Curcumin
Encyclopedia
Curcumin is the principal curcuminoid of the popular India
n spice turmeric
, which is a member of the ginger family (Zingiberaceae). The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenol
s and are responsible for the yellow color of turmeric
. Curcumin can exist in several tautomer
ic forms, including a 1,3-diketo
form and two equivalent enol
forms. The enol form is more energetically stable in the solid phase and in solution.
Curcumin can be used for boron quantification in the curcumin method. It reacts with boric acid
forming a red colored compound, known as rosocyanine
.
Curcumin is brightly yellow colored and may be used as a food coloring
. As a food additive
, its E number
is E100.
s are connected by two α,β-unsaturated carbonyl
groups. The diketones form stable enol
s or are easily deprotonated and form enolates, while the α,β-unsaturated carbonyl is a good Michael acceptor and undergoes nucleophilic addition
. The structure was first identified in 1910 by J. Miłobędzka, Stanisław Kostanecki and Wiktor Lampe.
Curcumin is used as a reagent for boron
in EPA Method 212.3.
. This is noteworthy because plant biosyntheses employing cinnamic acid as a starting point are rare compared to the more common use of p-coumaric acid. Only a few identified compounds, such as anigorufone and pinosylvin, use cinnamic acid
as their start molecule. An experimentally backed route was not presented until 2008. This proposed biosynthetic route follows both the first and second mechanisms suggested by Roughley and Whiting. However, the labeling data supported the first mechanism model in which 5 malonyl-CoA molecules react with cinnamic acid to form curcumin. However, the sequencing in which the functional groups, the alcohol and the methoxy, introduce themselves onto the curcuminoid seems to support more strongly the second proposed mechanism. Therefore, it was concluded the second pathway proposed by Roughly and Whiting was correct.
for the relief of pain associated with osteoarthritis
of the knee. An extensive survey of the literature shows a number of other potential uses and that daily doses over a 3 month period of up to 12 grams proved safe. Commercial capsules of curcumin contain piperine
, a compound found in pepper
which aids absorption of curcumin into the blood stream. However, as curcuma is known to inhibit blood clotting, it should be avoided for a two week period prior to major surgery and not used in conjunction with blood thinners such as warfarin and Plavix. It is also known to aggravate gallstone problems.
n Ayurvedic medicine since 1900 BC to treat a wide variety of ailments. Research in the latter half of the 20th century has identified curcumin as responsible for most of the biological activity of turmeric. In vitro
and animal studies have suggested a wide range of potential therapeutic or preventive effects associated with curcumin. At present, these effects have not been confirmed in humans. However, as of 2008, numerous clinical trial
s in humans were underway, studying the effect of curcumin on various diseases, including multiple myeloma
, pancreatic cancer
, myelodysplastic syndrome
s, colon cancer, psoriasis
, and Alzheimer's disease
.
In vitro and animal studies have proven that curcumin has antitumor, antioxidant
, antiarthritic
, antiamyloid
, anti-ischemic, and anti-inflammatory
properties. Anti-inflammatory properties may be due to inhibition of eicosanoid
biosynthesis. In addition it may be effective in treating malaria
, prevention of cervical cancer
, and may interfere with the replication of the human immunodeficiency virus (HIV
). In HIV, it appears to act by interfering with P300/CREB-binding protein (CBP). It is also hepatoprotective.
A 2008 study at Michigan State University
showed low concentrations of curcumin interfere with Herpes simplex virus-1 (HSV-1)
replication. The same study showed curcumin inhibited the recruitment of RNA polymerase II
to viral DNA, thus inhibiting its transcription
. This effect was shown to be independent of effect on histone acetyltransferase activities of p300/CBP. A previous (1999) study performed at University of Cincinnati
indicated curcumin is significantly associated with protection from infection by HSV-2 in animal models of intravaginal infections.
Curcumin acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation
and oxidative DNA damage. Curcuminoids induce glutathione S-transferase
and are potent inhibitors of cytochrome P450.
The Siegel Life Project funded an initial study on curcumin for Alzheimer's in 1997-1998 through the UCLA Center on Aging. UCLA/VA researchers Drs. Cole and Frautschy presented potent anti-Alzheimer's effects in 1997 and 2000 at the Society for Neuroscience. These data were then published in 2001, demonstrating that curcumin was particularly effective in reducing neurodegeneration, oxidative damage, diffuse plaque deposition, aberrant inflammation and impaired inflammatory clearance following beta-amyloid infusion, which was published in 2001. This led to testing in a transgenic animal model where it was shown to dramatically diminish plaque burden and overall inflammation, but also increase plaque associated inflammatory cells suggesting clearance. In 2004 this UCLA/Veterans group demonstrated that the effect was in part to the highly specific binding effects to beta-amyloid, whereby it could break apart amyloid aggregates in vitro, bind to plaques in vivo, and because of its fluorescent properties, it could be determined that plaques of transgenic mice ingesting curcumin fluoresced green, demonstrating brain penetration. A Harvard group showed that 7 days of tail vein injections of curcumin shrunk plaque size and reduced dystrophic neurites. The UCLA group also showed curcumin synerigizing with fish oil working to protect against cognitive deficits in another transgenic model. However humans show much more glucuronidation
than rodents, and glucuronidated curcumin does not pass the blood brain barrier (See section on curcumin formulations). Free curcumin but not glucuronidated curcumin readily passes through the barrier. But extensive glucuronidation in humans is the major barrier to translation in neurodegenerative diseases. Human intestinal cells glucuronidate more than rodent intestine (Ireson)
There is also circumstantial evidence curcumin improves mental functions; a survey of 1010 Asian people who ate yellow curry
and were between the ages of 60 and 93 showed those who ate the sauce "once every six months" or more had higher MMSE
results than those who did not. From a scientific standpoint, though, this does not show whether the curry caused it, or people who had healthy habits also tended to eat the curry, or some completely different relationship.
Numerous studies have demonstrated curcumin, amongst only a few other things, such as high impact exercise, learning, bright light, and antidepressant usage, has a positive effect on neurogenesis in the hippocampus
and concentrations of brain-derived neurotrophic factor
(BDNF), reductions in both of which are associated with stress, depression, and anxiety. Curcumin has also been demonstrated to be a selective monoamine oxidase inhibitor
(MAOI) of type MAO-A. Fluorescent imaging in a mouse model of Alzheimer's disease showed that curcumin crosses the blood-brain barrier
. Several studies have demonstrated that unlike glucuronidated curcumin, free curcumin, which is lipophilic, readily passes the blood brain barrier
In 2009, an Iranian group demonstrated the combination effect of curcumin with 24 antibiotic
s against Staphylococcus aureus
. In that study, in the presence of a subinhibitory concentration of curcumin, the antibacterial activities of cefixime
, cefotaxime
, vancomycin
and tetracycline were increased against test strain. The increase in inhibition zone surface area
for these antibiotic
s were 52.6% (cefixime), 24.9% (cephotaxime), 26.5% (vancomycin ) and 24.4% (tetracycline). Also it showed curcumin has an antagonist
effect on the antibacterial effect of nalidixic acid
against the test strain.
Although many preclinical studies suggest curcumin may be useful for the prevention and treatment of several diseases, the effectiveness of curcumin has not yet been demonstrated in randomized, placebo-controlled, double-blind clinical trials.
In 2008 scientists at the Salk Institute (Drs. Dave Schubert and Pam Maher) performed high throughput screening, identifying a curcumin pyrazole derivative, which improved memory, is broadly neuroprotective, stimulates BDNF in vitro and in vivo. This group showed in collaboration with UCLA that it was protective in brain trauma and in collaboration with Cedars Sinai/UCSD groups that it was protective in stroke.
in cancer cells without cytotoxic effects on healthy cells. Curcumin can interfere with the activity of the transcription factor NF-κB, which has been linked to a number of inflammatory diseases such as cancer
.
A 2009 study suggested curcumin may inhibit mTOR complex I via a novel mechanism.
Another 2009 study on curcumin effects on cancer states it "modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK)".
A 2010 study in malignant brain tumors showed curcumin effectively inhibits tumor cell proliferation, as well as migration and invasion, and these effects may be mediated through interference with the STAT3 signaling pathway.
When 0.2% curcumin is added to diet given to rats or mice previously given a carcinogen, it significantly reduces colon carcinogenesis.
Curcumin has recently been shown to have phyto-estrogenic activity that might contribute to activity against breast cancer. In the murine model of breast cancer metastasis, curcumin inhibits the formation of lung metastases probably through the NF-kappa-B dependent regulation of protumorigenic inflammatory cytokines.
Curcumin might be potentially useful in some kidney diseases by preventing renal inflammation.
The first formulation to improve bioavailability was curcumin supplements with piperine ("bioperine", manufactured by Sabinsa Corp, New Jersey) and distributed by several companies. Co-supplementation with 20 mg of piperine
(extracted from black pepper) significantly increased the absorption of curcumin by 2000% in a study funded by the manufacturer of piperine. However, the increase in absorption in plasma only occurred during the first hour, after which the difference between the piperine curcumin and the regular curcumin was almost the same as far as absorption. It is important to recognize that rapid clearance from plasma after acute administration does not necessarily represent levels in tissues such as adispose, breast or brain. Glucuronidation inhibitors should be taken cautiously (if at all) by individuals taking other medications, but whether the doses of piperine used can dramatically alter pharmacokinetics of other drugs is unclear.
The second major commercial innovation of curcumin bioavailability was made in 2006, when UC Regents and the Veterans Administration filed a provisional patent, which led to Longvida Optimized Curcumin. In July 2008, the inventors described a new form of "lipidated curcumin" from Verdure Sciences as "Longvida" that was noted to achieve more than 5 micromolar in the brain in vivo. Pharmacokinetics of Longvida in humans shows superior absorption of free curcumin. Extensive toxicity studies have been performed showing Longvida to have an excellent safety profile. as was found in the NIH cancer toxicity studies with tumeric oleoresin leading it to be placed on the FDA's GRAS (generally recognized as safe) list.
Another method to increase the bioavailability of curcumin was later developed as Meriva, patent pending since 2006 and involves a simple procedure creating a complex with soy phospholipids. However, there was no plasma concentration of free curcumin found in humans. In animals, free curcumin reaching 33.4 nanomolar while in humans, none was detected.
Another curcumin proprietary formulation was introduced in 2008 (BCM-95®, Biocurcumax, Arjuna) mixed with turmeric oils, was shown in human cross-over bioavailability comparison tests to have 8 times the bioavailability and greater blood retention time than standard 95% and up to 5 times more than curcumin combined with lecithin and piperine. This same formula was also shown to remain above 200 ng/g for 12 hours in a human clinical study. Plain curcumin remained above 200 ng/g for less than 2 hours. Two hours after ingestion, BCM-95 levels of free curcumin were 10-fold over that of plain curcumin. However these data were in contrast to a six-month placebo-controlled, double-blind clinical trial for Alzheimer's disease, individuals in the BCM-95 groups even doses as high as 4 g failed to yield any significant free curcumin in the plasma. Interestingly there was a non-significant increase in serum amyloid beta with the high dose, which may relate to some effect on amyloid clearance from the brain. ”.
There are other formulations for curcumin in the pipeline, that have not yet become commercial. In 2007, a polymeric nanoparticle
-encapsulated formulation of curcumin ("nanocurcumin"). Nanocurcumin particles have a size of less than 100 nanometers on average, and demonstrate comparable to superior efficacy compared to free curcumin in human cancer cell line models. However, actual in vivo absorption (injected or oral) should be tested with this nanoparticle.
In 2010, a food-grade polymer micellar encapsulation system was shown to increase curcumin's water solubility and in vitro anti-cancer activity. It was found that hydrophobically modified starch, usually used to encapsulate flavors, was able to form polymer micelles. Using a simple high-speed homogenization method, it can load curcumin into its hydrophobic core, and thus solubilize curcumin. Cell culture experiments revealed an enhanced anti-cancer activity on HepG2 cell line. However, more in vivo studies are needed to further prove its efficacy in the aspect of bioavailability.
Populations ingesting high amounts of curcumin in foods may have reduced risk for some diseases (Parkinson's), which may be due to an effect of cooking or dissolution in oil. Some benefits of curcumin, such as the potential protection from colon cancer, may not require systemic absorption. Alternatively, dissolving curcumin in warm oils prior to ingestion increases bioavailability; however, other than abstracts presented at Society for Neuroscience in 2009 "Efficacy of curcumin formulations in relation to systemic availability in the brain and different blood compartments in neuroinflammatory and AD models. Society for Neuroscience, Oct 18. 2009, #211.7, Chicago Ill 36:2009", no manuscripts to date have documented this. The poor stability in aqueous solution as opposed to high stability in lipid solutions argues that cooking with curcumin and oil may increase absorption. Curcumin is not stable in water because it is prone to hydrolysis, that convert it to vanillin and ferulic acid. In addition to curries, one can purchase food products containing turmeric (~5% curcumin) such as Nutmeric, which provide turmeric in an oil-solubilized form similar to Indian curry preparations. The amount of curcumin in such foods compares readily to the typical Indian diet. .
Bioavailability of curcumin can be increased by preparing matrix tablet for colon targeted using natural polymer.
tumor suppressor pathway, an important factor in human colon cancer. Carcinogenic and tests in mice and rats, however, have failed to establish a clear relationship between tumorogenesis and administration of curcumin in turmeric oleoresin at >98% concentrations. Other in vitro and in vivo studies suggest that curcumin may cause carcinogenic effects under specific conditions.
Clinical studies in humans with high doses (2–12 grams) of curcumin have shown few side effects, with some subjects reporting mild nausea or diarrhea. More recently, curcumin was found to alter iron metabolism
by chelating
iron and suppressing the protein hepcidin
, potentially causing iron deficiency
in susceptible patients. Further studies seem to be necessary to establish the benefit/risk profile of curcumin.
There is no or little evidence to suggest curcumin is either safe or unsafe for pregnant women. However, there is still some concern medicinal use of products containing curcumin could stimulate the uterus
, which may lead to a miscarriage, although there is not much evidence to support this claim. According to experiments done on rats and guinea pigs, there is no obvious effect (neither positive, nor negative) on the pregnancy rate or number of live or dead embryos. Curcumin has embryotoxic and teratogenic effects on zebrafishes (Danio rerio
) embryos.
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
n spice turmeric
Turmeric
Turmeric is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. It is native to tropical South Asia and needs temperatures between 20 °C and 30 °C and a considerable amount of annual rainfall to thrive...
, which is a member of the ginger family (Zingiberaceae). The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenol
Natural phenol
Natural phenols, bioavailable phenols, plant phenolics, low molecular weight phenols or phenoloids are a class of natural products. They are small molecules containing one or more phenolic group. These molecules are smaller in size than polyphenols, containing less than 12 phenolic groups...
s and are responsible for the yellow color of turmeric
Turmeric
Turmeric is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. It is native to tropical South Asia and needs temperatures between 20 °C and 30 °C and a considerable amount of annual rainfall to thrive...
. Curcumin can exist in several tautomer
Tautomer
Tautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond...
ic forms, including a 1,3-diketo
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
form and two equivalent enol
Enol
Enols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates...
forms. The enol form is more energetically stable in the solid phase and in solution.
Curcumin can be used for boron quantification in the curcumin method. It reacts with boric acid
Boric acid
Boric acid, also called hydrogen borate or boracic acid or orthoboric acid or acidum boricum, is a weak acid of boron often used as an antiseptic, insecticide, flame retardant, as a neutron absorber, and as a precursor of other chemical compounds. It exists in the form of colorless crystals or a...
forming a red colored compound, known as rosocyanine
Rosocyanine
Rosocyanine and Rubrocurcumin are two red colored materials, which are formed by the reaction between curcumin and borates.-Application:The color reaction between borates and curcumin is used within the spectrophotometrical determination and quantification of boron present in food or materials...
.
Curcumin is brightly yellow colored and may be used as a food coloring
Food coloring
Food coloring is a substance, liquid or powder, that is added to food or drink to change its color. Food coloring is used both in commercial food production and in domestic cooking...
. As a food additive
Food additive
Food additives are substances added to food to preserve flavor or enhance its taste and appearance.Some additives have been used for centuries; for example, preserving food by pickling , salting, as with bacon, preserving sweets or using sulfur dioxide as in some wines...
, its E number
E number
E numbers are number codes for food additives that have been assessed for use within the European Union . They are commonly found on food labels throughout the European Union. Safety assessment and approval are the responsibility of the European Food Safety Authority...
is E100.
Chemistry
Curcumin incorporates several functional groups. The aromatic ring systems, which are polyphenolPolyphenol
Polyphenols are a structural class of natural, synthetic, and semisynthetic organic chemicals characterized by the presence of large multiples of phenol structural units...
s are connected by two α,β-unsaturated carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
groups. The diketones form stable enol
Enol
Enols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates...
s or are easily deprotonated and form enolates, while the α,β-unsaturated carbonyl is a good Michael acceptor and undergoes nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
. The structure was first identified in 1910 by J. Miłobędzka, Stanisław Kostanecki and Wiktor Lampe.
Curcumin is used as a reagent for boron
Boron
Boron is the chemical element with atomic number 5 and the chemical symbol B. Boron is a metalloid. Because boron is not produced by stellar nucleosynthesis, it is a low-abundance element in both the solar system and the Earth's crust. However, boron is concentrated on Earth by the...
in EPA Method 212.3.
Biosynthesis
The biosynthetic route of curcumin has proven to be very difficult for researchers to determine. In 1973 Roughly and Whiting proposed two mechanisms for curcumin biosynthesis. The first mechanism involved a chain extension reaction by cinnamic acid and 5 malonyl-CoA molecules that eventually arylized into a curcuminoid. The second mechanism involved two cinnamate units being coupled together by malonyl-CoA. Both mechanisms use cinnamic acid as their starting point, which is derived from the amino acid phenylalaninePhenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
. This is noteworthy because plant biosyntheses employing cinnamic acid as a starting point are rare compared to the more common use of p-coumaric acid. Only a few identified compounds, such as anigorufone and pinosylvin, use cinnamic acid
Cinnamic acid
Cinnamic acid is a white crystalline organic acid, which is slightly soluble in water.It is obtained from oil of cinnamon, or from balsams such as storax. It is also found in shea butter and is the best indication of its environmental history and post-extraction conditions...
as their start molecule. An experimentally backed route was not presented until 2008. This proposed biosynthetic route follows both the first and second mechanisms suggested by Roughley and Whiting. However, the labeling data supported the first mechanism model in which 5 malonyl-CoA molecules react with cinnamic acid to form curcumin. However, the sequencing in which the functional groups, the alcohol and the methoxy, introduce themselves onto the curcuminoid seems to support more strongly the second proposed mechanism. Therefore, it was concluded the second pathway proposed by Roughly and Whiting was correct.
Demonstrated medical uses
A daily dose of 2 grams of Curcuma domestica extract was found to provide pain relief that was equivalent to ibuprofenIbuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....
for the relief of pain associated with osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
of the knee. An extensive survey of the literature shows a number of other potential uses and that daily doses over a 3 month period of up to 12 grams proved safe. Commercial capsules of curcumin contain piperine
Piperine
Piperine is the alkaloid responsible for the pungency of black pepper and long pepper, along with chavicine . It has also been used in some forms of traditional medicine and as an insecticide. Piperine forms monoclinic needles, is slightly soluble in water and more so in alcohol, ether or...
, a compound found in pepper
Pepper
- Plants and plant products :The genus Piper of the pepper family , including for example:* Black pepper, white and green pepper, Piper nigrum* Cubeb, Piper cubeba, also known as Java pepper* Long pepper, Piper longum...
which aids absorption of curcumin into the blood stream. However, as curcuma is known to inhibit blood clotting, it should be avoided for a two week period prior to major surgery and not used in conjunction with blood thinners such as warfarin and Plavix. It is also known to aggravate gallstone problems.
Potential medical uses
Turmeric has been used historically as a component of IndiaIndia
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
n Ayurvedic medicine since 1900 BC to treat a wide variety of ailments. Research in the latter half of the 20th century has identified curcumin as responsible for most of the biological activity of turmeric. In vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and animal studies have suggested a wide range of potential therapeutic or preventive effects associated with curcumin. At present, these effects have not been confirmed in humans. However, as of 2008, numerous clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s in humans were underway, studying the effect of curcumin on various diseases, including multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
, pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
, myelodysplastic syndrome
Myelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
s, colon cancer, psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, and Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
In vitro and animal studies have proven that curcumin has antitumor, antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
, antiarthritic
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
, antiamyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
, anti-ischemic, and anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
properties. Anti-inflammatory properties may be due to inhibition of eicosanoid
Eicosanoid
In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....
biosynthesis. In addition it may be effective in treating malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
, prevention of cervical cancer
Cervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
, and may interfere with the replication of the human immunodeficiency virus (HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
). In HIV, it appears to act by interfering with P300/CREB-binding protein (CBP). It is also hepatoprotective.
A 2008 study at Michigan State University
Michigan State University
Michigan State University is a public research university in East Lansing, Michigan, USA. Founded in 1855, it was the pioneer land-grant institution and served as a model for future land-grant colleges in the United States under the 1862 Morrill Act.MSU pioneered the studies of packaging,...
showed low concentrations of curcumin interfere with Herpes simplex virus-1 (HSV-1)
Herpesviridae
The Herpesviridae are a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word herpein , referring to the latent, recurring infections typical of this group of viruses...
replication. The same study showed curcumin inhibited the recruitment of RNA polymerase II
RNA polymerase II
RNA polymerase II is an enzyme found in eukaryotic cells. It catalyzes the transcription of DNA to synthesize precursors of mRNA and most snRNA and microRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase...
to viral DNA, thus inhibiting its transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
. This effect was shown to be independent of effect on histone acetyltransferase activities of p300/CBP. A previous (1999) study performed at University of Cincinnati
University of Cincinnati
The University of Cincinnati is a comprehensive public research university in Cincinnati, Ohio, and a part of the University System of Ohio....
indicated curcumin is significantly associated with protection from infection by HSV-2 in animal models of intravaginal infections.
Curcumin acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation
Lipid peroxidation
Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism...
and oxidative DNA damage. Curcuminoids induce glutathione S-transferase
Glutathione S-transferase
Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...
and are potent inhibitors of cytochrome P450.
The Siegel Life Project funded an initial study on curcumin for Alzheimer's in 1997-1998 through the UCLA Center on Aging. UCLA/VA researchers Drs. Cole and Frautschy presented potent anti-Alzheimer's effects in 1997 and 2000 at the Society for Neuroscience. These data were then published in 2001, demonstrating that curcumin was particularly effective in reducing neurodegeneration, oxidative damage, diffuse plaque deposition, aberrant inflammation and impaired inflammatory clearance following beta-amyloid infusion, which was published in 2001. This led to testing in a transgenic animal model where it was shown to dramatically diminish plaque burden and overall inflammation, but also increase plaque associated inflammatory cells suggesting clearance. In 2004 this UCLA/Veterans group demonstrated that the effect was in part to the highly specific binding effects to beta-amyloid, whereby it could break apart amyloid aggregates in vitro, bind to plaques in vivo, and because of its fluorescent properties, it could be determined that plaques of transgenic mice ingesting curcumin fluoresced green, demonstrating brain penetration. A Harvard group showed that 7 days of tail vein injections of curcumin shrunk plaque size and reduced dystrophic neurites. The UCLA group also showed curcumin synerigizing with fish oil working to protect against cognitive deficits in another transgenic model. However humans show much more glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
than rodents, and glucuronidated curcumin does not pass the blood brain barrier (See section on curcumin formulations). Free curcumin but not glucuronidated curcumin readily passes through the barrier. But extensive glucuronidation in humans is the major barrier to translation in neurodegenerative diseases. Human intestinal cells glucuronidate more than rodent intestine (Ireson)
There is also circumstantial evidence curcumin improves mental functions; a survey of 1010 Asian people who ate yellow curry
Yellow curry
Yellow curry is one of three major kinds of Thai curry, commonly found in Thai restaurants in the West. There are many more types in Thailand, several of which are yellow...
and were between the ages of 60 and 93 showed those who ate the sauce "once every six months" or more had higher MMSE
Mini-mental state examination
The mini–mental state examination or Folstein test is a brief 30-point questionnaire test that is used to screen for cognitive impairment. It is commonly used in medicine to screen for dementia...
results than those who did not. From a scientific standpoint, though, this does not show whether the curry caused it, or people who had healthy habits also tended to eat the curry, or some completely different relationship.
Numerous studies have demonstrated curcumin, amongst only a few other things, such as high impact exercise, learning, bright light, and antidepressant usage, has a positive effect on neurogenesis in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and concentrations of brain-derived neurotrophic factor
Brain-derived neurotrophic factor
Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF...
(BDNF), reductions in both of which are associated with stress, depression, and anxiety. Curcumin has also been demonstrated to be a selective monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
(MAOI) of type MAO-A. Fluorescent imaging in a mouse model of Alzheimer's disease showed that curcumin crosses the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. Several studies have demonstrated that unlike glucuronidated curcumin, free curcumin, which is lipophilic, readily passes the blood brain barrier
In 2009, an Iranian group demonstrated the combination effect of curcumin with 24 antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s against Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
. In that study, in the presence of a subinhibitory concentration of curcumin, the antibacterial activities of cefixime
Cefixime
Cefixime is an oral third generation cephalosporin antibiotic. Cefixime is a cephalosporin antibiotic used to treat infections caused by bacteria such as pneumonia; bronchitis; gonorrhea; and ear, lung, throat, and urinary tract infections...
, cefotaxime
Cefotaxime
Cefotaxime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram positive and Gram negative bacteria...
, vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
and tetracycline were increased against test strain. The increase in inhibition zone surface area
Agar diffusion test
The agar diffusion test, or the Kirby-Bauer disk-diffusion method, is a means of measuring the effect of an antimicrobial agent against bacteria grown in culture....
for these antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s were 52.6% (cefixime), 24.9% (cephotaxime), 26.5% (vancomycin ) and 24.4% (tetracycline). Also it showed curcumin has an antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
effect on the antibacterial effect of nalidixic acid
Nalidixic acid
Nalidixic acid is the first of the synthetic quinolone antibiotics...
against the test strain.
Although many preclinical studies suggest curcumin may be useful for the prevention and treatment of several diseases, the effectiveness of curcumin has not yet been demonstrated in randomized, placebo-controlled, double-blind clinical trials.
In 2008 scientists at the Salk Institute (Drs. Dave Schubert and Pam Maher) performed high throughput screening, identifying a curcumin pyrazole derivative, which improved memory, is broadly neuroprotective, stimulates BDNF in vitro and in vivo. This group showed in collaboration with UCLA that it was protective in brain trauma and in collaboration with Cedars Sinai/UCSD groups that it was protective in stroke.
Anticarcinogenic effects
Its potential anticancer effects stem from its ability to induce apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in cancer cells without cytotoxic effects on healthy cells. Curcumin can interfere with the activity of the transcription factor NF-κB, which has been linked to a number of inflammatory diseases such as cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
A 2009 study suggested curcumin may inhibit mTOR complex I via a novel mechanism.
Another 2009 study on curcumin effects on cancer states it "modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK)".
A 2010 study in malignant brain tumors showed curcumin effectively inhibits tumor cell proliferation, as well as migration and invasion, and these effects may be mediated through interference with the STAT3 signaling pathway.
When 0.2% curcumin is added to diet given to rats or mice previously given a carcinogen, it significantly reduces colon carcinogenesis.
Curcumin has recently been shown to have phyto-estrogenic activity that might contribute to activity against breast cancer. In the murine model of breast cancer metastasis, curcumin inhibits the formation of lung metastases probably through the NF-kappa-B dependent regulation of protumorigenic inflammatory cytokines.
Curcumin might be potentially useful in some kidney diseases by preventing renal inflammation.
Bioavailability
There have been several commercial products developed to provide an alternative route to curcumin. Several trials with unformulated curcumin show extensive glucuronidation and sulfation and typically undetectable levels of free curcumin. For example, trials show that ingestion from 2 to 10 grams of unformulated curcumin lead to undetectable or very low serum levels of free curcumin. For neurodegenerative diseases, it is important that curcumin is absorbed predominantly as 'free" as opposed to glucuronidated, since glucuronidated curcumin does not penetrate the blood brain barrier, while free curcumin is readily brain penetrant.The first formulation to improve bioavailability was curcumin supplements with piperine ("bioperine", manufactured by Sabinsa Corp, New Jersey) and distributed by several companies. Co-supplementation with 20 mg of piperine
Piperine
Piperine is the alkaloid responsible for the pungency of black pepper and long pepper, along with chavicine . It has also been used in some forms of traditional medicine and as an insecticide. Piperine forms monoclinic needles, is slightly soluble in water and more so in alcohol, ether or...
(extracted from black pepper) significantly increased the absorption of curcumin by 2000% in a study funded by the manufacturer of piperine. However, the increase in absorption in plasma only occurred during the first hour, after which the difference between the piperine curcumin and the regular curcumin was almost the same as far as absorption. It is important to recognize that rapid clearance from plasma after acute administration does not necessarily represent levels in tissues such as adispose, breast or brain. Glucuronidation inhibitors should be taken cautiously (if at all) by individuals taking other medications, but whether the doses of piperine used can dramatically alter pharmacokinetics of other drugs is unclear.
The second major commercial innovation of curcumin bioavailability was made in 2006, when UC Regents and the Veterans Administration filed a provisional patent, which led to Longvida Optimized Curcumin. In July 2008, the inventors described a new form of "lipidated curcumin" from Verdure Sciences as "Longvida" that was noted to achieve more than 5 micromolar in the brain in vivo. Pharmacokinetics of Longvida in humans shows superior absorption of free curcumin. Extensive toxicity studies have been performed showing Longvida to have an excellent safety profile. as was found in the NIH cancer toxicity studies with tumeric oleoresin leading it to be placed on the FDA's GRAS (generally recognized as safe) list.
Another method to increase the bioavailability of curcumin was later developed as Meriva, patent pending since 2006 and involves a simple procedure creating a complex with soy phospholipids. However, there was no plasma concentration of free curcumin found in humans. In animals, free curcumin reaching 33.4 nanomolar while in humans, none was detected.
Another curcumin proprietary formulation was introduced in 2008 (BCM-95®, Biocurcumax, Arjuna) mixed with turmeric oils, was shown in human cross-over bioavailability comparison tests to have 8 times the bioavailability and greater blood retention time than standard 95% and up to 5 times more than curcumin combined with lecithin and piperine. This same formula was also shown to remain above 200 ng/g for 12 hours in a human clinical study. Plain curcumin remained above 200 ng/g for less than 2 hours. Two hours after ingestion, BCM-95 levels of free curcumin were 10-fold over that of plain curcumin. However these data were in contrast to a six-month placebo-controlled, double-blind clinical trial for Alzheimer's disease, individuals in the BCM-95 groups even doses as high as 4 g failed to yield any significant free curcumin in the plasma. Interestingly there was a non-significant increase in serum amyloid beta with the high dose, which may relate to some effect on amyloid clearance from the brain. ”.
There are other formulations for curcumin in the pipeline, that have not yet become commercial. In 2007, a polymeric nanoparticle
Nanoparticle
In nanotechnology, a particle is defined as a small object that behaves as a whole unit in terms of its transport and properties. Particles are further classified according to size : in terms of diameter, coarse particles cover a range between 10,000 and 2,500 nanometers. Fine particles are sized...
-encapsulated formulation of curcumin ("nanocurcumin"). Nanocurcumin particles have a size of less than 100 nanometers on average, and demonstrate comparable to superior efficacy compared to free curcumin in human cancer cell line models. However, actual in vivo absorption (injected or oral) should be tested with this nanoparticle.
In 2010, a food-grade polymer micellar encapsulation system was shown to increase curcumin's water solubility and in vitro anti-cancer activity. It was found that hydrophobically modified starch, usually used to encapsulate flavors, was able to form polymer micelles. Using a simple high-speed homogenization method, it can load curcumin into its hydrophobic core, and thus solubilize curcumin. Cell culture experiments revealed an enhanced anti-cancer activity on HepG2 cell line. However, more in vivo studies are needed to further prove its efficacy in the aspect of bioavailability.
Populations ingesting high amounts of curcumin in foods may have reduced risk for some diseases (Parkinson's), which may be due to an effect of cooking or dissolution in oil. Some benefits of curcumin, such as the potential protection from colon cancer, may not require systemic absorption. Alternatively, dissolving curcumin in warm oils prior to ingestion increases bioavailability; however, other than abstracts presented at Society for Neuroscience in 2009 "Efficacy of curcumin formulations in relation to systemic availability in the brain and different blood compartments in neuroinflammatory and AD models. Society for Neuroscience, Oct 18. 2009, #211.7, Chicago Ill 36:2009", no manuscripts to date have documented this. The poor stability in aqueous solution as opposed to high stability in lipid solutions argues that cooking with curcumin and oil may increase absorption. Curcumin is not stable in water because it is prone to hydrolysis, that convert it to vanillin and ferulic acid. In addition to curries, one can purchase food products containing turmeric (~5% curcumin) such as Nutmeric, which provide turmeric in an oil-solubilized form similar to Indian curry preparations. The amount of curcumin in such foods compares readily to the typical Indian diet. .
Bioavailability of curcumin can be increased by preparing matrix tablet for colon targeted using natural polymer.
Potential risks and side effects
Extensive in vivo toxicity studies have been performed with turmeric Oleoresin (85% curcumin) which led to it being placed on the FDA's GRAS (generally recognized as safe) list [54]. Kawanishi et al. (2005) remarked that curcumin, like many antioxidants, can be a "double-edged sword" where, in the test tube, anticancer and antioxidant effects may be seen in addition to pro-oxidant effects. Carcinogenic effects are inferred from interference with the p53P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
tumor suppressor pathway, an important factor in human colon cancer. Carcinogenic and tests in mice and rats, however, have failed to establish a clear relationship between tumorogenesis and administration of curcumin in turmeric oleoresin at >98% concentrations. Other in vitro and in vivo studies suggest that curcumin may cause carcinogenic effects under specific conditions.
Clinical studies in humans with high doses (2–12 grams) of curcumin have shown few side effects, with some subjects reporting mild nausea or diarrhea. More recently, curcumin was found to alter iron metabolism
Human iron metabolism
Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron. Iron is an essential element for most life on Earth, including human beings. The control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease...
by chelating
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
iron and suppressing the protein hepcidin
Hepcidin
Hepcidin is a peptide hormone produced by the liver. It was discovered in 2000, and appears to be the master regulator of iron homeostasis in humans and other mammals. In humans, HAMP is the gene that encodes for hepcidin.-Structure:...
, potentially causing iron deficiency
Iron deficiency (medicine)
Iron deficiency is one of the most common of the nutritional deficiencies. Iron is present in all cells in the human body, and has several vital functions...
in susceptible patients. Further studies seem to be necessary to establish the benefit/risk profile of curcumin.
There is no or little evidence to suggest curcumin is either safe or unsafe for pregnant women. However, there is still some concern medicinal use of products containing curcumin could stimulate the uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
, which may lead to a miscarriage, although there is not much evidence to support this claim. According to experiments done on rats and guinea pigs, there is no obvious effect (neither positive, nor negative) on the pregnancy rate or number of live or dead embryos. Curcumin has embryotoxic and teratogenic effects on zebrafishes (Danio rerio
Danio rerio
The zebrafish, Danio rerio, is a tropical freshwater fish belonging to the minnow family of order Cypriniformes. It is a popular aquarium fish, frequently sold under the trade name zebra danio, and is an important vertebrate model organism in scientific research.-Taxonomy:The zebrafish are...
) embryos.
External links
- Turmeric and curcumin, from Memorial Sloan-Kettering Cancer CenterMemorial Sloan-Kettering Cancer CenterMemorial Sloan–Kettering Cancer Center is a cancer treatment and research institution founded in 1884 as the New York Cancer Hospital...
- Turmeric and curcumin, from M.D. Anderson Cancer Center
- Turmeric, from the University of Maryland Medical CenterUniversity of Maryland Medical CenterThe University of Maryland Medical Center is a teaching hospital with 705 beds based in Baltimore, Maryland, that provides the full range of health care to people throughout Maryland and the Mid-Atlantic region. It gets more than 35,000 inpatient admissions and 165,000 outpatient visits each year...