The Biological Potentials of Indian Traditional Medicine ...

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Cardiovascular & Hematological Agents in Medicinal Chemistry, 2017, 15, 000-000 1

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The Biological Potentials of Indian Traditional Medicine, Curcumin for Treating Human Diseases

C.S. Sumathi1,*, P. Rajesh1 and V. Rajesh Kannan2

1Department of Microbiology, K.S.Rangasamy College of Arts and Science, Tiruchengode - 637215, TamilNadu, India

and 2Department of Microbiology, Bharathidasan University, Tiruchirappalli 620 024, TamilNadu, India

Abstract: Curcumin is an active compound extracted from the rhizomes of Curcuma longa L. (Turmer-

ic). It possesses a di-phenolic structure and there are three important fractions of curcumin namely cur-

cumin, mono-desmethoxycurcumin and bis-desmethoxycurcumin. Curcumin is having high medicinal

value. It is widely available in Ayurveda, Siddha and Unani medicine formulations to treat various dis-

eases. It is effective against microbial pathogens like bacteria, virus and fungi. It is highly potent and

kills cancerous cells. Curcumin exhibits antioxidant activity and reduces lipoperoxidation. Cardiopro-

tective nature of curcumin is also reported. It can protect the brain from neurodegenerative disorders

caused by oxidative stress. It is safe to use in humans and animals. In addition to its medicinal value, it

is also having numerous commercial applications like dyeing, cooking purposes, antiseptics, etc. The

cultivation of turmeric by means of inorganic inputs making it contaminated with heavy metals is re-

ported. Improving the biological use of curcumin provides healthy humankind and increases the eco-

nomic status of a country.

A R T I C L E H I S T O R Y

Received: March 11, 2016

Revised: August 15, 2017

Accepted: August 22, 2017

DOI:

10.2174/1871525715666170830130555

Keywords: Curcumin, di-phenolic structure, mono-desmethoxycurcumin, bis-desmethoxycurcumin, Ayurveda, antioxidant activity, Cardioprotective nature.

1. INTRODUCTION

In India, plant materials are the field of medicine to cure

a varying range of diseases like anorexia, biliary disorders,

coryza, cough, diabetic wounds, rheumatism and sinusitis

[1]. One such plant plays a significant role in Ayurveda, Sid-

dha and Unani medicines is Turmeric [2].Turmeric is also

known as Indian saffron, turmeric root and yellow root. In

Ayurvedic medicine systems, it is used as a tonic to treat

digestive and hepatic disorder [3, 4].

Turmeric is originated from India and found in South

American countries [5]. Turmeric belongs to the Zingibera-

ceae family, grown in various parts of the world like China,

India, Indonesia, Jamaica, Haili and Peru [6] and is botani-

cally named as Curcuma, consists of species and belongs to

the group of aromatic spices. It is well known worldwide for

its medicinal properties [7] and having economic importance

as a spice due to its characteristic aroma [8]. The present

chapter provides detailed information about the turmeric and

its potential. The special highlight is given on cardioprotec-

tive activity of curcumin.

*Address correspondence to this author at the Department of Microbiology, K.S.Rangasamy College of Arts and Science, Tiruchengode - 637215, Ta-

milNadu, India; E-mail: [email protected]

2. PHYTOCHEMISTRY OF TURMERIC

Curcuma longa Linn. (Turmeric) contains protein (6.3%), fat (5.1%), minerals (3.5%), carbohydrates (69.4%), moisture (13.1%) and oleoresin [9]. The essential oil compo-sition of turmeric leaves constitutes -pinene 2.88%, -pinene 2.36%, sabinen 0.40%, myrcene 1.17%, -phellandrene 38.24%, 1,8-cineole 8.64%, Ρ-cymene 6.05%, C8-aldehyde 20.58%, linalool 0.58%, caryophyllene 0.70%, geraniol 1.77% and methyl heptanone 0.055% [10]. The dried rhizomes of C. longa have been reported to contain 3-5% essential oil and 0.02-2.0% aromatic yellow curcumi-noids [11]. The rhizome of turmeric constitutes both volatile (imparts characteristic aroma) and nonvolatile oils (imparts the distinctive yellow-orange color). The major compounds include ar-turmerone, zingiberene, tumerone (and ) and curlone and phenolic compounds or curcuminoids [12]. Cur-cuminoids have di phenolic structure, composed of curcu-min, mono-desmethoxycurcumin, and bis-desmethoxycurcumin (Fig. 1). These phytochemicals possess a wide range of beneficial properties.

2.1. Physical Properties of Curcumin

Curcumin was first isolated in 1815 [13, 14]. Curcumin is unstable at basic pH and undergoes alkaline hydrolysis in alkali/ higher pH solution. It undergoes photodegradation when exposed to light in solution as well as in solid form. It

2 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2017, Vol. 15, No. 1 Sumathi et al.

has a melting point of 176-177˚C. It is yellow in color and forms a reddish-brown salt with alkali [15]. It is soluble in ethanol, alkali, ketone, acetic acid and chloroform [15]. On UV spectrophotometric analysis, the light absorption maxi-mum of curcumin is 420nm [16, 17].

HO

R1

O OH

OH

R2

Curcumin R1=R2=OCH3

Demethoxycurcumin R1=H, R2=OCH3

Bisdeemethoxycurcumin R1=R2=H

Fig. (1). The Diphenolic structure of curcumin.

2.2. Chemistry of Curcumin

The molecular weight of curcumin is 368.3799 g/mol. The molecular formula is C21H20O6. Curcumin is also called as curcumin I, desmethoxycurcumin is curcumin II and bis-demethoxycurcumin is curcumin III and its structure was confirmed [18, 19]. The structure of curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), the first known diarylheptanoid, containing a 7-carbon chain flanked by an aromatic ring on either side. The chemistry of curcumin is in unique structure with a molecular weight of 368.37. It exists in two isomeric forms namely, enol and β-diketone form [20] (Fig. 2).

The diketo group exhibits ketoenol tautomerism, depending upon the environment it exists in different types of conformers [21]. The enol form of curcumin has three dissociable protons, the enolic one and the two equivalentenol forms phenolic ones. The enolic proton, the easily dissociable proton exists predom-inantly in solution as an acidic form than the other two dissoci-able phenolic protons [22]. The enol structure enables curcu-min to form additional inter- and intramolecular hydrogen bonds [23]. In nonpolar and moderately polar solvents, the enol form is generally more stabilized than the keto form by 5-8kcal/mol depending on the nature of the solvent. It is insoluble in water and readily soluble in polar solvents like DMSO, methanol, ethanol, chloroform, acetonitrile, ethyl acetate etc. Spectrophotometrically, Curcumin absorbs maximally at 420-430 nm in organic solvents, in the UV range maximum at 265nm [24] and 1% solution of pure curcumin has an optical density of 1.650 absorbance units [25].

Curcumin degrades faster when exposed to sunlight. The photodegradation products of curcumin were identified as vanillin, ferulic acid, and other small phenols [26]. The pho-

todegradation is accelerated in presence of TiO2 nanoparti-cles, and this method can be employed to remove turmeric stains from cotton fabrics [27].

A new method of curcumin synthesis by the reaction of acetylacetone difluroboronite with an aromatic aldehyde in the presence of n-butylamine as a catalyst was introduced [28]. The new intermediate products, curcuminoid diflurobo-ronites, of symmetrically substituted curcuminoids produced are stable and pure. The same method applied for the synthe-sis of unsymmetrical curcuminoid synthesis.

3. BIOLOGICAL AND PHARMACOLOGICAL PO-TENTIALS OF CURCUMIN

The biological activities attributed to curcumin/turmeric include anti-cancer, anti-inflammatory, anti-oxidant, anti-microbial, anti-angiogenic, neuroprotective, immunomodula-tory effects and enhanced wound healing [29]. The various biological properties of curcumin are represented in Fig. (3).

3.1. Antimicrobial Activity

The antimicrobial property of turmeric is well known from early days [30]. The rhizome extracts of turmeric showed a wide range of activity against both Gram positive and Gram negative bacteria clinical bacterial isolates [6] and several Lactobacilli and Helicobacter pylori Cag A strains in vitro [31]. Curcumin is active against Methicillin-Resistant Staphylococcus aureus (MRSA) with MIC value of 125-250µg/ml [32]. Further invitro studies confirmed the antibacterial property against S. aureus, Streptococcus epi-dermidis, E. coli and P. aeruginosa [33]. Curcumin inhibited the growth of 24 pathogenic isolates of bacteria isolated from chicken and shrimp [34].

Curcumin showed potential antagonism against dermato-phyte fungi, pathogenic molds and other fungi like Aspergil-lus flavus, A. parasiticus, F. moniliforme and P. digita-tum[35]. MIC values of 128µg and 256µg/ml exerted inhibi-tory activity against pathogenic fungi Cryptococcus neofor-mans and Candida albicans respectively [36]. Significant antifungal activity against Paracoccoides brasilensis by cur-cumin was comparatively higher than fluconazole [37].

The curcumin has potent antiviral property. The Anti HIV1 and HIV2 property are due to the inhibition of inte-grase (IN) and protease (PR) enzymes. The O-hydroxyl and/or keto-enol structures are responsible for the inhibition of IN and PR. Curcuminoids change the -helix of gluco-sidase into other secondary structural confirmations thereby inhibiting the pathogenesis of HIV 1 [38]. Curcumin therapy of 2g/day given to HIV patients for 127 days showed a sig-

O

H

O

CH3

CH

O O

H

O

H

O

CH3

O

H

O

CH3

CH2

O O

O

H

O

CH3

Enol (1) Diketone (2)

Fig. (2). The two isomeric forms of Curcumin.

The Biological Potentials of Indian Traditional Medicine Cardiovascular & Hematological Agents in Medicinal Chemistry, 2017 Vol. 15 No. 1 3

nificant count of CD4 and CD8 lymphocytes and combinato-rial therapy of 3’azidothymidine (AZT) with turmerin has reduced infection by 37% [39].

3.2. Anti-Cancer Activity

Cancer is a growing health problem around the world, particularly with the steady rise in life expectancy, increasing urbanization and the subsequent changes in environmental conditions, including lifestyle. According to a recent report of World Health Organization (WHO), there are now more than 10 million cases of cancer per year worldwide. In early days the consumption of turmeric has reduced the risk of cancer and offered protective biological effects. The antican-cerous effects of turmeric are due to its bioactive component curcumin, which can able to act upon colon cancer, breast cancer and leukemia. The natural curcuminoids and salicyl-curcuminoid, which have free hydroxy groups, showed sig-nificant anticarcinogenic activity [40]. Curcumin has been successfully used in several experimental carcinogenic ani-mal models.

Curcumin takes up various mechanisms to kill cancerous cells like down-regulate the expression of transcription fac-tors nuclear factor-κB (NF- κB), activating protein-1 (AP-1) and Egr-1; the expression of cycloxygenase (COX2), lipoxy-genase (LOX), nitric oxide synthase (NOS), Matrix Metallo Proteins-9 (MMP-9), urokinase-activated plasminogen acti-vator (uPA), Tumor necrosis factor (TNF), chemokines, cell surface adhesion molecules, cyclin D1 growth factor recep-tors (such as epidermal growth factor receptor EGFR and HER2). Curcumin is not a selective LOX inhibitor and has been shown to affect several other enzymes [41]. Curcumin

synthesized analogs were selective COX-1 inhibitors with submicromolar to micromolar IC50 values and promising selectivities [42]. Especially lipophilic and polar substituents on the phenyl ring, like methoxy or methyl ester groups im-proved the specificity of the compounds. The biological data were also confirmed by docking studies which revealed good Van der Waals interaction and hydrogen bonding towards COX-1 isoenzyme performed by curcuminoids. The antican-cerous activity of curcumin by inhibiting a novel pathway called thioredoxin reductase (Trx R) enzyme [43]. A novel analog of curcumin modulates the extent of LPO and nitric oxide (NO), augments the antioxidant activity to protect against lung cancer induced by nicotine [44]. Curcumin has also been shown to inhibit protein kinase C, a marker en-zyme for tumorigenesis [45]. Curcumin showed inhibitory activity against c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases and thereby inhibits oncogene activation.

The dietary administration of synthetic curcumin signifi-cantly inhibited the incidence of AOM-induced colon adeno-carcinomas in F344 rats [46,47]. Curcumin acts on pathways that may inhibit cell proliferation and enhance apoptosis [48].The dietary feeding of curcumin during the initiation as well as post-initiation phase inhibits tumor development and cell proliferation in the target epithelium in the rat model with N-Nitrosomethylbenzylamine (NMBA) [49].

Curcumin and alkylphosphocholines caused cell growth inhibition and cell death in a concentration-dependent man-ner on two human urinary bladder carcinoma cell lines [50]. Curcumin inhibits the epidermal growth factor receptor ac-tivity responsible for prostate carcinoma. It works with the

Fig. (3). The various biological role of curcumin.


same principle against various other tumors. Cancerous cells undergo autophagy, programmed cell death type II character-ized by the formation of vacuoles inside the cytoplasm. The process is regulated by simultaneous inhibition and stimula-tion of the Akt/mTOR/p70S6K pathway and ERK1/2 path-way respectively [51].

Curcumin downregulates the prostate specific and andro-gen-regulated homebox gene, NKX3.1 and disturbs the AR gene expression to block NKX3.1 DNA-binding activity in prostate cancer cell LNCaP [48]. The expression of NKK3.1 was inhibited at the level of promoter, mRNA and protein by curcumin. The curcumin could significantly inhibit the growth and induce apoptosis in Ho-8910 human ovarian cancer cells [52]. A decrease in expression of Bcl-2, Bcl-XL and pro-caspase-3 was observed after exposure to 40 mM curcumin, while the levels of p53 and Bax were increased in the curcumin-treated cells [53].

Laboratory studies of curcumin shown to inhibit telomer-ase activity (an important factor of tumorigenesis) by down regulating human telomerase reverse transcriptase (HTERT) expression in breast cancer cells [54]. Several reports proved that curcumin decreased cell proliferation, microvessel den-sity and induced apoptosis in prostate tumors. The admin-istration of curcumin in rats during initiation stage delayed the appearance of a palpable tumor for 6 months. Histologi-cal examination confirmed 50% decrease in tumor propor-tion. Topical application of pure curcumin halted the tumor formation induced by benz(a)pyren, 7,12-dimethylbenz(a)anthracen and as well as 12-O-tetradeconoyl phorbol-13 acetate (TPA)on mouse skin and cultured mouse fibroblast cells [55]. Curcumin also suppressed superoxide production in macrophages activated by TPA [23]. Curcumin blocks the TRE-binding activity ofc-jun/AP1 induced by TPA, is responsible for the tumor promotion [56]. Curcumin treatment increased the tumoricidal effect by downregulation of cytokine response and nitric oxide (NO) production by macrophages and upregulation of both cytokine and NO in natural killer cells, in the immune system of the host [57].

Apoptosis is termed as programmed cell death, plays a critical role in both normal development and pathogenesis of various tissues leading to leakage of cytoplasmic contents, nuclear condensation and DNA fragmentation [58]. The mechanism of apoptosis is helpful in the suppression of vari-ous cancers and other diseases. Curcumin induces apoptosis against various cancers like liver, colon, breast, stomach and duodenal. This activity is active against proliferation of tu-mor cells, certain cancer cell lines and tumoral cell lines [59, 60]. This spice is described to efficiently induce apoptosis in various cell lines including HL-60, K562, MCF-7 and HeLa [61]. In the case of atherosclerosis, curcumin inhibited cell proliferation, stops cell cycle progression and induced apop-tosis in vascular smooth muscle [62]. The apoptic function is mediated through inhibition of protein kinase C by curcumin was studied in rat aortic smooth muscle cell line (A7r5) [63]. Curcuminoids had an antiproliferative effect on MCF-7 hu-man breast tumor cells [64]. Curcumin also leads to apopto-sis in scleroderma lung fibroblasts (SLF) without affecting normal lung fibroblasts (NLF). This effect seems to be due to the weak level of protein kinase (PK) C3 in SLF, generat-ing low levels of glutathione S-transferase (GST) P1-1.

Angiogenesis is responsible for the transition of premalignant lesions into hyperactive malignancy. The ex-pression of angiogenic growth factors correlates with the development of various cancers [65]. Shortly saying angio-genesis is the initial step of cancer. Curcumin is also an an-giogenesis inhibitor that inhibits multistep progression of angiogenesis in vitro and in vivo. The therapeutic potentials of curcumin cannot be underestimated. Curcumin is used in the treatment of diabetic retinopathy due to its anti-angiogenic effects. Expression of angiogenic growth factors correlates with prognosis for lung and other cancers. Inhibi-tion of angiogenesis by curcumin (10 M and above) has been demonstrated in vivo using a mouse corneal model [66]. Inhibition of angiogenic growth factor production, integral to the formation vessels, has also been affected by curcumin in non-malignant and malignant cells [67].

Curcumin suppresses the proliferation of certain normal cells such as hepatocytes, epithelial cells, human vascular endothelial cells (HVEC), human vascular smooth muscle cells (HVSMC), osteoclasts, peripheral blood mononuclear cells (PBMC), and T lymphocytes [68]. Depending on the cell type, the inhibition of cell proliferation at different phas-es of the cell cycle has been reported [69]. Inhibition of cell proliferation could also be mediated through suppression of ornithine decarboxylase (ODC) [70]. In addition, curcumin could affect cellular proliferation through modulation of var-ious cell-signaling pathways. These may include transcrip-tion factors (e.g, NF-ÎB and AP-1), mitogen-activated pro-tein kinases, growth factor receptor kinases and cyclooxy-genases. Various pharmacological properties of curcumin are helpful for the prevention of cancer and its side effects.

Curcumin was administered along with docetaxel to pa-tients with chemotherapy for naive metastatic castration-resistant prostate cancer (CRPC). The phase I trial resulted that curcumin was feasible, safe and tolerable with the dose of (6,000 mg/day).The curcumin showed the good response rate, good tolerability and patient acceptability in first phase II trial [71].A phase II randomized study was conducted on women with human cervical cancer infected by human papil-loma virus (HPV). They were treated with curcumin soft gelatin vaginal capsules for 30 consecutive days and found elimination rate of HPV was higher compared to placebo curcumin capsule arm [72].The patients with high risk of cancer and pre malignant lesions were observed with histo-logic improvement on phase II studies [73].

3.3. Cardio-Protective Activity

Atherosclerosis is a disease affecting the arterialblood vessel by the chronic inflammatory response in the walls of arteries, in large part to the deposition of lipoproteins (plas-ma proteins that carry cholesterol and triglycerides). Anti-atherogenic action of curcumin may depend on the induction of heme oxygenase-1 (HO-1), a potent antioxidant and vas-culoprotective enzyme [74]. Induction of HO-1 has been claimed to inhibit the development of atherosclerosis in Ap-oE deficient mice [75]. Oral treatment with curcumin de-creases the development of atherosclerosis in apoE/LDLR - DKO mice.

Antioxidant enzyme (GP and catalase) levels are modu-lated and elevated to protect the heart against the deleterious


effects of hydrogen peroxide [76]. Curcumin has been shown to reduce myocardial infarct size and improve postischemic cardiac functions of amiodarone-induced lung fibrosis [77] and normal cardiac function was observed in Adriamycin induced myocardial toxicity [78].

The effects of curcumin on nitric oxide (NO) pathway in cardiac tissues and cultured cells were studied [79]. Treatment of diabetic rats with curcumin reduced for endothelial NO syn-thase (eNOS) and inducible NO synthase (iNOS) levels in as-sociation with reduced oxidative DNA and protein damage. Interestingly, curcumin further increased vasoconstrictor ET-1 in the heart. Curcumin prevents diabetes-induced oxidative protein and DNA damage, by decreasing NOS levels in cardiac tissues. In addition, the anti-atherogenic effect was accompa-nied by curcumin, antioxidant-induced normalization of the fibrinogen plasma levels and apo B/apo A ratio, that decreases the cardiovascular risk [80].

3.4. Anti-Inflammatory Activity

Numerous lines of evidence, both in vitro and in vivo, suggest that curcumin is a potent anti-inflammatory agent; the anti-inflammatory effects of curcumin are associated with a reduction in (i) upregulation of proinflammatory Th1 cytokine response leading to the suppression of iNOS and attenuation of the recruitment of neutrophils, (ii) lipid perox-idation and (iii) ultimately tissue injury. In an arthritis animal model, IL-1b [81] and TNF- [82] are increased by inflam-matory stimulation, and IL-1b induces COX-2 transcription in inflammatory cells. Cyclooxygenase (COX)-2 activities were significantly inhibited by the methanol extract ofC. phaeocaulis. The administration of 200mg/Kg curcumin suppressed diethyl nitrosamine-induced liver inflammation and hyperplasia in rats [83]. Such effects are due to the inhi-bition of lipoxygenase enzyme [84]. The suppression of ser-ine protease activity in curcumin-treated mice correlates well with the attenuation of mucosal injury in TNBS-induced colitis.

Anti-inflammatory activity was measured using a human promyelocytic leukemia cell line, the HL-60 cell, differenti-ated by phorbol myristate acetate (PMA) and stimulated by lipopolysaccharide (LPS), in vitro. Crude organic turmeric extracts were capable of inhibiting LPS-induced (IC50 value ¼ 15.2 mg/ml) and prostaglandin E2 (PGE2) (IC50 value ¼ 0.92 mg/ml) production [84]. The formation of arachidonate metabolites like PGE2, leukotrienes and the lysosomal en-zyme secretion-elastase, collagenase and hyaluronidase by macrophages were inhibited by curcumin [85]. The effect of curcumin on arachidonic acid metabolism and secretion of lysosomal enzymes by rat peritoneal macrophages was ex-amined [86]. The effect of rhizomes of C. longa was evalu-ated in a randomized, double-blind, placebo-controlled, cross-over study in 42 patients with osteoarthritis for three months. Treatment with the herbo-mineral formulation pro-duced a significant drop in severity of pain and disability score [87]. Curcumin treatment ameliorates colonic damage in DNCB-induced colitic rats, an effect associated with an improvement in intestinal oxidative stress and a downregula-tion in colonic iNOS and NFκ-B expression [88]. Treatment of mice with curcumin (50, 100 or 300mg/kg) resulted in a significant decrease in the extent and severity of the injury of

the large intestine as evidenced by macroscopic damage score as well as histopathological assessment. The anti-inflammatory treatment against Angiostrongyluscantonensis-induced eosinophilic meningitis with curcumin alone has low efficacy, but the treatment does not interfere with MMP-9 expression and is not useful for larvicidal effects [89].

Pulmonary fibrosis is thickening of the lung tissues by scarring. Animals with fibrosis induced by bleomycin (BLM) showed severe lung damage with infiltration of in-flammatory cells followed by infiltration of the interstitium with fibroblasts with excessive collagen deposition. The ad-ministration of curcumin prevents BLM-induced pulmonary fibrosis: (1) by interfering with the influx of inflammatory cells, (2) by suppressing the activation of alveolar macro-phages and subsequent release of toxic mediators, and (3) by preventing excess collagen accumulation in lungs.

The down-regulation of collagen mRNA expression by curcumin might inhibit collagen gene transcription in amio-darone-induced lung fibrosis in rats [90]. Curcumin amelio-rated the amiodarone-induced fibrosis, increases in c- Jun protein expression contributes to downregulation of a battery of genes involved in fibrotic tissue remodeling [91]. Curcu-min inhibition of amiodarone-induced elevated production of TNF-, Tumor Growth Factor-, collagen deposition and c-Jun protein had reducted the fibrotic changes seen after amiodarone challenge and the antifibrotic properties of cur-cumin are proved.

3.5. Anti-Oxidant Activity

Antioxidant activity of curcumin has been reported earli-er by many researchers. Reactive Oxygen species (ROS) are generated by the induction of environmental/ chemical stress that includes superoxide radicals, hydroxyl radicals [92] and nitrogen dioxide radicals [93]. These free radicals initiate lipid peroxidation plays a major role in various serious dis-eases like cancer, myocardial ischemia, cerebral ischemia-reperfusion injury and hemorrhage and shock neuronal cell injury.

Curcumin act as a potent free radical scavenger due to its hydroxyl group or the methylene group of the β-diketone (heptadiene-dione) moiety [94]. It inhibits the lipid peroxida-tion by enhancing the activity of endogenous antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase and glutathione transferase [95, 96, 97] and against necrosis in the rat skin flap model [98]. The curcu-min, resveratrol and melatonin pre-treatment effectively pro-tect against cadmium-induced lipid peroxidation and amelio-rate the adverse effect of cadmium [99]. In human healthy subjects, the daily intake of 200 mg of turmeric extract re-sults in a decrease in total blood lipid peroxides as well as in high density lipoprotein (HDL), low-density lipoprotein (LDL)-lipid peroxidation [80] and confers antioxidant pro-tection against ethanol-induced lipid peroxidation in neu-ronal cells functioning as a scavenger for oxidant radicals [100].

Oxidative stress plays a major role in the pathogenesis of diabetes mellitus [101]. Daily intake of curcumin reduced the fasting blood sugar level and also lowered the insulin dosage for normoglycemia. Both turmeric and curcumin de-


crease blood sugar level in alloxan-induced diabetes in rat [102]. The administration of curcumin to rats in which diabe-tes had been induced by streptozotocin decreased the levels of LDL and VLDL cholesterol, triglycerides and phospholip-ids in blood [103]. Several clinical trials of type II diabetic patients showed that curcumin inhibited the -glucosidase enzyme, which improved the long-term glycemic control as measured by decreased hemoglobin Alc (HbAlc) and de-layed the development of type II diabetes impaired glucose tolerant patients [104]. The administration of a hydro-alcoholic extract of turmeric to rabbits decreased the plasma cholesterol level and the susceptibility of the LDL to oxida-tion [105]. The ethanol extracts of C.longa L. suppressed the increase in blood glucose levels in type 2 diabetic KK-Ay

mice and stimulated human adipocyte differentiation which is associated with the PPAR-γ ligand binding activity [106].

Hypocholesterolemic and hypotriglyceridemic action of dietary curcumin have also been evidenced in the experimen-tally induced diabetic condition in rats [103]. Curcumin is found to be effective as hypocholesterolemic agents under various conditions of experimentally induced hypercholes-terolemia/hyperlipidemia in rats [107]. Beneficial hypoli-pidemic effect of dietary curcumin was also seen in experi-mentally induced hypertriglyceridemic rats [108].

There are several reports which explain about the hypo-cholesterolemic activity of curcumin. Curcumin is known to prevent and regressed the cholesterol gallstone disease and diabetic nephropathy by hypolipidemic influence in mice and hamsters maintained on a lithogenic diet [109]. It also showed protective effects in the altered fluidity of erythro-cytes in fat-fed rats. Curcumin feeding in experimental ani-mals has been reported to lower blood and liver triglycerides (both total and High-Density Lipoprotein associated) in die-tary sucrose-induced hypertriglyceridemia [108].

Curcumin repaired both oxidative and reductive damage caused to proteins by radiation [110]. Administration of cur-cumin and curcumin analog (CA) shown a hepatoprotective effect against alcohol-induced oxidative liver damage by decreasing LPO, GGT and ALP enzymes [111]. Curcumin and its analogs are effective antioxidants which can protect human red blood cells from free radical- induced oxidative hemolysis and the H-atom abstraction from the phenolic group is responsible for the activity [112].

Iron chelators prevent the participation of iron in the Fen-ton reaction, which reductively cleaves hydrogen peroxide to produce the hydroxyl radical. By inhibiting this and other iron-catalyzed pathways of oxidative stress [113], iron chela-tors substantially reduce oxidative injury to critical cellular targets, including DNA, lipids, and protein [114]. Such an ability to protect against oxidative stress is a hallmark of a chemopreventive agent [115]. Curcumin acts as an iron che-lator; mice that were fed diets supplemented with curcumin exhibited a decline in levels of ferritin protein in the liver. These results suggest that iron chelation may be an addition-al mode of action of curcumin.

3.6. Dermatological Effect

Turmeric is used as a folk medicine to treat skin ailments from early days. Turmeric is known to cure certain skin dis-

eases, which includes urticaria, ringworm, scabies, dry skin/cracks, wrinkled skin and prickly heat. The people who reside in the remote areas of Assam use turmeric for the treatment of eczema and also for other fungal diseases like pyoderma and scabies [116]. Turmeric is used in combina-tions with other herbal plants for dermal infections, skin burns, prickly heat and pimples [117].

3.7. Gastrointestinal Effect

Curcumin shows positive effects on gastrointestinal or-gans like stomach, intestine, liver and pancreas. It possesses antiulcer, antispasmodic, gastroprotection, antiflatulent and hepatoprotective activity [8] by increasing the activities of gastrointestinal and pancreatic enzymes like lipase, sucrase, maltase and pancreatic lipase, amylase, trypsin and chymo-trypsin respectively [118]. Increasing the secretion of bile is known to responsible for its hepatoprotective function [119].

Curcumin suppressed the spontaneous contractions of rabbit jejunum from 0.03-0.3 mg/mL with an EC50 value of 0.110 F 0.006 mg/mL thus showing spasmolytic activity. When tested against high K+ (80 mM)-induced contractions, crude turmeric extracts concentration-dependently (0.03-0.3 mg/mL) relaxed this induced contraction with an EC50 value of 0.082 F 0.008 mg/mL. The crude turmeric extract relaxed spontaneous K+ (80 mM)-induced contractions in isolated rabbit jejunum as well as shifted the CaCl2 concentration-response curves [120].

3.8. Immunomodulatory Property

Curcumin is used in the treatment of asthma and allergy for many centuries [121]. Animals sensitized with latex showed allergic response by stimulating serum Immuno-globulin E (IgE), latex specific Immunoglobulin G1 (IgG1), Interleukins: IL-4, IL-5, IL-13, eosinophils and inflammation in the lungs. The treatment of mice with curcumin has re-duced the eosinophils, co-stimulatory molecule expression (CD80, CD86, and OX40L) on antigen-presenting cells was decreased, and expression of MMP-9, Ornithine Amino Transferase (OAT), and Thymic Stromal LymphoPoietin (TSLP) genes was also attenuated. By reducing the eosino-phil counts curcumin ameliorates bronchial epithelial cell hyperplasia, predominant in the case of latex-sensitized mice. Curcumin controls the allergic response induced by latex by decreasing in IL-4, IL-5, and IL-13 expressing cells, T helper2 (Th2) response downregulation and reduced lung inflammation [122]. In vitro studies in human reports that curcumin has decreased IL1, IL8 and TNF levels [123].

3.9. Neuroprotective Function

Aging is the major risk factor for neurodegenerative dis-orders like Alzheimer's disease, Parkinson's disease and cer-ebral ischemia. As a potent antioxidant, curcumin could be used for the amelioration of neurodegenerative diseases be-cause the neuronal damage is induced by oxidative stress, finally leading to neuronal death which occurs by apoptosis or necrosis and many types of research have been carried out in recent years. Curcumin from the dried rhizome of C. lon-ga may be useful for the prevention and/or treatment of some age-related degenerative diseases like Alzheimer’s and Par-


kinson’s. Dietary supplementation of curcumin had benefi-cial effects on neurodegenerative disease [124]. The patho-genesis of cerebral ischemia by nitric oxide (NO), a free rad-ical acts both as a signaling molecule and a neurotoxin [125] leading to inflammation-induced disruption of blood -brain barrier [126]. Curcumin has protective effects against cere-bral ischemia in rats and gerbils [127] by interacting peroxy-nitrite anion and nitration of the phenoxyl group of curcumin in-vitro [128]. Administration of curcumin by supplementa-tion to the AIN76 diet (2.0 g/kg) for 2 months significantly attenuated ischemia-induced neuronal death as well as glial activation in a cerebral ischemia model induced in Mongoli-an gerbil [127].

Alzheimer's disease (AD) is an age-dependent accumula-tion of lipophilic material in multicellular plaque lesions, oxidative damage, inflammation along with amyloid accu-mulation and neurodegeneration. Curcumin is known to tar-get AD pathogenesis at multiple sites. Curcumin inhibits cytokines active sites, inflammatory and oxidative damage induction of BACE1, the β-secretase enzyme that makes the initial step in amyloid production. Curcumin could chelate toxic metals (viz., cadmium), and potentially reduces their neurotoxicity and tissue damage in rat brain homogenate [129]. An in vitro study in which they measured the effects of curcumin on the formation of Aβ fibrils from Aβ1-40 and Aβ1-42 peptides was performed [130]. They found that cur-cumin inhibits formation and extension of Aβ fibrils and destabilized preformed Aβ fibrils in a dose-dependent fash-ion at a range between 0.1 and 1 micro-molar concentration. Curcumin also inhibits neurotoxic Aβ oligomer formation and oligomer-dependent Aβ toxicity in vitro. The multiple direct and indirect anti-amyloid actions of curcumin include metal chelating, phagocytosis enhancing, antioxidant and cholesterol lowering activity [131]. Curcumin works in a dual manner i.e., hydrophobic and polar binding, penetrates the blood-brain barrier and to bind to amyloid plaques re-spectively. The compound is neuroprotective against Aβ toxicity in vitro[132] while also being anti-amyloidogenic [133]. Furthermore, aged transgenic Tg2576 mice with high amyloid plaque load either fed or injected with curcumin had less brain amyloid load and plaque burden, and curcumin labeled plaques [134]. A single injection of curcumin (1 and 2 mg/kg, i.v.) 30 min after focal cerebral ische-mia/reperfusion in rats significantly diminished infarct vol-ume, improved neurological deficit, decreased mortality, brain water content and the extravasation of Evans blue dye in ipsilateral hemisphere in a dose-dependent manner [134]. Natural antioxidants curcumin and ginkgo extract have mod-est but positive effects in slowing AD development. There-fore, drugs that target the oxidative pathways in AD could have genuine therapeutic efficacy [135]. The neuro protec-tive effect of curcumin appears multifactorial via regulation of transcription factors, cytokines and enzymes associated with (Nuclear factor kappa beta) NFκB activity [136].

Parkinson's disease is a neurological syndrome manifest-ed by any combination of tremor at rest, rigidity, bradykine-sia and loss of postural reflexes. The neuropathalogical hallmark of PD is selective degeneration of dopaminergic neurons in the nigrostriatal system. These neurons synthesize and release dopamine (DA), and loss of dopaminergic influ-ence on other structures in the basal ganglia leads to classical

Parkinsonian symptoms. Activated microglia (aM) are thought to contribute to neuronal damage via the release of proinflammatory and neurotoxic factors like TNFa, IL-1, RNS, and ROS, etc. Two neuroprotective clinical trials are available with antioxidants: (i) Deprenyl and Tocopherol antioxidant therapy of Parkinson's study observed that deprenyl [137], an antioxidant molecule and also MAO-B inhibitor slowed early progression of symptoms and delayed the emergence of disability by an average of nine months.

4. SAFETY ASPECTS OF CURCUMIN

Curcumin is generally recognized as safe, a phase I hu-man clinical trial indicates no dose-limiting toxicity when administered at doses up to 8 g/d curcumin for 3 months [138] and higher doses are well tolerated [139]. Five other human trials using 1.1- 2.5g of curcumin per day also showed no toxicity [140]. Human trials of curcumin with dosage up to 2.2g/d showed low oral availability, absorbed and metabolized fast within 72h after oral administration [65]. Major factors are the chemical instability of curcumin at neutral and slightly alkaline pH, its susceptibility to autox-idation, its avid reductive and conjugative metabolism, and its poor permeation from the intestinal lumen to the portal blood [141].Most of the curcumin is excreted through feces and minor amount through urine. Based on these observa-tions WHO/FAO expert committee on food additives has approved curcumin as the natural food colors. More im-portantly, turmeric and curcumin were evaluated as effective cancer chemopreventive agents by the National Cancer Insti-tute, Bethesda, USA [142]. The average intake of turmeric (2-2.5g/d) through diet by Indian population over 6000 yrs is a strong proof for its safety. Chemopreventive products like curcumin showed low side effects and toxicity, neutraliza-tion of carcinogens as well as their effects on cells [143]. Dietary administration of curcumin 1g/Kg daily for 2 genera-tions has not shown any toxic effects on the reproductive capacity of Wistar rats [144].

Though the dietary supplement of curcumin is generally recognized as safe, the adverse effects have also been report-ed. Gastrointestinal irritation was observed in the prolonged use of curcumin in higher doses. Epigastric burning was ob-served in duodenal ulcer patients given with 6g of turmeric [145]. In guinea pigs, curcumin administration of 50mg/kg dose is shown to protect the stomach from ulcer induced by phenylbutazone and 20mg/Kg is protective against 5hydroxytryptamine induced ulcer [146,147]. Caution should be taken before treating the patients with gastrointes-tinal disorders.

The clinical trials of curcumin with the dosage of 6000 mg/day administration did not show any toxic effects. The phase I studies of curcumin have shown that this was well tolerated and safe at oral doses of up to 8,000 mg/day and up to 12,000 mg/day with only grade I diarrhea and headache as AE. The phase II, curcumin as administered in the form of capsules and found 12 per day for 7 consecutive days was the limitation based on consideration of patient’s age [148].

4.1. Bioavailability of Curcumin

The curcumin has low bioavailability is only 1% due to poor absorption [149,150]. The clinical applications of cur-


cumin are limited for the reasons of poor aqueous solubility at acidic pH, instability at pH 7 and above, multidrugpumpP-gpefflux,extensiveinvivometabolismandrapideliminationdue to glucuronidation/sulfation.The problem of low oral absorp-tion requires several alternative approaches encapsulation of Cur in liposomes and polymeric micelles, the formation of inclusion complexes and polymeric conjugates, and synthe-sis of new heterocyclic Cur derivatives and analogs [151]. Novelcurcuminloadedmixedmicelles(CUR-MM) of Pluronic F-127(PF127) was prepared toenhanceitsoralbioavailability and the cytotoxic effect was active against human lung can-cer cells [152]. The mixed micelles were highly stable and efficient in drug loading [153]. To increase the bioavailabil-ity of curcumin, it was subjected to clinical and human trials in the forms of capsules, gel capsules, the capsule containing colloidal particles, curcuminoids with bioperine, liposomes, cyclodextrin, phospholipid complexes, nanoparticles and phytosomes [154]. Such formulations increased longer circu-lation, better permeability and resistant to metabolic process.

In these clinical trials, curcumin has been used either alone or in combination with other agents such as quercetin, gemcitabine, piperine, docetaxel, soy isoflavones, bioperine, sulfasalazine, mesalamine, prednisone, lactoferrin, N-acetylcysteine, and pantoprazole. To enhance the bioavaila-bility, curcumin was reconstituted with non-curcuminoid compounds [155, 150].

The oral administration of curcumin in human and exper-imental animals showed antioxidant, anti-inflammatory, an-ticancer and antidiabetic activity. The beneficial effects were reported for anticancer activity. Phase I clinical trial of oral curcumin was well tolerated [156]. Microparticle formula-tion was delivered subcutaneously to treat cancer. Intraperi-toneal injection of curcumin in animal models had shown inhibitory action tumor, cancer, inflammation and asthma. Curcumin when injected intravenously exhibited anticancer activity in an animal model. The topical application of cur-cumin in the form of gel showed effective on wound healing, psoriasis and skin cancer. The intranasal treatment of curcu-min prevented airway inflammations and bronchocon-strictions in asthma without side effect. To increase the bioa-vailability of curcumin different nano curcumin formulations like nanoglobules based nanoemulsions, hydrogel nanoparti-cles, colloidal nanoparticles were made [157].

4.2. Quality Aspects of Curcumin and Microbial Bioferti-lizers

There are several reports showing certain herbal products to be contaminated with heavy metals like lead, mercury and arsenic and other toxic chemicals [158]. In India, 31 Ayur-vedic medicines were found to contain mercury contamina-tion [159] and cause serious harmful effects to patients. The samples collected in India contained significant amounts of heavy metals like mercury, arsenic and cadmium. This may lead to serious intoxication [160]. The presence of various heavy metals in turmeric and other edible crops and irriga-tion of plants with industrial effluent will make food toxic [161]. Herbal product contamination may be due to the pro-longed use of chemical fertilizers, pesticides and insecti-cides. Nowadays herbal products are preferred as medicines to avoid the side effects of allopathic medicines.

The microbial biofertilizers are efficient candidates to remediate heavy metals from the cultivation of herbs itself. The microbial inoculants possess essential beneficial proper-ties they can be able to improve the plant growth, increase in nutrient uptake by plants, mineralize insoluble nutrients and make available for plants, provide disease resistance to plants, increase native soil microbial density and remove toxic chemicals in the soil [162]. By these multiple actions microbial fertilizers not only improve the plant growth but also improve the soil quality. The cultivation of herbs in or-ganic methods and using biofertilizers will help to obtain a good quality of herbal products.

4.3. Commercial Applications of Turmeric/ Curcumin

India is the largest producer, consumer and exporter of spices. The rhizome (underground stem) or root of turmeric are also been used in Asian cookery, medicine, cosmetics, and fabric dying for more than 2,000 years.Curcumin is commer-cially available in the forms of capsules, tablets, ointments, energy drinks, soaps and cosmetics.The phytochemicals pre-sent in the Curcuma leaf essential oils are used as raw materials for making pharmaceutical products, perfumes, soap and cos-metic industries [10]. For a cosmetic application, curcumin encapsulated in chitosan nanospheres reduce the bacterial in-fections of the skin and used as cosmetic [163].

Curcumin, a common natural dye used for fabric and food colorations, was used as an antimicrobial finish due to its bactericidal properties on dyed textiles [164]. Cotton and wool samples dyed with curcumin with the same depths of dyeing [0.5 and 2.0% on the mass of fibre (omf)] after treat-ment [164], with aluminium sulphate, zinc chloride and so-dium potassium tartrate, which have been traditionally used as mordants for natural pigments [165]. The antiseptic activi-ty of an aqueous extract of turmeric was exploited by John-son and Johnson in Band-Aid (patent), available in the mar-ket over the last few years. P54, an oral product patented and developed by Phytopharm6, the UK drug delivery company, consists of curcumin together with the essential oils of both Curcuma domestica and Curcuma xanthorrhiza, suspended in a soft gelatin capsule. Phase II clinical study of P54 for inflammatory bowel disease was conducted in 2001 for pos-sible commercial use [166]. Turmeric in recent days is used as feed additives to improve the overall performance of broiler chicks [167].

5. CONCLUSION

Turmeric generally known as ‘solid gold', possess varie-ties of biological and pharmacological properties. Such bene-ficial properties have been in use by mankind from ancient days and proved by numerous research reports. Several re-ports in this review chapter in order to make a detailed pro-file on curcumin that will be helpful for the researchers.

It has been cancer of the colon, breast, prostate and lung, is most common in the United States but it is not as prevalent in countries such as India where turmeric is frequently consumed. The Epidemiology of digestive tract cancers within India was reported [168]. They found a low incidence of large bowel cancers in Indians is due to high intake of starch and the pres-ence of natural antioxidants such as curcumin in Indian cook-ing. Adenoma is rare in elderly Indians undergoing colonosco-


py, even in those with large bowel cancers. They also reported that small bowel cancers are extremely rare in India. The basic concept behind the disease control by curcumin is antioxidant and antiinflammatory potentials. Moreover, curcumin is very much specific in acting against various disorders.

The commercial applications of turmeric are colorants, cosmetics and spice which catches a strong place in the mar-ket and the annual income of the country counts about 83-122 crores per year by its export. Improving the biological use of curcumin provides healthy humankind and increases the economic status of a country.

LIST OF ABBREVIATIONS

DMSO = Dimethyl Sulfoxide

MIC = Minimum Inhibitory Concentration

HIV = Human Immunodeficiency Virus

CD4 = Cluster of Differentiation 4

CD8 = Cluster of Differentiation 8

EGFR = Estimated Glomerular Filtration Rate

HER2 = Human Epithelial Growth Factor Receptor 2

LOX = Lipoxygenase

LPO = Lactoperoxidase

AOM = Azoxymethane

Bcl-2 = B-cell lymphoma 2

TRE = Tumour Response Element

AP = Activator Protein

GP = Glutathione Peroxidase

IL = Interleukin

TNF = Tumor Necrosis Factor

TNBS = Trinitrobenzene sulfonic acid

DNCB = 2,4 Dinitrochlorobenzene

VLDL = Very Low Density Lipoprotein

GGT = Gamma Glutamyl Transferase

ALP = Alkaline Phosphatase

RNS = Reactive Nitrogen Species

MAO-B = Monoamine Oxygenase B

WHO/FAO = World Health Organization / Food and Agri-

culture Organization

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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