{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:00:06Z","timestamp":1789506006245,"version":"build-2803163510"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T00:00:00Z","timestamp":1585785600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T00:00:00Z","timestamp":1585785600000},"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":["Inflammation"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title><jats:italic>Abstract<\/jats:italic>\n<\/jats:title><jats:p>Sanggenon C (SC), a natural flavonoid extracted from Cortex Mori (<jats:italic>Sang Bai Pi<\/jats:italic>), is reported to possess anti-inflammatory and antioxidant properties in hypoxia. The present study aimed to investigate the therapeutic potential and the underlying mechanisms of SC in cerebral ischemia-reperfusion (I\/R) injury. A rat model of reversible middle cerebral artery occlusion (MCAO) was used to induce cerebral I\/R injury <jats:italic>in vivo<\/jats:italic>, and SC was administrated intragastrically. Brain injuries were evaluated using Bederson scores, brain water content, and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The levels of inflammatory factors and oxidative stress were examined using corresponding kits. Cell apoptosis was evaluated by TUNEL. Moreover, the expressions of apoptosis-related and RhoA\/ROCK signaling-related proteins were detected through western blotting. <jats:italic>In vitro<\/jats:italic>, RhoA was overexpressed in oxygen-glucose deprivation and reperfusion (OGD\/R)-induced PC12 cells to confirm the contribution of RhoA-ROCK signaling inhibition by SC to the neuroprotective effects post OGD\/R. Pretreatment with SC significantly ameliorated the neurologic impairment, brain edema, and cerebral infarction post MCAO-reperfusion, associated with reductions of inflammation, oxidative stress, and cell apoptosis in the brain. Furthermore, SC remarkably downregulated the expression of RhoA\/ROCK signaling-related proteins post MCAO-reperfusion in rats, while overexpression of RhoA reversed the beneficial effects of SC on protecting against inflammation and oxidative stress in OGD\/R-induced PC12 cells. Taken together, these findings demonstrated that SC exerts neuroprotective effects after cerebral I\/R injury <jats:italic>via<\/jats:italic> inhibiting inflammation and oxidative stress through regulating RhoA-ROCK signaling, suggesting a therapeutic potential of SC in cerebral I\/R injury.<\/jats:p>","DOI":"10.1007\/s10753-020-01225-w","type":"journal-article","created":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T13:03:33Z","timestamp":1585832613000},"page":"1476-1487","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Sanggenon C Ameliorates Cerebral Ischemia-Reperfusion Injury by Inhibiting Inflammation and Oxidative Stress through Regulating RhoA-ROCK Signaling"],"prefix":"10.1007","volume":"43","author":[{"given":"Yilei","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingfeng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,4,2]]},"reference":[{"issue":"3","key":"1225_CR1","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1161\/01.str.17.3.472","volume":"17","author":"JB Bederson","year":"1986","unstructured":"Bederson, J.B., L.H. Pitts, M. Tsuji, M.C. Nishimura, R.L. Davis, and H. Bartkowski. 1986. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17 (3): 472\u2013476. https:\/\/doi.org\/10.1161\/01.str.17.3.472.","journal-title":"Stroke"},{"key":"1225_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejphar.2017.03.025","volume":"806","author":"J Chen","year":"2017","unstructured":"Chen, J., W. Yin, Y. Tu, S. Wang, X. Yang, Q. Chen, X. Zhang, Y. Han, and R. Pi. 2017. L-F001, a novel multifunctional ROCK inhibitor, suppresses neuroinflammation in vitro and in vivo: Involvement of NF-kappaB inhibition and Nrf2 pathway activation. European Journal of Pharmacology 806: 1\u20139. https:\/\/doi.org\/10.1016\/j.ejphar.2017.03.025.","journal-title":"European Journal of Pharmacology"},{"issue":"4","key":"1225_CR3","doi-asserted-by":"publisher","first-page":"2123","DOI":"10.3892\/or.2017.5912","volume":"38","author":"LD Chen","year":"2017","unstructured":"Chen, L.D., Z.H. Liu, L.F. Zhang, J.N. Yao, and C.F. Wang. 2017. Sanggenon C induces apoptosis of colon cancer cells via inhibition of NO production, iNOS expression and ROS activation of the mitochondrial pathway. Oncology Reports 38 (4): 2123\u20132131. https:\/\/doi.org\/10.3892\/or.2017.5912.","journal-title":"Oncology Reports"},{"issue":"10159","key":"1225_CR4","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1016\/S0140-6736(18)32203-7","volume":"392","author":"Collaborators, G. B. D. Causes of Death","year":"2018","unstructured":"Collaborators, G. B. D. Causes of Death. 2018. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392 (10159): 1736\u20131788. https:\/\/doi.org\/10.1016\/S0140-6736(18)32203-7.","journal-title":"Lancet"},{"key":"1225_CR5","doi-asserted-by":"publisher","first-page":"7","DOI":"10.4137\/JCNSD.S13194","volume":"6","author":"FA Desland","year":"2014","unstructured":"Desland, F.A., A. Afzal, Z. Warraich, and J. Mocco. 2014. Manual versus automated rodent behavioral assessment: comparing efficacy and ease of Bederson and Garcia neurological deficit scores to an open field video-tracking system. J Cent Nerv Syst Dis 6: 7\u201314. https:\/\/doi.org\/10.4137\/JCNSD.S13194.","journal-title":"J Cent Nerv Syst Dis"},{"issue":"10159","key":"1225_CR6","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1016\/S0140-6736(18)32279-7","volume":"392","author":"GBD Disease","year":"2018","unstructured":"Disease, G.B.D., Incidence Injury, and Collaborators Prevalence. 2018. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392 (10159): 1789\u20131858. https:\/\/doi.org\/10.1016\/S0140-6736(18)32279-7.","journal-title":"Lancet"},{"key":"1225_CR7","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.brainres.2013.07.053","volume":"1534","author":"MA Fard","year":"2013","unstructured":"Fard, M.A., K.B. Ebrahimi, and N.R. Miller. 2013. RhoA activity and post-ischemic inflammation in an experimental model of adult rodent anterior ischemic optic neuropathy. Brain Research 1534: 76\u201386. https:\/\/doi.org\/10.1016\/j.brainres.2013.07.053.","journal-title":"Brain Research"},{"issue":"7","key":"1225_CR8","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/s41582-018-0023-x","volume":"14","author":"I Fyfe","year":"2018","unstructured":"Fyfe, I. 2018. Positive trials in ischaemic stroke reported at ESOC 2018. Nature Reviews. Neurology 14 (7): 379. https:\/\/doi.org\/10.1038\/s41582-018-0023-x.","journal-title":"Nature Reviews. Neurology"},{"issue":"6","key":"1225_CR9","doi-asserted-by":"publisher","first-page":"8130","DOI":"10.3892\/mmr.2017.7646","volume":"16","author":"Y Gu","year":"2017","unstructured":"Gu, Y., L. Gao, Y. Chen, Z. Xu, K. Yu, D. Zhang, G. Zhang, and X. Zhang. 2017. Sanggenon C protects against cardiomyocyte hypoxia injury by increasing autophagy. Molecular Medicine Reports 16 (6): 8130\u20138136. https:\/\/doi.org\/10.3892\/mmr.2017.7646.","journal-title":"Molecular Medicine Reports"},{"issue":"8","key":"1225_CR10","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/nrneurol.2017.99","volume":"13","author":"C Hetz","year":"2017","unstructured":"Hetz, C., and S. Saxena. 2017. ER stress and the unfolded protein response in neurodegeneration. Nature Reviews. Neurology 13 (8): 477\u2013491. https:\/\/doi.org\/10.1038\/nrneurol.2017.99.","journal-title":"Nature Reviews. Neurology"},{"key":"1225_CR11","first-page":"1315","volume":"3","author":"H Huang","year":"2011","unstructured":"Huang, H., N. Liu, K. Zhao, C. Zhu, X. Lu, S. Li, W. Lian, P. Zhou, X. Dong, C. Zhao, H. Guo, C. Zhang, C. Yang, G. Wen, L. Lu, X. Li, L. Guan, C. Liu, X. Wang, Q.P. Dou, and J. Liu. 2011. Sanggenon C decreases tumor cell viability associated with proteasome inhibition. Frontiers in Bioscience (Elite Edition) 3: 1315\u20131325.","journal-title":"Frontiers in Bioscience (Elite Edition)"},{"issue":"1","key":"1225_CR12","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.trsl.2009.04.005","volume":"154","author":"W Jiang","year":"2009","unstructured":"Jiang, W., F. Xia, J. Han, and J. Wang. 2009. Patterns of Nogo-A, NgR, and RhoA expression in the brain tissues of rats with focal cerebral infarction. Translational Research 154 (1): 40\u201348. https:\/\/doi.org\/10.1016\/j.trsl.2009.04.005.","journal-title":"Translational Research"},{"issue":"5","key":"1225_CR13","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1002\/jcb.10722","volume":"90","author":"A Lakshmikuttyamma","year":"2003","unstructured":"Lakshmikuttyamma, A., P. Selvakumar, R. Kakkar, R. Kanthan, R. Wang, and R.K. Sharma. 2003. Activation of calcineurin expression in ischemia-reperfused rat heart and in human ischemic myocardium. Journal of Cellular Biochemistry 90 (5): 987\u2013997. https:\/\/doi.org\/10.1002\/jcb.10722.","journal-title":"Journal of Cellular Biochemistry"},{"key":"1225_CR14","doi-asserted-by":"publisher","unstructured":"Li, X., Z. Ren, Z. Wu, Z. Fu, H. Xie, L. Deng, X. Jiang, and D. Chen. 2018. Steric effect of antioxidant Diels-Alder-type adducts: a comparison of sanggenon C with sanggenon D. Molecules 23 (10). https:\/\/doi.org\/10.3390\/molecules23102610.","DOI":"10.3390\/molecules23102610"},{"issue":"1","key":"1225_CR15","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1161\/01.str.20.1.84","volume":"20","author":"EZ Longa","year":"1989","unstructured":"Longa, E.Z., P.R. Weinstein, S. Carlson, and R. Cummins. 1989. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20 (1): 84\u201391. https:\/\/doi.org\/10.1161\/01.str.20.1.84.","journal-title":"Stroke"},{"issue":"10","key":"1225_CR16","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1038\/s12276-018-0156-4","volume":"50","author":"TJ Ma","year":"2018","unstructured":"Ma, T.J., Z.W. Zhang, Y.L. Lu, Y.Y. Zhang, D.C. Tao, Y.Q. Liu, and Y.X. Ma. 2018. CLOCK and BMAL1 stabilize and activate RHOA to promote F-actin formation in cancer cells. Experimental & Molecular Medicine 50 (10): 130\u2013115. https:\/\/doi.org\/10.1038\/s12276-018-0156-4.","journal-title":"Experimental & Molecular Medicine"},{"issue":"7","key":"1225_CR17","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.1161\/STROKEAHA.117.017286","volume":"49","author":"A Mizuma","year":"2018","unstructured":"Mizuma, A., J.S. You, and M.A. Yenari. 2018. Targeting reperfusion injury in the age of mechanical thrombectomy. Stroke 49 (7): 1796\u20131802. https:\/\/doi.org\/10.1161\/STROKEAHA.117.017286.","journal-title":"Stroke"},{"issue":"6","key":"1225_CR18","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1038\/aps.2012.35","volume":"33","author":"ZT Mo","year":"2012","unstructured":"Mo, Z.T., Y.Q. Fang, Y.P. He, and S. Zhang. 2012. Beta-Asarone protects PC12 cells against OGD\/R-induced injury via attenuating Beclin-1-dependent autophagy. Acta Pharmacologica Sinica 33 (6): 737\u2013742. https:\/\/doi.org\/10.1038\/aps.2012.35.","journal-title":"Acta Pharmacologica Sinica"},{"issue":"12","key":"1225_CR19","doi-asserted-by":"publisher","first-page":"2283","DOI":"10.1016\/j.cellsig.2012.07.025","volume":"24","author":"V Rajapurohitam","year":"2012","unstructured":"Rajapurohitam, V., F. Izaddoustdar, E. Martinez-Abundis, and M. Karmazyn. 2012. Leptin-induced cardiomyocyte hypertrophy reveals both calcium-dependent and calcium-independent\/RhoA-dependent calcineurin activation and NFAT nuclear translocation. Cellular Signalling 24 (12): 2283\u20132290. https:\/\/doi.org\/10.1016\/j.cellsig.2012.07.025.","journal-title":"Cellular Signalling"},{"issue":"8","key":"1225_CR20","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/s41582-019-0221-1","volume":"15","author":"G Stoll","year":"2019","unstructured":"Stoll, G., and B. Nieswandt. 2019. Thrombo-inflammation in acute ischaemic stroke-implications for treatment. Nature Reviews. Neurology 15 (8): 473\u2013481. https:\/\/doi.org\/10.1038\/s41582-019-0221-1.","journal-title":"Nature Reviews. Neurology"},{"key":"1225_CR21","doi-asserted-by":"publisher","unstructured":"Wang, H., T. Feng, D. Guo, M. Zhang, L. Chen, and Y. Zhou. 2018. Sanggenon C stimulates osteoblastic proliferation and differentiation, inhibits osteoclastic resorption, and ameliorates prednisone-induced osteoporosis in zebrafish model. Molecules 23 (9). https:\/\/doi.org\/10.3390\/molecules23092343.","DOI":"10.3390\/molecules23092343"},{"issue":"1","key":"1225_CR22","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1161\/01.RES.0000109415.17511.18","volume":"94","author":"BJ Wilkins","year":"2004","unstructured":"Wilkins, B.J., Y.S. Dai, O.F. Bueno, S.A. Parsons, J. Xu, D.M. Plank, F. Jones, T.R. Kimball, and J.D. Molkentin. 2004. Calcineurin\/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circulation Research 94 (1): 110\u2013118. https:\/\/doi.org\/10.1161\/01.RES.0000109415.17511.18.","journal-title":"Circulation Research"},{"issue":"7","key":"1225_CR23","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1038\/s41582-018-0015-x","volume":"14","author":"H Wood","year":"2018","unstructured":"Wood, H. 2018. Selective neuronal loss could limit penumbral rescue after stroke. Nature Reviews. Neurology 14 (7): 380\u2013381. https:\/\/doi.org\/10.1038\/s41582-018-0015-x.","journal-title":"Nature Reviews. Neurology"},{"issue":"4","key":"1225_CR24","doi-asserted-by":"publisher","first-page":"5338","DOI":"10.3892\/mmr.2017.7288","volume":"16","author":"L Xiao","year":"2017","unstructured":"Xiao, L., Y. Gu, L. Gao, J. Shangguan, Y. Chen, Y. Zhang, and L. Li. 2017. Sanggenon C protects against pressure overloadinduced cardiac hypertrophy via the calcineurin\/NFAT2 pathway. Molecular Medicine Reports 16 (4): 5338\u20135346. https:\/\/doi.org\/10.3892\/mmr.2017.7288.","journal-title":"Molecular Medicine Reports"},{"key":"1225_CR25","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.brainres.2007.04.013","volume":"1154","author":"K Yamashita","year":"2007","unstructured":"Yamashita, K., Y. Kotani, Y. Nakajima, M. Shimazawa, S. Yoshimura, S. Nakashima, T. Iwama, and H. Hara. 2007. Fasudil, a Rho kinase (ROCK) inhibitor, protects against ischemic neuronal damage in vitro and in vivo by acting directly on neurons. Brain Research 1154: 215\u2013224. https:\/\/doi.org\/10.1016\/j.brainres.2007.04.013.","journal-title":"Brain Research"},{"issue":"22","key":"1225_CR26","doi-asserted-by":"publisher","first-page":"5275","DOI":"10.26355\/eurrev_201711_13852","volume":"21","author":"RY Yan","year":"2017","unstructured":"Yan, R.Y., S.J. Wang, G.T. Yao, Z.G. Liu, and N. Xiao. 2017. The protective effect and its mechanism of 3-n-butylphthalide pretreatment on cerebral ischemia reperfusion injury in rats. Eur Rev Med Pharmacol Sci 21 (22): 5275\u20135282. https:\/\/doi.org\/10.26355\/eurrev_201711_13852.","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"1225_CR27","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.brainres.2019.01.018","volume":"1711","author":"X Yu","year":"2019","unstructured":"Yu, X., L. Jia, W. Yu, and H. Du. 2019. Dephosphorylation by calcineurin regulates translocation of dynamin-related protein 1 to mitochondria in hepatic ischemia reperfusion induced hippocampus injury in young mice. Brain Research 1711: 68\u201376. https:\/\/doi.org\/10.1016\/j.brainres.2019.01.018.","journal-title":"Brain Research"},{"issue":"6","key":"1225_CR28","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1021\/np401025f","volume":"77","author":"H Zelova","year":"2014","unstructured":"Zelova, H., Z. Hanakova, Z. Cermakova, K. Smejkal, S. Dall Acqua, P. Babula, J. Cvacka, and J. Hosek. 2014. Evaluation of anti-inflammatory activity of prenylated substances isolated from Morus alba and Morus nigra. Journal of Natural Products 77 (6): 1297\u20131303. https:\/\/doi.org\/10.1021\/np401025f.","journal-title":"Journal of Natural Products"},{"issue":"10","key":"1225_CR29","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/S1875-5364(17)30107-3","volume":"15","author":"JX Zhang","year":"2017","unstructured":"Zhang, J.X., J.M. Guo, H.J. Lin, T.T. Zhang, Z.G. Li, J.C. Zhou, and Z.Z. Zhang. 2017. Neuroprotective effects of Yiqihuoxue calm wind capsule on ischemic stroke in rats. Chinese Journal of Natural Medicines 15 (10): 758\u2013765. https:\/\/doi.org\/10.1016\/S1875-5364(17)30107-3.","journal-title":"Chinese Journal of Natural Medicines"},{"issue":"1","key":"1225_CR30","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1080\/13880209.2019.1698619","volume":"58","author":"YM Zhang","year":"2020","unstructured":"Zhang, Y.M., X.Y. Qu, L.N. Tao, J.H. Zhai, H. Gao, Y.Q. Song, and S.X. Zhang. 2020. XingNaoJing injection ameliorates cerebral ischaemia\/reperfusion injury via SIRT1-mediated inflammatory response inhibition. Pharmaceutical Biology 58 (1): 16\u201324. https:\/\/doi.org\/10.1080\/13880209.2019.1698619.","journal-title":"Pharmaceutical Biology"},{"issue":"9","key":"1225_CR31","first-page":"1206","volume":"37","author":"P Zhou","year":"2017","unstructured":"Zhou, P., X.X. Dong, and P. Tang. 2017. Sanggenon C induces apoptosis of prostate cancer PC3 cells by activating caspase 3 and caspase 9 pathways. Nan Fang Yi Ke Da Xue Xue Bao 37 (9): 1206\u20131210.","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao"}],"container-title":["Inflammation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10753-020-01225-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10753-020-01225-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10753-020-01225-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T23:35:03Z","timestamp":1617320103000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s10753-020-01225-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,2]]},"references-count":31,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,8]]}},"alternative-id":["1225"],"URL":"https:\/\/doi.org\/10.1007\/s10753-020-01225-w","relation":{},"ISSN":["0360-3997","1573-2576"],"issn-type":[{"value":"0360-3997","type":"print"},{"value":"1573-2576","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,2]]},"assertion":[{"value":"2 April 2020","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"The authors declare that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}},{"value":"All animal experiments in the present study were approved by the Animal Care and Use Committee of the First Affiliated Hospital, Zhejiang University School of Medicine.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval and Consent to Participate"}}]}}