3-4-dihydroxyphenyllactic-acid and Liver-Cirrhosis

Fuzheng Huayu recipe (FZHY) is a herbal product for the treatment of liver fibrosis approved by the Chinese State Food and Drug Administration (SFDA), but its pharmacokinetics and tissue distribution had not been investigated. In this study, the liver fibrotic model was induced with intraperitoneal injection of dimethylnitrosamine (DMN), and FZHY was given orally to the model and normal rats. The plasma pharmacokinetics and tissue distribution profiles of four major bioactive components from FZHY were analyzed in the normal and fibrotic rat groups using an ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Results revealed that the bioavailabilities of danshensu (DSS), salvianolic acid B (SAB) and rosmarinic acid (ROS) in liver fibrotic rats increased 1.49, 3.31 and 2.37-fold, respectively, compared to normal rats. There was no obvious difference in the pharmacokinetics of amygdalin (AMY) between the normal and fibrotic rats. The tissue distribution of DSS, SAB, and AMY trended to be mostly in the kidney and lung. The distribution of DSS, SAB, and AMY in liver tissue of the model rats was significantly decreased compared to the normal rats. Significant differences in the pharmacokinetics and tissue distribution profiles of DSS, ROS, SAB and AMY were observed in rats with hepatic fibrosis after oral administration of FZHY. These results provide a meaningful basis for developing a clinical dosage regimen in the treatment of hepatic fibrosis by FZHY.

Topics: Administration, Oral; Amygdalin; Animals; Area Under Curve; Benzofurans; Chromatography, High Pressure Liquid; Cinnamates; Depsides; Drugs, Chinese Herbal; Fibrosis; Kidney; Lactates; Liver Cirrhosis; Lung; Male; Rats; Rats, Wistar; Rosmarinic Acid; Tandem Mass Spectrometry; Tissue Distribution

The culprit of hepatic fibrosis (HF) is linked to suprathreshold deposition of collagen. Thus, collagen reduction by improved metabolism contributes to HF management. In this study, we aimed to investigate the hepatoprotective effects of Danshensu (DSS) against carbon tetrachloride (CCl4)-induced HF rats. The results showed that DSS-administrated rats resulted in decreasing in hepatosomatic indexes, and lowering serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Meanwhile, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) were increased, while the content of malonaldehyde (MDA) was lessened in liver tissue of DSS administration group. In addition, the pro-fibrotic markers of hydroxyproline (Hyp), type III procollagen (PCIII) and hyaluronic acid (HA) contents were decreased. Histopathological examination confirmed that the hepatotoxicity in CCl4-injured rats was alleviated following the DSS administration. Furthermore, intrahepatic protein expressions of alpha-smooth muscle actin (α-SMA), phosphorylated JAK2 (p-JAK2) and phosphorylated STAT3 (p-STAT3) were effectively down-regulated, respectively. Overall, this work demonstrates that DSS played the protective effect against CCl4-induced cytotoxicity in liver tissue, which the probable mechanism is associated with attenuation of lipid peroxidation, collagen accumulation and enhancement of anti-oxidative defense capability, as well as regulation of intrahepatic JAK/STAT pathway for maintaining collagenic homoeostasis.

Topics: Animals; Body Weight; Carbon Tetrachloride; Cytoprotection; Lactates; Liver; Liver Cirrhosis; Liver Function Tests; Male; Organ Size; Rats; Rats, Wistar

To investigate the inhibitory effect of danshensu on the activation of JNK signaling in rat hepatic stellate cells (HSCs) induced by IL-1beta.. The proliferation of primary rat HSCs treated with different concentration of Danshensu was checked by MTT colorimetric assay. The expression and phosphorylation of JNK and P-JNK was detected by western blotting. Synthesis and secretion of collagen I were detected by the quantitative immunocytochemical assay and ELISA.. Danshensu inhibited the proliferation of HSCs in a dose-dependent manner. At the concentration of 0.0625 to 0.25 mmol/L, Danshensu significantly repressed the proliferation of HSC induced by IL-1beta (P < 0.05). Synthesis and secretion of Type I collagen was significantly decreased 24 hours after 0.25 mmol/L Danshensu treatment (P < 0.01). The phosphorylation of JNK induced by IL-1beta was significantly inhibited by Danshensu treatment (P < 0.05), however, the expression of JNK was not regulated by Danshensu.. Danshensu represses the activation and proliferation of HSCs, and inhibits the synthesis and secretion of Type I collagen, possibly via the repression of the JNK signal transduction.

Topics: Animals; Blotting, Western; Cell Proliferation; Cells, Cultured; Collagen Type I; Dose-Response Relationship, Drug; Down-Regulation; Hepatic Stellate Cells; Immunohistochemistry; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Lactates; Liver Cirrhosis; Male; Mitogen-Activated Protein Kinases; Rats; Rats, Wistar; Signal Transduction