Phenolic Acids Rescue Iron-Induced Damage in Murine Pancreatic Cells and Tissues

Abstract

Iron is an essential element involved in a variety of physiological functions. However, excess iron catalyzes the generation of reactive oxygen species (ROS) via the Fenton reaction. Oxidative stress, caused by an increase in intracellular ROS production, can be a contributory factor to metabolic syndromes such as dyslipidemia, hypertension, and type 2 diabetes (T2D). Accordingly, interest has grown recently in the role and use of natural antioxidants to prevent iron-induced oxidative damage. This study investigated the protective effect of the phenolic acids; ferulic acid (FA) and its metabolite ferulic acid 4-O-sulfate disodium salt (FAS) against excess iron-related oxidative stress in murine MIN6 cells and the pancreas of BALB/c mice. Rapid iron overload was induced with 50 μmol/L ferric ammonium citrate (FAC) and 20 μmol/L 8-hydroxyquinoline (8HQ) in MIN6 cells, while iron dextran (ID) was used to facilitate iron overload in mice. Cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay, ROS levels were determined by dihydrodichlorofluorescein (H2DCF) cell-permeant probe, iron levels were measured by inductively coupled plasma mass spectrometry (ICP-MS), glutathione, SOD (superoxide dismutase) and lipid peroxidation, and mRNA were assayed with commercially available kits. The phenolic acids enhanced cell viability in iron-overloaded MIN6 cells in a dose-dependent manner. Furthermore, MIN6 cells exposed to iron showed elevated levels of ROS, glutathione (GSH) depletion and lipid peroxidation (p < 0.05) compared to cells that were protected by treatment with FA or FAS. The treatment of BALB/c mice with FA or FAS following exposure to ID increased the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) gene levels in the pancreas. Consequently, levels of its downstream antioxidant genes, HO-1, NQO1, GCLC and GPX4, increased in the pancreas. In conclusion, this study shows that FA and FAS protect pancreatic cells and liver tissue from iron-induced damage via the Nrf2 antioxidant activation mechanism.

Potential Benefits of Antioxidant Phytochemicals in Type 2 Diabetes

“…A summary of polyphenols as biomarkers of oxidative stress in diabetes[152,161,[235][236][237][238][239][240].…”

Recent Advances in the Inhibition of Membrane Lipid Peroxidation by Food-Borne Plant Polyphenols via the Nrf2/GPx4 Pathway

“…119 In a mouse model with tumor-induced liver injury, a dietary As a result, the levels of its downstream antioxidant genes, such as HO-1, NQO1, GCLC, and GPx4, increased in the pancreas. 121 In the same year, Ni et al reported that resveratrol (200 mg/kg) promoted the recovery of motor function in spinal cord injured (SCI) mice by inhibiting lipid peroxides production and iron accumulation through activation of the Nrf2/GPx4 pathway. 122 Deng et al found that quercetin (40 mg/kg) upregulated the expression of antioxidant enzymes such as Sirt1, Nrf2, GPx4, SOD, and GSH in a mouse model of lipopolysaccharide-induced acute lung injury, which in turn mitigated the lung injury.…”

“…Treatment of mice with FA or FAS (20 μmol/L) increased the level of nuclear translocation of the Nrf2 gene in the pancreas. As a result, the levels of its downstream antioxidant genes, such as HO-1, NQO1, GCLC, and GPx4, increased in the pancreas . In the same year, Ni et al reported that resveratrol (200 mg/kg) promoted the recovery of motor function in spinal cord injured (SCI) mice by inhibiting lipid peroxides production and iron accumulation through activation of the Nrf2/GPx4 pathway .…”