{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T16:24:27Z","timestamp":1784564667756,"version":"3.55.0"},"reference-count":48,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:00:00Z","timestamp":1643846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion Science,  Grant-in-Aid for Scientific Research (C)","award":["19K08850"],"award-info":[{"award-number":["19K08850"]}]},{"name":"Japan Society for the Promotion Science, Grant-in-Aid for Challenging Exploratory Research","award":["18H05299"],"award-info":[{"award-number":["18H05299"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>We previously reported that rhamnan sulfate (RS) purified from Monostroma nitidum significantly suppressed lipopolysaccharide (LPS)-induced inflammation in cultured human vascular endothelial cells. Here, we analyzed the effect of orally administered RS on LPS-induced damage to mouse organs and vascular endothelium. RS (1 mg) was orally administered daily to BALB\/c mice, 50 \u03bcg of LPS was intraperitoneally administered on day 8, and Evans blue was injected into the tail vein 6 h later. After 30 min, LPS-treated mice showed pulmonary Evans blue leakage and elevated plasma levels of liver damage markers, whereas this reaction was suppressed in LPS + RS-treated mice. Immunohistochemical and Western blot analysis of mouse organs 24 h after LPS treatment showed significant neutrophil infiltration into the lung, liver, and jejunum tissues of LPS-treated mice and high expression levels of inflammation-related factors in these tissues. Expression levels of these factors were significantly suppressed in LPS + RS-treated mice. Analysis of lung glycocalyx showed a significant reduction in glycocalyx in LPS-treated mice but not in LPS + RS-treated mice. Levels of syndecan-4, one of the glycocalyx components, decreased in LPS-treated mice and increased in LPS + RS-treated mice. The current results suggest that orally administered RS protects organs and vascular endothelium from LPS-induced inflammation and maintains blood circulation.<\/jats:p>","DOI":"10.3390\/md20020121","type":"journal-article","created":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T11:35:17Z","timestamp":1643974517000},"page":"121","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Anti-Inflammatory Activity of Orally Administered Monostroma nitidum Rhamnan Sulfate against Lipopolysaccharide-Induced Damage to Mouse Organs and Vascular Endothelium"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1250-1569","authenticated-orcid":false,"given":"Masahiro","family":"Terasawa","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Minamitamagaki-cho 3500-3, Suzuka 513-8670, Mie, Japan"},{"name":"Konan Chemical Manufacturing, Co., Ltd., 1515 Kitagomizuka, Yokkaichi 510-0103, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Hiramoto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Minamitamagaki-cho 3500-3, Suzuka 513-8670, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Uchida","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Minamitamagaki-cho 3500-3, Suzuka 513-8670, Mie, Japan"},{"name":"Konan Chemical Manufacturing, Co., Ltd., 1515 Kitagomizuka, Yokkaichi 510-0103, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Minamitamagaki-cho 3500-3, Suzuka 513-8670, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.carbpol.2010.03.014","article-title":"Structure of rhamnan sulfate from the green alga Monostroma nitidum and its anti-herpetic effect","volume":"81","author":"Lee","year":"2010","journal-title":"Carbohydr. Polym."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"38","DOI":"10.11648\/j.ajac.20170502.13","article-title":"Structure-Function Relationship of Rhamnan Sulfate Isolated from Commercially Cultured Edible Green Seaweed, Monostroma nitidum","volume":"5","author":"Tako","year":"2017","journal-title":"Am. J. Appl. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.biortech.2012.03.025","article-title":"Preparation, structure and anticoagulant activity of a low molecular weight fraction produced by mild acid hydrolysis of sulfated rhamnan from Monostroma latissimum","volume":"114","author":"Li","year":"2012","journal-title":"Bioresour. Technol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1271\/bbb.62.1647","article-title":"Chemical structure of antithrombin-active Rhamnan sulfate from Monostrom nitidum","volume":"62","author":"Harada","year":"1998","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Song, Y., He, P., Rodrigues, A.L., Datta, P., Tandon, R., Bates, J.T., Bierdeman, M.A., Chen, C., Dordick, J., and Zhang, F. (2021). Anti-SARS-CoV-2 Activity of Rhamnan Sulfate from Monostroma nitidum. Mar. Drugs, 19.","DOI":"10.3390\/md19120685"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Suzuki, K., and Terasawa, M. (2020). Biological Activities of Rhamnan Sulfate Extract from the Green Algae Monostroma nitidum (Hitoegusa). Mar. Drugs, 18.","DOI":"10.3390\/md18040228"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Terasawa, M., Hayashi, K., Lee, J.B., Nishiura, K., Matsuda, K., Hayashi, T., and Kawahara, T. (2020). Anti-Influenza A Virus Activity of Rhamnan Sulfate from Green Algae Monostroma nitidum in Mice with Normal and Compromised Immunity. Mar. Drugs, 18.","DOI":"10.3390\/md18050254"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1007\/s11418-019-01289-5","article-title":"Rhamnan sulfate extracted from Monostroma nitidum attenuates blood coagulation and inflammation of vascular endothelial cells","volume":"73","author":"Okamoto","year":"2019","journal-title":"J. Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.carbpol.2018.07.067","article-title":"Antiviral activity against enterovirus 71 of sulfated rhamnan isolated from the green alga Monostroma latissimum","volume":"200","author":"Wang","year":"2018","journal-title":"Carbohydr. Polym."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Liu, X., Wang, S., Cao, S., He, X., Qin, L., He, M., Yang, Y., Hao, J., and Mao, W. (2018). Structural Characteristics and Anticoagulant Property In Vitro and In Vivo of a Seaweed Sulfated Rhamnan. Mar. Drugs, 16.","DOI":"10.3390\/md16070243"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.jff.2015.05.041","article-title":"Rhamnan sulphate from Monostroma nitidum attenuates hepatic steatosis by suppressing lipogenesis in a diet-induced obesity zebrafish model","volume":"17","author":"Zang","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_12","first-page":"37","article-title":"Anticoagulant Activity of Rhamnan Sulfate Isolated from Commercially Cultured Monostroma nitidum","volume":"5","author":"Yamashiro","year":"2017","journal-title":"Int. J. Biomed. Mater. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1055\/s-2006-960804","article-title":"Antiviral activities against HSV-1, HCMV, and HIV-1 of rhamnan sulfate from Monostroma latissimum","volume":"65","author":"Lee","year":"1999","journal-title":"Planta Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13384","DOI":"10.1038\/s41598-021-92459-7","article-title":"Rhamnan sulphate from green algae Monostroma nitidum improves constipation with gut microbiome alteration in double-blind placebo-controlled trial","volume":"11","author":"Shimada","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/j.1748-1716.2009.01964.x","article-title":"Endothelial dysfunction and vascular disease","volume":"196","author":"Vanhoutte","year":"2009","journal-title":"Acta Physiol. (Oxf.)"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.bcp.2009.04.029","article-title":"Inflammatory cytokines in vascular dysfunction and vascular disease","volume":"78","author":"Sprague","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1097\/00001721-199506001-00005","article-title":"Tissue factor expression in endothelial cells in health and disease","volume":"6","author":"Wada","year":"1995","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1182\/blood.V71.1.1.1","article-title":"Tissue factor and hemostasis","volume":"71","author":"Nemerson","year":"1988","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1055\/s-0038-1648824","article-title":"Adenosine nucleotides and serotonin stimulate von Willebrand factor release from cultured human endothelial cells","volume":"72","author":"Palmer","year":"1994","journal-title":"Thromb. Haemost."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1084\/jem.173.6.1553","article-title":"Adhesion of human basophils, eosinophils, and neutrophils to interleukin 1-activated human vascular endothelial cells: Contributions of endothelial cell adhesion molecules","volume":"173","author":"Bochner","year":"1991","journal-title":"J. Exp. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0167-5699(97)81662-3","article-title":"Cytokine regulation of endothelial cell function: From molecular level to the bedside","volume":"18","author":"Mantovani","year":"1997","journal-title":"Immunol. Today"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/0092-8674(94)90337-9","article-title":"Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm","volume":"76","author":"Springer","year":"1994","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1146\/annurev.bioeng.9.060906.151959","article-title":"The structure and function of the endothelial glycocalyx layer","volume":"9","author":"Weinbaum","year":"2007","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s13239-020-00485-9","article-title":"The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases","volume":"12","author":"Weinbaum","year":"2021","journal-title":"Cardiovasc. Eng. Technol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s00424-007-0212-8","article-title":"The endothelial glycocalyx: Composition, functions, and visualization","volume":"454","author":"Reitsma","year":"2007","journal-title":"Pflugers Arch."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/jth.14371","article-title":"Derangement of the endothelial glycocalyx in sepsis","volume":"17","author":"Iba","year":"2019","journal-title":"J. Thromb. Haemost."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1089\/ars.2013.5751","article-title":"The mechanisms and physiological relevance of glycocalyx degradation in hepatic ischemia\/reperfusion injury","volume":"21","author":"Reiniers","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"H1672","DOI":"10.1152\/ajpheart.00832.2003","article-title":"Inflammation- and ischemia-induced shedding of venular glycocalyx","volume":"286","author":"Mulivor","year":"2004","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"47483","DOI":"10.1074\/jbc.M106268200","article-title":"Syndecan-4 deficiency leads to high mortality of lipopolysaccharide-injected mice","volume":"276","author":"Ishiguro","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s40560-014-0051-6","article-title":"Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation","volume":"2","author":"Iba","year":"2014","journal-title":"J. Intensive Care"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1186\/cc4822","article-title":"Clinical review: Molecular mechanisms underlying the role of antithrombin in sepsis","volume":"10","author":"Wiedermann","year":"2006","journal-title":"Crit. Care"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.thromres.2018.09.042","article-title":"Protection of the endothelial glycocalyx by antithrombin in an endotoxin-induced rat model of sepsis","volume":"171","author":"Iba","year":"2018","journal-title":"Thromb. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1016\/j.ajpath.2021.05.015","article-title":"Recombinant Antithrombin Attenuates Acute Respiratory Distress Syndrome in Experimental Endotoxemia","volume":"191","author":"Okamoto","year":"2021","journal-title":"Am. J. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s000110050579","article-title":"Endothelium function in sepsis","volume":"49","author":"Volk","year":"2000","journal-title":"Inflamm. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1100\/tsw.2010.88","article-title":"Sepsis-induced degradation of endothelial glycocalix","volume":"10","author":"Henrich","year":"2010","journal-title":"TheScientificWorldJournal"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1161\/01.RES.0000065917.53950.75","article-title":"The endothelial glycocalyx protects against myocardial edema","volume":"92","author":"Vink","year":"2003","journal-title":"Circ. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14185","DOI":"10.1096\/fj.201901048RR","article-title":"Glycocalyx breakdown is increased in African children with cerebral and uncomplicated falciparum malaria","volume":"33","author":"Yeo","year":"2019","journal-title":"FASEB J."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Bar, A., Targosz-Korecka, M., Suraj, J., Proniewski, B., Jasztal, A., Marczyk, B., Sternak, M., Przybylo, M., Kurpinska, A., and Walczak, M. (2019). Degradation of Glycocalyx and Multiple Manifestations of Endothelial Dysfunction Coincide in the Early Phase of Endothelial Dysfunction Before Atherosclerotic Plaque Development in Apolipoprotein E\/Low-Density Lipoprotein Receptor-Deficient Mice. J. Am. Heart Assoc., 8.","DOI":"10.1161\/JAHA.118.011171"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13054-015-0741-z","article-title":"Glycocalyx and sepsis-induced alterations in vascular permeability","volume":"19","author":"Chelazzi","year":"2015","journal-title":"Crit. Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jss.2019.03.018","article-title":"Sevoflurane Promotes Regeneration of the Endothelial Glycocalyx by Upregulating Sialyltransferase","volume":"241","author":"Kazuma","year":"2019","journal-title":"J. Surg. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13334","DOI":"10.1096\/fj.201901148R","article-title":"Uric acid induced the phenotype transition of vascular endothelial cells via induction of oxidative stress and glycocalyx shedding","volume":"33","author":"Ko","year":"2019","journal-title":"FASEB J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1161\/01.ATV.0000085630.24353.3D","article-title":"Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface","volume":"23","author":"Constantinescu","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Mensah, S.A., Cheng, M.J., Homayoni, H., Plouffe, B.D., Coury, A.J., and Ebong, E.E. (2017). Regeneration of glycocalyx by heparan sulfate and sphingosine 1-phosphate restores inter-endothelial communication. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186116"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1271\/bbb.90705","article-title":"Development of a fucoidan-specific antibody and measurement of fucoidan in serum and urine by sandwich ELISA","volume":"74","author":"Tokita","year":"2010","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"48","DOI":"10.3390\/md13010048","article-title":"Intestinal absorption of fucoidan extracted from the brown seaweed, Cladosiphon okamuranus","volume":"13","author":"Nagamine","year":"2014","journal-title":"Mar. Drugs"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"607306","DOI":"10.3389\/fimmu.2021.607306","article-title":"Glycocalyx as Possible Limiting Factor in COVID-19","volume":"12","author":"Wadowski","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1111\/exd.12499","article-title":"Skin disruption is associated with indomethacin-induced small intestinal injury in mice","volume":"23","author":"Yokoyama","year":"2014","journal-title":"Exp. Dermatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.biopha.2016.02.013","article-title":"The amelioration effect of tranexamic acid in wrinkles induced by skin dryness","volume":"80","author":"Hiramoto","year":"2016","journal-title":"Biomed. Pharmacother."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/20\/2\/121\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:13:44Z","timestamp":1760134424000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/20\/2\/121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,3]]},"references-count":48,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["md20020121"],"URL":"https:\/\/doi.org\/10.3390\/md20020121","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,3]]}}}