Earlier studies have reported that turmeric enhances the activity of glutathione-S-transferase, which is an important enzyme in the detoxification process. The authors of this study postulate that it is likely that turmeric acts by inhibiting aflatoxin, inhibiting activation and by increasing its detoxification.

In view of the chemopreventive effects of curcumin, a study was performed to evaluate the translactational transfer of these health benefits to suckling mouse neonates. It was observed that turmeric (4.0 g/kg/day) and curcumin (0.4 g/kg/day) had modulatory effects on the hepatic levels of glutathione-S-transferase, acid soluble sulfhydryl (-SH), levels, cytochrome b5 and cytochrome P450 in both the mother and the pup. The authors concluded that modulation in competing potential pathways of biotransformation system enzymes in the lactating mother may affect the rate and extent of maternal detoxication and thus influence the passage of metabolites of administered xenobiotics to the suckling neonate.

One study reported that curcumin strongly inhibits cytochrome 4501A1/1A2 in the liver. These are isoenzymes involved in the bioactivation of several toxins including benzo[a]pyrene. Curcumin was also found to offer protection against ethanol toxicity. The effect of curcumin on liver toxicity induced by ethanol was evaluated in rats. 25% ethanol was intragastrically administered for 30 days to induce ethanol toxicity. The levels of the liver enzymes, aspartate transaminase and alkaline phosphatase increased and lipid peroxidation products as measured by the thiobarbituric acid test also increased. After 30 days, the test animals were divided into two groups: one group(IIa) received alcohol as described mixed with saline and the other received curcumin (80 mg/kg body weight)with 25% alcohol (group IIb). The curcumin treated rats showed a significant decrease in the levels of the marker liver enzymes as well as in the formation of thiobarbituric acid reactive products. This study thus reveals that curcumin has protective effects against ethanol-induced liver toxicity. The results are summarized in Figure 5.

A recent study detailed the modulating effect of curcumin on apoptosis in tumors. Curcumin was administered to the test animals at 0.2% and 0.6% level in the diet late in the premalignant stage, during the promotion/progression stage of colon carcinogenesis in male rats. 0.2% curcumin significantly inhibited colon tumorigenesis in treated rats as compared to untreated controls. The inhibition of adenocarcinomas of the colon was found to be dose-dependent. The authors confirmed that the chemopreventive activity of curcumin is observed when it is administered prior to, during and after carcinogen treatment as well as late in the premalignant stage of colon carcinogenesis.

One study reports the comparative chemopreventive effects of carotenoids curcumin and tetrahydrocurcumin on the development of putative preneoplastic aberrant crypt foci in colons of mice, initiated with 1,2-dimethylhydrazine dihydrochloride (DMH). The mice were divided into three groups. Each animal in the first group received

DMH (20 mg/kg body weight) subcutaneously twice a week for three weeks. Animals in group 1 were treated with one of the test compounds, lycopene (0.005% and 0.0025%) or fucoxanthin (0.01%) in the drinking water and lutein (0.05%), curcumin (0.5%) or THC (0.5% and 0.2%) in the diet from weeks 5-12. It was observed that fucoxanthin, lutein and THC (0.5%) significantly decreased the number of aberrant crypts as compared to the control group.

An interesting study explored the synergistic inhibitory effects of curcumin and genistein on the growth of human breast cancer MCF-7 cells induced by estrogenic pesticides or 17-beta estradiol. Pesticides such as endosulfane/chlordane/DDT mixtures are known to have high estrogenic activity and are therefore implicated in the development of hormone related cancers such as breast cancer. It was observed that when curcumin and genistein were added together in micromolar concentrations to estrogen -positive MCF-7 cells, there was a marked synergistic effect, resulting in total inhibition of the induction of these cells. The authors concluded that these results suggest that a combination of curcumin and genistein in the diet may potentially reduce the proliferation of estrogen-positive human breast cells rendered cancerous by the action of pesticides or 17-beta estradiol. A subsequent study confirmed that a mixture of curcumin and isoflavonoids is the most potent inhibitor against the growth of breast cancer cells. The study was directed towards the development of dietary strategies to prevent the stimulated growth of breast tumors by environmental estrogens. The inhibitory action of curcumin and a combination of curcumin and isoflavonoids (genistein) was studied in estrogen positive human breast cancer cells (MCF-7 and T47D) as well as estrogen negative MDA-MB-231 cells. Tumorigenesis was induced by the pesticide o,p'DDT and the environmental pollutants 4-octylphenol and 4-nonylphenol. A combination of curcumin and genistein was able to inhibit the growth of estrogen positive cells by 95%. The authors state that these data suggest that combinations of natural plant compounds may have preventive and therapeutic applications against the growth of breast tumors induced by environmental estrogens.

Dietary administration of turmeric (1%) or the ethanolic extract of turmeric (0.05%) was found to modulate the initiation as well as post-initiation phases of DMBA-induced mammary tumors in female rats, favorably. There was significant reduction in the number of tumors. The curcumin-free aqueous turmeric extract, in contrast was weakly chemopreventive and only when administered during the post-initiation phase.

One study compared the efficacy of dietary curcumin (2%) and dibenzoylmethane (1%) in inhibiting the formation of DMBA induced mammary tumors and lymphomas/leukemias in rats. Dibenzoylmethane completely inhibited the incidence of lymphomas/leukemias and inhibited mammary tumors by 97%. Curcumin had little effect on the formation of mammary tumors and inhibited the incidence of lymphomas/leukemias by 53% at the dose level used. However, in another study which employed intraperitoneal administration of curcumin at 100 mg/kg and 200 mg/kg, a significant decrease in the number of DMBA-induced palpable mammary tumors and mammary adenocarcinomas was observed. The in vivo formation of mammary DMBA-DNA adducts was also depressed for animals administered curcumin doses from 50 mg/kg to 200 mg/kg.

In a study which examined the antiproliferative effects of curcumin against several breast tumor cell lines including hormone dependent and independent as well as multidrug resistant (MDR) lines, the growth inhibitory effect was reported to be time and dose dependent and correlated positively with the inhibition of carcinogen-induced increase in ornithine decarboxylase activity .

The use of curcuminoids in the treatment of skin tumors has been reported in earlier studies. A subsequent controlled study was designed to investigate the chemopreventive action of dietary curcumin on 7,12-dimethylbenz(a)anthracene (DMBA) -initiated and 12-(O)-tetradecanoylphorbol (TPA)-promoted skin tumor formation in mice. Dietary administration of curcumin (1%) significantly inhibited the number of tumors per mouse and the tumor volume as well as the percentage of tumor bearing mice in the treated group as compared to the control group which did not receive dietary curcumin.

Another study explored the effects of topical application of commercial grade curcumin and individual curcuminoids on 12-O-tetradecanoylphorbol-13-acetate (TPA) induced increases in ornithine decarboxylase activity and TPA-induced tumor promotion (in tumors initiated by DMBA) in mouse skin. Commercial grade curcumin, pure curcumin and demethoxycurcumin had an equally potent inhibitory effect while bisdemethoxycurcumin and tetrahydrocurcumin were less active. A similar study explored the effects of topical applications of very low doses of curcumin on TPA-induced oxidation (initiated with 200 nmol DMBA) of DNA bases in the epidermis and on tumor promotion in mouse skin. 1, 10, 100 and 300 nmol of curcumin applied with 5 nmol TPA twice a week for 20 weeks inhibited the TPA-induced oxidation of DNA bases by 62-77% while 100 and 300 nmol concentrations inhibited tumor promotion by 62-79%(in terms of number of tumors per mouse and tumor volume). The authors reported that in a second experiment 20 or 100 nmol (but not 10 nmol) of curcumin when applied with 5 nmol of TPA twice a week for 18 weeks markedly inhibited TPA-induced tumor promotion. Curcumin had a strong inhibitory effect on DNA and RNA synthesis in cultured HeLa cells with little or no effect on protein synthesis.

Long wavelength, high power Ultraviolet radiation (UVA radiation) is believed to aggravate skin tumors. One study examined the enhancing effects of UVA on changes in mouse skin mediated by the tumor promoter TPA and examined the effects of curcumin on these changes, in terms of ornithine decarboxylase activity. A combination of TPA and UVA irradiation produced significantly greater increase in ornithine decarboxylase activity after 4 hours as compared to TPA alone. Pretreatment with curcumin significantly inhibited these enhancing effects.

Oral administration of curcumin has been shown in several earlier studies to inhibit oral, forestomach, duodenal and colon cancer. One study also reports the cytotoxicity of curcuminoids (isolated from Curcuma zeodaria ) against human ovarian cancer OVCAR-3 cells. Another study was directed towards oral cancer. An experimental model of 7,12-dimethylbenzanthracene-induced buccal pouch tumors in Syrian Golden hamsters was used to evaluate the tumor retardation effects of turmeric and curcumin. Turmeric and/or curcumin was administered in the diet and/or applied locally for 14 weeks along with 7,12-dimethylbenzanthracene. The results of the study suggest that turmeric or curcumin in the diet and/or applied locally significantly reduced DNA adducts at the target site. The number of tumors were significantly lower (p < 0.05) in the animals that received turmeric in the diet and applied locally. Suggesting that curcumin and turmeric may have a plausible chemopreventive effect on oral precancerous lesions.

In recent years, much of the research focus was directed towards elucidating the mechanism of chemoprotective and chemopreventive actions of the curcuminoids.

Curcuminoids are proven to have a dual-pronged mechanism of antioxidant action, viz., inhibiting the formation as well as propagation of free radicals. Most drugs and xenobiotics are lipophilic compounds that are biotransformed in the body to water soluble metabolites. Highly reactive intermediates (such as free radicals, reactive oxygen species etc.) are formed which can be deactivated enzymatically or non-enzymatically by GSH (glutathione). If this deactivation process is inefficient, the reactive intermediates covalently bind to macromolecules, such as proteins, membrane phospholipids and cellular DNA leading to dysfunction or damage to the cells. This in turn triggers inflammatory processes resulting in tissue necrosis. The cytoprotective action of curcumin is believed to be through the following pathways:

Decreased covalent binding of drugs and toxicants to the macromolecules by inhibition of the activating enzyme systems (such as cyclooxygenase and lipoxygenase in the skin or P450 isoenzymes) in the liver. A recent study showed that curcumin is an extremely potent inhibitor of cytochrome P4501A1 which is the important isoenzyme in the initial bioactivation of benzo(a)pyrene. Curcumin in a dose-dependent manner also prevented the formation of covalent adduct between cytochrome P450 and DNA, as shown in one study where the authors postulate that curcumin may inhibit chemical carcinogenesis by modulating P450 function.

Earlier studies on the protective activity of curcumin against paracetamol-induced hepatotoxicity, established the dose-dependent hepatoprotective effects. This information was provided in the earlier booklet. These studies suggest that curcumin may decrease the formation of reactive intermediates indirectly, by stimulating non-bioactivating enzyme systems by enzyme induction.

The properties of curcumin as a scavenger of free radicals such as superoxide anion radicals, hydroxyl radicals and nitrogen dioxide radicals was detailed in the earlier booklet. The ability of curcumin to inhibit lipid peroxidation and the peroxidation of arachidonic acid by iron/ascorbate was also detailed. Studies on the ability of curcumin to scavenge electrophilic reactive intermediates formed by metabolic activation of drugs and lipid peroxidation were published recently and are summarized here.

One study explored the mechanism of the chemopreventive effect of curcumin in an in vitro model comprised of HT-29 and HCT-15 human colon cancer cell lines. The results revealed that cancer cell proliferation was inhibited in both cell lines in a dose-dependent manner and no apoptosis was detected. This effect is therefore not linked to the ability of curcumin to inhibit arachidonic acid metabolism, as these cell lines differ in their ability to produce prostaglandins. The fact that curcumin failed to induce apoptosis prompted the authors to surmise that curcumin reduces the cell number by an exclusively or predominantly antiproliferative effect. This mechanism is different from the effect of the NSAID's, conventionally used in the therapy of colon cancer. These compounds induce apoptosis in both cell lines both in vitro and in vivo . However, the authors state that induction of apoptosis by curcumin cannot be totally excluded.

In further studies on the mechanisms of anti-carcinogenic anti-inflammatory effects of curcumin, its effect on the glutathione linked detoxification enzymes in rat liver was detailed. When rats were fed curcumin at doses from 1 to 500 mg/kg body weight for 14 days, the induction of liver glutathione-S-transferase activity towards 1-chloro-2,4-dinitrobenzene was found to be biphasic, with maximal induction of about 1.5 fold at 25 to 50 mg/kg body weight dosage. Curcumin caused a dose-dependent induction of an isozyme which is known to detoxify a highly toxic product of lipid peroxidation, 4-hydroxynonenal. These results suggest that the induction of enzymes involved in the detoxification of the electrophilic products of lipid peroxidation could explain the mechanism of action of curcumin as an anticancer and antiinflammatory agent.

Another study proposed that the antiinflammatory and anticancer action of curcumin is partly due to the inhibition of the enzyme G protein-mediated phospholipase D (PLD). The authors studied the effects of curcumin on a number of phospholipases in a cell free system. They also reported that curcumin inhibits 12-O-tetradeconoylphorbol-13-acetate induced PLD activation in intact J774.1 cells in a dose-dependent manner. This suggests that PLD inhibition may contribute to the mechanism of chemopreventive action of curcumin.

The presumption that the chemoprotective effects of curcumin are linked to the ability of curcumin to prevent the formation of arachidonic acid metabolites (through inhibition of cyclooxygenase and lipoxygenase) was proved to be wrong in one study, where arachidonic acid failed to exhibit tumorogenic effects when applied in high doses to mouse skin treated with 7,12-dimethylbenz[a]anthracene, a tumor initiator. The authors therefore explored the possibility that the chemopreventive effects of curcumin are mediated through its effects on cell differentiation. This possibility was investigated in an in vitro study with human promyelocytic HL-60 leukemia cell model system. Although curcumin alone had no effect on cellular differentiation, when it was combined with all-trans retinoic acid or 1 alpha, 25-dihydroxyvitamin D3, a synergistic effect was observed.

A study performed on rat T lymphocytes revealed that curcumin inhibits their proliferation and apoptosis. Curcumin (50 mM) inhibited the proliferation of rat thymocytes stimulated with concanavalin A (con A). Human Jurkat lymphoblastoid cells in the logarithmic growth phase behaved similarly. Curcumin also inhibited apoptosis in rat thymocytes treated with dexamethasone. Similar effects were observed in UV-irradiated Jurkat cells as judged by DNA ladder formation, cellular morphology changes and flow cytometry analysis. These observations reveal that curcumin has the capacity to inhibit both cell growth and cell death, implying that these processes share a common pathway. At some point along this pathway, curcumin affects a common step. This according to the authors, presumably involves a modulation of the AP-1 transcription factor. In earlier studies, curcumin has been shown to suppress the activity of the AP-1 transcription factor in cells stimulated to proliferate. A subsequent study explored the involvement of cellular thiols (such as glutathione which play a role in the redox regulation of apoptosis) in the anti-apoptopic effects of curcumin in rat thymocytes. The authors observed that curcumin exerted a glutathione-independent mechanism of cell protection.

In another study, curcumin was found to induce apoptopic cell death in promyelocytic leukemia HL-60 cells in a dose-dependent manner and even at comparatively low concentrations (3.5 mg/ml). The antioxidants N-acetyl-L-cysteine (NAC), L-ascorbic acid, alpha-tocopherol, catalase and superoxide dismutase all effectively prevented curcumin-induced apoptosis. The authors therefore suggest that curcumin-induced cell death is mediated by reactive oxygen species. Additionally, they state that the overexpression of antiapoptopic protein bcl-2 in the cells could delay the onset of curcumin-induced apoptosis.

Alternative mechanisms for the antiproliferative effects of curcumin have been proposed. One study suggests that curcumin suppresses the activation of protein kinase C initiated by carcinogens such as Aflatoxin B1. Constitutive activation of protein kinase C is believed to induce cells to proliferate resulting in the cancerous state.

One study suggests the involvement of apoptosis-independent alterations in membrane dynamics which in turn could lead to false conclusions regarding "curcumin-induced apoptosis", as apoptosis measurements are based on membrane changes. Curcumin was found to expand the cell membrane in erythrocytes, inducing echinocytosis. Another study substantiates that the ability of curcumin to induce apoptosis-like reversible changes in plasma membrane asymmetry and permeability as well as impart transient modifications in mitochondrial membrane potential may be responsible for its ability to exert either proapoptopic or antiapoptiopic effects in different cell types. A study performed on transformed as well as non-transformed cell types revealed that inhibition of cell proliferation by curcumin was not always associated with apoptosis. In immortalized mouse embryo fibroblast cells, curcumin was found to induce cell shrinkage, chromatin condensation and DNA fragmentation, all characteristic of apoptosis. The authors state that in some immortalized and transformed cells, blocking the cellular signal transduction may trigger apoptosis.

Curcumin may also prevent the development of angiogenesis, as determined in a study on the proliferation and cell cycle progression of human umblical vein endothelial cells (HUVEC). Curcumin inhibited the growth of these cells which was stimulated with fibroblast growth factor and endothelial growth supplement. Curcumin inhibited DNA synthesis through inhibition of the enzyme, thymidine kinase. As the migration, proliferation and differentiation of HUVEC leads to angiogenesis, facilitating tumor initiation and development, curcumin prevents tumor development as well.

The synergism between natural antioxidants as tumor inhibitors implies that different antioxidants are active at different stages of cell growth and proliferation , offering greater protection when used in combination than when used singly. The synergistic chemopreventive effects of the potent antioxidant fraction from green tea (-) epigallocatechin gallate and curcumin was examined in an in vitro study on normal, premalignant and malignant human oral epithelial cells. The effective doses required to inhibit the proliferation of cancer cells fell significantly when the antioxidants were used in combination. The combination reduced the ED value by 4.4 to 8.5 fold as compared to EGCG alone and 2.2 to 2.8 fold as compared to curcumin alone. This synergistic effect is attributed to the differential growth inhibition mechanisms of EGCG and curcumin. The compounds are active at different stages of cell growth and proliferation.

Curcumin was found to inhibit interleukin-1(IL-1)-alpha and tumor necrosis factor -(TNF) alpha activted kappaB (NFkappaB) in whole cells. The authors of this study propose that curcumin inhibits NFkappaB-dependent gene transcription, thereby exerting antitumor effects. NFkappaB is believed to be a factor influencing cell differentiation. The anti-mutagenic properties of curcumin are well-known. The ethyl acetate extract from Curcuma longa rhizomes was fractionated to yield the constituent curcuminoids which were assayed for topoisomerase I and II inhibitory activity. Topoisomerases are enzymes that change the degree of supercoiling in DNA by cutting one or both strands, thereby inducing mutations. Type I topoisomerases cut only one strand of DNA, Type II topoisomerases cut both strands of DNA. Bisdemethoxycurcumin was the most active curcuminoid, inhibiting topoisomerase at a concentration of 25 mg/mL. Curcumin and Demethoxycurcumin inhibited the topoisomerases at a concentration of 50 mg/mL.

Suppression of protein kinase C and nuclear oncogene expression have also been proposed as molecular mechanisms for the cancer chemopreventive effects of curcumin. Tumor promotion in mouse skin mediated by TPA, an activator of protein kinase was effectively suppressed by treatment with 15-20 microM curcumin for 15 minutes. The expression of the oncogene c-jun in the TPA- treated fibroblasts was also suppressed by curcumin.

The antioxidant and antiinflammatory properties of curcuminoids were discussed in detail in the earlier booklet. Recent studies were directed towards elucidating the mechanism of action and obtaining further insight into the role of curcuminoids in the management of inflammatory conditions such as arthritis as well as autoimmune disorders.

Curcuminoids protected normal human keratinocytes from hypoxanthine/xanthine oxidase injury. Since curcuminoids synergistically inhibited nitroblue tetrazolium reduction, a decrease in superoxide radical formation leading to lower levels of hydrogen peroxide is probable. The authors propose that lower levels of hydrogen peroxide, leading to decreased cytotoxic effects, may be responsible for the protective effects of curcuminoids. This study suggests that curcuminoids offer protection to the skin and could be included in antioxidant topical preparations.

Another study investigated the effects of curcuminoids on the inflammatory mediators secreted by macrophages which play an important role in autoimmune diseases. The influence of curcuminoids and capsaicin on arachidonic acid metabolism and secretion of lysosomal enzymes by macrophages was investigated. Rat peritoneal macrophages preincubated with 10 microM curcumin or capsaicin for 1 h inhibited the incorporation of arachidonic acid into membrane lipids, leukotriene B4 and leukotriene C4, but did not affect the release of arachidonic acid from macrophages stimulated by phorbol myristate acetate. Curcumin and capsaicin also inhibited the secretion of collagenase, elastase, and hyaluronidase. These results summarized in Figures 9 and 10 demonstrate that curcumin and capsaicin can control the release of inflammatory mediators such as eicosanoids and hydrolytic enzymes secreted by macrophages and thereby may exhibit antiinflammatory properties.

These results validate the potential role of curcumin in antiinflammatory formulations for maintaining tissue texture and integrity.

A similar study explored the effect of curcumin on certain lysosomal hydrolases in isoproterenol-induced myocardial infarction in rats. Rats treated with isoprenetol (30 mg/100g body weight) showed a significant increase in the activities of serum hydrolases The activities of enzymes such as beta-glucuronidase, beta-N-acetyl glucosaminidase, cathepsin B, cathepsin D and acid phosphatase were normalized after curcumin treatment. Isoprenetol administration to rats resulted in decreased stability of the membranes which was reflected by the lowered activity of cathepsin D in mitochondrial, lysosomal and microsomal fractions. A histopathological examination revealed decreased necrosis in the infracted hearts of the rats. In another study, was found to have a protective effect against acute adriamycin myocardial toxicity. Adriamycin (30 mg/kg) administered intraperitoneally to rats elevated the serum levels of creatine kinase and lactate dehydrogenase and products of lipid peroxidation. Myocardial glutathione content and glutathione peroxidase activity are reduced. Curcumin treatment seven days before and two days after adriamycin treatment at the level of 200 mg/kg significantly inhibited lipid peroxidation and increased the levels of endogenous antioxidants.

Curcumin was also found to offer protection against bleomycin-induced lung injury in rats. Bleomycin is known to induce inflammatory and oxidant lung injury, resulting in increases in certain biomarker enzyme activities, lipid peroxidation products and superoxide dismutase activity. Lower levels of reduced glutathione (an index of antioxidant status) were observed. Curcumin treatment resulted in restoration of antioxidant status and lowered the levels of the biomarker enzymes. These data suggest that curcumin treatment reduces the development of inflammation and oxidation induced by bleomycin. The authors mention that curcumin therefore offers a potential natural pharmacological approach to the management of drug or chemical-induced lung injury. Similarly, curcumin had a protective effect on radiation -induced toxicity in rats when orally administered at 200 micromole/kg body weight. The protective effects were assessed based on lung collagen hydroxyproline levels, liver superoxide dismutase, glutathione peroxidase and catalase activities which decreased in treated animals as compared to untreated controls.

Levels of various serum proteins were found to change in adjuvant induced arthritis. Increased levels of a glycoprotein with an apparent molecular weight of 72 kDa (Gp A72) were observed in the sera of arthritic rats. Gp A72 is an acidic glycoprotein with a pI of 5.1. The appearance of Gp A72 in the serum preceded the onset of paw inflammation in arthritic rats and persisted in the chronic phase. Oral administration of capsaicin (from red pepper) and curcumin (from turmeric) lowered the levels of Gp A72 by 88 and 73% respectively with concomitant lowering of paw inflammation in arthritic rats.

Curcumin in aqueous solution does not inhibit dioxygenation of fatty acids by Lipoxygenase 1 (LOX1). But, when bound to Phosphatidylcholine (PC) micelles, it inhibits the oxidation of fatty acids. A recent study showed that 8.6 microM of curcumin bound to the PC micelles is required for 50% inhibition of linoleic acid peroxidation. Lineweaver-Burk plot analysis has indicated that curcumin is a competitive inhibitor of lipxygenase (LOX1)with Ki of 1.7 microM for linoleic and 4.3 microM for arachidonic acids, respectively. Based on spectroscopic measurements, the authors concluded that the inhibition of LOX1 activity by curcumin can be due to binding to active center iron and curcumin after binding to the PC micelles acts as an inhibitor of LOX1.

Turmeric has been traditionally used in wound healing. Tissue repair and wound healing are complex processes that involve a series of structural changes in the tissue. These include inflammation, granulation, and remodeling of the tissue. The effect of curcumin on wound healing was studied in rats and guinea pigs. Punch wounds in treated animals were found to heal more rapidly as compared to untreated controls.

Biopsies of the wound showed renewal of the epidermis and increased migration of various cells including myofibroblasts, fibroblasts, and macrophages in the wound bed.

Several areas within the dermis showed extensive development of new blood vessels, and greater collagen deposition in curcumin-treated wounds.

The localization of transforming growth factor-beta1 and fibronectin which are important criteria in wound healing, showed increases in curcumin-treated wounds as compared with untreated wounds. The authors state that because transforming growth factor-beta1 is known to enhance wound healing, this may be the mechanism of wound healing by curcumin.

Cell injury by oxidative stress has been implicated in renal epithelial cell destruction during the progression of kidney diseases. One study observed the protective effect of turmeric and its constituents on H2O2 -induced injury. Porcine renal tubular epithelial cells LLC-PK1 were labeled with 3H-arachidonic acid then further labeled with Cr. Turmeric and its constituents, turmerin and curcumin (in various concentrations), known antioxidants such as vitamin E and 21-aminosteroid were added and incubated for 3 h at 37° C. The dose dependent effects of these compounds are represented in Figure 11. While curcumin and turmeric showed significant protection against lipid peroxidation comparable to Vitamin E, turmerin and 21-aminosteroid offered no protection.

Another study explored the role of antioxidants such as curcumin and quercetin in the management of non-immune renal injury. This type of injury plays an important role in acute and chronic rejection of kidney transplants by triggering an injury response through cytokine and chemokine release. Rat models with induced ischemia-reperfusion injury were selected. Pretreatment with quercetin or curcumin resulted in preservation of histological integrity, with a decrease in tubular damage and interstitial inflammation. The authors concluded that these bioflavonoids hold promise as agents that can reduce immune and nonimmune renal injury, the key risk factors in chronic graft loss.

One study found that ethanolic Curcuma extract may be protective in preventing lipoperoxidation of subcellular membranes in a dosage-dependent manner thereby preventing the progression of degenerative diseases such as atherosclerosis. Atherosclerosis is characterized by oxidative damage which affects lipoproteins, the walls of blood vessels and subcellular membranes. The study evaluated the antioxidant capacity of a Curcuma longa extract on the lipid peroxidation of liver mitochondria and microsome membranes in atherosclerotic rabbits. Male rabbits fed a 3% (w/w) lard and 1.3% (w/ cholesterol diet were randomly assigned to three groups and lipid peroxidation was chemically induced. Two of the groups were treated with different dosages of a turmeric extract and the third group (control) with a curcumin-free solution. The levels of hydroperoxides and thiobarbituric acid reaction substances were determined. In both microsomes and mitochondria, the basal hydroperoxide levels were similar in all groups but, after the induction of oxidation, group C registered the highest value. Thus the ethanol water extract of Curcuma longa (containing curcuminoids), is potentially useful in the prevention of atherosclerosis.

Many of the beneficial actions of natural compounds may be attributed to their immunomodulating effects. The effects of dietary curcumin on three major types of immune function were examined in rats. Antibody (IgG) production, delayed-type hypersensitivity and natural killer cell activity were evaluated after 5 weeks of dietary exposure to 1, 20 or 40 mg/kg curcumin. The highest dose of curcumin significantly enhanced IgG levels. Neither delayed-type hypersensitivity nor natural killer cell activity was different from control values at any dietary concentration of curcumin. In vitro incubation of tumor cells (two types YAC-1 and EL4) and normal splenocytes in varying concentrations of curcumin for different periods of time revealed differences between cell types in curcumin's effects on cell proliferation and viability. Although no cytotoxic effect was seen in EL4 cells treated with 125 micrograms/ml curcumin even after incubation for 48 hours, cell proliferation was reduced by almost 50% after 24 hrs. YAC-1 cell viability and cell numbers were diminished at longer incubations. A lower curcumin concentration (1.25 micrograms/ml) enhanced cell growth in the YAC-1 cells at 24 and 48 hr. This enhancement was not seen in spleen or EL4 cells.

Earlier reports described the antineoplastic and immunosuppressive properties of curcumin as seen in in vitro experiments. The authors of this study hypothesized that Curcumin, a tyrosine kinase inhibitor, would block cyclosporineA-resistant CD28 costimulatory pathway of human T cell proliferation. CyclosporineA is a commonly used immunosuppressant. However, curcumin was found to block this pathway as well as antibody stimulated T-cell proliferation, leading the authors to surmise that curcumin may have novel adjuvant immunosuppressive properties.

A significant study suggested that curcumin may have a potential effect on controlling allergic diseases through inhibiting the production of cytokines which affect

eosinophil function and IgE synthesis. These results have relevance in the potential use of curcumin in the management of bronchial asthma. This study examined the effect of curcumin on the production of interleukin (IL)-2, IL-5, granulocyte macrophage-colony stimulating factor (GM-CSF), and IL-4 by lymphocytes from atopic asthmatics in response to house dust mites. Curcumin inhibited induced lymphocyte proliferation and production of IL-2 , GM-CSF and IL-4 in a concentration-dependent manner (Figure 12).

* Lymphocytes from atopic asthmatics were stimulated with Df in the presence or absence of curcumin (Cr, 10 mM). The results indicated are on day 7 after cultivation for proliferation and day 3 after cultivation for IL-2.

One study examined the effects of curcumin on chemotactic cytokines or chemokine expression in bone marrow cells. The production of chemokines and colony stimulating factors by bone marrow stromal cells requires inflammatory conditions. As curcumin is an antiinflammatory agent, a detailed analysis of its regulatory effects on chemokine expression by IL-1alpha was performed. It was found that curcumin lowered mRNA levels by inhibition of the transcription of chemokine genes, effecting immunomodulation.

Another study found that the growth and toxigenesis of selected Aspergillus flavus strains was weak on curcumin, indicating its antifungal effects and inhibition of aflatoxin production. Curcumin was also found to have marked antiparasitic activity, showing cytotoxicity against African trypanosomes in vitro. The LD50 values were 4.77± 0.91 microM for bloodstream forms and 46.52± 4.94 microM for procyclic forms of Trypanosoma brucei brucei.

Curcumin has been reported to inhibit the replication of human immunodeficiency virus. A recent study suggests that curcumin inhibits the virus-cell fusion stage in the replication cycle of HIV. The inhibitory activity of curcumin against HIV-1 integrase has also been reported with certain curcumin analogs such as dicaffeoylmethane and rosmarinic acid being useful as well, in this regard.

One study suggests that curcumin and curcumin derivatives inhibit Tat-mediated transactivation of HIV1 long terminal repeat (HIV1-LTR). Tat protein secreted by HIV1 –infected cells is believed to have additional action in the pathogenesis of AIDS due to its ability to be taken up by non-infected cells as well. Curcumin at concentrations of 10 to 100nM inhibited Tat transactivation of HIV1-LTR lacZ by 70 to 80% in HeLa cells. Reduced curcumin, tocopheryl curcumin (with enhanced antioxidant activity) and allyl curcumin (a metal chelator) showed greater inhibitory activity than curcumin.

Cyclosporine A use in solid-organ transplantation as an immunosuppressant often induces post-transplant lymphoproliferative disorder (PTLD) mediated through Epstein-Barr virus (EBV). In an in vitro study, human B lymphocytes were immortalized with EBV while being subjected to oxidative stress with hydrogen peroxide in the presence of cyclosporine A. The effect of curcumin on this process was observed. Curcumin blocked B-cell immortalization in a dose-dependent manner with nearly complete inhibition at a concentration of 20 microM. Thus curcumin is an useful adjunct to therapeutic measures in the prevention of PLTD in patients under cyclosporine A therapy.