{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T04:38:45Z","timestamp":1776832725144,"version":"3.51.2"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T00:00:00Z","timestamp":1670803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","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","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>This study aimed to explore the efficacy of zunyimycin C in the immunological enhancement of hypoimmune mice and improvement of cognitive impairment in a mice model of Alzheimer\u2019s disease (AD). Zunyimycin C was administered intranasally to interfere with AD mouse models or gavage to hypoimmune animals. Results of the Morris water maze (MWM) showed that zunyimycin may improve the learning and memory abilities of the AD mice model. The results of differential expression analysis of mRNA levels of inflammatory factors and pathways in brain tissues of the AD mouse model suggested that differential expression was more obvious under Zun-Int L. Western blot revealed that the relative expression of glial fibrillary acidic protein in the brain tissue of the AD mouse model in the Zun-Pre group was significantly higher than that in the other groups, and the difference was statistically significant. The relative expression of interleukin (IL)-6 protein in the brain tissue of mice in the low-dose intervention group was significantly lower than that in the other groups, and the difference was statistically significant. As for hypoimmune animals, short chain fatty acids (SCFAs) assay and intestinal flora assay results showed that zunyimycin C may change intestinal flora diversity and SCFA biosynthesis. The prophylactic administration of zunyimycin C could not inhibit acute neuroinflammation in AD mice. Zunyimycin C may participate in the immune response by activating the Ras-Raf-MEK-ERK signaling pathway to stimulate microglia to produce more inflammatory factors. Zunyimycin C may inhibit autophagy by activating the PI3K-AKT-mTOR signaling pathway, promote cell survival, mediate neuroprotective effects of reactive microglia and reactive astrocytes, and reduce IL-1\u03b2 in brain tissue and IL-6 secretion, thereby attenuating neuroinflammation in AD mice and achieving the effect of improving learning and memory impairment. Zunyimycin C may play a role in immunological enhancement by changing intestinal flora diversity and SCFAs. <\/jats:p>","DOI":"10.3389\/fcimb.2022.1081243","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T05:46:32Z","timestamp":1670823992000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Zunyimycin C enhances immunity and improves cognitive impairment and its mechanism"],"prefix":"10.3389","volume":"12","author":[{"given":"Xuemei","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zexin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueli","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruirui","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangyi","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingxin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wujuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanlin","family":"Qu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuoling","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhong","family":"L\u00fc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changwu","family":"Yue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"147517","DOI":"10.1016\/j.brainres.2021.147517","article-title":"Investigation of therapeutic effect of curcumin \u03b1 and \u03b2 glucoside anomers against alzheimer\u2019s disease by the nose to brain drug delivery","volume":"1766","author":"Ahmadi","year":"2021","journal-title":"Brain Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"9583","DOI":"10.3390\/ijms22179583","article-title":"Deciphering the potential neuroprotective effects of luteolin against A\u03b21\u201342-Induced alzheimer\u2019s disease","volume":"22","author":"Ahmad","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1992","DOI":"10.1212\/WNL.53.9.1992","article-title":"Gender differences in the incidence of AD and vascular dementia: The EURODEM studies","volume":"53","author":"Andersen","year":"1999","journal-title":"Neurology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"26043","DOI":"10.1074\/jbc.M115.679043","article-title":"Apolipoprotein e is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2)","volume":"290","author":"Atagi","year":"2015","journal-title":"J. Biol. Chem."},{"key":"B5","first-page":"700","article-title":"2022 Alzheimer's disease facts and figures","volume-title":"Alzheimers dement","year":"2022"},{"key":"B6","doi-asserted-by":"publisher","first-page":"247","DOI":"10.7861\/clinmedicine.16-3-247","article-title":"Drug treatments in alzheimer\u2019s disease","volume":"16","author":"Briggs","year":"2016","journal-title":"Clin. Med. (Lond.)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s13024-020-00378-4","article-title":"Microbial involvement in Alzheimer disease development and progression","volume":"15","author":"Bulgart","year":"2020","journal-title":"Mol. Neurodegeneration"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1517\/17460441.2014.930124","article-title":"Epigenetic drug discovery for alzheimer\u2019s disease","volume":"9","author":"Cacabelos","year":"2014","journal-title":"Expert Opin. Drug Discovery"},{"key":"B9","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1046\/j.1532-5415.2002.50006.x","article-title":"Incidence of dementia, alzheimer's disease, and vascular dementia in Italy","volume":"50","author":"Di Carlo","year":"2002","journal-title":"ILSA Study J. Am. Geriatr. Soc."},{"key":"B10","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1007\/s12035-012-8375-5","article-title":"A non-transgenic mouse model (icv-STZ mouse) of alzheimer\u2019s disease: Similarities to and differences from the transgenic model (3xTg-AD mouse)","volume":"47","author":"Chen","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1038\/aps.2017.28","article-title":"Amyloid beta: structure, biology and structure-based therapeutic development","volume":"38","author":"Chen","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"B12","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.neuron.2016.09.025","article-title":"Amygdala and ventral striatum make distinct contributions to reinforcement learning","author":"Costa","year":"2016","journal-title":"Neuron"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2903","DOI":"10.1016\/j.neurobiolaging.2012.02.016","article-title":"Berberine ameliorates \u03b2-amyloid pathology, gliosis, and cognitive impairment in an alzheimer's disease transgenic mouse model","volume":"33","author":"Durairajan","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"B14","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1177\/1039856218762308","article-title":"Alzheimer's disease: clinical update on epidemiology, pathophysiology and diagnosis","volume":"26","author":"Eratne","year":"2018","journal-title":"Australas. Psychiatry"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1038\/s41598-017-01868-01","article-title":"Identification and activation of TLR4-mediated signalling pathways by alginate-derived guluronate oligosaccharide in RAW264.7 macrophages","volume":"7","author":"Fang","year":"2017","journal-title":"Sci. Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1146\/annurev-neuro-070815-014015","article-title":"Alzheimer's disease mechanisms and emerging roads to novel therapeutics","author":"Frigerio","year":"2016","journal-title":"Annu. Rev. Neurosci."},{"key":"B17","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1007\/s43440-021-00264-w","article-title":"Roflumilast and tadalafil improve learning and memory deficits in intracerebroventricular A\u03b21\u201342 rat model of alzheimer\u2019s disease through modulations of hippocampal cAMP\/cGMP\/BDNF signaling pathway","volume":"73","author":"Hasan","year":"2021","journal-title":"Pharmacol. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/s41398-022-01862-9","article-title":"Inhibition of the ISR abrogates mGluR5-dependent long-term depression and spatial memory deficits in a rat model of alzheimer\u2019s disease","volume":"12","author":"Hu","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0928-0987(00)00087-7","article-title":"Transport of drugs from the nasal cavity to the central nervous system","volume":"11","author":"Illum","year":"2000","journal-title":"Eur. J. Pharm. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/S0168-3659(02)00363-2","article-title":"Nasal drug delivery\u2013possibilities, problems and solutions","volume":"87","author":"Illum","year":"2003","journal-title":"J. Control Release"},{"key":"B21","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1080\/1061186021000001823","article-title":"Visualization of in vivo olfactory uptake and transfer using fluorescein dextran","volume":"10","author":"Jansson","year":"2002","journal-title":"J. Drug Target"},{"key":"B22","doi-asserted-by":"publisher","first-page":"108852","DOI":"10.1016\/j.exer.2021.108852","article-title":"Microglia-derived TNF-\u03b1 mediates m\u00fcller cell activation by activating the TNFR1-NF-\u03baB pathway","volume":"214","author":"Ji","year":"2022","journal-title":"Exp. Eye Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.2174\/1570159X19666211202124239","article-title":"Current and near-future treatment of alzheimer\u2019s disease","volume":"20","author":"G\u0105siorowski","year":"2022","journal-title":"Curr. Neuropharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s13041-022-00941-8","article-title":"mTORC1 function in hippocampal parvalbumin interneurons: regulation of firing and long-term potentiation of intrinsic excitability but not long-term contextual fear memory and context discrimination","volume":"15","author":"Khlaifia","year":"2022","journal-title":"Mol. Brain"},{"key":"B25","doi-asserted-by":"publisher","first-page":"53308","DOI":"10.3791\/53308","article-title":"Intracerebroventricular injection of amyloid-\u03b2 peptides in normal mice to acutely induce Alzheimer-like cognitive deficits","author":"Kim","year":"2016","journal-title":"J. Vis. Exp."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2713","DOI":"10.1016\/S0140-6736(16)32457-6","article-title":"Alzheimer\u2019s disease expedition into the unknown","volume":"388","author":"Lancet","year":"2016","journal-title":"Lancet"},{"key":"B27","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/ene.13439","article-title":"Alzheimer\u2019s disease","volume":"25","author":"Lane","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1039\/C6CS00731G","article-title":"Towards an understanding of amyloid-\u03b2 oligomers: Characterization, toxicity mechanisms, and inhibitors","volume":"46","author":"Lee","year":"2017","journal-title":"Chem. Soc. Rev."},{"key":"B29","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.neuroscience.2018.05.033","article-title":"Effects of cholinergic lesions and cholinesterase inhibitors on aromatase and estrogen receptor expression in different regions of the rat brain","volume":"384","author":"Li","year":"2018","journal-title":"Neuroscience"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.648636","article-title":"PI3K\/AKT signal pathway: A target of natural products in the prevention and treatment of alzheimer's disease and parkinson's disease","volume":"12","author":"Long","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"251","DOI":"10.3390\/molecules22020251","article-title":"Zunyimycins b and c, new chloroanthrabenzoxocinones antibiotics against methicillin-resistant staphylococcus aureus and enterococci from streptomyces sp","volume":"22","author":"L\u00fc","year":"2017","journal-title":"FJS31-2 Molecules"},{"key":"B32","doi-asserted-by":"publisher","first-page":"711","DOI":"10.3390\/molecules21060711","article-title":"Molecular genetic characterization of an anthrabenzoxocinones gene cluster in streptomyces sp. FJS31-2 for the biosynthesis of BE-24566B and zunyimycin ale","volume":"21","author":"L\u00fc","year":"2016","journal-title":"Molecules"},{"key":"B33","doi-asserted-by":"publisher","first-page":"118635","DOI":"10.1016\/j.ijpharm.2019.118635","article-title":"Strategies to facilitate or block nose-to-brain drug delivery","volume":"570","author":"Martins","year":"2019","journal-title":"Int. J. Pharm."},{"key":"B34","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.exger.2013.02.025","article-title":"PI3-kinase\/Akt\/mTOR signaling: Impaired on\/off switches in aging, cognitive decline and alzheimer's disease","volume":"2013","author":"Neill","year":"2013","journal-title":"Exp. Gerontol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1007\/BF00239813","article-title":"Hippocampal place units in the freely moving rat: why they fire where they fire","author":"O'keefe","year":"1978","journal-title":"Exp. Brain Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1538\/expanim.21-0120","article-title":"Morris water maze: a versatile and pertinent tool for assessing spatial learning and memory","volume":"71","author":"Othman","year":"2022","journal-title":"Exp. Anim."},{"key":"B37","doi-asserted-by":"publisher","first-page":"113750","DOI":"10.1016\/j.bbr.2022.113750","article-title":"Nitric oxide impairs spatial learning and memory in a rat model of alzheimer\u2019s disease via disturbance of glutamate response in the hippocampal dentate gyrus during spatial learning","volume":"422","author":"Ren","year":"2022","journal-title":"Behav. Brain Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"S195","DOI":"10.3233\/JAD-2012-129009","article-title":"Elucidating the triggers, progression, and effects of alzheimer's disease","author":"Rodrigo","year":"2013","journal-title":"J. Alzheimers Di"},{"key":"B39","doi-asserted-by":"publisher","first-page":"3128758","DOI":"10.1155\/2018\/3128758","article-title":"Immunosenescence of natural killer cells, inflammation, and alzheimer's disease","volume":"2018","author":"Solana","year":"2018","journal-title":"Int. J. Alzheimer's Dis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1093\/cercor\/bhaa241","article-title":"Effects of amygdala lesions on object-based versus action-based learning in macaques","volume":"31","author":"Taswell","year":"2021","journal-title":"Cereb. Cortex"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1016\/j.drudis.2022.01.016","article-title":"Challenges and hopes for alzheimer\u2019s disease","volume":"27","author":"Tatulian","year":"2022","journal-title":"Drug Discovery Today"},{"key":"B42","volume-title":"Analysis of anti-MRSA activity of anthrone antibiotic zunyimycin c","author":"Wang","year":"2018"},{"key":"B43","doi-asserted-by":"publisher","first-page":"532","DOI":"10.14283\/jpad.2022.46","article-title":"Clinical research investigating alzheimer\u2019s disease in China: Current status and future perspectives toward prevention","volume":"9","author":"Wang","year":"2022","journal-title":"J. Prev. Alzheimers Dis."},{"key":"B44","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1124\/jpet.119.258152","article-title":"Nose-to-Brain delivery","volume":"370","author":"Wang","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B45","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1097\/WNR.0000000000001550","article-title":"The m6A methyltransferase METTL3 promotes LPS-induced microglia inflammation through TRAF6\/NF-\u03baB pathway","volume":"33","author":"Wen","year":"2022","journal-title":"Neuroreport"},{"key":"B46","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.cell.2020.02.013","article-title":"Repopulating microglia promote brain repair in an IL-6-Dependent manner","volume":"180","author":"Willis","year":"2020","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","first-page":"2041","DOI":"10.7150\/thno.68636","article-title":"Phage display derived peptides for alzheimer's disease therapy and diagnosis","volume":"12","author":"Zhang","year":"2022","journal-title":"Theranostics"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1081243\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T05:46:37Z","timestamp":1670823997000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1081243\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,12]]},"references-count":47,"alternative-id":["10.3389\/fcimb.2022.1081243"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.1081243","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,12]]},"article-number":"1081243"}}