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Presented By: Chantele Casimir Seminar 475 Oct. 31, 2003

Paradoxical Protective Effect of Aminoguanidine toward Low-Density Lipoprotein Oxidation: Inhibition of Apolipoprotein B Fragmentation without Preventing It’s Carbonylation. Mechanism of Action of Aminoguanidine. Presented By: Chantele Casimir Seminar 475 Oct. 31, 2003

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Presented By: Chantele Casimir Seminar 475 Oct. 31, 2003

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  1. Paradoxical Protective Effect of Aminoguanidine toward Low-Density Lipoprotein Oxidation: Inhibition of Apolipoprotein B Fragmentation without Preventing It’s Carbonylation. Mechanism of Action of Aminoguanidine Presented By: Chantele Casimir Seminar 475 Oct. 31, 2003 Bonnefont-Rousselot, D., C. Cosson, M. Couturier, M.Gardes-Albert, I. Jedidi, D. Jore, A. Legrand, C. Massot, P. Therond, and S. Zarev. 2003. Paradoxical Protective Effect of Aminoguanidine toward Low-Density Lipoprotein Oxidation: Inhibition of Apolipoprotein B Fragmentation without Preventing Its Carbonylation. Mechanism of Action of Aminoguanidine. Biochemistry 42: 11356-11365.

  2. Background Information on both Aminoguanidine and Low-Density Lipoproteins.

  3. What are Low Density Lipoproteins?

  4. Low-Density Lipoproteins (LDL) • The major cholesterol carrier in the blood • Composed of phospholipids, triglyceride, apolipoprotein B-100 (apoB), cholesterol ester and free cholesterol.

  5. Phospholipids • Any of various phosphorous containing lipids • Composed mainly of fatty acids, a phosphate group and a simple organic molecule.

  6. Hydrophobic tails-water fearing tails. • Hydrophilic heads-water-loving heads.

  7. Triglyceride • Naturally occurring ester • Contains three fatty acids • Contains Glycerol (chief constituent of fats and oil)

  8. Triglyceride • Carboxyl group ends of three fatty acid molecules • Contains one molecule of glycerol

  9. Apolipoprotein B-100 (apoB) • Plays essential role in lipoprotein metabolism • Involved in clearance of LDL particles from the blood stream • Functions as membrane stabilizer

  10. Cholesterol Ester • Fatty acid esters of cholesterol • Constitute about 2/3 of cholesterol in plasma • Intima (inner lining) of the artery • May become feature of atherosclerosis

  11. Free Cholesterol • Derived from normal tornover of cell • Membrane is transported by High-Density Lipoproteins (HDL) into the plasma

  12. LDL • Carries cholesterol towards the walls for the arteries • An abundance results in plaque • Ultimately clogs arteries • Atherosclerosis forms

  13. What is Aminoguanidine?

  14. Aminoguanidine (AMG) • Inhibitor of Advanced glycation end product (anti-aging therapy) • Reduces bad form of Cholesterol know as LDL in humans. • Has the potential to slow the aging process by protecting the proteins that make up the human body. Ex: proteins of the skin, eye lens, nerve and kidney.

  15. Paradoxical Protective Effect of Aminoguanidine toward Low-Density Lipoprotein Oxidation: Inhibition of Apolipoprotein B Fragmentation without Preventing Its Carbonylation. Mechanism of Action of Aminoguanidine

  16. Overall Rationale • The simultaneous assessment of the oxidation of LDL lipid and protein moieties in order to characterize the molecular sites of AMG protection.

  17. AMG resulted in a protection of LDL’s against lipid peroxidation and against apoB fragmentation in a concentration-dependent manner. • Due to the scavenging effect of AMG toward lipid peroxyl radicals. • AMG-poorly efficient against apoB carbonylation

  18. Most Important Observation • AMG inhibited LDL hydroperoxide formation • AMG did not protect against apoB carbonylation

  19. Independent vs. Dependent Variable • Conjugated Diene Measurement (CD) total hydroperoxide formation was described as a function of the radiation doses in the presence or absence of AMG at .2, .5 and 1 mM concentrations

  20. Phosphatidylcholines (PCOOH) total hydroperoxide formation was described as a function of the radiation doses in the presence or absence of AMG at .2, .5, and 1mM concentrations.

  21. Cholesteryl Esters (CEOOH) total hydroperoxide formation was described as a function of the radiation doses in the presence or absence of AMG at .2, .5, 1mm concentrations

  22. AMG acted at two phases: • Lag phase-results from the presence of endogenous antioxidants. • Propagation phase- results from lipid peroxyl radical formation (LOO*) • AMG was able to extend the lag phase in a concentration-dependent manner.

  23. AMG was able to inhibit the propagation stages for both PCOOH and CEOOH • When AMG was not present, the progpagation phase for CD began around 80 Gy (gray). • When AMG was introduced into the samples in a concentration dependent manner, the propagation phase of CD formation happened at a noticeable amount of Gy’s later. (130, 200, & 300 Gy).

  24. continued • When AMG was not present there was an increase of PCOOH and CEOOH formation. • In the PCOOH graph, the cause for the observable degradation was due to secondary attacks by free radicals on PCOOH. • When AMG was present, hydroperoxide formation was inhibited in a concentration dependent manner.

  25. Independent vs. Dependent Variable • Figure 3 further explains that CD and hydroperoxide formation inversely correlates with AMG concentrations. • CD, PCOOH, and CEOOH formation are shown as a function of AMG concentrations.

  26. CD formation • Shows the yield of CD formation decreased by the presence of AMG.

  27. PCOOH formation • Shows the yield of PCOOH formation decreased by the presence of AMG

  28. CEOOH formation • Shows the yield of CEOOH formation decreased by the presence of AMG.

  29. AMG Does Not Prevent LDL Apo B Carbonylation • No matter the radiation dose • No matter the AMG concentration • Due to the hydroxyl radicals that would react with LDL’s by initiation protein oxidation. • Would create carbonylation of apo-B whatever the AMG concentration.

  30. continued • Due to weak reactivity of OH free radicals toward the AMG molecule.

  31. AMG Inhibits apoB Fragmentation • When AMG is not present, fragmentationn was detected just after the propagation phase and increase as the radiation dose increased. • With AMG present, carbonylated apoB fragments appeared but from radiation dose 204 with .2 and 300 with .5 and mM.

  32. continued • This shows that until 150 Gy the presence of AMG apoB fragmentation is inhibited. • Due to scavenging lipid-derived peroxyl radicals.

  33. Conclusion • AMG is proven to protect LDL’s against peroxidation and apoB fragmentation but it does not protect apoB carbonylation. This information is very important because this proves that AMG is effective as being age defying. It reduces the aging process in humans and it proves to do the same for this experiment.

  34. References • Bonnefont-Rousselot, D., C. Cosson, M. Couturier, M.Gardes-Albert, I. Jedidi, D. Jore, A. Legrand, C. Massot, P. Therond, and S. Zarev. 2003. Paradoxical Protective Effect of Aminoguanidine toward Low-Density Lipoprotein Oxidation: Inhibition of Apolipoprotein B Fragmentation without Preventing Its Carbonylation. Mechanism of Action of Aminoguanidine. Biochemistry 42: 11356-11365 • www.biocarta.com/pathfiles/h_LDLpathway.asp • www.books.md/C/dic/cholesterolesters.php • www.chandlerssoaps.com/chemistry-of-soap.html • www.cwru.edu/artsci/chem/faculty/salomon/CardiovascularDisease.htm • www.place.dawsoncollege.qc.ca/~rhanna/Membrane.htm

  35. Are There Any Questions? Thank You For Your Time!!!

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