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      Cell death regulation: A new way for natural products to treat osteoporosis

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      Pharmacological Research
      Elsevier BV

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          Abstract

          <p class="first" id="d589151e115">Osteoporosis is a common metabolic bone disease that results from the imbalance of homeostasis within the bone. Intra-bone homeostasis is dependent on a precise dynamic balance between bone resorption by osteoclasts and bone formation by mesenchymal lineage osteoblasts, which comprises a series of complex and highly standardized steps. Programmed cell death (PCD) (e.g., apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis) is a cell death process that involves a cascade of gene expression events with tight structures. These events play a certain role in regulating bone metabolism by determining the fate of bone cells. Moreover, existing research has suggested that natural products derived from a wide variety of dietary components and medicinal plants modulate the PCDs based on different mechanisms, which show great potential for the prevention and treatment of osteoporosis, thus revealing the emergence of more acceptable complementary and alternative drugs with lower costs, fewer side effects and more long-term application. Accordingly, this review summarizes the common types of PCDs in the field of osteoporosis. Moreover, from the perspective of targeting PCDs, this review also discussed the roles of currently reported natural products in the treatment of osteoporosis and the involved mechanisms. Based on this, this review provides more insights into new molecular mechanisms of osteoporosis and provides a reference for developing more natural anti-osteoporosis drugs in the future. </p>

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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: 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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              Regulation of ferroptotic cancer cell death by GPX4.

              Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Pharmacological Research
                Pharmacological Research
                Elsevier BV
                10436618
                January 2023
                January 2023
                : 187
                : 106635
                Article
                10.1016/j.phrs.2022.106635
                36581167
                82932ec5-16b7-43e1-bcb2-7093087c002e
                © 2023

                https://www.elsevier.com/tdm/userlicense/1.0/

                http://creativecommons.org/licenses/by-nc-nd/4.0/

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