Professional Documents
Culture Documents
Antioxidants:
A New Understanding
Kerry Bone
Co-Founder and Director R&D
MediHerb
Adjunct Associate Professor
University of New England, Australia
Topics Covered
Basic redox chemistry and definitions
Herbal (phytochemical) antioxidants: important
considerations and controversies
The essential aspects of the Nrf2/ARE pathway a new insight into clinically relevant antioxidant
protection
The clinical relevance of the pathway for health,
wellness and normal processes of aging
Herbs and phytochemicals shown to act via the
Nrf2/ARE pathway
Current and novel clinical applications informed
by this new understanding
3
Controversies Over
Antioxidants
The oxidative stress theory of aging (and hence
the value of consuming antioxidant supplements)
has been challenged by many researchers, even
former advocates (see later in slide 13)
Antioxidants might become pro-oxidants in the
right environment: examples include vitamin C
and the negative clinical results for isolated betacarotene in smokers
The discovery of ROS signalling: demonstrated in
a variety of physiological processes including
glucose-stimulated insulin secretion and induction
of host defenses1
1
ORAC Values
13
14
A New Perspective
However, a common denominator exists in
several studies: cells from long-living animals
show greater levels of cytoprotection
They are more resistant to oxidative and
chemical insults
This strong relationship between species
longevity and cellular resistance to oxidative
insults has been reported in a wide variety of
species across the animal kingdom (see later
in slide 23)
15
Important
Cellular
Protector
Pathways
16
18
19
20
Functions of the
Nrf2/ARE Pathway
As noted, Nrf2 is expressed in all tissues, but
levels vary, with higher levels in key detoxifying
organs: the liver and kidneys
Activation of Nrf2 activates
more than 200 genes
Nrf2 activation enhances
DNA repair, heme metabolism,
efflux transport of toxins and
glutathione synthesis
It activates detoxification, stabilizes proteins,
strengthens cellular integrity and moderates the
inflammatory response process
21
Functions of the
Nrf2/ARE Pathway
Key antioxidant enzymes are induced, including
catalase, superoxide dismutase (SOD),
thioredoxin, peroxiredoxin, sulfiredoxin, ferritin,
metallothionein and haem oxygenase 1 (HO-1)
Key phase II enzymes are also induced, including
glutathione S-transferases (GSTs) and NAD(P)H:
quinone oxidoreductase 1 (NQO1)
These functions likely represent only a fraction of
the true function of Nrf2 activity, some of which
are only beginning to be understood
Maher J, Yamamoto M. Toxicol Appl Pharmacol 2010; 244(1): 4-15
Lewis KN, Mele J, Hayes JD et al. Integr Comp Biol 2010; 50(5): 829-843
Itoh K, Mimura J, Yamamoto M. Antioxid Redox Signal 2010; 13(11): 1665-1678
22
Lewis KN, Mele J, Hayes JD et al. Integr Comp Biol 2010; 50(5): 829-843
24
25
27
lung support
cardiovascular support
immune system support
blood glucose support
Key Herbs/Phytochemicals
with Nrf2/ARE Activity
EGCG from Green Tea is also very active (in vitro
and in vivo - 20 mg/kg, oral)
Curcumin from Turmeric is
positive in many studies
(in vitro and in vivo, oral)
Resveratrol shows marked
in vitro and in vivo activities
and was also positive in an
human trial (see later)
Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the
cellular signaling involved in the induction of cytoprotective genes by some
chemopreventive phytochemicals. Planta Med 2008; 74(13): 1526-1539
Hur W, Gray NS. Small molecule modulators of antioxidant response pathway.
Curr Opin Chem Biol 2011; 15(1): 162-173
29
Key Herbs/Phytochemicals
with Nrf2/ARE Activity
Carnosol from Rosemary is another wellstudied phytochemical
Various phytochemicals from Garlic are
active in vitro
Several flavonoids exhibit in vitro activity,
but this may not translate to clinical
relevance because of their low oral
bioavailability
Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the
cellular signaling involved in the induction of cytoprotective genes by some
chemopreventive phytochemicals. Planta Med 2008; 74(13): 1526-1539
Hur W, Gray NS. Small molecule modulators of antioxidant response pathway.
Curr Opin Chem Biol 2011; 15(1): 162-173
30
10
Rosemary
Rosemary contains the antioxidant
molecules carnosol and carnosic acid
Both of these are now understood to be potent
primers of the Nrf2/ARE pathway
For example both compounds have demonstrated
potential neuroprotective activity mediated by
this pathway, which reflects on its traditional use
for memory1,2
Recently a single 750 mg dose of Rosemary
improved speed of memory and alertness in
healthy older adults1
1
2
3
31
32
Turmeric/Curcumin
Multiple in vivo studies have demonstrated
the activities of curcumin and Turmeric1
The Nrf2/ARE pathway is thought to be an
important basis for these effects
For example, the epigenetic silencing of Nrf2
during the progression of prostate challenge
in a mouse model was reversed by
curcumin2
1
2
Aggarwal BB, Surh YJ, Shisodia S (eds). Adv Exptl Med Biol 2007; 595;
1-489
Khor TO, Huang Y, Wu TY et al. Biochem Pharmacol 2011; 82(9): 1073-1078
33
11
Turmeric/Curcumin
In other relevant models, chemically induced
oxidative stress was reduced by curcumin in
vivo in parallel with Nrf2/ARE upregulation1
Brain and liver were supported in vivo by
curcumin through Nrf2-mediated induction of
HO-12,3
Dietary curcumin led to increased Nrf2
protein levels and enhanced ARE binding in
liver and lungs of mice4
1
2
3
4
35
36
12
Resveratrol
Resveratrol is a highly active primer of the
Nrf2/ARE pathway
Favorable Nrf2-mediated activity has been
demonstrated in many body systems
including the endocrine, cardiovascular and
nervous systems
For example, the endothelial (circulatory)
protective effects of resveratrol against a
high-fat diet were largely diminished in Nrf2
knockout mice1
Hask G, Pacher P. Am J Physiol Heart Circ Physiol 2010; 299(1): H10-H12
37
Resveratrol
In a recent double blind, randomized,
crossover study, 10 normal, healthy men and
women were given a high-fat, highcarbohydrate (HFHC) meal (930 kcal) either
with a placebo or a product containing 100
mg of resveratrol from Polygonum
cuspidatum plus 75 mg of total polyphenols
from a grape extract1
Profound benefits were observed
1
Ghanim H, Sia CL, Korzeniewski K et al. J Clin Endocrinol Metab 2011; 96(5):
1409-1414
38
Resveratrol
DNA binding activity of Nrf2 in white cells
was significantly increased by 15039%
over baseline (p<0.05) at 3 hours after meal
and supplement intake, whereas meal
consumption in the placebo group resulted in
a significant reduction in Nrf2 binding
activity at 5 hours
This was associated with a significant
reduction of Keap-1 by 486% (p<0.05) in
the supplement group and a significant
increase by 6610% (p<0.05) in the
placebo group
39
13
40
Ginkgo
Ginkgo is now well known as a powerful
clinical antioxidant. Its antioxidant properties
could play an important role in cellular
protection and appear to be mediated by Nrf2
In an uncontrolled trial conducted in 1995,
Ginkgo extract supported cellular health in
Russian workers1
More recently the same dose of extract
(120 mg/day) supported cellular health in
patients with thyroid challenges receiving
conventional therapies1
1
2
Ginkgo
There have been many trials of Ginkgo and brain
health in China and the Cochrane Collaboration
published a systematic review and metaanalysis1
While the review expressed concerns about the
quality of most trials, it found that Ginkgo was
associated with a significant increase in the
number of improved patients, based on
neurological function
Induction of HO-1 via Nrf2/ARE activation by
Ginkgo was suggested as a significant
mechanism for neuroprotection and support2,3
1
2
3
14
43
Korean Ginseng
Epidemiological and clinical studies support
the role of Korean Ginseng as a significant
promoter of cellular health
Emerging evidence suggests that priming of
the Nrf2/ARE pathway could be a key
mechanism involved1,2
1
2
44
Vitanox
Each tablet contains:
Rosemary leaf 5:1 extract
from Rosmarinus officinalis leaf 1.0 g
Green Tea leaf 25:1 extract
from Camellia sinensis leaf 4.2 g
Containing catechins 83.35 mg
Turmeric rhizome 25:1 extract
from Curcuma longa rhizome 2.0 g
Containing curcuminoids 70.4 mg
Grape seed 120:1 extract
from Vitis vinifera seed 6.0 g
Containing procyanidins 42.5 mg
Dosage: 2 to 3 tablets per day
200 mg
166.7 mg
80 mg
50 mg
45
15
HerbaVital
Each tablet contains:
Japanese Knot Weed root extract 100:1
from Polygonum cuspidatum root 8.0 g
Containing resveratrol 36 mg
Milk Thistle seed extract 70:1
from Silybum marianum seed 4.2 g
Containing flavanolignans calc. as silybin 48 mg
Korean Ginseng root extract 5:1
from Panax ginseng root 250 mg
Containing ginsenosides calculated as Rg1 and Rb1
Masson Pine bark extract 100:1
from Pinus massoniana bark 5.0 g
Containing proanthocyanidins 37.5 mg
Ginkgo leaf extract 50:1
from Ginkgo biloba leaf 1.5 g
Containing ginkgo flavonglycosides 7.2 mg
Containing ginkgolides and bilobalide 1.8 mg
Dosage: 2 to 4 tablets per day
80 mg
60 mg
50 mg
4.2 mg
50 mg
30 mg
46
A New Understanding
Providing clinically relevant, safe, targeted
antioxidant cover
Healthy aging and longevity protocols
Supporting detoxification pathways
Protecting against ANY physical or biological
stressor
47
A New Understanding
As key supporting agents for neurological
health across a range of health challenges
As key moderators in any chronic
musculoskeletal or immune system
challenges
As key supporting agents for the
cardiovascular system, especially arterial and
endothelial function
48
16
A New Understanding
Countering the negative metabolic effects
of a high-fat and/or high-fried/food diet
Providing protective cover during
weight loss
For metabolic modulation
For lung support
49
A Cautionary Note
Nrf2 and its downstream genes are overexpressed in many experimental cancer cell
lines and human cancers, giving cancer cells
an advantage for survival and growth
Also Nrf2 is upregulated in cancer cells
resistant to chemotherapy and is thought to
be responsible for acquired chemoresistance1
Lau A, Villeneuve NF, Sun Z et al. Pharmacol Res 2008; 58(5-6): 262-270
50
A Cautionary Note
There are still many questions to be
answered
However, caution dictates that any known
Nrf2/ARE upregulating herbs should not be
taken at least 48 hours either side of each
chemotherapy or radiotherapy treatment
51
17
A Final Reminder
The key herbs/phytochemicals identified by
current research that are most active at
priming the Nrf2/ARE pathway are found in:
Vitanox
Turmeric/curcumin, Rosemary and Green
Tea/ EGCG
HerbaVital
Resveratrol plus OPCs, Ginkgo and Korean
Ginseng
52
Questions
53
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