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Control of Systemic Inflammation and
Chronic Diseases—The Use of Turmeric
and Curcuminoids

The world suffers an epidemic of both critical illness(CI) and chronic diseases (ChDs), and both groups of diseases increase from year to year, and have doneso for several decades. It is strongly associated to Modern medicine has to a large extent failed in its the modern, so-called Western, lifestyle: stress, lack ambition to control both acute and chronic diseases.
of exercise, abuse of tobacco and alcohol, and the The world suffers an epidemic of chronic diseases transition from natural unprocessed foods to pro- of a dimension never seen before, and these dis- cessed, calorie-condensed, and heat-treated foods.
eases are like a prairie fire also spreading to the There is a strong association between reduced in- so-called developing countries. As an example, there take of plant fibers and plant antioxidants and in- are more cases of diabetes reported in China (24 creased consumption of industrially produced and million) and India (44 million) than in the United processed products especially dairy, refined sugars, States (17 million), and the increase in incidence and starch products and ChDs. Heating up foods is faster in these countries than in Western soci- such as milk (pasteurization) and production and eties. Today, chronic diseases—for example, diseases storage of milk powder produce large amounts of such as cardiovascular and neurodegenerative condi- advanced glycation end products (AGEs) and ad- tions, diabetes, stroke, cancers, and chronic respira- vanced lipid oxidation end products (ALEs), known tory diseases—constitute 46% of the global disease as potent inducers of inflammation (see further burden and 59% of the global deaths; each year ap- proximately 35 million individuals die in conditions related to chronic diseases, and the numbers are fast derived, substances, often referred to as chemopre- increasing and have done so for several years (World ventive agents, have documented anti-inflammatory effects and are believed to reduce speed of aging and Also acute diseases, often referred to as med- prevent degenerative malfunctions of organs and also ical and surgical emergencies—myocardial in- development of acute and chronic diseases. Among farction, stroke and severe pancreatitis, or dis- these are various curcumenoids, active ingredients in eases/complications following advanced medical and turmeric curry foods, and thousands more of hitherto surgical treatments such as organ and stem cell trans- little or totally unexplored substances. This chapter plantation and other large operations—have an un- focuses on documented experimental and clinical ef- acceptably high morbidity and mortality. Sepsis, the fects of supplementation of turmeric, various curcu- most common medical and surgical complication, menoids, and pure curcumin. Regrettably, only few is estimated to annually affect as many as 751,000 clinical studies in human have been performed in individuals only in the United States (Angus et al.
contrast to an abundance of studies in experimental 2001; Arias and Smith 2003) and cause death of approximately 215,000 patients/year (29%) (Angus et al. 2001), making sepsis the tenth most common PLANT-DERIVED PROTECTION
cause of death in this country. It is especially alarm-ing that both morbidity and mortality in critical ill- Common to those suffering from ChD as well as ness (CI), and septis, is fast increasing worldwide CI is that they suffer an increased degree of sys- and has done so for several decades. With a doc- temic inflammation. We are increasingly aware that umented 1.5% rate of increase per year, the inci- plant-derived substances, often referred to as chemo- dence is forcasted to double within the coming 50 to preventive agents, have an important role to play in control of inflammation. These substances are gener-ally inexpensive, easy available, and have no or lim-ited toxicity. Among the numerous chemopreventive LIFESTYLE ASSOCIATED
agents are a whole series of phenolic and other com-pounds believed to reduce the speed of aging and DISEASES
prevent degenerative malfunctions of organs, among Accumulating evidence supports the association of them various curcumenoids found in turmeric curry ChDs to modern lifestyle, stress, lack of exercise, and foods and thousands of other hitherto little or not at abuse of tobacco and alcohol, and most important, the transition from natural unprocessed foods to pro- Curcumin and many other plant-derived sub- cessed, calorie-condensed and heat-treated foods are stances are increasingly regarded as shields against contributing to this development. The strong associa- disease (Bengmark 2006b). Curcumin is the most ex- tion between ChD and reduced intake of plant fibers plored of a family of the so-called active chemopre- and plant antioxidants, and increased consumption ventive substances in the spice turmeric, collectively of industrially produced and processed dairy prod- referred to as curmenoids. The health-promoting ef- ucts, refined sugars, and starch products is well docu- fects of turmeric is widely recognized as the spice mented. The per capita consumption of refined sugar has been used for centuries, especially in Indian has increased from about 0.5 kg/person/year in 1850 Ayurveda medicine, to treat a wide variety of disor- to almost 50 kg/person/year in the year 2000 and ders such as pains and colics, rheumatism, skin dis- the per cow milk production from 2 to 50 liters/day.
eases, intestinal worms, diarrhea, intermittent fevers, Dairy products, especially milk (mostly from preg- hepatic disorders, urinary problems, dyspepsia, in- nant cows), are rich in proinflammatory molecules: testinal conditions such as colitis and constipation, hormones such as estrogens (Howie and Shultz 1985; amenorrhea, and inflammatory conditions in general.
Malekinejad et al. 2006) and growth factors such However, it is only in the most recent years that the as IGF-1 (Holmes et al. 2002). Consumption of interest has exploded, much in parallel to the avail- bovine milk has also been shown to release inflam- ability of molecular biological techniques, but also matory mediators, increase intestinal permeability, due to increasing concern for severe side effects of and induce leakage of larger molecules such as al- synthetic cyclooxygenase-2 (COX-2) inhibitors that bumin and hyaluronan into the body (Bengtsson et pharmaceutical industry is marketing. Most of the al. 1996). Heating up milk (pasteurization), and es- curcumin studies reported in the literature are exper- pecially production and storage of milk powder, pro- imental and few clinical studies are this far presented.
duces large amounts of advanced glycation end prod-ucts (AGEs) and advanced lipoxidation end products TURMERIC—APPROVED AS
(ALEs) (Baptista and Carvalho 2004), known as po- FOOD ADDITIVE
tent inducers of inflammation. This information is es-pecially important as many foods such as ice cream, industrially produced enteral nutrition solutions, and baby formulas are based on milk powder. Such for- available in turmeric, is received from dried rhizo- mulas are reported to increase inflammation and in- zomes of the perennial herb Curcuma longa Linn, duce microbial intestinal translocation (Deitch et al.
a member of the ginger family. Turmeric is since 2002; Mosenthal 2002; Xu et al. 1998). Bread, es- long known to be an excellent food preservative and pecially when from gluten-containing grains, is rich is approved as such in most Western countries. It in molecules with documented proinflammatory ef- is mainly produced in Asian and South American fects, and bread crusts often used experimentally to countries. Only in India about 500,000 metric tonnes induce inflammation. See further Bengmark (2004, are produced each year, of which about half is exported. The content of curcumin in turmeric is Control of Systemic Inflammation and Chronic Diseases usually 4–5%. The molecule of curcumin resembles cancers (Amit and Ben-Neriah 2003). Activation of ubiquinols and other polyphenols known to possess NF-κB is linked with apoptotic cell death, either pro- strong antioxidant activities. Its bioavailability on moting or inhibiting apoptosis, depending on cell oral supplementation is relatively low, but can be type and condition. The expression of several genes improved by dissolution in ambivalent solvents such as COX-2, matrix metalloproteinase-9 (MMP- (glycerol, ethanol, DMSO). (Sharma et al. 2001).
9), inducible nitric oxide synthase (iNOS), TNF, IL-8, It is also reported to be dramatically elevated by eotaxin, various cell surface adhesion molecules, and co-ingestion of peperine (a component of pepper), antiapoptotic proteins are regulated by NF-κB (Pahl as demonstrated both in experimental animals 1999). COX-2 is inducible and barely detectable un- and humans (Shoba et al. 1998). Several studies der normal physiological conditions, but is rapidly, have demonstrated that curcumin is atoxic, also but transiently, induced as an early response to proin- in very high doses Bravani Shankar et al. 1980; flammatory mediators and mitogenic stimuli includ- Shainani-Wu 2003). Treatment of humans for 3 ing cytokines, endotoxins, growth factors, oncogenes months with 8,000 mg curcumin per day lead to no and phorbol esters. iNOS, activated by NF-κB is side effects (Shainani-Wu 2003). It is estimated that another enzyme that plays a pivotal role in medi- adult Indians consume daily 80–200 mg curcumin ating inflammation, especially as it acts in synergy per day (Grant and Schneider 2000). A common therapeutic dose is 400–600 mg curcumin three Curcumin is not only an inexpensive atoxic and po- times daily, corresponding to up to 60 g fresh tent COX-2 and iNOS inhibitor (Surh et al. 2001), but turmeric root or about 15 g turmeric powder.
also a potent inducer of heat shock proteins (Hsps)and a cytoprotector (Chang 2001; Dunsmore et al.
2001) Curcumin inhibits not only COX-2, but also INFLAMMATION—CENTRAL TO
LOXs and leukotreines such as LBT4 and 5HETE DEVELOPMENT AND
(Wallace 2002), especially when bound to phos- PREVENTION OF DISEASE
phatidylcholine micelles (Began et al. 1999). Cur-cumin is also reported to inhibit cytochrome P450 The process of inflammation is well known. Ac- isoenzymes and thereby activation of carcinogens tivated monocytes and macrophages release proin- (Thapliyal and Maru 2001). Curcumin has the abil- flammatory cytokines such as tumor necrosis factor ity to intercept and neutralize potent prooxidants alpha (TNFα) and interleukin-1 (IL-1), which in- and carcinogens, both ROS (superoxide, peroxyl, hy- duce inflammation in the tissues. Also important for droxyl radicals) and NOS (nitric oxide, peroxynitrite) the development of inflammation is the production (Jovanovic et al. 2001). It is also a potent inhibitor by macrophages and neutrophils of prostaglandins, of TGF-β and fibrogenesis (Gaedeke et al. 2004), thromboxanes, and leukotrienes, collectively known which is one of the reasons why it can be expected as eicosanoids, which are mediators of inflamma- to have positive effects in diseases such as kidney tion synthesized through enzymatic degradation by fibrosis, lung fibrosis, liver cirrhosis, and Crohn’s COX-2 or lipooxygenase (LOX) of arachidonicacid disease and prevent formation of tissue adhesions (AA). COX-2 is induced by physical and mental (Srinisan and Libbus 2004). Curcumin is suggested stress, and a variety of inflammatory stimuli, in- to be especially effective in Th1-mediated immune cluding endotoxins, cytokines, growth factors, tu- diseases, as it effectively inhibits Th1 cytokine profile mor promoters, and COX-2, catalyze the synthesis in CD4+ T cells by activation of IL-12 (Kang et al.
by mononuclear phagocytes, endothelial cells, poly- morphonuclear leukocytes, and platelets of series-2 prostaglandins (e.g., PGE2, PGF2α, PGI2, PGD2)and thromboxanes (e.g., TXA2, TXB2). PGE2 is a r Inhibit the release of AA through hydrolysis of well-known promoter of production both of IL-10, membrane phospholipids (Hong et al. 2004).
a potent immunosuppressive cytokine, produced es- r Inhibit the induction of COX-2 mRNA and pecially by lymphocytes and macrophages, and sup- protein expression (Zhang et al. 1999).
pressor of IL-12 (Stolina et al. 2000).
r Inhibit extracellular signal-regulated kinase Nuclear factor-kappa B (NF-κB) plays a critical role for induction of several signal transduction path- r Inhibit 5-hydroxyeicosatetraenoic acid (5-HETE) ways involved in inflammatory diseases (Bernes and production in human neutrophils (Flynn et al.
Karin 1997) such as asthma, arthritis and various r Inhibit the so-called Janus kinase (JAK)–STAT for absorption into the intestinal epithelial cells and signaling cascade (Kim et al. 2005a).
the rest of the body by digestion/fermentation in the r Inhibit the production of superoxide and nitric intestine by microbial flora (Shapiro et al. 1998).
oxide by inflammatory cells. (Bhaumik et al.
2000; Brouet and Ohshima 1995).
Moderately increase the number of T-and B-cells CHRONIC DISEASES
without altering the numbers of phagocyticmacrophages (Gautam et al. 2007).
Increase the phagocytic activity of macrophages(Antony et al. 1999; Li and Liu 2005).
Oxidative stress is believed to play a major role in r Increase the numbers of B-cells in the small the aging process and in pathogenesis of diseases intestinal mucosa (Churchill et al. 2000).
most commonly responsible for morbidity and mor- r Suppress surface expression of costimulatory tality in older age. Dietary factors influence consid- erably both disease processes and longevity by mod- histocompatibility complex (MHC) II, but not ifying oxidative stress. Bala et al. (2006) investigated the influence of chronically administered curcumin r Impair the production by dendritic cells of IL-12, on normal aging-related parameters—lipid peroxida- IL-1, IL-6, and TNFα (Kim et al. 2005a).
tion, lipofuscin concentration and intraneuronal lipo- r Inhibit the activation of mitogen-activated protein fuscin accumulation—and on activities of a series kinase (MAPK) and nuclear translocation of of other factors—superoxide dismutase (SOD), glu- nuclear factor-beta (NF-β) (Gautam et al. 2007; tathione peroxidase (GPx), and Na+, K+-adenosine triphosphatase (Na+, K+-ATPase) in different brain regions (cerebral cortex, hippocampus, cerebellum proinflammatory molecules such as AGEs and and medulla) in 6- and 24-month-old rats. Chronic curcumin supply to both 6- and 24-month-old rats re- r Induce apotosis of various tumor cells by a sulted in significant decreases in lipid peroxide and variety of mechanisms: decreasing cellular levels lipofuscin content in the brain regions, and was ac- of antiapoptotic Bcl-2, Bcl-xL, and cIAP proteins, companied by significant increases in activities of increasing levels of proapoptotic Bax, inhibiting SOD, GPx and Na+, K+-ATPase in various brain re- constitutively active JAK–STAT pathways, gions. In a rat study, supply of tetrahydrocurcumin, a biotransformed metabolite of curcumin, was demon- receptor/caspase-8 pathway independent of p53.
strated to increase average life span by 12% (P < 0.01) and average life expectancy after 24 months of age by 126% (Kitani et al. 2004). However, no redox-sensitive inducible protein that provides protection against various forms of stress Curcumin has a potential therapeutic value for con- See also Jagetia and Aggarwal (2007) for further trol of allergic responses to exposure to allergens.
Intragastric treatment of latex-sensitized mice with Many medicinal herbs and pharmaceutical drugs curcumin demonstrated a diminished Th2 response are therapeutic at one dose and toxic at another, and and a concurrent reduction in lung inflammation interactions between herbs and drugs, even if struc- (Kurup et al. 2007). In addition, in curcumin-treated turally unrelated, may increase or decrease the phar- mice eosinophilia was markedly reduced, costim- macological and toxicological effects of either com- ulatory molecule expression (CD80, CD86, and ponent (Fugh-Berman 2002; Groten et al. 2000). It is OX40L) on antigen-presenting cells decreased, and suggested that curcumin may increase the bioavail- expression of MMP-9, OAT, and TSLP genes attenu- ability of vitamins such as vitamin E and decrease ated. Another recent study suggests that that the hy- blood levels of cholesterol, as in experimental stud- droxy groups of curcumin play a significant role in ies curcumin will significantly raise the concentra- exerting both antioxidative and antiallergic activities, tion of α-tocopherol in tissues such as lung and de- and that most of the compounds develop antialler- crease plasma cholesterol (Kamal-Eldin et al. 2000).
gic activities through mechanisms related to antiox- Polyphenols, isothiocyanates such as curcumin, and idative activities, but some most likely also through flavonoids such as resveratrol are all made accessible antioxidation unrelated mechanisms. A significant Control of Systemic Inflammation and Chronic Diseases decrease in histamine release from rat basophilic tions, especially when used for longer periods and in leukemia cells, RBL-2 H3, was observed when cells conditions such as osteoarthritis and other rheuma- were cultivated with curcumin or tetrahydrocurcumin (Suzuki et al. 2005). No human study in allergy isthis far reported.
Curcumin has a strong capacity to prevent lipid per- ARTHRITIS
oxidation, stabilize cellular membranes, inhibit pro- Treatment in vitro of chondrocytes with curcumin is liferation of vascular smooth muscle cells, and in- shown to suppress IL-1b-induced NF-κB activation hibit platelet aggregation, all important ingredients via inhibition of IκBα phosphorylation, IκBα degra- in the pathogenesis of arteriosclerosis. Curcumin is dation, p65 phosphorylation, p65 nuclear translo- also found to be the most effective, when the ability of cation and inhibition of upstream protein kinase B butylated hydroxy anisole, curcumin, quercetin, and Akt, events which correlate well with downregula- capsaicin to inhibit the initiation and propagation tion of NF-κB targets including COX-2 and MMP-9 phases of low-density lipoprotein (LDL) oxidation (Shakibaei et al. 2007). IL-18 is a novel proinflam- was compared (Naidu and Thippeswamy 2002). Sup- matory cytokine that has been suggested to play a ply of not only curcumin, but also capsaicin and garlic pathogenic key role in a number of autoimmune dis- (allecin), to rats fed a cholesterol-rich diet prevented eases such as inflammatory bowel diseases (IBD), both increases in membrane cholesterol and fragility psoriasis, and rheumatoid arthritis (RA) (McInnes et of the erythrocytes (Kempaiah and Srinivasan 2002).
al. 2000). Vascular endothelial growth factor (VEGF) Significant prevention of early atherosclerotic lesions is deeply involved in angiogenesis in rheumatoid in thoracic and abdominal aorta in rabbits fed an synoviocytes and IL-18 will dose-dependently in- atherogenic diet for 30 days was observed, accom- crease both production of VEGF IL-18 and VEGF panied by significant increases in plasma concentra- levels of sera and synovial fluids of RA patients.
tions of coenzyme Q, retinol, and α-tocopherol and These factors were found to be significantly higher reductions in LDL-conjugated dienes and TBARS in RA than in osteoarthritis A patients. Curcumin (thiobarbituric acid-reactive substances, an expres- did dose-dependently abrogate the effect of IL-18 sion of ongoing oxidation) (Quiles et al. 2002).
on VEGF production (Cho et al. 2006). A recent in Curcumin is also shown to protect the myocardium vitro study compared the potential anti-inflammatory per se against ischemic insults. A single oral dose effects of curcumin and quercetin. Both agents in- of curcumin (15 mg/kg), administered 30 min be- hibited neutrophil activation, synoviocyte prolifera- fore and/or after the onset of isoprenaline-induced tion, and angiogenesis (Jackson et al. 2006). In ad- ischemia in rats not only prevented decrease in levels dition, curcumin also strongly inhibited collagenase of xanthine oxidase, superoxide anion, lipid perox- and stromelysin expression, effects not obtained by ides, and myeloperoxidase (MPO) and increase in levels of SOD, catalase (CAT), GPx, glutathione-S- In 1980, Deodhar and colleagues had already per- transferase (GST) activities, but also reduced my- formed a clinical study in which 18 RA patients ocardial damage as documented by histopathology were treated with curcumin and comparisons were and electron microscopy (Manikandan et al. 2004).
made with phenylbutazone. Improvements in morn- It is especially observed in in vitro studies that treat- ing stiffness, walking time, and joint swelling were ment with curcumin will produce a pronounced in- observed after 2 weeks of curcumin supplementation duction of the defensive protein HO-1, which will, (1,200 mg/day), and reported to be equal to those when added to Celsior preservation solution, signifi- induced by phenylbutazone therapy (300 mg/day) cantly prevent storage-induced damage of atrial my- (Deodhar et al. 1980). Another now classical study did also conclude that five days of oral curcumin sup- Studies on mice have also demonstrated that oral plementation (1,200 mg/day) is equally effective as administration of curcumin will suppress aortic wall phenylbutazone to reduce postsurgical edema, ten- degeneration and prevent development of abdominal derness, and pain (Satoskar et al. 1986). Most in- aortic aneurysms. Curcumin preserves medial elastin teresting are recent observations that curcumin has fibers and reduces aortic wall expression of cy- the ability to potentiate the effects of pharmaceutical tokines, chemokines, and proteinases, known to me- COX-2 inhibitors such as celecoxib (Lev-Ari et al.
diate aneurysmal degeneration (Parodi et al. 2006).
2006a). Such combinations might enable to use phar- Recent studies on isolated porcine coronary arter- maceutical drugs at much lower and safer concentra- ies also demonstrate in a concentration-dependent manner a considerable relaxant effect of curcumin far most of the mechanisms are not fully understood.
via mechanisms involving NO, cGMP, and adren- NF-κB is most likely playing a central role, as several ergic β-receptor, but not by prostaglandins (Xu genes, known to mediate these processes, are known et al. 2007). Studies on porcine coronary arteries also demonstrate that curcumin effectively reverses Different analogs of curcumin present in turmeric homocysteine-induced endothelial dysfunction (Ra- (curcumenoids) exhibit variable anti-inflammatory maswami et al. 2004). Curcumin, in doing so, blocks and antiproliferative activities, which, however, do the homocysteine-induced superoxide anion produc- not entirely correlate with their ability to modulate tion and downregulation of eNOS. However, no hu- the ROS status (Sandur et al. 2007). A comparison of the ability of curcumin and 20 curcumin ana-logues to suppress TNF-induced NF-κB activationdemonstrated that the strongest effects are obtained by curcumin in itself, achieved by inhibition of NF- Genomic approaches to cancer prevention and treat- κB-regulated gene expression and inhibition of IκB ment are becoming increasingly important. In addi- kinase (IKK) and Akt activation (Aggarwal et al.
tion to characterizing potential mechanisms of can- 2006b). Later studies by the same group, but also cer prevention, significant issues for future research others, demonstrate that other mechanisms are also are identification and selection of specific dietary bioactive food components, and especially identify-ing individuals with special nutrient requirements for r curcumin-induced downregulation of expression Dietary bioactive food components that interact proliferation of human prostate and breast cancer with the immune response have a considerable poten- tial to reduce the risk of cancer. Numerous substances r curcumin-induced enhancement of expression of identified in fruits and vegetables have the ability tumor cyclin-dependent kinase (CDK) inhibitors to modulate the effects of deregulated cell cycle p21 and p27 and tumor suppressor protein p53 checkpoints and contribute to prevention of cancer.
Not only curcumin, but numerous other plant-origin agents, possess this potential, among them apigenin (celery, parsley), epigallocatechin-3-gallate (green chemoresistance and radioresistance (Aggarwal et tea), resveratrol (red grape, peanuts, and berries), al. 2006a; Chakravarti et al. 2006). Curcumin is genistein (soybean), and silymarin (milk thistle).
also known to inhibit JAK2, Src, Erb2, and There is also accumulating evidence that cancer pre- vention can be achieved by some probiotic bacteria activation (see further Aggarwal et al. 2006b).
[AU: Kindly
alone or in combination with prebiotic fibers, known r curcumin-induced inhibition of both COX and spell out the
to have a similarly strong effect on the immune sys- LOX pathways of eicosanoid metabolism.
term “EGFR,”
tem as plant antioxidants (see further Ferguson and if necessary.]
Curcumin is reported to inhibit 12-folded block proliferation of human breast cancer cells (MCF-7 Curcumin has been tried in various animal models ADRs) in cell cultures (Hammamieh et al. 2007).
in order to achieve dietary prevention of developmentand spreading of cancer. Injection of human mam- Curcumin has been reported to augment cyto- mary cancer cells (MDA-MB-231) into the mam- toxic effects of both chemotherapy and radiation mary fat pad of nude mice leads to the formation of therapy (Aggarwal et al. 2005; Hour et al. 2002).
tumors and distant metastases in lungs, brain, and There is also some evidence that subtoxic concentra- lymph nodes. This spreading was to a great extent tion of curcumin might promote apoptosis by lig- prevented by curcumin treatment: 68% of curcumin- ands such as TNF-related apoptosis-inducing lig- treated in contrast to only 17% of untreated animals and (TRAIL). Prostate cancer cells, for example, are showed no or very few lung metastases (Bachmeier generally resistant to induction of apoptosis by an- et al. 2007). Curcumin has in experimental models ticancer agents and death ligands. However, in re- also demonstrated the ability to inhibit intrahepatic cent years, it has been demonstrated that a combi- nation of subtoxic concentrations of curcumin and Curcumin seems to suppress several steps in tu- TRAIL induces apoptosis of prostate cancer cell morogenesis: cellular transformation, proliferation, lines, mainly through inhibition of NF-κB and ac- invasion, angiogenesis, and metastasis. However, this tivation of extrinsic and intrinsic pathways of apop- Control of Systemic Inflammation and Chronic Diseases tosis (Deeb et al. 2005, 2007). When in an orthotopic the main purpose of the study was to document that murine model the effects of curcumin on two ovar- curcumin is not toxic to humans when administered ial cancer cell lines (SKOV3ip1, HeyA8) were stud- by mouth for 3 months in a dose of up to 8,000 ied, curcumin alone did induce 49% (P = 0.08) and 55% (P = 0.01), respectively, reductions in meantumor growth, an effect that was further increased DIABETES
by combining curcumin with the chemotherapeuticdrug docetaxel, and demonstrating 96% (P < 0.001) The oxidative stress observed in diabetic rats is and 77% reductions, respectively (Lin et al. 2007).
clearly reduced significantly by curcumin adminis- Also in mice with multidrug-resistant HeyA8-MDR tration. As a consequence of curcumin supply, nonen- tumors, treatment with curcumin alone and in com- zymic antioxidants such as vitamin C, vitamin E, and bination with docetaxel resulted in significant reduc- glutathione are preserved at near normal levels and tions in tumor growth, 47% and 58%, respectively accumulation of lipid peroxidation products is sig- (P = 0.05). SKOV3ip1 and HeyA8 tumors treated with curcumin alone or in combination with doc- Curcumin is also reported to prevent the acceler- etaxel demonstrated not only decreased prolifera- ated accumulation of glycated collagen in diabetic tion (P < 0.001), but also reduced microvessel den- animals. An interesting study reports significant pre- sity (P < 0.001) and increased tumor cell apoptosis vention by curcumin of the extensive cross-linking (P < 0.05). The growth of induced colorectal can- of collagen in tendons and skin normally seen in cer, measured as average number of aberrant crypt diabetic animals (Sajithlal et al. 1998). Also inter- foci (ACF), was 64.2 ± 3 in the control group, 39 ± esting is the observation that curcumin contributes 5 in the curcumin-treated group, 47 ± 10 and in to control of hyperglycemia and also to some ex- celecoxib-treated group, but only 24.5 ± 6 in the tent prevents islet cell death. In a streptozotocin- group that had received both agents (Shpitz et al.
induced islet damage model, the in vitro islet viabil- [AU: Reference
2006). Another nude mice study undertaken with ity and secreted insulin remained significantly higher "Shpitz et al.
four different head and neck squamous cell carci- after exposure to curcumin than in the controls. Fur- (2006)" has not
noma (HNSCC) cell lines documented that topical thermore, curcumin pretreatment significantly pre- been given in
application as a curcumin paste is superior even to vented streptozotocin-induced changes in isolated the reference
intratumoral injection of curcumin (LoTempio et al.
mouse islets such as DNA fragmentation, and re- list. Kindly
2005). Curcumin induces apoptosis in vitro in almost duced the concentrations of peroxynitrite, nitric ox- provide the
all cell lines: breast cancer (Xia et al. 2007; Zhang ide, and poly(ADP-ribose) polymerase-1 (Meghana complete
et al. 2007), head and neck cancer (Chakravarti et al.
et al. 2007). Curcumin administration also prevented details for this
2006; LoTempio et al. 2005), hepatocellular cancer the formation of the AGE-related malonyl dialdehyde reference.]
(Labbozzetta et al. 2006), laryngeal cancer (Mitra et in streptozotocin-treated islets. Oral administration al. 2006), leukemia (Liao et al. 2008; L´opez-L´azaro of diabetic rats for 45 days with tetrahydrocurcumin et al. 2007), lung cancer (Lee et al. 2005; Lev-Ari at 80 mg/kg body weight significantly reduced blood et al. 2006b), myeloma (Bharti et al. 2003, 2004), glucose and increased plasma insulin levels parallel melanoma (Mar´ın et al. 2007; Siwak et al. 2005), to significant increases in activities of SOD, CAT, neuroblastoma (Liontas and Yeger 2004; Vanisree GPx, GST, reduced glutathione, vitamin C, and vita- and Ramanan 2007), oral cancer (Atsumi et al. 2005; min E. Furthermore, significant decreases in TBARS Sharma et al. 2006), osteosarcoma (Huang et al.
and hydroperoxide formation in liver and kidney 2005; Walters et al. 2008) pancreatic cancer (Lev- were observed, all suggesting a protective role of Ari et al. 2006b, 2007), and prostatic cancer (Deeb curcumin against lipid peroxidation-induced mem- et al. 2007; Shankar and Srivastava 2007).
brane damage, observations supported by observed Although encouraging results have been obtained improvements on histopathological examination of in in vitro and animal studies, only a small number liver and kidney sections (Murugan and Pari 2006a).
of small clinical studies are this far reported (see Subsequent studies by the same group demon- further Steward and Gescher 2008). A study intended strated that these changes are also accompanied by: as a phase I study reports histologic improvement ofprecancerous lesions in one out of two patients with resected bladder cancer, two out of seven patients of hydroperoxides) and reduced levels of lipids oral leucoplakia, one out of six patients of intestinal (cholesterol, triglycerides, free fatty acids, and metaplasia of the stomach, and two out of six patients phospholipids) in serum and tissues (Murugan with Bowen’s disease (Cheng et al. 2001). However, r normalization of liver cholesterol, triglycerides, MMP-9 activity (Swarnakar et al. 2005). Curcumin as well as turmeric have both the capacity to inhibit gastric acid secretion by blocking histamine recep- lipoprotein (VLDL), LDL, and high-density tors (Kim et al. 2005b). A potential use of turmeric lipoprotein (HDL) cholesterol (Pari and Murugan or curcumin as alternative or complementary thera- peutic agents against pathogenic processes initiated r decreased levels of not only blood glucose, but by Helicobacter pylori infection is supported by ob- also glycosylated hemoglobin and erythrocyte servations that curcumin has the capacity to inhibit TBARS, and increased levels of plasma insulin, H. pylori-induced NF-κB activation, subsequent re- lease of IL-8, degradation of IκB-α, IκB kinases α and β (IKKα and β) activity, and NF-κB DNA bind- ing (Foryst-Ludwig et al. 2004). When the in vitro effects of turmeric and curcumin against 19 differ- ent strains, including five cagA+ strains (cag A is r normalization of total protein, albumin, globulin, the strain-specific H. pylori gene linked to premalig- nant and malignant lesions), were investigated and normalization of urea, uric acid, and creatinine compared, both treatments were equally effective to significantly reduce the growth of all the H. pylori r decreased levels of brain lipid peroxidative strains studied (Mahady et al. 2002).
markers: TBARS and hydroperoxides andincreased brain activities of SOD, CAT, GPx, HEPATIC DISEASES
r decreased to near normal tissue levels of hexose, Several studies have demonstrated the unique abil- ity of turmeric and curcumin to preserve the in- tegrity and function of liver cells. Studies have been r reduced cross-linking of collagen (Pari and undertaken with various models of acute toxic in- juries to the liver, chronic supply of hepatotoxins r Similar observations are made in alloxan-induced and with liver perfusion and preservation. Curcumin diabetes (Giltay et al. 1998). It is also observed has also been shown to protect the hepatocytes from that cryopreserved islets will be better preserved oxidative injury, most likely and to a large extent in the presence of curcumin (Kanitkar and through activation of HO-1. In a recent study acute hepatotoxicity was induced by oral administration Furthermore, it was observed in these studies of CCl4 (4 g/kg) and curcumin supplemented orally of cryopreserved islets that curcumin increases (200 mg/kg), both before and 2 h after the CCl4 the release of heat shock response proteins, administration. The CCl4-induced translocation of Hsp70 and HO-1, which significantly contributes NF-κB to the nucleus, CCl4-induced NF-κB DNA- binding activity, and increases of TNF-α and IL-1βprotein were blocked by curcumin, and most impor- No human clinical trials in diabetes with curcumin tantly, the destruction of hepatic tissues totally abol- ished (Reyes-Gordillo et al. 2007). Similar observa-tions are also made in a model of endotoxin-inducedhepatic dysfunction (Kaur et al. 2006). In another GASTRIC DISEASES
rat study, fulminant hepatic failure (FHF) was in- Curcuma longa is since long used commonly as a duced by two intraperitoneal injections of 300 mg/kg traditional remedy for gastritis and gastric ulcer. A thioacetamide (TAA) at 24-h intervals. The experi- recent study suggests that supply of 60 mg/kg body mental groups received intraperitoneally either a low weight (bw) of curcumin is as effective as 20 mg/kg dose (200 mg/kg/day) or a high dose (400 mg/kg/day) bw of omedprazole to restore suppressed MMP-2 of curcumin, initiated 48 h prior to the first TAA in- gene transcription and translation and oxidative inac- jection. Curcumin significantly improved survival, tivation of basal MMP-2 and thereby prevent/reduce minimized oxidative stress, reduced hepatocellular development of induced gastric ulcer in rats (Gan- injury, hepatic necroinflammation, NF-κB binding guly et al. 2006). Curcumin is shown not only to and iNOS expression, and hepatic levels of TBARS protect from formation of gastric ulcers but also (Shapiro et al. 2006). Furthermore, it inhibited nu- to accelerate healing, mainly through attenuation of clear binding of NF-κB and iNOS protein expression.
Control of Systemic Inflammation and Chronic Diseases Biochemical parameters of liver injury, blood am- are especially interesting as downregulation of PPAR monia, and hepatic necroinflammation were signifi- in other models and by other tools has produced sim- cantly reduced in the low-dose curcumin group but ilar effects (Thiemermann 2006.) In animal models, were further reduced in the high-dose group (P < curcumin is shown to prevent endotoxin-induced pul- 0.05 and P < 0.01 respectively) (Shapiro et al. 2006).
monary sequestration of neutrophils via mechanisms Curcumin induced, when cold preservation of human such as induction of HO-1 and inhibition of endothe- hepatocytes was applied, a significant elevation of lial ICAM-1 expression (Olszanecki et al. 2007).
HO-1 and exhibited a strong cytoprotection through- Curcumin will also attenuate endotoxin-induced co- out the cold storage and rewarming (McNally et al.
agulopathy and prevent disseminated intravascular 2006). Injection of curcumin (50 mg/kg) into the por- coagulation (DIC) (Chen et al. 2007). These observa- tal system 30 min before applying hepatic warm is- tions are of even greater interest as curcumin in itself chemia/reperfusion (I/R) did significantly reduce the demonstrates antibacterial (Di Mario at al 2007), an- postperfusion increases in iNOS activity and content tiviral (Kutluay et al. 2008), antifungal (Apisariyakul of malondialdehyde (MDA) in liver tissue and pre- et al. 1995), antimalarial (Reddy et al. 2005), and vent the reductions in CAT and SOD activities (Shen antiprotozoal (P´erez-Arriaga et al. 2006) effects. No et al. 2007). It also increased the expression of other human clinical trial is this far reported except a study Hsps such as Hsp70, reduced the rate of apoptosis, demonstrating great effects on scabies from topical and, most importantly, significantly increased the sur- treatment with a turmeric paste for 3–15 days in 814 vival. No human clinical trial is this far reported in patients (Charles and Charles 1992).
It is clear from what has been discussed above Sepsis is a leading cause of death. It affects each that curcumin to a large extent mediates its anti- year about three quarters of a million North Amer- inflammatory effects through inhibition of activation icans and results in death of almost one quarter of of NF-κB. This makes curcumin a promising candi- a million. The challenge in CI is less infection than date for treatment of IBD, alone or combined with the exuberant inflammatory response (Taneja et al.
other treatment modalities. Several successful exper- 2004), often presented as a syndrome of prolonged imental studies with curcumin in induced colitis are systemic inflammation, frequently leading to a po- reported in recent years (for summary, see Camacho- tentially lethal condition of irreversible organ system Barquero et al. 2007). A recent study in experimental dysfunction. The development seems to occur espe- animals with trinitrobenzenesulfonic acid (TNBS)- cially in individual with a chronically dysfunction- induced colitis focussed on MAPKs such as the p38 ing innate immune system and sustained elevated and the c-Jun N-terminal kinase (JNK), known to reg- inflammation. Apoptosis of circulating neutrophils ulate NF-κB activation and modulate the transcrip- in patients with clinical sepsis is through a mecha- tion of many genes involved in the inflammatory pro- nism that involves NF-κB activation profoundly sup- cess. Oral supply of curcumin (50–100 mg/kg/day) pressed, and also associated with reduced activity of not only dramatically reduced morphological signs cystein proteases (caspases-9 and -3) (Taneja et al.
of cell damage and stimulate the healing process, but 2004). Suppression of this inflammation seems to re- also significantly reduced colonic levels of nitrites, duce the inflammation and prevent development of colonic mucosa activity of MPO and TNF-α, and infection and organ dysfunction. In a recent study, downregulated the expression of COX-2 and iNOS, attempts were made to suppress inflammation by in- and reduced activation of p38 MAPK (Camacho- travenous administration of curcumin for three days Barquero et al. 2007). Few human studies have this before sepsis was induced by the method called far been performed. In an open study one capsule of cecal ligation and puncture (CLP). The curcumin pure curcumin (360 mg) was administered 3–4 times treatment did significantly attenuate tissue injury, a day for 3 months to five patients with ulcerative reduce mortality, decrease the expression of TNF- proctitis and to five with Crohn’s disease. All proctitis α, downregulate peroxisome proliferator-activated patients had improved reductions; other concomitant receptor-gamma (PPARγ ) in organs like the liver and medications could be done in four patients (Holt et al.
also prevent morphologic alterations in macrophages 2005). Four of five Crohn’s disease patients demon- [AU: This
(Siddiqui et al. 2006). Most importantly, the same strated reduced Crohn’s disease activity index scores sentence is not
results were obtained even if curcumin was only ad- and lower erythrocyte sedimentation rates. The abil- clear. Kindly
ministered after the onset of sepsis. These findings check and
ity of curcumin to prevent relapse was studied in amend as

a randomized, double-blind, multicenter trial in pa- effects of treatment will most likely be obtained if tients with quiescent ulcerative colitis (Hanai et al.
undertaken in a group of patients who are at risk but 2006). Curcumin was administered for 6 months as have not developed clinical signs of Alzheimer as 1 g after breakfast and 1 g after the evening meal.
yet. Panels of markers of inflammation should make All patients received in addition to curcumin either it possible to identify such patients years before oc- sulfasalazine or mesalamine. Two of the 43 patients (4.65%) who received curcumin relapsed within 6months, compared to 8 out of 39 patients (20.51%)in the placebo group (P = 0.040). Some effects were OCULAR DISEASES
also reported in clinical activity index (P = 0.038) Age-related cataractogenesis, for example, develop- and especially in endoscopic index (P = 0.0001) ment of opacity of the eye lens, constitutes a signifi- cant health problem worldwide. Cataract is the lead-ing cause of blindness worldwide, responsible for NEURODEGENERATIVE DISEASES
blindness of more than 20 million in the world. Nu-tritional deficiencies, especially lack of consumption Biochemical and physiologic stimuli: perturbation of enough antioxidants, diabetes, excessive sunlight, in redox status, accumulation and expression of mis- smoking, and other environmental factors, are known folded proteins, altered glyc(osyl)ation and glucose to increase the risk of cataracts. Oxidative stress is deprivation, overloading of products of polyunsatu- regarded as the common mechanism behind catarac- rated fatty acid peroxidation, cholesterol oxidation togenesis, and augmentation of the antioxidant de- and decomposition are among the factors that lead fenses of the ocular lens has been shown to prevent or to the accumulation of unfolded or misfolded pro- delay cataractogenesis. Curcumin feeding to experi- teins in brain cells. Alzheimer’s (AD), Parkinson’s mental animals prevents the loss of alpha-crystallin (PD), Huntington’s diseases (HD), amyothrophic lat- chaperone activity and delays the progression and eral sclerosis (ALS), and Friedreich’s ataxia (FRDA) maturation of diabetic cataract (Kumar et al. 2005).
are all major neurological disorders, strongly associ- Several other experimental studies report significant ated with the production of abnormal proteins and, as preventive effects of curcumin against cataracts when such, belong to the so-called “protein conformational induced by various methods: naphthalene (Pandya diseases” (Calabrese et al. 2006). Furthermore, a de- et al. 2000), galactose (Suryanarayana et al. 2003, fect elimination/phagocytosis of amyloid-beta (Aβ) Raju et al. 2006), and selenium (Padmaja and Raju and clearance of Aβ plaques by the innate immune [AU: Reference
cells, monocyte/macrophages, are reported to further In two uncontrolled studies, oral curcumin (1,125 "Raju et al.
contribute to the development of these neurodegener- mg/day) for 12 weeks to 22 months was found to (2006)" has not
[AU: Reference
ative diseases (Zhang et al. 2006). Hsps and particu- been given in
improve chronic anterior uveitis, idiopathic inflam- "Zhang et al.
larly HO-1 are also in this group of diseases identified the reference
matory orbital pseudotumor, and other inflammatory (2006)" has not
to play a key role in cellular defense (Calabrese et list. Kindly
conditions of the eye (Lal et al. 1999, 2000).
been given in
al. 2003). Since it has been demonstrated that the ex- provide the
the reference
pression of HO is closely related to amyloid precursor complete
list. Kindly
protein (APP), an increasing interest has focused on details for this
provide the
identifying dietary compounds that have the poten- reference.]
tial to inhibit, retard, or reverse the multistage patho- There are remarkable similarities in the pathogenesis details for this
physiological events underlying these pathologies.
of periodontal diseases and RA. Increased incidences reference.]
Not only curcuminoids but also other antioxidants of plaque, calculus, and gingival inflammation and such as ferulic acid are known to be strong inducers increased prevalence and severity of destructive pe- of the heat shock response, which might provide ex- riodontal diseases are seen in most other chronic dis- iting candidates for chemoprevention and treatment eases. Periodontitis is clearly a sign of an increased of these diseases (Calabrese et al. 2007). One small systemic inflammatory burden, also manifested in clinical pilot study was just concluded in AD pa- signs such as elevation of C-reactive protein (CRP).
tients. Unfortunately the treatment period was only 6 Only one plant polyphenol, green tea polyphenol epi- months and did not allow any definite conclusions to gallocatechin gallate (EGCG) is far tried and reported the clinical effects of curcumin treatment. However, to reduce gingival inflammation and prevent peri- the investigators showed that the treatment is safe odontal diseases (Sakanaka and Okada 2004), but and recommended that larger controlled studies are no human clinical study with curcumin is this far undertaken (Baum et al. 2008). More pronounced Control of Systemic Inflammation and Chronic Diseases PANCREATIC DISEASES
ing that reducing the calcium levels might liberatethe mutant CFTR and increase its odds of reach- The effect of curcumin to reduce the damage ing the cell surface. A dramatic increase in survival to pancreas was studied in two different models: rate and in normal cAMP-mediated chloride trans- cerulein-induced and ethanol and cholecystokinin port across nasal and gastrointestinal epithelia was (CCK)-induced pancreatitis (Gukocvsky et al. 2003).
observed when curcumin was supplemented to gene- Curcumin was administered intravenously in par- allel with the induction of pancreatitis. A total of 2000). CF is characterized by at least three major bio- 200 mg/kg bw of curcumin was administered dur- chemical deficits: diminished expression and activity ing a treatment period of six hours. Curcumin treat- of PPARs, increased PGE2 production, and elevated ment significantly reduced histological injuries, the oxidative tissue injury. Curcumin should have the ca- acinar cell vacuolization and neutrophil infiltration pacity to activate the PPAR anti-inflammatory path- of the pancreatic tissue, the intrapancreatic activa- way, typically underexpressed in CF, inhibit PGE2 tion of trypsin, the hyperamylasemia and hyperli- synthesis, and protect against oxidative stress. Cur- pasemia, and the pancreatic activation of NF-κB, IκB cumin treatment in CF might function as an alterna- degradation, activation of activator protein (AP)-1, tive until gene or other therapies aimed at restoring and various inflammatory molecules such as IL-6, the CF transmembrane conductance function are re- TNF-α, chemokine KC, iNOS and acidic ribosomal alized (Emanuele et al. 2007). No human studies are, [AU: This
phosphoprotein. Curcumin did significantly stimu- however, yet reported for CF. Significant reductions sentence is not
late pancreatic activation of caspase-3 in both models were observed in both airway constriction and airway clear. Kindly
check and
hyperreactivity to histamine when the antiasthmatic effect of curcumin was tested in guinea pigs sensi- necessary.]
tized with ovalbumin (Ram et al. 2003).
Acute and chronic inflammatory lung diseases due SKELETO-MUSCULAR DISEASES
to occupational and environmental exposures tomineral dusts, airborne pollutants, cigarette smoke, Osteoporosis represents a major healthcare burden, chemotherapy and radiotherapy are increasingly affecting only in the United States approximately 10 common. Curcumin offers a wide spectrum of thera- million people aged over 50 years and with another peutic properties for these conditions. Curcumin is, 30 million or more at risk. Human and animal ex- as mentioned above, a potent inhibitor of TGF-β and periments indicate that proinflammatory cytokines fibrogenesis (Gaedeke et al. 2004), and suggested to such as IL-1, IL-6, and TNFα are primary mediators have positive effects in various fibrotic diseases in of osteoclastic bone resorption in aging individuals kidneys, liver, intestine (Crohn’s disease), pancreas, and in a variety of chronic diseases with acceler- and in body cavities (prevention of fibrous adhesions) ated bone loss (Mundy 2007). Increased production and on conditions with lung fibrosis, including cystic of proinflammatory cytokines is regularly associated fibrosis (CF). CF is of special interest as it is espe- with osteoclastic bone resorption both in chronic dis- cially linked to glutathione deficiency. The effect of ease states and in individuals after estrogen with- curcumin against amiodarone-induced lung fibrosis drawal. The fact that the activation of NF-κB is, as was studied in rats. Significant inhibition of LDH discussed above, strongly linked with a large number activity, infiltration of neutrophils, eosinophils, and of chronic diseases (see above) and that polyphe- macrophages in lung tissue, LPS-stimulated TNF-α nols like curcumin have the ability to inhibit this release, phorbole myristate acetate-stimulated super- activation makes plant polyphenols, especially cur- oxide generation, MPO activity, TGF- β1 activity, cumin, an ideal candidate for prevention and treat- lung hydroxyproline content, and expression of type ment of incipient osteoporosis. However, the only I collagen and c-Jun protein were observed when studies with polyphenolic and other bioactive plant curcumin was supplemented in a dose of 200 mg/kg constituents, which have demonstrated preventive ef- bw weight in parallel with intratracheal instillation fects, have been performed with soy phytoestrogens of 6.25 mg/kg bw of amiodarone (Punithavatihi et and green tea polyphenols (Siddiqui et al. 2004).
al. 2003). Curcumin exhibits structural similarities Another obscure common disease, fibromyalgia, to isoflavonoid compounds that bind directly to the which has dramatically increased in the last decades, CFTR protein and alter its channel properties. Egan is also increasingly associated with increased sys- et al. (2004) observed that curcumin inhibits the temic inflammation. Higher levels of IL-10, IL-8, calcium pump in endoplasmic reticulum, suggest- and TNF-α are also reported in fibromyalgia patients compared to healthy controls (Bazzichi et al. 2007).
have this far been performed and presented. It is Although no studies with treatment with polyphenols a general experience that it is easier to get excel- have yet been undertaken, there are good reasons to lent results in young healthy animals with induced assume that this category of patients could benefit diseases than in humans with spontaneous diseases.
Over the years numerous treatment modalities, suc-cessful in animals, have failed when tried in humans.
One contributing factor most certainly is that hu- SKIN DISORDERS
mans under treatment usually continue with the un- Curcumenoids have been recommended in a series of healthy lifestyle that has led to the disease. Further- skin diseases from acne to psoriasis, but few studies more, treatments with natural products take a long have been undertaken. There exist many anecdotal time, often years, before results are seen. Modern reports of patients’ successful treatment with cur- day humans are often not prepared to spend that time cumin, especially patients with psoriasis. A phase waiting for clinical results. The whole idea of chemo- II, open-label trial was done with supplementation prevention is that the plant-origin nutraceuticals are of 4.5 g/day of curcuminoids orally to patients with used regularly for the rest of the life.
[AU: This
psoriasis (Kurd et al. 2008). Eight of 12 patients However, the high incidence of side effects of sentence seems
concluded a 16-week trial, with supplementation of pharmaceuticals has made an increasing number of incomplete.
4.5 g/day of curcumin (3 pills of 500 mg, 3 times individuals, especially among those with higher ed- Kindly check
daily). Only a minority were reported to respond, but ucation, to turn to alternative and complementary and amend as
those who did respond achieved after 12 weeks ex- compounds. Using medicinal plants and their active necessary.]
cellent responses of 83% and 88% improvement in components remains an attractive approach for the psoriasis area and severity index (PASI) scores. It prevention and treatment of various chronic diseases is a general experience that polyphenol treatments all based in impaired innate immunity and increased often need to be continued for 6–12 months be- systemic inflammation. Food derivates have the ad- fore results are seen. Unfortunately many patients vantage of being relatively nontoxic. Combination do not have enough patience to wait that long. Large with other “nutraceuticals” such as other polyphe- and long-lasting placebo-controlled studies are nec- nols and/or probiotic bacteria constitutes attractive essary before oral curcumin can be recommended as but not explored treatment modalities. Preliminary a treatment of psoriasis. However, most interesting observations suggest that such compounds have the animal experiments suggest that curcumin reduces ability to potentiate the effects of each other.
aging effects on skin (Rattan and Ali 2007), reducesthe skin destruction in irradiation (Okunieff et al.
2006) and burns (Singer et al. 2007), and promotesuneventful healing of skin (Panchatcharam et al.
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