Metabolite Of Curcumin Research Articles

Gut microbiota dictate metabolic Fate of Curcumin in the colon

The metabolic fate of dietary bioactive compounds play critical roles in their health effects. Herein, we determined the metabolic fate of curcumin in the gastrointestinal (GI) tract of mice after long‐term dietary administration of curcumin for 6 weeks. Our results demonstrated that in the GI tract curcumin underwent phase I metabolism to yield three metabolites, namely tetrahydro‐curcumin (M1), hexahydro‐curcumin (M2) and octahydro‐curcumin (M3). Curcumin and these phase I metabolites then were subject to phase II metabolism to yield their corresponding conjugated phase II metabolites. The above‐mentioned metabolism of curcumin occurred in the stomach but to a much less extent than that in the small intestine. Only phase II metabolites of curcumin could be found in the small intestine (i.e., conjugated forms of curcumin, M1 and M2), while only phase I metabolites of curcumin could be detected in the cecum and colon (i.e., M1 and M2). This suggested that gut microbiota might be responsible for the deconjugation of phase II metabolites that converted them back to the corresponding phase I metabolites in the cecum and colon. Indeed, anaerobic fermentation of phase II metabolites (isolated from the small intestine of curcumin‐fed mouse) by both mouse and human fecal bacteria deconjugated them to yield phase I metabolites. Moreover, fecal bacteria were able to transform curcumin to yield M1, M2, and M3, and they can further breakdown these four compounds to yield fission products such as ferulic acid. To confirm the role of gut microbiota in biotransformation of curcumin, curcumin‐fed mice were treated with or without dextran sulfate sodium (DSS) in the drinking water (DSS is an agent capable of altering gut microbiota, and we confirmed the altered microbiota by DSS via next generation sequencing of fecal microbiota). Analyses of colonic content by LC/MS demonstrated that in comparison with the control mice, DSS‐treated mice had a completely different curcumin metabolite profile in the colon, i.e., much higher levels of phase II metabolites and much lower levels of fission products of curcumin. Overall, our results demonstrated that composition of gut microbiota had a profound impact on the biotransformation of curcumin in the colon, which might have a significant influence on the health effects of dietary curcumin, especially in the colon.Support or Funding InformationThis study was partially supported by fund from USDA.

Biological and pharmacological evaluation of dimethoxycurcumin: A metabolically stable curcumin analogue with a promising therapeutic potential.

Dimethoxycurcumin (DiMC) is a synthetic analog of curcumin with superior inter-related pro-oxidant and anti-cancer activity, and metabolic stability. Numerous studies have shown that DiMC reserves the biologically beneficial features, including anti-inflammatory, anti-carcinogenic, and cytoprotective properties, almost to the same extent as curcumin exhibits. DiMC lacks the phenolic-OH groups as opposed to curcumin, dimethoxycurcumin, and bis-demethoxycurcumin that all vary in the number of methoxy groups per molecule, and has drawn the attentions of researchers who attempted to discover the structure-activity relationship (SAR) of curcumin. In this regard, tetrahydrocurcumin (THC), the reduced and biologically inert metabolite of curcumin, denotes the significance of the conjugated α,β diketone moiety for the curcumin activity. DiMC exerts unique molecular activities compared to curcumin, including induction of androgen receptor (AR) degradation and suppression of the transcription factor activator protein-1 (AP-1). The enhanced AR degradation on DiMC treatment suggests it as a novel anticancer agent against resistant tumors with androgenic etiology. Further, DiMC might be a potential treatment for acne vulgaris. DiMC induces epigenetic alteration more effectively than curcumin, although both showed no direct DNA hypomethylating activity. Given the metabolic stability, nanoparticulation of DiMC is more promising for in vivo effectiveness. However, studies in this regard are still in its infancy. In the current review, we portray the various molecular and biological functions of DiMC reported so far. Whenever possible, the efficiency is compared with curcumin and the reasons for DiMC being more metabolically stable are elaborated. We also provide future perspective investigations with respect to varying DiMC-nanoparticles.

Abstract P6-18-01: Site-specific activation of curcuminoids in the breast cancer bone metastases microenvironment

Abstract The majority of women with advanced breast cancer (BCa) develop incurable osteolytic bone metastases. Our laboratory has previously demonstrated that curcuminoids, bioactive compounds isolated from turmeric rhizomes, prevent the development of lytic bone lesions in a murine xenograft model of human BCa bone metastasis and inhibit tumor cell secretion of TGFβ-stimulated parathyroid-related protein (PTHrP), a signaling pathway known to drive bone metastasis progression. In both humans and mice, glucuronidated phase II metabolites of curcumin, which are thought to be biologically inactive, are the primary form detected in circulation after consuming curcuminoid-containing foods or supplements. This has led to an untested postulate that curcuminoids may be deglucuronidated at sites of action to form bioactive, aglycone (free) curcumin. Studies were therefore undertaken to test this hypothesis in the context of the murine BCa bone metastasis model, assessing site-specific deconjugation of curcuminoids in the tumor-bone microenvironment. Effects of curcumin-glucuronide (G-CURC) vs. curcumin (CURC) on TGFβ-stimulated PTHrP secretion by bone-tropic MDA-MB-231 (MDA) cells was determined by immunoradiometric assay. G-CURC and CURC levels were quantified by LC-MS in plasma and bone marrow specimens isolated from curcuminoid-treated female nude mice. Endogenous β-glucuronidase enzyme expression was localized by immunohistochemical (IHC) staining in paraffin-embedded sections of decalcified, MDA metastases-containing hind limbs of nude mice inoculated, via intracardiac injection 21 days prior, with MDA cells. Glucuronide deconjugation activity of bone marrow lysates was determined by colorimetric assay. In contrast to the inhibitory effects of a naturally occurring curcuminoid mixture or pure CURC, G-CURC did not alter TGFβ-stimulated PTHrP secretion, confirming its postulated lack of biologic activity. In mice treated with curcuminoids, the majority of circulating curcumin was conjugated (91%). In contrast, the majority of curcumin in the bone marrow (56%) was unconjugated free (aglycone) curcumin (p <0.01). IHC staining of MDA tumor-bearing hind limbs of nude mice demonstrated expression of β-glucuronidase (GUSB), an enzyme that deconjugates compounds in mice and humans, by bone marrow cells, but not by tumor cells. Consistent with IHC, bone marrow from female nude mice displayed significantly higher (30-fold) deconjugation enzyme activity compared to MDA cells (p < 0.01). Female C3H/HeJ mice, which possess a partial loss-of-function mutation in the GUSB gene, had significantly decreased (66% lower) deconjugation enzyme activity compared to normal female C57BL/6 (p < 0.001) or nude (p < 0.01) mice. In addition, treatment with the β-glucuronidase inhibitor, saccharolactone (SL), also decreased deconjugation enzyme activity in marrow lysates from female nude mice. These results suggest that curcuminoids, in the setting of breast cancer bone metastases, may act as a pro-drug, becoming activated within the tumor-bone microenvironment by glucuronidase-expressing hematopoietic bone marrow cells, to limit the progression of osteolytic lesion formation in a murine model of BCa bone metastasis. Supported by: R01CA174926-01, R01AT006896, and R03CA159382. Citation Format: Kunihiro AG, Frye JB, Brickey JA, Luis PB, Schneider C, Funk JL. Site-specific activation of curcuminoids in the breast cancer bone metastases microenvironment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-18-01.

Curcumin and Natural Derivatives Inhibit Ebola Viral Proteins: An In silico Approach.

Background:Ebola viral disease is a severe and mostly fatal disease in humans caused by Ebola virus. This virus belongs to family Filoviridae and is a single-stranded negative-sense virus. There is no single treatment for this disease which puts forth the need to identify new therapy to control and treat this fatal condition. Curcumin, one of the bioactives of turmeric, has proven antiviral property.Objective:The current study evaluates the inhibitory activity of curcumin, bisdemethoxycurcumin, demethoxycurcumin, and tetrahydrocurcumin against Zaire Ebola viral proteins (VPs).Materials and Methods:Molecular simulation of the Ebola VPs followed by docking studies with ligands comprising curcumin and related compounds was performed.Results:The highest binding activity for VP40 is −6.3 kcal/mol, VP35 is −8.3 kcal/mol, VP30 is −8.0 kcal/mol, VP24 is −7.7 kcal/mol, glycoprotein is −7.1 kcal/mol, and nucleoprotein is 6.8 kcal/mol.Conclusion:Bisdemethoxycurcumin shows better binding affinity than curcumin for most VPs. Metabolite tetrahydrocurcumin also shows binding affinity comparable to curcumin. These results indicate that curcumin, curcuminoids, and metabolite tetrahydrocurcumin can be potential lead compounds for developing a new therapy for Ebola viral disease.SUMMARY Curcumin, bisdemethoxycurcumin, and demethoxycurcumin are active constituents of turmeric. Tetrahydrocurcumin is the major metabolite of curcumin formed in the body after consumption and absorption of curcuminoidsCurcuminoids have proven antiviral activityBisdemethoxycurcumin showed maximum inhibition of Ebola viral proteins (VPs) among the curcuminoids in the docking procedure with a docking score as high as −8.3 kcal/molTetrahydrocurcumin showed inhibitory activity against Ebola VPs close to that of curcumin’s inhibitory action. Abbreviations Used: EBOV: Ebola virus, GP: Glycoprotein, NP: Nucleoprotein, NPT: Isothermal-isobaric Ensemble, amount of substance (N), pressure (P) and temperature (T) conserved, NVE: Canonical ensemble, amount of substance (N), volume (V) and temperature (T) conserved, VP: Viral protein.

Therapeutic Effects of Curcumin on Ultrasonic Morphological Characteristics of Liver in Patients with Metabolic Syndrome.

Introduction:Metabolic syndrome (METS) represent a simultaneous presence of multiple metabolic disorders in one person. Prevalence is increasing worldwide, which is probably related to increased obesity and sedentary lifestyle. Non-alcoholic steatosis or “fatty liver” is a metabolic disease caused by fat dysfunction. It can be a sign of some other disease, and can often be found in patients with metabolic disorders. Ultrasound is an acceptable method for the identification of fatty steatosis. There is evidence that when turmeric is used as a herbal diet, with its active metabolite of curcumin, can repair fatty acidosis and thus prevent progression of fatty steatosis complications such as cirrhosis and liver cancer. Goal. The aim of the study was to determine the effects of 400 mg curcuminaddition to the nutrition on ultrasound morphological characteristics of the liver in METS patients.Methodology:A prospective cohort study was conducted on 100 subjects with METS, treated in the family medicine practice of the Tuzla Canton, aged 35-70 years. The therapeutic effects of 400 mg curcumin on ultrasound-morphological characteristics of the liver were followed, validated by ultrasound in 50 respondents of experimental groups with METS. The data were processed by the IBM SPSS Statistics 21 statistical analysis program using parametric techniques andStudent’s t-test for paired samples.Results:There were 65% of women in the study. There were no statistically significant differences in the age of respondents within the analyzed groups. The use of 400 mg curcumin per day was statistically significantly improved ultrasound morphological characteristics of the liver in subjects with METS.Conclusion:All respondents with METS who used curcumin had beneficial effects on the morphological characteristics of the liver. Curcumin had stronger effects on subjects with METS and DM type 2 than others.

Investigating the Neuroprotective Effects of Turmeric Extract: Structural Interactions of β-Amyloid Peptide with Single Curcuminoids.

A broad biophysical analysis was performed to investigate the molecular basis of the neuroprotective action of Curcuma longa extracts in Alzheimer’s disease. By combining circular dichroism and electron paramagnetic resonance experiments with molecular modeling calculations, the minor components of Curcuma longa extracts, such as demethoxycurcumin (2, DMC), bisdemethoxycurcumin (3, BDMC) and cyclocurcumin (4, CYC), were analyzed in a membrane environment mimicking the phospholipid bilayer. Our study provides the first evidence on the relative role of single curcuminoids interacting with Aβ-peptide. When the CYC and curcumin metabolite tetrahydrocurcumin (5, THC) were inserted into an anionic lipid solution, a significant modification of the Aβ CD curves was detected. These data were implemented by EPR experiments, demonstrating that CYC reaches the inner part of the bilayer, while the other curcuminoids are localized close to the membrane interface. Computational studies provided a model for the curcuminoid-Aβ interaction, highlighting the importance of a constrained “semi-folded” conformation to interact with Aβ analogously to the pattern observed in α-helical coiled-coil peptide structures. This combined approach led to a better understanding of the intriguing in vitro and in vivo activity of curcuminoids as anti-Alzheimer agents, paving a new path for the rational design of optimized druggable analogues.

Bioavailability of curcumin and curcumin glucuronide in the central nervous system of mice after oral delivery of nano-curcumin

Curcumin is a bioactive molecule extracted from Turmeric roots that has been recognized to possess a wide variety of important biological activities. Despite its great pharmacological activities, curcumin is highly hydrophobic, which results in poor bioavailability. We have formulated this hydrophobic compound into stable polymeric nanoparticles (nano-curcumin) to enhance its oral absorption. Pharmacokinetic analysis after oral delivery of nano-curcumin in mice demonstrated approximately 20-fold reduction in dose requirement when compared to unformulated curcumin to achieve comparable plasma and central nervous system (CNS) tissue concentrations. This investigation corroborated our previous study of curcumin functionality of attenuating opioid tolerance and dependence, which shows equivalent efficacy of low-dose (20mg/kg) nano-curcumin and high-dose (400mg/kg) pure curcumin in mice. Furthermore, the highly selective and validated liquid chromatography⿿mass spectrometry (LC⿿MS) method was developed to quantify curcumin glucuronide, the major metabolite of curcumin. The results suggest that the presence of curcumin in the CNS is essential for prevention and reversal of opioid tolerance and dependence.

Use of basic mobile phase to improve chromatography and boost sensitivity for quantifying tetrahydrocurcumin in human plasma by LC-MS/MS.

Tetrahydrocurcumin (THC), a major metabolite of curcumin, is often quantified by LC-MS or LC-MS/MS using acidic mobile phases due to the concern of its instability in a basic medium. However, acidic mobile phases often lead to poor chromatography (e.g. split or double peaks) and reduced detection sensitivity in the commonly used negative ionization mode. To overcome these shortcomings, a basic mobile phase was used for the first time in the LC-MS/MS quantification of THC. In comparison with the acidic mobile phases, a single symmetrical chromatographic peak was obtained and the sensitivity increased by 7-fold or more under the equivalent conditions. The new LC-MS/MS method using the basic mobile phase has been successfully validated for the quantification of THC in human EDTA plasma over the concentration range of 5-2500ng/ml. The within-batch accuracy (% nominal concentration) was between 88.7 and 104.9 and the between-batch accuracy ranged from 96.7 to 108.6. The CVs for within- and between-batch precisions were equal to or less than 5.5% and 9.1%, respectively. No significant matrix interference or matrix effect was observed from normal or lipemic and hemolytic plasma matrices. In addition, the common stabilities with adequate durations were established, including up to 5days of post-preparative stability. Furthermore, when the validated method was applied to a clinical study, the passing rate of ISR samples was 83%, indicating the good reproducibility of the method. The success of the unconventional approach presented in this article demonstrates that a mobile phase could be selected based mainly on its merits to facilitate LC separation and/or MS detection. There is no need for excessive concern about the stability of the compound(s) of interest in the selected mobile phase because the run time of modern LC-MS or LC-MS/MS methods is typically only a few minutes.

Metabolic fate of poly-(lactic-co-glycolic acid)-based curcumin nanoparticles following oral administration.

PurposeCurcumin (CUR), the main polyphenol in turmeric, is poorly absorbed and rapidly metabolized following oral administration, which severely curtails its bioavailability. Poly-(lactic-co-glycolic acid)-based CUR nanoparticles (CUR-NP) have recently been suggested to improve CUR bioavailability, but this has not been fully verified. Specifically, no data are available about curcumin glucuronide (CURG), the major metabolite of CUR found in the plasma following oral administration of CUR-NP. Herein, we investigated the absorption and metabolism of CUR-NP and evaluated whether CUR-NP improves CUR bioavailability.MethodsFollowing oral administration of CUR-NP in rats, we analyzed the plasma and organ distribution of CUR and its metabolites using high-performance liquid chromatography-tandem mass spectrometry. To elucidate the mechanism of increased intestinal absorption of CUR-NP, we prepared mixed micelles comprised of phosphatidylcholine and bile salts and examined the micellar solubility of CUR-NP. Additionally, we investigated the cellular incorporation of the resultant micelles into differentiated Caco-2 human intestinal cells.ResultsFollowing in vivo administration of CUR-NP, CUR was effectively absorbed and present mainly as CURG in the plasma which contained significant amounts of the metabolite compared with other organs. Thus, CUR-NP increased intestinal absorption of CUR rather than decreasing metabolic degradation and conversion to other metabolites. In vitro, CUR encapsulated in CUR-NP was solubilized in mixed micelles; however, whether the micelles contained CUR or CUR-NP had little influence on cellular uptake efficiency. Therefore, we suggest that the high solubilization capacity of CUR-NP in mixed micelles, rather than cellular uptake efficiency, explains the high intestinal absorption of CUR-NP in vivo.ConclusionThese findings provide a better understanding of the bioavailability of CUR and CUR-NP following oral administration. To improve the bioavailability of CUR, future studies should focus on enhancing the resistance to metabolic degradation and conversion of CUR to other metabolites, which may lead to novel discoveries regarding food function and disease prevention.

Effects of curcumin metabolites on human colon adenocarcinoma cells

Stepwise cancer development involves metastatic migration as well as uncontrolled cell growth. Cancer cells undergo migration and invasion which allow them to translocate within tissues. Tetrahydrocurcumin (THC), a major metabolite of curcumin, exhibits anti‐carcinogenesis and antioxidation in vivo. In the present study, we found that THC and two other metabolites of curcumin, tetrahydrodemethoxycurcumin (THDC) and tetrahydrobisdemethoxycurcumin (THBC), could reduce the survival ratio of human colon adenocarcinoma cells, COLO205, HCT116, and HT29, in a dose‐dependent manner. The results also indicated that the fewer the methoxy groups of the curcumim metabolites, the more the inhibitory effects. However, curcumin metabolites did not trigger apoptotic cell death in COLO205 cells significantly, whereas curcumin did. Our data also strongly suggest a role of THBC in inhibiting cellular migration in HCT116 cells. Taken together, these results demonstrated the anticancer efficacy of curcumin metabolites which provides a potential application basis for the prevention of human colon cancer.Support or Funding InformationThis study was supported by NSC102‐2320‐B‐309‐001‐MY3 to M‐F Lee and NSC100‐2313‐B‐309‐003 to A‐C Cheng.

Site‐Specific Deglucuronidation of Turmeric‐Derived Curcuminoids in Bone

IntroductionThe majority of women with advanced breast cancer (BCa) develop osteolytic bone metastases. Our laboratory has previously demonstrated that curcuminoids, bioactive components isolated from turmeric rhizomes, prevent the progression of osteolytic bone lesions in a murine xenograft model of human BCa bone metastasis and inhibit tumor cell secretion of TGFβ‐stimulated parathyroid‐related protein (PTHrP), a signaling pathway known to drive bone metastasis progression. In humans ingesting curcuminoid‐enriched turmeric dietary supplements, glucuronidated phase II metabolites of curcumin are the primary form detected in the circulation. This has given rise to the untested postulate that curcuminoids may be deglucuronidated at sites of action to form bioactive aglycone (free) curcumin. Studies were therefore performed to compare tumor cell (human MDA‐MB‐231 breast cancer cell [MDA])‐specific effects of glucuronidated curcumin (G‐CURC) vs. curcumin (CURC) in vitro and to assess site‐specific deglucuronidation of circulating G‐CURC in the bone microenvironment in the BCa bone metastases model.MethodsDose dependent effects of G‐CURC vs. CURC on Smad‐mediated TGFβ‐stimulated PTHrP secretion and their relative effects on constitutive Smad2 and 3 expression in MDA cells were determined by RIA and Western, respectively. G‐CURC and CURC levels were quantified directly, or after hydrolysis using β‐glucuronidase, by LC‐MS in either positive or negative modes in: 1) conditioned media of G‐CURC‐treated murine bone marrow (isolated from nude mice hind legs) or MDA BCa cells, or in 2) plasma and bone marrow specimens isolated from female nude mice treated in vivo with curcuminoids (100 mg/kg ip). Endogenous β‐glucuronidase enzyme was localized by immunohistochemical (IHC) staining in paraffin sections of decalcified metastases‐containing hind limbs of nude mice inoculated, via intracardiac injection 21 days previously, with MDA cells (1 × 105 cells).ResultsCURC dose‐dependently inhibited TGFβ stimulated PTHrP secretion from MDA cells and decreased constitutive Smad2 and 3 levels, while G‐CURC was without effect. G‐CURC levels in conditioned media after 4 hours of G‐CURC treatment of MDA cells were no different from levels detected in cell‐free media incubated under the same conditions. In contrast, G‐CURC levels were 37% lower (p < 0.05) in conditioned media obtained from bone marrow cells cultured under the same conditions. As has been reported in humans, the majority of circulating curcumin in mice was glucuronidated (94.5 ± 1.5%). Free curcumin levels were 4‐fold higher (p < 0.01) in the bone marrow (vs. plasma) of curcuminoid‐treated nude mice, representing 23.3 ± 5.2 % of total detectable curcumin (glucuronidated plus aglycone). Within the tumor/bone microenvironment, bone marrow cells expressed β‐glucuronidase, while MDA BCa tumor cells expressed little or no β‐glucuronidase.ConclusionResults from these studies suggest that G‐CURC may essentially act as a prodrug that is specifically activated (deconjugated) by murine bone marrow cells to form CURC, which can mediate anti‐tumor cell effects within bone that limit the progression of osteolytic human BCa metastases in turmeric‐treated mice. To our knowledge, these data provide the first evidence of bone‐specific targeting of active turmeric metabolites in vertebrates.Support or Funding InformationR01CA174926‐01, R01AT006896, and R03CA159382

Curcumin and tetrahydrocurcumin both prevent osteoarthritis symptoms and decrease the expressions of pro-inflammatory cytokines in estrogen-deficient rats.

BackgroundMenopausal symptoms are associated with inflammation. Curcumin is a well-known anti-inflammatory bioactive compound from turmeric whereas tetrahydrocurcumin (THC) is a major metabolite of curcumin that may have different efficacies. However, they have not been studied for anti-menopausal symptoms and anti-osteoarthritis effects. We compared the efficacies of curcumin and THC for preventing postmenopausal and osteoarthritis symptoms in ovariectomized (OVX) obese rats with monoiodoacetate (MIA) injections into the right knee to generate a similar pathology as osteoarthritis.MethodsOVX rats were provided a 45 % fat diet containing either (1) 0.4 % curcumin (curcumin), (2) 0.4 % THC, (3) 30 μg/kg body weight 17β-estradiol + 0.4 % dextrin (positive control), (4) 0.4 % dextrin (placebo; control), or (5) 0.4 % dextrin with no MIA injection (normal control) for 4 weeks. At the beginning of the fifth week, OVX rats were given articular injections of MIA or normal-control saline into the right knee and the assigned diets were provided for an additional 3 weeks.ResultsCurcumin and THC had similar efficacies for skin tail temperature in OVX rats whereas THC, but not curcumin, prevented glucose intolerance, which might be involved in exacerbating osteoarthritis. Both protected against osteoarthritis symptoms and pain-related behaviors better than 17β-estradiol treatment in estrogen-deficient rats. Curcumin and THC prevented the deterioration of articular cartilage compared to control. They also maintained lean body mass and lowered fat mass as much as 17β-estradiol treatment. The improvement in osteoarthritis symptoms was associated with decreased gene expressions of matrix metalloproteinase (MMP)3 and MMP13 and tumor necrosis factor-α, interleukin (IL)1β, and IL6 in the articular cartilage.ConclusionsTHC and curcumin are effective for treating postmenopausal and osteoarthritis symptoms in OVX rats with MIA-induced osteoarthritis-like symptoms and may have potential as interventions for menopausal and osteoarthritic symptoms in humans.

Enhanced bioavailability and relative distribution of free (unconjugated) curcuminoids following the oral administration of a food-grade formulation with fenugreek dietary fibre: A randomised double-blind crossover study

Despite the various reports on enhanced bioavailable formulations of curcumin, systemic oral bioavailability of unconjugated curcuminoids remains a challenge. Considering the differences in plasma bioactivity and membrane permeability of free curcuminoids over conjugated metabolites, herein we report a randomised double-blinded crossover study (n = 50) to investigate the relative bioavailability and pharmacokinetics of free curcuminoids following the oral administration of high (1000 mg) and low (250 mg) doses of a food-grade formulation of curcumin with fenugreek dietary fibre as curcumagalactomannosides (CGM), which was reported to exhibit improved blood-brain – barrier permeability in rats. CGM administration provided over 45.5-fold enhancement in free curcuminoids bioavailability with improved pharmacokinetics when compared to unformulated standard curcumin. Further investigations with and without enzymatic hydrolysis of plasma collected over 5 h post-administration of CGM at 1000 mg dose revealed higher free curcuminoids in plasma (74 ± 8%) as compared to conjugated curcuminoids (26 ± 12%) indicating a significant distribution of free curcuminoids over conjugated curcumin metabolites.

Effects of Tetrahydrocurcumin on Tumor Growth and Cellular Signaling in Cervical Cancer Xenografts in Nude Mice.

Tetrahydrocurcumin (THC) is a stable metabolite of curcumin (CUR) in physiological systems. The mechanism underlying the anticancer effect of THC is not completely understood. In the present study, we investigated the effects of THC on tumor growth and cellular signaling in cervical cancer xenografts in nude mice. Cervical cancer cells (CaSki) were subcutaneously injected in nude mice to establish tumors. One month after the injection, mice were orally administered vehicle or 100, 300, and 500 mg/kg of THC daily for 30 consecutive days. Relative tumor volume (RTV) was measured every 3-4 days. COX-2, EGFR, p-ERK1&2, p-AKT, and Ki-67 expressions were measured by immunohistochemistry whereas cell apoptosis was detected by TUNELS method. THC treatments at the doses of 100, 300, and 500 mg/kg statistically retarded the RTV by 70.40%, 76.41%, and 77.93%, respectively. The CaSki + vehicle group also showed significantly increased COX-2, EGFR, p-ERK1&2, and p-AKT; however they were attenuated by all treatments with THC. Ki-67 overexpression and a decreasing of cell apoptosis were found in CaSki + vehicle group, but these findings were reversed after the THC treatments.

Inhibitory effects and molecular mechanisms of tetrahydrocurcumin against human breast cancer MCF-7 cells

BackgroundTetrahydrocurcumin (THC), an active metabolite of curcumin, has been reported to have similar biological effects to curcumin, but the mechanism of the antitumor activity of THC is still unclear.MethodsThe present study was to investigate the antitumor effects and mechanism of THC in human breast cancer MCF-7 cells using the methods of MTT assay, LDH assay, flow cytometry analysis, and western blot assay.ResultsTHC was found to have markedly cytotoxic effect and antiproliferative activity against MCF-7 cells in a dose-dependent manner with the IC50 for 24 h of 107.8 μM. Flow cytometry analysis revealed that THC mediated the cell-cycle arrest at G0/G1 phase, and 32.8% of MCF-7 cells entered the early phase of apoptosis at 100 μM for 24 h. THC also dose-dependently led to apoptosis in MCF-7 cells via the mitochondrial pathway, as evidenced by the activation of caspase-3 and caspase-9, the elevation of intracellular ROS, a decrease in Bcl-2 and PARP expression, and an increase in Bax expression. Meanwhile, cytochrome C was released to cytosol and the loss of mitochondria membrane potential (Δψm) was observed after THC treatment.ConclusionTHC is an excellent source of chemopreventive agents in the treatment of breast cancer and has excellent potential to be explored as antitumor precursor compound.

Synthesis and Evaluation of the Anti-Oxidant Capacity of Curcumin Glucuronides, the Major Curcumin Metabolites.

Curcumin metabolites namely curcumin monoglucuronide and curcumin diglucuronide were synthesized using an alternative synthetic approach. The anti-oxidant potential of these curcumin glucuronides was compared with that of curcumin using DPPH scavenging method and Oxygen Radical Absorbance Capacity (ORAC) assay. The results show that curcumin monoglucuronide exhibits 10 fold less anti-oxidant activity (DPPH method) and the anti-oxidant capacity of curcumin diglucuronide is highly attenuated compared to the anti-oxidant activity of curcumin.

Curcumin inhibits lymphangiogenesis in vitro and in vivo.

Curcumin, a dietary compound from turmeric, has potent antimetastatic effects; however, the underlying mechanisms are not well understood. The aim of this study is to investigate the effects and mechanisms of curcumin on lymphangiogenesis (formation of new lymphatic vessels), which plays a critical role in tumor metastasis. Curcumin inhibited vascular endothelial growth factor-C (VEGF-C) induced lymphangiogenesis in a Matrigel plug assay in mice, and VEGF-C induced tube formation in human dermal lymphatic endothelial cells, demonstrating its antilymphangiogenic action in vivo and in vitro. Curcumin inhibited lymphangiogenesis, in part through suppression of proliferation, cell-cycle progression and migration of lymphatic endothelial cells, while it had little effect on matrix metalloproteinase activities. Curcumin inhibited expressions of VEGF receptors (VEGFR2 and VEGFR3), as well as downstream signaling such as phosphorylation of ERK and FAK. Finally, curcumin sulfate and curcumin glucuronide, which are two major metabolites of curcumin in vivo, had little inhibitory effect on proliferation of human dermal lymphatic endothelial cells. Our results demonstrate that curcumin inhibits lymphangiogenesis in vitro and in vivo, which could contribute to the antimetastatic effects of curcumin.

Mechanisms of Vasorelaxation Induced by Hexahydrocurcuminin Isolated Rat Thoracic Aorta.

This study was designed to examine the vasorelaxant effects of hexahydrocurcumin (HHC), one of the major natural metabolites of curcumin from Curcuma longa, on rat isolated aortic rings, and the underlying mechanisms. Isometric tension of the aortic rings was recorded using organ bath system. HHC (1 nM to 1 mM) relaxed the endothelium-intact aortic rings pre-contracted with PE and KCl in a concentration-dependent manner. Removal of the endothelium did not alter the effect of HHC-induced relaxation. In Ca(2+)-free Krebs solution, HHC significantly inhibited the CaCl2-induced contraction in high K(+) depolarized rings and suppressed the transient contraction induced by PE and caffeine in a concentration-dependent manner. HHC was also observed to relax phobal-12-myristate-13-acetate (PMA), an activator of protein kinase C (PKC), precontracted aortic rings in a concentration-dependent manner with EC50 values equivalent to 93.36 ± 1.03 μM. In addition, pre-incubation with propranolol (a β-adrenergic receptor blocker) significantly attenuated the HHC-induced vasorelaxation. These results suggest that the vasorelaxant effect of HHC is mediated by the endothelium-independent pathway, probably because of the inhibition of extracellular Ca(2+) influx through voltage-operated Ca(2+) channels and receptor-operated Ca(2+) channels, the inhibition of Ca(2+) mobilization from intracellular stores, as well as inhibition of PKC-mediated Ca(2+)-independent contraction. Moreover, HHC produces vasorelaxant effects probably by stimulating the β-adrenergic receptor.

Therapeutic potential of curcumin and curcumin analogues in rheumatology

Therapeutic potential of curcumin and curcumin analogues in rheumatology

Ameliorative efficacy of tetrahydrocurcumin against arsenic induced oxidative damage, dyslipidemia and hepatic mitochondrial toxicity in rats

Arsenic (As) is a well-known human carcinogen and a potent hepatotoxin. Environmental exposure to arsenic imposes a serious health hazard to humans and other animals worldwide. Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, exhibits many of the same physiological and pharmacological activities as curcumin and in some systems may exert greater antioxidant activity than the curcumin. It has been reported that THC has antioxidant efficacy attributable to the presence of identical β-diketone of 3rd and 5th substitution in heptane moiety. In the present study, rats were orally treated with arsenic alone (5mgkg-1bw/day) with THC (80mgkg-1bw/day) for 28days. Hepatotoxicity was measured by the increased activities of serum hepatospecific enzymes, namely aspartate transaminase, alanine transaminase, alkaline phosphatase and bilirubin along with increased elevation of lipid peroxidative markers, thiobarbituric acid reactive substances. And also elevated levels of serum cholesterol, triglycerides, free fatty acids and phospholipids were observed in arsenic intoxicated rats. These effects of arsenic were coupled with enhanced mitochondrial swelling, inhibition of cytochrome c oxidase, Ca2+ATPase and a decrease in mitochondrial calcium content. The toxic effect of arsenic was also indicated by significantly decreased activities of enzymatic antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase along with non-enzymatic antioxidant such as reduced glutathione. Administration of THC exhibited significant reversal of arsenic induced toxicity in hepatic tissue. All these changes were supported by the reduction of arsenic concentration and histopathological observations of the liver. These results suggest that THC has a protective effect over arsenic induced toxicity in rat.