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    Antioxidative Effects of Curcumin on Erastin-Induced Ferroptosis Through GPX4 Signalling
    (MDPI, 2025) Kose, T; Sharp, PA; Latunde-Dada, GO
    Background/Objectives: Pancreatic cancer is a common gastrointestinal cancer with high risk of mortality. Currently, the therapeutic strategies for pancreatic cancers are surgery, chemotherapy, and radiotherapy, none of which are effective treatments. Ferroptosis is a new form of cell death that is iron (Fe)-dependent and characterized by lipid peroxidation, which is a new approach for treatment of pancreatic cancer. Therefore, this study was dedicated to investigating the effect of erastin and Ras-selective lethal small molecule 3 (RLS3) as ferroptosis inducers as well as focusing on the antioxidant effects of two natural products, curcumin and (-)-epigallocatechin-3-gallate (EGCG), against ferroptosis. Methods: PANC1 cells were treated with 20 mu mol/L curcumin or EGCG and then exposed to 20 mu mol/L erastin. Cell viability was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay, Reactive Oxygen Species (ROS) were measured by dihydrodichlorofluorescein (H2DCF) cell-permeant probe, Fe levels were determined by inductively coupled plasma mass spectrometry (ICP-MS), and glutathione (GSH), lipid peroxidation, Western blot, and mRNA were assayed with commercially available kits. Results: Curcumin and EGCG enhanced cell viability in erastin-treated PANC1 cells in a dose-and time-dependent manner. Erastin-treated PANC1 cells exhibited the elevated levels of GSH depletion, ROS productions, and lipid peroxidation while curcumin reversed the erastin-induced ferroptotic effects. The treatment of erastin-induced PANC1 cells with curcumin increased the GPX4 mRNA gene and protein levels. Also, curcumin decreased the FTH1 mRNA gene levels as a strong Fe chelator. Conclusions: In conclusion, this study shows that erastin can be potentially a therapeutic strategy for treatment of cancer cells. Additionally, curcumin might play an antioxidant role at the specific concentrations, potentially mitigating ferroptosis in cells.
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    Effect of histidine and carnosine on haemoglobin recovery in anaemia induced-kidney damage and iron-loading mouse models
    (SPRINGER WIEN, 2025) Vera-Aviles, M; Moreno-Fernandez, J; Kose, T; Hider, R; Latunde-Dada, GO
    Histidine and carnosine can form complexes with divalent metal ions such as Fe2+, potentially providing stability to intracellular labile iron. Anaemia is a common comorbidity in the late stages of kidney disease, and patients are treated with erythropoiesis-stimulating agents (ESAs) and iron supplementation. However, iron supplementation is also associated with worse long-term outcomes. The purpose of this study is to investigate how histidine and carnosine supplementation can reduce symptoms of anaemia of chronic kidney disease (CKD) and the effects associated with iron-overloaded conditions. Adenine-induced chronic kidney disease mice were treated with histidine and carnosine by oral gavage for 10 days. Additionally, a model involving iron overload in mice was established, and these mice received concurrent treatment with histidine and carnosine. Haemoglobin, non-haem iron, malondialdehyde (MDA) and iron parameters were measured. Carnosine increased erythropoietin (EPO) levels (35.62 mu g/ml +/- 11.43) and resulted in haemoglobin repletion (16.7 g/dL +/- 3.4). When iron was supplemented alongside with histidine or carnosine, there were better effects on haemoglobin repletion (14.22 +/- 1.7 and 13.82 +/- 2.15 g/ dL respectively), ferritin (59.5 +/- 16.4, 52 +/- 29.5 mu g/ml) and non-haem iron (0.8 +/- 0.21, 0.7 +/- 0.38 nmol/mg), than the group receiving iron alone (p < 0.05). Furthermore, histidine and carnosine reduced non-haem iron and MDA, in iron-loaded conditions (p < 0.05). These positive effects observed in histidine and carnosine could be associated with reactive oxygen species (ROS) scavenging. EPO restoring levels in CKD model and the increment in haemoglobin and ferritin in carnosine treatments suggested the potential formation of a ternary complex with iron-glutathione. In conclusion, our results indicate the beneficial effect of histidine and carnosine in the context of iron supplementation for the correction of haemoglobin and protection against iron-loaded conditions.