{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:32:55Z","timestamp":1788975175519,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T00:00:00Z","timestamp":1627257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Acute kidney injury (AKI) following Eastern Russell\u2019s viper (Daboia siamensis) envenoming is a significant symptom in systemically envenomed victims. A number of venom components have been identified as causing the nephrotoxicity which leads to AKI. However, the precise mechanism of nephrotoxicity caused by these toxins is still unclear. In the present study, we purified two proteins from D. siamensis venom, namely RvPLA2 and RvMP. Protein identification using LCMS\/MS confirmed the identity of RvPLA2 to be snake venom phospholipase A2 (SVPLA2) from Thai D. siamensis venom, whereas RvMP exhibited the presence of a factor X activator with two subunits. In vitro and in vivo pharmacological studies demonstrated myotoxicity and histopathological changes of kidney, heart, and spleen. RvPLA2 (3\u201310 \u00b5g\/mL) caused inhibition of direct twitches of the chick biventer cervicis muscle preparation. After administration of RvPLA2 or RvMP (300 \u00b5g\/kg, i.p.) for 24 h, diffuse glomerular congestion and tubular injury with minor loss of brush border were detected in envenomed mice. RvPLA2 and RvMP (300 \u00b5g\/kg; i.p.) also induced congestion and tissue inflammation of heart muscle as well as diffuse congestion of mouse spleen. This study showed the significant roles of PLA2 and SVMP in snake bite envenoming caused by Thai D. siamensis and their similarities with observed clinical manifestations in envenomed victims. This study also indicated that there is a need to reevaluate the current treatment strategies for Thai D. siamensis envenoming, given the potential for irreversible nephrotoxicity.<\/jats:p>","DOI":"10.3390\/toxins13080521","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T09:25:52Z","timestamp":1627291552000},"page":"521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A Biochemical and Pharmacological Characterization of Phospholipase A2 and Metalloproteinase Fractions from Eastern Russell\u2019s Viper (Daboia siamensis) Venom: Two Major Components Associated with Acute Kidney Injury"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2367-8792","authenticated-orcid":false,"given":"Janeyuth","family":"Chaisakul","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Phramongkutklao College of Medicine, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orawan","family":"Khow","sequence":"additional","affiliation":[{"name":"Queen Saovabha Memorial Institute, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kulachet","family":"Wiwatwarayos","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Ministry of Public Health, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhamad Rusdi Ahmad","family":"Rusmili","sequence":"additional","affiliation":[{"name":"Kulliyyah of Pharmacy, International Islamic University Malaysia, Bandar Indera Mahkota, Kuantan 25200, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Watcharamon","family":"Prasert","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Phramongkutklao College of Medicine, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9225-3678","authenticated-orcid":false,"given":"Iekhsan","family":"Othman","sequence":"additional","affiliation":[{"name":"Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 46150, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8249-7668","authenticated-orcid":false,"given":"Syafiq Asnawi Zainal","family":"Abidin","sequence":"additional","affiliation":[{"name":"Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 46150, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mongkon","family":"Charoenpitakchai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Phramongkutklao College of Medicine, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9919-0144","authenticated-orcid":false,"given":"Wayne C.","family":"Hodgson","sequence":"additional","affiliation":[{"name":"Monash Venom Group, Department of Pharmacology, Biomedical Discovery Institute, Monash University, Clayton, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2425-5000","authenticated-orcid":false,"given":"Lawan","family":"Chanhome","sequence":"additional","affiliation":[{"name":"Queen Saovabha Memorial Institute, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3207-0885","authenticated-orcid":false,"given":"Narongsak","family":"Chaiyabutr","sequence":"additional","affiliation":[{"name":"Queen Saovabha Memorial Institute, Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,26]]},"reference":[{"key":"ref_1","unstructured":"WHO (2016). Venomous snakes of the South-East Asia Region, their venoms and pathophysiology of human envenoming. Guidelines for the Management of Snake-Bites, WHO. [2nd ed.]."},{"key":"ref_2","first-page":"33","article-title":"The genus Daboia (Serpentes: Viperidae): Russell\u2019s viper","volume":"23","author":"Wuster","year":"1998","journal-title":"Hamadryad"},{"key":"ref_3","unstructured":"O\u2019 Shea, M. (2011). Venomous Snake of the World, Princeton University Press."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.trstmh.2005.07.020","article-title":"Antivenom treatment and renal dysfunction in Russell\u2019s viper snakebite in Taiwan: A case series","volume":"100","author":"Hung","year":"2006","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/S0140-6736(85)91550-8","article-title":"Bites by Russell\u2019s viper (Vipera russelli siamensis) in Burma: Haemostatic, vascular, and renal disturbances and response to treatment","volume":"2","author":"Myint","year":"1985","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/j.1440-1797.2006.00599.x","article-title":"Snakebite nephropathy","volume":"11","author":"Sitprija","year":"2006","journal-title":"Nephrology"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Maduwage, K., and Isbister, G.K. (2014). Current treatment for venom-induced consumption coagulopathy resulting from snakebite. PLoS Negl. Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0003220"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Silva, A., Samarasinghe, R., Pilapitiya, S., Dahanayake, N., and Siribaddana, S. (2014). Viper bites complicate chronic agrochemical nephropathy in rural Sri Lanka. J. Venom. Anim. Toxins Incl. Trop. Dis., 20.","DOI":"10.1186\/1678-9199-20-33"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Su, H.Y., Huang, S.W., Mao, Y.C., Liu, M.W., Lee, K.H., Lai, P.F., and Tsai, M.J. (2018). Clinical and laboratory features distinguishing between Deinagkistrodon acutus and Daboia siamensis envenomation. J. Venom. Anim. Toxins Incl. Trop. Dis., 24.","DOI":"10.1186\/s40409-018-0179-2"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1016\/j.ekir.2019.05.017","article-title":"Acute Kidney Injury Following Eastern Russell\u2019s Viper (Daboia siamensis) Snakebite in Myanmar","volume":"4","author":"Alfred","year":"2019","journal-title":"Kidney Int. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kularatne, S.A., Silva, A., Weerakoon, K., Maduwage, K., Walathara, C., Paranagama, R., and Mendis, S. (2014). Revisiting Russell\u2019s viper (Daboia russelii) bite in Sri Lanka: Is abdominal pain an early feature of systemic envenoming?. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090198"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s12640-016-9650-4","article-title":"Neurotoxicity in Sri Lankan Russell\u2019s Viper (Daboia russelii) Envenoming is Primarily due to U1-viperitoxin-Dr1a, a Pre-Synaptic Neurotoxin","volume":"31","author":"Silva","year":"2017","journal-title":"Neurotox. Res."},{"key":"ref_13","first-page":"691","article-title":"Paralysis, rhabdomyolysis and haemolysis caused by bites of Russell\u2019s viper (Vipera russelli pulchella) in Sri Lanka: Failure of Indian (Haffkine) antivenom","volume":"68","author":"Phillips","year":"1988","journal-title":"Q. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8545","DOI":"10.1038\/s41598-018-25955-y","article-title":"Venom proteomics and antivenom neutralization for the Chinese eastern Russell\u2019s viper, Daboia siamensis from Guangxi and Taiwan","volume":"8","author":"Tan","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.toxicon.2013.10.001","article-title":"Mechanism of in vivo anticoagulant and haemolytic activity by a neutral phospholipase A(2) purified from Daboia russelii russelii venom: Correlation with clinical manifestations in Russell\u2019s Viper envenomed patients","volume":"76","author":"Saikia","year":"2013","journal-title":"Toxicon"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1023\/A:1016591318855","article-title":"Purification and characterization of a potent hemolytic toxin with phospholipase A2 activity from the venom of Indian Russell\u2019s viper","volume":"237","author":"Chakraborty","year":"2002","journal-title":"Mol. Cell Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.jprot.2009.01.006","article-title":"Snake venomics of the Siamese Russell\u2019s viper (Daboia russelli siamensis)\u2014Relation to pharmacological activities","volume":"72","author":"Risch","year":"2009","journal-title":"J. Proteom."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.toxicon.2012.10.017","article-title":"Effects of phospholipase A2 and metalloprotease fractions of Russell\u2019s viper venom on cytokines and renal hemodynamics in dogs","volume":"61","author":"Mitrmoonpitak","year":"2013","journal-title":"Toxicon"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1016\/j.biochi.2008.05.012","article-title":"P-III hemorrhagic metalloproteinases from Russell\u2019s viper venom: Cloning, characterization, phylogenetic and functional site analyses","volume":"90","author":"Chen","year":"2008","journal-title":"Biochimie"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Silva, A., Johnston, C., Kuruppu, S., Kneisz, D., Maduwage, K., Kleifeld, O., Smith, A.I., Siribaddana, S., Buckley, N.A., and Hodgson, W.C. (2016). Clinical and Pharmacological Investigation of Myotoxicity in Sri Lankan Russell\u2019s Viper (Daboia russelii) Envenoming. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0005172"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chaiyabutr, N., Chanhome, L., Vasaruchapong, T., Laoungbua, P., Khow, O., Rungsipipat, A., and Sitprija, V. (2020). The pathophysiological effects of Russell\u2019s viper (Daboia siamensis) venom and its fractions in the isolated perfused rabbit kidney model: A potential role for platelet activating factor. Toxicon X, 7.","DOI":"10.1016\/j.toxcx.2020.100046"},{"key":"ref_22","first-page":"42","article-title":"Purification of a phospholipase A(2) from Daboia russelii siamensis venom with anticancer effects","volume":"2","author":"Khunsap","year":"2011","journal-title":"J. Venom Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/j.bbapap.2007.04.012","article-title":"Venom phospholipases of Russell\u2019s vipers from Myanmar and eastern India--cloning, characterization and phylogeographic analysis","volume":"1774","author":"Tsai","year":"2007","journal-title":"Biochim. Biophys."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1111\/j.1742-4658.2008.06466.x","article-title":"Insights into and speculations about snake venom metalloproteinase (SVMP) synthesis, folding and disulfide bond formation and their contribution to venom complexity","volume":"275","author":"Fox","year":"2008","journal-title":"FEBS J."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bernardoni, J.L., Sousa, L.F., Wermelinger, L.S., Lopes, A.S., Prezoto, B.C., Serrano, S.M., Zingali, R.B., and Moura-da-Silva, A.M. (2014). Functional variability of snake venom metalloproteinases: Adaptive advantages in targeting different prey and implications for human envenomation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109651"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10644","DOI":"10.1016\/S0021-9258(17)34108-X","article-title":"Factor X-activating glycoprotein of Russell\u2019s viper venom. Polypeptide composition and characterization of the carbohydrate moieties","volume":"269","author":"Gowda","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chaisakul, J., Alsolaiss, J., Charoenpitakchai, M., Wiwatwarayos, K., Sookprasert, N., Harrison, R.A., Chaiyabutr, N., Chanhome, L., Tan, C.H., and Casewell, N.R. (2019). Evaluation of the geographical utility of Eastern Russell\u2019s viper (Daboia siamensis) antivenom from Thailand and an assessment of its protective effects against venom-induced nephrotoxicity. PLoS Negl. Trop. Dis., 13.","DOI":"10.1101\/591305"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Charoenpitakchai, M., Wiwatwarayos, K., Jaisupa, N., Rusmili, M.R.A., Mangmool, S., Hodgson, W.C., Ruangpratheep, C., Chanhome, L., and Chaisakul, J. (2018). Non-neurotoxic activity of Malayan krait (Bungarus candidus) venom from Thailand. J. Venom. Anim. Toxins Incl. Trop. Dis., 24.","DOI":"10.1186\/s40409-018-0146-y"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1093\/oxfordjournals.jbchem.a003164","article-title":"Platelet-activating factor receptor","volume":"131","author":"Honda","year":"2002","journal-title":"J. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.ekir.2019.03.014","article-title":"Snake Envenoming horizontal line An Underreported Cause of Acute Kidney Injury","volume":"4","author":"Gopalakrishnan","year":"2019","journal-title":"Kidney Int. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.toxicon.2012.06.012","article-title":"Renal effects and injury induced by animal toxins","volume":"60","author":"Sitprija","year":"2012","journal-title":"Toxicon"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/ki.1989.70","article-title":"Snake-bite-induced acute renal failure in India","volume":"35","author":"Chugh","year":"1989","journal-title":"Kidney Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1093\/ckj\/sfx121","article-title":"Clinical profile and outcome of pigment-induced nephropathy","volume":"11","author":"Sakthirajan","year":"2018","journal-title":"Clin. Kidney J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.toxicon.2010.06.026","article-title":"Hyponatraemia, rhabdomyolysis, alterations in blood pressure and persistent mydriasis in patients envenomed by Malayan kraits (Bungarus candidus) in southern Viet Nam","volume":"56","author":"Trinh","year":"2010","journal-title":"Toxicon"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"604","DOI":"10.3109\/15563650.2014.914526","article-title":"Pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis (mulga snake) in the anesthetised rat","volume":"52","author":"Hart","year":"2014","journal-title":"Clin. Toxicol"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/0041-0101(89)90039-1","article-title":"A new muscle damaging toxin, myotoxin II, from the venom of the snake Bothrops asper (terciopelo)","volume":"27","author":"Lomonte","year":"1989","journal-title":"Toxicon"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/0041-0101(94)90078-7","article-title":"Screening of snake venoms for neurotoxic and myotoxic effects using simple in vitro preparations from rodents and chicks","volume":"32","author":"Harvey","year":"1994","journal-title":"Toxicon"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Chaisakul, J., Rusmili, M.R.A., Alsolaiss, J., Albulescu, L.O., Harrison, R.A., Othman, I., and Casewell, N.R. (2020). In Vitro Immunological Cross-Reactivity of Thai Polyvalent and Monovalent Antivenoms with Asian Viper Venoms. Toxins, 12.","DOI":"10.3390\/toxins12120766"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Silva, A., Pilapitiya, S., and Siribaddana, S. (2012). Acute myocardial infarction following a possible direct intravenous bite of Russell\u2019s viper (Daboia russelli). BMC Res. Notes, 5.","DOI":"10.1186\/1756-0500-5-500"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1186\/s13256-017-1484-z","article-title":"Acute myocardial infarction associated with thrombotic microangiopathy following a hump-nosed viper bite: A case report","volume":"11","author":"Gooneratne","year":"2017","journal-title":"J. Med. Case Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/0041-0101(96)00057-8","article-title":"An aqueous endpoint assay of snake venom phospholipase A2","volume":"34","author":"Holzer","year":"1996","journal-title":"Toxicon"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1085\/jgp.22.1.79","article-title":"The Estimation of Pepsin, Trypsin, Papain, and Cathepsin with Hemoglobin","volume":"22","author":"Anson","year":"1938","journal-title":"J. Gen. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of structural proteins during the assembly of the head of bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/13\/8\/521\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:35:06Z","timestamp":1760164506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/13\/8\/521"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,26]]},"references-count":43,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["toxins13080521"],"URL":"https:\/\/doi.org\/10.3390\/toxins13080521","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,26]]}}}