new findings on antioxidants super antioxidants taiwan nuskin presentation medical symposium...
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New Findings on antioxidants Super Antioxidants
Taiwan NuSkin presentationMedical SymposiumNovember 3, 2007
Prof. Lester Packer
Prostate Cancer Rate
Shanghai born Chinese 1.7
China born Chinese
(live in US < 5 yrs)1.8
China born Chinese
(live in US > 5 yrs)23
US born Chinese 37
US born Caucasian 58
US
China
Asiancountries
Westerncountries
Int.J. Cancer (2000) 85:60-7Courtesy Emily Ho
Oxidative StressOxidative Stress
• Free radicals cause oxidative stress
• Leads to tissue damage, aging and disease
ROS formationRedox Signaling
Oxidative StressDamage vs. RepairAdaptive Signaling
ApoptoticSignaling Necrosis
Oxidant burdenOxidant burden
ROS formationRedox Signaling
Oxidative StressDamage vs. Repair Adaptive Signaling
ApoptoticSignalingOxidant burden
Oxidant burdenNecrosis
Oxidant induced cell signaling and damage
Oxidative Stress
“An imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage.”
Jones, D.P. Redefining oxidative stress. Antioxid. Redox Signal. 2006, 8: 1865-1879.
Glutathione is the cell’s major antioxidant
GSSG + NADPH 2 GSH + NADP+
Gluthathione Peroxidase
Gluthathione Reductase
GSSG oxidized
GSH reduced
2 GSH + H2O2 GSSG + 2 H2O
Oxidative Stress can be estimated from the ratio of reduced to oxidized antioxidants
Proliferation
Apoptosis
Differentiation
Ratio of GSH/GSSG becomes progressively oxidized during the life cycle of cells
-150-150
Kirlin WG, Cai J, Thompson SA, Diaz D, Kavanagh TJ, Jones DP. Glutathione redox potential in response to differentiation and enzyme inducers.Free Radic Biol Med. 1999 Dec;27(11-12):1208-18.
-250
-200
-250
-200 1:1
1:10
10:1
100:1
Redox State
-(SH)2:-SS-
Eh,
mV
Increased Carotid Intima Media Thickness
Cigarette Smoking
Type 2 Diabetes
Reversible myocardial Ischemia perfusion injury
PathophysiologyOxidative Stress-80 mV
-20 mV(-80 mV)
-50 mV(-110 mV)
Cys/CySS Redox(GSH/GSSG Redox)
(-140 mV)
Jones D.P., Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1865-79.
• Vitamins C and E
• Polyphenols (Flavonoids)
• Low molecular weight thiols:
Cysteine, Methionine, Glutathione, R- Lipoic Acid,
• Co-enzyme Q
• L-Carnitine
Antioxidants
•Carotenoids
Redox
Radical Scavenging
The Antioxidant Network in Membranes
Vit. E•cycle
Q10 H •cycle
Vit. C•cycle
Lipid Free Radicals
LOO• LO•Carotenoids
Metabolism
FatSoluble
Water Soluble
Water Soluble
OxygenMetabolism
Inducers Of Phase 2 enzymes and proteins
Dinkova-Kostova, A.T., Holtzclaw, W.D., Cole, R.N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., Talalay, P., PNAS USA, 99(18):11908-13, 2002.Fahey JW, Stephenson KK, Dinkova-Kostova AT, Egner PA, Kensler TW, Talalay P.Carcinogenesis 2005 Jul;26(7):1247-55
“The capacity of these compounds to induce the phase 2 response depends upon their ability or that of their metabolites to react with thiol groups, a property shared with all other classes of phase 2 inducers, which show few other structural similarities”
INDUCERINDUCER
IND
UC
ER
IND
UC
ER
CYTOPLASM
smallMaf
NUCLEUS
Keap 1
Keap 1
Nrf2
Nrf2
Nrf2
S S
S S
Phase 2 Genes
or
or
Keap 1
S SSH SHKeap 1
ARE
Inducers of Nrf2 transcription, the phase II response, all have in common the ability to react with suphydryl groups
PolyphenolsBioflavanoidsChlorophyllCarotenoids
Heme, H2O2, NO● Carotenoid oxidation products
Chemicals reacting with Sulphydryl groups, e.g.,
Isothioyonates (sulforaphane), Dithiolanes,
1,2-dithiol-3-thiones, α-Lipoic acid
HO-l
GCL
GSHincreases
Mn Superoxide Dismutase
Thioredoxin, Trx reductaseMitochondrial and other
Antioxidant enzymes
Alkyl and Aryl Halides, Metal Ions, e.g., HgCl2, CdCl2
NAD(P)H-Quinone reductase,Ferritin, Epoxide hydrolase
GSH, Gluconic acid,methyl and other transferases
Antioxidant Defense, Detoxification, Chemoprevention
Nrf2-Keap-1system(ARE/EpRE)
• Inducers of enzymes & proteins
needed for antioxidant defense
Carotenoids in Humans are
• Vitamin A precursors
cyclic hydrocarbon carotenoids
• Free radical scavengers
protect against oxidation
Carotenoids in fruits & vegetables
Lycopene (20-40%)
β-cryptoxanthin (13-20%)
Lutein (10-20%)
carotene (5-10%)
-carotene (15-30%)
Zeaxanthin (1-5%)
Spinach, Green peas, Green Beans , Lima Beans Broccoli, Brussel sprouts, Cabbage, kale, Kiwi, Lettuce
Carrots, Pumpkin, Sweet Potatoes, Apricots, Cantaloupe, Watermelon
Tomatoes, Pink Grapefruit
Carotenoids in Human Plasma
Raman ScatteringSir C. V. Raman, Nobel Prize in Physics 1930
Carotenoids shift blue laser light to green:
from 473 nm to 510 nm
Laser light
Raman scattered light
Raman scattering studies are used to measure carotenoids in the Eye and to diagnose age-
related macular degeneration
Macula
Lutein & Zeoxanthin
Gellermann W, Ermakov IV, McClane RW, Bernstein PS. Raman imaging of human macular pigments. Optics Letters. 2002;27:833
C. Smidt and D.S. Burke, Nutritional Significance and Measurement of Carotenoids, Current Topics in Nutraceutical Research 2004, 2, 79-91
0
20000
40000
60000
0 0.5 1 1.5 2 2.5 3 3.5 4
Total Serum Carotenoids (μg/ml)
Skin Raman Intensity (n = 372)
r = 0.84 (p<0.0001)
p<0.01 p<0.01 p<0.01
Std. Error 44
Std. Error 38
Std. Error 61
Std. Error 106
24793
26639
29704
31507
10000
15000
20000
25000
30000
35000
1 or less 2 to 3 4 to 5 6 or more
Courtesy Stephen Poole, Pharmanex
Skin Raman Intensity(2005 US data of 209,628 Non-Supplement Users)
Daily servings of fruits and vegetables
Lifestyle affects raman scattering intensity
4 mg Lutein
¼ cup of cooked spinach
1 & 1/3 medium carrots or ¼ cup pumpkin
4 mg -Carotene 4 mg Lycopene
1 medium tomatoor ¾ Tsp tomato paste
Carotenoids in human supplements equivalent to amounts in food (courtesy KJ Yuem)
Plasma Carotenoid Concentration Is increased after Supplementation
Time, Day
D1 D15 D29 D43 D57
Pla
sma
To
tal
Car
ote
no
id (g
/dL
)
0
20
40
60
80
100
120
140
160
180Placebo Mixed Car Lutein -Carotene Lycopene
** *
**
***
**
*
**
*
* * *
*
*
Significantly different from baseline * p<0.05Courtesy KJ Yuem, et al.
Carotenoid Supplementation protects DNA Damage of human
lymphocytesThe comet assay
Day 57Day 1
(Subject # 35563)Courtesy KJ Yuem, et al.
Carotenoid Supplementation protects DNA damage in human lymphocytes
0.4
0.6
0.8
1.0
1.2
1.4
1.6
(D1/D1) (D15/D1) (D29/D1) (D43/D1) (D57/D1)
Placebo Mixed Car Lutein
-Carotene Lycopene
Comet tail factor ratio compared with day 1
Closed symbols indicate significant differences from Placebo group (p<0.05)
Courtesy KJ Yuem, et al.
Physiological doses of a β-carotene, lycopene, lutein or a mixture of these carotenoids protect against endogenous or hydrogen peroxide (H2O2 ) induced DNA damage in white human blood cell lymphocytes
Genes effected by carotenoids in lung tissue of cigaraette exposed exposed mice
Nrf2 Transcription
Inflammatory and immune responses
Metabolism and Ion channels
Receptors Growth factors Apoptosis UnknownGenes
Others
Genes Up or down regulated
Control diet
Β-carotene
Lycopene
Lutein
Mixed 3-Carotenoids-20
0
20
-20
0
20
-20
0
20
-20
0
20
-20
0
20
Gene chip studies show carotenoids…
… have specific effects on gene expression
… effect expression of genes for transcription factors which enhance the biosynthesis of antioxidant enzymes and proteins
… modify genes affecting xenobiotic metabolism and immune system response
Vitamin A levels are increased in healthy centenarians compared to younger subjects
Vit
amin
A (
µM
)
Centenarians< 60 yrs 60-79 yrs 80-99 yrs
153 Italian centenarians, * p < 0.0001
* * *
0
1
2
3
4
5
6
Christina Polidori, Eur J Clin Nutr 2007
• Substances in plant fruits and vegetables have a wide range of different molecular structures. Some like bioflavonoids are powerful direct free radical scavengers.
• These and other small molecules also can induce the biosynthesis of antioxidants.
• These are bifunctional antioxidants or “Super Antioxidants”
because they…
…scavenge free radicals directly and immediately
…but also act indirectly by inducing genes and thus have long lasting effects
Super Antioxidants
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