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However, our studies could not address if these restorations by WFA were mediated by its anti-tumorigenic properties that might, in turn, reduce the tumor burden or WFA\u2019s direct, inherent anti-cachectic properties. To address this important issue, in our present study, we used a cachectic model induced by the continuous infusion of Ang II by implanting osmotic pumps in immunocompetent C57BL\/6 mice. The continuous infusion of Ang II resulted in the loss of the normal functions of the left ventricle (LV) (both systolic and diastolic), including a significant reduction in fractional shortening, an increase in heart weight and LV wall thickness, and the development of cardiac hypertrophy. The infusion of Ang II also resulted in the development of cardiac fibrosis, and significant increases in the expression levels of genes (ANP, BNP, and MHC\u03b2) associated with cardiac hypertrophy and the chemical staining of the collagen abundance as an indication of fibrosis. In addition, Ang II caused a significant increase in expression levels of inflammatory cytokines (IL-6, IL-17, MIP-2, and IFN\u03b3), NLRP3 inflammasomes, AT1 receptor, and a decrease in AT2 receptor. Treatment with WFA rescued the LV functions and heart hypertrophy and fibrosis. Our results demonstrated, for the first time, that, while WFA has anti-tumorigenic properties, it also ameliorates the cardiac dysfunction induced by Ang II, suggesting that it could be an anticachectic agent that induces direct effects on cardiac muscles.<\/jats:p>","DOI":"10.3390\/cells13090783","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T09:39:47Z","timestamp":1714729187000},"page":"783","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Withaferin A as a Potential Therapeutic Target for the Treatment of Angiotensin II-Induced Cardiac Cachexia"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5280-3212","authenticated-orcid":false,"given":"Vasa","family":"Vemuri","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Kratholm","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darini","family":"Nagarajan","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dakotah","family":"Cathey","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Anesthesiology and Perioperative Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Abdelbaset-Ismail","sequence":"additional","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Straughn","sequence":"additional","affiliation":[{"name":"Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3048-1135","authenticated-orcid":false,"given":"Lu","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4794-8400","authenticated-orcid":false,"given":"Jiapeng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Anesthesiology and Perioperative Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sham S.","family":"Kakar","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Louisville, Louisville, KY 40202, USA"},{"name":"Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1200\/JCO.20.00611","article-title":"Management of Cancer Cachexia: ASCO Guideline","volume":"38","author":"Roeland","year":"2020","journal-title":"J. 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