{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T10:25:50Z","timestamp":1763115950385,"version":"3.45.0"},"reference-count":55,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["24K19013","25K02537"],"award-info":[{"award-number":["24K19013","25K02537"]}]},{"name":"Toyo University Top Priority Research Program","award":["2023T1"],"award-info":[{"award-number":["2023T1"]}]},{"name":"Grant-in-Aid for the Enryo Inoue Memorial from Toyo University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objective: Dendritic cells (DCs) act as sentinels bridging innate and adaptive immunity, and their functions are strongly influenced by dietary and environmental factors. Phytochemicals such as \u03b1-Mangostin (A phytochemical, a xanthone derivative from Garcinia mangostina, known for its anti-inflammatory and antioxidant properties) are widely recognized for their antioxidant and anti-inflammatory effects, but their potential to modulate antiviral pattern recognition pathways remains unclear.\u00a0This study investigated whether phytochemicals activate retinoic acid\u2013inducible gene I (RIG-I: DDX58, a cytosolic receptor recognizing viral RNA and inducing antiviral responses)\u2013dependent signaling in human monocyte-derived dendritic cells (MoDCs) and affect downstream T cell responses. Methods: MoDCs were generated from peripheral blood and stimulated with selected phytochemicals. RIG-I pathway\u2013related transcripts were quantified by qPCR, and protein expression was assessed by Western blotting, intracellular flow cytometry, and immunofluorescence staining. Functional outcomes were evaluated by co-culturing MoDCs with T cells, followed by phenotypic analysis via flow cytometry and measurement of IFN-\u03b3 production by ELISA. Results: \u03b1-Mangostin stimulation increased RIG-I (DDX58) mRNA levels in MoDCs and induced time-dependent changes in intracellular protein expression. In co-culture, \u03b1-Mangostin\u2013treated MoDCs tended to increase the proportion of OX40+\u00a04-1BB+ CD4+ T cells, accompanied by a significant elevation of IFN-\u03b3 levels in supernatants. Experiments with CpG-ODN (synthetic oligodeoxynucleotides mimicking bacterial DNA that activate TLR9) suggested context-dependent crosstalk between the TLR9 and RIG-I signaling axes. Conclusions: Phytochemicals, exemplified by \u03b1-Mangostin, prime antiviral responses in human DCs through upregulation of RIG-I and promote Th1-dependent immune responses. These findings suggest that phytochemicals may represent promising nutritional strategies to enhance antiviral immunity while mitigating excessive inflammation under infectious conditions.<\/jats:p>","DOI":"10.3390\/nu17223539","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T09:59:09Z","timestamp":1763027949000},"page":"3539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phytochemicals Prime RIG-I Signaling and Th1-Leaning Responses in Human Monocyte-Derived Dendritic Cells"],"prefix":"10.3390","volume":"17","author":[{"given":"Kaho","family":"Ohki","sequence":"first","affiliation":[{"name":"Department of Nutrition Sciences, Graduate School of Health and Sports Sciences, Toyo University, Tokyo 115-8650, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9278-6464","authenticated-orcid":false,"given":"Takumi","family":"Iwasawa","sequence":"additional","affiliation":[{"name":"Institution of Life Innovation Studies, Toyo University, Tokyo 115-8650, Japan"},{"name":"Shizuoka Medical Research Center for Disaster, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazunori","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Nutrition Sciences, Graduate School of Health and Sports Sciences, Toyo University, Tokyo 115-8650, Japan"},{"name":"Institution of Life Innovation Studies, Toyo University, Tokyo 115-8650, Japan"},{"name":"Department of Nutrition Sciences, Faculty of Health and Sports Sciences, Toyo University, Tokyo 115-8650, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1084\/jem.137.5.1142","article-title":"Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution","volume":"137","author":"Steinman","year":"1973","journal-title":"J. Exp. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1158\/2326-6066.CIR-13-0102","article-title":"Dendritic cells: Master regulators of the immune response","volume":"1","author":"Mellman","year":"2013","journal-title":"Cancer Immunol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"920","DOI":"10.3390\/v3060920","article-title":"Pattern recognition receptors and the innate immune response to viral infection","volume":"3","author":"Thompson","year":"2011","journal-title":"Viruses"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.cell.2010.01.022","article-title":"Pattern recognition receptors and inflammation","volume":"140","author":"Takeuchi","year":"2010","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/s41423-020-00602-7","article-title":"Regulation of RIG-I-Like receptor-mediated signaling: Interaction between host and viral factor","volume":"18","author":"Onomoto","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/imr.13022","article-title":"The molecular mechanism of RIG-I activation and signaling","volume":"304","author":"Thoresen","year":"2021","journal-title":"Immunol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1158\/1078-0432.CCR-10-1114","article-title":"Direct effects of type I interferons on cells of the immune system","volume":"17","author":"Rouzaut","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gallo, P.M., and Gallucci, S. (2013). The dendritic cell response to classic, emerging, and homeostatic danger signals. Implications for autoimmunity. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00138"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1084\/jem.20101159","article-title":"Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8\u03b1+ dendritic cells","volume":"208","author":"Fuertes","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1073\/pnas.63.1.51","article-title":"Increased survival in mice inoculated with tumor cells and treated with interferon preparations","volume":"63","author":"Gresser","year":"1969","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00018-022-04219-z","article-title":"Type I interferon-mediated tumor immunity and its role in immunotherapy","volume":"79","author":"Yu","year":"2022","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gardner, A., de Mingo Pulido, \u00c1., and Ruffell, B. (2020). Dendritic Cells and Their Role in Immunotherapy. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00924"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ziegler-Heitbrock, L. (2015). Blood Monocytes and Their Subsets: Established Features and Open Questions. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00423"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Robbins, S.H., Walzer, T., Demb\u00e9l\u00e9, D., Thibault, C., Defays, A., Bessou, G., Xu, H., Vivier, E., Sellars, M., and Pierre, P. (2008). Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling. Genome Biol., 9.","DOI":"10.1186\/gb-2008-9-1-r17"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1189\/jlb.0603255","article-title":"Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells","volume":"74","author":"Izaguirre","year":"2003","journal-title":"J. Leukoc. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nature01783","article-title":"Viral infection switches non-plasmacytoid dendritic cells into high interferon producers","volume":"424","author":"Diebold","year":"2003","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.immuni.2011.10.014","article-title":"Plasmacytoid dendritic cells are crucial for the initiation of inflammation and T cell immunity in vivo","volume":"35","author":"Takagi","year":"2011","journal-title":"Immunity"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Jounai, K., Ikado, K., Sugimura, T., Ano, Y., Braun, J., and Fujiwara, D. (2012). Spherical lactic acid bacteria activate plasmacytoid dendritic cells immunomodulatory function via TLR9-dependent crosstalk with myeloid dendritic cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032588"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Jounai, K., Sugimura, T., Ohshio, K., and Fujiwara, D. (2015). Oral administration of Lactococcus lactis subsp. lactis JCM5805 enhances lung immune response resulting in protection from murine parainfluenza virus infection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119055"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.virusres.2006.07.006","article-title":"Difference in production of infectious wild-type measles and vaccine viruses in monocyte-derived dendritic cells","volume":"123","author":"Ohgimoto","year":"2007","journal-title":"Virus Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1002\/ptr.1074","article-title":"Chemistry and pharmacology of the Citrus bioflavonoid hesperidin","volume":"15","author":"Garg","year":"2001","journal-title":"Phytother. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sweidan, N., Abu Rayyan, W., Mahmoud, I., and Ali, L. (2023). Phytochemical analysis, antioxidant, and antimicrobial activities of Jordanian Pomegranate peels. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0295129"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e70101","DOI":"10.1002\/fsn3.70101","article-title":"Dietary Phytochemicals in Health and Disease: Mechanisms, Clinical Evidence, and Applications-A Comprehensive Review","volume":"13","author":"Hossain","year":"2025","journal-title":"Food Sci. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Park, K. (2023). The Role of Dietary Phytochemicals: Evidence from Epidemiological Studies. Nutrients, 15.","DOI":"10.3390\/nu15061371"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"21138","DOI":"10.3390\/molecules201219753","article-title":"Antioxidant Phytochemicals for the Prevention and Treatment of Chronic Diseases","volume":"20","author":"Zhang","year":"2015","journal-title":"Molecules"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1007\/s11418-025-01929-z","article-title":"Metabolite derived from green tea polyphenol increases and activates plasmacytoid dendritic cells","volume":"79","author":"Kumazoe","year":"2025","journal-title":"J. Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1038\/s41375-025-02627-1","article-title":"Sulforaphane promotes natural killer cell-mediated anti-tumor immune responses partially via cGAS-STING pathway in classical Hodgkin lymphoma","volume":"39","author":"Xagoraris","year":"2025","journal-title":"Leukemia"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lee, Y.J., and Kim, J. (2020). Resveratrol Activates Natural Killer Cells through Akt- and mTORC2-Mediated c-Myb Upregulation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249575"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1136\/jim-2016-000158","article-title":"Green tea EGCG, T-cell function, and T-cell-mediated autoimmune encephalomyelitis","volume":"64","author":"Wu","year":"2016","journal-title":"J. Investig. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"191","DOI":"10.4110\/in.2011.11.4.191","article-title":"Stimulatory Effect of \u03b2-glucans on Immune Cells","volume":"11","author":"Kim","year":"2011","journal-title":"Immune Netw."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"233","DOI":"10.4110\/in.2016.16.4.233","article-title":"Vanilloid Receptor 1 Agonists, Capsaicin and Resiniferatoxin, Enhance MHC Class I-restricted Viral Antigen Presentation in Virus-infected Dendritic Cells","volume":"16","author":"Lee","year":"2016","journal-title":"Immune Netw."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/j.foodchem.2010.12.004","article-title":"3,10-Dihydroxy-decanoic acid, isolated from royal jelly, stimulates Th1 polarising capability of human monocyte-derived dendritic cells","volume":"126","author":"Tanja","year":"2011","journal-title":"Food Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wang, Y., Petrikova, E., Gross, W., Sticht, C., Gretz, N., Herr, I., and Karakhanova, S. (2020). Sulforaphane Promotes Dendritic Cell Stimulatory Capacity Through Modulation of Regulatory Molecules, JAK\/STAT3- and MicroRNA-Signaling. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.589818"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1111\/j.1365-2249.2010.04232.x","article-title":"Curcumin induces maturation-arrested dendritic cells that expand regulatory T cells in vitro and in vivo","volume":"162","author":"Rogers","year":"2010","journal-title":"Clin. Exp. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6815","DOI":"10.4049\/jimmunol.0903991","article-title":"Immunosuppressive effect of quercetin on dendritic cell activation and function","volume":"184","author":"Huang","year":"2010","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Choudhari, A.S., Mandave, P.C., Deshpande, M., Ranjekar, P., and Prakash, O. (2020). Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01614"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.tjnut.2024.11.007","article-title":"Health Benefits and Future Research of Phytochemicals: A Literature Review","volume":"155","author":"Yang","year":"2025","journal-title":"J. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1084\/jem.179.4.1109","article-title":"Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte\/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha","volume":"179","author":"Sallusto","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/bs.mie.2019.05.046","article-title":"Protocol to assess the suppression of T-cell proliferation by human MDSC","volume":"632","author":"Bruger","year":"2020","journal-title":"Methods Enzymol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/s41577-020-0288-3","article-title":"RIG-I-Like Receptors: Their Regulation and Roles in RNA Sensing","volume":"20","author":"Rehwinkel","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"906","DOI":"10.3390\/v3060906","article-title":"RIG-I-Like Receptors in Antiviral Immunity and Therapeutic Applications","volume":"3","author":"Ireton","year":"2011","journal-title":"Viruses."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Schiavoni, G., Mattei, F., and Gabriele, L. (2013). Type I Interferons as Stimulators of Dendritic Cell-Mediated Cross-Priming: Impact on Anti-Tumor Response. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00483"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5895","DOI":"10.3748\/wjg.v23.i32.5895","article-title":"(-)-Epigallocatechin-3-Gallate Enhances Poly I:C-induced induced interferon-\u03bb1 production and inhibits hepatitis C virus replication in hepatocytes","volume":"23","author":"Wang","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ranjith-Kumar, C.T., Lai, Y., Sarisky, R.T., and Kao, C.C. (2010). Green Tea Catechin Epigallocatechin Gallate Suppresses Signaling by the dsRNA Innate Immune Receptor RIG-I. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012878"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1007\/s00705-021-05017-x","article-title":"Alpha-mangostin inhibits dengue virus production and pro-inflammatory cytokine\/chemokine expression in dendritic cells","volume":"166","author":"Yongpitakwattana","year":"2021","journal-title":"Arch. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Tarasuk, M., Songprakhon, P., Chieochansin, T., Choomee, K., Na-Bangchang, K., and Yenchitsomanus, P.T. (2022). Alpha-mangostin inhibits viral replication and suppresses nuclear factor kappa B (NF-\u03baB)-mediated inflammation in dengue virus infection. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-20284-7"},{"key":"ref_47","first-page":"195","article-title":"Collaboration of Toll-Like and RIG-I-Like Receptors in Human Dendritic Cells: tRIGgering Antiviral Innate Immune Responses","volume":"2","author":"Szabo","year":"2013","journal-title":"Am. J. Clin. Exp. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.addr.2008.12.008","article-title":"Immunotherapeutic Applications of CpG Oligodeoxynucleotide TLR9 Agonists","volume":"61","author":"Vollmer","year":"2009","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9237","DOI":"10.1073\/pnas.161293498","article-title":"Human TLR9 Confers Responsiveness to Bacterial DNA via species-specific CpG motif recognition","volume":"98","author":"Bauer","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1600-065X.2009.00766.x","article-title":"The Significance of OX40 and OX40L to T-Cell biology and immune disease","volume":"229","author":"Croft","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"122","DOI":"10.5483\/BMBRep.2014.47.3.283","article-title":"4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy","volume":"47","author":"Vinay","year":"2014","journal-title":"BMB Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"661","DOI":"10.4049\/jimmunol.168.2.661","article-title":"OX40 Costimulation enhances the development of T cell responses induced by dendritic cells in vivo","volume":"168","author":"Smith","year":"2002","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.cell.2011.06.041","article-title":"MAVS Forms Functional Prion-Like Aggregates to Activate and Propagate Antiviral Innate Immune Responses","volume":"146","author":"Hou","year":"2011","journal-title":"Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e01489","DOI":"10.7554\/eLife.01489","article-title":"Structural Basis for the Prion-like MAVS Filaments in Antiviral Innate Immunity","volume":"3","author":"Xu","year":"2014","journal-title":"eLife"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1126\/science.1132505","article-title":"5\u2032-Triphosphate RNA Is the Ligand for RIG-I","volume":"314","author":"Hornung","year":"2006","journal-title":"Science"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/22\/3539\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T10:22:01Z","timestamp":1763115721000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/22\/3539"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,12]]},"references-count":55,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["nu17223539"],"URL":"https:\/\/doi.org\/10.3390\/nu17223539","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2025,11,12]]}}}