{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T15:11:21Z","timestamp":1769181081611,"version":"3.49.0"},"reference-count":31,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences","award":["2021-I2M-1-030"],"award-info":[{"award-number":["2021-I2M-1-030"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cytokine storm is a critical driver of acute respiratory distress syndrome and multiple organ failure. Human \u03b2-defensin 2 (HBD-2) is the first inducible defensin discovered in human body. Defensin can resist pathogenic microorganisms invading the body through direct bactericidal effect and also modulates acquired immune response. Albumin exhibits immunomodulatory properties and can reduce the level of inflammatory cytokines to improve the systemic inflammatory response. We previously engineered a recombinant fusion protein, DF2-HSA, comprising two HBD-2 molecules linked to human serum albumin. Here, we evaluated its effect on cytokine storm using a lipopolysaccharide (LPS)-induced cytokine storm murine model (BALB\/c athymic mice, female). DF2-HSA reduced the mortality in cytokine storm murine model and prolonged the retention time of HBD-2 in the body. A Luminex assay showed that DF2-HSA reduced the production of multiple inflammatory cytokines in cytokine storm murine model. Evans blue staining showed that DF2-HSA reduced vascular leakage. Transmission electron microscopy showed that DF2-HSA reduced the lung injury of cytokine storm mice. The pathological results showed that DF2-HSA alleviated the lung and small intestine damage of cytokine storm mice. In summary, DF2-HSA effectively inhibits cytokine storms and ameliorates associated tissue damage.<\/jats:p>","DOI":"10.3390\/cells15020202","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T13:59:54Z","timestamp":1769003994000},"page":"202","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Human \u03b2-Defensin-Based Recombinant Protein DF2-HSA Ameliorates Cytokine Storm"],"prefix":"10.3390","volume":"15","author":[{"given":"Yibo","family":"Du","sequence":"first","affiliation":[{"name":"Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuojun","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weijin","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Hou","sequence":"additional","affiliation":[{"name":"Experimental Animal Center, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9552-8411","authenticated-orcid":false,"given":"Yanbo","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1865-1162","authenticated-orcid":false,"given":"Xiujun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongsu","family":"Zhen","sequence":"additional","affiliation":[{"name":"Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jarczak, D., and Nierhaus, A. (2022). Cytokine Storm-Definition, Causes, and Implications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911740"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1056\/NEJMra2026131","article-title":"Cytokine Storm","volume":"383","author":"Fajgenbaum","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1182\/blood-2014-05-552729","article-title":"Current concepts in the diagnosis and management of cytokine release syndrome","volume":"124","author":"Lee","year":"2014","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/S1357-2725(99)00013-8","article-title":"Human beta-defensin-2","volume":"31","author":"Harder","year":"1999","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Cie\u015blik, M., Bagi\u0144ska, N., G\u00f3rski, A., and Jo\u0144czyk-Matysiak, E. (2021). Human \u03b2-Defensin 2 and Its Postulated Role in Modulation of the Immune Response. Cells, 10.","DOI":"10.3390\/cells10112991"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10486","DOI":"10.1021\/bi1011749","article-title":"Interaction of human \u03b2-defensin 2 (HBD2) with glycosaminoglycans","volume":"49","author":"Seo","year":"2010","journal-title":"Biochemistry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2740","DOI":"10.1128\/IAI.67.6.2740-2745.1999","article-title":"Production of beta-defensin antimicrobial peptides by the oral mucosa and salivary glands","volume":"67","author":"Mathews","year":"1999","journal-title":"Infect. Immun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1136\/gut.49.4.481","article-title":"Expression of human beta-defensin 2 (hBD-2) in Helicobacter pylori induced gastritis: Antibacterial effect of hBD-2 against Helicobacter pylori","volume":"49","author":"Hamanaka","year":"2001","journal-title":"Gut"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Fusco, A., Savio, V., Donniacuo, M., Perfetto, B., and Donnarumma, G. (2021). Antimicrobial Peptides Human Beta-Defensin-2 and -3 Protect the Gut During Candida albicans Infections Enhancing the Intestinal Barrier Integrity: In Vitro Study. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.666900"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.ijbiomac.2018.11.053","article-title":"Structure, enzymatic activities, glycation and therapeutic potential of human serum albumin: A natural cargo","volume":"123","author":"Rabbani","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Li, C., Zhang, D., Pan, Y., and Chen, B. (2023). Human Serum Albumin Based Nanodrug Delivery Systems: Recent Advances and Future Perspective. Polymers, 15.","DOI":"10.3390\/polym15163354"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1893888","DOI":"10.1080\/19420862.2021.1893888","article-title":"Extended plasma half-life of albumin-binding domain fused human IgA upon pH-dependent albumin engagement of human FcRn in vitro and in vivo","volume":"13","author":"Mester","year":"2021","journal-title":"mAbs"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"115057","DOI":"10.1016\/j.bcp.2022.115057","article-title":"The recombinant defensin\/HSA fusion protein that inhibits NF-\u03bab associated with intensive macropinocytosis shows potent efficacy against pancreatic cancer","volume":"201","author":"Du","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41586-018-0774-y","article-title":"Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome","volume":"564","author":"Staedtke","year":"2018","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113431","DOI":"10.1016\/j.intimp.2024.113431","article-title":"The triple combination DBDx alleviates cytokine storm and related lung injury","volume":"143","author":"Yu","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.molmed.2004.12.007","article-title":"The \u201ccytokine profile\u201d: A code for sepsis","volume":"11","author":"Ulloa","year":"2005","journal-title":"Trends Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1111\/joim.12331","article-title":"Endothelial barrier dysfunction in septic shock","volume":"277","author":"Opal","year":"2015","journal-title":"J. Intern. Med."},{"key":"ref_19","unstructured":"Alderson, P., Bunn, F., Lefebvre, C., Li, W.P., Li, L., Roberts, I., and Schierhout, G. (2004). Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.ijantimicag.2009.09.024","article-title":"Antibacterial and lipopolysaccharide (LPS)-neutralising activity of human cationic antimicrobial peptides against periodontopathogens","volume":"35","author":"Lee","year":"2010","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Altomare, A.A., Brioschi, M., Eligini, S., Bonomi, A., Zoanni, B., Iezzi, A., Jemos, C., Porro, B., D\u2019Alessandra, Y., and Guarino, A. (2022). N-Acetylcysteine Regenerates In Vivo Mercaptoalbumin. Antioxidants, 11.","DOI":"10.3390\/antiox11091758"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1007\/s11095-006-9933-1","article-title":"Recombinant human serum albumin dimer has high blood circulation activity and low vascular permeability in comparison with native human serum albumin","volume":"23","author":"Matsushita","year":"2006","journal-title":"Pharm. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101623","DOI":"10.1016\/j.tmaid.2020.101623","article-title":"Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis","volume":"34","year":"2020","journal-title":"Travel Med. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1089\/ars.2020.8142","article-title":"Is Albumin Predictor of Mortality in COVID-19? Antioxid","volume":"35","author":"Violi","year":"2021","journal-title":"Redox Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.ajem.2007.10.031","article-title":"The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome","volume":"26","author":"Wang","year":"2008","journal-title":"Am. J. Emerg. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.chest.2018.10.022","article-title":"Lung Repair and Regeneration in ARDS: Role of PECAM1 and Wnt Signaling","volume":"155","author":"Villar","year":"2019","journal-title":"Chest"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102833","DOI":"10.1016\/j.ebiom.2020.102833","article-title":"Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients","volume":"57","author":"Wang","year":"2020","journal-title":"eBioMedicine"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wu, X., Jing, H., Wang, C., Wang, Y., Zuo, N., Jiang, T., Novakovic, V.A., and Shi, J. (2022). Intestinal Damage in COVID-19: SARS-CoV-2 Infection and Intestinal Thrombosis. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.860931"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Cho, H., Jeon, S.I., Ahn, C.H., Shim, M.K., and Kim, K. (2022). Emerging Albumin-Binding Anticancer Drugs for Tumor-Targeted Drug Delivery: Current Understandings and Clinical Translation. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14040728"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41577-022-00685-5","article-title":"Intestinal barrier protection","volume":"22","author":"Minton","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.ebiom.2019.02.055","article-title":"STING-mediated intestinal barrier dysfunction contributes to lethal sepsis","volume":"41","author":"Hu","year":"2019","journal-title":"eBioMedicine"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/202\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T14:00:21Z","timestamp":1769176821000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/202"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":31,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15020202"],"URL":"https:\/\/doi.org\/10.3390\/cells15020202","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,21]]}}}