Turmeric: Background. Actions

2010

Common Name

Turmeric

Other Names

Chiang huang, curcuma, curcumae longae rhizoma, curcuma rhizome, e zhu, haridra, Indian saffron, jiang huang, jiang huang curcumae rhizoma, turmeric rhizome, turmeric root, yellow root, yu jin, zedoary

Botanical Name / Family

Curcuma longa (family Zingiberaceae [ginger])

Plant Part Used

Dried secondary rhizome (containing not less than 3% curcuminoids calculated as curcumin and not less than 3% volatile oil, calculated on dry-weight basis).

Chemical Components

Turmeric rhizome contains 5% phenolic curcuminoids (diarylheptanoids), which give turmeric the yellow colour. The most significant curcuminoid is curcumin (diferuloymethane).

It also contains up to 5% essential oil including sesquiterpene (e.g. Zingerberene), sesquiterpene alcohols and ketones, and monoterpenes.

Turmeric also contains immune stimulating polysaccharides, including acid glucans known as ukonan A, B and C.

Historical Note

Turmeric is a perennial herb, yielding a rhizome that produces a yellow powder that gives curry its characteristic yellow colour and is used to colour French mustard and the robes of Hindu priests. Turmeric was probably first cultivated as a dye, and then as a condiment and cosmetic. It is often used as an inexpensive substitute for saffron in cooking and in the 13th century Marco Polo marvelled at its similarities to saffron. Both Indian Ayurvedic and Chinese medicines use turmeric for the treatment of inflammatory and digestive disorders and turmeric has also been used in tooth powder or paste. Research has focused on turmeric‘s antioxidant, hepatoprotective, anti-inflammatory, anticarcinogenic and antimicrobial properties, in addition to its use in cardiovascular disease and gastrointestinal disorders.

Turmeric:  Main Actions

Most research has focused on a series of curcumin constituents found in the herb. Many of the animal studies; however, involve parenteral administration and oral curcumin or turmeric is likely to be far less active because curcumin is poorly absorbed by the gastrointestinal tract and only trace amounts appear in the blood after oral intake. Curcumin may, however, have significant activity in the gastrointestinal tract, and systemic effects may take place as a consequence of local gastrointestinal effects or be associated with metabolites of the curcuminoids.

ANTIOXIDANT

Studies have shown that turmeric, as well as curcumin, has significant antioxidant activity. Turmeric not only exerts direct free radical scavenging activity, it also appears to enhance the antioxidant activity of endogenous antioxidants, such as glutathione peroxidase, catalase and quinine reductase. Curcumin has been shown to induce phase II detoxifying enzymes (glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and catalase). Additionally, its antioxidant effects are 10-fold more potent than ascorbic acid or resveratrol. In addition to curcumin, turmeric contains the antioxidants protocatechuic acid and ferulic acid and exhibits significant protection to DNA against oxidative damage in vitro.

Turmeric’s antioxidant activity may mediate damage produced by myocardial ischaemia and diabetes. Turmeric has been shown to restore myocardial antioxidant status, inhibit lipid peroxidation and protect against ischaemia-reperfusion induced myocardial injuries in an animal model with enhancement of functional recovery. Curcumin has also been found to prevent protein glycosylation and lipid peroxidation caused by high glucose levels in vitro (Jain et al 2006) and to improve diabetic nephropathy. Turmeric has also been shown to suppress cataract development and collagen cross-linking, promote wound healing, and lower blood lipids and glucose levels.

NF-KAPPA-B INHIBITION

The many and varied effects of curcumin may be partly associated with the inhibition of transcription factor nuclear factor-kappa beta (NF-kappa-B) and induction of heat shock proteins. NF-kappa-B is a transcription factor pivotal in the regulation of inflammatory genes and is also closely associated with the heat shock response, which is a cellular defence mechanism that confers broad protection against various cytotoxic stimuli. Inhibition of NF-kappa-B may reduce inflammation and protect cells against damage and curcumin has been found to attenuate experimental colitis in animal models through a mechanism correlated with the inhibition of NF-kappa-B. The clinical significance of this is unclear.

ANTI-INFLAMMATORY

There have been a large number of studies examining the anti-inflammatory effects of curcumin. Turmeric is a dual inhibitor of the arachidonic acid cascade. Curcumin has been shown to exert anti-inflammatory effects via phospholipase, lipo-oxygenase, COX-2, leukotrienes, thromboxane, PGs, NO, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1, IFN-inducible protein, TNF and IL-12.

The anti-inflammatory effect of curcumin was tested in adjuvant-induced chronic inflammation rats which found that curcumin significantly reduced C-reactive protein, TNF-alpha, IL-1 and NO, with no significant changes observed in PGE2 and leukotriene B4 levels or lymphocyte proliferation. Curcumin has also been shown to inhibit inflammation in experimental pancreatitis via inhibition of NF-kappa-B and activator protein-1 in two rat models.

GASTROINTESTINAL EFFECTS

Hepatoprotective

Curcumin prevents carbon tetrachloride-induced liver injury both in vivo and in vitro, reverses aflatoxin-induced liver damage in experimental animals and effectively suppresses the hepatic microvascular inflammatory response to lipopolysaccharides in vivo. An ethanol soluble fraction of turmeric was shown to contain three antioxidant compounds, curcumin, demethoxycurcumin and bisdemethoxycurcumin, which exert similar hepatoprotective activity to silybin and silychristin in vitro.

Several different mechanisms may contribute to turmeric’s hepatoprotective activity. Curcumin has been shown to prevent lipoperoxidation of subcellular membranes in a dosage-dependent manner, due to an antioxidant mechanism and turmeric may also protect the liver via inhibition of NF-kappa-B (see above), which has been implicated in the pathogenesis of alcoholic liver disease. Curcumin also blocked endotoxin-mediated activation of NF-kappa-B and suppressed the expression of cytokines, chemokines, COX-2, and iNOS in Kupffer cells.

Cholagogue and hypolipidaemic

Turmeric extract or curcumin extract has shown dose-dependent hypolipidaemic activity in vivo. One in vivo study suggests that curcumin may stimulate the conversion of cholesterol into bile acids, and therefore, increase the excretion of cholesterol. A further study demonstrated that supplementation with turmeric reduces fatty streak development and oxidative stress. Oral curcumin has also been shown to stimulate contraction of the gall bladder and promote the flow of bile in healthy subjects.

Antispasmodic

Curcuminoids exhibit smooth muscle relaxant activity possibly mediated through calcium-channel blockade, although additional mechanisms cannot be ruled out. Curcuminoids produced antispasmodic effects on isolated guinea pig ileum and rat uterus by receptor-dependent and independent mechanisms.

CANCER

Curcumin has been studied for its wide-ranging effects on tumorigenesis, angiogenesis, apoptosis and signal transduction pathways. It is known to inhibit oncogenesis during both the promotion and progression periods in a variety of cancers. Recently, curcumin was found to possess chemopreventive effects against skin cancer, stomach cancer, colon cancer and oral cancer in mice.

Chemoprevention

Chemoprevention refers to reversing, suppressing or preventing the process of carcinogenesis. Carcinogenesis results from the accumulation of multiple sequential mutations and alterations in nuclear and cytoplasmic molecules, culminating in invasive neoplasms. These events have traditionally been separated into three phases: initiation, promotion and progression. Typically, initiation is rapid, whereas promotion and progression can take many years. Ultimately, chemoprevention aims at preventing the growth and survival of cells already committed to becoming malignant.

Curcumin has been found to effectively block carcinogen-induced skin, colon and liver carcinogenesis in animals. It has been suggested that the chemoprotective activity of curcumin occurs via changes in enzymes involved in both carcinogen bioactivation and oestrogen metabolism. This is supported by the findings that curcumin treatment produced changes in CYP1A, CYP3Aand GST in mice and alleviated the CCI4-induced inactivation of CYPs 1A, 2B, 2C and 3A isozymes in rats, possibly through its antioxidant properties, without inducing hepatic CYPs.

Oral curcumin inhibited chemically induced skin carcinogenesis in mice and curcumin prevented radiation-induced mammary and pituitary tumors in rats. Curcumin and genistein (from soybeans) inhibited the growth of oestrogen-positive human breast MCF-7 cells induced individually or by a mixture of the pesticides endosulfane, DDT and chlordane, or 17-beta oestradiol.

Apoptosis

Apoptosis (programmed cell death) plays a crucial role in regulating cell numbers by eliminating damaged or cancerous cells. Curcumin induced apoptosis in vitro and may act via reactive oxygen species and other mechanisms. Curcumin has been demonstrated to induce apoptosis in human basal cell carcinoma cells associated with the p53 signalling pathway, which controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Curcumin has also been found to induce apoptosis in human mutant p53 melanoma cell lines and block the NF-kappa-B cell survival pathway and suppress the apoptotic inhibitor known as XIAP. Because melanoma cells with mutant p53 are strongly resistant to conventional chemotherapy, curcumin may overcome the chemoresistance of these cells and provide potential new avenues for treatment.

Curcumin has also been found to inhibit prostate cancer cell growth in mice and decrease proliferation and induce apoptosis in androgen-dependent and androgen-independent prostate cancer cells in vitro. This was found to be mediated through modulation of apoptosis suppressor proteins and interference with growth factor receptor signalling pathways. In a further study with rats, however, curcumin did not prevent prostate carcinogenesis.

Antiproliferative

Reduction in proliferation and/or increased apoptosis will lead to tumour regression; however, a more potent effect will be achieved if the two mechanisms occur simultaneously. Curcumin has been shown to do this. The inhibition of cell proliferation is partly related to inhibition of various kinases, such as protein kinase and phosphorylase kinase, and inhibition of several oncogenes and transcription factors. For example, turmeric inhibited epidermal growth factor receptor (EGF-R) signalling via multiple mechanisms including downregulation of the EGF-R protein, inhibition of intrinsic EGF-R tyrosine kinase activity and inhibition of ligand-induced activation of the EGF-R. These mechanisms may be particularly important in preventing prostate cancer cells from progressing to a hormone refractory state. Curcumin has also been found to suppress the growth of multiple breast cancer cell lines and deplete p185neu, the protein product of the HER2/neu proto-oncogene that is thought to be important in human carcinogenesis.

Antimetastatic

Curcumin demonstrated the ability to reduce lung metastases from melanoma cells in mice. The activity of curcumin is varied.

  • In cell adhesion assays, curcumin-treated cells showed a dose-dependent reduction in their binding to four extracellular matrix proteins (binding to proteins is associated with the spreading of the cancer).
  • Curcumin-treated cells showed a marked reduction in the expression of integrin receptors (integrins functionally connect the cell interior with the extracellular matrix, another process necessary for metastases).
  • Curcumin also enhanced the expression of antimetastatic proteins, tissue inhibitor metalloproteinase, non-metastatic gene 23 and E-cadherin (a cell adhesion factor).

Chemotherapy

Curcumin enhanced the cytotoxicity of chemotherapeutic agents in prostate cancer cells in vitro by inducing the expression of certain androgen receptor and transcription factors and suppressing NF-kappa-B activation. Curcumin also enhanced the antitumour effect of cisplatin against fibrosarcoma.

Curcumin, however, was found to significantly inhibit cyclophosphamide-induced tumour regression in an in vivo model of human breast cancer. It is suspected that this occurred as a result of inhibition of free radical generation and blockade of JNK function. As such, curcumin intake should be limited in people undergoing treatment for breast cancer with cyclophosphamide until further investigation can clarify the significance of these findings.

Immunomodulation

Curcumin administration was found to significantly increase the total white blood cell count and circulating antibodies in mice. A significant increase in macrophage phagocytic activity was also observed in curcumin-treated animals. However, curcumin has also been demonstrated to have some immunosuppressive activity. Curcumin inhibits PAR2-and PAR4-mediated human mast cell activation by block of ERK pathway.

An in vivo study using a cardiac transplant model found that curcumin also significantly reduced expression of IL-2, IFN-gamma and granzyme B (a serine protease associated with the activity of killer T-lymphocytes and NK cells) and increased mean survival time. Curcumin was further shown to work synergistically with the anti-rejection drug cyclosporine.

Curcumin also modulates other interleukins and has been shown in vitro to be a potent inhibitor of the production of the pro-inflammatory cytokine IL-8, thereby reducing tumour growth and carcinoma cell viability. Curcumin not only inhibited IL-8 production but also inhibited signal transduction through IL-8 receptors and to inhibit cell proliferation, cell-mediated cytotoxicity and cytokine production most likely by inhibiting NF-kappa-B target genes.

CARDIOVASCULAR EFFECTS

Antiplatelet

Curcumin has been shown to inhibit platelet aggregation in vivo and in vitro. The anticoagulant effect of curcumin is weaker than that of aspirin, which is four-fold more potent than curcumin in treatment of collagen- and noradrenalin-induced thrombosis. Curcumin 100 mg/kg and aspirin 25 mg/kg resulted in 60% protection from thrombosis.

Anti-atherogenic

A hydro-ethanolic extract of turmeric was found to decrease LDL oxidation, have a vitamin E-sparing effect and lower the oxidation of erythrocyte and liver membranes in rabbits fed a diet high in saturated fat and cholesterol. The atheroscleroprotective potential of turmeric was further demonstrated by an animal study that found turmeric lowered blood pressure and reduced the atherogenic properties of cholesterol.

Dietary curcumin has also been shown to significantly lower blood cholesterol in diabetic animals. Cholesterol decrease was exclusively from the LDL-VLDL fraction. Significant decrease in blood triglyceride and phospholipids was also brought about by dietary curcumin in diabetic rats. In a parallel study in which diabetic animals were maintained on a high cholesterol diet, curcumin lowered cholesterol and phospholipid and countered the elevated liver and renal cholesterol and triglyceride levels seen in the diabetic animals.

WOUND HEALING

Wound healing is a highly ordered process, requiring complex and coordinated interactions involving peptide growth factors, of which transforming growth factor-beta (TGF-beta) is one of the most important. Nitric oxide is also an important factor in healing, and its production is regulated by iNOS. Topical application of curcumin accelerated wound healing in normal and diabetic rats. The wound healing is partly associated with the regulation of the growth factor TGF-beta-1 and iNOS. Curcumin’s wound healing ability has been confirmed in several other animal studies. Wounds of animals treated with curcumin showed earlier re-epithelialisation, improved neovascularisation, increased migration of various cells including dermal myofibroblasts, fibroblasts, and macrophages into the wound bed, and a higher collagen content. It appears to be effective when used orally or as a local application.

Curcumin has also demonstrated powerful inhibition against hydrogen peroxide damage in human keratinocytes and fibroblasts and pretreatment with curcumin significantly enhanced the rate of wound contraction, decreased mean wound healing time, increased synthesis of collagen, hexosamine, DNA and NO, and improved fibroblast and vascular densities in full thickness wounds in mice exposed to whole-body [gamma]-radiation.

ANTIMICROBIAL

Turmeric is used as an antimicrobial for preserving food and has been found to have antifungal activity, as well as inhibiting aspergillus growth and aflatoxin production in feeds.

Curcumin has also been found to have dose-dependent, antiprotozoan activity against Giardia lamblia with inhibition of parasite growth and adherent capacity, induction of morphological alterations and apoptosis-like changes in vitro. Curcumin has also shown in vitro and in vivo activity against malaria, with inhibition of growth of chloroquine-resistant Plasmodium falciparum in vitro and enhancement of survival in mice infected with P. berghei.

PSORIASIS

Topical curcumin reduced the severity of active, untreated psoriasis as assessed by clinical, histological and immunohistochemical criteria in an observational study of 10 patients. Curcumin was also found to decrease phosphorylase kinase, which is involved in signalling pathways, including those involved with cell migration and proliferation. Topical administration of curcumin also induced normal skin formation in the modified mouse tail test. The effects are thought to be due to immune-modulating, anti-inflammatory and cyclo-oxygenase inhibitory actions. The downregulation of pro-inflammatory cytokines supports the view that turmeric antioxidants may exert a favourable effect on psoriasis-linked inflammation. Moreover, because IL-6 and IL-8 are growth factors for keratinocytes, their inhibition by those antioxidants may reduce psoriasis-related keratinocyte hyperproliferation.

Turmeric:  Other Actions

Curcumin’s anti-inflammatory and antioxidant actions may be useful in preventing neurodegenerative diseases, such as Alzheimer’s dementia and Parkinson’s disease, and curcumin has been found to target multiple pathogenic cascades in preclinical models (transgenic and amyloid infusion models) of AD. Curcumin has also been found to dose-dependently inhibit neuroglial proliferation, with low doses being as effective as higher doses given a longer period of treatment.

Curcumin had anti-asthmatic activity in animal models of induced asthma. Curcumin (20 mg/kg body weight) treatment significantly inhibited chemical (ovalbumin)-induced airway constriction and airway hyperreactivity. The results demonstrate that curcumin is effective in improving the impaired airways features in ovalbumin-sensitised guinea pigs.

Curcumin has been found to have inhibitory effects on P-glycoprotein in numerous test tube studies. The clinical significance of this observation has yet to be determined.