Co-administration Of Curcumin Research Articles

Paclitaxel and curcumin coadministration in novel cationic PEGylated niosomal formulations exhibit enhanced synergistic antitumor efficacy

BackgroundThe systemic administration of cytotoxic chemotherapeutic agents for cancer treatment often has toxic side effects, limiting the usage dose. To increase chemotherapeutic efficacy while reducing toxic effects, a rational design for synergy-based drug regimens is essential. This study investigated the augmentation of therapeutic effectiveness with the co-administration of paclitaxel (PTX; an effective chemotherapeutic drug for breast cancer) and curcumin (CUR; a chemosensitizer) in an MCF-7 cell line.ResultsWe optimized niosome formulations in terms of surfactant and cholesterol content. Afterward, the novel cationic PEGylated niosomal formulations containing Tween-60: cholesterol:DOTAP:DSPE-mPEG (at 59.5:25.5:10:5) were designed and developed to serve as a model for better transfection efficiency and improved stability. The optimum formulations represented potential advantages, including extremely high entrapment efficiency (~ 100% for both therapeutic drug), spherical shape, smooth-surface morphology, suitable positive charge (zeta potential ~ + 15 mV for both CUR and PTX), sustained release, small diameter (~ 90 nm for both agents), desired stability, and augmented cellular uptake. Furthermore, the CUR and PTX kinetic release could be adequately fitted to the Higuchi model. A threefold and 3.6-fold reduction in CUR and PTX concentration was measured, respectively, when the CUR and PTX was administered in nano-niosome compared to free CUR and free PTX solutions in MCF-7 cells. When administered in nano-niosome formulations, the combination treatment of CUR and PTX was particularly effective in enhancing the cytotoxicity activity against MCF-7 cells.ConclusionsMost importantly, CUR and PTX, in both free form and niosomal forms, were determined to be less toxic on MCF-10A human normal cells in comparison to MCF-7 cells. The findings indicate that the combination therapy of PTX with CUR using the novel cationic PEGylated niosome delivery is a promising strategy for more effective breast cancer treatment.

Protective effects of curcumin against doxorubicin-induced toxicity and resistance: A review.

Doxorubicin (DOX)-induced toxicity and resistance are major obstacles in chemotherapeutic approaches. Despite effective in the treatment of numerous malignancies, some clinicians have voiced concern that DOX has the potential to cause debilitating consequences in organ tissues, especially the heart. The mechanisms of toxicity and resistance are respectively related to induction of reactive oxygen species (ROS) and up-regulation of ATP-binding cassette (ABC) transporter. Curcumin (CUR) with several biological and pharmacological properties is expected to restore DOX-mediated impairments to tissues. This review is intended to address the current knowledge on DOX adverse effects and CUR protective actions in the heart, kidneys, liver, brain, and reproductive organs. Coadministration of CUR and DOX is capable of ameliorating DOX toxicity pertained to antioxidant, apoptosis, autophagy, and mitochondrial permeability.

Evaluation of Acetamiprid Mediated Oxidative Stress and Pathological Changes in Male Rats: Ameliorative Effect of Curcumin

Present study was undertaken to evaluate the acetamiprid-mediated toxicity and possible protective effect of curcumin in rats. Rats were divided into seven different groups. They received curcumin (100 mg/kg, b.wt. p.o.) and acetamiprid (26.25 and 105 mg/kg b.wt., p.o.) alone and in their combinations for period of 28 days. Lipid peroxidation and antioxidant enzyme activities were determined in liver, kidney and brain and cellular changes histopathologically. Study shows that administration of acetamiprid caused a significant induction in oxidative damage in liver, kidney and brain as evidenced by increased level of lipid peroxidation (LPO) and altered activities of reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR). Co-administration of curcumin with acetamiprid significantly decreased LPO, caused marked restoration in the non-enzymatic (GSH) and enzymatic antioxidants system (CAT, SOD and, GR) and protected from acetamiprid-mediated structural alterations of liver, kidney and brain. The results of present study indicates that curcumin ameliorate the acetamiprid-induced toxic damage to vital organ mediated via oxidative stress.

Effects of curcumin on sperm parameters abnormalities induced by morphine in rat

Opioids are the most potent and effective analgesics available and have become accepted as appropriate treatment for acute, cancer and non-cancer. Morphine, which is commonly used for the treatment of severe pain, gastrointestinal tract and kidneys. Curcumin petals consist of, glycosides, flavonoids, and anthocyanin. The study aims at evaluating curcumin effect and morphine on sperm parameters, testis tissue and serum testosterone level in rat. In this experimental study, 48 male rats with 28 weeks of age and limited weight of 270 to 300g were selected. They were divided into eight groups of 6, untreated control group; morphine – treated group (20 mg/kg/day); curcumin -treated groups (10, 30, 60 mg/kg/day); and morphine and curcumin treated group intraperitoneal administration for successive 28 days. After 24hours animals were killed. Sperm motility was measured using WHO protocols. The sperm parameter such as motility, sperm count, morphology, seminiferous tubules diameter, weight testis, and serum testosterone level were analyzed (oneway ANOVA). Curcumin (10, 30 and 60 mg/kg) significantly increased mean percentage of sperm motility, count, testis weight, and serum testosterone level compared to control group (p<0.05). Testosterone level decreased significantly in rats treated with morphine. Co-administration of curcumin to morphine-treated rats improved the histopathological alterations induced by morphine in testis and increased the sperm count. Curcumin has a very strong antioxidant effects at applied doses and it can probably be used as an antioxidant and food supplement in reproductive disorders.Journal of Medical and Biomedical Sciences (2017) 6(2), 1-10

TOXICITY OF MONOSODIUM GLUTAMATE ON MALE RAT REPRODUCTIVE SYSTEM AND EFFECT OF CURCUMIN AND PROPOLIS CO-ADMINISTERATION

The safety of monosodium glutamate (MSG) usage has generated much controversy locally and globally. MSG is known to affect the structure and function of male reproductive system as well as fertility. The aim of the present work was to study the toxic effect of MSG on reproductive system of adult male albino rats and to determine the possibility to reverse this effect using curcumin and propolis. Seventy sexually mature male albino rats were used for this study and divided into 7 groups. The first 3 were control groups administered (distelled water, curcumin, and propolis), the 4th group was the experimental and administered MSG at a dose of 4 g/kg body weight for 6ws, the 5 th and 6th groups, MSG was co-administered with curcumin or propolis at the doses of 10 mg, and 50 mg/kg body weight respectively and the 7th group received combination of MSG, curcumin and propolis. It was found that MSG has adverse impacts on male rat reproduction including decrease testicular weight, with histological structure alternation, decrease sperm count and plasma level of testosterone and luteinizing hormone (LH). Coadministration of curcumin and propolis either separately or combined ameliorate these effects where testicular weight and structure of seminiferous tubules with their lumens full of sperms were regained compared to MSG treated animals. Sperm count; testosterone and LH levels were improved.

Oral administration of curcumin and salsalate attenuates high fat diet‐induced up‐regulation of pro‐inflammatory colonic cytokines and suppresses Akt/NFκB signaling in azoxymethane‐treated mice

BackgroundObesity, a robust risk factor for colorectal cancer (CRC), is known to elevate the concentrations of pro‐inflammatory cytokines in the murine colon. Also, signaling through the Akt pathway, which is known to be activated by pro‐inflammatory cytokines, is thought to play a role in colorectal carcinogenesis, in part by enhancing NFκB signaling. Further, we have previously demonstrated that high fat diets (HFD) and excess adiposity each alter the expression of the regulators of colonic Akt signaling in a pattern suggestive of Akt activation.ObjectiveWe sought to determine whether the combination of a pharmacologic agent and a dietary component that each possesses anti‐inflammatory properties might suppress obesity‐induced elevations in colonic cytokines and Akt/NFκB signaling, with the ultimate intent of mitigating the cancer‐promoting effect of obesity.MethodsCurcumin (CUR), a natural polyphenol in turmeric, and salsalate (SAL) a non‐steroidal anti‐inflammatory drug (NSAID) that lacks the gastrointestinal toxicity of other NSAIDs, were tested alone and in combination in the azoxymethane (AOM) model of colonic carcinogenesis in 110 A/J mice, randomized to five groups including a control group receiving a low‐fat diet. AOM (7 mg/kg body weight, 4 weekly injections) in combination with a HFD that contained 60% kcals as fat was used induce a pro‐tumorigenic milieu in the colons of mice.ResultsThe results showed that HFD‐mice had 30.4% greater fat mass and a lower lean mass than did low‐fat diet (10% kcal fat, LFD, p<0.005)‐mice. In the colonic mucosa of the obese mice addition of CUR and SAL (0.2% and 0.15% w/w, respectively) to the diet significantly diminished concentrations of IL‐1β and IL‐6 (p<0.015). Moreover, CUR/SAL co‐treatments also profoundly suppressed phosphorylation of Akt (p<0.044) and concurrently suppressed NF‐κB p65 signaling (p<0.042).ConclusionsOur results demonstrate, for the first time, that co‐administration of CUR and SAL in very low, well‐tolerated, concentrations attenuates inflammatory cytokine levels, Akt activation, and NFkB signaling in the colons of AOM/HFD mice, providing a scientific rationale for using this combination as a chemopreventive regimen to mitigate the risk of obesity‐associated colon cancer.Support or Funding InformationTufts Collaborates Grant; United States Department of Agriculture, Cooperative Agreements #58‐1950‐0‐014 and #58‐1950‐4‐003

Protective effect of co-administration of curcumin and sildenafil in alcohol induced neuropathy in rats

Neuropathic pain associated with chronic alcohol consumption is a medico-socioeconomical problem that affects both central and peripheral nervous system and has no satisfactory treatment till date. The present study was designed to investigate the protective effect of co-administration of curcumin and sildenafil on alcohol induced neuropathic pain in rats. In order to carry out this, ethanol (35% v/v, 10g/kg, p.o.) was administered for 10 weeks to induce neuropathic pain. Curcumin (30 and 60mg/kg, i.p.) and sildenafil (5 and 10mg/kg, i.p.) were given alone and in combination at their lower doses (30mg/kg curcumin and 5mg/kg, sildenafil, i.p.) to investigate the changes in thermal and mechanical hyperalgesia, allodynia and histopathological parameters. Biochemical estimations of thiobarbituric acid reactive species, glutathione and protein was also carried out to evaluate oxidative stress. The results revealed that chronic alcohol consumption for 10 weeks caused significant thermal and mechanical hyperalgesia, allodynia and increased oxidative stress. Individual administration of both the drugs at their low as well as high doses were able to improve the symptoms of alcohol induced neuropathic pain. Whereas co-administration of curcumin and sildenafil at their lower doses itself were found to significantly improve nerve functions, biochemical and histopathological parameters as compared to their individual administration. It is therefore proposed that co-administration of curcumin and sildenafil may bring new dimension towards attenuation of alcohol induced neuropathic pain affecting central as well as peripheral nervous system.

Evidence against the participation of a pharmacokinetic interaction in the protective effect of single-dose curcumin against gastrointestinal damage induced by indomethacin in rats

ObjectiveTo determine the role of a pharmacokinetic interaction in the protective effect of curcumin against the gastric damage induced by indomethacin administration as such or as its prodrug acemetacin. MethodsWistar rats orally received single dose of indomethacin (30 mg/kg) with and without curcumin (30 mg/kg); gastric injury was evaluated by determining the total damaged area. Additional groups of rats received an oral single dose of indomethacin (30 mg/kg) or its prodrug acemetacin (34.86 mg/kg) in the presence or absence of curcumin (30 mg/kg). Indomethacin and acemetacin concentrations in plasma from blood draws were determined by high-performance liquid chromatography. Plasma concentration-against-time curves were constructed, and bioavailability parameters, maximal concentration (Cmax) and area under the curve to the last sampling time (AUC0-t) were estimated. ResultsConcomitant administration of indomethacin and curcumin resulted in a significantly reduced gastric damage compared to indomethacin alone. However, co-administration of curcumin did not produce any significant alteration in the bioavailability parameters of indomethacin and acemetacin after administration of either the active compound or the prodrug. ConclusionCurcumin exhibits a protective effect against indomethacin-induced gastric damage, but does not produce a reduction of the bioavailability of this nonsteroidal anti-inflammatory drug, indomethacin. Data thus suggest that a pharmacokinetic mechanism of action is not involved in curcumin gastroprotection.

Improvement of the Solubility and Intestinal Absorption of Curcumin by N-Acyl Taurates and Elucidation of the Absorption-Enhancing Mechanisms.

In this study, the effects of N-acyl taurates (NATs) on the intestinal absorption of curcumin (CUR), a water-insoluble and poorly absorbed compound, were examined in rats. Sodium methyl lauroyl taurate (LMT) and sodium methyl cocoyl taurate (CMT) were the most effective in increasing the solubility and intestinal absorption of CUR. The intestinal membrane toxicity of the NATs was also evaluated by measuring the activity of lactate dehydrogenase (LDH), a toxicity marker. NATs did not increase the activity of LDH, suggesting that they may be safely administered orally. We further elucidated the absorption-enhancing mechanisms of NATs by using Caco-2 cells. In cellular transport studies, LMT and CMT reduced the transepithelial electrical resistance value of Caco-2 cells and increased the transport of 5(6)-carboxyfluorescein and CUR. Hence, the intestinal absorption enhancement by LMT and CMT was attributed to the synergistic effect of higher solubility and greater permeability of the cell layer towards CUR in the presence of the surfactants. In summary, co-administration of CUR with either LMT or CMT is a simple and effective method to enhance oral delivery of CUR.

Curcumin-docetaxel co-loaded nanosuspension for enhanced anti-breast cancer activity

ABSTRACTPurpose: A curcumin-docetaxel co-loaded nanosuspension with increased anti-breast cancer activity was developed. Curcumin is a potential anticancer agent with p-glycoprotein (p-gp) inhibiting activity may be co-administered with docetaxel as a nanosuspension to enhance its anticancer effect by increasing the oral bioavailability and decreasing drug efflux.Methods: Nanosuspensions of curcumin and docetaxel were prepared by precipitation-homozenisation technique and evaluated for particle size, polydispersity, zeta potential and drug release. The in vitro MTT assay was conducted using MCF-7 for anti-breast cancer activity. The in vivo biodistribution by radiolabeling and tumor inhibition study was conducted in mice.Results: Homogenous nanosuspensions of 80 ± 20 nm were obtained with increased solubility. The drugs as nanosuspensions showed higher cytotoxicity on MCF-7 cell line compared to their suspensions due to the increased in vitro cellular uptake. Due to this increased solubility, sensitization of tumor cells and inhibition of p-gp the in-vivo results showed greater tumor inhibition rate of up to 70% in MCF-7 treated mice. Histopathological results showed higher apoptotic activity and reduced level of angiogenesis.Conclusions: The in vitro and in vivo study of the nanosuspensions has shown that Co-administration of Curcumin as a p-gp inhibitor with docetaxel may have the potential to increase the anti-breast cancer efficacy of both drugs.

Impact of curcumin on the pharmacokinetics of rosuvastatin in rats and dogs based on the conjugated metabolites

1. Plasma concentrations of curcumin-O-glucuronide (COG) and curcumin-O-sulfate (COS) significantly increased after Sprague-Dawley rats dealt with the Oatp inhibitor rifampicin, with the Cmax ascending 2.9 and 6.7 times, and the AUC0–∞ ascending 4.4 and 10.8 times, respectively. When pretreated with the Oat inhibitor probenecid, the Cmax increased 4.4 and 20 times, and the AUC0–∞ increased 3.2 and 13.9 times, respectively. The results suggested that COG and COS may be the substrates of Oatp and Oat.2. The accumulation of curcumin significantly increased in organic anion transporting polypeptide (OATP)- and organic anion transporter (OAT)-transfected human embryonic kidney (HEK) 293 systems, which suggested that curcumin was a substrate of OATP1B1, OATP1B3, OATP2B1, OAT1, and OAT3; and COG was a substrate of OATP1B1, OATP1B3, and OAT3.3. Inhibition study using rosuvastatin as the substrate in OATP1B1- and OATP1B3-transfected cells indicated that curcumin was an OATP1B1 and 1B3 inhibitor, with IC50 at 5.19 ± 0.05 and 3.68 ± 0.05 μM, respectively; the data for COG were 1.04 ± 0.01 and 1.08 ± 0.02 μM, respectively. COS was speculated to be an inhibitor of hepatic OATP1B1 as calculated using the ADMET Predictor.4. COG and COS are substrates and inhibitors of OATP/Oatp. Co-administration of curcumin significantly increased rosuvastatin concentration in rat and dog plasma.

Piperine Augments the Protective Effect of Curcumin Against Lipopolysaccharide-Induced Neurobehavioral and Neurochemical Deficits in Mice.

The aim of the present study was to investigate the protective effects of curcumin alone and in combination with piperine against lipopolysaccharide (LPS)-induced neurobehavioral and neurochemical deficits in the mice hippocampus. Mice were treated with curcumin (100, 200, and 400mg/kg, p.o.) and piperine (20 mg/kg, p.o.) for 7days followed by LPS (0.83mg/kg, i.p.) administration. Animals exhibited anxiety and depressive-like phenotype after 3 and 24h of LPS exposure, respectively. LPS administration increased the oxido-nitrosative stress as evident by elevated levels of malondialdehyde, nitrite, and depletion of glutathione level in the hippocampus. Furthermore, we found raised level of pro-inflammatory cytokines (IL-1β and TNF-α) in the hippocampus of LPS-treated mice. Pretreatment with curcumin alleviated LPS-induced neurobehavioral and neurochemical deficits. Furthermore, co-administration of curcumin with piperine significantly potentiated the neuroprotective effect of curcumin. These results demonstrate that piperine enhanced the neuroprotective effect of curcumin against LPS-induced neurobehavioral and neurochemical deficits.

Evidence of a subcommissural organ involvement in the brain response to lead exposure and a modulatory potential of curcumin.

Substantial evidence supports the neurochemical vulnerability to lead (Pb) as one of the most potent neurotoxic heavy metals. In the present study, we aimed to assess: (i) The subcommissural organ (SCO) responsiveness as a secretory circumventricular organ to chronic and acute Pb intoxication together with its serotoninergic innervation. (ii) The possible restorative effect of curcumin against Pb intoxication under the same pathological conditions. We used immunohistochemistry with antibodies against Reissner's fiber and serotonin [5-hydroxytryptophan (5-HT)] in Wistar rats following chronic as well as acute Pb administration, respectively, at 25 mg/kg intraperitoneally for 3 days and 0.3% in drinking water from the intrauterine stage until 2 months of adult age. Our data showed a significant decrease in Reissner's fiber material immunoreactivity concomitant with an overall increased 5-HT innervation of the SCO and the ventricular borders. Coadministration of curcumin (50 mg/kg body weight) restores this impairment by reversing the effect of chronic and acute Pb on the secretory activity and the 5-HTergic innervation of the SCO. The investigation showed, on the one hand, the involvement of the SCO in the response to heavy metals, especially Pb, and on the other, the beneficial corrector role of curcumin. As a part of the circumventricular organ, known as a privileged area of brain-blood exchanges, the SCO may play a key role in the mechanism of brain defense against heavy metal neurotoxicity in rats.

The possible protective effect of curcumin on monosodium glutamate-induced retinal changes in adult male albino rats

Introduction Monosodium glutamate (MSG) is widely used as a flavor-enhancing food additive for its unique taste. It is added to fast foods, children’s foods, snacks, soups, and many other canned foods all over the world. Recently, it has been proved that MSG has neurotoxic effects, including retinal degeneration. Curcumin is a naturally occurring compound with known antioxidative activity. Experimentally, it has been observed that curcumin has a significant retinal neuroprotective effect. Aim The present study was carried out to investigate the possible protective effect of curcumin against the retinal toxicity of MSG. Materials and methods Thirty adult male albino rats were used. The animals were divided as follows: group I was the control group; group II received curcumin at a dose of 150 mg/kg body weight; group III received MSG at a dose of 1 g/kg body weight; and group IV received MSG concomitantly with curcumin at the same previous doses. Both curcumin and MSG were given orally once daily for 4 weeks. Retinal sections were stained with H&E and immunohistochemically stained to detect glial fibrillary acidic protein (GFAP) and caspase-3 antibodies. Retinal thickness and area% of GFAP staining were measured. Results MSG caused several histological retinal changes, including separation of pigment epithelium, distortion and disorganization of photoreceptors, pyknosis in many nuclei of the outer nuclear layer, degeneration in the cells of the inner nuclear layer and the ganglion cell layer, dilatation and congestion of some blood vessels, and interruption of the internal limiting membrane. A statistically significant decrease in the retinal thickness and increase in area% reaction with GFAP antibodies were also detected. Such abnormalities were, to a large extent, prevented with the use of curcumin. Conclusion Several histological alterations were observed in the retinas of rats treated with MSG, and coadministration of curcumin with MSG improved these alterations to a large extent.

Cancer-selective cytotoxic Ca2+ overload in acute myeloid leukemia cells and attenuation of disease progression in mice by synergistically acting polyphenols curcumin and carnosic acid.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by extremely heterogeneous molecular and biologic abnormalities that hamper the development of effective targeted treatment modalities. While AML cells are highly sensitive to cytotoxic Ca2+ overload, the feasibility of Ca2+- targeted therapy of this disease remains unclear. Here, we show that apoptotic response of AML cells to the synergistically acting polyphenols curcumin (CUR) and carnosic acid (CA), combined at low, non-cytotoxic doses of each compound was mediated solely by disruption of cellular Ca2+ homeostasis. Specifically, activation of caspase cascade in CUR+CA-treated AML cells resulted from sustained elevation of cytosolic Ca2+ (Ca2+cyt) and was not preceded by endoplasmic reticulum stress or mitochondrial damage. The CUR+CA-induced Ca2+cyt rise did not involve excessive influx of extracellular Ca2+ but, rather, occurred due to massive Ca2+ release from intracellular stores concomitant with inhibition of Ca2+cyt extrusion through the plasma membrane. Notably, the CUR+CA combination did not alter Ca2+ homeostasis and viability in non-neoplastic hematopoietic cells, suggesting its cancer-selective action. Most importantly, co-administration of CUR and CA to AML-bearing mice markedly attenuated disease progression in two animal models. Collectively, our results provide the mechanistic and translational basis for further characterization of this combination as a prototype of novel Ca2+-targeted pharmacological tools for the treatment of AML.

Gonadotropin-mediated chemoresistance: Delineation of molecular pathways and targets.

BackgroundHuman chorionic gonadotropin (hCG) has essential roles in pregnancy. Reports linking hCG in non-trophoblastic tumors with poor patient prognosis has spurred interest in patho-physiological roles the hormone might play.MethodsThe ability of hCG to prevent tumor cell death and sustain viability in the presence of chemotherapeutic drugs was assessed and potential synergies with TLR ligands explored. hCG-induced up-modulation of genes involved in chemoresistance was documented and targets validated by siRNA knock-down. Whether hCG could drive collaboration between tumor cells and macrophages in the production of IL-6 and consequent chemoresistance was assessed. The effects of concurrent anti-hCG immunization and chemotherapy on the growth of syngeneic murine tumors were evaluated.ResultshCG maintained basal levels of cytokine secretion by tumor cells exposed to chemotherapeutic drugs, and enhanced viability and proliferation; pre-treatment with hCG also decreased apoptosis, as assessed by Annexin-V binding and the cleavage of caspase 3. While co-incubation with hCG along with several TLR ligands mediated heightened chemo-resistance, TLR-2/6 and TLR-9 ligands increased the phosphorylation of JNK, and TLR-2 and TLR-8 ligands the phosphorylation of ERK in presence of hCG and curcumin, providing evidence of tri-molecular synergy. The hormone increased the transcription and/or expression of molecular intermediates (SURVIVIN, HIF-1α, PARP-1, Bcl-2, c-FLIP, KLK-10, XIAP, c-IAP-1) associated with chemo-resistance and increased levels of stress modulators (PON2, HO-1, HSP27 and NRF-2). siRNAs to SURVIVIN, NRF-2, HO-1 and HIF-1α attenuated hCG-mediated chemo-resistance. hCG-conditioned tumor cell supernatants induced heightened secretion of IL-6 and TNF-α from peripheral blood adherent cells and secreted IL-6 imparted chemo-resistance to naïve tumor cells. Co-administration of curcumin along with an anti-hCG vaccine (hCGβ conjugated to Tetanus Toxoid (TT)) to mice carrying syngeneic tumors resulted in significantly enhanced benefits on animal survival; synergy was demonstrated between anti-hCG antibodies and curcumin in the reduction of tumor cell viability.ConclusionsThe data suggest that hCG, via direct as well as collaborative effects with TLR ligands and accessory cell-secreted cytokines, mediates chemo-resistance in gonadotropin-sensitive tumors and outlines the potential benefits of combination therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1938-x) contains supplementary material, which is available to authorized users.

Curcumin Affects Phase II Disposition of Resveratrol Through Inhibiting Efflux Transporters MRP2 and BCRP.

To evaluate the impact of curcumin on the disposition of resveratrol phase II metabolites in vivo, and explain the observations by performing in vitro studies in transporter-overexpressed cells. Pharmacokinetic studies of resveratrol with and without the co-administration of curcumin were performed in both FVB wild-type and Bcrp1 (-/-) mice. Human UGT1A9-overexpressing HeLa cells and human MRP2-overexpressing MDCK II-UGT1A1 cells were used as in vitro tools to further determine the impact of curcumin as a transporter inhibitor on resveratrol metabolites. We observed higher exposure of resveratrol conjugates in Bcrp1 (-/-) mice compared to wild-type mice. In wild-type mice, curcumin increased the AUC of resveratrol glucuronide by 4-fold compared to the mice treated without curcumin. The plasma levels of resveratrol and its sulfate conjugate also increased moderately. In Bcrp1 (-/-) mice, there was a further increase (6-fold increase) in AUC of resveratrol glucuronide observed when curcumin was co-administered compared to AUC values obtained in wild-type mice without curcumin treatment. In the presence of 50nM curcumin, the clearance of resveratrol-3-O-glucuronide and resveratrol-3-O-sulfate reduced in both MRP2-overexpressing MDCKII-UGT1A1 cells and Human UGT1A9-overexpressing HeLa cells. These results suggest that curcumin alters the phase II distribution of resveratrol through inhibiting efflux transporters including MRP2 and BCRP.

1H NMR-based metabonomics of the protective effect of Curcuma longa and curcumin on cinnabar-induced hepatotoxicity and nephrotoxicity in rats

Curcuma longa is a perennial herb that is widely cultivated extensively in Asia and Africa. Curcumin is a major constituent of C. longa. A metabonomics approach based on high-resolution 1H nuclear magnetic resonance spectroscopy was applied to investigate the toxicity protective effects of C. longa and curcumin in rats under cinnabar induced hepatotoxicity and nephrotoxicity. Partial least squares-discriminant analysis (PLS-DA) was performed to identify different metabolic profiles of urine and serum from rats. Liver and kidney histopathology examinations and serum clinical chemistry analysis were also performed. The significant difference in metabolic profiling of urine and serum of the rats was observed among cinnabar treated group, control group, co administration of C. longa and cinnabar, co administration of curcumin and cinnabar group. The results suggested that C. longa and curcumin have the effective protection function through regulating the energy metabolism, intestinal microflora and amino acid metabolism to the liver and kidney injury induced by cinnabar.

Interaction between the antioxidant activity of curcumin and cholinergic system on memory retention in adult male Wistar rats.

The cholinergic system plays an important role in learning and memory. This study investigated the effects of curcumin (turmeric extract) and the cholinergic system and their interaction on memory retention of passive avoidance learning in adult male Wistar rats. At first, an injection cannula was implanted in right ventricles of the animals. One week after the surgery, the animals were trained with a shuttle box set up. Post-training, injections were performed in all experiments. Administration of curcumin increased memory retention. Also administrations of nicotine and pilocarpine, the cholinergic receptor agonists, increased memory retention, while it is decreased by succinylcholine and scopolamine, the cholinergic receptor antagonists. Then co-administration of curcumin and cholinergic drugs were performed. Intraperitoneal and intracerebroventricular injections were applied for the curcumin and cholinergic drugs, respectively. Co-administration of curcumin (45 mg/kg) with a low dose of nicotine (0.1 µg/rat) or pilocarpine (0.5 µg/rat) increased memory retention significantly. Effects of succinylcholine (0.01, 0.1 and 0.5 µg/rat) or scopolamine (0.1, 1 and 5 µg/rat) were attenuated by curcumin markedly (45 mg/kg). The results suggest that curcumin has a close interaction with cholinergic system in memory retention process.

Molecular and Histopathological Study on the Ameliorative Effects of Curcumin Against Lead Acetate-Induced Hepatotoxicity and Nephrototoxicity in Wistar Rats.

Lead (Pb(2+)) toxicity is the most common form of heavy metal intoxication in humans and animals. Therefore, the current study was conducted to evaluate the potential ameliorative effects of curcumin on lead acetate (LA)-induced deleterious effects in the liver and kidney. Forty male Wistar rats were divided into four equal groups; first group was used as a control and given both corn oil orally and vehicle of lead acetate intraperitoneally (i.p). Groups from 2-4 were treated with lead acetate (LA; 50mg/kg BW i.p), curcumin (200mg/kg BW orally), and curcumin plus lead acetate, respectively. Curcumin was administered 3weeks before LA injection for 7days. Pb(2+)-intoxicated rats have higher Pb(2+) levels compared to other treated groups. Results revealed that lead acetate significantly increased the serum levels of hepatic transaminases (GPT and GOT), urea and creatinine, while albumin was significantly decreased. In parallel, serum IgG, IgM, and IgA were significantly decreased in LA-injected rats. LA groups showed decrease in messenger RNA (mRNA) expression of catalase, SOD, GST, GPx, and alpha-1 acid glycoprotein (AGP), while the gene expression of desmin, vimentin, transforming growth factor-β1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), and alpha-2 macroglobulin (α-2M) was increased. Prior and coadministration of curcumin with LA for 7days significantly improved the ameliorated changes in liver and kidney, immunoglobulins, and mRNA expression. Moreover, curcumin ameliorated LA-induced congestion of hepatic and renal blood vessels and decreased fibrous tissue proliferation and necrosis of hepatocytes. In the kidney, LA-induced degeneration in tubular epithelium and intraluminal hyaline casts and prior curcumin administration restored normal renal structure with mild congestion of renal blood vessels. The results clarify the potential of curcumin to counteract the immunosuppressive alteration in gene expression as well as hepatic and renal damage occurred after Pb(2+) intoxication.