{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T14:02:47Z","timestamp":1785333767505,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["1R01DK120866-01"],"award-info":[{"award-number":["1R01DK120866-01"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["R01-CA-221813"],"award-info":[{"award-number":["R01-CA-221813"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Institute of Cancer (NCI)","doi-asserted-by":"publisher","award":["1R01DK120866-01"],"award-info":[{"award-number":["1R01DK120866-01"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Institute of Cancer (NCI)","doi-asserted-by":"publisher","award":["R01-CA-221813"],"award-info":[{"award-number":["R01-CA-221813"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Advent Health","award":["1R01DK120866-01"],"award-info":[{"award-number":["1R01DK120866-01"]}]},{"name":"Advent Health","award":["R01-CA-221813"],"award-info":[{"award-number":["R01-CA-221813"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Doxorubicin (DOX) is an incessantly used chemotherapeutic drug that can cause detrimental dose-dependent effects such as cardiotoxicity and congestive heart failure. Hence, there is a need to discover innovative therapeutic approaches to counteract DOX-induced cardiotoxicity (DIC). MSC-Exos have shown to reduce apoptosis and cardiac fibrosis and promote cardiomyocyte proliferation in myocardial infracted mice. However, the effect of MSC-Exos on ameliorating DOX-induced pyroptosis has not been investigated. In this current study, H9c2 were first exposed to DOX to stimulate pyroptosis, followed by subsequent treatment with MSC-Exos, with further analysis performed through immunocytochemistry, western blotting, and RT-PCR. Our data depicted that post-treatment with MSC-Exos significantly (p &lt; 0.05) reduced the HMGB1\/TLR4 axis, inflammasome formation (NLRP3), pyroptotic markers (caspase-1, IL-1\u03b2, and IL-18), and the pyroptotic executioner (GSDMD) in DOX-treated H9c2 cells. In conclusion, our data show that MSC-Exos attenuates inflammation-induced pyroptosis in our in vitro DIC model. Our findings indicate that MSC-Exos may serve as a promising therapeutic intervention for mitigating DIC, as they maintain the therapeutic capabilities of MSCs while circumventing the drawbacks associated with traditional stem cell therapy.<\/jats:p>","DOI":"10.3390\/ph17010093","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T09:39:57Z","timestamp":1704879597000},"page":"93","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mesenchymal Stem Cell-Derived Exosomes Ameliorate Doxorubicin-Induced Cardiotoxicity"],"prefix":"10.3390","volume":"17","author":[{"given":"Sawdah A.","family":"Ali","sequence":"first","affiliation":[{"name":"Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5030-2785","authenticated-orcid":false,"given":"Dinender K.","family":"Singla","sequence":"additional","affiliation":[{"name":"Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.ejphar.2017.10.043","article-title":"Molecular Mechanism of Doxorubicin-Induced Cardiomyopathy\u2014An Update","volume":"818","author":"Renu","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rawat, P.S., Jaiswal, A., Khurana, A., Bhatti, J.S., and Navik, U. (2021). Doxorubicin-Induced Cardiotoxicity: An Update on the Molecular Mechanism and Novel Therapeutic Strategies for Effective Management. Biomed. Pharmacother., 139.","DOI":"10.1016\/j.biopha.2021.111708"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Arora, D., Sharma, C., Jaglan, S., and Lichtfouse, E. (2019). Pharmaceuticals from Microbes: The Bioengineering Perspective, Springer International Publishing. Environmental Chemistry for a Sustainable World.","DOI":"10.1007\/978-3-030-01881-8"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"119527","DOI":"10.1016\/j.lfs.2021.119527","article-title":"A Comprehensive Review on Time-Tested Anticancer Drug Doxorubicin","volume":"278","author":"Sritharan","year":"2021","journal-title":"Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"853","DOI":"10.4103\/0973-1482.139267","article-title":"An Overview of Doxorubicin Formulations in Cancer Therapy","volume":"10","author":"Rivankar","year":"2014","journal-title":"J. Cancer Res. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41419-021-03614-x","article-title":"Regulated Cell Death Pathways in Doxorubicin-Induced Cardiotoxicity","volume":"12","author":"Christidi","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1007\/s10741-020-09968-2","article-title":"Anthracycline-Induced Cardiotoxicity: Mechanisms of Action, Incidence, Risk Factors, Prevention, and Treatment","volume":"26","author":"Saleh","year":"2021","journal-title":"Heart Fail. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Singla, D.K., Johnson, T.A., and Tavakoli Dargani, Z. (2019). Exosome Treatment Enhances Anti-Inflammatory M2 Macrophages and Reduces Inflammation-Induced Pyroptosis in Doxorubicin-Induced Cardiomyopathy. Cells, 8.","DOI":"10.3390\/cells8101224"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"H460","DOI":"10.1152\/ajpheart.00056.2019","article-title":"Embryonic Stem Cell-Derived Exosomes Inhibit Doxorubicin-Induced TLR4-NLRP3-Mediated Cell Death-Pyroptosis","volume":"317","author":"Singla","year":"2019","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"760","DOI":"10.7150\/ijbs.65258","article-title":"Underlying the Mechanisms of Doxorubicin-Induced Acute Cardiotoxicity: Oxidative Stress and Cell Death","volume":"18","author":"Kong","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.trsl.2022.05.001","article-title":"Gasdermin D Mediates Doxorubicin-Induced Cardiomyocyte Pyroptosis and Cardiotoxicity via Directly Binding to Doxorubicin and Changes in Mitochondrial Damage","volume":"248","author":"Ye","year":"2022","journal-title":"Transl. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ketelut-Carneiro, N., and Fitzgerald, K.A. (2022). Apoptosis, Pyroptosis, and Necroptosis\u2014Oh My! The Many Ways a Cell Can Die. J. Mol. Biol., 434.","DOI":"10.1016\/j.jmb.2021.167378"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sumneang, N., Tanajak, P., and Oo, T.T. (2023). Toll-like Receptor 4 Inflammatory Perspective on Doxorubicin-Induced Cardiotoxicity. Molecules, 28.","DOI":"10.3390\/molecules28114294"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s00395-012-0267-3","article-title":"Role of HMGB1 in Doxorubicin-Induced Myocardial Apoptosis and Its Regulation Pathway","volume":"107","author":"Yao","year":"2012","journal-title":"Basic. Res. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1016\/j.apsb.2021.02.006","article-title":"Gasdermin D in Pyroptosis","volume":"11","author":"Burdette","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s13287-015-0109-y","article-title":"Mesenchymal Stem Cell Therapy for Doxorubicin Cardiomyopathy: Hopes and Fears","volume":"6","author":"Ezquer","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"152041","DOI":"10.1016\/j.acthis.2023.152041","article-title":"Advantages of Mesenchymal Stem Cell over the Other Stem Cells","volume":"125","author":"Gopalarethinam","year":"2023","journal-title":"Acta Histochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1089\/scd.2012.0375","article-title":"Induced Pluripotency and Oncogenic Transformation Are Related Processes","volume":"22","author":"Riggs","year":"2013","journal-title":"Stem Cells Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1016\/j.ymthe.2018.05.009","article-title":"Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges","volume":"26","author":"Bagno","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13287-021-02138-7","article-title":"Advances in Mesenchymal Stem Cell Exosomes: A Review","volume":"12","author":"Tang","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12964-021-00730-1","article-title":"The Exosome Journey: From Biogenesis to Uptake and Intracellular Signalling","volume":"19","author":"Gurung","year":"2021","journal-title":"Cell Commun. Signal"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/s41419-022-05034-x","article-title":"Mesenchymal Stem Cell-Derived Extracellular Vesicles for Immunomodulation and Regeneration: A next Generation Therapeutic Tool?","volume":"13","author":"Kou","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s12265-020-09966-7","article-title":"Exosomes: Cell-Free Therapy for Cardiovascular Diseases","volume":"13","author":"He","year":"2020","journal-title":"J. Cardiovasc. Trans. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1016\/j.bbrc.2018.08.012","article-title":"Intravenous Mesenchymal Stem Cell-Derived Exosomes Ameliorate Myocardial Inflammation in the Dilated Cardiomyopathy","volume":"503","author":"Sun","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Lee, J.Y., Chung, J., Byun, Y., Kim, K.H., An, S.H., and Kwon, K. (2021). Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Protect Cardiomyocytes from Doxorubicin-Induced Cardiomyopathy by Upregulating Survivin Expression via the miR-199a-3p-Akt-Sp1\/P53 Signaling Pathway. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22137102"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chen, L.-M., Chai, J.C., Liu, B., Strutt, T.M., McKinstry, K.K., and Chai, K.X. (2021). Prostasin Regulates PD-L1 Expression in Human Lung Cancer Cells. Biosci. Rep., 41.","DOI":"10.1042\/BSR20211370"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Hwang, S., Kim, S.-H., Yoo, K.H., Chung, M.-H., Lee, J.W., and Son, K.H. (2022). Exogenous 8-Hydroxydeoxyguanosine Attenuates Doxorubicin-Induced Cardiotoxicity by Decreasing Pyroptosis in H9c2 Cardiomyocytes. BMC Mol. Cell Biol., 23.","DOI":"10.1186\/s12860-022-00454-1"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"103501","DOI":"10.1016\/j.amsu.2022.103501","article-title":"Doxorubicin Induced Immune Abnormalities and Inflammatory Responses via HMGB1, HIF1-\u03b1 and VEGF Pathway in Progressive of Cardiovascular Damage","volume":"76","author":"Syukri","year":"2022","journal-title":"Ann. Med. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/jcsm.12662","article-title":"Amelioration of Diabetes-Induced Inflammation Mediated Pyroptosis, Sarcopenia, and Adverse Muscle Remodelling by Bone Morphogenetic Protein-7","volume":"12","author":"Singla","year":"2021","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1111\/jcmm.17309","article-title":"Effect of TLR4\/MyD88\/NF-kB Axis in Paraventricular Nucleus on Ventricular Arrhythmias Induced by Sympathetic Hyperexcitation in Post-Myocardial Infarction Rats","volume":"26","author":"Wang","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1038\/s41598-020-79356-1","article-title":"Late P65 Nuclear Translocation in Glioblastoma Cells Indicates Non-Canonical TLR4 Signaling and Activation of DNA Repair Genes","volume":"11","author":"Moretti","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/cr.2015.139","article-title":"Gasdermin D Is an Executor of Pyroptosis and Required for Interleukin-1\u03b2 Secretion","volume":"25","author":"He","year":"2015","journal-title":"Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1007\/s12012-022-09721-1","article-title":"Doxorubicin-Induced Cardiotoxicity: An Overview on Pre-Clinical Therapeutic Approaches","volume":"22","author":"Sheibani","year":"2022","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1016\/j.stemcr.2021.05.003","article-title":"Mesenchymal Stromal Cell-Derived Exosomes in Cardiac Regeneration and Repair","volume":"16","author":"Sun","year":"2021","journal-title":"Stem Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.neuro.2022.07.005","article-title":"Galangin Mitigates DOX-Induced Cognitive Impairment in Rats: Implication of NOX-1\/Nrf-2\/HMGB1\/TLR4 and TNF-\u03b1\/MAPKs\/RIPK\/MLKL\/BDNF","volume":"92","author":"AbdElrahman","year":"2022","journal-title":"Neurotoxicology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s13046-021-01959-x","article-title":"Pyroptosis: A New Paradigm of Cell Death for Fighting against Cancer","volume":"40","author":"Tan","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.yjmcc.2018.04.012","article-title":"Exosomal miR-21a-5p Mediates Cardioprotection by Mesenchymal Stem Cells","volume":"119","author":"Luther","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s41589-022-01251-9","article-title":"Site-specific encoding of photoactivity and photoreactivity into antibody fragments","volume":"19","author":"Bridge","year":"2023","journal-title":"Nat. Chem. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e15629","DOI":"10.14814\/phy2.15629","article-title":"PTEN-AKT Pathway Attenuates Apoptosis and Adverse Remodeling in Ponatinib-Induced Skeletal Muscle Toxicity Following BMP-7 Treatment","volume":"11","author":"Srivastava","year":"2023","journal-title":"Physiol. 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