{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:30:57Z","timestamp":1791307857770,"version":"4.3.1"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2016,11,22]],"date-time":"2016-11-22T00:00:00Z","timestamp":1479772800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["30500093"],"award-info":[{"award-number":["30500093"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81274162"],"award-info":[{"award-number":["81274162"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Major Scientific and Technological Special Project for \u201cSignificant New Drugs Development\u201d","award":["2009ZX09103-690"],"award-info":[{"award-number":["2009ZX09103-690"]}]},{"name":"Innovation Program of Shanghai Municipal Education Commission","award":["14ZZ077"],"award-info":[{"award-number":["14ZZ077"]}]},{"name":"Shanghai Science and Technology Innovation Action Plan","award":["16431904400"],"award-info":[{"award-number":["16431904400"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tumor necrosis factor (TNF)-\u03b1 is a pleiotropic cytokine with intense pro-inflammatory and immunomodulatory properties, and anti-TNF-\u03b1 biologics are effective therapies for various inflammatory diseases such as inflammatory bowel disease (IBD) and sepsis. Snake venom, as a traditional Chinese medicine, has been used in the treatment of inflammatory diseases in China for centuries. In this research, we constructed a venom gland T7 phage display library of the sea snake Hydrophis cyanocinctus to screen bioactive compounds that antagonize TNF-\u03b1 and identified a novel nine-amino-acid peptide, termed hydrostatin-TL1 (H-TL1). In enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) analyses, H-TL1 inhibited the interaction between TNF-\u03b1 and TNF receptor 1 (TNFR1). Further, H-TL1 attenuated the cytotoxicity of TNF-\u03b1 in L929 cells as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. H-TL1 also decreased the mRNA expression of TNF-\u03b1\/TNFR1 downstream targets and suppressed the phosphorylation of well-characterized proteins of downstream signal transduction pathways in HEK-293 cells. In vivo data demonstrated that H-TL1 protects animals against dextran sodium sulfate (DSS)-induced acute colitis and lipopolysaccharide (LPS)-induced acute shock. Given its significant anti-inflammatory activity in vitro and in vivo, H-TL1 is a potential peptide for the development of new agents to treat TNF-\u03b1-associated inflammatory diseases.<\/jats:p>","DOI":"10.3390\/ijms17111940","type":"journal-article","created":{"date-parts":[[2016,11,22]],"date-time":"2016-11-22T11:13:07Z","timestamp":1479813187000},"page":"1940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Hydrostatin-TL1, an Anti-Inflammatory Active Peptide from the Venom Gland of Hydrophis cyanocinctus in the South China Sea"],"prefix":"10.3390","volume":"17","author":[{"given":"Ningyuan","family":"Wang","sequence":"first","affiliation":[{"name":"School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ka","family":"Li","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1126\/science.1071924","article-title":"TNF-R1 signaling: A beautiful pathway","volume":"296","author":"Chen","year":"2002","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/sj.cdd.4401189","article-title":"Tumor necrosis factor signaling","volume":"10","author":"Wajant","year":"2003","journal-title":"Cell Death Differ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S0962-8924(00)89088-1","article-title":"Two tumour necrosis factor receptors: Structure and function","volume":"5","author":"Vandenabeele","year":"1995","journal-title":"Trends Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1038\/nn738","article-title":"TNF\u03b1 promotes proliferation of oligodendrocyte progenitors and remyelination","volume":"4","author":"Arnett","year":"2001","journal-title":"Nat. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.4049\/jimmunol.1202659","article-title":"TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T Cell phenotype in the inflammatory environment","volume":"190","author":"Chen","year":"2013","journal-title":"J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/(SICI)1521-4141(199801)28:01<257::AID-IMMU257>3.0.CO;2-G","article-title":"TNF receptor type 2 mediates thymocyte proliferation independently of TNF receptor type 1","volume":"28","author":"Grell","year":"1998","journal-title":"Eur. J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/ibd.21048","article-title":"World gastroenterology organization practice guidelines for the diagnosis and management of IBD in 2010","volume":"16","author":"Bernstein","year":"2010","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"69","DOI":"10.4155\/fmc.12.192","article-title":"Small-molecule inhibitors of the interaction between TNF and TNFR","volume":"5","author":"Davis","year":"2013","journal-title":"Future Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/med.20042","article-title":"Small molecular anti-cytokine agents","volume":"26","author":"Wagner","year":"2006","journal-title":"Med. Res. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.drudis.2006.06.002","article-title":"Modulating TNF-\u03b1 signaling with natural products","volume":"11","author":"Paul","year":"2006","journal-title":"Drug Discov. Today"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/0092-8674(93)90132-A","article-title":"Crystal structure of the soluble human 55 kD TNF receptor-human TNF \u03b2 complex: Implications for TNF receptor activation","volume":"73","author":"Banner","year":"1993","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1021\/cr960065d","article-title":"Phage display","volume":"97","author":"Smith","year":"1997","journal-title":"Chem. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12954","DOI":"10.1073\/pnas.211439598","article-title":"T7 phage display: A novel genetic selection system for cloning RNA-binding proteins from cDNA libraries","volume":"98","author":"Danner","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","first-page":"883","article-title":"Identification of receptor ligands with phage display peptide libraries","volume":"40","author":"Koivunen","year":"1999","journal-title":"J. Nucl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sclavons, C., Burtea, C., Boutry, S., Laurent, S., Vander Elst, L., and Muller, R.N. (2013). Phage display screening for tumor necrosis factor-\u03b1-binding peptides: Detection of inflammation in a mouse model of hepatitis. Int. J. Pept., 2013.","DOI":"10.1155\/2013\/348409"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5621","DOI":"10.4049\/jimmunol.161.10.5621","article-title":"A peptidomimetic antagonist of TNF-\u03b1-mediated cytotoxicity identified from a phage-displayed random peptide library","volume":"161","author":"Steward","year":"1998","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1146\/annurev.bi.42.070173.001315","article-title":"Neurotoxins of animal venoms: Snakes","volume":"42","author":"Tu","year":"1973","journal-title":"Annu. Rev. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.intimp.2015.01.017","article-title":"Antimicrobial peptide Cathelicidin-BF prevents intestinal barrier dysfunction in a mouse model of endotoxemia","volume":"25","author":"Song","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.intimp.2015.05.034","article-title":"Cathelicidin-BF suppresses intestinal inflammation by inhibiting the nuclear factor-\u03ba signaling pathway and enhancing the phagocytosis of immune cells via STAT-1 in weanling piglets","volume":"28","author":"Yi","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"162","DOI":"10.3390\/toxins1020162","article-title":"Isolation and chemical characterization of a toxin isolated from the venom of the sea snake, Hydrophis torquatus aagardi","volume":"1","author":"Nagamizu","year":"2009","journal-title":"Toxins"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16633","DOI":"10.1074\/jbc.M115.642645","article-title":"Identification and characterization of the first Cathelicidin from sea snakes with potent antimicrobial and anti-inflammatory activity and special mechanism","volume":"290","author":"Wei","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zheng, Z., Jiang, H., Huang, Y., Wang, J., Qiu, L., Hu, Z., Ma, X., and Lu, Y. (2016). Screening of an anti-inflammatory peptide from Hydrophis cyanocinctus and analysis of its activities and mechanism in DSS-induced acute colitis. Sci. Rep., 6.","DOI":"10.1038\/srep25672"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/0022-1759(84)90147-9","article-title":"Comparison of in vitro cell cytotoxic assays for tumor necrosis factor","volume":"68","author":"Flick","year":"1984","journal-title":"J. Immunol. Methods"},{"key":"ref_24","first-page":"254","article-title":"A spin decay assay for tumor necrosis factor cytotoxicity","volume":"32","author":"Mishra","year":"1995","journal-title":"Indian J. Biochem. Biophys."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1016\/j.bcp.2012.08.025","article-title":"Japonicone a antagonizes the activity of TNF-\u03b1 by directly targeting this cytokine and selectively disrupting its interaction with TNF receptor-1","volume":"84","author":"Hu","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1093\/intimm\/dxl004","article-title":"c-Fos suppresses systemic inflammatory response to endotoxin","volume":"18","author":"Ray","year":"2006","journal-title":"Int. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1007\/s10620-014-3459-x","article-title":"Accuracy of rapid fecal calprotectin test in monitoring inflammatory bowel diseases under treatment with TNF\u03b1 antagonists","volume":"60","author":"Tursi","year":"2015","journal-title":"Dig. Dis. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"594","DOI":"10.2307\/3283783","article-title":"Immune and inflammatory responses to reproductive tract infection with Tritrichomonas foetus in immunized and control heifers","volume":"82","author":"Anderson","year":"1996","journal-title":"J. Parasitol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1038\/onc.2010.109","article-title":"Inflammatory bowel disease and intestinal cancer: A paradigm of the yin-yang interplay between inflammation and cancer","volume":"29","author":"Danese","year":"2010","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nature04870","article-title":"Nuclear factor-\u03baB in cancer development and progression","volume":"441","author":"Karin","year":"2006","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/1097-0029(20000801)50:3<229::AID-JEMT6>3.0.CO;2-H","article-title":"Anti-TNF therapies in rheumatoid arthritis, Crohn\u2019s disease, sepsis, and myelodysplastic syndromes","volume":"50","author":"Raza","year":"2000","journal-title":"Microsc. Res. Tech."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0749-0704(18)30449-4","article-title":"Role of tumor necrosis factor in sepsis and acute lung injury","volume":"5","author":"Simpson","year":"1989","journal-title":"Crit. Care Clin."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Song, Z., Song, Y., Yin, J., Shen, Y., Yao, C., Sun, Z., Jiang, J., Zhu, D., Zhang, Y., and Shen, Q. (2012). Genetic variation in the TNF gene is associated with susceptibility to severe sepsis, but not with mortality. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046113"},{"key":"ref_34","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"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.jep.2012.07.008","article-title":"Orally administered aqueous extract of Inonotus obliquus ameliorates acute inflammation in dextran sulfate sodium (DSS)-induced colitis in mice","volume":"143","author":"Mishra","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ouyang, N., Zhu, C., Zhou, D., Nie, T., Go, M.F., Richards, R.J., and Rigas, B. (2012). MC-12, an annexin A1-based peptide, is effective in the treatment of experimental colitis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041585"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1538\/expanim.49.9","article-title":"Histological analysis of murine colitis induced by dextran sulfate sodium of different molecular weights","volume":"49","author":"Kitajima","year":"2000","journal-title":"Exp. Anim."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1006\/jsre.2001.6223","article-title":"Role of appendix and spleen in experimental colitis","volume":"101","author":"Krieglstein","year":"2001","journal-title":"J. Surg. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ejphar.2010.06.003","article-title":"Phenyl methimazole suppresses dextran sulfate sodium-induced murine colitis","volume":"643","author":"Benavides","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0014-2999(03)01570-X","article-title":"The adenosine A3 receptor agonist, N6-(3-iodobenzyl)-adenosine-5\u2032-N-methyluronamide, is protective in two murine models of colitis","volume":"466","author":"Mabley","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.toxicon.2012.03.004","article-title":"Local inflammatory events induced by Bothrops atrox snake venom and the release of distinct classes of inflammatory mediators","volume":"60","author":"Moreira","year":"2012","journal-title":"Toxicon"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ruan, Y., Yao, L., Zhang, B., Zhang, S., and Guo, J. (2013). Anti-inflammatory effects of Neurotoxin-Nna, a peptide separated from the venom of Naja naja atra. BMC Complement. Altern. Med., 13.","DOI":"10.1186\/1472-6882-13-86"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.toxicon.2014.08.001","article-title":"Bothrops jararacussu snake venom-induces a local inflammatory response in a prostanoid- and neutrophil-dependent manner","volume":"90","author":"Wanderley","year":"2014","journal-title":"Toxicon"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.toxicon.2004.11.004","article-title":"Inflammatory events induced by Lys-49 and Asp-49 phospholipases A2 isolated from Bothrops asper snake venom: Role of catalytic activity","volume":"45","author":"Zuliani","year":"2005","journal-title":"Toxicon"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/11\/1940\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:27:12Z","timestamp":1760210832000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/11\/1940"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,22]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2016,11]]}},"alternative-id":["ijms17111940"],"URL":"https:\/\/doi.org\/10.3390\/ijms17111940","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,22]]}}}