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      Therapeutic framework nucleic acid complexes targeting oxidative stress and pyroptosis for the treatment of osteoarthritis

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          Abstract

          Osteoarthritis (OA) is one of the most prevalent joint diseases and severely affects the quality of life in the elderly population. However, there are currently no effective prevention or treatment options for OA. Oxidative stress and pyroptosis play significant roles in the development and progression of OA. To address this issue, we have developed a novel therapeutic approach for OA that targets oxidative stress and pyroptosis. We synthesized tetrahedral framework nucleic acid (tFNAs) to form framework nucleic acid complexes (TNCs), which facilitate the delivery of the naturally occurring polymethoxyflavonoid nobiletin (Nob) to chondrocytes. TNC has demonstrated favorable bioavailability, stability, and biosafety for delivering Nob. Both in vitro and in vivo experiments have shown that TNC can alleviate OA and protect articular cartilage from damage by eliminating oxidative stress, inhibiting pyroptosis, and restoring the extracellular matrix anabolic metabolism of chondrocytes. These findings suggest that TNC has significant potential in the treatment of OA and cartilage injury.

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          Most cited references62

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          Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death.

          Pyroptosis was long regarded as caspase-1-mediated monocyte death in response to certain bacterial insults. Caspase-1 is activated upon various infectious and immunological challenges through different inflammasomes. The discovery of caspase-11/4/5 function in sensing intracellular lipopolysaccharide expands the spectrum of pyroptosis mediators and also reveals that pyroptosis is not cell type specific. Recent studies identified the pyroptosis executioner, gasdermin D (GSDMD), a substrate of both caspase-1 and caspase-11/4/5. GSDMD represents a large gasdermin family bearing a novel membrane pore-forming activity. Thus, pyroptosis is redefined as gasdermin-mediated programmed necrosis. Gasdermins are associated with various genetic diseases, but their cellular function and mechanism of activation (except for GSDMD) are unknown. The gasdermin family suggests a new area of research on pyroptosis function in immunity, disease, and beyond.
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            Osteoarthritis.

            Osteoarthritis (OA) is the most common joint disorder, is associated with an increasing socioeconomic impact owing to the ageing population and mainly affects the diarthrodial joints. Primary OA results from a combination of risk factors, with increasing age and obesity being the most prominent. The concept of the pathophysiology is still evolving, from being viewed as cartilage-limited to a multifactorial disease that affects the whole joint. An intricate relationship between local and systemic factors modulates its clinical and structural presentations, leading to a common final pathway of joint destruction. Pharmacological treatments are mostly related to relief of symptoms and there is no disease-modifying OA drug (that is, treatment that will reduce symptoms in addition to slowing or stopping the disease progression) yet approved by the regulatory agencies. Identifying phenotypes of patients will enable the detection of the disease in its early stages as well as distinguish individuals who are at higher risk of progression, which in turn could be used to guide clinical decision making and allow more effective and specific therapeutic interventions to be designed. This Primer is an update on the progress made in the field of OA epidemiology, quality of life, pathophysiological mechanisms, diagnosis, screening, prevention and disease management.
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              Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.

              Osteoarthritis (OA) is associated with cartilage destruction, subchondral bone remodeling and inflammation of the synovial membrane, although the etiology and pathogenesis underlying this debilitating disease are poorly understood. Secreted inflammatory molecules, such as proinflammatory cytokines, are among the critical mediators of the disturbed processes implicated in OA pathophysiology. Interleukin (IL)-1β and tumor necrosis factor (TNF), in particular, control the degeneration of articular cartilage matrix, which makes them prime targets for therapeutic strategies. Animal studies provide support for this approach, although only a few clinical studies have investigated the efficacy of blocking these proinflammatory cytokines in the treatment of OA. Apart from IL-1β and TNF, several other cytokines including IL-6, IL-15, IL-17, IL-18, IL-21, leukemia inhibitory factor and IL-8 (a chemokine) have also been shown to be implicated in OA and could possibly be targeted therapeutically. This Review discusses the current knowledge regarding the role of proinflammatory cytokines in the pathophysiology of OA and addresses the potential of anticytokine therapy in the treatment of this disease.
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                Author and article information

                Contributors
                Journal
                Mater Today Bio
                Mater Today Bio
                Materials Today Bio
                Elsevier
                2590-0064
                20 August 2024
                October 2024
                20 August 2024
                : 28
                : 101202
                Affiliations
                [a ]Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, China
                [b ]Department of Orthopedics, People's Hospital of Changshan County, Quzhou, China
                Author notes
                [* ]Corresponding author. Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China. xusanzhong@ 123456zju.edu.cn
                [∗∗ ]Corresponding author. 1507130@ 123456zju.edu.cn
                [∗∗∗ ]Corresponding author. mds@ 123456zju.edu.cn
                [1]

                Contributed equally.

                Article
                S2590-0064(24)00263-1 101202
                10.1016/j.mtbio.2024.101202
                11399809
                39280111
                19e6c881-e1db-47b8-acbe-317557a29ecc
                © 2024 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 7 June 2024
                : 3 August 2024
                : 12 August 2024
                Categories
                Full Length Article

                tetrahedral framework nucleic acids,nobiletin,osteoarthritis,oxidative stress,pyroptosis

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