Control of Systemic Inflammation and
Chronic Diseases—The Use of Turmeric
AN EPIDEMIC OF CHRONIC
DISEASES AND CRITICAL
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
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
agents are a whole series of phenolic and other com-pounds believed to reduce the speed of aging and
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
(ALEs) (Baptista and Carvalho 2004), known as po-
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
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
B 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-κ
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-κ
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
LOXs and leukotreines such as LBT4 and 5HETE
(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
) 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,
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-κ
B) 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).
CURCUMIN IN ACUTE AND
Moderately increase the number of T-and B-cells
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-
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-κ
hibit platelet aggregation, all important ingredients
via inhibition of Iκ
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-κ
B 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
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-
B is most likely playing a central role, as several
-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-κ
B activationdemonstrated that the strongest effects are obtained
by curcumin in itself, achieved by inhibition of NF-
Genomic approaches to cancer prevention and treat-
B-regulated gene expression and inhibition of Iκ
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).
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.
tem as plant antioxidants (see further Ferguson and
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-κ
B 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
= 0.01), respectively, reductions in meantumor growth, an effect that was further increased
by combining curcumin with the chemotherapeuticdrug docetaxel, and demonstrating 96% (P
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-
= 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
< 0.001), but also reduced microvessel den-
animals. An interesting study reports significant pre-
< 0.001) and increased tumor cell apoptosis
vention by curcumin of the extensive cross-linking
< 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-
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
intratumoral injection of curcumin (LoTempio et al.
mouse islets such as DNA fragmentation, and re-
2005). Curcumin induces apoptosis in vitro in almost
duced the concentrations of peroxynitrite, nitric ox-
all cell lines: breast cancer (Xia et al. 2007; Zhang
ide, and poly(ADP-ribose) polymerase-1 (Meghana
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
(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,
B activation, subsequent re-
lease of IL-8, degradation of Iκ
B kinases α
) activity, and NF-κ
B 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,
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
B to the nucleus, CCl4-induced NF-κ
binding activity, and increases of TNF-α
protein 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
rat study, fulminant hepatic failure (FHF) was in-
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-κ
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-κ
B 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
B. 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
B 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-κ
B 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
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
, downregulate peroxisome proliferator-activated
patients had improved reductions; other concomitant
) 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-
(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-
ministered after the onset of sepsis. These findings
ity of curcumin to prevent relapse was studied in
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
also reported in clinical activity index (P
Age-related cataractogenesis, for example, develop-
and especially in endoscopic index (P
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
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
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
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
matory orbital pseudotumor, and other inflammatory
(2006)" has not
to play a key role in cellular defense (Calabrese et
conditions of the eye (Lal et al. 1999, 2000).
been given in
al. 2003). Since it has been demonstrated that the ex-
pression of HO is closely related to amyloid precursor
protein (APP), an increasing interest has focused on
details for this
ORAL CAVITY DISEASES
identifying dietary compounds that have the poten-
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
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
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-κ
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-
, chemokine KC, iNOS and acidic ribosomal
alized (Emanuele et al. 2007). No human studies are,
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
hyperreactivity to histamine when the antiasthmatic
effect of curcumin was tested in guinea pigs sensi-
tized with ovalbumin (Ram et al. 2003).
Acute and chronic inflammatory lung diseases due
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. C
30 million or more at risk. Human and animal ex-
as mentioned above, a potent inhibitor of TGF-β
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-κ
B 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- β
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-
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-
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.
psoriasis (Kurd et al. 2008). Eight of 12 patients
However, the high incidence of side effects of
concluded a 16-week trial, with supplementation of
pharmaceuticals has made an increasing number of
4.5 g/day of curcumin (3 pills of 500 mg, 3 times
individuals, especially among those with higher ed-
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
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.
Abuarqoub H, Green CJ, Foresti R, and Motterlini R.
2007. Curcumin reduces cold storage-induceddamage in human cardiac myoblasts. Exp Mol Med.
Aggarwal BB, Banerjee S, Bharadwaj U, Sung B,
Shishodia S, and Sethi G. 2007. Curcumin induces
Exposure to tobacco results in increased lipoxidation
the degradation of cyclin E expression through
in the body and also dramatically increased activation
ubiquitin-dependent pathway and up-regulates
and expression of NF-κ
B and its downstream target
cyclin-dependent kinase inhibitors p21 and p27 in
COX-2, and significant decreases in the levels of an-
tioxidants such as ascorbic acid, vitamin E, reduced
glutathione, GPx, SOD, and CAT. Animal studies
Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Pandey
demonstrate that such tobacco- and nicotine-induced
MK, Kunnumakkara AB, Sung B, and Ichikawa H.
changes are effectively counteracted by regular sup-
2006a. Targeting signal-transducer-and-activator-of-
ply of turmeric and curcumin (Kalpana and Menon
transcription-3 for prevention and therapy of cancer:
Modern target but ancient solution. Ann N Y AcadSci. 1091:151–169.
Aggarwal BB, Shishodia S, Takada Y, Banerjee S,
Newman RA, Bueso-Ramos CE, and Price JE. 2005.
It is a great disappointment that only a few con-
Curcumin suppresses the paclitaxel-induced nuclear
trolled clinical studies with curcumin or turmeric
factor-kappaB pathway in breast cancer cells and
Control of Systemic Inflammation and Chronic Diseases
inhibits lung metastasis of human breast cancer in
nude mice. Clin Cancer Res. 11:7490–7498.
Aggarwal S, Ichikawa H, Takada Y, Sandur SK,
Bazzichi L, Rossi A, Massimetti G, Giannaccini G,
Shishodia S, and Aggarwal BB. 2006b. Curcumin
Giuliano T, De Feo F,Ciapparelli A, Dell’Osso L,
(diferuloylmethane) down-regulates expression of
and Bombardieri S. 2007. Cytokine patterns in
cell proliferation and antiapoptotic and metastatic
fibromyalgia and their correlation with clinical
gene products through suppression of IkappaBalpha
manifestations. Clin Exp Rheumatol. 25:225–
kinase and Akt activation. Mol Pharmacol.
Began G, Sudharshan E, Udaya Sankar K, and Appu
Rao AG. 1999. Interaction of curcumin with
activation in cancer: A challenge for ubiquitination-
phosphatidylcholine: A spectrofluorometric study. J
and proteasome-based therapeutic approach. Semin
Bengmark S. 2004. Acute and “chronic” phase
Angus DC, Linde-Zwirble WT, and Lidicker J. 2001.
response—A mother of disease. Clin Nutr.
Epidemiology of severe sepsis in the United States:
Analysis of incidence, outcome and associated costs
Bengmark S. 2006a. Bioecological control of
of care. Crit Care Med. 29:1303–1310.
inflammation and infection in critical illness.
Antony S, Kuttan R, and Kuttan G. 1999.
Anaesthesiol Clin North Amer. 24:299–323.
Immunomodulatory activity of curcumin. Immunol
Bengmark S. 2006b. Curcumin: An atoxic antioxidant
and natural NF-κ
B, COX-2, LOX and iNOS
Apisariyakul A, Vanittanakom N, and Buddhasukh D.
inhibitor—A shield against acute and chronic
1995. Antifungal activity of turmeric oil extracted
diseases. J Parenter Enteral Nutr JPEN. 30:45–51.
from Curcuma longa
lipoxidation end products—Amplifiers of
Arias E and Smith BL. 2003. Deaths: Preliminary data
inflammation: The role of food. J Parent Ent Nutr
for 2001. Natl Vital Stat Rep. 51:1–44.
Atsumi T, Fujisawa S, and Tonosaki K. 2005.
Bengtsson U, Knutson TW, Knutson L, Dannaeus A,
Relationship between intracellular ROS production
H¨allgren R, and Ahlstedt S. 1996. Increased levels
of hyaluronan and albumin after intestinal challenge
tetrahydrocurcumin-treated human gingival
in adult patients with cow’s milk intolerance. Clin
fibroblasts and human submandibular gland
carcinoma cells. Oral Dis. 11:236–242.
Bernes PJ and Karin M. 1997. Nuclear factor-kappaB:
Bachmeier B, Nerlich AG, Iancu CM, Cilli M,
A pivotal transcription factor in chronic
Schleicher E, Ven´e R, Dell’Eva R, Jochum M,
inflammatory diseases. N Engl J Med.
Albini A, and Pfeffer U. 2007. The chemopreventive
polyphenol Curcumin prevents hematogenous breast
Bharti AC, Donato N, and Aggarwal BB. 2003.
cancer metastases in immunodeficient mice. Cell
Curcumin (diferuloylmethane) inhibits constitutive
and IL-6-inducible STAT3 phosphorylation in
Bala K, Tripathy BC, and Sharma D. 2006.
human multiple myeloma cells. J Immunol.
Neuroprotective and anti-ageing effects of curcumin
in aged rat brain regions. Biogerontology. 7:81–89.
Bharti AC, Shishodia S, Reuben JM, Weber D,
Balogun E, Hoque M, Gong P, Killeen E, Green CJ,
Alexanian R, Raj-Vadhan S, Estrov Z, Talpaz M,
Foresti R, Alam J, and Motterlini R. 2003. Curcumin
and Aggarwal BB. 2004. Nuclear factor-kappaB and
activates the haem oxygenase-1 gene via regulation
STAT3 are constitutively active in CD138+ cells
of Nrf2 and the antioxidant-responsive element.
derived from multiple myeloma patients, and
suppression of these transcription factors leads to
Baptista JAB and Carvalho RCB. 2004. Indirect
determination of Amadori compounds in milk-based
Bhaumik S, Jyothi MD, and Khar A. 2000. Differential
products by HPLC/ELSD/UV as an index of protein
modulation of nitric oxide production by curcumin
deterioration. Food Res Internat. 37:739–747.
in host macrophages and NK cells. FEBS Lett.
Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J,
Lam L, Leung V, Hui E, Ng C, et al. 2008.
Bravani Shankar TN, Shantha NV, Ramesh HP, Murthy
Six-month randomized, placebo-controlled,
IA, and Murthy VS. 1980. Toxicity studies on
double-blind, pilot clinical trial of curcumin in
Turmeric (Curcuma longa
): Acute toxicity studies in
rats, guinea pigs & monkeys. Indian J Exp Biol.
Cho ML, Jung YO, Moon YM, Min SY, Yoon CH, Lee
SH, Park SH, Cho CS, Jue DM, and Kim HY. 2006.
Brouet I and Ohshima H. 1995. Curcumin, an
Interleukin-18 induces the production of vascular
anti-tumour promoter and anti-inflammatory agent,
endothelial growth factor (VEGF) in rheumatoid
inhibits induction of nitric oxide synthase in
arthritis synovial fibroblasts via AP-1-dependent
activated macrophages. Biochem Biophys Res
pathways. Immunol Lett. 103:159–166.
Chun KS, Keum YS, Han SS, Song YS, Kim SH, and
Calabrese V, Butterfield DA, and Stella AM. 2003.
Nutritional antioxidants and the heme oxygenase
ester-induced expression of cyclooxygenase-2 in
pathway of stress tolerance: Novel targets for
mouse skin through suppression of extracellular
neuroprotection in Alzheimer’s disease. Ital J
signal-regulated kinase activity and NF-kappaB
activation. Carcinogenesis. 24:1515–1524.
Calabrese V, Guagliano E, Sapienza M, Mancuso C,
Churchill M, Chadburn A, Bilinski RT, and Bertagnolli
Butterfield DA, and Stella AM. 2006. Redox
MM. 2000. Inhibition of intestinal tumors by
regulation of cellular stress response in
curcumin is associated with changes in the
neurodegenerative disorders. Ital J Biochem.
intestinal immune cell profile. J Surg Res. 89:
Calabrese V, Guagliano E, Sapienza M, Panebianco M,
Deeb D, Jiang H, Gao X, Al-Holou S, Danyluk AL,
Calafato S, Puleo E, Pennisi G, Mancuso C,
Dulchavsky SA, and Gautam SC. 2007. Curcumin
Butterfield DA, and Stella AG. 2007. Redox
regulation of cellular stress response in aging and
heptadine-3,5-dione; C21H20O6] sensitizes human
neurodegenerative disorders: Role of vitagenes.
prostate cancer cells to tumor necrosis factor-related
Camacho-Barquero L, Villegas I, S´anchez-Calvo JM,
apoptosis by suppressing nuclear factor-kappaB via
Talero E, S´anchez-Fidalgo S, Motilva V, and
inhibition of the prosurvival Akt signaling pathway.
Alarc´on de la Lastra C. 2007. Curcumin, a Curcuma
J Pharmacol Exp Ther. 321:616–625.
constituent, acts on MAPK p38 pathway
Deeb DD, Jiang H, Gao X, Divine G, Dulchavsky SA,
modulating COX-2 and iNOS expression in chronic
and Gautam SC. 2005. Chemosensitization of
experimental colitis. Int Immunopharmacol.
hormone-refractory prostate cancer cells by
curcumin to TRAIL-induced apoptosis. J Exp Ther
Chakravarti N, Myers JN, and Aggarwal BB. 2006.
Targeting constitutive and interleukin-6-inducible
Deitch EA, Shorshtein A, Houghton J, Lu Q, and Xu
signal transducers and activators of transcription 3
D. 2002. Inducible nitric oxide synthase knockout
pathway in head and neck squamous cell carcinoma
mice are resistant to diet-induced loss of gut barrier
cells by curcumin (diferuloylmethane). Int J Cancer.
function and intestinal injury. J Gastrointest Surg.
Chang D-M. 2001. Curcumin: A heat shock response
Deodhar SD, Sethi R, and Srimal RC. 1980.
inducer and potential cytoprotector. Crit Care Med.
Preliminary study on antirheumatic activity of
curcumin (diferuloyl methane). Indian J Med Res.
Charles V and Charles SX. 1992. The use and efficacy
of Azadirachta indica
ADR (‘Neem’) and Curcuma
Di Mario F, Cavallaro LG, Nouvenne A, Stefani N,
(‘Turmeric’) in scabies. A pilot study. Trop
Cavestro GM, Iori V, Maino M, Comparato G,
Chen HW, Kuo HT, Chai CY, Ou JL, and Yang RC.
2007. Pretreatment of curcumin attenuates
eradication of Helicobacter pylori
coagulopathy and renal injury in LPS-induced
Something to learn from failure? Helicobacter.
Dunsmore KE, Chen PG, and Wong HR. 2001.
Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen
Curcumin, a medicinal herbal compound capable of
TS, Ko JY, Lin JT, Lin BR, Ming-Shiang W, et al.
inducing the heat shock response. Crit Care Med.
2001. Phase I clinical trial of curcumin, a
chemopreventive agent, in patients with high-risk or
Egan ME, Pearson M, Weiner SA, Rajendran V, Rubin
pre-malignant lesions. Anticancer Res.
D, Gl¨ockner-Pagel J, Canny S, Du K, Lukacs GL,
Control of Systemic Inflammation and Chronic Diseases
constituent of turmeric, corrects cystic fibrosis
Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama
Y, Andoh A, Tsujikawa T, Fujiyama Y, Mitsuyama
Emanuele E, Elia C, and Venturini L. 2007. Potential
K, Sata M, et al. 2006. Curcumin maintenance
usefulness of curcumin in cystic fibrosis. Med
therapy for ulcerative colitis: Randomized,
multicenter, double-blind, placebo-controlled trial.
Ferguson LR and Philpott M. 2007. Cancer prevention
Clin Gastroenterol Hepatol. 4:1502–1506.
by dietary bioactive components that target the
Holmes MD, Pollak MN, Willett WC, and Hankinson
immune response. Curr Cancer Drug Targets.
SE. 2002. Dietary correlates of plasma insulin-like
growth factor I and insulin-like growth factor
Flynn DL, Rafferty MF, and Boctor AM. 1986.
binding protein 3 concentrations. Cancer Epidemiol
Inhibition of human neutrophil 5- lipooxygenase
activity by gingerdione, shogaol, capsaicin and
Holt PR, Katz S, and Kirshoff R. 2005. Curcumin
related pungent compounds. Prostaglandins Leukot
therapy in inflammatory bowel disease: A pilot
Foryst-Ludwig A, Neumann M, Schneider-Brachert W,
Hong J, Bose M, Ju J, Ryu JH, Chen X, Sang S, Lee
and Naumann M. 2004. Curcumin blocks NF-κ
MJ, and Yang CS 2004. Modulation of arachidonic
and the mitogenic response in Helicobacter
-infected epithelial cells. Biochem Biophys
beta-diketone derivatives: Effects on cytosolic
Fugh-Berman A. 2002. Herb-drug interactions.
5-lipoxygenase. Carcinogenesis. 25:1671–
Gaedeke J, Noble NA, and Border WA. 2004.
Hour TC, Chen J, Huang CY, Guan JY, Lu SH, and Pu
Curcumin blocks multiple sites of the TGF-β
YS. 2002. Curcumin enhances cytotoxicity of
chemotherapeutic agents in prostate cancer cells by
Ganguly K, Kundu P, Banerjee A, Reiter RJ, and
expressions and suppressing NF-kappaB activation.
Swarnakar S. 2006. Hydrogen peroxide-mediated
downregulation of matrix metalloprotease-2 in
Howie BJ and Shultz TD. 1985. Dietary and hormonal
indomethacin-induced acute gastric ulceration is
interrelationships among vegetarian Seventh-Day
blocked by melatonin and other antioxidants. Free
Adventists and nonvegetarian men. Am J Clin Nutr.
Gautam SC, Gao X, and Dulchavsky S. 2007.
Huang CY, Chen JH, Tsai CH, Kuo WW, Liu JY, and
Immunomodulation by curcumin. Adv Exp Med
Chang YC. 2005. Regulation of extracellular
signal-regulated protein kinase signaling in human
Giltay EJ, Hoogeveen EK, Elbers JMH, Gooren LJ,
osteosarcoma cells stimulated with nicotine. J
Asscheman H, and Stehouwer CD. 1998. Insulin
resistance is associated with elevated plasma total
Illek B, Lizarzaburu ME, Lee V, Nantz MH, Kurth MJ,
homocysteine levels in healthy, non-obese subjects.
and Fischer H. 2000. Structural determinants for
Letter to the Editor. Atherosclerosis. 139:197–198.
activation and block of CFTR-mediated chloride
Grant KL and Schneider CD. 2000. Turmeric. Am J
currents by apigenin. Am J Physiol Cell Physiol.
Groten JP, Butler W, Feron VJ, Kozianowski G,
Jackson JK, Higo T, Hunter WL, and Burt HM. 2006.
Renwick AG, and Walker R. 2000. An analysis of
The antioxidants curcumin and quercetin inhibit
the possibility for health implications of joint
inflammatory processes associated with arthritis.
actions and interactions between food additives. Reg
Jagetia GC and Aggarwal BB. 2007. “Spicing up” of
Gukocvsky I, Reyes CN, Vaquero EC, Gukovskaya AS,
the immune system by curcumin. J Clin Immunol.
and Pandol SJ. 2003. Curcumin ameliorates ethanol
and nonethanol experimental pancreatitis. Am J
Jovanovic SV, Boone CW, Steenken S, Trinoga M, and
Physiol Gastrointest Liver Physiol. 284:G85–G95.
Kaskey RB. 2001. How curcumin preferentially
Hammamieh R, Sumaida D, Zhang X, Das R, and Jett
works with water soluble antioxidants. J Am Chem
M. 2007. Control of the growth of human breast
cancer cells in culture by manipulation of
Kalpana C and Menon VP. 2004. Modulatory effects of
arachidonate metabolism. BMC Cancer. 7:138.
curcumin on lipid peroxidation and antioxidant
status during nicotine-induced toxicity. Pol J
simplex virus immediate-early gene expression by a
mechanism independent of p300/CBP histone
Kamal-Eldin A, Frank J, Razdan A, Tengblad S, Basu
acetyltransferase activity. Virology. 373:239–247.
S, and Vessby B. 2000. Effects of dietary phenolic
compounds on tocopherol, cholesterol and fatty
Giannitrapani L, Cervello M, Montalto G, and
acids in rats. Lipids. 35:427–435.
D’Alessandro N. 2006. Significance of autologous
Kang BY, Song YJ, Kim KM, Choe YK, Hwang SY,
interleukin-6 production in the HA22 T/VGH cell
and Kim TS. 1999. Curcumin inhibits Th1 cytokine
model of hepatocellular carcinoma. Ann N Y Acad
interleukin-12 production in macrophages. Br J
Lal B, Kapoor AK, Agrawal PK, Asthana OP, and
Srimal RC. 2000. Role of curcumin in idiopathic
inflammatory orbital pseudotumours. Phytother Res.
treatment enhances islet recovery by induction of
heat shock response proteins, Hsp70 and heme
Lal B, Kapoor AK, Asthana OP, Agrawal PK, Prasad
oxygenase-1, during cryopreservation. Life Sci.
R, Kumar P, and Srimal RC. 1999. Efficacy of
curcumin in the management of chronic anterior
Kaur G, Tirkey N, Bharrhan S, Chanana V, Rishi P, and
uveitis. Phytother Res. 13:318–322.
Chopra K. 2006. Inhibition of oxidative stress and
Lee J, Im YH, Jung HH, Kim JH, Park JO, Kim K,
cytokine activity by curcumin in amelioration of
Kim WS, Ahn JS, Jung CW, ParkYS, Kang WK,
endotoxin-induced experimental hepatoxicity in
rodents. Clin Exp Immunol. 145:313–321.
interferon-alpha induced NF-kappaB and COX-2 in
Kempaiah RK and Srinivasan K. 2002. Integrity of
human A549 non-small cell lung cancer cells.
erythrocytes of hypercholesterolemic rats during
Biochem Biophys Res Commun. 334:313–318.
spices treatment. Mol Cell Biochem. 236:155–161.
Lev-Ari S, Starr A, Vexler A, et al. 2006b. Inhibition
Kim DC, Kim SH, Choi BH, Hur EM, Kim SH, Choi
of pancreatic and lung adenocarcinoma cell survival
BH, and Kim KT. 2005b. Curcuma longa
by curcumin is associated with increased apoptosis,
protects against gastric ulcers by blocking H2
down-regulation of COX-2 and EGFR and inhibition
histamine receptors. Biol Pharm Bull.
of Erk1/2 activity. Anticancer Res. 26:4423–4430.
Lev-Ari S, Strier L, Kazanov D, Elkayam O,
Kim GY, Kim KH, Lee SH, Yoon MS, Lee HJ, Moon
Lichtenberg D, Caspi D, and Arber N. 2006a.
DO, Lee CM, Ahn SC, Park YC, and Park YM.
2005a. Curcumin inhibits immunostimulatory
growth-inhibitory and pro-apoptotic effects of
celecoxib in osteoarthritis synovial adherent cells.
translocation of NF-kappa B as potential targets. J
Lev-Ari S, Vexler A, Starr A, Ashkenazy-Voghera M,
Kitani K, Yokozawa T, and Osawa T. 2004.
Greif J, Aderka D, and Ben-Yosef R. 2007.
Interventions in aging and age-associated
Curcumin augments gemcitabine cytotoxic effect on
pathologies by means of nutritional approaches. Ann
pancreatic adenocarcinoma cell lines. Cancer Invest.
Kumar PA, Suryanarayana P, Reddy PY, and Reddy
Li X and Liu X. 2005. Effect of curcumin on immune
GB. 2005. Modulation of alpha-crystallin chaperone
function of mice. J Huazhong Univ Sci Technolog
activity in diabetic rat lens by curcumin. Mol Vis.
Liao YF, Hung HC, Hour TC, Hsu PC, Kao MC, Tsay
Kurd SK, Smith N, Vanvoorhees A, Troxel AB,
GJ, and Liu GY. 2008. Curcumin induces apoptosis
Badmaev V, Seykora JT, and Gelfand JM. 2008.
through an ornithine decarboxylase-dependent
Oral curcumin in the treatment of moderate to
pathway in human promyelocytic leukemia HL-60
severe psoriasis vulgaris: A prospective clinical
trial. J Am Acad Dermatol. 58:625–631.
Lin YG, Kunnumakkara AB, Nair A, Merritt WM,
Kurup VP, Barrios CS, Raju R, Johnson BD, Levy MB,
Han LY, Armaiz-Pena GN, Kamat AA, Spannuth
and Fink JN. 2007. Immune response modulation by
WA, Gershenson DM, Lutgendorf SK, Aggarwal
curcumin in a latex allergy model. Clin Mol Allergy.
BB, and Sood AK. 2007. Curcumin inhibits tumor
growth and angiogenesis in ovarian carcinoma by
targeting the nuclear factor-kappaB pathway. Clin
Triezenberg SJ. 2008. Curcumin inhibits herpes
Control of Systemic Inflammation and Chronic Diseases
Liontas A and Yeger H. 2004. Curcumin and
nonfermentable fiber. Crit Care Med. 30:396–
translocation and activation of p53 in human
Mundy GR. 2007. Osteoporosis and inflammation.
neuroblastoma. Anticancer Res. 24:987–998.
L´opez-L´azaro M, Willmore E, Jobson A, Gilroy KL,
Murugan P and Pari L. 2006a. Antioxidant effect of
Curtis H, Padget K, and Austin CA. 2007. Curcumin
tetrahydrocurcumin in streptozotocin-nicotinamide
induces high levels of topoisomerase I- and II-DNA
induced diabetic rats. Life Sci. 79:1720–1728.
complexes in K562 leukemia cells. J Nat Prod.
tetrahydrocurcumin on lipid peroxidation and lipids
LoTempio MM, Veena MS, Steele HL, Ramamurthy
in streptozotocin-nicotinamide-induced diabetic
B, Ramalingam TS, Cohen AN, Chakrabarti R,
rats. Basic Clin Pharmacol Toxicol. 99:122–127.
Srivatsan ES, and Wang MB. 2005. Curcumin
Murugan P and Pari L. 2007a. Influence of
suppresses growth of head and neck squamous cell
tetrahydrocurcumin on erythrocyte membrane bound
carcinoma. Clin Cancer Res. 11:6994–7002.
enzymes and antioxidant status in experimental type
Mahady GB, Pendland SL, Yun G, and Lu ZZ. 2002.
2 diabetic rats. J Ethnopharmacol. 113:479–486.
Turmeric (Curcuma longa
) and curcumin inhibit the
Murugan P and Pari L. 2007b. Influence of
growth of Helicobacter pylori
, a group 1
etrahydrocurcumin on hepatic and renal functional
carcinogen. Anticancer Res. 22:4179–4182.
has not been
markers and protein levels in experimental type 2
Malekinejad H, Scherpenisse P, and Bergwerff A.
diabetic rats. Basic Clin Pharmacol Toxicol.
2006. Naturally occurring estrogens in processed
in the text.
milk and in raw milk (from gestated cows). J Agric
Either cite it at
Naidu KA and Thippeswamy NB. 2002. Inhibition of
human low density lipoprotein oxidation by active
Manikandan P, Sumitra M, Aishwarya S, Manohar
principles from spices. Mol Cell Biochem.
place or delete
BM, Lokanadam B, and Puvanakrishnan R. 2004.
it from the
Curcumin modulates free radical quenching in
Ohadshi Y, Tsuchia Y, Koizumi K, Sakurai H, and
myocardial ischaemia in rats. Int J Biochem Cell
Saiki I. 2003. Prevention of intrahepatic metastasis
by curcumin in an orthotopic implantation model.
Mar´ın YE, Wall BA, Wang S, Namkoong J, Martino JJ,
Suh J, Lee HJ, Rabson AB, Yang CS, Chen S, and
Okunieff P, Xu J, Hu D, Liu W, Zhang L, Morrow G,
Pentland A, Ryan JL, and Ding I. 2006. Curcumin
constitutive activity of NF-kappaB and induces
protects against radiation-induced acute and chronic
apoptosis in novel mouse melanoma cells.
cutaneous toxicity in mice and decreases mRNA
expression of inflammatory and fibrogenic
McInnes IB, Gracie JA, Leung BP, Wei XQ, and Liew
cytokines. Int J Radiat Oncol Biol Phys.
FY. 2000. Interleukin 18: A pleiotropic participant in
chronic inflammation. Immunol Today. 21:312–315.
Olszanecki R, Gebska A, and Korbut R. 2007. The role
McNally SJ, Harrison EM, Ross JA, Garden OJ, and
of haem oxygenase-1 in the decrease of endothelial
intercellular adhesion molecule-1 expression by
oxygenase-1 in hepatocytes and is protective in
curcumin. Basic Clin Pharmacol Toxicol.
simulated cold preservation and warm reperfusion
injury. Transplantation. 81:623–626.
Padmaja S and Raju TN. 2004. Antioxidant effects in
Meghana K, Sanjeev G, and Ramesh B. 2007.
selenium induced cataract of Wistar rats. Ind J Exp
Curcumin prevents streptozotocin-induced islet
damage by scavenging free radicals: A prophylactic
Pahl HL. 1999. Activators and target genes of Rel/
and protective role. Eur J Pharmacol. 577:183–191.
B transcription factors. Oncogene.
Mitra A, Chakrabarti J, Banerji A, Chatterjee A, and
Das BR. 2006. Curcumin, a potential inhibitor of
Panchatcharam M, Miriyala S, Gayathri VS, and
MMP-2 in human laryngeal squamous carcinoma
Suguna L. 2006. Curcumin improves wound healing
cells HEp2. J Environ Pathol Toxicol Oncol.
by modulating collagen and decreasing reactive
oxygen species. Mol Cell Biochem. 290:87–96.
Mosenthal AC, Xu D, and Deitch EA. 2002. Elemental
Pandya U, Saini MK, Jin GF, Awasthi S, Godley BF,
and intravenous total parenteral nutrition
and Awasthi YC. 2000. Dietary curcumin prevents
diet-induced gut barrier failure is intestinal site
ocular toxicity of naphthalene in rats. Toxicol Lett.
Pari L and Murugan P. 2007a. Antihyperlipidemic
Reddy RC, Vatsala PG, Keshamouni VG, Padmanaban
effect of curcumin and tetrahydrocurcumin in
G, Rangarajan PN. 2005. Curcumin for malaria
experimental type 2 diabetic rats. Ren Fail.
therapy. Biochem Biophys Res Commun.
Pari L and Murugan P. 2007b. Tetrahydrocurcumin
Reyes-Gordillo K, Segovia J, Shibayama M, Vergara P,
Moreno MG, and Muriel P. 2007. Curcumin protects
streptozotocin-induced diabetic rats. J Med Food.
against acute liver damage in the rat by inhibiting
NF-kappaB, proinflammatory cytokines production
Pari L and Murugan P. 2007c. Changes in glycoprotein
and oxidative stress. Biochim Biophys Acta.
components in streptozotocin–nicotinamide induced
type 2 diabetes: Influence of tetrahydrocurcumin
Sajithlal GB, Chithra P, and Chandrakasan G. 1998.
from Curcuma longa
. Plant Foods Hum Nutr.
Effect of curcumin on the advanced glycation and
cross-linking of collagen in diabetic rats. Biochem
Pari L and Murugan P. 2007d. Influence of
tetrahydrocurcumin on tail tendon collagen contents
Sakanaka S and Okada Y. 2004. Inhibitory effects of
green tea polyphenols on the production of a
streptozotocin-nicotinamide-induced type 2
virulence factor of the periodontal-disease-causing
diabetes. Fundam Clin Pharmacol. 21:665–
anaerobic bacterium Porphyromonas gingivalis
Parodi FE, Mao D, Ennis TL, Pagano MB, and
Sandur SK, Pandey MK, Sung B, Ahn KS, Murakami
Thompson RW. 2006. Oral administration of
A, Sethi G, Limtrakul P,Badmaev V, and Aggarwal
proinflammatory cytokines and destructive
bisdemethoxycurcumin, tetrahydrocurcumin and
connective tissue remodeling in experimental
turmerones differentially regulate anti-inflammatory
abdominal aortic aneurysms. Ann Vasc Surg.
and anti-proliferative responses through a
ROS-independent mechanism. Carcinogenesis.
P´erez-Arriaga L, Mendoza-Maga˜na ML, Cort´es-Z´arate
Satoskar RR, Shah SJ, and Shenoy SG. 1986.
Troyo-Sanrom´an R, and Ram´ırez-Herrera MA.
Evaluation of anti-inflammatory property of
2006. Cytotoxic effect of curcumin on Giardia
curcumin (diferuloyl methane) in patients with
trophozoites. Acta Trop. 98:152–161.
postoperative inflammation. Int J Clin Pharmacol
Punithavatihi DP, Venkatesan N, and Babu M. 2003.
Shainani-Wu N. 2003. Safety and anti-inflammatory
amimodarone-induced pulmonary fibrosis in rats. Br
activity of curcumin: A component of turmeric
). J Altern Complement Med.
Quiles JL, Mesa MD, Ram´ırez-Tortosa CL, Aguilera
CM, Battino M, Gil A, and Ram´ırez-Tortosa MC.
Shakibaei M, John T, Schulze-Tanzil G, Lehmann I,
2002. Curcuma longa
and Mobasheri A. 2007. Suppression of NF-kB
reduces oxidative stress and attenuates aortic fatty
activation by curcumin leads to inhibition of
streak development in rabbits. Arterioscler Throm
expression of cyclo-oxygenase-2 and matrix
Ram A, Das M, and Ghosh B. 2003. Curcumin
chondrocytes: Implications for the treatment of
attenuates allergen-induced hyperresponsiveness in
osteoarthritis. Biochem Pharmacol. 73:1434–1445.
sensitized guinea pigs. Biol Pharm Bull.
Shankar S and Srivastava RK. 2007. Involvement of
Bcl-2 family members, phosphatidylinositol
Ramaswami G, Chai H, Yao Q, Lin PH, Lumsden AB,
3 -kinase/AKT and mitochondrial p53 in curcumin
(diferulolylmethane)-induced apoptosis in prostate
homocysteine-induced endothelial dysfunction in
porcine coronary arteries. J Vasc Surg.
Shapiro H, Ashkenazi M, Weizman N, Shahmurov M,
Aeed H, and Bruck R. 2006. Curcumin ameliorates
Rattan SI and Ali RE. 2007. Hormetic prevention of
acute thioacetamide-induced hepatotoxicity. J
molecular damage during cellular aging of human
Gastroenterol Hepatol. 21:358–366.
skin fibroblasts and keratinocytes. Ann N Y Acad
Shapiro TA, Fahey JW, Wade KL, Stephenson KK, and
Talalay P. 1998. Human metabolism and excretion
Control of Systemic Inflammation and Chronic Diseases
of cancer chemoprotective glucoisonolates and
Stolina M, Sharma S, Lin Y, Dohadwala M, Gardner
isothiocyanates of cruciferious vegetables. Cancer
B, Luo J, Zhu L, Kronenberg M, Miller PW,
Epidemiol Biomarkers Prev. 7:1091–1100.
Portanova J, Lee JC, and Dubinett SM. 2000.
Sharma C, Kaur J, Shishodia S, Aggarwal BB, and
Specific inhibition of cyclooxygenase-2 restores
antitumor reactivity by altering the balance of IL-10
smokeless tobacco-induced NF-kappaB activation
and IL-12 synthesis. J Immunol. 164:361–370.
and COX-2 expression in human oral premalignant
Surh Y-J, Chun K-S, Cha H-H, Han SS, Keum YS,
and cancer cells. Toxicology. 228:1–15.
Park KK, and Lee SS. 2001. Molecular mechanisms
Sharma RA, Ireson CR, Verschoyle RD, Hill KA,
underlying chemo-preventive activities of
Williams ML, Leuratti C, Manson MM, Marnett LJ,
anti-inflammatory phytochemicals: Downregulation
Steward WP, and Gescher A. 2001. Effects of
of COX-2 and iNOS through suppression of NF-κ
dietary curcumin on glutathione S-transferase and
activation. Mut Res. 480–481:243–268.
malonaldehyde-DNA adducts in rat liver and
Suryanarayana P, Krishnaswamy K, and Reddy B.
colonic mucosa: Relationship with drug levels. Clin
2003. Effects on galactose-induced cataractogenesis
in rats. Molecular Vision. 9:223–230.
Shen SQ, Zhang Y, Xiang JJ, and Xiong CL. 2007.
Suzuki M, Nakamura T, Iyoki S, Fujiwara A,
Protective effect of curcumin against liver warm
Watanabe Y, Mohri K, Isobe K, Ono K, and Yano S.
ischemia/reperfusion injury in rat model is
2005. Elucidation of anti-allergic activities of
associated with regulation of heat shock protein and
curcumin-related compounds with a special
antioxidant enzymes. World J Gastroenterol.
reference to their anti-oxidative activities. Biol
Shoba G, Joy D, Joseph T, Majeed M, Rajendran R,
Swarnakar S, Ganguly K, Kundu P, Banerjee A, Maity
and Srinivas PS. 1998. Influence of peperine on the
P, and Sharma AV. 2005. Curcumin regulates
pharmacokinetics of curcumin in animals and
expression and activity of matrix metalloproteinases
human volunteers. Planta Med. 64:1167–1172.
Siddiqui AM, Cui X, Wu R, Dong W, Zhou M, Hu M,
indomethacin-induced gastric ulcer. J Biol Chem.
anti-inflammatory effect of curcumin in an
Taneja R, Parodo J, Jia SH, Kapus A, Rotstein OD, and
experimental model of sepsis is mediated by
Marshall JC. 2004. Delayed neutrophil apoptosis in
up-regulation of peroxisome proliferator-activated
receptor-gamma. Crit Care Med. 34:1874–1882.
mitochondrial transmembrane potential and reduced
Siddiqui IA, Afaq F, Adhami VM, Ahmad N, and
caspase-9 activity. Crit Care Med. 32:1460–
Mukhtar H. 2004. Antioxidants of the beverage tea
in promotion of human health. Antioxid Redox
Thapliyal R, Dolas SS, Pakhale SS, and Maru GB.
2004. Evaluation of DNA damage in mice topically
Singer AJ, McClain SA, Romanov A, Rooney J, and
exposed to total particulate matter from mainstream
and sidestream smoke from cigarettes and bidis.
progression in rats. Acad Emerg Med.
Thapliyal R and Maru GB. 2001. Inhibition of
Siwak DR, Shishodia S, Aggarwal BB, and Kurzrock
cytochrome P450 isoenzymes by curcumins in vitro
R. 2005. Curcumin-induced antiproliferative and
and in vivo. Food Chem Toxicol. 39:541–547.
proapoptotic effects in melanoma cells are
Thiemermann C. 2006. The spice of life: Curcumin
associated with suppression of IkappaB kinase and
reduces the mortality associated with experimental
nuclear factor kappaB activity and are independent
sepsis. Crit Care Med. 34:2009–2011.
of the B-Raf/mitogen-activated/extracellular
Vanisree AJ and Ramanan R. 2007. In vitro assessment
signal-regulated protein kinase pathway and the Akt
of curcumin against murine neuroblastoma cells.
Neuro Endocrinol Lett. 28:204–212.
Srinisan P and Libbus B. 2004. Mining MEDLINE for
Wallace JM. 2002. Nutritional and botanical
implicit links between dietary substances and
diseases. Bioinformatics. 20(Suppl 1):1290–1296.
cascade—Eicosanoids, cyclooxygenases and
Steward WP and Gescher AJ. 2008. Curcumin in
lipooxygenases—As an adjunct in cancer therapy.
cancer management: Recent results of analogue
design and clinical studies and desirable future
Walters DK, Muff R, Langsam B, Born W, and Fuchs
research. Mol Nutr Food Res. 52:1005:1009.
B. 2008. Cytotoxic effects of curcumin on
osteosarcoma cell lines. Invest New Drugs.
Xu PH, Long Y, Dai F, and Liu ZL. 2007. The relaxant
effect of curcumin on porcine coronary arterial ring
World Health Organization. 2003. Process for a global
segments. Vascul Pharmacol. 47:25–30.
strategy on diet, physical activity and health. WHO,
Zhang F, Altorki NK, Mestre JR, Subbaramaiah K, and
Xia Y, Jin L, Zhang B, Xue H, Li Q, and Xu Y. 2007.
cyclooxygenase-2 transcription in bile acid- and
The potentiation of curcumin on insulin-like growth
phorbol ester-treated human gastrointestinal
factor-1 action in MCF-7human breast carcinoma
epithelial cells. Carcinogenesis. 20:445–451.
Zhang HG, Kim H, Liu C, Yu S, Wang J, Grizzle WE,
Xu D, Lu Q, and Deitch EA. 1998. Elemental
Kimberly RP, and Barnes S. 2007. Curcumin
diet-induced bacterial translocation associated with
reverses breast tumor exosomes mediated immune
systemic and intestinal immune suppression. J
suppression of NK cell tumor cytotoxicity. Biochim
Parenter Enteral Nutr JPEN. 22:37–41.
W I S S E N S C H A F TN A R R AT I V E R R E V I E WEffekte trainingstherapeutischer Maßnahmen bei Morbus Parkinson Extrinsische Trainingsmaßnahmen Mareike Schwed, Christian T. Haas 20. Morris ME, Iansek R, Matyas TA, Summers JJ. Gruendlinger L, Peretz C, Giladi N. 2007. 1994. Ability to modulate walking cadenceRhythmic auditory stimulation modulates gaitremains intact in Parkinson’s
Diabetes Leaders Urge Patients to Talk with their Doctor before Making Changes to their Medication Use Diabetes Australia, the Australian Diabetes Society and the Australian Diabetes Educators Association issued a joint statement 16 July 2010 in response to the US Food and Drug Administration panel’s recommendation to keep rosiglitazone (Avandia) on the market. The U.S. Food and Dr