Leonurine has been reported to have cardioprotective effects against ischemia-induced myocardial injury by reducing intracellular reactive oxygen species levels and increasing antiapoptosis-associated protein expression [19]. In addition, some studies have reported that leonurine can reduce the infarction area of the cerebral cortex and repair neurological damage [12, 20, 21]. In this study, we found that leonurine had neuroprotective effects on OGD-induced PC12 cells through downregulating the protein expression of Cx36 and pCaMKII/CaMKII.
Under ischemic conditions, the lack of glucose, oxygen, ATP, and phosphocreatine [32] leads to uncontrolled membrane depolarization and rapid increase in intracellular Ca2+, which is a result of influx through a variety of Ca2+-permeable ion channels and release from intracellular stores [33]. Extracellular accumulation of glutamate and other neurotransmitters also activates receptors that lead to further depolarization and increases intracellular Ca2+ and Na+, a self-reinforcing cycle of events known as excitotoxicity. The rise in intracellular Ca2+ rapidly activates CaMKII through binding of Ca2+-calmodulin. Although CaMKII is only one of many Ca2+-stimulated enzymes that are activated following ischemia, CaMKII appears to be one of the major upstream regulators in postischemia neurotoxicity because its inhibition can prevent the majority of infarct formation processes [34]. The neuroprotective effect of CaMKII inhibitors was observed in this study, although a cytotoxic effect was also noted. We speculate that the inhibition of CaMKII may affect multiple Ca2+-dependent processes aside from cell death induction. This requires further study.
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Radiation-induced lung injury (RILI) is one of the most common, serious, and dose-limiting toxicities of thoracic radiotherapy. A primary cause for this is the radiation-induced cell death. Ferroptosis is a recently recognized form of regulated cell death, characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). The ROS generated by irradiation might be the original trigger of ferroptosis in RILI. In addition, activation of the P62-Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (NRF2) pathway has been shown to blunt ferroptosis and thus acts as a protective factor. Therefore, this study aimed to explore the protective effect of the P62-Keap1-NRF2 pathway against radiation-induced ferroptosis in alveolar epithelial cells. First, we found that radiation induced ferroptosis in vitro using a RILI cell model, which could be significantly reduced by ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor. Additionally, overexpression of P62 interacted with Keap1 to facilitate the translocation of NRF2 into the nucleus and promote the expression of its target proteins, including quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO1), and ferritin heavy chain 1 (FTH1). In summary, our results demonstrated that the activation of the P62-Keap1-NRF2 pathway prevents radiation-induced ferroptosis in RILI cells, providing a theoretical basis of finding a potential therapeutic approach for RILI.
Therefore, in this study, we developed a RILI cell model in which alveolar epithelial cells were exposed to 10Gy and explored the critical signal transduction pathways involved in ferroptosis induction in RILI. We demonstrated that radiation-induced oxidative stress inhibited ferroptosis by activating the P62-Keap1-NRF2 pathway in RILI cells. Furthermore, upregulation of NRF2 protected the RILI cells against ferroptosis by upregulating several antioxidant proteins that participate in iron and ROS metabolism, including quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO1), and ferritin heavy chain 1 (FTH1). Together, our results revealed a novel therapeutic strategy for preventing and managing RILI. 2ff7e9595c
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