{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:12:41Z","timestamp":1792174361904,"version":"4.4.0"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,7,29]],"date-time":"2019-07-29T00:00:00Z","timestamp":1564358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002642","name":"Korea University","doi-asserted-by":"publisher","award":["L1900451"],"award-info":[{"award-number":["L1900451"]}],"id":[{"id":"10.13039\/501100002642","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the National Research Foundation of Korea","award":["R1706903"],"award-info":[{"award-number":["R1706903"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Immunomodulation involves two mechanisms, immunostimulation and immunosuppression. It is a complex mechanism that regulates the pathophysiology and pathogenesis of various diseases affecting the immune system. Immunomodulators can be used as immunostimulators to reduce the side effects of drugs that induce immunosuppression. In this study, we characterized the chemical composition of high molecular weight fucoidan (HMWF) and low molecular weight fucoidan and compared their functions as natural killer (NK) cell-derived immunostimulators in vitro. We also tested the effectiveness of HMWF, which has a relatively high function in vitro, as an immunostimulator in immunosuppressed animal models. In these models, HWMF significantly restored NK cell cytotoxicity and granzyme B release to the control group level. In addition, the expression of interleukin (IL)-1\u03b2, IL-2, IL-4, IL-5, IL-12, interferon (IFN)-\u03b3, and tumor necrosis factor (TNF)-\u03b1 also increased in the spleen. This study suggests that HMWF acts as an effective immunostimulant under immunosuppressive conditions.<\/jats:p>","DOI":"10.3390\/md17080447","type":"journal-article","created":{"date-parts":[[2019,7,29]],"date-time":"2019-07-29T11:20:18Z","timestamp":1564399218000},"page":"447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Characterization and Immunomodulatory Effects of High Molecular Weight Fucoidan Fraction from the Sporophyll of Undaria pinnatifida in Cyclophosphamide-Induced Immunosuppressed Mice"],"prefix":"10.3390","volume":"17","author":[{"given":"Hee Joon","family":"Yoo","sequence":"first","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Ju","family":"You","sequence":"additional","affiliation":[{"name":"Haerim Fucoidan, Wando-gun, Jeollanam-do 59108, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwang-Won","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3500","DOI":"10.1158\/0008-5472.CAN-06-4626","article-title":"Cancer immunologists and cancer biologists: Why we didn\u2019t talk then but need to now","volume":"67","author":"Prendergast","year":"2007","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s00280-016-3152-1","article-title":"The effect of cyclophosphamide on the immune system: Implications for clinical cancer therapy","volume":"78","author":"Ahlmann","year":"2016","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"194","DOI":"10.2165\/00003088-199120030-00002","article-title":"Clinical pharmacokinetics of cyclophosphamide","volume":"20","author":"Moore","year":"1991","journal-title":"Clin. Pharmacokinet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1158\/1078-0432.CCR-06-1209","article-title":"Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration","volume":"13","author":"Bracci","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"749","DOI":"10.4172\/pharmaceutical-sciences.1000416","article-title":"Immunomodulating properties of polygonum multiflorum extracts on cyclophosphamide-induced immunosuppression model","volume":"80","author":"Yang","year":"2018","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_6","first-page":"141","article-title":"Different mechanisms for anti-tumor effects of low-and high-dose cyclophosphamide","volume":"16","author":"Motoyoshi","year":"2006","journal-title":"Oncol. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.3390\/molecules13081671","article-title":"Fucoidan: Structure and Bioactivity","volume":"13","author":"Li","year":"2008","journal-title":"Molecules"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1093\/glycob\/cwm014","article-title":"A comparative study of the anti-inflammatory, anticoagulant, antiangiogenic, and antiadhesive activities of nine different fucoidans from brown seaweeds","volume":"17","author":"Cumashi","year":"2007","journal-title":"Glycobiology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.carbpol.2013.02.047","article-title":"Fucoidan from New Zealand Undaria pinnatifida: Monthly variations and determination of antioxidant activities","volume":"95","author":"Mak","year":"2013","journal-title":"Carbohydr. Polym."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1248\/cpb.52.1091","article-title":"Novel antiviral fucoidan from sporophyll of Undaria pinnatifida (Mekabu)","volume":"52","author":"Lee","year":"2004","journal-title":"Chem. Pharm. Bull."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Zheng, Y., Wang, J., Ma, S., Yu, Y., White, W.L., Yang, S., Yang, F., and Lu, J. (2018). Fucoidan Extracted from Undaria pinnatifida: Source for Nutraceuticals\/Functional Foods. Mar. Drugs, 16.","DOI":"10.3390\/md16090321"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lu, J., Shi, K., Chen, S., Wang, J., Hassouna, A., White, L., Merien, F., Xie, M., Kong, Q., and Li, J. (2018). Fucoidan extracted from the New Zealand Undaria pinnatifida\u2014Physicochemical comparison against five other fucoidans: Unique low molecular weight fraction bioactivity in breast cancer cell lines. Mar. Drugs, 16.","DOI":"10.3390\/md16120461"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"333","DOI":"10.4490\/ALGAE.2007.22.4.333","article-title":"Immunomodulating activity of a fucoidan isolated from Korean Undaria pinnatifida sporophyll","volume":"22","author":"Yoo","year":"2007","journal-title":"Algae"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10721","DOI":"10.1021\/acs.jafc.8b03698","article-title":"Immune activation of RAW264. 7 macrophages by low molecular weight fucoidan extracted from New Zealand Undaria pinnatifida","volume":"66","author":"Bi","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_15","first-page":"245","article-title":"Antitumor activity and immune response of Mekabu fucoidan extracted from Sporophyll of Undaria pinnatifida","volume":"17","author":"Maruyama","year":"2003","journal-title":"In Vivo"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1055\/s-2006-951703","article-title":"The role of NK cells in antitumor activity of dietary fucoidan from Undaria pinnatifida sporophylls (Mekabu)","volume":"72","author":"Maruyama","year":"2006","journal-title":"Planta Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.3945\/jn.113.179036","article-title":"Supplementation of elderly Japanese men and women with fucoidan from seaweed increases immune responses to seasonal influenza vaccination","volume":"143","author":"Negishi","year":"2013","journal-title":"J. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1080\/09168451.2014.930323","article-title":"The enhancing effect of fucoidan derived from Undaria pinnatifida on immunoglobulin production by mouse spleen lymphocytes","volume":"78","author":"Takai","year":"2014","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1089\/jmf.2005.8.446","article-title":"Immunomodulating activity of arabinogalactan and fucoidan in vitro","volume":"8","author":"Choi","year":"2005","journal-title":"J. Med. Food"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.carbpol.2010.01.052","article-title":"Structure and antitumour activity of fucoidan isolated from sporophyll of Korean brown seaweed Undaria pinnatifida","volume":"81","author":"Synytsya","year":"2010","journal-title":"Carbohydr. Polym."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.3390\/md9102106","article-title":"Important determinants for fucoidan bioactivity: A critical review of structure-function relations and extraction methods for fucose-containing sulfated polysaccharides from brown seaweeds","volume":"9","author":"Ale","year":"2011","journal-title":"Mar. Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.carbpol.2011.12.029","article-title":"Biological activities and potential industrial applications of fucose rich sulfated polysaccharides and fucoidans isolated from brown seaweeds: A review","volume":"88","author":"Wijesinghe","year":"2012","journal-title":"Carbohydr. Polym."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1160\/TH07-10-0603","article-title":"Slight differences in sulfation of algal galactans account for differences in their anticoagulant and venous antithrombotic activities","volume":"99","author":"Fonseca","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/0049-3848(91)90072-5","article-title":"The influence of sulfate content and molecular weight of a fucan sulfate from the brown seaweed Ecklonia kurome on its antithrombin activity","volume":"64","author":"Nishino","year":"1991","journal-title":"Thrombos. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"291","DOI":"10.3390\/molecules16010291","article-title":"Relationship between oversulfation and conformation of low and high molecular weight fucoidans and evaluation of their in vitro anticancer activity","volume":"16","author":"Cho","year":"2011","journal-title":"Molecules"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.ijbiomac.2008.08.006","article-title":"Effects of molecular weight and hydrolysis conditions on anticancer activity of fucoidans from sporophyll of Undaria pinnatifida","volume":"43","author":"Yang","year":"2008","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/0008-8749(91)90290-R","article-title":"Increased proliferation, lytic activity, and purity of human natural killer cells cocultured with mitogen-activated feeder cells","volume":"135","author":"Rabinowich","year":"1991","journal-title":"Cell. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/icb.1996.78","article-title":"NK cell proliferation and inflammation","volume":"74","author":"Warren","year":"1996","journal-title":"Immunol. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nri1083","article-title":"Cell death and immunity: The ABCs of granule-mediated cytotoxicity: New weapons in the arsenal","volume":"3","author":"Lieberman","year":"2003","journal-title":"Nat. Rev. Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/ni1582","article-title":"Functions of natural killer cells","volume":"9","author":"Vivier","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.ijbiomac.2017.01.108","article-title":"Structural effects of sulfated polysaccharides from Codium fragile on NK cell activation and cytotoxicity","volume":"98","author":"Surayot","year":"2017","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lori, A., Perrotta, M., Lembo, G., and Carnevale, D. (2017). The spleen: A hub connecting nervous and immune systems in cardiovascular and metabolic diseases. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18061216"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.jep.2009.06.015","article-title":"Antitumor and immunomodulatory activity of polysaccharides from the roots of Actinidia eriantha","volume":"125","author":"Xu","year":"2009","journal-title":"J. Ethnopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev.iy.07.040189.001045","article-title":"TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties","volume":"7","author":"Mosmann","year":"1989","journal-title":"Ann. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/BF02786470","article-title":"The paradigm of Th1 and Th2 cytokines","volume":"20","author":"Singh","year":"1999","journal-title":"Immunol. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1146\/annurev.immunol.15.1.297","article-title":"Induction of Th1 and Th2 CD4+ T cell responses: The alternative approaches","volume":"15","author":"Constant","year":"1997","journal-title":"Ann. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/0167-5699(96)80606-2","article-title":"The expanding universe of T-cell subsets: Th1, Th2 and more","volume":"17","author":"Mosmann","year":"1996","journal-title":"Immunol. Today"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/BF01742376","article-title":"Cyclophosphamide and abrogation of tumor-induced suppressor T cell activity","volume":"31","author":"Hoover","year":"1990","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Monmai, C., You, S., and Park, W.J. (2019). Immune-enhancing effects of anionic macromolecules extracted from Codium fragile on cyclophosphamide-treated mice. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211570"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.ijbiomac.2017.09.051","article-title":"Characterization and protective effect of Polygonatum sibiricum polysaccharide against cyclophosphamide-induced immunosuppression in Balb\/c mice","volume":"107","author":"Liu","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.ijbiomac.2018.01.090","article-title":"Purification, characterization and immunomodulatory activity of a novel polysaccharide from Grifola frondosa","volume":"111","author":"Li","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_42","first-page":"545","article-title":"Enhancement of immunomodulatory activities of low molecular weight fucoidan isolated from Hizikia fusiforme","volume":"40","author":"Ha","year":"2008","journal-title":"Korean J. Food. Sci. Technol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1248\/jhs.51.394","article-title":"Proportion of murine cytotoxic T cells is increased by high molecular-weight fucoidan extracted from Okinawa mozuku (Cladosiphon okamuranus)","volume":"51","author":"Shimizu","year":"2005","journal-title":"J. Health Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.fct.2014.03.024","article-title":"Differential effects of fucoidans with low and high molecular weight on the viability and function of spleen cells","volume":"68","author":"Jang","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1021\/ac60111a017","article-title":"Colorimetric method for determination of sugars and related substances","volume":"28","author":"Dubois","year":"1956","journal-title":"Anal. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0003-2697(91)90372-Z","article-title":"Measurement of uronic acids without interference from neutral sugars","volume":"197","author":"Carpita","year":"1991","journal-title":"Anal. Biochem."},{"key":"ref_47","first-page":"315","article-title":"Cyclophosphamide induces a Fas\/FasL-dependent apoptotic cell death in rat thymus","volume":"16","author":"Li","year":"2000","journal-title":"Immunol. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1046\/j.1365-2249.1998.00568.x","article-title":"1, 25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes","volume":"112","author":"Casteels","year":"1998","journal-title":"Clin. Exp. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"10675","DOI":"10.3168\/jds.2018-15137","article-title":"Enhancing the natural killer cell activity and anti-influenza effect of heat-treated Lactobacillus plantarum nF1-fortified yogurt in mice","volume":"101","author":"Chung","year":"2018","journal-title":"J. Dairy Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1099\/jmm.0.000938","article-title":"Heat-treated Lactobacillus plantarum increases the immune responses through activation of natural killer cells and macrophages on in vivo and in vitro models","volume":"68","author":"Moon","year":"2019","journal-title":"J. Med. Microbiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/17\/8\/447\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:10:55Z","timestamp":1760188255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/17\/8\/447"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,29]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["md17080447"],"URL":"https:\/\/doi.org\/10.3390\/md17080447","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,29]]}}}