Abstract
Sipjeondaebo-tang (SDT) is used frequently as a herbal prescription to treat deficiency syndromes in traditional Korean medicine. We investigated the hepatoprotective effects of SDT against oxidative stress and attempted to clarify the underlying molecular mechanisms. SDT pretreatment reduced arachidonic acid (AA) plus iron-mediated cytotoxicity in a concentration-dependent manner and prevented changes in apoptosis-related protein expression. In addition, SDT pretreatment significantly reduced glutathione depletion, hydrogen peroxide production, and mitochondrial dysfunction via treatment with AA plus iron. SDT increased the phosphorylation of AMP-activated protein kinase (AMPK) in accordance with the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Experiments using an AMPK chemical inhibitor (Compound C) or CaMKK2 chemical inhibitor (STO-609) suggested that the CaMKK2-AMPK signaling pathway contributes to SDT-mediated protection of mitochondria and cells. Moreover, administration of SDT for 4 consecutive days to mice significantly reduced the alanine aminotransferase and aspartate aminotransferase activities induced by carbon tetrachloride, and the numbers of degenerated hepatocytes, infiltrated inflammatory cells, nitrotyrosine-positive cells, and 4-hydroxynonenal-positive cells in liver tissue. Therefore, SDT protects hepatocytes from oxidative stress via CaMKK2-dependent AMPK activation and has the therapeutic potential to prevent or treat oxidative stress-related liver injury.
Highlights
Oxidative stress, caused by an imbalance between reactive oxygen species (ROS) and the antioxidant defense system, plays an essential role in the pathogenesis of various types of liver disease, including hepatitis, steatosis, and fibrosis [1]
Because the maximal preventive effect against arachidonic acid (AA) plus iron-mediated cytotoxicity was observed with pretreatment above 300 μg/mL of SDT, 300 μg/mL of SDT was used in subsequent experiments
These results indicate that SDT can prevent oxidative stress-mediated apoptosis in HepG2 cells
Summary
Oxidative stress, caused by an imbalance between reactive oxygen species (ROS) and the antioxidant defense system, plays an essential role in the pathogenesis of various types of liver disease, including hepatitis, steatosis, and fibrosis [1]. Excess ROS generation, i.e., that beyond the adaptive capacity, provokes oxidation of biomolecules in hepatocytes, reduces their cellular function, and promotes cell death. AA induces mitochondriadependent apoptosis of hepatocytes [3]. In the presence of iron, AA promotes ROS generation in cells and mitochondria, depletes reduced glutathione (GSH), induces mitochondrial membrane leakage, and accelerates apoptosis of hepatocytes [3, 4]. To cope with oxidative stress, cells regulate the activity of diverse signaling pathways. Among these, AMPactivated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase and is regarded as a redoxsensitive master regulator that protects cells from oxidative
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