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Angel A. Yanagihara, Ph.D.

Associate Researcher, PBRC
Director, Pacific Cnidaria Research Lab

Education

Research Interests

The overall objective of our research program is the systematic biochemical and pathophysiological characterization of novel toxins and bioactive compounds from venomous marine invertebrates of regional importance.

Advances in the field of natural toxin and bioactive compound identification from venomous animals by researchers worldwide typically involve a combined iterative strategy of biochemical separation and bioactivity assay. Over the past 7 years, we have utilized an array of biochemical, physiological, morphological, and molecular biological approaches to elucidate the biochemical properties and the mechanisms of action of venom constituents, which initiate the pathophysiological responses observed in human envenomation by the Hawaiian box jellyfish, Carybdea alata. This systems-based research effort involves a classic array of conventional and sophisticated research tools including density-gradient separations, high pressure liquid chromatography using normal-phase, reverse-phase and specialized resins, Fourier transform infrared spectrometry, enzyme assays, tissue culture assays (96-well plate chemotaxis and calcium flux) cardiac doppler recording, and scanning and transmission electron microscopy. Successful isolation and characterization of a profoundly hemolytic protein from Carybdea alata by our laboratory demonstrates the success of such a strategy. The target of the current research program is the identification and characterization of neuroactive compounds from this potent paralytic venom such as identifying the constituent(s) eliciting crayfish nerve cord block and heart-rate effects in crude venom and hydrophobic extracts. Further bioassays to continue to characterize these bioactive lipids are now being developed. After successful purification of bioactive fractions, various bioassay and electrophysiological techniques (in collaboration) will be used to carefully elucidate the mechanism of action. Parallel mass spectrometry (MS) studies have led to the molecular identification of several bioactive lipid compounds.

The systematic biochemical characterization of this cnidarian venom has resulted in unanticipated discoveries as well. For instance, initial work to optimize the recovery of nematocyst venom for biochemical characterization led to the discovery of a novel and unprecedented structure, the lancet, which underscores the highly specialized nature of cubozoans as compared to other cnidarian species. Similarly, while characterizing phospholipase proteins, a family of novel fluorophores was identified (which prompt questions about the absorbance properties of visual pigments of invertebrate and/or fish prey) and may potentially indicate a new photic lure predation strategy.

Selected Publications

Yanagihara, A.A., Wilcox, C., Smith, J., Surrett, G.W. Cubozoan envenomations: Clinical features, pathophysiology and management. In: Goffredo, S., Dubinsky, Z., editors, The Cnidaria, Past, Present and Future. The world of Medusa and her sisters. ISBN 978-3-319-31305-4, 1st ed. Springer International Publisher Switzerland 2016: pp. 637-652.

Yanagihara, A.A., Wilcox, C., King, R., Hurwitz, K., Castelfranco, A.M. Experimental assays to assess the efficacy of vinegar and other topical first-aid approaches on cubozoan (Alatina alata) tentacle firing and venom toxicity. Toxins (Basel) 2016;8(1). pii: E19. doi: 10.3390/toxins8010019. PMCID: PMC4728541

Yanagihara, A.A., Shohet, R.V. Cubozoan venom-induced acute cardiovascular collapse is caused by hyperkalemia and prevented by zinc gluconate. PLoS One. 2012;7(12):e51368. doi: 10.1371/journal.pone.0051368. Epub 2012 Dec 12. PMCID: PMC3520902

Wilcox CL, Headlam JL, Doyle, TK, Yanagihara AA, Assessing the Efficacy of First-Aid Measures in Physalia sp. Envenomation, Using Solution- and Blood Agarose-Based Models, Toxins, 01 April 2017, Vol.9(5), p.149

 Yanagihara AA, Wilcox CL, Cubozoan Sting-Site Seawater Rinse, Scraping, and Ice Can Increase Venom Load: Upending Current First Aid Recommendations Toxins 2017, 9(3), 105; doi: 10.3390/toxins9030105

 Wilcox, C.L., Yanagihara, A.A. Heated debates: hot-water immersion or ice packs as first aid for cnidarian envenomations? Toxins (Basel). 2016 Apr 1;8(4):97. doi: 10.3390/toxins8040097 PMCID: PMC4848624

 Doyle TK, Headlam JL, Wilcox CL, Macloughlin E, Yanagihara AA, Evaluation of Cyanea capillata Sting Management Protocols Using Ex Vivo and In Vitro Envenomation Models, Toxins, 01 July 2017, Vol.9(7), p.215

Jouiaei, M., Yanagihara, A.A., Madio, B., Nevalainen, T.J., Alewood, P.F., Fry, B.G. Ancient venom systems: A review on cnidaria toxins. Toxins (Basel) 2015;7(6):2251-2271. PMCID: PMC4488701

Yanagihara, A.A., Chen, J.J. The effect of vinegar on discharged nematocysts of Chironex fleckeri. Diving Hyperbaric Medicine 2014;44(3):172.

Chiaverano, L.M., Holland, B.S., Crow, G.L., Blair, L., Yanagihara, A.A. Long-term fluctuations in circalunar Beach aggregations of the box jellyfish Alatina moseri in Hawaii, with links to environmental variability. PLoS One. 2013 Oct 23;8(10):e77039. doi: 10.1371/journal.pone.0077039. eCollection 2013. PMCID: PMC3806728

Lee, A, Yanagihara, A.A. Insights into the Mechanistic Basis of the Irukandji Syndrome by evaluating the Hematologic and Immunologic Responses in Whole Blood 2011, http://hdl.handle.net/10125/29642

Tibballs, J., Yanagihara, A.A., Turner, H., Winkel, K. Immunological and toxicological responses to jellyfish stings. Inflammation and Allergy Drug Targets. 2011 Oct 1;10(5):438-446. PMCID: PMC3773479

Bentlage, B., Cartwright, P., Yanagihara, A.A., Lewis, C., Richards, G.S., Collins, A.G. Evolution of box jellyfishes (Cnidaria: Cubozoa), a group of highly toxic invertebrates. Proceedings of the Royal Society B: Biological Sciences 2010;277:493-501. PMCID: PMC2842657

Yanagihara, A.A., Kuroiwa, J.M.Y., Oliver, L., Kunkel, D.D. The ultrastructure of nematocysts from the fishing tentacle of the Hawaiian bluebottle, Physalia utriculus (Cnidaria, Hydrozoa, Siphonophora). Hydrobiologia 2002;489:139-150.

Yanagihara, A.A., Kuroiwa, J.M.Y., Kunkel, D.D. Ultrastructural characterization of nematocysts from the Hawaiian box jellyfish (Carybdea alata). Cell and Tissue Research 2002;308:307-318.

Yoshimoto, C.M., Yanagihara, A.A. Cnidarian (coelenterate) envenomations in Hawai’i improve following heat application. Transactions of the Royal Society for Tropical Medicine and Hygiene 2002;96: 300-303.

Chung, J.J., Ratnapala, L.A., Cooke, I.M., Yanagihara, A.A. Partial purification and characterization of a hemolysin (CAH1) from Hawaiian box jellyfish (Carybdea alata) venom. Toxicon 2001;39:981-990.

Contact Info

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(808) 956-8328 (ph)
(808) 956-6984(fax)
1993 East-West Road, Biomed A-204
Honolulu, HI 96822

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