ElBaset Marwan A, Salem Rana S, Ayman Fairouz, Ayman Nadeen, Shaban Nooran, Afifi Sherif M, Esatbeyoglu Tuba, Abdelaziz Mahmoud, Elalfy Zahraa S
Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, 33 El-Bohouth St., Dokki, Cairo P.O. Box 12622, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt.
Antioxidants (Basel). 2022 Oct 30;11(11):2152. doi: 10.3390/antiox11112152.
Hepatic fibrosis causes severe morbidity and death. No viable treatment can repair fibrosis and protect the liver until now. We intended to discover the empagliflozin's (EMPA) hepatoprotective efficacy in thioacetamide (TAA)-induced hepatotoxicity by targeting AMPK/SIRT-1 activity and reducing HIF-1α. Rats were treated orally with EMPA (3 or 6 mg/kg) with TAA (100 mg/kg, IP) thrice weekly for 6 weeks. EMPA in both doses retracted the serum GGT, ALT, AST, ammonia, triglycerides, total cholesterol, and increased serum albumin. At the same time, EMPA (3 or 6 mg/kg) replenished the hepatic content of GSH, ATP, AMP, AMPK, or SIRT-1 and mitigated the hepatic content of MDA, TNF-α, IL-6, NF-κB, or HIF-1α in a dose-dependent manner. Likewise, hepatic photomicrograph stained with hematoxylin and eosin or Masson trichrome stain of EMPA (3 or 6 mg/kg) revealed marked regression of the hepatotoxic effect of TAA with minimal injury. Similarly, in rats given EMPA (3 or 6 mg/kg), the immunohistochemically of hepatic photomicrograph revealed minimal stain of either α-SMA or caspase-3 compared to the TAA group. Therefore, we concluded that EMPA possessed an antifibrotic effect by targeting AMPK/SIRT-1 activity and inhibiting HIF-1α. The present study provided new insight into a novel treatment of liver fibrosis.
肝纤维化会导致严重的发病和死亡。到目前为止，尚无可行的治疗方法能够修复纤维化并保护肝脏。我们旨在通过靶向AMPK/SIRT-1活性并降低HIF-1α，来发现恩格列净（EMPA）在硫代乙酰胺（TAA）诱导的肝毒性中的肝保护作用。大鼠每周三次口服EMPA（3或6 mg/kg）并腹腔注射TAA（100 mg/kg），持续6周。两种剂量的EMPA均使血清γ-谷氨酰转移酶（GGT）、谷丙转氨酶（ALT）、谷草转氨酶（AST）、氨、甘油三酯、总胆固醇水平降低，并使血清白蛋白水平升高。同时，EMPA（3或6 mg/kg）以剂量依赖的方式补充肝脏中谷胱甘肽（GSH）、三磷酸腺苷（ATP）、单磷酸腺苷（AMP）、AMPK或SIRT-1的含量，并减轻肝脏中丙二醛（MDA）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、核因子-κB（NF-κB）或HIF-1α的含量。同样，用苏木精和伊红或Masson三色染色法对EMPA（3或6 mg/kg）处理的肝脏显微照片进行染色，结果显示TAA的肝毒性作用明显减轻，损伤最小。同样，与TAA组相比，给予EMPA（3或6 mg/kg）的大鼠肝脏显微照片免疫组化显示α-平滑肌肌动蛋白（α-SMA）或半胱天冬酶-3（caspase-3）的染色最少。因此，我们得出结论，EMPA通过靶向AMPK/SIRT-1活性并抑制HIF-1α具有抗纤维化作用。本研究为肝纤维化的新治疗方法提供了新的见解。
