Potential Health Benefits of Tumeric
Turmeric is an Indian rhizomatous herbal plant (Curcuma longa) of the ginger family (Zingiberaceae) of well-known medical benefits. The medicinal benefits of turmeric could be attributed to the presence of active principles called curcuminoids. Curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are collectively known as curcuminoids. These yellow colored curcuminoids are isolated from Curcuma longa L. (turmeric) rhizomes.
One of the most interesting components of curcuminoid is curcumin, which is a small molecular weight polyphenolic compound and lipophillic in nature, hence insoluble in water and also in ether but soluble in ethanol, dimethylsulfoxide, and other organic solvents. Curcumin is stable at the acidic pH of the stomach. The other constituents present are volatile oils including tumerone, atlantone and zingiberone and sugars, proteins and resins.
The active constituent of turmeric- curcumin is isolated from curcuma longa and it provides colour to turmeric. Such bioactive component has been thoroughly investigated. Curcumin (1, 7-bis (4-hydroxy-3methoxyphenyl)-1, 6- heptadiene-3, 5- dione) is also called diferuloylmethane. It is a tautomeric compound existing in enolic form in organic solvents and as a keto form in water. Turmeric is a plant known by its medicinal use, dating back to 4000 years ago in the Vedic culture in India, where it was used as a culinary spice and had some religious significance.
Curcumin is a symmetric molecule, also known as diferuloylmethane. IUPAC name of this compound is (1E-6E)-1, 7-bis (4-hydroxy-3-methoxy phenyl)-1, 6- heptadiene-3, 5-dione. The chemical formula of curcumin is C21H20O6 and the molecular mass is 368.385g/mole. The structure of curcumin contains three chemical entities: two oxy-substituted aryl moieties containing ortho-methoxy phenolic OH– groups, connected through a seven carbon chain consisting of a α, βunsaturated β-diketone moiety. Curcumin is the most abundantly occurring natural analogue of a crude extract at 60%-70%, followed by demethoxycurcumin(DMC; 20%-30%) in which one methoxy group is absent, then bisdemethoxycurcumin(BDMC; 10%-15%) in which the methoxy group is absent from both the aryl rings, along with numerous and less abundant secondary metabolites.
Important chemical reactions associated with the biological activity of curcumin are the hydrogen-atom donation reactions leading to oxidation of curcumin, reversible and irreversible nucleophilic addition reactions, hydrolysis, degradation and enzymatic reactions. All these play important role in different biological activities of curcumin. Curcumin is a hydrophobic molecule with a calculated log P value is 3.43; however it is insoluble in aqueous physiologic media, which displays poor distribution and bioavailability. Curcumin is soluble in polar solvents like DMSO, methanol, acetone and ethanol.
Thus, it tends to accumulate in hydrophobic regions, for example, the membrane of cells. Taken together, curcumin can perform as a hydrophobic reducing (antioxidant) agent and thereby scavenge various reactive oxygen species (ROS). It has also been demonstrated that curcumin was better than vitamin E in suppressing oxidative stress.
The regeneration reaction of phenoxyl radicals by water-soluble antioxidants like Vitamin C restores curcumin for consecutive ROS elimination reactions. Curcumin is as efficient as intrinsic and lipid soluble antioxidants in the removal of superoxide radicals and stimulates the function of superoxide dismutase. The hydrogen donor site, α, β-unsaturated β-diketone moiety, is also considered the breakdown point in the curcumin structure, resulting in curcumin hydrolysis and degradation in water at room temperature and neutral pH. It has been reported that 90% of curcumin degrades within 30min in aqueous alkaline buffer, Being lipophilic in nature, the water solubility of curcumin could be enhanced when the diketo reaction site is binding in polymers, cyclodextrins, lipids, proteins and other macromolecular structures as the reaction site becomes protected from hydrolysis.
It has been demonstrated that solvolysis is a minor pathway, and the primary pathway is autoxidation. Pharmacokinetic studies showed that after oral consumption, curcumin is metabolized to give sulfate and glucuronide derivatives. The chemical stability of curcumin can be enhanced by encapsulation with lipids or nanoparticles. Other methods to enhancing stability have included synthetic manipulations to eliminate or protect the oxidation sites (phenolic-OH and enolicOH) and derivatization of the β-diketone to decrease the activity of the enolate Michael acceptor. Besides, analogues of curcumin could be a more feasible way to for clinical application, further clinical studies are needed to evaluate and potentially confirm the beneficial effects of them.
Curcumin reduces the response of specific proteins – cytokines that occur in the processes of inflammation, such as TNF-α, interleukins (IL-1, IL-2, IL-6, IL-8, IL12), chemokines, through the inhibitory effect on NF-κB (cellular factor kappa B), and even directly binding to TNF-α (Anthwal al., 2014). A series of studies on animals have shown that the dose of 100-200 mg per kg of body weight indicates good anti-inflammatory activity (Kohli et al., 2004).
Curcumin reduces the inflammation associated with colitis by significantly reducing the activity of myeloperoxidase and TNF-α (Basnet et al., 2011). Liu et al. (2015) have shown that curcumin reduces the pathological changes in the lungs and the accumulation of inflammatory cells in the airways of asthmatic mice by downregulating the expression of proinflammatory cytokines with the activation of the Nrf2 / HO-1 (nuclear factor erythroid 2-related factor / heme oxygenase-1) signaling pathway. Nuclear factor erythroid 2-related factor (Nrf2) is a cytoprotective factor which regulates the expression of gene coding for antioxidant, anti-inflammatory, and detoxifying proteins.
Pancreatitis is another inflammatory process associated with the secretion of NF-κB cytokines. Curcumin significantly reduces the activation of this cytokine and AP-1 (activator protein 1), and reduces the mRNA induction of iNOS (nitric oxide synthase), TNF-α and IL6 cytokines in the pancreas (Gulcubuk et al., 2013).
Studies on the effects of curcumin on allergies have shown that curcumin inhibits the NF-κB in the airway, together with the transcription factor GATA3, reduces IgE in serum, and inhibits the Notch1-GTA3 signaling pathway (Chong et al., 2014).
It has been demonstrated that curcumin as a plant derivative has a wide range of antiviral activity against different viruses: papillomavirus virus (HPV), influenza virus, Hepatitis B virus (HBV), Hepatitis C virus (HCV), adenovirus, coxsackie virus, Human norovirus (HuNoV), Respiratory syncytial virus (RSV) and Herpes simplex 1 (HSV-1).
Curcumin functionalized graphene oxide shown synergistic antiviral effect against respiratory syncytial virus infection. Respiratory syncytial virus (RSV), which is considered as the major viral pathogen of the lower respiratory tract of infants, has been implicated in severe lung disease.
Developing a β-cyclodextrin (CD) functionalized graphene oxide (GO) composite, which displayed excellent antiviral activity and curcumin loading efficiently, showed that the composite could prevent RSV from infecting the host cells by directly inactivating virus and inhibiting the viral attachment, which possessed the prophylactic and therapeutic effects towards virus. The antiviral effect of curcumin was a dose-dependent manner.
Unnikrishnan and Rao (1995) studied the antioxidative properties of curcumin and its three derivatives (demethoxy curcumin, bisdemethoxy curcumin and diacethyl curcumin). The authors demonstrated that these substances provide a protection of hemoglobin from oxidation at a concentration as low as 0.08 mM, except the diacethyl curcumin which has little effect in the inhibition of nitrite induced oxidation of hemoglobin.
The effect of curcumin on lipid peroxidation has also been studied in various models by several authors. Curcumin is a good antioxidant and inhibits lipid peroxidation in rat liver microsomes, erythrocyte membranes and brain homogenates (Pulla Reddy & Lokesh 1994). The lipid peroxidation has a main role in the inflammation, in heart diseases, and in cancer.
Turmeric can lower lipid peroxidation by maintaining the activities of antioxidant enzymes like superoxide dismutase, catalase and glutathione peroxidase at higher levels. These enzymes play an important role in the regulation of lipid peroxidation (Pulla Reddy & Lokesh 1992). Pulla Reddy and Lokesh (1992) observed that curcumin is capable of scavenging oxygen free radicals such as superoxide anions and hydroxyl radicals, which are important to the initiation of lipid peroxidation.
Another article about curcuminoids as potent inhibitors of lipid peroxidation was described by Sreejayan Rao (1994), in which the authors showed that three curcuminoids were inhibitors of lipid peroxidation in rat brain homogenates and rat liver microsomes. All of these compounds were more active than α-Tocopherol (drug reference) and curcumin showed the better results. In the case of curcumin, the methoxy group seems to play a major role.
The phenolic and the methoxy group on the phenyl ring and the 1,3 – diketone system seems to be important structural features that can contribute to these effects. The diketone system is a potent ligand for metals such as iron, used in these experiments. Another fact proposed in the literature is that the antioxidant activity increases when the phenolic group with a methoxy is at the ortho position. The mechanism of action of curcumin is still unknown.
The first work to relate the activity of curcumin and some semi-synthetic derivatives in the literature against tripanosomatids was studied in promastigotes (extracellular) and amastigotes (intracellular) forms of Leishmania amazonensis. The authors showed that curcumin (a phenolic curcuminoid) in experiments in vitro has an excellent activity (LD50 = 24 µM or 9 mg/ml) and the semi-synthetic derivative, methylcurcumin (a non-phenolic curcuminoid), has the best action with a LD50 < 5 µg/ml and LD90 = 35 µM against promastigotes forms. This derivative was tested in vivo in mice and showed a good activity with 65.5% of inhibition of the lesion size of the footpad of the animals, when compared with the group inoculated with the parasites alone (Araújo et al. 1998, 1999).
Another interesting point mentioned by the authors is that they did not observe any inflammatory reaction in the area where the drugs were injected, perhaps because curcuminoids are potent inhibitors of inflammation. Rasmussen et al. (2000) reported the efficacy of an ethanolic extract from C. longa against Plasmodium falciparum and L. major, which was able to inhibit the in vitro growth of these parasites.
Curcuma oil was studied on Paramecium caudatum in different concentrations, varying from 1 in 2,000 to 1 in 5,000. The ciliates became sluggish and ultimately died (Chopra et al. 1941). Kiuchi et al. (1993) demonstrated the activity of fractions (methanolic and chloroformic) of turmeric against Toxocara canis. In this work they isolated a new curcuminoid, the cyclocurcumin. All the substances did not show activity when applied independently, but the activity was observed when they were mixed, suggesting a synergistic action between them.
Curcuma oil was tested against cultures of Staphylococcus albus, S. aureus and Bacillus typhosus, inhibiting the growth of S. albus and S. aureus in concentrations up to 1 to 5,000 (Chopra et al. 1941).
Bhavani Shankar and Murthy (1979) investigated the activity of turmeric fractions against some intestinal bacteria in vitro. In this work, total inhibition of growth of Lactobacilli in the presence of whole turmeric was observed (4.5-90 µl/100 ml). The other fraction, the alcoholic extract, was effective too (10-200 mg/ml), but the inhibition was not equal as the whole turmeric. Curcumin (2.5- 50 mg/ml) only inhibited S. aureus.
A potent antivenom was tested against snakebite. The fraction consisting of ar-turmerone, isolated from C. longa L., neutralized both the hemorrhagic activity and lethal effect of venom in mice. In this study ar-turmerone was capable of abolishing the hemorrhagic activity of Bothrops venom and about 70% of the lethal effect of Crotalus venom. Ar-turmerone can act as an enzymatic inhibitor in the case of venom enzymes, with proteolytic and hemorrhagic activities (Ferreira et al. 1992).
Treatment of asthma and allergy
Curcumin decreased the nasal airflow resistance by alleviating sneezing, rhinorrhea and nasal congestion. It also suppresses the IL-4, IL-8, and tumor necrosis factor α as well as also enhanced the levels of IL-10 and soluble intercellular adhesion molecule. Curcumin administered through nasal route inhibited allergic airway inflammations and maintaining structural integrity in allergic asthma mices model. The different treatments of curcumin (2.5 and 5.0mg/kg) in ovalbumin (OVA) of Balb/c mice markedly regulates airway inflammation and airway obstruction mainly by modulating cytokine levels (IFN-ƴ, IL-4, 5, and TNF-α) and sPLA2 activity thereby inhibiting PGD2 release and COX-2 expression. Furthermore, curcumin suppressed the ERK 42/44, p38 MAPK (mitogen-activated protein kinase) and JNK54/56activation in asthma progression rats.
Due to extensive traditional use of curcumin in food products, various researches have been done in order to study curcumin with the aspect of controlling fungal related spoilage and fungal pathogens. The study of addition the curcumin powder in plant tissue culture showed that curcumin at the 0.8 and 1.0 g/L had appreciable inhibitory activity against fungal contaminations. Reduction in proteinase secretion and alteration of membrane-associated properties of ATPase activity are other possible critical factors for antifungal activity of curcumin. Finding new anti-candida substances seems to be crucial due to development of resistant strain against existing antifungal drug.
The investigation of curcumin mediation for photo- dynamic therapy can reduce the biofilm biomass of C. albicans, C. glabrata and C. tropicalis. The results demonstrated that association of four LED influences for light excitation with 40 μM concentration of curcumin at 18 J/cm2 inhibited up to 85% metabolic activity of the tested Candida species. The use of curcumin with light proved to be an effective method for noteworthy improvement in the antifungal activity against planktonic form of the yeasts. Photodynamic effect considerably decreased C. albicans viability in either planktonic or biofilm cultures probably through increasing the uptake of curcumin by cells. However, to a lesser extent, photodynamic therapy was found to be phototoxic to the macrophages.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by hyperplasia of the synovial fibroblasts. Curcumin is known to possess potent anti-inflammatory and anti-arthritic properties. Curcumin treatment was carried out on patients with active rheumatoid arthritis and compared with diclofenac sodium reference group. Interestingly, the curcumin group showed the highest percentage of improvement in overall rheumatoid arthritis scores and these scores were significantly better than the patients in the diclofenac sodium group. More importantly, curcumin group was found to be safe and did not relate with any adverse events compared to diclofenac sodium group. It is believed that curcumin antioxidant, antiproliferative, antiinflammatory and immunesuppressive activities shared in the improvement of symptoms to patients suffering from rheumatoid arthritis.
Curcumin was reported to possess anti-diabetic activity. The effect of antidiabetic activity could be attributed to the antioxidant property of curcumin. In their study, researchers demonstrated curcumin positive effect through the improvement of diabetes-induced endothelial dysfunction by decreasing superoxide production and vascular protein kinase C inhibition. Interestingly, recent studies demonstrated the ability of curcumin to have the capacity to directly quench reactive oxygen species (ROS) that can contribute to oxidative damage.
This property is known to contribute to the overall protective effects of curcumin. Curcumin can attenuate cell death caused by oxidative stress, indirectly through induction and/or activation of antioxidant/ cytoprotective enzymes, such as heme oxygenase-1 (HO-1 ). The protective mechanisms of HO-1 in diabetes could present some emerging therapeutic options for HO -1 expression in treating diabetic diseases.
Curcumin was evaluated for the prevention of type 2 diabetes in pre-diabetic human population. The subjects received curcumin capsules for 9 month period versus placebo capsule group. The curcumin-treated group showed a better overall function of β-cells, with higher HOMA-β and lower C-peptide. The curcumin treated group showed a lower level of HOMA-IR (insulin resistance index) and higher adiponectin, when compared with the placebo group. The results indicated that curcumin intervention may have positive effect to a prediabetic population.