User:JoeGabriell/Curcumin

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Curcumin is one of the constituents of tumeric and is responsible for the spice's yellow color. It has been used in Indian medicine for ~4000 years to treat a variety of ailments. Recently, research has begun at an alarming rate, investigating curcumin's potential as an anti-oxidant, anti-inflammatory, anti-depressant, and anti-cancer drug. And the research is promising.

It should be noted that curcumin's bioavailability is quite low, but ingesting large doses may circumvent any problems with absorption. Moreover, ingestion with piperine has been shown to increase absorption by approximately an order of magnitude. (Couldn't find a good citation, but mention of this is widespread in peer-reviewed articles.}} Moreover, recent efforts have begun to encapsulate curcumin in lipid solvents, thereby improving absorption.

Cancer[edit]

It's rare to see a drug that is shown, in study after study, to have remarkable and significant anti-cancer properties both in vivo and in vitro. But curcumin is such a drug, and it induces tumor apoptosis with no apparent toxicity.

PMID 20145189 curcumin has shown activity against oral cancers. Remarkably, curcumin arrests the growth of immortalized normal cells and malignant cells, but not normal oral cells.

PMID 20127174 Curcumin sensitizes lung cancer cells to apoptosis by reducing expression of Bcl-2, an anti-apoptotic signaling molecule.

PMID 19898931 Curcumin and piperine, both separately and in combination, inhibit breast stem cell self-renewal, but do not cause toxicity to differentiated cells. This action may prevent breast cancer.

PMID 16584595 Curcumin reduces BDNF, inhibits TrkB expression, and reduces angiogenesis (which is stimulated by BDNF}} in multiple myeloma cells. This is the first of many paradoxical results, as curcumin has been shown to increase BDNF in chronic stress.

PMID 20387230 Curcumin induces apoptosis in oral cancer cells.

PMID 20358476 Curcumin causes mitochondrial damage to prostate cancer cells, leading to apoptosis.

PMID 20305684 Curcumin treatment enhanced the ability of effector T cells to kill cancer cells in vitro.

PMID 20332461 Curcumin induces apoptosis in brain cancer cells.

PMID 20044614 Curcumin induces cell death in bone cancer cells.

PMID 20032896 Curcumin is effective against leukemia; abstract notes that tumor cells are more sensitive to the effects of curcumin than are normal cells.

PMID 19901561 Phase I trial of curcumin, combined with chemotherapy, in breast cancer in humans. Curcumin given orally at 500mg/day and escalated from there. 6000mg/day was most effective, and curcumin seemed to improve efficacy.

PMID 20373902 Curcumin induces apoptotis in melanoma cells through a mitochondrial pathway.

PMID 20393484 Curcumin induces apoptotis in T-cell lymphoma cells by inhibiting STAT-3 and NF-kappaB.

PMID 20077433 Curcumin inhibits lung cancer growth in vivo.

PMID 20363232 Curcumin restrains cancer cell growth by suppressing activity of telomerase, and this study suggests it does so by (paradoxical}} ROS production.

PMID 20360934 Curcumin promotes apoptosis in esophageal cancer.

PMID 20057137 Curcumin inhibits inosine monophosphate dehydrogenase, a therapeutic target for anti-cancer therapy and key step in DNA synthesis.

Summary Curcumin shows activity (in a mix of in vivo and in vitro studies}} in esophageal cancer, lung cancer, melanoma, lymphoma, breast cancer, leukemia, bone cancer, brain cancer, prostate cancer, and oral cancer. And this is just a sampling of the literature.

It seems that curcumin's effects are mediated by a variety of factors, ranging from a reduction in Bcl-2 (an anti-apoptotic protein), inhibition of STAT-3 and NF-kappaB, increased ROS production in cancer cells, suppression of telomerase activity, and increased T cell efficacy.

Anti-ROS, Injury, Inflammation, and Inflammation-related Disease[edit]

Inhibiting NF-kappaB and TNF-alpha is just the beginning for curcumin, as the compound seems to have widespread anti- inflammatory effects.

PMID 20227282 Curcumin induces glutathione synthesis.

PMID 20132469 Clinically achievable concentrations of curcumin reduced glial activation, inflammation, and cerebral edema following traumatic brain injury in mice.

PMID 20018302 In rats with spinal cord injury, curcumin inhibited apoptosis and neuron loss and also "quenched astrocyte activation", improving neural deficit. By attenuating astrocyte activation, curcumin improves neuron survival.

PMID 19917353 Curcumin is known to be a potent inhibitor of NF-kappaB and attenuates ischemia-reperfusion injury. In reperfusion injury, curcumin increases glutathione and reduced NO levels (among other effects), reducing inflammatory damage.

PMID 16364299 Pre-supplementation (and post-supplementation, possibly to a lesser extent}} with curcumin dramatically reduced effects of traumatic brain injury, normalizing levels of BDNF, CREB, and synapsin I.

PMID 20214332 Curcumin inhibits fibroblast proliferation, potentially indicating effectiveness against fibrotic disease.

PMID 20180411 In rat chronic nonbacterial prostatitis, curcumin lowers TNF-alpha and IL-8, leading to amelioration of symptoms.

PMID 20125031 Curcumin protects myocardium against ischemic injury.

PMID 20056736 Curcumin protects against arsenic-induced DNA damage by reducing ROS generation and lipid peroxidation and increasing antioxidant activity.

PMID 19878610 Curcumin may have efficacy against inflammatory bowel disease. Curcumin enhances IL-10 and reduces IL-1beta.

PMID 20112103 Curcumin has hepatoprotective potency by reducing lipid peroxidation and increasing GSH, CAT, and SOD. Indeed, curcumin (but not resveratrol}} is effective against aflatoxin-induced liver injury.

PMID 20056776 Curcumin inhibits pneumonia-related lung inflammation without decreasing bacterial load, and may combine very well with antibiotics. (Curcumin reduced TNF-alpha, NO, and other inflammatory mediators.}}

PMID 19932168 Curcumin may help prevent cataracts by limiting free-radical induced Ca2+ influx in the eye.

PMID 20188213 At least in mice, curcumin may treat arthritis by reducing TNF-alpha, IL-1beta, and serum IgG2. By inhibiting NF-kappaB, curcumin also inhibited PGE2 production and COX-2 expression.

PMID 20080166 Curcumin exerts hepatoprotective actions against ethanol.

PMID 20229497 In merucury-exposed rats, curcumin reduces mercury-associatd oxidative stress and its serum markers. Curcumin also reduced tissue mercury concentrations. Curcumin may be both an effective treatment and pre-treatment to mercury exposure.

PMID 20026275 In rats given streptozotocin (a toxin), curcumin prevents memory deficit and normalizes elevated AChE levels in the hippocampus. Curcumin also attenuated reduced glutathione levels in the cortex and hippocampus due to the toxin. Finally, curcumin also restored insulin receptor protein levels altered by the toxin.

PMID 20025056 Curcumin is protective against selenium toxicity in the liver and kidney by means of regulating iNOS expression.

PMID 16387899 A good review summarizing effects of curcumin. Curcumin inhibits NF-kappaB, COX-2, LOX, and iNOS.

PMID 19919835 Curcumin can prevent acetominophen overdose-induced damage to kidney and renal cells.

PMID 20026325 Curcumin may have therapeutic potential in dry eye disease.

Summary[edit]

Curcumin protects the liver against ethanol, may heal dry eye disease, prevents acetominophen toxicity, protects against selenium, mercury, and arsenic toxicity, has shown efficacy against arthritis, may prevent cataracts, may reduce sickness-associated inflammation, reduces liver inflammation, may have efficacy against inflammatory bowel disease, reduces inflammation in prostatitis, reduces damage due to ischemia/reperfusion, reduces the effects of traumatic brain injury (both in preventative and treatment capacities), increases glutathione, and improves neuron survival in spinal cord injury.

It accomplishes these remarkable and diverse feats by increasing glutathione, inhibiting NF-kappaB, inhibiting PGE2 and COX- 2, reducing TNF-alpha, IL-8, and IL-1beta, scavenging ROS, reducing iNOS and nitric oxide, increases catalase and superoxide dismutase expression, increasing IL-10, reducing TGF-beta1 activation, reducing astrocyte activation in traumatic brain injury, and normalizing brain levels of BDNF and CREB.


Stress and Depression[edit]

Curcumin has shown remarkable efficacy in reducing the neurological consequences of chronic stress. Many of these benefits seem to derive from increased BDNF expression, but there may also be other mechanisms at work. At any rate, curcumin may have potential as both an antidepressant and an "adaptogen".

PMID 19879308 Curcumin increases BDNF and CREB.

PMID 17022948 Chronic stress increased plasma corticosterone and reduced GR expression, and these changes were reversed by curcumin administration. Chronic stress also reduced BDNF levels and pCREB/CREB ratio in the hippocampus and frontal cortex of rats. Curcumin blocked these effects.

PMID 18766332 Curcumin showed antidepressant effects in mice, increased 5-HT and DA (at higher doses}} at higher levels, and (at higher doses}} inhibited both MAO-A and MAO-B. Curcumin also appears to synergize with SSRI and NRI antidepressants, but not tricyclics. Coadministration of piperine (known to increase bioavailability}} enhanced effects.

PMID 17942093 Curcumin has anti-depressant like effects in the forced swimming test. These effects appear to be mediated by alterations in 5-HT1A/1B and 5-HT2C. More specifically, both 5-HT1A and 5-HT1B antagonism separately blocks the effects of curcumin, but 5-HT1A agonism, 5-HT1B agonism, and 5-HT2C antagonism synergize with the effects of curcumin. Thus curcumin may act, directly or indirectly, as a 5-HT1A/1B agonist and a 5-HT2C antagonist. This is very good.

PMID 17846884 Ethanol withdrawal did not restore rhythmicity or levels of 5-HT or 5-HIAA in the SCN of male rats, but curcumin administration partially restored 5-HT/5-HIAA ratio and daily phase shifts. This may have relevance for circadian rhythm disruptions.

PMID 17846884 Rats subjected to chronic mild stress developed increased TNF-alpha and IL-6 levels, as well as reduced NK cell counts. These rats also showed increased CRH and serum cortisol, without an elevation in ACTH. Administration of curcumin reversed these effects, demonstrating antidepressant-like effects.

PMID 17617388 Curcumin increases hippocampal neurogenesis in chronically stressed rats in a way similar to imipramine. Curcumin also prevented stress-induced reductions in 5-HT1A mRNA and BDNF levels in the hippocampus.

These last two studies are strange; they are in vitro studies in bovine adrenocortical cells, but show largely opposite actions of curcumin on cortisol. Not sure what to think, and haven't had time to analyze them.

PMID 18406348 In bovine adrenocortical cells, curcumin increased cortsiol secretion, and this increase lasted for 24 hours. Secretion was increased as much as 10-fold. This was accomplished by curcumin inhibition of bTREK1 K+ channels.

PMID 19653644 Also in bovine adrenocortical cells, curcumin decreased ACTH-induced cortisol secretion as well as angiotensin-II-induced cortisol secretion. (Contradicts another study.}}

Summary Curcumin prevents stress-induced reductions in 5-HT1A and BDNF in the cortex and hippocampus, normalizes stress- induced increases in TNF-alpha and IL-6, reduces stress-induced increases in serum corticosterone, negates stress-induced downregulation of GR expression, restores disturbed 5-HT circadian rhythm consequent to ethanol withdrawal, increases BDNF and CREB, shows considerable antidepressant efficacy, and may directly or indirectly be a 5-HT1A/1B agonist and 5-HT2C antagonist.

Insulin, Skeletal Muscle, Fat, and Metabolism[edit]

Though the data are, my comparison, scant, curcumin also seems to have positive effects on blood lipids, insulin sensitivity, fat cells, and skeletal muscle.

PMID 20227862 Curcumin dose-dependently decreases lipids and glucose in diabetic rats. Curcumin also increased AMPK both in vivo and in vitro. Thus curcmin improves insulin resistance in rat skeletal muscle.

PMID 20222050 Curcumin reduced insulin and leptin in frucrose-fed rats. Thus curcumin led to improved leptin and insulin signaling as well as PPAR alpha expression. It also reduced LDL cholesterol and tryglycerides.

PMID 20205235 Another study noting curcumin activates AMPK in skeletal muscle, leading to increased glucose uptake.

PMID 10444409 Curcumin acts directly on muscle cells to stimulate proliferation. Inhibitors of NF-kappaB, like curcumin, also stimulate muscle differentiation in vitro. Curcumin has a "striking" effect on myogenesis and accelerated healing after injury.

PMID 19093868 AMPK activation by curcumin may inhibit both cancer cell and adipocyte differentiation.

PMID 20357182 Curcumin suppresses adipogenesis.

PMID 20395228 Curcumin appears to have hypoglycemic action and stimulates insulin secretion from pancreatic cells, suggesting potential efficacy in diabetes.

Summary Curcumin has hypoglycemic action, likely by a combination of reducing insulin sensitivity and increasing pancreatic insulin output; the compound may thus have anti-diabetic activity. Moreover, curcumin activates AMPK (leading to improved glucose uptake in muscle), suppresses adipogenesis, inhibits adipocyte differentiation, stimulates skeletal muscle proliferation (with a "striking" effect on myogenesis), speeds healing after injury, improves insulin and leptin signaling, increases PPAR-alpha expression, and reduces both LDL cholesterol and triglycerides.

Other Good Stuff[edit]

PMID 20040737 Curcumin inhibits TRPV1-mediated hyperalgesia/pain hypersensitivity, but does not inhibit heat-induced TRPV1 currents. (Curcumin may have direct action at TRPV1.}}

PMID 20153625 Curcumin activates the nuclear vitamin D receptor, and this receptor has been associated with chemoprotection against intestinal cancers.

PMID 20026048 Curcumin has anti-viral activity against influenza, adenovirus, coxsackievirus, and HIV. This study further showed that curcumin reduces hepatitis C gene expression through the Akt-SREBP-1 pathway.

PMID 20017731 Curucmin has anti-fungal properties against Candida via generation of oxidative stress. Curcumin's effects were prevented by the addition of anti-oxidants. (Excessive doses used?}}

PMID 18420184 Glutamate excitotoxicity reduced BDNF and reduced cell viability; pretreatment with curcumin prevented these effects. However, a Trk (BDNF receptor}} receptor inhibitor blocked these effects, suggesting that the neuroprotective effects of curcumin are mediated by BDNF/TrkB.

PMID 19033880 Curcumin abolished upregulation of BDNF transcription and morphine analgesic tolernance after administration of morphine for six days.

PMID 20369229 Curcumin inhibits the effects of streptozotocin-induced dementia through PPAR-gamma activation.

PMID 20230279 Curcumin reduces DA cell death consequent to application of MPTP. Importantly, this effect is not due exclusively to anti-inflammatory or anti-oxidant activity; rather, curcumin inhibits phosphorylation of JNK1/2 and c-Jun, leading to increased DA neuron survival.

PMID 20209961 "Several animal gastric ulcer models prove that curcumin SDs has anti-gastric ulcer effects by inhibiting gastric acid secretion, reducing gastric juice acidity, inhibiting the activity of pepsin and promoting healing of ulcer."

PMID 20337222 Another study showing curcumin has activity against gastric ulcers.

PMID 20170701 Here's one for ATB: curcumin prevents against genotoxic effects of arsenic and flouride.

PMID 20346917 Curcumin enhances retinoic acid-induced superoxide radical generating activity, and thus may be an immune potentiator.

Summary Curcumin potentiates the immune system, prevents against genotoxic effects of flouride and arsenic, prevents and treats gastric ulcers, reduces DA cell death upon administration of DA neurotoxin (and do so through more than just anti- inflammatory pathways], reduces tolerance to morphine, provides neuroprotection against glutamate excitotoxicity, shows anti-fungal properties, shows anti-viral properties, is a vitamin D receptor agonist, and may reduce certain types of hyperalgesia.

The Caveats[edit]

At this point, curcumin has mostly been shown to have no known toxicity and very few negative effects. Still, there are a handful of studies that are worthy of mention.

PMID 20029958 Like many other antioxidants, low doses of curcumin scavange ROS, but higher doses may induce ROS and lead to damage. This was seen in a rat model of myocardial necrosis.

PMID 11815407 Curcumin is extensively metabolized in the GI tract. Not necessarily a bad thing, but could lead to variable effects.

PMID 20346654 Curcumin has some activity at inhibiting 17beta-HSD3, the enzyme catalyzing the final step of testosterone biosynthesis. It is unclear how substantial this effect is, however it could potentially lead to reduced testosterone levels.

PMID 19879924 In vitro, curcumin increases LRRK2 mRNA and protein. LRRK2 is a gene whose expression has been positively assocaited with Parkinson's disease. This could, in theory, lead to increased risk of Parkinson's disease, but this is also just a single factor out of many.

PMID 20198619 Letter with concerns: curcumin may induce DNA damage in vitro and in vivo and may have carcinogenic activity. Curcumin dissolved in water does not bind to DNA, though in solution with ethanol it does. It is not clear if these effects are due to curcumin, curcumin + ethanol, or ethanol. However, the letter suggests that these counter-results may not be appropriate, and curcumin may actually be genotoxic.

PMID 20198612 Paper referenced above showing curcumin dissolved in water does not bind or intercalate with DNA. However, doses were low and ROS generation could still result in DNA damage without binding.

Summary In short, there is evidence to suggest curcumin could increase Parkinson's risk and there is some [controversial] evidence that may suggest curcumin could cause genotoxic damage. Moreover, like other ROS scavengers, excessively high doses of curcumin may actually create ROS. It is not clear if these are the same doses as used in the cancer studies.

Other Noteworthy Studies and Reviews[edit]

PMID 20087857 Curcumin easily crosses the BBB. Moreover, curcumin inhibits glioma-induced angiogenesis, again suggesting efficacy in brain cancer.

PMID 20172017 Curcumin appears to activate M1 muscarinic receptors.

PMID 20388102 Review suggesting that curcumin, by blocking NF-kappaB, may slow down aging.

PMID 20100380 Extensive review.

PMID 20205886 Review of curcumin and age-related disease.

PubMed Curcumin, a potential therapeutic candidate for retinal diseases (including diabetic retinopathy, glaucoma, and age-related macular degeneration).

PubMed Meriva®, a lecithinized curcumin delivery system, in diabetic microangiopathy and retinopathy.