{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:23:29Z","timestamp":1784550209798,"version":"3.55.0"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,3,29]],"date-time":"2016-03-29T00:00:00Z","timestamp":1459209600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,3,29]],"date-time":"2016-03-29T00:00:00Z","timestamp":1459209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Paeonol and danshensu is the representative active ingredient of traditional Chinese medicinal herbs Cortex Moutan and Radix Salviae Milthiorrhizae, respectively. Paeonol and danshensu combination (PDSS) has putative cardioprotective effects in treating ischemic heart disease (IHD). However, the evidence for the protective effect is scarce and the pharmacological mechanisms of the combination remain unclear. The present study was designed to investigate the protective effect of PDSS on isoproterenol (ISO)-induced myocardial infarction in rats and to elucidate the potential mechanism. Assays of creatine kinase-MB, cardiac troponin I and T and histopathological analysis revealed PDSS significantly prevented myocardial injury induced by ISO. The ISO-induced profound elevation of oxidative stress was also suppressed by PDSS. TUNEL and caspase-3 activity assay showed that PDSS significantly inhibited apoptosis in myocardia. In exploring the underlying mechanisms of PDSS, we found PDSS enhanced the nuclear translocation of Nrf2 in myocardial injured rats. Furthermore, PDSS increased phosphorylated PI3K and Akt, which may in turn activate antioxidative and antiapoptotic signaling events in rat. These present findings demonstrated that PDSS exerts significant cardioprotective effects against ISO-induced myocardial infarction in rats. The protective effect is, at least partly, via activation of Nrf2\/HO-1 signaling and involvement of the PI3K\/Akt cell survival signaling pathway.<\/jats:p>","DOI":"10.1038\/srep23693","type":"journal-article","created":{"date-parts":[[2016,3,29]],"date-time":"2016-03-29T14:00:54Z","timestamp":1459260054000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":149,"title":["Paeonol and danshensu combination attenuates apoptosis in myocardial infarcted rats by inhibiting oxidative stress: Roles of Nrf2\/HO-1 and PI3K\/Akt pathway"],"prefix":"10.1038","volume":"6","author":[{"given":"Hua","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin-Rui","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan-Juan","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Hua","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian-Qian","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bang-Le","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Wang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,3,29]]},"reference":[{"key":"BFsrep23693_CR1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/0033-0620(90)90039-5","volume":"33","author":"P Anversa","year":"1990","unstructured":"Anversa, P. & Sonnenblick, E. H. Ischemic cardiomyopathy: pathophysiological mechanisms. Prog Cardiovasc Dis. 33, 49\u201370 (1990).","journal-title":"Prog Cardiovasc Dis."},{"key":"BFsrep23693_CR2","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1007\/BF00788732","volume":"89","author":"AC Hegstad","year":"1994","unstructured":"Hegstad, A. C., Ytrehus, K., Myklebust, R. & Jorgensen, L. Ultrastructural changes in myocardial myocytic mitochondria: crucial step in the development of oxygen radical induced damage in isolated rat hearts. Basic Res Cardiol. 89, 128\u2013138 (1994).","journal-title":"Basic Res Cardiol."},{"key":"BFsrep23693_CR3","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.ijcard.2010.08.008","volume":"147","author":"NA Strobel","year":"2011","unstructured":"Strobel, N. A., Fassett, R. G., Marsh, S. A. & Coombes, J. S. Oxidative stress biomarkers as predictors of cardiovascular disease. Int J Cardiol. 147, 191\u2013201 (2011).","journal-title":"Int J Cardiol."},{"key":"BFsrep23693_CR4","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/j.jnutbio.2014.06.003","volume":"25","author":"SY Lin","year":"2014","unstructured":"Lin, S. Y., et al. Beneficial effect of quercetin on cholestatic liver injury. J Nutr Biochem. 25, 1183\u20131195 (2014).","journal-title":"J Nutr Biochem."},{"key":"BFsrep23693_CR5","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.vph.2010.07.001","volume":"53","author":"YJ Li","year":"2010","unstructured":"Li, Y. J., Bao, J. X., Xu, J. W., Murad, F. & Bian, K. Vascular dilation by paeonol\u2013A mechanism study. Vasc Pharmacol. 53, 169\u2013176 (2010).","journal-title":"Vasc Pharmacol"},{"key":"BFsrep23693_CR6","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1055\/s-2007-993775","volume":"74","author":"IT Nizamutdinova","year":"2008","unstructured":"Nizamutdinova, I. T. et al. Paeonol and Paeoniflorin, the main active principles of Paeonia albiflora, protect the heart from myocardial ischemia\/reperfusion injury in rats. Planta Med. 74, 14\u201318 (2008).","journal-title":"Planta Med."},{"key":"BFsrep23693_CR7","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.ejphar.2006.06.064","volume":"545","author":"YL Ma","year":"2006","unstructured":"Ma, Y. L., Bates, S. & Gurney, A. M. The effects of paeonol on the electrophysiological properties of cardiac ventricular myocytes. Eur J Pharmacol. 545, 87\u201392 (2006).","journal-title":"Eur J Pharmacol."},{"key":"BFsrep23693_CR8","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.phymed.2011.05.007","volume":"18","author":"YQ Tang","year":"2011","unstructured":"Tang, Y. Q. et al. Antioxidant and cardioprotective effects of Danshensu (3-(3,4-dihydroxyphenyl)-2-hydroxy-propanoic acid from Salvia miltiorrhiza) on isoproterenol-induced myocardial hypertrophy in rats. Phytomedicine 18, 1024\u20131030 (2011).","journal-title":"Phytomedicine"},{"key":"BFsrep23693_CR9","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1016\/S0024-3205(01)01267-X","volume":"69","author":"J Liu","year":"2001","unstructured":"Liu, J., Shen, H. M. & Ong, C. N. Role of intracellular thiol depletion, mitochondrial dysfunction and reactive oxygen species in Salvia miltiorrhiza-induced apoptosis in human hepatoma HepG2 cells. Life Sci. 69, 1833\u20131850 (2001).","journal-title":"Life Sci."},{"key":"BFsrep23693_CR10","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1055\/s-0031-1280269","volume":"78","author":"H Li","year":"2012","unstructured":"Li, H. et al. Influence of co-administered danshensu on pharmacokinetic fate and tissue distribution of paeonol in rats. Planta Med. 78, 135\u2013140 (2012).","journal-title":"Planta Med."},{"key":"BFsrep23693_CR11","doi-asserted-by":"crossref","first-page":"14565","DOI":"10.3390\/ijms131114565","volume":"13","author":"J Hu","year":"2012","unstructured":"Hu, J. et al. Chronic supplementation of paeonol combined with danshensu for the improvement of vascular reactivity in the cerebral basilar artery of diabetic rats. Int J Mol Sci. 13, 14565\u201314578 (2012).","journal-title":"Int J Mol Sci."},{"key":"BFsrep23693_CR12","first-page":"40","volume":"19","author":"ZG Geng","year":"2000","unstructured":"Geng, Z. G., Ma, Q., Ren, S. F. & Mao, X. Z. Sixty cases study on ShuangDan Decoction for the treatment of coronary heart disease. Herald of Med. 19, 40\u201341 (2000).","journal-title":"Herald of Med"},{"key":"BFsrep23693_CR13","first-page":"722","volume":"29","author":"FY Gao","year":"2005","unstructured":"Gao, F. Y. & Wang, H. H. Clinical observation of 102 cases on ShuangDan Decoction for the treatment of coronary heart disease. J Hei Long Jiang Med. 29, 722 (2005).","journal-title":"J Hei Long Jiang Med"},{"key":"BFsrep23693_CR14","unstructured":"Lv, J. S. Clinical experiences of Shi Jin Mo herb pairs. Shanxi people\u2019s Publishing House, Shanxi 1982."},{"key":"BFsrep23693_CR15","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.jpba.2011.07.016","volume":"56","author":"H Li","year":"2011","unstructured":"Li, H. et al. Simultaneous quantitative determination of 9 active components in traditional Chinese medicinal preparation ShuangDan oral liquid by RP-HPLC coupled with photodiode array detection. J Pharm Biomed Anal. 56, 820\u2013824 (2011).","journal-title":"J Pharm Biomed Anal."},{"key":"BFsrep23693_CR16","doi-asserted-by":"crossref","first-page":"20","DOI":"10.5740\/jaoacint.11-234","volume":"96","author":"H Li","year":"2013","unstructured":"Li, H. et al. Simultaneous determination of danshensu, salvianolic acid B and paeonol in ShuangDan Oral Liquid by HPLC. J AOAC Int. 96: 20\u201323 (2013).","journal-title":"J AOAC Int."},{"key":"BFsrep23693_CR17","first-page":"251","volume":"17","author":"H Li","year":"2011","unstructured":"Li, H., Wang, S. W., Yang, Q. & Cui, X. N. Determination of paeonol in Shuangdan Capsules by high performance liquid chromatography. Pharm J Chin PLA. 17, 251\u2013253 (2011).","journal-title":"Pharm J Chin PLA"},{"key":"BFsrep23693_CR18","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.phymed.2012.08.011","volume":"19","author":"XL Zhou","year":"2012","unstructured":"Zhou, X. L. et al. Danshensu is the major marker for the antioxidant and vasorelaxation effects of Danshen (Salvia miltiorrhiza) water-extracts produced by different heat water-extractions. Phytomedicine ; 19, 1263\u20131269 (2012).","journal-title":"Phytomedicine"},{"key":"BFsrep23693_CR19","first-page":"3861","volume":"9","author":"Q Yang","year":"2009","unstructured":"Yang, Q., Wang, S. W. & Xie, Y. H. Protective effect of Shuangdan capsule on cerebral ischemia injury-reperfusion in rats. Prog Mod Biomed. 9, 3861\u20133863 (2009).","journal-title":"Prog Mod Biomed"},{"key":"BFsrep23693_CR20","doi-asserted-by":"crossref","first-page":"e48872","DOI":"10.1371\/journal.pone.0048872","volume":"7","author":"H Li","year":"2012","unstructured":"Li, H. et al. Cardioprotective effect of Paeonol and Danshensu combination on isoproterenol-induced myocardial injury in rats. Plos one 7, e48872 (2012).","journal-title":"Plos one"},{"key":"BFsrep23693_CR21","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.neuro.2007.03.002","volume":"28","author":"GK Shinomol","year":"2007","unstructured":"Shinomol, G. K. Differential induction of oxidative impairments in brain regions of male mice following subchronic consumption of Khesari dhal (Lathyrus sativus) and detoxified Khesari dhal. Neurotoxicology 28, 798\u2013806 (2007).","journal-title":"Neurotoxicology"},{"key":"BFsrep23693_CR22","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1016\/j.febslet.2005.04.058","volume":"579","author":"H Zhu","year":"2005","unstructured":"Zhu, H., Itoh, K., Yamamoto, M., Zweier, J. L. & Li, Y. B. Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett. 579, 3029\u20133036 (2005).","journal-title":"FEBS Lett."},{"key":"BFsrep23693_CR23","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/s11418-012-0641-3","volume":"67","author":"N Zhang","year":"2013","unstructured":"Zhang, N. et al. Pharmacokinetics of the main compounds absorbed into blood after oral administration of Liu Wei Di Huang Wan, a typical combinatorial intervention of Chinese medical formula. J Nat Med. 67, 36\u201341 (2013).","journal-title":"J Nat Med."},{"key":"BFsrep23693_CR24","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/S0022-2828(85)80130-9","volume":"17","author":"G Rona","year":"1985","unstructured":"Rona, G. Catecholamine cardiotoxicity. J Mol Cell Cardiol. 17, 291\u2013300 (1985).","journal-title":"J Mol Cell Cardiol."},{"key":"BFsrep23693_CR25","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s12012-014-9263-1","volume":"15","author":"BD Sahu","year":"2015","unstructured":"Sahu, B. D., Kuncha, M., Rachamalla, S. S. & Sistla, R. Lagerstroemia speciosa L. Attenuates apoptosis in isoproterenol-induced cardiotoxic mice by inhibiting oxidative stress: Possible role of Nrf2\/HO-1. Cardiovasc Toxicol. 15, 10\u201322 (2015).","journal-title":"Cardiovasc Toxicol."},{"key":"BFsrep23693_CR26","first-page":"443","volume":"67","author":"G Rona","year":"1959","unstructured":"Rona, G. Chappel, C. I., Balazas, T. & Gaundry, R. An infarct like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat. Arch Pathol. 67, 443\u2013445 (1959).","journal-title":"Arch Pathol"},{"key":"BFsrep23693_CR27","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1139\/y82-207","volume":"60","author":"PK Singal","year":"1982","unstructured":"Singal, P. K., Kapur, N., Dhillon, K. S., Beamish, R. E. & Dhalla, N. S. Role of free radicals in catecholamine-induced cardiomyopathy. Can J Physiol Pharmacol. 60, 1390\u20131397 (1982).","journal-title":"Can J Physiol Pharmacol."},{"key":"BFsrep23693_CR28","unstructured":"Li, H. Study on the therapeutic material bases of ShuangDan prescription and the cardioprotective effect of combination of its bioactive components paeonol and danshensu on isoproterenol-induced myocardial injury in rats. PhD thesis, Fourth Military Medical University (2015)."},{"key":"BFsrep23693_CR29","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/S0008-6363(98)00244-2","volume":"40","author":"PK Singal","year":"1998","unstructured":"Singal, P. K., Khaper, N., Palace, V. & Kumar, D. The role of oxidative stress in the genesis of heart disease. Cardiovasc Res. 40, 426\u2013432 (1998).","journal-title":"Cardiovasc Res."},{"key":"BFsrep23693_CR30","first-page":"174","volume":"40","author":"AL Tappel","year":"1981","unstructured":"Tappel, A. L. & Dillard, C. J. In vivo lipid peroxidation: measurement via exhaled pentane and protection by vitamin E. Fed Proc. 40, 174\u2013178 (1981).","journal-title":"Fed Proc"},{"key":"BFsrep23693_CR31","doi-asserted-by":"crossref","first-page":"4581","DOI":"10.1021\/jf000404a","volume":"48","author":"MI Gil","year":"2000","unstructured":"Gil, M. I. et al. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem. 48, 4581\u20134589 (2000).","journal-title":"J Agric Food Chem."},{"key":"BFsrep23693_CR32","doi-asserted-by":"crossref","first-page":"3325","DOI":"10.1021\/jf9902494","volume":"47","author":"GX Pan","year":"1999","unstructured":"Pan, G. X., Spencer, L. & Leary, G. J. Reactivity of ferulic acid and its derivative towards hydrogen peroxide and peracetic acid. J Agric Food Chem. 47, 3325 (1999).","journal-title":"J Agric Food Chem."},{"key":"BFsrep23693_CR33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.fct.2007.06.034","volume":"46","author":"GR Zhao","year":"2008","unstructured":"Zhao, G. R. et al. Characterization of the radical scavenging and antioxidant activities of danshensu and salvianolic acid B. Food Chem Toxicol. 46, 73\u201381 (2008).","journal-title":"Food Chem Toxicol."},{"key":"BFsrep23693_CR34","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1248\/cpb.49.69","volume":"49","author":"H Matsuda","year":"2011","unstructured":"Matsuda, H., Ohta, T., Kawaguchi, A. & Yoshikawa, M. Bioactive constituents of chinese natural medicines. VI. Moutan cortex. (2): structures and radical scavenging effects of suffruticosides A, B, C, D and E and galloyl-oxypaeoniflorin. Chem Pharm Bull. 49, 69\u201372 (2011).","journal-title":"Chem Pharm Bull."},{"key":"BFsrep23693_CR35","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.addr.2009.01.005","volume":"61","author":"J Wu","year":"2009","unstructured":"Wu, J., Hecker, J. G. & Chiamvimonvat, N. Antioxidant enzyme gene transfer for ischemic diseases. Adv Drug Deliver Rev. 61, 351\u2013363 (2009).","journal-title":"Adv Drug Deliver Rev"},{"key":"BFsrep23693_CR36","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0163-7258(00)00114-5","volume":"89","author":"SK Wattanapitayakul","year":"2001","unstructured":"Wattanapitayakul, S. K. & Bauer, J. A. Oxidative pathways in cardiovascular disease Roles, mechanisms and therapeutic implications. Pharmacol Therapeut. 89, 187\u2013206 (2001).","journal-title":"Pharmacol Therapeut"},{"key":"BFsrep23693_CR37","first-page":"134862","volume":"2014","author":"JC Han","year":"2014","unstructured":"Han, J. C. et al. Cardioprotection against ischemia\/reperfusion by licochalcone B in isolated rat hearts. Oxid Med Cell Longev. 2014, 134862 (2014).","journal-title":"Oxid Med Cell Longev"},{"key":"BFsrep23693_CR38","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.freeradbiomed.2011.01.003","volume":"50","author":"CXC Santos","year":"2011","unstructured":"Santos, C. X. C., Anilkumar, N., Zhang, M., Brewer, A. C. & Shah, A. M. Redox signaling in cardiac myocytes. Free Radic Biol Med. 50, 777\u2013793 (2011).","journal-title":"Free Radic Biol Med."},{"key":"BFsrep23693_CR39","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.freeradbiomed.2011.10.002","volume":"52","author":"JD Su","year":"2012","unstructured":"Su, J. D. et al. 3\u2032,4\u2032-Didemethylnobiletin induces phase II detoxification gene expression and modulates PI3K\/Akt signaling in PC12 cells. Free Radic Biol Med. 52, 126\u2013141 (2012).","journal-title":"Free Radic Biol Med."},{"key":"BFsrep23693_CR40","doi-asserted-by":"crossref","first-page":"13291","DOI":"10.1074\/jbc.R900010200","volume":"284","author":"T Nguyen","year":"2009","unstructured":"Nguyen, T., Nioi, P. & Pickett, C. B. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 284, 13291\u201313295 (2009).","journal-title":"J Biol Chem."},{"key":"BFsrep23693_CR41","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.yjmcc.2010.05.011","volume":"49","author":"Y Zhang","year":"2010","unstructured":"Zhang, Y. et al. 4-Hydroxy-2-nonenal protects against cardiac ischemia-reperfusion injury via the Nrf2-dependent pathway. J Mol Cell Cardiol. 49, 576\u2013586 (2010).","journal-title":"J Mol Cell Cardiol."},{"key":"BFsrep23693_CR42","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1093\/cvr\/cvp107","volume":"83","author":"H Dreger","year":"2009","unstructured":"Dreger, H. et al. Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res. 83, 354\u2013361 (2009).","journal-title":"Cardiovasc Res."},{"key":"BFsrep23693_CR43","doi-asserted-by":"crossref","first-page":"22925","DOI":"10.1074\/jbc.M414635200","volume":"280","author":"AY Shih","year":"2005","unstructured":"Shih, A. Y. et al. Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J Biol Chem. 280, 22925\u201322936 (2005).","journal-title":"J Biol Chem."},{"key":"BFsrep23693_CR44","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.ijcard.2011.03.033","volume":"160","author":"S Liu","year":"2012","unstructured":"Liu, S. et al. Upregulation of heme oxygenase-1 expression by hydroxysafflor yellow A conferring protection from anoxia\/reoxygenation-induced apoptosis in H9c2 cardiomyocytes. Int J Cardiol. 160, 95\u2013101 (2012).","journal-title":"Int J Cardiol."},{"key":"BFsrep23693_CR45","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/nrcardio.2012.122","volume":"9","author":"K Thygesen","year":"2012","unstructured":"Thygesen, K. et al. Third universal definition of myocardial infarction. Nat Rev Cardiol. 9, 620\u2013633 (2012).","journal-title":"Nat Rev Cardiol"},{"key":"BFsrep23693_CR46","first-page":"591241","volume":"2012","author":"YP Hsiao","year":"2012","unstructured":"Hsiao, Y. P. et al. Triggering apoptotic death of human malignant melanoma a375. s2 cells by bufalin: involvement of caspase cascade-dependent and independent mitochondrial signaling pathways. Evid Based Complement Alternat Med. 2012, 591241 (2012).","journal-title":"Evid Based Complement Alternat Med."},{"key":"BFsrep23693_CR47","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1152\/ajpheart.00777.2002","volume":"284","author":"P Lee","year":"2003","unstructured":"Lee, P. et al. Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemiareperfusion in vivo. Am J Physiol Heart Circ Physiol. 284, 456\u2013463 (2003).","journal-title":"Am J Physiol Heart Circ Physiol."},{"key":"BFsrep23693_CR48","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/S0022-2143(03)00148-3","volume":"142","author":"D Kumar","year":"2003","unstructured":"Kumar, D. & Jugdutt, B. I. Apoptosis and oxidants in the heart. J Lab Clin Med. 142, 288\u2013297 (2003).","journal-title":"J Lab Clin Med."},{"key":"BFsrep23693_CR49","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.etap.2012.11.010","volume":"35","author":"J Guo","year":"2013","unstructured":"Guo, J. et al. Salvianic acid A protects L-02 cells against \u03b3-irradiation-induced apoptosis via the scavenging of reactive oxygen species. Environ Toxicol Pharmacol. 35, 117\u201330 (2013).","journal-title":"Environ Toxicol Pharmacol."},{"key":"BFsrep23693_CR50","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1165\/ajrcmb.12.6.7539275","volume":"12","author":"PP Simeonova","year":"1995","unstructured":"Simeonova, P. P. & Luster, M. I. Iron and reactive oxygen species in the asbestos-induced tumor necrosis factor-alpha response from alveolar macrophages. Am J Respir Cell Mol Biol. 12, 676\u2013683 (1995).","journal-title":"Am J Respir Cell Mol Biol."},{"key":"BFsrep23693_CR51","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1254\/jjp.86.355","volume":"86","author":"YZ Zhu","year":"2011","unstructured":"Zhu, Y. Z. et al. Time-dependent apoptotic development and pro-apoptotic genes expression in rat heart after myocardial infarction. Jpn J Pharmacol. 86, 355\u2013358 (2011).","journal-title":"Jpn J Pharmacol."},{"key":"BFsrep23693_CR52","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/ajh.2010.43","volume":"23","author":"MS Mozaffari","year":"2010","unstructured":"Mozaffari, M. S., Liu, J. Y. & Schaffer, S. W. Effect of pressure overload on cardioprotection via PI3K-Akt: comparison of postconditioning, insulin and pressure unloading. Am J Hypertens. 23, 668\u2013674 (2010).","journal-title":"Am J Hypertens."},{"key":"BFsrep23693_CR53","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.cardiores.2003.09.024","volume":"61","author":"DJ Hausenloy","year":"2004","unstructured":"Hausenloy, D. J. & Yellon, D. M. New directions for protecting the heart against ischaemia\u2013reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res. 61, 448\u2013460 (2004).","journal-title":"Cardiovasc Res."},{"key":"BFsrep23693_CR54","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1080\/08941930701366471","volume":"20","author":"CJ Mullonkal","year":"2007","unstructured":"Mullonkal, C. J. & Toledo-Pereyra, L. H. Akt in ischemia and reperfusion. J Invest Surg. 20, 195\u2013203 (2007).","journal-title":"J Invest Surg."},{"key":"BFsrep23693_CR55","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0092-8674(00)80405-5","volume":"91","author":"SR Datta","year":"1997","unstructured":"Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231\u2013241 (1997).","journal-title":"Cell"},{"key":"BFsrep23693_CR56","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.282.5392.1318","volume":"282","author":"MH Cardone","year":"1998","unstructured":"Cardone, M. H. et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 1318\u20131321 (1998).","journal-title":"Science"},{"key":"BFsrep23693_CR57","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0014-5793(03)00517-9","volume":"546","author":"K Nakaso","year":"2003","unstructured":"Nakaso, K. et al. PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett. 546, 181\u2013184 (2003).","journal-title":"FEBS Lett."},{"key":"BFsrep23693_CR58","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.taap.2009.09.009","volume":"242","author":"YP Hwang","year":"2010","unstructured":"Hwang, Y. P. & Jeong, H. G. Ginsenoside Rb1 protects against 6-hydroxydopamine-induced oxidative stress by increasing heme oxygenase-1 expression through an estrogen receptor-related PI3K\/Akt\/Nrf2-dependent pathway in human dopaminergic cells. Toxicol Appl Pharmacol. 242, 18\u201328 (2010).","journal-title":"Toxicol Appl Pharmacol."},{"key":"BFsrep23693_CR59","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1016\/j.ijcard.2012.12.012","volume":"168","author":"G Cui","year":"2013","unstructured":"Cui, G. et al. A novel Danshensu derivative confers cardioprotection via PI3K\/Akt and Nrf2 pathways. Int J Cardiol. 168, 1349\u20131359 (2013).","journal-title":"Int J Cardiol."},{"key":"BFsrep23693_CR60","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1055\/s-0030-1271033","volume":"77","author":"X Wang","year":"2011","unstructured":"Wang, X. et al. Paeonol prevents excitotoxicity in rat pheochromocytoma PC12 cells via downregulation of ERK activation and inhibition of apoptosis. Planta Med. 77, 1695\u20131701 (2011).","journal-title":"Planta Med."},{"key":"BFsrep23693_CR61","doi-asserted-by":"crossref","first-page":"484269","DOI":"10.1155\/2014\/484269","volume":"2014","author":"J Chen","year":"2014","unstructured":"Chen, J., Dai, M. & Wang, Y. Paeonol Inhibits Proliferation of Vascular Smooth Muscle Cells Stimulated by High Glucose via Ras-Raf-ERK1\/2 Signaling Pathway in Coculture Model. Evid Based Complement Alternat Med. 2014, 484269 (2014).","journal-title":"Evid Based Complement Alternat Med."},{"key":"BFsrep23693_CR62","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.jep.2013.01.019","volume":"146","author":"MH Bao","year":"2013","unstructured":"Bao, M. H., Zhang, Y. W. & Zhou, H. H. Paeonol suppresses oxidized low-density lipoprotein induced endothelial cell apoptosis via activation of LOX-1\/p38MAPK\/NF-\u03baB pathway. J Ethnopharmacol. 146, 543\u2013551 (2013).","journal-title":"J Ethnopharmacol."},{"key":"BFsrep23693_CR63","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.freeradbiomed.2005.03.026","volume":"39","author":"KE Iles","year":"2005","unstructured":"Iles, K. E. et al. HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells. Free Radic Biol Med. 39, 355\u2013364 (2005).","journal-title":"Free Radic Biol Med."},{"key":"BFsrep23693_CR64","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.neuint.2014.06.003","volume":"75","author":"G Jiang","year":"2014","unstructured":"Jiang, G. et al. Gastrodin protects against MPP+-induced oxidative stress by up regulates heme oxygenase-1 expression through p38 MAPK\/Nrf2 pathway in human dopaminergic cells. Neurochem Int. 75, 79\u201388 (2014).","journal-title":"Neurochem Int."},{"key":"BFsrep23693_CR65","doi-asserted-by":"crossref","first-page":"8863","DOI":"10.3390\/ijms15058863","volume":"15","author":"DS Lee","year":"2014","unstructured":"Lee, D. S. et al. The Cytoprotective Effect of Sulfuretin against tert-Butyl Hydroperoxide-Induced Hepatotoxicity through Nrf2\/ARE and JNK\/ERK MAPK-Mediated Heme Oxygenase-1 Expression. Int J Mol Sci. 15, 8863\u20138877 (2014).","journal-title":"Int J Mol Sci."},{"key":"BFsrep23693_CR66","doi-asserted-by":"crossref","first-page":"7973","DOI":"10.1038\/srep07973","volume":"5","author":"M Liu","year":"2015","unstructured":"Liu, M. et al. Potent effects of dioscin against obesity in mice. Sci Rep. 5, 7973 (2015).","journal-title":"Sci Rep"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep23693","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep23693.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep23693.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:50:52Z","timestamp":1748825452000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep23693"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,29]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,7,26]]}},"alternative-id":["BFsrep23693"],"URL":"https:\/\/doi.org\/10.1038\/srep23693","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,29]]},"assertion":[{"value":"5 January 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 March 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 March 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"23693"}}