 groups for studying the changes: 1 d, 3 ds, 1 week, 2 weeks, 3 weeks and 4 weeks after starting the ip injections (intoxicating phase), and 1 week, 2 weeks and 4 weeks after stopping the injections (5th w, 7th w and 8th w, recovery phase). Each group included 5 to 8 rats. In addition, 10 non-treated rats served as normal controls. The rat liver tissues were examined. Collagen deposition was stained with Sirius red, and hydroxyproline (Hyp) was measured with Jamall' method. SARA spatial expression in the livers was detected by immunohistochemistry, and the expressions of TGFbeta1, alpha-SMA and SARA protein were detected by Western blot. The relationships of SARA with Hyp, TGFbeta1 and alpha-SMA were analyzed.</p><p><b>RESULTS</b>During the intoxicating phase, the rat hepatic collagen production (Hyp content) and deposition increased as DMN intoxication continued, and there was marked fibrous septum and pseudo-lobule formation at the end of the 4th w. During the recovery phase, the rat hepatic collagen deposition and fibrous septum formation were lessened, but the Hyp content in the livers of the model rats at the end of 4th w, 5th w, 6th w and 8th w was still higher than that of the controls (193.04+/-39.15, 188.49+/-39.92, 174.39+/-21.22, 163.59+/-31.47 vs 125.64+/-19.51; t from 3.43 to 4.9, P<0.01). SARA was mainly stained positively in interstitial cells surrounding the hepatic sinusoids in both normal and fibrotic livers, and the number of the positive stained cells decreased as liver fibrosis developed, and gradually returned to normal after stopping the intoxication. The expressions of TGFbeta1 and alpha-SMA were gradually increased, as shown with Western blot, but SARA decreased as liver fibrosis developed. The expressions of TGFbeta1 and alpha-SMA were slightly decreased, SARA expression recovered to the normal level after stopping the DMN intoxication. During liver fibrosis developing and recovery phases, SARA was significantly negatively correlated with TGFbeta1 and alpha-SMA expressions and Hyp contents.</p><p><b>CONCLUSIONS</b>SARA was mainly expressed in the liver interstitial cells, and it was negatively correlated with liver fibrosis formation.</p>

Effects of syndrome dependent umbilical sticking with shizhang cataplasm and xuzhang cataplasm in treating Cirrhosis caused ascites / 中国中西医结合杂志

<p><b>UNLABELLED</b>To investigate the effects of Shizhang Cataplasm (SC) and Xuzhang Cataplasm (XC) in treating liver cirrhosis caused ascites of excessive syndrome (ES) type and deficient syndrome (DS) type respectively.</p><p><b>METHODS</b>All the 77 patients (37 of ES type and 40 of DS type) enrolled were treated by conventional treatment but with restrictive use of diuretics. SC and XC were given respectively to 26 patients of ES type and 26 of DS type additionally by umbilical sticking, they were regarded as the treated group, and those (11 of ES type and 14 of DS type) not received the cataplasm treatment were regarded as the control group. The changes of symptoms, body weight, abdominal perimeter and amount of urine before and after treatment were observed, and amount of ascites was examined with B-ultrasound to evaluate the efficacy according to comprehensive grading criteria. Also, the toxicity was observed.</p><p><b>RESULTS</b>Sixty-two cases completed the full course, 15 were withdrawn. As compared with the corresponding control group, body weight, abdominal perimeter and amount of ascites decreased, while amount of urine and flatus discharging increased remarkably in the treated group (P < 0.05). The comprehensive efficacy in patients of ES type was better than that in DS type (P < 0.05). The effective rate of grade I/II was 7.1% and 9.1% for patients in the control group of DS type and ES type respectively, while it was 57.2% and 69.2% in the treated group of DS and ES type respectively. Better therapeutic effect was shown in patients of ES type treated with SC.</p><p><b>CONCLUSION</b>SC and XC showed good assistant effects in treating patients with liver cirrhosis caused ascites of ES and DS type respectively.</p>