title: Protective effects of batimastat against hemorrhagic injuries in delayed jellyfish envenomation syndrome models.
abstract: Previously, we established delayed jellyfish envenomation syndrome (DJES) models and proposed that the hemorrhagic toxins in jellyfish tentacle extracts (TE) play a significant role in the liver and kidney injuries of the experimental model. Further, we also demonstrated that metalloproteinases are the central toxic components of the jellyfish Cyanea capillata (C. capillata), which may be responsible for the hemorrhagic effects. Thus, metalloproteinase inhibitors appear to be a promising therapeutic alternative for the treatment of hemorrhagic injuries in DJES. In this study, we examined the metalloproteinase activity of TE from the jellyfish C. capillata using zymography analyses. Our results confirmed that TE possessed a metalloproteinase activity, which was also sensitive to heat. Then, we tested the effect of metalloproteinase inhibitor batimastat (BB-94) on TE-induced hemorrhagic injuries in DJES models. Firstly, using SR-based X-ray microangiography, we found that BB-94 significantly improved TE-induced hepatic and renal microvasculature alterations in DJES mouse model. Secondly, under synchrotron radiation micro-computed tomography (SR-μCT), we also confirmed that BB-94 reduced TE-induced hepatic and renal microvasculature changes in DJES rat model. In addition, being consistent with the imaging results, histopathological and terminal deoxynucleotidyl transferase-mediated UTP end labeling (TUNEL)-like staining observations also clearly corroborated this hypothesis, as BB-94 was highly effective in neutralizing TE-induced extensive hemorrhage and necrosis in DJES rat model. Although it may require further clinical studies in the near future, the current study opens up the possibilities for the use of the metalloproteinase inhibitor, BB-94, in the treatment of multiple organ hemorrhagic injuries in DJES.
authors.affiliation: Marine Bio-pharmaceutical Institute, Second Military Medical University, Shanghai 200433, China; Department of Marine Biotechnology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China.
authors.forename: Beilei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Marine Bio-pharmaceutical Institute, Second Military Medical University, Shanghai 200433, China; Department of Marine Biotechnology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Marine Bio-pharmaceutical Institute, Second Military Medical University, Shanghai 200433, China; Department of Marine Biotechnology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China.
authors.forename: Guoyan
authors.initials: G
authors.lastname: Liu
authors.affiliation: The Third Cadet Battalion of Naval Medicine Department, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Marine Bio-pharmaceutical Institute, Second Military Medical University, Shanghai 200433, China; Department of Marine Biotechnology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Marine Bio-pharmaceutical Institute, Second Military Medical University, Shanghai 200433, China; Department of Marine Biotechnology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China.
authors.forename: Jiemin
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Marine Bio-pharmaceutical Institute, Second Military Medical University, Shanghai 200433, China; Department of Marine Biotechnology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Gynecology, Third Affiliated Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: heqian@smmu.edu.cn.
authors.forename: Qian
authors.initials: Q
authors.lastname: He
authors.affiliation: Marine Bio-pharmaceutical Institute, Second Military Medical University, Shanghai 200433, China; Department of Marine Biotechnology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China. Electronic address: lmzhang@smmu.edu.cn.
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000792:Angiography; D000818:Animals; D001733:Bites and Stings / Q000188:drug therapy*; D003064:Cnidarian Venoms / Q000633:toxicity*; D006470:Hemorrhage / Q000517:prevention & control*; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity; D051379:Mice; D009336:Necrosis / Q000517:prevention & control; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020011:Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D037401:Scyphozoa; D013577:Syndrome; D013876:Thiophenes / Q000627:therapeutic use*; D055114:X-Ray Microtomography
chemical_list: D003064:Cnidarian Venoms; D020011:Protective Agents; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D045726:Metalloproteases
keywords: Batimastat; Cyanea capillata; Delayed jellyfish envenomation syndrome; Jellyfish; Metalloproteinase