salvianolic-acid-a and Chemical-and-Drug-Induced-Liver-Injury

E-DRS is a novel salvianolic acid A (SAA) analog, which was synthesized from resveratrol (RES) and methyldopate. Its structure is similar to that of SAA, but the 3',4'-dihydroxy-trans-stilbene group and the ester structure in SAA were replaced by the RES structure and an amine group, respectively. E-DRS scavenged free oxygen radicals effectively, including superoxide anion (ascorbic acid > E-DRS > SAA ≥ rutin > RES) and DPPH radical (rutin > E-DRS ≥ ascorbic acid > SAA > RES), and exhibited powerful total antioxidant capacity (ascorbic acid > E-DRS > SAA ≥ rutin > RES) in vitro. Furthermore, oral administration of E-DRS dose-dependently and significantly decreased CCl

Topics: Animals; Antioxidants; Biphenyl Compounds; Caffeic Acids; Carbon Tetrachloride; Catalase; Chemical and Drug Induced Liver Injury; Glutathione; Lactates; Liver; Male; Malondialdehyde; Mice; Picrates; Resveratrol; Superoxide Dismutase; Superoxides

Salvianolic acid A (Sal A) was considered to be the compound with highest activity in Salvia miltiorrhiza (danshen). Due to its low content in raw materials, many studies reported its preparation from salvianolic acid B (Sal B). However, the process of this transformation is still unknown. Our objective was to find the chemical change of the transformation from Sal B to Sal A. The results showed that Sal B was hydrolyzed to lithospermic acid (LA) first, and the latter was transformed into Sal A in thermal aqueous solution. The radical scavenging ability of Sal A, Sal B, and LA was tested through DPPH, and Sal A showed higher radical elimination ability compared to Sal B and LA. In vitro liver damage was induced by CCl4 in human hepatic WRL68 cell line. Sal A, Sal B, and LA showed liver protective ability in a dose-dependent manner, while Sal A possessed a much higher ability compared to Sal B and LA.

Topics: Antioxidants; Benzofurans; Biphenyl Compounds; Caffeic Acids; Carbon Tetrachloride; Cell Line; Chemical and Drug Induced Liver Injury; Depsides; Drugs, Chinese Herbal; Hot Temperature; Humans; In Vitro Techniques; Lactates; Liver; Phytotherapy; Picrates; Salvia miltiorrhiza; Water

Salvianolic acid A (SalA) is a phenolic carboxylic acid derivative extracted from Salvia miltiorrhiza. It has many biological and pharmaceutical activities. The purpose of this study was to investigate the effect of SalA on concanavalin A (ConA)-induced acute hepatic injury in Kunming mice and to explore the role of SIRT1 in such an effect. The results showed that in vivo pretreatment with SalA significantly reduced ConA-induced elevation in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and decreased levels of the hepatotoxic cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Moreover, the SalA pretreatment ameliorated the increases in NF-κB and in cleaved caspase-3 caused by ConA exposure. Whereas, the pretreatment completely reversed expression of the B-cell lymphoma-extra large (Bcl-xL). More importantly, the SalA pretreatment significantly increased the expression of SIRT1, a NAD(+)-dependent deacetylase, which was known to attenuate acute hypoxia damage and metabolic liver diseases. In our study, the increase in SIRT1 was closely associated with down-regulation of the p66 isoform (p66shc) of growth factor adapter Shc at both protein and mRNA levels. In HepG2 cell culture, SalA pretreatment increased SIRT1 expression in a time and dose-dependent manner and such an increase was abrogated by siRNA knockdown of SIRT1. Additionally, inhibition of SIRT1 significantly reversed the decreased expression of p66shc, and attenuated SalA-induced p66shc down-regulation. Collectively, the present study indicated that SalA may be a potent activator of SIRT and that SalA can alleviate ConA-induced hepatitis through SIRT1-mediated repression of the p66shc pathway.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; bcl-X Protein; Caffeic Acids; Caspase 3; Chemical and Drug Induced Liver Injury; Concanavalin A; Down-Regulation; Epigenetic Repression; Hep G2 Cells; Hepatitis; Humans; Interferon-gamma; Lactates; Liver; Male; Mice; NF-kappa B; RNA, Messenger; RNA, Small Interfering; Shc Signaling Adaptor Proteins; Sirtuin 1; Src Homology 2 Domain-Containing, Transforming Protein 1; Tumor Necrosis Factor-alpha

Previous research has shown that salvianic acid A [2-(3,4-dihydroxyphenyl)-2-hydroxy-propanoic acid, SA] extracted from Salvia miltiorrhiza BGE (Danshen) markedly inhibits lipid peroxidation of mitochondrial membrane of hepatic cells in vitro. The present study was conducted to examine protective effect of SA on liver injury induced by carbon tetrachloride (CCl4) and its possible mechanism in vivo. Male Sprague-Dawley rats weighing 180-200 g were used in the experiments. Five mmol/kg CCl4 in olive oil was given to rats i.p. Spectrophotometrical method was used to measure activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum, activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) as well as malondialdehyde (MDA) level in hepatic tissue and the rate of superoxide anion (O2*-) generation in hepatic submitochondrial particles. Hepatic histological structure was observed under light microscopy. CCl4 caused significant changes of activities of the enzymes, MDA level, and the rate of O2*- generation and histopathological changes of acute hepatic injury were noted. SA reversed the significant changes induced by CCl4. These results demonstrate that SA produces protective action on acute hepatic injury induced by CCl4 via an antioxidative mechanism.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Caffeic Acids; Carbon Tetrachloride; Catalase; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Glutathione Peroxidase; Lactates; Liver; Liver Diseases; Male; Malondialdehyde; Necrosis; Plant Extracts; Rats; Rats, Sprague-Dawley; Salvia miltiorrhiza; Superoxide Dismutase; Superoxides

In the present study, we investigated the hepatoprotective effects of salvianolic acid A, a novel antioxidant, against oxidative stress and acute liver injury induced by carbon tetrachloride (CCl(4)) in rats, and the mechanisms underlying its protective effects. Administration of CCl(4) to rats caused severe hepatic damage, as demonstrated by the significant increase in the levels of serum alanine aminotransferase, aspartate aminotransferase and classic histological changes including hepatocyte necrosis or apoptosis, haemorrhage, fatty degeneration, etc. Co-treatment with salvianolic acid A (20 mg/kg, intraperitoneally), a water-soluble extract from a Chinese traditional drug, Radix Salvia miltiorrhiza, significantly decreased CCl(4)-induced hepatotoxicity. Salvianolic acid A not only decreased serum alanine aminotransferase, aspartate aminotransferas levels and ameliorated histopathological manifestations in CCl(4)-treated rats, but also reduced oxidative stress, as evidenced by decreased reactive oxygen species production and malondialdehyde concentrations in the liver tissues, combined with elevated hepatic superoxide dismutase activity and gluthathione content. In addition, salvianolic acid A treatment remarkably reduced intrahepatic tumour necrosis factor-alpha concentrations and caspase-3 activities as compared with the CCl(4)-treated rats. The results suggested that treatment with salvianolic acid A provides a potent protective effect against acute hepatic damage caused by CCl(4) in rats, which may mainly be related to its antioxidative effect.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Caffeic Acids; Carbon Tetrachloride; Caspase 3; Chemical and Drug Induced Liver Injury; Glutathione; Lactates; Liver; Liver Diseases; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Tumor Necrosis Factor-alpha

To study the actions of salvianolic acid A (SA-A) on liver injury and liver fibrosis.. The liver fibrotic rat was made by i.p. injection of CCl4. The model rats were divided into 3 groups treated with SA-A, colchicine (Col), and Salvia miltiorrhiza Bunge (SMB), respectively. Six wk later the rat liver pathology was examined, type I and III collagen in the liver were examined by immunohistochemistical method. Also hydroxyproline (Hyd) and malondialdehyde (MDA) in the liver, alanine aminotransferase (AlaAT), aspartate aminotransferase (AspAT), and albumin (Alb) levels in the serum were measured.. SA-A inhibited serum AlaAT and AspAT activities, decreased MDA and Hyd contents, alleviated liver fibrogenesis, protected deposition of type I and III collagen in liver matrix. The actions of SA-A on liver fibrosis were similar to those of Col and SMB, action of SA-A decreasing MDA was better than that of Col.. SA-A has marked effects against liver injury and fibrosis, associated with its anti-lipid peroxidation actions.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Caffeic Acids; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Lactates; Liver; Liver Cirrhosis, Experimental; Male; Malondialdehyde; Random Allocation; Rats; Rats, Wistar