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Complete Summary

Table of Contents:
1. Sources and Structure
1. Sources
2. Structure and Properties
3. Variants of Curcumin Supplements
2. Molecular Targets
1. Direct
2. Junction points
3. Indirect/Downstream
3. Pharmacology
1. Absorption
2. Systemic
3. Metabolism
4. Excretion and Clearance
4. Longevity
1. Autophagy
2. Interventions
5. Neurology
1. Glutaminergic Neurotransmission
2. Cognition
3. Stress
4. Neuronal Injury
5. Alzheimer's Disease
6. Analgesia
6. Cardiovascular Health
1. Cardiac Tissue
2. Red Blood Cells
3. Artherosclerosis
4. Endothelium
5. Blood Flow
6. Triglycerides
7. Cholesterol and Lipoproteins
7. Interactions with Glucose Metabolism
1. Mechanisms
2. Blood glucose
3. Diabetes
8. Fat mass and Obesity
1. Mechanisms
2. Inflammation (Adipose Tissue)
3. Adipokines
4. Interventions
5. Side-effects related to Obesity
9. Interactions with Skeletal Muscle
1. Acute Protective Effects
2. Catabolism/Anabolism
3. Glucose metabolism
10. Oxidation and Anti-Oxidation
1. Direct Antioxidative Effects
2. Interventions
11. Interactions with Inflammation and Immunology
1. Mechanisms
2. Joint Inflammation and Arthritis
3. Virology
12. Interactions with Hormones
1. Testosterone
2. Estrogen
13. Implications in Cancer Metabolism
1. General (Not mechanisms)
2. General (Mechanisms)
3. Prostate Cancer
14. Intestinal Interactions
1. The Colon and Ulcerative Colitis
15. Interactions with other Organ Systems
1. Liver
2. Kidneys
16. Nutrient-Nutrient Interactions
1. Turmeric
2. Piperine
3. Ginger
4. Soy Isoflavones
5. Docosahexaenoic acid
6. Vincristine
7. Rolipram
8. Iron
9. Itself
10. Garcinol
17. Safety and Toxicology
1. General Safety
2. Side-effects

Edit1. Sources and Structure
1.1. Sources
Curcumin (chemically known as Diferuloylmethane) is the main active ingredient of
the spice Turmeric (Curcuma Longa or JiangHuang) and is the main 'curcuminoid'
compound (80% of curcuminoid weight is curcumin
[1]
) alongside the other three
curcuminoids known as demethoxycurcumin, bisdemethoxycurcumin, and
cyclocurcumin.
[2][3]
Curcuminoids in general are known to exist in
the curcuma genus
[4]
(just in highest amounts in curcuma longa) although they are
not exclusive to this plant.
Curcumin is the main molecule in the curcuminoid class of molecules (similar to
how Resveratrol is the main molecule in the stilbene class of molecules), and is most
commonly associated with turmeric as that is its largest naturally occurring source
Curcuminoids are known to exist in:
Turmeric (Curcuma longa or JiangHuang) at around 22.21-40.36mg/g in the rhizomes
and 1.94mg/g in the tuberous roots
[4]
as well as other curcuma species such
as phaeocaulis (0.098mg/g)
Common Ginger (Zingiber officinale) and shampoo ginger (Zingiber zerumbet)
[5]

Commercially available extracts of 'curcumin' may not be wholly curcumin, but a
blend consisting of 77% curcumin (17% demethoxycurcumin, 3%
bisdemethoxycurcumin, last 3% not classified but assumed to possess a
cyclocurcumin content).
[6]
Curcumin can also be referred to as NCB-02 (a
standardized mixture of curcuminoids)
[7][8]
or E100 (the code for curcumin in the
usage of food coloring).
[9]

1.2. Structure and Properties
The structure of curcumin, officially known as diferuloylmethane, is two ferulic acid
moeities bound together with an additional carbon (methane) to abridge the carboxyl
groups. It can exist in a enol form (pictured below) or a keto form, which is
molecularily symmetrical with two ketone groups on the backbone.

The curcumin molecule is bright yellow (as it is used as an industrial food colorant
known as E100)
[10][9]
and highly lipophilic.
[11]
Curcumin is acid stable in the pH of the
stomach.
[11]

1.3. Variants of Curcumin Supplements
Curcumin inherently is poorly absorbed when orally ingested by itself
[12]
insofar that
8,000mg of curcumin sometimes fails to significantly increase serum
levels
[13]
(although other studies note small spikes with 4,000mg
[14]
or 8,000mg being
able to reach 22-41ng/mL
[15]
). Due to this, modifications to curcumin supplements are
investigated to enhance the amount of curcumin that reaches circulation.
The combination of curcumin with piperidine from black pepper extract (inhibitor of
glucuronidation) is known to increase the bioavailability of curcumin 20-fold when
20mg piperidine is used alongside 2,000mg curcumin.
[16]

Complexing curcumin with phospholipids (a phosphatidylcholine-curcumin complex
known as Meriva) can increase its incorporation into lipophilic membranes,
increasing Cmax and AUC five-fold in rats
[17]
and making 450mg Meriva as effective as
4g curcumin in humans (unpublished trial).
[18]
Other trials suggest a factor of 29-fold
higher absorption in humans, although said enhanced absorption favors
demethoxycurcumin rather than curcumin.
[19]

THERACURCUMIN emulsions (nanoparticles) possesses a 40-fold higher AUC
(Area-under-Curve) when compared to basic curcumin power in rats, and a 27-fold
higher AUC in humans.
[20]
although another study found merely a 10-fold increase in
AUC and a 40-fold increase in Cmax in rodents.
[21]
This increased bioavailability is, in
part, due to increased water-solubility.
[22]
Usage of nanoparticles can be used up to
210mg without any apparent saturation in absorption, and increase to Cmax to 275+/-
67ng/mL, an AUC of 3,649+/-430 ng/ml/h, and a half-life of 13+/-3.3 hours.
[22]

When looking at ways to increase curcumin absorption, either using a nanoparticulate form
(THERACURCUMIN) or phytosome delivery (Meriva) seem to be efficacious while pairing
basic curcumin with a low dose of piperidine is also effective

Edit2. Molecular Targets
Curcumin is able to induce effects either directly (the first domino in a series) or
downstream of the primary effect (subsequent dominoes). This section serves to
differentiate the two and harmonize mechanisms.
2.1. Direct
AP-1, a class of transcription factors made of dimerizations of c-Fos, c-Jun and
related proteins that is involved with cell proliferation, survival, and
differentiation
[23]
bind to their receptor on the cell nuclear (TPA response element) to
induce effects associated with AP-1.
[24][25]
The effects of AP-1 differ depending on the
proteins that make it up, but curcumin is able to interfere with the AP-1 released by
tumor promoters
[26]
and is able to enhance some phase II (anti-oxidant) enzymes by
moderating some better AP-1 confirmations.
[27]

Curcumin is also seen as a direct mTOR inhibitor, able to prevent the association of
the raptor subset with the TOR protein, inhibiting mTORC1 activity directly without
significant influence from AMPK-TSC or Protein Phosphatase A2.
[28][29]

Curcumin can also directly inhibit DNA polymerase lambda,
[30]
focal adhesion kinase
(FAK),
[31]
Src,
[31]
Protein Kinase C,
[32]
p300 (CREB Binding Protein),
[33]
Thioredoxin
reductase,
[34]
Lipoxygenase (LOX),
[35]
and tubulin.
[36]

It may also directly affect (negatively) 17beta-HSD3
[37]
and 5-alpha reductase.
[38]

Curcumin has been noted to directly and potently inhibit the Glycogen Synthase
Kinase-3 (GSK3) enzyme with an IC50 of 66.3nM.
[39]

2.2. Junction points
Junction points are defined as proteins or receptors that, by their activation or
inactivation, influence a great deal of related proteins.
nF-kB, a proinflammatory transcription factor, is inhibited by curcumin via a two-fold
mechanism of preventing p65 translocation to the nucleus, and by preventing the
degradation of the molecule which holds nF-kB in a dormant state, IkB.
[40]
The co-
activator of nF-kB, Notch-1, is also suppressed by curcumin although abnormally
high levels of Notch-1 can reduce the inhibitory effects of curcumin on nF-kB.
[41]
nF-
kB moderates over 200 related proteins related to cell proliferation, invasion,
metastasis, chemoresistance, and/or inflammation.
[42][6]

As mentioned previously, the proteins of AP-1 are also seen as a sort of junction
point mediating cell proliferation and survival.
[23]

2.3. Indirect/Downstream
The main proteins and molecules that are downstream of nF-kB, and thus are
reduced in potency when nF-kB is inhibited, are Bcl-2, Bcl-xL, cyclin D1, interleukin-6
(IL6), cyclooxygenase 2 (COX2) and matrix metallopeptidase-9 (MMP9).
[43][44][45]


Edit3. Pharmacology
3.1. Absorption
Due to the poor intestinal absorption, however, curcumin is effective in reaching
colonic tissue. An oral dose of 3.6g curcumin (which has been shown to increase
plasma levels to 11.1+/-0.6nmol/L
[46]
) is able to increase the levels of curcumin in
colorectal tissue to 7.7+/-1.8nmol/g (normal) and 12.7+/-5.7umol/g (malignant).
[46]

3.2. Systemic
Curcumin, due to its lipophilicity, is transported in the blood via transports; most likely
binding to Human Serum Albumin.
[47]

Without aiding absorption, an oral dose of 500mg/kg bodyweight in rats results in
peak plasma levels of 1.8ng/mL.
[48]

When investigating humans oral dosages of 2, 4, and 8g curcumin daily for 3 months
results in circulating levels of 0.51+/-0.11, 0.63+/-0.06, and 1.77+/-1.87uM;
respectively. These Cmax values were attained around 1-2 hours post-administration
and then rapidly declined.
[14]
Another human study found that 3.6g of curcumin
resulted in levels of 11.1+/-0.6nmol/L an hour after consumption, with the lower dose
tested (0.45g) not able to influence serum levels of curcumin;
[46]
this dose is about
1/45th the circulating amount of the 4g curcumin dosage in the previous study, and
the reason for discrepancy is unclear.
[14][46][18]
Higher dosages induce a Cmax of 2.30+/-
0.26 g/mL (10g) and 1.73+/-0.19 g/mL (12g); the reason for the drop in Cmax is
unknown, but hypothesized to be due to saturation of the transporters.
[49]

Increasing the oral dose to 10g induces an AUC of 35.33+/-3.78 g/mL, and a 12g
dose induces an AUC of 26.57+/-2.97 g/mL.
[49]

3.3. Metabolism
The major metabolites of curcumin in humans are curcumin sulfate (via sulfation
enzymes of P450) and curcumin glucuronide (via glucuronidation by P450).
[48][46][49]

In the bile, tetrahydrocurcumin and hexahydrocurcumin have been noted in rats, and
to a lesser degree dihydroferulic acid and ferulic acid.
[50]

3.4. Excretion and Clearance
One study using an intravenous dose of curcumin at 40mg/kg bodyweight in rats
noted that the dose of curcumin was essentially cleared from plasma after one
hour.
[48]


Edit4. Longevity
4.1. Autophagy
Autophagy is a Longevity associated process involving selective destruction of
damaged cellular organelles, sometimes described as cellular housekeeping or
maintenance;
[51][52]
autophagy appears to activated by many polyphenols
[53]
including
curcumin, Resveratrol, silybin (from Milk Thistle), Quercetin, and catechin (common,
but usually known to be a component of the four Green Tea Catechins).
Curcumin (and the metabolite tetrahydrocurcumin
[54]
) appear to induce autophagy
via Akt/mTOR/p70S6K and ERK1/2 signalling pathways (inhibition and activation,
respectively
[55]
) and so far has been detected in glioma,
[55]
uterine,
[56]
oral
cancer,
[57]
and leukemic cells.
[54]
In drosophilia, flies with mutations in the osr-1, sek-1,
mek-1, skn-1, unc-43, sir-2.1, or age-1 genes fail to have life extension from
curcumin
[58]
although mev-1 and daf-16 appear to be indepednent.
[58]

Beyond the possible roles in longevity, autophagy promotion from curcumin is
thought to be protective against gliomas
[59][60]
as glioma cells are resistant to
apoptosis but readily destroyed by autophagy.
[61][62]
Parkinson's pathology may be
attenuated with curcumin via preservation of autophagy
[63]

Curcumin appears to induce autophagy secondary to beneficial modulation of mTOR and
ERK1/2 signalling (inhibition and activation, respectively) which may underlie both
longevity promoting and select anti-cancer effects
4.2. Interventions
In drosophilia, curcumin can induce longevity via antioxidative
properties
[58]
independent of caloric restriction yet is not complementary with caloric
restriction (suggesting acting upon the same pathway)
[64][65][66]
with most efficacy at
100mM of the feed.
[64]
Interesting, administration of curcumin for an entire lifespan
has been shown to have a possible suppressive effect on longevity but
administration for youth (drosophilia health span, which is about the first 30% of life)
prolonged median and maximum lifespan by 49% while administration during middle
age (up to 45% of lifespan) had less promotion and administration in older age
(senesence) reduced median lifespan by 4% (although maximum still increased
11%).
[64]

Curcumin has been shown to promote longevity independent of caloric restriction in fruit
flies, and appears to have more potency in youth than in older individuals (where some
suppressive effects on lifespan are noted)
The metabolite of curcumin, tetrahydrocurcumin, appears to promote longevity in
male mice by 11.7% at a dietary intake of 0.2% tetrahydrocurcumin, but is
dependent on administration as youth.
[67]
This study failed to note an effect when
mice started curcumin feeding at 19 months (the above results noted with earlier
feeding at the 13th month), suggesting the youth requirement extends to
mammals.
[67]
Longevity enhancement in mice has been noted elsewhere.
[68]

Conversely, one mouse study has noted a failure of curcumin to enhance lifespan
when given at similar doses and times in F1 hybrid mice, despite caloric restriction
being effective
[69]
and lifetime administration of curcumin (0.2%) starting at 4 months
has also failed to promote lifespan in UM-HET3 mice.
[70]
Assuming a food intake of
around 8.55g/45g bodyweight
[71]
and body weights around 45g for the majority of the
life
[69][70][67]
an estimated intake of curcumin daily would be 17.1mg (converting to
380mg/kg bodyweight and an estimated human dose
[72]
of 22.8mg/kg or 1.5g for a
150lb person)
There is some promising, but currently mixed, evidence to support the role of curcumin in
anti-aging. This may follow the same motifs of requiring ingestion of curcumin in youth or at
least prior to midlife,
It is an unproven but attractive theory that curcumin works via Chaperone-mediated
autophagy (covered on the Longevity page) due to both being prolongevity yet less effective
in aged subjects (due to decreasing LAMP-2A expression)

Edit5. Neurology
5.1. Glutaminergic Neurotransmission
Curcumin is able to preserve cells in response to glutamate excitotoxicity secondary
to acting on the TrkB receptor (molecular target of BDNF)
[73]
with peak efficacy
appears to occur at 10M (98.57% of control) and 24 hour pretreatment (99.81% of
control);
[73]
absolute protection has been noted elsewhere in hippocampal cells with
15M curcumin.
[74]
Since the glutamate-induced decline in BDNF is fully reversed
with 2.5-10M of curcumin
[73]
it is thought that this plays a significant role.
The protective effect of curcumin against glutamate-induced toxicity extends to
cerebellar granule cells,
[75]
hippocampal cells (5-15M),
[74]
and retinal cells (15M).
[76]

Phosphorylation of the NR1 subunit has been noted to be decreased with 15M
curcumin pretreatment
[76]
and the NR2A subunit appears to be upregulated
[74]
both of
which have been attributed to the reduction in calcium signalling following stimulation
with glutamate.
[74][76]
AMPA and kainate receptors are unaffected by curcumin
treatment,
[74]
and the upregulation of NR2A is thought to play a role since protein
synthesis is required for neuroprotection.
[74]

Curcumin, at least in vitro appears to be remarkably neuroprotective against glutamate
induced cell death, which is either due to a modification of the NMDA receptors or due to
preserving BDNF concentrations
5.2. Cognition
One study assess curcumin and cognitive injury noted that, in control rats that were
not injured, curcumin at 500ppm was able to increase BDNF levels to approximately
140% of control; this was independent of significant changes to CREB (105%) and
phosphorylated CREB (93%).
[77]

5.3. Stress
In vitro, curcumin can abolish the induction of the NMDA receptor subunit R2B
mRNA by corticosterone
[78]
when corticosterone is incubated at 0.1mM and curcumin
at concentrations as low as 0.62uM;
[79]
this may be related to the ability of
curcumin in vitro to prevent corticosterone-induced neuronal death.
[79]

Curcumin at 5, 10, and 20mg/kg was fed to rats daily for 21 days, and upon being
subject to acute stress and subsequent cognitive testing; curcumin dose-
dependently reduced the negative influence of stress on spatial memory with both
higher doses (10, 20mg/kg) being significant and slightly less effective than 10mg/kg
imipramine.
[79]

5.4. Neuronal Injury
Curcumin at 500ppm in rats (a dose similar to some anti-Alzheimer's dosages
[80]
) for
4 weeks on either a high fat or normal diet who were then subject to a fluid
percussion injury noted that the increased oxidation in the brain (139% normal diet,
239% high fat diet; high fat did not induce oxidation without neural injury) was
reduced to 45-47% in both groups and BDNF was normalized despite its inherent
reduction in neural injury,
[77]
and other proteins that tend to be reduced in this form of
injury are somewhat normalized with curcumin.
[81]
Cognitive performance was
declined after injury, and the reduction was attenuated but not normalized.
[77]

5.5. Alzheimer's Disease
Curcumin is able to inhibit aggregation of beta-amyloid proteins in the brain, and thus
prevent neural inflammation which would normally be downstream from said
aggregation. The former has been noted in vivo
[82]
and has been hypothesized to be
the reason as to why higher circulating levels of Beta-Amyloid have been noted
(statistically insignificant) with curcumin supplementation
[83]
as beta-amyloid is
prevented from aggregating in the brain,
[84]
and thus must circulate somewhere.
Mechanistically, curcumin may be able to reduce Beta-amyloid build-up in neural tissue
In a rodent model with advanced Alzheimer's Disease characterized by beta-amyloid
accrual, curcumin was able to attenuate the decline in neural performance and was
synergistic with DHA; a component fatty acids from Fish Oil.
[85]
This synergism may
be related to how both agents can reduce beta-amyloid aggregation, but by differing
mechanisms;
[86][87]
some authors hypothesize that this synergism may be further
enhanced by exercise
[88]
due to an interaction with exercise and fish oil on neuronal
plasticity.
[89]

A 6-month trial has been conducted on Curcumin and Alzheimer's, using basic
curcumin at either 1 or 4g daily for 6 months in a population of 50+ year old chinese
persons suffering from cognitive decline for at least 6 months prior to trial onset.
Scores on the MMSE, a rating scale for Alzheimer's, increased progressively in the
placebo (indicating cognitive decline) but were mostly static in both curcumin
groups.
[83]
This trial is limited in statistical power due to its sample size of 27
completions and multiple confounds, however.
[83]

Some therapeutic promise, but evidence is limited
5.6. Analgesia
Curcumin (or more specifically, turmeric) appears to have a historical usage as pain
relief following trauma.
[90]

Curcumin at 400mg (2,000mg of Meriva) in persons with acute algesic episodes
appears to have a potency comparable to 1,000mg acetominophen and 100mg
nimesulide (trending to be more potent than acetominophen yet less potent than
nimesulide).
[91]
It appeared to start working within two hours (slower than nimesulide)
with maximal efficacy at 3-4 hours and a loss of efficacy but not yet normalized
within 12 hours.
[91]
This same supplement (2g Meriva) seems effective in reducing
pain in osteoarthritic persons over three months
[92]
and eight months.
[93]

In patients of laparoscopic cholecystectomy (associated with pain and fatigue
following the operation) given 500mg curcumin once every six hours noted that
supplementation was associated with a reduction in pain as reported by a 100 point
VAS (rating scale), where although no difference was noted on day three followup at
weeks 1-3 was associated with significantly less (approximately half) the pain.
[94]

High dose curcumin supplementation appears to be effective in treating post-operative pain,
arthritic pain, and in persons who suffer from pain routinely. High doses of curcumin seem
comparable in potency to some reference drugs

Edit6. Cardiovascular Health
6.1. Cardiac Tissue
Curcumin is suspected to be able to protect against cardiac hypertrophy,
inflammation, and thrombosis via inhibition of the protein p300, a Histone
acetyltransferase (HAT) and it's downstream pathways. This inhibition has been
shown to prevent heart failure in rats.
[95]

6.2. Red Blood Cells
Ex vivo incubation of red blood cells from healthy volunteers in the concentration
range of 1-100g/mL (0.368-36.8M) noted that 10g/mL (3.68M) was able to form
echinocytes (small and even spiky protrusions on red blood cells) within 30 minutes,
and was deemed to be indicative of a toxic effect.
[96]

6.3. Artherosclerosis
Plasma levels of sICAM (involved in the pathology of artherosclerosis
[97]
) appear to
be very slightly but significantly reduced with 80mg curcumin (bioavailability
enhanced form) daily for four weeks in otherwise healthy middle aged persons.
[98]

6.4. Endothelium
Via induction of Heme-Oxygenase 1 (HO-1), curcumin can prevent the endothelial
(blood vessel) dysfunction associated with high blood glucose in a dose dependent
manner and may offer protection from side-effects associated with diabetes.
[99]
In an
animal model of diabetes, curcumin has also preserved a degree of endothelial
health during disease progression (although it was unable to, at 200mg/kg
bodyweight, prevent changes).
[100]

This protective effect has also been demonstrated with LPS insult, a pro-
inflammatory condition, and curcumin dosed at 50-100mg/kg bodyweight in
rats;
[101]
changes in endothelial contractability (via TNF-a) have also been reduced
with curcumin.
[102]

The concentration of curcumin that induces HO-1 minimally (2M) also appears to
perturb endothelial cell replication, and 100nM curcumin has been noted to cause
disproportionate DNA segregation and increase micronucleation.
[103]

Appears to hold protective effects on blood vessels, but its clinical significance is not known;
seems promising, and most likely mediated through Heme Oxygenase-1
6.5. Blood Flow
Supplementation of 150mg curcumin (enhanced absorption) was associated with an
increase in blood flow as assessed by flow mediated vasodilation over the course of
8 weeks, the potency being comparable to thrice weekly physical exercise.
[104]

Oral ingestion of curcumin at 0.2% of the rat diet is able to restore the age-related
decline in endothelial reactivity and nitric oxide to the levels of a youthful control,
although the youthful rats experienced no such benefit.
[105]

Oral supplementation of 80mg bioavailability enhanced curcumin daily for four weeks
in otherwise healthy persons has resulted in a significant (about 40%) increase in
circulating nitric oxide
[98]
which coincided with a similarly large spike in catalase
activity.
[98]

In regards to nitric oxide, orally ingested curcumin appears to increase nitric oxide
concentrations in serum. This has been noted in humans, and the degree of increase appears
to be quite large
Protection from L-NAME induced hypertension
[106]
and cyclosporin-A induced
endothelial dysfunction
[107]
has been noted with curcumin at 200mg/kg or 50-
100mg/kg of its metabolite (tetrahydrocurcumin).
One human study using 500mg Turmeric thrice daily (22.1mg curcumin each time)
has noted significant decreases in blood pressure in persons with nephritis.
[108]

In postmenopausal women given 150mg curcumin daily (colloidal nanoparticles)
daily for eight weeks, supplementation was associated with slightly decreased
systolic blood pressure (112+/-10mmHg to 107+/-10mmHG) and no changes in
diastolic pressure nor heart rate.
[104]

6.6. Triglycerides
500mg curcumin daily has been shown to reduce triglycerides by 47% (110+/-
21mg/dL to 58+/-9mg/dL) over 7 days, while a higher dose of 6g reduces
triglycerides by 15% (93+/-13mg/dL to 79+/-11mg/dL); the cause for the lowered
efficacy of high doses is not known.
[109]
These were seen in otherwise normal weight
and healthy young subjects.
[109]

In otherwise healthy postmenopausal women, 150mg curcumin daily (enhanced
absorption) has failed to reduce triglycerides
[104]
while another study using 80mg of a
lipidated form for four weeks in otherwise healthy middle aged persons slightly
reduced triglycerides.
[98]

6.7. Cholesterol and Lipoproteins
500mg curcumin daily has been demonstrated to reduce total cholesterol levels by
17% while a higher dose of 6,000mg reduces total cholesterol by 5% in otherwise
healthy subjects.
[109]

150mg of bioavailability enhanced curcumin in otherwise healthy postmenopausal
women has failed to reduce total cholesterol, HDL-C, and LDL-C over eight
weeks.
[104]


Edit7. Interactions with Glucose Metabolism
7.1. Mechanisms
In liver cells, Curcumin at 20uM appears to activate Adenosine Monophosphate
Kinase (AMPK) to the same degree as Metformin (2mM), which is 400-fold more
potent on a concentration basis.
[110]
Although glucose uptake into cells tends to be
secondary to AMPK activation
[111]
and has been noted with both Metformin and
another potent AMPK activator Berberine, this study noted that Curcumin failed to
induce glucose uptake, instead noting a trend to reduce glucose uptake.
[110]
This
inhibition of glucose uptake has been noted elsewhere, where 100uM Curcumin was
shown to inhibit insulin-stimulated GLUT4 translocation
[112]
despite curcumin twice
being shown to not significantly interact with the insulin receptor itself (not cell type
specific).
[113][110]

Remarkably potent AMPK activator, yet seems to fail at inducing glucose uptake into cells
(and thus undermines many of the inherent benefits of AMPK as it pertains to diabetes)
7.2. Blood glucose
The effect of curcumin to lower blood glucose was one of the first effects to be seen
with curcumin, seen in 1972.
[114][115]

One of the mechanisms of this blood glucose lowering effect is by stimulating
Adenosine Monophosphate Kinase (AMPK) in skeletal muscle, drawing in
glucose.
[116]
This effect is enhanced with the presence of insulin, and since insulin
also activates the PI3K pathway curcumin appears to be synergistic with insulin in
regards to reducing blood sugar levels.
[117]
Curcumin can also activate AMPK in other
cells, such as liver cells
[110]
and some cancer cells.
[118]

7.3. Diabetes
Curcumin is able to alleviate the downstream inflammatory reactions that occur
during times of diabetes and metabolic syndrome in rats
[119]
and, vicariously through
its anti-inflammatory effects, improve insulin resistance.
[120][119]

Supplementation of curcumin to a prediabetic population over the course of nine
months appears to preserve pancreatic function and improve both insulin sensitivity
and adiponectin relative to control, and curcumin was able to prevent any occurrence
of diabetes during this time frame (whereas 16.4% of control developed it).
[121]


Edit8. Fat mass and Obesity
8.1. Mechanisms
Curcumin has been noted to attenuate lipolysis induced by TNF- and isoproterenol
(representative of catecholamines) in 3T3-L1 adipocytes, which was thought to be
secondary to suppression of ERK1/2 activation.
[122]
ERK1/2 is known to be regulated
by AMPK
[123]
which curcumin has been found to activate
[124]
(in liver cells, this was
noted to be of comparable potency to Metformin but requiring 20uM to Metformins
2mM
[110]
); all of these events being similar to the known AMPK activatorBerberine.
Fatty Acid Synthase (FAS) is inhibited by Curcumin with an IC50 of 26.8M (59.1M
in regards to -ketoacyl reduction); the inhibition was noncompetitive when NADPH
was the substrate, but mixed competitive with either acetyl or malonyl Coenzyme
A
[125]
and had both slow and fast acting components in a concentration and time
dependent manner.
[125]
20uM of Curcumin abolished lipid accumulation in isolated
3T3-L1 cells undergoing differentiation, which may have been due to downregulation
of PPAR and CD36;
[125]
another study notes that PPARy activation by Curcumin is
dependent on AMPK activation.
[124]

Curcumin appears to be a potency activator of AMPK
8.2. Inflammation (Adipose Tissue)
Inflammation appears to play a role in obesity, particularly one cytokine known as
TNF-; adipose of genetically obese mice overexpress TNF- which is also seen in
adipocytes of overweight individuals
[126]
and TNF- expression appears to negatively
correlate with LPL activity.
[127]
TNF- itself does exert lipolytic activity,
[128]
so its
elevation in obesity may be as a biomarker of underlying dysregulation rather than
a per se contributor; the possibility of TNF- resistance (a phenomena similar to
insulin resistance, as TNF- has its own receptor class on adipocytes
[129]
) also being
possible.
[126]
TNF- is a potent activator of nF-kB (nuclear receptor) which mediates
many of its effects,
[130]
and overactivity of nF-kB and TNF- in adipocytes are both
highly correlated with metabolic syndrome and obesity.
[126]

In general, excessive inflammation in adipocytes (assessed by looking at biomarkers thought
to be representative of inflammation such as TNF-) is highly correlated with obesity and
metabolic syndrome; interventions which reduce inflammation in adipocytes tend to also be
those that can reduce fat mass in persons suffering from excessive inflammation
A reduction in immune cell infiltration in adipose tissue has been noted in vivo when
mice are given 3% curcumin in the diet for up to 4 weeks, as assessed by
histological examination.
[119]

8.3. Adipokines
Curcumin appears to be associated with an increased FOX01 transcription activity
and increased adiponectin production in vivo (with higher circulating levels of
adiponectin noted in both genetic and diet induced obesity, but lean control mice did
not experience an increase);
[119]
FOXO1 is known to positively influence adiponectin
transcription in fat cells.
[131][132]

Leptin secretion from adipocytes appears to be suppressed with 12 and 24 hour
incubation with Curcumin in a concentration and time dependent manner.
[133]

8.4. Interventions
In obese mice given curcumin (3% of feed), despite noting an increase in food intake
relative to control; this reduction in body fat was not observed in normal mice.
[119]

8.5. Side-effects related to Obesity
In a study on rats, sympathetic activation from circulating fatty acids (commonly seen
in obesity) is reduced via curcumin's lipid lowering effects; the resulting state is
cardioprotective independent of weight loss.
[134]

Curcumin can also suppress angiogenesis in rat fat cells, a longer term adaptation
associated with prolonged obesity.
[135]
This is a general mechanism that applies to
more cell types as well.
[136]


Edit9. Interactions with Skeletal Muscle
9.1. Acute Protective Effects
Through it's anti-oxidant effects, curcumin can ameliorate oxidative damage to
skeletal muscle via Ischemia/Reperfusion when preloaded at 100mg/kg (I.P
injection) to rats, with a potency greater than Vitamin E.
[137]
Curcumin also
ameliorates the increase in inflammatory cytokines associated with
Ischemia/Reperfusion injury.
[137][138]

As for the mechanisms of the above, curcucmin (5-10uM) appears to increase
Glucose-Regulated Protein 94 (Grp94) expression, which regulates calcium
homeostasis; this regulation of calcium homeostasis appears to precede the
standard inhibition of nF-kB activation and reduce the state of oxidation when an
oxidative insult is produced.
[139]
Interestingly, curcumin can also inhibit upregulation
and damage from lead via preventing Grp94 upregulation,
[140]
and general protection
against cadmium as well.
[141]

9.2. Catabolism/Anabolism
Curcumin (via injection) is also implicated in increasing the recovery of skeletal
muscle capacity associated with deloading, although it was not able to preserve
skeletal muscle mass during deloading.
[142]
These results differ from earlier ones
showing a 100mg/kg oral dose of curcumin in rats was able to reduce muscular
atrophy while a higher dose of 250mg/kg actually improved skeletal muscle
weight.
[143]

Curcumin is able to inhibit Atrogin1/MAFbx and its subsequent ubiquitin ligase
activity in vitro at 25uM,
[144]
which induces skeletal muscle catabolism downstream of
p38/MAPK induced by TNF-a. This has been confimed in rats with injections of 10-
60ug/kg curcumin daily for 4 days which preserved lean mass in the face of LPS, by
preventing p38 activation and the subsequent Atrogin1/MAFbx activation.
[144]

9.3. Glucose metabolism
Skeletal muscle, via glucose uptake and oxidation, is a tissue regulator of glucose
metabolism.
Some fatty acids, such as palmitic acid, can activate (phosphorylize) IRS-1 which
causes negative feedback to the insulin receptor and desensitizes muscle cells to
insulin-stimulated glucose uptake; curcumin appears to prevent this from
occurring.
[145]
This effect is shared by Green Tea Catechins.
[145]
Improvements in this
mechanism of insulin resistance have been seenin vivo with dose-dependent oral
doses of curcumin at 50, 150, and 250mg/kg bodyweight.
[146]
AMPK activation
appears to be a key intermediate in these effects.
[146][116]
Beyond acting upon IRS,
curcumin may also increase glucose uptake into skeletal muscles by acting on
muscarinic acetylcholine receptors and then through PLC and PI3K.
[147]

Curcumin has been implicated in reversing some abberations in skeletal muscle
associated with type II diabetes, such as upregulation of beta-adrenergic receptors
and Akt,
[148]
the downregulation of NRF2 and Heme Oxygenase-1,
[149]
and
downregulation of AMPK and CPT-1.
[146]
At least one study has suggested that the
state of diabetes may be a prerequisite, and although it didn't measure all above
parameters it did note no effects of curcumin in non-diabetic mice.
[150]


Edit10. Oxidation and Anti-Oxidation
10.1. Direct Antioxidative Effects
Curcumin has been noted to sequester superoxide (O2-) radicals with an IC50 of
5.84g/mL.
[151]

10.2. Interventions
When comparing 500mg curcumin against 6g curcumin, the anti-oxidative potential
of the two does not significantly differ; if anything, 500mg curcumin seems superior
due to insignificantly higher AUC of the increase in anti-oxidant abilities as measured
by ORAC.
[109]
This is thought to be due to a possible pro-oxidant effect of curcumin at
higher dosages, seen with other anti-oxidants.
[152][153]


Edit11. Interactions with Inflammation and Immunology
11.1. Mechanisms
One of curcumin's most well-researched effects on inflammation is inhibiting TNF-a
induced activation and nuclear translocation of nF-kB, a protein that influences the
genetic code to produce inflammatory cytokines. This has been seen in immune cells
after oral ingestion of 150mg curcumin (Resveratrol at 75mg, Green Tea
Catechins at 150mg, and soy at 125mg as confounders)
[154]
but also in isolation in
vitro
[155]
and in vivo.
[156][157][15][158]
Activation of nF-kB can increase protein content
(amounts) of Cyclooxygenase-2 (COX-2), a pro-inflammatory enzyme; pretreatment
with curcumin reduces COX-2 upregulation induced by inflammatory
cytokines.
[159]
Other pro-inflammatory enzymes that are suppressed by curcumin are
iNOS, LOX (directly inhibited), and Phospholipase A2 (directly.)
[160]

Curcumin appears to be able to suppress most adhesion molecules investigated,
including E-selectin and P-selectin, ICAM-1, VCAM-1, and ELAM-1, the latter three
are due to nF-kB inhibition downstream of Akt.
[161][162]

Curcumin can reduce inflammation through a variety of means; preventing pro-inflammatory
signals from acting on the nucleus (nF-kB related), reducing the ability of immune cells to get
to sites of inflammation (adhesion related), and reducing the exacerbation of already present
inflammation by reducing the activity of inflammatory enzymes (COX2, LOX related).
11.2. Joint Inflammation and Arthritis
Curcumin is associated with reducing a variety of inflammatory signals, and a lot of
them that are associated with arthritis and inflammatory joints.
[163]

When dosed equally (200mg/kg in rats), curcuminoids from turmeric are 4.6-8.3%
more effective than the active components ofGinger in suppressing inflammation
associated with cytokine release in arthritis.
[164]
Both herbs are more potent than
indomethacin.
[164]

A pilot study over three months has noted that Meriva is able to improve symptoms
of osteoarthritis as assessed by WOMAC by 58%
[92]
and a later study with 1,000mg
turmeric as Meriva tablets (200mg curcuminoids of 75% curcumin) over eight months
noted that the total symptoms of knee osteoarthritis were reduced to 41% of baseline
values with improvements in pain, stiffness, and physical functioning (as assessed
by treadmill testing).
[93]

Orally administrated curcumin appears to be highly effective in reducing symptoms of knee
osteoarthritis, with the potency being comparable to other highly efficacious supplements
like Boswellia serrata or S-Adenosyl Methionine
11.3. Virology
One study found that curcumin was able to suppress replication of the Rift Valley
fever virus and its fully virulent form (ZH501) in vitro.
[165]
A modification to the IKK-
protein (which inhibits IB and serves to enhance nF-kB signalling) keeps IKK- in
an active state and exacerbates inflammatory signalling, curcumin can bind to IKK-
and allow IB to suppress nF-kB activation and inflammation, which prevents virus
replication.
[165]


Edit12. Interactions with Hormones
12.1. Testosterone
Curcumin, at 100mg/kg bodyweight in rats, has been shown to preserve testosterone
levels when coadministered with a drug (Metronidazole) that causes testosterone
reductions and worsens parameters of sperm.
[166]

Protective effects on the testes have also been noted with curcumin in regards to
alcohol, where curcumin (80mg/kg bodyweight) was able to preserve testicle
structure and testosterone levels despite alcohol consumption,
[167]
most likely though
preventing the oxidation of ethanol to acetylaldehyde.
[168]
Other compounds that
damage the testicles and reduce testosterone, but are protected against by
curcumin, include excessive chromium levels
[169]
and cadmium.
[170]

When looking at the 17beta-HSD3, the final step in testicular testosterone synthesis,
curcumin was found to be a noncompetitive inhibitor with an IC50 of 2.3uM, and
brought Luteinizing-Hormone stimulated testoterone levels down to 34% of control at
a concentration of 10uM.
[37]
This effect was not dose-dependent, and concentrations
of 1uM were not significantly different from 0.1uM and control cells.
[37]

Curcumin may also possess inhibitory actions against 5-alpha reductase, the
enzyme that converts testosterone into the more potent androgen DHT. The
IC50 value is reportedly between 5-10uM.
[38]

Given the above two mechanisms (17beta-HSD3 and 5AR inhibition) are anti-
androgenic in nature, it would be prudent to observe in vivo effects of curcumin. The
only current study on the matter used injections of PEG-curcumin at 0.5mg (giving a
Cmax of 7ug/mL to then decline to 1ug/mL) noted a decrease in circulating
testosterone levels and function of seminal vesicles, although testicle weight did not
decline.
[171]

In regards to aromatase, the enzyme that converts testosterone to estrogen (and
thus higher activity would mean a more anti-androgenic profile), curcumin does not
directly inhibit aromatase in vitro
[172]
but appears to reduce the catalytic activity of
aromatase (also known as CYP1A) in mice.
[173]
Clinical relevance of these effects is
not known.
Curcumin appears to have protective effects on testicular functions, but possesses anti-
androgenic activity. The concentration required for inhibition is high, but it appears to
occur in vivo when it is met; it is uncertain what oral dose is needed for these effects, but it
might occur with superloading and increasing bioavailability. Low doses of curcumin may
have no adverse effect whatsoever
12.2. Estrogen
In regards to possible anti-estrogen effects, the lack of inhibition on aromatase
[172]
but
potential to reduce catalytic activity of aromatase
[173]
suggests some interactions may
exist at this stage. One study comparing normal rats versus a Menopausal model
(ovariectomized) noted that 10mg/kg oral ingestion in the normal mice was able to
reduce circulating estrogen levels.
[174]

100nM of Curcumin is able to act as an agonist at estrogen receptors in MCF7
breast cancer cells, but has low activation of target genes relative to estradiol,
although more potent than Quercetin and Enterolactone (from Sesamin).
[175]
It is
possible that Curcumin may act as a Selective Estrogen Receptor Modulator
(SERM) and compete for the more potent estradiol, as it has been noted to reduce
estrogen-induced cell proliferation elsewhere (was not tied directly to the estrogen
receptor in this study).
[176]

In regards to anti-estrogenic activity, limited but theoretical potential of Curcumin to be
antiestrogenic via either reducing the effects of aromatase or via acting as a SERM (not yet
wholly established)
A pegylated curcumin derivative (similar bioactivity, designed for ingections) at
500mg in rats is able to exert estrogenic effects as assessed by sex organs (uterine
changes indicative of estrogenicity in females).
[171]

High doses appear to be estrogenic

Edit13. Implications in Cancer Metabolism
13.1. General (Not mechanisms)
Curcumin has the ability to protect DNA from oxidation via the heavy metal
arsenic
[177]
, and this protection has been demonstrated in human trials after oral
ingestion 1g of a 20:1 curcumin:piperine (Black Pepper) combination for 3
months.
[178]
Blood lymphocytes were the biomarker for DNA damage.
In rats fed a low dose of curcumin (0.03% of the diet), curcumin was able to prevent
formation of adducts in hepatic DNA induced by an injection of the carcinogenic
benzo(a)pyrene.
[179]
Curcumin also prevented adducts in colonic cells when
administered at 2% of the diet with meals.
[180]

13.2. General (Mechanisms)
One of the mechanisms under investigation for chemoprotective effects of curcumin
is the inhibitory effect on nF-kB, a protein that can influence genetic coding and
transcription when activated. Normally, TNF-a (a pro-inflammatory cytokine)
positively influences nF-kB activity and induces cell growth, survival, and
inflammation. Curcumin can inhibit the interaction between the two molecules
without reducing TNF-a levels, and aside from the inhibition of cytoprotection the
elevated levels of TNF-a can induce cellular death via Fas-associated protein cell
death and caspase-8.
[181]
This mechanism appears to 'sensitize' cells to cell death
induced by TNF-a by inhibiting cellular survival via nF-kB
[182][183]
and is most likely due
to curcumin's ability to prevent or reduce activation of p38 in the face of other
activators.
[184][185][186]

Curcumin is also able to suppress a transcription factor associated with nF-kB, the
Notch family of proteins; this potentiates the suppressive effects on nF-kB, but
Notch-1 overexpression is able to act in reverse and attenuate curcumin's
suppressive effects on nF-kB.
[41]

Other notable products downstream of nF-kB that are reduced by curcumin
administration are cyclooxygenase-2 (COX-2), cyclin D1, adhesion molecules,
MMPs, inducible nitric oxide synthase, Bcl-2, Bcl-xL, and tumor necrosis factor
(TNF); most of which are associated with cancer metabolism in some
manner.
[45][44][159]
Curcumin appears to directly inhibit IKK as the method of reducing
nF-kB translocation.
[187]

In a B-CLL cell culture, curcumin was able to induce apoptosis with an IC50 of 5.5uM
while its effects in healthy mononucleated (non-cancerous) cells were associated
with an IC50 of 21.8uM.
[155]

13.3. Prostate Cancer
Secondary to inhibiting expression of the cytokines CXCL1 and CXCL2 (a
downstream effect of nF-kB translocation inhibition), curcumin appears to negatively
regulate several factors that can lead to prostatic tumor meta-stasis (COX2, SPARC
and EFEMP) which can lead to less metastasis in vivo.
[187]
As siRNA inhibition of
CXCL1/2 also had these effects, this appears to be the metabolic lever of concern.
[187]


Edit14. Intestinal Interactions
Curcumin tends to be most relevant to the colon due to its poor oral bioavailability.
Oral bioavailability is a measure of how much of a molecule as a percentage is
absorbed from the gut, and whatever is left over (in this case, a large amount) is
carried on to the colon where it may interact with colonic microflora or the colonic
walls.
14.1. The Colon and Ulcerative Colitis
One double-blinded multicenter study noted that, in conjunction with standard
therapy for Ulcerative Colitis, 2g of curcumin daily (1g with two different meals) was
able to confer significant protection against colonic inflammation and improve
symptoms of Ulcerative Colitis for as long as it was used.
[188]
Less mortality and
relapse was noted with curcumin usage, but the difference was not significant 6
months after cessation of usage like it was for the 6 months it was being used
for.
[188]
These effects were seen earlier in both Ulcerative Colitis and Crohn's Disease,
two human conditions associated with intestinal inflammation.
[189]


Edit15. Interactions with other Organ Systems
15.1. Liver
Curcumin appears to be able to reduce diet-induced liver fat builded (steatohepatitis)
at 0.15% of the diet which is thought to be secondary to activation of AMPK and
induction of PPAR.
[190]

15.2. Kidneys
At least one human intervention showed that curcumin was able to suppress diabetic
nephropathy (related to kidney function) and decrease proteinuria at a dose of
500mg turmeric (22.1mg curcumin) thrice a day with meals for 2 months.
[191]
The
mechanism of action appears to be suppressing pro-inflammatory cytokines like
TGF-b and IL-8.
[191]
These benefits have been shown to extend to nephritis
associated with lupus at the same dosing protocol in humans.
[108]

Curcumin exerts this apparent kidney protection via suppressing inflammation and
related cytokines or mRNA associated with inflammation (MCP-1, IL-8, nF-
kB).
[192]
Curcumin at 5mg/kg bodyweight (rats) is able to prevent histological changes
(related to macrophage infiltration) in kidney structure associated with experimental
LPS injections when administered simultaneously
[192]
and in delaying the inevitable
progression of renal failure.
[193]

Some protective changes are also present, as curcumin can upregulate Heme-
Oxygenase 1 in kidney cells partially via nF-kB suppression
[194]
and this mechanism is
linked to kidney protection effects.
[195]

Demonstrated to have protective effects on the kidneys in clinical settings, and animal
studies suggest this may extend to preventative measures as well

Edit16. Nutrient-Nutrient Interactions
16.1. Turmeric
Turmeric is the Spice that curcumin and other curcuminoids were initially derived
from as it is the best natural source of curcumin.
Essential oil compounds of turmeric (turmerones) appear to be either additive or
synergistic with curcumin in suppressing dextran sulfate sodium induced colitis, with
the combination able to abolish the effects of the toxin.
[196]

16.2. Piperine
Pairing Curcumin with Piperine, a Black Pepper extract that is also an inhibitor of
glucuronidation enzymes in the intestines and liver, is able to increase bioavailability
20-fold (2000% of baseline values) when 20mg piperine is paired with 2g
curcumin.
[16]

The pairing of the two has been demonstrated synergistic in attenuating
benzo(a)pyrene toxicity in various tissues
[197][198]
as well as mitigating DNA damage.
[199]

Interestingly, this synergism does not seem to apply to preventing hypertension
induced by L-NAME; both compounds are effective in attenuating high blood
pressure from a lack of Nitric Oxide, but their effects are not even additive.
[200]

16.3. Ginger
Ginger and Turmeric are both plants in the same family of plants, and may have
related phytonutrient profiles due to this association.
One study investigating the combination of 6-gingerol enhanced ginger and turmeric
topical solution (at 3% and 10% respectively) found enhanced wound healing with
both compounds in isolation and slightly better recovery with the combination,
although not synergistic.
[201]

The combination appears to be more effective than either compound in isolation in
suppressing some adverse blood parameters associated with metabolic syndrome,
such as high blood sugar and lipids.
[202]

16.4. Soy Isoflavones
The soy isoflavones, particularly genistein and daidzein, appear to be synergistic
with curcumin as it pertains to reducing androgen receptor content and circulatin
Prostate-Specific Antigen (PSA) levels in otherwise healthy men; insinuating the
combination could be useful against prostate cancer.
[203]
The dosages used were
fairly low in this study, 40mg of isoflavones (66% daidzein, 10% genistein) and
100mg curcumin daily for 6 months, and dropped PSA from 18.8+/-12.4 to 10.2+/-
6.2ng/mL.
[203]

16.5. Docosahexaenoic acid
One component of Fish Oil, docosahexaenoic acid (DHA), exert synergistic effects in
anti-cancer signalling in breast cancer cells which is apparently unique when looking
at the mechanisms of either compound in isolation.
[204]
This synergism apparently
extends over into each compounds anti-inflammatory effects, and this mechanism
extends to EPA.
[205]

16.6. Vincristine
Curcumin at 1uM concentration in cancerous leukemia cells has been shown to
synergistically enhance the actions of Vincristine, an alkaloid isolated from
Madagascar Periwinkle (not to be confused with Vinpocetine, from another species
of Periwinkle). This occurred in 4 out of 5 samples when Vincristine was incubated at
10uM.
[155]

16.7. Rolipram
Curcumin shows synergism with Rolipram (a potent PDE4 inhibitor); PDE4 inhibitors
increase cAMP levels via PKA in cancerous leukemia cells.
[155]
Additive in 1 out of 5
tested samples and synergistic in the other four.
[155]

A nutraceutical PDE4 inhibitor (at the moment, synergism untested) is Resveratrol.
16.8. Iron
A wide variety of phenolic compounds (of which curcumin is one) are able to bind to
dietary non-heme iron and inhibit its absorption; this is seen with Green Tea
Catechins and Quercetin mostly. Curcumin has been found to interact with some
ions after digestion.
[206][207]

When testing for the interaction of turmeric and iron, whole turmeric at 0.5g was
found to not adversely affect iron absorption.
[208]

16.9. Itself
Curcumin is one of the four curcuminoids, a curcuminoid being defined as a
molecule with two ferulic acid moieties bound together. At least one study has looked
at the effects of each ingredient in isolation and the combination, and in regards to its
nematocidal effects the four curcuminoids show synergism with each other.
[2]

16.10. Garcinol
Garcinol is a polyisoprenylated benzophenone chalcone molecule that is found in
Garcinia Indica, a plant in the mangosteen family of fruits.
[209]
It was found synergistic
in inducing apoptosis in pancreatic tumor cells with an apparent synergism 2-10 fold
higher than the sum of the two.
[210]


Edit17. Safety and Toxicology
17.1. General Safety
According to human interventions investigating anti-cancerous effects of curcumin,
doses up to 10g daily of curcumin are not associated with any acute or salient signs
of toxicity.
[211]
When using enhanced formulations to increase circulating levels of
curcumin, 1g of MERIVA (Curcumin bound to lecithin) over 8 months is not
associated with any side-effects.
[93]

17.2. Side-effects
Dosages of 6g daily have been associated with minor flatulence and a yellowing of
the stool, both of which stopped after supplement cessation.
[109]

Scientific Support & Reference Citations
References
1. Chemistry and biological activities of C. longa
2. Kiuchi F, et al. Nematocidal activity of turmeric: synergistic action of curcuminoids. Chem Pharm Bull (Tokyo). (1993)
3. Changtam C, et al. Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species. Eur J Med Chem. (2010)
4. Qualitative and quantitative analysis of curcuminoids in herbal medicines derived from Curcuma species
5. Chang CJ, et al. Beneficial impact of Zingiber zerumbet on insulin sensitivity in fructose-fed rats. Planta Med. (2012)
6. Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets. (2011)
7. Usharani P, et al. Effect of NCB-02, atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients
with type 2 diabetes mellitus: a randomized, parallel-group, placebo-controlled, 8-week study. Drugs R D. (2008)
8. Venkataranganna MV, et al. NCB-02 (standardized Curcumin preparation) protects dinitrochlorobenzene- induced colitis through down-
regulation of NFkappa-B and iNOS. World J Gastroenterol. (2007)
9. Esatbeyoglu T, et al. Curcumin-from molecule to biological function. Angew Chem Int Ed Engl. (2012)
10. Scotter MJ. Methods for the determination of European Union-permitted added natural colours in foods: a review. Food Addit Contam Part A
Chem Anal Control Expo Risk Assess. (2011)
11. Wang YJ, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal. (1997)
12. Sharma RA, et al. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res.
(2001)
13. Lao CD, et al. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med. (2006)
14. Cheng AL, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer
Res. (2001)
15. Dhillon N, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. (2008)
16. Shoba G, et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. (1998)
17. Marczylo TH, et al. Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine. Cancer
Chemother Pharmacol. (2007)
18. Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical
research. Altern Med Rev. (2009)
19. Cuomo J, et al. Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod. (2011)
20. Sasaki H, et al. Innovative preparation of curcumin for improved oral bioavailability. Biol Pharm Bull. (2011)
21. Zhongfa L, et al. Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice. Cancer
Chemother Pharmacol. (2012)
22. Kanai M, et al. Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved
bioavailability, in healthy human volunteers.Cancer Chemother Pharmacol. (2012)
23. Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol. (1997)
24. Angel P, et al. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. (1987)
25. Dhandapani KM, Mahesh VB, Brann DW. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and
NFkappaB transcription factors. J Neurochem. (2007)
26. Bierhaus A, et al. The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA
and activation of NF-kappa B. Thromb Haemost. (1997)
27. Dickinson DA, et al. Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. FASEB J.
(2003)
28. Beevers CS, et al. Curcumin disrupts the Mammalian target of rapamycin-raptor complex. Cancer Res. (2009)
29. Yu S, et al. Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism. Mol Cancer
Ther. (2008)
30. Takeuchi T, et al. Structural relationship of curcumin derivatives binding to the BRCT domain of human DNA polymerase lambda. Genes
Cells. (2006)
31. Leu TH, et al. Direct inhibitory effect of curcumin on Src and focal adhesion kinase activity. Biochem Pharmacol. (2003)
32. Reddy S, Aggarwal BB. Curcumin is a non-competitive and selective inhibitor of phosphorylase kinase. FEBS Lett. (1994)
33. Lee CW, et al. Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-alpha in human tracheal smooth muscle cells:
involvement of MAPKs, NF-kappaB, p300, and histone acetylation. J Cell Physiol. (2006)
34. Fang J, Lu J, Holmgren A. Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer
activity. J Biol Chem. (2005)
35. Skrzypczak-Jankun E, et al. Structure of curcumin in complex with lipoxygenase and its significance in cancer. Int J Mol Med. (2003)
36. Gupta KK, et al. Dietary antioxidant curcumin inhibits microtubule assembly through tubulin binding. FEBS J. (2006)
37. Hu GX, et al. Curcumin derivatives inhibit testicular 17beta-hydroxysteroid dehydrogenase 3. Bioorg Med Chem Lett. (2010)
38. Liao S, et al. Growth suppression of hamster flank organs by topical application of catechins, alizarin, curcumin, and myristoleic acid. Arch
Dermatol Res. (2001)
39. Bustanji Y, et al. Inhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in
vivo evaluation. J Enzyme Inhib Med Chem. (2009)
40. Shin HK, et al. Inhibitory effect of curcumin on motility of human oral squamous carcinoma YD-10B cells via suppression of ERK and NF-
kappaB activations. Phytother Res. (2010)
41. Wang Z, et al. Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in
pancreatic cancer cells. Cancer. (2006)
42. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. (1999)
43. Aggarwal S, et al. Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of
nuclear factor-kappaB signaling. Int J Cancer. (2004)
44. Singh S, Aggarwal BB. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) {corrected}. J Biol
Chem. (1995)
45. Sung B, et al. Cancer cell signaling pathways targeted by spice-derived nutraceuticals. Nutr Cancer. (2012)
46. Garcea G, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the
colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev. (2005)
47. Mandeville JS, Froehlich E, Tajmir-Riahi HA. Study of curcumin and genistein interactions with human serum albumin. J Pharm Biomed Anal.
(2009)
48. Ireson C, et al. Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and
evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production. Cancer Res. (2001)
49. Vareed SK, et al. Pharmacokinetics of curcumin conjugate metabolites in healthy human subjects. Cancer Epidemiol Biomarkers Prev. (2008)
50. Holder GM, Plummer JL, Ryan AJ. The metabolism and excretion of curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-
dione) in the rat. Xenobiotica. (1978)
51. Lionaki E, Markaki M, Tavernarakis N. Autophagy and ageing: insights from invertebrate model organisms. Ageing Res Rev. (2013)
52. Markaki M, Tavernarakis N. The role of autophagy in genetic pathways influencing ageing. Biogerontology. (2011)
53. Pallauf K, Rimbach G. Autophagy, polyphenols and healthy ageing. Ageing Res Rev. (2013)
54. Wu JC, et al. Tetrahydrocurcumin, a major metabolite of curcumin, induced autophagic cell death through coordinative modulation of
PI3K/Akt-mTOR and MAPK signaling pathways in human leukemia HL-60 cells. Mol Nutr Food Res. (2011)
55. Aoki H, et al. Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of
Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol. (2007)
56. Li B, et al. Curcumin Induces Cross-Regulation Between Autophagy and Apoptosis in Uterine Leiomyosarcoma Cells. Int J Gynecol Cancer.
(2013)
57. Kim JY, et al. Curcumin-induced autophagy contributes to the decreased survival of oral cancer cells. Arch Oral Biol. (2012)
58. Liao VH, et al. Curcumin-mediated lifespan extension in Caenorhabditis elegans. Mech Ageing Dev. (2011)
59. Zhuang W, et al. Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy. Cancer Sci. (2012)
60. Zanotto-Filho A, et al. Curcumin-loaded lipid-core nanocapsules as a strategy to improve pharmacological efficacy of curcumin in glioma
treatment. Eur J Pharm Biopharm. (2012)
61. Daido S, et al. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res.
(2004)
62. Inhibition of the DNA-dependent protein kinase catalytic subunit radiosensitizes malignant glioma cells by inducing autophagy
63. Jiang TF, et al. Curcumin Ameliorates the Neurodegenerative Pathology in A53T -synuclein Cell Model of Parkinson's Disease Through the
Downregulation of mTOR/p70S6K Signaling and the Recovery of Macroautophagy. J Neuroimmune Pharmacol. (2013)
64. Soh JW, et al. Curcumin is an early-acting stage-specific inducer of extended functional longevity in Drosophila. Exp Gerontol. (2013)
65. Lifespan Extension by the Antioxidant Curcumin in Drosophila Melanogaster
66. Lee KS, et al. Curcumin extends life span, improves health span, and modulates the expression of age-associated aging genes in Drosophila
melanogaster. Rejuvenation Res. (2010)
67. Kitani K, Osawa T, Yokozawa T. The effects of tetrahydrocurcumin and green tea polyphenol on the survival of male C57BL/6
mice. Biogerontology. (2007)
68. Kitani K, Yokozawa T, Osawa T. Interventions in aging and age-associated pathologies by means of nutritional approaches. Ann N Y Acad Sci.
(2004)
69. Spindler S, et al. Influence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, Pycnogenol,
quercetin and taxifolin fed isocalorically to long-lived, outcrossed mice. Rejuvenation Res. (2013)
70. Strong R, et al. Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of
genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. (2013)
71. Food Intake, Water Intake, and Drinking Spout Side Preference of 28 Mouse Strains
72. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Healthy Adult Volunteers
73. Wang R, et al. Curcumin protects against glutamate excitotoxicity in rat cerebral cortical neurons by increasing brain-derived neurotrophic
factor level and activating TrkB. Brain Res. (2008)
74. Matteucci A, et al. Curcumin protects against NMDA-induced toxicity: a possible role for NR2A subunit. Invest Ophthalmol Vis Sci. (2011)
75. Chen RW, et al. Regulation of c-Jun N-terminal kinase, p38 kinase and AP-1 DNA binding in cultured brain neurons: roles in glutamate
excitotoxicity and lithium neuroprotection. J Neurochem. (2003)
76. Matteucci A, et al. Curcumin treatment protects rat retinal neurons against excitotoxicity: effect on N-methyl-D: -aspartate-induced
intracellular Ca(2+) increase. Exp Brain Res. (2005)
77. Wu A, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity,
and cognition. Exp Neurol. (2006)
78. Nair SM, et al. Corticosteroid regulation of ion channel conductances and mRNA levels in individual hippocampal CA1 neurons. J Neurosci.
(1998)
79. Xu Y, et al. Curcumin reverses impaired cognition and neuronal plasticity induced by chronic stress. Neuropharmacology. (2009)
80. Frautschy SA, et al. Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging.
(2001)
81. Sharma S, et al. Dietary curcumin supplementation counteracts reduction in levels of molecules involved in energy homeostasis after brain
trauma. Neuroscience. (2009)
82. Yang F, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem.
(2005)
83. Baum L, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J
Clin Psychopharmacol. (2008)
84. Reinke AA, Gestwicki JE. Structure-activity relationships of amyloid beta-aggregation inhibitors based on curcumin: influence of linker length
and flexibility. Chem Biol Drug Des. (2007)
85. Ma QL, et al. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase
signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci. (2009)
86. Curcumin Inhibits Formation of Amyloid Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo
87. A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model
88. Gomez-Pinilla F. Collaborative effects of diet and exercise on cognitive enhancement. Nutr Health. (2011)
89. Wu A, Ying Z, Gomez-Pinilla F. Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and
cognition. Neuroscience. (2008)
90. Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as "Curecumin": from kitchen to clinic. Biochem Pharmacol. (2008)
91. Di Pierro F, et al. Comparative evaluation of the pain-relieving properties of a lecithinized formulation of curcumin (Meriva()), nimesulide,
and acetaminophen. J Pain Res. (2013)
92. Belcaro G, et al. Product-evaluation registry of Meriva, a curcumin-phosphatidylcholine complex, for the complementary management of
osteoarthritis. Panminerva Med. (2010)
93. Belcaro G, et al. Efficacy and safety of Meriva, a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis
patients. Altern Med Rev. (2010)
94. Agarwal KA, et al. Efficacy of turmeric (curcumin) in pain and postoperative fatigue after laparoscopic cholecystectomy: a double-blind,
randomized placebo-controlled study. Surg Endosc. (2011)
95. Morimoto T, et al. The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats. J Clin
Invest. (2008)
96. Storka A, et al. Effect of liposomal curcumin on red blood cells in vitro. Anticancer Res. (2013)
97. Tang W, et al. Association of sICAM-1 and MCP-1 with coronary artery calcification in families enriched for coronary heart disease or
hypertension: the NHLBI Family Heart Study.BMC Cardiovasc Disord. (2007)
98. DiSilvestro RA, et al. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutr J. (2012)
99. Fang XD, et al. Curcumin ameliorates high glucose-induced acute vascular endothelial dysfunction in rat thoracic aorta. Clin Exp Pharmacol
Physiol. (2009)
100. Majithiya JB, Balaraman R. Time-dependent changes in antioxidant enzymes and vascular reactivity of aorta in streptozotocin-induced diabetic
rats treated with curcumin. J Cardiovasc Pharmacol. (2005)
101. Sompamit K, et al. Curcumin improves vascular function and alleviates oxidative stress in non-lethal lipopolysaccharide-induced endotoxaemia
in mice. Eur J Pharmacol. (2009)
102. El-Bassossy HM, et al. Haem oxygenase-1 induction protects against tumour necrosis factor alpha impairment of endothelial-dependent
relaxation in rat isolated pulmonary artery.Br J Pharmacol. (2009)
103. Curcumin binds tubulin, induces mitotic catastrophe, and impedes normal endothelial cell proliferation
104. Akazawa N, et al. Curcumin ingestion and exercise training improve vascular endothelial function in postmenopausal women. Nutr Res. (2012)
105. Fleenor BS, et al. Curcumin ameliorates arterial dysfunction and oxidative stress with aging. Exp Gerontol. (2013)
106. Nakmareong S, et al. Antioxidant and vascular protective effects of curcumin and tetrahydrocurcumin in rats with L-NAME-induced
hypertension. Naunyn Schmiedebergs Arch Pharmacol. (2011)
107. Sagiroglu T, et al. Protective effect of curcumin on cyclosporin A-induced endothelial dysfunction, antioxidant capacity, and oxidative
damage. Toxicol Ind Health. (2012)
108. Khajehdehi P, et al. Oral supplementation of turmeric decreases proteinuria, hematuria, and systolic blood pressure in patients suffering from
relapsing or refractory lupus nephritis: a randomized and placebo-controlled study. J Ren Nutr. (2012)
109. Pungcharoenkul K, Thongnopnua P. Effect of different curcuminoid supplement dosages on total in vivo antioxidant capacity and cholesterol
levels of healthy human subjects.Phytother Res. (2011)
110. Kim T, et al. Curcumin activates AMPK and suppresses gluconeogenic gene expression in hepatoma cells. Biochem Biophys Res Commun.
(2009)
111. AMP-activated protein kinase: the energy charge hypothesis revisited
112. Ikonomov OC, et al. Requirement for PIKfyve enzymatic activity in acute and long-term insulin cellular effects. Endocrinology. (2002)
113. Yang X, et al. Curcumin inhibits platelet-derived growth factor-stimulated vascular smooth muscle cell function and injury-induced neointima
formation. Arterioscler Thromb Vasc Biol. (2006)
114. Srinivasan M. Effect of curcumin on blood sugar as seen in a diabetic subject. Indian J Med Sci. (1972)
115. Aggarwal BB, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends
Pharmacol Sci. (2009)
116. Kim JH, et al. Curcumin stimulates glucose uptake through AMPK-p38 MAPK pathways in L6 myotube cells. J Cell Physiol. (2010)
117. Kang C, Kim E. Synergistic effect of curcumin and insulin on muscle cell glucose metabolism. Food Chem Toxicol. (2010)
118. Pan W, et al. AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells. Oncol Rep. (2008)
119. Weisberg SP, Leibel R, Tortoriello DV. Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse
models of diabesity. Endocrinology. (2008)
120. Yekollu SK, Thomas R, O'Sullivan B. Targeting curcusomes to inflammatory dendritic cells inhibits NF-B and improves insulin resistance in
obese mice. Diabetes. (2011)
121. Chuengsamarn S, et al. Curcumin extract for prevention of type 2 diabetes. Diabetes Care. (2012)
122. Xie XY, et al. Curcumin attenuates lipolysis stimulated by tumor necrosis factor- or isoproterenol in 3T3-L1 adipocytes. Phytomedicine.
(2012)
123. Soltoff SP, Hedden L. Regulation of ERK1/2 by ouabain and Na-K-ATPase-dependent energy utilization and AMPK activation in parotid
acinar cells. Am J Physiol Cell Physiol. (2008)
124. Lee YK, et al. Curcumin exerts antidifferentiation effect through AMPKalpha-PPAR-gamma in 3T3-L1 adipocytes and antiproliferatory effect
through AMPKalpha-COX-2 in cancer cells. J Agric Food Chem. (2009)
125. Zhao J, et al. Suppression of fatty acid synthase, differentiation and lipid accumulation in adipocytes by curcumin. Mol Cell Biochem. (2011)
126. Aggarwal BB. Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annu Rev Nutr. (2010)
127. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase
128. Zhang HH, et al. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-
related kinase and elevation of intracellular cAMP. Diabetes. (2002)
129. Patton JS, et al. Interferons and tumor necrosis factors have similar catabolic effects on 3T3 L1 cells. Proc Natl Acad Sci U S A. (1986)
130. Ruan H, et al. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1
adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes. (2002)
131. Qiao L, Shao J. SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex. J Biol
Chem. (2006)
132. Subauste AR, Burant CF. Role of FoxO1 in FFA-induced oxidative stress in adipocytes. Am J Physiol Endocrinol Metab. (2007)
133. Ciardi C, et al. Food additives such as sodium sulphite, sodium benzoate and curcumin inhibit leptin release in lipopolysaccharide-treated
murine adipocytes in vitro. Br J Nutr. (2012)
134. Pongchaidecha A, et al. Effects of curcuminoid supplement on cardiac autonomic status in high-fat-induced obese rats. Nutrition. (2009)
135. Ejaz A, et al. Curcumin inhibits adipogenesis in 3T3-L1 adipocytes and angiogenesis and obesity in C57/BL mice. J Nutr. (2009)
136. Arbiser JL, et al. Curcumin is an in vivo inhibitor of angiogenesis. Mol Med. (1998)
137. Bank J, Song DH. Curcumin Protects Against Ischemia/Reperfusion Injury in Rat Skeletal Muscle. J Surg Res. (2011)
138. Avci G, et al. Curcumin protects against ischemia/reperfusion injury in rat skeletal muscle. J Surg Res. (2012)
139. Pizzo P, et al. Grp94 acts as a mediator of curcumin-induced antioxidant defence in myogenic cells. J Cell Mol Med. (2010)
140. Shinkai Y, Yamamoto C, Kaji T. Lead induces the expression of endoplasmic reticulum chaperones GRP78 and GRP94 in vascular endothelial
cells via the JNK-AP-1 pathway.Toxicol Sci. (2010)
141. Sevgiler Y, Karaytug S, Karayakar F. Antioxidative effects of N-acetylcysteine, lipoic acid, taurine, and curcumin in the muscle of Cyprinus
carpio L. exposed to cadmium. Arh Hig Rada Toksikol. (2011)
142. Vazeille E, et al. Curcumin treatment prevents increased proteasome and apoptosome activities in rat skeletal muscle during reloading and
improves subsequent recovery. J Nutr Biochem. (2012)
143. Siddiqui RA, et al. Attenuation of proteolysis and muscle wasting by curcumin c3 complex in MAC16 colon tumour-bearing mice. Br J Nutr.
(2009)
144. Li YP, et al. TNF-alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB J.
(2005)
145. Deng YT, et al. Suppression of free fatty acid-induced insulin resistance by phytopolyphenols in C2C12 mouse skeletal muscle cells. J Agric
Food Chem. (2012)
146. Na LX, et al. Curcumin improves insulin resistance in skeletal muscle of rats. Nutr Metab Cardiovasc Dis. (2011)
147. Cheng TC, et al. Activation of muscarinic M-1 cholinoceptors by curcumin to increase glucose uptake into skeletal muscle isolated from Wistar
rats. Neurosci Lett. (2009)
148. Xavier S, et al. (2)-Adrenoceptor and insulin receptor expression in the skeletal muscle of streptozotocin induced diabetic rats: Antagonism by
vitamin D(3) and curcumin. Eur J Pharmacol. (2012)
149. He HJ, et al. Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice. World J
Diabetes. (2012)
150. Seo KI, et al. Effect of curcumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in
diabetic db/db mice. Mol Nutr Food Res. (2008)
151. Chaudhary A, Bhandari A, Pandurangan A. Antioxidant potential and total phenolic content of methanolic bark extract of Madhuca indica
(koenig) Gmelin. Anc Sci Life. (2012)
152. Koren E, et al. Supplementation with antioxidants fails to increase the total antioxidant capacity of several cell lines in culture. Biomed
Pharmacother. (2008)
153. Voronin MV, et al. Total antioxidant capacity of blood plasma from healthy donors receiving vitamin and mineral complex. Bull Exp Biol Med.
(2004)
154. Dominiak K, et al. Critical need for clinical trials: an example of a pilot human intervention trial of a mixture of natural agents protecting
lymphocytes against TNF-alpha induced activation of NF-kappaB. Pharm Res. (2010)
155. Everett PC, et al. Preclinical assessment of curcumin as a potential therapy for B-CLL. Am J Hematol. (2007)
156. Chun KS, et al. Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular
signal-regulated kinase activity and NF-kappaB activation. Carcinogenesis. (2003)
157. Kunnumakkara AB, et al. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through
suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. (2007)
158. Ponnurangam S, et al. Urine and serum analysis of consumed curcuminoids using an IkappaB-luciferase surrogate marker assay. In Vivo.
(2010)
159. Aggarwal S, et al. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene
products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol. (2006)
160. Dileep KV, Tintu I, Sadasivan C. Molecular docking studies of curcumin analogs with phospholipase A2. Interdiscip Sci. (2011)
161. Binion DG, et al. Vascular cell adhesion molecule-1 expression in human intestinal microvascular endothelial cells is regulated by PI 3-
kinase/Akt/MAPK/NF-kappaB: inhibitory role of curcumin. Am J Physiol Gastrointest Liver Physiol. (2009)
162. Kumar A, et al. Curcumin (Diferuloylmethane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells
by suppression of cell surface expression of adhesion molecules and of nuclear factor-kappaB activation. Biochem Pharmacol. (1998)
163. Jackson JK, et al. The antioxidants curcumin and quercetin inhibit inflammatory processes associated with arthritis. Inflamm Res. (2006)
164. Ramadan G, Al-Kahtani MA, El-Sayed WM. Anti-inflammatory and anti-oxidant properties of Curcuma longa (turmeric) versus Zingiber
officinale (ginger) rhizomes in rat adjuvant-induced arthritis. Inflammation. (2011)
165. Narayanan A, et al. Curcumin Inhibits Rift Valley Fever Virus Replication in Human Cells. J Biol Chem. (2012)
166. Karbalay-Doust S, Noorafshan A. Ameliorative effects of curcumin on the spermatozoon tail length, count, motility and testosterone serum
level in metronidazole-treated mice.Prague Med Rep. (2011)
167. Giannessi F, et al. Curcumin protects Leydig cells of mice from damage induced by chronic alcohol administration. Med Sci Monit. (2008)
168. Quintans LN, Castro GD, Castro JA. Oxidation of ethanol to acetaldehyde and free radicals by rat testicular microsomes. Arch Toxicol. (2005)
169. Chandra AK, et al. Effect of curcumin on chromium-induced oxidative damage in male reproductive system. Environ Toxicol Pharmacol.
(2007)
170. Aktas C, et al. Anti-apoptotic effects of curcumin on cadmium-induced apoptosis in rat testes. Toxicol Ind Health. (2012)
171. Murphy CJ, et al. Reproductive effects of a pegylated curcumin. Reprod Toxicol. (2012)
172. White EL, et al. Screening of potential cancer preventing chemicals as aromatase inhibitors in an in vitro assay. Anticancer Res. (1999)
173. Valentine SP, et al. Curcumin modulates drug metabolizing enzymes in the female Swiss Webster mouse. Life Sci. (2006)
174. Folwarczna J, Zych M, Trzeciak HI. Effects of curcumin on the skeletal system in rats. Pharmacol Rep. (2010)
175. Bachmeier BE, et al. Reference profile correlation reveals estrogen-like trancriptional activity of Curcumin. Cell Physiol Biochem. (2010)
176. Singh M, Singh N. Curcumin counteracts the proliferative effect of estradiol and induces apoptosis in cervical cancer cells. Mol Cell Biochem.
(2011)
177. Kinoshita A, et al. Carcinogenicity of dimethylarsinic acid in Ogg1-deficient mice. Cancer Sci. (2007)
178. Biswas J, et al. Curcumin protects DNA damage in a chronically arsenic-exposed population of West Bengal. Hum Exp Toxicol. (2010)
179. Mukundan MA, et al. Effect of turmeric and curcumin on BP-DNA adducts. Carcinogenesis. (1993)
180. Sharma RA, et al. Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa:
relationship with drug levels. Clin Cancer Res. (2001)
181. Bhattacharyya S, et al. Tumor-induced oxidative stress perturbs nuclear factor-kappaB activity-augmenting tumor necrosis factor-alpha-
mediated T-cell death: protection by curcumin. Cancer Res. (2007)
182. Deeb D, et al. Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear
factor-kappaB through suppression of IkappaBalpha phosphorylation. Mol Cancer Ther. (2004)
183. Deeb D, et al. Curcumin {1,7-bis(4-hydroxy-3-methoxyphenyl)-1-6-heptadine-3,5-dione; C21H20O6} sensitizes human prostate cancer cells to
tumor necrosis factor-related apoptosis-inducing ligand/Apo2L-induced apoptosis by suppressing nuclear factor-kappaB via inhibition of the
prosurvival Akt signaling pathway. J Pharmacol Exp Ther. (2007)
184. Song WB, et al. Curcumin protects intestinal mucosal barrier function of rat enteritis via activation of MKP-1 and attenuation of p38 and NF-
B activation. PLoS One. (2010)
185. Kim YS, et al. Curcumin attenuates inflammatory responses of TNF-alpha-stimulated human endothelial cells. J Cardiovasc Pharmacol.
(2007)
186. Camacho-Barquero L, et al. Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in
chronic experimental colitis. Int Immunopharmacol. (2007)
187. Curcumin Inhibits Prostate Cancer Metastasis in vivo by Targeting the Inflammatory Cytokines CXCL1 and -2
188. Hanai H, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin
Gastroenterol Hepatol. (2006)
189. Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci. (2005)
190. Um MY, et al. Curcumin Attenuates Diet-Induced Hepatic Steatosis by Activating AMPK. Basic Clin Pharmacol Toxicol. (2013)
191. Khajehdehi P, et al. Oral supplementation of turmeric attenuates proteinuria, transforming growth factor- and interleukin-8 levels in patients
with overt type 2 diabetic nephropathy: a randomized, double-blind and placebo-controlled study. Scand J Urol Nephrol. (2011)
192. Zhong F, et al. Curcumin attenuates lipopolysaccharide-induced renal inflammation. Biol Pharm Bull. (2011)
193. Ghosh SS, et al. Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation. Am J Physiol Renal Physiol. (2009)
194. Hill-Kapturczak N, et al. Mechanism of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule cells. Am J Physiol
Renal Physiol. (2001)
195. Gaedeke J, Noble NA, Border WA. Curcumin blocks fibrosis in anti-Thy 1 glomerulonephritis through up-regulation of heme oxygenase
1. Kidney Int. (2005)
196. Murakami A, et al. Curcumin combined with turmerones, essential oil components of turmeric, abolishes inflammation-associated mouse colon
carcinogenesis. Biofactors. (2013)
197. Sehgal A, et al. Synergistic effects of piperine and curcumin in modulating benzo(a)pyrene induced redox imbalance in mice lungs. Toxicol
Mech Methods. (2012)
198. Sehgal A, et al. Piperine as an adjuvant increases the efficacy of curcumin in mitigating benzo(a)pyrene toxicity. Hum Exp Toxicol. (2012)
199. Sehgal A, et al. Combined effects of curcumin and piperine in ameliorating benzo(a)pyrene induced DNA damage. Food Chem Toxicol. (2011)
200. Hlavakov L, et al. Spice up the hypertension diet - curcumin and piperine prevent remodeling of aorta in experimental L-NAME induced
hypertension. Nutr Metab (Lond). (2011)
201. Bhagavathula N, et al. A combination of curcumin and ginger extract improves abrasion wound healing in corticosteroid-impaired hairless rat
skin. Wound Repair Regen. (2009)
202. Madkor HR, Mansour SW, Ramadan G. Modulatory effects of garlic, ginger, turmeric and their mixture on hyperglycaemia, dyslipidaemia and
oxidative stress in streptozotocin-nicotinamide diabetic rats. Br J Nutr. (2011)
203. Ide H, et al. Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate. (2010)
204. Altenburg JD, et al. A synergistic antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells: unique
signaling not explained by the effects of either compound alone. BMC Cancer. (2011)
205. Saw CL, Huang Y, Kong AN. Synergistic anti-inflammatory effects of low doses of curcumin in combination with polyunsaturated fatty acids:
docosahexaenoic acid or eicosapentaenoic acid. Biochem Pharmacol. (2010)
206. Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J
Alzheimers Dis. (2004)
207. Ishihara M, Sakagami H. Re-evaluation of cytotoxicity and iron chelation activity of three beta-diketones by semiempirical molecular orbital
method. In Vivo. (2005)
208. Tuntipopipat S, et al. Chili, but not turmeric, inhibits iron absorption in young women from an iron-fortified composite meal. J Nutr. (2006)
209. Padhye S, et al. Emerging role of Garcinol, the antioxidant chalcone from Garcinia indica Choisy and its synthetic analogs. J Hematol Oncol.
(2009)
210. Parasramka MA, Gupta SV. Synergistic effect of garcinol and curcumin on antiproliferative and apoptotic activity in pancreatic cancer cells. J
Oncol. (2012)
211. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. (2003)
212. Baum L, et al. Curcumin effects on blood lipid profile in a 6-month human study. Pharmacol Res. (2007)
213. Kuptniratsaikul V, et al. Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. J Altern Complement Med.
(2009)
214. Wickenberg J, Ingemansson SL, Hlebowicz J. Effects of Curcuma longa (turmeric) on postprandial plasma glucose and insulin in healthy
subjects. Nutr J. (2010)
215. Appendino G, et al. Potential role of curcumin phytosome (Meriva) in controlling the evolution of diabetic microangiopathy. A pilot
study. Panminerva Med. (2011)
216. Chainani-Wu N, et al. High-dose curcuminoids are efficacious in the reduction in symptoms and signs of oral lichen planus. J Am Acad
Dermatol. (2012)
217. Koosirirat C, et al. Investigation of the anti-inflammatory effect of Curcuma longa in Helicobacter pylori-infected patients. Int
Immunopharmacol. (2010)
218. Kalpravidh RW, et al. Improvement in oxidative stress and antioxidant parameters in beta-thalassemia/Hb E patients treated with
curcuminoids. Clin Biochem. (2010)
219. Alwi I, et al. The effect of curcumin on lipid level in patients with acute coronary syndrome. Acta Med Indones. (2008)
220. Durgaprasad S, et al. A pilot study of the antioxidant effect of curcumin in tropical pancreatitis. Indian J Med Res. (2005)
221. Carroll RE, et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila). (2011)
222. He ZY, et al. Upregulation of p53 expression in patients with colorectal cancer by administration of curcumin. Cancer Invest. (2011)
223. Shimouchi A, et al. Effect of dietary turmeric on breath hydrogen. Dig Dis Sci. (2009)
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