期刊
JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
卷 36, 期 1, 页码 -出版社
WILEY
DOI: 10.1002/jbt.22885
关键词
Akt/GSK-3 beta; cardiac dysfunction; ginsenoside-Rg1; mitochondrial dysfunction; P2X7 receptors; sepsis
资金
- Research Project of Hunan Provincial Health Commission [B2019066]
- Renshu fund project [RS201903]
- Key Research and Development Project in Hunan Province [2019SK 2021-3]
- Hutchison Research Fund [2019017]
- Hunan Provincial Natural Science Foundation Project [2020JJ2153, 2020JJ4406]
- Excellent Youth Project of Hunan Education Department [18B036]
The study demonstrates that G-Rg1 inhibits sepsis-induced cardiac dysfunction and mitochondrial dysfunction by activating the Akt/GSK-3 beta pathway through P2X7 receptors.
Ginsenoside-Rg1 (G-Rg1), a saponin that is a primary component of ginseng, is effective against inflammatory diseases. The P2X purinoceptor 7 (P2X7) receptor is an ATP-gated ion channel that is predominantly expressed in immune cells and plays a key role in inflammatory processes. We investigated the role of G-Rg1 in sepsis-related cardiac dysfunction and the underlying mechanism involving the regulation of the P2X7 receptor. We detected cell viability, cytotoxicity, cellular reactive oxygen species (ROS) levels, and mitochondrial membrane potential (MMP) with or without G-Rg1 in lipopolysaccharide (LPS)- or hypoxia/reoxygenation (H/R)-induced H9c2 cell models of ischemia/reperfusion injury. We applied cecal ligation and puncture (CLP) to induce a mouse model of sepsis and measured the survival duration and cardiac function of CLP mice. Next, we quantified the ROS level, MMP, respiratory chain complex I-IV enzymatic activity, and mitochondrial fusion in CLP mouse heart tissues. We then investigated the role of G-Rg1 in repairing LPS-induced cell mitochondria! damage, including mitochondrial superoxidation products. The results showed that G-Rg1 inhibited LPS- or H/R-induced cardiomyocyte apoptosis, cytotoxicity, ROS levels, and mitochondrial damage. In addition, G-Rg1 prolonged the survival time of CLP mice. G-Rg1 attenuated LPS-induced superoxide production in the mitochondria of cardiomyocytes and the excessive release of cytochrome c from mitochondria into the cytoplasm. Most importantly, G-Rg1 suppressed LPS-mediated induction of proapoptotic Bax, activated Akt, induced GSK-3 beta phosphorylation, and balanced mitochondria! calcium levels. Overall, G-Rg1 activates the Akt/GSK-3 beta pathway through P2X7 receptors to inhibit sepsis-induced cardiac dysfunction and mitochondrial dysfunction.
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