Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
Singapore Nuclear Research and Safety Initiative, National University of Singapore, Singapore 138602, Singapore.
Int J Mol Sci. 2020 Feb 6;21(3):1084. doi: 10.3390/ijms21031084.
The present study aimed to explore the possible radioprotective effects of celastrol and relevant molecular mechanisms in an in vitro cell and in vivo mouse models exposed to gamma radiation. Human keratinocytes (HaCaT) and foreskin fibroblast (BJ) cells were exposed to gamma radiation of 20Gy, followed by treatment with celastrol for 24 h. Cell viability, reactive oxygen species (ROS), nitric oxide (NO) and glutathione (GSH) production, lipid peroxidation, DNA damage, inflammatory cytokine levels, and NF-κB pathway activation were examined. The survival rate, levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in blood, and p65 and phospho-p65 expression were also evaluated in mice after exposure to gamma radiation and celastrol treatment. The gamma irradiation of HaCaT cells induced decreased cell viability, but treatment with celastrol significantly blocked this cytotoxicity. Gamma irradiation also increased free radical production (e.g., ROS and NO), decreased the level of GSH, and enhanced oxidative DNA damage and lipid peroxidation in cells, which were effectively reversed by celastrol treatment. Moreover, inflammatory responses induced by gamma irradiation, as demonstrated by increased levels of IL-6, TNF-α, and IL-1β, were also blocked by celastrol. The increased activity of NF-κB DNA binding following gamma radiation was significantly attenuated after celastrol treatment. In the irradiated mice, treatment with celastrol significantly improved overall survival rate, reduced the excessive inflammatory responses, and decreased NF-κB activity. As a NF-κB pathway blocker and antioxidant, celastrol may represent a promising pharmacological agent with protective effects against gamma irradiation-induced injury.
本研究旨在探讨雷公藤红素在体外细胞和体内小鼠模型中对 γ 射线辐射的可能放射防护作用及其相关分子机制。将人角质形成细胞（HaCaT）和包皮成纤维细胞（BJ）暴露于 20Gy γ 射线辐射，然后用雷公藤红素处理 24 小时。检测细胞活力、活性氧（ROS）、一氧化氮（NO）和谷胱甘肽（GSH）的产生、脂质过氧化、DNA 损伤、炎症细胞因子水平以及 NF-κB 通路的激活。还评估了小鼠在 γ 射线辐射和雷公藤红素处理后血液中白细胞介素 6（IL-6）和肿瘤坏死因子α（TNF-α）的水平以及 p65 和磷酸化 p65 的表达。γ 射线照射 HaCaT 细胞会导致细胞活力下降，但雷公藤红素处理可显著阻断这种细胞毒性。γ 射线照射还会增加自由基的产生（如 ROS 和 NO），降低 GSH 水平，并增强细胞中的氧化 DNA 损伤和脂质过氧化，这些都可被雷公藤红素处理有效逆转。此外，由 γ 射线照射引起的炎症反应，表现为 IL-6、TNF-α 和 IL-1β 水平的升高，也被雷公藤红素阻断。γ 射线照射后 NF-κB DNA 结合活性的增加在雷公藤红素处理后明显减弱。在照射的小鼠中，雷公藤红素治疗显著提高了总体存活率，降低了过度的炎症反应，并降低了 NF-κB 活性。作为 NF-κB 通路抑制剂和抗氧化剂，雷公藤红素可能是一种有前途的药理学药物，具有对抗 γ 射线辐射损伤的保护作用。
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