Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia, 61111, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Oct;397(10):7981-7994. doi: 10.1007/s00210-024-03119-2. Epub 2024 May 18.
The defect in the hepatobiliary transport system results in an impairment of bile flow, leading to accumulation of toxic compounds with subsequent liver disorders. Vincamine, a plant indole alkaloid that is utilized as a dietary supplement, has been known for its promising pharmacological activities. For the first time, the present study was planned to estimate, at the molecular level, the potentiality of vincamine against alfa-naphthyl isothiocyanate (ANIT)-induced hepatic cholestasis. Liver function tests were analyzed. Hepatic activity of SOD and levels of GSH and MDA were assessed. Hepatic contents of bax, bcl2, NF-kB, PPARγ, catalase, heme-oxygenase-1, NTCP, and BSEP were evaluated using ELISA. mRNA levels of NF-kB, IL-1β, IL-6, TNFα, PDGF, klf6, PPARγ, and P53 were examined using qRT-PCR. PI3K, Akt and cleaved caspase-3 proteins were assessed using western blotting. Histopathological analyses were performed using hematoxylin & eosin staining. ANIT-induced hepatic cholestasis elevated liver function tests, including AST, ALT, GGT, ALP, and total bilirubin. ANIT reduced the protein expression of NTCP and BSEP hepatic transporters. It induced the expression of the inflammatory genes, TNFα, IL-6, IL-1β, and PDGF, and the expression of NF-kB at the genetic and protein level and suppressed the anti-inflammatory genes, klf6 and PPARγ. Also, antioxidant markers were reduced during ANIT induction such as GSH, SOD, catalase, heme-oxygenase-1 and PI3K/Akt pathway, while MDA levels were elevated. Furthermore, the expression of P53 gene, bax and cleaved caspase 3 proteins were activated, while bcl2 was inhibited. Also, the histopathological analysis showed degeneration of hepatocytes and inflammatory cellular infiltrates. However, vincamine treatment modulated all these markers. It improved liver function tests. It inhibited the expression of NF-kB, TNFα, IL-6, IL-1β and PDGF and activated the expression of klf6 and PPARγ. Furthermore, vincamine reduced MDA levels and induced GSH, SOD, catalase, heme-oxygenase-1 and PI3K/Akt pathway. Additionally, it inhibited expression of P53 gene, bax and cleaved caspase 3 proteins. More interestingly, vincamine showed better outcomes on the hepatic histopathological analysis and improved the alterations induced by ANIT. Vincamine alleviated hepatic dysfunction during ANIT-induced intrahepatic cholestasis through its anti-inflammatory and antioxidant efficacies by the modulation of NF-kB/PDGF/klf6/PPARγ and PI3K/Akt pathways.
肝胆转运系统的缺陷导致胆汁流动受损，导致有毒化合物的积累，随后出现肝脏疾病。长春胺是一种植物吲哚生物碱，用作膳食补充剂，其具有有前途的药理学活性。本研究首次计划从分子水平评估长春胺对α-萘基异硫氰酸酯（ANIT）诱导的肝内胆汁淤积的潜在作用。分析肝功能试验。评估肝组织中超氧化物歧化酶（SOD）的活性以及谷胱甘肽（GSH）和丙二醛（MDA）的水平。使用 ELISA 评估肝组织中 bax、bcl2、NF-kB、PPARγ、过氧化氢酶、血红素加氧酶-1、NTCP 和 BSEP 的含量。使用 qRT-PCR 检测 NF-kB、IL-1β、IL-6、TNFα、PDGF、klf6、PPARγ 和 P53 的 mRNA 水平。使用 Western blot 检测 PI3K、Akt 和裂解的 caspase-3 蛋白。使用苏木精和伊红（H&E）染色进行组织病理学分析。ANIT 诱导的肝内胆汁淤积症会升高 AST、ALT、GGT、ALP 和总胆红素等肝功能测试指标。ANIT 降低了 NTCP 和 BSEP 肝转运蛋白的蛋白表达。它诱导 TNFα、IL-6、IL-1β 和 PDGF 等炎症基因以及 NF-kB 在遗传和蛋白水平上的表达，并抑制抗炎基因 klf6 和 PPARγ 的表达。此外，在 ANIT 诱导期间，抗氧化标记物如 GSH、SOD、过氧化氢酶、血红素加氧酶-1 和 PI3K/Akt 途径减少，而 MDA 水平升高。此外，P53 基因、bax 和裂解的 caspase 3 蛋白的表达被激活，而 bcl2 被抑制。此外，组织病理学分析显示肝细胞变性和炎症细胞浸润。然而，长春胺治疗调节了所有这些标志物。它改善了肝功能测试。它抑制了 NF-kB、TNFα、IL-6、IL-1β 和 PDGF 的表达，并激活了 klf6 和 PPARγ 的表达。此外，长春胺降低了 MDA 水平，并诱导了 GSH、SOD、过氧化氢酶、血红素加氧酶-1 和 PI3K/Akt 途径。此外，它抑制了 P53 基因、bax 和裂解的 caspase 3 蛋白的表达。更有趣的是，长春胺在肝组织病理学分析中表现出更好的结果，并改善了 ANIT 诱导的改变。长春胺通过调节 NF-kB/PDGF/klf6/PPARγ 和 PI3K/Akt 途径，通过其抗炎和抗氧化作用，减轻了 ANIT 诱导的肝内胆汁淤积症中的肝功能障碍。
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