{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T07:21:24Z","timestamp":1774509684888,"version":"3.50.1"},"reference-count":66,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2024,8,4]],"date-time":"2024-08-04T00:00:00Z","timestamp":1722729600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U21A20400"],"award-info":[{"award-number":["U21A20400"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Huanglian Jiedu decoction (HLJD) has been used to treat ischemic stroke in clinic. However, the detailed protective mechanisms of HLJD on ischemic stroke have yet to be elucidated. The aim of this study is to elucidate the underlying pharmacological mechanisms of HLJD based on the inhibition of neuroinflammation and the amelioration of nerve cell damage. A middle cerebral artery occlusion reperfusion (MCAO\/R) model was established in rats and received HLJD treatment. Effects of HLJD on neurological function was assessed based on Bederson's score, postural reflex test and asymmetry score. 2, 3, 5\u2010Triphenyltetrazolium chloride (TTC) staining, Hematein and eosin (HE) and Nissl staining were used to observe the pathological changes in brain. Then, transcriptomics was used to screen the differential genes in brain tissue in MCAO\/R model rats following HLJD intervention. Subsequently, the effects of HLJD on neutrophil extracellular trap (NET) formation\u2010related neuroinflammation, gamma\u2010aminobutyric acid (GABA)ergic synapse activation, nerve cell damage and proliferation were validated using immunofluorescence, western blot and enzyme\u2010linked immunosorbent assay (ELISA). Our results showed that HLJD intervention reduced the Bederson's score, postural reflex test score and asymmetry score in MCAO\/R model rats. Pathological staining indicated that HLJD treatment decreased the cerebral infarction area, mitigated neuronal damage and increased the numbers of Nissl bodies. Transcriptomics suggested that HLJD affected 435 genes in MCAO\/R rats. Among them, several genes involving in NET formation and GABAergic synapses pathways were dysregulated. Subsequent experimental validation showed that HLJD reduced the MPO<jats:sup>+<\/jats:sup>CitH3<jats:sup>+<\/jats:sup> positive expression area, reduced the protein expression of PAD4, p\u2010P38\/P38, p\u2010ERK\/ERK and decreased the levels of IL\u20101\u03b2, IL\u20106 and TNF\u2010\u03b1, reversed the increase of Iba1<jats:sup>+<\/jats:sup>TLR4<jats:sup>+<\/jats:sup>, Iba1<jats:sup>+<\/jats:sup>p65<jats:sup>+<\/jats:sup> and Iba1<jats:sup>+<\/jats:sup>NLRP3<jats:sup>+<\/jats:sup> positive expression area in brain. Moreover, HLJD increased GABA levels, elevated the protein expression of GABRG1 and GAT3, decreased the TUNEL positive expression area and increased the Ki67 positive expression area in brain. HLJD intervention exerts a multifaceted positive impact on ischemia\u2010induced cerebral injury in MCAO\/R rats. This intervention effectively inhibits neuroinflammation by mitigating NET formation, and concurrently improves nerve cell damage and fosters nerve cell proliferation through activating GABAergic synapses.<\/jats:p>","DOI":"10.1111\/jcmm.18528","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T04:41:40Z","timestamp":1722832900000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Huanglian Jiedu decoction alleviates ischemia\u2010induced cerebral injury in rats by mitigating <scp>NET<\/scp> formation and activiting <scp>GABAergic<\/scp> synapses"],"prefix":"10.1111","volume":"28","author":[{"given":"Youxiang","family":"Cui","sequence":"first","affiliation":[{"name":"Key Laboratory of Neurological Rehabilitation Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine  Cangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyue","family":"Cui","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neurological Rehabilitation Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine  Cangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leilei","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neurological Rehabilitation Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine  Cangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"First School of Clinical Medicine Yunnan University of Chinese Medicine  Kunming China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Chen","sequence":"additional","affiliation":[{"name":"First School of Clinical Medicine Yunnan University of Chinese Medicine  Kunming China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuquan","family":"Lv","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neurological Rehabilitation Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine  Cangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Limin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neurological Rehabilitation Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine  Cangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congai","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing University of Chinese Medicine  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanwen","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neurological Rehabilitation Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine  Cangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neurological Rehabilitation Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine  Cangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lichun","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neurological Rehabilitation Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine  Cangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0820-5436","authenticated-orcid":false,"given":"Huantian","family":"Cui","sequence":"additional","affiliation":[{"name":"First School of Clinical Medicine Yunnan University of Chinese Medicine  Kunming China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,8,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113518"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2019.07.015"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30030-4"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.317596"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-019-05705-y"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/17474930211006303"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1159\/000518524"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/10600280211073009"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000012801"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.120.032810"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110458"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12576"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1159\/000525822"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.782569"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.115.011238"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/1756286418774254"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.21220"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-021-02635-z"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000068"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2019.10.048"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.714943"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2010.01.030"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2022.108328"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.590453"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/5788602"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2015.3515"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctim.2015.01.001"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2012.09.028"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105464"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctim.2019.08.015"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1080\/13880209.2021.1942505"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2022.115244"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2022.154469"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13020-020-00327-9"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2017.128"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.17.3.472"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29981"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17121971"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118221"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2018.1531196"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.680636"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2019.03.028"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23030564"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2020.113355"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-11-844530"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.141110"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1170"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370221989263"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3RU0620-375R"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13538"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2022.11505"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.683803"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2013.00165"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2019.112426"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH17-02-0130"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16191-y"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.23190"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-019-00694-y"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15313"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetimm.2021.110234"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2023.176018"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.22580"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2018.01.015"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0028-3908(99)00233-6"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD009622.pub4"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-017-0463-7"}],"container-title":["Journal of Cellular and Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jcmm.18528","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T11:55:40Z","timestamp":1723636540000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jcmm.18528"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8]]},"references-count":66,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["10.1111\/jcmm.18528"],"URL":"https:\/\/doi.org\/10.1111\/jcmm.18528","archive":["Portico"],"relation":{},"ISSN":["1582-1838","1582-4934"],"issn-type":[{"value":"1582-1838","type":"print"},{"value":"1582-4934","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8]]},"assertion":[{"value":"2024-04-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e18528"}}