Micronutrient Research for Optimum Health:13 Years and Counting as Primus Inter Pares of the Linus Pauling Institute<br />...
The Evolution of LPI at OSUFrom ½ PI in 1996 to 12 PIs and 4 RAPs today<br />Number of PIs and RAPs<br />
Orthomolecular MedicineThe right molecule at the right concentration<br />“Orthomolecular medicine is the preservation of ...
The LINUS PAULING INSTITUTEOregon State University<br />MISSION<br /><ul><li>Determine the function and role of vitamins a...
Determine the role of oxidative stress and inflammation in human health and disease, and the protective effects of dietary...
Why micronutrients, diet, and lifestyle matterNATURE VS. NURTURE (Darwin and Lamarck) <br /><ul><li>Because they are major...
A person’s genetic makeup (family history, “polymorphisms” = GENETICS) determines his/her predisposition to disease, but w...
Comparative Epigenetic Mechanisms of Cancer Chemoprevention (P01CA90890, Dashwood)<br />
Percentage of major chronic diseases in U.S. that is <br />potentially preventable by diet and lifestyle modifications<br ...
Danaei et al., 2009; 6(4):e1000058<br />
ATHEROSCLEROSIS<br /><ul><li>Hardening, loss of elasticity, and thickening of arterial walls with narrowing of the lumen o...
Principal cause of myocardial infarction and stroke.
Almost 1 million Americans die of cardiovascular diseases (CVD) every year (34% of all deaths; No. 1 killer every year sin...
The cost of CVD in the U.S. is estimated by AHA to be more than $500 billion in 2010 (including health care expenditures a...
Oxidative modification hypothesis of atherosclerosis<br />Diaz, Frei et al.New Engl. J. Med. 1997;337:408-416<br />
Mechanisms of antioxidant action in atherosclerosis<br />Cell-specific antioxidant action<br />Diaz, Frei et al.New Engl. ...
<ul><li>“LDL-Specific” Antioxidant Action: Antioxidant protection of LDL against oxidative modification in plasma and the ...
“Cell-Specific” Antioxidant Action:Antioxidant protection of vascular cells against “dysfunction,” including decreased syn...
Enzymatic: Superoxide Dismutases, Catalase, GSH Peroxidases, Peroxiredoxins: mainly intracellular</li></ul>Small Molecule ...
How effectively do the endogenous antioxidants in human plasma (vitamin C, uric acid, bilirubin) and LDL (vitamin E) preve...
AAPH-induced Lipid Peroxidation<br />AAPH<br />2,2’-Azobis(2-Amidino)Propane Hydrochloride<br />37ºC, pH 7.4<br />Generati...
Frei B, Stocker R, Ames BN. Proc Natl Acad Sci USA. 1988;85:9748-52.<br />
Total Citations: 819 (#2)<br />
Frei B, England L, Ames BN. Proc Natl Acad Sci USA. 1989;86:6377-81.<br />
Total Citations: 1,128 (#1)<br />
Vitamin C effectively inhibits lipid peroxidation in human plasma and/or isolated LDL induced by:<br /><ul><li>Aqueous per...
The gas-phase of cigarette smokeFrei et al., Biochem J 1991
Activated polymorphonuclear leukocytesFrei et al., PNAS 1988, Stocker et al., PNAS 1991
HOCl and MPO/H2O2/Cl- +/- NO2-(apoB modification) Carr et al., Biochem J 2000; Carr and Frei, J BiolChem 2001
Human aortic endothelial cellsMartin and Frei, ATVB 1997
Superoxide radicals and hydrogen peroxide (X/XO system)Frei et al., Adv Exp Med Biol1990
CopperRetskyet al., J BiolChem 1993, BiochimBiophysActa1995, Suhet al., FRBM 2003
IronBerger et al., J BiolChem 1997, Suhet al., FRBM 2003</li></li></ul><li>     16 papers, 1999-2002<br />Total Citations:...
Does vitamin C act as an antioxidant in humans?<br />
F2-Isoprostane Formation from Arachidonic Acid<br />Morrow et al. (1995) New Engl. J. Med. 332, 1198<br />
Total Citations: 817 (#3)<br />
CE-OOH<br />F2-Isoprostanes<br />b-Carotene, Lycopene<br />a-Tocopherol<br />Ubiquinol-10<br />PL-OOH<br />
Elevated 8-iso-PGF2a Levels in:<br /><ul><li>Cigarette smokers
Human atherosclerotic lesions
Diabetics
Hypercholesterolemics
Alzheimer’s disease patients
Alcoholics/patients with liver cirrhosis
Obese subjects
During vascular reperfusion
Etc.</li></li></ul><li>Vitamin C (but not vitamin E) supplementation lowers urinary F2-isoprostane levels in smokers<br />...
Vitamin C and E supplementation prevents the increase in plasma F2-isoprostanes following a 50-km ultramarathon<br />Suppl...
<ul><li>“LDL-Specific” Antioxidant Action: Antioxidant protection of LDL against oxidative modification in plasma and the ...
“Cell-Specific” Antioxidant Action:Antioxidant protection of vascular cells against “dysfunction,” including decreased syn...
L-Arginine<br />L-Citrulline<br />cGMP<br />[Ca2+i]<br /> NADPH<br />  O2   BH4<br />NO•<br />NO Synthase<br />+<br />AK...
<ul><li> Rate Constant = 1.9 x 1010 M-1  s-1
 Nitric oxide combines readily with superoxide</li></ul>Beckman et al. PNAS 1990<br />Kissner et al. Chem. Res. Toxicol. 1...
<ul><li> Rate Constant = 1.9 x 1010 M-1  s-1
 Nitric oxide combines readily with superoxide</li></ul>Beckman et al. PNAS 1990<br />Kissner et al. Chem. Res. Toxicol. 1...
Total Citations: 378 (#7)<br />Levine, Frei, et al. Circulation 1996;93:1107-1113<br />
Brachial Endothelial Dysfunction Independently Predicts Long-Term CVD Events<br /><ul><li>199 PAD patients undergoing vasc...
34 CVD events (death, MI, stroke, unstable angina)
Baseline endothelial dysfunction (FMD) independently predicts CVD events
Odds Ratio 9.3 (2.2 – 39) P<0.001, adjusting for other risk factors</li></ul>Gokce et al. J Am CollCardiol2003; 41:1769<br />
Vitamin C Lowers Blood Pressure in Patients with Essential Hypertension<br /><ul><li>39 patients with hypertension,   age ...
Randomized, double-blind, placebo controlled study
Visit One: blood pressure measured at baseline and 2 hours after 2 grams of ascorbic acid
Visit Two: blood pressure measured after 30 days of 500 mg/day of ascorbic acid</li></ul>Duffy et al.Lancet 1999;354:2048-...
Plasma Vitamin C correlates with Unstable Coronary Syndrome (Angina Class) in CAD Patients (n = 149)<br />	               ...
Working ModelVitamin CO2l- + NOl___//ONOO- <br />NOl(k2 = 1.9 x 1010 M-1 s-1)<br />(~ 0.1 µM)<br />O2l-<br />Ascorbic Ac...
Oxidation, Enzyme<br />Turnover<br />O<br />O<br />H<br />OH<br />OH<br />N<br />N<br />HN<br />N<br />OH<br />OH<br />Asc...
<ul><li>“LDL-Specific” Antioxidant Action: Antioxidant protection of LDL against oxidative modification in plasma and the ...
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  1. 1. Micronutrient Research for Optimum Health:13 Years and Counting as Primus Inter Pares of the Linus Pauling Institute<br />Balz Frei, Ph.D.<br />Director and Endowed Chair<br />Linus Pauling Institute<br />Oregon State University<br />Corvallis, OR 97331<br />
  2. 2. The Evolution of LPI at OSUFrom ½ PI in 1996 to 12 PIs and 4 RAPs today<br />Number of PIs and RAPs<br />
  3. 3. Orthomolecular MedicineThe right molecule at the right concentration<br />“Orthomolecular medicine is the preservation of good health and the treatment of disease by varying the concentrations in the human body of substances that are normally present in the body and required for health.”<br />Linus Pauling (1986) “How to Live Longer and Feel Better”<br />
  4. 4.
  5. 5. The LINUS PAULING INSTITUTEOregon State University<br />MISSION<br /><ul><li>Determine the function and role of vitamins and essential minerals (micronutrients) and chemicals from plants (phytochemicals) in promoting optimum health and preventing or treating disease.
  6. 6. Determine the role of oxidative stress and inflammation in human health and disease, and the protective effects of dietary factors with antioxidant or anti-inflammatory properties.</li></li></ul><li>The LINUS PAULING INSTITUTEOregon State University<br />MISSION (continued)<br /><ul><li>Help people everywhere achieve a healthy and productive life, full of vitality, without suffering, and free of cancer and other debilitating diseases.</li></li></ul><li>Cancer Chemo- Protection<br />Cardiovascular & Metabolic Disease Prevention<br />Healthy Aging Program<br />LPI Research Priorities<br />Cell Signaling, <br />Growth, and <br />Apoptosis <br />Immune Function, Inflammation, and<br />Anti-inflammatories<br />Micronutrients, Diet, and Lifestyle<br />Oxidative Stress and Antioxidants<br />
  7. 7. Why micronutrients, diet, and lifestyle matterNATURE VS. NURTURE (Darwin and Lamarck) <br /><ul><li>Because they are major determinants of chronic disease risk and how well we age.
  8. 8. A person’s genetic makeup (family history, “polymorphisms” = GENETICS) determines his/her predisposition to disease, but whether and when this predisposition is being expressed as disease is largely determined by diet, lifestyle, and micronutrients, i.e.,gene-diet interactions(EPI-GENETICS).</li></li></ul><li>“At its most basic, epigenetics is the study of changes in gene activity [caused by environmental factors like diet, stress and prenatal nutrition] that do not involve alterations to the genetic code but still get passed down to at least one successive generation.”<br />
  9. 9. Comparative Epigenetic Mechanisms of Cancer Chemoprevention (P01CA90890, Dashwood)<br />
  10. 10. Percentage of major chronic diseases in U.S. that is <br />potentially preventable by diet and lifestyle modifications<br />Lung cancer: 90% caused by smoking<br />Willett, WC. Science 2002; 296, 695-698<br />
  11. 11.
  12. 12. Danaei et al., 2009; 6(4):e1000058<br />
  13. 13. ATHEROSCLEROSIS<br /><ul><li>Hardening, loss of elasticity, and thickening of arterial walls with narrowing of the lumen of the artery.
  14. 14. Principal cause of myocardial infarction and stroke.
  15. 15. Almost 1 million Americans die of cardiovascular diseases (CVD) every year (34% of all deaths; No. 1 killer every year since 1900, save 1918).
  16. 16. The cost of CVD in the U.S. is estimated by AHA to be more than $500 billion in 2010 (including health care expenditures and lost productivity from deaths and disability). </li></li></ul><li>
  17. 17.
  18. 18.
  19. 19. Oxidative modification hypothesis of atherosclerosis<br />Diaz, Frei et al.New Engl. J. Med. 1997;337:408-416<br />
  20. 20. Mechanisms of antioxidant action in atherosclerosis<br />Cell-specific antioxidant action<br />Diaz, Frei et al.New Engl. J. Med. 1997;337:408-416<br />Total Citations: 774 (#5)<br />
  21. 21. <ul><li>“LDL-Specific” Antioxidant Action: Antioxidant protection of LDL against oxidative modification in plasma and the vascular wall
  22. 22. “Cell-Specific” Antioxidant Action:Antioxidant protection of vascular cells against “dysfunction,” including decreased synthesis of endothelium-derived relaxing factor (EDRF, nitric oxide) and increased expression of inflammatory molecules</li></li></ul><li>ANTIOXIDANT DEFENSES IN HUMAN PLASMA AND LDL<br />Antioxidant Proteins<br /><ul><li>Non-Enzymatic: Fe- and Cu-Binding Proteins (Albumin, Transferrin, Ceruloplasmin?, etc.)
  23. 23. Enzymatic: Superoxide Dismutases, Catalase, GSH Peroxidases, Peroxiredoxins: mainly intracellular</li></ul>Small Molecule Antioxidants Typical Plasma Concentrations <br /><ul><li>Water-Soluble: µM</li></ul> Uric Acid 300 <br /> Ascorbic Acid (Vitamin C) 50 <br /> Albumin-Bound Bilirubin 15 <br /> Glutathione (GSH) < 2 <br /><ul><li>Lipid-Soluble (Lipoprotein-Associated): mol/mol LDL</li></ul>a-Tocopherol (Vitamin E) 25 10<br /> Ubiquinol-10 (Coenzyme Q10) 1.0 0.4<br />b-Carotene (Pro-Vitamin A) 0.5 0.2<br />Lycopene 0.5 0.2<br />
  24. 24. How effectively do the endogenous antioxidants in human plasma (vitamin C, uric acid, bilirubin) and LDL (vitamin E) prevent lipid peroxidation and oxidative (atherogenic) modification of LDL?<br />
  25. 25. AAPH-induced Lipid Peroxidation<br />AAPH<br />2,2’-Azobis(2-Amidino)Propane Hydrochloride<br />37ºC, pH 7.4<br />Generation of peroxyl radicals<br />k2= 109 M-1 s-1<br />•<br />Initiation<br />•<br />•<br />Lipid peroxidation<br />•<br />•<br />Propagation<br />•<br />•<br />
  26. 26. Frei B, Stocker R, Ames BN. Proc Natl Acad Sci USA. 1988;85:9748-52.<br />
  27. 27. Total Citations: 819 (#2)<br />
  28. 28. Frei B, England L, Ames BN. Proc Natl Acad Sci USA. 1989;86:6377-81.<br />
  29. 29.
  30. 30. Total Citations: 1,128 (#1)<br />
  31. 31. Vitamin C effectively inhibits lipid peroxidation in human plasma and/or isolated LDL induced by:<br /><ul><li>Aqueous peroxyl radicals (AAPH)Frei et al., PNAS 1988, 1989; Polidoriet al., Arch BiochemBiophys 2004
  32. 32. The gas-phase of cigarette smokeFrei et al., Biochem J 1991
  33. 33. Activated polymorphonuclear leukocytesFrei et al., PNAS 1988, Stocker et al., PNAS 1991
  34. 34. HOCl and MPO/H2O2/Cl- +/- NO2-(apoB modification) Carr et al., Biochem J 2000; Carr and Frei, J BiolChem 2001
  35. 35. Human aortic endothelial cellsMartin and Frei, ATVB 1997
  36. 36. Superoxide radicals and hydrogen peroxide (X/XO system)Frei et al., Adv Exp Med Biol1990
  37. 37. CopperRetskyet al., J BiolChem 1993, BiochimBiophysActa1995, Suhet al., FRBM 2003
  38. 38. IronBerger et al., J BiolChem 1997, Suhet al., FRBM 2003</li></li></ul><li> 16 papers, 1999-2002<br />Total Citations: 256 (#11)<br />NO!<br />
  39. 39. Does vitamin C act as an antioxidant in humans?<br />
  40. 40. F2-Isoprostane Formation from Arachidonic Acid<br />Morrow et al. (1995) New Engl. J. Med. 332, 1198<br />
  41. 41. Total Citations: 817 (#3)<br />
  42. 42.
  43. 43. CE-OOH<br />F2-Isoprostanes<br />b-Carotene, Lycopene<br />a-Tocopherol<br />Ubiquinol-10<br />PL-OOH<br />
  44. 44. Elevated 8-iso-PGF2a Levels in:<br /><ul><li>Cigarette smokers
  45. 45. Human atherosclerotic lesions
  46. 46. Diabetics
  47. 47. Hypercholesterolemics
  48. 48. Alzheimer’s disease patients
  49. 49. Alcoholics/patients with liver cirrhosis
  50. 50. Obese subjects
  51. 51. During vascular reperfusion
  52. 52. Etc.</li></li></ul><li>Vitamin C (but not vitamin E) supplementation lowers urinary F2-isoprostane levels in smokers<br />Supplementation with 2 g/d of vitamin C <br />and/or 800 IU/d of vitamin E for 5 days<br />n = 4-7 heavy smokers/group<br />*<br />*<br />Reilly et al. (1996) Circulation 94, 19-25<br />
  53. 53. Vitamin C and E supplementation prevents the increase in plasma F2-isoprostanes following a 50-km ultramarathon<br />Supplementation with 300 mg RRR-α-tocopheryl acetate and 1000 mg vitamin C daily for 21 days<br />Mastaloudis et al. (2004) Free Radic Biol Med. 36:1329-41.<br />
  54. 54. <ul><li>“LDL-Specific” Antioxidant Action: Antioxidant protection of LDL against oxidative modification in plasma and the vascular wall
  55. 55. “Cell-Specific” Antioxidant Action:Antioxidant protection of vascular cells against “dysfunction,” including decreased synthesis of endothelium-derived relaxing factor (EDRF, nitric oxide) and increased expression of inflammatory molecules</li></li></ul><li>The Endothelium and Vascular Homeostasis<br />Vasodilation<br />Platelet<br />Inhibition<br />Anti-inflammatory<br />NO<br />Inhibition of <br />Smooth Muscle Cell<br />Proliferation<br />Angiogenesis<br />Vascular<br />Compliance<br />
  56. 56. L-Arginine<br />L-Citrulline<br />cGMP<br />[Ca2+i]<br /> NADPH<br /> O2 BH4<br />NO•<br />NO Synthase<br />+<br />AKT<br />Platelet<br />[Ca2+i]<br />Endothelial Cell<br />Guanylyl Cyclase<br /> Shear stress<br />Thrombin<br />Acetylcholine<br />GTP<br />cGMP<br />Vasodilation<br />Smooth Muscle Cell<br /> Synthesis and Action of EDRF/EDNO<br />
  57. 57. <ul><li> Rate Constant = 1.9 x 1010 M-1  s-1
  58. 58. Nitric oxide combines readily with superoxide</li></ul>Beckman et al. PNAS 1990<br />Kissner et al. Chem. Res. Toxicol. 1997<br />Superoxide Inactivates Nitric Oxide<br />O2l-+ NOl ONOO-<br />
  59. 59. <ul><li> Rate Constant = 1.9 x 1010 M-1  s-1
  60. 60. Nitric oxide combines readily with superoxide</li></ul>Beckman et al. PNAS 1990<br />Kissner et al. Chem. Res. Toxicol. 1997<br />Superoxide Inactivates Nitric Oxide<br />O2l-+ NOl //ONOO-<br />Vitamin C<br />
  61. 61. Total Citations: 378 (#7)<br />Levine, Frei, et al. Circulation 1996;93:1107-1113<br />
  62. 62. Brachial Endothelial Dysfunction Independently Predicts Long-Term CVD Events<br /><ul><li>199 PAD patients undergoing vascular surgery
  63. 63. 34 CVD events (death, MI, stroke, unstable angina)
  64. 64. Baseline endothelial dysfunction (FMD) independently predicts CVD events
  65. 65. Odds Ratio 9.3 (2.2 – 39) P<0.001, adjusting for other risk factors</li></ul>Gokce et al. J Am CollCardiol2003; 41:1769<br />
  66. 66. Vitamin C Lowers Blood Pressure in Patients with Essential Hypertension<br /><ul><li>39 patients with hypertension, age 49±13 years
  67. 67. Randomized, double-blind, placebo controlled study
  68. 68. Visit One: blood pressure measured at baseline and 2 hours after 2 grams of ascorbic acid
  69. 69. Visit Two: blood pressure measured after 30 days of 500 mg/day of ascorbic acid</li></ul>Duffy et al.Lancet 1999;354:2048-2049 <br />
  70. 70. Plasma Vitamin C correlates with Unstable Coronary Syndrome (Angina Class) in CAD Patients (n = 149)<br /> Angina Class (1-4)<br />Antioxidant Marker (Plasma) R P<br />a-Tocopherol -.06 .68 <br />a-Tocopherol (LDL) -.18 .27 <br />g-Tocopherol -.08 .56<br />b-Carotene .07 .66<br />Lycopene -.01 .95<br />Retinol -.15 .36<br />Ascorbic Acid -.43 .001<br />Uric Acid .20 .12 <br />Thiols -.19 .15 <br />Ceruloplasmin .00 .97<br />Superoxide Dismutase (RBCs) -.08 .64<br />Lag Phase (LDL Diene Conjugation) -.13 .43 <br />F2-Isoprostanes .02 .87 <br />Vita et al. (1998) J. Am. Coll. Cardiol. 31, 980-986<br />
  71. 71. Working ModelVitamin CO2l- + NOl___//ONOO- <br />NOl(k2 = 1.9 x 1010 M-1 s-1)<br />(~ 0.1 µM)<br />O2l-<br />Ascorbic Acid <br />(k2 = 2 x 105 M-1 s-1)<br />(~ 0.1 µM x 105 = 10 mM)<br />
  72. 72. Oxidation, Enzyme<br />Turnover<br />O<br />O<br />H<br />OH<br />OH<br />N<br />N<br />HN<br />N<br />OH<br />OH<br />Ascorbate<br />H2N<br />H2N<br />N<br />N<br />N<br />N<br />H<br />H<br />Tetrahydrobiopterin<br />(BH4)<br />Quinoid dihydrobiopterin<br />(QBH2)<br /> Mechanism of Ascorbate Action<br />
  73. 73. <ul><li>“LDL-Specific” Antioxidant Action: Antioxidant protection of LDL against oxidative modification in plasma and the vascular wall
  74. 74. “Cell-Specific” Antioxidant Action:Antioxidant protection of vascular cells against “dysfunction,” including decreased synthesis of endothelium-derived relaxing factor (EDRF, nitric oxide) and increased expression of inflammatory molecules</li></li></ul><li>
  75. 75.  <br /> <br />  <br /> <br /> <br />  <br /> <br /> <br /> CVD is an inflammatory disease<br />Relative Risk of Cardiovascular Events among Apparently Healthy Postmenopausal Women According to Base-Line Levels of Total Cholesterol and Markers of Inflammation. Each marker of inflammation improved risk-prediction models based on lipid testing alone, an effect that was strongest for hs-CRP and serum amyloid A.<br />Ridker et al. (2000) N Engl J Med 342:836–843<br />
  76. 76. The serum concentration of circulating VCAM-1 correlates with angiographically determined athero-sclerotic area in 52 patients with peripheralarterial vascular disease. The solid line represents the regression line (r=0.8, P<.001); the dotted lines represent the 95% confidence interval. Peter, K. et al., Arteriosclerosis, Thrombosis, and Vascular Biology 1997;17:505-512<br />
  77. 77. Role of endothelial adhesion molecules and MCP-1 in arterial <br /> monocyte/macrophage recruitment and atherosclerosis<br />Monocyte<br />adherence to<br />endothelium<br />ICAM-1<br />E-selectin<br />Libby (2002) Nature 420:868-874<br />
  78. 78. NF-kB as an inflammatory regulator<br />(NOX)<br />IkB kinase<br />IkB<br />P<br />UbUbUbUb<br />IkB<br />Barnes & Karin, NEJM, 1997, 336, 1066<br />
  79. 79. a-Lipoic Acid<br />+2H+, +2e-<br />-2H+, -2e-<br />Dihydrolipoic Acid<br />Lipoic Acid<br />Eo=-320 mV<br /><ul><li>Synthesized in the body and obtained from the diet (high abundance in green leafy and cruciferous vegetables).
  80. 80. Essential cofactor for mitochondrial -ketodehydrogenases.
  81. 81. In doses achievable by supplementation, can act as an antioxidant by:
  82. 82. Upregulating GSH synthesis by Nrf2/ARE-dependent mechanism (g-GCL)
  83. 83. Scavenging reactive oxygen species
  84. 84. Chelating transition metal ions
  85. 85. Clinically used to treat diabetes-associated polyneuropathies, renal nephropathies, and heavy metal and mushroom poisoning.</li></li></ul><li>Lipoic acid dose-dependently inhibits TNF-induced adhesion molecule expression in human aortic endothelial cells (HAEC)<br />Zhang and Frei (2001) FASEB J. 15, 2423-2432<br />
  86. 86. Zhang and Frei (2001) FASEB J. 15:2423-2432<br />
  87. 87. Zhang and Frei (2001) FASEB J. 15, 2423-2432<br />
  88. 88.
  89. 89. Lipoic acid inhibits body weight gain in apoE-/- and apoE/LDLR-/- mice<br />Zhang et al. (2008) Circulation 117:421-428<br />
  90. 90. Nature Medicine 10, 727-733 (2004) Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinaseMin-Seon Kim et al.<br />
  91. 91. Lipoic acid lowers triglycerides in serum and in VLDL and LDL of apoE-/- and apoE/LDLR-/- mice<br />VLDL<br />LDL<br />HDL<br />Zhang et al. (2008) Circulation 117:421-428<br />
  92. 92. Lipoic acid inhibits aortic gene expression of adhesion molecules, cytokines, and CD68 in apoE/LDLR-/- mice<br />Zhang et al. (2008) Circulation 117:421-428<br />
  93. 93. En face aortic atherosclerotic lesion analysis in apoE-/- and apoE/LDLR-/- mice <br />(aortic arch and thoracic and abdominal aorta)<br />Control<br />LA-<br />treated<br />ApoE-/-<br />ApoE/LDLR-/-<br />Zhang et al. (2008) Circulation 117:421-428<br />
  94. 94. Lipoic acid inhibits aortic atherosclerosis (by 55% and 40%, respectively) in apoE-/- and apoE/LDLR-/- mice<br />Zhang et al. (2008) Circulation 117:421-428<br />
  95. 95. Physiological Effects of Lipoic Acid<br />
  96. 96. Suna (left, 13 yrs old, 22.5 mg/kg/day of (R)-a-lipoic acid for 7 years) and her niece, Willow (right, 3 yrs)<br />Slide courtesy of David Carlson, GeroNova Research Inc<br />
  97. 97. Center of Excellence for Research on CAM Antioxidant Therapies (CERCAT) (5P01AT002034-08, Frei)<br />
  98. 98. Project 1: Specific Aims (Two RCTs at OHSU’s CTRC, Purnell)<br /><ul><li>Aim 1: Determine the preventative value of R-lipoic acid in CVD by reducing plasma triglycerides, body weight, and other atherosclerosis risk factors in overweight and obese human subjects with hypertriglyceridemia.
  99. 99. Aim 2: Determine the therapeutic value of R-lipoic acid in CVD by reducing vascular inflammation, oxidative stress, and other atherosclerosis risk factors in coronary heart disease patients who have increased levels of oxidative stress and inflammation.</li></li></ul><li>The Frei Laboratory<br />
  100. 100. Acknowledgements<br /><ul><li>Frei lab, past and present
  101. 101. Faculty and Staff of the Linus Pauling Institute
  102. 102. Barbara McVicar and Simone Frei
  103. 103. Bruce N. Ames (UC Berkeley, CHORI)
  104. 104. John F. Keaney and Joseph Vita (Boston University School of Medicine)
  105. 105. Jason Morrow (Vanderbilt University)</li></ul>Funding provided by:<br />AHA, NHLBI, NCCAM, NIEHS <br />
  106. 106. Linus Pauling Science Center<br />LPSC Design<br />View of NW Elevation<br />A new home for Chemistry and the Linus Pauling Institute<br />

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