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Cephalochordata (“lancelets”)

Phylum Chordata. Cephalochordata (“lancelets”). Urochordata (“tunicates). Agnatha (jawless fish, e.g. lampreys). Placodermi (“jawfish”) -EXTINCT. Chondrichthyes (sharks and rays). Osteichthyes (“bony fish”). Amphibia. Vertebrates. Reptilia. Aves (birds). Mammalia. Phylum Chordata.

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Cephalochordata (“lancelets”)

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  1. Phylum Chordata Cephalochordata (“lancelets”) Urochordata (“tunicates) Agnatha (jawless fish, e.g. lampreys) Placodermi (“jawfish”) -EXTINCT Chondrichthyes (sharks and rays) Osteichthyes (“bony fish”) Amphibia Vertebrates Reptilia Aves (birds) Mammalia

  2. Phylum Chordata Cephalochordata (“lancelets”) Urochordata (“tunicates) Agnatha (jawless fish, e.g. lampreys) Placodermi (“jawfish”) -EXTINCT Chondrichthyes (sharks and rays) Osteichthyes (“bony fish”) Amphibia Vertebrates Reptilia Aves (birds) Mammalia

  3. Marine Mammals

  4. Marine Fish Class Chondrichthyes (“cartilaginous fish”) Class Osteichthyes (“bony fish”)

  5. Bioactive Compounds from Osteichthyes: Tetrodotoxin Fugu spp. (“Pufferfish”) …and others. Tetrodotoxin (TTX)

  6. Voltage-Gated Sodium Channels + + + + + + + + + + - - - - - - - - Voltage-Gated Ion Channels K+ Na+

  7. Action Potential Action Potential + 50 Depolarizing Phase 0 Repolarizing Phase Membrane Potential (mV) - 50 Threshold Resting Potential - 70 Time (milliseconds)

  8. Voltage-Gated Sodium Channels + + + + + + + + - - - ++ -- - - - - Action Potential K+ Na+

  9. TTX Inhibits Depolarization (Action Potential) in Neurons TTX Cell-Specific

  10. TTX Binds and Blocks Voltage-Gated Sodium Channels

  11. Bioactive Compounds from Chondrichthyes Other Myths/Misconceptions? “Sharks Don’t Have Immune Systems, But Don’t Get Infections”

  12. “Dietary Supplements” from Sharks

  13. Shark Oil or “Snake Oil?”

  14. Shark Liver Oil Ingredients 71.9% Petrolatum 14% Mineral Oil 3% Shark Liver Oil 0.25% Phenylephrine HCl

  15. Bioactive Compounds from Chondrichthyes: Squalamine Stomach Tissue (400 g) Squalus acanthias (“Dogfish Shark”) Extract: 60% CH3CN/1% TFA Extract Lipids: “Folch Method” 2:1 CHCl3/MeOH, Salt Wash Aqueous Phase Gel Filtration (Bio-Gel P-30) C18 HPLC SCX HPLC (Ion Exchange) C4 HPLC FAB-MS, 1H- and 13C-NMR, 2-D NMR (NOESY, HMQC) Moore et al. (1993) Proc. Natl. Acad. Sci., 90: 1354-8.

  16. Squalamine MW 628.4739 Moore et al. (1993) Proc. Natl. Acad. Sci., 90: 1354-8.

  17. Condensation of Squalene and Spermidine Spermidine Squalene

  18. Tissue Distribution of Squalamine Amount Tissue (µg/g tissue) Stomach 1 Liver 4-7 Gallbladder 4-7 Spleen 2 Testes 2 Gills 0.5 Intestine 0.02

  19. Squalamine Inhibits Na+/H+ Exchanger (NHEs) Brush Border Cells

  20. 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) Squalamine Inhibits Na+/H+ Exchanger (NHEs) PS120 Fibroblasts (No NHE) Akhter et al. (1999) Am. J. Physiol., 276: 136-44.

  21. Squalamine Inhibits H+ Efflux in NHE3-Transformed Cells Akhter et al. (1999) Am. J. Physiol., 276: 136-44.

  22. Squalamine Inhibition is Dose-Dependent Akhter et al. (1999) Am. J. Physiol., 276: 136-44.

  23. Squalamine Does NOT Inhibit H+ Efflux in NHE1- or NHE2-Transformed Cells Akhter et al. (1999) Am. J. Physiol., 276: 136-44.

  24. Squalamine Inhibition of NHE3-Transformed Cells Requires –COOH Terminal (76 Amino Acids) Akhter et al. (1999) Am. J. Physiol., 276: 136-44.

  25. Squalamine Inhibits Na+/H+ Exchange in Rabbit Illeal Brush Border Vesicles 22Na+ Uptake Akhter et al. (1999) Am. J. Physiol., 276: 136-44.

  26. Squalamine Inhibits Tumor Angiogenesis

  27. Tumors Recruit Vascular Endothelial Cells in Angiogenesis

  28. Vascular Endothelial Growth Factor (VEGF) Stimulates Vessel Formation

  29. VEGF Acts Via Mitogen-Associated Protein Kinase (MAPK)

  30. MAPK Phosphorylation is pH Dependent Stathopoulou et al. (2006) J. Exp. Biol., 209: 1344-54.

  31. Squalamine Inhibits VEGF-Induced Phosphorylation of MAPK

  32. Squalamine Inhibition of NHE3-Transformed Cells Requires –COOH Terminal (76 Amino Acids)

  33. Pre-Clinical Trials with Squalamine Xenograft Mice: Lung, Breast, Ovarian and Prostate Cancer Allograft Rats: Brain and Breast Cancer Inhibit Tumor Growth and Angiogenesis Phase I/IIa Clinical Trials with Squalamine Lung and Ovarian Cancer MTD = 384 mg/m2/day; 120-h Continuous Infusion Co-Administration with Other Drugs

  34. Co-Administration of Squalamine Control Cisplatin + Squalamine Cisplatin + Squalamine Schiller and Bittner (1999) Clin. Cancer Res., 5: 4287-94

  35. Squalamine and Macular Degeneration Squalamine Lactate (MSI-1256F) EVIZON™ (Genaera® Pharmaceuticals)

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