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      Xinnaotongluo liquid protects H9c2 cells from H/R-induced damage by regulating MDM2/STEAP3

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          Abstract

          Xinnaotongluo liquid has been used to improve the clinical symptoms of patients with myocardial infarction. However, the molecular mechanism of Xinnaotongluo liquid is not completely understood. H9c2 cells exposed to hypoxia/reoxygenation (H/R) was used to simulate damage to cardiomyocytes in myocardial infarction in vitro. The biological indicators of H9c2 cells were measured by cell counting kit-8, enzyme linked immunoabsorbent assay, and western blot assay. In H/R-induced H9c2 cells, a markedly reduced murine double minute 2 (MDM2) was observed. However, the addition of Xinnaotongluo liquid increased MDM2 expression in H/R-induced H9c2 cells. And MDM2 overexpression strengthened the beneficial effects of Xinnaotongluo liquid on H9c2 cells from the perspective of alleviating oxidative damage, cellular inflammation, apoptosis and ferroptosis of H/R-induced H9c2 cells. Moreover, MDM2 overexpression reduced the protein expression of p53 and Six-Transmembrane Epithelial Antigen of Prostate 3 (STEAP3). Whereas, STEAP3 overexpression hindered the function of MDM2-overexpression in H/R-induced H9c2 cells. Our results insinuated that Xinnaotongluo liquid could protect H9c2 cells from H/R-induced damage by regulating MDM2/STEAP3, which provide a potential theoretical basis for further explaining the working mechanism of Xinnaotongluo liquid.

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy

            The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11 high ) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucose- and glutamine-dependency in SLC7A11 high cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11 high cancer. In this review, we summarize diverse regulatory mechanisms of SLC7A11 in cancer, discuss ferroptosis-dependent and -independent functions of SLC7A11 in promoting tumor development, explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells, and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment. This review will provide the foundation for further understanding SLC7A11 in ferroptosis, nutrient dependency, and tumor biology and for developing novel effective cancer therapies.
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              Ferroptosis as a novel therapeutic target for cardiovascular disease

              Cell death is an important component of the pathophysiology of cardiovascular disease. An understanding of how cardiomyocytes die, and why regeneration of cells in the heart is limited, is a critical area of study. Ferroptosis is a form of regulated cell death that is characterized by iron overload, leading to accumulation of lethal levels of lipid hydroperoxides. The metabolism of iron, lipids, amino acids and glutathione tightly controls the initiation and execution of ferroptosis. Emerging evidence shows that ferroptosis is closely associated with the occurrence and progression of various diseases. In recent years, ferroptosis has been found to play critical roles in cardiomyopathy, myocardial infarction, ischemia/reperfusion injury, and heart failure. This article reviews the mechanisms by which ferroptosis is initiated and controlled and discusses ferroptosis as a novel therapeutic target for various cardiovascular diseases.
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                Author and article information

                Contributors
                Role: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: Writing – original draftRole: Writing – review & editing
                Role: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: Funding acquisitionRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 April 2024
                2024
                : 19
                : 4
                : e0302407
                Affiliations
                [1 ] Department of Cardiology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang, P. R. China
                [2 ] Out-Patient Department, Beijing Garrison District Haidian Retired Cadres Twenty-Sixth, Beijing Garrison District Haidian Retired Cadres Twenty-Sixth, Beijing, China
                [3 ] Department of Cardiology, Beidahuang Group General Hospital, Harbin, 150088, Heilongjiang, P. R. China
                Instituto Nacional de Cardiologia Ignacio Chavez, MEXICO
                Author notes

                Competing Interests: All authors declare no conflict of interest.

                Author information
                https://orcid.org/0000-0001-9602-7563
                Article
                PONE-D-24-04312
                10.1371/journal.pone.0302407
                11029650
                38640125
                2c524050-6c4e-4570-80ea-273a7b389868
                © 2024 Cui et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 January 2024
                : 1 April 2024
                Page count
                Figures: 4, Tables: 0, Pages: 11
                Funding
                Funded by: Heilongjiang Natural Science Foundation Project
                Award ID: LH2022H074
                Award Recipient :
                This study was supported by Heilongjiang Natural Science Foundation Project, LH2022H074. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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