Abdel-Zaher Ahmed O, Bakr Marwa H, Gad Yomna H, Abdelhafez Alaa T
Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Feb 6. doi: 10.1007/s00210-025-03837-1.
Metformin exerts antidiabetic and pleiotropic effects. This study investigated the function and mechanisms of gasotransmitters and autophagy in the metformin-induced protection against ischemia/reperfusion injury (I/RI). According to measurements of serum hepatic function indicators and histopathological evaluation, metformin protected against hepatic I/RI-induced impairment of liver function and structure. In addition, metformin inhibited hepatic I/RI-induced hepatic oxidative stress, nitrosative stress, inflammation, and apoptosis. Also, it suppressed hepatic I/RI-induced decrease in hepatic heme oxygenase-1 (HO-1) and hydrogen sulfide (HS) levels and increase in nitric oxide (NO) production. Furthermore, metformin inhibited hepatic I/RI-induced decrease in protein expressions of endothelial NO synthase (eNOS), HO-1, cystathionine γ-lyase (CSE), and Beclin-1 and increase in the protein expression of inducible NO synthase (iNOS) in the liver tissue. Co-administration of the NO biosynthesis inhibitor, L-NAME, carbon monoxide(CO)-releasing molecule-A (CORM-A), the HS donor, NaHS, or the autophagy stimulator, rapamycin (RAPA), enhanced all effects of metformin. The NO donor, L-arginine, the CO biosynthesis inhibitor, zinc protoporphyrin, the HS biosynthesis inhibitor, DL-propargylglycine, or the autophagy inhibitor, chloroquine (CQ), antagonized the effects of metformin. These findings reveal, for the first time, that increasing CO, HS, and autophagy levels with subsequent decreasing NO level play a critical role in metformin's protective action against hepatic I/RI. The ability of L-NAME, CORM-A, NaHS, and RAPA to boost metformin's protective effect in hepatic I/RI may positively be attributed to their ability to lower hepatic oxidative stress, nitrosative stress, inflammation, and apoptosis.
二甲双胍具有抗糖尿病和多效性作用。本研究调查了气体信号分子和自噬在二甲双胍诱导的抗缺血/再灌注损伤（I/RI）中的作用及机制。根据血清肝功能指标测量和组织病理学评估，二甲双胍可保护肝脏免受I/RI诱导的肝功能和结构损害。此外，二甲双胍可抑制肝脏I/RI诱导的肝脏氧化应激、亚硝化应激、炎症和细胞凋亡。同时，它还可抑制肝脏I/RI诱导的肝脏血红素加氧酶-1（HO-1）和硫化氢（HS）水平降低以及一氧化氮（NO）生成增加。此外，二甲双胍可抑制肝脏I/RI诱导的肝脏组织中内皮型一氧化氮合酶（eNOS）、HO-1、胱硫醚γ-裂解酶（CSE）和Beclin-1蛋白表达降低以及诱导型一氧化氮合酶（iNOS）蛋白表达增加。联合使用NO生物合成抑制剂L-NAME、一氧化碳（CO）释放分子A（CORM-A）、HS供体NaHS或自噬刺激剂雷帕霉素（RAPA）可增强二甲双胍的所有作用。NO供体L-精氨酸、CO生物合成抑制剂锌原卟啉、HS生物合成抑制剂DL-炔丙基甘氨酸或自噬抑制剂氯喹（CQ）可拮抗二甲双胍的作用。这些发现首次揭示，提高CO、HS水平并随后降低NO水平在二甲双胍对肝脏I/RI的保护作用中起关键作用。L-NAME、CORM-A、NaHS和RAPA增强二甲双胍对肝脏I/RI保护作用的能力可能正归因于它们降低肝脏氧化应激、亚硝化应激、炎症和细胞凋亡的能力。
