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

Abstract

In the present study, the health-protective and therapeutic properties of MET are revisited, giving 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 anticancer, antioxidant, anti-inflammatory, and neuroprotective effects. The MET actually 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 antioxidant 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.

Targeting Nrf2 signaling pathway by quercetin in the prevention and treatment of neurological disorders: An overview and update on new developments

“…Six extremely preserved structural domains (Neh1-6) make up Nrf2 [68]. The human Nrf2 gene, also called a nuclear factor, erythroid 2-like 2 (NFE2L2), is found on chromosome 2, at locus 2q31.2, and is responsible for encoding a variety of isoforms that are created through alternative splicing [66,69,70]. Seven Nrf2-derived CNC homology (ECH; Neh) domains (Neh1-Neh7), which are essential for Nrf2 suppression and function, make up the Nrf2 microstructure [71,72].…”

A review of experimental and clinical studies on the therapeutic effects of pomegranate (Punica granatum) on non‐alcoholic fatty liver disease: Focus on oxidative stress and inflammation

“…Under normal conditions, Nrf2 is anchored in the cytoplasm by Kelch‐like ECH‐associated protein 1 (Keap1) and undergoes degradation (Zamanian, Giménez‐Llort, et al, 2023; Zamanian, Parra, et al, 2023). However, when exposed to OS, Nrf2 dissociates from Keap1 and translocates into the nucleus, where it binds to the antioxidant response element (ARE) and initiates the transcription of genes involved in antioxidative defense (Lv et al, 2023; Zamanian, Soltani, et al, 2023).…”

“…Nuclear factor E2‐related factor 2 (Nrf2) is a vital endogenous antioxidant transcription factor that has been shown to play a critical role in protecting cells from the damaging effects of OS (Zamanian, Giménez‐Llort, et al, 2023 ).…”