Curcumin in Inflammatory Diseases
Young Sup Lee*
School of Life Sciences, College of Natural Sciences, Kyungpook National
University, Daegu 702-701, Korea
extracted from turmeric is also used as a remedy for the treat-
ment and prevention of inflammatory diseases. Acute and
chronic inflammation is a major factor in the progression of
obesity, type II diabetes, arthritis, pancreatitis, cardiovascular,
neurodegenerative and metabolic diseases, as well as certain
types of cancer. Turmeric has a long history of use in Ayurve-
dic medicine for the treatment of inflammatory disorders.
Recent studies on the efficacy and therapeutic applicability of
turmeric have suggested that the active ingredient of tumeric
is curcumin. Further, compelling evidence has shown that cur-
cumin has the ability to inhibit inflammatory cell proliferation,
invasion, and angiogenesis through multiple molecular targets
and mechanisms of action. Curcumin is safe, non-toxic, and
mediates its anti-inflammatory effects through the down-regu-
lation of inflammatory transcription factors, cytokines, redox
status, protein kinases, and enzymes that all promote inflam-
mation. In addition, curcumin induces apoptosis through mito-
activation of caspase cascades. In the current study, the anti-
inflammatory effects of curcumin were evaluated relative to
various chronic inflammatory diseases. Based on the available
pharmacological data obtained from in vitro and in vivo
research, as well as clinical trials, an opportunity exists to
translate curcumin into clinics for the prevention of inflamma-
tory diseases in the near future. V
C 2012 BioFactors, 39(1):69–
Keywords: curcumin; inflammation; infection; diseases; prevention
Inflammation is an adaptive physiological response induced by
deleterious circumstances including infection and tissue injury.
Observational studies have revealed that inflammation is the
product of a complex series of responses triggered by the
immune system. Inflammation also harbors a wide range of
research has shown that inflammation is associated with alter-
ation of signaling pathways, which results in increased levels
of inflammatory markers, lipid peroxides, and free radicals. It
has also been hypothesized that inflammation plays a central
role in the wound healing and combating infection. However,
persistent inflammation can activate the immune system for
long durations, which stimulates the progression of chronic
diseases such as pulmonary, cardiovascular, metabolic, and
neurologic diseases, as well as cancers [1,2].
Curcumin is a turmeric polyphenol derived from the rhi-
zomes of Curcuma Longa, which belongs to the Zingiberaceae
family, and it is cultivated in most parts of Southeast Asia.
Turmeric contains curcumin, demethoxycurcumin, and bisde-
methoxycurcumin, as well as volatile oils (zingiberone, tumer-
one, and atlantone), sugars, proteins, and resins . Curcu-
min, first identified in 1910 by Lampe and Milobedzka, is
responsible for the vibrant yellow color associated with tur-
meric. Curcumin is a lipophilic agent that is nearly insoluble in
water yet quite stable in the acidic pH of the stomach. Further-
more, it has been prized since ancient times for its various
pharmacological benefits associated with its antioxidant and
anti-inflammatory properties . Several reports have shown
that curcumin induces apoptosis, via deactivation of nuclear
factor-kappa B (NF-jB) and its regulated gene products, in
addition to suppression of cell proliferation, invasion, and
angiogenesis. Curcumin was also found to suppress several
inflammatory cytokines such as tumor necrosis factor-alpha
(TNF-a), interleukins (IL-1, -1b, -6, and -8), and cyclooxygen-
ase-2 (COX-2) .
Volume 39, Number 1, January/February 2013, Pages 69–77
*Address for correspondence to: Young Sup Lee, Ph.D., School of Life
Sciences, College of Natural Sciences, Kyungpook National University,
þ82-53-950-6353; Fax: þ82-53-943-2762; E-mail: firstname.lastname@example.org.
Received 3 August 2012; accepted 10 October 212
Published online 22 December 2012 in Wiley Online Library
C 2012 International Union of Biochemistry and Molecular Biology, Inc.
The current study mainly focused on the multiple pharma-
cological and therapeutic effects of curcumin as well as its
application to the prevention of inflammatory diseases. Based
on the results of the clinical trials, ample evidence validates
the therapeutic use of curcumin for the treatment of inflam-
2. Molecular Targets of Curcumin in
It has been shown that curcumin regulates diverse molecular
targets implicated in inflammation. Specifically, curcumin
inhibits inflammatory cytokines such as TNF-a, IL-1, -2, -6, -8,
-12, mitogen-activated protein kinase (MAPK), and c-Jun N-
terminal kinase (JNK), as well as suppresses the inducible ni-
tric oxide synthase (iNOS), COX-2, and lipoxygenase (LOX) in a
variety of cancer cells . Recently, it has been shown that
curcumin inhibits NF-jB activation, matrix metalloproteinase
(MMP-1, -9, and -13) secretion, COX-2 expression, and anti-ap-
optotic protein such as Bcl2, as well as activates Bax and cas-
pase-3. Furthermore, curcumin suppresses IL-1b-induced NF-
jB activation and nuclear translocation as well as IL-1b-
induced phosphatidylinositol 3-kinase (PI3K/Akt) activation
through the decreased phosphorylation and degradation of in-
hibitory kappa B alpha (IjBa) . Curcumin abrogates the
TNF-a-induced expression of intercellular adhesion molecule-1
(ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), dis-
rupts TNF-a-induced secretion of IL-6 and -8, and monocyte
chemotactic protein-1 (MCP-1), and inhibits NF-jB activity in
endometriotic stromal cells . Curcumin has also been
reported to decrease the expression of inflammatory markers
such as NF-jB, COX-2, 5-LOX, macrophage inflammatory pro-
tein-1a (MIP-1a), adhesion molecules, C-reactive protein, and
chemokine receptor type 4 (CXCR-4) . Curcumin decreases
inflammation in the adipose liver steatosis through the phos-
phorylation of the signal transducer and activator of transcrip-
tion 3 (STAT3), as well as through down-regulation of suppres-
sor of cytokine signaling 3 (SOCS3) and sterol regulatory
element-binding protein-1c (SREBP-1c) in livers of obese mice.
Curcumin was also found to decrease gene expression of mito-
chondrial DNA (mtDNA), nuclear respiratory factor 1 (NRF1),
and mitochondrial transcription factor A (Tfam), as well as
reduce hepatic NF-jB activities and the levels of thiobarbituric
acid reactive substances (TBARS) . Thus, curcumin sup-
presses inflammation through multiple pathways which are
summarized (Fig. 1).
3. Therapeutic Uses of Curcumin in
Treating Inflammatory Diseases
Curcumin has the ability to mediate multiple anti-inflamma-
tory effects for the treatment of various chronic inflammatory
diseases including obesity, diabetes, cardiovascular and neuro-
degenerative diseases, cerebral edema, allergy, bronchial
asthma, inflammatory bowel disease (IBD), rheumatoid arthri-
tis (RA), renal ischemia, psoriasis, scleroderma, acquired im-
munodeficiency syndrome (AIDS), and certain types of cancers
(Fig. 1). These inflammatory diseases are discussed in detail
under the following headings.
Obesity is a weight-related disorder and serious global epi-
demic resulting in reduced quality of life, morbidity, and mor-
tality. Inflammation is considered a major risk factor for the
development of co-morbidities such as obesity, type II diabetes,
cardiovascular disease, hepatic steatosis, and cancer . Cur-
cumin has been shown to mediate a variety of inhibitory
effects through suppression of the MAPK and Wnt/b-catenin
signaling pathways, which are closely associated with obesity.
Curcumin treatment has also been shown to inhibit MAPK
(ERK, JNK, and p38) and b-catenin phosphorylation through
repression of casein kinase 1a (CK1a), glycogen synthase
kinase-3b (GSK-3b), and axin. These components are believed
to be associated with the differentiation of 3T3-L1 cells into
adipocytes . Additionally, curcumin possesses in vitro and
in vivo activities that ameliorate vascular endothelial growth
factor (VEGF) and VEGF receptor 2. Curcumin augments AMP-
activated protein kinase (AMPK) phosphorylation and glycerol-
3-phosphate acyl transferase-1, as well as mediates carnitine
palmitoyltransferase-1 expression. It was also shown to lower
the serum cholesterol level and expression of PPARc and
CCAAT/enhancer binding protein alpha (C/EBPa) in adipogene-
sis and angiogenesis . Several studies have shown that cur-
cumin reduces macrophage infiltration of white adipose tissue,
leptin, and leptin receptor (Ob-R) levels, and increases adipo-
nectin expression in inflammation-related obesity. Increased
production of adiponectin associated with curcumin might
negatively regulate obesity by decreasing the activities of NF-
jB, as well as those of obesity-related inflammatory and meta-
bolic markers . Recently, it has been shown that curcumin
reduced levels of nuclear factor erythroid-2-related factor-2
(Nrf2) and heme oxygenase-1 (HO-1) in high fat diet (HFD)-
induced mice. Curcumin was also found to improve glucose
tolerance in HFD-induced mice by mediating oxidative stress
through the activation of Nrf2 and its downstream target, HO-
Diabetes is an epidemic and hyperglycemic condition that
affects the liver, heart, brain, and kidneys, and inflammation
is considered a main cause of the development of type II diabe-
tes. Various inflammatory cytokines, transcription factors, and
enzymes play important roles in the initiation and progression
of diabetes . Curcumin treatment was shown to suppress
blood glucose levels in diabetics by increasing the antioxidant
status of pancreatic b-cells and by activating peroxisome pro-
liferator-activated receptor gamma (PPAR-c) . Further-
Curcumin in Inflammatory Diseases
investigated in HFD-induced obese and leptin-deficient ob/ob
male C57BL/6J mice, wherein curcumin improved obesity-
associated diabetes condition by decreasing macrophage infil-
tration of white adipose tissue, inhibited levels of NF-jB
related markers of hepatic inflammation, and increased adipo-
nectin expression . Furthermore, curcumin was shown to
prevent diabetes-induced reduction of antioxidant capacity,
and diabetes-induced increase in IL-1b, VEGF, and NF-jB ac-
tivity [17,18]. Curcumin was also found to suppress blood glu-
cose levels through the enhancement of PPAR-c ligand-binding
activity in type II diabetic KK-Ay mice . Several studies
have evaluated the effect of curcumin in streptozotocin (STZ)-
nicotinamide-induced diabetic rats. In these reports, curcumin
prevented hyperlipidemia by suppressing the levels of serum
and liver cholesterol, triglyceride, free fatty acid and phospho-
lipid, very low-density lipoprotein (VLDL) and low-density lipo-
protein (LDL) cholesterol, and HMG CoA reductase activity, as
well as by normalizing the levels of high-density lipoprotein
(HDL) cholesterol . Additionally, curcumin pre-treatment
was shown to protect lindane-induced oxidative damage in liv-
ers of Wistar rats through augmentation of the anti-oxidant
enzyme system, such as lipid peroxidation, and also decreased
the levels of glutathione, superoxide dismutase (SOD), catalase,
glutathione-S-transferase (GST), glutathione peroxidase (GPx),
glutathione reductase, and NADPH .
Curcumin has been approved for the treatment of type II
diabetes-associated hepatic fibrogenesis. Curcumin treatment
abolishes the activating effects of advanced glycation end-
products (AGEs) on hepatic stellate cells (HSCs), possibly
through induction of AGE receptor-1 (AGE-R1). Curcumin fur-
ther promotes the induction of AGE-R1 through activation of
PPARc and inhibition of ERK . Furthermore, the effects of
curcumin on hyperalgesia in STZ-induced diabetic male SD
rats have been investigated. Curcumin dose dependently
diminished thermal hyperalgesia and hot-plate latencies by
modulating the release of TNF-a and NO .
Studies have shown that the diabetic retina over-expresses
VEGF in comparison to control retina. Curcumin treatment
has been shown to decrease VEGF expression at both the pro-
tein and mRNA levels in rats with STZ-induced diabetic retina
. Diabetes is also a major cause of nephropathy character-
ized by increased production of extracellular matrix (ECM)
A model of the multiple molecular targets of curcumin is illustrated. The upward pointing arrows represent up-regulation or
activation, and the molecules without arrows represent down-regulation or inhibition by curcumin.
Shehzad et al.
proteins through transforming growth factor-beta1 (TGF-b1),
NF-jB, and p300 in the kidneys. Curcumin decreases the pro-
duction of ECM proteins through inhibition of p300. Further, it
was found to suppress the activation of NF-jB, and decrease
the levels of TGF-b1, endothelial nitric oxide synthase, and
endothelin-1 as a treatment for diabetic nephropathy . In
rats, curcumin has been shown to remarkably decrease the
levels of blood urea nitrogen and creatinine, and increased al-
bumin, followed by the inhibition of HSP-27 and p38 expres-
sion associated with diabetic nephropathy. Curcumin also
inhibits the translational expression of histone H3 . Dia-
betic encephalopathy is characterized by impaired cognitive
functions along with neurochemical structural abnormalities
caused by intracellular glucose, and it is directly involved in
neuronal damage. In a previous work, curcumin administra-
tion (60 mg/kg) extensively attenuated cognitive deficits, cho-
linergic dysfunction, oxidative stress, and inflammation in dia-
beticrats . Altogether,
curcumin plays an important role in attenuating diabetes and
these studies revealedthat
3.3. Cardiovascular Diseases
Several reports have pointed out that inflammation plays a
large role in the development of cardiovascular diseases
(CVDs). In most CVD complications, there are increased pro-
duction and enhanced release of pro-inflammatory cytokines
such as TNF-a, IL-1b, IL-2, -6, -8, -10, -13, -18, and monocyte
chemo-attractant protein-1 (MCP-1) . Atherosclerosis is a
chronic inflammatory disorder characterized by oxidative
damage that affects lipoproteins, and blood vessels walls, as
well as promotes the deposition of excess lipids within the ar-
terial internal layer. Excess lipids accumulation in foam cells
and oxidation of LDL cholesterols play important roles in the
development of atherosclerosis .
Extensive research has suggested that curcumin treatment
mediates anti-inflammatory effects against CVDs through
diverse mechanisms. Curcumin has been shown to induce HO-
1 expressionby activating
response element (ARE), and inhibits the proliferation of vari-
ous cardiovascular cells including vascular endothelial cells,
vascular smooth muscle cells, and human aortic smooth mus-
cle cells. Curcumin also inhibits TNF-a and increases p21
expression via HO-1 in vascular and human aortic smooth
muscle cells [30,31]. Curcumin has been reported to be an
excellent inhibitor of p300 in combating cardiomyocytes hyper-
trophy. Further, where curcumin suppresses the acetylation of
transcription factor GATA binding protein 4 (GATA4), inhibi-
ting the GATA4/p300 complex and its DNA-binding capacity,
thereby enhancing nuclear histone acetylation. Curcumin
administration (50 mg/kg) has also been shown to improve sys-
tolic function and prevent heart failure in salt-sensitive Dahl
rats model of hypertensive heart disease as well as in rats sur-
gically induced to present myocardial infarction . The
effects of curcumin treatment against myocardial ischemia
have been investigated in the rat myocardium. It was found
that curcumin treatment improves post-ischemic cardiac func-
tion, decreases myocardial infarct size, and lactate dehydro-
genase release into the coronary flow, and reduces the num-
ber of apoptotic cardiomyocytes through the JAK/STAT3, Bcl2,
and caspase pathways . Furthermore, curcumin reduced
cardiac ischemia-reperfusion injury due to augmentation of
oxidative stress and inflammation. This effect is mediated by
decreasing the expression of toll-like receptor 2 (TLR2), MCP-
1, macrophage infiltration (CD68), and fibrosis. Curcumin has
also restored the function of connexin 43 and heart contractil-
ity and also prevented myocardial infarction . Previous
studies have examined the protective role of curcumin in ex-
perimental abdominal aortic aneurysms. Specifically, it was
shown that curcumin decreases the AP-1 expression and NF-
jB-DNA-binding activities as well as suppresses the secretions
of IL-1b, IL-6, MCP-1, and MMP-9 in aortic tissue of mice .
Furthermore, a microarray study revealed that curcumin
mediates the differential expression of 179 genes between
sham-operated rats and coronary artery-ligated rats. Finally,
curcumin mediates a preventive effect in cardiac hypertrophy,
inflammation, and fibrosis through the inhibition of p300 and
cytokines that mediate signaling pathways [36,37].
3.4. Cerebral Edema
The main causes of cerebral edema include structural damage
and osmotic differences induced by traumatic brain injuries
associated with poor prognosis. Currently available drugs are
ineffective in preventing cerebral edema. Thus, novel thera-
peutics are urgently needed to treat this condition. It has been
shown that pre- (150 mg/kg) or post-administration (300 mg/
kg) of curcumin was effective in reducing brain water content
through the inhibition of IL-1b-induced aquaporin-4 expression
with moderate controlled cortical impact in mice. Attenuation
of aquaporin-4 by curcumin was found to be mediated through
suppression of both NF-jB subunit p65 in cultured astrocytes,
as well as astrocytic water channel associated with cellular
edema following head trauma, in vivo . Curcumin was
administered and brain edema measured following intra-cere-
bral hemorrhage and blood–brain barrier disruption. Interest-
ingly, curcumin treatment prevented intra-cerebral hemor-
rhage, and decreased blood–brain barrier disruption and brain
edema through modulation of MMP cells . Additionally, the
role of curcumin has been investigated in oxidative stress and
inflammatory pathways in a hypoxia-induced cerebral edema
model. Hypoxic conditions reduced anti-oxidant enzyme activ-
ity followed by increased gene expression of NF-jB and pro-
inflammatory cytokines, as well as increased the levels of cell
adhesion molecules. Moreover, curcumin pre-treatment (100
mg/kg) decreased the levels of brain NF-jB and markedly atte-
nuated hypoxia-induced cerebral edema .
3.5. Neurodegenerative Diseases
Inflammation is a leading cause of neurodegenerative disease
which may be triggered by injured neurons and noxious pro-
Curcumin in Inflammatory Diseases
development pattern of proteins in neurodegenerative diseases
results in gene mutations such as human amyloid precursor
protein (hAPP) or presenilins 1 or 2 in Alzheimer’s disease
(AD), which is characterized by inflammation and oxidative
damage . Curcumin treatment was found to repress the
gene transcription of early growth response gene-1 (Egr-1),
which mediates TNF-a, IL-1b, IL-8, MIP-1b, and MCP-1 in PBM
and THP-1 cells through the interaction of amyloid-b-proteins
(Ab). In the AD transgenic Tg2576 mouse brain, curcumin sig-
nificantly lowered the levels of oxidized proteins and IL-1b,
and decreased the levels of insoluble and soluble Ab and pla-
que burden without affecting amyloid precursor protein. Cur-
cumin has been evaluated in a clinical trial for the prevention
of AD . Curcumin was also proven to be a neuroprotective
agent in 6-OHDA model of Parkinson’s disease (PD). Specifi-
cally, curcumin was shown to protect a number of tyrosine
hydroxylase-positive cells in the substantia nigra and maintain
dopamine levels in the striatum, possibly through its antioxi-
dant activity and efficient dispersion into the brain . In
another study, curcumin was administered orally to pentylene-
tetrazole (PTZ)-induced kindled epileptic rat, resulting in pre-
vention of seizures, seizure-induced memory impairment, oxi-
dative stress, and cognitive impairment . The potential
efficacy of curcumin for the prevention of multiple sclerosis
has been well documented. Curcumin also inhibited the differ-
entiation and development of Th17 cells, which are responsi-
ble for initiating multiple sclerosis through the down-regula-
tion of NF-jB, IL-6, IL-21, and STAT3-phosphorylation .
Curcumin also protected against ischemia-reperfusion injury
in the rat forebrain by suppressing xanthine oxidase activity,
superoxide anion production, malondialdehyde level, as well as
GPx, SOD, and lactate dehydrogenase activities . Chronic
administration of haloperidol increases vacuous chewing move-
ments, tongue protrusion, and facial jerking by modulating the
antioxidant system in rats. However, pre-treatment with curcu-
min was shown to dose dependently repress these effects. Curcu-
min also increased the levels of dopamine, norepinephrine, and
serotonin levels in the cortical and subcortical regions, which
were reduced as a result of the haloperidol chronic administra-
tion . Neurochemical evidence has also demonstrated the
protective role of curcumin in spongiform encephalopathies
(Creutzfeld–Jakob disease) through binding of prion protein (PrP)
. Recently, the antinociceptive effects of curcumin were inves-
tigated for treatment of neuropathic pain. It was revealed that
the antinociceptive effects curcumin are mediating, at least in
part, through inhibition of the monoamine system that is coupled
with spinal b2-adrenoceptor and 5-HT1A receptor .
3.6. Allergy and Bronchial Asthma
Allergy and asthma are pro-inflammatory diseases mediated
through inflammatory cytokines. Curcumin has been reported
to provide protection from allergies through the repression of
mast cell histamine release . In an allergy and asthma
model, it was shown that a hydroxyl group in diferuloylme-
thane (curcumin) decreased allergic reactions as well as
improved constricted airways and antioxidant levels . In
another study, a latex allergy model (BALB/c mice) over-
expressing Th2 type immune response was treated intragastri-
cally with curcumin. Curcumin inhibited Th2 responses fol-
lowed by suppression of lung inflammation, peripheral blood
eosinophilia, and decreased expression of co-stimulatory mole-
cules (CD80, CD86, and OX40L) on antigen-presenting cells,
MMP-9, ornithine amino transferase, and thymic stromal lym-
phopoietin . Furthermore, the disruption of oxidative stress
attributed to resistance to steroid therapy in chronic obstruc-
tive pulmonary disease (COPD) and asthma through NF-jB
activation and unbalanced acetylation and deacetylation state
of histone deacetylase. Curcumin is a powerful antioxidant
that scavenges free radicals (O2 and NO) through decreased
activation of NF-jB and MAPK as well as down-regulates pro-
inflammatory mediators such as MMPs, adhesion molecules,
and growth factor receptor genes in inflammatory lung disease
. Curcumin was also found to reduce lung tumor progres-
sion in non-typeable hemophilus influenzae (NTHi)-induced by
COPD, which increases neutrophil chemoattractant keratino-
cyte-derived chemokine and neutrophils in bronchoalveolar la-
vage fluid. An in vitro study revealed the anti-tumor effects of
curcumin as evidenced by cell viability, colony formation, and
3.7. Inflammatory Bowel Disease
IBD is a debilitating immune disorder most commonly involv-
ing chronic inflammation of the digestive tract, and it includes
Crohn’s disease (CD) and ulcerative colitis (UC). Curcumin has
been found to reduce colitis in several chemically induced in
vitro and in vivo colitis models . It has been shown that
curcumin prevents NF-jB translocation as well as inhibits
COX-2, 5-LOX, and iNOS expression in IBD. Curcumin also
suppressed TLR4-induced NF-jB activation in experimental
colitis . The effects of curcumin treatment were previously
investigated in a small, pilot study on five approved patients
with UC/proctitis (curcumin dose of 550 mg/kg) and five
patients with CD (curcumin dose of 300 mg/kg) for 1 month.
The UC/proctitis group showed improvement in the form of
reduced CD activity index (CDAI) and erythrocyte sedimenta-
tion rate, whereas C-reactive protein was observed in the CD.
The curcumin-treated group showed improved bowel move-
ments and reduction of diarrhea, abdominal pain, and cramp-
ing . A different randomized, multicenter, double-blinded,
placebo-controlled 6-month clinical trial including 89 patients
with UC was conducted using curcumin plus sulfasalazine or
mesalamine (45 patients), or placebo plus sulfasalazine or
mesalamine. Curcumin decreased the relapse rate, suppressed
the disease-associated clinical activity index and the endo-
scopic index in UC . All of these data show that curcumin
possesses efficacy for the prevention and treatment of IBD.
3.8. Rheumatoid Arthritis
RA, including osteoarthritis (OA), is an inflammatory disorder
that causes body jointdistortion, lossoffunction and
Shehzad et al.
demolition, particularly in cartilage and bone. OA is the most
common form of arthropathy and is characterized by degener-
ation of articular cartilage and subsequent malfunction of car-
tilage structure due to combination of genetic, physiological,
and biochemical processes . In a previous study on patients
with RA, curcumin treatment dose-dependently down-regu-
lated Bcl-2 and Bcl-xL, up-regulated Bax, activated caspase-3
and -9, and degraded poly(ADP-ribose) polymerase (PARP) in
the synovial fibroblasts. Curcumin also inhibited the inflamma-
tory response in synovial fibroblasts through suppression of
COX-2, followed by inhibition of prostaglandin E2 synthesis
. In another study, curcumin inhibited inflammatory proc-
esses through suppression of collagenase and stromelysin
expression in HIG-82 synoviocytes . Furthermore, the
effects of curcumin were investigated in IL-1b- and TNF-a-
stimulated human articular chondrocytes. Curcumin sup-
pressed IL-1b-induced NF-jB and AKT activation by decreas-
ing IjBa phosphorylation and degradation correlated with
down-regulation of COX-2 and MMP-9. Very similar results
were obtained when curcumin was analyzed in TNFa-stimu-
lated chondrocytes . A clinical study (WOMAC) that treated
curcumin to 50 OA patients found that curcumin could prevent
joint inflammation through the down-regulation of enzymes
(COX-2 and LOX), and inflammatory transcription factors (NF-
jB and STAT3) . Recently, a randomized pilot study was
conducted in order to evaluate the effectiveness of curcumin
(500 mg in 14 patients) and curcumin with diclofenac sodium
(50 mg in 12 patients) treatment to patients with active RA.
The curcumin treated group showed improvement relative to
the diclofenac sodium treatment group as indicated by Disease
Activity Score (DAS) and American College of Rheumatology
(ACR) score .
3.9. Renal Ischemia
Renal ischemia/reperfusion injury (IRI) is a complex intercon-
nected outcome of renal transplantation, possibly caused by
acute kidney injuries associated with poor prognosis. IRI is
characterized by the up-regulation of inflammatory markers in
the kidney as a result of oxidative stress and NF-jB activation
. The potential roles of curcumin, either alone or in con-
comitant administration have been investigated in IRI and skin
allograft models. It was noted that curcumin increases serum
creatinine levels and decreases tubular damage and renal
inflammation in IRI, as well as prolongs skin graft survival
. The anti-IRI role of curcumin has been well documented
in kidney and brain tissue. Recently, curcumin was used to
treat IRI in rat skeletal muscles. Curcumin prevented IRI via
reduction of pro-inflammatory cytokines and enhancement of
anti-oxidant systems such as SOD and GPx, as well as catalase
activation followed by up-regulation of malondialdehyde, NO,
and carbonyl proteins . In another study, liposomal curcu-
min was fed to C57/B6 mice with bilateral renal ischemia. Cur-
cumin induced apoptosis through the down-regulation of TLR-
4, heat shock protein-70, and TNF-a expression, as well as
normalized serum creatinine with improved healing of histo-
logical injury. Curcumin also enhanced SOD and reduced
superoxide generation through inhibition of NF-jB, MAPK, and
phospho-S6 ribosomal protein, and also inhibited neutrophil
infiltration and inflammatory chemokine activation in the renal
IRI . These studies revealed the protective role of curcumin
for the prevention of IRI via its anti-inflammatory activities.
Psoriasis is chronic disease characterized by inflammation of
the skin through abnormal keratinocyte proliferation and dif-
ferentiation. Inflammatory markers that mediate psoriasis
include NF-jB, survivin, STAT3, and TNF-a . Several lines
of evidence suggest that curcumin may provide protection
against psoriasis, as it decreases the expression of pro-inflam-
matory cytokines in psoriatic keratinocytes. Similar to other
anti-psoriatic drugs, curcumin also inhibits keratinocyte prolif-
eration . Recently, it has been shown that curcumin treat-
ment induces apoptosis in both TNF-a and TRAIL stimulated
HaCaT cells through the down-regulation of anti-apoptotic
proteins such as inhibitor of apoptosis protein 1 and 2 (IAP1,
IAP2) and Bcl-xL, as well as inhibits activation of NF-jB subu-
nit p65. These results imply that curcumin can be used to cure
psoriasis . Furthermore, a phase II, open-label, Simon’s
two-stage clinical trial using orally administered curcuminoid
C3 complex (4.5 g/day) was conducted on patients with plaque
psoriasis. Despite the absence of a placebo group, the results
suggest that curcumin is successful in suppressing psoriasis
Scleroderma is an autoimmune rheumatic disease that typi-
cally results in vasculopathy and fibrosis of skin and other
organs. In scleroderma, there is abnormal regulation of
inflammatory cytokines and NF-jB which are involved in
angiogenesis and fibrosis . In scleroderma lung fibroblasts
(SLF), curcumin treatment induces apoptosis through the
induction of HO-1 and GST P1, which are regulated by epsilon
isoform of protein kinase C (PKCe). Curcumin selectively medi-
ates expression of PKCe expression, which regulates phase 2
detoxification enzymes in normal fibroblasts and SLFs as well
as in fibrotic lung tissue, in vivo . Additionally, curcumin
selectively inhibited the TGF-b-induced phosphorylation of
Smad2 and induced apoptosis in systemic scleroderma patient
cells through up-regulation of TGF-b-induced factor (TGIF). As
TGIF is a negative regulator of TGF-b signaling, curcumin may
thus decrease ubiquitination of TGIF, which also inhibits TGF-
3.12. Curcumin Safety
The development of therapeutic strategies of featuring neutra-
ceuticals such as curcumin for the treatment of inflammatory
diseases has gained significant attention recently. A very early
report by the Food and Agriculture Organization and the
World Health Organization demonstrated that the optimal
daily intake of curcumin is 0–1 mg/kg body weight .
Curcumin in Inflammatory Diseases
Curcumin is safe and well tolerated in humans for a variety of
inflammatory diseases. In 2001, Cheng and coworkers investi-
gated the toxicology, pharmacokinetics, pharmacodynamics,
and physiologically effective doses of curcumin in different
human inflammatory conditions. In a phase I clinical trial, cur-
cumin was administered at a dose of 500 mg/day, followed by
increases to 1, 2, 4, 8, and 12 g/day for 3 months. No dose-lim-
iting toxicity was observed in any subject under any condition
. In addition, curcumin (C3 Complextrade mark, Sabinsa
Corporation) was administered at doses of 500 mg–12,000 mg
to healthy volunteers. This study revealed that only 7 of 24
subjects experienced minimal toxicity, which was not dose-
related . Recently, a randomized-pilot study was conducted
in order to assess the safety and efficacy of curcumin treat-
ment to patients with RA. Curcumin exhibited potent anti-
inflammatory effects and was found to be safe with no adverse
effects . Despite its proven efficacy over centuries of use in
ancient times and safety demonstrated in several human stud-
ies, its application has not yet been translated to clinics for the
treatment of inflammation.
The current study summarized the definitive association of
inflammatory pathways with the initiation and progression of
chronic inflammatory diseases, as well as the role that curcu-
min may perform in managing these diseases. We have clearly
shown that curcumin modulates multiple molecular targets
and exerts multifaceted pharmacological activities, including
anti-inflammation effects for the treatment and prevention of
chronic inflammatory diseases. Curcumin is a non-toxic and
highly promising natural anti-inflammatory compound with a
long history of use and is already being administered in phase
II and III clinical trials. Further human studies are required in
order to validate the clinical use of curcumin for treating a
wide variety of inflammatory diseases. Tailored agents derived
from curcumin or its use in combination with other drugs may
provide improved anti-inflammatory effects in the near future.
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