{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:07:53Z","timestamp":1740146873202,"version":"3.37.3"},"reference-count":27,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T00:00:00Z","timestamp":1677024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Mediforum Co., Ltd","award":["C10-020"],"award-info":[{"award-number":["C10-020"]}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 110-2320-B-400-007"],"award-info":[{"award-number":["MOST 110-2320-B-400-007"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008903","name":"Ministry of Health and Welfare","doi-asserted-by":"publisher","award":["CS-111-GP-02"],"award-info":[{"award-number":["CS-111-GP-02"]}],"id":[{"id":"10.13039\/100008903","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Stroke is a major cause of long-term disability world-wide. Limited pharmacological therapy has been used in stroke patients. Previous studies indicated that herb formula PM012 is neuroprotective against neurotoxin trimethyltin in rat brain, and improved learning and memory in animal models of Alzheimer\u2019s disease. Its action in stroke has not been reported. This study aims to determine PM012-mediated neural protection in cellular and animal models of stroke. Glutamate-mediated neuronal loss and apoptosis were examined in rat primary cortical neuronal cultures. Cultured cells were overexpressed with a Ca++ probe (gCaMP5) by AAV1 and were used to examine Ca++ influx (Ca++i). Adult rats received PM012 before transient middle cerebral artery occlusion (MCAo). Brain tissues were collected for infarction and qRTPCR analysis. In rat primary cortical neuronal cultures, PM012 significantly antagonized glutamate-mediated TUNEL and neuronal loss, as well as NMDA-mediated Ca++i. PM012 significantly reduced brain infarction and improved locomotor activity in stroke rats. PM012 attenuated the expression of IBA1, IL6, and CD86, while upregulated CD206 in the infarcted cortex. ATF6, Bip, CHOP, IRE1, and PERK were significantly down-regulated by PM012. Using HPLC, two potential bioactive molecules, paeoniflorin and 5-hydroxymethylfurfural, were identified in the PM012 extract. Taken together, our data suggest that PM012 is neuroprotective against stroke. The mechanisms of action involve inhibition of Ca++i, inflammation, and apoptosis.<\/jats:p>","DOI":"10.1371\/journal.pone.0281421","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T18:33:41Z","timestamp":1677090821000},"page":"e0281421","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Herbal formula PM012 induces neuroprotection in stroke brain"],"prefix":"10.1371","volume":"18","author":[{"given":"Kuo-Jen","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Syuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsai-Wei","family":"Hung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun-Kyung","family":"Bae","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Hsiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chan-Kyu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dai-Won","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyeong-Soon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7500-5883","authenticated-orcid":true,"given":"Seong-Jin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,2,22]]},"reference":[{"key":"pone.0281421.ref001","first-page":"542081","article-title":"The neuroprotective effect of gugijihwang-tang on trimethyltin-induced memory dysfunction in the rat","volume":"2013","author":"EY Jung","year":"2013","journal-title":"Evid Based Complement Alternat Med"},{"issue":"8","key":"pone.0281421.ref002","doi-asserted-by":"crossref","first-page":"5401","DOI":"10.1007\/s12035-015-9458-x","article-title":"Standardized Herbal Formula PM012 Decreases Cognitive Impairment and Promotes Neurogenesis in the 3xTg AD Mouse Model of Alzheimer\u2019s Disease","volume":"53","author":"M Ye","year":"2016","journal-title":"Mol Neurobiol"},{"key":"pone.0281421.ref003","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1472-6882-12-24","article-title":"Safety and efficacy assessment of standardized herbal formula PM012","volume":"12","author":"SH Sohn","year":"2012","journal-title":"BMC Complement Altern Med"},{"issue":"8","key":"pone.0281421.ref004","first-page":"589","article-title":"Effect of radix Rehmanniae preparata on the expression of c-fos and NGF in hippocampi and learning and memory in rats with damaged thalamic arcuate nucleus","volume":"27","author":"Y Cui","year":"2004","journal-title":"Zhong Yao Cai"},{"issue":"5","key":"pone.0281421.ref005","first-page":"307","article-title":"Inhibition of fructus Corni on experimental inflammation","volume":"17","author":"Y Dai","year":"1992","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"issue":"12","key":"pone.0281421.ref006","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1016\/j.intimp.2004.07.001","article-title":"Methanol extract of Dioscoreae Rhizoma inhibits pro-inflammatory cytokines and mediators in the synoviocytes of rheumatoid arthritis","volume":"4","author":"MJ Kim","year":"2004","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"pone.0281421.ref007","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1081\/IPH-120029948","article-title":"Effects of the Geiji-Bokryung-Hwan on carrageenan-induced inflammation in mice and cyclooxygenase-2 in hepatoma cells of HepG2 and Hep3B","volume":"26","author":"WH Park","year":"2004","journal-title":"Immunopharmacol Immunotoxicol"},{"issue":"10","key":"pone.0281421.ref008","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1089\/jmf.2019.4429","article-title":"Effect of E-Beam Irradiation on Microbial Load, Stability of Active Components, and Anti-Inflammatory Activity of Cnidii Rhizoma and Alismatis Rhizoma","volume":"22","author":"ME Baek","year":"2019","journal-title":"J Med Food"},{"issue":"8","key":"pone.0281421.ref009","first-page":"e153","article-title":"Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association","volume":"145","author":"CW Tsao","year":"2022","journal-title":"Circulation"},{"issue":"9","key":"pone.0281421.ref010","doi-asserted-by":"crossref","first-page":"e139","DOI":"10.1161\/CIR.0000000000000757","article-title":"Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association","volume":"141","author":"SS Virani","year":"2020","journal-title":"Circulation"},{"issue":"18","key":"pone.0281421.ref011","article-title":"Human Milk Oligosaccharide 2\u2019-Fucosyllactose Induces Neuroprotection from Intracerebral Hemorrhage Stroke.","volume":"22","author":"TW Hung","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"4","key":"pone.0281421.ref012","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1039\/C7FO01406F","article-title":"Paeoniflorin prevents endoplasmic reticulum stress-associated inflammation in lipopolysaccharide-stimulated human umbilical vein endothelial cells via the IRE1alpha\/NF-kappaB signaling pathway","volume":"9","author":"J Chen","year":"2018","journal-title":"Food Funct"},{"issue":"12","key":"pone.0281421.ref013","first-page":"896","article-title":"5-Hydroxymethylfurfural protects against ER stress-induced apoptosis in GalN\/TNF-alpha-injured L02 hepatocytes through regulating the PERK-eIF2alpha signaling pathway","volume":"13","author":"ZQ Jiang","year":"2015","journal-title":"Chin J Nat Med"},{"issue":"2","key":"pone.0281421.ref014","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/adb.12193","article-title":"Methamphetamine induces a rapid increase of intracellular Ca(++) levels in neurons overexpressing GCaMP5","volume":"21","author":"SJ Yu","year":"2016","journal-title":"Addict Biol."},{"issue":"10","key":"pone.0281421.ref015","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1007\/s12272-018-1059-6","article-title":"Paeoniflorin attenuates atRAL-induced oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress in retinal pigment epithelial cells via triggering Ca(2+)\/CaMKII-dependent activation of AMPK","volume":"41","author":"X Zhu","year":"2018","journal-title":"Arch Pharm Res"},{"issue":"2","key":"pone.0281421.ref016","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1159\/000478626","article-title":"Astragaloside-IV Alleviates Heat-Induced Inflammation by Inhibiting Endoplasmic Reticulum Stress and Autophagy","volume":"42","author":"Z Dong","year":"2017","journal-title":"Cell Physiol Biochem"},{"issue":"4","key":"pone.0281421.ref017","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/nrneurol.2010.17","article-title":"Microglia in neurodegenerative disease","volume":"6","author":"VH Perry","year":"2010","journal-title":"Nat Rev Neurol"},{"issue":"Pt 5","key":"pone.0281421.ref018","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1093\/brain\/awv066","article-title":"Roles of microglia in brain development, tissue maintenance and repair","volume":"138","author":"MA Michell-Robinson","year":"2015","journal-title":"Brain"},{"issue":"1","key":"pone.0281421.ref019","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrneurol.2014.207","article-title":"Microglial and macrophage polarization-new prospects for brain repair","volume":"11","author":"X Hu","year":"2015","journal-title":"Nat Rev Neurol"},{"issue":"11","key":"pone.0281421.ref020","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1161\/STROKEAHA.112.659656","article-title":"Microglia\/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia","volume":"43","author":"X Hu","year":"2012","journal-title":"Stroke"},{"issue":"4","key":"pone.0281421.ref021","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s00011-007-7141-z","article-title":"BML-111, a lipoxin receptor agonist, modulates the immune response and reduces the severity of collagen-induced arthritis","volume":"57","author":"L Zhang","year":"2008","journal-title":"Inflamm Res"},{"key":"pone.0281421.ref022","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.canlet.2019.04.032","article-title":"IL-6 induced M1 type macrophage polarization increases radiosensitivity in HPV positive head and neck cancer","volume":"456","author":"X Chen","year":"2019","journal-title":"Cancer Lett"},{"key":"pone.0281421.ref023","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1476-511X-10-1","article-title":"Different responses to oxidized low-density lipoproteins in human polarized macrophages","volume":"10","author":"K Hirose","year":"2011","journal-title":"Lipids Health Dis"},{"key":"pone.0281421.ref024","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.biomaterials.2018.02.030","article-title":"3D-3-culture: A tool to unveil macrophage plasticity in the tumour microenvironment","volume":"163","author":"SP Rebelo","year":"2018","journal-title":"Biomaterials"},{"issue":"1","key":"pone.0281421.ref025","doi-asserted-by":"crossref","first-page":"14982","DOI":"10.1038\/s41598-017-14808-9","article-title":"Antibiotics induce polarization of pleural macrophages to M2-like phenotype in patients with tuberculous pleuritis","volume":"7","author":"S Wang","year":"2017","journal-title":"Sci Rep"},{"issue":"5","key":"pone.0281421.ref026","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1007\/s12975-019-00774-z","article-title":"Human Milk Oligosaccharide 2\u2019-Fucosyllactose Reduces Neurodegeneration in Stroke Brain.","volume":"11","author":"KJ Wu","year":"2020","journal-title":"Transl Stroke Res"},{"issue":"1","key":"pone.0281421.ref027","doi-asserted-by":"crossref","first-page":"4512","DOI":"10.1038\/s41598-017-04048-2","article-title":"9-cis retinoic acid induces neurorepair in stroke brain","volume":"7","author":"SJ Yu","year":"2017","journal-title":"Sci Rep"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0281421","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T18:34:10Z","timestamp":1677090850000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0281421"}},"subtitle":[],"editor":[{"given":"Cesar V.","family":"Borlongan","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,2,22]]},"references-count":27,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0281421","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2023,2,22]]}}}