{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T02:19:37Z","timestamp":1788401977418,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T00:00:00Z","timestamp":1709596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Midwestern University-College of Pharmacy intramural grant and laboratory funding"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Anthracycline antibiotics, namely, doxorubicin (DOX) and daunorubicin, are among the most widely used anticancer therapies, yet are notoriously associated with severe myocardial damage due to oxidative stress and mitochondrial damage. Studies have indicated the strong pharmacological properties of Berberine (Brb) alkaloid, predominantly mediated via mitochondrial functions and nuclear networks. Despite the recent emphasis on Brb in clinical cardioprotective studies, pharmaceutical limitations hamper its clinical use. A nanoformulation for Brb was developed (mMic), incorporating a cationic lipid, oleylamine (OA), into the TPGS-mixed corona of PEGylated-phosphatidylethanolamine (PEG-PE) micelles. Cationic TPGS\/PEG-PE mMic with superior Brb loading and stability markedly enhanced both intracellular and mitochondria-tropic Brb activities in cardiovascular muscle cells. Sub-lethal doses of Brb via cationic OA\/TPGS mMic, as a DOX co-treatment, resulted in significant mitochondrial apoptosis suppression. In combination with an intense DOX challenge (up to ~50 \u00b5M), mitochondria-protective Brb-OA\/TPGS mMic showed a significant 24 h recovery of cell viability (p \u2264 0.05\u20130.01). Mechanistically, the significant relative reduction in apoptotic caspase-9 and elevation of antiapoptotic Bcl-2 seem to mediate the cardioprotective role of Brb-OA\/TPGS mMic against DOX. Our report aims to demonstrate the great potential of cationic OA\/TPGS-mMic to selectively enhance the protective mitohormetic effect of Brb to mitigate DOX cardiotoxicity.<\/jats:p>","DOI":"10.3390\/molecules29051155","type":"journal-article","created":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T05:31:19Z","timestamp":1709616679000},"page":"1155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Cationic Vitamin E-TPGS Mixed Micelles of Berberine to Neutralize Doxorubicin-Induced Cardiotoxicity via Amelioration of Mitochondrial Dysfunction and Impeding Apoptosis"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-6395","authenticated-orcid":false,"given":"Abdelkader A.","family":"Metwally","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Health Science Center (HSC), Kuwait University, P.O. Box 24923, Safat 13110, Kuwait"},{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Abbasseya, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samayita","family":"Ganguly","sequence":"additional","affiliation":[{"name":"Parkinson\u2019s Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, Dignity Health\/St. Joseph\u2019s Hospital and Medical Center, 350 W. Thomas Rd., Phoenix, AZ 85013, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Biomi","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Program, New College of Interdisciplinary Arts and Sciences, West Valley Campus, Arizona State University, N. 47th Ave & University Way, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8972-5926","authenticated-orcid":false,"given":"Mingyi","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Glendale Campus (CPG), College of Pharmacy, Midwestern University, 218-Cholla Hall, 19555 N. 59th Ave., Glendale, AZ 85308, USA"},{"name":"College of Graduate Studies, Midwestern University, Dr. Arthur G. Dobbelaere Science Hall 350D, 19555 N. 59th Ave., Glendale, AZ 85308, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9173-2167","authenticated-orcid":false,"given":"Tamer","family":"Elbayoumi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Glendale Campus (CPG), College of Pharmacy, Midwestern University, 218-Cholla Hall, 19555 N. 59th Ave., Glendale, AZ 85308, USA"},{"name":"College of Graduate Studies, Midwestern University, Dr. Arthur G. Dobbelaere Science Hall 350D, 19555 N. 59th Ave., Glendale, AZ 85308, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/1097-0142(197308)32:2<302::AID-CNCR2820320205>3.0.CO;2-2","article-title":"A clinicopathologic analysis of adriamycin cardiotoxicity","volume":"32","author":"Lefrak","year":"1973","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chen, Y., Shi, S., and Dai, Y. (2022). Research progress of therapeutic drugs for doxorubicin-induced cardiomyopathy. Biomed. Pharmacother., 156.","DOI":"10.1016\/j.biopha.2022.113903"},{"key":"ref_3","first-page":"529","article-title":"The cardiotoxicity of chemotherapeutic drugs","volume":"19","author":"Allen","year":"1992","journal-title":"Semin. Oncol."},{"key":"ref_4","first-page":"460","article-title":"Effect of anthracycline antibiotics on oxygen radical formation in rat heart","volume":"43","author":"Doroshow","year":"1983","journal-title":"Cancer Res."},{"key":"ref_5","first-page":"5721","article-title":"Protective effect of berberine on acute cardiomyopathy associated with doxorubicin treatment","volume":"15","author":"Xiong","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_6","first-page":"154130","article-title":"Bcl-xL is required for the protective effects of low-dose berberine against doxorubicin-induced cardiotoxicity through blocking apoptosis and activating mitophagy-mediated ROS elimination","volume":"101","author":"Chen","year":"2022","journal-title":"Phytomed. Int. J. Phytother. Phytopharm."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Wang, Y., Liao, J., Luo, Y., Li, M., Su, X., Yu, B., Teng, J., Wang, H., and Lv, X. (2023). Berberine Alleviates Doxorubicin-Induced Myocardial Injury and Fibrosis by Eliminating Oxidative Stress and Mitochondrial Damage via Promoting Nrf-2 Pathway Activation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043257"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s10020-020-0136-8","article-title":"The mitohormetic response as part of the cytoprotection mechanism of berberine: Berberine induces mitohormesis and mechanisms","volume":"26","author":"Zhu","year":"2020","journal-title":"Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3953","DOI":"10.3892\/mmr.2016.5017","article-title":"Protective effect of berberine on doxorubicin-induced acute hepatorenal toxicity in rats","volume":"13","author":"Chen","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"982145","DOI":"10.3389\/fendo.2022.982145","article-title":"Research progress on the pharmacological effects of berberine targeting mitochondria","volume":"13","author":"Fang","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"41712","DOI":"10.1038\/srep41712","article-title":"Mitochondria play an important role in the cell proliferation suppressing activity of berberine","volume":"7","author":"Yan","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1002\/ptr.7032","article-title":"Berberine\u2014A potent chemosensitizer and chemoprotector to conventional cancer therapies","volume":"35","author":"Devarajan","year":"2021","journal-title":"Phytother. Res. PTR"},{"key":"ref_13","first-page":"334","article-title":"Effects of berberine on proliferation, cell cycle distribution and apoptosis of human breast cancer T47D and MCF7 cell lines","volume":"18","author":"Barzegar","year":"2015","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_14","first-page":"1687","article-title":"Development and evaluation of vitamin E d-alpha-tocopheryl polyethylene glycol 1000 succinate-mixed polymeric phospholipid micelles of berberine as an anticancer nanopharmaceutical","volume":"11","author":"Shen","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jconrel.2019.12.011","article-title":"Mitochondria-targeting nanomedicine self-assembled from GSH-responsive paclitaxel-ss-berberine conjugate for synergetic cancer treatment with enhanced cytotoxicity","volume":"318","author":"Cheng","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2150394","DOI":"10.1155\/2019\/2150394","article-title":"Berberine Ameliorates Doxorubicin-Induced Cardiotoxicity via a SIRT1\/p66Shc-Mediated Pathway","volume":"2019","author":"Wu","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3247","DOI":"10.1007\/s11064-021-03428-5","article-title":"Neuroprotective Potential of Berberine Against Doxorubicin-Induced Toxicity in Rat\u2019s Brain","volume":"46","author":"Ahmed","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101612","DOI":"10.1016\/j.tice.2021.101612","article-title":"The protective impact of berberine against doxorubicin-induced nephrotoxicity in rats","volume":"73","author":"Ahmed","year":"2021","journal-title":"Tissue Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.1016\/j.bbadis.2017.07.030","article-title":"Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts","volume":"1863","author":"Coelho","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.2174\/1386207325666220617113744","article-title":"Solid Lipid Nanoformulation of Berberine Attenuates Doxorubicin Triggered in vitro Inflammation in H9c2 Rat Cardiomyocytes","volume":"25","author":"Rawal","year":"2022","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6856","DOI":"10.1039\/C6TB01730D","article-title":"Development of a novel berberine-mediated mitochondria-targeting nano-platform for drug-resistant cancer therapy","volume":"4","author":"Tuo","year":"2016","journal-title":"J. Mater. Chem. B"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.ajps.2019.04.007","article-title":"Ratiometric delivery of doxorubicin and berberine by liposome enables superior therapeutic index than Doxil\u00ae","volume":"15","author":"Zhang","year":"2020","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_23","first-page":"127","article-title":"Preparation of an anhydrous reverse micelle delivery system to enhance oral bioavailability and anti-diabetic efficacy of berberine","volume":"44","author":"Wang","year":"2011","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/978-1-60761-609-2_9","article-title":"Polymeric micelles: Polyethylene glycol-phosphatidylethanolamine (PEG-PE)-based micelles as an example","volume":"624","author":"Sawant","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ijpharm.2005.08.026","article-title":"Mixed micelles made of poly(ethylene glycol)-phosphatidylethanolamine conjugate and d-alpha-tocopheryl polyethylene glycol 1000 succinate as pharmaceutical nanocarriers for camptothecin","volume":"306","author":"Mu","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3510","DOI":"10.1002\/jps.24547","article-title":"Development and In Vitro Evaluation of Vitamin E-Enriched Nanoemulsion Vehicles Loaded with Genistein for Chemoprevention Against UVB-Induced Skin Damage","volume":"104","author":"Brownlow","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.1158\/0008-5472.CAN-14-3763","article-title":"Drug combination studies and their synergy quantification using the Chou-Talalay method\u2013letter","volume":"75","author":"Ashton","year":"2015","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"232","DOI":"10.3109\/09687688.2010.516276","article-title":"Multifunctionality of lipid-core micelles for drug delivery and tumour targeting","volume":"27","author":"Sawant","year":"2010","journal-title":"Mol. Membr. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-1-4939-9516-5_3","article-title":"Anionic and Cationic Vitamin E-TPGS Mixed Polymeric Phospholipid Micellar Vehicles","volume":"2000","author":"Yao","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_30","first-page":"51","article-title":"Mixed PEG-PE\/vitamin E tumor-targeted immunomicelles as carriers for poorly soluble anti-cancer drugs: Improved drug solubilization and enhanced in vitro cytotoxicity","volume":"70","author":"Sawant","year":"2008","journal-title":"Eur. J. Pharm. Biopharm. Off. J. Arbeitsgemeinschaft Pharm. Verfahrenstechnik e.V"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s11596-020-2185-1","article-title":"Recent Advances of D-alpha-tocopherol Polyethylene Glycol 1000 Succinate Based Stimuli-responsive Nanomedicine for Cancer Treatment","volume":"40","author":"Guan","year":"2020","journal-title":"Curr. Med. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/nnano.2011.166","article-title":"Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size","volume":"6","author":"Cabral","year":"2011","journal-title":"Nat. Nanotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1049\/nbt2.12018","article-title":"Nanomicelles: Types, properties and applications in drug delivery","volume":"15","author":"Bose","year":"2021","journal-title":"IET Nanobiotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Vuddanda, P.R., Rajamanickam, V.M., Yaspal, M., and Singh, S. (2014). Investigations on agglomeration and haemocompatibility of vitamin E TPGS surface modified berberine chloride nanoparticles. BioMed Res. Int., 2014.","DOI":"10.1155\/2014\/951942"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1208\/s12249-011-9632-z","article-title":"Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats","volume":"12","author":"Chen","year":"2011","journal-title":"AAPS PharmSciTech"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.ijpharm.2014.01.023","article-title":"Solid dispersion of berberine-phospholipid complex\/TPGS 1000\/SiO2: Preparation, characterization and in vivo studies","volume":"465","author":"Zhang","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3789","DOI":"10.1021\/mp4004892","article-title":"Mitochondria-specific pro-apoptotic activity of genistein lipidic nanocarriers","volume":"10","author":"Pham","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1002\/mbo3.1027","article-title":"A protocol for recombinant protein quantification by densitometry","volume":"9","author":"Kraiem","year":"2020","journal-title":"MicrobiologyOpen"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/5\/1155\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:09:27Z","timestamp":1760105367000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/5\/1155"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,5]]},"references-count":38,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["molecules29051155"],"URL":"https:\/\/doi.org\/10.3390\/molecules29051155","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,5]]}}}