1. Studies on the protective functions of natural compounds against iron-induced toxicity in cell and mouse models
- Author
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Kose, Tugba, Latunde-Dada, Gladys Oluyemisi, and Sharp, Paul Anthony
- Subjects
613.2 - Abstract
Type 2 diabetes (T2D) is a chronic metabolic condition characterized by insulin resistance and pancreatic ß-cell failure. Over the past decade, the incidence of T2D has been increasing, and is of growing concern, as T2D is often associated with obesity. Excess iron has been shown to induce ferroptotic pancreatic cell damaged caused by oxidative stress due to increased production of reactive oxygen species (ROS). This facilitates the progressive impairment of ß-cell function in the pathogenesis of T2D. The present thesis presents two novel therapeutic strategies for iron related damage in T2D management; the first approach sought to attenuate oxidative stress with different polyphenols and the second is an inducing antioxidant pathway by polyphenols against excess iron. Studies were conducted to gather evidence on the protective functions of various polyphenols in both in vitro cell and in vivo mouse models. This research presents data on the protective effect of curcumin and (-)- epigallocatechin-3-gallate (EGCG), against iron loading and erastin-mediated ferroptosis in MIN6 cells. Curcumin and EGCG both significantly protected pancreatic cells against iron-induced oxidative damage and erastin-induced ferroptosis. The polyphenols enhanced cell viability in erastintreated MIN6 cells in a dose- and time-dependent manner. Furthermore, MIN6 cells exposed to erastin alone showed elevated levels of iron, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) degradation and lipid peroxidation compared to cells that were protected by co-treatment with curcumin or EGCG. Taken together, the data identify curcumin and EGCG as novel ferroptosis inhibitors, which might exert their protective effects by acting as iron chelators and preventing GSH depletion, GPX4 inactivation, and lipid peroxidation in MIN6 cells. The implications of the findings on the effects of iron overload and ferroptosis represent a potential therapeutic strategy against ironrelated diseases. Antioxidant therapy is a promising therapeutic strategy to prevent or even reverse the progression of iron-induced oxidative stress and ferroptosis by activating nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Thus, phenolic acids, ferulic acid (FA) and, its metabolite Ferulic Acid 4-O-Sulfate Disodium Salt (FAS) were evaluated against oxidative stress and ferroptosis in both in vitro cell and in vivo mouse models. FA and FAS both significantly protected MIN6 and HepG2 cells against erastininduced ferroptosis and iron related oxidative stress. Phenolic acids corrected oxidative stress markers in iron overloaded mice models. The prospects of those phenolic acids to reduce oxidative stress and ferroptotic cell damage will be of immense benefit in improving patient outcomes.
- Published
- 2022