{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:17:57Z","timestamp":1760059077515,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kiron Wellness Lab (Bologna, Italy)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Statins, in addition to their main beneficial lipid-lowering effects (lowering cholesterol and LDL levels), have many additional adverse effects. Among them, the most common is skeletal myopathy. Mitochondria not only play a pivotal role in statin-induced adverse skeletal muscle effects but also seem to be involved in the adverse effects of statins on human cardiac function. However, given that similar oxidative phosphorylation pathways are relevant in skeletal and cardiac muscles, whether long-term statin treatment may alter cardiac muscle is currently unknown. Natural products have been widely employed in skeletal muscle disorders thanks to their antioxidant and anti-inflammatory properties. The purpose of this study was to evaluate the effects of a novel phytotherapic formulation (PF) composed of Curcuma and Boswellia essential oils, Harpagophytum procumbens root, and Bromelain on the human AC16 cell line in an in vitro model of atorvastatin-induced cardiomyopathy. Our results showed that atorvastatin decreased cell viability by approximately 50% and induced ROS production and mitochondrial structural damage. Interestingly, supplementation of cells with PF reduced oxidative stress by 20%, improved mitochondrial reshape and function, and restored the expression of the Nrf2\/HO-1\/GPX4 axis. These results provide new insights into statin-induced cardiomyopathy and suggest the employment of PF as a promising agent in the recovery of cardiac function.<\/jats:p>","DOI":"10.3390\/ijms26104917","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T11:50:31Z","timestamp":1747741831000},"page":"4917","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Activity of Phytotherapic Extracts Combined in a Unique Formulation Alleviates Oxidative Stress and Protects Mitochondria Against Atorvastatin-Induced Cardiomyopathy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2078-7774","authenticated-orcid":false,"given":"Maria Gemma","family":"Nasoni","sequence":"first","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9719-2381","authenticated-orcid":false,"given":"Serena","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1088-0729","authenticated-orcid":false,"given":"Erik","family":"Bargagni","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Burattini","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riham","family":"Osman","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4028-0652","authenticated-orcid":false,"given":"Michela","family":"Battistelli","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Luchetti","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1059344","article-title":"Structural Mechanism for Statin Inhibition of HMG-CoA Reductase","volume":"292","author":"Istvan","year":"2001","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Morofuji, Y., Nakagawa, S., Ujifuku, K., Fujimoto, T., Otsuka, K., Niwa, M., and Tsutsumi, K. (2022). Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer. Pharmaceuticals, 15.","DOI":"10.3390\/ph15020151"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"782","DOI":"10.2174\/1874467214666210210123206","article-title":"Statins Attenuate Fibrotic Manifestations of Cardiac Tissue Damage","volume":"14","author":"Gorabi","year":"2021","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.ejim.2012.01.004","article-title":"Statin induced myotoxicity","volume":"23","author":"Sathasivam","year":"2012","journal-title":"Eur. J. Intern. Med."},{"key":"ref_5","first-page":"e37708","article-title":"Correlates of Myopathy in Diabetic Patients Taking Statins","volume":"15","author":"Tariq","year":"2023","journal-title":"Cureus"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1002\/jcsm.12654","article-title":"Effects of statins on mitochondrial pathways","volume":"12","author":"Mollazadeh","year":"2021","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1007\/s00018-006-6235-z","article-title":"Kr\u00e4henb\u00fchl, Toxicity of statins on rat skeletal muscle mitochondria","volume":"63","author":"Kaufmann","year":"2006","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.pharmthera.2018.10.004","article-title":"Statins: Adverse reactions, oxidative stress and metabolic interactions","volume":"195","author":"Liu","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_9","first-page":"e51433","article-title":"Oxidative Stress-Induced Adverse Effects of Three Statins Following Single or Repetitive Treatments in Mice","volume":"16","author":"Mohammad","year":"2024","journal-title":"Cureus"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"106052","DOI":"10.1016\/j.tiv.2025.106052","article-title":"Prolonged exposure to simvastatin affects coenzyme Q9\/10 status leading to impaired mitochondrial respiratory capacity and reduced viability of cultured cardiac cells","volume":"106","author":"Mthembu","year":"2025","journal-title":"Toxicol. In Vitro"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1096\/fj.201800876R","article-title":"Atorvastatin, but not pravastatin, inhibits cardiac Akt\/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes","volume":"33","author":"Godoy","year":"2019","journal-title":"FASEB J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1093\/jalm\/jfaa031","article-title":"Unexpected Troponin Elevation in a Patient Treated with Atorvastatin","volume":"5","author":"Collinson","year":"2020","journal-title":"J. Appl. Lab. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Qu, H., Chen, Y., Luo, X., Chen, C., Xiao, B., Ding, X., Zhao, P., Lu, Y., and Chen, A.F. (2022). Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT\/GPx4 Axis. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.806081"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1055\/s-2007-985823","article-title":"Apoptosis in patients with dilated cardiomyopathy and diabetes: A feature of diabetic cardiomyopathy?","volume":"39","author":"Kuethe","year":"2007","journal-title":"Horm. Metab. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3105","DOI":"10.1007\/s00018-020-03729-y","article-title":"Molecular mechanisms of doxorubicin-induced cardiotoxicity: Novel roles of sirtuin 1-mediated signaling pathways","volume":"78","author":"Zhang","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"174995","DOI":"10.1016\/j.ejphar.2022.174995","article-title":"Natural products: Potential therapeutic agents to prevent skeletal muscle atrophy","volume":"925","author":"Yadav","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4602715","DOI":"10.1155\/2017\/4602715","article-title":"SIRT1 Activation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice","volume":"2017","author":"Ma","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Somers, T., Siddiqi, S., Morshuis, W.J., Russel, F.G.M., and Schirris, T.J.J. (2023). Schirris, Statins and Cardiomyocyte Metabolism, Friend or Foe?. J. Cardiovasc. Dev. Dis., 10.","DOI":"10.3390\/jcdd10100417"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.fct.2015.05.016","article-title":"Atorvastatin induced hepatic oxidative stress and apoptotic damage via MAPKs, mitochondria, calpain and caspase12 dependent pathways","volume":"83","author":"Pal","year":"2015","journal-title":"Food Chem. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Stockwell, Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nrm3737","article-title":"Vandenabeele, Regulated necrosis: The expanding network of non-apoptotic cell death pathways","volume":"15","author":"Linkermann","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Liu, D., Meng, X., Wu, D., Qiu, Z., and Luo, H. (2019). A Natural Isoquinoline Alkaloid with Antitumor Activity: Studies of the Biological Activities of Berberine. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00009"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Nikawa, T., Ulla, A., and Sakakibara, I. (2021). Polyphenols and Their Effects on Muscle Atrophy and Muscle Health. Molecules, 26.","DOI":"10.3390\/molecules26164887"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s12263-015-0469-z","article-title":"Direct comparison of metabolic health effects of the flavonoids quercetin, hesperetin, epicatechin, apigenin and anthocyanins in high-fat-diet-fed mice","volume":"10","author":"Hil","year":"2015","journal-title":"Genes Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Okon, E., Kukula-Koch, W., Jarzab, A., Halasa, M., Stepulak, A., and Wawruszak, A. (2020). Advances in Chemistry and Bioactivity of Magnoflorine and Magnoflorine-Containing Extracts. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041330"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s00421-019-04104-x","article-title":"Mechanisms of vitamin D on skeletal muscle function: Oxidative stress, energy metabolism and anabolic state","volume":"119","author":"Dzik","year":"2019","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Majeed, Y., Halabi, N., Madani, A.Y., Engelke, R., Bhagwat, A.M., Abdesselem, H., Agha, M.V., Vakayil, M., Courjaret, R., and Goswami, N. (2021). SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-87759-x"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Liu, Y.-P., Wen, R., Liu, C.-F., Zhang, T.-N., and Yang, N. (2023). Cellular and molecular biology of sirtuins in cardiovascular disease. Biomed. Pharmacother., 164.","DOI":"10.1016\/j.biopha.2023.114931"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yan, R., Lin, B., Jin, W., Tang, L., Hu, S., and Cai, R. (2023). NRF2, a Superstar of Ferroptosis. Antioxidants, 12.","DOI":"10.20944\/preprints202308.1554.v1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.freeradbiomed.2015.04.036","article-title":"Abramov, The emerging role of Nrf2 in mitochondrial function","volume":"88","author":"Abramov","year":"2015","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Dodson, M., Castro-Portuguez, R., and Zhang, D.D. (2019). NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol., 23.","DOI":"10.1016\/j.redox.2019.101107"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.chembiol.2020.03.011","article-title":"Breakdown of an Ironclad Defense System: The Critical Role of NRF2 in Mediating Ferroptosis","volume":"27","author":"Anandhan","year":"2020","journal-title":"Cell Chem. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"126726","DOI":"10.1016\/j.foodchem.2020.126726","article-title":"Quantification of 2- and 3-isopropylmalic acids in forty Italian wines by UHPLC-MS\/MS triple quadrupole and evaluation of their antimicrobial, antioxidant activities and biocompatibility","volume":"321","author":"Ricciutelli","year":"2020","journal-title":"Food Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Catalani, S., Palma, F., Battistelli, S., and Benedetti, S. (2017). Oxidative stress and apoptosis induction in human thyroid carcinoma cells exposed to the essential oil from Pistacia lentiscus aerial parts. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172138"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"105705","DOI":"10.1016\/j.tiv.2023.105705","article-title":"New insights into the cytotoxic effects of Thymus vulgaris essential oil on the human triple-negative breast cancer cell line MDA-MB-231","volume":"93","author":"Benedetti","year":"2023","journal-title":"Toxicol. Vitr."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4917\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:36:03Z","timestamp":1760031363000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4917"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,20]]},"references-count":35,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26104917"],"URL":"https:\/\/doi.org\/10.3390\/ijms26104917","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,5,20]]}}}