{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T19:51:08Z","timestamp":1792439468529,"version":"4.5.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T00:00:00Z","timestamp":1460419200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T00:00:00Z","timestamp":1460419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Influenza is one of the most common human respiratory diseases, and represents a serious public health concern. However, the high mutability of influenza viruses has hampered vaccine development, and resistant strains to existing anti-viral drugs have also emerged. Novel anti-influenza therapies are urgently needed, and in this study, we describe the anti-viral properties of a Spirulina (<jats:italic>Arthrospira platensis<\/jats:italic>) cold water extract. Anti-viral effects have previously been reported for extracts and specific substances derived from Spirulina, and here we show that this Spirulina cold water extract has low cellular toxicity, and is well-tolerated in animal models at one dose as high as 5,000\u2009mg\/kg, or 3,000\u2009mg\/kg\/day for 14 successive days. Anti-flu efficacy studies revealed that the Spirulina extract inhibited viral plaque formation in a broad range of influenza viruses, including oseltamivir-resistant strains. Spirulina extract was found to act at an early stage of infection to reduce virus yields in cells and improve survival in influenza-infected mice, with inhibition of influenza hemagglutination identified as one of the mechanisms involved. Together, these results suggest that the cold water extract of Spirulina might serve as a safe and effective therapeutic agent to manage influenza outbreaks, and further clinical investigation may be warranted.<\/jats:p>","DOI":"10.1038\/srep24253","type":"journal-article","created":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T09:38:43Z","timestamp":1460453923000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Well-tolerated Spirulina extract inhibits influenza virus replication and reduces virus-induced mortality"],"prefix":"10.1038","volume":"6","author":[{"given":"Yi-Hsiang","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gi-Kung","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Ming","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Yu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Chen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Lun","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Ru","family":"Shih","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,12]]},"reference":[{"key":"BFsrep24253_CR1","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1146\/annurev.pathmechdis.3.121806.154316","volume":"3","author":"JK Taubenberger","year":"2008","unstructured":"Taubenberger, J. K. & Morens, D. M. The pathology of influenza virus infections. Annu. Rev. Pathol. 3, 499\u2013522 (2008).","journal-title":"Annu. Rev. Pathol."},{"key":"BFsrep24253_CR2","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1289\/ehp.1002383","volume":"119","author":"J Tamerius","year":"2011","unstructured":"Tamerius, J. et al. Global influenza seasonality: reconciling patterns across temperate and tropical regions. Environ. Health Perspect. 119, 439\u2013445 (2011).","journal-title":"Environ. Health Perspect."},{"key":"BFsrep24253_CR3","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1353\/bhm.2002.0022","volume":"76","author":"NP Johnson","year":"2002","unstructured":"Johnson, N. P. & Mueller, J. Updating the accounts: global mortality of the 1918\u20131920 \u201cSpanish\u201d influenza pandemic. Bull. Hist. Med. 76, 105\u2013115 (2002).","journal-title":"Bull. Hist. Med."},{"key":"BFsrep24253_CR4","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/S1473-3099(12)70121-4","volume":"12","author":"FS Dawood","year":"2012","unstructured":"Dawood, F. S. et al. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. Lancet Infect. Dis. 12, 687\u2013695 (2012).","journal-title":"Lancet Infect. Dis."},{"key":"BFsrep24253_CR5","doi-asserted-by":"publisher","first-page":"e1003657","DOI":"10.1371\/journal.ppat.1003657","volume":"9","author":"S Tong","year":"2013","unstructured":"Tong, S. et al. New world bats harbor diverse influenza A viruses. PLoS pathogens 9, e1003657, 10.1371\/journal.ppat.1003657 (2013).","journal-title":"PLoS pathogens"},{"key":"BFsrep24253_CR6","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1038\/nature08157","volume":"459","author":"G Neumann","year":"2009","unstructured":"Neumann, G., Noda, T. & Kawaoka, Y. Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 459, 931\u2013939 (2009).","journal-title":"Nature"},{"key":"BFsrep24253_CR7","doi-asserted-by":"publisher","first-page":"8091","DOI":"10.1073\/pnas.0711942105","volume":"105","author":"BJ Zheng","year":"2008","unstructured":"Zheng, B. J. et al. Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A\/H5N1 virus. Proc. Natl. Acad. Sci. USA 105, 8091\u20138096 (2008).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep24253_CR8","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.bcp.2009.08.025","volume":"79","author":"J Geiler","year":"2010","unstructured":"Geiler, J. et al. N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus. Biochem. Pharmacol. 79, 413\u2013420 (2010).","journal-title":"Biochem. Pharmacol."},{"key":"BFsrep24253_CR9","doi-asserted-by":"publisher","first-page":"e33","DOI":"10.1111\/j.1755-5922.2010.00200.x","volume":"28","author":"R Deng","year":"2010","unstructured":"Deng, R. & Chow, T. J. Hypolipidemic, antioxidant, and antiinflammatory activities of microalgae Spirulina. Cardiovasc. Ther. 28, e33\u2013e45 (2010).","journal-title":"Cardiovasc. Ther."},{"key":"BFsrep24253_CR10","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1080\/10408391003721719","volume":"51","author":"RJ Marles","year":"2011","unstructured":"Marles, R. J. et al. United States pharmacopeia safety evaluation of spirulina. Crit. Rev. Food Sci. Nutr. 51, 593\u2013604 (2011).","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"BFsrep24253_CR11","doi-asserted-by":"publisher","first-page":"531053","DOI":"10.1093\/ecam\/nen058","volume":"2011","author":"PD Karkos","year":"2011","unstructured":"Karkos, P. D., Leong, S. C., Karkos, C. D., Sivaji, N. & Assimakopoulos, D. A. Spirulina in clinical practice: evidence-based human applications. Evid. Based Complement. Alternat. Med. 2011, 531053 (2011).","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"BFsrep24253_CR12","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/1423-0127-17-13","volume":"17","author":"SR Shih","year":"2010","unstructured":"Shih, S. R. et al. Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity. J. Biomed. Sci. 17, 13 (2010).","journal-title":"J. Biomed. Sci."},{"key":"BFsrep24253_CR13","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1056\/NEJMra1208802","volume":"370","author":"HV Fineberg","year":"2014","unstructured":"Fineberg, H. V. Pandemic preparedness and response\u2014lessons from the H1N1 influenza of 2009. N Engl J Med. 370, 1335\u20131342 (2014).","journal-title":"N Engl J Med."},{"key":"BFsrep24253_CR14","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/j.coviro.2011.09.002","volume":"1","author":"MG Ison","year":"2011","unstructured":"Ison, M. G. Antivirals and resistance: influenza virus. Curr. Opin. Virol. 1, 563\u2013573 (2011).","journal-title":"Curr. Opin. Virol."},{"key":"BFsrep24253_CR15","doi-asserted-by":"publisher","first-page":"g2545","DOI":"10.1136\/bmj.g2545","volume":"348","author":"T Jefferson","year":"2014","unstructured":"Jefferson, T. et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 348, g2545 (2014).","journal-title":"BMJ"},{"key":"BFsrep24253_CR16","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1159\/000088889","volume":"49","author":"J Simpore","year":"2005","unstructured":"Simpore, J. et al. Nutrition rehabilitation of HIV-infected and HIV-negative undernourished children utilizing spirulina. Ann Nutr Metab. 49, 373\u2013380 (2005).","journal-title":"Ann Nutr Metab."},{"key":"BFsrep24253_CR17","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/S1567-5769(01)00166-7","volume":"2","author":"T Hirahashi","year":"2002","unstructured":"Hirahashi, T. et al. Activation of the human innate immune system by Spirulina: augmentation of interferon production and NK cytotoxicity by oral administration of hot water extract of Spirulina platensis . Int. Immunopharmacol. 2, 423\u2013434 (2002).","journal-title":"Int. Immunopharmacol."},{"key":"BFsrep24253_CR18","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1089\/jmf.2005.8.27","volume":"8","author":"TK Mao","year":"2005","unstructured":"Mao, T. K., Van de Water, J. & Gershwin, M. E. Effects of a Spirulina-based dietary supplement on cytokine production from allergic rhinitis patients. J. Med. Food 8, 27\u201330 (2005).","journal-title":"J. Med. Food"},{"key":"BFsrep24253_CR19","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1007\/s00405-008-0642-8","volume":"265","author":"C Cingi","year":"2008","unstructured":"Cingi, C., Conk-Dalay, M., Cakli, H. & Bal, C. The effects of spirulina on allergic rhinitis. Eur. Arch. Otorhinolaryngol. 265, 1219\u20131223 (2008).","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"BFsrep24253_CR20","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1002\/ptr.2650070118","volume":"7","author":"K Hayashi","year":"1993","unstructured":"Hayashi, K., Hayashi, T., Morita, N. & Kojima, I. An extract from Spirulina platensis is a selective inhibitor of herpes simplex virus type 1 penetration into HeLa cells. Phytother. Res. 7, 76\u201380 (1993).","journal-title":"Phytother. Res."},{"key":"BFsrep24253_CR21","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1021\/np960017o","volume":"59","author":"T Hayashi","year":"1996","unstructured":"Hayashi, T., Hayashi, K., Maeda, M. & Kojima, I. Calcium spirulan, an inhibitor of enveloped virus replication, from a blue-green alga Spirulina platensis . J. Nat. Prod. 59, 83\u201387 (1996).","journal-title":"J. Nat. Prod."},{"key":"BFsrep24253_CR22","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1089\/aid.1996.12.1463","volume":"12","author":"K Hayashi","year":"1996","unstructured":"Hayashi, K., Hayashi, T. & Kojima, I. A natural sulfated polysaccharide, calcium spirulan, isolated from Spirulina platensis: in vitro and ex vivo evaluation of anti-herpes simplex virus and anti-human immunodeficiency virus activities. AIDS Res. Hum. Retroviruses 12, 1463\u20131471 (1996).","journal-title":"AIDS Res. Hum. Retroviruses"},{"key":"BFsrep24253_CR23","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1248\/cpb.49.108","volume":"49","author":"JB Lee","year":"2001","unstructured":"Lee, J. B. et al. Effects of structural modification of calcium spirulan, a sulfated polysaccharide from Spirulina platensis, on antiviral activity. Chem. Pharm. Bull. (Tokyo) 49, 108\u2013110 (2001).","journal-title":"Chem. Pharm. Bull. (Tokyo)"},{"key":"BFsrep24253_CR24","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.phymed.2014.12.006","volume":"22","author":"ND Pugh","year":"2015","unstructured":"Pugh, N. D. et al. Oral administration of a Spirulina extract enriched for Braun-type lipoproteins protects mice against influenza A (H1N1) virus infection. Phytomedicine 22, 271\u2013276 (2015).","journal-title":"Phytomedicine"},{"key":"BFsrep24253_CR25","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1002\/jmv.10363","volume":"70","author":"SR Shih","year":"2003","unstructured":"Shih, S. R., Tsai, K. N., Li, Y. S., Chueh, C. C. & Chan, E. C. Inhibition of enterovirus 71-induced apoptosis by allophycocyanin isolated from a blue-green alga Spirulina platensis . J. Med. Virol. 70, 119\u2013125 (2003).","journal-title":"J. Med. Virol."},{"key":"BFsrep24253_CR26","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1097\/00042560-199805010-00002","volume":"18","author":"S Ayehunie","year":"1998","unstructured":"Ayehunie, S., Belay, A., Baba, T. W. & Ruprecht, R. M. Inhibition of HIV-1 replication by an aqueous extract of Spirulina platensis (Arthrospira platensis). J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 18, 7\u201312 (1998).","journal-title":"J. Acquir. Immune Defic. Syndr. Hum. Retrovirol."},{"key":"BFsrep24253_CR27","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1016\/j.lfs.2007.09.009","volume":"81","author":"SC Cherng","year":"2007","unstructured":"Cherng, S. C., Cheng, S. N., Tarn, A. & Chou, T. C. Anti-inflammatory activity of c-phycocyanin in lipopolysaccharide-stimulated RAW 264.7 macrophages. Life Sci. 81, 1431\u20131435 (2007).","journal-title":"Life Sci."},{"key":"BFsrep24253_CR28","first-page":"916590","volume":"2013","author":"PO Leung","year":"2013","unstructured":"Leung, P. O., Lee, H. H., Kung, Y. C., Tsai, M. F. & Chou, T. C. Therapeutic effect of C-phycocyanin extracted from blue green algae in a rat model of acute lung injury induced by lipopolysaccharide. Evid. Based Complement. Alternat. Med. 2013, 916590 (2013).","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"BFsrep24253_CR29","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1213\/ane.0b013e318193e919","volume":"108","author":"CM Shih","year":"2009","unstructured":"Shih, C. M., Cheng, S. N., Wong, C. S., Kuo, Y. L. & Chou, T. C. Antiinflammatory and antihyperalgesic activity of C-phycocyanin. Anesth. Analg. 108, 1303\u20131310 (2009).","journal-title":"Anesth. Analg."},{"key":"BFsrep24253_CR30","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1006\/bbrc.2000.3725","volume":"277","author":"CM Reddy","year":"2000","unstructured":"Reddy, C. M. et al. Selective inhibition of cyclooxygenase-2 by C-phycocyanin, a biliprotein from Spirulina platensis . Biochem. Biophys. Res. Commun. 277, 599\u2013603 (2000).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"BFsrep24253_CR31","doi-asserted-by":"publisher","first-page":"e58215","DOI":"10.1371\/journal.pone.0058215","volume":"8","author":"JH Hwang","year":"2013","unstructured":"Hwang, J. H., Chen, J. C. & Chan, Y. C. Effects of C-phycocyanin and Spirulina on salicylate-induced tinnitus, expression of NMDA receptor and inflammatory genes. PLoS One 8, e58215 (2013).","journal-title":"PLoS One"},{"key":"BFsrep24253_CR32","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1086\/590499","volume":"198","author":"SM Lee","year":"2008","unstructured":"Lee, S. M. et al. Hyperinduction of cyclooxygenase-2-mediated proinflammatory cascade: a mechanism for the pathogenesis of avian influenza H5N1 infection. J. Infect. Dis. 198, 525\u2013535 (2008).","journal-title":"J. Infect. Dis."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep24253.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep24253","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep24253.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T03:43:10Z","timestamp":1672890190000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep24253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,12]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,4,26]]}},"alternative-id":["BFsrep24253"],"URL":"https:\/\/doi.org\/10.1038\/srep24253","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,12]]},"assertion":[{"value":"28 October 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 April 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24253"}}