School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China.
School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China.
Int Immunopharmacol. 2020 Nov;88:106959. doi: 10.1016/j.intimp.2020.106959. Epub 2020 Sep 9.
Arsenic trioxide (ATO)-induced renal toxicity through oxidative stress and apoptosis restricts the therapeutic action of acute myelogenous leukemia. Crocetin (Crt) possesses antioxidant and antiapoptosis properties, and has certain renal protective effects, but it has not been reported that it has protective effect on renal injury caused by ATO. The current study explored the effects and mechanisms of Crt on kidney damage induced by ATO. Fifty Sprague-Dawley rats were randomly divided into five groups. Adult rats were given Crt concurrently with ATO for 1 week. On the 8th day, rats were killed and blood and kidney tissues were collected. Histopathological changes were measured, and kidneytissues and serum were used to determine renal function and antioxidant enzyme activity. In addition, the protein expression levels of P-PI3K, PI3K, P-AKT, AKT, CytC, Bax, Bcl-2 and Caspase-3 were determined via western blot analysis. Results revealed ATO induced renal morphological alterations and activated serum BUN and CRE. Compared with the control group, ROS, MDA, IL-1β, TNF-α, protein carbonyls (PC), lipid hydroperoxides (LOOH) and arsenic concentration levels were found to be significantly increased and SOD, CAT, GSH-Px, GSH and total sulphydryl groups (TSH) levels were attenuated in the ATO group. Crt markedly reduced oxidative stress in ATO-induced nephrotoxicity. Further, ATO induced apoptosis by significantly enhancing CytC, Bax and Caspase-3 and inhibiting Bcl-2. Administration with Crt markedly improved the expression of apoptosis factor. Moreover, Crt treatment stimulated the expressions of P-PI3K, PI3K, P-AKT, AKT induced by ATO. This study indicates Crt could prevent renal injury caused by ATO through inhibiting oxidative stress, inflammation and apoptosis, and its mechanism may be related to activation of PI3K/Akt signaling pathway.
三氧化二砷（ATO）通过氧化应激和细胞凋亡引起的肾毒性限制了急性髓系白血病的治疗作用。西红花酸（Crt）具有抗氧化和抗凋亡作用，对肾脏具有一定的保护作用，但尚未有报道称其对 ATO 引起的肾损伤具有保护作用。本研究探讨了 Crt 对 ATO 诱导的肾损伤的作用及其机制。将 50 只 Sprague-Dawley 大鼠随机分为五组。成年大鼠同时给予 Crt 和 ATO 1 周。第 8 天处死大鼠，采集血液和肾脏组织。测量组织病理学变化，检测肾脏功能和抗氧化酶活性。此外，通过 Western blot 分析测定肾脏组织和血清中 P-PI3K、PI3K、P-AKT、AKT、CytC、Bax、Bcl-2 和 Caspase-3 的蛋白表达水平。结果表明，ATO 诱导肾脏形态改变并激活血清 BUN 和 CRE。与对照组相比，ATO 组 ROS、MDA、IL-1β、TNF-α、蛋白羰基（PC）、脂质过氧化物（LOOH）和砷浓度显著增加，SOD、CAT、GSH-Px、GSH 和总巯基（TSH）水平降低。Crt 显著减轻 ATO 诱导的肾毒性中的氧化应激。此外，ATO 通过显著增强 CytC、Bax 和 Caspase-3 并抑制 Bcl-2 诱导细胞凋亡。Crt 给药可显著改善凋亡因子的表达。此外，Crt 处理可刺激 ATO 诱导的 P-PI3K、PI3K、P-AKT、AKT 的表达。本研究表明，Crt 通过抑制氧化应激、炎症和凋亡可预防 ATO 引起的肾损伤，其机制可能与激活 PI3K/Akt 信号通路有关。
