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Curcumin, Inflammation, and Chronic Diseases: How Are They Linked?

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It is extensively verified that continued oxidative stress and oxidative damage may lead to chronic inflammation, which in turn can mediate most chronic diseases including cancer, diabetes, cardiovascular, neurological, inflammatory bowel disease and pulmonary diseases. Curcumin, a yellow coloring agent extracted from turmeric, shows strong anti-oxidative and anti-inflammatory activities when used as a remedy for the prevention and treatment of chronic diseases. How oxidative stress activates inflammatory pathways leading to the progression of chronic diseases is the focus of this review. Thus, research to date suggests that chronic inflammation, oxidative stress, and most chronic diseases are closely linked, and the antioxidant properties of curcumin can play a key role in the prevention and treatment of chronic inflammation diseases.
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Molecules 2015, 20, 9183-9213; doi:10.3390/molecules20059183
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Review
Curcumin, Inflammation, and Chronic Diseases: How Are
They Linked?
Yan He 1,†, Yuan Yue 1,†, Xi Zheng 1,2, Kun Zhang 1, Shaohua Chen 3 and Zhiyun Du 1,*
1 Institute of Natural Medicine & Green Chemistry, School of Chemical Engineering and Light Industry,
Guandong University of Technology, 232 Wai Huan West Road, Guangzhou Higher Education
Mega Center, Guangzhou 510006, China; E-Mails: hxg_129@126.com (Y.H.);
yueyuan00@126.com (Y.Y.); xizheng@pharmacy.rutgers.edu (X.Z.); kzhang@wyu.edu.cn (K.Z.)
2 Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology,
Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway,
NJ 08854, USA
3 Department of Otorhinolaryngology, Guangdong General Hospital & Guangdong Academy of
Medical Sciences, Guangzhou 510030, China; E-Mail: csh_rl@163.com
These authors contributed equally to this work.
* Author to whom correspondence should be addressed; E-Mail: zhiyundu@gdut.edu.cn;
Tel.: +86-20-3932-2235.
Academic Editors: Bharat B. Aggarwal and Sahdeo Prasad
Received: 25 January 2015 / Accepted: 14 May 2015 / Published: 20 May 2015
Abstract: It is extensively verified that continued oxidative stress and oxidative damage
may lead to chronic inflammation, which in turn can mediate most chronic diseases including
cancer, diabetes, cardiovascular, neurological, inflammatory bowel disease and pulmonary
diseases. Curcumin, a yellow coloring agent extracted from turmeric, shows strong
anti-oxidative and anti-inflammatory activities when used as a remedy for the prevention
and treatment of chronic diseases. How oxidative stress activates inflammatory pathways
leading to the progression of chronic diseases is the focus of this review. Thus, research to
date suggests that chronic inflammation, oxidative stress, and most chronic diseases are
closely linked, and the antioxidant properties of curcumin can play a key role in the
prevention and treatment of chronic inflammation diseases.
Keyword: curcumin; antioxidant; inflammation; chronic diseases
OPEN ACCESS
Molecules 2015, 20 9184
1. Introduction
Curcuma longa (turmeric) is a curry spice and a traditional Chinese medicinal herb with a long history
of use as a treatment for inflammatory conditions in China and Southeast Asia [1]. Turmeric constituents
include three curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin), volatile oils
(natlantone, tumerone and zingiberone), proteins, sugars and resins. It controls inflammation, cell growth
and apoptosis, being thus useful to prevent and treat some diseases thanks to its anti-oxidant, and
anti-inflammatory activities and excellent safety profile, most of which are attributed to the presence of
curcumin [2]. Curcumin has been shown to be a highly pleiotropic molecule interacting with numerous
inflammatory molecular targets. In vitro and in vivo studies, especially clinical trials, indicate curcumin
may be a potential therapeutic agent in many chronic diseases such as inflammatory bowel disease,
arthritis, pancreatitis, chronic anterior uveitis, and cancers [3]. Owing to its valuable properties, almost
100 companies are currently providing various curcumin products in the form of drinks, tablets, capsules,
creams, gels, nasal sprays, extracts and coloring agents for both edible and medical needs [4].
Inflammation is an adaptive physiological response induced by deleterious circumstances including
infection and tissue injuries. Observational studies have revealed that inflammation is the product of
complex series of responses triggered by the immune system. Inflammation also causes a wide range of
physiological and pathological morbidities [5]. Extensive research has shown that inflammation is
associated with alteration 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 process and in combating infection. Two stages of inflammation exist—acute
and chronic inflammation. Acute inflammation is an initial stage of inflammation (innate immunity)
mediated through the activation of the immune system, which persists only for a short time and is usually
beneficial for the host. If the inflammation lasts for a longer time, the second stage of inflammation
(chronic inflammation) starts and may initialize various chronic diseases such as obesity, diabetes,
arthritis, pancreatitis, cardiovascular, neurodegenerative and metabolic diseases, as well as certain types
of cancer [6]. Oxidative stress and oxidative damage are involved in the pathophysiology of many
chronic inflammatory and degenerative disorders, which is followed by a decrease in health status and
increasing probability of chronic diseases such as cancer, atherosclerosis, Alzheimer’s disease,
metabolic disorders and so on. They are likely caused by low grade inflammation driven by oxygen
stress as indicated by the increase of pro-inflammatory cytokines such as IL-6, IL-1 and TNF-α, genes
encoded by activation of nuclear factor kappa-B (NF-κB) [7].
Curcumin shows strong anti-oxidation and anti-inflammatory activities. In the past two decades over
7000 articles have discussed the molecular basis of curcumin’s attributed antioxidant, anti-inflammatory,
antibacterial, antiapoptosis, anticancer and related activities. Over 100 clinical trials have focused on the
role of curcumin in various chronic diseases, including diabetes and cancers, as well as autoimmune,
cardiovascular, neurological and psychological diseases [8]. In this review we try to clarify the possible
link between curcumin, inflammation and chronic diseases.
Molecules 2015, 20 9185
2. Anti-inflammatory Mechanisms of Curcumin
Extensive research has demonstrated the mechanism by which persistent oxidative stress can lead to
chronic inflammation, which in turn could cause many chronic diseases including cardiovascular
diseases, neurological diseases, pulmonary diseases, diabetes and cancers [9]. Oxidative stress is defined
as a disturbance in the balance between the production of reactive oxygen species (free radicals and
reactive metabolites) and antioxidant defenses as their elimination by protective mechanisms. This imbalance
causes the damage of important biomolecules and cells, as well as potential impacts on the organisms [10].
ROS play a central role both upstream and downstream of NF-κB and TNF-α pathways, which are
located at the center of the inflammatory response. The hydroxyl radical is the most harmful of all the
ROS. A schematic representation indicates the three loops involved in amplification of inflammation
where loop 1 demonstrates the NF-κB-TNF-α positive feedback loop and loop 2 shows the redox sensing
loop by ROS-NF-κB-TNF-α. Both loops can be blocked by using antioxidant like H2 that scavenges
hydroxyl radicals directly or via NF-κB pathways. ROS are generated by Nox system and amplified
through these loops. In addition, the modified proteins by ROS may generate a loop 3 which may
promote the autoimmune response by feeding back into loops 1 and 2 [11,12].
Nuclear factor erythroid-2 related factor 2 (Nrf2) is highly related to oxidative stress in inflammation [13].
The role of Nrf2 has been addressed in kidney and heart in a model of chronic renal injury as well as in
models of neuronal damage induced by quinolinic acid and in cerebellar granule neurons in culture [14–17].
There are also notably reports showing reciprocal regulation of Nrf2 and NF-κB, suggesting an
anti-inflammatory role of Nrf2 and a large number of documents reported that Nrf2 is associated with
MAPK, NF-κB, PI3K and PKC pathways [18,19]. Thus, Nrf may play an important role in pathologic
study of multi-organ protector against oxidative damages [20]. Furthermore, evidence also suggested
that mitochondrial dysfunction is a significant pathological mechanism in neurodegenerative diseases,
renal damage, obesity, diabetes, liver and lung injuries [21].
Numerous mechanisms by which curcumin can display anti-inflammatory activity have been
proposed (Figures 1 and 2). It was suggested that curcumin alleviates oxidative stress, inflammation in
chronic diseases through the Nrf2-keap1 pathway. Curcumin can suppress pro-inflammatory pathways
related with most chronic diseases and block both the production of TNF and the cell signaling mediated
by TNF in various types of cells. Curcumin may also be a TNF blocker from in vitro and in vivo studies
by binding to TNF directly [22–24].
Due to its chemical structure, curcumin may act as a natural free radical scavenger. Curcumin can
decrease the release of different interleukins through NF-κB. Curcumin could act as a stress response
mimetic that induces some components of the protein homeostasis network or as it is known to bind amyloid,
directly acts in the misfolded cascade [25]. The antioxidant activity and the free radical reactions of
curcumin are closely related to its phenolic O-H and the C-H. It was found that the antioxidant
mechanism of curcumin was based on the H-atom abstraction from the phenolic group, not on the central
CH2 group in the heptadienone link. Curcumin, methylcurcumin, and half-curcumin with similar
structure of O-H BDEs, indicated that the two phenolic groups were independent of each other [26,27].
Molecules 2015, 20 9186
Figure 1. Inflammatory targets modulated by curcumin.
Figure 2. Relationship among ROS, chronic inflammation diseases and the antioxidative
properties of curcumin.
Molecules 2015, 20 9187
3. Curcumin in Inflammation Induced Chronic Diseases
Curcumin has been used as a remedy for the prevention and treatment of many organ and tissue
disorders, most of which are associated with inflammation and oxidative stress. Curcumin alleviates
oxidative stress, inflammation in chronic diseases and regulates inflammatory and pro-inflammatory
pathways related with most chronic diseases (Figure 3).
Psoriasis
Scleroderma
Chronic Kidney Disease
Obesity
Diabetes
Rheumatoid Arthritis
Allergy,Asthma,Bronchitis
Cardiovascular Diseases
Neurodegenerative Diseases
Pancreatitis
Inflammatory Bowel Disease
Diseases of gastrointestinal tract
and associated glands
Diseases of other organs
Metabolic diseases
Skin diseases
Cancer
Figure 3. The main chronic diseases curcumin is active against.
3.1. Diseases of the Gastrointestinal Tract and Associated Glands
3.1.1. Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a chronic relapsing inflammation disease characterized by
oxidative and nitrosative stress, leucocyte infiltration and up-regulation of proinflammatory cytokines.
NF-κB is a key target for numerous IBD therapies, which is involved in the production of cytokines and
chemokines integral for inflammation [28].
Many studies have been conducted to evaluate curcumin’s potential in patients with IBD for its
efficacy as an anti-inflammatory without significant side effects [29–32]. McCann et al., found different
turmeric extracts could benefit the variants of SLC22A4 and IL-10 associated with IBD, by reducing
inappropriate epithelial cell transport (SLC22A4, 503F) and increasing anti-inflammatory cytokine gene
promoter activity (IL-10, -1082A) [33]. Beloqui et al., designed a local delivery of curcumin using
pH-sensitive polymeric nanoparticles and found it significantly decreased neutrophil infiltration and
TNF-α secretion [34]. Curcumin is considered as an orally bioavailable blocker of TNF and other
pro-inflammatory biomarkers [35].
Topcu evaluated the effects of curcumin on epithelial cell apoptosis, the immunoreactivity of the
phospho-c-Jun N-terminal kinase (JNK) and phospho-p38 mitogen-activated protein kinases (MAPKs)
in inflamed colon mucosa, and oxidative stress in a rat model of ulcerative colitis induced by acetic acid.
Molecules 2015, 20 9188
Curcumin (100 mg/kg per day, intragastrically) was administered 10 days before the induction of colitis
and was continued for two additional days. Curcumin treatments were associated with amelioration of
macroscopic and microscopic colitis sores, decreased MPO activity, and decreased MDA levels in acetic
acid-induced colitis rats. Oral supplementation of curcumin obviously prevented programmed cell death
and restored immunreactivity of MAPKs in the colons. The results of this study suggest that oral
curcumin treatment decreases colon injury and is associated with decreased inflammatory reactions, lipid
peroxidation, apoptotic cell death, and modulating p38- and JNK-MAPK pathways [36].
Larmonier et al., found that curcumin attenuated lipopolysaccharide (LPS)-stimulated expression and
secretion of macrophage inflammatory protein (MIP)-2, IL-1β, keratinocyte chemoattractant (KC), and
MIP-1α in colonic epithelial cells (CECs) and in macrophages. Curcumin significantly inhibited PMN
chemotaxis against MIP-2, KC, or against conditioned media from LPS-treated macrophages or CEC, a
well as the IL-8-mediated chemotaxis of human neutrophils. Curcumin inhibited random neutrophil
migration with no toxic effects, suggesting a direct effect on neutrophil chemokinesis. Curcumin
inhibited PMN motility by the downregulation of PI3K activity, AKT phosphorylation, and F-actin
polymerization [37]. Epstein also demonstrated reduced p38 MAPK activation and IL-1β, enhanced
IL-10 and dose-dependent suppression of MMP-3 in CMF in curcumin-treated mucosal biopsies [38].
Curcumin has been shown to attenuate colitis in the dinitrobenzenesulfonic acid (DNB)-induced murine
model of colitis with a reduction in MPO activity, IL-1β expression, and reduction of p38 MAPK.
Binion et al., found curcumin may inhibit VEGF-mediated angiogenesis in human intestinal
microvascular endothelial cells via down regulation of the COX-2 and MAPK [39,40]. Curcumin also
inhibited the expression of VCAM-1 in HIMECs through the block of p38 MAPK, Akt, and NF-κB.
Thus curcumin may represent a novel therapeutic agent targeting endothelial activation in IBD [41,42].
Curcumin showed a protective effects on 2,4,6-trinitrobenzenesulphonic acid-induced colitis in mice.
Curcumin also reduced NO and O2 levels, which were associated with the effective expression of Th1
and Th2 cytokines and inducible NO synthase. NF-κB activation in colonic mucosa was also suppressed
in the curcumin-treated mice [43].
3.1.2. Pancreatitis
Chronic pancreatitis (CP) is associated with progressive fibrosis, pain and/or loss of exocrine and
endocrine functions, of which pain is the main symptom [44]. The key etiological factors in CP are
alcohol and tobacco abuse, genetic, environmental, hypertriglyceridemia, hypercalcemia, autoimmune
and sometimes idiopathic [45]. Alcohol and its metabolites could produce oxidative stress, regulate a
series of oxidant-related factors and eventually result in chronic pancreatitis. They regulate the NF-κB,
activator protein-1 (AP-1) in acinar cells and three classes of MAP kinases, which were inhibited by
antioxidants [46,47]. Alcohol metabolism also produces free radical and induces the CYP450 enzymes
resulting in bioactivation [48]. The pathologies of pancreatitis are difficult to clearly define [49].
Recently progresses in chronic pancreatitis mainly concern the early diagnosis of the disease, the
prediction of the fibrosis degree of the gland, the medical and surgical treatment of abdominal pain and
the knowledge of the natural history of the autoimmune pancreatitis [50].
In recent years, it has been shown that curcumin has a highly pleiotropic molecule capable to contact
numerous molecular targets with pancreatitis [51]. In view of early cell culture and animal model
Molecules 2015, 20 9189
research methods, clinical trials reveal curcumin may be therapeutic candidate in pancreatitis [52]. In
the rats model of induced pancreatitis, curcumin reduced inflammation by dramatically decreasing
activation of NF-κB and AP-1 as well as suppressing mRNA induction of iNOS, TNF-a, and IL-6 in the
pancreas [53]. In addition, curcumin acted on inflammatory mediators to improve disease’s severity as
measured by histology, serum amylase, pancreatic trypsin, and neutrophil infiltration in both
ethanol- and cerulein- induced pancreatitis [54]. In one clinical study, 25 patients, aged 43–77 years old,
were needed to consider the biological activity and safety of curcumin in pancreatic cancer patients by
oral administration with 8 g of curcumin capsules, the down-regulation of NF-κB and COX-2 suggested
curcumin was effective enough in pancreatic cancer [55]. Another pilot study was undertaken to
investigate the clinical efficacy of oral curcumin (500 mg) with piperine (5 mg) on the pain and the
markers of oxidative stress in patient with pancreatitis, and showed that this oral administration regime
was able to suppress the lipid peroxidation in patients who had pancreatitis following with downgrade
of the levels of malonyldialdehyde (MDA) and glutathione (GSH) in red blood cell [56].
3.2. Diseases of Other Organs
3.2.1. Neurodegenerative Diseases
Neurodegenerative diseases may affect millions of people yearly and the incidence is increasing as
the population ages. About one in five Americans over the age of 65 will be diagnosed with a
neurodegenerative disease by 2030 as shown by the NIH [57]. Over the last several decades a broad
range of studies have demonstrated the progression of age-dependent neurodegeneration is associated
with decreased antioxidants and increased oxidative damage to proteins, DNA and lipids [58,59].
Modification of oxidative protein occurs at a persistent low level in diverse cells and tissues, and
accumulates in neurodegenerative diseases [60].
The considerable excitement about curcumin’s preclinical efficacy for neurodegenerative diseases
mainly focused on its lack of toxicity and low cost. Kim et al., summarized that curcuminoids possess
diverse biological properties that modulate debilitating biochemical processes involved in Alzheimer’s
diseases, that include attenuation of mitochondrial dysfunction-induced oxidative stress and
inflammatory responses to inflammatory cytokines, COX-2, and nitric oxide synthase (iNOS), in
addition to neurodamage caused by heavy metal poisoning [61]. Banji et al., observed the expression of
histological assessment of the CA1 region of the hippocampus, caspase-3 and cleaved caspase-3,
showing curcumin can effectively reduce the levels of proteins, cleaved caspase-3 and mitochondrial
enzymes to protect the brain [62]. Thus mitochondrial dysfunction plays an important role in
pathogenesis of neurodegenerative diseases including AD [63]. Curcumin treatment was found to repress
the gene transcription of early growth response gene-1 (Egr-1), which mediates TNF-a, IL-1β, IL-8,
MIP-1β, 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 significantly lowered the levels of oxidized proteins and
IL-1β, and decreased the levels of insoluble and soluble Ab and plaque burden without affecting amyloid
precursor protein. Curcumin has been evaluated in a clinical trial for the prevention of AD [64,65].
Molecules 2015, 20 9190
3.2.2. Cardiovascular Diseases
Cardiovascular Diseases (CVDs), including heart disease, vascular disease and atherosclerosis, are
the most critical current global health threat. Epidemiological and clinical trials have shown strongly
consistent relationships between the inflammation markers and risk of cardiovascular diseases [66]. It is
widely appreciated that the key mechanisms in the development of CVDs are inflammation and oxidant
stress, activation of pro-inflammatory cytokines, chronic transmural inflammation and C reactive protein
(CRP) [67]. Thus cytokines, other bioactive molecules, and cells that are characteristic of inflammation
are believed to be involved in atherogenesis.
Abundant evidence suggests that curcumin mediates its effects against CVDs through diverse
mechanisms such as oxidative stress, inflammation and cell death [67–70]. Curcumin was able to protect
against inflammation, cardiac hypertrophy and fibrosis by the inhibition of p300-HAT activity and
downstream NF-κB, GATA4 and other signal pathways. Curcumin suppressed lipopolysaccharide
(LPS)-induced overexpression of inflammatory mediators in vascular smooth muscle cells (VSMCs) of
rats via inhibition of the TLR4-MAPK/NF-κB pathways, partly due to block of NADPH-mediated
intracellular ROS production [71]. LPS not only dramatically increased expression of inflammatory
cytokines (MCP-1, TNF-α, TLR4 and iNOS) and NO production, but also significantly increased
phosphorylation of IκBα, nuclear translocation of NF-κB (p65) and phosphorylation of MAPKs in
VSMCs. Furthermore, LPS significantly increased production of intracellular ROS, and decreased
expression of p47 (phox) subunit of NADPH oxidase. Curcumin concentration-dependently attenuated
all the aberrant changes in LPS-treated VSMCs [72]. Parodi et al., demonstrated that curcumin-treated
mice exhibited relative decreases in aortic tissue activator protein-1 and NF-κB DNA binding activities
and significant lower concentrations of IL-1β, IL-6, MCP-1, and MMP-9 in experimental AAAs [73].
Curcumin may affect signal transduction (e.g., Akt, AMPK) and modulate specific transcription factors
(such as SREBP1/2, NRF2, FOXO1/3a, CREBH, CREB, PPARγ, and LXRα) which regulate the
expression of genes in free radicals scavenging (MnSOD, catalase, and heme oxygenase-1) and lipid
homeostasis (CD36, aP2/FABP4, HMG-CoA reductase, and CPT-1). Curcumin could induce mild
oxidative and lipid-metabolic stresses, which lead to an adaptive cellular stress response, by stimulating
the cellular antioxidant defense systems and lipid metabolic enzymes [74]. Duan et al., indicated the
post-treatment of curcumin have an effects against myocardial ischemia and reperfusion by the activation
of JAK2/STAT3 pathway, which reflected by the annulment of the curcumin-induced down-regulation
of Caspase3 and up-regulation of Bcl2 [75]. Curcumin was also found to be a novel heart failure therapy
by the GATA4/p300 transcriptional signal pathway which is recognized as a critical role in the
cardiomyocyte hypertrophy and heart failure therapy [76]. Also, curcumin may inhibit PI3K/Akt/NF-κB
signaling pathway, reduce the inflammatory response, and thus provide a protective effect against
CVB3-induced myocarditis [77]. Curcumin was found to stimulate the apoptotic cell death of H9c2 cells
by upregulating ROS generation and triggering activation of JNKs [78]. Interestingly, curcumin
exerts a pro-oxidative activity, with 2,7-dichlorofluorescin diacetate (DCFH-DA) staining revealing
up-regulation of ROS levels and anti-oxidants found to abrogate PARP cleavage.
Molecules 2015, 20 9191
3.2.3. Allergy, Asthma and Bronchitis
The initiation and maintenance of asthma and allergy and bronchitis underlies the inflammation
pathways relevant to the perplexing rise of these chronic inflammatory disorders. That allergy, a
proinflammatory disease, is normally mediated through inflammatory cytokines, such as T helper-2 CD4 T
(Th2) cells and Th2-associated cytokines, as well as IL-17-associated neutrophilic airway inflammation [79].
Asthma is also an inflammatory disease in which eotaxin, MCP-1 and MCP-3 play a crucial role [80].
Eosinophils are key cells of allergic inflammation and their adhesion onto human bronchial epithelial
cells is mediated by a CD18-intracellular adhesion molecule (ICAM)-1-dependent interaction.
As shown in in vivo and in vitro experiments, curcumin can help clear constricted airways and
increase antioxidant levels. Curcumin was reported to have a major role in reducing the allergic response
using a murine model of allergy [81]. Nilani et al., studied selected plants extracts with anti-asthmatic
constituents. The results showed that curcumin could be utilized in alternate anti-asthmatic therapy for
they play a vital role in scavenging nitric oxide (NO) which could prevent the bronchial inflammation
in asthmatic patients [82]. Rennolds et al., determined that two distinct pathways controlled secretion of
IL-6 and IL-8 where the cadmium-induced IL-6 secretion occurs via a NF-κB pathway and the IL-8
secretion involves the Erk1/2 signaling pathway [83]. The natural antioxidant curcumin could prevent
both secretions by human airway epithelial cells. Ammar et al., designed a study for the inhibitory effects
of curcumin on the asthma related biological changes and studied the effects on serum IgE and the
changes in the mRNA levels of iNOS, TNF-α and TGF-β1. Serum IgE was significantly decreased by
curcumin. Curcumin was more potent in inhibiting mRNA expression of TNF-α [84]. Curcumin clearly
attenuates allergic airway inflammation by inhibition of NF-κB and its downstream transcription factor
GATA3. Chong et al., investigated the anti-inflammatory effect of curcumin on acute allergic asthma in
BALB/c mice. Notch1 and Notch2 receptor, especial Notch1 receptor, were found to be important in the
development of allergic airway inflammation. Curcumin-treatment improved the airway inflammatory
cells infiltration and down regulated the levels of Notch1/2 receptors and GATA3. The inhibition of
Notch1-GATA3 signaling pathway by curcumin can prevent the development and deterioration of the
allergic airway inflammation [85]. Thakare et al., found curcumin could prevent significantly elevation
of eosinophil peroxidase in nasal homogenate and serum IgE, NO, IL-4 in nasal lavage with an
ovalbumin induced allergic rhinitis in guinea pig model [86]. Curcumin markedly attenuated allergic
airway inflammation in asthma model by regulating Treg/Th17 balance where obvious inhibition of
Th17 cells and significant increase of Treg cells were observed [87]. These findings support the possible
use of curcumin as a therapeutic drug for patients with allergic asthma. Chung et al., found curcumin
administration markedly suppressed IgE-mediated and eosinophil-dependent conjunctival inflammation
with less IL-4 and IL-5 (Th2 type cytokine) production in conjunctiva, spleen and cervical lymph nodes
in the curcumin-administered mice [88]. OVA challenge stimulated the activation of the production of
iNOS and curcumin treatment inhibited iNOS production in the conjunctiva. Curcumin also has wide
pharmacokinetic effects as an inhibitor of NF-κB, eIF-2α dephosphorylation, proteasome and COX2 [89].
Molecules 2015, 20 9192
3.2.4. Rheumatoid Arthritis
Rheumatoid arthritis (RA) could give rise to a systemic chronic inflammatory disorder and may
impact many organs and tissues but mainly attack flexible (synovial) joints [90]. It was reported that
oxidative stress made an important contribution to joint destruction in RA [91–93]. ROS is a significant
mediator that activates a variety of transcription factors including NF-κB and AP-1, thus regulating the
expression of over 500 different genes, such as growth factors, chemokines, cell cycle regulatory
molecules, inflammatory cytokines and anti-inflammatory molecules [94]. Therefore, transcription
factors and genes, involved in inflammation and anti-oxidation, are suspected to play a crucial adjective
function in RA.
The main treatment of RA is to reduce arthritis reaction, inhibit disease development and irreversible
bone destruction, protect the joints and muscle function, and ultimately achieve complete remission or
low disease activity. Treatment principles include patient education, early treatment and combination
therapy [95]. Drug therapy includes non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting
antirheumatic drugs, immunosuppressive agents, immune and biological agents and botanicals. NSAIDs
are most common [96]. Curcumin is one of the NSAIDs with anti-inflammatory and anti-oxidant actions
both in vivo and in vitro [97]. Many studies with animal and cells have elucidated the biological effects
and molecular mechanisms of curcumin. A few clinical trials are underway now. Curcumin has raised
interest as an agent of potential use in therapy of RA with the regulatory function of the related
inflammatory factors associated with anti-oxidation [98]. Curcumin treatment activated caspase-3 and -9,
up-regulated Bax, down-regulated Bcl-2 and Bcl-xL, and degraded poly (ADP-ribose) polymerase
(PARP) with dose-dependent in the synovial fibroblasts from a previous study on patients with RA [99].
There also presented an inflammatory response in synovial fibroblasts by suppression of COX-2 after
inhibition of prostaglandin E2 synthesis accompanied by curcumin [100]. Lee et al., studied the effects
of a curcumin-like diarylpentanoid [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] in cellular
targets of rheumatoid arthritis in vitro and demonstrated the compound abolished the p65 NF-κB nuclear
translocation as well as binding activity of NF-κB DNA in the PMA-stimulated synovial fibroblasts via
inhibited COX-2, IL-6, MMP-3, collagenase and pro-gelatinase B(pro-MMP-9) [101]. Curcumin inhibited
AKT and IL-1β-induced NF-κB activation on account of degradation correlated with down-regulation
of COX-2 and MMP-9 and reducing IκBα phosphorylation in IL-1β- and TNF-α- stimulated human
articular chondrocytes. It showed the similar results when curcumin was analyzed in TNF-α-stimulated
articular chondrocytes [102]. In another study, curcumin (500 mg) and diclofenac sodium (50 mg), alone
or together, were administered to three groups of patients with RA. Curcumin may be the RA therapy
candidate with the best improvement in the overall Disease Activity Score and American College of
Rheumatology scores (tests used in clinical practice and clinical trials to evaluate symptoms of RA and
disease progression) of all three groups [103].
3.2.5. Chronic Kidney Diseases
Chronic kidney disease (CKD), an inflammatory disease, is defined by either a progressive atrophy
of glomerular filtration rate (GFR) and/or the presence of abnormalities in the urine such as white blood
cells, protein and red blood cells [104,105]. Two main causes of CKD can be attributed to hypertension
Molecules 2015, 20 9193
and diabetes mellitus (DM) which major pathological and are end-stage interstitial fibrosis, glomerular
hypertrophy and sclerosis, accumulation of extracellular matrix (ECM) in the glomerular basement
membrane and mesangial cell proliferation [106,107]. Since biological markers of oxidative stress are
markedly elevated in CKD patients, oxidative stress gains concern as a contributing factor to CKD
pathology [108]. Nrf2 regulates the expression of a wide array of thiol molecules and their generating
enzymes, detoxifying enzymes, genes encoding antioxidant proteins and stress response proteins [109].
Currently, there is no definite treatment to improve kidney function in CKD. It has been well
document that curcumin could disrupt the Nrf2-Keap1 complex with upregulation of the activity and
expression of HO-1 in renal cells as a consequence to protect the kidney functions [110]. There is
considerable evidence suggesting that Nrf2 signaling plays a protective role in renal injuries [111,112].
In addition, impaired Nrf2 consequent target gene repression and activity have been observed in CKD
animals [107]. Therefore, a pharmacological intervention activating Nrf2 signaling can be benefit for
protecting against kidney dysfunction in CKD [113]. Moreover, curcumin treatment has been shown to
decrease macrophage infiltration in the kidneys of chronic renal failure rats and to block transactivation
of NF-κB, indicating that the anti-inflammatory property of curcumin may be responsible for alleviating
disease in this animal model [114]. In addition to the above reports, Waly et al., reported that curcumin
significantly ameliorates oxidative stress by reduction the levels of TAC and GSH as well as inhibition
of the activities of CAT, GPX enzymes and SOD in human embryonic kidney (HEK) 293 cells [115].
Gaedeke et al., found that curcumin blocks TGF-β-induced expression of several mediators of fibrosis
by inhibition of the transcription factor c-jun/AP-1, or through down-regulation of TβRII expression [116].
Siddhartha et al., summarized that curcumin can blunt and/or strengthen the action and generation of
some inflammatory mediators playing a role in CKD, such as eicosanoids, cytokines, reactive oxygen
species (ROS), growth factors and transcription factors, thus showing potential anti-inflammatory effects
in CKD [104]. Jane et al., showed that curcumin could inhibit p300 and NF-κB actions and decrease
oxidative stress through down-regulation of vasoactive factors (endothelial nitric oxide synthase and
enothelin-1), transforming growth factor-β and extracellular matrix proteins in the kidneys with real-time
reverse transcriptase polymerase chain reaction analyses [117]. In one animal experiment, Sprague-Dawley
rats were subjected to 5/6 nephrectomy and randomly assigned to untreated (Nx), sham-operated rats
served as controls, telmisartan-treated groups (10 mg/kg/day, orally; as positive control) curcumin-treated
(75 mg/kg/day, orally). This research showed curcumin and telmisartan treatment can decrease
creatinine clearance. The Nx rats demonstrated reduced Nrf2 protein expression. Moreover, curcumin
had been reported that it ameliorated NF-κB p65, nicotinamide adenine dinucleotide phosphatase oxidase
subunit (p67phox and p22phox), TGF-β1, cyclooxygenase-2, TNF-α and fibronectin accumulation to
lower glutathione peroxidase activity and higher kidney malondialdehyde concentration in remnant
kidney in Nx animals [118]. On the other animal research, the authors evaluated the link of renal,
mitochondrial function and oxidant stress through K2Cr2O7-induced schemes, and revealed the
therapeutic effect of curcumin on oxidant stress, renal dysfunction, histological damage and antioxidant
enzyme activity both in kidney tissue and in mitochondria [119].
Molecules 2015, 20 9194
3.3. Metabolic Diseases
3.3.1. Diabetes
Type 2 diabetes is a chronic disease where cells have reduced insulin signaling, leading to hyperglycemia
and long-term complications, such as heart, kidney and liver disease. Recently, more and more studies
have shown the critical roles of oxidative stress and inflammatory reactions in the pathogenesis of
diabetes. When macrophages are activated by dying or stressed cells, the transcription factor NF-κB is
induced and thus leads to the production of pro-inflammatory cytokines including TNF and IL-6.
Curcumin is an anti-oxidant and NF-κB inhibitor and can be considered helpful for the prevention
and amelioration of diabetes [120,121]. It is determined that curcumin can inhibit the enzymes linked to
diabetes such as a-glucosidase, aldose reductase and aldose reductase inhibitors [122–124]. Aldebasi et al.,
reported that curcumin has a therapeutic potential in the inhibition or slowing down progression of
diabetic retinopathy through antioxidant, anti-inflammatory, inhibition of vascular endothelial growth
and nuclear transcription factors [125]. Zhang et al., summarized the recent applications of curcumin for
the glycemia and diabetes-related liver disorders, neuropathy, adipocyte dysfunction, vascular diseases,
nephropathy and pancreatic disorders. They also discussed its antioxidant and anti-inflammatory
properties (Figure 4).
Figure 4. The anti-oxidative and anti-inflammatory molecular targets of diabetes for curcumin [126].
3.3.2. Obesity
Numerous researchers has revealed that obesity is a proinflammatory disease, which is a major risk
for atherosclerosis, cancer, type 2 diabetes, and other chronic diseases. Curcumin exhibits its activity
against obesity by anti-inflammatory and antioxidant mechanisms. Curcumin as a treatment for obesity
and obesity-related metabolic diseases has been shown extensively through suppressing the proinflammatory
NF-κB, signal transducer and activators of STAT3, and Wnt/β-catenin. It activates peroxisome
proliferator-activated receptor-gamma and Nrf2 cell signaling pathways, which could lead to not
only the down-regulation of adipokines, including tumor necrosis factor, IL-6, leptin, resistin and
Molecules 2015, 20 9195
monocyte chemotactic protein-1, but also the up-regulation of adiponectin and other gene products [127].
Mangge et al., reported that curcumin can suppress the level of leptin release and chronic immune-mediated
inflammation through its antioxidant to relieve the obese state [128]. Bradford et al., showed the
experimental evidence for the activity of curcumin in promoting the weight loss and reducing the
incidence of obesity-related diseases [129]. Administration of Meriva (curcumin and phosphatidylcholine)
was provided for at least 4 weeks and was found to be helpful for patients with diabetic microangiopathy
and retinopathy at a dose of two tablets/day (corresponding to 100 mg of curcumin) [130]. Further study
in diabetic patients also revealed that curcumin lowers the atherogenic risks by reducing the insulin
resistance, triglyceride, uric acid, visceral fat and total body fat. Curcumin also helps to improve the
relevant metabolic profiles in type 2 diabetic population [131,132]. And another clinical trial for pilot
study of curcumin for women with obesity and high risk for breast cancer is in recruiting [133].
3.4. Skin Diseases
3.4.1. Scleroderma
Scleroderma is a kind of connective tissue disease, typically resulting in vasculopathy and fibrosis of
skin and other organs, [134]. The cause of scleroderma is still not clear, but fibrosis, vascular abnormalities
and increased extracellular matrix production may be the causes [135]. Recently, oxidative stress plays
an important role in the development of disease [136]. Several studies have verified the increased content
of free radicals such as hydroxyl and peroxynitrite radicals, and increased serum levels of 8-isoprostane,
a marker of oxidative stress in patients with scleroderma in human patients with scleroderma [137].
Additionally, mice treated with releasing agents of free radicals show cutaneous fibrosis [138]. So, many
skin diseases may be connected with oxidative stress, which leads to inflammatory diseases.
Immune-suppression has been considered to be an anchor treatment, since perivascular infiltrate
of inflammatory cells and activation of the immune system are key features of scleroderma [139].
Excessive accumulation of extracellular matrix (ECM) is the hallmark of scleroderma and results in
inflammation [140,141]. Inflammation can be initiated and propagated by ECM disruption in all tissues.
Molecules of ECM, newly liberated by injury or inflammation, include hyaluronan fragments, tenascins
and sulfated proteoglycans. These act as ‘damage-associated molecular patterns’ or ‘alarmins’ that
trigger and subsequently amplify inflammation [138]. Curcumin possess the effects of the anti-fibrosis,
which is characterized by the reduction of collagen deposition, ECM production in pulmonary fibrosis
and keloid formation [142]. The two PKC isoforms (δ and ε) play an important role in scleroderma.
Wermuth et al., suggested that curcumin administration could down-regulate the levels of PKC δ that
cause ECM excessive accumulation and fibrosis in vivo and in vitro [143]. There is abnormal regulation
of inflammatory cytokines and NF-κB involved in angiogenesis and fibrosis in scleroderma [144].
Curcumin can induce apoptosis in scleroderma lung fibroblasts (SLF), by inducting GST P1 and HO-1
which involve the inhibition of protein kinase C epsilon (PKCε). Thus PKC epsilon and phase 2
detoxification enzymes provide protection against curcumin-induced apoptosis in SLF. Song observed
that curcumin effectively inhibited the down-regulation of TGF-β- induced factor (TGIF) to modulate
TGF-β cascade [145]. Another study suggested that curcumin may have therapeutic effect in the
treatment of scleroderma for it could protect rats against lung fibrosis induced by a large number of
Molecules 2015, 20 9196
agents [146]. In conclusion, curcumin has a potentially function in the treatment of scleroderma, but
plentiful researches are also needed.
3.4.2. Psoriasis
Skin diseases seriously affect people’s health wih common and multiple features, of which psoriasis
is the most common [147,148]. Psoriasis is a chronic inflammatory skin disease characterized by thick,
red and scaly lesions on any part of the body which affects approximately 2% of the population
worldwide [149]. Recent investigations revealed that there was a great success to link oxidative stress
and autoimmune skin diseases [150]. The skin is continually under attack by ROS from both exogenous
and endogenous sources. Researchers have demonstrated that dermal γδ T cells play an important role
in the disease development. Many cytokines, including interleukin-23(IL-23), IL-17A, TNF-α, IL-6, IL-1β
and IL-22, are also involved in the pathogenesis of psoriasis [151].
Curcumin is well known for its protective properties in treating various disorders of skin diseases.
Curcumin protects skin by reducing inflammation and quenching free radicals through modulating TGF-β,
NF-κB and mitogen-activated protein kinase pathway. Curcumin also regulates the phase II detoxification
enzymes which are crucial in detoxification reactions and oxidative stress [152]. There are strong
scientific rational suggestions that curcumin is potential herb to suppress psoriasis by inhibiting
keratinocyte proliferation [153]. Sun et al., revealed that curcumin is capable of relieving TPA-induced
skin inflammation by down-regulating IFN-γ production and TPA-induced Th1 inflammation in K14-VEGF
transgenic mice [154]. Curcumin could also demonstrate the inhibitory effect in lmiquimod-induced
psoriasis-like inflammation by decreasing the levels of IL-1β and IL-6 [155]. Furthermore, Kurd’s clinical
trial suggested that orally administered curcumin had a therapeutic effect without adverse events in
patients with psoriasis according to some endpoints like psoriasis area, severity index score and safety [156].
3.5. Cancer
Inflammation plays decisive roles in all the ways of tumorigenesis and therapy response [157,158].
Activation and interaction between STAT3 and NF-κB are very vital in the control of cancer cells and
inflammatory cells [159,160]. TNF-α, VEGF, IL-10, MMP-2 and MMP-9, MCP, CD4+ T, AP-1, Akt,
PPAR-γ, MAP kinases and mTORC1 are also important linking factors between inflammation and
cancer [161,162].
Curcumin has been found to have clinical therapeutic and prevention potential for cancer patients in
in vitro and in vivo animal and human clinical studies for colorectal, liver, pancreatic, lung, breast, uterine,
ovarian, prostate, bladder, kidney, renal, brain, non-Hodgkin lymphoma and leukemia cancers [163–167].
Regular consumption of turmeric has been associated to lower cancer rates in India although without
quantitative cause-and-effect relationship data [168,169]. Curcumin acted as a modulator of intracellular
signaling pathways on multiple targets which control tumor growth, angiogenesis, metastasis, inflammation,
invasion and apoptosis [170]. Most carcinogens activate NF-κB pathways which leads to the expression
of inflammatory enzymes and mediators, including COX-2, LOX-2, iNOS, inflammatory cytokines,
especially TNF-α and chemokines [171]. Curcumin has shown anti-proliferative effect and is an inhibitor
of the transcription factor NF-κB and downstream gene products (including fas, p53, VEGF, Cdc42,
Bcl-2, COX-2, NOS, cyclin D1, TNF-α, interleukins and MMP-9) [172–177]. Curcumin provided a
Molecules 2015, 20 9197
possibility for multiple myeloma treatment by down-regulating activation of NF-ΚB and STAT3 and
suppressing COX-2 expression [178]. Karunagaran et al., revealed that curcumin-induced apoptosis
mainly involves the mitochondria-mediated pathway in various cancer cells. Kronski et al., showed that
as a chemopreventive curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2
leading to diminished formation of breast and prostate cancer metastases. MiR181b is induced by the
chemopreventive curcumin and inhibits breast cancer metastasis via down-regulation of the
inflammatory cytokines CXCL1 and -2 [179,180]. Thus curcumin could serve as a simple bridge to
bring metastamir modulation into the clinic in preventive and therapeutic effects. Prusty and Das
explored the redox regulatory pathway involved in the HPV expression which can be modulated by an
antioxidant-induced reconstitution of the AP-1 transcription [181]. Later they observed curcumin
completely down-regulated the AP-1 binding activity and reversed the c-fos/fra-1 transcription to a
normal state in cervix HeLa cancer cells which was a novel mechanism controlling transcription of
pathogenic HPVs during keratinocyte differentiation and progression of cervical cancer.
3.6. Bioavailability of Curcumin
Despite curcumin’s highly promising features for treatment and prevention of various diseases,
clinical uses have been hindered by poor absorption, rapid metabolism, short biological half-life, and
low oral bioavailability (only 1% in rats) [182,183]. Very high doses (>3.6 g/day in humans) are required
to produce any medicinal effect [184].
Wahlstrom and Blennow first reported in 1978 that negligible amounts of curcumin were observed in
blood plasma after oral administration of 1 g/kg of curcumin in Sprague-Dawley rats due to its poor
absorption from the gut [185]. Curcumin bioavailability may also be poor in humans, as either
undetectable or extremely low serum levels of curcumin (0.006 ± 0.005 µg/mL at 1 h) were observed in
humans after an oral dose of 2 g/kg [186]. It has been found that 10 mg/kg of curcumin given
intravenously in rats gave a maximum serum curcumin level of 0.36 µg/mL, whereas a 50-fold higher
curcumin dose administered orally gave only 0.06 ± 0.01 µg/mL maximum serum level in rat [187].
Intravenous administration of 2 mg/kg curcumin to rats showed better availability with the concentration
was 6.6 µg/mL of blood plasma shown by Sun et al. [188]. A number of studies have cited extremely
low blood curcumin concentrations (Table 1), indicating that curcumin bioavailability needs to be
improved to exert significant medical effects.
Molecules 2015, 20 9198
Table 1. Previously reported blood curcumin concentrations in humans.
Subject Dose (g/Day) Sample Size Plasma Curcumin Level (Means ± SE) Ref.
Healthy volunteers
2 8 6 ± 5 ng/mL [186]
8 6 0.6 μg/mL [189]
12 1 57.6 ng/mL (t = 2 h) [190]
Persons with Alzheimer’s Disease 4 30 7.76 ± 3.23 ng/mL [191]
Patients with precancerous lesions 8 2 1.77 ± 1.87 mM [192]
Patients with chronic
inflammatory bowel disease 4 4
2
Pre-intervention 7.3 ± 8.1 ng/mL
Post- intervention 3.8 ± 1.3 ng/mL [193]
Patients with pancreatic cancer 8 5 134 ± 70 ng/mL [194]
Patients with colorectal cancer 3.6 4 12.7 ± 5.7 nmol/g (normal tissue)
7.7 ± 1.8 nmol/g (malignant colorectal tissue) [195]
Despite its generally low bioavailability, curcumin has been shown to have distant or indirect effects [104]
through the upregulation of the enzyme intestinal alkaline phopshatase (IAP), which is a fantastic
anti-oxidant and anti-inflammatory endogenous component produced at the gut epithelial level and that
has been shown to have local and also distant protective effects though oxidation and inflammation
down-regulation [196].
To improve the bioavailability of curcumin, numerous attempts have been made for challenges
through the use of adjuvants like piperine [197], curcumin structural analogues [198], and development of
improved delivery technologies such as nanodisks [199], polymeric micelles [200], nanoparticles [201]
and polymeric implants [202].Combination therapy containing curcumin and a bio-enhancer such as
piperine, quercetin or silibinin could enhance the cellular uptake of curcumin and modulate the in vivo
pharmacokinetics of curcumin due to albumin-binding interactions which are expected to enhance the
efficacy of curcumin [203]. Curcumin also binds to a variety of biopolymers and is known to retain its
medicinal activity in the bound states [204]. Kanai et al., reported the first nanoparticle formulation of
curcumin that demonstrates improved bioavailability in human subjects and C (max) for nanoparticle
curcumin (named THERACURMIN) at 150 and 210 mg was 189 ± 48 and 275 ± 67 ng/mL (mean ± SEM),
respectively in healthy human volunteers [205]. Enhanced bioavailability of curcumin in the near future
is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of
human disease. Recent and ongoing clinical trials have indicated curcumin’s therapeutic potential
against a wide range of human diseases with numerous signaling molecules targets. These preclinical
studies have formed a solid basis for evaluating curcumin’s efficacy in clinical trials. In clinical trials,
curcumin has been used either alone or in combination with other agents. A search on www.clinicaltrials.gov
(accessed in February 2015) indicated that about 108 clinical trials with curcumin for the chronic
diseases listed in this paper have been conducted, among which 31 clinical trials have been completed
(Table 2). The most common evaluated human diseases for curcumin are cancer and inflammatory bowel
disease. Most of these clinical trials are from the United States.
Molecules 2015, 20 9199
Table 2. Completed and on-going clinical studies of curcumin.
Diseases Number of Clinical Studies Mainly Completed Clinical Studies
Completed On-Going
Neurodegenerative
Diseases 3 2
1. A pilot study of curcumin and ginkgo for treating
Alzheimer’s disease
2. Curcumin in patients with mild to moderate
Alzheimer’s disease
3. A randomized, double-blind, placebo-controlled trial of
curcumin in Leber’s hereditary optic neuropathy (LHON)
Diabetes 2 3
1. Effects of curcumin on postprandial blood glucose, and
insulin in healthy subjects
2. Diabetes visual function supplement study
Obesity 0 1
1. Pilot study of curcumin for women with obesity and high
risk for breast cancer
Cardiovascular
Diseases 3 7
1. Curcumin (diferuloylmethane derivative) with or without
bioperine in patients with multiple myeloma
2. Role of turmeric on oxidative modulation in ESRD patients
3. Diabetes visual function supplement study
Chronic Kidney
Disease 2 2
1. Effect of oral supplementation with curcumin (turmeric) in
patients with proteinuric chronic kidney disease
2. Role of turmeric on oxidative modulation in end-stage renal
disease (ESRD) patients
Inflammatory
Bowel Disease 5 14
1. Curcumin in pediatric inflammatory bowel disease
2. Curcumin + aminosalicylic acid (5ASA) versus 5ASA alone
in the treatment of mild to moderate ulcerative colitis
3. Curcumin (tumeric) in the treatment of irritable bowel
syndrome: A randomized-controlled trial
4. Curcumin biomarkers
5. Curcumin for the prevention of colon cancer
Allergy, asthma
and bronchitis 1 2
1. Effect of supplemental oral curcumin in patients
with atopic asthma
Cancer 16 35
1. Curcumin (siferuloylmethane derivative) with or without
bioperine in patients with multiple myeloma
2. A nutritional supplement capsule containing curcumin,
green tea extract, Polygonum cuspidatum extract, and soybean
extract in healthy participants
3. Curcumin for the prevention of radiation-induced dermatitis
in breast cancer patients
Rheumatoid
Arthritis 0 1 1. Curcumin in rheumatoid arthritis
Pancreatitis 0 1 1. Gemcitabine with curcumin for pancreatic cancer
Scleroderma / / /
Psoriasis 1 1 1. Curcuminoids for the treatment of chronic psoriasis vulgaris
Molecules 2015, 20 9200
4. Conclusions
Curcumin has been demonstrated to have therapeutic potential for various chronic inflammatory
diseases, essentially due to its anti-inflammatory and anti-oxidative properties against a vast array of
molecular targets. Studies on the biological evaluation of curcumin have revealed that curcumin is a
pro-drug, which inhibits the growth of cells by releasing active free thiol group within the target site.
A large body of investigation has provided important insights into the anti-inflammation effects of
curcumin which will constitute the basis for the further design and clinical application of extraordinarily
potent drugs with potential therapeutic significance. As the problems of curcumin absorption,
biodistribution, metabolism and elimination are overcome to enhance its bioavailability, many chronic
inflammatory diseases will be at the forefront as promising targets for curcumin therapy.
Acknowledgments
We thank the China Postdoctoral Science Foundation (2013M540649) for financial supports. The present
study was supported by grants from the National Natural Science Foundation of China (21272043 and
81272452), Project of Guangdong Science & Technology Collaboration (2012b091000170), and
Guangdong Province Leadership Grant.
Author Contributions
All authors performed research; Yan He, Yuan Yue and Zhiyun Du contributed to the writing and
formatting of this review article; Xi Zheng, Kun Zhang, Shaohua Chen examined and revised the initial
manuscript; All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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... of 21 have uncovered that curcumin is supportive of medication, which represses the development of cells by delivering dynamic free thiol bunch inside the objective site.[36] ...
Preprint
In this review, the following information describes the manifestation of sleep deprivation by human beings and its adverse effect on their health. Sleep deprivation has been demonstrated into namely two types known as REM sleep and NREM sleep affecting our health in so a problematic way that it is making our body immune to many diseases leading to lethal problems. Therefore, great research by many scientists has discovered that the turmeric “Curcuma longa” which is been used in every Indian kitchen since ancient times, has shown a remarkable effect on the problem caused by sleep deprivation but due to its poor solubility and low bioavailability drawn it into a great disadvantage. But the help of the study of nanotechnology and the evolution of curcumin into nano–curcumin made the possibility of the remarkable effect by making the curcumin more potent and enhancing its stability. Immunological changes due to sleep deprivation lead to Alzheimer’s disease, glioma, neuropathic pains, and many more. Therefore, this review has been summarized as it is been providing information related to curcumin and its affection for sleep deprivation.
... of 21 have uncovered that curcumin is supportive of medication, which represses the development of cells by delivering dynamic free thiol bunch inside the objective site.[36] ...
Preprint
Full-text available
In this review, the following information describes the manifestation of sleep deprivation by human beings and its adverse effect on their health. Sleep deprivation has been demonstrated into namely two types known as REM sleep and NREM sleep affecting our health in so a problematic way that it is making our body immune to many diseases leading to lethal problems. Therefore, great research by many scientists has discovered that the turmeric “Curcuma longa” which is been used in every Indian kitchen since ancient times, has shown a remarkable effect on the problem caused by sleep deprivation but due to its poor solubility and low bioavailability drawn it into a great disadvantage. But the help of the study of nanotechnology and the evolution of curcumin into nano–curcumin made the possibility of the remarkable effect by making the curcumin more potent and enhancing its stability. Immunological changes due to sleep deprivation lead to Alzheimer’s disease, glioma, neuropathic pains, and many more. Therefore, this review has been summarized as it is been providing information related to curcumin and its affection for sleep deprivation.
... Curcumin is the active component of turmeric (Curcuma longa), with a variety of therapeutic properties (Tamaddonfard et al., 2012;Li et al., 2018). Potent antioxidant and antiinflammatory activities of this medicinal plant, indicated in many previous studies (Arshami et al., 2012;Li et al., 2012;Yu et al., 2012;He et al., 2015;Zhang et al., 2016;Wang et al., 2017;Zhao et al., 2017;Kadam et al., 2018;Yang et al., 2018;Safali et al., 2019;Yasbolaghi Sharahi et L., 2020), might positively affect the healing process (Alaseirlis et al., 2005;Park et al., 2010;Güleç et al., 2018;Ferreira-Junior et al., 2020). Currently, some evidence in the literature supports the role of curcumin in the bone remodeling process, by its negative effect on RANKL and inhibiting osteoclastogenesis (Chen et al., 2012;Moon et al., 2012;Rohanizadeh et al., 2016). ...
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Objective: Following bone trauma, several factors participate in making a balance between the activity of osteoblasts and osteoclasts. The receptor activator of nuclear factor kappa B ligand (RANKL), receptor activator of nuclear factor kappa B (RANK), and osteoprotegerin (OPG) molecules play critical roles in the healing process via regulation of osteoclasts function. Turmeric is suggested to have an anti-osteogenic potential; however, its effect on accelerating bone healing has not been adequately studied. Here, we used a rat model of femur fracture to explore the effect of treatment with turmeric extract on the bone repair and the expression of RANK, RANKL, and OPG molecules. Materials and methods: Eight rats were subjected to surgery, randomly divided into two groups, and treated orally with turmeric (200 mg/kg), or olive oil. Four oil-treated rats without bone fracture were used as control group. After six weeks of treatment, the femurs of animals were examined for radiological, histological, and gene expression analysis. Results: X-ray radiography showed thicker callus and a more obscure fracture line in the turmeric group. Furthermore, higher osteoblast percentages but no osteoclasts were observed in turmeric-treated animals, representing better repair of bone in the fracture site. Also, real-time analyses showed that treatment with turmeric reduced RANK and RANKL expression (p<0.0001) and lowered RANKL/OPG ratio (p=0.01) in femoral bone tissue. Conclusion: Our findings indicated the turmeric ability to facilitate bone hemostasis and optimize the expression of key markers involved in the bone metabolism.
... 29,30 Curcumin also downregulates and directly inhibits lipoxygenase (LOX) and downregulates inducible nitric oxide synthase, mitogen-activated protein kinases, and Janus kinases, which are associated with inflammatory processes. 29,31 Downstream effects of curcumin through these pathways include inhibition of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-mediated gene expression of cytokines, including reduced production of tumor necrosis factor-alpha (TNF-α), interleukins (ILs-1, -2, -6, -8, and -12), monocyte chemoattractant protein (MCP), migration inhibitory protein, prostaglandin E 2 (PGE 2 ), matrix metalloproteinase (MMP)-2,-3,-9, inflammasome NLRP3, and reactive oxygen species. 28,32-38 IL-10, a cytokine associated with reducing inflammation, is increased by curcumin supplementation in various inflammatory diseases, and the anti-inflammatory activity of IL-10 is enhanced through blocking pathways associated with inflammation. ...
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For several thousand years (~4000) Boswellia serrata and Curcuma longa have been used in Aryuvedic medicine for treatment of various illnesses, including asthma, peptic ulcers, and rheumatoid arthritis, all of which are mediated through pathways associated with inflammation and pain. Although the in vivo pharmacology of both these natural ingredients is difficult to study because of poor bioavailability, in vitro data suggest that both influence gene expression mediated through nuclear factor kappa B (NF-κB). Therefore, the activity of pathways associated with inflammation (including NF-κB and lipoxygenase- and cyclooxygenase-mediated reduction in leukotrienes/prostaglandins) and those involved in matrix degradation and apoptosis are reduced, resulting in a reduction in pain. Additive activity of boswellic acids and curcumin was observed in preclinical models and synergism was suggested in clinical trials for the management of osteoarthritis (OA) pain. Overall, studies of these natural ingredients, alone or in combination, revealed that these extracts relieved pain from OA and other inflammatory conditions. This may present an opportunity to improve patient care by offering alternatives for patients and physicians, and potentially reducing nonsteroidal anti-inflammatory or other pharmacologic agent use. Additional research is needed on the effects of curcumin on the microbiome and the influence of intestinal metabolism on the activity of curcuminoids to further enhance formulations to ensure sufficient anti-inflammatory and antinociceptive activity. This narrative review includes evidence from in vitro and preclinical studies, and clinical trials that have evaluated the mechanism of action, pharmacokinetics, efficacy, and safety of curcumin and boswellic acids individually and in combination for the management of OA pain.
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Subjects: Plant Sciences Contributor: Bashar Saad Numerous scientific papers published highlight the immunological role of adipocytes and their role in inflammatory responses through the secretion of adipocytokines (adipokines), which regulate the adipocyte phenotype through complex mechanisms of action. Normally, adipose tissue produces anti-inflammatory mediators, but with increasing cell hypertrophy, adipose tissue secretes a number of pro-inflammatory cytokines and hormones, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), angiotensinogen, transforming growth factor-β (TGF-β), leptin, adiponectin, resistin, and monocyte chemoattractant protein-1 (MCP-1). They also produce the pro-inflammatory hormone leptin, which inhibits the secretion of the anti-inflammatory hormone adiponectin. Compared with subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) has a higher rate of lipolysis, a higher infiltration rate of macrophages, and a higher secretion of IL-6, MCP-1, and other inflammation-related markers. With increasing obesity, monocytes infiltrate into adipose tissues, where they mature into macrophages. obesity inflammation medicinal plants 1. Curcuma Longa Rhizomes (Turmeric) Curcuma longa rhizomes (Turmeric) have a long history of use as a health-promoting agent. The roots of turmeric have been known for their health values for hundreds of years in Ayurveda, Chinese, and Greco-Arab and Islamic medicine. Over 800 scientific reports and more than 100 clinical trials have investigated the cellular, molecular, and pharmacological effects of curcumin. Many of these reports emphasize the potential benefits of curcumin in the treatment of chronic diseases such as cardiovascular disease, T2D, overweight/obesity, cancer, autoimmune diseases, neurological and mental disorders. Most published reports have linked the benefits of turmeric to its antioxidant and anti-inflammatory properties. Curcumin, the major polyphenol from turmeric, has been reported to promote weight loss and reduce the incidence of obesity-related diseases. Curcumin intake reduces levels of TNF-α and IL-6 and increases the level of adiponectin in the plasma of obese and overweight individuals. In addition, curcumin regulates a number of biochemical and molecular targets, including transcription factors (NF-kB, NLP3), signaling pathways, and other complex regulatory systems, resulting in attenuation of the chronic low-grade inflammatory response in adipose tissue. Several clinical studies have shown that the interaction of curcumin with transcription factors, cellular receptors, growth factors, enzymes, cytokines, and chemokines reduces inflammation in obese individuals by restoring the balance between pro-inflammatory and anti-inflammatory mediators. Several published studies clearly indicate that curcumin significantly decreases pro-inflammatory cytokine levels and increases plasma adiponectin levels in obese and overweight individuals. Furthermore, curcumin can affect multiple molecular targets, including transcription factors (NF-kB, NLP3), signaling pathways, and other complex regulatory systems in adipose tissue, resulting in the attenuation of chronic low-grade inflammatory response. In [1][2][3][4][5][6][7] [8][9] [4][10][11][12][13] [14] [12][13][15] [16][17]
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Purpose Turmeric has renop rotective effects that can act to reduce oxidative stress and inflammation in hemodialysis (HD) patients. Piperine has been indicated as a bioavailability enhancer of turmeric and consequently of its biological effects. However, data on the efficacy of the turmeric/piperine combination in HD patients are limited. We aimed to verify whether turmeric supplementation in combination with piperine has a superior effect to turmeric alone in increasing antioxidant capacity and reducing oxidative stress and inflammation in HD patients. Methods This randomized, double-blind clinical trial was conducted in HD patients (age 20–75 years). Patients were supplemented with turmeric (3 g/day) or turmeric/piperine (3 g turmeric + 2 mg piperine/day) for 12 weeks. Malondialdehyde (MDA), antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), high-sensitivity C-reactive protein (hs-CRP), and ferritin were evaluated at baseline and the end of the study. Results There was a reduction in the MDA and ferritin levels in the turmeric/piperine group and in the comparison between groups at the end of the study [MDA: −0.08(−0.14/0.01) nmol/mL versus −0.003(−0.10/0.26) nmol/mL, p = 0.003; ferritin: −193.80 ± 157.29 mg/mL versus 51.99 ± 293.25 mg/mL, p = 0.018]. In addition, GPx activity reduced in the turmeric group (p = 0.029). No changes were observed for CAT, GR, and hs-CRP. Conclusion Turmeric plus piperine was superior to turmeric alone in decreasing MDA and ferritin levels. The use of a combination of turmeric and piperine as a dietary intervention may be beneficial for modulating the status oxidative and inflammation in HD patients. Brazilian Registry of Clinical Trials Number RBR-2t5zpd; Registration Date: May 2, 2018.
Chapter
The evidence has been shown that mitochondrial-derived reactive oxygen species (ROS) act as central regulators, checkpoints, and arbitrators in the inflammatory responses. It has been reported that mitochondrial ROS contributes to specific aspects of mitochondrial inflammation (mito-inflammation) in different inflammatory-related diseases such as diabetes, cardiovascular diseases, neurodegenerative disorders, cancer and pulmonary diseases. Mitochondrial-related oxidative stress stimulates oxidation of mitochondrial DNA (mtDNA), proteins, and lipids and leads to the release of the damage-associated molecular patterns (DAMPs) such as cardiolipin and mtDNA into cytosol. These DAMPs and oxidative stress can promote inflammatory responses by stimulating the generation of transcription factors, cytokines and related growth factors via oxidation of factors involved in inflammation such as nuclear factor κB (NF-κB). The activation of NF-κB as a key regulator of tissue inflammation increases the expression of eicosanoids, chemokines, cytokines, adhesion molecules and inducible nitric oxide synthase. Therefore, mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades in inflammatory-related diseases. Mitochondrial protection and mitochondrial ROS reduction can have an important effect on reducing inflammatory responses. Curcumin as an active compound found in turmeric has shown promising effects in reducing mitochondrial damage and mitochondrial-dependent oxidative stress. It seems that curcumin applies the mitochondrial protection effects and its subsequent antiinflammatory properties via different mechanisms such as ROS scavengers, enhancing of mitochondrial antioxidants, the activation of Nrf2, targeting of Sirtuins, p66Shc and uncoupling proteins, inhibition of cyclooxygenase-2, and monoamine oxidase enzymes. In this chapter we discuss the relationship between oxidative stress and inflammation, inflammation and mitochondria, and finally the importance of curcumin for protecting mitochondria and downregulating inflammation.
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Curcuma longa (turmeric) has a long history of use in Ayurvedic medicine as a treatment for inflammatory conditions. Turmeric constituents include the three curcuminoids: curcumin (diferuloylmethane; the primary constituent and the one responsible for its vibrant yellow color), demethoxycurcumin, and bisdemethoxycurcumin, as well as volatile oils (tumerone, atlantone, and zingiberone), sugars, proteins, and resins. While numerous pharmacological activities, including antioxidant and antimicrobial properties, have been attributed to curcumin, this article focuses on curcumin's anti-inflammatory properties and its use for inflammatory conditions. Curcumin's effect on cancer (from an anti-inflammatory perspective) will also be discussed; however, an exhaustive review of its many anticancer mechanisms is outside the scope of this article. Research has shown curcumin to be a highly pleiotropic molecule capable of interacting with numerous molecular targets involved in inflammation. Based on early cell culture and animal research, clinical trials indicate curcumin may have potential as a therapeutic agent in diseases such as inflammatory bowel disease, pancreatitis, arthritis, and chronic anterior uveitis, as well as certain types of cancer. Because of curcumin's rapid plasma clearance and conjugation, its therapeutic usefulness has been somewhat limited, leading researchers to investigate the benefits of complexing curcumin with other substances to increase systemic bioavailability. Numerous in-progress clinical trials should provide an even deeper understanding of the mechanisms and therapeutic potential of curcumin.
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Purpose of review Acute pancreatitis is associated with a significant morbidity and a mortality as high as 10%. This review summarizes the most relevant articles in the past year that have contributed to understanding and management of this disease. Recent findings Pathologic activation of both digestive zymogens and the transcription factor nuclear factor kappaB are early events in acute pancreatitis; these pathologic processes are inhibited in experimental pancreatitis by curcumin and the pH modulator chloroquine. Primary sensory neurons may constitute a final common pathway for pancreatic inflammation. Experimental acute pancreatitis and associated lung injury are attenuated by inhibiting the prostanoid mediators cyclo-oxygenase-2 and 5-lipoxygenase and CC chemokine receptor antagonist Met-RANTES. Endoscopic retrograde cholangiopancreatography-induced acute pancreatitis can be reduced experimentally by intraductal neurokinin-1 receptor antagonist and clinically by use of diclofenac and pancreatic duct stenting. MRI in the setting of acute pancreatitis is a reliable method of staging disease severity, Distinct patterns of cytokine response are observed in acute pancreatitis. Summary Early events within the acinar cell and the regulation of inflammation by transcription factors continue to be elucidated Although experimental acute pancreatitis can be successfully ameliorated by use of cytokine and inflammatory inhibitors, this has not been demonstrated in clinical disease. The finding of a compartmentalization of the inflammatory response in acute pancreatitis may be important for planning therapeutic interventions. Pancreatic duct stenting reduces the risk of developing postendoscopic retrograde cholangiopancreatography pancreatitis in high-risk people.
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Curcumin has been confirmed to have anti-inflammatory properties in addition to the ability to decrease the expression of pro-inflammatory cytokines in keratinocytes. It was suggested that the interleukin-23 (IL-23)/IL-17A cytokine axis played a critical role in the pathogenesis of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate (TPA)-induced K14-VEGF transgenic psoriasis-like mice model. Here, we report that topical use of a curcumin gel formulation inhibited TPA-induced Th1 inflammation in K14-VEGF transgenic mice ears but not Th17 inflammation as expected. Real-time PCR showed that mRNA levels of IL-23, IL-17A, IL-22, IL-6 and TNFα cytokines failed to increase after TPA-induction in K14-VEGF transgenic mice ear skin; but the mRNA level of IFNγ increased significantly at the same time. Furthermore, TPA-induction up-regulated the TCRγδ protein but failed to impact the CCR6 protein, which means that the proliferation of γδ T cells is incapable of IL-17A production. We find that curcumin is capable of relieving TPA-induced inflammation by directly down-regulating IFNγ production. In conclusion, curcumin inhibits TPA-induced Th1 inflammation in K14-VEGF transgenic mice which has not been previously described. Copyright © 2015. Published by Elsevier B.V.
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Oxidative stress plays a main role in the pathogenesis of type 2 diabetes mellitus (T2DM). Cocoa and (-)-epicatechin (EC), a main cocoa flavanol, have been suggested to exert beneficial effects in T2DM because of their protective effects against oxidative stress and insulin-like properties. In this study, the protective effect of EC and a cocoa phenolic extract (CPE) against oxidative stress induced by a high glucose challenge, which causes insulin resistance, was investigated on hepatic HepG2 cells. Oxidative status, phosphorylated mitogen-activated protein kinases (MAPKs), nuclear factor E2-related factor 2 (Nrf2) and p-(Ser)-IRS-1 expression, and glucose uptake were evaluated. EC and CPE regulated antioxidant enzymes and activated ERK and Nrf2. EC and CPE pre-treatment prevented high glucose-induced antioxidant defences and p-MAPKs, and maintained Nrf2 stimulation. The presence of selective MAPK inhibitors induced changes in redox status, glucose uptake, p-(Ser)- and total IRS-1 levels that were observed in CPE-mediated protection. EC and CPE recovered redox status of insulin-resistant HepG2 cells, suggesting that the functionality in EC- and CPE-treated cells was protected against high glucose-induced oxidative insult. CPE beneficial effects on redox balance and insulin resistance were mediated by targeting MAPKs. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.