1. Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways.
- Author
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Lin M, Zhai X, Wang G, Tian X, Gao D, Shi L, Wu H, Fan Q, Peng J, Liu K, and Yao J
- Subjects
- Animals, Benzofurans isolation & purification, Chemical and Drug Induced Liver Injury etiology, Glutamate-Cysteine Ligase genetics, Glutamate-Cysteine Ligase metabolism, Heme Oxygenase-1 genetics, Heme Oxygenase-1 metabolism, Hep G2 Cells, Humans, Male, Mice, Inbred Strains, Salvia miltiorrhiza chemistry, Up-Regulation drug effects, Up-Regulation genetics, Acetaminophen toxicity, Anti-Inflammatory Agents, Antioxidants, Benzofurans pharmacology, Cell Death drug effects, Chemical and Drug Induced Liver Injury genetics, Chemical and Drug Induced Liver Injury prevention & control, Gene Expression drug effects, Metabolic Detoxication, Phase II genetics, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Phosphatidylinositol 3-Kinases physiology, Protein Kinase C physiology, Signal Transduction drug effects, Signal Transduction genetics
- Abstract
Acetaminophen (APAP) is used drugs worldwide for treating pain and fever. However, APAP overdose is the principal cause of acute liver failure in Western countries. Salvianolic acid B (SalB), a major water-soluble compound extracted from Radix Salvia miltiorrhiza, has well-known antioxidant and anti-inflammatory actions. We aimed to evaluate the ability of SalB to protect against APAP-induced acute hepatotoxicity by inducing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. SalB pretreatment ameliorated acute liver injury caused by APAP, as indicated by blood aspartate transaminase levels and histological findings. Moreover, SalB pretreatment increased the expression of Nrf2, Heme oxygenase-1 (HO-1) and glutamate-l-cysteine ligase catalytic subunit (GCLC). Furthermore, the HO-1 inhibitor zinc protoporphyrin and the GCLC inhibitor buthionine sulfoximine reversed the protective effect of SalB. Additionally, siRNA-mediated depletion of Nrf2 reduced the induction of HO-1 and GCLC by SalB, and SalB pretreatment activated the phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) signaling pathways. Both inhibitors (PI3K and PKC) blocked the protective effect of SalB against APAP-induced cell death, abolishing the SalB-induced Nrf2 activation and decreasing HO-1 and GCLC expression. These results indicated that SalB induces Nrf2, HO-1 and GCLC expression via activation of the PI3K and PKC pathways, thereby protecting against APAP-induced liver injury., (Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.)
- Published
- 2015
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