Hamed Ahmed B, El-Abhar Hanan S, Abdallah Dalaal M, Ahmed Kawkab A, Abulfadl Yasmin S
Department of Pharmacology, Toxicology, and Biochemistry, Faculty of Pharmacy, Future University in Egypt, Cairo 11835, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Saudi Pharm J. 2023 Nov;31(11):101818. doi: 10.1016/j.jsps.2023.101818. Epub 2023 Oct 5.
The potential health benefits of phytochemicals in preventing and treating diseases have gained increasing attention. Here, we proved that the methylated isoflavone prunetin possesses a reno-therapeutic effect against renal ischemia/reperfusion (I/R) insult by activating G protein-coupled receptor 30 (GPR30). After choosing the therapeutic dose of prunetin against renal I/R injury in the pilot study, male Sprague Dawley rats were allocated into 5 groups; viz., sham-operated (SO), SO injected with 1 mg/kg prunetin intraperitoneally for three successive days, untreated I/R, I/R treated with prunetin, and I/R treated with G-15, the selective GPR30 blocker, followed by prunetin. Treatment with prunetin reversed the I/R renal injury effect and majorly restored normal renal function and architecture. Mechanistically, prunetin restored the I/R-induced depletion of renal GPR30, an impact that was canceled by the pre-administration of G-15. Additionally, post-administration of prunetin normalized the boosted inflammatory markers indoxyl sulfate, TLR4, and TRIF and abrogated renal cell demise by suppressing necroptotic signaling, verified by the inactivation of p-RIPK1, p-RIPK3, and p-MLKL while normalizing the inhibited caspase-8. Besides, prunetin reversed the I/R-mediated mitochondrial fission by inhibiting the protein expression of PGMA5 and p-DRP-1. All these favorable impacts of prunetin were nullified by G-15. To sum up, prunetin exhibited a significant reno-therapeutic effect evidenced by the enhancement of renal morphology and function, the suppression of the inflammatory cascade indoxyl sulfate/TLR4/TRIF, which turns off the activated/phosphorylated necroptotic trajectory RIPK1/RIPK3/MLKL, while enhancing caspase-8. Additionally, prunetin opposed the mitochondrial fission pathway RIPK3/PGMA5/DRP-1, effects that are mediated via the activation of GPR30.
植物化学物质在预防和治疗疾病方面的潜在健康益处日益受到关注。在此，我们证明甲基化异黄酮李属素通过激活G蛋白偶联受体30（GPR30）对肾缺血/再灌注（I/R）损伤具有肾脏治疗作用。在前期研究中选择了李属素对肾I/R损伤的治疗剂量后，将雄性Sprague Dawley大鼠分为5组；即假手术组（SO）、连续三天腹腔注射1mg/kg李属素的SO组、未治疗的I/R组、用李属素治疗的I/R组以及先用选择性GPR30阻滞剂G-15治疗然后用李属素治疗的I/R组。用李属素治疗可逆转I/R肾损伤效应，并主要恢复正常肾功能和结构。从机制上讲，李属素恢复了I/R诱导的肾脏GPR30耗竭，而预先给予G-15可消除这一影响。此外，李属素给药后使升高的炎症标志物硫酸吲哚酚、TLR4和TRIF恢复正常，并通过抑制坏死性凋亡信号消除肾细胞死亡，这通过p-RIPK1、p-RIPK3和p-MLKL的失活以及使受抑制的caspase-8恢复正常得到证实。此外，李属素通过抑制PGMA5和p-DRP-1的蛋白表达逆转I/R介导的线粒体分裂。G-15使李属素的所有这些有利影响无效。综上所述，李属素表现出显著的肾脏治疗作用，表现为肾脏形态和功能的改善、炎症级联反应硫酸吲哚酚/TLR4/TRIF的抑制，这关闭了激活/磷酸化的坏死性凋亡轨迹RIPK1/RIPK3/MLKL，同时增强了caspase-8。此外，李属素对抗线粒体分裂途径RIPK3/PGMA5/DRP-1，这些作用是通过GPR30的激活介导的。
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