{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T04:06:02Z","timestamp":1768881962957,"version":"3.49.0"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T00:00:00Z","timestamp":1572825600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T00:00:00Z","timestamp":1572825600000},"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>Venomous snakebites can induce local tissue damage, including necrosis of soft tissues, haemorrhage, blistering and local swelling associated with plasma extravasation, which can lead to lethal complications such as hypovolemic shock. However, the details of the underlying mechanisms remain unknown. In this study, we showed that intradermal treatment of mice with venom rhodocytin from the Malayan viper <jats:italic>Calloselasma rhodostoma<\/jats:italic> induced plasma extravasation, dependent on C-type lectin-like receptor 2 (CLEC-2) on platelets. Rhodocytin-induced plasma extravasation also relied on mast cells and histamine. <jats:italic>In vitro<\/jats:italic> co-culture of rhodocytin-activated platelets with mast cells induced histamine release from mast cells in an ATP\/P2X7-dependent manner. Consistent with this, blockade or deficiency of P2X7 in mast cells suppressed rhodocytin-induced plasma extravasation in the skin. Together, these findings indicate that rhodocytin induces plasma extravasation by triggering platelet activation via CLEC-2, followed by activation of mast cells and histamine release via the ATP\/P2X7 pathway. These results reveal a previously unrecognized mechanism by which snake venom increases vascular permeability via complex venom toxin\u2013mediated interactions between platelets and mast cells.<\/jats:p>","DOI":"10.1038\/s41598-019-52449-2","type":"journal-article","created":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T11:03:13Z","timestamp":1572865393000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Snake venom rhodocytin induces plasma extravasation via toxin-mediated interactions between platelets and mast cells"],"prefix":"10.1038","volume":"9","author":[{"given":"Yuki","family":"Nakamura","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chihiro","family":"Mochizuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayoko","family":"Ishimaru","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Schuichi","family":"Koizumi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9864-8371","authenticated-orcid":false,"given":"Hideyuki","family":"Shinmori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsue","family":"Suzuki-Inoue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuhito","family":"Nakao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,11,4]]},"reference":[{"key":"52449_CR1","unstructured":"World Health Organization. \u201cSnake antivenoms: Fact sheet N\u00b0337\u2033. February 2015. Archived from the original on 18 April 2017. WHO Available at, https:\/\/www.who.int\/en\/news-room\/fact-sheets\/detail\/snakebite-envenoming."},{"key":"52449_CR2","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1056\/NEJMra013477","volume":"347","author":"BS Gold","year":"2002","unstructured":"Gold, B. S., Dart, R. C. & Barish, R. A. Bites of venomous snakes. N Engl J Med 347, 347\u201356, https:\/\/doi.org\/10.1056\/NEJMra013477 (2002).","journal-title":"N Engl J Med"},{"key":"52449_CR3","doi-asserted-by":"publisher","first-page":"17063","DOI":"10.1038\/nrdp.2017.63.","volume":"3","author":"JM Guti\u00e9rrez","year":"2017","unstructured":"Guti\u00e9rrez, J. M. et al. Snakebite envenoming. Nat Rev Dis Primers 3, 17063, https:\/\/doi.org\/10.1038\/nrdp.2017.63. (2017).","journal-title":"Nat Rev Dis Primers"},{"key":"52449_CR4","doi-asserted-by":"publisher","first-page":"3464","DOI":"10.1182\/blood-2009-05-222273","volume":"114","author":"F May","year":"2009","unstructured":"May, F. et al. CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood 114, 3464\u20133472, https:\/\/doi.org\/10.1182\/blood-2009-05-222273 (2009).","journal-title":"Blood"},{"key":"52449_CR5","doi-asserted-by":"publisher","first-page":"380","DOI":"10.3109\/09537104.2011.556274","volume":"22","author":"K Suzuki-Inoue","year":"2011","unstructured":"Suzuki-Inoue, K., Inoue, O. & Ozaki, Y. The novel platelet activation receptor CLEC-2. Platelets 22, 380\u2013384, https:\/\/doi.org\/10.3109\/09537104.2011.556274 (2011).","journal-title":"Platelets"},{"key":"52449_CR6","doi-asserted-by":"publisher","first-page":"665","DOI":"10.3390\/toxins5040665","volume":"5","author":"\u00d8 Bruserud","year":"2013","unstructured":"Bruserud, \u00d8. The snake venom rhodocytin from Calloselasma rhodostoma- a clinically important toxin and a useful experimental tool for studies of C-type lectin-like receptor 2 (CLEC-2). Toxins (Basel) 5, 665\u2013674, https:\/\/doi.org\/10.3390\/toxins5040665 (2013).","journal-title":"Toxins (Basel)"},{"key":"52449_CR7","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1042\/bj3091021","volume":"309","author":"TF Huang","year":"1995","unstructured":"Huang, T. F., Liu, C. Z. & Yang, S. H. Aggretin, a novel platelet-aggregation inducer from snake (Calloselasma rhodostoma) venom, activates phospholipase C by acting as a glycoprotein Ia\/IIa agonist. Biochem J 309, 1021\u20131027, https:\/\/doi.org\/10.1042\/bj3091021 (1995).","journal-title":"Biochem J"},{"key":"52449_CR8","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1006\/bbrc.1998.8516","volume":"245","author":"Y Shin","year":"1998","unstructured":"Shin, Y. & Morita, T. Rhodocytin, a functional novel platelet agonist belonging to the heterodimeric C-type lectin family, induces platelet aggregation independently of glycoprotein Ib. Biochem Biophys Res Commun 245, 741\u2013745, https:\/\/doi.org\/10.1006\/bbrc.1998.8516 (1998).","journal-title":"Biochem Biophys Res Commun"},{"key":"52449_CR9","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.4269\/ajtmh.1986.35.1235","volume":"35","author":"DA Warrell","year":"1986","unstructured":"Warrell, D. A. et al. Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern Thailand: Clinical and laboratory correlations. Am J Trop Med Hyg 35, 1235\u20131247, https:\/\/doi.org\/10.4269\/ajtmh.1986.35.1235 (1986).","journal-title":"Am J Trop Med Hyg"},{"key":"52449_CR10","doi-asserted-by":"publisher","first-page":"579","DOI":"10.4269\/ajtmh.1986.35.579","volume":"35","author":"M Ho","year":"1986","unstructured":"Ho, M. et al. Clinical significance of venom antigen levels in patients envenomed by the Malayan pit viper (Calloselasma rhodostoma). Am J Trop Med Hyg 35, 579\u2013587, https:\/\/doi.org\/10.4269\/ajtmh.1986.35.579 (1986).","journal-title":"Am J Trop Med Hyg"},{"issue":"Suppl 1","key":"52449_CR11","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s12959-016-0099-8","volume":"14","author":"Y Ozaki","year":"2016","unstructured":"Ozaki, Y., Tamura, S. & Suzuki-Inoue, K. New horizon in platelet function: with special reference to a recently-found molecule, CLEC-2. Thromb J 14(Suppl 1), 27, https:\/\/doi.org\/10.1186\/s12959-016-0099-8 (2016).","journal-title":"Thromb J"},{"key":"52449_CR12","doi-asserted-by":"publisher","first-page":"149","DOI":"10.4172\/2332-0877.1000149","volume":"2","author":"Y Ferrer-Acosta","year":"2014","unstructured":"Ferrer-Acosta, Y., Gonz\u00e1lez, M. & Fern\u00e1ndez, M. & Balance, W. A. Emerging Roles for Platelets in Inflammation and Disease. J Infect Dis Ther 2, 149, https:\/\/doi.org\/10.4172\/2332-0877.1000149 (2014).","journal-title":"J Infect Dis Ther"},{"key":"52449_CR13","doi-asserted-by":"publisher","first-page":"24494","DOI":"10.1074\/jbc.M110.130575","volume":"285","author":"K Suzuki-Inoue","year":"2010","unstructured":"Suzuki-Inoue, K. et al. Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic\/neonatal lethality of CLEC-2-deficient mice by blood\/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. J Biol Chem 285, 24494\u201324507, https:\/\/doi.org\/10.1074\/jbc.M110.130575 (2010).","journal-title":"J Biol Chem"},{"key":"52449_CR14","doi-asserted-by":"publisher","first-page":"2328","DOI":"10.1111\/j.1538-7836.2010.04006.x","volume":"8","author":"CE Hughes","year":"2010","unstructured":"Hughes, C. E. et al. CLEC-2 is not required for platelet aggregation at arteriolar shear. J Thromb Haemost 8, 2328\u20132332, https:\/\/doi.org\/10.1111\/j.1538-7836.2010.04006.x (2010).","journal-title":"J Thromb Haemost"},{"key":"52449_CR15","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1055\/s-0037-1604090","volume":"44","author":"K Suzuki-Inoue","year":"2018","unstructured":"Suzuki-Inoue, K. et al. Platelet CLEC-2: Roles Beyond Hemostasis. Semin Thromb Hemost 44, 126\u2013134, https:\/\/doi.org\/10.1055\/s-0037-1604090 (2018).","journal-title":"Semin Thromb Hemost"},{"key":"52449_CR16","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/nature12501","volume":"502","author":"BH Herzog","year":"2013","unstructured":"Herzog, B. H. et al. Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature 502, 105\u2013109, https:\/\/doi.org\/10.1038\/nature12501 (2013).","journal-title":"Nature"},{"key":"52449_CR17","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1172\/JCI65154","volume":"123","author":"Y Boulaftali","year":"2013","unstructured":"Boulaftali, Y. et al. Platelet ITAM signaling is critical for vascular integrity in inflammation. J Clin Invest 123, 908\u2013916, https:\/\/doi.org\/10.1172\/JCI65154 (2013).","journal-title":"J Clin Invest"},{"key":"52449_CR18","doi-asserted-by":"publisher","first-page":"2224","DOI":"10.1182\/blood-2017-03-771907","volume":"130","author":"EJ Haining","year":"2017","unstructured":"Haining, E. J. et al. CLEC-2 contributes to hemostasis independently of classical hemITAM signaling in mice. Blood 130, 2224\u20132228, https:\/\/doi.org\/10.1182\/blood-2017-03-771907 (2017).","journal-title":"Blood"},{"key":"52449_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02402-6","volume":"8","author":"J Rayes","year":"2017","unstructured":"Rayes, J. et al. The podoplanin-CLEC-2 axis inhibits inflammation in sepsis. Nat Commun 8, 2239, https:\/\/doi.org\/10.1038\/s41467-017-02402-6 (2017).","journal-title":"Nat Commun"},{"key":"52449_CR20","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1016\/j.jaci.2013.07.040","volume":"133","author":"Y Nakamura","year":"2014","unstructured":"Nakamura, Y. et al. Circadian regulation of allergic reactions by the mast cell clock in mice. J Allergy Clin Immunol 133, 568\u2013575, https:\/\/doi.org\/10.1016\/j.jaci.2013.07.040 (2014).","journal-title":"J Allergy Clin Immunol"},{"key":"52449_CR21","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1111\/jth.13987","volume":"16","author":"T Sasaki","year":"2018","unstructured":"Sasaki, T. et al. Functional characterization of recombinant snake venom rhodocytin: rhodocytin mutant blocks CLEC-2\/podoplanin- dependent platelet aggregation and lung metastasis. J Thromb Haemost 16, 960\u2013972, https:\/\/doi.org\/10.1111\/jth.13987 (2018).","journal-title":"J Thromb Haemost"},{"key":"52449_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/srep39934","volume":"7","author":"Y Nakamura","year":"2017","unstructured":"Nakamura, Y., Ishimaru, K., Shibata, S. & Nakao, A. Regulation of plasma histamine levels by the mast cell clock and its modulation by stress. Sci Rep 7, 39934, https:\/\/doi.org\/10.1038\/srep39934 (2017).","journal-title":"Sci Rep"},{"key":"52449_CR23","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1110\/ps.035568.108","volume":"17","author":"AA Watson","year":"2008","unstructured":"Watson, A. A., Eble, J. A. & O\u2019Callaghan, C. A. Crystal structure of rhodocytin, a ligand for the platelet-activating receptor CLEC-2. Protein Sci 17, 1611\u20131616, https:\/\/doi.org\/10.1110\/ps.035568.108 (2008).","journal-title":"Protein Sci"},{"key":"52449_CR24","doi-asserted-by":"publisher","first-page":"7831","DOI":"10.1021\/bi800528t","volume":"47","author":"E Hooley","year":"2008","unstructured":"Hooley, E. et al. The crystal structure of the platelet activator aggretin reveals a novel (alphabeta) 2 dimeric structure. Biochemistry 47, 7831\u20137837, https:\/\/doi.org\/10.1021\/bi800528t (2008).","journal-title":"Biochemistry"},{"key":"52449_CR25","first-page":"557","volume":"23","author":"ES Russell","year":"1959","unstructured":"Russell, E. S., Bernstein, S. E., Lawson, F. A. & Smith, L. J. Long-continued function of normal blood-forming tissue transplanted into genetically anemic hosts. J. Natl. Cancer Inst 23, 557\u2013566 (1959).","journal-title":"J. Natl. Cancer Inst"},{"key":"52449_CR26","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1083\/jcb.101.3.880","volume":"101","author":"PE Stenberg","year":"1985","unstructured":"Stenberg, P. E., McEver, R. P., Shuman, M. A., Jacques, Y. V. & Bainton, D. F. A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation. J Cell Biol 101, 880\u2013886, https:\/\/doi.org\/10.1083\/jcb.101.3.880 (1985).","journal-title":"J Cell Biol"},{"key":"52449_CR27","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1182\/blood.V52.2.447.447","volume":"52","author":"Y Kitamura","year":"1978","unstructured":"Kitamura, Y., Go, S. & Hatanaka, K. Decrease of mast cells in W\/Wv mice and their increase by bone marrow transplantation. Blood 52, 447\u2013452 (1978).","journal-title":"Blood"},{"key":"52449_CR28","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1159\/000237312","volume":"110","author":"K Ohmori","year":"1996","unstructured":"Ohmori, K. et al. Effects of KW-4679, a new orally active antiallergic drug, on antigen-induced bronchial hyperresponsiveness, airway inflammation and immediate and late asthmatic responses in guinea pigs. Int Arch Allergy Immunol 110, 64\u201372, https:\/\/doi.org\/10.1159\/000237312 (1996).","journal-title":"Int Arch Allergy Immunol"},{"key":"52449_CR29","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/0162-3109(87)90048-8","volume":"13","author":"J Casals-Stenzel","year":"1987","unstructured":"Casals-Stenzel, J. Effects of WEB 2086, a novel antagonist of platelet activating factor, in active and passive anaphylaxis. Immunopharmacology 13, 117\u2013124 (1987).","journal-title":"Immunopharmacology"},{"key":"52449_CR30","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1242\/jcs.01730","volume":"118","author":"PA Lang","year":"2005","unstructured":"Lang, P. A. et al. Stimulation of erythrocyte ceramide formation by platelet-activating factor. J Cell Sci 118, 1233\u20131243, https:\/\/doi.org\/10.1242\/jcs.01730 (2005).","journal-title":"J Cell Sci"},{"key":"52449_CR31","doi-asserted-by":"publisher","first-page":"531","DOI":"10.4049\/jimmunol.173.1.531","volume":"173","author":"H Matsushima","year":"2004","unstructured":"Matsushima, H., Yamada, N., Matsue, H. & Shimada, S. TLR3-, TLR7-, and TLR9-mediated production of proinflammatory cytokines and chemokines from murine connective tissue type skin-derived mast cells but not from bone marrow-derived mast cells. J Immunol 173, 531\u2013541, https:\/\/doi.org\/10.4049\/jimmunol.173.1.531 (2004).","journal-title":"J Immunol"},{"key":"52449_CR32","doi-asserted-by":"publisher","first-page":"e29925","DOI":"10.1371\/journal.pone.0029925","volume":"7","author":"K Blatt","year":"2012","unstructured":"Blatt, K. et al. The PI3-kinase\/mTOR-targeting drug NVP-BEZ235 inhibits growth and IgE-dependent activation of human mast cells and basophils. PLoS One 7, e29925, https:\/\/doi.org\/10.1371\/journal.pone.0029925 (2012).","journal-title":"PLoS One"},{"key":"52449_CR33","doi-asserted-by":"publisher","first-page":"2214","DOI":"10.1182\/bloodadvances.2018016261","volume":"2","author":"N Tsukiji","year":"2018","unstructured":"Tsukiji, N. et al. Cobalt-hematoporphyrin inhibits CLEC-2\/podoplanin interaction, tumor metastasis, and arterial\/venous thrombosis in mice. Blood Advances 2, 2214\u20132225, https:\/\/doi.org\/10.1182\/bloodadvances.2018016261 (2018).","journal-title":"Blood Advances"},{"key":"52449_CR34","doi-asserted-by":"crossref","unstructured":"Robert, F. Platelet secretion. In: Alan DM, ed. PLATELETS 3rd ed. Amsterdam, NX: Elsevier; 343\u2013366 (2013).","DOI":"10.1016\/B978-0-12-387837-3.00018-3"},{"key":"52449_CR35","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s11302-009-9173-z","volume":"6","author":"E Bulanova","year":"2010","unstructured":"Bulanova, E. & Bulfone-Paus, S. P2 receptor-mediated signaling in mast cell biology. Purinergic Signal 6, 3\u201317, https:\/\/doi.org\/10.1007\/s11302-009-9173-z (2010).","journal-title":"Purinergic Signal"},{"key":"52449_CR36","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1074\/jbc.M006781200","volume":"276","author":"M Solle","year":"2001","unstructured":"Solle, M. et al. Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem 276, 125\u2013132, https:\/\/doi.org\/10.1074\/jbc.M006781200 (2001).","journal-title":"J Biol Chem"},{"key":"52449_CR37","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1111\/cei.13005","volume":"190","author":"NJ Geraghty","year":"2017","unstructured":"Geraghty, N. J. et al. The P2X7 receptor antagonist Brilliant Blue G reduces serum human interferon-\u03b3 in a humanized mouse model of graft-versus-host disease. Clin Exp Immunol 190, 79\u201395, https:\/\/doi.org\/10.1111\/cei.13005 (2017).","journal-title":"Clin Exp Immunol"},{"key":"52449_CR38","doi-asserted-by":"publisher","first-page":"13576","DOI":"10.1074\/jbc.272.21.13576","volume":"272","author":"J Polg\u00e1r","year":"1997","unstructured":"Polg\u00e1r, J. et al. Platelet activation and signal transduction by convulxin, a C-type lectin from Crotalus durissus terrificus (tropical rattlesnake) venom via the p62\/GPVI collagen receptor. J Biol Chem 272, 13576\u201313583, https:\/\/doi.org\/10.1074\/jbc.272.21.13576 (1997).","journal-title":"J Biol Chem"},{"key":"52449_CR39","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1182\/blood.V72.5.1530.1530","volume":"72","author":"A Burt","year":"1988","unstructured":"Burt, A., Alex, R. & Elizabeth, H. Plasminogen interaction with platelets in plasma. Blood 72, 1530\u20131535 (1988).","journal-title":"Blood"},{"key":"52449_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2023","volume":"3","author":"Y Kurashima","year":"2012","unstructured":"Kurashima, Y. et al. Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors. Nat Commun 3, 1034, https:\/\/doi.org\/10.1038\/ncomms2023 (2012).","journal-title":"Nat Commun"},{"key":"52449_CR41","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1016\/j.immuni.2014.01.014","volume":"40","author":"Y Kurashima","year":"2014","unstructured":"Kurashima, Y. et al. The enzyme Cyp26b1 mediates inhibition of mast cell activation by fibroblasts to maintain skin-barrier homeostasis. Immunity 40, 530\u2013541, https:\/\/doi.org\/10.1016\/j.immuni.2014.01.014 (2014).","journal-title":"Immunity"},{"key":"52449_CR42","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.immuni.2015.01.015","volume":"42","author":"SH Tsai","year":"2015","unstructured":"Tsai, S. H. et al. The ectoenzyme E-NPP3 negatively regulates ATP-dependent chronic allergic responses by basophils and mast cells. Immunity 42, 279\u2013293, https:\/\/doi.org\/10.1016\/j.immuni.2015.01.015 (2015).","journal-title":"Immunity"},{"key":"52449_CR43","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1126\/science.1128877","volume":"313","author":"M Metz","year":"2006","unstructured":"Metz, M. et al. Mast cells can enhance resistance to snake and honeybee venoms. Science 313, 526\u2013530, https:\/\/doi.org\/10.1126\/science.1128877 (2006).","journal-title":"Science"},{"key":"52449_CR44","doi-asserted-by":"publisher","first-page":"2629","DOI":"10.1084\/jem.20071262","volume":"204","author":"LA Schneider","year":"2007","unstructured":"Schneider, L. A. et al. Molecular mechanism of mast cell mediated innate defense against endothelin and snake venom sarafotoxin. J Exp Med 204, 2629\u20132639, https:\/\/doi.org\/10.1084\/jem.20071262 (2007).","journal-title":"J Exp Med"},{"key":"52449_CR45","doi-asserted-by":"publisher","first-page":"4180","DOI":"10.1172\/JCI46139","volume":"121","author":"M Akahoshi","year":"2011","unstructured":"Akahoshi, M. et al. Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice. J Clin Invest 121, 4180\u20134191, https:\/\/doi.org\/10.1172\/JCI46139 (2011).","journal-title":"J Clin Invest"},{"key":"52449_CR46","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.coi.2015.07.001","volume":"36","author":"M Tsai","year":"2015","unstructured":"Tsai, M., Starkl, P., Marichal, T. & Galli, S. J. Testing the \u2018toxin hypothesis of allergy\u2019: mast cells, IgE, and innate and acquired immune responses to venoms. Curr Opin Immunol 36, 80\u201387, https:\/\/doi.org\/10.1016\/j.coi.2015.07.001 (2015).","journal-title":"Curr Opin Immunol"},{"key":"52449_CR47","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1016\/j.molimm.2010.05.005","volume":"47","author":"I Willox","year":"2010","unstructured":"Willox, I., Mirkina, I., Westwick, J. & Ward, S. G. Evidence for PI3K-dependent CXCR3 agonist-induced degranulation of human cord blood-derived mast cells. Mol Immunol 47, 2367\u20132377, https:\/\/doi.org\/10.1016\/j.molimm.2010.05.005 (2010).","journal-title":"Mol Immunol"},{"key":"52449_CR48","doi-asserted-by":"publisher","first-page":"2105","DOI":"10.1182\/blood-2003-07-2483","volume":"103","author":"CH Chung","year":"2004","unstructured":"Chung, C. H., Wu, W. B. & Huang, T. F. Aggretin, a snake venom-derived endothelial integrin alpha 2 beta 1 agonist, induces angiogenesis via expression of vascular endothelial growth factor. Blood 103, 2105\u20132013, https:\/\/doi.org\/10.1182\/blood-2003-07-2483 (2004).","journal-title":"Blood"},{"key":"52449_CR49","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.jprot.2016.07.006","volume":"148","author":"EL Tang","year":"2016","unstructured":"Tang, E. L., Tan, C. H., Fung, S. Y. & Tan, N. H. Venomics of Calloselasma rhodostoma, the Malayan pit viper: A complex toxin arsenal unraveled. J Proteomics 148, 44\u201356, https:\/\/doi.org\/10.1016\/j.jprot.2016.07.006 (2016).","journal-title":"J Proteomics"},{"key":"52449_CR50","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1007\/s11302-013-9357-4.","volume":"3","author":"F Jacob","year":"2013","unstructured":"Jacob, F., P\u00e9rez, N. C., Bachert, C. & Van, C. K. Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Shignal 3, 285\u2013306, https:\/\/doi.org\/10.1007\/s11302-013-9357-4 (2013).","journal-title":"Purinergic Shignal"},{"key":"52449_CR51","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.immuni.2017.06.020","volume":"47","author":"DV Francesco","year":"2017","unstructured":"Francesco, D. V., Diego, D. B., Alba, C. S., Anna, L. G. & Simonetta, F. The P2X7 Receptor in Infection and Inflammation. Immunity 47, 15\u201331, https:\/\/doi.org\/10.1016\/j.immuni.2017.06.020 (2017).","journal-title":"Immunity"},{"key":"52449_CR52","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1111\/jth.13604","volume":"15","author":"T Shirai","year":"2017","unstructured":"Shirai, T. et al. C-type lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice. J Thromb Haemost 15, 513\u2013525, https:\/\/doi.org\/10.1111\/jth.13604 (2017).","journal-title":"J Thromb Haemost"},{"key":"52449_CR53","doi-asserted-by":"publisher","first-page":"2520","DOI":"10.1182\/blood.V96.7.2520","volume":"96","author":"B Nieswandt","year":"2000","unstructured":"Nieswandt, B., Bergmeier, W., Rackebrandt, K., Gessner, J. E. & Zirngibl, H. Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice. Blood 96, 2520\u20132527 (2000).","journal-title":"Blood"},{"key":"52449_CR54","doi-asserted-by":"publisher","first-page":"1974","DOI":"10.1271\/bbb.69.1974","volume":"69","author":"T Tokura","year":"2005","unstructured":"Tokura, T. et al. Inhibitory effect of polyphenol-enriched apple extracts on mast cell degranulation in vitro targeting the binding between IgE and FcepsilonRI. Biosci Biotechnol Biochem 69, 1974\u20131977, https:\/\/doi.org\/10.1271\/bbb.69.1974 (2005).","journal-title":"Biosci Biotechnol Biochem"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52449-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52449-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52449-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T15:20:33Z","timestamp":1671290433000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52449-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,4]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["52449"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-52449-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,4]]},"assertion":[{"value":"14 August 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15958"}}