{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:49:35Z","timestamp":1787921375101,"version":"build-2784847793"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Effects of Triad1\/UBE2Q1 via the ubiquitin-proteasome pathway on secondary neurological injury after traumatic brain injury and its network regulatory mechanisms","award":["81371367"],"award-info":[{"award-number":["81371367"]}]},{"name":"Effects of Triad1\/UBE2Q1 via the ubiquitin-proteasome pathway on secondary neurological injury after traumatic brain injury and its network regulatory mechanisms","award":["81371367"],"award-info":[{"award-number":["81371367"]}]},{"name":"Effects of Triad1\/UBE2Q1 via the ubiquitin-proteasome pathway on secondary neurological injury after traumatic brain injury and its network regulatory mechanisms","award":["81371367"],"award-info":[{"award-number":["81371367"]}]},{"name":"Effects of Triad1\/UBE2Q1 via the ubiquitin-proteasome pathway on secondary neurological injury after traumatic brain injury and its network regulatory mechanisms","award":["81371367"],"award-info":[{"award-number":["81371367"]}]},{"name":"Effects of Triad1\/UBE2Q1 via the ubiquitin-proteasome pathway on secondary neurological injury after traumatic brain injury and its network regulatory mechanisms","award":["81371367"],"award-info":[{"award-number":["81371367"]}]},{"name":"Effects of Triad1\/UBE2Q1 via the ubiquitin-proteasome pathway on secondary neurological injury after traumatic brain injury and its network regulatory mechanisms","award":["81371367"],"award-info":[{"award-number":["81371367"]}]},{"name":"Effects of Triad1\/UBE2Q1 via the ubiquitin-proteasome pathway on secondary neurological injury after traumatic brain injury and its network regulatory mechanisms","award":["81371367"],"award-info":[{"award-number":["81371367"]}]},{"name":"Effects of Triad1\/UBE2Q1 via the ubiquitin-proteasome pathway on secondary neurological injury after traumatic brain injury and its network regulatory mechanisms","award":["81371367"],"award-info":[{"award-number":["81371367"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Indole-3-carbinol(I3C) is a tumor chemopreventive substance that can be extracted from cruciferous vegetables. Indole-3-carbinol (I3C) has been shown to have antioxidant and anti-inflammatory effects. In this study, we investigated the cerebral protective effects of I3C in an in vivo rats model of middle cerebral artery occlusion (MCAO). 8\u201310 Week-Old male SD rat received I3C (150\u00a0mg\/kg, once daily) for 3\u00a0days and underwent 3\u00a0h of middle cerebral artery occlusion (MCAO) followed by reperfusion. The results showed that I3C pretreatment (150\u00a0mg\/kg, once daily) prevented CIRI-induced cerebral infarction in rats. I3C pretreatment also decreased the mRNA expression levels of several apoptotic proteins, including Bax, caspase-3 and caspase-9, by increasing the mRNA expression levels of the anti-apoptotic protein Bcl-2. Inhibited apoptosis in the brain cells of MCAO rats. In addition, we found that I3C pretreatment reduced neuronal loss, promoted neurological recovery after ischemia\u2013reperfusion injury and increased seven-day survival in MCAO rats. I3C pretreatment also significantly reduced the expression of inducible nitric oxide synthase (INOS), interleukin-1\u03b2 (IL-1\u03b2) and interleukin-6 (IL-6) mRNA in ischemic brain tissue; Increased expression of interleukin-4 (IL-4) and interleukin-10 (IL-10) mRNA. At the same time, I3C pretreatment significantly decreased the expression of the M1 microglial marker IBA1 after cerebral ischemia\u2013reperfusion injury and increased the expression of these results in the M2 microglial marker CD206. I3C pretreatment also significantly decreased apoptosis and death of HAPI microglial cells after hypoxia induction, decreased interleukin-1\u03b2 (IL-1\u03b2) and interleukin-6 (IL-6) mRNA The expression of interleukin-4 (IL-4) and interleukin-10 (IL-10) mRNAs was increased. These results suggest that I3C protects the brain from CIRI by regulating the anti-inflammatory and anti-apoptotic effects of microglia.<\/jats:p>","DOI":"10.1038\/s41598-024-53636-6","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T08:02:32Z","timestamp":1707292952000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Indole-3-carbinol (I3C) reduces apoptosis and improves neurological function after cerebral ischemia\u2013reperfusion injury by modulating microglia inflammation"],"prefix":"10.1038","volume":"14","author":[{"given":"Long","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingjia","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoji","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaochao","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peipei","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,7]]},"reference":[{"key":"53636_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13287-015-0175-1","volume":"6","author":"H Abeysinghe","year":"2015","unstructured":"Abeysinghe, H. et al. Pre-differentiation of human neural stem cells into GABAergic neurons prior to transplant results in greater repopulation of the damaged brain and accelerates functional recovery after transient ischemic stroke. Stem Cell Res. Therapy 6, 1\u201319 (2015).","journal-title":"Stem Cell Res. Therapy"},{"key":"53636_CR2","doi-asserted-by":"publisher","first-page":"e3080","DOI":"10.1038\/cddis.2017.465","volume":"8","author":"L Gong","year":"2017","unstructured":"Gong, L. et al. RTN1-C mediates cerebral ischemia\/reperfusion injury via ER stress and mitochondria-associated apoptosis pathways. Cell Death Dis. 8, e3080\u2013e3080 (2017).","journal-title":"Cell Death Dis."},{"key":"53636_CR3","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1056\/NEJMoa1414792","volume":"372","author":"BC Campbell","year":"2015","unstructured":"Campbell, B. C. et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N. Engl. J. Med. 372, 1009\u20131018 (2015).","journal-title":"N. Engl. J. Med."},{"key":"53636_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-019-1406-7","volume":"16","author":"J Duan","year":"2019","unstructured":"Duan, J. et al. Neuroprotective effect of Apelin 13 on ischemic stroke by activating AMPK\/GSK-3\u03b2\/Nrf2 signaling. J. Neuroinflam. 16, 1\u201316 (2019).","journal-title":"J. Neuroinflam."},{"key":"53636_CR5","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1001\/jama.282.13.1233","volume":"282","author":"KJ Joshipura","year":"1999","unstructured":"Joshipura, K. J. et al. Fruit and vegetable intake in relation to risk of ischemic stroke. Jama 282, 1233\u20131239 (1999).","journal-title":"Jama"},{"key":"53636_CR6","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1182\/blood-2004-12-4589","volume":"106","author":"Y Takada","year":"2005","unstructured":"Takada, Y., Andreeff, M. & Aggarwal, B. Indole-3-carbinol suppresses NF-kappaB and IkappaBalpha kinase activation, causing inhibition of expression of NF-kappaB-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells. Blood 106, 641\u2013649. https:\/\/doi.org\/10.1182\/blood-2004-12-4589 (2005).","journal-title":"Blood"},{"key":"53636_CR7","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/S0009-2797(96)03745-3","volume":"103","author":"DT Verhoeven","year":"1997","unstructured":"Verhoeven, D. T., Verhagen, H., Goldbohm, R. A., van den Brandt, P. A. & van Poppel, G. A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chemico-Biol Interact 103, 79\u2013129 (1997).","journal-title":"Chemico-Biol Interact"},{"key":"53636_CR8","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/ptr.2260","volume":"22","author":"MK Park","year":"2008","unstructured":"Park, M. K. et al. Antiplatelet and antithrombotic activity of indole-3-carbinol in vitro and in vivo. Phytother Res 22, 58\u201364 (2008).","journal-title":"Phytother Res"},{"key":"53636_CR9","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jnutbio.2004.10.007","volume":"16","author":"YS Kim","year":"2005","unstructured":"Kim, Y. S. & Milner, J. Targets for indole-3-carbinol in cancer prevention. J. Nutr. Biochem. 16, 65\u201373 (2005).","journal-title":"J. Nutr. Biochem."},{"key":"53636_CR10","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1080\/10799893.2017.1360351","volume":"37","author":"S Mohammadi","year":"2017","unstructured":"Mohammadi, S., Seyedhosseini, F. S., Behnampour, N. & Yazdani, Y. Indole-3-carbinol induces G1 cell cycle arrest and apoptosis through aryl hydrocarbon receptor in THP-1 monocytic cell line. J. Recept. Signal Transduct. 37, 506\u2013514 (2017).","journal-title":"J. Recept. Signal Transduct."},{"key":"53636_CR11","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1080\/08916934.2018.1494161","volume":"51","author":"S Mohammadi","year":"2018","unstructured":"Mohammadi, S., Memarian, A., Sedighi, S., Behnampour, N. & Yazdani, Y. Immunoregulatory effects of indole-3-carbinol on monocyte-derived macrophages in systemic lupus erythematosus: a crucial role for aryl hydrocarbon receptor. Autoimmunity 51, 199\u2013209 (2018).","journal-title":"Autoimmunity"},{"key":"53636_CR12","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.jss.2017.03.019","volume":"215","author":"E Ampofo","year":"2017","unstructured":"Ampofo, E. et al. Indole-3-carbinol is a potent inhibitor of ischemia\u2013reperfusion\u2013induced inflammation. J. Surg. Res. 215, 34\u201346 (2017).","journal-title":"J. Surg. Res."},{"key":"53636_CR13","doi-asserted-by":"publisher","first-page":"1732","DOI":"10.1016\/j.jnutbio.2011.12.005","volume":"23","author":"Y Choi","year":"2012","unstructured":"Choi, Y., Kim, Y., Park, S., Lee, K. W. & Park, T. Indole-3-carbinol prevents diet-induced obesity through modulation of multiple genes related to adipogenesis, thermogenesis or inflammation in the visceral adipose tissue of mice. J. Nutr. Biochem. 23, 1732\u20131739 (2012).","journal-title":"J. Nutr. Biochem."},{"key":"53636_CR14","first-page":"132","volume-title":"Seminars in cancer biology","author":"A Popolo","year":"1991","unstructured":"Popolo, A. et al. Seminars in cancer biology 132\u2013137 (Elsevier, 1991)."},{"key":"53636_CR15","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1093\/carcin\/bgv054","volume":"36","author":"JM Song","year":"2015","unstructured":"Song, J. M. et al. Combinations of indole-3-carbinol and silibinin suppress inflammation-driven mouse lung tumorigenesis by modulating critical cell cycle regulators. Carcinogenesis 36, 666\u2013675 (2015).","journal-title":"Carcinogenesis"},{"key":"53636_CR16","doi-asserted-by":"crossref","unstructured":"Li, Q. et al. Indole-3-Carbinol (I3C) protects the heart from ischemia\/reperfusion injury by inhibiting oxidative stress, inflammation, and cellular apoptosis in mice. Front. Pharmacol. 13 (2022).","DOI":"10.3389\/fphar.2022.924174"},{"key":"53636_CR17","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1007\/s00210-018-1488-2","volume":"391","author":"P Paliwal","year":"2018","unstructured":"Paliwal, P. et al. Indole-3-carbinol improves neurobehavioral symptoms in a cerebral ischemic stroke model. Naunyn-Schmiedeberg\u2019s Arch. Pharmacol. 391, 613\u2013625 (2018).","journal-title":"Naunyn-Schmiedeberg's Arch. Pharmacol."},{"key":"53636_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-020-01999-8","volume":"17","author":"AS Khan","year":"2020","unstructured":"Khan, A. S. & Langmann, T. Indole-3-carbinol regulates microglia homeostasis and protects the retina from degeneration. J. Neuroinflam. 17, 1\u201314 (2020).","journal-title":"J. Neuroinflam."},{"key":"53636_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2021.113700","volume":"341","author":"X Liu","year":"2021","unstructured":"Liu, X. et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate cerebral ischemia-reperfusion injury-induced neuroinflammation and pyroptosis by modulating microglia M1\/M2 phenotypes. Exp. Neurol. 341, 113700 (2021).","journal-title":"Exp. Neurol."},{"key":"53636_CR20","first-page":"127","volume-title":"Methods in Enzymology","author":"NR Sodha","year":"2015","unstructured":"Sodha, N. R. & Sellke, F. W. Methods in Enzymology Vol. 555, 127\u2013144 (Elsevier, 2015)."},{"key":"53636_CR21","first-page":"5275","volume":"21","author":"R Yan","year":"2017","unstructured":"Yan, R., Wang, S., Yao, G., Liu, Z. & Xiao, N. The protective effect and its mechanism of 3-n-butylphthalide pretreatment on cerebral ischemia reperfusion injury in rats. Eur. Rev. Med. Pharmacol. Sci. 21, 5275\u20135282 (2017).","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"53636_CR22","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nrneurol.2014.207","volume":"11","author":"X Hu","year":"2015","unstructured":"Hu, X. et al. Microglial and macrophage polarization\u2014New prospects for brain repair. Nat. Rev. Neurol. 11, 56\u201364 (2015).","journal-title":"Nat. Rev. Neurol."},{"key":"53636_CR23","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.612439","volume":"13","author":"L Lian","year":"2021","unstructured":"Lian, L. et al. Neuroinflammation in ischemic stroke: Focus on MicroRNA-mediated polarization of microglia. Front. Mol. Neurosci. 13, 612439 (2021).","journal-title":"Front. Mol. Neurosci."},{"key":"53636_CR24","unstructured":"Yan, R.-Y., Wang, S.-J., Yao, G.-T., Liu, Z.-G. & Xiao, N. The protective effect and its mechanism of 3-n-butylphthalide pretreatment on cerebral ischemia reperfusion injury in rats. Eur. Rev. Med. Pharmacol. Sci. 21 (2017)."},{"key":"53636_CR25","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1038\/s41590-018-0107-1","volume":"19","author":"R Shinde","year":"2018","unstructured":"Shinde, R. et al. Apoptotic cell\u2013induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. Nat. Immunol. 19, 571\u2013582 (2018).","journal-title":"Nat. Immunol."},{"key":"53636_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.biopen.2018.05.001","volume":"7","author":"L Larigot","year":"2018","unstructured":"Larigot, L., Juricek, L., Dairou, J. & Coumoul, X. AhR signaling pathways and regulatory functions. Biochim. Open 7, 1\u20139 (2018).","journal-title":"Biochim. Open"},{"key":"53636_CR27","doi-asserted-by":"publisher","first-page":"9553","DOI":"10.3892\/mmr.2017.7788","volume":"16","author":"K Liang","year":"2017","unstructured":"Liang, K., Qian, W. H. & Zong, J. 3, 3\u2032-Diindolylmethane attenuates cardiomyocyte hypoxia by modulating autophagy in H9c2 cells. Mol. Med. Rep. 16, 9553\u20139560 (2017).","journal-title":"Mol. Med. Rep."},{"key":"53636_CR28","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008656","volume":"5","author":"DR McIlwain","year":"2013","unstructured":"McIlwain, D. R., Berger, T. & Mak, T. W. Caspase functions in cell death and disease. Cold Spring Harbor Perspect. Biol. 5, a008656 (2013).","journal-title":"Cold Spring Harbor Perspect. Biol."},{"key":"53636_CR29","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1016\/j.bbalip.2013.03.001","volume":"1831","author":"T Zhang","year":"2013","unstructured":"Zhang, T. & Saghatelian, A. Emerging roles of lipids in BCL-2 family-regulated apoptosis. Biochim. Biophys. Acta 1831, 1542\u20131554 (2013).","journal-title":"Biochim. Biophys. Acta"},{"key":"53636_CR30","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1146\/annurev-physiol-021909-135846","volume":"72","author":"JM Olefsky","year":"2010","unstructured":"Olefsky, J. M. & Glass, C. K. Macrophages, inflammation, and insulin resistance. Ann. Rev. physiol. 72, 219\u2013246 (2010).","journal-title":"Ann. Rev. physiol."},{"key":"53636_CR31","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1096\/fj.13-235440","volume":"28","author":"J Galvao","year":"2014","unstructured":"Galvao, J. et al. Unexpected low-dose toxicity of the universal solvent DMSO. FASEB J. 28, 1317\u20131330 (2014).","journal-title":"FASEB J."},{"key":"53636_CR32","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.924174","volume":"13","author":"Q Li","year":"2022","unstructured":"Li, Q. et al. Indole-3-carbinol (I3C) protects the heart from ischemia\/reperfusion injury by inhibiting oxidative stress, inflammation, and cellular apoptosis in mice. Front. Pharmacol. 13, 924174 (2022).","journal-title":"Front. Pharmacol."},{"key":"53636_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2021.115853","volume":"435","author":"KA Mohamad","year":"2022","unstructured":"Mohamad, K. A., El-Naga, R. N. & Wahdan, S. A. Neuroprotective effects of indole-3-carbinol on the rotenone rat model of Parkinson\u2019s disease: impact of the SIRT1-AMPK signaling pathway. Toxicol. Appl. pharmacology 435, 115853 (2022).","journal-title":"Toxicol. Appl. pharmacology"},{"key":"53636_CR34","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1038\/aps.2017.128","volume":"39","author":"F-J Wang","year":"2018","unstructured":"Wang, F.-J. et al. Xueshuantong injection (lyophilized) combined with salvianolate lyophilized injection protects against focal cerebral ischemia\/reperfusion injury in rats through attenuation of oxidative stress. Acta Pharmacol. Sin. 39, 998\u20131011 (2018).","journal-title":"Acta Pharmacol. Sin."},{"key":"53636_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-020-01764-x","volume":"17","author":"L Peng","year":"2020","unstructured":"Peng, L. et al. DJ-1 exerts anti-inflammatory effects and regulates NLRX1-TRAF6 via SHP-1 in stroke. J. Neuroinflamm. 17, 1\u201313 (2020).","journal-title":"J. Neuroinflamm."},{"key":"53636_CR36","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.neuroscience.2022.09.016","volume":"504","author":"T Wang","year":"2022","unstructured":"Wang, T. et al. DJ-1 protein inhibits apoptosis in cerebral ischemia by regulating the notch1 and nuclear factor erythroid2-related factor 2 signaling pathways. Neuroscience 504, 33\u201346 (2022).","journal-title":"Neuroscience"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53636-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53636-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53636-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T08:16:15Z","timestamp":1707293775000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53636-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,7]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["53636"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-53636-6","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3146521\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,7]]},"assertion":[{"value":"6 July 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3145"}}