{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:29:51Z","timestamp":1791473391361,"version":"4.3.4"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T00:00:00Z","timestamp":1605052800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T00:00:00Z","timestamp":1605052800000},"content-version":"vor","delay-in-days":0,"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":["81800089"],"award-info":[{"award-number":["81800089"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82000095"],"award-info":[{"award-number":["82000095"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["22120180576"],"award-info":[{"award-number":["22120180576"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Clinical research fund of Zhongshan Hospital to Xu Wu","award":["2020ZSQN083"],"award-info":[{"award-number":["2020ZSQN083"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroinflammation"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Intermittent hypoxia (IH) caused by obstructive sleep apnea (OSA) leads to neuroinflammation. Pinocembrin has been shown to have neuroprotective effects, while the therapeutic functions under IH condition are still unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An OSA model was established by CIH exposure inside custom-made chambers. C57BL\/6 mice were intraperitoneally injected with pinocembrin (40\u2009mg\/kg, i.p.) or vehicle (PBS containing 5% povidone; i.p.), and the changes of behavior on mice were detected by the Morris water maze test. Immunohistochemical staining, western blotting, immunofluorescence assays, and immunoprecipitation were used to investigate the association between NLRP3 inflammasome and BNIP3-dependent mitophagy. The mitochondrial morphology and mitophagosomes were detected under a transmission electron microscope. The detrimental effects of IH were tested by annexin V-FITC\/PI staining, Mito SOX Red staining, and JC-1 mitochondrial membrane potential assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, our observations in vivo indicated that the administration of pinocembrin can restore spatial learning and memory ability and reduce neuronal apoptosis and hippocampal inflammation. Pinocembrin treatment significantly inhibited the formation of NLRP3 inflammasome and infiltration of microglia and enhanced BNIP3-mediated mitophagy in the hippocampus of IH mice. Additionally, our in vitro results show that pinocembrin protects microglial cells against IH-induced cytotoxicity by activating BNIP3-dependent mitophagy through the JNK-ERK signaling pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In summary, our findings demonstrated that pinocembrin can act as a potential therapeutic strategy for IH-induced neuroinflammation.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12974-020-02014-w","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T07:02:59Z","timestamp":1605078179000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["Pinocembrin ameliorates intermittent hypoxia-induced neuroinflammation through BNIP3-dependent mitophagy in a murine model of sleep apnea"],"prefix":"10.1186","volume":"17","author":[{"given":"Lin-Jing","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Yuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yu","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,11]]},"reference":[{"issue":"3","key":"2014_CR1","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1002\/cphy.c100060","volume":"2","author":"SXL Zhang","year":"2012","unstructured":"Zhang SXL, Wang Y, Gozal D. Pathological consequences of intermittent hypoxia in the central nervous system. Compr Physiol. 2012;2(3):1767.","journal-title":"Compr Physiol."},{"key":"2014_CR2","first-page":"1077","volume":"9","author":"Q Yang","year":"2013","unstructured":"Yang Q, Wang Y, Feng J, Cao J, Chen B. Intermittent hypoxia from obstructive sleep apnea may cause neuronal impairment and dysfunction in central nervous system: the potential roles played by microglia. Neuropsychiatr Dis Treat. 2013;9:1077\u201386.","journal-title":"Neuropsychiatr Dis Treat."},{"issue":"4, Supplement","key":"2014_CR3","doi-asserted-by":"publisher","first-page":"A577","DOI":"10.1016\/j.chest.2016.02.602","volume":"149","author":"S Liu","year":"2016","unstructured":"Liu S, Wang Z, Xu B, Chen K, Ren L, Sun J. Intermittent hypoxia reduces microglia proliferation and induces DNA damage in vitro. Chest. 2016;149(4, Supplement):A577.","journal-title":"Chest"},{"issue":"12","key":"2014_CR4","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1089\/ars.2014.6204","volume":"22","author":"H Wu","year":"2015","unstructured":"Wu H, Chen Q. Hypoxia activation of mitophagy and its role in disease pathogenesis. Antioxid Redox Signal. 2015;22(12):1032\u201346.","journal-title":"Antioxid Redox Signal."},{"issue":"2","key":"2014_CR5","doi-asserted-by":"publisher","first-page":"124","DOI":"10.5114\/fn.2017.68579","volume":"55","author":"S Liu","year":"2017","unstructured":"Liu S, Sun JY, Ren LP, Chen K, Xu B. Propofol attenuates intermittent hypoxia induced up-regulation of proinflammatory cytokines in microglia through inhibiting the activation of NF-Bkappa\/p38 MAPK signalling. Folia Neuropathol. 2017;55(2):124\u201331.","journal-title":"Folia Neuropathol."},{"key":"2014_CR6","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.bbi.2018.06.012","volume":"73","author":"Y Shi","year":"2018","unstructured":"Shi Y, Guo X, Zhang J, Zhou H, Sun B, Feng J. DNA binding protein HMGB1 secreted by activated microglia promotes the apoptosis of hippocampal neurons in diabetes complicated with OSA. Brain, Behavior, and Immunity. 2018;73:482\u201392.","journal-title":"Brain, Behavior, and Immunity."},{"issue":"10","key":"2014_CR7","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1002\/glia.23663","volume":"67","author":"I Karunakaran","year":"2019","unstructured":"Karunakaran I, Alam S, Jayagopi S, Frohberger SJ, Hansen JN, Kuehlwein J, H\u00f6lbling BV, Schumak B, H\u00fcbner MP, Gr\u00e4ler MH, Halle A, van Echten-Deckert G. Neural sphingosine 1-phosphate accumulation activates microglia and links impaired autophagy and inflammation. Glia. 2019;67(10):1859\u201372.","journal-title":"Glia."},{"issue":"3","key":"2014_CR8","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1007\/s12035-015-9125-2","volume":"53","author":"X Lan","year":"2016","unstructured":"Lan X, Wang W, Li Q, Wang J. The natural flavonoid pinocembrin: molecular targets and potential therapeutic applications. Mol Neurobiol. 2016;53(3):1794\u2013801.","journal-title":"Mol Neurobiol."},{"issue":"5","key":"2014_CR9","doi-asserted-by":"publisher","first-page":"385","DOI":"10.3390\/cells8050385","volume":"8","author":"M Borriello","year":"2019","unstructured":"Borriello M, Iannuzzi C, Sirangelo I. Pinocembrin protects from AGE-induced cytotoxicity and inhibits non-enzymatic glycation in human insulin. Cells-Basel. 2019;8(5):385.","journal-title":"Cells-Basel."},{"issue":"10","key":"2014_CR10","doi-asserted-by":"publisher","first-page":"15786","DOI":"10.3390\/molecules191015786","volume":"19","author":"G Zhao","year":"2014","unstructured":"Zhao G, Zhang W, Li L, Wu S, Du G. Pinocembrin protects the brain against ischemia-reperfusion injury and reverses the autophagy dysfunction in the penumbra area. Molecules. 2014;19(10):15786\u201398.","journal-title":"Molecules."},{"key":"2014_CR11","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.ejphar.2015.06.003","volume":"761","author":"LT Zhou","year":"2015","unstructured":"Zhou LT, Wang KJ, Li L, Li H, Geng M. Pinocembrin inhibits lipopolysaccharide-induced inflammatory mediators production in BV2 microglial cells through suppression of PI3K\/Akt\/NF-kappaB pathway. Eur J Pharmacol. 2015;761:211\u20136.","journal-title":"Eur J Pharmacol."},{"key":"2014_CR12","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.bbi.2016.12.012","volume":"61","author":"X Lan","year":"2017","unstructured":"Lan X, Han X, Li Q, Li Q, Gao Y, Cheng T, Wan J, Zhu W, Wang J. Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia. Brain Behav Immunity. 2017;61:326\u201339.","journal-title":"Brain Behav Immunity"},{"issue":"3","key":"2014_CR13","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.molmed.2014.11.008","volume":"21","author":"P Gurung","year":"2015","unstructured":"Gurung P, Lukens JR, Kanneganti T. Mitochondria: diversity in the regulation of the NLRP3 inflammasome. Trends Mol Med. 2015;21(3):193\u2013201.","journal-title":"Trends Mol Med."},{"issue":"12","key":"2014_CR14","doi-asserted-by":"publisher","first-page":"9404","DOI":"10.1002\/jcp.26784","volume":"233","author":"X Wu","year":"2018","unstructured":"Wu X, Chang SC, Jin J, Gu W, Li S. NLRP3 inflammasome mediates chronic intermittent hypoxia-induced renal injury implication of the microRNA-155\/FOXO3a signaling pathway. J Cell Physiol. 2018;233(12):9404\u201315.","journal-title":"J Cell Physiol."},{"issue":"12","key":"2014_CR15","doi-asserted-by":"publisher","first-page":"2297","DOI":"10.1016\/j.bbamcr.2012.08.007","volume":"1823","author":"M Frank","year":"2012","unstructured":"Frank M, Duvezin-Caubet S, Koob S, Occhipinti A, Jagasia R, Petcherski A, Ruonala MO, Priault M, Salin B, Reichert AS. Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim Biophys Acta. 2012;1823(12):2297\u2013310.","journal-title":"Biochim Biophys Acta"},{"issue":"10","key":"2014_CR16","doi-asserted-by":"publisher","first-page":"529","DOI":"10.5483\/BMBRep.2016.49.10.115","volume":"49","author":"M Kim","year":"2016","unstructured":"Kim M, Yoon J, Ryu J. Mitophagy: a balance regulator of NLRP3 inflammasome activation. Bmb Rep. 2016;49(10):529\u201335.","journal-title":"Bmb Rep."},{"key":"2014_CR17","doi-asserted-by":"crossref","unstructured":"Xu Y, Shen J, Ran Z. Emerging views of mitophagy in immunity and autoimmune diseases. Autophagy. 2020;16(1):3-17.","DOI":"10.1080\/15548627.2019.1603547"},{"key":"2014_CR18","doi-asserted-by":"crossref","unstructured":"Wang Y, Liu N, Lu B. Mechanisms and roles of mitophagy in neurodegenerative diseases. Cns Neurosci Ther. 2019;25(7):859-75.","DOI":"10.1111\/cns.13140"},{"issue":"2","key":"2014_CR19","doi-asserted-by":"publisher","first-page":"e2576","DOI":"10.1038\/cddis.2017.4","volume":"8","author":"M Moriyama","year":"2017","unstructured":"Moriyama M, Moriyama H, Uda J, Kubo H, Nakajima Y, Goto A, Morita T, Hayakawa T. BNIP3 upregulation via stimulation of ERK and JNK activity is required for the protection of keratinocytes from UVB-induced apoptosis. Cell Death Dis. 2017;8(2):e2576.","journal-title":"Cell Death Dis."},{"issue":"4","key":"2014_CR20","doi-asserted-by":"publisher","first-page":"307","DOI":"10.4161\/auto.2947","volume":"2","author":"A Hamacher-Brady","year":"2006","unstructured":"Hamacher-Brady A, Brady NR, Gottlieb RA, Gustafsson AB. Autophagy as a protective response to Bnip3-mediated apoptotic signaling in the heart. Autophagy. 2006;2(4):307\u20139.","journal-title":"Autophagy."},{"issue":"6","key":"2014_CR21","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1007\/s10571-016-0440-6","volume":"37","author":"O Iyalomhe","year":"2017","unstructured":"Iyalomhe O, Swierczek S, Enwerem N, Chen Y, Adedeji MO, Allard J, Ntekim O, Johnson S, Hughes K, Kurian P, TO O. The role of hypoxia-inducible factor 1 in mild cognitive impairment. Cell Mol Neurobiol. 2017;37(6):969\u201377.","journal-title":"Cell Mol Neurobiol."},{"key":"2014_CR22","doi-asserted-by":"crossref","unstructured":"Lei Q, Tan J, Yi S, Wu N, Wang Y, Wu H. Mitochonic acid 5 activates the MAPK\u2013ERK\u2013yap signaling pathways to protect mouse microglial BV-2 cells against TNF\u03b1-induced apoptosis via increased Bnip3-related mitophagy. Cell Mol Biol Lett. 2018;23(1):14.","DOI":"10.1186\/s11658-018-0081-5"},{"issue":"1","key":"2014_CR23","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.intimp.2012.06.009","volume":"14","author":"LW Soromou","year":"2012","unstructured":"Soromou LW, Chu X, Jiang L, Wei M, Huo M, Chen N, Guan S, Yang X, Chen C, Feng H, Deng X. In vitro and in vivo protection provided by pinocembrin against lipopolysaccharide-induced inflammatory responses. Int Immunopharmacol. 2012;14(1):66\u201374.","journal-title":"Int Immunopharmacol."},{"issue":"1","key":"2014_CR24","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/0165-0270(84)90007-4","volume":"11","author":"R Morris","year":"1984","unstructured":"Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Meth. 1984;11(1):47\u201360.","journal-title":"J Neurosci Meth."},{"key":"2014_CR25","first-page":"1","volume":"2016","author":"H Li","year":"2016","unstructured":"Li H, Miao W, Ma J, Xv Z, Bo H, Li J, Zhang Y, Ji LL. Acute exercise-induced mitochondrial stress triggers an inflammatory response in the myocardium via NLRP3 inflammasome activation with mitophagy. Oxid Med Cell Longev. 2016;2016:1\u201311.","journal-title":"Oxid Med Cell Longev."},{"issue":"5","key":"2014_CR26","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1111\/cns.13086","volume":"25","author":"X Jin","year":"2019","unstructured":"Jin X, Liu MY, Zhang DF, Zhong X, Du K, Qian P, Yao WF, Gao H, Wei MJ. Baicalin mitigates cognitive impairment and protects neurons from microglia-mediated neuroinflammation via suppressing NLRP3 inflammasomes and TLR4\/NF-\u03baB signaling pathway. Cns Neurosci Ther. 2019;25(5):575\u201390.","journal-title":"Cns Neurosci Ther."},{"key":"2014_CR27","doi-asserted-by":"crossref","unstructured":"Thangaraj A, Periyasamy P, Guo M, Chivero ET, Callen S, Buch S. Mitigation of cocaine-mediated mitochondrial damage, defective mitophagy and microglial activation by superoxide dismutase mimetics. Autophagy. 2019:1\u201324.","DOI":"10.1080\/15548627.2019.1607686"},{"key":"2014_CR28","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.canlet.2018.05.026","volume":"431","author":"Y Zheng","year":"2018","unstructured":"Zheng Y, Wang K, Wu Y, Chen Y, Chen X, Hu CW, Hu F. Pinocembrin induces ER stress mediated apoptosis and suppresses autophagy in melanoma cells. Cancer Lett. 2018;431:31\u201342.","journal-title":"Cancer Lett."},{"key":"2014_CR29","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1016\/j.biopha.2018.07.026","volume":"106","author":"J Tao","year":"2018","unstructured":"Tao J, Shen C, Sun Y, Chen W, Yan G. Neuroprotective effects of pinocembrin on ischemia\/reperfusion-induced brain injury by inhibiting autophagy. Biomed Pharmacother. 2018;106:1003\u201310.","journal-title":"Biomed Pharmacother."},{"issue":"1","key":"2014_CR30","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1083\/jcb.201111063","volume":"198","author":"Y Qi","year":"2012","unstructured":"Qi Y, Tian X, Liu J, Han Y, Graham AM, Simon MC, Penninger JM, Carmeliet P, Li S. Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis. J Cell Biol. 2012;198(1):103\u201314.","journal-title":"J Cell Biol."},{"issue":"4","key":"2014_CR31","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1038\/cdd.2010.146","volume":"18","author":"S Rikka","year":"2011","unstructured":"Rikka S, Quinsay MN, Thomas RL, Kubli DA, Zhang X, Murphy AN, Gustafsson \u00c5B. Bnip3 impairs mitochondrial bioenergetics and stimulates mitochondrial turnover. Cell Death Differ. 2011;18(4):721\u201331.","journal-title":"Cell Death Differ."},{"key":"2014_CR32","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.redox.2017.07.004","volume":"13","author":"HJ Lee","year":"2017","unstructured":"Lee HJ, Jung YH, Choi GE, Ko SH, Lee S, Lee SH, Han HJ. BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells. Redox Biol. 2017;13:426\u201343.","journal-title":"Redox Biol."},{"key":"2014_CR33","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.freeradbiomed.2017.08.010","volume":"112","author":"A Dhingra","year":"2017","unstructured":"Dhingra A, Jayas R, Afshar P, Guberman M, Maddaford G, Gerstein J, Lieberman B, Nepon H, Margulets V, Dhingra R, Kirshenbaum LA. Ellagic acid antagonizes Bnip3-mediated mitochondrial injury and necrotic cell death of cardiac myocytes. Free Radic Bio Med. 2017;112:411\u201322.","journal-title":"Free Radic Bio Med."}],"container-title":["Journal of Neuroinflammation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-020-02014-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12974-020-02014-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-020-02014-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,27]],"date-time":"2022-11-27T17:08:45Z","timestamp":1669568925000},"score":1,"resource":{"primary":{"URL":"https:\/\/jneuroinflammation.biomedcentral.com\/articles\/10.1186\/s12974-020-02014-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,11]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["2014"],"URL":"https:\/\/doi.org\/10.1186\/s12974-020-02014-w","relation":{},"ISSN":["1742-2094"],"issn-type":[{"value":"1742-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,11]]},"assertion":[{"value":"6 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 November 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All animal experimental protocols were approved by the Fudan University institutional animal care and use committee in accordance with the Helsinki Declaration of 1975.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no conflict of interest. All the authors listed have approved the manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"337"}}