Abdou Heba M, Elmageed Ghada M Abd, Hussein Hussein K, Yamari Imane, Chtita Samir, El-Samad Lamia M, Hassan Mohamed A
Department of Zoology, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.
Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, Casablanca P. O. Box 7955, Morocco.
J Xenobiot. 2025 Jan 19;15(1):16. doi: 10.3390/jox15010016.
Type 2 diabetes mellitus (T2DM) is an intricate disease correlated with many metabolic deregulations, including disordered glucose metabolism, oxidative stress, inflammation, and cellular apoptosis due to hepatic gluconeogenesis aberrations. However, there is no radical therapy to inhibit hepatic gluconeogenesis disturbances yet. We thus sought to probe the effectiveness and uncover the potential mechanism of quercetin (QCT) and silk sericin (SS) in mitigating hyperglycemia-induced hepatic gluconeogenesis disorder, which remains obscure. Administration of QCT and SS to diabetic male albino rats markedly restored the levels of glucose, insulin, advanced glycation end-products (AGEs), liver function enzymes, alpha-fetoprotein (AFP), globulin, and glycogen, in addition to hepatic carbohydrate metabolizing enzymes and gluconeogenesis in comparison with diabetic rats. Furthermore, treatment with QCT and SS modulated hepatic malondialdehyde (MD), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), nitric oxide, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β), in addition to serum interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), implying their effectiveness in safeguarding cells against oxidative impairment and inflammation. Remarkably, QCT and SS treatments led to the upregulation of expression of phosphatidylinositol 3-kinases (PI3K), phospho-Akt (p-Akt), and forkhead box-O1 (FOXO1) genes in hepatic tissues compared to diabetic rats, orchestrating these singling pathways for curtailing hyperglycemia and pernicious consequences in hepatic tissues. Importantly, immunohistochemical investigations exhibited downregulation of caspase-3 expression in rats treated with QCT and SS compared to diabetic animals. Beyond that, the histopathological results of hepatic tissues demonstrated notable correlations with biochemical findings. Interestingly, the in silico results supported the in vivo findings, showing notable binding affinities of QCT and SS to PI3K, GPx, and TNF-α proteins. These results imply that QCT and SS could mitigate oxidative stress and inflammation and regulate hepatic gluconeogenesis in diabetic rats. However, QCT revealed greater molecular interactions with the studied proteins than SS. Overall, our results emphasize that QCT and SS have significant therapeutic effects on attenuating hyperglycemia-induced hepatic gluconeogenesis, with QCT showing superior effectiveness.
2型糖尿病（T2DM）是一种复杂的疾病，与许多代谢失调相关，包括葡萄糖代谢紊乱、氧化应激、炎症以及由于肝糖异生异常导致的细胞凋亡。然而，目前尚无根治方法来抑制肝糖异生紊乱。因此，我们试图探究槲皮素（QCT）和丝素蛋白（SS）在减轻高血糖诱导的肝糖异生紊乱方面的有效性，并揭示其潜在机制，而这一机制仍不清楚。与糖尿病大鼠相比，给糖尿病雄性白化大鼠施用QCT和SS可显著恢复血糖、胰岛素、晚期糖基化终产物（AGEs）、肝功能酶、甲胎蛋白（AFP）、球蛋白和糖原的水平，以及肝脏碳水化合物代谢酶和糖异生水平。此外，QCT和SS处理还可调节肝脏丙二醛（MD）、还原型谷胱甘肽（GSH）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GPx）、一氧化氮、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β），以及血清白细胞介素-6（IL-6）和环氧合酶-2（COX-2），这表明它们在保护细胞免受氧化损伤和炎症方面具有有效性。值得注意的是，与糖尿病大鼠相比，QCT和SS处理导致肝组织中磷脂酰肌醇3激酶（PI3K）、磷酸化Akt（p-Akt）和叉头框O1（FOXO1）基因的表达上调，协调这些信号通路以减少高血糖及其在肝组织中的有害后果。重要的是，免疫组织化学研究显示，与糖尿病动物相比，用QCT和SS处理的大鼠中caspase-3表达下调。除此之外，肝组织的组织病理学结果与生化结果显示出显著相关性。有趣的是，计算机模拟结果支持了体内实验结果，表明QCT和SS与PI3K、GPx和TNF-α蛋白具有显著的结合亲和力。这些结果表明，QCT和SS可以减轻糖尿病大鼠的氧化应激和炎症，并调节肝糖异生。然而，QCT与所研究蛋白质的分子相互作用比SS更强。总体而言，我们的结果强调，QCT和SS在减轻高血糖诱导的肝糖异生方面具有显著的治疗效果，其中QCT显示出更好的有效性。
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