Jiang Huang – Turmeric rhizome – Curcuma longa – “Ginger Yellow”

Nature: acrid, bitter, warm

Enters: Liver, Spleen, Stomach

Actions: Strongly promotes blood circulation; dispels blood stasis from the channels and collaterals; relieves pain; unblocks menstruation; disperses wind-cold; promotes Qi circulation.

• Blood stasis: pain in the shoulder, chest, hypochondria, abdomen, and amenorrhea, dysmenorrhea. Especially effective for shoulder pain.
• Wind-cold-dampness: Bi syndrome, especially in shoulders, limbs.
• Blood stasis due to cold from deficiency.
• Topical: stops bleeding and pain.
• Can be made into an ointment with oil.
• Cholagogue.
• Stimulates the uterus.
• Lowers blood pressure.
• Curcuminoids, thought to be the primary active components (with curcumin being the most researched), are notoriously poorly absorbed. In Ayurveda, turmeric is often routinely combined with pippali (Bi Bo) and/or black pepper (Hu Jiao), to help its absorption. Interesting, a number of classic martial arts hit formulas (die da jiao) include the combination of Jiang Huang and Bi Bo. It’s now known that Bi Bo and Hu Jiao contain piperine, which enhances absorption of other compounds (and is used commercially as an absorption enhancer with a variety of nutritional supplements).
• One study showed piperine (the active pungent compound in black pepper – hu jiao – and pippali – bi bo) can dramatically increase the absorption of curcumin (perhaps as much as 2000%). [Planta Med. 1998 May;64(4):353-6. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.]
MLT: Increases bile flow, reduces liver enzymes SGOT and SGPT, prevents and dissolves gall stones.
• Anti-inflammatory, analgesic for sports injury, musculoskeletal trauma, inflammatory bowel disease, arthritis, rheumatoid arthritis.
BII: Contains curcumin – a powerful and safe anti-inflammatory; protective against cancer development.
• Possible uses in: atherosclerosis, cancer, gallbladder disease (curcumin increases bile acid output over 100%, and greatly increases the solubility of bile – may prevent and treat gall stones), rheumatoid arthritis, general inflammation.
Yoga: Haridra: K-; P, V+ (in excess)
• Stimulant, carminative, alterative, vulnerary, antibiotic while improving digestive flora.
• Gives the energy of the Divine Mother and grants prosperity.
• Cleanses the chakras, purifies the channels of the subtle-body.
• Helps stretch the ligaments, good for the practice of hatha yoga.
• Promotes proper metabolism.
• Topical: sprains, strains, bruises, itching.
Hsu: Increases the detoxifying abilities of liver.
• Stimulates the uterus to contract (paroxysmally).
• The ethanol extract is hypotensive.
CHA: (Karen S. Vaughan, 8-30-2001) Fungal infections of the feet: soaking the feet in a turmeric footbath is part of Ayurveda and is also done in traditional Hawaiian medicine.
Weil: Knee arthritis: This research, from Italy, was a three-month trial involving 50 patients diagnosed by x-ray with osteoarthritis of the knee. The Italian team was investigating the effect on arthritis symptoms of a special formulation of turmeric designed to improve its absorption by the body. Half the participating patients took the turmeric formulation in addition to standard medical treatment; those in the second group continued following their physicians’ recommendations.
After 90 days, the researchers found a 58 percent decrease in overall reported pain and stiffness as well as an improvement in physical functioning among the turmeric group compared to the controls. These changes were documented with a standard medical scoring method used to assess symptoms of knee and hip osteoarthritis. In addition, another scoring method showed a 300 percent improvement in the emotional well being of the turmeric patients compared with the others. And blood tests showed a 16-fold decline in C-reactive protein, a marker for inflammation. Patients in the turmeric group were able to reduce their use of non-steroidal anti-inflammatory drugs by 63 percent, compared to the other group.
Results of this study are very good news for the millions of people worldwide who suffer from osteoarthritis and haven’t been adequately helped by available treatments. The dose of the turmeric formulation used in the study was one gram per day. It is now commercially available in the United States and Europe.
Turmeric may also be useful for prevention of symptoms of rheumatoid arthritis, but this evidence comes from animal studies, not human trials.
Research also suggests that turmeric may prevent changes that lead to Alzheimer’s disease, and animal studies have shown that turmeric may be effective in the prevention or treatment of colon, breast and prostate cancers.

Dose: 3-9g

On Curcumin/Curcuminoids from Examine.com:
Curcumin is the yellow pigment associated with the curry spice, Turmeric, and to a lesser extent Ginger. It is a small molecule that is the prototypical ‘curcuminoid’, and has effects similar to other polyphenols but unique in a way as it is a different class of polyphenol (relative to the other classes of ‘flavonoid’, ‘stilbene’, etc.)

It exerts potent anti-inflammatory effects, and these anti-inflammatory effects seem to be quite protective against some form of cancer progression. However, curcumin has additional anti-cancer effects that are independent of its anti-inflammatory effects and thus is a heavily researched molecule for both cancer prevention and treatment.

Other areas of interest as it pertains to curcumin are alleviating cognitive decline associated with aging, being heart healthy by both electrical means and reducing lipid and plaque levels in arteries, and both reducing the risk of diabetes and being a good treatment for the side-effects associated with diabetes.

It has a poor oral bioavailability (a low percentage of what you consume is absorbed) and thus should be enhanced with other agents such as black pepper extract, called piperine. This is unless you want the curcumin in your colon (as it is a colon anti-inflammatory and can help with digestion), in which case you wouldn’t pair it with an enhancement.

Doses up to 8g curcuminoids in humans have been shown to not be associated with much adverse effects at all, and in vitro tests suggest curcumin has quite a large safety threshold.

A good general intake of curcumin, as a supplement, would be 500mg of curcuminoids that is enhanced in some manner. 500mg of curcumin with 20mg piperine, or 500mg of curcumin microsomes or curcumin phosphatidylcholine.

For any effects on colon and intestinal tissue (colon cancer prevention, reducing inflammation associated with Crohn’s, etc.) it would be good to use a dose of 2-4g curcumin or turmeric without any enhancement.

Benefits have been seen with as little as 100-200mg turmeric sprinkled on curry, so even if you don’t supplement it would be prudent to use some turmeric in daily life.

1.1. Sources

Curcumin (Diferuloylmethane) is the main active ingredient of the spice Turmeric (also known as Curcuma Longa or JiangHuang), which consists of Curcumin as well as thee other curcuminoids (Demethoxycurcumin , Bisdemethoxycurcumin, and Cyclocurcumin)[1][2] in which curcumin can consist of up to 80% of curcuminoids by weight, dependent on location of growth.[3] Both curcumin and Ginger belong to the family of Zingiberaceae known as the ‘Ginger Family’.

Curcuminoids appear in the entire Curcumin genus, although most commonly in Longa. Curcumoinds exist in:

Curcuma Longa (Turmeric, or JiangHuang) at around 22.21-40.36mg/g in the rhizomes and 1.94mg/g in the tuberous roots
Curcuma Phaeocaulis at 0.098mg/g in the rhizomes
Shampoo ginger (Zingiber zerumbet L)

Other names for curcumin can be NCB-02 (a standardized mixture of curcuminoids), E100 (code used for food coloring), MERIVA (curcumin bound to soy lecithin, or phosphatidylcholine) and THERACURMIN (curcumin microsomes).

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).[11]

1.2. Structure and Properties

The structure of curcumin, officially known as diferuloylmethane, is two ferulic acid moeities bound together with an additional carbon 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.

Curcumin is the compound in Turmeric which exert the characteristic bright, yellow color of Turmeric. Due to its intense coloration, it is sometimes used as a food additive with the code of E100.[12][8]

Curcumin is lipophilic and highly insoluble in water, and is acid-stable when measured around the pH of the stomach.[13]

2. Pharmacology

2.1. 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[14]) 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).[14]

2.2. Systemic

Curcumin, due to its lipophilicity, is transported in the blood via transports; most likely binding to Human Serum Albumin.[15]

Without aiding absorption, an oral dose of 500mg/kg bodyweight in rats results in peak plasma levels of 1.8ng/mL.[16]

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.[17] 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;[14] 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.[17][14][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.[19]

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.[19]

2.3. Bioavailability

The efficiency of an oral dose in increasing plasma levels of curcumin (bioavailability) is poor;[20] due to this, methods are being investigated to increase bioavailability. One clinical toxicology study in humans looking at oral curcumin found that doses below 8,000mg didn’t influence serum levels significantly, but only doses of 10g or 12g[21] (although some studies do note serum spikes at 4g).[17]

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.[22]

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[23] 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.[24]

Beyond Piperine and Phospholipids, nanoparticle emulsions show promise. THEACURCUMIN emulsion (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.[10] although another study found merely a 10-fold increase in AUC and a 40-fold increase in Cmax in rodents.[25] This increased bioavailability is, in part, due to increased water-solubility.[26] 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.[26]

For any systemic purpose, it would be wise to increase curcumin bioavailability; either by taking it with a meal and piperine (Black Pepper) or one of the enhanced delivery systems. If using curcumin for any effects on the colon, poor bioavailability is desirable (if not absorbed, it heads to the colon) and no measures for bioavailability enhancement should be made

2.4. Metabolism

The major metabolites of curcumin in humans are curcumin sulfate (via sulfation enzymes of P450) and curcumin glucuronide (via glucuronidation by P450).[16][14][19]

In the bile, tetrahydrocurcumin and hexahydrocurcumin have been noted in rats, and to a lesser degree dihydroferulic acid and ferulic acid.[27]

2.5. 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.[16]

3. Longevity and Life Extension

3.1. Autophagy

Autophagy is a Longevity associated process involving selective destruction of damaged cellular organelles, sometimes described as cellular housekeeping or maintenance;[28][29] autophagy appears to activated by many polyphenols[30] 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 [31]) appear to induce autophagy via Akt/mTOR/p70S6K and ERK1/2 signalling pathways (inhibition and activation, respectively[32]) and so far has been detected in glioma,[32] uterine,[33] oral cancer,[34] and leukemic cells.[31] 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[35] although mev-1 and daf-16 appear to be indepednent.[35]

Beyond the possible roles in longevity, autophagy promotion from curcumin is thought to be protective against gliomas[36][37] as glioma cells are resistant to apoptosis but readily destroyed by autophagy.[38][39] Parkinson’s pathology may be attenuated with curcumin via preservation of autophagy[40]

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

3.2. Interventions

In drosophilia, curcumin can induce longevity via antioxidative properties[35] independent of caloric restriction yet is not complementary with caloric restriction (suggesting acting upon the same pathway)[41][42][43] with most efficacy at 100mM of the feed.[41] 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%).[41]

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.[44] 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.[44] Longevity enhancement in mice has been noted elsewhere.[45]

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[46] and lifetime administration of curcumin (0.2%) starting at 4 months has also failed to promote lifespan in UM-HET3 mice.[47] Assuming a food intake of around 8.55g/45g bodyweight[48] and body weights around 45g for the majority of the life[46][47][44] an estimated intake of curcumin daily would be 17.1mg (converting to 380mg/kg bodyweight and an estimated human dose[49] 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)

4. Cellular Mechanisms

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.

4.1. 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[50] bind to their receptor on the cell nuclear (TPA response element) to induce effects associated with AP-1.[51][52] 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[53] and is able to enhance some phase II (anti-oxidant) enzymes by moderating some better AP-1 confirmations.[54]

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.[55][56]

Curcumin can also directly inhibit DNA polymerase lambda,[57] focal adhesion kinase (FAK),[58] Src,[58] Protein Kinase C,[59] p300 (CREB Binding Protein),[60] Thioredoxin reductase,[61] Lipoxygenase (LOX),[62] and tubulin.[63]

It may also directly affect (negatively) 17beta-HSD3[64] and 5-alpha reductase.[65]

Curcumin has been noted to directly and potently inhibit the Glycogen Synthase Kinase-3? (GSK3?) enzyme with an IC50 of 66.3nM.[66]

4.2. 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.[67] 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.[68] nF-kB moderates over 200 related proteins related to cell proliferation, invasion, metastasis, chemoresistance, and/or inflammation.[69][11]

As mentioned previously, the proteins of AP-1 are also seen as a sort of junction point mediating cell proliferation and survival.[50]

4.3. 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).[70][71][72]

5. Cardiovascular Health

5.1. 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.[73]

5.2. 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.[74] 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).[75]

This protective effect has also been demonstrated with LPS insult, a pro-inflammatory condition, and curcumin dosed at 50-100mg/kg bodyweight in rats;[76] changes in endothelial contractability (via TNF-a) have also been reduced with curcumin.[77] Protection from L-NAME induced hypertension has also been seen.[78]

In regards to blood pressure, one human study has noted significant decreases in blood pressure but was conducted in a nephritic disease state.[79] Not much human evidence looks at the effects on blood pressure in otherwise healthy individuals.

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

5.3. 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.[80] These were seen in otherwise normal weight and healthy young subjects.[80]

5.4. Cholesterol

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.[80]

6. Interactions with Neurology

6.1. 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%).[81]

6.2. Stress

In vitro, curcumin can abolish the induction of the NMDA receptor subunit R2B mRNA by corticosterone[82] when corticosterone is incubated at 0.1mM and curcumin at concentrations as low as 0.62uM;[83] this may be related to the ability of curcumin in vitro to prevent corticosterone-induced neuronal death.[83]

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.[83]

6.3. Neuronal Injury

Curcumin at 500ppm in rats (a dose similar to some anti-Alzheimer’s dosages[84]) 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,[81] and other proteins that tend to be reduced in this form of injury are somewhat normalized with curcumin.[85] Cognitive performance was declined after injury, and the reduction was attenuated but not normalized.[81]

6.4. 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[86] 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[87] as beta-amyloid is prevented from aggregating in the brain,[88] 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.[89] This synergism may be related to how both agents can reduce beta-amyloid aggregation, but by differing mechanisms;[90][91] some authors hypothesize that this synergism may be further enhanced by exercise[92] due to an interaction with exercise and fish oil on neuronal plasticity.[93]

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.[87] This trial is limited in statistical power due to its sample size of 27 completions and multiple confounds, however.[87]

Some therapeutic promise, but evidence is limited

7. Implications for Digestion and the Intestines

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.

7.1. 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.[94] 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.[94] These effects were seen earlier in both Ulcerative Colitis and Crohn’s Disease, two human conditions associated with intestinal inflammation.[95]

8. Interactions with Glucose Metabolism

8.1. 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.[96] Although glucose uptake into cells tends to be secondary to AMPK activation[97] 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.[96] This inhibition of glucose uptake has been noted elsewhere, where 100uM Curcumin was shown to inhibit insulin-stimulated GLUT4 translocation[98] despite curcumin twice being shown to not significantly interact with the insulin receptor itself (not cell type specific).[99][96]

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)

8.2. Blood glucose

The effect of curcumin to lower blood glucose was one of the first effects to be seen with curcumin, seen in 1972.[100][101]

One of the mechanisms of this blood glucose lowering effect is by stimulating Adenosine Monophosphate Kinase (AMPK) in skeletal muscle, drawing in glucose.[102] 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.[103] Curcumin can also activate AMPK in other cells, such as liver cells[96] and some cancer cells.[104]

8.3. Diabetes

Curcumin is able to alleviate the downstream inflammatory reactions that occur during times of diabetes and metabolic syndrome in rats[105] and, vicariously through its anti-inflammatory effects, improve insulin resistance.[106][105]

9. Interactions with Fat Mass

9.1. 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.[107] ERK1/2 is known to be regulated by AMPK[108] which curcumin has been found to activate[109] (in liver cells, this was noted to be of comparable potency to Metformin but requiring 20uM to Metformins 2mM[96]); all of these events being similar to the known AMPK activator Berberine.

Fatty Acid Synthase (FAS) is inhibited by Curcumin with an IC50 of 26.8?M (59.1?M in regards to ?-ketoacyl reduction); the inhibition was noncompetitive when NADPH was the substrate, but mixed competitive with either acetyl or malonyl Coenzyme A[110] and had both slow and fast acting components in a concentration and time dependent manner.[110] 20uM of Curcumin abolished lipid accumulation in isolated 3T3-L1 cells undergoing differentiation, which may have been due to downregulation of PPAR? and CD36;[110] another study notes that PPARy activation by Curcumin is dependent on AMPK activation.[109]

Curcumin appears to be a potency activator of AMPK

9.2. 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[111] and TNF-? expression appears to negatively correlate with LPL activity.[112] TNF-? itself does exert lipolytic activity,[113] 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[114]) also being possible.[111] TNF-? is a potent activator of nF-kB (nuclear receptor) which mediates many of its effects,[115] and overactivity of nF-kB and TNF-? in adipocytes are both highly correlated with metabolic syndrome and obesity.[111]

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.[105]

9.3. 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);[105] FOXO1 is known to positively influence adiponectin transcription in fat cells.[116][117]

Leptin secretion from adipocytes appears to be suppressed with 12 and 24 hour incubation with Curcumin in a concentration and time dependent manner.[118]

9.4. 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.[105]

9.5. 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.[119]

Curcumin can also suppress angiogenesis in rat fat cells, a longer term adaptation associated with prolonged obesity.[120] This is a general mechanism that applies to more cell types as well.[121]

10. Oxidation and Anti-Oxidation

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.[80] This is thought to be due to a possible pro-oxidant effect of curcumin at higher dosages, seen with other anti-oxidants.[122][123]

11. 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)[124] but also in isolation in vitro[125] and in vivo.[126][127][128][129] 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.[130] Other pro-inflammatory enzymes that are suppressed by curcumin are iNOS, LOX (directly inhibited), and Phospholipase A2 (directly.)[131]

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.[132][133]

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. Treatment of Arthritis

Curcumin is associated with reducing a variety of inflammatory signals, and a lot of them that are associated with arthritis and inflammatory joints.[134]

When dosed equally (200mg/kg in rats), curcuminoids from turmeric are 4.6-8.3% more effective than the active components of Ginger in suppressing inflammation associated with cytokine release in arthritis.[135] Both herbs are more potent than indomethacin.[135]

12. Bacteria and Viral interactions

12.1. Virus replication

One study found that curcumin was able to suppress replication of the Rift Valley fever virus and its fully virulent form (ZH501) in vitro.[136] A modification to the IKK-? protein (which inhibits I?B? and serves to enhance nF-kB signalling) keeps IKK-? in an active state and exacerbates inflammatory signalling, curcumin can bind to IKK-? and allow I?B? to suppress nF-kB activation and inflammation, which prevents virus replication.[136]

13. Implications in Cancer Metabolism

13.1. General (Not mechanisms)

Curcumin has the ability to protect DNA from oxidation via the heavy metal arsenic[137], 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.[138] 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.[139] Curcumin also prevented adducts in colonic cells when administered at 2% of the diet with meals.[140]

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.[141] This mechanism appears to ‘sensitize’ cells to cell death induced by TNF-a by inhibiting cellular survival via nF-kB[142][143] and is most likely due to curcumin’s ability to prevent or reduce activation of p38 in the face of other activators.[144][145][146]

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.[68]

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.[72][71][130] Curcumin appears to directly inhibit IKK? as the method of reducing nF-kB translocation.[147]

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.[125]

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.[147] As siRNA inhibition of CXCL1/2 also had these effects, this appears to be the metabolic lever of concern.[147]

14. Interactions with Hormones

14.1. 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.[148]

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,[149] most likely though preventing the oxidation of ethanol to acetylaldehyde.[150] Other compounds that damage the testicles and reduce testosterone, but are protected against by curcumin, include excessive chromium levels[151] and cadmium.[152]

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.[64] This effect was not dose-dependent, and concentrations of 1uM were not significantly different from 0.1uM and control cells.[64]

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.[65]

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.[153]

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[154] but appears to reduce the catalytic activity of aromatase (also known as CYP1A) in mice.[155] 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

14.2. Estrogen

In regards to possible anti-estrogen effects, the lack of inhibition on aromatase[154] but potential to reduce catalytic activity of aromatase[155] 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.[156]

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).[157] 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).[158]

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).[153]

High doses appear to be estrogenic

15. Interactions with Skeletal Muscle

15.1. 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.[159] Curcumin also ameliorates the increase in inflammatory cytokines associated with Ischemia/Reperfusion injury.[159][160]

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.[161] Interestingly, curcumin can also inhibit upregulation and damage from lead via preventing Grp94 upregulation,[162] and general protection against cadmium as well.[163]

15.2. 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.[164] 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.[165]

Curcumin is able to inhibit Atrogin1/MAFbx and its subsequent ubiquitin ligase activity in vitro at 25uM,[166] 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.[166]

15.3. 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.[167] This effect is shared by Green Tea Catechins.[167] Improvements in this mechanism of insulin resistance have been seen in vivo with dose-dependent oral doses of curcumin at 50, 150, and 250mg/kg bodyweight.[168] AMPK activation appears to be a key intermediate in these effects.[168][102] 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.[169]

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,[170] the downregulation of NRF2 and Heme Oxygenase-1,[171] and downregulation of AMPK and CPT-1.[168] 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.[172]

16. Interactions with other Organ Systems

16.1. 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?.[173]

16.2. 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. The mechanism of action appears to be suppressing pro-inflammatory cytokines like TGF-b and IL-8. These benefits have been shown to extend to nephritis associated with lupus at the same dosing protocol in humans.

Curcumin exerts this apparent kidney protection via suppressing inflammation and related cytokines or mRNA associated with inflammation (MCP-1, IL-8, nF-kB). 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 and in delaying the inevitable progression of renal failure.

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

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

17. Nutrient-Nutrient Interactions

17.1. 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.

The pairing of the two has been demonstrated synergistic in attenuating benzo(a)pyrene toxicity in various tissues[179][180] as well as mitigating DNA damage.

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.

17.2. 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.

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.

17.3. 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. 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.

17.4. 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. This synergism apparently extends over into each compounds anti-inflammatory effects, and this mechanism extends to EPA.

17.5. 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.

17.6. Rolipram

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

A nutraceutical PDE4 inhibitor (at the moment, synergism untested) is Resveratrol.

17.7. 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.

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

17.8. 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.

17.9. Garcinol

Garcinol is a polyisoprenylated benzophenone chalcone molecule that is found in Garcinia Indica, a plant in the mangosteen family of fruits. 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.

18. Safety and Toxicology

18.1. 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. When using enhanced formulations to increase circulating levels of curcumin, 1g of MERICA (Curcumin bound to lecithin) over 8 months is not associated with any side-effects.

18.2. 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.

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