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PubMed2006

Tetrahydrocurcumin: effect on chloroquine-mediated oxidative damage in rat kidney.

Tetrahydrocurcumin is an antioxidative substance, which is derived from curcumin, the component of turmeric. In the present investigation, the effect of tetrahydrocurcumin and curcumin against chloroquine-induced nephrotoxicity were studied in female wistar rats. Oral administration of tetrahydrocurcumin significantly prevented the occurrence of chloroquine (970 mg/kg body weight)-induced renal damage. Upon administration of tetrahydrocurcumin to chloroquine-treated rats, the level of lipid peroxidation was significantly decreased while the levels of non-enzymic and enzymic antioxidants were significantly increased in kidney. Oral administration (80 mg/kg body weight) attenuated the chloroquine-induced nephrotoxicity by significantly decreased levels of serum urea and creatinine with significant normalization of creatinine clearance. On administration of tetrahydrocurcumin, the depleted renal antioxidant defense system (enzymatic and non-enzymatic antioxidants) was significantly increased in rats treated with chloroquine. These biochemical observations were supplemented by histopathological examination of kidney section. These results suggest that administration of chloroquine imposes an oxidative stress to renal tissue and that tetrahydrocurcumin protects the oxidative damage associated with chloroquine.

Administration, Oral↗

PubMed1994

Curcuminoids as potent inhibitors of lipid peroxidation.

Earlier studies showed that curcumin is a potent inhibitor iron-catalysed lipid peroxidation. Demethoxycurcumin, bisdemethoxycurcumin and acetylcurcumin were tested for their ability to inhibit iron-stimulated lipid peroxidation in rat brain homogenate and rat liver microsomes. Comparison of the results with curcumin showed that all compounds are equally active, and more potent than alpha-tocopherol. These results showed that the methoxy and phenolic groups contribute little to the activity. Spectral studies showed that all compounds could interact with iron. Thus, the inhibition of iron-catalysed lipid peroxidation by curcuminoids may involve chelation of iron.

Animals↗

PubMed2004

Differential activation of heme oxygenase-1 by chalcones and rosolic acid in endothelial cells.

The induction of heme oxygenase-1 (HO-1) is widely recognized as an effective cellular strategy to counteract a variety of stressful events. We have shown that curcumin and caffeic acid phenethyl ester, two naturally occurring phytochemicals that possess antioxidant, anti-inflammatory, and anticarcinogenic activities, induce HO-1 in many cell types. This suggests that stimulation of HO-1 could partly underlie the beneficial effects exerted by these plant-derived constituents. Here we examined the ability of additional plant constituents to up-regulate heme oxygenase activity and HO-1 in aortic endothelial cells. Incubation of endothelial cells with a series of polyphenolic chalcones (5-50 microM) resulted in increased heme oxygenase activity; interestingly, the chemical structure dictated the pattern of heme oxygenase induction, which was unique to each particular compound employed. We also found that rosolic acid, a constituent isolated from the rhizome of Plantago asiatica L. dramatically increased HO-1 in a concentration- and time-dependent manner. Severe cytotoxicity was observed after prolonged exposure (24 or 48 h) of cells to curcumin and caffeic acid phenethyl ester, whereas 2'-hydroxychalcone and rosolic acid did not affect cell viability. By using different mitogen-activated protein kinase inhibitors, we determined that the extracellular signal-regulated kinase, p38, and c-Jun NH(2)-terminal protein kinase pathways play only a minor role in the induction of HO-1 by rosolic acid and 2'-hydroxychalcone. On the other hand, increased intra- and extracellular thiols markedly reduced the rise in heme oxygenase activity elicited by rosolic acid. Thus, this study identified novel plant constituents that highly induce HO-1 in endothelial cells and investigated some of the mechanisms involved in this effect.

Animals↗

PubMed2005

The GI-GPx gene is a target for Nrf2.

The gastrointestinal glutathione peroxidase (GI-GPx, GPx2) is a selenoprotein that was suggested to act as barrier against hydroperoxide absorption but has also been implicated in the control of inflammation and malignant growth. In CaCo-2 cells, GI-GPx was induced by t-butyl hydroquinone (tBHQ) and sulforaphane (SFN), i.e., "antioxidants" known to activate the "antioxidant response element" (ARE) via electrophilic thiol modification of Keap1 in the Nrf2/Keap1 system. The functional significance of a putative ARE in the GI-GPx promoter was validated by transcriptional activation of reporter gene constructs upon exposure to electrophiles (tBHQ, SFN, and curcumin) or overexpression of Nrf2 and by reversal of these effects by mutation of the ARE in the promoter and by overexpressed Keap1. Binding of Nrf2 to the ARE sequence in authentic gpx2 was corroborated by chromatin immunoprecipitation. Thus, the presumed natural antioxidants sulforaphane and curcumin may exert their anti-inflammatory and anticarcinogenic effects not only by induction of phase 2 enzymes but also by the up-regulation of the selenoprotein GI-GPx.

Animals↗

PubMed1999

AP-1 mediates stretch-induced expression of HB-EGF in bladder smooth muscle cells.

Mechanical induction of growth factor synthesis may mediate adaptive responses of smooth muscle cells (SMC) to increases in physical load. We previously demonstrated that cyclic mechanical stretch induces expression of the SMC, fibroblast, and epithelial cell mitogen heparin-binding epidermal growth factor-like growth factor (HB-EGF) in bladder SMC, an observation that suggests that this growth factor may be involved in compensatory bladder hypertrophy. In the present study we provide evidence that the activator protein-1 (AP-1) transcription factor plays a critical role in this mechanoinduction process. Rat bladder SMC were transiently transfected with a series of 5' deletion mutants of a promoter-reporter construct containing 1. 7 kb of the mouse HB-EGF promoter that was previously shown to be stretch responsive. The stretch-mediated increase in promoter activity was completely ablated with deletion of nucleotide positions -1301 to -881. Binding of AP-1, as evaluated by electrophoretic mobility shift assay, to a synthetic oligonucleotide containing an AP-1 binding site increased in response to stretch, and binding was inhibited by excess unlabeled DNA corresponding to nucleotides -993 to -973 from the HB-EGF promoter, a region that contains a previously recognized composite AP-1/Ets site. Stretch-induced promoter activity was significantly inhibited by site-directed mutagenesis of the AP-1 or Ets components of this site. Consistent with the promoter and gel-shift studies, curcumin, an inhibitor of AP-1 activation, suppressed the HB-EGF mRNA induction after stretch. Stretch also specifically increased mRNA levels for matrix metalloproteinase (MMP)-1, the promoter of which contains a functional AP-1 element, but not for MMP-2, the promoter of which does not contain an AP-1 element. The stretch response of the MMP-1 gene was also completely inhibited by curcumin. Collectively, these findings indicate that AP-1-mediated transcription plays an important role in the regulation of gene expression in bladder muscle in response to mechanical forces.

Animals↗

PubMed2006

Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway.

Cisplatin resistance occurs, at least in part, through the function of the Fanconi anemia (FA)/BRCA pathway, a DNA-damage response pathway required for repair of cisplatin cross-links. In the current study, we designed a cell-based screening strategy to identify small-molecule inhibitors of the FA/BRCA pathway with the hypothesis that such molecules could restore sensitivity to platinum agents. We identified four inhibitors, including three protein kinase inhibitors (wortmannin, H-9, and alsterpaullone) and one natural compound (curcumin) that inhibit the FA/BRCA pathway. We show that curcumin, a compound that is generally regarded as safe, inhibits the monoubiquitination of the FANCD2 protein as predicted by the screen and consequently sensitizes ovarian and breast tumor cell lines to cisplatin through apoptotic cell death. We believe that this study shows an efficient, high-throughput method for identifying new compounds that may sensitize cancer cells to DNA-damaging chemotherapy.

Androstadienes↗

PubMed1994

Studies on anti-inflammatory activity of spice principles and dietary n-3 polyunsaturated fatty acids on carrageenan-induced inflammation in rats.

The antioxidant spice principles curcumin and eugenol when given by gavage lowered the carrageenan-induced edema in the foot pads of rats. This lowering effect was dependent on the concentration, the time gap between the administration of spice principles and the induction of inflammation by carrageenan. Dietary lipids also influenced the extent of inflammation. Animals fed 10% cod liver oil [containing n-3 polyunsaturated fatty acids (PUFA)] for 10 weeks showed a significantly lower inflammation compared to that observed in animals fed diets supplemented with 10% groundnut oil (rich in n-6 PUFA) or 10% coconut oil (rich in medium-chain saturated fatty acids). Supplementation of diets with 1 weight% of curcumin did not affect the inflammatory responses of animals to carrageenan injection. However, supplementation of diets with 0.17 weight% eugenol further lowered inflammation by 16, 32 and 30% in animals fed coconut oil, groundnut oil and cod liver oil, respectively. Therefore, combinations of dietary lipids with spice principles like eugenol can help in lowering inflammation.

Administration, Oral↗

PubMed2006

A specific method for measurement of equine active myeloperoxidase in biological samples and in in vitro tests.

An original method called SIEFED (specific immunological extraction followed by enzymatic detection) was developed for the specific detection of the activity of equine myeloperoxidase (MPO). The method consists of the extraction of MPO from aqueous solutions by immobilized anti-MPO antibodies followed by washing (to eliminate proteins and interfering molecules) and measurement of MPO activity using a detection system containing a fluorogenic substrate, hydrogen peroxide, and nitrite as reaction enhancer. The SIEFED technique was applied to study active MPO in horse biological fluids and the effects of 2 polyphenolic molecules, curcumin and resveratrol, on MPO activity. The detection limit of the SIEFED was 0.23 mU/ml. The SIEFED exhibited good precision with intra-assay and interassay coefficients of variation below 10% and 20%, respectively, for MPO activities ranging from 0.25 to 6.4 mU/ml. The activity of MPO was generally higher than 1 mU/ml in the fluids collected from horses with inflammatory diseases. Curcumin and resveratrol exerted a dose-dependent inhibition on MPO activity and, as they were removed before the enzymatic detection of MPO, the results suggest a direct drug-nzyme interaction or an enzyme structure modification by the drug. The SIEFED is a new tool that would be useful for specific detection of active MPO in complex media and for selection of MPO activity modulators.

Animals↗

PubMed2003

Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis.

Chemoresistance is a major problem in the treatment of patients with multiple myeloma (MM). Because of the central role of the nuclear transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) in chemoresistance, cell survival, and proliferation, we investigated whether MM cells derived from patients express activated NF-kappaB and STAT3 and if their suppression induces apoptosis. We assayed CD138+ cells from the bone marrow of 22 MM patients and checked for the activated forms of NF-kappaB and STAT3 by immunocytochemistry. We found that MM cells from all the patients expressed the activated forms of NF-kappaB and STAT3 but to a variable degree (NF-kappaB: low, 3 of 22; moderate, 5 of 22; or high, 14 of 22; STAT3: none, 1 of 22; low, 3 of 22; moderate, 5 of 22; or high, 14 of 22). Constitutive activation of NF-kappaB was in some cases also independently confirmed by electrophoretic mobility gel shift assay. In contrast to MM patients, activated forms of NF-kappaB and STAT3 were absent in cells from healthy individuals. Suppression of NF-kappaB and STAT3 activation in MM cells by ex vivo treatment with curcumin (diferuloylmethane) resulted in a decrease in adhesion to bone marrow stromal cells, cytokine secretion, and in the viability of cells. When compared with curcumin, dexamethasone was less effective in suppression of NF-kappaB activation and induction of apoptosis in myeloma cells. Overall, our results indicate that fresh cells from MM patients express constitutively active NF-kappaB and STAT3, and suppression of these transcription factors inhibits the survival of the cells.

Adult↗

PubMed2006

Modest induction of phase 2 enzyme activity in the F-344 rat prostate.

BACKGROUND: Prostate cancer is the most commonly diagnosed malignancy in men and is thought to arise as a result of endogenous oxidative stress in the face of compromised carcinogen defenses. We tested whether carcinogen defense (phase 2) enzymes could be induced in the prostate tissues of rats after oral feeding of candidate phase 2 enzyme inducing compounds. METHODS: Male F344 rats were gavage fed sulforaphane, beta-naphthoflavone, curcumin, dimethyl fumarate or vehicle control over five days, and on the sixth day, prostate, liver, kidney and bladder tissues were harvested. Cytosolic enzyme activities of nicotinamide quinone oxidoreductase (NQO1), total glutathione transferase (using DCNB) and mu-class glutathione transferase (using CDNB) were determined in the treated and control animals and compared. RESULTS: In prostatic tissues, sulforaphane produced modest but significant increases in the enzymatic activities of NQO1, total GST and GST-mu compared to control animals. beta-naphthoflavone significantly increased NQO1 and GST-mu activities and curcumin increased total GST and GST-mu enzymatic activities. Dimethyl fumarate did not significantly increase prostatic phase 2 enzyme activity. Compared to control animals, sulforaphane also significantly induced NQO1 or total GST enzyme activity in the liver, kidney and, most significantly, in the bladder tissues. All compounds were well tolerated over the course of the gavage feedings. CONCLUSION: Orally administered compounds will induce modestly phase 2 enzyme activity in the prostate although the significance of this degree of induction is unknown. The 4 different compounds also altered phase 2 enzyme activity to different degrees in different tissue types. Orally administered sulforaphane potently induces phase 2 enzymes in bladder tissues and should be investigated as a bladder cancer preventive agent.

Animals↗

PubMed2005

Protective role of antioxidative food factors in oxidative stress caused by hyperglycemia.

Hyperglycemia causes the autoxidation of glucose, glycation of proteins, and the activation of polyol metabolism. These changes accelerate generation of reactive oxygen species (ROS) and increases in oxidative chemical modification of lipids, DNA, and proteins in various tissues. Oxidative stress may play an important role in the development of complications in diabetes such as lens cataracts, nephropathy, and neuropathy. Glycation reactions, especially Maillard reactions, occur in vivo as well as in vitro and are associated with the chronic complications of diabetes mellitus and aging and age-related diseases by increases in oxidative chemical modification of lipids, DNA, and proteins. In particular, long-lived proteins such as lens crystallines, collagens, and hemoglobin may react with reducing sugars to form advanced glycation end products (AGEs). Recently, we found a novel type of AGE, named MRX, and we found that MRX is a good biomarker for detecting oxidative stress produced during Maillard reaction. We also examined in detail the role of lipid peroxidation reaction in hyperglycemia and found that hexanoyl modification formed by the reaction of oxidized lipids and proteins must be important for oxidative stress. Detailed analyses of the formation mechanism of hexanoyl lysine (HEL) moiety in proteins were conducted, and excretion of HEL into urine was quantified by using LC/MS/MS. Macrophages and neutrophils play an important role in oxidative stress during hyperglycemia, and we determined that oxidatively modified tyrosines are a good biomarker for formation of oxidative stress at an early stage. Immunochemical analyses by application of monoclonal antibodies specific to lipid hydroperoxide-modified proteins produced by polyunsaturated fatty acids including docosahexaenoic acid (DHA) in oxidative stress caused by hyperglycemia were conducted, and the relationship between glycation and lipid peroxidation reactions both by chemical and immunochemical approaches are discussed. Recently, we put much more focus on dietary antioxidants for prevention of diabetic complications. Curcuminoids, the main yellow pigments in Curcuma longa (turmeric), have been used widely and for a long time in the treatment of sprain and inflammation in indigenous medicine. Curcumin is the main component of turmeric, and two minor components are also present as the curcuminoids. Curcuminoids possess antioxidant activity. Protective effects of curcumin (U1) and one of its major metabolites, tetrahydrocurcumin (THU1), have been examined for development of diabetic cataract in 25% galactose-fed SD rats. Through detailed examination of protective mechanisms of THU1, it was found that THU1 showed that scavenger ROS not only formed during hyperglycemia, but also induced antioxidative enzymes including detoxification enzymes such as glutathine S-transferase. THU1 also showed significant increase of glutathione concentration in the cultured rat lens. Glutathione (gamma-glutamylcysteinyl glycine [GSH]) is thought to be an important factor in cellular function and defense against oxidative stress, and we found that dietary GSH suppresses oxidative stress in vivo in prevention of diabetic complications such as diabetic nephropathy and neuropathy.

Animals↗

PubMed2002

Requirement for PIKfyve enzymatic activity in acute and long-term insulin cellular effects.

PIKfyve is a phosphoinositide 5-kinase that can also act as a protein kinase. PIKfyve's role in acute insulin action has been suggested on the basis of its association with the insulin stimulatable phosphatidylinositol-3-kinase and the ability of acute insulin to recruit and phosphorylate PIKfyve on intracellular membranes of 3T3-L1 adipocytes. Here we have examined several classical insulin-regulated long- and short-term responses in insulin-sensitive cells expressing high levels of either active PIKfyve or kinase-dead mutants with a dominant-negative effect. Up-regulation of PIKfyve protein expression was documented in the early stages of differentiation of cultured 3T3-L1 fibroblasts into adipocytes and a kinase-dead mutant, PIKfyveDeltaK, introduced into the preadipocyte stage profoundly delayed the hormone-induced adipogenesis. Next, insulin-induced mitogenesis was markedly inhibited in HEK293 stable cell lines, inducibly expressing the dominant-negative kinase-dead PIKfyve(K1831E) mutant but not in cells expressing PIKfyve(WT). Similarly, expression of the dominant negative mutants PIKfyve(K1831E) or PIKfyveDeltaK strongly inhibited insulin-stimulated translocation of GLUT4 in 3T3-L1 adipocytes, or GLUT1-mediated glucose uptake in Chinese hamster ovary T cells expressing the human insulin receptor. Expression of PIKfyveDeltaK and PIKfyve(WT) in Chinese hamster ovary T cells decreased or increased, respectively, insulin-stimulated Akt phosphorylation at Ser473 but not at Thr308. Furthermore, a powerful inhibition of PIKfyve was documented at a very low concentration (ID(50) = 6 micro M) of the cell-permeable kinase inhibitor curcumin. When introduced into 3T3-L1 adipocytes, curcumin markedly inhibited insulin-induced GLUT4 translocation and glucose transport. Together these data indicate that PIKfyve enzymatic activity functions as a positive regulatory intermediate in insulin acute and long-term biological responses and identify Ser473 in Akt as one potential PIKfyve downstream target.

3T3 Cells↗

PubMed1993

Nematocidal activity of turmeric: synergistic action of curcuminoids.

A new curcuminoid, cyclocurcumin (IV), was isolated from the nematocidally active fraction of turmeric, the rhizome of Curcuma longa, together with three known curcuminoids, curcumin (I), demethoxycurcumin (II) and bisdemethoxycurcumin (III). The structure of IV was elucidated on the basis of spectral data and confirmed by the partial synthesis from curcumin (I). Although the above curcuminoids were ineffective when they were applied independently, the nematocidal activity increased remarkably when they were mixed, suggesting a synergistic action between them.

Animals↗

PubMed1997

New curcuminoids isolated from Zingiber cassumunar protect cells suffering from oxidative stress: a flow-cytometric study using rat thymocytes and H2O2.

Effects of new complex curcuminoids (cassumunin A and cassumunin B) isolated from tropical ginger, Zingiber cassumunar, were examined in dissociated rat thymocytes suffering from oxidative stress induced by 3 mM hydrogen peroxide by using a flow cytometer and ethidium bromide. The effects were compared with those of curcumin, a natural antioxidant, whose chemical structure is included in those of cassumunins A and B. Pretreatment of rat thymocytes with the respective cassumunins at concentrations ranging from 100 nM to 3 microM dose-dependently prevented the hydrogen peroxide (H2O2)-induced decrease in cell viability. It had the same action, although less effective, against the treatment with cassumunin A or B (3 microM) immediately after or 60 min after start of the oxidative stress. Respective potencies of cassumunins A and B in protecting the cells suffering from H2O2-induced oxidative stress were greater than that of curcumin. It is suggested that cassumunins A and B may possess a potent protective action on living cells suffering from oxidative stress.

Animals↗

PubMed2004

In vivo modulation of signaling factors involved in cell survival.

In vivo expression of cell survival factors protein kinase C (PKC), nuclear factor kappaB (NFkappaB), and extracellular signal-regulated kinase (Erk), which may contribute to the development of radioresistance following radiotherapy, was looked for. Their modulation with natural compounds (curcumin, rutin or nicotinamide) was attempted in mice bearing a serially transplanted fibrosarcoma. Expression of protein kinase C was isoform specific. No translocation of any of the isozymes was noticed following gamma-irradiation as has been reported elsewhere. None of the isoforms could be significantly inhibited by the modulators. However, significant inhibition of radiation-induced ERK and NFkappaB was observed with both curcumin and nicotinamide. Therefore we conclude that use of inhibitors of MAP kinases or NFkappaB may be a more promising strategy to enhance tumour cell killing or to prevent the development of radioresistance during radiotherapy.

Animals↗

PubMed2000

Inhibition of radiation-induced lipid peroxidation by tetrahydrocurcumin: possible mechanisms by pulse radiolysis.

The antioxidant property of tetrahydrocurcumin (THC), a reduced derivative of curcumin, was examined by its ability to inhibit radiation-induced lipid peroxidation in rat liver microsomes and compared with curcumin. The lipid peroxidation caused by irradiation of N2O-purged and aerated buffered aqueous solutions was found to be inhibited by THC in a dose- and concentration-dependent manner. In order to understand the actual reaction mechanisms involved in the inhibition process, pulse radiolysis investigation of THC with radiolytically produced radicals like hydroxyl, model peroxyl radicals, and azide radicals were done and the transients were detected by kinetic spectrophotometry. The reaction of THC with hydroxyl and azide radicals gave rise to transient absorption in the region 200-400 nm with two peaks at 310 nm and 390 nm. From the spectral properties and kinetics of these radicals, a suitable mechanism is discussed to explain the antioxidant actions of THC.

Animals↗

PubMed2005

Radioprotection of turmeric extracts in bacterial system.

The present study investigates the possible role of crude turmeric extracts in radioprotection by a variety of methods. Although curcumin, the main bioactive component of turmeric, has been extensively used in such studies, the efficiency of the crude extracts has been poorly investigated. This study revealed that dimethyl sulfoxide (DMSO) extracts of turmeric produces a significant amount of radioprotection, which is very similar in nature and extent to that imparted by curcumin. Field Inversion Gel Electrophoresis (FIGE) studies also clearly showed the protection offered by turmeric extracts against X-ray induced DNA damage of E. coli WP2s(lambda) cells.

Cell Survival↗

PubMedDate not supplied

Studies on the effectiveness of diarylheptanoids derivatives against Leishmania amazonensis.

In a previous work we demonstrated that diarylheptanoids extracted from Centrolobium sclerophyllum are very active against Leishmania amazonensis promastigotes. In order to continue our studies with these class of compounds, we decided to evaluate the activity of several diarylheptanoids derived from curcumin (diferuloyl methane) against the extracellular form (promastigotes) of L. amazonensis. Furthermore, an experiment against the intracellular form of the parasite (amastigotes) was carried out, comparing the most active compound among the curcumin derivatives (the methylcurcumin) with des-O-methylcentrolobine, the most active diarylheptanoid derived from C. sclerophyllum.

Animals↗