Combination of metformin and luteolin synergistically protects carbon tetrachloride‐induced hepatotoxicity: Mechanism involves antioxidant, anti‐inflammatory, antiapoptotic, and Nrf2/HO‐1 signaling pathway

Abstract

Liver diseases are one of the fatal disorders due to the vital role of the liver. Carbon tetrachloride (CCl4) is the most perceived chemical substance utilized in developing models of hepatic damage. Metformin (Met) is a potent antidiabetic and redox modulatory agent that has shown anticancer and protective effects on various organs. Therefore, addition of therapy with natural antioxidative agents or herbal extracts shows defensive impacts against different injuries inside the body. Luteolin (Lut) can be found in several customary Chinese remedies. It has been reported for various pharmacological actions such as antitumor, antioxidative, and anti‐inflammatory impacts. Here, the liver injury rat model was established using CCl4 (1.00 mL/kg body weight) in vivo. The protective roles of Met and Lut separately or in combination were observed in hepatotoxicity induced by CCl4. The result was shown that both Met and Lut, while individually used, were normally active in diminishing CCl4‐caused hepatotoxicity. The combination of two drugs performed synergistically to improve liver damage caused by CCl4, as shown by the considerably improved liver dysfunction. Met and Lut showed highly antioxidative effects on CCl4‐treated rats moderately by increasing the activities and expression of the antioxidant enzymes. Along with this, a combination of Met and Lut significantly suppressed inflammatory responses, which is evidenced by the reduced level of inflammatory cytokines together with interleukin 1 beta (IL‐1β), tumor necrosis factor alpha (TNF‐α), and interleukin 6 (IL‐6). Additionally, CCl4‐agitated apoptosis was intensely reduced by Met and Lut through reducing cleaved caspase‐3 and Bax (pro‐apoptotic factor) while increasing Bcl‐2 (antiapoptotic factor) signaling pathways. Cotreatments of Met and Lut upregulated nuclear factor erythroid 2‐related factor 2 (NRF2) and heme oxygenase‐1 (HO‐1) expression in the CCl4‐intoxicated rat's liver. The above result recommended that combination of Met and Lut may have a substantial potential and synergizing impact against CCl4‐induced hepatotoxicity.

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

“…During the process of HG-caused oxidative stress and angiogenic impairment, Nrf2 has been identified as a potential target of MET for promoting angiogenesis under the HG situation. Substantial previous reports have demonstrated the antioxidative activity of MET via Nrf2 and its target genes ( Yan et al., 2019 ; Jia et al., 2020 ), indicating that MET could exert its antioxidative effect, at least partially through Nrf2. In this study, we found that Nrf2 expression was suppressed by GDM/HG, and administration of MET could reversely increase the Nrf2 level and its nuclear stabilization under GDM/HG condition to enhance the angiogenic ability.…”

“…Numerous studies have shown that Nrf2 may be a key molecule through which risk factors elicit oxidative and inflammatory response to induce angiogenic disorders ( Yan et al., 2019 ). In our study, we found the Nrf2 level was decreased in GDM placenta tissues ( Figure 2A ).…”

Development of A Novel Anti-Liver Fibrosis Formula with luteolin, licochalcone A, aloe-emodin and acacetin by network pharmacology and transcriptomics analysis

“…Specifically, luteolin is in a variety of dietary sources, such as celery, broccoli, green pepper, and parsley [27,28]. In addition, luteolin can attenuate the inflammatory responses in dendritic cells, indicating its therapeutic potential against ulcerative colitis [29], and protects against CCl 4 -induced hepatotoxicity in combination with metformin [30]. Moreover, licochalcone A, a chalconoid, can be found in the roots of Glycyrrhiza glabra or Glycyrrhiza inflata [31][32][33][34].…”

Mast Cells in Liver Fibrogenesis

“…Nowadays, there are many reports testing mast cell stabilizers, such as luteolin and curcumin in vivo for their efficacy at protecting against inflammation, disease-associated apoptosis, tumorigenesis, and overshooting oxidative stress in the liver [183,184,185,186,187]. Unfortunately, in all these studies, the impact of these stabilizers on mast cell activity was not analyzed systematically.…”