{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:17:37Z","timestamp":1792700257459,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82272601"],"award-info":[{"award-number":["82272601"]}]},{"name":"National Natural Science Foundation of China","award":["21330089963007"],"award-info":[{"award-number":["21330089963007"]}]},{"name":"National Natural Science Foundation of China","award":["ZR2021MH330"],"award-info":[{"award-number":["ZR2021MH330"]}]},{"name":"Shandong University","award":["82272601"],"award-info":[{"award-number":["82272601"]}]},{"name":"Shandong University","award":["21330089963007"],"award-info":[{"award-number":["21330089963007"]}]},{"name":"Shandong University","award":["ZR2021MH330"],"award-info":[{"award-number":["ZR2021MH330"]}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["82272601"],"award-info":[{"award-number":["82272601"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["21330089963007"],"award-info":[{"award-number":["21330089963007"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2021MH330"],"award-info":[{"award-number":["ZR2021MH330"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Doxorubicin (DOX) has received attention due to dose-dependent cardiotoxicity through abnormal redox cycling. Native fibroblast growth factor 1 (FGF1) is known for its anti-oxidative benefits in cardiovascular diseases, but possesses a potential tumorigenic risk. Coincidentally, the anti-proliferative properties of resveratrol (RES) have attracted attention as alternatives or auxiliary therapy when combined with other chemotherapeutic drugs. Therefore, the purpose of this study is to explore the therapeutic potential and underlying mechanisms of co-treatment of RES and FGF1 in a DOX-treated model. Here, various cancer cells were applied to determine whether RES could antagonize the oncogenesis effect of FGF1. In addition, C57BL\/6J mice and H9c2 cells were used to testify the therapeutic potential of a co-treatment of RES and FGF1 against DOX-induced cardiotoxicity. We found RES could reduce the growth-promoting activity of FGF1. Additionally, the co-treatment of RES and FGF1 exhibits a more powerful cardio-antioxidative capacity in a DOX-treated model. The inhibition of SIRT1\/NRF2 abolished RES in combination with FGF1 on cardioprotective action. Further mechanism analysis demonstrated that SIRT1 and NRF2 might form a positive feedback loop to perform the protective effect on DOX-induced cardiotoxicity. These favorable anti-oxidative activities and reduced proliferative properties of the co-treatment of RES and FGF1 provided a promising therapy for anthracycline cardiotoxicity during chemotherapy.<\/jats:p>","DOI":"10.3390\/nu14194017","type":"journal-article","created":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T03:30:37Z","timestamp":1664335837000},"page":"4017","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Resveratrol and FGF1 Synergistically Ameliorates Doxorubicin-Induced Cardiotoxicity via Activation of SIRT1-NRF2 Pathway"],"prefix":"10.3390","volume":"14","author":[{"given":"Guangping","family":"Lu","sequence":"first","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingbo","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology at the First Hospital of China Medical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ou","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Mao","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjie","family":"Xiao","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanfang","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junlian","family":"Gu","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"178513","DOI":"10.1155\/2015\/178513","article-title":"High Throughput Screening Identifies a Novel Compound Protecting Cardiomyocytes from Doxorubicin-Induced Damage","volume":"2015","author":"Gergely","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s13046-020-01595-x","article-title":"TFEB-NF-\u03baB inflammatory signaling axis: A novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity","volume":"39","author":"Wang","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.lfs.2018.03.023","article-title":"Toxicity of Doxorubicin (Dox) to different experimental organ systems","volume":"200","author":"Pugazhendhi","year":"2018","journal-title":"Life Sci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tossetta, G., Fantone, S., Montanari, E., Marzioni, D., and Goteri, G. (2022). Role of NRF2 in Ovarian Cancer. Antioxidants, 11.","DOI":"10.3390\/antiox11040663"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.2174\/092986709788803312","article-title":"Doxorubicin: The good, the bad and the ugly effect","volume":"16","author":"Carvalho","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.freeradbiomed.2015.07.016","article-title":"Protective effect of cilostazol against doxorubicin-induced cardiomyopathy in mice","volume":"89","author":"Koh","year":"2015","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.3389\/fphar.2018.01262","article-title":"Updates in Anthracycline-Mediated Cardiotoxicity","volume":"9","author":"Nebigil","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105596","DOI":"10.1016\/j.phrs.2021.105596","article-title":"Regulatory role of endogenous and exogenous fibroblast growth factor 1 in the cardiovascular system and related diseases","volume":"169","author":"Xiao","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102219","DOI":"10.1016\/j.redox.2021.102219","article-title":"A new FGF1 variant protects against adriamycin-induced cardiotoxicity via modulating p53 activity","volume":"49","author":"Xiao","year":"2022","journal-title":"Redox Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.jconrel.2015.12.030","article-title":"Prevent diabetic cardiomyopathy in diabetic rats by combined therapy of aFGF-loaded nanoparticles and ultrasound-targeted microbubble destruction technique","volume":"223","author":"Zhao","year":"2016","journal-title":"J. Control Release"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yjmcc.2020.03.003","article-title":"CHIR99021 and fibroblast growth factor 1 enhance the regenerative potency of human cardiac muscle patch after myocardial infarction in mice","volume":"141","author":"Fan","year":"2020","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"R209","DOI":"10.1530\/ERC-13-0171","article-title":"Resveratrol and cancer: Focus on in vivo evidence","volume":"21","author":"Carter","year":"2014","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1006\/excr.1999.4471","article-title":"Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines","volume":"249","author":"Hsieh","year":"1999","journal-title":"Exp. Cell Res."},{"key":"ref_14","first-page":"441","article-title":"Resveratrol inhibits cell proliferation and induces apoptosis of human breast carcinoma MCF-7 cells","volume":"11","author":"Kim","year":"2004","journal-title":"Oncol. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/S0006-2952(02)01296-0","article-title":"The antiproliferative activity of resveratrol results in apoptosis in MCF-7 but not in MDA-MB-231 human breast cancer cells: Cell-specific alteration of the cell cycle","volume":"64","year":"2002","journal-title":"Biochem. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101811","DOI":"10.1016\/j.redox.2020.101811","article-title":"aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt\/\u03b2-catenin-mediated upregulation of HXK2","volume":"39","author":"Sun","year":"2021","journal-title":"Redox Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1111\/bph.13492","article-title":"Antioxidant effects of resveratrol in the cardiovascular system","volume":"174","author":"Xia","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1002\/hep.31568","article-title":"Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection from Nonalcoholic Fatty Liver Disease in Mice","volume":"73","author":"Lin","year":"2021","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.ccr.2008.09.001","article-title":"Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice","volume":"14","author":"Wang","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1186\/s12935-021-02280-5","article-title":"Resveratrol mediates its anti-cancer effects by Nrf2 signaling pathway activation","volume":"21","author":"Alavi","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.yjmcc.2013.01.008","article-title":"Prevention by sulforaphane of diabetic cardiomyopathy is associated with up-regulation of Nrf2 expression and transcription activation","volume":"57","author":"Bai","year":"2013","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/35077213","article-title":"Proliferation, cell cycle and apoptosis in cancer","volume":"411","author":"Evan","year":"2001","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e124","DOI":"10.1002\/ctm2.124","article-title":"Osteocrin attenuates inflammation, oxidative stress, apoptosis, and cardiac dysfunction in doxorubicin-induced cardiotoxicity","volume":"10","author":"Hu","year":"2020","journal-title":"Clin. Transl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.yjmcc.2017.10.008","article-title":"CTRP3 protected against doxorubicin-induced cardiac dysfunction, inflammation and cell death via activation of Sirt1","volume":"114","author":"Yuan","year":"2018","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15087","DOI":"10.1038\/s41598-019-51614-x","article-title":"Procyanidin A1 Alleviates Inflammatory Response induced by LPS through NF-\u03baB, MAPK, and Nrf2\/HO-1 Pathways in RAW264.7 cells","volume":"9","author":"Han","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41419-017-0198-x","article-title":"Nrf2 antioxidant pathway suppresses Numb-mediated epithelial-mesenchymal transition during pulmonary fibrosis","volume":"9","author":"Zhang","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.bbrc.2013.07.042","article-title":"Resveratrol protects cardiomyocytes from oxidative stress through SIRT1 and mitochondrial biogenesis signaling pathways","volume":"438","author":"Li","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ijcard.2015.12.008","article-title":"SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy","volume":"205","author":"Cappetta","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"154002","DOI":"10.1016\/j.metabol.2019.154002","article-title":"Protective effects of sulforaphane on type 2 diabetes-induced cardiomyopathy via AMPK-mediated activation of lipid metabolic pathways and NRF2 function","volume":"102","author":"Sun","year":"2020","journal-title":"Metabolism"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.redox.2017.12.013","article-title":"MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2","volume":"15","author":"Zhao","year":"2018","journal-title":"Redox Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.redox.2018.02.026","article-title":"Protective effect of dioscin against doxorubicin-induced cardiotoxicity via adjusting microRNA-140-5p-mediated myocardial oxidative stress","volume":"16","author":"Zhao","year":"2018","journal-title":"Redox Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Baguma-Nibasheka, M., Feridooni, T., Zhang, F., and Pasumarthi, K.B.S. (2021). Regulation of Transplanted Cell Homing by FGF1 and PDGFB after Doxorubicin Myocardial Injury. Cells, 10.","DOI":"10.3390\/cells10112998"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/j.freeradbiomed.2009.03.011","article-title":"Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway","volume":"46","author":"Danz","year":"2009","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"873","DOI":"10.3892\/ijmm.2015.2291","article-title":"Resveratrol prevents doxorubicin-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway","volume":"36","author":"Lou","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_35","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":"Wang","year":"2021","journal-title":"Cell Mol. Life Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1152\/physrev.00023.2017","article-title":"The KEAP1-NRF2 System: A Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis","volume":"98","author":"Yamamoto","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.arcmed.2016.11.008","article-title":"Protective Effect of Acetyl-L-Carnitine against Doxorubicin-induced Cardiotoxicity in Wistar Albino Rats","volume":"47","author":"Dundar","year":"2016","journal-title":"Arch. Med. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10228","DOI":"10.1093\/nar\/gks827","article-title":"Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks","volume":"40","author":"Hirotsu","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_39","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":"Oxidative Med. Cell. Longev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1089\/ars.2016.6643","article-title":"Oxidative Stress-Induced miR-200c Disrupts the Regulatory Loop among SIRT1, FOXO1, and eNOS","volume":"27","author":"Carlomosti","year":"2017","journal-title":"Antioxid. Redox Signal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.tox.2019.05.003","article-title":"JNK activation-mediated nuclear SIRT1 protein suppression contributes to silica nanoparticle-induced pulmonary damage via p53 acetylation and cytoplasmic localisation","volume":"423","author":"Zhao","year":"2019","journal-title":"Toxicology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.3389\/fimmu.2019.01511","article-title":"Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation through the SIRT1\/Nrf2 Pathway","volume":"10","author":"Arioz","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.yexcr.2017.09.042","article-title":"The crosstalk between Sirt1 and Keap1\/Nrf2\/ARE anti-oxidative pathway forms a positive feedback loop to inhibit FN and TGF-\u03b21 expressions in rat glomerular mesangial cells","volume":"361","author":"Huang","year":"2017","journal-title":"Exp. Cell Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/19\/4017\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:40:49Z","timestamp":1760143249000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/19\/4017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,27]]},"references-count":43,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["nu14194017"],"URL":"https:\/\/doi.org\/10.3390\/nu14194017","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,27]]}}}