Department of Biotechnology, Assam University, Silchar 788011, Assam, India.
Department of Biotechnology, Assam University, Silchar 788011, Assam, India.
Life Sci. 2021 Feb 1;266:118870. doi: 10.1016/j.lfs.2020.118870. Epub 2020 Dec 10.
Betel-nut, a popular masticatory among Southeast Asian populations is a class I carcinogen, previously associated with dyslipidemia and aberrant lipid metabolism, and is reported to be used more frequently by females, than males. This study investigates the potential of repurposing the anti-diabetic drug, vildagliptin, a dipeptidyl peptidase-4 inhibitor, for alleviating the oncogenic condition in female Swiss Albino mice administered an aqueous extract of betel-nut (AEBN) orally (2 mg ml) for 24 weeks.
Tissues were investigated by histopathological, immunohistochemical and apoptosis assays. Biochemical analyses of oxidative stress markers and lipid profile were performed using different tissues and sera. The expressions of different proteins involved in lipid metabolism and oncogenic pathways were evaluated by Western blotting.
AEBN induced carcinogenesis primarily in the liver by significantly impairing AMPK signaling, inducing oxidative stress, activating Akt/mTOR signaling, increasing Ki-67 immunoreactivity and cyclin D1 expression, and significantly diminishing apoptosis. Co-administration of AEBN with vildagliptin (10 mg kg body weight) for 8 weeks reduced liver dysplasia, and significantly decreased free palmitic acid, increased free oleic acid, normalized lipid profile, decreased oxidative stress, cyclin D1 expression, Ki-67 immunoreactivity, and Bcl2 expression, and increased the ratio of apoptotic/non-apoptotic cells. Mechanistically, vildagliptin elicited these physiological and molecular alterations by restoring normal AMPK signaling and reducing the cellular expressions of FASN and HMGCR, restoring AMPK-dependent phosphorylation of p53 at Ser-15 and reducing Akt/mTOR signaling.
These results indicate that vildagliptin may alleviate betel-nut induced carcinogenesis in the liver of female mice.
槟榔是东南亚地区流行的咀嚼物，属于 I 类致癌物质，先前与血脂异常和脂质代谢异常有关，据报道其使用频率女性高于男性。本研究旨在探讨将抗糖尿病药物维格列汀（一种二肽基肽酶-4 抑制剂）重新用于缓解女性瑞士白化小鼠的致癌状态，这些小鼠经口给予槟榔水提物（AEBN）（2mg/ml）24 周。
通过组织病理学、免疫组织化学和细胞凋亡检测来研究组织。使用不同的组织和血清进行生化分析，以评估氧化应激标志物和脂质谱。通过 Western blot 评估参与脂质代谢和致癌途径的不同蛋白质的表达。
AEBN 通过显著损害 AMPK 信号通路、诱导氧化应激、激活 Akt/mTOR 信号通路、增加 Ki-67 免疫反应性和细胞周期蛋白 D1 的表达，显著减少细胞凋亡，从而主要在肝脏诱导致癌作用。AEBN 与维格列汀（10mg/kg 体重）共同给药 8 周可减轻肝发育不良，并显著降低游离棕榈酸，增加游离油酸，使脂质谱正常化，降低氧化应激、细胞周期蛋白 D1 的表达、Ki-67 免疫反应性和 Bcl2 的表达，增加凋亡/非凋亡细胞的比例。从机制上讲，维格列汀通过恢复正常的 AMPK 信号通路和降低 FASN 和 HMGCR 的细胞表达，恢复 AMPK 依赖性 p53 在 Ser-15 的磷酸化并降低 Akt/mTOR 信号通路，引起这些生理和分子变化。
这些结果表明，维格列汀可能缓解槟榔诱导的雌性小鼠肝脏致癌作用。
