{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:12:46Z","timestamp":1790115166800,"version":"4.0.1"},"reference-count":103,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,12,12]],"date-time":"2018-12-12T00:00:00Z","timestamp":1544572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cerebral ischemia-reperfusion is a complicated pathological process. The injury and cascade reactions caused by cerebral ischemia and reperfusion are characterized by high mortality, high recurrence, and high disability. However, only a limited number of antithrombotic drugs, such as recombinant tissue plasminogen activator (r-TPA), aspirin, and heparin, are currently available for ischemic stroke, and its safety concerns is inevitable which associated with reperfusion injury and hemorrhage. Therefore, it is necessary to further explore and examine some potential neuroprotective agents with treatment for cerebral ischemia and reperfusion injury to reduce safety concerns caused by antithrombotic drugs in ischemic stroke. Ginseng Rg1 (G-Rg1) is a saponin composed of natural active ingredients and derived from the roots or stems of Panax notoginseng and ginseng in traditional Chinese medicine. Its pharmacological effects exert remarkable neurotrophic and neuroprotective effects in the central nervous system. To explore and summarize the protective effects and mechanisms of ginsenoside Rg1 against cerebral ischemia and reperfusion injury, we conducted this review, in which we searched the PubMed database to obtain and organize studies concerning the pharmacological effects and mechanisms of ginsenoside Rg1 against cerebral ischemia and reperfusion injury. This study provides a valuable reference and clues for the development of new agents to combat ischemic stroke. Our summarized review and analysis show that the pharmacological effects of and mechanisms underlying ginsenoside Rg1 activity against cerebral ischemia and reperfusion injury mainly involve 4 sets of mechanisms: anti-oxidant activity and associated apoptosis via the Akt, Nrf2\/HO-1, PPAR\u03b3\/HO-1, extracellular regulated protein kinases (ERK), p38, and c-Jun N-terminal kinase (JNK) pathways (or mitochondrial apoptosis pathway) and the caspase-3\/ROCK1\/MLC pathway; anti-inflammatory and immune stimulatory-related activities that involve apoptosis or necrosis via MAPK pathways (the JNK1\/2 + ERK1\/2 and PPAR\u03b3\/HO-1 pathways), endoplasmic reticulum stress (ERS), high mobility group protein1 (HMGB1)-induced TLR2\/4\/9 and receptor for advanced glycation end products (RAGE) pathways, and the activation of NF-\u03baB; neurological cell cycle, proliferation, differentiation, and regeneration via the MAPK pathways (JNK1\/2 + ERK1\/2, PI3K-Akt\/mTOR, PKB\/Akt and HIF-1\u03b1\/VEGF pathways); and energy metabolism and the regulation of cellular ATP levels, the blood-brain barrier and other effects via N-methyl-D-aspartic acid (NMDA) receptors, ERS, and AMP\/AMPK-GLUT pathways. Collectively, these mechanisms result in significant neuroprotective effects against cerebral ischemic injury. These findings will be valuable in that they should further promote the development of candidate drugs and provide more information to support the application of previous findings in stroke clinical trials.<\/jats:p>","DOI":"10.3390\/cells7120270","type":"journal-article","created":{"date-parts":[[2018,12,12]],"date-time":"2018-12-12T10:54:26Z","timestamp":1544612066000},"page":"270","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":161,"title":["Protective Effects and Target Network Analysis of Ginsenoside Rg1 in Cerebral Ischemia and Reperfusion Injury: A Comprehensive Overview of Experimental Studies"],"prefix":"10.3390","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5062-7843","authenticated-orcid":false,"given":"Weijie","family":"Xie","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China"},{"name":"Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhou","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China"},{"name":"Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Medical Information, Chinese Academy of Medical Sciences, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangbao","family":"Meng","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China"},{"name":"Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziru","family":"Dai","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China"},{"name":"Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guibo","family":"Sun","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China"},{"name":"Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Sun","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China"},{"name":"Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1750-1326-6-11","article-title":"Pathophysiology, treatment, and animal and cellular models of human ischemic stroke","volume":"6","author":"Woodruff","year":"2011","journal-title":"Mol. Neurodegener."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1038\/nm.2507","article-title":"Ischemia and reperfusion\u2014From mechanism to translation","volume":"17","author":"Eltzschig","year":"2011","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1080\/08941930591004449","article-title":"Molecular mechanisms in the pathogenesis and treatment of acute ischemic stroke","volume":"18","author":"Turley","year":"2005","journal-title":"J. Investig. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4385","DOI":"10.2174\/138161212802481282","article-title":"Effects of ACE-inhibitors and angiotensin receptor blockers on inflammation","volume":"18","author":"Raimondo","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.ijcard.2010.06.005","article-title":"Effects of clinical and laboratory variables and of pretreatment with cardiovascular drugs in acute ischaemic stroke: A retrospective chart review from the GIFA study","volume":"151","author":"Tuttolomondo","year":"2011","journal-title":"Int. J. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/j.addr.2009.05.009","article-title":"Mitochondria and reactive oxygen and nitrogen species in neurological disorders and stroke: Therapeutic implications","volume":"61","author":"Moro","year":"2009","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1016\/j.freeradbiomed.2005.01.019","article-title":"Reactive oxygen species and the modulation of stroke","volume":"38","author":"Crack","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.freeradbiomed.2011.06.003","article-title":"The role of free radical generation in increasing cerebrovascular permeability","volume":"51","author":"Fraser","year":"2011","journal-title":"Free Radic. Boil. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s00062-009-8033-0","article-title":"Acute Stroke Therapy 1981\u20132009","volume":"19","author":"Eckert","year":"2009","journal-title":"Clin. Neuroradiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Xie, W., Meng, X., Zhai, Y., Zhou, P., Ye, T., Wang, Z., Sun, G., and Sun, X. (2018). Panax Notoginseng Saponins: A Review of Its Mechanisms of Antidepressant or Anxiolytic Effects and Network Analysis on Phytochemistry and Pharmacology. Molecules.","DOI":"10.20944\/preprints201803.0117.v1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.3892\/mmr.2014.2328","article-title":"Antiinflammatory effects of Panax notoginseng saponins ameliorate acute lung injury induced by oleic acid and lipopolysaccharide in rats","volume":"10","author":"Chen","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1248\/bpb.33.1324","article-title":"Panax notoginseng saponins attenuate atherogenesis accelerated by zymosan in rabbits","volume":"33","author":"Liu","year":"2010","journal-title":"Biol. Pharm. Bull."},{"key":"ref_13","first-page":"1399","article-title":"Effects of Panax notoginseng saponins on antioxidation and preventing DNA damage caused by hydroxyl radical","volume":"31","author":"Gao","year":"2008","journal-title":"Zhong Yao Cai"},{"key":"ref_14","first-page":"52","article-title":"Study on the anti-apopotosis induced by hypoxia\/hypoglycemia and reoxygenation of panax notoginseng saponins in cultured rat hippocampal neurons","volume":"28","author":"Zhu","year":"2003","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.phymed.2013.12.005","article-title":"Ginsenoside Rg1 provides neuroprotection against blood brain barrier disruption and neurological injury in a rat model of cerebral ischemia\/reperfusion through downregulation of aquaporin 4 expression","volume":"21","author":"Zhou","year":"2014","journal-title":"Phytomedicine"},{"key":"ref_16","first-page":"2009","article-title":"Simultaneous determination of sixteen ginsenosides in Panax ginseng and its preparation by HPLC","volume":"45","author":"Guo","year":"2014","journal-title":"J. Ginseng Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"457","DOI":"10.5142\/jgr.2013.37.457","article-title":"Simultaneous determination of 30 ginsenosides in Panax ginseng preparations using ultra performance liquid chromatography","volume":"37","author":"Park","year":"2013","journal-title":"J. Ginseng Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.jchromb.2008.02.012","article-title":"Simultaneous determination of two Amadori compounds in Korean red ginseng (Panax ginseng) extracts and rat plasma by high-performance anion-exchange chromatography with pulsed amperometric detection","volume":"865","author":"Joo","year":"2008","journal-title":"J. Chromatogr. B"},{"key":"ref_19","first-page":"3352","article-title":"Effects of different steaming methods on saponins in taproots of Panax notoginseng","volume":"46","author":"Wu","year":"2015","journal-title":"Chinese Traditional & Herbal Drugs."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1002\/tox.22416","article-title":"Impairment of preimplantation and postimplantation embryonic development through intrinsic apoptotic processes by ginsenoside Rg1 in vitro and in vivo","volume":"32","author":"Anggelia","year":"2017","journal-title":"Environ. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.neuropharm.2018.01.009","article-title":"MiR-134 modulates chronic stress-induced structural plasticity and depression-like behaviors via downregulation of Limk1\/cofilin signaling in rats","volume":"131","author":"Fan","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.jgr.2017.03.010","article-title":"Ginsenoside Rg1 modulates medial prefrontal cortical firing and suppresses the hippocampo-medial prefrontal cortical long-term potentiation","volume":"42","author":"Ghaeminia","year":"2018","journal-title":"J. Ginseng Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Guo, Y.H., Zhao, S., Du, Y.X., Xing, Q.J., Chen, B.L., and Yu, C.Q. (2017). Effects of ginsenoside Rg1-loaded alginate-chitosan microspheres on human bone marrow stromal cells. Biosci. Rep., 37.","DOI":"10.1042\/BSR20160566"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7842082","DOI":"10.1155\/2017\/7842082","article-title":"Neuroprotective Effect of the Ginsenoside Rg1 on Cerebral Ischemic Injury In Vivo and In Vitro Is Mediated by PPARgamma-Regulated Antioxidative and Anti-Inflammatory Pathways","volume":"2017","author":"Li","year":"2017","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2163053","DOI":"10.1155\/2017\/2163053","article-title":"A Preclinical Systematic Review of Ginsenoside-Rg1 in Experimental Parkinson\u2019s Disease","volume":"2017","author":"Song","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.biopha.2018.01.136","article-title":"Protective effect and mechanism of ginsenoside Rg1 in cerebral ischaemia-reperfusion injury in mice","volume":"99","author":"Wang","year":"2018","journal-title":"Biomed. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.jep.2017.06.031","article-title":"Ginsenoside Rg1 alleviates corticosterone-induced dysfunction of gap junctions in astrocytes","volume":"208","author":"Xia","year":"2017","journal-title":"J. Ethnopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.1159\/000492684","article-title":"Ginsenoside Rg1 Prevents Chronic Stress-Induced Depression-Like Behaviors and Neuronal Structural Plasticity in Rats","volume":"48","author":"Yu","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.3892\/ijmm.2017.3092","article-title":"Ginsenoside Rg1 protects against neuronal degeneration induced by chronic dexamethasone treatment by inhibiting NLRP-1 inflammasomes in mice","volume":"40","author":"Zhang","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/j.1745-7254.2005.00034.x","article-title":"Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action","volume":"26","author":"Cheng","year":"2005","journal-title":"Acta Pharm. Sin."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3109\/03639045.2013.858734","article-title":"Pharmacokinetics and efficiency of brain targeting of ginsenosides Rg1 and Rb1 given as Nao-Qing microemulsion","volume":"41","author":"Li","year":"2015","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.apsb.2015.02.001","article-title":"Ginsenoside Rg1 protects against transient focal cerebral ischemic injury and suppresses its systemic metabolic changes in cerabral injury rats","volume":"5","author":"Lin","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1089\/ars.2013.5757","article-title":"The use of microRNAs to modulate redox and immune response to stroke","volume":"22","author":"Ouyang","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"698","DOI":"10.2174\/1871527311312050015","article-title":"Oxidative stress and pathophysiology of ischemic stroke: Novel therapeutic opportunities","volume":"12","author":"Rodrigo","year":"2013","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.cbi.2017.11.012","article-title":"Astaxanthin-antioxidant impact on excessive Reactive Oxygen Species generation induced by ischemia and reperfusion injury","volume":"279","author":"Zuluaga","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jns.2016.12.036","article-title":"Protective effects of ginsenoside Rg1 against oxygen-glucose-deprivation-induced apoptosis in neural stem cells","volume":"373","author":"Li","year":"2017","journal-title":"J. Neurol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2183026","DOI":"10.1155\/2016\/2183026","article-title":"ROS-Mediated NLRP3 Inflammasome Activation in Brain, Heart, Kidney, and Testis Ischemia\/Reperfusion Injury","volume":"2016","author":"Minutoli","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.lfs.2014.12.002","article-title":"Neuroprotective effect of ginsenoside-Rg1 on cerebral ischemia\/reperfusion injury in rats by downregulating protease-activated receptor-1 expression","volume":"121","author":"Xie","year":"2015","journal-title":"Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7790","DOI":"10.1038\/srep07790","article-title":"A systematic review and meta-analysis of Ginsenoside-Rg1 (G-Rg1) in experimental ischemic stroke","volume":"5","author":"Xie","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.freeradbiomed.2018.01.024","article-title":"ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection","volume":"117","author":"Cadenas","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1161\/CIRCRESAHA.117.311401","article-title":"Reactive Oxygen Species in Metabolic and Inflammatory Signaling","volume":"122","author":"Forrester","year":"2018","journal-title":"Circ. Res."},{"key":"ref_42","first-page":"483","article-title":"Ischemic preconditioning modulates ROS to confer protection in liver ischemia and reperfusion","volume":"16","author":"Bystrom","year":"2017","journal-title":"EXCLI J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.pathophys.2017.09.003","article-title":"Reperfusion therapy-What\u2019s with the obstructed, leaky and broken capillaries?","volume":"24","author":"Granger","year":"2017","journal-title":"Pathophysiology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.smrv.2014.07.003","article-title":"Oxidative stress in obstructive sleep apnea and intermittent hypoxia--revisited--the bad ugly and good: Implications to the heart and brain","volume":"20","author":"Lavie","year":"2015","journal-title":"Sleep Med. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1007\/s00204-014-1437-x","article-title":"Molecular responses to ischemia and reperfusion in the liver","volume":"89","author":"Quesnelle","year":"2015","journal-title":"Arch. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1007\/s11596-016-1612-9","article-title":"Neuroprotective potential of cerium oxide nanoparticles for focal cerebral ischemic stroke","volume":"36","author":"Zhou","year":"2016","journal-title":"J. Huazhong Univ. Sci. Technol. Med. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.bbabio.2006.03.002","article-title":"Apoptotic interactions of cytochrome c: Redox flirting with anionic phospholipids within and outside of mitochondria","volume":"1757","author":"Bayir","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1042\/BST0391538","article-title":"Achievements and perspectives in yeast acetic acid-induced programmed cell death pathways","volume":"39","author":"Guaragnella","year":"2011","journal-title":"Biochem. Soc. Trans."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/01616412.2016.1251711","article-title":"Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders","volume":"39","author":"Islam","year":"2017","journal-title":"Neurol. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.freeradbiomed.2013.08.182","article-title":"Modulation of mitochondrial functions by the indirect antioxidant sulforaphane: A seemingly contradictory dual role and an integrative hypothesis","volume":"65","author":"Tapia","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.jconrel.2013.05.021","article-title":"Hypoxia as a target for tissue specific gene therapy","volume":"172","author":"Rhim","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.apsb.2014.11.002","article-title":"Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia\/reperfusion-induced cerebral microcirculatory disturbances and neuron damage","volume":"5","author":"Sun","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4299","DOI":"10.2147\/IJN.S32385","article-title":"Core-shell hybrid liposomal vesicles loaded with panax notoginsenoside: Preparation, characterization and protective effects on global cerebral ischemia\/reperfusion injury and acute myocardial ischemia in rats","volume":"7","author":"Zhang","year":"2012","journal-title":"Int. J. Nanomed."},{"key":"ref_54","first-page":"229","article-title":"Effects of ginsenoside Rg1 on the expressions of p-eRK1\/2 and p-JNK in local cerebral ischemia\/reperfusion injury rats","volume":"33","author":"Wang","year":"2013","journal-title":"Zhongguo Zhong Xi Yi Jie He Za Zhi"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12974-015-0264-1","article-title":"MCP-induced protein 1 mediates the minocycline-induced neuroprotection against cerebral ischemia\/reperfusion injury in vitro and in vivo","volume":"12","author":"Jin","year":"2015","journal-title":"J. Neuroinflammation"},{"key":"ref_56","first-page":"2484","article-title":"Ginsenoside Rg1 suppressed inflammation and neuron apoptosis by activating PPARgamma\/HO-1 in hippocampus in rat model of cerebral ischemia-reperfusion injury","volume":"8","author":"Yang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Deng, Y., Yang, M., Xu, F., Zhang, Q., Zhao, Q., Yu, H., Li, D., Zhang, G., Lu, A., and Cho, K. (2015). Combined Salvianolic Acid B and Ginsenoside Rg1 Exerts Cardioprotection against Ischemia\/Reperfusion Injury in Rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135435"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.mito.2015.11.003","article-title":"Rg1 prevents myocardial hypoxia\/reoxygenation injury by regulating mitochondrial dynamics imbalance via modulation of glutamate dehydrogenase and mitofusin 2","volume":"26","author":"Dong","year":"2016","journal-title":"Mitochondrion"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.neuint.2010.11.004","article-title":"Ginsenoside Rg1 protects against hydrogen peroxide-induced cell death in PC12 cells via inhibiting NF-kappaB activation","volume":"58","author":"Liu","year":"2011","journal-title":"Neurochem. Int."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.4103\/1673-5374.187057","article-title":"Protective effects of ginsenoside Rg1 against hydrogen peroxide-induced injury in human neuroblastoma cells","volume":"11","author":"Sun","year":"2016","journal-title":"Neural Regen. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1038\/aps.2015.70","article-title":"An integrated pathway interaction network for the combination of four effective compounds from ShengMai preparations in the treatment of cardio-cerebral ischemic diseases","volume":"36","author":"Li","year":"2015","journal-title":"Acta Pharm. Sin."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"402","DOI":"10.4103\/0973-1296.141765","article-title":"Effects of Astragaloside IV combined with the active components of Panax notoginseng on oxidative stress injury and nuclear factor-erythroid 2-related factor 2\/heme oxygenase-1 signaling pathway after cerebral ischemia-reperfusion in mice","volume":"10","author":"Huang","year":"2014","journal-title":"Pharm. Mag."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.jep.2014.05.024","article-title":"Effect of the total saponins of Aralia elata (Miq) Seem on cardiac contractile function and intracellular calcium cycling regulation","volume":"155","author":"Wang","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"204840","DOI":"10.1155\/2014\/204840","article-title":"Protective Effects of Panax Notoginseng Saponins on Cardiovascular Diseases: A Comprehensive Overview of Experimental Studies","volume":"2014","author":"Yang","year":"2014","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1089\/rej.2015.1697","article-title":"Cocktail of Four Active Components Derived from Sheng Mai San Inhibits Hydrogen Peroxide-Induced PC12 Cell Apoptosis Linked with the Caspase-3\/ROCK1\/MLC Pathway","volume":"18","author":"Shen","year":"2015","journal-title":"Rejuv. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"756346","DOI":"10.1155\/2015\/756346","article-title":"Synergistic Use of Geniposide and Ginsenoside Rg1 Balance Microglial TNF-alpha and TGF-beta1 following Oxygen-Glucose Deprivation In Vitro: A Genome-Wide Survey","volume":"2015","author":"Wang","year":"2015","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1248\/bpb.b14-00394","article-title":"Protective effects of ginsenoside Rg1 on astrocytes and cerebral ischemic-reperfusion mice","volume":"37","author":"Sun","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"579","DOI":"10.3389\/fimmu.2018.00579","article-title":"Systemic Inflammation and Cardiovascular Comorbidity in Psoriasis Patients: Causes and Consequences","volume":"9","author":"Boehncke","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.gdata.2017.08.006","article-title":"Stroke-associated pattern of gene expression previously identified by machine-learning is diagnostically robust in an independent patient population","volume":"14","author":"Chantler","year":"2017","journal-title":"Genom. Data"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"6527","DOI":"10.1523\/JNEUROSCI.0111-18.2018","article-title":"Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection","volume":"38","author":"Alawieh","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s12974-018-1117-5","article-title":"Lentivirus-mediated overexpression of OTULIN ameliorates microglia activation and neuroinflammation by depressing the activation of the NF-kappaB signaling pathway in cerebral ischemia\/reperfusion rats","volume":"15","author":"Xu","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/nm.2399","article-title":"The immunology of stroke: From mechanisms to translation","volume":"17","author":"Iadecola","year":"2011","journal-title":"Nat. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1749-8546-9-13","article-title":"Chinese herbs and their active ingredients for activating xue (blood) promote the proliferation and differentiation of neural stem cells and mesenchymal stem cells","volume":"9","author":"Si","year":"2014","journal-title":"Chin. Med."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"He, P., Li, P., Hua, Q., Liu, Y., Staufenbiel, M., Li, R., and Shen, Y. (2013). Chronic administration of anti-stroke herbal medicine TongLuoJiuNao reduces amyloidogenic processing of amyloid precursor protein in a mouse model of Alzheimer\u2019s disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058181"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1159\/000489241","article-title":"Current Mechanistic Concepts in Ischemia and Reperfusion Injury","volume":"46","author":"Wu","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.jss.2014.03.067","article-title":"Ginsenoside Rg1 protects mouse liver against ischemia-reperfusion injury through anti-inflammatory and anti-apoptosis properties","volume":"191","author":"Tao","year":"2014","journal-title":"J. Surg. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.jep.2016.10.052","article-title":"Identification of NF-kappaB inhibitors following Shenfu injection and bioactivity-integrated UPLC\/Q-TOF-MS and screening for related anti-inflammatory targets in vitro and in silico","volume":"194","author":"Li","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/jgh.12072","article-title":"Sterile inflammation in hepatic ischemia\/reperfusion injury: Present concepts and potential therapeutics","volume":"28","author":"Reiniers","year":"2013","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_79","first-page":"3186","article-title":"Protective effects of geniposide and ginsenoside Rg1 combination treatment on rats following cerebral ischemia are mediated via microglial microRNA1555p inhibition","volume":"17","author":"Wang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1142\/S0192415X15500809","article-title":"Effects of the Combination of the Main Active Components of Astragalus and Panax notoginseng on Inflammation and Apoptosis of Nerve Cell after Cerebral Ischemia-Reperfusion","volume":"43","author":"Huang","year":"2015","journal-title":"Am. J. Chin. Med."},{"key":"ref_81","first-page":"91","article-title":"Compatibility of geniposide and ginsenoside rgl: Their regulating roles in secretion of anoxia induction injured microglia inflammatory cytokines","volume":"34","author":"Wang","year":"2014","journal-title":"Hong Zhong Xi Yi Jie He Za Zhi"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.cbi.2010.04.007","article-title":"Methylmercury-induced neurotoxicity and apoptosis","volume":"188","author":"Ceccatelli","year":"2010","journal-title":"Chem. Biol. Interact."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.fct.2018.01.057","article-title":"Oxidative stress, caspase-3 activation and cleavage of ROCK-1 play an essential role in MeHg-induced cell death in primary astroglial cells","volume":"113","author":"Farina","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.toxlet.2017.03.001","article-title":"Site-specific neural hyperactivity via the activation of MAPK and PKA\/CREB pathways triggers neuronal degeneration in methylmercury-intoxicated mice","volume":"271","author":"Fujimura","year":"2017","journal-title":"Toxicol. Lett."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.neuro.2015.11.007","article-title":"Methylmercury upregulates RE-1 silencing transcription factor (REST) in SH-SY5Y cells and mouse cerebellum","volume":"52","author":"Guida","year":"2016","journal-title":"Neurotoxicology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.cbi.2016.12.020","article-title":"Hydrogen sulfide may attenuate methylmercury-induced neurotoxicity via mitochondrial preservation","volume":"263","author":"Han","year":"2017","journal-title":"Chem. Biol. Interact."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.toxlet.2016.09.007","article-title":"Atg5-dependent autophagy plays a protective role against methylmercury-induced cytotoxicity","volume":"262","author":"Takanezawa","year":"2016","journal-title":"Toxicol. Lett."},{"key":"ref_88","first-page":"349","article-title":"Ginsenoside Rg1 protects cardiomyocytes from hypoxia-induced injury through the PI3K\/AKT\/mTOR pathway","volume":"73","author":"Qin","year":"2018","journal-title":"Pharmazie"},{"key":"ref_89","first-page":"433","article-title":"Protein kinases role in adaptive phenomenon of heart ischemic postconditioning development","volume":"99","author":"Maslov","year":"2013","journal-title":"Ross Fiziol Zh Im I M Sechenova"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/pr.2016.178","article-title":"An in vivo study of hypoxia-inducible factor-1alpha signaling in ginsenoside Rg1-mediated brain repair after hypoxia\/ischemia brain injury","volume":"81","author":"Tang","year":"2017","journal-title":"Pediatr. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.neures.2009.07.006","article-title":"Alteration of NRSF expression exacerbating 1-methyl-4-phenyl-pyridinium ion-induced cell death of SH-SY5Y cells","volume":"65","author":"Mei","year":"2009","journal-title":"Neurosci. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2174\/187152711794480456","article-title":"Targeting hypoxia inducible factor-1alpha: A novel mechanism of ginsenoside Rg1 for brain repair after hypoxia\/ischemia brain damage","volume":"10","author":"Tang","year":"2011","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_93","first-page":"503","article-title":"Effect of ginsenoside Rg1 on angiogenesis after neonatal hypoxia ischemia brain damage in rats","volume":"42","author":"Wang","year":"2011","journal-title":"Sichuan Da Xue Xue Bao Yi Xue Ban"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1159\/000430217","article-title":"Combination of ginsenoside Rg1 and bone marrow mesenchymal stem cell transplantation in the treatment of cerebral ischemia reperfusion injury in rats","volume":"37","author":"Bao","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0304-3940(03)00318-5","article-title":"Ginsenoside Rg1 increases ischemia-induced cell proliferation and survival in the dentate gyrus of adult gerbils","volume":"344","author":"Shen","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"732","DOI":"10.4103\/0973-1296.165572","article-title":"Effects of the main active components combinations of Astragalus and Panax notoginseng on energy metabolism in brain tissues after cerebral ischemia-reperfusion in mice","volume":"11","author":"Huang","year":"2015","journal-title":"Pharm. Mag."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"5328","DOI":"10.3892\/mmr.2015.4094","article-title":"Synergistic neuroprotective effect of microglialconditioned media treated with geniposide and ginsenoside Rg1 on hypoxia injured neurons","volume":"12","author":"Wang","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jcma.2014.01.001","article-title":"Neuroprotective effects of ginsenoside Rg1 against oxygen-glucose deprivation in cultured hippocampal neurons","volume":"77","author":"He","year":"2014","journal-title":"J. Chin. Med. Assoc."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1179\/016164107X159144","article-title":"NMDA receptor and iNOS are involved in the effects of ginsenoside Rg1 on hippocampal neurogenesis in ischemic gerbils","volume":"29","author":"Shen","year":"2007","journal-title":"Neurol. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.ymgme.2018.08.014","article-title":"Development and clinical consequences of white matter lesions in Fabry disease: A systematic review","volume":"125","author":"Korver","year":"2018","journal-title":"Mol. Genet. MeTable"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jns.2018.10.009","article-title":"Brain MRI findings in children and adolescents with Fabry disease","volume":"395","author":"Marchesoni","year":"2018","journal-title":"J. Neurol. Sci."},{"key":"ref_102","first-page":"1039","article-title":"Advances in pharmacological studies of Panax notoginseng saponins on brain ischemia-reperfusion injury","volume":"51","author":"Yang","year":"2016","journal-title":"Yao Xue Xue Bao"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Meng, X., Xie, W., Xu, Q., Liang, T., Xu, X., Sun, G., and Sun, X. (2018). Neuroprotective Effects of Radix Scrophulariae on Cerebral Ischemia and Reperfusion Injury via MAPK Pathways. 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