{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T14:53:24Z","timestamp":1775487204454,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T00:00:00Z","timestamp":1727913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FD Farm Co., Ltd"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In this study, a mixture of Platycodon grandiflorum, Pyrus serotina, Chaenomeles sinensis, and Raphanus sativus (PPCRE) was investigated for their immuno-enhancing effects, as well as the molecular mechanism of PPCRE in RAW264.7 cells. PPCRE dramatically increased nitric oxide (NO) and prostaglandin E2 (PGE2) generation depending on the concentration while exhibiting no cytotoxicity. PPCRE markedly upregulated the mRNA and protein expression of immune-related cytotoxic factors such as cyclooxygenase (COX)-1, COX-2, and inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines such as interleukin (IL)-1\u03b2, IL-6, and tumor necrosis factor alpha (TNF-\u03b1), as well as the mRNA level of IL-4. PPCRE increased the mitogen-activated protein kinase (MAPK) signaling pathway by upregulating the phosphorylation of extracellular signal-regulated kinase (ERK), stress-activated protein kinase\/Jun N-terminal-kinase (SAPK\/JNK), and p38. Furthermore, PPCRE considerably activated the nuclear factor kappa B (NF-\u03baB) signaling pathway by increasing phosphorylation of NF-\u03baB-p65. PPCRE-stimulated RAW264.7 cells increased macrophage phagocytic capacity. In conclusion, our study found that PPCRE improved immune function by modulating inflammatory mediators and regulating the MAPK and NF-\u03baB pathway of signaling in macrophages.<\/jats:p>","DOI":"10.3390\/ijms251910660","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T06:45:52Z","timestamp":1727937952000},"page":"10660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immunostimulatory Activity of a Mixture of Platycodon grandiflorum, Pyrus serotine, Chaenomeles sinensis, and Raphanus sativus in RAW264.7 Macrophages"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4036-1420","authenticated-orcid":false,"given":"Weerawan","family":"Rod-in","sequence":"first","affiliation":[{"name":"Department of Marine Bio Food Science, Gangneung-Wonju National University, Gangneung 25457, Gangwon, Republic of Korea"},{"name":"Department of Agricultural Science, Faculty of Agriculture Natural Resources and Environment, Naresuan University, Phitsanulok 65000, Thailand"},{"name":"Center of Excellence in Research for Agricultural Biotechnology, Naresuan University, Phitsanulok 65000, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minji","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Wellness-Bio Industry, Gangneung-Wonju National University, Gangneung 25457, Gangwon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A-yeong","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Marine Bio Food Science, Gangneung-Wonju National University, Gangneung 25457, Gangwon, Republic of Korea"},{"name":"Department of Food Science and Technology, Gangneung-Wonju National University, Gangneung 25457, Gangwon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu Suk","family":"Nam","sequence":"additional","affiliation":[{"name":"NAAAMYUUU FNC Co., Ltd., 20, Juheung, Seocho, Seoul 06540, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tae Young","family":"Yoo","sequence":"additional","affiliation":[{"name":"FD FARM Co., Ltd., Icheon 17300, Gyeonggi, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9804-3444","authenticated-orcid":false,"given":"Woo Jung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Marine Bio Food Science, Gangneung-Wonju National University, Gangneung 25457, Gangwon, Republic of Korea"},{"name":"Department of Wellness-Bio Industry, Gangneung-Wonju National University, Gangneung 25457, Gangwon, Republic of Korea"},{"name":"KBIoRANCh Co., Ltd., Gangneung 25457, Gangwon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kim, Y.-S., Kim, E.-K., Nawarathna, W.P., Dong, X., Shin, W.-B., Park, J.-S., Moon, S.-H., and Park, P.-J. (2017). Immune-stimulatory effects of Althaea rosea flower extracts through the MAPK signaling pathway in RAW264.7 cells. Molecules, 22.","DOI":"10.3390\/molecules22050679"},{"key":"ref_2","first-page":"4943","article-title":"Exopolysaccharide from Paecilomyces lilacinus modulates macrophage activities through the TLR4\/NF-\u03baB\/MAPK pathway","volume":"20","author":"He","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100504","DOI":"10.1016\/j.hermed.2021.100504","article-title":"Immunostimulatory activity of stem bark of Kalopanax pictus in RAW 264.7 macrophage","volume":"32","author":"Kim","year":"2022","journal-title":"J. Herb. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.biotno.2022.05.002","article-title":"Immunomodulatory effects of Abelmoschus esculentus water extract through MAPK and NF-\u03baB signaling in RAW264.7 cells","volume":"3","author":"Ko","year":"2022","journal-title":"Biotechnol. Notes"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Hwang, Y.P., Lee, G.H., Pham, T.H., Kim, M.Y., Kim, C.Y., Lee, S.Y., Han, E.H., Choi, C.Y., Hwang, S.D., and Ahn, S. (2022). Immune-enhancing effect of submerged culture of Ceriporia lacerata mycelia on cyclophosphamide-induced immunosuppressed mice and the underlying mechanisms in macrophages. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020597"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1039\/C6FO01545J","article-title":"Immune enhancement effects and extraction optimization of polysaccharides from Citrus aurantium L. var","volume":"8","author":"Shen","year":"2017","journal-title":"amara Engl. Food Funct."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kwon, H.-Y., Choi, S.-I., Han, X., Men, X., Jang, G.-W., Choi, Y.-E., Kim, S.-H., Kang, J.-C., Cho, J.-H., and Lee, O.-H. (2020). Enhancement of immune activities of mixtures with Sasa quelpaertensis Nakai and Ficus erecta var. sieboldii. Foods, 9.","DOI":"10.3390\/foods9070868"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Park, Y.M., Lee, H.Y., Shin, D.Y., Kim, D.S., Yoo, J.J., Yang, H.J., Kim, M.J., and Bae, J.S. (2022). Immune-enhancing effects of co-treatment with Kalopanax pictus Nakai Bark and Nelumbo nucifera Gaertner leaf extract in a cyclophosphamide-induced immunosuppressed rat model. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.898417"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3109\/08923973.2011.576254","article-title":"Immune-enhancing effect of Danggwibohyeoltang, an extract from Astragali Radix and Angelicae gigantis Radix, in vitro and in vivo","volume":"34","author":"Kim","year":"2012","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"114893","DOI":"10.1016\/j.jep.2021.114893","article-title":"The immune-enhancing effects of a mixture of Astragalus membranaceus (Fisch.) Bunge, Angelica gigas Nakai, and Trichosanthes Kirilowii (Maxim.) or its active constituent nodakenin","volume":"285","author":"Han","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"320","DOI":"10.4297\/najms.2011.3320","article-title":"Immune enhancing effects of WB365, a novel combination of Ashwagandha (Withania somnifera) and Maitake (Grifola frondosa) extracts","volume":"3","author":"Vetvicka","year":"2011","journal-title":"N. Am. J. Med. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1111\/1750-3841.14611","article-title":"A mixture of functional complex extracts from Lycium barbarum and grape seed enhances immunity synergistically in vitro and in vivo","volume":"84","author":"You","year":"2019","journal-title":"J. Food Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"154422","DOI":"10.1016\/j.phymed.2022.154422","article-title":"Platycodon grandiflorum (Jacq.) A. DC.: A review of phytochemistry, pharmacology, toxicology and traditional use","volume":"106","author":"Zhang","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3746\/pnf.2014.19.2.059","article-title":"Platycosides from the roots of Platycodon grandiflorum and their health benefits","volume":"19","author":"Nyakudya","year":"2014","journal-title":"Prev. Nutr. Food Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/fsn3.1297","article-title":"Chemical characterization of balloon flower (Platycodon grandiflorum) sprout extracts and their regulation of inflammatory activity in lipopolysaccharide-stimulated RAW264.7 murine macrophage cells","volume":"8","author":"Kim","year":"2020","journal-title":"Food Sci. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1248\/bpb.b-y110129","article-title":"Anti-atherosclerotic activity of Platycodin D derived from roots of Platycodon grandiflorum in human endothelial cells","volume":"35","author":"Wu","year":"2012","journal-title":"Biol. Pharm. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Xiao, W., Zhou, P., Wang, X., Zhao, R., and Wang, Y. (2022). Comparative characterization and immunomodulatory activities of polysaccharides extracted from the radix of Platycodon grandiflorum with different extraction methods. Molecules, 27.","DOI":"10.3390\/molecules27154759"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.jep.2004.04.017","article-title":"Antioxidant and anticancer activities of organic extracts from Platycodon grandiflorum A. De Candolle roots","volume":"93","author":"Lee","year":"2004","journal-title":"J. Ethnopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"H195","DOI":"10.1111\/j.1750-3841.2008.00915.x","article-title":"Hypocholesterolemic and anti-obesity effects of saponins from Platycodon grandiflorum in hamsters fed atherogenic diets","volume":"73","author":"Zhao","year":"2008","journal-title":"J. Food Sci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhao, X., Wang, Y., Yan, P., Cheng, G., Wang, C., Geng, N., Wang, X., and Liu, J. (2017). Effects of polysaccharides from Platycodon grandiflorum on immunity-enhancing activity in vitro. Molecules, 22.","DOI":"10.3390\/molecules22111918"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"453","DOI":"10.4162\/nrp.2020.14.5.453","article-title":"Immunomodulatory effects of fermented Platycodon grandiflorum extract through NF-\u03baB signaling in RAW264.7 cells","volume":"14","author":"Park","year":"2020","journal-title":"Nutr. Res. Pract."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Noh, E.-M., Kim, J.-M., Lee, H.Y., Song, H.-K., Joung, S.O., Yang, H.J., Kim, M.J., Kim, K.S., and Lee, Y.-R. (2019). Immuno-enhancement effects of Platycodon grandiflorum extracts in splenocytes and a cyclophosphamide-induced immunosuppressed rat model. BMC Complement. Altern. Med., 19.","DOI":"10.1186\/s12906-019-2724-0"},{"key":"ref_23","first-page":"2783","article-title":"Anti-obesity effects of a mixed extract containing Platycodon grandiflorum, Apium graveolens and green tea in high-fat-diet-induced obese mice","volume":"19","author":"Cho","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"844","DOI":"10.3746\/jkfn.2013.42.6.844","article-title":"Inhibition of nitric oxide production and hyaluronidase activities from the combined extracts of Platycodon grandiflorum, Astragalus membranaceus, and Schisandra chinensis","volume":"42","author":"Kang","year":"2013","journal-title":"J. Korean Soc. Food Sci. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Han, Y.-K., Kim, Y.-S., Natarajan, S.B., Kim, W.-S., Hwang, J.-W., Jeon, N.-J., Jeong, J.-H., Moon, S.-H., Jeon, B.-T., and Park, P.-J. (2016). Antioxidant and anti-inflammatory effects of Chaenomeles sinensis leaf extracts on LPS-stimulated RAW264.7 cells. Molecules, 21.","DOI":"10.3390\/molecules21040422"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"43","DOI":"10.12729\/jbtr.2022.23.2.43","article-title":"Protective effect of an ethanol extract mixture of Aralia elata, Chaenomeles sinensis fruit, and Glycyrrhizae radix against cerebral ischemia-reperfusion injury in rats and excitotoxic and oxidative neuronal damage","volume":"23","author":"Seong","year":"2022","journal-title":"J. Biomed. Transl. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0304-4238(94)90064-7","article-title":"The influence of water deficit on water relations, photosynthesis and fruit growth in Asian pear (Pyrus serotina Rehd.)","volume":"60","author":"Behboudian","year":"1994","journal-title":"Sci. Hortic."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hong, S.-Y., Lansky, E., Kang, S.-S., and Yang, M. (2021). A review of pears (Pyrus spp.), ancient functional food for modern times. BMC Complement. Altern. Med., 21.","DOI":"10.1186\/s12906-021-03392-1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.jep.2013.11.003","article-title":"4-Methylthio-butanyl derivatives from the seeds of Raphanus sativus and their biological evaluation on anti-inflammatory and antitumor activities","volume":"151","author":"Kim","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1007\/s00705-017-3270-z","article-title":"Antiviral effects of extracts from Celosia cristata and Raphanus sativus roots against viral hemorrhagic septicemia virus","volume":"162","author":"Park","year":"2017","journal-title":"Arch. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"104639","DOI":"10.1016\/j.jff.2021.104639","article-title":"Evaluation of antitumor metastasis via immunostimulating activities of pectic polysaccharides isolated from radish leaves","volume":"85","author":"Son","year":"2021","journal-title":"J. Funct. Foods"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Jang, A.y., Kim, M., Rod-in, W., Nam, Y.S., Yoo, T.Y., and Park, W.J. (2024). In vitro immune-enhancing effects of Platycodon grandiflorum combined with Salvia plebeian via MAPK and NF-\u03baB signaling in RAW264.7 cells. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0297512"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"498","DOI":"10.7732\/kjpr.2012.25.4.498","article-title":"Antioxidant activity of Pyrus serotina fruit in different cultivars and parts","volume":"25","author":"Jin","year":"2012","journal-title":"Korean J. Plant Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Yang, E.J., and Lee, S.H. (2023). Anti-Inflammatory effects of Chaenomeles sinensis extract in an ALS animal model. Front. Biosci., 28.","DOI":"10.31083\/j.fbl2812326"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Di Sotto, A., Vitalone, A., and Di Giacomo, S. (2020). Plant-derived nutraceuticals and immune system modulation: An evidence-based overview. Vaccines, 8.","DOI":"10.3390\/vaccines8030468"},{"key":"ref_36","first-page":"8916618","article-title":"Synergistic herb-herb interaction of the antinociceptive and anti-inflammatory effects of Syzygium aromaticum and Rosmarinus officinalis combination","volume":"2021","year":"2021","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_37","first-page":"217","article-title":"In vitro studies of baicalin alone or in combination with Salvia miltiorrhiza extract as a potential anti-cancer agent","volume":"26","author":"Franek","year":"2005","journal-title":"Int. J. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Bach, T.J., and Rohmer, M. (2013). Saponin Synthesis and Function. Isoprenoid Synthesis in Plants and Microorganisms: New Concepts and Experimental Approaches, Springer.","DOI":"10.1007\/978-1-4614-4063-5"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1016\/j.lfs.2004.10.042","article-title":"Inhibition of inducible nitric oxide synthase and cyclooxygenase II by Platycodon grandiflorum saponins via suppression of nuclear factor-\u03baB activation in RAW 264.7 cells","volume":"76","author":"Ahn","year":"2005","journal-title":"Life Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.intimp.2004.04.005","article-title":"Platycodin D and D3 isolated from the root of Platycodon grandiflorum modulate the production of nitric oxide and secretion of TNF-\u03b1 in activated RAW 264.7 cells","volume":"4","author":"Wang","year":"2004","journal-title":"Int. Immunopharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1016\/S1567-5769(01)00086-8","article-title":"Nitric oxide in immunity and inflammation","volume":"1","author":"Coleman","year":"2001","journal-title":"Int. Immunopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0090-6980(02)00024-2","article-title":"Cyclooxygenase isozymes and their gene structures and expression","volume":"68\u201369","author":"Tanabe","year":"2002","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"281","DOI":"10.2174\/1568010054022024","article-title":"Macrophages in inflammation","volume":"4","author":"Fujiwara","year":"2005","journal-title":"Curr. Drug Targets Inflamm. Allergy"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1002\/fsn3.2020","article-title":"Heracleum moellendorffii root extracts exert immunostimulatory activity through TLR2\/4-dependent MAPK activation in mouse macrophages, RAW264.7 cells","volume":"9","author":"Son","year":"2021","journal-title":"Food Sci. Nutr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nri910","article-title":"NF-\u03baB regulation in the immune system","volume":"2","author":"Li","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_46","unstructured":"Vancurova, I. (2014). Assessment of phagocytic activity of cultured macrophages using fluorescence microscopy and flow cytometry. Cytokine Bioassays: Methods and Protocols, Springer."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kim, J.-H., Ku, B.-H., Ko, G.-P., Kang, M.-J., Son, K.-H., Bang, M.-A., and Park, H.-Y. (2023). Enzyme feed additive with arazyme improve growth performance, meat quality, and gut microbiome of pigs. Animals, 13.","DOI":"10.3390\/ani13030423"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10660\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:09:55Z","timestamp":1760112595000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10660"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,3]]},"references-count":47,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms251910660"],"URL":"https:\/\/doi.org\/10.3390\/ijms251910660","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,3]]}}}