{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:49:41Z","timestamp":1790999381538,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,12]],"date-time":"2022-02-12T00:00:00Z","timestamp":1644624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chicoric acid (CA), a polyphenolic acid compound extracted from chicory and echinacea, possesses antiviral, antioxidative and anti-inflammatory activities. Growing evidence supports the pivotal roles of brain\u2013spleen and brain\u2013gut axes in neurodegenerative diseases, including Parkinson\u2019s disease (PD), and the immune response of the spleen and colon is always the active participant in the pathogenesis and development of PD. In this study, we observe that CA prevented dopaminergic neuronal lesions, motor deficits and glial activation in PD mice, along with the increment in striatal brain-derived neurotrophic factor (BDNF), dopamine (DA) and 5-hydroxyindoleacetic acid (5-HT). Furthermore, CA reversed the level of interleukin-17(IL-17), interferon-gamma (IFN-\u03b3) and transforming growth factor-beta (TGF-\u03b2) of PD mice, implicating its regulatory effect on the immunological response of spleen and colon. Transcriptome analysis revealed that 22 genes in the spleen (21 upregulated and 1 downregulated) and 306 genes (190 upregulated and 116 downregulated) in the colon were significantly differentially expressed in CA-pretreated mice. These genes were functionally annotated with GSEA, GO and KEGG pathway enrichment, providing the potential target genes and molecular biological mechanisms for the modulation of CA on the spleen and gut in PD. Remarkably, CA restored some gene expressions to normal level. Our results highlighted that the neuroprotection of CA might be associated with the manipulation of CA on brain\u2013spleen and brain\u2013gut axes in PD.<\/jats:p>","DOI":"10.3390\/ijms23042031","type":"journal-article","created":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T21:08:43Z","timestamp":1644786523000},"page":"2031","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Chicoric Acid Prevents Neuroinflammation and Neurodegeneration in a Mouse Parkinson\u2019s Disease Model: Immune Response and Transcriptome Profile of the Spleen and Colon"],"prefix":"10.3390","volume":"23","author":[{"given":"Ning","family":"Wang","sequence":"first","affiliation":[{"name":"School of Food Science and Technology, Jiangnan University, Wuxi 214122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"name":"Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bainian","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliang","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Food Science and Technology, Jiangnan University, Wuxi 214122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6512-355X","authenticated-orcid":false,"given":"Yahui","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Food Science and Technology, Jiangnan University, Wuxi 214122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Qian","sequence":"additional","affiliation":[{"name":"School of Food Science and Technology, Jiangnan University, Wuxi 214122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1146\/annurev.neuro.22.1.123","article-title":"Etiology and pathogenesis of Parkinson\u2019s disease","volume":"22","author":"Olanow","year":"1999","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1056\/NEJM198804073181402","article-title":"Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson\u2019s disease. Pathophysiologic and clinical implications","volume":"318","author":"Kish","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/bs.pmbts.2020.11.001","article-title":"Inflammation and Parkinson\u2019s disease pathogenesis: Mechanisms and therapeutic insight","volume":"177","author":"Forloni","year":"2021","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107480","DOI":"10.1016\/j.pharmthera.2020.107480","article-title":"Natural products-based polypharmacological modulation of the peripheral immune system for the treatment of neuropsychiatric disorders","volume":"208","author":"Mok","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s12016-010-8242-y","article-title":"Immunology, autoimmunity, and autoantibodies in Parkinson\u2019s disease","volume":"42","author":"Benkler","year":"2012","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nrn2297","article-title":"From inflammation to sickness and depression: When the immune system subjugates the brain","volume":"9","author":"Dantzer","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3389\/fnagi.2018.00160","article-title":"Partial depletion of peripheral M1 macrophages reverses motor deficits in MPTP-treated mouse by suppressing neuroinflammation and dopaminergic neurodegeneration","volume":"10","author":"Yan","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1007\/s13311-020-00877-8","article-title":"Neuroprotective activities of long-acting granulocyte-macrophage colony-stimulating factor (mPDM608) in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Intoxicated Mice","volume":"17","author":"Olson","year":"2020","journal-title":"Neurotherapeutics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"104575","DOI":"10.1016\/j.nbd.2019.104575","article-title":"RANTES-induced invasion of Th17 cells into substantia nigra potentiates dopaminergic cell loss in MPTP mouse model of Parkinson\u2019s disease","volume":"132","author":"Dutta","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.bbi.2012.08.013","article-title":"Neuro-protective effects of bee venom by suppression of neuroinflammatory responses in a mouse model of Parkinson\u2019s disease: Role of regulatory T cells","volume":"26","author":"Chung","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.neuroscience.2020.02.030","article-title":"The link between gut dysbiosis and neuroinflammation in Parkinson\u2019s Disease","volume":"432","year":"2020","journal-title":"Neuroscience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.cell.2016.11.018","article-title":"Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson\u2019s Disease","volume":"167","author":"Sampson","year":"2016","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1017\/S0317167100013202","article-title":"Increased intestinal permeability and Parkinson Disease patients: Chicken or Egg?","volume":"39","author":"Tran","year":"2012","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.neuroscience.2008.02.074","article-title":"Alpha-synuclein-immunopositive myenteric neurons and vagal preganglionic terminals: Autonomic pathway implicated in Parkinson\u2019s disease?","volume":"153","author":"Phillips","year":"2008","journal-title":"Neuroscience"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1089\/jmf.2018.0211","article-title":"The bioactive effects of chicoric acid as a functional food ingredient","volume":"22","author":"Peng","year":"2019","journal-title":"J. Med. Food"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1096\/fj.201601071R","article-title":"Chicoric acid supplementation prevents systemic inflammation-induced memory impairment and amyloidogenesis via inhibition of NF-kappaB","volume":"31","author":"Liu","year":"2017","journal-title":"FASEB J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.1021\/acs.jnatprod.5b00668","article-title":"Effect of chicoric acid on mast cell-mediated allergic inflammation In Vitro and In Vivo","volume":"78","author":"Lee","year":"2015","journal-title":"J. Nat. Prod."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.neuropharm.2011.01.001","article-title":"Augmentation of immune response by chicoric acid through the modulation of CD28\/CTLA-4 and Th1 pathway in chronically stressed mice","volume":"60","author":"Kour","year":"2011","journal-title":"Neuropharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/s41575-019-0157-3","article-title":"The role of short-chain fatty acids in microbiota-gut-brain communication","volume":"16","author":"Dalile","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.nbd.2012.09.007","article-title":"Colonic inflammation in Parkinson\u2019s disease","volume":"50","author":"Devos","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1159\/000511532","article-title":"Intralymphatic administration of metagonimus yokogawai-extracted protein attenuates experimental murine allergic rhinitis model","volume":"182","author":"Yang","year":"2021","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1007\/s11481-019-09888-5","article-title":"Treg cells attenuate neuroinflammation and protect neurons in a mouse model of Parkinson\u2019s Disease","volume":"15","author":"Huang","year":"2020","journal-title":"J. Neuroimmune Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.bbi.2015.08.006","article-title":"Transforming growth factor-beta 1 acts via T beta R-I on microglia to protect against MPP+-induced dopaminergic neuronal loss","volume":"51","author":"Liu","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/nm.1927","article-title":"Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke","volume":"15","author":"Liesz","year":"2009","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1189\/jlb.0507296","article-title":"Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson\u2019s disease","volume":"82","author":"Reynolds","year":"2007","journal-title":"J. Leukocyte. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zielinska, D., Zielinski, H., Laparra-Llopis, J.M., Szawara-Nowak, D., Honke, J., and Gimenez-Bastida, J.A. (2021). Caffeic acid modulates processes associated with intestinal inflammation. Nutrients, 13.","DOI":"10.3390\/nu13020554"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/nsmb.3074","article-title":"Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6","volume":"22","author":"Park","year":"2015","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1083\/jcb.201002032","article-title":"A two-tiered mechanism of EGFR inhibition by RALT\/MIG6 via kinase suppression and receptor degradation","volume":"189","author":"Frosi","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1152\/physrev.00030.2015","article-title":"Expression and function of the epidermal growth factor receptor in physiology and disease","volume":"96","author":"Chen","year":"2016","journal-title":"Physiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.lfs.2011.11.017","article-title":"Mitogen-activated protein kinase phosphatase (MKP)-1 in immunology, physiology, and disease","volume":"90","author":"Wancket","year":"2012","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1042\/BST0341018","article-title":"Dual-specificity phosphatase 1: A critical regulator of innate immune responses","volume":"34","author":"Abraham","year":"2006","journal-title":"Biochem. Soc. Trans."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1007\/s12035-020-02251-3","article-title":"Phosphoenolpyruvate carboxykinase (PCK) in the brain gluconeogenic pathway contributes to oxidative and lactic injury after stroke","volume":"58","author":"Geng","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3399","DOI":"10.1074\/jbc.M117.819136","article-title":"Macrophages with a deletion of the phosphoenolpyruvate carboxykinase 1 (Pck1) gene have a more proinflammatory phenotype","volume":"293","author":"Ko","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, N., Feng, B., Hu, B., Cheng, Y., Guo, Y., and He, Q. (Food Funct., 2022). Neuroprotection of chicoric acid in a mouse model of Parkinson\u2019s disease involves gut microbiota and TLR4 signaling pathway, Food Funct., in press.","DOI":"10.1039\/D1FO02216D"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0959-4388(00)00211-7","article-title":"Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway","volume":"11","author":"Brunet","year":"2001","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3671","DOI":"10.1007\/s00204-020-02936-7","article-title":"Inhibition and induction of CYP enzymes in humans: An update","volume":"94","author":"Hakkola","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Wagner, N., and Wagner, K.D. (2020). The role of PPARs in Disease. Cells, 9.","DOI":"10.3390\/cells9112367"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"949","DOI":"10.3233\/JPD-212671","article-title":"Role and mechanism of vitamin a metabolism in the pathophysiology of Parkinson\u2019s Disease","volume":"11","author":"Marie","year":"2021","journal-title":"J. Parkinsons Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"105439","DOI":"10.1016\/j.jsbmb.2019.105439","article-title":"Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review","volume":"194","author":"Schiffer","year":"2019","journal-title":"J. Steroid. Biochem. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"259","DOI":"10.2217\/fca-2016-0059","article-title":"PPARs: Regulators of metabolism and as therapeutic targets in cardiovascular disease. Part I: PPAR-alpha","volume":"13","author":"Han","year":"2017","journal-title":"Future Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.taap.2017.01.019","article-title":"Amentoflavone protects dopaminergic neurons in MPTP-induced Parkinson\u2019s disease model mice through PI3K\/Akt and ERK signaling pathways","volume":"319","author":"Cao","year":"2017","journal-title":"Toxicol Appl. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1254\/jjp.27.117","article-title":"Effects of central depressants on rota-rod and traction performances in mice","volume":"27","author":"Kuribara","year":"1977","journal-title":"Jpn. J. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/2031\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:18:09Z","timestamp":1760134689000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/2031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,12]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23042031"],"URL":"https:\/\/doi.org\/10.3390\/ijms23042031","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,12]]}}}