Nrf2 study_Summary Feb. 2015

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Service
of
the
National
Library
of
Medicine
and
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Institutes
of
Health

RESEARCH
ON
Nutrition’s
Health
Promoting
Factors
and
Nrf2
AT
PUBMED

Acta
Physiologica
Sinica,
February
25,
2015,
67(1):
1–18
DOI:
10.13294/j.aps.2015.0001

Nrf2,
a
master
regulator
of
detoxification
and
also
antioxidant,
anti-‐inflammatory
and
other
cytoprotective

mechanisms,
is
raised
by
health
promoting
factors.

Authors:

Pall
ML
1,
Levine
S
2

Source:

1
Washington
State
University,
Portland,
Oregon
97232-‐3312,
USA.

2
Allergy
Research
Group,
Alameda,
California
94502,
USA.

Abstract:

The
transcription
factor
Nrf2,
nuclear
factor
erythroid-‐2-‐related
factor
2,
activates
the
transcription
of
over

500
genes
in
the
human
genome,
most
of
which
have
cytoprotective
functions.

Nrf2
produces
cytoprotection
by

detoxification
mechanisms
leading
to
increased
detoxification
and
excretion
of
both
organic
xenobiotics
and
toxic

metals;
its
action
via
over
two
dozen
genes
increases
highly
coordinated
antioxidant
activities;
it
produces
major
anti-‐
inflammatory
changes;
it
stimulates
mitochondrial
biogenesis
and
otherwise
improves
mitochondrial
function;
and
it

stimulates
autophagy,
removing
toxic
protein
aggregates
and
dysfunctional
organelles.

Health-‐promoting
nutrients
and

other
factors
act,
at
least
in
part
by
raising
Nrf2
including:
many
phenolic
antioxidants;
gamma-‐
and
delta-‐tocopherols

and
tocotrienols;
long
chain
omega-‐3
fatty
acids
DHA
and
EPA;
many
carotenoids
of
which
lycopene
may
be
the
most

active;
isothiocyanates
from
cruciferous
vegetables;
sulfur
compounds
from
allium
vegetables;
terpenoids.

Other
health

promoting,
Nrf2
raising
factors
include
low
level
oxidative
stress
(hormesis),
exercise
and
caloric
restriction.

Raising

Nrf2
has
been
found
to
prevent
and/or
treat
a
large
number
of
chronic
inflammatory
diseases
in
animal
models
and/or

humans
including
various
cardiovascular
diseases,
kidney
diseases,
lung
diseases,
diseases
of
toxic
liver
damage,
cancer

(prevention),
diabetes/metabolic
syndrome/obesity,
sepsis,
autoimmune
diseases,
inflammatory
bowel
disease,

HIV/AIDS
and
epilepsy.

Lesser
evidence
suggests
that
raising
Nrf2
may
lower
16
other
diseases.

Many
of
these
diseases

are
probable
NO/ONOO(-‐)
cycle
diseases
and
Nrf2
lowers
effects
of
NO/ONOO(-‐)
cycle
elements.

The
most
healthful

diets
known,
traditional
Mediterranean
and
Okinawan,
are
rich
in
Nrf2
raising
nutrients
as
apparently
was
the

Paleolithic
diet
that
our
ancestors
ate.

Modern
diets
are
deficient
in
such
nutrients.

Nrf2
is
argued
to
be
both
lifespan

and
healthspan
extending…

Ref:

https://www.ncbi.nlm.nih.gov/pubmed/25672622

PMID:
25672622
[PubMed
-‐
in
process]
Free
Article

Martin
L
Pall
et
al.:
Nrf2,
Master
Cytoprotection
&
Detoxification
Regulator,
is
Raised
by
Many
Health
Promoting
Factors

Fig.
1.
Outline
of
the
Nrf2
regulatory
system.

Pg
1
of
3

Excerpts
from
the
full
study.

Introduction:

“Nrf2
has
been
known
for
over
10
years,
to
be
an
important
transcriptional
activator
of
antioxidant
genes,
producing

important
antioxidant
protective
responses.

It
has
also
been
known
for
about
the
same
time
period,
to
be
activated
by

many,
but
not
all,
phenolic
antioxidants,
such
that
much
of
the
antioxidant
effects
of
these
compounds
are
produced

through
this
regulatory
response,
rather
than
exclusively
through
direct
chain
breaking
antioxidant
chemistry.”

“However
Nrf2
has
been
shown
more
recently
to
have
many
cytoprotective
effects
that
go
far
beyond
antioxidant

effects.
These
include
activation
of
over
two
dozen
genes
involved
in
detoxification
of
a
wide
variety
of
xenobiotic

toxicants.

Nrf2
and
the
system
that
regulates
Nrf2
lower
inflammatory
responses,
improve
mitochondrial
function
and

stimulate
autophagy,
a
process
by
which
both
toxic
protein
aggregates
and
dysfunctional
organelles
can
be
degraded.

Three
of
these
effects,
the
lowering
of
oxidative
stress,
inflammatory
biochemistry
and
improving
mitochondrial

function
should
lower
the
pathophysiology
involved
in
dozens
of
chronic
inflammatory
diseases
and
so
may
be
expected

to
be
useful
in
the
prevention
or
treatment
of
many
common
chronic
diseases.”

“It
has
also
been
shown,
in
recent
years,
that
many
health
promoting
factors
other
than
phenolic
antioxidants
act
to

raise
Nrf2
activity.

Most
of
these
recent
findings
have
been
reviewed
in
a
whole
series
of
recent
reviews
and
it
is
the
role

of
this
paper
to
summarize
the
vast
scope
of
these
new
findings,
including
the
health-‐promoting
and
disease-‐preventing

effects
of
Nrf2.”

“The
important
detoxification
roles
of
Nrf2
mean
that
raising
Nrf2
activity
is
likely
to
be
of
particular
importance
to
the

hundreds
of
millions
of
people
around
the
globe
who
are
regularly
exposed
to
toxic
chemicals
that
cause
diseases

characterized
by
oxidative
stress,
inflammation
and
mitochondrial
dysfunction,
diseases
which
include
most
of
the

chronic
diseases
of
21st
century
life.”

“There
are
a
very
large
number
of
chronic
diseases,
listed
in
Table
1
that
have
been
shown
to
be
prevented
and/or

treated
by
raising
Nrf2.

Conversely,
lowering
or
knocking
out
Nrf2
function
has
often
been
shown
to
increase
sus-‐

ceptibility
to
the
same
diseases.

Most
of
these
studies
have
been
done
in
animal
models
although
there
are
also
an

increasing
number
of
human
studies
being
reported.”

“The
finding
that
raising
Nrf2
may
be
useful
in
prevention
and/or
treatment
of
this
list
of
diseases
seems
almost
too
good

to
be
true.

However
these
diseases
all
have
both
oxidative
stress
and
inflammatory
aspects
to
them
and
many
of
them

are
also
known
to
involve
mitochondrial
dysfunction.

Protein
aggregates
have
causal
roles
of
several
of
them,

aggregates
that
may
be
removed
by
Nrf2-‐dependent
autophagy.

A
number
of
these
diseases
are
caused
by
toxic

exposure
and
may
be
lowered
by
Nrf2-‐dependent
detoxification.

The
data
on
obesity
are
mixed,
but
with
most
data

showing
that
Nrf2
acts
to
lower
obesity.”

Table
1.
Diseases
where
raising
Nrf2
is
reported
to
be
useful
in
prevention
and/or
treatment
in
animal
models
and/or
humans

Citation
Diseases

2,
4,
9,
16,
22,
23
Cardiovascular
diseases
including
atherosclerosis,
ischemic
cardiovascular
disease,
vascular

endothelial
dysfunction,
and
heart
failure

2,
4,
5,
6,
12,
13,
19,
23,
24
Neurodegenerative
diseases
including
Alzheimer’s,
Parkinson’s,
ALS,
Huntington’s
diseases

2,
3,
4,
13,
19
Cancer
(prevention)

2,
6,
7,
15,
19,
23
Chronic
kidney
diseases

2,
8,
10,
20,
23
Metabolic
diseases:
Type
2
diabetes;
metabolic
syndrome;
obesity

2,
8,
19,
20,
23
Several
types
of
toxic
liver
disease

2,
6,
16,
21,
23,
25,
27
Chronic
lung
diseases
including
emphysema,
asthma,
and
pulmonary
fibrosis

4,
14,
26
Sepsis

2,
4,
16,
23,
27–30
Autoimmune
diseases

4,
13,
23,
31
Inflammatory
bowel
disease

4,
32
HIV/AIDS

11,
12
Multiple
sclerosis

17,
18,
33,
34
Epilepsy

Pg
2
of
3

Summary: ”The
two
most
healthful
diets
known,
the
traditional
Mediterranean
and
Okinawan
diets,
and
the
Paleolithic

diet
are
all
thought
to
be
rich
in
Nrf2
raising
nutrients,
whereas
modern
diets
are
deficient
in
such
nutrients.

These

findings
strongly
suggest
that
health-‐promotion
by
these
diets
acts,
to
a
great
extent
via
Nrf2
but
that
most
of
us
are

currently
deficient
in
Nrf2
raising
nutrients.

Nrf2
acts,
in
turn
via
transcription
of
roughly
500
genes,
to
raise
antioxidant

responses,
mitochondrial
biogenesis
and
energy
metabolism,
detoxification
of
carbon-‐containing
xenobiotics
and
toxic

metals,
autophagy
of
toxic
protein
aggregates
and
dysfunctional
organelles
and
greatly
lowering
many
inflammatory

responses
(Fig.
1,
lower
right).

It
is
not
surprising,
therefore,
that
a
large
number
of
chronic
diseases
characterized
by

oxidative
stress,
inflammation
and
often
mitochondrial
function
can
be
treated
and/or
prevented
by
raising
Nrf2,
at
least

in
animal
models
(Fig.
1,
right).

Nor
should
it
be
surprising
that
Nrf2
has
been
proposed
to
produce
both
lifespan
and

healthspan
extension,
given
the
many
diseases
of
aging
characterized
by
oxidative
stress,
inflammation
and

mitochondrial
dysfunction
(Fig.
1,
upper
right).”

“While
no
doubt
it
is
too
early
to
make
a
conclusion,
it
is
difficult
to
escape
the
suggestion
that
we
may
be
on
the
verge

of
a
new
literature
on
health
effects
of
Nrf2
which
may
well
become
the
most
extraordinary
therapeutic
and
most

extraordinary
preventive
breakthrough
in
the
history
of
medicine.

It
is
our
opinion
that
raising
Nrf2
is
likely
to
be
the

most
important
health
promoting
approach
into
the
foreseeable
future.”

“The
stunning
apparent
breadth
of
the
effects
of
Nrf2
on
diverse
diseases
produces
a
challenge
for
medicine.

Medicine

has
historically
focused
mainly
on
the
ways
in
which
these
various
diseases
differ
from
one
another,
as
a
way
of

understanding
their
differences.

However
it
is
possible
that
these
diverse
chronic
inflammatory
diseases
all
have
a

similar
underlying
mechanism
and
differ
from
one
another
primarily
in
their
localization
in
the
body,
with
the
differences

in
localization
being
responsible
for
any
differences
in
their
etiologies.”

(Note:
The
entire
study
is
available
for
review
should
anyone
desire
to
see
the
complete
study.

Please
advise.)

The
graphic
below
is
from
another
study
cited
(Citation
#82)
by
the
authors
of
this
study.

Graphic
representation
of
the
impact
of
dietary
phytochemicals
on
the
regulation
of
Nrf2-‐dependent

pharmacogenomics.

Some
of
the
representative
groups
of
genes
are
presented.

Ref:
https://www.ncbi.nlm.nih.gov/pubmed/23041058

Pg
3
of
3

Nrf2 study_Summary Feb. 2015

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