curcumin and ferric-nitrilotriacetate

This study was designed to reveal the protective effects of dietary supplementation of curcumin against renal cell tumours and oxidative stress induced by renal carcinogen iron nitrilotriacetate (Fe-NTA) in ddY male mice. The results showed that mice treated with a renal carcinogen, Fe-NTA, a 35% renal cell tumour incidence was noticed, whereas renal cell tumour occurrence was elevated to 80% in Fe-NTA promoted and N-diethylnitrosamine (DEN)-initiated mice as compared with saline- treated mice. No incidence of tumours has been observed in DEN-initiated non-promoted mice. Diet complemented with 0.5% and 1.0% curcumin fed prior to, during and after treatment with Fe-NTA in DEN-initiated animals, tumour incidence was reduced dose-dependently to about 45% and 30% respectively. Immunohistochemical studies also revealed the increased formation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in kidney tissue of mice treated with an intraperitoneal injection of Fe-NTA (6.0 mg Fe/kg body weight.). Furthermore, Fe-NTA treatment of mice also resulted in significant elevation of malondialdehyde (MDA), serum urea, and creatinine and decreases renal glutathione. However, the changes in most of these parameters were attenuated dose-dependently by prophylactic treatment of animals with 0.5% and 1% curcumin diet, this may be due to its antioxidative impact of curcumin. These results suggest that intake of curcumin is beneficial for the prevention of renal cell tumours and oxidative stress damage mediated by renal carcinogen, Fe-NTA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Blood Urea Nitrogen; Carcinogens; Carcinoma, Renal Cell; Creatinine; Curcumin; Diet; Diethylnitrosamine; Dose-Response Relationship, Drug; Ferric Compounds; Kidney Neoplasms; Male; Mice; Nitrilotriacetic Acid; Oxidative Stress

Iron overload disorders may be treated by chelation therapy. This study describes a novel method for isolating iron chelators from complex mixtures including plant extracts. We demonstrate the one-step isolation of curcuminoids from turmeric, the medicinal food spice derived from Curcuma longa. The method uses iron-nitrilotriacetic acid (NTA)-agarose, to which curcumin binds rapidly, specifically, and reversibly. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin each bound iron-NTA-agarose with comparable affinities and a stoichiometry near 1. Analyses of binding efficiencies and purity demonstrated that curcuminoids comprise the primary iron binding compounds recovered from a crude turmeric extract. Competition of curcuminoid binding to the iron resin was used to characterize the metal binding site on curcumin and to detect iron binding by added chelators. Curcumin-Iron-NTA-agarose binding was inhibited by other metals with relative potency: (>90% inhibition) Cu

Topics: Aluminum; Animals; Binding, Competitive; Calcium; Cell Line; Chromatography, Affinity; Copper; Curcuma; Curcumin; Deferoxamine; Diarylheptanoids; Edetic Acid; Epithelial Cells; Ferric Compounds; Iron; Iron Chelating Agents; Kinetics; Liver; Magnesium; Manganese; Nitrilotriacetic Acid; Plant Extracts; Rats; Zinc

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive cognitive impairment of patients, affecting around 12% of people older than 65 years old. WHO estimated that over 48.6 million all over the world suffer this disease. On the basis of cumulative results on our research, we have postulated the neuroimmunomodulation hypothesis that appears to provide a reasonable explanation of both the preclinical and clinical observations. In this context, the long-term activation of the innate immune system triggers an anomalous cascade of molecular signals, finally leading to tau oligomerization in the pathway to neuronal degeneration. In the present scenario of the failure of many anti-AD drugs, nutraceutical compounds provide an avenue for AD prevention and possibly as coadjuvants in the treatment of this disease. Recent discoveries point to the relevance of curcumin, a natural anti-inflammatory agent, in controlling oxidative stress and improving cholinergic function in the brain, even though the mechanisms underlying these actions are unknown. We investigated the effects of curcumin in cultures of neuronal cells. For this study, we exposed cells to prooxidant conditions, both in the presence and absence of curcumin. Our data reveal that curcumin exert a strong neuroprotective effect in N2a cells, thus preventing toxicity by oxidative agents H2O2 and Fe+3. This is supported by results that indicate that curcumin control the neurodegenerative effects of both oxidative agents, relieving cells from the loss of neuritogenic processes induced by prooxidants. In addition, curcumin was able to slow down the tau aggregation curve and disassemble tau pathological oligomeric structures. Data suggest that curcumin could be a potential compound for prevention of cognitive disorders associated with AD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Transformed; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Ferric Compounds; HEK293 Cells; Humans; Hydrogen Peroxide; Mice; Microscopy, Confocal; Microscopy, Electron; Neuroblastoma; Nitrilotriacetic Acid; Oxidative Stress; Protein Aggregates; tau Proteins; Time Factors

Curcumin (diferuloylmethane), a biologically active ingredient derived from rhizome of the plant Curcuma longa, has potent anticancer properties as demonstrated in a plethora of human cancer cell lines/animal carcinogenesis model and also acts as a biological response modifier in various disorders. We have reported previously that dietary supplementation of curcumin suppresses renal ornithine decarboxylase (Okazaki et al. Biochim Biophys Acta 1740:357-366, 2005) and enhances activities of antioxidant and phase II metabolizing enzymes in mice (Iqbal et al. Pharmacol Toxicol 92:33-38, 2003) and also inhibits Fe-NTA-induced oxidative injury of lipids and DNA in vitro (Iqbal et al. Teratog Carcinog Mutagen 1:151-160, 2003). This study was designed to examine whether curcumin possess the potential to suppress the oxidative damage caused by kidney-specific carcinogen, Fe-NTA, in animals. In accord with previous report, at 1 h after Fe-NTA treatment (9.0 mg Fe/kg body weight intraperitoneally), a substantial increased formation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts in renal proximal tubules of animals was observed. Likewise, the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and protein reactive carbonyl, an indicator of protein oxidation, were also increased at 1 h after Fe-NTA treatment in the kidneys of animals. The prophylactic feeding of animals with 1.0% curcumin in diet for 4 weeks completely abolished the formation of (i) HNE-modified protein adducts, (ii) 8-OHdG, and (iii) protein reactive carbonyl in the kidneys of Fe-NTA-treated animals. Taken together, our results suggest that curcumin may afford substantial protection against oxidative damage caused by Fe-NTA, and these protective effects may be mediated via its antioxidant properties. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Antioxidants; Carcinogens; Chemoprevention; Curcumin; Deoxyguanosine; Ferric Compounds; Kidney; Kidney Tubules, Proximal; Male; Mice; Neoplasms; Nitrilotriacetic Acid; Oxidative Stress; Proteins

The influence of melatonin, curcumin, quercetin, and resveratrol pretreatment on ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage was studied. Male Wistar rats were treated orally once daily for 3 days with melatonin (10 mg/kg), curcumin (50 mg/kg), quercetin (15 mg/kg), and resveratrol (10 mg/kg). One hour after the last dose of antioxidants, a single dose of Fe-NTA was administered (8 mg of Fe/kg body weight, i.p.) to pre-treated animals. Twenty-four hours after Fe-NTA administration, the lipid peroxidation (LP), reduced glutathione (GSH), catalase (CAT), and glutathione peroxidase (GSH-Px) were estimated in kidney homogenates. Iron, zinc, and copper concentrations were estimated in kidney tissue. Administration of Fe-NTA to rats induced renal LP (170%, P < 0.001) and inhibited catalase (78%, P < 0.05) in the kidney. The oral pretreatment with melatonin, curcumin, quercetin, and resveratrol each one was effective in decreasing the Fe-NTA-induced LP (P < 0.001); however, it did not influence the FeNTA-induced inhibition of renal CAT activity. No changes were found in renal GSH level and GSH-Px activity compared to control animals. The pretreatment with antioxidants did not affect the increase in renal iron content, blood urea nitrogen/creatinine ratio, and relative kidney weight of FeNTA-intoxicated rats. The results indicate that the pretreatment with natural antioxidants, curcumin, melatonin, quercetin, and resveratrol, significantly and equally suppressed lipid peroxidation induced by Fe-NTA but had no effect on other markers of FeNTA nephrotoxicity and iron deposition in kidneys.

Topics: Animals; Antioxidants; Blood Urea Nitrogen; Catalase; Curcumin; Disease Models, Animal; Ferric Compounds; Glutathione; Glutathione Peroxidase; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Melatonin; Metals, Heavy; Nitrilotriacetic Acid; Organ Size; Oxidative Stress; Quercetin; Rats; Rats, Wistar; Resveratrol; Stilbenes

Curcumin, a natural, biologically active compound extracted from rhizomes of Curcuma species, has been shown to act as a biological response modifier in various disorders. We have reported previously that the dietary supplementation of curcumin enhances the activities of antioxidant and phase II metabolizing enzymes in mice (M. Iqbal, S.D. Sharma, Y. Okazaki, M. Fujisawa, S. Okada, Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY mice: possible role in protection against chemical carcinogenesis and toxicity, Pharmacol and Toxicol. 92 (2003) 33_38.) and inhibits ferric nitrilotriacetate (Fe-NTA) induced oxidative injury of lipids and DNA in vitro (M. Iqbal, Y. Okazaki, S. Okada, In vitro curcumin modulates Ferric Nitrilotriacetate (Fe-NTA) and hydrogen peroxide (H(2)O(2))-induced peroxidation of microsomal membrane lipids and DNA damage, Teratogenesis Carcinogenesis and Mutagenesis Supplement 23 (2003) 151-160.). In our present study, Fe-NTA, a known complete renal carcinogen, which generate ROS in vivo, was given intraperitoneally to mice and curcumin was tested for its ability to inhibits oxidative stress and the activity of ornithine decarboxylase (ODC) as well as histopathological changes in the kidney. Substantial changes in glutathione, antioxidant enzymes as well as changes in phase II metabolizing enzymes were observed in the kidney at 12 h after treatment with Fe-NTA (9.0 mg Fe/kg body weight). Effect of oxidative stress induced by Fe-NTA were also demonstrated by the increase in lipid peroxidation as monitored by formation of thiobarbituric acid-reactive substances and 4-hydroxy-2-nonenal (HNE)-modified proteins in kidney. Likewise, the level of protein carbonyl contents, an indicator of protein oxidation was also increased after Fe-NTA administration. However, the changes in these parameters were restored to normal in curcumin-pretreated mice. The ODC activity in the kidney was significantly increased by Fe-NTA, while the increased ODC activity induced by Fe-NTA was normalized in curcumin-pretreated mice. In addition, curcumin pretreatment almost completely prevented kidney biomolecules from oxidative damage and protected the tissue against observed histopathological alterations.

Topics: Analysis of Variance; Animals; Antibodies, Monoclonal; Curcumin; Ferric Compounds; Glutathione; Immunohistochemistry; Kidney; Lipid Peroxidation; Male; Mice; Microsomes; Nitrilotriacetic Acid; Ornithine Decarboxylase Inhibitors; Oxidative Stress

A number of investigations have implicated the involvement of free radicals in various pathogenic process including initiation/promotion stages of carcinogenesis and antioxidants have been considered to be a protective agent for this reason. An iron chelate, ferric nitrilotriacetate (Fe-NTA), is a potent nephrotoxic agent and induces acute and subacute renal proximal tubular necrosis by catalyzing the decomposition of hydrogen peroxide-derived production of hydroxyl radicals, which are known to cause lipid peroxidation and DNA damage. The latter is associated with a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation and DNA damage are the principal manifestation of Fe-NTA-induced toxicity, which could be mitigated by antioxidants. In this study, we therefore investigated the effect of curcumin, a polyphenolic compound from Curcuma longa for a possible protection against lipid peroxidation and DNA damage induced by Fe-NTA and hydrogen peroxide in vitro. Incubation of renal microsomal membrane/and or calf thymus DNA with hydrogen peroxide (40 mM) in the presence of Fe-NTA (0.1 mM) induces renal microsomal lipid peroxidation and DNA damage to about 2.2-and 5.6-fold, respectively, as compared to saline treated control (P<0.001). Induction of renal microsomal lipid peroxidation and DNA damage was modulated by curcumin dose dependently. In lipid peroxidation protection studies, curcumin treatment showed a dose-dependent strong inhibition (18-80% inhibition, P<0.05-0.001) of Fe-NTA and hydrogen peroxide-induced lipid peroxidation as measured by MDA formation in renal microsomes. Similarly, in DNA-sugar damage protection studies, curcumin treatment also showed a dose dependent inhibition (22-57% inhibition, P<0.05-0.001) of DNA-sugar damage. From these studies, it was concluded that curcumin modulates Fe-NTA and hydrogen peroxide-induced peroxidation of microsomal membrane lipids and DNA damage. Curcumin might, therefore, be a suitable candidate for the chemoprevention of Fe-NTA-associated cancer.

Topics: Animals; Anticarcinogenic Agents; Curcuma; Curcumin; DNA; DNA Damage; Dose-Response Relationship, Drug; Ferric Compounds; Hydrogen Peroxide; Kidney; Lipid Peroxidation; Male; Membrane Lipids; Mice; Microsomes; Nitrilotriacetic Acid

Protective effects of curcumin (U1), one of the major yellow pigments in turmeric and its derivative, tetrahydrocurcumin (THU1), against ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage were studied in male ddY mice. Single Fe-NTA treatment (5 mg Fe/kg body intraperitoneally) transiently causes oxidative stress, as shown by the accumulation of lipid peroxidation products and 8-hydroxy-2'-deoxyguanosine in the kidney. Mice were fed with a diet containing 0.5 g/100 g U1 or THU1 for 4 wk. THU1 significantly inhibited 2-thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine formation in the kidney; U1 inhibited only 4-hydroxy-2-nonenal-modified protein formation. To elucidate the mechanisms of protection by U1 and THU1, the pharmacokinetics and radical-scavenging capacities of U1 and THU1 were investigated by HPLC and electron spin resonance spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide, respectively. Induction of antioxidant enzymes was also investigated. The amounts of THU1 and its conjugates (as sulfates and glucuronides) in the liver and serum were larger in the THU1 group than in the U1 group. The amounts of U1 and its conjugates were small even in the U1 group. These results suggest that THU1 is more easily absorbed from the gastrointestinal tract than U1. Furthermore, THU1 induced antioxidant enzymes, such as glutathione peroxidase, glutathione S-transferase and NADPH: quinone reductase, as well as or better than U1 and scavenged Fe-NTA-induced free radicals in vitro better than U1. These results suggest that U1 is converted to THU1 in vivo and that THU1 is a more promising chemopreventive agent.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Chromatography, High Pressure Liquid; Curcumin; Electron Spin Resonance Spectroscopy; Ferric Compounds; Free Radical Scavengers; Intestinal Absorption; Kidney; Kinetics; Lipid Peroxidation; Liver; Male; Mice; Nitrilotriacetic Acid; Oxidative Stress; Thiobarbituric Acid Reactive Substances