curcumin and 4-hydroxy-2-nonenal

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

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Anti-Mullerian Hormone; Apoptosis; Curcumin; Cyclin-Dependent Kinase Inhibitor p16; Deoxyguanosine; Disease Models, Animal; Female; Galactose; Gonads; Hypothalamo-Hypophyseal System; Mice, Inbred C57BL; Ovary; Oxidative Stress; Primary Ovarian Insufficiency; Protective Agents; RNA, Messenger; Tyrosine

Aroclor 1254 is a widespread toxic compound of Polychlorinated Biphenyls (PCBs), which can create significant nervous problems. No remedies have been found to date. The aim of this study was to reveal the damage that occurs in the central nervous system of rat pups exposed to Aroclor 1254 in the prenatal period and to show the inhibiting effect of curcumin, which is a strong anti-oxidant and neuroprotective substance.. The study established 3 groups of adult female and male Wistar albino rats. The rats were mated within these groups and the offspring rats were evaluated within the group given Aroclor 1254 only (n=10) and the group was given both Aroclor 1254 and curcumin (n=10) and the control group (n=10). The groups were compared in respect of pathomorphological damage. The immunohistochemical evaluation was made of 8-hydroxdeoxyguanosine (8-OHdG), 4-hydroxynoneal (4HNE), myelin basic protein (MBP) expressions and TUNEL reaction. The biochemical evaluation was made of the changes in the TAS-TOS and Neuron Specific Enolase (NSE) levels. Damage was seen to have been reduced with curcumin in the 8OHdG and TUNEL reactions, especially in the forebrain and the midbrain, although the dosage applied did not significantly change TAS and TOS levels. Consequently, it was understood that Aroclor 1254 caused damage in the central nervous system of the pup in the prenatal period, and curcumin reduced these negative effects, particularly in the forebrain and the midbrain.. It was concluded that curcumin could be a potential neuroprotective agent and would be more effective at higher doses.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Antioxidants; Brain; Chlorodiphenyl (54% Chlorine); Curcumin; Deoxyguanosine; Female; Immunohistochemistry; Male; Myelin Basic Protein; Neuroprotective Agents; Oxidants; Phosphopyruvate Hydratase; Pregnancy; Prenatal Exposure Delayed Effects; Rats

We sought to determine the preventive effects of curcumin and its highly bioavailable preparation on noise-induced hearing loss in a novel murine model of permanent hearing loss developed by repeated exposure to noise. Upon exposure to noise (8-kHz octave band noise, 90 dB sound pressure level, 1 h), hearing ability was impaired in a temporary and reversible manner. During repeated noise exposure (1-h exposure per day, 5 days), there was a progressive increase in the auditory threshold shift at 12 and 20 kHz. The threshold shift persisted for at least 6 days after noise exposure. Oral administration of curcumin for 3 days before and each day during noise exposure significantly alleviated the hearing loss induced by repeated noise exposure. Curcumin abolished intranuclear translocation of nuclear factor-κB-p65 and generation of 4-hydroxynonenal-adducted proteins found in the cochlea after noise exposure. Theracurmin

Topics: Active Transport, Cell Nucleus; Administration, Ophthalmic; Aldehydes; Animals; Biological Availability; Cochlea; Curcumin; Differential Threshold; Disease Models, Animal; Dosage Forms; Environmental Exposure; Hearing; Hearing Loss, Sensorineural; Mice, Inbred Strains; Noise; Phytotherapy; Transcription Factor RelA

Curcumin, an antioxidant compound found in Asian spices, was evaluated for its protective effects against ethanol-induced hepatosteatosis, liver injury, antiatherogenic markers, and antioxidant status in rats fed with Lieber-deCarli low menhaden (2.7% of total calories from ω-3 polyunsaturated fatty acids (PUFA)) and Lieber-deCarli high menhaden (13.8% of total calories from ω-3 PUFA) alcohol-liquid (5%) diets supplemented with or without curcumin (150 mg/kg/day) for 8 weeks. Treatment with curcumin protected against high ω-3 PUFA and ethanol-induced hepatosteatosis and increase in liver injury markers, alanine aminotransferase, and aspartate aminotransferase. Curcumin upregulated paraoxonase 1 (PON1) mRNA and caused significant increase in serum PON1 and homocysteine thiolactonase activities as compared to high ω-3 PUFA and ethanol group. Moreover, treatment with curcumin protected against ethanol-induced oxidative stress by increasing the antioxidant glutathione and decreasing the lipid peroxidation adduct 4-hydroxynonenal. These results strongly suggest that chronic ethanol in combination with high ω-3 PUFA exacerbated hepatosteatosis and liver injury and adversely decreases antiatherogenic markers due to increased oxidative stress and depletion of glutathione. Curcumin supplementation significantly prevented these deleterious actions of chronic ethanol and high ω-3 PUFA. Therefore, we conclude that curcumin may have therapeutic potential to protect against chronic alcohol-induced liver injury and atherosclerosis.

Topics: Aldehydes; Animals; Antioxidants; Aryldialkylphosphatase; Atherosclerosis; Biomarkers; Chemical and Drug Induced Liver Injury; Curcumin; Diet; Ethanol; Fatty Acids, Omega-3; Fatty Liver; Female; Glutathione; Lipid Metabolism; Lipid Peroxidation; Oxidative Stress; Rats; Rats, Wistar

The pathogenesis of cervical spondylotic myelopathy (CSM) is related to both primary mechanical and secondary biological injury. The authors of this study explored a novel, noninvasive method of promoting neuroprotection in myelopathy by using curcumin to minimize oxidative cellular injury and the capacity of omega-3 fatty acids to support membrane structure and improve neurotransmission.. An animal model of CSM was created using a nonresorbable expandable polymer placed in the thoracic epidural space, which induced delayed myelopathy. Animals that underwent placement of the expandable polymer were exposed to either a diet rich in docosahexaenoic acid and curcumin (DHA-Cur) or a standard Western diet (WD). Twenty-seven animals underwent serial gait testing, and spinal cord molecular assessments were performed after the 6-week study period.. At the conclusion of the study period, gait analysis revealed significantly worse function in the WD group than in the DHA-Cur group. Levels of brain-derived neurotrophic factor (BDNF), syntaxin-3, and 4-hydroxynonenal (4-HNE) were measured in the thoracic region affected by compression and lumbar enlargement. Results showed that BDNF levels in the DHA-Cur group were not significantly different from those in the intact animals but were significantly greater than in the WD group. Significantly higher lumbar enlargement syntaxin-3 in the DHA-Cur animals combined with a reduction in lipid peroxidation (4-HNE) indicated a possible healing effect on the plasma membrane.. Data in this study demonstrated that DHA-Cur can promote spinal cord neuroprotection and neutralize the clinical and biochemical effects of myelopathy.

Topics: Aldehydes; Animals; Brain-Derived Neurotrophic Factor; Chronic Disease; Curcuma; Diet; Disease Models, Animal; Docosahexaenoic Acids; Male; Neuroprotective Agents; Qa-SNARE Proteins; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries

We have assessed potential mechanisms associated with the deleterious effects of TBI on the integrity of plasma membranes in the hippocampus, together with consequences for behavioral function. In addition, we have investigated the efficacy of a dietary intervention based on a pyrazole curcumin derivative with demonstrated bioactivity and brain absorption, to re-establish membrane integrity. We report that moderate fluid percussion injury (FPI) increases levels of 4-Hydroxynonenal (HNE), an intermediary for the harmful effects of lipid peroxidation on neurons. A more direct action of FPI on membrane homeostasis was evidenced by a reduction in calcium-independent phospholipase A2 (iPLA₂) important for metabolism of membrane phospholipids such as DHA, and an increase in the fatty acid transport protein (FATP) involved in translocation of long-chain fatty acids across the membrane. A potential association between membrane disruption and neuronal function was suggested by reduced levels of the NR2B subunit of the transmembrane NMDA receptor, in association with changes in iPLA2 and syntaxin-3 (STX-3, involved in the action of membrane DHA on synaptic membrane expansion). In addition, changes in iPLA2, 4-HNE, and STX-3 were proportional to reduced performance in a spatial learning task. In turn, the dietary supplementation with the curcumin derivative counteracted all the effects of FPI, effectively restoring parameters of membrane homeostasis. Results show the potential of the curcumin derivative to promote membrane homeostasis following TBI, which may foster a new line of non-invasive therapeutic treatments for TBI patients by endogenous up-regulation of molecules important for neural repair and plasticity.

Topics: Aldehydes; Animals; Behavior, Animal; Blotting, Western; Brain Injuries; Cell Membrane; Cognition; Curcumin; Homeostasis; Immunohistochemistry; Lipid Peroxidation; Male; Maze Learning; Nerve Tissue Proteins; Neuronal Plasticity; Pyrazoles; Rats; Rats, Sprague-Dawley; Synapses

Topics: Administration, Oral; Aldehydes; Biological Availability; Clinical Trials as Topic; Curcumin; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Hot Temperature; Humans; Neoplasms; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

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

Topics: Aldehydes; Antineoplastic Agents; Biological Availability; Curcumin; Hot Temperature; Oxidation-Reduction; Solubility

Cellular oxidative stress and alterations in redox metabolisms have been implicated in the etiology and pathology of many diseases including cancer. Antioxidant treatments have been proven beneficial in controlling these diseases. We have recently shown that 4-hydroxynonenal (4-HNE), a by-product of lipid peroxidation, induces oxidative stress in PC12 cells by compromising the mitochondrial redox metabolism. In this study, we have further investigated the deleterious effects of 4-HNE on mitochondrial respiratory functions and apoptosis using the same cell line. In addition, we have also compared the effects of two antioxidants, curcumin and melatonin, used as chemopreventive agents, on mitochondrial redox metabolism and respiratory functions in these cells. 4-HNE treatment has been shown to cause a reduction in glutathione (GSH) pool, an increase in reactive oxygen species (ROS), protein carbonylation and apoptosis. A marked inhibition in the activities of the mitochondrial respiratory enzymes, cytochrome c oxidase and aconitase was observed after 4-HNE treatment. Increased nuclear translocation of NF-kB/p65 protein was also observed after 4-HNE treatment. Curcumin and melatonin treatments, on the other hand, maintained the mitochondrial redox and respiratory functions without a marked effect on ROS production and cell viability. These results suggest that 4-HNE-induced cytotoxicity may be associated, at least in part, with the altered mitochondrial redox and respiratory functions. The alterations in mitochondrial energy metabolism and redox functions may therefore be critical in determining the difference between cell death and survival.

Topics: Aldehydes; Animals; Antioxidants; Apoptosis; Curcumin; Cytochrome P-450 CYP2E1; Flow Cytometry; Glutathione; In Situ Nick-End Labeling; Lipid Peroxidation; Melatonin; Mitochondria; Oxidants; Oxidation-Reduction; Oxidative Stress; PC12 Cells; Rats; Superoxide Dismutase

Free radical mediated lipid peroxidation has been implicated in multiple diseases. A major oxidation by-product of this deleterious process is 4-hydroxy-2-nonenal (HNE). HNE is cytotoxic, mutagenic and genotoxic and is involved in disease pathogenesis. Curcumin, a non-steroidal anti-inflammatory agent (occurring as the yellow pigment found in the rhizomes of the perennial herb Curcuma longa known as turmeric), has emerged as the newest "nutraceutical" agent that has been shown to be efficacious against colon cancer and other disorders, including correcting cystic fibrosis defects. Since curcumin has been reported to have anti-oxidant properties we hypothesized that it will inhibit HNE-modification of a protein substrate. Using an ELISA that employed HNE-modification of solid phase antigen following immobilization, we found that the curcumin solubilized in dilute alkali (5mM sodium hydroxide, pH 11) inhibited HNE-protein modification by 65%. Turmeric also inhibited HNE-protein modification similarly (65%) but at a much lower alkali level (130muM sodium hydroxide, pH 7.6). Alkali by itself (5mM sodium hydroxide, pH 11) was found to enhance HNE modification by as much as 267%. Curcumin/turmeric has to inhibit this alkali enhanced HNE-modification prior to inhibiting the normal HNE protein modification induced by HNE. Thus, inhibition of HNE-modification could be a mechanism by which curcumin exerts its antioxidant effects. The pH at which the inhibition of HNE modification of substrate was observed was close to the physiological pH, making this formulation of curcumin potentially useful practically.

Topics: Aldehydes; Antioxidants; Curcuma; Curcumin; Dietary Supplements; Enzyme-Linked Immunosorbent Assay; Free Radicals; Hydrogen-Ion Concentration; Lipid Peroxidation; Peptides; Proteins; Rhizome; Sodium Hydroxide; Solubility

Lipid peroxidation has been implicated in a variety of diseases. 4-Hydroxy-2-nonenal (HNE), a major oxidation by-product, is cytotoxic, mutagenic, and genotoxic, being involved in disease pathogenesis. Naturally occurring pharmacologically active small molecules are very attractive as natural nonsteroidal anti-inflammatory agents. Interest has greatly increased recently in the pharmacotherapeutic potential of curcumin, the yellow pigment found in the rhizomes of the perennial herb Curcuma longa (turmeric). Curcumin is efficacious against colon cancer, cystic fibrosis, and a variety of other disorders. Curcumin's full pharmacological potential is limited owing to its extremely limited water solubility. We report here that the water solubility of curcumin could be increased from 0.6 microg/ml to 7.4 microg/ml (12-fold increase) by the use of heat. Spectrophotometric (400-700 nm) and mass spectrometric profiling of the heat-extracted curcumin displays no significant heat-mediated disintegration of curcumin. Using an enzyme-linked immunosorbent assay that employed HNE modification of solid-phase antigen, we found that the heat-solubilized curcumin inhibited HNE-protein modification by 80%. Thus, inhibition of HNE modification may be a mechanism by which curcumin exerts its effect. We also report a simple assay to detect curcumin spectrophotometrically. Curcumin was solubilized in methanol and serially diluted in methanol to obtain a set of standards that were then read for optical density at 405 nm. Curcumin in the heat-solubilized samples was determined from this standard. Heat-solubilized curcumin should be considered in clinical trials involving curcumin, especially in the face of frustrating results obtained regarding curcumin-mediated correction of cystic fibrosis defects.

Topics: Aldehydes; Anticarcinogenic Agents; Antigens; Antioxidants; Cross-Linking Reagents; Curcumin; Hot Temperature; Peptides; Reference Standards; Solubility; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrophotometry, Ultraviolet; Surface Plasmon Resonance

In the present study the irreversible inhibition of human glutathione S-transferase P1-1 (GSTP1-1) by alpha, beta-unsaturated aldehydes and ketones was studied. When GSTP1-1 was incubated with a 50-fold molar excess of the aldehydes acrolein (ACR) and 4-hydroxy-2-nonenal (HNE) and the ketones curcumin (CUR) and ethacrynic acid (EA) at 22 degrees C, all of them inactivated GSTP1-1. The remaining activity after 4 h of incubation in all cases was lower than 10%. The aldehydes crotonaldehyde (CRA), cinnamaldehyde (CA) and trans-2-hexenal were found to inhibit GSTP1-1 only at a 5000-fold molar excess and even then, for example, for CA a higher remaining activity of 17% was observed. The same inhibition experiments were conducted with 3 mutants of GSTP1-1: the C47S and C101S mutants and the double mutant C47S/C101S. Remaining activity for C47S varied between +/- 40% for CRA, CA, CUR and HEX and +/- 80% for ACR, EA and HNE. For C101S it varied between 0 and 9% and for the double mutant C47S/C101S, activity after 4 h of incubation was variable. Again it varied between +/- 40% for CRA, CA, CUR and HEX and +/- 80% for ACR, EA and HNE. EA is known to react almost exclusively with cysteine 47. When [14C]EA was incubated with the GSTP1-1, modified by the alpha, beta-unsaturated carbonyl compounds, no [14C]EA was incorporated in the enzyme, indicating that in all cases this cysteine residue was one of the major targets. Since Michael addition with these reagents is known to be reversible, the results of incubation of the inactivated enzymes with an excess of glutathione (GSH) were determined. For all compounds, a restoration of the catalytic activity was observed. The results indicate that alpha, beta-unsaturated carbonyl derivatives inhibit GSTP1-1 irreversibly mainly by binding to cysteine residues of GSTP1-1, especially Cys-47, This means that some of these compounds (e.g. CUR) might modify GST activity in vivo when GSH concentrations are low by covalent binding to the enzyme.

Topics: Acrolein; Aldehydes; Curcumin; Cysteine Proteinase Inhibitors; Enzyme Inhibitors; Ethacrynic Acid; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Isoenzymes; Ketones; Mutagenesis, Site-Directed

Age-related cataractogenesis is a significant health problem worldwide. Oxidative stress has been suggested to be a common underlying mechanism of cataractogenesis, and augmentation of the antioxidant defenses of the ocular lens has been shown to prevent or delay cataractogenesis. The present studies were designed to test the efficacy of curcumin, an antioxidant present in the commonly used spice turmeric, in preventing cataractogenesis in an in vitro rat model. Rats were maintained on an AIN-76 diet (ICN Pharmaceuticals Inc, Cleveland) for 2 wk, after which they were given a daily dose of corn oil alone or 75 mg curcumin/kg in corn oil for 14 d. Their lenses were removed and cultured for 72 h in vitro in the presence or absence of 100 mumol 4-hydroxy-2-nonenal (4-HNE)/L, a highly electrophilic product of lipid peroxidation. The results of these studies showed that 4-HNE caused opacifications of cultured lenses as indicated by the measurements of transmitted light intensity using digital image analysis. However, the lenses from curcumin-treated rats were much more resistant to 4-HNE-induced opacification than were lenses from control animals. Curcumin treatment caused a significant induction of the glutathione S-transferase (GST) isozyme rGST8-8 in rat lens epithelium. Because rGST8-8 utilizes 4-HNE as a preferred substrate, we suggest that the protective effect of curcumin may be mediated through the induction of this GST isozyme. These studies suggest that curcumin may be an effective protective agent against cataractogenesis induced by lipid peroxidation.

Topics: Aldehydes; Animals; Antioxidants; Cataract; Curcumin; Disease Models, Animal; Epithelium; Glutathione Transferase; Immunohistochemistry; Lens, Crystalline; Lipid Peroxidation; Organ Culture Techniques; Oxidative Stress; Random Allocation; Rats