{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T16:25:58Z","timestamp":1776356758297,"version":"3.51.2"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2017,2,21]],"date-time":"2017-02-21T00:00:00Z","timestamp":1487635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"key laboratory program of the Education Commission of Shanghai Municipality","award":["No. ZDSYS14005"],"award-info":[{"award-number":["No. ZDSYS14005"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 81330080"],"award-info":[{"award-number":["No. 81330080"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Major Scientific and Technology Special Project","award":["(No. 2012ZX09103101i-064, 2012ZX09501001-001-003"],"award-info":[{"award-number":["(No. 2012ZX09103101i-064, 2012ZX09501001-001-003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Nox-dependent signaling plays critical roles in the development of heart failure, cardiac hypertrophy, and myocardial infarction. NADPH oxidase 4 (Nox4) as a major source of oxidative stress in the heart offers a new therapeutic target in cardiovascular disease. In the present work, a novel flavonoid was isolated from Zanthoxylum bungeanum. Its structure was elucidated as Quercetin-3-O-(6\u2032\u2032-O-\u03b1-l-rhamnopyransoyl)-\u03b2-d-glucopyranoside-7-O-\u03b2-d-glucopyranoside (ZYZ-772) for the first time. ZYZ-772 exhibited significant cardio-protective property against CoCl2 induced H9c2 cardiomyocyte cells injury. In CoCl2 stimulated cardiomyocyte injury, ZYZ-772 inhibited expression of Nox4, and alleviated ROS overproduction. Importantly, ROS triggered MAPKs phosphorylation and P53 signaling mediated apoptosis were restored by ZYZ-772. Our findings present the first piece of evidence for the therapeutic properties of ZYZ-772 in preventing cardiomyocyte injury, which could be attributed to the suppression of Nox4\/MAPKs\/P53 axis. This will offer a novel therapeutic strategy for the treatment of cardiac ischemia disease.<\/jats:p>","DOI":"10.3390\/molecules22020331","type":"journal-article","created":{"date-parts":[[2017,2,22]],"date-time":"2017-02-22T11:40:52Z","timestamp":1487763652000},"page":"331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["ZYZ-772 Prevents Cardiomyocyte Injury by Suppressing Nox4-Derived ROS Production and Apoptosis"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8566-875X","authenticated-orcid":false,"given":"Ying","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangjie","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinhua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China"},{"name":"School of Pharmacy, Macao University of Science and Technology, Macao"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1161\/hh1501.094115","article-title":"Oxidative stress\u2013Mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy","volume":"89","author":"Cesselli","year":"2001","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1161\/01.RES.87.10.856","article-title":"Apoptosis during cardiovascular development","volume":"87","author":"Fisher","year":"2000","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/jcp.10174","article-title":"Pathophysiologic role of myocardial apoptosis in post-infarction left ventricular remodeling","volume":"193","author":"Abbate","year":"2002","journal-title":"J. Cell. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0167-5273(02)00189-4","article-title":"Oxidative stress and neutrophil activation\u2014The two keystones of ischemia\/reperfusion injury","volume":"86","author":"Kaminski","year":"2002","journal-title":"Int. J. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1172\/JCI119709","article-title":"Oxidative stress activates extracellular signal-Regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats","volume":"100","author":"Aikawa","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1089\/152308603770380098","article-title":"Oxidative stress-induced signal transduction pathways in cardiac myocytes: Involvement of ROS in heart diseases","volume":"5","author":"Takano","year":"2003","journal-title":"Antioxid. Redox Signal."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15565","DOI":"10.1073\/pnas.1002178107","article-title":"NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart","volume":"107","author":"Kuroda","year":"2010","journal-title":"PNAS"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1161\/CIRCRESAHA.109.213116","article-title":"Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes","volume":"106","author":"Ago","year":"2010","journal-title":"Circul. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1007\/s12265-010-9184-8","article-title":"NADPH oxidase and cardiac failure","volume":"3","author":"Kuroda","year":"2010","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Wang, D., Yang, L., Zhou, D., and Zhang, J. (2014). Purification and characterization of flavonoids from the leaves of Zanthoxylum bungeanum and correlation between their structure and antioxidant activity. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105725"},{"key":"ref_11","first-page":"572","article-title":"GC-MS analysis of supercritical carbon dioxide extraction products from pericarp of Zanthoxylum bungeanum","volume":"24","author":"Li","year":"2001","journal-title":"J. Chin. Med. Mater."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1080\/10412905.1994.9698372","article-title":"Volatile constituents of the fruit secretory glands of Zanthoxylum bungeanum Maxim","volume":"6","author":"Tirillini","year":"1994","journal-title":"J. Essent. Oil Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.jphs.2014.12.002","article-title":"The effects of Zanthoxylum bungeanum extract on lipid metabolism induced by sterols","volume":"127","author":"Wu","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1097\/TA.0000000000000987","article-title":"Valproic acid\u2013Mediated myocardial protection of acute hemorrhagic rat via the BCL-2 pathway","volume":"80","author":"Wang","year":"2016","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1089\/ars.2012.4550","article-title":"NADPH oxidases in heart failure: Poachers or gamekeepers?","volume":"18","author":"Zhang","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1161\/CIRCRESAHA.112.279760","article-title":"Increased oxidative stress in the nucleus caused by Nox4 mediates oxidation of HDAC4 and cardiac hypertrophy","volume":"112","author":"Matsushima","year":"2013","journal-title":"Circul. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1161\/CIRCRESAHA.109.213025","article-title":"Silencing Nox4 in the Paraventricular Nucleus Improves Myocardial Infarction\u2013Induced Cardiac Dysfunction by Attenuating Sympathoexcitation and Periinfarct Apoptosis","volume":"106","author":"Infanger","year":"2010","journal-title":"Circul. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1078\/0171-9335-00159","article-title":"The role of intracellular oxidation in death induction (apoptosis and necrosis) in human promonocytic cells treated with stress inducers (cadmium, heat, X-rays)","volume":"80","author":"Troyano","year":"2001","journal-title":"Eur. J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29820","DOI":"10.1038\/srep29820","article-title":"The discovery of a novel inhibitor of apoptotic protease activating factor-1 (Apaf-1) for ischemic heart: Synthesis, activity and target identification","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1089\/ars.2006.8.2187","article-title":"Redox control of apoptosis: An update","volume":"8","author":"Filomeni","year":"2006","journal-title":"Antioxid. Redox Signal."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1038\/sj.onc.1204353","article-title":"Regulation of p53 expression by the RAS-MAP kinase pathway","volume":"20","author":"Agarwal","year":"2001","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"156","DOI":"10.4161\/cbt.3.2.614","article-title":"The functional interactions between the MAPK and p53 signaling pathways","volume":"3","author":"Wu","year":"2004","journal-title":"Cancer Biol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.tiv.2009.12.012","article-title":"Okadaic acid induces apoptosis in Down syndrome fibroblasts","volume":"24","author":"Dogliotti","year":"2010","journal-title":"Toxicol. In Vitro"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1023\/A:1022945107762","article-title":"The mitochondrial membrane potential (\u0394\u03c8m) in apoptosis; An update","volume":"8","author":"Ly","year":"2003","journal-title":"Apoptosis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2339","DOI":"10.1038\/cddis.2016.209","article-title":"Gp130-mediated STAT3 activation by S-propargyl-cysteine, an endogenous hydrogen sulfide initiator, prevents doxorubicin-induced cardiotoxicity","volume":"7","author":"Wu","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yang, Q., Cao, W., Zhou, X., Cao, W., Xie, Y., and Wang, S. (2014). Anti-thrombotic effects of \u03b1-linolenic acid isolated from Zanthoxylum bungeanum Maxim seeds. BMC Complement. Alternat. Med., 14.","DOI":"10.1186\/1472-6882-14-348"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1111\/jnc.13161","article-title":"Tetramethylpyrazine inhibits CoCl2-induced neurotoxicity through enhancement of Nrf2\/GCLc\/GSH and suppression of HIF1alpha\/NOX2\/ROS pathways","volume":"134","author":"Guan","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.2174\/1568026616666160216152138","article-title":"Repositioning of Drugs in Cardiometabolic Disorders: Importance and Current Scenario","volume":"16","author":"Katare","year":"2016","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/nature06800","article-title":"Stem-cell therapy for cardiac disease","volume":"451","author":"Segers","year":"2008","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1089\/ars.2014.5909","article-title":"miRNA-30 family inhibition protects against cardiac ischemic injury by regulating cystathionine-\u03b3-lyase expression","volume":"22","author":"Shen","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.tips.2015.06.004","article-title":"Novel therapeutics in myocardial infarction: Targeting microvascular dysfunction and reperfusion injury","volume":"36","author":"Fordyce","year":"2015","journal-title":"Trends Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.2174\/0929867043365116","article-title":"Natural products in the process of finding new drug candidates","volume":"11","author":"Vuorela","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yang, Q., Cao, W., Zhou, X., Cao, W., Xie, Y., and Wang, Si. (2014). Anti-thrombotic effects of \u03b1-linolenic acid isolated from Zanthoxylum bungeanum Maxim seeds. BMC Complement. Altern. Med., 14.","DOI":"10.1186\/1472-6882-14-348"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1009816207172","article-title":"Activated oxygen species in heart failure","volume":"4","author":"Kukreja","year":"1999","journal-title":"Heart Fail. Rev."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/2\/331\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:28:48Z","timestamp":1760207328000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/2\/331"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,21]]},"references-count":34,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,2]]}},"alternative-id":["molecules22020331"],"URL":"https:\/\/doi.org\/10.3390\/molecules22020331","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,21]]}}}