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      Emerging Potential Therapeutic Targets of Ferroptosis in Skeletal Diseases

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          Abstract

          Ferroptosis is a new programmed cell death characterized by the accumulation of lipid peroxidation mediated by iron and inflammation. Since the transcentury realization of ferroptosis as an iron-dependent modality of nonapoptotic cell death in 2012, there has been growing interest in the function of ferroptosis and its relationship to clinical diseases. Recent studies have shown that ferroptosis is associated with multiple diseases, including degenerative diseases, ischemia reperfusion injury, cardiovascular disease, and cancer. Cell death induced by ferroptosis has also been related to several skeletal diseases, such as inflammatory arthritis, osteoporosis, and osteoarthritis. Research on ferroptosis can clarify the pathogenesis of skeletal diseases and provide a novel therapeutic target for its treatment. In this review, we summarize current information about the molecular mechanism of ferroptosis and describe its emerging role and therapeutic potential in skeletal diseases.

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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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            Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

            Summary Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1–4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0–8·4) while the total sum of global YLDs increased from 562 million (421–723) to 853 million (642–1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6–9·2) for males and 6·5% (5·4–7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782–3252] per 100 000 in males vs s1400 [1279–1524] per 100 000 in females), transport injuries (3322 [3082–3583] vs 2336 [2154–2535]), and self-harm and interpersonal violence (3265 [2943–3630] vs 5643 [5057–6302]). Interpretation Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury. Funding Bill & Melinda Gates Foundation.
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              Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

              Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2022
                30 July 2022
                : 2022
                : 3112388
                Affiliations
                1Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
                2School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Tianjin 300350, China
                3Orthopedics Institute, Medical College, Soochow University, Suzhou 215000, China
                4State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Soochow University, Suzhou, 215123, China
                Author notes

                Academic Editor: Lianxiang Luo

                Author information
                https://orcid.org/0000-0002-8681-5096
                https://orcid.org/0000-0001-8334-2476
                https://orcid.org/0000-0002-0493-4391
                https://orcid.org/0000-0001-6551-9469
                https://orcid.org/0000-0003-1182-290X
                https://orcid.org/0000-0002-9168-2929
                https://orcid.org/0000-0002-3485-5563
                https://orcid.org/0000-0003-4375-2803
                Article
                10.1155/2022/3112388
                9356861
                35941905
                c3c33462-e946-4cfd-946e-04e97f769460
                Copyright © 2022 Xin Liu et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 8 June 2022
                : 12 July 2022
                Funding
                Funded by: Special Project of Diagnosis and Treatment Technology for Key Clinical Diseases in Suzhou
                Award ID: LCZX201824
                Award ID: LCZX202003
                Funded by: Natural Science Foundation of Jiangsu Province
                Award ID: BE2021650
                Award ID: BK20200198
                Funded by: Young Medical Talents of Jiangsu Province
                Award ID: QNRC2016751
                Funded by: National Natural Science Foundation of China
                Award ID: 82074473
                Award ID: 82072498
                Award ID: 82072425
                Funded by: Priority Academic Program Development of Jiangsu Higher Education Institutions
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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