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      Acetyl zingerone ameliorates osteoarthritis by inhibiting chondrocyte programmed cell death

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          Abstract

          Osteoarthritis (OA) is a degenerative disease that ultimately leads to joint deformity. The pathogenesis of OA is believed to involve abnormal chondrocyte death, with ferroptosis serving a key role in chondrocyte damage. The present study investigated whether acetyl zingerone (AZ), a newly identified antioxidant derived from curcumin, can alleviate the progression of OA. To investigate this, the present study performed various experiments, including crystal violet staining, flow cytometry, immunofluorescence and western blot analysis. In addition, dual validation was performed using in vivo and in vitro experiments; a mouse OA model was constructed for the in vivo experiments, and chondrocytes were used for the in vitro experiments. Destabilization of the medial meniscus (DMM) surgery was performed to establish an OA model in mice and IL-1β was used to induce an OA model in vitro. The results indicated that AZ may promote chondrocyte viability and the expression of extracellular matrix components. Furthermore, AZ reduced the occurrence of ferroptosis by promoting the expression of glutathione peroxidase 4, inhibiting cartilage destruction and osteophyte formation, and alleviating damage to articular cartilage caused by DMM surgery. Mechanistically, the activation of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 may be responsible for the anti-ferroptosis effects of AZ on chondrocytes. These findings indicated that AZ may be considered a promising candidate for OA therapy.

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          Most cited references71

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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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            Ferroptosis: mechanisms, biology and role in disease

            The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.
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              Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.

              Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.
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                Author and article information

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                November 2023
                11 September 2023
                11 September 2023
                : 28
                : 5
                : 202
                Affiliations
                [1 ]Department of Orthopedics, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou Second People's Hospital, Changzhou Medical Center, Changzhou, Jiangsu 213003, P.R. China
                [2 ]Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Jiangsu Province Key Laboratory of Fine Petrochemical Engineering, School of Petrochemical Engineering, Changzhou University, Changzhou, Jiangsu 213164, P.R. China
                Author notes
                Correspondence to: Dr Rongbin Sun or Dr Su Ni, Department of Orthopedics, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou Second People's Hospital, Changzhou Medical Center, 68 Ge Hu Middle Road, Changzhou, Jiangsu 213003, P.R. China, E-mail: rongbin_sunsina.com vivian.nisu@ 123456gmail.com
                [*,**]

                Contributed equally

                Article
                MMR-28-5-13089
                10.3892/mmr.2023.13089
                10540024
                37711057
                65e59747-b726-432b-a231-4f24e261fb09
                Copyright: © Chen et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 12 May 2023
                : 16 August 2023
                Funding
                Funded by: Top Talent of Changzhou ‘The 14th Five-Year Plan’ High-Level Health Talents Training Project
                Award ID: 2022CZBJ078 to SN
                Funded by: Major Research Project of Changzhou Commission of Health
                Award ID: ZD202218 to SN
                This work was supported by the Top Talent of Changzhou ‘The 14th Five-Year Plan’ High-Level Health Talents Training Project (grant no. 2022CZBJ078 to SN) and the Major Research Project of Changzhou Commission of Health (grant no. ZD202218 to SN).
                Categories
                Articles

                chronic pain,inflammation,arthritis,oxidative stress
                chronic pain, inflammation, arthritis, oxidative stress

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