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Cephalochordata (“lancelets”) Urochordata (“tunicates) Agnatha (jawless fish, e.g. lampreys) Placodermi (“jawfish”) -EXTINCT Chondrichthyes (sharks and rays) Osteichthyes (“bony fish”) Amphibia Reptilia Aves (birds) Mammalia Phylum Chordata Vertebrates
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Cephalochordata (“lancelets”) Urochordata (“tunicates) Agnatha (jawless fish, e.g. lampreys) Placodermi (“jawfish”) -EXTINCT Chondrichthyes (sharks and rays) Osteichthyes (“bony fish”) Amphibia Reptilia Aves (birds) Mammalia Phylum Chordata Vertebrates
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Marine Mammals
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Marine Fish Class Chondrichthyes (“cartilaginous fish”) Class Osteichthyes (“bony fish”)
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Fugu spp. (“Pufferfish”) …and others. Tetrodotoxin (TTX) Bioactive Compounds from Osteichthyes: Tetrodotoxin
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Voltage-Gated Sodium Channels + + - - - - - - - - + + + + Na + K+K+ Voltage-Gated Ion Channels
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- 70 0 - 50 + 50 Action Potential Resting Potential Threshold Membrane Potential (mV) Time (milliseconds) Action Potential Depolarizing Phase Repolarizing Phase
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- - - ++ -- - - - - + + + + Na + K+K+ Action Potential Voltage-Gated Sodium Channels
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TTX Inhibits Depolarization (Action Potential) in Neurons Cell-Specific TTX
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TTX Binds and Blocks Voltage-Gated Sodium Channels
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Bioactive Compounds from Chondrichthyes Other Myths/Misconceptions? “Sharks Don’t Have Immune Systems, But Don’t Get Infections”
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“Dietary Supplements” from Sharks
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Shark Oil or “Snake Oil?”
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Shark Liver Oil Ingredients 71.9% Petrolatum 14% Mineral Oil 3% Shark Liver Oil 0.25% Phenylephrine HCl
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Squalus acanthias (“Dogfish Shark”) Stomach Tissue (400 g) Extract: 60% CH 3 CN/1% TFA Extract Lipids: “Folch Method” 2:1 CHCl 3 /MeOH, Salt Wash Aqueous Phase Gel Filtration (Bio-Gel P-30) C18 HPLC SCX HPLC (Ion Exchange) C4 HPLC FAB-MS, 1 H- and 13 C-NMR, 2-D NMR (NOESY, HMQC) Bioactive Compounds from Chondrichthyes: Squalamine Moore et al. (1993) Proc. Natl. Acad. Sci., 90: 1354-8.
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Squalamine MW 628.4739
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Condensation of Squalene and Spermidine Spermidine Squalene
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Amount Tissue(µg/g tissue) Stomach1 Liver4-7 Gallbladder4-7 Spleen2 Testes2 Gills0.5 Intestine0.02 Tissue Distribution of Squalamine
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Squalamine Inhibits Na+/H+ Exchanger (NHEs) Brush Border Cells
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Squalamine Inhibits Na+/H+ Exchanger (NHEs) PS120 Fibroblasts (No NHE) NHE1, 2 and 3 cDNA (Transformed) 40 mM NH4Cl for 2- 10 min.; Perfuse with Medium (Acidification) 2’, 7’-bis(2-carboxyethyl)- 5(6)-carboxyfluorescein (BCECF)-AM (Intracellular pH Indicator) Akhter et al. (1999) Am. J. Physiol., 276: 136-44.
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Squalamine Inhibits H+ Efflux in NHE3-Transformed Cells Akhter et al. (1999) Am. J. Physiol., 276: 136-44.
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Squalamine Inhibition is Dose- Dependent Akhter et al. (1999) Am. J. Physiol., 276: 136-44.
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Squalamine Does NOT Inhibit H+ Efflux in NHE1- or NHE2- Transformed Cells Akhter et al. (1999) Am. J. Physiol., 276: 136-44.
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Squalamine Inhibition of NHE3- Transformed Cells Requires –COOH Terminal (76 Amino Acids) Akhter et al. (1999) Am. J. Physiol., 276: 136-44.
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Squalamine Inhibits Na+/H+ Exchange in Rabbit Illeal Brush Border Vesicles Akhter et al. (1999) Am. J. Physiol., 276: 136-44. 22 Na + Uptake
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Squalamine Inhibits Tumor Angiogenesis
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Tumors Recruit Vascular Endothelial Cells in Angiogenesis
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Vascular Endothelial Growth Factor (VEGF) Stimulates Vessel Formation
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VEGF Acts Via Mitogen-Associated Protein Kinase (MAPK)
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MAPK Phosphorylation is pH Dependent Stathopoulou et al. (2006) J. Exp. Biol., 209: 1344-54.
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Squalamine Inhibits VEGF-Induced Phosphorylation of MAPK
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Squalamine Inhibition of NHE3- Transformed Cells Requires –COOH Terminal (76 Amino Acids)
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Pre-Clinical Trials with Squalamine Phase I/IIa Clinical Trials with Squalamine Xenograft Mice: Lung, Breast, Ovarian and Prostate Cancer Allograft Rats: Brain and Breast Cancer Inhibit Tumor Growth and Angiogenesis Lung and Ovarian Cancer MTD = 384 mg/m2/day; 120-h Continuous Infusion Co-Administration with Other Drugs
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Control Cisplatin + Squalamine Cisplatin + Squalamine Schiller and Bittner (1999) Clin. Cancer Res., 5: 4287-94 Co-Administration of Squalamine
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Squalamine and Macular Degeneration Squalamine Lactate (MSI-1256F) EVIZON™ (Genaera® Pharmaceuticals)
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