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Int J Biochem Cell Biol. Author manuscript; available in PMC 2010 January 1.
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Int J Biochem Cell Biol. 2009 ; 41(1): 40–59. doi:10.1016/j.biocel.2008.06.010.

Potential Therapeutic Effects of Curcumin, the Anti-inflammatory

Agent, Against Neurodegenerative, Cardiovascular, Pulmonary,
Metabolic, Autoimmune and Neoplastic Diseases

Bharat B. Aggarwal1 and Kuzhuvelil B. Harikumar

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas
M. D. Anderson Cancer Center, Houston, Texas

Abstract
Although safe in most cases, ancient treatments are ignored because neither their active component
nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-
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pigment substance and component of turmeric (Curcuma longa), which was identified more than a
century ago. For centuries it has been known that turmeric exhibits anti-inflammatory activity, but
extensive research performed within the past two decades has shown that the this activity of turmeric
is due to curcumin, a diferuloylmethane. This agent has been shown to regulate numerous
transcription factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes that
have been linked to inflammation. The process of inflammation has been shown to play a major role
in most chronic illnesses, including neurodegenerative, cardiovascular, pulmonary, metabolic,
autoimmune and neoplastic diseases. In the current review, we provide evidence for the potential
role of curcumin in the prevention and treatment of various pro-inflammatory chronic diseases. These
features, combined with the pharmacological safety and negligible cost, render curcumin an attractive
agent to explore further.

Keywords
Curcumin; NSAIDs; Diabetes; Inflammation; Arthritis; Allergy; CVDs; Psoriasis

1. Introduction
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Within the past half-century, there has been a major breakthrough in our understanding of the
cellular, molecular, genetic, and biochemical mechanisms of most chronic diseases. The
discovery of growth factors, hormones, and cytokines; their receptors; protein kinases; and
transcription factors have provided the basis for signal transduction at the cellular level. How
these signals mediate different diseases, has also become apparent. It is now common
knowledge that the products of approximately 25,000 different genes regulate the human body
and that most diseases are caused by dysregulation of multiple gene products. Using microarray
technology, it has been estimated that as many as 300–500 different genes may control any

1To whom correspondence should be addressed at Department of Experimental Therapeutics, Unit 143, The University of Texas M. D.
Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; phone: 713-794-1817 or 713-792-6459; Fax: 713-794-1613; e-
mail: aggarwal@mdanderson.org.
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given chronic illness. Until now, few of these genes have been targeted for therapy. Tumor
necrosis factor (TNF), cyclo-oxygenase 2 (COX-2) inhibitor, vascular epithelial growth factor
(VEGF), CD20, and epidermal growth factor receptor are perhaps the best-known examples
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(Aggarwal et al., 2007). Another intriguing revelation is that most chronic illnesses are caused
by dysregulated inflammation. For instance, inflammation has been found to play a major role
in cancer, cardiovascular diseases (CVDs), pulmonary diseases, metabolic diseases, neurologic
diseases, and even psychological diseases (Aggarwal et al., 2006a); (Hansson et al., 2006);
(Garodia et al., 2007) (Khanna et al., 2007) (Libby, 2007) (Odrowaz-Sypniewska, 2007)
(Robinson et al., 2007) (Selmi et al., 2007) (Packard and Libby, 2008) (Hold and El-Omar,
2008) (Dantzer et al., 2008).

Almost 2 decades ago, our laboratory was the first to isolate 2 different cytokines (TNF-α and
TNF-β) as antitumor agents (Aggarwal et al., 1985a) (Aggarwal et al., 1985b). It has now
become clear, however, that TNF-α is a major mediator of inflammation in most diseases, and
this effect is regulated by the activation of a transcription factor, nuclear factor (NF)-κB.
Whereas TNF is the most potent NF-κB activator yet described, the expression of TNF-α is
also regulated by NF-κB (Aggarwal, 2003). Besides TNF, NF-κB is activated by most
inflammatory cytokines; gram-negative bacteria; various disease-causing viruses;
environmental pollutants; chemical, physical, mechanical, and psychological stress; high
glucose; fatty acids; ultraviolet radiation; cigarette smoke; and other disease-causing factors
(Aggarwal, 2004) (Kumar et al., 2004) (Sethi et al., 2008); (Tergaonkar, 2006) (Karin and
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Greten, 2005) (Ahn and Aggarwal, 2005). Interestingly, most mediators of inflammation that
have been identified up to now are also regulated by NF-κB, including inflammatory cytokines,
chemokines, adhesion molecules, enzymes, and kinases (see Fig. 1). Thus, NF-κB and NF-
κB–regulated gene products have been closely linked with most chronic illnesses. Therefore,
agents that downregulate NF-κB and NF-κB–regulated gene products have potential efficacy
against several of these diseases.

Suppression of NF-κB activation is a topic actively being pursued in the academic and
industrial settings. Our laboratory was the first to demonstrate that curcumin is a potent blocker
of NF-κB activation induced by different inflammatory stimuli (Singh and Aggarwal, 1995).
We and others subsequently showed that curcumin blocks NF-κB activation through inhibition
of IκBα kinase and AKT (Aggarwal et al., 2005) (Shishodia et al., 2005) (Siwak et al., 2005)
(Aggarwal et al., 2006c) (Kamat et al., 2007) (Deeb et al., 2007) (Aoki et al., 2007), thus
resulting in the suppression of NF-κB–dependent gene products that suppress apoptosis and
mediate proliferation, invasion, and angiogenesis. Our laboratory more recently showed that
curcumin also suppresses NF-κB activation in most tumor cells, leading to suppression of anti-
apoptotic proteins and resulting in apoptosis (Aggarwal et al., 2004); (Kunnumakkara et al.,
2007). We also showed that curcumin could downregulate the expression of interleukin (IL)-6
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protein, TNF, and various other chemokines (Jagetia and Aggarwal, 2007). Abe et al (Abe et
al., 1999) showed that curcumin inhibited the production of IL-8, MIP-1α, MCP-1, IL-1α, and
TNF-α induced by inflammatory stimuli in human peripheral blood monocytes and alveolar
macrophages. We and others subsequently showed that curcumin downregulates the expression
of the NF-κB –regulated gene products such as COX-2, TNF, 5-LOX, IL-1, IL-6, IL-8,
MIP-1α, adhesion molecules, c-reactive protein (CRP), CXCR-4, and others (Skommer et al.,
2007) (Shakibaei et al., 2005) (Shishodia et al., 2005) (Li et al., 2004) (see Fig. 1). Curcumin
has also been reported to bind to COX-2 and 5-LOX and to inhibit their activity (Hong et al,
2004). Recent work from our laboratory has shown that curcumin directly binds to IkBα kinase
needed for NF-κB activation (Aggarwal et al., 2006c). Our laboratory was the first to
demonstrate that curcumin is a potent inhibitor of STAT 3, another transcription factor through
which proinflammatory cytokine IL-6 mediates its effects (Bharti et al., 2003a). Thus curcumin
could suppress inflammation through multiple pathways.

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The effect of curcumin against various pro-inflammatory diseases is discussed in detail in this
report.
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2. Role of Curcumin in the Treatment of Chronic Inflammatory Diseases

In various chronic illnesses in which inflammation is known to play a major role, curcumin
has been shown to exhibit therapeutic potential. These diseases include Alzheimer’s disease
(AD), Parkinson’s disease, multiple sclerosis, epilepsy, cerebral injury, CVDs, cancer, allergy,
asthma, bronchitis, colitis, rheumatoid arthritis, renal ischemia, psoriasis, diabetes, obesity,
depression, fatigue, and AIDS (see Table 1). How curcumin mediates its activity against these
diseases is described in this section.

2.1. Neurodegenerative diseases

The brain is a highly oxidative organ that consumes 20% of the body’s oxygen despite
accounting for only 2% of the total body weight. With normal aging, the brain accumulates
metals ions such as iron (Fe), zinc (Zn), and copper (Cu). Consequently, the brain is abundant
in antioxidants that control and prevent the detrimental formation of reactive oxygen species
(ROS) generated via Fenton chemistry involving redox-active metal-ion reduction and
activation of molecular oxygen (Smith et al., 2007). Curcumin has been shown to exhibit
activity against various neurologic diseases, including AD (Lim et al., 2001), multiple sclerosis
(Natarajan and Bright, 2002), Parkinson disease (Zbarsky et al., 2005), epilepsy (Sumanont et
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al., 2006), cerebral injury (Ghoneim et al., 2002), age-associated neurodegeneration (Calabrese
et al., 2003), schizopherenia (Bishnoi et al., 2008), Spongiform encephalopathies (Creutzfeld-
Jakob disease) (Hafner-Bratkovic et al., 2008), neuropathic pain (Sharma et al., 2006a), and
depression (Xu et al., 2005) (Fig. 2).

AD is a neurodegenerative disease that involves inflammation, oxidative damage, and Abeta

accumulation. Inhibition of the accumulation of Abeta and the formation fibrillar (f) Abeta
(fAbeta) from Abeta and the destabilization of preformed fAbeta in the central nervous system
are potential therapeutic targets for the treatment of AD. In AD, an over-accumulation of Abeta
is due to either an elevated generation of amyloid precursor protein (APP) or inefficient
clearance of Abeta from the brain. Abeta can efficiently generate ROS in the presence of the
transition metals (Cu and Fe) in vitro. Under oxidative conditions, Abeta will form stable
dityrosine cross-linked dimers that are generated from free-radical attack on the tyrosine
residue. There are elevated levels of urea and SDS-resistant, stable-linked Abeta oligomers as
well as dityrosine cross-linked peptides and proteins in AD brain (Huang et al., 2004) (Tschape
and Hartmann, 2006) (Smith et al., 2007) (Annaert and De Strooper, 2002) (Atwood et al.,
2004).
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Extensive research has revealed that curcumin may mediate its effects against AD through the
8 mechanisms:
1. Kim et al (2001) found that curcumin and its analogues demethoxycurcumin (DMC)
and bis-demethoxycurcumin (BDMC) can protect PC12 rat pheochromocytoma and
normal human umbilical vein endothelial cells from Abeta-induced oxidative stress,
and these compounds were better antioxidants than alpha-tocopherol (Kim et al.,
2001).
2. Inflammation in AD patients is characterized by increased expression of inflammatory
cytokines and activated microglia. Lim et al (Lim et al., 2001) investigated whether
curcumin could affect AD-like pathology in the APPsw mice, as suggested by
inflammation, oxidative damage, and plaque pathology. Curcumin significantly
lowered levels of oxidized proteins and IL-1β elevated in the brains of these mice.
Interestingly, with low-dose curcumin, but not with high-dose curcumin, the

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astrocytic marker glial fibrillary acidic protein was reduced, and insoluble Abeta,
soluble Abeta, and plaque burden were significantly decreased (by 43%–50%).
However, levels of APP in the membrane fraction were not reduced. Microgliosis was
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also suppressed in neuronal layers but not adjacent to plaques.

3. In studies conducted to determine whether curcumin can modulate the formation,
extension, and destabilization of fAbeta(1–40) and fAbeta(1–42) in vitro, curcumin
was found to inhibit the formation and extension of fAbeta from Abeta(1–40) and
Abeta(1–42); curcumin also destabilized preformed fAbeta (Ono et al., 2004).
4. In animal models of AD, curcumin reduced levels of amyloid and oxidized proteins
and prevented cognitive deficits. Metals can induce Abeta aggregation and toxicity
and are concentrated in AD brain. Thus chelation of metals can reduce amyloid
aggregation and oxidative neurotoxicity. Each Cu2+ or Fe2+ ion can bind at least 2
curcumin molecules. The interaction of curcumin with Cu and Fe suggested another
potential mechanism by which it could mediate its effects against AD animal models
(Baum and Ng, 2004). Because curcumin binds the redox-active metals Fe and Cu, it
may also not only protect against Abeta toxicity but may also suppress inflammatory
damage by preventing metal induction of NF-κB.
5. That curcumin can suppress oxidative damage, inflammation, cognitive deficits, and
amyloid accumulation has been established. Yang et al (Yang et al., 2005) showed
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that curcumin could inhibit aggregated as well as disaggregated fAbeta40. For this
application, curcumin was found to be a better Abeta40 aggregation inhibitor than
ibuprofen or naproxen. Curcumin decreased Abeta formation. This effect did not
depend on Abeta sequence but rather on fibril-related conformation. AD and Tg2576
mice brain sections incubated with curcumin revealed preferential labeling of amyloid
plaques. In vivo studies showed that curcumin injected peripherally into aged Tg2576
mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576
mice with advanced amyloid accumulation, curcumin labeled plaques and reduced
amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid
species to block aggregation and fibril formation in vitro and in vivo. These data
suggest that low-dose curcumin effectively disaggregates Abeta and prevents fibril
and oligomer formation.
6. Atamna and Boyle (Atamna and Boyle, 2006) showed that beta-amyloid peptide binds
with heme to form a peroxidase. This action plays a major role in the cytopathologies
of AD, and curcumin inhibits this peroxidase.
7. Patients with AD have defects in phagocytosis of Abeta by the macrophages and in
clearance of Abeta plaques. Curcumin was found to enhance Abeta uptake by
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macrophages of patients with AD (Zhang et al., 2006). How curcumin enhances the
phagocytosis of Abeta was examined by Fiala et al (Fiala et al., 2007) who found that
macrophages of a majority of patients with AD do not transport Abeta into endosomes
and lysosomes and that AD monocytes do not efficiently clear Abeta from the sections
of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal
subjects transport Abeta to endosomes and lysosomes, and monocytes of these
subjects clear Abeta in AD brain sections. Upon Abeta stimulation, mononuclear cells
of normal subjects upregulate the transcription of beta-1,4-mannosyl-glycoprotein 4-
beta-N-acetylglucosaminyltransferase (MGAT3) and other genes, including Toll-like
receptors (TLRs), whereas mononuclear cells of patients with AD generally
downregulate these genes. Defective phagocytosis of Abeta may be related to
downregulation of MGAT3, as suggested by inhibition of phagocytosis by using
MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5,
bditTLR7, TLR8, TLR9, and TLR10 upon Abeta stimulation is severely depressed

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in mononuclear cells of AD patients in comparison to those of control subjects. In

mononuclear cells of some AD patients, the BDMC may enhance defective
phagocytosis of Abeta, the transcription of MGAT3 and TLRs, and the translation of
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TLR2-4. Thus, BDMC may correct immune defects in patients with AD and provide
a previously uncharacterized approach to AD immunotherapy.
8. Garcia-Alloza et al (Garcia-Alloza et al., 2007) also showed that curcumin labels
amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted
neurites in an AD mouse model. They found that curcumin crosses the blood-brain
barrier and labels senile plaques and cerebrovascular amyloid angiopathy in APPswe/
PS1dE9 mice. Moreover, systemic treatment of mice with curcumin for 7 days cleared
and reduced the existing plaques, suggesting a potent disaggregation effect. Curcumin
also led to a limited, but significant reversal of structural changes in dystrophic
dendrites, including abnormal curvature and dystrophy size.
These studies led to a 6-month randomized, placebo-controlled, double-blind, clinical pilot
study of curcumin in patients with AD (Baum et al., 2008). Thirty four subjects started the six-
month trial and 27 completed (8 subjects on 0 g, 9 on 1g, 11 on 4g curcumin per day). The
serum levels of curcumin reached maximum (250 nM) at 1.5h when given with food and 270
nM at 4h when given with water. No difference was observed between 1 and 4g groups. The
inability to detect any relative protective effect of curcumin, was assigned to the lack of
cognitive decline in the placebo group in this 6-month trial. Curcumin group when compared
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with placebo control, however, showed increased plasma levels of Vitamin E and increased
serum Aβ40. The latter reflects an ability of curcumin to disaggregate Aβ-deposits in the brain,
thus releasing Aβ for circulation and disposal. The authors recommended, longer and larger
trials to determine the efficacy of curcumin in AD patients.

2.2. Cardiovascular Diseases

Numerous reports have indicated that inflammation plays a major role in most CVDs (Hansson
et al., 2006). First, it is widely appreciated that inflammation and oxidant stress contribute to
atherogenesis. Atherosclerosis is characterized by oxidative damage, which affects
lipoproteins, the walls of blood vessels, and subcellular membranes. The oxidation of low-
density lipoproteins (LDLs) plays an important role in the development of atherosclerosis
(Ansell, 2007) (Mach, 2005). Second, following cardiopulmonary bypass (CPB) and cardiac
global ischemia and reperfusion (I/R), pro-inflammatory cytokines regulated by NF-κB are
activated and cause cardiomyocytic injury (Yeh et al., 2005). Third, chronic transmural
inflammation and proteolytic destruction of medial elastin are key mechanisms in the
development of abdominal aortic aneurysms (AAAs) (McCormick et al., 2007). Fourth, CRP,
which is also regulated by NF-κB, is an inflammatory marker and a well-known predictor of
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CVD (Kawanami et al., 2006). Numerous lines of evidence suggest that curcumin mediates its
effects against CVDs through diverse mechanisms, several of which are discussed in this report.

Several studies have suggested that curcumin protects the heart from I/R injury (Srivastava et
al., 1985) (Manikandan et al., 2004) (Yeh et al., 2005). Perhaps one of the earliest reports about
the effects of curcumin against CVD was by Srivastava et al (Srivastava et al., 1985). They
examined the effect of curcumin on myocardial ischemia induced by the ligation of the left
descending coronary artery. Curcumin was administered 30 min before ligation, and the hearts
were removed 4 h prior to coronary artery ligation and examined for glutathione (GSH),
malonaldialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), catalase
(CAT), and lactate dehydrogenase (LDH). Curcumin protected the animals against decreases
in the heart rate and blood pressure following ischemia. Curcumin also prevented the ischemia-
induced elevation in MDA contents and LDH release. Manikandan et al (Manikandan et al.,
2004) investigated the protective effect of curcumin against isoprenaline-induced myocardial

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ischemia in rat myocardium. The effect of a single oral dose of curcumin, administered 30 min
before and/or after the onset of ischemia, was investigated. Curcumin given before and after
treatment decreased the levels of xanthine oxidase, superoxide anion, lipid peroxides (LPs),
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and myeloperoxidase and the levels of SOD, CAT, GSH peroxidase, and GSH-S-transferase
activities were significantly increased after curcumin treatment. Thus curcumin was found to
protect rat myocardium against ischemic insult.

Following CPB and cardiac global I/R, proinflammatory genes are upregulated, and NF-κB is
involved in this regulation. Whether inactivation of NF-κB could decrease myocardial I/R
injury with cardioplegia during CPB, attenuate matrix metalloproteinase (MMP) activation
and prevent cardiac mechanical dysfunction in rabbits was examined by Yeh et al (Yeh et al.,
2005). Postoperative expression of myocardial mRNA levels of IL-6, MCP-1, and TNF-α;
post-reperfusion plasma level of troponin I; and cardiac mechanical dysfunction were
significantly decreased in the curcumin groups. The myocardial levels of activated MMP-2
and -9 were also significantly reduced compared with the levels in the control group. Thus
inhibition of NF-κB activation by curcumin led to suppression of the upregulation of cardiac
proinflammatory genes and activation of MMPs during CPB, thereby lessening the severity of
the cardiac mechanical dysfunction after global cardiac I/R injury. In another study, the same
group examined whether curcumin could decrease myocardial I/R injury with cardioplegia
during CPB and attenuate the apoptosis of cardiomyocytes in rabbits (Yeh et al., 2005). They
showed that curcumin significantly decreased plasma levels of IL-8, IL-10, TNF-α, and cardiac
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troponin I. The appearance of apoptotic cardiomyocytes significantly decreased in the

curcumin groups. Thus curcumin ameliorated the surge of pro-inflammatory cytokines during
CPB and decreased the occurrence of cardiomyocytic apoptosis after global cardiac I/R injury.

Nirmala and Puvanakrishnan (1996) showed that isoproterenol-induced myocardial infaraction

in rats is prevented by curcumin (Nirmala and Puvanakrishnan, 1996) (Nirmala and
Puvanakrishnan, 1996). Histopathologic studies of the infarcted rat heart also showed a
decrease in necrosis after curcumin treatment. Cardiotoxicity induced by chemotherapeutic
agents in cancer patients is a common problem. Venkatesan (Venkatesan, 1998) showed that
curcumin decreased acute Adriamycin (ADR)-induced myocardial toxicity in rats. Treatment
with curcumin treatment 7 days before and 2 days following administration of ADR
ameliorated the cardiotoxicity, prevented the rise in serum and LDH, and induced a significant
inhibition of lipid peroxidation and augmentation of endogenous antioxidants.

Another line of evidence suggested by Quiles et al showed that curcumin exhibits a potential
effect against CVD where they examined the effect of curcumin in atherosclerotic rabbits
(Quiles et al., 1998). The researchers showed that curcumin exhibited protective effects as
indicated by inhibition of lipoperoxidation of subcellular membranes. In another study, they
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showed that oral curcumin inhibits LDL oxidation and has hypocholesterolemic effects in
rabbits with experimental atherosclerosis (Ramirez-Tortosa et al., 1999). Interestingly, they
found that rabbits treated with 1.6 mg/kg of curcumin had lower levels of cholesterol,
phospholipids, and triglycerides in LDL than those treated at a higher dose (3.2 mg/kg). In a
more recent study, these researchers showed that curcumin reduces oxidative stress and
attenuates aortic fatty streak development in rabbits (Quiles et al., 2002), as indicated by lower
plasma lipid peroxide and significantly higher α-tocopherol and coenzyme Q levels. Histologic
results for the fatty streak lesions revealed damage in the thoracic and abdominal aorta that
was significantly lower in the curcumin-treated group than in the control group.

Olszanecki et al (2005) examined the effect of low-dose curcumin on atherosclerosis in apoE/

LDL receptor (LDLR)-double knockout mice. The mice were fed a Western diet (21% fat,
0.15% cholesterol w/w, without cholic acid). Curcumin (purity ± 98%) premixed with diet was
given to each mouse for 4 months at a dose of 0.3 mg/per day. In this model, curcumin inhibited

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atherogenesis but did not influence the concentrations of cholesterol or triglycerides in blood
or animal body weight (Olszanecki et al., 2005).
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Vascular smooth muscle cell (VSMC) migration, proliferation, and collagen synthesis are key
events in the pathogenesis of CVD. Growth factors, such as platelet-derived growth factor
(PDGF) and fibroblast growth factor, which are released during vascular injury, play a pivotal
role in regulating these events. Yang et al (2006) assessed whether curcumin could inhibit
PDGF-stimulated migration, proliferation, and collagen synthesis in cultured VSMCs and
neointima formation after carotid artery injury in rats (Yang et al., 2006). Curcumin inhibited
PDGF-elicited VSMC migration, proliferation, and collagen synthesis assessed by chemotaxis,
[3H]thymidine incorporation, and [3H]-L-proline incorporation, respectively. Curcumin also
blocked PDGF-induced VSMC actin-cytoskeleton reorganization, attenuated PDGF signal
transduction, and inhibited the binding of PDGF to its receptors. Carotid artery neointima
formation was significantly attenuated by perivascular curcumin compared with vehicle
controls 14 days after injury, characterized by reduced DNA synthesis, collagen synthesis, and
PDGF receptor phosphorylation. Thus curcumin is a potent inhibitor of PDGF-stimulated
VSMC functions and may play a critical role in regulating these events after vascular injury.

Ramaswami et al (2004) showed that curcumin blocks homocysteine (HE)-induced endothelial

dysfunction in porcine coronary arteries (Ramaswami et al., 2004). They found that curcumin
could effectively block HC-induced impairment of endothelium-dependent vasorelaxation,
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inhibit the HC-induced epithelial nitric oxide synthase (NOS) expression, and block the effect
of homocysteine on superoxide anion production.

Parodi et al (2006) examined the effect of oral administration of curcumin on proinflammatory

cytokines and destructive connective tissue remodeling in experimental AAAs. Curcumin-
treated mice exhibited relative decreases in aortic tissue activator protein (AP)-1 and NF-κB
DNA binding activities and significantly lower aortic tissue concentrations of IL-1β, IL-6,
MCP-1, and MMP-9. Curcumin suppressed the development of experimental AAAs along with
the structural preservation of medial elastin fibers and reduced aortic wall expression of several
cytokines, chemokines, and proteinases known to mediate aneurismal degeneration. (Parodi et
al., 2006)

That curcumin plays an important role in the hypertrophy of the heart is evidenced by the results
of 2 recent reports (Li et al., 2008) (Morimoto et al., 2008). This activity is based on the ability
of curcumin to inhibit histone acetyltransferase (HAT), also called p300, which plays a critical
role in the progression of pathologic cardiac hypertrophy and heart failure. Li et al (2008)
showed that curcumin-blocked phenylephrin (PE) induces cardiac hypertrophy in vitro.
Curcumin also prevented and reversed mouse cardiac hypertrophy induced by aortic banding
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(AB) and PE infusion and abrogated histone acetylation, GATA4 acetylation, and DNA-
binding activity through blocking p300-HAT activity. Curcumin also blocked AB-induced
inflammation and fibrosis through disrupting p300-HAT–dependent-signaling pathways (Li
et al., 2008). Similarly, Morimoto et al (2008) showed that curcumin inhibited the hypertrophy-
induced acetylation and DNA-binding abilities of GATA4, a hypertrophy-responsive
transcription factor, in rat cardiomyocytes. Curcumin also disrupted the p300/GATA4 complex
and repressed agonist- and p300-induced hypertrophic responses in these cells. Both the
acetylated form of GATA4 and the relative levels of the p300/GATA4 complex markedly
increased in rat hypertensive hearts in vivo. In 2 different heart-failure models, hypertensive
heart disease in salt-sensitive Dahl rats and surgically induced myocardial infarction in rats,
curcumin prevented deterioration of systolic function and heart failure-induced increases in
both myocardial wall thickness and diameter (Morimoto et al., 2008). Thus curcumin can
protect against cardiac hypertrophy, inflammation, and fibrosis through suppression of p300-
HAT activity and downstream GATA4, NF-κB, and other signaling pathways. Inhibition of

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p300-HAT activity by the nontoxic dietary compound curcumin may provide a novel
therapeutic strategy for heart failure in humans.
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Curcumin has also been shown to improve the blood compatibility of the rapamycin-eluting
stent (Pan et al., 2007b) (Pan et al., 2007a). The rapamycin- and rapamycin/curcumin-loaded
poly (dl-lactic acid-co-glycolic acid (PLGA) coatings were fabricated. The data showed that
incorporating curcumin in rapamycin-loaded PLGA coating can significantly decrease platelet
adhesion and activation, prolong clotting time, and decrease fibrinogen adsorption, thus
improving the blood compatibility of rapamycin-eluting stents. This ability of curcumin can
be used to fabricate a drug-eluting stent for use in preventing thrombosis formation (Pan et al.,
2007b).

2.3. Diabetes
Diabetes is a hyperglycemic disorder that affects the brain, kidney, heart, liver, and other
organs. Inflammation has been shown to play a major role in development of type II diabetes
(Pillarisetti and Saxena, 2004). The role of various inflammatory cytokines and transcription
factors (such as NF-κB, NRF2, PPAR-γ) and various enzymes have been implicated in this
process. Both TNF and NF-κB activation have been linked with insulin resistance (Moller and
Berger, 2003). In diabetes, curcumin can suppress blood glucose levels, increase the
antioxidant status of pancreatic β-cells, and enhance the activation of PPAR-γ (Nishiyama et
al., 2005). That curcumin can modulate blood sugar levels in human subjects with diabetes
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was shown almost 35 years ago (Srinivasan, 1972). Years later. Babu and Srinivasan (1995)
showed in curcumin feeding in rats improves the metabolic status in diabetic conditions (Babu
and Srinivasan, 1995). That curcumin treatment can induce hypoglycemia in rats with
streptozotocin (STZ)-induced diabetes has been confirmed by others (Mahesh et al., 2004).
The mechanism by which curcumin improves this situation is probably its hypocholesterolemic
influence, antioxidant nature, and free-radical scavenging property. In another study, Babu and
Srinivasan (1997) showed that curcumin exhibits hypolipidemic activity in rats with STZ-
induced diabetes (Babu and Srinivasan, 1997). The decrease in cholesterol level was due
exclusively to the LDL-very LDL (VLDL) fraction. A significant decrease in blood triglyceride
and phospholipids was also brought about by dietary curcumin in diabetic rats. When the
mechanism of hypocholesterolemic activity in dietary curcumin was examined, it was found
that hepatic cholesterol-7α-hydroxylase activity was markedly higher in curcumin-fed diabetic
animals, suggesting a higher rate of cholesterol catabolism in these animals (Babu and
Srinivasan, 1997). Curcumin was found to be more effective in rats than turmeric in attenuating
diabetes mellitus–related changes (Arun and Nalini, 2002). Hyperlipidemia is a complication
of diabetes mellitus. The ability of curcumin to modulate the lipid profile in rats with STZ-
nicotinamide-induced diabetes was investigated by Pari and Murugan (Pari and Murugan,
2007a). Curcumin caused a significant reduction in the blood glucose levels and a significant
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increase in the plasma insulin levels in these rats and a significant reduction in serum and liver
cholesterol, triglycerides, free fatty acids, phospholipids, HMG coenzyme A reductase activity,
VLDL, and LDL cholesterol levels. The decreased serum high-density lipoprotein (HDL)
cholesterol in diabetic rats was also reversed toward normalization after the treatment
(Murugan and Pari, 2006).

Obesity is a major risk factor for type 2 diabetes, and it is now recognized that significant
inflammatory components underly the pathophysiologies of both of these conditions (Vazquez
et al., 2007). The ability of curcumin to ameliorate diabetes and inflammation in murine models
of insulin-resistant obesity was examined by Weisberg et al (2008). Curcumin ameliorated
diabetes in high-fat diet-induced obese and leptin-deficient ob/ob male C57BL/6J mice as
determined by glucose and insulin tolerance testing and hemoglobin A1c percentages.
Curcumin treatment also significantly reduced macrophage infiltration of white adipose tissue,

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increased adipose tissue adiponectin production, and decreased hepatic nuclear NF-κB activity,
hepatomegaly, and markers of hepatic inflammation. Thus orally ingested curcumin reverses
many of the inflammatory and metabolic dearrangements associated with obesity and improves
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glycemic control in mouse models of type 2 diabetes (Weisberg et al., 2008).

Both curcumin and its metabolite tetrahydrocurcumin (THC) have been shown to decrease
blood glucose levels, increase plasma insulin levels, and modulate hepatic key enzyme levels
in STZ-induced diabetic rats(Murugan and Pari, 2005) through modulation of oxidative stress
(Murugan and Pari, 2006) and reduction in lipids and lipid peroxidation (Murugan and Pari,
2006). In another study, these authors showed that oral curcumin decreased the blood glucose
and plasma glycoprotein levels in diabetic rats (Murugan and Pari, 2007a). The levels of plasma
insulin and tissue sialic acid were increased, whereas the levels of tissue hexose, hexosamine,
and fucose were near normal in diabetic rats treated with curcumin. These findings show that
the effect of THC is more prominent than that of curcumin (Murugan and Pari, 2007b).

Studies have been conducted to determine whether curcumin’s direct stimulatory effect on the
pancreatic beta-cell can contribute to the hypoglycemic activity of this compound. In a study
by Best et al (2007), curcumin induced electrical activity in rat pancreatic beta-cells by
activating the volume-regulated anion channel f. Single-channel studies have indicated that
activation is the result of increased channel open probability. This effect was accompanied by
depolarization of the cell membrane potential, the generation of electrical activity, and
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enhanced insulin release (Best et al., 2007). Curcumin also decreased beta-cell volume,
presumably reflecting loss of Cl(−), and hence water, as a result of anion channel activation.
These findings are consistent with the suggestion that Cl(−) fluxes play an important role in
regulating beta-cell function the stimulation of beta-cell function by curcumin might contribute
to the hypoglycemic actions of this compound.. Additionally, curcumin was found to induce
heme oxygenase-1 expression, which has been reported to have cytoprotective effects in mouse
pancreatic beta-cells (Pugazhenthi et al., 2007). These effects were mediated through the
activation of NF-E2-related factor 2 (Nrf2). Another report indicated that in addition to heme
ozygenase-1, curcumin treatment enhances islet recovery by inducing heat-shock protein 70,
a response protein, during cryopreservation (Kanitkar and Bhonde, 2008).

Pancreatic islet cell death is the cause of deficient insulin production in diabetes mellitus.
Approaches to preventing cell death have prophylactic significance in the management of
hyperglycemia. Generation of oxidative stress is implicated in STZ, a beta-cell–specific, toxin-
induced islet cell death. The role of curcumin in STZ-induced islet damage was examined in
vitro by Meghana et al (2007). Curcumin retarded islet ROS generation and inhibited apoptosis,
indicating that curcumin protects islets against STZ-induced oxidative stress by scavenging
free radicals (Meghana et al., 2007).
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How curcumin mediates its hypoglycemic effects has also been examined. Curcumin was
found to suppress an increase in blood glucose levels in KK-AY mice with type 2 diabetes
through PPAR-γ ligand-binding activity (Kuroda et al., 2005) (Nishiyama et al., 2005).
Increased oxidative stress and hyperglycemia has been postulated to contribute to the
accelerated accumulation of advanced glycation end-products (AGEs) and the cross-linking
of collagen in diabetes mellitus. Curcumin administration for the prevention of AGE-induced
complications of diabetes mellitus (Sajithlal et al., 1998). Sidhu et al showed that curcumin
enhances wound healing in genetically engineered rats with STZ-induced diabetes. Curcumin
was effective via both oral and topical administration and enhanced wound repair in diabetic-
impaired healing (Sidhu et al., 1999, Sidhu et al., 1998). Another study showed that curcumin
inhibits protein glycosylation, lipid peroxidation, and oxygen radical generation in human red
blood cells exposed to high glucose levels (Jain, 2006). This finding provides evidence for a
novel mechanism by which curcumin supplementation may prevent the cellular dysfunction

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associated with diabetes. Administration of curcumin to diabetic rats showed a significant

beneficial effect on erythrocyte membrane-bound enzymes and antioxidant defense in addition
to its antidiabetic effect (Murugan and Pari, 2007a).
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Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is

recognized as one of the most difficult types of pain to treat. In a study by Sharma et al
(2006), curcumin attenuated thermal hyperalgesia in a diabetic mouse model of neuropathic
pain. (Sharma et al., 2006a) Curcumin also inhibited TNF-α and NO release in a dose-
dependent manner. These results indicate an anti-nociceptive activity of curcumin, possibly
through its inhibitory action on NO and TNF-α release and point to its potential to attenuate
diabetic neuropathic pain. In a later study, the same authors showed the antinociceptive activity
of curcumin in combination with insulin in attenuating diabetic neuropathic pain through the
participation of NO and TNF-α (Sharma et al., 2007b).

Diabetic retinopathy is one of the most devastating microvascular complications of

longstanding type 1 and type 2 diabetes. Oxidative stress and inflammation are implicated in
the pathogenesis of retinopathy in diabetes (Haidara et al., 2006) (Kowluru and Chan, 2007).
Curcumin administration was found to prevent a diabetes-induced decrease in the antioxidant
capacity and an increase in 8-OHdG and nitrotyrosine (Kowluru and Kanwar, 2007). Curcumin
also inhibited diabetes-induced elevation in the levels of IL-1β, VEGF, and NF-κB. The effects
of curcumin were achieved without amelioration of the severity of hyperglycemia. In another
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study, curcumin was found to prevent the development of STZ-induced diabetic cataracts in
rats by inhibition of hyperglycemia-induced aggregation and insolubilization of lens proteins
(Suryanarayana et al., 2005, Suryanarayana et al., 2007). Interestingly, these authors showed
that turmeric was the ocular lens, is composed of 2 subunits: αA and αB. Of these, αB-crystallin
has been shown to present widely in nonlenticular tissues, whereas αA-crystallin is largely lens
specific. Kumar et al (2005) showed an elevated expression of αA- and αB-crystallins in rats
with STZ-induced diabetes, and feeding curcumin to these rats attenuated the enhanced
expression of αB-crystallin (Kumar et al., 2005). Curcumin was also found to protect
endothelial dysfunction in the iris tissues of STZ-induced diabetic rats (Patumraj et al.,
2006). Curcumin decreased the blood glucose, glycosylated hemoglobin, dyslipidemia, and
MDA levels significantly. Neovascularization stimulated by hyperglycemia-mediated
induction of VEGF has been implicated in the pathogenesis of diabetic retinopathy. The ability
of curcumin to inhibit VEGF expression in rats with STZ-induced diabetic retina was examined
by (Mrudula, 2007). Curcumin induced a decrease in VEGF expression in diabetic retina
compared to control retina at both the transcription and protein levels.

Chronic hyperglycaemia in diabetes leads to the development of diabetic nephropathy. Sharma

et al (2006) showed that treatment with curcumin for 2 weeks significantly attenuated both
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renal dysfunction and oxidative stress in diabetic animals (Sharma et al., 2006b). Curcumin
was also found to improve hepatic and renal function markers and protein levels in experimental
type 2 diabetic rats (Murugan and Pari, 2007b). Curcumin reversed the diabetes-induced total
protein, albumin, globulin, and albumin/globulin ratio; the activities of hepatic and renal
markers; and the levels of urea, uric acid, and creatinine. Tikoo et al (2008) examined the
changes in histone modification by curcumin treatment, which prevents development of type
I diabetic. At the nuclear level, curcumin prevented the decrease in dephosphorylation and the
increase in acetylation of histone H3 suggesting that protection against the development of
diabetic nephropathy by curcumin treatment involves changes in post-translational
modifications of histone H3 (Tikoo et al., 2008).

Cardiomyopathy has been associated with the pathogenesis of chronic diabetic complications.
Treatment of STZ-induced diabetic rats with curcumin reduced eNOS and inducible NOS
levels in association with reduced oxidative DNA and protein damage in the heart

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(Farhangkhoee et al., 2006). Curcumin prevented NOS alteration and oxidative stress, which
was mediated by NF-κB and AP-1. Exposure to curcumin also increased ET-1 levels in the
microvascular endothelial cells. These studies indicate the differential effects of curcumin in
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vasoactive factor expression in the heart and indicate the importance of the tissue
microenvironment in the treatment of diabetic complications.

Diabetic cardiomyopathy, structurally characterized by cardiomyocyte hypertrophy,

eventually leads to heart failure. Transcriptional co-activator p300 and its interaction with
myocyte enhancer factor 2 (MEF2) play a major role in diabetes-induced cardiomyocyte
hypertrophy. Whether curcumin, a p300 blocker, can prevent these abnormalities, was
examined by Feng et al (2008). Treatment with curcumin prevented diabetes-induced
upregulation of these transcripts, suggesting the existence in curcumin of a novel glucose-
induced epigenetic mechanism regulating gene expression and cardiomyocyte hypertrophy in
diabetes (Feng et al., 2008).

Emerging epidemiologic data indicate that diabetes is a potential predisposing factor for
neuropsychiatric deficits such as stroke, cerebrovascular diseases, diabetic encephalopathy,
depression, and anxiety. Diabetic encephalopathy, characterized by impaired cognitive
functions and neurochemical and structural abnormalities, involves direct neuronal damage
caused by intracellular glucose. In a study by Kuhad and Chopra (2007), chronic treatment
with curcumin significantly attenuated cognitive deficit, cholinergic dysfunction, oxidative
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stress and serum levels of TNF in diabetic rats (Kuhad and Chopra, 2007). Thus, curcumin
could be used as an adjuvant therapy to conventional anti-hyperglycemic regimens for the
prevention and treatment of diabetic encephalopathy. The ability of curcumin to affect the
occurrence of oxidative stress in the brains of rats with diabetes was also examined. Curcumin
was found to prevent brain lipid peroxidation in rats with STZ-induced diabetes (Pari and
Murugan, 2007b).

Altogether, these studies reveal that curcumin plays an important role in attenuating diabetes
and diabetes-associated symptoms.

2.4. Allergy, asthma, and bronchitis

That allergy is a proinflammatory disease is indicated by the fact that this disease is normally
mediated through inflammatory cytokines and is treated with steroids. Asthma is also an
inflammatory disease in which eotaxin, MCP-1, and MCP-3 play a crucial role. These
chemokines have been shown to be expressed and produced by IL-1β-stimulated human airway
smooth muscle cells in culture. For instance, house dust mite is a common allergen of allergic
asthma. Eosinophils are principal effector cells of allergic inflammation and their adhesion
onto human bronchial epithelial cells is mediated by a CD18-intracellular adhesion molecule
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(ICAM)-1-dependent interaction. As shown in experiments in vivo (in guinea pigs) and in vitro
(basophils), curcumin can help clear constricted airways and increase antioxidant levels. Ju et
al (1996) examined the effect of dietary fats and curcumin on immunoglobulin E (IgE)-
mediated degranulation of intestinal mast cells in brown Norway rats (Ju et al., 1996). Rats
were primed intraperitoneally with β-lactoglobulin for 3 weeks to induce reaginic antibody,
during which time they were fed diets containing 10% each of coconut oil (CO), high oleic
safflower oil, safflower oil (SO), or fish oil and were then challenged for 3 hours orally with
the antigen. The dietary SO, compared to other dietary fats, resulted in lower circulatory release
of rat chymaseII (RChyII), an indicator of degranulation of mucosal mast cells in the intestine,
in response to the antigen. The addition of 0.5% curcumin to the CO or SO diets lowered the
release. The SO diet, compared to the CO diet, tended to increase the concentration of reaginic
antibody, but the influence of curcumin was not prominent, suggesting that dietary ingredients
differently influence the synthesis of IgE and degranulation of mast cells.

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South et al (1997) examined the effects of dietary curcumin (1, 20 or 40 mg/kg) for 5 weeks
on antibody (IgG) production, delayed-type hypersensitivity, and natural killer cell activity in
rats. The highest doses of curcumin, but not the lower doses, significantly enhanced IgG levels.
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Neither delayed-type hypersensitivity nor natural killer cell activity was different from control
values at any dietary concentration of curcumin (South et al., 1997).

To clarify the potential effect of curcumin against allergic diseases, Kobayashi et al (1997)
examined the effect of curcumin on the production of IL-2, IL-5, granulocyte macophage-
colony stimulating factor (GM-CSF), and IL-4 by lymphocytes from atopic asthmatics in
response to house dust mites (Dermatophagoides farinea: Df). Curcumin inhibited Df-induced
lymphocyte proliferation and production of IL-2. Furthermore, curcumin inhibited IL-5, GM-
CSF, and IL-4 production. These results indicate that curcumin may have a potential effect on
controlling allergic diseases through inhibiting the production of cytokines affecting eosinophil
function and IgE synthesis (Kobayashi et al., 1997).

Ram et al (2003) examined the anti-asthma property of curcumin in a guinea pig model of
airway hyper-responsiveness (Ram et al., 2003). Guinea pigs sensitized with ovalbumin (OVA)
develop certain features characteristic of asthma: allergen-induced airway constriction and
airway hyper-reactivity to histamine. Treatment with curcumin was done during sensitization
(preventive) or after developing impaired airway features (therapeutic). Curcumin treatment
(20 mg/kg body weight) significantly inhibited OVA-induced airway constriction and airway
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hyper-reactivity. The results demonstrate that curcumin is effective in improving the impaired
airway features in OVA-sensitized guinea pigs.

Kurup et al used a murine model of latex allergy to investigate the role of curcumin as an
immunomodulator. BALB/c mice were exposed to latex allergens and developed latex allergy
with a thyroid hormone (Th)2-type immune response. These animals were treated with
curcumin and the immunologic and inflammatory responses were evaluated. Animals exposed
to latex showed enhanced serum IgE, latex-specific IgG1, IL-4, IL-5, IL-13, and eosinophils;
and inflammation in the lungs. Intragastric treatment of latex-sensitized mice with curcumin
demonstrated a diminished Th2 response with a concurrent reduction in lung inflammation.
Eosinophilia in curcumin-treated mice was markedly reduced, co-stimulatory molecule
expression (CD80, CD86, and OX40L) on antigen-presenting cells was decreased, and
expression of MMP-9, OAT, and TSLP genes was also attenuated. These results suggest that
curcumin has potential therapeutic value for controlling allergic responses resulting from
exposure to allergens (Kurup and Barrios, 2008, Kurup et al., 2007).

In patients with severe asthma or chronic obstructive pulmonary disease (COPD), an

inflammatory condition exists that leads to activation of the NF-κB pathway. A change also
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occurs in the histone acetylation and deacetylation balance via post-translational modification
of histone deacetylases (HDACs). HDAC2 plays a major role in insensitivity to corticosteroid
treatment in asthma and COPD. It has been shown that curcumin can restore HDAC activity,
thereby restoring corticosteroid function (Marwick et al., 2007) (Biswas and Rahman, 2008).

2.5. Inflammatory bowel disease

Inflammatory bowel disease (IBD), a major risk factor for colon cancer, is characterized by
oxidative and nitrosative stress, leucocyte infiltration, and upregulation of proinflammatory
cytokines (Jess et al., 2005) (Danese, 2008). Numerous therapies used for IBD target NF-kB,
which is involved in the production of cytokines and chemokines integral for inflammation.
Curcumin has been shown to attenuate colitis in the dinitrobenzene sulfonic acid (DNB)-
induced murine model of colitis (Salh et al., 2003). This was accompanied by a reduction in
MPO activity, IL-1β expression, and reduction of p38 MAPK. Additionally, an
immunohistochemical signal was dramatically attenuated at the level of the mucosa by

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curcumin. Together, these results suggest that curcumin may have therapeutic implications for
human IBD. Ukil et al (2003) investigated the protective effects of curcumin on 2,4,6-
trinitrobenzene sulphonic acid (TNBS)-induced colitis in mice, a model for IBD (Ukil et al.,
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2003). Intestinal lesions were associated with neutrophil infiltration, increased serine protease
activity, and high levels of malondialdehyde. Pretreatment of mice with curcumin (50 mg/kg
daily intragastrically, for 10 days) significantly ameliorated the appearance of diarrhea and the
disruption of colonic architecture. Higher doses (100 and 300 mg/kg) had comparable effects.
In curcumin-pretreated mice, there was a significant reduction in the degree of both neutrophil
infiltration and lipid peroxidation in the inflamed colon as well as decreased serine protease
activity. Curcumin also reduced the levels of NO and O2(−) associated with the favorable
expression of Th1 and Th2 cytokines and inducible NOS. Consistent with these observations,
NF-κB activation in colonic mucosa was suppressed in the curcumin-treated mice, suggesting
that curcumin can exert beneficial effects in experimental colitis and may, therefore, be useful
in the treatment of IBD.

Jian et al (2005) also assessed the use of curcumin in the prevention and treatment of TNBS-
induced colitis in rats (Jian et al., 2005). Sixty rats with TNBS-induced colitis were treated
with 2.0% curcumin in the diet. Thirty positive control rats were treated with 0.5% sulfasalazine
(SASP). Thirty negative control rats and 30 model rats were treated with a general diet.
Treatment with curcumin prevented and treated both wasting and histopathologic signs of rats
with TNBS-induced intestinal inflammation. In accordance with these findings, NF-kB
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activation in colonic mucosa was suppressed in the curcumin-treated groups. Degradations of

cytoplasmic IκBα protein in colonic mucosa were blocked by curcumin treatment.
Proinflammatory cytokine messenger RNA expression in colonic mucosa was also suppressed
(Jian et al., 2005).

Reduced bone mass is a common complication of IBD, although the mechanisms that
contribute to osteopenia are not completely understood (Rodriguez-Bores et al., 2007). TNF-
α is upregulated in patients with IBD and has detrimental effects on osteoblasts. Phex gene is
expressed predominantly in osteoblasts, and its disruption results in defective bone
mineralization. Uno (2006) examined whether TNF-α regulates Phex gene expression thus
contributing to the abnormal bone metabolism observed in IBD (Uno et al., 2006). Phex gene
expression was evaluated in calvaria of 6- to 7-week-old mice administered TNBS with or
without neutralizing anti-TNF-alpha antibody, dietary curcumin, or systemically with
recombinant TNF-α. TNF-α-treated UMR-106 osteoblasts were also examined. Compared
with control animals, Phex mRNA expression decreased by 40%-50% in both TNBS colitis
and TNF-alpha-injected mice. Dietary curcumin and anti-TNF-α antibody counteracted the
detrimental effect of TNBS on Phex gene expression. TNF-α-treated UMR-106 cells showed
a decrease in Phex mRNA and gene promoter activitis. Coinciding with decreased Phex protein
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level, TNF-α drastically reduced mineralization in UMR-106 osteoblasts. Acute colitis and
TNF-α decrease Phex mRNA and protein expression via a transcriptional mechanism. TNF-
α-mediated reduction in Phex protein is at least partially responsible for inhibition of osteoblast
mineralization, and the described mechanism may contribute to the abnormal bone metabolism
associated with IBD.

Deguchi et al (2007) evaluated the effects of curcumin on the development of dextran sulfate
sodium (DSS)-induced experimental colitis (Deguchi et al., 2007). BALB/c mice were fed a
chow containing either 3.5% (wt/wt) DSS or 3.5% DSS + 2.0% (wt/wt) curcumin. The body
weight loss was more apparent in DSS-treated mice than in DSS + curcumin-treated mice. The
disease activity index, histologic colitis score, and MPO activity were all significantly higher
in DSS-treated mice than in DSS + curcumin-treated mice. Microscopically, mucosal edema,
cellular infiltration, and epithelial disruption were more severe in DSS-treated mice than in
DSS + curcumin-treated mice. In DSS + curcumin-treated mice, NF-κB activation was blocked

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in the mucosa. Overall, the development of DSS-induced colitis was significantly attenuated
by curcumin.
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TNBS-induced colitis in NKT-deficient SJL/J mice has been described as Th1-mediated

inflammation, whereas BALB/c mice are believed to exhibit a Th1/Th2 response. Billerey-
Larmonier et al (2008) investigated the effect of dietary curcumin in colitis induced in these 2
strains (Billerey-Larmonier et al., 2008). In the BALB/c mice, curcumin significantly increased
survival, prevented weight loss, and normalized disease activity. In the SJL/J mice, curcumin
demonstrated no protective effects. Genome-wide microarray analysis of colonic gene
expression was employed to define the differential effect of curcumin in these 2 strains. This
analysis not only confirmed the disparate responses of the 2 strains to curcumin but also
indicated different responses to TNBS. Curcumin inhibited proliferation of splenocytes from
naive BALB/c mice but not SJL/J mice when nonspecifically stimulated in vitro with
concanavalin A (ConA). Proliferation of CD4(+) splenocytes was inhibited in both strains,
albeit with about a 2-fold higher IC(50) in SJL/J mice. Secretion of IL-4 and IL-5 by CD4(+)
lymphocytes of BALB/c mice but not SJL/J mice was significantly augmented by Con A and
reduced to control levels by curcumin. Why BALB/c strain of mice responds to curcumin and
SJL/J mouse strain does not, is not clear but suggests that the therapeutic value of dietary
curcumin may differ depending on the nature of immune dysregulation in IBD.

On the basis of these study results in rodents, Holt et al (2005) performed a pilot clinical study
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with curcumin in patients with IBD. A pure curcumin preparation was administered in an open-
label study to 5 patients with ulcerative proctitis and 5 with Crohn’s disease. All proctitis
patients improved, with reductions in concomitant medications in 4, and 4 of the 5 patients
with Crohn’s disease patients had lowered CDAI scores and sedimentation rates (Holt et al.,
2005). The results of this encouraging pilot study suggest the need for double-blind placebo-
controlled follow-up studies.

Thus curcumin, overall, exhibits a protective role in mouse models of IBD and to reduce the
relapse rate in human ulcerative colitis (UC), thus making it a potentially viable supportive
treatment option.

2.6. Rheumatoid arthritis (RA) and other arthritide diseases

There are more than 100 different arthritides; however, the 3 most commonly occurring
subtypes in the Western world are gout, osteoarthritis (OS), and RA. Gout occurs in response
to the presence of crystals of monosodium urate in joints, bones, and soft tissues, and is treated
with non-steroidal anti-inflammatory agents (NSAIDs); oral or intravenous colchicines; and
oral, intravenous, or intra-articular glucocorticoids (Li, 2004) (Liote and Ea, 2007) (Schlesinger
et al., 2006). All are effective in aborting acute attacks of gout; however, they have severe side
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effects. Osteo arthritis (OA), the second most common arthritis worldwide, results from
articular cartilage failure induced by a combination of genetic, metabolic, biochemical, and
biomechanical factors. OA is normally treated with analgesics such as acetaminophen and
opioids, NSAIDs, and intra-articular therapies such as glucocorticoids and hyaluronans.

The third most common arthritide, RA, is a chronic proinflammatory disease that is
characterized by hyperplasia of the synovial fibroblasts, which is partly the result of decreased
apoptosis, and joint stiffness and swelling, often manifesting in a symmetrical pattern on both
sides of the body. Like most other autoimmune diseases, arthritis is more prevalent in the
Western world than in other countries. Although the precise reason for this predilection is not
well understood, lifestyle is known to play a major role. RA occurs in women more often than
men (75% vs 25%), suggesting the role of hormones in its etiology. The roles of inflammatory
cytokines, such as TNF, IL-1, IL-6, and chemokines; inflammatory enzymes such as COX-2,
5-LOX, and MMP-9; and adhesion molecules in the pathogenesis of arthritis are well

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documented. Almost all the mediators of inflammation linked with arthritis have been shown
to be regulated by the transcription factor NF-κB. Smoking and stress are thought to contribute
to RA.
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The goals of management of patients with RA are to control pain and swelling, delay disease
progression, minimize disability, and improve quality of life. For pain control and swelling,
the treatment includes analgesics such as acetaminophen and opioids, NSAIDs, and intra-
articular therapies such as glucocorticoids. In addition, diseases modifying antirheumatic drugs
are used to modify the clinical and radiological courses of RA (Smolen and Aletaha, 2008a).
Examples include methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, and newer
therapies such as anti-TNF-α therapy (etanercept, infliximab, and adalimumab), anti-CD20
therapy (rituximab), and abatacept. All of these agents are associated with numerous side
effects (Smolen and Aletaha, 2008b). Because current treatments for arthritis are inefficient,
produce substantial side effects, and tend to be expensive, natural products, which are devoid
of such disadvantages, offer a novel treatment opportunities (Hak and Choi, 2008) (Sale et al.,
2008). Numerous reports suggest that curcumin has potential in the treatment of arthritis. Joe
et al examined the effect of curcumin on acidic glycoprotein in the sera of rats with adjuvant-
induced arthritis (Joe et al., 1997). Increased levels of a glycoprotein with an apparent
molecular weight of 72 kDa (Gp A72), an acidic protein with a pI of 5.1 with antitryptic activity,
were observed in the sera of arthritic rats. The appearance of Gp A72 in these sera preceded
the onset of paw inflammation in arthritic rats and persisted in the chronic phase. Oral
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administration of curcumin lowered the levels of Gp A72 by 73% with concomitant lowering
of paw inflammation in arthritic rats.

Neutral matrix metalloproteinases (MMPs) are responsible for the pathologic features of RA
and causes the degradation of cartilage. Onodera et al (2000) examined the effect of curcumin
on the upregulation of MMP-1 and MMP-3 mRNAs on the cultured synovial fibroblasts
retrieved from patients with RA in response to MIF. They showed that mRNA upregulation
of MMPs was inhibited by curcumin (Onodera et al., 2000).

How curcumin could affect the immune response of the body during adjuvant-induced chronic
inflammation in rats has also been investigated (Banerjee et al, 2003). Inflammatory mediators
were estimated on day 21 and day 35 after adjuvant injection. The level of CRP increased to
200% on day 21 and then reduced to 50% on day 35 compared to controls. Curcumin further
reduced the increased levels at both time intervals. The haptoglobin level decreased to 42% on
day 21 but increased to 5 times that of controls on day 35. Curcumin reduced the increased
levels at day 35. No significant change was observed in prostaglandin-E (PGE) 2 and
leukotriene-B4 levels nor in lymphocyte proliferation. The level of TNF-α increased 3-fold on
day 21, but reduced to 88% on day 35. Ibuprofen treatment decreased the raised level on day
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21 and increased the reduced level on day 35. IL-1β increased 2-folds on day 21 and 10-fold
on day 35, both of which were significantly reduced by curcumin (Banerjee et al., 2003). In
another study, Liacini et al (2003) showed that curcumin suppressed TNF-α-induced MMP-13
expression in primary chondrocytes; thus curcumin may reduce cartilage breakdown by
MMP-13 in arthritis (Liacini et al., 2003).

OA is the leading cause of disability in the Western world. COX-2 inhibitors are efficient anti-
inflammatory agents commonly used in the treatment of OA (Chen et al., 2008). However,
recent studies have shown that their long-term use may be limited due to cardiovascular toxicity
(Kean and Buchanan, 2005). Whether curcumin can augment the growth-inhibitory and pro-
apoptotic effects of celecoxib in OA synovial adherent cells was examined by Lev-Ari et al
(2006). OA synovial adherent cells were prepared from human synovial tissue collected during
total knee replacement surgery. A synergistic effect was observed in inhibition of cell growth
when the cells were exposed to celecoxib combined with curcumin. The inhibitory effect of

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the combination of these drugs on cell growth resulted in an increased induction of apoptosis.
The synergistic effect was mediated through a mechanism that involves inhibition of COX-2
activity. Thus the use of celecoxib at lower and safer concentrations in combination with
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curcumin may provide a novel combination treatment in OA and other rheumatologic disorders
(Lev-Ari et al., 2006).

Funk et al (2006) examined the in vivo efficacy of curcumin in the prevention and treatment
of arthritis using streptococcal cell wall–induced arthritis, a well-described animal model of
RA (Funk et al., 2006). Arthritic index, a clinical measure of joint swelling, was used as the
primary end point for assessing the effect of extracts on joint inflammation. Curcumin was
found to prevent joint inflammation when treatment was started before, but not after, the onset
of joint inflammation. These data document the in vivo anti-arthritic efficacy of curcumin.
Jackson et al recently reported that curcumin can inhibit inflammatory processes associated
with arthritis (Jackson et al., 2006).

Park et al (2006) showed that curcumin induces apoptosis and inhibits PGE(2) production in
synovial fibroblasts of patients with RA. Curcumin caused the downregulation of anti-
apoptotic Bcl-2 and the X-linked inhibitor of the apoptosis protein as well as the upregulation
of pro-apoptotic Bax expression. Curcumin-induced apoptosis was also associated with the
proteolytic activation of caspase-3 and caspase-9 and the concomitant degradation of poly
(ADP-ribose) polymerase protein. Furthermore, curcumin decreased the expression levels of
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the COX-2 mRNA and protein without causing significant changes in the COX-1 levels, which
was correlated with the inhibition of PGE (2) synthesis (Park et al., 2007).

A clinical pilot study of curcumin 1200 mg/per day administered to a small number of patients
also revealed the anti-rheumatic activity of curcumin (Deodhar et al., 1980).

2.7. Renal ischemia

Nonimmune renal injury plays an important role in acute and chronic rejection by triggering
an I/R injury response through cytokine and chemokine release. Shoskes (1998) examined the
effect of curcumin on I/R in rats. Pretreatment with curcumin resulted in preservation of
histologic integrity, with a decrease in tubular damage and interstitial inflammation and
reversal of changes in creatinin levels. I/R induced RANTES, MCP-1, and AIF proteins at high
levels in kidneys, but pretreatment with curcumin strongly attenuated this expression (Shoskes,
1998). Chronic renal allograft nephropathy is associated with both immune and ischemic
injury, which may act synergistically to promote an inflammatory response. Whether curcumin
can ameliorate such injury, was examined by Jones and Shoskes (2000). The effects of
curcumin in models of ischemic renal injury and skin allograft rejection were examined (Jones
and Shoskes, 2000). Curcumin decreased the tubular damage, attenuated renal inflammation,
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and prolonged skin graft survival; decreased serum creatinine; inhibited apoptosis at day 2;
and attenuated the expression levels of RANTES, MCP-1, and AIF. Thus curcumin was found
to be renoprotective. The same groups also showed that curcumin can upregulate antioxidant
gene expression in rat kidney after ureteral obstruction or I/R injury (Shahed et al., 2001). Renal
ischemia followed by reperfusion leads to acute renal failure in both native kidneys and renal
allografts. Curcumin significantly improved the I/R-induced changes in urea and cystatin C
levels and reversed changes in serum GSH-Px; however, the drug had no effect on SOD enzyme
activity. Treatment with curcumin also resulted in significant reduction in serum and tissue
MDA, NO, and PC. On histologic examination, the rats treated with curcumin had nearly
normal morphology of the kidney (Bayrak et al., 2008). Thus it is clear that curcumin protects
the kidneys against I/R injury via its antioxidant effects.

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 Aggarwal and Harikumar Page 17

2.8. Psoriasis
Psoriasis is a proinflammatory skin disease in which the roles of NF-kB, STAT3, and TNF are
well documented (Aggarwal et al., 2006b) (Liu et al., 2006) (Abdou and Hanout, 2008). TNF
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blockers have been approved for the treatment of psoriasis (Vamvouris and Hadi, 2006).
Furthermore, skin-specific STAT3 transgenic animals are known to develop psoriasis (Sano
et al., 2005). Numerous lines of evidence suggest that curcumin may be an effective treatment
for psoriasis. Topical application of 1% curcumin gel to psoriatic areas reduced the density of
CD8+ T cells compared to their density in untreated areas; in fact, the density of CD8+ T cells
was elevated. These study results and those of others suggest that curcumin could be an
effective paradigm in the treatment of psoriasis as it could also reduce the activity of PhK.
Decreased PhK activity in patients with psoriasis who were treated with curcumin and
calcipotriol was associated with corresponding decreases in keratinocyte transferrin receptor
expression, severity of parakeratosis, and density of epidermal CD8+ T cells. These results
suggest that curcumin-induced suppression of PhK activity is associated with resolution of
psoriatic activity as assessed by clinical, histologic, and immunohistochemical criteria.

Curcumin, at a very low concentration, has been shown to be a photosensitizer in killing

bacteria such as Salmonella typhimurium and Escherichia coli (Tonnesen et al., 1987). The
photosensitizing effects of curcumin may approve effective in the treatment of psoriasis.

Pharmacological treatments for psoriasis are generally based on antiproliferative, anti-

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inflammatory, or differentiation-modifying activity or some combination of these actions. Like

most anti-psoriatic drugs, curcumin was found to inhibit the keratinocyte proliferation (Pol et
al., 2003), suggesting its potential in suppressing posriasis.

Kurd and colleagues (2008) assessed the safety and efficacy of oral curcumin in patients with
psoriasis. They conducted a phase II, open-label, Simon’s two-stage trial of 4.5 g/d oral
curcumin in patients with plaque psoriasis. The study end points included improvement in
Physicians Global Assessment score, Psoriasis Area and Severity Index score, and safety
throughout the study. The intent-to-treat analysis response rate was 16.7% (95% confidence
interval 2%–48%), and both responders achieved a Psoriasis Area and Severity Index score of
75. There were no study-related adverse events that necessitated participant withdrawal. The
researchers concluded that large placebo-controlled studies are necessary before
recommending oral curcumin as treatment for psoriasis (Kurd et al., 2008).

2.9. Scleroderma
Because scleroderma is a disease that involves excessive collagen deposition and
hyperproliferation of fibroblasts, curcumin may be able to provide a therapeutic benefit through
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its ability to suppress the proliferation of lung fibroblasts in a process involving the inhibition
of protein kinase C epsilon (PKCε) (Tourkina et al., 2004). In the study by Tourkina and
colleagues, curcumin was found to induce apoptosis in scleroderma lung fibroblasts (SLFs)
but not in normal lung fibroblasts (NLF), and the effect was related to the expression of
PKCepsilon. Thus PKC epsilon and phase 2 detoxification enzymes provide protection against
curcumin-induced apoptosis in NLF and are defective in SLF. Curcumin may have therapeutic
value in treating scleroderma, just as it has already been shown to protect rats from lung fibrosis
induced by a variety of agents (Thresiamma et al., 1996) (Punithavathi et al., 2000) (Xu et al.,
2007).

2.10. Acquired immunodeficiency disease (AIDS)

There are several reports indicating that curcumin may be an effective treatment for AIDS
(Vlietinck et al., 1998). These effects of curcumin are mediated through suppression of
replication of the human immunodeficiency virus (HIV) virus by inhibition of HIV long-

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 Aggarwal and Harikumar Page 18

terminal repeats (Barthelemy et al., 1998), HIV protease (Vajragupta et al., 2005), inhibition
of HIV-1 integrase (Mazumder et al., 1995), inhibition of p300/CREB-binding protein-specific
acetyltransferase, repression of the acetylation of histone/nonhistone proteins, and histone
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acetyltransferase-dependent chromatin transcription (Balasubramanyam et al., 2004). Thus

curcumin has a great potential as a treatment for AIDS.

2.11. Cancer
Till now more than 800 reports have been published demonstrating the anticancer potential of
curcumin. Various in vitro as well as in vivo studies demonstrated that curcumin can inhibit
the growth of various cancer cells from different organs including blood, brain, breast,
gastrointestinal system, head and neck, liver, pancreas, colon, prostate, ovary and skin cancers
(Anand et al., 2008) (Kunnumakkara et al., 2008). Various clinical trials with curcumin, those
that have been completed and those that are ongoing have been recently reviewed (Goel et al.,
2008). These trials have shown promise in patients with familial adenomatous polyposis (Cruz-
Correa et al., 2006), advanced pancreatic cancer (Dillon et al, 2007), and multiple myeloma
(Vadhan et al, 2008). Another study reported by Sharma et al demonstrated that in advance
colon cancer patients curcumin is well tolerated at all doses and no dose limiting toxicity was
observed (Sharma et al., 2004). However no partial response to treatment was observed. They
concluded that systemic pharmacological properties of a daily dose of 3.6 g of curcumin are
suitable for its evaluation in the prevention of malignancies at sites other than the
gastrointestinal tract.
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3. Bioavailability of curcumin
That curcumin exhibits poor bioavailability is well documented (Anand et al., 2007) (Sharma
et al., 2007a). The major reasons attributed to the low bioavailability of curcumin are poor
absorption, rapid metabolism, and rapid systemic elimination. In humans a comprehensive
pharmacokinetic data do not exist. The pilot studies summarized that low systemic
bioavailability is observed in humans following oral dosing. First phase I clinical trial of
curcumin was done in 25 patients with high-risk or pre-malignant lesions (Cheng et al.,
2001). The starting dose was 500 mg/day and if no toxicity was noted, the dose was then
escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. There
was no treatment-related toxicity up to 8 g/day but the bulky volume of the drug was
unacceptable to the patients beyond 8 g/day. The serum concentration of curcumin usually
peaked at 1 to 2 hours after oral intake of curcumin and gradually declined within 12 hours.
The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of
curcumin were 0.51 +/− 0.11 μM, 0.63 +/− 0.06 μM and 1.77 +/− 1.87 μM, respectively.
Urinary excretion of curcumin was undetectable. Lao et al conducted a pilot study in 24 healthy
subjects and they administered curcumin up to 12g/day. They detected curcumin in the serum
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samples of only those who took 10 and 12g/day (Lao et al., 2006). It was reported that a daily
oral dose of 3.6g of curcumin results in detectable levels in colorectal tissue, which might be
sufficient to exert pharmacological activity (Sharma et al., 2004). Curcumin undergoes
metabolism in the liver particularly via glucuronidation and sulfation. The metabolites of
curcumin such as glucoronides appear to lack any pharmacological activity.

The systemic elimination of curcumin is another contributing factor for low bioavailability of
curcumin. The initial reports by Wahlstorm and Blennow showed that after oral administration
of 1g/kg curcumin to rats, more than 75% of curcumin was excreted in feces and negligible
amount was detected in urine (Wahlstrom and Blennow, 1978).

How to increase the bioavailability of curcumin, is also being explored. The roles of adjuvants,
which can block the metabolism of curcumin, are of great interest. Combining curcumin with
piperine has been shown to increase the bioavailability in rats and in human subjects. Piperine

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 Aggarwal and Harikumar Page 19

is an inhibitor of glucuronidation of curcumin. The study conducted by Shobha et al

demonstrated that concomitant administration of curcumin with piperine produced 150%
increase in bioavailability in rats and 2000% increase in man (Shoba et al., 1998) (Shoba et al,
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1998). Other ways to improve the bioavailability of curcumin is by making curcumin

nanoparticles (Bisht et al., 2007), liposomes (Li et al., 2005), micelles and phoshoplipid
complexes (Maiti et al., 2007) (Marczylo et al., 2007). The possible advantages attributed to
such formulations are (a) provide longer circulation; (b) increase the cellular permeability and
(c) induce resistance to metabolic processes.

4. Potential side effects of curcumin

Food and drug administration has declared curcumin as “generally regarded as safe” GRAS.
Even though curcumin exhibits a wide variety of pharmacological activities and has been found
to be quite safe in animals and humans, there are some reports concerning its toxicity (Lopez-
Lazaro, 2008). The National Toxicology Program (NTP) evaluated the short term as well as
long-term toxicity of turmeric oleoresin (79–85% curcumin) in F344/N rats and B6C3F1 mice.
Animals were fed diets containing the turmeric extract at different concentrations (1000, 5000,
10, 000, 25,000 or 50,000 ppm that delivers daily doses of 50, 250, 480, 1300 or 2600 mg/kg
body weight) for periods of 13 weeks or two years. In 13-week study, no death was attributed
to curcumin and only toxicity noted was relative increase in liver weight, stained fur, discolored
faces, and hyperplasia of the mucosal epithelium in the cecum and colon of rats that received
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50,000 ppm. No sign of carcinogenic lesions was observed. In 2 years study, the turmeric
administration did not have any effect on the food consumption when compared to controls
and no mortality was observed in both male and female rats. In 50,000 ppm group, however,
rats developed ulcers, chronic active inflammation, hyperplasia of the cecum, and forestomach,
increased incidences of clitoral gland adenomas, the development of hepatocellular adenoma
and intestinal carcinoma (NTP, 1993).

Although numerous reports have been published on the synergistic effects of curcumin with
chemotherapy (Bharti et al., 2003b) (Aggarwal et al., 2005) (Kamat et al., 2007)
(Kunnumakkara et al., 2007) (Lin et al., 2007), a report by Somasundaram et al (2002) showed
that administration of curcumin (2.5% curcumin w/w) abolished the effect of
cyclophosphamide on reduction of tumor size in human breast cancer xenografts in nude mice
(Somasundaram et al., 2002). The major draw back of the study was very short duration (3
days) of treatment of mice with curcumin. Why curcumin exhibits such opposing effects is not
clear. It has been reported that curcumin exhibit both antioxidant and prooxidant activities
(Sandur et al., 2007a, Sandur et al., 2007b). It is possible that these opposing activities of
curcumin are regulated by the concentration when the effect of curcumin may switches from
antioxidant to prooxidant. This may correspond to the switch from anticarcinogenic to
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carcinogenic agent, from chemoresistant to chemosensitizer or from radioresistant to

radiosensensitizer.

So far there has not been any long-term study with curcumin, which shows its toxic or adverse
effects. Such studies are necessary in both rodents as well as in human subjects to determine
the safety of curcumin. The available epidemiological evidence, however, shows that the
incidence several types of cancer are low in populations taking curcumin around 100–200 mg/
day over long periods of time.

5. Conclusions
The wisdom and scientific credentials of curcumin in the Ayurvedic and Chinese systems of
medicine have been corroborated by numerous studies conducted over the past 30 years. These
observations are also supported by epidemiological data suggesting lower incidence of chronic

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 Aggarwal and Harikumar Page 20

diseases in people from countries where curcumin is consumed. The various effects of
curcumin has been widely studied in Western systems of medicine for decades, and has been
found to possess antioxidant and anti-inflammatory activities. Considering that inflammation
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plays a major role in most chronic illnesses, anti-inflammatory agents are needed for prevention
purposes. Although several different steroids and NSAIDS (such as celecoxib, aspirin,
ibuprofen, phenylbutazole, etc) have been approved for treatment of inflammatory conditions,
most of them have side effects, especially when consumed over long periods of time. Because
curcumin inhibits multiple proinflammatory pathways and is affordable, this phytochemical
should be further explored for prevention and treatment of various chronic diseases. Further
clinical trials are needed to fully develop the potential of this “age-old NSAID”.

Acknowledgements
We would like to thank Vickie J Williams for carefully proofreading the manuscript and providing valuable comments.
We would like to thank Preetha Anand and Vijayalekshmi Nair for assistance with references. Dr. Aggarwal is a
Ransom Horne, Jr., Professor of Cancer Research. This work was supported by a grant from the Clayton Foundation
for Research to B. B. A., and the National Institutes of Health core grant (CA16672).

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Fig. 1.
Inhibition of inflammatory pathways by curcumin.
BACE-1, beta-site APP-cleaving enzyme 1; CRP, C-reactive protein; CTGF, connective tissue
growth factor; ELAM-1, endothelial leukocyte adhesion molecule-1; HAT, histone acetyl
transferase; HIF, hypoxia inducible factor; ICAM-1, intracellular adhesion molecule-1; LPO,
lipid peroxidation; MMP, matrix metalloprotease ; NF-κB, nuclear factor kappa B; ODC,
ornithine decarboxylase; STAT, signal transducers and activator of transcription protein; TNF,
tumor necrosis factor; VCAM, vascular cell adhesion molecule-1; VEGF, vascular endothelial
growth factor.
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 Aggarwal and Harikumar Page 32
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Fig. 2.
Effect of curcumin on various proinflammatory diseases.
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 Aggarwal and Harikumar Page 33

Table 1
Effect of curcumin on neurodegenerative, cardiovascular, neoplastic, pulmonary,
metabolic, and autoimmune diseases
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Disease Dose Effects References

Neurodegenerative diseases
Alzheimer Disease:
In vitro Protects nerve cells and EC from A beta-induced Kim et al, 2001
cytotoxicity.
In vitro 0.1–1μM Inhibits A beta fibril formation Ono et al, 2004
In vitro Curcumin interacts with Cu and Fe Baum et al, 2004
In vitro 0.1–10μM Inhibits the peroxidase activity of A beta-heme Atamna et al, 2006
complex
In vitro 0.1μM Enhances uptake of A beta by macrophages from AD Zhang et al, 2006
In vitro 0.1μM Enhances Abeta uptake by increasing exp of MGAT3 Fiala et al, 2007
and TLRs
Tg mice 160, 5000 ppm, diet Reduces oxidative damage and oxidative pathology Lim et al, 2001
Tg mice 500 ppm, diet, 50μM, i.v Inhibits A beta oligomers & fibrils, binds plaques and Yang et al, 2005
reduces amyloid1
Mice 7.5, i.v Clears and reduces existing plaques; reversed Garcia-Alloza et al, 2007
changes in dystrophic dendrities, abnormal curvature
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and dystrophy size

Patients Capsule or diet No side effects, increased the level of A beta in serum Baum et al, 2008
Multiple sclerosis:
In vitro Modulates IFN-β and IL-12 signaling Fahey et al, 2007
Mice 50,100μg, i.p Decreased EAE and IL-12 production, Inhibited Natarajan et al, 2002
IL-12 induced JAK2 and TYK2 phosphorylation
Mice 2.5 mg/mL, d.w Delays recovery from EAE Verbeek et al, 2005
Parkinson Disease:
In vitro 50μM Reverses peroxynitrate mediated inhibition brain Mythri et al, 2007
mitochondria complex I
Rats 50mg/kg, p.o Attenuated the loss of dopaminergic neurons, Zbarsky et al, 2005
protects rats from 6-OHDA induced Parkinson
disease
Epilepsy:
Mice 3,30 mg/kg, i.p Decrease the severity of epilepsy, attenuated kainate Sng et al, 2006
induced histone modifications
Rats 50 mg/kg, i.p Protects from KA induced neuronal damage, reduced Sumanont et al, 2006, 2007
the level of NO, decrease the expression of c-jun,
COX-2, BDNF, and iNOS2
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Cerebral injury:
Rat 50,100,200 mg/kg, ip Protects rat brain against I/R injury through Ghoneim et al, 2002
modulation of XO, O2−, MDA, GPx SOD and LDH
Rats 100, 300, mg/kg, ip Protects rat brain from cerebral ischemia, modulate Thiyagarajan et al, 2004
the activity of GPx, and SOD
Mangolian 30 mg/kg, ip or Protects I/R-induced neuronal cell death and glial Wang, et al, 2005
activation; decreased LPO
Gerbils 2 g/kg, diet mitochondrial dysfunction and the apoptosis;
curcumin levels goes up in plasma and brain within
1h
Rats 200mg/kg, i.p Reduced the neuronal damage, decreased the level of Al-Omar et al, 2006
LPO, increased the level of GSH and activities of
SOD and CAT

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Disease Dose Effects References

Rats 500mg/kg, i.p Delayed neuronal death, increase antioxidant system Rathore et al, 2008
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and levels of peroxynitrite3

Rats 1,2 mg/kg, i.v Prevent blood-brain barrier damage, improved Jiang et al, 2008
neurological deficit, decreased mortality and the
level of iNOS,
Cardiovascular diseases:
In vitro 10 μmol/L Inhibits high glucose-induced foam cell formation by Li et al, 2004
inhibition of NF-κB
In vitro 1–25 uM Inhibited PDGF-induced migration, proliferation and Yang et al, 2006
collagen synthesis in cultured VSMCs
In vitro 10μM Inhibited CRP-induced PAI-1 mRNA expression in Chen et al, 2007
HCAEC
In vitro 100μg Improved blood compatibility of rapamycin-eluting Pan et al, 2007
stent
Mice 25–100 mg/kg, i.p Antithrombotic effects Srivastava et al, 1985
Rats 200 mg/kg, p.o Prevents isoproterenol-induced myocardial Nirmala et al, 1996 a&b
infaraction
Rats 200 mg/kg, po Protects from adriamycin-induced myocardial Venkatesan et al, 1998
toxicity
Rabbits 1.6,3.2 mg/kg, p.o Decreases the LPO of liver microsomes and Quiles et al, 1998
mitochondria4
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Rabbits 1.6,3.2 mg/kg, p.o Inhibits LDL oxidation & has hyocholesteromic Ramirez-Tortosa et al, 1999
effects4
Rabbits 1.6 mg/kg, p.o Reduces oxidative stresss and reduces aortic fatty Quiles et al, 2002
streak4
Rats 15 mg/kg, p.o Decreases the levels of O2−, XO, MPO. LPO in Manikandan et al, 2004
myocardium elevated the levels of GPX, SOD, CAT
and GST
Mice 0.3mg/day, diet Inhibits the development of atherosclerosis in apoE/ Olszanecki et al, 2005
LDLR-DKO mice
Rabbits 7, 70 mM/kg, i.p Attenuate global cardiac I/R injury; decreases Yeh et al, 2005a
myocardial MMP-9, IL-6, MCP-1, TNF-α
Rabbits 70,100 mM/kg, i.p Decreased plasma IL-8, IL-10, TNF-α and cardiac Yeh et al, 2005b
troponin 1, decreased apoptosis in cardiomyocytes &
myocardial MPO
Mice 100 mg/kg, p.o Decreased AP-1, NF-κB, IL-1, IL-6. MCP-1, MMP-9 Parodi et al, 2006
in aortic tissue; inhibits
Rats 72 μg in gel Inhibit VSMC function; attenuated carotid artery Yang et al, 2006
neointima formation destructive connective tissue
remodeling in experimental AAAs
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Mice 75 mg/kg, p.o Blocked phenylephrin (PE)-induced cardiac Li et al, 2008

hypertrophy, prevented and reversed mouse cardiac
hypertrophy induced by AB and PE infusion,
abrogated histone acetylation, GATA4 acetylation,
and DNA-binding by blocking p300-HAT
Rats 50 mg/kg, p.o Inhibited the hypertrophy-induced acetylation and Morimoto et al, 2008
DNA-binding abilities of GATA4, disrupted the
p300/GATA4 complex and repressed hypertrophic
responses. Prevented deterioration of systolic
function and heart failure-induced increase in both
myocardial wall thickness and diameter
Ex-vivo 5 μmol/L Blocks homocystein induced endothelial dysfunction Ramaswami et al, 2004
& O2− production,
Allergy, Asthma and Bronchitis:

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Disease Dose Effects References

In vitro 10μM Inhibited the allergen-induced lymphocyte (from Kobayashi et al, 1997
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bronchial asthmatics), proliferation and production

of IL-2, IL-5, GM-CSF and IL-4
In vitro 1μM Inhibits IL-1β induced chemokine release from Wuyts et al, 2003
human airway HASMC
In vitro 100μg/ml Caused a marked decrease in histamine release from Suzuki et al, 2005
basophils
In vitro Reverses steroid resistance in asthma and COPD by Marwick et al, 2007;
inducing HDAC2 Biswas et al, 2008
Rats 0.5%; diet Lowered the IgE-mediated degranulation of Ju et al, 1996
intestinal mast cells
Rats 1,2,40 mg/kg, diet Enhanced IgG levels South et al, 1997
Guinea pigs 10, 24,40 mg/kg, p.o Attenuates OVA-induced airway constriction & Ram et al, 2003
hyperresponsiveness
Mice 250μg, i.g Diminished Th2 response, reduction in lung Kurup et al, 2007
inflammation, reduced eosinephilia; decrease in
expression of CD80,CD86, OX40L, MMP9, OAT,
TSLP in latex allergy model
Inflammatory Bowel Disease and Colitis:
Mice 0.25%, diet Attenuates DNB-induced colitis; reduces Salh et al, 2003
macroscopic damage and NF-κB activation reduces
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MPO, IL-1β, p38 activation

Mice 50 mg/kg, i.g, Decreased TNBS-induced colitis, decreased diarrhea Ukil et al, 2003
and disruption of colonic architecture, reduction in
MPO, LPO, serine protease activity, iNOS and O2−
Mice 2%, diet Prevents TNBS-induced downregulation of Phex Uno et al, 2006
gene expression in osteoblasts involved bone
formation
Mice 2%, diet Prevents development of DSS-induced colitis; Deguchi et al, 2007
inhibits NF-κB in mucosa
Mice 2%, diet Protects BALB/c but not SJL/J mice from TNBS- Billerey-Larmonier et al,
induced colitis 2008
Rats 2%, diet Prevents and treats TNBS-induced colitis; suppresses Jian, 2005
NF-κB and NF-κB-regulated inflammatory cytokine
expression in colonic mucosa
Rats 25,50,100 mg/kg, p.o Inhibits DNCB-induced ulcerative colitis through Venkataranganna et al,
inhibition of NF-κB and iNOS. Effects were 2007
comparable with sulfasalazine
Rheumatoid Arthritis:
In vitro 0, 1,10 μM Inhibits MMIF-induced MMP expression in synovial Onodera et al, 2000
fibroblasts from RA
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In vitro 10,15 μM Suppressed TNF-induced MMP-13 expression in Liacini et al, 2003

primary chondrocytes
In vitro 0–20 μM Potentiates the apoptotic effect of celecoxib on Lev-Ari et al, 2006
synovial fibroblast
In vitro 0–100 μM Curcumin induces apoptosis and reduces PGE2 Park et al, 2007
production from synovial fibroblasts of RA pts.
Rats 30 mg/kg, p.o Lowered the levels of acidic glycoprotein in serum Joe et al, 1997
and paw inflammation of arthritis rats
Rats 100 mg/kg, p.o Reduced adjuvant-induced CRP, haptoglobin, IL-1β Banerjee et al, 2003
Rats 0.5–1 L/g, p.o, i.p Reduces streptococcal cell wall-induced arthritis Funk et al, 2006
(joint swelling) 5
Renal Ischemia:
Rats 30 mg/kg, i.p Prevents ischemic renal injury; decreased the Shoskes et al, 1998
elevation of RANTES, MCP-1 and AIF

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Disease Dose Effects References

Rats 30 mg/kg, i.p Inhibits renal ischemia reperfusion injury; prolongs Jones et al, 2000
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skin graft survival

Rat 30 mg/kg, i.p Upregulates antioxidant gene expression in rat Shahed et al, 2001
kidney after ureteral obstruction or I/R injury
Rats 30 mg/kg, i.p Potentiates the effect of mycophenolate mofetil in Shokes et al, 2000
prevention of immune & ischemic injury
Rat 200 mg/kg, p.o Protects kidneys against I/R injury via modulation of Bayrak et al, 2008
antioxidant system
Psoriasis:
In vitro Acts as a photosensitizer for skin cells Tonnesen et al, 1987
In vitro 0.1–10 μM Inhibits keratinocyte proliferation associated with Pol et al, 2003
psoriasis
Pateints 1%, topical Suppresses phosphorylase kinase activity and Heng et al, 2000
keratinocyte transferring receptor connected with
psoriasis
Patients 4.5g/d, p.o 16.7% patients responded Kurd et al, 2008
Scleroderma:
In vitro 10μM Induced apoptosis in lung fibroblasts from Tourkina et al, 2004
scleroderma pts but not from normal. mediated
through PKC-e regulated GST-PI expression
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Diabetes and metabolic disorders:

Rats 0.1,0.25,0.5%, diet Decreased cholesterol level in serum and liver Rao SD et al, 1970
Rats 0.5%, diet Ameliorate renal lesions associated with diabetes in Babu et al, 1998
diabetic rats
Rats 200 mg/kg, p.o Inhibits AGE and cross-linking of collagen in Sajithlal et al, 1998
diabetic rats
Mice, rats 40 mg/kg, p.o Enhances wound healing in diabetic rats and Sidhu et al, 1999
genetically diabetic mice
Rats 0.002, 0.01% diet Prevents the loss of chaperone-like activity of alpha- Kumar et al, 2005
crystallin in the lens of diabetic rats
Rats 0.002, 0.01% diet Delays diabetic cataract Suryanarayana et al, 2005
Mice 0.2,1.0 g/100 g of diet Induces hypoglycemia in genetically diabetic KK-Ay Kuroda et al, 2005,
mice via binding to PPAR-γ Nishiyama et al, 2005
Rats 80 mg/kg, p.o Reduces the accumulation and cross-linking of Pari and Murugan, 2005,
collagen in diabetic rats 2007
Mice 15,30,60 mg/kg, i.p Attenuates thermal hyperalgesia in a diabetic mouse Sharma et al, 2006
model of neuropathic pain
Rats 80 mg/kg, p.o Antihyperlipidemic: reduced the blood glucose and Murugan and Pari, 2006
increased in plasma insulin indiabetic rats; significant
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reduction in LPO and lipids in serum and tissues

Rats 150 mg/kg, i.p Modulates vasoactive factors in the diabetic rat heart; Farhangkhoee et al, 2006
reduces eNOS, iNOS oxidative DNA and protein
damage; increased vasoconstrictor ET-1 in the heart
Rats 15,30 mg/kg, p.o Ameliorates diabetic nephropathy in rats Sharma et al, 2006
Rats 80 mg/kg, p.o Reduces blood glucose and increase plasma insulin Pari, and Murugan 2007a;
Murugan and Pari 2007a
Rats 80 mg/kg, p.o Decreases blood glucose, glycosylated haemoglobin Murugan and Pari, 2007b
and erythrocyte TBARS and increases plasma
insulin, HG, erythrocyte antioxidants and the
activities of membrane bound enzymes
Rats 80 mg/kg, p.o Reduces serum and liver lipid levels, HMG CoA Pari, and Murugan, 2007b
reductase activity, and increased HDL
Rats 0.002 or 0.01% diet Prevents diabetes-induced oxidative stress Suryanarayana et al, 2007

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Disease Dose Effects References

Rats 80 mg/kg, p.o Prevents brain lipid peroxidation in diabetic rats Pari, and Murugan 2007b
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Rats 60 mg/kg, p.o Attenuate cognitive deficit, cholinergic dysfunction, Kuhad et al, 2007
oxidative stress and inflammation
Rats 0.002, 0.01% diet Inhibits hyperglycemia-induced VEGF expression in Mrudula et al, 2007
diabetic retina
Rats 0.05%, diet Suppresses retinal oxidative stress and inflammation. Kowluru et al, 2007
Rats 60 mg/kg, p.o Suppresses diabetic neuropathic pain through Sharma et al, 2007
inhibition of NO and TNF
Mice 3% diet Inhibits diabetes and inflammation in murine models Weisberg et al, 2008
of insulin-resistant obesity
Patients 5mg, diet Lowers blood glucose level Srinivasan, 1970
Patients 10mg, oral Lowers plasma fibrinogen levels Ramirez-Bosca et al, 2000
Depression :
Mice 5,10 mg/kg, p.o Reduce the depressive like behaviour in mice, Xu et al, 2005
increase the levels of Serotonin and dopamine and
decrease monoamine oxidase activity
Rats 1.25,2.5, mg/kg, p.o Demosnstrate antidepressant effect the forced Xu et al, 2005
swimming test and bilateral olfactory bulbectomy
models of depression in rats
Rats 5,10,20 mg/kg, p.o Decreased the stress, reverses impaired hippocampal Xu et al, 2007, 2006
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neurogenesis, Elevated the expression of serotonin

receptor 1A mRNA and brain-derived neurotrophic
factor
Rats 60 mg/kg, p.o Inhibuts diabetic encephalopathy Kuhad et al, 2007
Mice 10 mg/kg, p.o Shows antidepressant-like effect in the forced Wang et al, 2008
swimming test
Fatigue :
Mice 20μg/kg, i,p Stimulates muscle regeneration after traumatic Thaloor et al, 1999
injury, inhibits NF-κB
Mice 10mg, diet Reduces inflammation, decreased the expression of Davis et al, 2007
IL-1, IL-6 and TNF
AIDS/HIV:
In vitro 40μM Inhibits HIV integrase Mazumder et al, 1995
In vitro 10–100μM Inhibits tat transactivation Barthelemy et al, 1998
In vitro 50, 100, 200, 300 μM Inhibits acetylation of Tat-1 protein and replication Balasubramanyam et al,
of HIV in culture 2004
In vitro Binds to HIV protease and integrase Vajragupta et al, 2005
In vitro, 10μM, Enhance IDV antiretroviral activity in HIV-1 Riva et al, 2008
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persistently infected cells

1
mice were given 500ppm curcumin in diet and on day of perfusin 50μM curcumin was given i.v ;
2
used manganese complex of curcumin;
3
curcuma oil was used;
4
Used hydroalcoholic extract of rhizome of Curcuma longa (~ 10% concentration of curcumin);
5
Turmeric extract is used; AAAs, Abdominal aortic aneurysms; AB, aortic banding; A-beta, amyloid beta; AGE, advanced glycation; CRP, C-reactive
protein; DSS, dextran sulfate sodium; ET-1, endothelin-1; GST-PI, glutathions-S-transferase; HASMC, human airway smooth muscle cells, i.p, intra
peritoneal; I/R, ischemia-reperfusion; i.v, intra venous; IDV, idinavir; IL, interleukin; LPO, lipid peroxidation; MCP-1, macrophage chemotactic protein-1;
MMIF, macrophage migration inhibitory factor; MPO, myeloperoxidase; MVEC, microvascular endothelial cells; NF-κB, nuclear factor kappa B; NOS,
nitric oxide synthese; p.o, orally; RA, rheumatoid arthritis; RANTES, regulated upon activation, normal T cell expressed and secreted; TBARS,

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thiobarbituric acid reacting substances; TNBS, 2,4,6-trinitrobenzene sulphonic acid; TNF, tumor necrosis factor; VEGF, vascular endothelial growth
factor.
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