Combined exposure to manganese and iron decreases oxidative stress-induced nerve damage by increasing Nrf2/HO-1/NQO1 expression. Ecotoxicology and environmental safety BACKGROUND:Manganese (Mn) and iron (Fe) are essential trace elements for humans, yet excessive exposure to Mn or Fe can accumulate in the central nervous system (CNS) and cause neurotoxicity. The purpose of this study was to investigate the effects of Mn and Fe exposure, alone or in combination, on inducing oxidative stress-induced neurological damage in rat cortical and SH-SY5Y cells, and to determine whether combined exposure to these metals increases their individual toxicity. METHODS:SH-SY5Y cells and male Sprague-Dawley rats were used to observe the effects of oxidative stress-induced neurological damage induced by exposure to manganese and iron alone or in combination. To detect the expression of anti-oxidative stress-related proteins, Nrf2, HO-1, and NQO1, and the apoptosis-related proteins, Bcl2 and Bax, and the neurological damage-related protein, α-syn. To detect reactive oxygen species generation and apoptosis. To detect the expression of the rat cortical protein Nrf2. To detect the production of proinflammatory cytokines. RESULTS:We demonstrate that juvenile developmental exposure to Mn and Fe and their combination impairs cognitive performance in rats by inducing oxidative stress causing neurodegeneration in the cortex. Mn, Fe, and their combined exposure increased the expression of ROS, Bcl2, Bax, and α-syn, activated the inflammatory factors IL-6 and IL-12, inhibited the activities of SOD and GSH, and induced oxidative stress-induced neurodegeneration both in rats and SH-SY5Y cells. Combined Mn-Fe exposure attenuated the oxidative stress induced by Mn and Fe exposure alone by increasing the expression of antioxidant factors Nrf2, HO-1, and NQO1. CONCLUSION:In both in vivo and in vitro studies, manganese and iron alone or in combination induced oxidative stress, leading to neuronal damage. In contrast, combined exposure to manganese and iron mitigated the oxidative stress induced by exposure to manganese and iron alone by increasing the expression of antioxidant factors. Therefore, studies to elucidate the main causes of toxicity and establish the molecular mechanisms of toxicity should help to develop more effective therapeutic modalities in the future. 10.1016/j.ecoenv.2023.115853

Daphnetin induces ferroptosis in ovarian cancer by inhibiting NAD(P)H:Quinone oxidoreductase 1 (NQO1). Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Ferroptosis, an emerging nonapoptotic, modulated cell death process characterized by iron accumulation and subsequent lipid peroxidation, has been intimately implicated in the development and progression of ovarian cancer (OC). Daphnetin (Daph), a natural product isolated from Daphne Korean Nakai, exhibits anticancer efficacy against various solid tumors. However, the specific role and potential mechanism underlying Daph-mediated modulation of ferroptosis in OC cells remain elusive. PURPOSE:This study aims to analyze the proferroptotic impacts of Daph on OC cells and to further explore the underlying mechanisms involved. STUDY DESIGN AND METHODS:We used CCK-8, wound healing and Transwell assays to assess whether Daph can inhibit the proliferation and migration of OC cells. Additionally, transmission electron microscopy (TEM), iron measurement, reactive oxygen species (ROS) analysis, lipid peroxidation assays, qRT-PCR and western blotting were utilized to evaluate the impact of Daph on ferroptosis and elucidate the potential underlying mechanism. Furthermore, RNA sequencing analysis, molecular docking analysis, cellular thermal shift assays (CETSAs) and NQO1 activity assays were used to predict and validate the binding and mechanistic interactions between Daph and NQO1. Subcutaneous tumorigenesis models were utilized to examine the effectiveness of Daph (and/or cisplatin) in vivo. RESULTS:Daph exerted antitumor effects by inducing the death and suppressing the migration of A2780 and SKOV3 cells. Further, Daph induced ferroptosis in OC cells, as evidenced by the accumulation of intracellular ferrous iron (Fe2+), ROS and lipid peroxides, as well as the decreases in the glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio and the expression of ferroptosis indicators (SLC7A11 and GPX4). RNA sequencing and molecular docking analyses revealed that the direct interaction between NQO1 and Daph reduced both the activity and expression of NQO1. Importantly, NQO1 overexpression effectively alleviated the effects of Daph on proliferation, migration, and ferroptosis in vitro and in vivo. Interestingly, we also found that combination treatment with Daph, a negative regulator of NQO1, and cisplatin synergistically induced cytotoxicity in OC cells. CONCLUSION:Our findings are the firstly demonstrated that Daph acts as a novel ferroptosis inducer in OC cells by specifically targeting NQO1 and is thus a promising candidate agent for OC treatment. 10.1016/j.phymed.2024.155876