Key words
anti-inflammatory drugs - cardiovascular pharmacology - pharmacology - pulmonary & respiratory pharmacology - inflammation - cardiovascular diseases
Introduction
Historically plants were used in India for medicinal purposes. Turmeric is an herbal
medicine. It belongs to species of Curcuma longa Linn. It is a medicinal
plant broadly employed in Ayurveda, Unani and Siddha system of medicine. It is also
used as home remedy for various diseases [1].
Curcumin (diferuloylmethane) is the main constituent of the popular Indian spice
turmeric, turmeric belongs to the ginger family (Zingiberaceae)
[2]. The derivative of Curcumin is
curcuminoids (Curcuminoids is a linear diarylheptanoid, polyphenolic molecules). The
other two main forms of curcuminoids are desmethoxycurcumin and
bis-desmethoxycurcumin and it is important for the yellow colour of turmeric [3]. Curcumin has two tautomeric compound form
ketonic and enolic. The enolic group has more stability in the solid phase and
solution. Curcumin is a bright yellow colour compound and it is applied as a food
colouring agent [4].Curcumin has been acquired
a wide range of pharmacological and biological activities including
anti-inflammatory, anti-cancer, anti-oxidant, wound healing, anti-microbial and many
others biological properties [5]
[6]. Turmeric was characterized as C.
Longa Linn by Linnaeus, Liliopsida is the class of C. longa Linn,
subclass is commelinids, order is zingiberaceous, and the family is
Zingiberaceae, the genus is Curcuma and Species is Curcuma longa.
The primitive turmeric is C. aromatica and the domiciliary species is called
as C. longa Linn [3].
Physical and chemical properties of Curcumin
Curcumin is a brightly yellow color pigment compound with anti-oxidant and
anti-tumor activities. Chemical name - diferuloylmethane, IUPAC name is 1, 7-bis
(hydroxyl-3-methoxyphenyl)-1, 6-heptadiene 3,5-dione [7]
[8]. The molecular formula is
C21H20O6, appearance-bright yellow-orange
powder, melting point is 183°C (361°F; 456 K), molar
mass-368.385 g mol−1 and Curcumin solubility in DMSO
(>11mg/mL) [9], Curcumin
is rapidly soluble in organic solvents such as acetone, ethanol, DMSO, and
dimethyl formamide [10]. The maximum oral
dose of Curcumin is 8 g/day for 3 months (human) at this dose Curcumin
has not caused any toxic and hazardous effects [11].
Pharmacokinetics properties of Curcumin
Curcumin pharmacokinetics and bioavailability studies have been indicated low
intestinal absorption. Oral administration of 400 mg of Curcumin shows
absorption rate of 60–66% [12] and rapid clearance from the body. Curcumin clinical use is
limited largely because it has low solubility and fast metabolism that leads to
low bioavailability [10]. It is permeable
across blood-brain barrier [4]
[12]
[13].
Pharmacological properties of Curcumin
Curcumin possess so many properties like anti-oxidant, anti-inflammatory,
anti-viral and anti-fungal actions. Some investigators proved that Curcumin has
not been shown any toxic effect in humans. Curcumin prevents the growth of
Helicobacter pylori which induces gastric ulcers [13]. Curcumin shows anti-inflammatory
activity by inhibition of molecules that play an important role in inflammatory
disorder [14]. Turmeric is effective in
preventing post-surgical inflammation and exerts anti-osteoporotic activity.
Curcumin can bind with heavy metals such as cadmium and lead which can reduces
the toxic effect of these heavy metals [15]. Curcumin inhibits the pathway of cyclooxygenase, 5-lipoxygenase
and glutathione S-transferase. Curcumin prevents atherosclerosis by reducing the
formation of blood clumps [4]. Curcumin
has potential for scavenging superoxide radicals, hydrogen peroxide and nitric
oxide (NO) from activated macrophages, reduces the iron complex and lipid
peroxidation both in vitro and in vivo [16]
[17].
Role of Curcumin in Alzheimer disease
Curcumin has shown its beneficial action by binding the copper, lowering the
cholesterol level, inhibiting the enzyme acetylcholinesterase, modifying the
insulin signalling pathway, suppressing the tau and by enhancing the
phagocytosis of Aβ by microglia/microphages [18]
[19]
[20]
[21]
[22].
Effect of Curcumin on respiratory disorder (lungs cancer)
Curcumin inhibit the apoptosis through modulation of the miRNA pathways which is
important for inhibition of caspase-3, and which to prevent the Pi3K/Akt
pathway (implicated in growth factor-mediated cell survival) [23], and also inhibit the XIAP. Curcumin
has cytotoxic properties of NSCLC and SCLC, which are mediated by an increase of
ROS and apoptosis. Curcumin inhibited lung cancer cell proliferation via the
JAK/STAT3 pathway which is incriminated in tumor recurrence and drug
resistance [24]
[25]. This inhibition leads to the
prevention of abnormal cell growth and suppressed the proliferation, migration,
invasion and angiogenesis of SCLC cells. Another mechanism by which Curcumin
reduces the proliferation of SCLC cells is the induction of FOXO1, a
transcription factor that regulates cell proliferation, differentiation and DNA
damage repair. Curcumin's induction of FOXO1 upregulates p21 and p27
gene codes and down regulates cyclin D, inducing cycle arrest and apoptosis
[26].Inhibition of cell proliferation
by Curcumin also appears from epigenetic effects by reactivation of silenced
tumor cells suppressor genes. In NSCLC cells, Curcumin decreases the
RARβ (retinoic acid receptor beta) promoter methylation [27], which induces the expression of
RARβ and leads to prevent the tumor cells growth. The antineoplastic
role of Curcumin is also mediated by the decrease the cancer cell migration. In
patients of NSCLC Curcumin downregulates early growth response protein 1 (EGR-1)
and enhancement of cell-cell adhesion [28]. Furthermore, Curcumin prevents the production and activity of MMPs
(Metalloproteinases or matrixins) by several mechanisms [29]. In NSCLC patients Curcumin inhibits
phosphokinase A, with preventing the NADPH oxidase-2 and reduces ROS production.
ROS is important for activation of transcription factor-2 (ATF-2), induces MMP-9
production. Another mechanism is reducing the Rac1/PAK1 pathway [30], which leads to the downregulation of
MMP-2 and MMP-9 and reducing cell migration. Curcumin helps in downregulation of
adiponectin, a cytokine produced by adipose tissue and implicated in lung
cancer. This downregulation prevents the NF-κβ and reduces the
production of MMPs which causes the reduction in the migration and invasion
capability of these cells. Curcumin decreases the expression of DNA repair
proteins and enhances p53 levels, inducing apoptosis of cells [28]
[31]
[32].
Effect of Curcumin in Osteoarthritis (inflammatory disorder)
Osteoarthritis is a chronic joint disorder of the liftable joints affecting the
older-age population worldwide. It is estimated by loss of cartilage,
remodelling of adjacent bone and bony overgrowth [33].Mechanism-based antiarthritic potential
of Curcumin includes chondrocyte regeneration and apoptosis, inflammation, and
oxidative stress. Curcumin inhibits inflammation in osteoarthritis by
intraperitoneal administration of curcumin at 50 mM ([Fig. 1]) [34].
Fig. 1 Effect of Curcumin in osteoarthritis (inflammatory
disease).
Effect of Curcumin on cardiac disorder
Curcumin has anti-inflammatory and antioxidant properties thereby this compound
reduces cardiovascular complications, such as unstable angina, CHF and
arrhythmia [35]. Curcumin has an
antioxidative property which inhibits the oxidative stress. Inhibits the
apoptosis and also have anti-inflammatory properties. This compound exerts
cardioprotective role on myocardial ischemia [35]. It reduces the release of cardiac LDH and CK and increases the
post-ischemic cardiac function. Curcumin also plays a protective role in
cardiomyocyte structure, attenuating extracellular matrix (ECM) remodelling and
promotes cardiac contraction [36].
Oxidative stress is an important factor contributing to ischemic myocardial
injury (IMI). Curcumin reduces the isoproterenol-induced myocardial ischemia by
improving the levels of SOD catalase, glutathione, suppressing the production of
thiobarbituric acid reactive substances and the leakage of lactate dehydrogenase
(LDH) [37]. Wang et al. Study proved that
Curcumin reduces the mitochondrial hydrogen peroxide activity [38]. This compound also suppresses the
malondialdehyde levels [39]. Curcumin by
improving the anti-apoptotic protein Bcl-2 level favour a protective effect
against cerebral Ishemia/reperfusion injury (IRI) by the activation of
JAK2/STAT3 signaling pathway [40]
[41]. It also recovers post-ischemic
cardiac function, myocardial infarct size and lactate dehydrogenase release in
the coronary flow. This compound reduces the myocardial IRI by preventing
inflammation, which may be a critical pathway of myocardial ischemia. Curcumin
has been shown lowering the upregulation of IL-1, IL-6, IL8 and TNFα
([Fig. 2]) [42]. Curcumin releases the cytoplasmic
inflammatory cytokine NF-κβ. This compound also inhibits TLR2,
reduces infarct size, and myocardial injury [43]
[44]. Some studies have been proved that
inactivation of TLR2 reduces the myocardial IRI [34]. Curcumin ameliorates the heat stress and enhances the
stabilization of the cytoskeletal structures, it increases the level of
mitochondrial energy production to ensure sufficient energy supply and also
improves cardiac contractility [45].
Fig. 2 Curcumin increases the level of SOD, GSH, HO-1 (Heme
oxygenase) and reduces the level of MDA, ROS,
H2O2, inhibits lactate dehydrogenase, creatine
kinase, enhance post ischemic cardiac function, Curcumin improves the
anti-apoptotic protein Bcl-2, downregulates TNFα, NF- kβ
and IL-6 against inflammatory stimuli and also increases the level of
mitochondrial energy production and improves the cardiac
contractility.
Curcumin potential in hepatic disorder (liver disease)
Hepatic disorders covers all the problems that cause hepatic damage to perform
its functions [46]. Abuse drug is the most
common cause of hepatic disease. Toxic Drug effects on hepatic cells cause
hepatic cell damage and hepatic inflammation. Accumulation of fats occurs in
hepatic cells which affects their function in chronic alcohol abuse [47]
[48]. Curcumin lowers the level of
PGI2, LDL and increases the HDL [49].
-
Effect of Curcumin in non-alcoholic liver disease
Curcumin in the dose of 200 mg/kg/day (orally) for 3
weeks prevent the inflammation of non-alcoholic liver male Wistar-Albino
rat [50]. Curcumin prevents the
development and progression of fibrosis. Reduces the tissue inhibitor
metalloproteinase-1 (TIMP-1) secretion and prevents
8-OH-deoxyguanosine-mediated liver oxidative stress. Curcumin inhibits
the inflammation of non-alcoholic liver, by preventing the
proinflammatory cytokines, lipid perodixation products, PI3K/Akt
and hepatic stellate cells activation. It ameliorates non-alcoholic
steatohepatitis (NASH) via lipid reduction, increase insulin resistance,
improved anti-inflammatory and antioxidant effects which possibly
related to activation of Nrf2 [51]
[52]. Curcumin inhibits the
NF-κβ pathway which is responsible for the transcription
of DNA and protein [53].
-
Effect of Curcumin in alcoholic hepatic Disease
Curcumin acts in AMPK (adenosine monophosphate activated protein kinase)
to reduce the liver fat and serum alanine transaminase (ALT). Curcumin
prevents the impairment in lipid metabolism and it can prevent fatty
acid biosynthesis [54]. Curcumin
decreases the elevated biomarker AST, ALT, LDH, ALP and reduces the
damaged liver cell in animal ([Fig.
3]) [55].
-
Effect of Curcumin in oxidative stress in liver
ROS is the main principle for oxidative stress, generation of free
radicals and cellular abnormality. Curcumin inhibits initiation of
styrene oxidation and reduces chronic disorders and prevents bacterial
cell growth in the liver [15].
-
Effect of Curcumin in liver injury
Single dose at 100 mg/kg of Curcumin given by intraperitoneal route is
responsible for the inhibition of lipid peroxidation, free radical formation and
DNA abnormal function. Curcumin inhibits the D-galactosamine, protects the
impacted nitric oxide synthase-2 (NOS-2) down-regulation and reduces the level
of NO in the liver ([Fig. 3]) [56].
Fig. 3 Effect of Curcumin in liver disease.
Effect of Curcumin on glucose level and pancreatic B cell (diabetes
mellitus)
Curcumin acts as an antidiabetic in some experimental diabetes models. The
structural and functional fault in the deficiency of insulin-producing and
insulin- responsive tissues in the body have been shown some complicated
pathogenesis of T2DM. Wojcik et al. showed that Curcumin acts at multiple
molecular targets and pathways which shown effective role in diabetic patients
[57]. Jeenger et al declared that
Curcumin improves various micro vascular diabetic complications such as
retinopathies, nephropathies, cardiomyopathies and neurological disorders which
are eventually linked to diabetes induced oxidative stress and
inflammatory disorders [58].
Curcumin demonstrated its effect in diabetes by lowering blood glucose level,
enhancing carbohydrate metabolism and restoring the activities of multiple
antioxidant enzymes such as superoxide dismutase, glutathione peroxidase,
catalase and glutathione-S transferase. Curcumin also inhibits the lipid
peroxidation [59]. Curcumin can modulate
the functions of multiple cell signaling and it inhibits the level of
thiobarbituric acid reactive substances (TBARS) and reduces the sorbitol
dehydrogenase (SDH). Curcumin activates the liver enzyme connected with
gluconeogenesis, glycolysis and lipid metabolic pathways. It activates the
function of nuclear factor erythroid-2-related factor-2 (NRF2) [60]. It can also induce the peroxisome
proliferator-activated receptor gamma (PPAR-y) activation. Curcumin can also
increase the levels of plasma insulin and lipoprotein lipase (LPL) activity
[61]. Curcumin prevents the IL-6,
TNF-α, maintained the extracellular matrix proteins, vasoactive factors
and a key transcriptional co-activator (p300) in cultured human retinal
microvascular endothelial cells (HRECS) and dermal-derived human microvascular
endothelial cells (HMVECS) in hyperglycemic tissues [62]. Curcumin inhibits poly ADP-ribose
polymerase-1 activation and prevents cytokine (TNF-α, IL-1β,
etc.) Induced NF-kβ translocation which enhance islet neogenesis and
prevents the level of reactive oxygen species (ROS) production within the islet
([Fig. 4]) [63].
Fig. 4 Effect of Curcumin on diabetes.
Conclusion
Turmeric is a popular household remedy used in Indian food. Curcumin is a principal
constituent of turmeric. Although Curcumin has been found effective in patients with
rheumatoid arthritis, inflammatory eye diseases, inflammatory bowel disease, chronic
pancreatitis, psoriasis, hyperlipidemia, post-operative inflammation and cancers in
preliminary studies but well- controlled clinical trials are still needed. Further,
Keeping in view the biological safety, efficacy, cost effectiveness and easier
availability well controlled clinical studies are advocated to confirm its efficacy
in various other most running disorders such as diabetes, Alzheimer, cardiovascular,
liver injury and osteoarthritis as sufficient in vitro and preclinical data is
available to support for conducting clinical studies in these areas.
