Abstract：
Aim Hepatic ischemia reperfusion injury (HIRI) is a leading cause of mortality post liver transplantation, hypovolemic shock and trauma. In this study, we tested, on molecular bases, the possible protective role of two different derivatives of 2-oxindole in a preclinical model of HIRI in rats.
METHODS: HIRI was operated in male Wistar albino rats and prophylactic treatment with oxindole-curcumin (Coxi) or oxindole-vanillin (Voxi) was carried out before the operation. The biochemical and histopathological investigations, in addition to the mechanistic characterizations of the effect of the tested drugs were performed.
RESULTS: HIRI was assured with elevated liver enzymes and marked changes in histopathological features, inflammatory response and oxidative stress. Pretreatment with Coxi and Voxi improved the hepatic histopathological alterations, reduced the elevated serum liver enzymes level and hepatic Malondialdehyde (MDA) content, increased the hepatic Superoxide Dismutase (SOD) activity and reduced Glutathione (GSH) content, downregulated the expression of TNF-α, IL-6, Nod-Like Receptor p3 (NLRP3), Cleaved caspase1, Cleaved caspase 3 proteins, alongside the expression level of IL-1β, ICAM-1, VCAM-1 and BAX genes, attenuated NF-кB p-P65 Ser536 and Myeloperoxidase (MPO)-positive neutrophils, and activated the PI3K/AKT pathway.
CONCLUSIONS: Coxi and Voxi have promising hepatoprotective activity against HIRI in rats through ameliorating the biochemical and histopathological alterations, attenuating inflammatory and oxidative stress status by modulating the inflammatory TNF-α/ICAM-1, the pyroptosis NLRP3/Caspase-1, and the antioxidant PI3K/AKT pathways.
METHODS: HIRI was operated in male Wistar albino rats and prophylactic treatment with oxindole-curcumin (Coxi) or oxindole-vanillin (Voxi) was carried out before the operation. The biochemical and histopathological investigations, in addition to the mechanistic characterizations of the effect of the tested drugs were performed.
RESULTS: HIRI was assured with elevated liver enzymes and marked changes in histopathological features, inflammatory response and oxidative stress. Pretreatment with Coxi and Voxi improved the hepatic histopathological alterations, reduced the elevated serum liver enzymes level and hepatic Malondialdehyde (MDA) content, increased the hepatic Superoxide Dismutase (SOD) activity and reduced Glutathione (GSH) content, downregulated the expression of TNF-α, IL-6, Nod-Like Receptor p3 (NLRP3), Cleaved caspase1, Cleaved caspase 3 proteins, alongside the expression level of IL-1β, ICAM-1, VCAM-1 and BAX genes, attenuated NF-кB p-P65 Ser536 and Myeloperoxidase (MPO)-positive neutrophils, and activated the PI3K/AKT pathway.
CONCLUSIONS: Coxi and Voxi have promising hepatoprotective activity against HIRI in rats through ameliorating the biochemical and histopathological alterations, attenuating inflammatory and oxidative stress status by modulating the inflammatory TNF-α/ICAM-1, the pyroptosis NLRP3/Caspase-1, and the antioxidant PI3K/AKT pathways.
摘要：
目的肝缺血再灌注损伤(HIRI)是肝移植术后死亡的主要原因,低血容量性休克和创伤。在这项研究中,我们测试过,在分子基础上，2-羟吲哚的两种不同衍生物在大鼠HIRI临床前模型中的可能保护作用。
方法：在雄性Wistar白化病大鼠中进行HIRI手术，并在手术前用羟吲哚-姜黄素（Coxi）或羟吲哚-香兰素（Voxi）进行预防性治疗。生化和组织病理学研究，除了对所测试药物的作用进行机制表征之外。
结果：HIRI得到了保证，肝酶升高，组织病理学特征发生了明显变化，炎症反应和氧化应激。用Coxi和Voxi预处理改善了肝组织病理学改变，降低血清肝酶水平和肝脏丙二醛（MDA）含量升高，增加肝脏超氧化物歧化酶（SOD）活性和减少谷胱甘肽（GSH）含量，下调TNF-α的表达，IL-6，类蛋白受体p3（NLRP3），裂解的caspase1，裂解的caspase3蛋白，随着IL-1β的表达水平，ICAM-1，VCAM-1和BAX基因，减弱NF-κBp-P65Ser536和髓过氧化物酶（MPO）阳性中性粒细胞，并激活PI3K/AKT通路。
结论：Coxi和Voxi通过改善生化和组织病理学改变对大鼠HIRI具有良好的保肝活性，通过调节炎性TNF-α/ICAM-1，焦亡NLRP3/Caspase-1和抗氧化剂PI3K/AKT途径来减轻炎症和氧化应激状态。
方法：在雄性Wistar白化病大鼠中进行HIRI手术，并在手术前用羟吲哚-姜黄素（Coxi）或羟吲哚-香兰素（Voxi）进行预防性治疗。生化和组织病理学研究，除了对所测试药物的作用进行机制表征之外。
结果：HIRI得到了保证，肝酶升高，组织病理学特征发生了明显变化，炎症反应和氧化应激。用Coxi和Voxi预处理改善了肝组织病理学改变，降低血清肝酶水平和肝脏丙二醛（MDA）含量升高，增加肝脏超氧化物歧化酶（SOD）活性和减少谷胱甘肽（GSH）含量，下调TNF-α的表达，IL-6，类蛋白受体p3（NLRP3），裂解的caspase1，裂解的caspase3蛋白，随着IL-1β的表达水平，ICAM-1，VCAM-1和BAX基因，减弱NF-κBp-P65Ser536和髓过氧化物酶（MPO）阳性中性粒细胞，并激活PI3K/AKT通路。
结论：Coxi和Voxi通过改善生化和组织病理学改变对大鼠HIRI具有良好的保肝活性，通过调节炎性TNF-α/ICAM-1，焦亡NLRP3/Caspase-1和抗氧化剂PI3K/AKT途径来减轻炎症和氧化应激状态。
