The Therapeutic Activities of Metformin: Focus on the Nrf2 Signaling Pathway and Oxidative Stress Amelioration

Abstract

Abstract: In the present study, the health-protective and therapeutic properties of MET have been discussed, focusing on the effect of MET on the Nrf2 expression in patients with different pathological conditions. Metformin (MET) regulates high blood glucose, thus being an integral part of the antidiabetic medications used to treat type 2 diabetes mellitus. It belongs to biguanide class medications that are administered through the oral route. Moreover, the agent is widely known for its anti-cancer, anti-oxidant, anti-inflammatory, and neuroprotective effects. The MET modulates the nuclear factor erythroid-2 related factor-2 (Nrf2) signaling pathway, which in turn yields the above-mentioned medical benefits to patients. The Nrf2 signaling pathways are modulated in multiple ways described subsequently: 1) MET acts on the cancer cells and inactivates Raf-ERK signaling, thus reducing Nrf2 expression, 2) MET obstructs the expression of proteins that are involved in apoptosis of tumor cells and also prevents tumor cells from oxidation through an AMPK-independent pathway; 3) MET carries out Keap1-independent mechanism for reducing the levels of Nrf2 protein in cancer cells; 4) MET upregulates the Nrf2-mediated transcription to stimulate the anti-oxidant process that prevents oxidative stress in cells system and consequently gives neuroprotection from rotenone and 5) MET downregulates p65 and upregulates Nrf2 which helps improve the angiogenesis impairment stimulated by gestational diabetes mellitus. This article presents an analysis of the health-protective properties of MET and also sheds light on the effect of MET on the Nrf2 expression in patients with different pathological conditions.