curcumin and tetrahydrocurcumin

Tetrahydrocurcumin (THC) is a metabolite of curcumin (CUR). It shares many of CUR's beneficial biological activities in addition to being more water-soluble, chemically stable, and bioavailable compared to CUR. However, its mechanisms of action have not been fully elucidated. This paper addresses the preventive role of THC on various brain dysfunctions as well as its effects on brain redox processes, traumatic brain injury, ischemia-reperfusion injury, Alzheimer's disease, and Parkinson's disease in various animal or cell culture models. In addition to its strong antioxidant properties, the effects of THC on the reduction of amyloid β aggregates are also well documented. The therapeutic potential of THC to treat patterns of mitochondrial brain dysmorphic dysfunction is also addressed and thoroughly reviewed, as is evidence from experimental studies about the mechanism of mitochondrial failure during cerebral ischemia/reperfusion injury. THC treatment also results in a dose-dependent decrease in ERK-mediated phosphorylation of GRASP65, which prevents further compartmentalization of the Golgi apparatus. The PI3K/AKT signaling pathway is possibly the most involved mechanism in the anti-apoptotic effect of THC. Overall, studies in various animal models of different brain disorders suggest that THC can be used as a dietary supplement to protect against traumatic brain injury and even improve brain function in Alzheimer's and Parkinson's diseases. We suggest further preclinical studies be conducted to demonstrate the brain-protective, anti-amyloid, and anti-Parkinson effects of THC. Application of the methods used in the currently reviewed studies would be useful and should help define doses and methods of THC administration in different disease conditions.

Topics: Amyloid beta-Peptides; Animals; Brain; Brain Injuries, Traumatic; Curcumin; Phosphatidylinositol 3-Kinases

Tetrahydrocurcumin (THC), one of the major metabolites of CUR, possesses several CUR-like pharmacological effects; however, its mechanisms of action are largely unknown. This manuscript aims to summarize the literature on the preventive role of THC on vascular dysfunction and the development of hypertension by exploring the effects of THC on hemodynamic status, aortic elasticity, and oxidative stress in vasculature in different animal models. We review the protective effects of THC against hypertension induced by heavy metals (cadmium and iron), as well as its impact on arterial stiffness and vascular remodeling. The effects of THC on angiogenesis in CaSki xenografted mice and the expression of vascular endothelial growth factor (VEGF) are well documented. On the other hand, as an anti-inflammatory and antioxidant compound, THC is involved in enhancing homocysteine-induced mitochondrial remodeling in brain endothelial cells. The experimental evidence regarding the mechanism of mitochondrial dysfunction during cerebral ischemic/reperfusion injury and the therapeutic potential of THC to alleviate mitochondrial cerebral dysmorphic dysfunction patterns is also scrutinized and explored. Overall, the studies on different animal models of disease suggest that THC can be used as a dietary supplement to protect against cardiovascular changes caused by various factors (such as heavy metal overload, oxidative stress, and carcinogenesis). Additionally, the reviewed literature data seem to confirm THC's potential to improve mitochondrial dysfunction in cerebral vasculature during ischemic stroke through epigenetic mechanisms. We suggest that further preclinical studies should be implemented to demonstrate THC's vascular-protective, antiangiogenic, and anti-tumorigenic effects in humans. Applying the methods used in the presently reviewed studies would be useful and will help define the doses and methods of THC administration in various disease settings.

Topics: Animals; Curcumin; Disease Models, Animal; Endothelial Cells; Humans; Hypertension; Mice; Vascular Endothelial Growth Factor A

In recent decades, cancer has been one of the leading causes of death worldwide. Despite advances in understanding the molecular basis of tumorigenesis, diagnosis, and clinical therapies, the discovery and development of effective drugs is an active and vital field in cancer research. Tetrahydrocurcumin is a major curcuminoid metabolite of curcumin, naturally occurring in turmeric. The interest in tetrahydrocurcumin research is increasing because it is superior to curcumin in its solubility in water, chemical stability, bioavailability, and anti-oxidative activity. Many in vitro and in vivo studies have revealed that tetrahydrocurcumin exerts anti-cancer effects through various mechanisms, including modulation of oxidative stress, xenobiotic detoxification, inflammation, proliferation, metastasis, programmed cell death, and immunity. Despite the pharmacological similarities between tetrahydrocurcumin and curcumin, the structure of tetrahydrocurcumin determines its distinct and specific molecular mechanism, thus making it a potential candidate for the prevention and treatment of cancers. However, the utility of tetrahydrocurcumin is yet to be evaluated as only limited pharmacokinetic and oral bioavailability studies have been performed. This review summarizes research on the anti-cancer properties of tetrahydrocurcumin and describes its mechanisms of action.

Topics: Antineoplastic Agents; Curcumin; Humans; Neoplasms

Curcumin is one of the most valuable natural products due to its pharmacological activities. However, the low bioavailability of curcumin has long been a problem for its medicinal use. Large studies have been conducted to improve the use of curcumin; among these studies, curcumin metabolites have become a relatively new research focus over the past few years. Additionally, accumulating evidence suggests that curcumin or curcuminoid metabolites have similar or better biological activity than the precursor of curcumin. Recent studies focus on the protective role of plasma tetrahydrocurcumin (THC), a main metabolite of curcumin, against tumors and chronic inflammatory diseases. Nevertheless, studies of THC in eye diseases have not yet been conducted. Since ophthalmic conditions play a crucial role in worldwide public health, the prevention and treatment of ophthalmic diseases are of great concern. Therefore, the present study investigated the antioxidative, anti-inflammatory, antiangiogenic, and neuroprotective effects of THC on four major ocular diseases: age-related cataracts, glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). While this study aimed to show curcumin as a promising potential solution for eye conditions and discusses the involved mechanistic pathways, further work is required for the clinical application of curcumin.

Topics: Curcumin; Eye Diseases; Humans; Ophthalmology

Cadmium (Cd) is a non-essential heavy metal with high toxicity potential. Humans are exposed to Cd present in diet, polluted air, and cigarette smoke. Cd exposure has been associated with increased risk of chronic diseases, including hypertension, atherosclerosis, diabetes, and nephropathy, all of which could be attributable to dysfunctional endothelial and smooth muscle cells. Cd toxicity is correlated with increased reactive oxygen formation and depletion of antioxidants, resulting in an oxidative stress. Chelation of Cd has proved useful in the removal of the Cd burden. However, several chelating agents cause side effects in clinical usage. Recent studies have shown that the antioxidant compounds curcumin and tetrahydrocurcumin can alleviate vascular dysfunction and high blood pressure caused by Cd toxicity. In chronic Cd exposure, these antioxidants protect vascular endothelium by increasing nitric oxide (NO•) bioavailability and improving vascular function. Antioxidant activity against Cd intoxication results directly and/or indirectly through free radical scavenging, metal chelation, enhanced expression of the antioxidant defense system, regulation of inflammatory enzymes, increase in NO• bioavailability, and reduction of gastrointestinal absorption and tissue Cd accumulation. This review summarizes current knowledge of Cd-induced oxidative stress and cardiovascular dysfunction and a possible protective effect conferred by the antioxidants curcumin and tetrahydrocurcumin.

Topics: Animals; Cadmium; Curcumin; Heart Diseases; Humans; Oxidative Stress; Reactive Oxygen Species

Chemoprevention is a relatively new and promising strategy to prevent human degenerative diseases, including cancer, and is defined as the use of natural dietary compounds and/or synthetic substances to block, inhibit, reverse, or retard the progress of human diseases. Tetrahydrocurcumin (THC) is a major metabolite of curcumin (extracted from the roots of the Curcuma longa Linn). THC has been demonstrated to prevent oxidative stress and inflammation, to act against neurodegeneration, and to possess anti-cancer activity. In this review, we summarize the current knowledge and underlying molecular mechanisms of the chemopreventative activities of THC and its potential effects on the development of various human diseases.

Topics: Animals; Curcuma; Curcumin; Diet Therapy; Humans; Neoplasms; Plant Extracts

Curcumin (diferuloylmethane), a golden pigment from turmeric, has been linked with antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antidiabetic properties. Most of the these activities have been assigned to methoxy, hydroxyl, α,β-unsaturated carbonyl moiety or to diketone groups present in curcumin. One of the major metabolites of curcumin is tetrahydrocurcumin (THC), which lacks α,β-unsaturated carbonyl moiety and is white in color. Whether THC is superior to curcumin on a molecular level is unclear and thus is the focus of this review. Various studies suggest that curcumin is a more potent antioxidant than THC; curcumin (but not THC) can bind and inhibit numerous targets including DNA (cytosine-5)-methyltransferase-1, heme oxygenase-1, Nrf2, β-catenin, cyclooxygenase-2, NF-kappaB, inducible nitric oxide synthase, nitric oxide, amyloid plaques, reactive oxygen species, vascular endothelial growth factor, cyclin D1, glutathione, P300/CBP, 5-lipoxygenase, cytosolic phospholipase A2, prostaglandin E2, inhibitor of NF-kappaB kinase-1, -2, P38MAPK, p-Tau, tumor necrosis factor-α, forkhead box O3a, CRAC; curcumin can inhibit tumor cell growth and suppress cellular entry of viruses such as influenza A virus and hepatitis C virus much more effectively than THC; curcumin affects membrane mobility; and curcumin is also more effective than THC in suppressing phorbol-ester-induced tumor promotion. Other studies, however, suggest that THC is superior to curcumin for induction of GSH peroxidase, glutathione-S-transferase, NADPH: quinone reductase, and quenching of free radicals. Most studies have indicated that THC exhibits higher antioxidant activity, but curcumin exhibits both pro-oxidant and antioxidant properties.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Antiviral Agents; Curcumin; Humans; Signal Transduction

Topics: Altitude Sickness; Animals; Brain Edema; Cell Hypoxia; Curcumin; Disease Models, Animal; Humans; Inflammation; Male; Mice; NF-kappa B; Vascular Endothelial Growth Factor A

Experimental studies have shown that liposomal curcumin can exert a reduction in tumor growth in pancreatic and colorectal cancer. In this phase I clinical trial we investigated the pharmacokinetics, safety, and tolerability of intravenously administered liposomal curcumin in healthy subjects.. 50 male and female participants were included in this randomized, placebo-controlled double-blind phase I dose escalation study. Subjects received a single dose of liposomal curcumin (10 - 400 mg/m2; n = 2 - 6 per group) or placebo over 2 hours intravenously.. Dose-dependent increases in the plasma concentrations of curcumin and its metabolite tetrahydrocurcumin (THC) were detected. After the end of drug infusion, curcumin and THC plasma concentrations decreased within 6 - 60 minutes below the limit of quantification. Mean urinary excretion was ~ 0.1% of total systemic clearance. Liposomal curcumin was tolerated well, but a transient red blood cell echinocyte formation with concomitant increase in mean cellular volume was observed at dosages ≥ 120 mg/m2.. Short-term intravenous dosing of liposomal curcumin appears to be safe up to a dose of 120 mg/m2. Changes in red blood cell morphology may represent a dose limiting sign of toxicity.

Topics: Adolescent; Adult; Antineoplastic Agents, Phytogenic; Biotransformation; Curcumin; Dose-Response Relationship, Drug; Double-Blind Method; Erythrocytes; Female; Healthy Volunteers; Humans; Infusions, Intravenous; Liposomes; Male; Middle Aged; Renal Elimination; Risk Assessment; Young Adult

The potential health benefits of curcumin are limited by its poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination. The purpose of this study was the comparative measurement of the increases in levels of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and the metabolite tetrahydrocurcumin after oral administration of three different curcumin formulations in comparison to unformulated standard.. The relative absorption of a curcumin phytosome formulation (CP), a formulation with volatile oils of turmeric rhizome (CTR) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC) in comparison to a standardized curcumin mixture (CS) was investigated in a randomized, double-blind, crossover human study in healthy volunteers. Samples were analyzed by HPLC-MS/MS.. Total curcuminoids appearance in the blood was 1.3-fold higher for CTR and 7.9-fold higher for CP in comparison to unformulated CS. CHC showed a 45.9-fold higher absorption over CS and significantly improved absorption over CP (5.8-fold) and CTR (34.9-fold, all p < 0.001).. A formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants significantly increases curcuminoid appearance in the blood in comparison to unformulated standard curcumin CS, CTR and CP.

Topics: Administration, Oral; Adult; Curcumin; Diarylheptanoids; Female; Humans; Intestinal Absorption; Male; Solubility

The aim of this study was to compare the efficacy of targeted narrowband UVB phototherapy plus topical tetrahydrocurcuminoid with that of targeted narrowband UVB monotherapy for induction of repigmentation in vitiligo.. The 308-nm excimer laser and targeted narrowband UVB phototherapy have recently been shown to be effective in repigmenting vitiligo. Studies have suggested that the combination of the 308-nm excimer laser and various topical treatments is more effective than UV monotherapy in the treatment of vitiligo.. Ten subjects with focal or generalized vitiligo were enrolled in this study. Two similar lesions were treated with either targeted narrowband UVB plus topical tetrahydrocurcuminoid cream or targeted UVB alone. The UV treatments were carried out twice a week for 12 weeks. The degree of repigmentation, documented by monthly digital photography, was assessed by a blinded dermatologist.. On completion of the study, statistically significant repigmentation, compared with baseline, occurred in both treatment groups. The overall degree of repigmentation was slightly better in the combination group at 8 and 12 weeks (p = 0.078 and 0.158 respectively). Adverse effects were minor and well tolerated.. Targeted narrowband UVB phototherapy plus topical tetrahydrocurcuminoid cream was slightly more effective than targeted narrowband UVB monotherapy for vitiligo located in UV-sensitive areas. However, the differences in degrees of repigmentation did not reach statistically significant levels.

Topics: Administration, Cutaneous; Adult; Aged; Combined Modality Therapy; Curcumin; Double-Blind Method; Emollients; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Radiation Dosage; Reference Values; Severity of Illness Index; Skin Pigmentation; Statistics, Nonparametric; Treatment Outcome; Ultraviolet Therapy; Vitiligo

The PtO2-catalyzed hydrogenation of curcumin produced slightly predominant meso-octahydrocurcumin than raceme octahydrocurcumin. Similar result was found in the product obtained from tetrahydrocurcumin and NaBH4, whereas using palladium carbon as a catalyst increased the meso-octahydrocurcumin ratio. Compared with chemical methods, baker's yeast produced 3S,5S-octahydrocurcumin and meso-octahydrocurcumin from tetrahydrocurcumin. The different activity between raceme and meso-octahydrocurcumin was not found in our experiments.

Topics: Curcumin; Hydrogenation; Stereoisomerism

In traditional Chinese medicine, curcuma longa L has been applied to treat pain and tumour-related symptoms for over thousands of years. Curcuminoids, polyphenolic compounds, are the main pharmacological component from the rhizome of Curcuma longa L. Pharmacological investigations have found that curcuminoids have many pharmacological activities of anti-inflammatory, anti-tumour, and anti-metastasis.. 3β-Hydroxysteroid dehydrogenase (3β-HSD1) catalyses the production of steroid precursors for androgens and estrogens, which play an essential role in cancer metastasis. We explored the potency and mode of action of curcuminoids and their metabolites of inhibiting 3β-HSD1 activity and compared the species difference between human and rat.. In this study, we investigated the direct inhibition of 6 curcuminoids on human placental 3β-HSD1 activity and compared the species-dependent difference in human 3β-HSD1 and rat placental homolog 3β-HSD4.. Some curcuminoids are potent human placental 3β-HSD1 inhibitors, possibly being potential drugs to treat prostate cancer and breast cancer.

Topics: 3-Hydroxysteroid Dehydrogenases; Animals; Curcuma; Curcumin; Diarylheptanoids; Female; Humans; Hydroxysteroid Dehydrogenases; Placenta; Pregnancy; Rats; Structure-Activity Relationship

Curcumin (CUR), derived from the dietary spice turmeric, is a polyphenolic compound with various biological and pharmacological activities. Tetrahydrocurcumin (THC) is one of the major reductive metabolites of curcumin. A pharmacokinetic study using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) for the simultaneous determination of curcumin, THC, quercetin (QR), and paeoniflorin (PF) in rat plasma had been performed. In this study, the regional distributions of curcumin and tetrahydrocurcumin in the liver and the three segments of small intestine (duodenum, jejunum, and ileum) of rats when orally co-administered with quercetin and paeoniflorin were carried out. Drug concentrations were determined using UHPLC-MS/MS. The results showed that curcumin was well distributed in the small intestine, while the distributions of tetrahydrocurcumin in the liver, duodenum, jejunum were similar, but much more abundant in the ileum. When orally co-administered with quercetin and paeoniflorin, the tissue to plasma concentration ratios (K

Topics: Animals; Curcumin; Ileum; Liver; Quercetin; Rats; Tandem Mass Spectrometry

Topics: Chromatography, High Pressure Liquid; Curcumin; Drug Stability; Limit of Detection; Reproducibility of Results

Curcuminoids are functional food additives, and the effect on gonadal hormone biosynthesis remains unclear. Gonads contain 3β-hydroxysteroid dehydrogenase isoforms,

Topics: Animals; Curcumin; Gonads; Humans; Progesterone; Rats; Structure-Activity Relationship

Chitosan (Ch)-coated nanostructured lipid carriers (NLCs) have great potential for transdermal delivery with high localization of chemotherapeutics in breast cancer. This study used tetrahydrocurcumin (THC), a primary metabolite of curcumin with enhanced antioxidant and anticancer properties, as a model compound to prepare NLCs. Response surface methodology was employed to optimize THC-loaded Ch-coated NLCs (THC-Ch-NLCs) fabricated by high-shear homogenization. The optimized THC-Ch-NLCs had particle size of 244 ± 18 nm, zeta potential of -17.5 ± 0.5 mV, entrapment efficiency of 76.6 ± 0.2% and drug loading of 0.28 ± 0.01%. In vitro release study of THC-Ch-NLCs showed sustained release following the Korsmeyer-Peppas model with Fickian and non-Fickian diffusion at pH 7.4 and 5.5, respectively. THC-Ch-NLCs demonstrated significantly enhanced in vitro skin permeation, cell uptake, and remarkable cytotoxicity toward MD-MBA-231 breast cancer cells compared to the unencapsulated THC, suggesting Ch-NLCs as potential transdermal nanocarriers of THC for triple-negative breast cancer treatment.

Topics: Breast Neoplasms; Chitosan; Curcumin; Drug Carriers; Female; Humans; Lipids; Nanostructures; Particle Size

Preclinical safety and proof of concept studies for a topical ointment comprising of concentrated tetrahydrocurcumin loaded lipidic nanoparticles (THC-LNs) and tacrolimus ointment (TTO) is proposed in the present investigation. The skin irritation potential and acute dermal toxicity were performed in rats in compliance with the Organization for Economic Cooperation and Development (OECD) guidelines (402, 404 and 410) while the cytotoxic potential was performed in HaCaT cells. Finally, in vivo evaluation was performed in Imiquimod mice model of psoriasis. In primary skin irritation assessment, TTO formulation, marketed formulation (Tacroz® Forte), THC-LNs, and blank LNs were topically applied on intact skin sites in rats while another group served as a negative control group for 72 h. TTO did not induce any adverse reactions. Repeated 28 days dermal toxicity followed by biochemical and histopathological assessment showed negligible alternations and skin lesions. THC-LNs revealed negligible cytotoxic potential in HaCaT cells. TTO showed significantly high anti-psoriatic activity in comparison to marketed ointment. This was also confirmed via histopathological evaluation. Based on these findings, it can be ascertained that TTO showed minimal toxicity and has ample potential for further clinical analysis. The above studies affirm the potential of TTO as an alternative for psoriasis.

Topics: Animals; Curcumin; Mice; Mice, Inbred BALB C; Nanoparticles; Ointments; Psoriasis; Rats; Tacrolimus

Acute myocardial dysfunction in patients with sepsis is attributed to oxidative stress, inflammation, and cardiomyocyte loss; however, specific drugs for its prevention are still lacking. Tetrahydrocurcumin (THC) has been proven to contribute to the prevention of various cardiovascular diseases by decreasing oxidative stress and inflammation. This study was performed to investigate the functions and mechanism of action of THC in septic cardiomyopathy.. After the oral administration of THC (120 mg/kg) for 5 consecutive days, a mouse model of sepsis was established via intraperitoneal lipopolysaccharide (LPS, 10 mg/kg) injection. Following this, cardiac function was assessed, pathological section staining was performed, and inflammatory markers were detected.. Myocardial systolic function was severely compromised in parallel with the accumulation of reactive oxygen species and enhanced cardiomyocyte apoptosis in mice with sepsis. These adverse changes were markedly reversed in response to THC treatment in septic mice as well as in LPS-treated H9c2 cells. Mechanistically, THC inhibited the release of pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6, by upregulating mitogen-activated protein kinase phosphatase 1, to block the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK). Additionally, THC enhanced the levels of antioxidant proteins, including nuclear factor-erythroid 2-related factor 2, superoxide dismutase 2, and NAD(P)H quinone oxidoreductase 1, while decreasing gp91. Our findings indicate that THC exhibited protective potential against septic cardiomyopathy by reducing oxidative stress and inflammation through the regulation of JNK/ERK signaling. The findings of this study provide a basis for the further evaluation of THC as a therapeutic agent against septic cardiomyopathy.

Topics: Animals; Cardiomyopathies; Curcumin; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Oxidative Stress; Sepsis

Three new derivatives of tetrahydrocurcumin

Topics: Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Copper; Curcumin; Drug Screening Assays, Antitumor; Etoposide; Humans; Molecular Structure; Structure-Activity Relationship

Activation of the intrarenal renin-angiotensin system (RAS) is implicated in the pathogenesis of kidney injury and hypertension. We aimed to investigate the protective effect of tetrahydrocurcumin (THU) on intrarenal RAS expression, kidney injury, and systolic blood pressure (SBP) in high-fat diet (HFD)-induced type 2 diabetic mice.. Eight-week-old male mice were fed a regular diet (RD) or HFD for 12 weeks, and THU (50 or 100 mg/kg/day) was intragastrically administered with HFD. Physiological and metabolic changes were monitored and the expression of RAS components and markers of kidney injury were assessed.. HFD-fed mice exhibited hyperglycemia, insulin resistance, and dyslipidemia compared to those in the RD group (P<0.05). Kidney injury in these mice was indicated by an increase in the ratio of albumin to creatinine, glomerular hypertrophy, and the effacement of podocyte foot processes. Expression of intrarenal angiotensin-converting enzyme, angiotensin II type I receptor, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4, and monocyte chemoattractant protein-1 was also markedly increased in HFD-fed mice. HFD-fed mice exhibited elevated SBP that was accompanied by an increase in the wall thickness and vascular cross-sectional area (P<0.05), 12 weeks post-HFD consumption. Treatment with THU (100 mg/kg/day) suppressed intrarenal RAS activation, improved insulin sensitivity, and reduced SBP, thus, attenuating kidney injury in these mice.. THU alleviated kidney injury in mice with HFD-induced type 2 diabetes, possibly by blunting the activation of the intrarenal RAS/nicotinamide adenine dinucleotide phosphate oxidase IV (NOX4)/monocyte chemoattractant protein 1 (MCP-1) axis and by lowering the high SBP.

Topics: Animals; Blood Pressure; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Kidney; Male; Mice

Impairment of adiponectin production and function is closely associated with insulin resistance and type 2 diabetes, which are linked to obesity. Studies in animal models have documented the anti-diabetic effects of tetrahydrocurcumin (THC). Although several possible mechanisms have been proposed, the contribution of adiponectin signaling on THC-mediated antihyperglycemic effects remains unknown. Here, we report that adiposity, steatosis, and hyperglycemia were potently attenuated in high-fat diet/streptozotocin-induced diabetic obese mice after they received 20 and 100 mg/kg THC for 14 weeks. THC upregulated UCP-1 in adipose tissue and elevated adiponectin levels in the circulation. THC upregulated the AdipoR1/R2-APPL1-mediated pathway in the liver and skeletal muscle, which contributes to improved insulin signaling, glucose utilization, and lipid metabolism. Furthermore, THC treatment significantly (

Topics: Adiponectin; Animals; Apoptosis; Curcumin; Diabetes Mellitus, Experimental; Diet, High-Fat; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liver; Male; Mice; Mice, Inbred C57BL; Phytotherapy; Receptors, Adiponectin; Signal Transduction; Streptozocin; Up-Regulation

Curcumin was found to accelerate gastric ulcer healing by the main mechanism, i.e., the suppression of iNOS mediated inflammation. Although Tetrahydrocurcumin (THC) is claimed to be an active antioxidant element of curcumin, its antiulcer activity has not been systematically examined. The utility of Self-Microemulsifying Drug Delivery Systems (SMEDDSs) for curcumin and THC formulations in the liquid form was also found to increase the rate and extent of release of curcumin- and THC-SMEDDS. Nevertheless, the beneficial antiulcer effect of these nanoproducts has not yet been evaluated.. This study aimed to evaluate and compare the antiulcer efficacy of curcumin- and THCSMEDDS through the inhibition of the iNOS/NO system in the rat model.. Antiulcer efficacy was compared in terms of the ability to accelerate healing of gastric ulcer including the efficient inhibitory action on inflammatory NO production in activated macrophages and iNOS mRNA expression at the ulcerated area.. THC was found to have less ulcer healing capacity than curcumin with a lack of significant inhibitory effect on the iNOS/NO system. The SMEDDS used in the study significantly increased the inhibitory efficacy of THC on iNOS/NO production and iNOS mRNA expression compared to the inhibitory potency of curcumin. An oral administration of curcumin- or THC-SMEDDS once a day was appropriate for exerting a comparable curative efficacy to a twice-daily oral administration of curcumin or THC.. The SMEDDS used in the study was observed to enhance the inhibitory efficacy of the antiulcer drug on the iNOS/NO system, leading to a reduction of daily dosing and dosing frequency.

Topics: Administration, Oral; Animals; Curcumin; Drug Compounding; Emulsifying Agents; Macrophages; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; Stomach Ulcer

Envisaging the poor solubility (56 ngml1) and permeability of tetrahydrocurcumin (THCC), it was formulated into lipidic nanostructures to enhance its bioavailability upon topical application to promote the healing process for skin inflammatory disorders. Lack of literature on a suitable method for determining THCC per se and nanoformulations prompted us to develop an RP-HPLC method to detect the drug in its nanostructures and in pig ear skin post dermatokinetics.. The present investigation aimed to develop a simple, precise and RP-HPLC method for the quantitative estimation of THCC in prepared lipidic nanostructures, its ointment, and in skin homogenate obtained post dermatokinetic study.. THCC encapsulated nanostructures and ointment were formulated using a modified emulsification method and embedded into an ointment base to enhance its spreadability and improve patient compliance. A fast and sensitive reverse-phase high-performance liquid chromatography method was developed using a Hypersil BDS reverse phase C18 column (4.6 mm × 250 mm, 5 μm) with mobile phase comprising tetrahydrofuran (THF) and 1 mgmL-1 citric acid (4:6), at a flow rate of 1.0 mLmin-1 with a run time of 20 min.. THCC nanostructures were successfully prepared using the spontaneous microemulsification method. THCC was detected at 282 nm and revealed two peaks which were attributed to the keto-enol tautomerism in the molecule with retention times of 6.23 min and 11.06 min, respectively. The assay of THCC in nanostructures and ointment was found to be 98.30 % and 99.98 %, with an entrapment efficiency 77.00±2.74 %. The dermatokinetic studies revealed sufficient release of THCC from its ointment up to 24 hr with a concentration of 1382 μgcm-2, for causing a therapeutic effect.. The method was found to be reproducible and robust, as shown by the low coefficient of variation and a constant analyte/IS ratio. It was successfully employed for the estimation of THCC assay in nanostructures and its ointment and dermatokinetic analysis in the skin.

Topics: Animals; Chromatography, High Pressure Liquid; Curcumin; Lipids; Nanostructures; Swine

Tetrahydrocurcumin-hyaluronic acid (THC-HA) conjugate was synthesized in order to improve the bioaccessibility of tetrahydrocurcumin (THC). The successful conjugation was confirmed by the results from

Topics: Adhesiveness; Animals; Biological Availability; Curcumin; Diffusion; Drug Liberation; Elastic Modulus; Hyaluronic Acid; Models, Biological; Proton Magnetic Resonance Spectroscopy; Rheology; Swine; Viscosity; Water

Dietary factors can reshape the gut microbiota and consequently affect disease progression. We previously reported that tetrahydrocurcumin (THC), the major active metabolite of curcumin (Cur), could ameliorate allergic inflammation in asthmatic mice. Herein, we aimed to investigate whether THC or Cur exerts anti-inflammatory effects on allergic asthma via modulating gut microbiota. Ovalbumin (OVA)-induced asthmatic mice were treated with Cur or THC, and the gut microbiota profiles were analyzed by 16S rRNA sequencing. Fecal microbiota transplantation (FMT) from Cur- or THC-fed donor mice was administered to OVA-induced asthmatic mice. Nasal symptoms and inflammation patterns of lungs and colons were evaluated in control, OVA-induced and Cur-or THC-treated mice. Both Cur and THC treatment could alter the compositions of the gut microbiota in asthmatic mice, characterized by a significant decrease in the ratio of Firmicutes to Bacteroidetes; Cur or THC supplementation also reduced the relative abundances of pro-inflammatory bacteria, e.g., Proteobacteria, Intestinimonas, Unidentified-Ruminococcaceae, and Lachnospiraceae, in OVA-induced mice. The relative abundances of Unidentified-Ruminococcaceae, Romboutsia, Intestinimonas, Akkermansia, and Mucispirillum were positively associated with the levels of Th2-related factors in asthmatic mice upon Cur or THC treatment. Moreover, THC-FMT showed better preventive effects than Cur-FMT on the development of allergic inflammation in OVA-induced mice, resulting in a reduction in symptoms and Th2-mediated inflammation in both lung and colon tissues. The results reveal that Cur- or THC-mediated alleviation of airway allergic inflammation is dependent on gut microbiota modulation. THC-induced gut microbiota may have therapeutic potential for asthma treatment.

Topics: Animals; Asthma; Curcumin; Female; Gastrointestinal Microbiome; Inflammation; Lung; Mice; Mice, Inbred BALB C

Topics: Acute Kidney Injury; Animals; Apoptosis; Blood Urea Nitrogen; Curcumin; Cytokines; Inflammation; Kidney; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Protective Agents; Sepsis; Signal Transduction; Sirtuin 1

Curcuminoids are the main bioactive components of the well-known Asian spice and traditional medicine turmeric. Curcuminoids have poor chemical stability and bioavailability; in vivo they are rapidly metabolized to a set of bioreduced derivatives and/or glucuronide and sulfate conjugates. The reduced curcuminoid metabolites were also reported to exert various bioactivities in vitro and in vivo. In this work, we aimed to perform a comparative evaluation of curcuminoids and their hydrogenated metabolites from a medicinal chemistry point of view, by determining a set of key pharmacokinetic parameters and evaluating antioxidant potential in relation to such properties.Reduced metabolites were prepared from curcumin and demethoxycurcumin through continuous-flow hydrogenation. As selected pharmacokinetic parameters, kinetic solubility, chemical stability, metabolic stability in human liver microsomes, and parallel artificial membrane permeability assay (PAMPA)-based gastrointestinal and blood-brain barrier permeability were determined. Experimentally determined logP for hydrocurcumins in octanol-water and toluene-water systems provided valuable data on the tendency for intramolecular hydrogen bonding by these compounds. Drug likeness of the compounds were further evaluated by a in silico calculations. Antioxidant properties in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and oxygen radical absorbance capacity (ORAC) assays were comparatively evaluated through the determination of ligand lipophilic efficiency (LLE). Our results showed dramatically increased water solubility and chemical stability for the reduced metabolites as compared to their corresponding parent compound. Hexahydrocurcumin was found the best candidate for drug development based on a complex pharmacokinetical comparison and high LLE values for its antioxidant properties. Development of tetrahydrocurcumin and tetrahydro-demethoxycurcumin would be limited by their very poor metabolic stability, therefore such an effort would rely on formulations bypassing first-pass metabolism.

Topics: Antioxidants; Biological Availability; Biphenyl Compounds; Cell Membrane Permeability; Chemistry, Pharmaceutical; Curcuma; Curcumin; Diarylheptanoids; Glucuronides; Humans; Hydrogenation; Microsomes, Liver; Picrates; Solubility

Topics: Antifungal Agents; Biological Control Agents; Chitosan; Curcumin; Fusarium; Starch

Obesity can induce chronic low-grade inflammation via oxidative stress. Tetrahydrocurcumin (THC) is a major curcumin metabolite with anti-inflammatory and antioxidant effects, but little is known about its effects on the skin of obese individuals. Thus, the aim of this study was to investigate the effects of THC on inflammatory cytokine production, oxidative stress, and autophagy in the skin of mice with high-fat diet- (HFD-) induced obesity. Eight-week-old C57BL/6J mice were fed a regular diet, HFD (60% of total calories from fat), or HFD supplemented with THC (100 mg/kg/day orally) for 12 weeks. We measured their body weights during the experimental period. After 12-week treatments, we performed western blotting and real-time polymerase chain reaction analyses on skin samples to evaluate the expression of inflammatory cytokines, oxidative stress markers, and autophagy markers. We observed higher tumor necrosis factor-

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Autophagy; Body Weight; Curcumin; Cytokines; Diet, High-Fat; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxidative Stress; Signal Transduction; Skin; Skin Diseases; Temperature

Curcuminoids have been widely studied for human health and disease applications, yet bioavailability remains a hurdle to actualizing all the benefits ascribed to them. The lack of standardization in analysis method, confusion about what constitutes an ideal analyte, and conflicting thoughts around dosing strategies have made it difficult to draw parity between bioavailability and bioactivity and establish a baseline for formulation comparisons.. This randomized double-blinded, 2-way cross over, single oral dose, comparative bioavailability study differentially evaluates curcumin at the time of its absorption and along various biotransformation pathways, to include free curcumin, the readily usable form of curcumin; individual and composite totals of curcumin and its analogues as exogenously cleaved conjugates, for example, total curcumin, total demethoxycurcumin (DMC), total bisdemethoxycurcumin (BDMC), and total curcuminoids respectively; and the bioactive metabolite of curcumin, total tetrahydrocurcumin (THC). As a primary study objective, the relative bioavailability of CURCUGEN, a novel dispersible, 50% curcuminoids-concentrated turmeric extract was compared to the standard curcumin reference product, curcuminoids 95% standardized extract (C-95), using the maximum concentration (Cmax), and area under the curve (AUC0-t) of free curcumin, total curcumin, total DMC, total BDMC and the curcumin active metabolite, as total THC.. The evaluation of free curcumin demonstrated that the Cmax and AUC0-t of the CURCUGEN was 16.1 times and 39 times higher than the Cmax and AUC0-t of C-95. Furthermore, total curcumin, total DMC, total BDMC, and total curcuminoids resulted in AUC0-t of the CURCUGEN at 49.5-, 43.5-, 46.8-, and 52.5-fold higher than C-95, respectively. The relative bioavailability of CURCUGEN for total THC was found to be 31 times higher when compared to C-95.. As the first human pharmacokinetics study to apply best-practice recommendations and pharmaceutically-aligned guidance in the comprehensive evaluation of a novel curcuminoids formulation, we have established the novelty of said formulation while better standardizing for the common variances and discrepancies between curcuminoids and their derivatives in the literature and commercial marketing, alike.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Cross-Over Studies; Curcumin; Double-Blind Method; Humans; Male; Middle Aged; Plant Extracts; Young Adult

1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (tetrahydrocurcumin, THC) is a major bioactive metabolite of curcumin, demonstrating the potential anti-inflammatory, antioxidant and neuroprotective properties, etc. In this study, it was found that Aβ induced decreased cell viability, cell cycle arrest and apoptosis in BV-2 cells, which were ameliorated by THC. In vivo, THC administration rescued learning and memory, and reduced Aβ burden in the hippocampus of APP/PS1 mice. By proteomic analysis of the hippocampus of mice, 157 differentially expressed proteins were identified in APP/PS1 mice treated with THC (comparing with APP/PS1 mice), which also suggested that the effects of THC on the cell cycle and apoptosis were mostly related to the "Ras signaling pathway", etc. In APP/PS1 mice, the down-regulation of Gab2 and K-Ras, and the up-regulation of caspase-3, TGF-β1 and TNF-ɑ were observed; THC attenuated the abnormal expression of Gab2, K-Ras, caspase-3 and TNF-ɑ, and up-regulated TGF-β1 and Bag1 expression. In BV-2 cells, Aβ induced the down-regulation of Gab2, K-Ras and TGF-β1, and the overexpression of caspase-3, PARP1, cleaved-PARP1 and TNF-ɑ, which were restored by THC. Moreover, THC up-regulated Bag1 expression in Aβ-treated BV-2 cells. The decreased transcriptional expression of Ccnd2 and Cdkn1a were also observed in Aβ-treated BV-2 cells, and THC alleviated the down-regulation of Ccnd2. For the first time, we identified that the action of THC in preventing AD was associated with inhibition of cell cycle arrest and apoptosis of microglia via the Ras/ERK signaling pathway, shedding new light on the role of THC in alleviating the progression of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line; Curcumin; Cyclin D2; Disease Models, Animal; Down-Regulation; Hippocampus; Humans; MAP Kinase Signaling System; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Proteomics; ras Proteins; Signal Transduction; Up-Regulation

Diabetes is a worldwide healthy concern, which affects approximately 9% of the population. Tetrahydrocurcumin (THC) is the main metabolite of curcumin, which exerts the anti-diabetic activity. However, the underlying mechanism has not been clarified. In the research, we investigated whether THC could improve diabetes by regulating the gut microbiota and the expression of pancreatic glucagon-like peptide-1 (GLP-1) in the db/db mice. After 8-week THC administration (ig., once a day, THCH group: 200 mg/kg, THCL group: 100 mg/kg), the fasting blood glucose (FBG) was measured every two weeks. Serum insulin levels, the expression of GLP-1 in the pancreas, the histopathology of pancreas and the composition of gut microbiota were evaluated at the end of the experiment. Compared to the diabetic group, THC treatment decreased significantly blood glucose, increased the secretion of insulin and the expression of GLP-1 in the pancreas. Histomorphological analysis revealed that THC could protect pancreatic islet cells against hyperglycemic insult. Furthermore, the data from the sequencing of the 16S rDNA genes in gut microbiome displayed that THC could restore the intestinal dysbiosis, including the lowered relative abundance of Proteobacteria, Actinobacteria and the ratio of Firmicutes to Bacteroidetes. The linear regression analysis showed a close correlation between the GLP-1 expression and the proportion of the intestinal microflora. Altogether, these results demonstrated that THC might have a direct regulatory effect on gut microflora, which indirectly decrease the FBG levels by modulating GLP-1 expression in the pancreas.

Topics: Animals; Blood Glucose; Curcumin; Diabetes Mellitus, Experimental; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred CBA; Molecular Structure; Pancreas

Tetrahydrocurcumin (THC) is the major active metabolite of curcumin, which is a dietary factor derived from Curcuma species. Our previous study demonstrated a significant beneficial effect of THC in mice with allergic asthma. Glucocorticosteroids (GCs) are commonly used drugs in asthma. Whether THC supplementation could promote the beneficial effects of GC therapy on asthma has not yet been reported. The current study aimed to investigate the combined efficacy of GC and THC treatment in a mouse model of allergic asthma.. BALB/c mice were randomly divided into 5 groups: the control group, ovalbumin (OVA)-induced group, and OVA-induced mice treated with dietary THC only, intraperitoneal injection of dexamethasone (DEX) only, or THC combined with DEX. The nasal symptoms, histopathological alterations of lung tissues, lung cytokine production, and Th cell subsets were assessed.. THC or DEX had beneficial effects on nasal symptoms and pathological lung changes, and the therapeutic effects between THC and DEX treatment were comparable. Importantly, compared to the monotherapy groups (THC or DEX only), the combination of THC and DEX showed a significantly reduced nasal rubbing frequency, lower mucus hyperproduction, lower Th2 and Th17 cell numbers as well as lower related cytokine levels (IL-4, IL-5, and IL-17A).. Supplementation with THC can enhance the therapeutic effects of DEX to alleviate airway symptoms, lung inflammation, and the Th2 response. Our findings suggest that dietary administration of THC could act as an add-on therapy for asthma treated with GCs.

Topics: Allergens; Animals; Anti-Asthmatic Agents; Asthma; Curcuma; Curcumin; Dexamethasone; Dietary Supplements; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred BALB C; Ovalbumin; Th2 Cells

BACKGROUND This study aimed to prepare doxorubicin- and tetrahydrocurcumin-loaded and transferrin-modified PEG-PLGA nanoparticles (Tf-NPs-DOX-THC) for enhanced and synergistic chemoradiotherapy. MATERIAL AND METHODS Tf-NPs-DOX-THC were prepared via the double-emulsion method. The morphologies and particle sizes of the prepared nanoparticles were examined by TEM and DLS, respectively. The in vitro MTT, apoptosis, and clone formation assays were performed to detect the proliferation and radiosensitivity of cells with various treatments. Cellular uptake assay was also conducted. The tissue distribution of Tf-NPs was investigated by ex vivo DOX fluorescence imaging. The in vivo tumor growth inhibition efficiency of various treatments was evaluated in orthotopic C6 mouse models and C6 subcutaneously grafted mouse models. RESULTS Tf-NPs-DOX-THC exhibited high drug-loading efficiency (6.56±0.32%) and desirable particle size (under 250 nm). MTT, apoptosis, and clone formation assays revealed the enhanced anti-cancer activity and favorable radiosensitizing effect of Tf-NPs-DOX-THC. Strong fluorescence was observed in the brains of mice treated with Tf-NPs-DOX. The in vitro release of drug from nanoparticles was in a pH-sensitive manner. Tf-NPs-DOX-THC in combination with radiation also achieved favorable anti-tumor efficacy in vivo. CONCLUSIONS All results suggest that a combination of Tf-NPs-DOX-THC and radiation is a promising strategy for synergistic and sensitizing chemoradiotherapy of glioma.

Topics: Animals; Cell Line, Tumor; Chemoradiotherapy; Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Emulsions; Glioma; Humans; Lactates; Mice; Mice, Nude; Nanoparticles; Particle Size; Polyesters; Polyethylene Glycols; Rats; Tissue Distribution; Transferrin; Xenograft Model Antitumor Assays

Topics: Animals; Annexin A5; Calcium; Cell Death; Cell Line; Curcumin; Glutamic Acid; Hippocampus; MAP Kinase Signaling System; Mice; Oxidative Stress; Phosphorylation

Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Curcumin; Cytochrome P-450 CYP2E1; Humans; Hydrogenation; Kelch-Like ECH-Associated Protein 1; Liver; Male; Mice; NF-E2-Related Factor 2; Oxidative Stress; Protective Agents; Signal Transduction

Investigation of the impact of co-medication on the plasma levels of curcumin and tetrahydrocurcumin (THC) in cancer patients and a comparison of the pharmacokinetics of curcumin and plasma levels of THC between cancer patients and healthy individuals following intravenous infusion of Lipocurc™ (liposomal curcumin).. Correlation analysis was used to determine the impact of co-medication on infusion rate normalized plasma levels of curcumin and THC in cancer patients and to compare the plasma levels of curcumin and THC at different infusion rates between cancer patients and healthy individuals. In vitro hepatocyte and red blood cell distribution experiments were conducted with Lipocurc™ to support clinical findings. Plasma concentration time data were analyzed by the non-compartmental method to determine and compare the pharmacokinetic parameters of curcumin in cancer patients and healthy individuals.. Of 44 co-medications studied, three medications targeting the renin-angiotensin system, Lisinopril, Ramipril, and Valsartan elevated plasma levels of curcumin and THC in three cancer patients infused with Lipocurc™. Cell distribution experiments indicated that the disposition of curcumin in red blood cells may be a target for elevation of the plasma levels of curcumin. Plasma levels of curcumin in cancer patients increased to a greater extent with increased infusion rate compared to healthy individuals. Upon termination of infusion, the elimination phase for curcumin was shorter with a shorter terminal half-life and smaller volume of distribution for curcumin in cancer patients compared to healthy individuals.. Either co-medications or health status, or both, can impact the pharmacokinetics of curcumin infusion (as Lipocurc™) in cancer patients.

Topics: Animals; Case-Control Studies; Cells, Cultured; Curcumin; Dogs; Drug Therapy, Combination; Erythrocytes; Healthy Volunteers; Hepatocytes; Humans; Infusions, Intravenous; Liposomes; Male; Neoplasms; Tissue Distribution

Topics: Animals; Blood-Brain Barrier; Brain; Brain Ischemia; Curcumin; Infarction, Middle Cerebral Artery; Male; Mice, Inbred C57BL; Mitochondria; Reperfusion Injury; Stroke

Pelleted preparations were formulated from sacran (Sac), an anionic, sulfated, carboxyl-containing polysaccharide, which is extracted from the Japanese indigenous cyanobacterium Aphanothece sacrum, and surface-deacetylated chitin nanofibers (SDACNF). The use of this material as an extended-release excipient for tetrahydrocurcumin (THC), a model drug that is used to treat wounds via its radical scavenging ability was examined. The THC used in the study was complexed with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), which increases its water solubility. The radical scavenging activity of the THC/HP-β-CD complex (molar ratio of 1:1) was significantly higher than the values for SDACNF or Sac alone. The rate of release of THC from the Sac/SDACNF pellets containing the THC/HP-β-CD complex decreased with increasing Sac content in the pellet, suggesting that Sac/SDACNF (1:1) and Sac alone pellets function as extended-release excipients for THC. The findings reported here indicate that this can be attributed to the ability of the Sac component to retain fluids, thus extending the effects of the drug. In view of the above experimental outcomes, i.e. wound healing efficacy, fluid absorption, retention and the extended drug release of the system indicates that this preparation, in the appropriate ratios, has the potential for use as a controlled-release drug in wound healing.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Biphenyl Compounds; Chitin; Curcumin; Cyanobacteria; Delayed-Action Preparations; Drug Liberation; Excipients; Free Radical Scavengers; Kinetics; Male; Nanofibers; Picrates; Polysaccharides; Rats; Rats, Sprague-Dawley; Solubility; Surgical Wound; Water; Wound Healing

Most anticancer agents induce cancer cell death; however, multidrug-resistant cancers often lead to treatment failure. The effective use of curcumin as an anticancer agent has been demonstrated in clinical trials. Tetrahydrocurcumin, a major curcumin metabolite, exhibits pharmacological activities similar to those of curcumin. Curcumin induces cell death mainly through the apoptosis pathway, and tetrahydrocurcumin induces cell death mainly via an autophagy pathway in HL60 cells. Here, we investigated whether curcumin and tetrahydrocurcumin can induce apoptosis- and autophagy-mediated cell deaths in Ara-C-resistant cancer cells, respectively. The results demonstrated that curcumin and tetrahydrocurcumin induced cell death by apoptosis and autophagy, respectively, in Ara-C-resistant HL60 cells. Thus, curcumin and tetrahydrocurcumin have potential applications in the treatment of acute myeloid leukemia with Ara-C resistance.

Topics: Apoptosis; Autophagy; Cell Death; Curcumin; Female; Humans; Leukemia, Myeloid, Acute; Male

A vaginal microbicide is a front-line women-dependent approach and an alternative to a condom for prevention of unprotected sexual intercourse-associated HIV. The microbicide research is still in its infancy with several products in the clinical studies being reported to have good efficacy, safe, but with poor adherence. One such molecule reported with an excellent efficacy when tested preclinically is curcumin, a natural polyphenol derived from Curcuma longa. Despite its potential HIV-1 inhibitory activity, it has intense yellow color staining properties, which would result in poor consumer compliance and adherence for vaginal application. To address this issue, tetrahydrocurcumin (THC), a colorless derivative of curcumin, was subjected to in silico screening (molecular docking and dynamics simulation studies) using homology model of gp120-CD4 binding. It was found that THC exhibited equivalent gp120-CD4 binding inhibitory activity as compared with curcumin due to its stable hydrophobic interactions with residues Asp368 and Trp427 deeper in the Phe43 cavity of CD4 receptor. Hence, it can be effectively used as a potential microbicide candidate. THC, a BCS Class II molecule exhibits poor solubility, spreadability, and intracellular uptake when used in the conventional form. Thus, it was decided to develop a lipid-based nanomicrobicide gel for delivery of THC. The developed THC-loaded o/w microemulsion gel was characterized for physicochemical properties (globule size, drug content, drug release, and permeation) and further used for in vitro cell line studies (cell viability, cellular uptake, and anti-HIV activity). The developed formulation was found to be stable with coitus-independent release profile and exhibited a rapid time-independent intracellular uptake. In addition, it exhibited a fourfold increase in efficacy as compared with conventional THC. Thus, the novel THC-loaded o/w microemulsion gel exhibited the potential for prevention of HIV-1 infection associated with unprotected sexual intercourse.

Topics: Administration, Intravaginal; Anti-Infective Agents; CD4-Positive T-Lymphocytes; Cell Line; Cell Survival; Curcumin; Drug Liberation; Emulsions; Gels; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Lacticaseibacillus casei; Lactobacillus acidophilus; Molecular Docking Simulation; Nanoparticles; Pre-Exposure Prophylaxis

Curcumin (CUR) is a bioactive compound present in many composite prescriptions of traditional Chinese medicine together with quercetin (QR) and paeoniflorin (PF). Little is known about the influence of QR and PF on the absorption and metabolism of CUR when the three compounds are orally co-administered. In this study, a rapid, sensitive, and reliable ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous determination of CUR, tetrahydrocurcumin (THC), QR, and PF in rat plasma by using tinidazole as the internal standard (IS). A liquid-liquid extraction method with ethyl acetate was used to pre-treat the plasma samples. Chromatographic separation was conducted on a C18 column with isocratic elution using acetonitrile and 0.1% formic acid water solution (80:20, v/v) as the mobile phase at the flow rate of 0.3 mL/min. A TSQ Quantum Access Max API mass spectrometer equipped with electrospray ionisation (ESI) source in selection reaction monitoring (SRM) mode was employed to determine transitions of m/z 369.0 → 176.9, 373.1 → 137.0, 303.0 → 228.9, 478.9 → 120.9, 248.1 → 121.0 for CUR, THC, QR, PF, and IS, respectively. The selectivity, precision, accuracy, extraction recovery, matrix effect, and stability of the method were validated. This developed and validated method was successfully applied in the pharmacokinetic study of CUR, THC, QR, and PF in rats. The effects of QR and PF on the pharmacokinetics of CUR and its metabolite, THC, were evaluated in the plasma of Sprague-Dawley rats that were orally co-administered CUR, QR, and PF. The results showed that the combined use of QR, PF, and CUR has a possible influence on the metabolism and excretion of CUR. Our work provides a fundamental method for the rapid simultaneous determination of CUR, THC, QR, and PF in rat plasma. Furthermore, this study will provide a basic method for the analysis of pharmacokinetic interaction of CUR, QR, and PF and offer a scientific basis for a possible combination therapy with the three compounds.

Topics: Administration, Oral; Animals; Chromatography, High Pressure Liquid; Curcumin; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Drugs, Chinese Herbal; Glucosides; Limit of Detection; Liquid-Liquid Extraction; Male; Monoterpenes; Quercetin; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

Topics: Blood Coagulation; Curcumin; Diarylheptanoids; Humans; Platelet Aggregation; Platelet Function Tests

Topics: Alginates; Animals; Anti-Inflammatory Agents; Biological Products; Chitosan; Collagen; Curcumin; Drug Liberation; Humans; Male; Nanocapsules; Polyesters; Polyethylene Glycols; Rats, Sprague-Dawley; Wound Healing

Homocysteine (Hcy) causes endothelial dysfunction by inducing oxidative stress in most neurodegenerative disorders. This dysfunction is highly correlated with mitochondrial dynamics such as fusion and fission. However, there are no strategies to prevent Hcy-induced mitochondrial remodeling. Tetrahydrocurcumin (THC) is an anti-inflammatory and anti-oxidant compound. We hypothesized that THC may ameliorates Hcy-induced mitochondria remodeling in mouse brain endothelial cells (bEnd3) cells. bEnd3 cells were exposed to Hcy treatment in the presence or absence of THC. Cell viability and autophagic cell death were measured with MTT and MDC staining assay. Reactive oxygen species (ROS) production was determined using DCFH-DA staining by confocal microscopy. Autophagy flux was assessed using a conventional GFP-microtubule-associated protein 1 light chain 3 (LC3) dot assay. Interaction of phagophore marker LC-3 with mitochondrial receptor NIX was observed by confocal imaging. Mitochondrial fusion and fission were evaluated by western blot and RT-PCR. Our results demonstrated that Hcy resulted in cell toxicity in a dose-dependent manner and supplementation of THC prevented the detrimental effects of Hcy on cell survival. Furthermore, Hcy also upregulated fission marker (DRP-1), fusion marker (Mfn2), and autophagy marker (LC-3). Finally, we observed that Hcy activated mitochondrial specific phagophore marker (LC-3) and co-localized with the mitochondrial receptor NIX, as viewed by confocal microscopy. Pretreatment of bEnd3 with THC (15 μM) ameliorated Hcy-induced oxidative damage, mitochondrial fission/fusion, and mitophagy. Our studies strongly suggest that THC has beneficial effects on mitochondrial remodeling and could be developed as a potential therapeutic agent against hyperhomocysteinemia (HHcy) induced mitochondrial dysfunction.

Topics: Animals; Apoptosis; Autophagy; Brain; Cell Survival; Cells, Cultured; Curcumin; Cytoprotection; Endothelial Cells; Gene Expression Regulation; Homocysteine; Intracellular Space; Mice; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Models, Biological; Reactive Oxygen Species

Lung carcinoma is the leading cause of mortality due to cancer worldwide. Autophagy has a significant role in the development and progression of non‑small cell lung carcinoma (NSCLC). A previous study has revealed that tetrahydrocurcumin (THC), a traditional Chinese medicine isolated from Curcuma wenyujin (Chen & Ling, 1981), induces autophagy in human A549 NSCLC cells. The present study evaluated THC‑induced autophagy in A549 cells using various assays, including the Cell Counting Kit‑8, acridine orange staining, flow cytometry, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), and western blot analysis of the markers of autophagy. THC inhibited the growth and proliferation of A549 cells (P<0.05). Acridine orange staining and flow cytometry revealed that THC treatment significantly enhanced autophagic cell proliferation inhibition (P<0.05). The RT‑qPCR analysis revealed that THC treatment increased Beclin‑1 expression level and compared with the control group (P<0.05). The light chain 3 (LC3)‑II/LC3‑I ratio was reduced in THC‑treated cells when compared with the control group (P<0.05). Protein expression of various markers of autophagy, including p62, phosphorylated (p)‑mechanistic target of rapamycin (mTOR), phosphoinositide 3‑kinase (PI3K), p‑PI3K, protein kinase B (Akt), and p‑Akt was significantly reduced in THC‑treated cells (P<0.05). In conclusion, the present study revealed the underlying mechanisms associated with THC‑induced autophagy. A promising method of enhancing the therapeutic efficacy of THC against NSCLC cells may include inducing autophagy via inhibition of the PI3K/Akt/mTOR signaling pathway.

Topics: Autophagy; Beclin-1; Biomarkers; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Humans; Lung Neoplasms; Models, Biological; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Tetrahydrocurcumin (THC) is the principal metabolite of curcumin and has antioxidant properties. In the present investigation, the effect of THC on renal and cardiovascular outcomes was studied in rats with chronic kidney disease (CKD). CKD rats were randomized following 5/6 nephrectomy to a special diet for 9 weeks which contained 1% THC (CKD+THC group). Low-dose polyenylphosphatidylcholine was used as a lipid carrier to increase bioavailability. Endpoints included tail blood pressure, normalized heart weight, plasma and urine biochemical data, and kidney tissue analyses. CKD animals demonstrated increased proteinuria, decreased creatinine clearance, hypertension, and cardiac hypertrophy. The antioxidant proteins CuZn SOD and glutathione peroxidase were decreased in the remnant kidney, while apoptosis (caspase-3) and fibrosis (alpha-SM actin) were increased. Renal fibrosis was confirmed histologically on trichrome staining. These pathologic changes were ameliorated in the CKD+THC group with significant decrease in proteinuria, hypertension, and kidney fibrosis. THC therapy restored levels of CuZn SOD and glutathione peroxidase. Consistent with prior reports, dietary THC did not improve nuclear Nrf2 levels. In summary, dietary THC therapy improved expression of antioxidant proteins in the remnant kidney, decreased renal fibrosis and proteinuria, and ameliorated hypertension in 5/6 nephrectomized rats.

Topics: Animals; Antioxidants; Cardiomegaly; Curcumin; Disease Models, Animal; Female; Fibrosis; Kidney; Kidney Function Tests; Nephrectomy; Rats, Sprague-Dawley; Renal Insufficiency, Chronic

To evaluate the effects of tetrahydrocurcumin (THC) on the radiosensitivity of glioma cells and the possible molecular mechanism.. MTT assay, colony forming and wound healing assays were performed to detect the proliferation, radiosensitivity and migration of cells with various treatments. Cell apoptosis, cell cycle and GHS level were determined for exploring potent sensitization mechanism of THC. Meanwhile, protein expressions of cyclin D1 and PCNA were also measured. Furthermore, both orthotopic C6 mouse models and C6 subcutaneously grafted mouse models were established to test the tumour inhibitory effects of combined treatment in vivo.. Cells treated with combined THC and radiation demonstrated lower cell viability and higher apoptosis rate as compared to radiation group. Moreover, the intracellular GSH was also decreased in the THC co-treated C6 cells. More importantly, combinatorial treatment group significantly induced G0/G1 cell cycle arrest and a decrease in the S phase cell through the down-regulation of cyclin D1 and PCNA. The in-vivo therapeutic efficacy assay indicated that the growth of tumour was greatly inhibited in combinatorial group.. Tetrahydrocurcumin can synergistically enhance the radiosensitivity of glioma cells by inhibiting the expressions of cyclin D1 and PCNA.

Topics: Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Glioma; Glutathione; Humans; Mice; Radiation Tolerance; Rats; Wound Healing

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is latent but constitutively activated in many types of cancers. It is well known that STAT3 plays a key role in inflammation-associated tumorigenesis. Curcumin is an anti-inflammatory natural compound isolated from the turmeric (Curcuma longa L., Zingiberaceae) that has been extensively used in a traditional medicine over the centuries. In the present study, we have found that curcumin inhibits STAT3 signaling that is persistently overactivated in H-Ras transformed breast epithelial cells (H-Ras MCF10A). Specific cysteine residues present in STAT3 appear to be critical for the activity as well as conformation of this transcription factor. We identified the cysteine residue 259 of STAT3 as a putative site for curcumin binding. Site-directed mutation of this cysteine residue abolished curcumin-induced inactivation of STAT3 and apoptosis in H-Ras MCF10A cells. The α,β-unsaturated carbonyl moiety of curcumin appears to be essential in its binding to STAT3 in H-Ras MCF10A cells. Tetrahydrocurcumin that lacks such electrophilic moiety failed to interact with STAT3 and to induce apoptosis in the same cell line. Taken together, our findings suggest that curcumin can abrogate aberrant activation of STAT3 through direct interaction, thereby inhibiting STAT3-mediated mammary carcinogenesis.

Topics: Apoptosis; Cell Line, Transformed; Curcumin; Cysteine; Dimerization; DNA; Genes, ras; Humans; Mammary Glands, Human; STAT3 Transcription Factor; Sulfhydryl Compounds; Transcription, Genetic

Tetrahydrocurcumin (THC) is one of the major colourless metabolites of curcumin and shows even greater pharmacological and physiological benefits. The aim of this work was the manufacturing of porous scaffolds as a carrier of THC under physiological conditions. Fish-derived gelatin scaffolds were prepared by freeze-drying by two solutions concentrations (2.5% and 4% w/v), cross-linked via addition of lactose and heat-treated at 105 °C. This cross-linking reaction resulted in more water resistant scaffolds with a water uptake capacity higher than 800%. Along with the cross-linking reaction, the gelatin concentration affected the scaffold morphology, as observed by scanning electron microscopy images, by obtaining a reduced porosity but larger pores sizes when the initial gelatin concentration was increased. These morphological changes led to a scaffold's strength enhancement from 0.92 ± 0.22 MPa to 2.04 ± 0.18 MPa when gelatin concentration was increased. THC release slowed down when gelatin concentration increased from 2.5 to 4% w/v, showing a controlled profile within 96 h. Preliminary in vitro test with chondrocytes on scaffolds with 4% w/v gelatin offered higher metabolic activities and cell survival up to 14 days of incubation. Finally the addition of THC did not influence significantly the cytocompatibility and potential antibacterial properties were demonstrated successfully against Staphylococcus aureus.

Topics: Animals; Anti-Bacterial Agents; Cartilage; Curcumin; Drug Carriers; Fishes; Gelatin; Humans; Lactose; Mechanical Phenomena; Porosity; Pseudomonas aeruginosa; Regeneration; Staphylococcus aureus; Tissue Engineering; Water

Tetrahydrocurcumin (THC) also referred to as 'white curcumin', is a stable colorless hydrogenated product of curcumin with superior antioxidant and anti-inflammatory properties. The present study is an attempt to elevate the topical bioavailability of THC, post-incorporation into a nano-carrier system with its final dosage as a hydrogel. Lipid nanoparticles of THC (THC-SLNs) prepared by microemulsification technique were ellipsoidal in shape (revealed in transmission electron microscopy) with a mean particle size of 96.6 nm and zeta potential of -22 mV. Total drug content and entrapment efficiency of THC-SLNs was 94.51% ± 2.15% and 69.56% ± 1.35%, respectively. Differential scanning calorimetry and X-ray diffraction studies confirmed the formation of THC-SLNs. In vitro drug release studies showed the drug release from THC-SLNs gel to follow Higuchi's equation revealing a Fickian diffusion. Ex vivo permeation studies indicated a 17 times (approximately) higher skin permeation of THC-SLNs gel as compared with the free THC gel. Skin irritation, occlusion, and stability studies indicated the formulation to be nonirritating, and stable with a desired occlusivity. Pharmacodynamic evaluation in an excision wound mice model clearly revealed the enhanced anti-inflammatory activity of THC-SLNs gel and was further confirmed using biochemical and histopathological studies. It is noteworthy to report here that THC-SLNs gel showed significantly better (p ≤ 0.001) activity than free THC in gel. As inflammation is innate to all the skin disorders, the developed product opens up new therapeutic avenues for several skin diseases. To the best of our knowledge, this is the first paper elaborating the therapeutic usefulness of white curcumin-loaded lipidic nanoparticles for skin inflammation.

Topics: Administration, Cutaneous; Animals; Curcumin; Drug Delivery Systems; Male; Mice; Nanoparticles; Organ Culture Techniques; Skin Absorption; Swine; Treatment Outcome; Wound Healing

Elevated levels of free fatty acids (FFAs) in the liver, resulting from either increased lipolysis or imbalanced FFAs flux, is a key pathogenic factor of hepatic steatosis. This study was conducted to examine the therapeutic effect of tetrahydrocurcumin (THC), a naturally occurring curcuminoid and a metabolite of curcumin, on oleic acid (OA)-induced steatosis in human hepatocellular carcinoma cells and to elucidate the underlying mechanism. HepG2 cells were incubated with OA to induce steatosis, and then treated with various concentrations of THC. The results showed that THC treatment significantly decreased lipid accumulation in OA-treated HepG2 cells, possibly, by inhibiting the expression of the lipogenic proteins, sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, THC attenuated OA-induced hepatic lipogenesis in an adenosine monophosphate-activated protein kinase (AMPK)-dependent manner, which was reversed by pretreatment with an AMPK inhibitor. THC promoted lipolysis and upregulated the expression of genes involved in β-oxidation. Glucose uptake and insulin signaling impaired in HepG2 cells incubated with OA were abated by THC treatment, including phosphorylation of the insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt and downstream signaling pathways, forkhead box protein O1 (FOXO1) and glycogen synthase kinase 3 β (GSK3β), which are involved in gluconeogenesis and glycogen synthesis, respectively. Altogether, these results demonstrated the novel therapeutic benefit of THC against hepatic steatosis and, consequently, a potential treatment for non-alcoholic fatty liver disease (NAFLD).

Topics: Curcumin; Fatty Acid-Binding Proteins; Fatty Acids, Nonesterified; Fatty Liver; Glucose; Hep G2 Cells; Humans; Insulin Resistance; Lipogenesis; Oleic Acid; PPAR alpha; Sterol Regulatory Element Binding Protein 1

A simple composite electrospun nanofiber of cellulose acetate phthalate (CAP)-polyethylene glycol (PEG) loaded with tetrahydrocurcumin (THC) was developed in this study, and the in vitro diffusion of THC was evaluated. The nanofibers were characterized by scanning electron microscopy, powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR), and differential scanning calorimetry (DSC). The formulated nanofiber (NF) with THC has smooth morphology with diameter of around 300-500 nm. The complete entrapment and dispersion of THC was observed from the results of PXRD and DSC due to the loss of THC crystalline property. Further, FT-IR demonstrated that the vibration bands for the polymers used were dominant over the THC, and the vibrational bands of THC were not observed from the final formulation. The drug entrapment by the final CAP + PEG NF was found to be 95.5% with the high swelling index. From the in vitro release study, it was found that the formulated THC-loaded CAP + PEG NF has followed anomalous mechanism, demonstrating both diffusion and swelling controlled modes. The drug release extended up to 12 h with a final cumulative release of 94.24%.

Topics: Calorimetry, Differential Scanning; Cellulose; Curcumin; Drug Liberation; Microscopy, Electron, Scanning; Nanofibers; Polyethylene Glycols; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction

Curcumin (Cur), derived from Curcuma species, exhibits anti-inflammatory, antioxidant, and anticancer effects. Although Cur has some beneficial effects on asthma, its clinical application is limited by its low bioavailability. Tetrahydrocurcumin (THC), the major active metabolite of Cur, has multiple biological functions, similarly to Cur, and importantly, it showed enhanced bioavailability in tissues and plasma. However, the effect of THC on asthma has not been reported.. The current study sought to investigate the efficacy of dietary THC on allergic asthma compared to that of Cur in an animal model.. The anti-inflammatory effects of Cur and THC were evaluated in an ovalbumin-induced asthmatic mouse model. The nasal symptoms, pathological alterations of the lung tissues, oxidants and antioxidants, cytokine production, T cell subsets, and Th2-related signalling pathway activity were assessed.. Both THC and Cur had beneficial effects on asthmatic mice with regard to nasal symptoms, pathological changes (eosinophils and mucus hyper-production), oxidative stress (malondialdehyde), cytokine production (IL-13), Th17 and cytotoxic T cell subsets, and Th2 signalling pathway (IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2-Notch1/Notch2 axis) activity. THC was more effective than Cur in suppressing tissue eosinophilia, mucus production, and IL-4Rα/Jak1/STAT6 pathway activity. Furthermore, only THC inhibited peripheral eosinophil levels, Th2 cytokines (IL-4 and IL-5), and Th2 cell subsets and enhanced an antioxidant enzyme (glutathione).. The above results demonstrated for the first time that THC was superior to Cur in modulating allergic asthmatic phenotypes, especially attenuating the Th2 response. THC might be a potentially effective agent for asthma treatment.

Topics: Allergens; Animals; Asthma; Biomarkers; Curcumin; Cytokines; Disease Models, Animal; Female; Inflammation Mediators; Jagged-1 Protein; Jagged-2 Protein; Janus Kinase 1; Leukocytes; Mice; Oxidative Stress; Receptor, Notch1; Receptor, Notch2; Receptors, Cell Surface; Signal Transduction; STAT6 Transcription Factor; Th2 Cells

The potential protective effect of tricetinidin as novel antioxidant is investigated and compared with selected known antioxidant substances in vitro. Dihydroethidium staining was performed to detect intracellular ROS formation and the protective effect of the antioxidant substances in combination with the superoxide-inducer antimycin a (AMA). Glutathione level, mitochondrial membrane potential and HO-1 expression were analysed for further characterization of the cellular response. The cytokinesis block micronucleus test was applied to investigate the anti-genotoxic effect of the substances against insulin induced genomic damage. AMA treatment caused a significant increase in intracellular ROS formation and insulin treatment induced a significant micronucleus induction in NRK cells. Combination of the antioxidant substances with AMA or insulin protected from the oxidative stress and the micronucleus-induction. All analysed antioxidants showed comparable effects on GSH production and mitochondrial membrane potential. Only delphinidin and tricetinidin caused an increase in HO-1 expression. Tricetinidin and delphinidin might be good candidates for development as an antioxidant supplement. Further research is necessary to show possible therapeutic and preventive effects of tricetinidin and delphinidin in vivo.

Topics: Animals; Anthocyanins; Antioxidants; Cell Line; Curcumin; Epithelial Cells; Gene Expression Regulation, Enzymologic; Glutathione; Heme Oxygenase-1; Kidney; Membrane Potential, Mitochondrial; Micronucleus Tests; Oxidative Stress; Rats

The transplantation of isolated pancreatic islets is a promising treatment for diabetes. Curcumin has been used for its pharmacologic effects, such as antidiabetic and anti-inflammatory activities. Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, has been reported to have antioxidant and anti-inflammatory activities. This study examines the hypothesis that preoperative THC treatment can attenuate ischemic damage and apoptosis before islet transplantation.. Islets isolated from Balb/c mice were randomly divided into 2 groups and cultured in medium supplemented with or without THC. In vitro islet viability and function were assessed. After treatment with a cytokine cocktail consisting of tumor necrosis factor-α, interferon-β, and interleukin-1β, islet cell viability, function, and apoptotic status were determined. Proteins related to apoptosis were analyzed using INS-1 cell after streptozocin treatment.. There was no difference in cell viability between the 2 groups. Islets cultured in the medium supplemented with THC showed 1.3-fold higher glucose-induced insulin secretion than the islets cultured in the medium without THC. After treatment with a cytokine cocktail, glucose-induced insulin release, and NO of the islets were significantly improved in THC-treated islets compared with islets not treated with THC. Apoptosis was significantly decreased, and B-cell lymphoma-2 was elevated in the THC-treated group. The streptozocin-treated INS-1 cell produced significantly higher levels of and B-cell lymphoma-2-associated X protein, caspase-3, and caspase-9 than INS-1 treated with THC.. These results suggest that preoperative THC administration enhances islet function before transplantation and attenuates the cytokine-induced damage associated with apoptosis.

Topics: Animals; Antioxidants; Apoptosis; Curcumin; Cytokines; Ischemia; Islets of Langerhans; Islets of Langerhans Transplantation; Mice; Mice, Inbred BALB C

Calcineurin inhibitors are effective immunosuppressive agents, but associated adverse effects such as nephrotoxicity may limit efficacy. Tacrolimus (FK506) is an immunosuppressive drug used mainly to lower the risk of organ rejection after allogeneic organ transplant. Adverse effects of FK-506 can prompt patients to end treatment despite the efficacy. In the present study, we investigated the protective effect and mechanism of tetrahydrocurcumin (THC) on FK506-induced renal damage, apoptosis, and oxidative stress to evaluate its possible use for kidney protection.. The effect of THC on FK506-induced kidney cell damage was investigated in LLC-PK1 cells. LLC-PK1 cells were pretreated with THC at concentrations of dose for 2 hours followed by addition of FK506 for 24 hours. LLC-PK1 cells were treated with FK506 and THC, and cell viability and glutathione was measured. The number of apoptotic cells was measured using an annexin V/propidium iodide staining with flow cytometry. The effect of apoptosis by THC in LLC-PK1 cells was determined by measuring the caspase-9, caspase-3, B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein levels using Western blotting analyses.. FK506-induced LLC-PK1 renal cell damage was markedly ameliorated by THC treatment. THC protected LLC-PK1 cells by preventing FK506-induced glutathione decrease. THC protects against FK506-induced apoptosis in LLC-PK1 cells. Apoptosis was significantly decreased, and Bcl-2 was elevated in the THC-treated group. Bcl-2-associated X protein, caspase-3, and caspase-9 were decreased in the THC-treated group.. These results collectively provide therapeutic evidence that THC ameliorates the FK506-induced renal damage via antioxidant effect and apoptosis inhibition.

Topics: Animals; Antioxidants; Apoptosis; Cell Survival; Curcumin; Immunosuppressive Agents; Kidney; LLC-PK1 Cells; Oxidative Stress; Swine; Tacrolimus

Diet-induced obesity is strongly associated with nonalcoholic fatty-liver disease (NAFLD) and insulin resistance. We aimed to investigate the in vivo therapeutic value of tetrahydrocurcumin (THC) intervention in high-fat-diet (HFD)-induced obesity and hepatic steatosis. C57BL/6 mice were fed an HFD for 10 weeks, and then they received 20 or 100 mg/kg THC along with the HFD for another 10 weeks. Mice fed an HFD for 20 weeks experienced obesity, hepatic steatosis, hyperlipidemia, and insulin resistance. Tetrahydrocurcumin (THC) intervention for 10 weeks significantly reduced adiposity (epididymal-fat weights of 6.6 ± 0.4 g for the HFD-only group and 5.3 ± 0.8 and 5.6 ± 0.7 g for the HFD with 20 mg/kg THC and HFD with 100 mg/kg THC groups, respectively; p < 0.05) via downregulation of adipogenic factors. Inflammatory macrophage infiltration and polarization were decreased by THC in mouse epididymal adipose tissues. In the liver, THC markedly alleviated steatosis by approximately 28-37% ( p < 0.05) via the downregulation of lipogenesis, the activation of AMP-activated protein kinase (AMPK), and the increase of fatty acid oxidation. Elevated blood glucose and insulin resistance were also improved by THC, which might be caused by regulation of the hepatic insulin signaling cascade, gene transcription involved in glucose metabolism, and reduced macrophage infiltration in the liver and adipose tissue. Our results demonstrated the beneficial effects of THC-mediated intervention against obesity and NAFLD as well as other metabolic syndromes, revealing a novel therapeutic use of THC in obese populations.

Topics: Adipose Tissue; Adiposity; Animals; Curcumin; Diet, High-Fat; Glucose; Humans; Insulin; Lipid Metabolism; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity

Curcumin (CUR), a widely used food additive, is derived mainly from Curcuma species that has been applied traditionally for the treatment of various diseases, including hepatocellular carcinoma (HCC). However, its poor systemic bioavailability hampers its clinical application, which may be related to its wide metabolism. Tetrahydrocurcumin (THC) is a major metabolite of CUR and has been reported to have multiple biologic activities. We investigated, for the first time, the efficacy and associated mechanism of action of THC and CUR in a H22 ascites tumor-bearing model in mice. THC evoked a significant dose-dependent promotion of survival and was significantly more effective than CUR in inhibiting tumor growth, including increased body weight, abdominal circumference, ascites volume, and the viability of cancer cells. Experiments on essential immune organs indicated that THC had a more favorable margin of safety than the reference drug cyclophosphamide. THC induced the apoptosis of H22 cells obviously by increasing the level of p53 and decreasing the level of murine double minute 2. THC also decreased the expression of Bcl-2 significantly and increased the expression of Bcl2-associated X, resulting in the release of cytochrome C. THC significantly activated and induced cleavage of caspase-3 and caspase-9 to induce the apoptosis of H22 cells. Taken together, these results indicate that THC was more effective than CUR in inhibiting the apoptosis of H22-induced ascites tumor cells and achieved it via regulation of a mitochondrial apoptosis pathway. THC might be a bioactive anti-tumor form of CUR and represented a potentially effective agent for HCC treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Ascites; Cell Line, Tumor; Curcumin; Cytochromes c; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Mice; Mitochondria

The protective effect of tetrahydrocurcumin (THC) after experimental traumatic brain injury (TBI) has been demonstrated, as demonstrated by the inhibition of oxidative stress, mitochondrial dysfunction, and apoptosis. However, the mechanisms underlying this effect are still not well understood. This study was to investigate the neuroprotective effects of THC, and its potential mechanisms, in a rat model of TBI. To this end, rats were divided into 4 groups: the sham group, the TBI group, the TBI + vehicle (V) group, and the TBI + THC group. THC or V was administered via intraperitoneal injection to rats in the TBI + V and TBI + THC groups 30 min after TBI. After euthanasia (24 h after TBI), neurological scores, brain water content, and neuronal cell death in the cerebral cortex were recorded. Brain samples were collected after neurological scoring for further analysis. THC treatment alleviated brain edema, attenuated TBI-induced neuronal cell apoptosis, and improved neurobehavioral function. In addition, NFE2-related factor 2 (Nrf2) expression was upregulated following TBI. These results suggest that THC improves neurological outcome after TBI, possibly by activating the Nrf2 signaling pathway.

Topics: Animals; Brain Injuries, Traumatic; Curcumin; Male; Neuroprotective Agents; NF-E2-Related Factor 2; Rats; Rats, Sprague-Dawley; Signal Transduction

Curcumin as a natural product has drawn considerable attention in recent years for its multiple pharmacological activities against various diseases, but more studies are required to understand the curcumin pharmacological action considering its low bioavailability. Though numerous reasons contribute to the low bioavailability of curcumin, one of the important reasons is associated with biotransformation of curcumin through either conjugation or reduction depending on curcumin administration route. The orally administered curcumin (CUR) is metabolised into curcumin glucuronidase (CUR-GLR) and curcumin sulphate by conjugation, whereas dihydroxycurcumin, tetrahydrocurcumin, and hexahydrocurcumin (HHC) are formed by reduction after intraperitoneal administration of curcumin. The main aim of the current study was to investigate the pharmacological properties of curcumin and its biotransformed molecules and its inhibitory potential against CagA (cytotoxic-associated gene A) oncoprotein of Helicobacter pylori. All lead molecules followed the Lipinski's five rules for biological activities, except CUR-GLR, whereas druglikeness scores were obtained for all molecules. Subsequently, molecular docking was employed to analyse the binding affinity of molecules with CagA. The docking studies revealed that CUR-GLR has highest binding affinity with CagA, whereas less interactive affinity was observed in HHC. From the virtual screening and docking studies, the current study suggests that the biotransformation of curcumin through conjugation has more potential for inhibition of oncogenic activities of CagA+ H. pylori than reduction.

Topics: Biotransformation; Curcumin; Helicobacter pylori; Molecular Docking Simulation

In the present work, protective effect of tetrahydrocurcumin (THC) against oxidative damages in cadmium (Cd)-induced toxicity in rats was evaluated. Cd is an important environmental and industrial toxicant that affects almost all the organs, especially liver. Liver is the major organ responsible for the metabolism and the primary target for many toxic chemicals and drugs. Effect of THC, the curcumin-derived polyphenolic compound on Cd-induced oxidative stress and hepatic damage was evaluated using male albino Wistar rats. In Cd-administered rats (5 mg/kg body weight (b.w.), orally for 4 weeks), activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma glutamyl transferase (GGT) were significantly increased in serum with the elevated level of bilirubin. Red blood cells (RBC), haemoglobin contents and haematocrit values were also significantly decreased in Cd-treated rats. In addition, the levels of lipid peroxidation markers like thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LHP), protein carbonyl contents (PCC) and conjugated dienes (CD) were significantly increased followed by the significant decrease in the levels of reduced glutathione (GSH), total sulphydryl groups (TSH), ascorbic acid (vitamin C) and vitamin E in liver of Cd-administered rats. Oral administration of THC (20, 40 and 80 mg/kg b.w.) followed by Cd for 4 weeks showed a significant restoration of the above changes to near normal. Histopathological changes observed in Cd intoxicated hepatic tissues were minimized on treatment with THC. This study suggests that THC at the dose of 80 mg/kg b.w. effectively subdues the Cd-induced toxicity and controls the free radical-induced liver damage in rats.

Topics: Animals; Cadmium; Cadmium Poisoning; Curcumin; Liver; Male; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Wistar

Tetrahydrocurcumin (THC) demonstrated an anti-cancer and anti-angiogenic effects in cervical cancer. Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, have also shown anticancer effect. However, the combinational treatment effect of THC and celecoxib on tumor growth and tumor angiogenesis, especially, using cervical cancer (CaSki)-implanted nude mice has yet not been reported.. To evaluate the combinational treatment effect of THC and celecoxib on tumor progression and tumor angiogenesis in cervical cancer (CaSki)-implanted nude mice.. CaSki cells were inoculated in mice to establish subcutaneous tumors. One month after inoculation, vehicle, THC100 mg/kg, Celecoxib100 mg/kg, or THC50 + Celecoxib50 mg/kg was orally administered every day for 28 consecutive days. The tumor volume was measured every 3-4 days. The microvascular density (MVD) was evaluated using the CD31 expression. VEGF, COX-2, and EGFR expression were also detected by immunohistochemistry.. THC, celecoxib, and the combination treatments statistically retarded the tumor volume by 70.40, 65.11 and 77.04%, respectively. The MVD was significantly increased in CaSki + vehicle group, but THC, celecoxib, and the combination treatments markedly attenuated the MVD. VEGF, COX-2, and EGFR were up-regulated in CaSki + vehicle group; however, they were attenuated by THC, celecoxib, and the combination treatments.. The combinational treatment effect of THC and celecoxib causing inhibition of tumor growth and tumor\ angiogenesis via down-regulation of VEGF, COX-2 and EGFR expression. However, this combined treatment did not show the synergistic effect on inhibiting the tumor growth and tumor angiogenesis in cervical cancer (CaSki)-implanted nude mice model.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Celecoxib; Combined Modality Therapy; Curcumin; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Female; Mice; Mice, Nude; Neovascularization, Pathologic; Sulfonamides; Uterine Cervical Neoplasms

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.

Topics: Animals; Apoptosis; Cell Line, Tumor; Curcumin; Cyclooxygenase 2; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Humans; Ki-67 Antigen; MAP Kinase Signaling System; Mice; Proto-Oncogene Proteins c-akt; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays

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.

Topics: Antineoplastic Agents; Chromatography, High Pressure Liquid; Curcumin; Humans; Limit of Detection; Plasma; Reproducibility of Results; Tandem Mass Spectrometry

Curcumin (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.. Following 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.. Following 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.. These 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.

Topics: Administration, Oral; Animals; Biological Availability; Caco-2 Cells; Chromatography, High Pressure Liquid; Curcumin; Humans; Intestinal Mucosa; Lactic Acid; Male; Micelles; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats, Sprague-Dawley; Solubility

Excessive iron can generate reactive oxygen species (ROS), leading to oxidative stress that is closely associated with cardiovascular dysfunction. Iron overload was induced in male ICR mice by injection of iron sucrose (10mg/kg/day) for eight weeks. Iron overload was evidenced by increased serum iron indices. The mice developed increased blood pressure, impaired vascular function and blunted response of the autonomic nervous system. These effects were accompanied by increased malondialdehyde levels in various tissues, increased nitric oxide metabolites in plasma and urine, and decreased blood glutathione. Tetrahydrocurcumin (THU, 50mg/kg/day), deferiprone (or L1, 50mg/kg/day) or both was orally administered throughout the period of iron sucrose injection. The treatments significantly alleviated the deleterious cardiovascular effects of iron overload, and were associated with modulation of nitric oxide levels. An imbalance between endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) expression in response to iron overload was normalized by THU, L1 or the combination treatment. Moreover, the treatment decreased the upregulated expression levels of gp91

Topics: Administration, Oral; Animals; Baroreflex; Curcumin; Deferiprone; Disease Models, Animal; Drug Therapy, Combination; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hypertension; Iron Chelating Agents; Iron Overload; Male; Mice; Mice, Inbred ICR; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Pyridones

The aim of the present study was to assess the neuroprotective effects of tetrahydrocurcumin (THC) in a mouse model of cerebral ischemia/reperfusion (I/R) injury, and to investigate the involvement of Golgi reassembly and stacking protein 65 (GRASP65) and the extracellular signal‑regulated kinase (ERK) signaling pathway. Cerebral I/R injury was induced using the Pulsinelli four‑vessel occlusion method. After 5 min of reperfusion, mice received THC (5, 10 or 25 mg/kg) or saline by intraperitoneal injection. After 24 h of reperfusion, mice underwent neurological evaluation. Infarct volumes were determined by triphenyltetrazolium chloride staining, and levels of superoxide dismutase and malondialdehyde were measured in brain tissue homogenates. Expression of GRASP65, phosphorylated‑GRASP65, ERK and phosphorylated‑ERK was determined by western blotting. THC induced a dose‑dependent decrease in the phosphorylation of ERK and GRASP65. Thus, THC attenuated I/R injury‑induced activation of the ERK signaling pathway and reduced the phosphorylation of GRASP65. THC exhibited a dose‑dependent protective effect against cerebral I/R injury, mediated by suppression of the ERK signaling pathway and a subsequent reduction in GRASP65 phosphorylation. The current study provided new information in the research of the cerebral ischemia‑reperfusion injury mechanism.

Topics: Animals; Apoptosis; Brain Infarction; Brain Ischemia; Carrier Proteins; Curcumin; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Intracellular Signaling Peptides and Proteins; Male; Malondialdehyde; Membrane Proteins; Mice; Neurons; Neuroprotective Agents; Reperfusion Injury; Signal Transduction; Superoxide Dismutase

Tetrahydrocurcumin provides neuroprotection in multiple neurologic disorders by modulating oxidative stress, inflammatory responses, and autophagy. However, in traumatic brain injury (TBI), it is unclear whether a beneficial effect of tetrahydrocurcumin exists. In this study, we hypothesized that administration of tetrahydrocurcumin provides neuroprotection in a rat model of TBI.. Behavioral studies were performed by recording and analyzing beam-walking scores. The role of tetrahydrocurcumin on neurons death was assessed via Nissl staining. We then performed Western blot analyses, terminal deoxynucleotidyl transferase 2'-deoxyuridine-5'-triphosphate (dUTP) nick end labeling assays and immunofluorescence staining to evaluate autophagy and apoptosis. Phospho-protein kinase B (p-AKT) was also assessed via Western blotting.. Our data indicated that administration of tetrahydrocurcumin alleviated brain edema, attenuated TBI-induced neuron cell death, decreased the degree of apoptosis and improved neurobehavioral function, which were accompanied by enhanced autophagy and phospho-AKT after TBI. Moreover, the autophagy inhibitor 3-methyladenine and the PI3K kinase inhibitor LY294002 partially reversed the neuroprotection of tetrahydrocurcumin after TBI.. This study indicates that tetrahydrocurcumin protects neurons from TBI-induced apoptotic neuronal death, which may be through modulation autophagy and PI3K/AKT pathways. Thus, tetrahydrocurcumin may be an attractive therapeutic agent for TBI.

Topics: Animals; Apoptosis; Autophagy; Biomarkers; Blotting, Western; Brain Injuries, Traumatic; Curcumin; Fluorescent Antibody Technique; In Situ Nick-End Labeling; Male; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome

The aim of the present study was to investigate and compare the anti‑inflammatory activities of curcumin and its three metabolites, tetrahydrocurcumin, hexahydrocurcumin and octahydrocurcumin in lipopolysaccharide (LPS)‑stimulated RAW 264.7 macrophage cells. The results demonstrated that overproduction of nitric oxide (NO) was potently inhibited following treatment with curcumin and its three metabolites. In addition, curcumin and tetrahydrocurcumin significantly inhibited the release of prominent cytokines, including tumor necrosis factor‑α (TNF‑α) and interleukin‑6 (IL‑6); however, hexahydrocurcumin and octahydrocurcumin did not significantly alter cytokine release. Furthermore, the present study investigated the effect of curcumin and its metabolites on the expression of inducible NO synthase (iNOS), cyclooxygenase‑2 (COX‑2) and activated‑nuclear factor kappa B (NF‑κB); the results showed that curcumin and its three metabolites significantly inhibited LPS‑mediated upregulation of iNOS and COX‑2 as well as NF‑κB activation. However, curcumin exerted a more potent effect on LPS‑stimulated RAW 264.7 cells compared to that of its three metabolites, of which tetrahydrocurcuim was found to be the most pharmacologically active. In conclusion, the results of the present study demonstrated that curcumin and its major metabolites inhibited the LPS‑induced inflammatory response via the mechanism of inhibiting NF‑κB translocation to the nucleus.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cell Survival; Curcumin; Cyclooxygenase 2; Cytokines; Lipopolysaccharides; Macrophages; Male; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Protein Transport; Proteolysis; Rats

The adverse effects of anticancer drugs can prompt patients to end their treatment despite the efficacy. Cisplatin is a platinum-based molecule widely used to treat various forms of cancer, but frequent and long-term use of cisplatin is limited due to severe nephrotoxicity. In the present study, we investigated the protective effect and mechanism of tetrahydrocurcumin on cisplatin-induced kidney damage, oxidative stress, and inflammation to evaluate its possible use in renal damage. Cisplatin-induced LLC-PK1 renal cell damage was significantly reduced by tetrahydrocurcumin treatment. Additionally, the protective effect of tetrahydrocurcumin on cisplatin-induced oxidative renal damage was investigated in rats. Tetrahydrocurcumin was orally administered every day at a dose of 80 mg/kg body weight for ten days, and a single dose of cisplatin was administered intraperitoneally (7.5 mg/kg body weight) in 0.9 % saline on day four. The creatinine clearance levels, which were markers of renal dysfunction, in cisplatin-treated rats were recovered nearly back to normal levels after administration of tetrahydrocurcumin. Moreover, tetrahydrocurcumin exhibited protective effects against cisplatin-induced oxidative renal damage in rats by inhibiting cyclooxygenase-2 and caspase-3 activation. These results collectively provide therapeutic evidence that tetrahydrocurcumin ameliorates renal damage by regulating inflammation and apoptosis.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Biomarkers; Caspase 3; Cisplatin; Curcuma; Curcumin; Cyclooxygenase 2; In Vitro Techniques; Kidney; Kidney Diseases; LLC-PK1 Cells; Male; Oxidative Stress; Phytotherapy; Plant Extracts; Rats, Wistar; Swine

Tetrahydrocurcumin (THC), one of the important in vivo metabolites of curcumin, inhibits tumor angiogenesis. Its effects on angiogenesis in cervical cancer- (CaSki-) implanted nude mice and its mechanisms on hypoxia-inducible factor-1α and vascular endothelial growth factor expression were investigated. Female BALB/c nude mice were divided into control (CON) and CaSki-implanted groups (CaSki group). One month after the injection with cervical cancer cells, mice were orally administered vehicle or 100, 300, and 500 mg/kg of THC daily for 30 consecutive days. The microvascular density (MVD) was evaluated using the CD31 expression. VEGF, VEGFR-2, and HIF-1α expression were also detected by immunohistochemistry. The MVD in CaSki + vehicle group was significantly increased compared to the CON + vehicle group. Interestingly, when treated with THC at all doses, the CaSki group showed a significant smaller number of the MVD. The CaSki + vehicle group also showed significantly increased VEGF, VEGFR-2, and HIF-1α expressions, but they were downregulated when mice were treated with THC at all doses. THC demonstrated an inhibitory effect against tumor angiogenesis in CaSki-implanted nude mice model. This effect is likely to be mediated by the downregulation of HIF-1-α, VEGF expression, and its receptor. THC could be developed into a promising agent for cancer therapy in the future.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Curcumin; Down-Regulation; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

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 (5 mg kg(-1) bw/day) with THC (80 mg kg(-1) bw/day) for 28 days. 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, Ca(2+)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.

Topics: Alanine Transaminase; Animals; Antioxidants; Arsenic; Arsenic Poisoning; Aspartate Aminotransferases; Catalase; Chemical and Drug Induced Liver Injury; Curcumin; Dyslipidemias; Glutathione; Glutathione Peroxidase; Liver; Male; Mitochondria; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Cytochrome P450 (CYP), a superfamily of hepatic monooxygenase enzymes, catalyzes biotransformation of endogenous compounds and xenobiotics. Modification of CYPs associated with metabolic diseases and continuous consumption of diet with excessive energy levels. Tetrahydrocurcumin (THC) exhibited beneficial effects in metabolic syndromes such as diabetic mellitus and dyslipidemia. The present study aimed to investigate the effects of THC and vitamin E (vitE) on the expression profiles of CYPs in the livers of mice fed with the high fat and high fructose diet. In addition to ad libitum access to commercial regular diet, the high fat and high fructose diet (HFD) group of adult male ICR mice was administered a HFD, which consisted of intragastric administration of hydrogenated soybean oil (1mL/day) and the addition of 20% fructose to the drinking water for 8weeks. During the induction period, subgroups of mice (n=5) were daily intragastrically administered with THC (100 or 200mg/kg/day) or vitE (100mg/kg/day). The expressions of CYP mRNA and protein were quantified using real-time PCR and the levels of these proteins were quantified using immunoblotting. Continuous consuming of high fat and high fructose for 8weeks significantly increased the expressions of Cyp1a1, Cyp1a2, Cyp1b1, Cyp2c29, and Cyp3a11 while THC ultimately normalized these CYPs profiles. In the control mice, most of the investigated CYPs was unchanged by THC, with the exception that the Cyp1a1, Cyp2b9, and Cyp3a11 proteins were elevated. These findings provided additional important information on the effects of THC on diet induced-metabolic dysfunctions. However, drug interactions due to the use of THC as an alternative supplement are of concern, particularly in the combinations that include a drug that is a substrate of Cyp1a1, Cyp2b9, and Cyp3a11.

Topics: Animals; Curcumin; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1B1; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diet, High-Fat; Fructose; Gene Expression Regulation, Enzymologic; Herb-Drug Interactions; Inactivation, Metabolic; Liver; Male; Membrane Proteins; Mice, Inbred ICR

Hyperalgesia, allodynia, delayed motor nerve conduction velocity, oxidative stress and axonal damage are signs and symptoms of chemotherapy induced peripheral neuropathy (CIPN). Present treatment/preventive strategies of CIPN are futile and the neuropathy may even lead to discontinuation of chemotherapy. In this study, we evaluated the protective effect of tetrahydrocurcumin (THC) 40 and 80mg/kg in experimental vincristine induced neuropathy in rats. Hyperalgesia was assessed by hot plate (thermal), Randall-Selitto (mechanical) test, allodynia was assessed by cold plate (thermal) test, functional loss was measured by sciatic function index, nociception was evaluated by formalin test. Neurophysiological recordings were carried out to assess motor nerve conduction velocity. Total calcium levels, oxidative stress and TNF-α was measured in sciatic nerve tissue homogenate to assess neuropathy. Histopathological changes was observed on sciatic nerve to assess the protective effect of THC against the vincristine. Pregabalin was used as a standard in this study. Rats administered with THC at 80mg/kg significantly attenuated the vincristine induced neuropathic pain manifestations which may be due to its multiple actions including anti-nociceptive, anti-inflammatory, neuroprotective, calcium inhibitory and antioxidant effect. This study delineates that THC can be a promising candidate for the prevention of CIPN by chemotherapeutic agents.

Topics: Animals; Behavior, Animal; Calcium; Catalase; Cold Temperature; Curcumin; Glutathione; Hot Temperature; Lipid Peroxidation; Male; Neuralgia; Nitric Oxide; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Sciatic Nerve; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Vincristine

Wound healing represents a dynamic set of coordinated physiological processes observed in response to tissue injury. Several natural products are known to accelerate the process of wound healing. Tetrahydrocurcumin (THC), an in vivo biotransformed product/metabolite of curcumin, is known to exhibit a wide spectrum of biological activities similar to those of native curcuminoids. The poor bioavailability of these curcuminoids limits their clinical applications. The present study highlights the percutaneous absorption and wound healing activity of glucosyl-conjugated THC (glucosyl-THC) in male Wistar rats. A high plasma concentration of glucosyl-THC (4.35 μg/mL) was found in rats 3 hours after application. A significant enhanced wound healing activity and reduced epithelialization time were observed in rats that received glucosyl-THC. This may have been due to the improved bioavailability of the glucosyl compound. The nonstaining and lack of skin-sensitive side effects render the bioconjugated glucosyl-THC a promising therapeutic compound in the management of excision wounds and in cosmetic applications, in the near future.

Topics: Animals; Biological Availability; Curcumin; Glycosylation; Male; Rats; Rats, Wistar; Skin Absorption; Wound Healing

A liquid chromatographic method was developed for the simultaneous separation of curcumin, β-arteether, tetrahydrocurcumin and dihydroartemisinin based on the design of experiments and the design space methodology. The influence of the percentage of organic modifier, flow rate of the mobile phase and column temperature on the analytes separation was investigated. The optimal chromatographic separation was achieved on a C18 column (125mm×4mm, 5μm) using an isocratic elution with a mobile phase consisting of methanol-ammonium acetate (pH 4; 10mM) (80:20, v/v) at a flow rate of 0.45ml/min and a column temperature of 32.5°C. This method was then validated for simultaneous quantification of curcumin and β-arteether contained in lipid-based formulations taking into account the β-expectation tolerance interval for the total error measurement. Finally, the suitability of the proposed liquid chromatographic method for routine analysis of curcumin and β-arteether loaded in lipid-based formulations has been proven.

Topics: Acetates; Algorithms; Antimalarials; Artemisinins; Calibration; Chemistry Techniques, Analytical; Chemistry, Pharmaceutical; Chromatography, Liquid; Curcumin; Hydrogen-Ion Concentration; Limit of Detection; Lipids; Methanol; Reproducibility of Results; Temperature

Curcumin (CUR) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. In recent years, it has been reported that CUR exhibits significant anti-tumor activity in vivo. However, the pharmacokinetic features of CUR have indicated poor oral bioavailability, which may be related to its extensive metabolism. The CUR metabolites might be responsible for the antitumor pharmacological effects in vivo. Tetrahydrocurcumin (THC) is one of the major metabolites of CUR. In the present study, we examined the efficacy and associated mechanism of action of THC in human breast cancer MCF-7 cells for the first time. Here, THC exhibited significant cell growth inhibition by inducing MCF-7 cells to undergo mitochondrial apoptosis and G2/M arrest. Moreover, co-treatment of MCF-7 cells with THC and p38 MAPK inhibitor, SB203580, effectively reversed the dissipation in mitochondrial membrane potential (Δψm), and blocked THC-mediated Bax up-regulation, Bcl-2 down-regulation, caspase-3 activation as well as p21 up-regulation, suggesting p38 MAPK might mediate THC-induced apoptosis and G2/M arrest. Taken together, these results indicate THC might be an active antitumor form of CUR in vivo, and it might be selected as a potentially effective agent for treatment of human breast cancer.

Topics: Apoptosis; Breast Neoplasms; Cell Division; Curcumin; Enzyme Activation; G2 Phase; Humans; MCF-7 Cells; p38 Mitogen-Activated Protein Kinases

We have previously shown that curcumin (CUR) may increase lipid accumulation in cultured human acute monocytic leukaemia cell line THP-1 monocytes/macrophages, but that tetrahydrocurcumin (THC), an in vivo metabolite of CUR, has no such effect. In the present study, we hypothesised that the different cellular uptake and/or metabolism of CUR and THC might be a possible explanation for the previously observed differences in their effects on lipid accumulation in THP-1 monocytes/macrophages. Chromatography with tandem MS revealed that CUR was readily taken up by THP-1 monocytes/macrophages and slowly metabolised to hexahydrocurcumin sulphate. By contrast, the uptake of THC was low. In parallel with CUR uptake, increased lipid uptake was observed in THP-1 macrophages but not with the uptake of THC or another CUR metabolite and structurally related compounds. From these results, it is possible to deduce that CUR and THC are taken up and metabolised differently in THP-1 cells, which determine their biological activity. The remarkable differential cellular uptake of CUR, relative to THC and other similar molecules, may imply that the CUR uptake into cells may occur via a transporter.

Topics: Biological Transport; Carcinogens; Cell Differentiation; Cell Line; Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Glucuronides; Humans; Kinetics; Lipid Metabolism; Macrophages; Monocytes; Sulfates; Tandem Mass Spectrometry; Tetradecanoylphorbol Acetate

Several curcumin derivatives are now becoming increasingly of interest because of their bioactive attributes, especially their action as antioxidants and anti-carcinogenic activities. Tetrahydrocurcumin (THC), an active metabolite of curcumin, was selected to be a proper starting material for the work presented here as it is stable in physiological pH and has the typical pharmacological properties of curcumin. We have now reported that novel synthesized water-soluble polymeric macromolecule prodrugs can specifically deliver the drug to the colon. To study the drug loading and drug release, THC was conjugated with a hydrophilic polymer, carboxymethylcellulose (CMC) with the degree of substitution (DS) values of 0.7 and 1.2. THC was also attached to two different spacers including p-aminobenzoic acid (PABA) and p-aminohippuric acid (PAH) via an azo bond that was cleaved by the azoreductase activities of colonic bacteria. The novel active molecule, 4-amino-THC, was readily released from the conjugates in the colon (>62% within 24h) with only very small amounts released in the upper GI tract (<12% over 12h). The polymer conjugates showed chemical stability at various pH values along the gastrointestinal tract and increased water solubility of up to 5mg/mL. 4-Amino-THC demonstrated cytotoxic ability against the human colon adenocarcinoma cell lines (HT-29) with an IC50 of 28.67 ± 1.01 μg/mL, and even greater selectivity (∼ 4 folds) to inhibit HT-29 cells than to normal human colon epithelial cell lines while curcumin was a non-selective agent against both cell lines. Our study has demonstrated that the use of THC-CMC conjugates may be a promising colon-specific drug delivery system with its sustained release in the colon to be an effective treatment for colonic cancer.

Topics: Antineoplastic Agents; Carboxymethylcellulose Sodium; Cell Line, Tumor; Chromatography, High Pressure Liquid; Colon; Curcumin; Drug Screening Assays, Antitumor; Humans; Magnetic Resonance Spectroscopy; Solubility; Spectrophotometry, Infrared

Medicinal plants proved to be a rich source in exploring a variety of lead structures in the development of new drugs. The natural curcuminoids have gained considerable attention in recent years for their multiple beneficial pharmacological and biological activities. Clinical application of these curcuminoids is often impaired due to their poor water solubility, resulting in low in vivo bioavailability of the active compound in humans. The objective of the present study is to synthesize glucosyl conjugates of curcumin 1 and tetrahydrocurcumin 4 and to evaluate their biological activities. The study highlights the synthesis of curcumin-β-di-glucoside 3 (yield 71%) and tetrahydrocurcumin-β-di-glucoside 6 (yield 64%) in good yields in a biphasic reaction medium using a phase transfer catalyst under simple and ecofriendly conditions. Both the glucosyl curcuminoids showed enhanced antioxidant, tyrosinase enzyme inhibitory, antimicrobial and potent cytotoxic activity. The improved biological activity may be due to the increased solubility of the glucosyl conjugated compounds compared to the native curcuminoids; this was further confirmed by partition coefficient studies. Thus, the synthesized glucosyl curcumin may serve as promising future therapeutic molecule in the management of cancer, whereas glucosyl tetrahydrocurcumin can be a useful ingredient in achromatic food and in cosmetic applications.

Topics: Anti-Infective Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Cell Survival; Curcuma; Curcumin; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Glucosides; Glycosylation; HT29 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; MCF-7 Cells; Molecular Structure; Monophenol Monooxygenase; Phytotherapy; Plants, Medicinal; Solubility; Structure-Activity Relationship

Cadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti-diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice.. Male ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment.. Administration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues.. Our results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure.

Topics: Animals; Cadmium; Curcumin; Gene Expression Regulation; Humans; Hypertension; Mice; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Protective Agents; Vascular Remodeling; Vascular Stiffness

Tetrahydrocurcumin (THC), the hydrogenated and stable form of curcumin, exhibits physiological and pharmacological activities similar to curcumin. A protocol has been developed for the synthesis of novel conjugates of THC with alanine (2a), isoleucine (2b), proline (2c), valine (2d), phenylalanine (2e), glycine (2f) and leucine (2g) in high yields (43-82%). All the derivatives of THC exhibited more potent anti-microbial activity than THC against Bacillus cereus, Staphylococcus aureus, Escherichia coli and Yersinia enterocolitica. The MIC values of the derivatives were 24-37% of those for THC in case of both gram-positive and gram-negative bacteria. Derivatives 2g and 2d exhibited maximum anti-mutagenicity against Salmonella typhimurium TA 98 and TA 1538, respectively at a low concentration of 313 μg/plate, with comparable activity for THC evident only at 3750 μg/plate. These results clearly demonstrated that the conjugation of THC at the phenolic position with amino acids led to significant improvement of its in vitro biological attributes.

Topics: Amino Acids; Anti-Bacterial Agents; Antimutagenic Agents; Bacteria; Curcumin; Microbial Sensitivity Tests

Curcumin (Cur) is a commonly used colouring agent and spice in food. Previously, we reported that Cur inhibits type A influenza virus (IAV) infection by interfering with viral haemagglutination (HA) activity. To search for a stable Cur analogue with potent anti-IAV activity and to investigate the structure contributing to its anti-IAV activity, a comparative analysis of structural and functional analogues of Cur, such as tetrahydrocurcumin (THC) and petasiphenol (Pet), was performed. The result of time-of-drug addition tests indicated that these curcuminoids were able to inhibit IAV production in cell cultures. Noticeably, Pet and THC inhibit IAV to a lesser extent than Cur, which is in line with their effect on reducing plaque formation when IAV was treated with Cur analogues before infection. Unexpectedly, both THC and Pet did not harbour any HA inhibitory effect. It should be noted that the structure of Pet and THC differs from Cur with respect to the number of double bonds present in the central seven-carbon chain, and structure modelling of Cur analogues indicates that the conformations of THC and Pet are distinct from that of Cur. Moreover, simulation docking of Cur with the HA structure revealed that Cur binds to the region constituting sialic acid anchoring residues, supporting the results obtained by the inhibition of HA activity assay. Collectively, structure-activity relationship analyses indicate that the presence of the double bonds in the central seven-carbon chain enhanced the Cur -dependent anti-IAV activity and also that Cur might interfere with IAV entry by its interaction with the receptor binding region of viral HA protein.

Topics: Animals; Antiviral Agents; Binding Sites; Caffeic Acids; Curcumin; Dogs; Glutathione; Glutathione Disulfide; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Influenza A virus; Madin Darby Canine Kidney Cells; Models, Molecular; Molecular Conformation; Protein Conformation; Structure-Activity Relationship; Viral Plaque Assay

Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity.. Mice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation.. These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition.

Topics: Animals; Blood Glucose; Cell Movement; Curcuma; Curcumin; Cytokines; Diet, High-Fat; Dietary Fats; Dietary Supplements; Inflammation; Insulin; Leukocytes; Male; Mice; Mice, Inbred C57BL; Microbiota; Obesity; Piper nigrum; Plant Extracts; Subcutaneous Fat; Weight Gain

In dentistry, the use of metals in fillings, braces, implants, bridges and other prosthodontic restorations is a common practice. Previous studies revealed that zinc (Zn) and copper (Cu) released from gold alloys, and nickel (Ni) released from nickel-chromium alloys, have a highly cytotoxic effect on fibroblast cell cultures. Our working hypothesis is that oral fibroblasts are susceptible to damage from metals because they elevate reaction oxygen species (ROS). In this study, we investigated specific antioxidant (AO) combinations to determine if they counteract the effects of Cu, Ni and Zn on cultured oral fibroblast proliferation and oxidative damage.. Oral fibroblasts were pretreated with Cu, Ni and Zn for 60min. Thereafter, cells were treated with 10(-5)M combinations of bioactive AO resveratrol (R), ferulic acid (F), phloretin (P) and tetrahydrocurcuminoids (T) (RFT, PFR, PFT) for 24h. Cell viability and DNA synthesis were monitored by 3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium (MTS) and 5-bromo-2-deoxyuridine (BrDU) assays. ROS was measured using the fluorescence response of dichlorodihydrofluorescein diacetate (DCF).. AO compounds increased recovery of cells exposed to Cu and Zn. Moreover, AO treatment induced DNA synthesis in the presence of the metal stressors. Cu and Ni stimulated production of ROS. PFR treatment decreased ROS in the presence of Cu, Ni and Zn.. These data indicate that pure AOs counteracted the detrimental effects of Cu, Ni, Zn on oral fibroblasts in vitro by increasing cell viability, and DNA synthesis and decreasing ROS activity.

Topics: Antioxidants; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cells, Cultured; Copper; Coumaric Acids; Curcumin; Dental Materials; DNA; Dose-Response Relationship, Drug; Drug Combinations; Fibroblasts; Free Radical Scavengers; Gingiva; Humans; Metals; Nickel; Oxidative Stress; Periodontal Ligament; Phenols; Phloretin; Reactive Oxygen Species; Resveratrol; Ribonucleotide Reductases; Stilbenes; Time Factors; Zinc

Tetrahydrocurcumin (THC, 1) and zingerone (2) are biologically active molecules originating from the important spices turmeric and ginger, respectively. Novel quinoline derivatives of THC and zingerone have been synthesised by an efficient protocol involving their reaction with substituted 2-aminobenzophenones and 2-aminoacetophenone. Radical-scavenging activities (RSA) of THC, zingerone and their quinoline derivatives were evaluated. The amino-substituted quinoline derivative of THC, 1e, showed antioxidant activity superior to those of 1 and 1a. Derivatives 1b, 1c, 1d and 1f exhibited relatively lower RSA at equimolar concentrations (∼50-55 μmol). A similar trend was also seen in zingerone (2) and its derivatives (2a-2e), with 2e displaying the best RSA. Derivatives of THC (1a-1f) showed stronger antimicrobial activity than THC (1) against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Yersinia enterocolitica. Also, derivatives of zingerone (2b-2e) exhibited lower minimum inhibitory concentrations (MIC) values than zingerone (2) and its derivative, 2a for both Gram-positive and Gram-negative bacteria. The molecules may have potential pharmacological applications.

Topics: Anti-Bacterial Agents; Antioxidants; Bacteria; Curcumin; Guaiacol; Quinolines

Novel self-microemulsifying floating tablets were developed to enhance the dissolution and oral absorption of the poorly water-soluble tetrahydrocurcumin (THC). Their physicochemical properties and THC permeability across Caco-2 cell monolayers were assessed. The self-microemulsifying liquid containing THC was adsorbed onto colloidal silicon dioxide, mixed with HPMC, gas-generating agents (sodium bicarbonate and tartaric acid), lactose and silicified-microcrystalline cellulose and transformed into tablets by direct compression. The use of different types/concentrations of HPMC and sodium bicarbonate in tablet formulations had different effects on the floating characteristics and in vitro THC release. The optimum tablet formulation (F2) provided a short floating lag time (∼23 s) together with a prolonged buoyancy (>12 h). About 72% of THC was released in 12 h with an emulsion droplet size in aqueous media of 33.9±1.0 nm while that of a self-microemulsifying liquid was 29.9±0.3 nm. The tablet formulation was stable under intermediate and accelerated storage conditions for up to 6 months. The THC released from the self-microemulsifying liquid and tablet formulations provided an approximately three- to fivefold greater permeability across the Caco-2 cell monolayers than the unformulated THC and indicated an enhanced absorption of THC by the formulations. The self-microemulsifying floating tablet could provide a dosage form with the potential to improve the oral bioavailability of THC and other hydrophobic compounds.

Topics: Caco-2 Cells; Chromatography, High Pressure Liquid; Curcumin; Emulsions; Humans; Kinetics; Microscopy, Electron, Scanning; Permeability; Tablets

Tetrahydrocurcumin (THC), a major metabolite of curcumin, possesses strong antioxidant and cardioprotective properties. However, the activities of THC in hypertension and its associated complications remain unknown. The aim of this study was to investigate the effect of THC on hemodynamic status, aortic elasticity and oxidative stress in rats with N-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Hypertension was induced in male Sprague-Dawley rats by administration of L-NAME (50 mg kg(-1) body weight) in drinking water for 5 weeks. THC at a dose of 50 or 100 mg kg(-1) per day was administered daily during the fourth and fifth weeks when the hypertensive state had been established. The effects of THC on hemodynamics, aortic elasticity, endothelial nitric oxide synthase (eNOS) protein expression and oxidative stress markers were assessed. Marked increases in blood pressure, peripheral vascular resistance, aortic stiffness and oxidative stress were found in rats after L-NAME administration. THC significantly reversed these deleterious effects by reducing aortic wall thickness and stiffness. These effects were associated with increased aortic eNOS expression, elevated plasma nitrate/nitrite, decreased oxidative stress with reduced superoxide production and enhanced blood glutathione. Our results provide the first evidence that THC attenuates the detrimental effect of L-NAME by improving the hemodynamic status and aortic elasticity concomitant with reduction of oxidative stress. The present study suggests that THC might be used as a dietary supplement to protect against cardiovascular alterations under nitric oxide-deficient conditions.

Topics: Animals; Aorta; Curcumin; Endothelium, Vascular; Glutathione; Hemodynamics; Hypertension; Male; Malondialdehyde; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Protein Carbonylation; Rats; Rats, Sprague-Dawley; Superoxides; Vascular Resistance; Vascular Stiffness

High levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy), contribute to autophagy and ischemia/reperfusion injury (I/R). Previous studies have shown that I/R injury and HHcy cause increased cerebrovascular permeability; however, the associated mechanism remains obscure. Interestingly, during HHcy, cytochome-c becomes homocysteinylated (Hcy-cyto-c). Cytochrome-c (cyto-c) transports electrons and facilitates bioenergetics in the system. However, its role in autophagy during ischemia/reperfusion injury is unclear. Tetrahydrocurcumin (THC) is a major herbal antioxidant and anti-inflammatory agent. Therefore, the objective of this study was to determine whether THC ameliorates autophagy during ischemia/reperfusion injury by reducing homocysteinylation of cyto-c in hyperhomocysteinemia pathological condition. To test this hypothesis, we employed 8-10-week-old male cystathionine-beta-synthase heterozygote knockout (CBS⁺/⁻) mice (genetically hyperhomocystemic mice). Experimental group was: CBS⁺/⁻, CBS⁺/⁻ + THC (25 mg/kg in 0.1% DMSO dose); CBS ⁺/⁻/I/R, and CBS⁺/⁻/I/R + THC (25 mg/kg in 0.1% DMSO dose). Ischemia was performed for 30 min and reperfusion for 72 h. THC was injected intra-peritoneally (I.P.) once daily for a period of 3 days after 30 min of ischemia. The infarct area was measured using 2,3,5-triphenyltetrazolium chloride staining. Permeability was determined by brain edema and Evans Blue extravasation. The brain tissues were analyzed for oxidative stress, matrix metalloproteinase-9 (MMP-9), damage-regulated autophagy modulator (DRAM), and microtubule-associated protein 1 light chain 3 (LC3) by Western blot. The mRNA levels of S-adenosyl-L-homocysteine hydrolases (SAHH) and methylenetetrahydrofolate reductase (MTHFR) genes were measured by quantitative real-time polymerase chain reaction. Co-immunoprecipitation was used to determine the homocysteinylation of cyto-c. We found that brain edema and Evans Blue leakage were reduced in I/R + THC-treated groups as compared to sham-operated groups along with reduced brain infarct size. THC also decreased oxidative damage and ameliorated the homocysteinylation of cyto-c in-part by MMP-9 activation which leads to autophagy in I/R groups as compared to sham-operated groups. This study suggests a potential therapeutic role of dietary THC in cerebral ischemia.

Topics: Animals; Antioxidants; Autophagy; Brain Ischemia; Curcumin; Cytochromes c; Hyperhomocysteinemia; Male; Mice; Mice, Knockout; Reperfusion Injury

Cultured plant cells of Marchantia polymorpha, Nicotiana tabacum, Phytolacca americana, Catharanthus roseus, and Gossypium hirsutum were examined for their ability to reduce curcumin. Only M. polymorpha cells converted curcumin into tetrahydrocurcumin in 90% yield in one day. Time-course experiment revealed a two-step formation of tetrahydrocurcumin via dihydrocurcumin.

Topics: Cells, Cultured; Curcumin; Marchantia

Ca(2+) influx through Ca(2+)-release activated Ca(2+) channels (CRAC) is critical for activating immune cells. Orai and STIM proteins comprise the molecular components of CRAC. We previously observed that curcumin and caffeic acid phenethyl ester (CAPE) inhibit CRAC current in Orai1/STIM1-co-expressing HEK293 cells (Nam et al., 2009; Shin et al., 2011) [1,2]. Both compounds contain electrophilic α,β-unsaturated carbonyl groups that potentially form Michael addition with cysteine residues. We investigated the sensitivity of cysteine mutated Orai1 to curcumin and CAPE to delineate their inhibitory mechanism. Replacing the 195 cysteine residue with serine (C195S) reversed the effect of CAPE from inhibition to facilitation and significantly weakened the inhibitory effect of curcumin. Tetrahydrocurcumin, a curcumin metabolite, showed a less potent inhibitory effect on I(CRAC), and this effect was abolished in C195S Orai1. Additive mutation of other cysteines (C143S and C126S) had no further influence on the effects of CAPE and curcumin. These results indicate that the electrophilic addition to the Orai1 195Cys was responsible for the inhibitory effect of I(CRAC) by curcumin and CAPE.

Topics: Caffeic Acids; Calcium; Calcium Channels; Curcumin; Cysteine; HEK293 Cells; Humans; Mutation; ORAI1 Protein; Phenylethyl Alcohol

Curcumin's instability and its metabolite, tetrahydrocurcumin (THC) pose a major issue for the establishment of dependable pharmacokinetics and excretion profiles. Additional pharmacokinetic variances are associated with durations of intravenous infusions. We found that stabilizing curcumin with phosphoric acid allows accurate quantitative determinations of curcuminoids in the plasma and bile, by preventing degradation during the analytical processes. Two male and two females dogs were infused with Lipocurc™ 10 mg/kg over two hours, and another four dogs (two males and two females) were infused with Lipocurc™ 10 mg/kg over eight hours. Plasma levels of curcumin and THC were determined during the infusions and at necropsy. THC levels were 6.3-9.6-fold higher than curcumin during both infusion rates, suggesting a combination of a high-rate of enzymatic curcumin metabolism and a comparatively slower rate of blood THC clearance. When levels of curcumin and THC were compared during infusion durations, the two-hour infusion levels were significantly higher than the eight-hour infusion. The plasma half-lives of both compounds following the two-hour infusion ranged from 0.4-0.7 hours, and was a consequence of both hepatic and renal clearance However, at higher plasma concentrations renal excretion predominated, particularly with THC. Enhanced clearance rates were noted during eight-hour infusions, which prevented achieving a steady state. These observations suggest that for leukemias and lymphomas, the two-hour infusion may be advantageous based upon higher concentration profiles, and unstimulated clearance rates, however data on curcumin penetration into circulating hematopoietic cancer cells and efficacy data are required in order to confirm these suggestions.

Topics: Animals; Curcumin; Dogs; Female; Infusions, Intravenous; Kidney; Liposomes; Liver; Male; Metabolic Clearance Rate

This study interrogated whether different durations of intravenous infusions of lipocurc™ would alter curcumin metabolism, tissue distribution and whether treating necropsied tissues of Beagle dogs with phosphoric acid prior to measuring curcumin and its metabolite, tetrahydrocurcumin (THC), would stabilize the compounds allowing for accurate analytic measurements. Two cohorts comprising two male and two female dogs were infused each intravenously with 10 mg/kg lipocurc™, either over two hours or over eight hours. Tissue data from each cohort was averaged from four dogs. Curcumin and THC distributed among all 13 tissues were examined at necropsy. The highest curcumin level was observed in the lungs followed by the liver. Tissue levels of curcumin in the lung, spleen and liver increased substantially following the eight-hour infusion compared to the two-hour infusion. The pancreas, kidney and urinary bladder also contained relatively high curcumin levels. Tissue partition coefficients for curcumin and THC were also higher for the eight-hour infusion than the two-hour infusion. The tissue THC/curcumin ratio varied in a tissue-specific manner and was lower for the eight-hour compared to the two-hour infusion. In conclusion, this raised the possibility that prolonged infusion of curcumin may facilitate distribution into tissues via a transporter-dependent mechanism and elevated tissue concentrations of curcumin may inhibit or saturate a putative reductase enzyme converting curcumin to THC. The addition of phosphoric acid stabilized the levels of curcumin and THC in some but not all the examined tissues, raising issues of tissue-specific curcumin and THC stability.

Topics: Animals; Curcumin; Dogs; Female; Infusions, Intravenous; Liposomes; Male; Phosphoric Acids; Tissue Distribution

Amyloid plaques and neurofibrillary tangles are the hallmarks of Alzheimer's disease. Amyloid β, a primary component of the amyloid plaques, is neurotoxic. Considerable attention has been directed toward identifying compounds with neuroprotective properties. Using rat primary hippocampal cultures, we show that tetrahydrocurcumin (THC), a metabolite of curcumin, shows a protective effect against oligomeric amyloid-β-induced toxicity. We further show that THC reduces amyloid-β-induced (i) increase in the level of reactive oxygen species, (ii) decrease in mitochondrial membrane potential, and (iii) caspase activation. In addition, we show that THC protects human neurons from oligomeric amyloid-β-induced toxicity as well. Thus, THC confers protection against amyloid-β-induced toxicity, and the antioxidant activity may contribute to its protective effect.

Topics: Amyloid beta-Peptides; Animals; Antioxidants; Curcumin; Hippocampus; Humans; In Situ Nick-End Labeling; Membrane Potential, Mitochondrial; Neurons; Neuroprotective Agents; Organ Culture Techniques; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

The objectives of this study were to develop and evaluate a novel self-emulsifying floating drug delivery system (SEFDDS) that resulted in improved solubility, dissolution, and controlled release of the poorly water-soluble tetrahydrocurcumin (THC). The formulations of liquid self-emulsifying drug delivery system (SEDDS; mixtures of Labrasol, Cremophor EL, Capryol 90, Labrafac PG) were optimized by solubility assay and pseudo-ternary phase diagram analysis. The liquid SEDDS was mixed with adsorbent (silicon dioxide), glyceryl behenate, pregelatinized starch, sodium starch glycolate, and microcrystalline cellulose and transformed into pellets by the extrusion/spheronization technique. The resulting pellets with 22% liquid SEDDS had a uniform size and good self-emulsification property. The microemulsions in aqueous media of different self-emulsifying floating pellet formulations were in a particle size range of 25.9-32.5 nm. Use of different weight proportions of glyceryl behenate and sodium starch glycolate in pellet formulations had different effects on the floating abilities and in vitro drug release. The optimum formulation (F2) had a floating efficiency of 93% at 6 h and provided a controlled release of THC over an 8-h period. The release rate and extent of release of THC liquid SEDDS (80% within 2 h) and self-emulsifying floating pellet formulation (80% within 8 h) were significantly higher than that of unformulated THC (only 30% within 8 h). The pellet formulation was stable under intermediate and accelerated storage conditions for up to 6 months. Controlled release from this novel SEFDDS can be a useful alternative for the strategic development of oral solid lipid-based formulations.

Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Delayed-Action Preparations; Drug Delivery Systems; Drug Stability; Emulsifying Agents; Emulsions; Glycerol; Humans; Solubility

Many plant pathogens produce toxic metabolites when growing on food and feed. Some antioxidative components seem to prevent fungal growth and mycotoxin formation. Recently, we synthesized a new class of powerful antioxidative compounds, i.e. tetrahydrocurcuminoids, and its structure/antioxidant activity relationships have been established. The South West of France produces large amounts of corn, which can be infected by Fusarium species, particularly F. proliferatum. In this context, the efficiency of tetrahydrocurcuminoids, which can be obtained from natural curcuminoids, was investigated to control in vitro the growth of F. proliferatum and the production of its associated mycotoxin, fumonisin B₁. The relation between structure and antifungal activity was studied. Tetrahydrocurcumin (THC1), with two guaiacyl phenolic subunits, showed the highest inhibitory activity (measured as radial growth on agar medium) against the F. proliferatum development (67% inhibition at a concentration of 13.6 µmol ml⁻¹). The efficiencies of THC2 (36% at a concentration of 11.5 µmol ml⁻¹), which contains syringyl phenolic units, and THC3 (30% at a concentration of 13.6 µmol ml⁻¹), which does not have any substituent on the aromatic rings, were relatively close. These results indicate that the simultaneous presence of guaiacyl phenols and the enolic function of the β-diketone moiety play an important role in the inhibition mechanisms. The importance of this combination was confirmed using n-propylguaiacol and acetylacetone as molecular models. Under the same conditions, ferulic acid and eugenol, other natural phenolic antioxidants, were less efficient in inhibiting fungal growth. THC1 also reduced fumonisin B₁ production in liquid medium by approximately 35, 50 and 75% at concentrations of 0.8, 1.3, and 1.9 µmol ml⁻¹, respectively. These very low inhibitory concentrations show that tetrahydrocurcuminoids could be one of the most promising biobased molecules for the control of mycotoxinogen fungal strains.

Topics: Antioxidants; Curcumin; Fumonisins; Fungicides, Industrial; Fusarium; Microbial Sensitivity Tests; Models, Molecular; Mycelium; Mycotoxins; Structure-Activity Relationship; Time Factors

Inhibition of nitric oxide synthesis with N ( ω )-nitro-L-arginine methyl ester (L-NAME) induces marked hypertension and oxidative stress. Curcumin (CUR) has been shown strong antioxidant property. Tetrahydrocurcumin (THU), a major metabolite of CUR, possesses several pharmacological effects similar to CUR; however, it is less studied than CUR. We investigated whether CUR and THU could prevent vascular dysfunction and inhibit development of hypertension in L-NAME-treated rats. Male Sprague-Dawley rats were administered with L-NAME (50 mg/kg/day) in drinking water for 3 weeks. CUR or THU (50 and 100 mg/kg/day) was fed to animals simultaneously with L-NAME. L-NAME administration induced increased arterial blood pressure and elevated peripheral vascular resistance accompanied with impaired vascular responses to angiotensin II and acetylcholine. CUR and THU significantly suppressed the blood pressure elevation, decreased vascular resistance, and restored vascular responsiveness. The improvement of vascular dysfunction was associated with reinstating the marked suppression of eNOS protein expression in the aortic tissue and plasma nitrate/nitrite. Moreover, CUR and THU reduced vascular superoxide production, decreased oxidative stress, and increased the previously depressed blood glutathione (GSH) and the redox ratios of GSH in L-NAME hypertensive rats. The antihypertensive and some antioxidant effects of THU are apparently more potent than those of CUR. This study suggests that CUR and THU prevented the development of vascular dysfunction induced by L-NAME and that the effects are associated with alleviation of oxidative stress.

Topics: Animals; Antioxidants; Blood Pressure; Blotting, Western; Curcumin; Glutathione; Hypertension; Lipid Peroxidation; Male; Malondialdehyde; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Oxidative Stress; Protein Carbonylation; Rats; Rats, Sprague-Dawley; Vascular Resistance

Antioxidants (AOs) are the first line of defence against free radical damage and are critical for maintaining optimum health and well being. The need for AOs becomes even more critical with increased exposure to free radicals generated by pollution, cigarette smoke, drugs, illness, stress and exercise. Antioxidant supplementation is an excellent way of improving free radical protection. The aim of this study was to provide cytotoxicity, proliferation and migration data on the in vitro effects of bioactive AO mixtures on human oral fibroblasts.. Human oral fibroblasts were obtained from human gingival (HGF) and periodontal (HPDL) tissues. Each of these oral fibroblasts was cultured separately in three concentrations of the bioactive pure polyphenol and turmeric derivative mixtures; resveratrol (R), ferulic acid (F), phloretin (P) and tetrahydrocurcuminoids (T); [(RFT), (PFR), and (PFT)]. Cell viability, proliferation, morphology and migratory behaviour were analysed in vitro using high throughput in vitro 96 well plate wound assay.. RFT decreased (10(-3)M) and increased (10(-5)M) cell number in HGF cells. Three concentrations (10(-3), 10(-4), and 10(-5)M) of PFR and PFT increased DNA synthesis in HGF cells. PFT promoted cell migration but PFR and RFT had no significant change in HGF wound healing rates in a 96 well plate assay monolayer wound. In the HPDL cells, the 10(-4)M concentration of both RFT and PFT increased cell number at 72 h and 96 h whereas the lower concentration 10(-5)M of RFT significantly stimulated cell number at 96 h. PFR (10(-3)M and 10(-5)M) and PFT (10(-3)M) increased DNA synthesis after 48 h treatment in HPDL cells.. High and low concentrations (10(-3)-10(-5)M) of these AOs (RFT, PFR) may have beneficial effects on functional mechanisms regulating fibroblast migration and proliferation during gingival healing or periodontal repair.

Topics: Antioxidants; Apoptosis; Caspase 3; Cell Movement; Cell Proliferation; Cell Shape; Cell Survival; Cells, Cultured; Coumaric Acids; Curcuma; Curcumin; DNA; Fibroblasts; Free Radicals; Gingiva; Humans; Periodontal Ligament; Phloretin; Plant Preparations; Polyphenols; Resveratrol; Stilbenes

Tetrahydrocurcumin (THC), a major metabolite of curcumin (CUR), has been demonstrated to be anti-cancerogenic and anti-angiogenic and prevents type II diabetes. In this present study, we investigated the chemopreventive effects and underlying molecular mechanisms of dietary administration of CUR and THC in azoxymethane (AOM)-induced colon carcinogenesis in mice.. All mice were sacrificed at 6 and 23 wk, and colonic tissue was collected and examined. We found that dietary administration of both CUR and THC could reduce aberrant crypt foci and polyps formation, while THC showed a better inhibitory effect than CUR. At the molecular level, results from Western blot analysis and immunohistochemistry staining showed that dietary CUR and THC exhibited anti-inflammatory activity by decreasing the levels of inducible NOS and COX-2 through downregulation of ERK1/2 activation. In addition, both dietary CUR and THC significantly decreased AOM-induced Wnt-1 and β-catenin protein expression, as well as the phosphorylation of GSK-3β in colonic tissue. Moreover, dietary feeding with CUR and THC markedly reduced the protein level of connexin-43, an important molecule of gap junctions, indicating that both CUR and THC might interfer with the intercellular communication of crypt cells.. Taken together, these results demonstrated for the first time the in vivo chemopreventive efficacy and molecular mechanisms of dietary THC against AOM-induced colonic tumorigenesis.

Topics: Animals; Anticarcinogenic Agents; Azoxymethane; beta Catenin; Blotting, Western; Colon; Colonic Neoplasms; Curcumin; Down-Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Mice; Mice, Inbred ICR; Phosphorylation; Wnt1 Protein

Autophagy (type II programmed cell death) is crucial for maintaining cellular homeostasis. Several autophagy-deficient or knockout studies indicate that autophagy is a tumor suppressor. Tetrahydrocurcumin (THC), a major metabolite of curcumin, has been demonstrated with anti-colon carcinogenesis and antioxidation in vivo.. In the present study, we found that treatment with THC induced autophagic cell death in human HL-60 promyelocytic leukemia cells by increasing autophage marker acidic vascular organelle (AVO) formation. Flow cytometry also confirmed that THC treatment did not increase sub-G1 cell population whereas curcumin did with strong apoptosis-inducing activity. At the molecular levels, the results from Western blot analysis showed that THC significantly down-regulated phosphatidylinositol 3-kinase/protein kinase B and mitogen-activated protein kinase signalings including decreasing the phosphorylation of mammalian target of rapamycin, glycogen synthase kinase 3β and p70 ribosomal protein S6 kinase. Further molecular analysis exhibited that the pretreatment of 3-methyladenine (an autophagy inhibitor) also significantly reduced acidic vascular organelle production in THC-treated cells.. Taken together, these results demonstrated the anticancer efficacy of THC by inducing autophagy as well as provided a potential application for the prevention of human leukemia.

Topics: Adenine; Antineoplastic Agents, Phytogenic; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Cell Proliferation; Curcumin; Down-Regulation; HL-60 Cells; Humans; Leukemia, Myeloid; MAP Kinase Signaling System; Membrane Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

The O-type forkhead domain transcription factor (FOXO) is involved in many biological processes such as aging, the oxidative stress response, and growth regulation. FOXO activity is tightly controlled within cells. In particular, growth factor signaling pathways and the oxidative stress response can both stimulate nuclear translocation of this transcription factor. Here, we show that tetrahydrocurcumin (THC), a curcumin metabolite, regulates the oxidative stress response and aging via FOXO. In NIH3T3 cells, THC induced nuclear accumulation of FOXO4, a member of the FOXO family of transcription factors, by inhibiting phosphorylation of protein kinase B (PKB)/Akt. In Drosophila melanogaster, THC attenuated the oxidative stress response, an effect that was blocked in a foxo mutant background. THC also extended the life span of Drosophila under normal conditions, and loss of either foxo or Sir2 activity eliminated this effect. Based on these results, THC may regulate the aging process via an evolutionarily conserved signaling pathway that includes both foxo and Sir2.

Topics: Animals; Blotting, Western; Curcumin; Drosophila melanogaster; Forkhead Transcription Factors; Immunohistochemistry; Life Expectancy; Mice; NIH 3T3 Cells; Oxidative Stress; Signal Transduction

Advances in understanding the neurodegenerative pathologies are creating new opportunities for the development of neuroprotective therapies, such as antioxidant food factors, lifestyle modification and drugs. However, the biomarker by which the effect of the agent on neurodegeneration is determined is limited. We here address hexanoyl dopamine (HED), one of novel dopamine adducts derived from brain polyunsaturated acid, referring to its in vitro formation, potent toxicity to SH-SY5Y cells, and application to assess the neuroprotective effect of antioxidative food factors. Dopamine is a neurotransmitter, and its deficiency is a characterized feature in Parkinson's disease (PD); thus, HED provides a new insight into the understanding of dopamine biology and pathophysiology of PD and a novel biomarker for the assessment of neuroprotective therapies. We have established an analytical system for the detection of HED and its toxicity to the neuroblstoma cell line, SH-SY5Y cells. Here, we discuss the characteristics of the system and its applications to investigate the neuroprotective effect of several antioxidants that originate from food.

Topics: Antioxidants; Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Curcumin; Dioxoles; Dopamine; Humans; Lignans; Neuroblastoma; Parkinson Disease; Tandem Mass Spectrometry; Tocopherols; Tocotrienols; Xanthophylls

The present study evaluates the combined effect of tetrahydrocurcumin and chlorogenic acid on oxidative stress in streptozotocin-nicotinamide-induced diabetic rats. Rats were rendered diabetic by a single intraperitoneal injection (i.p) of streptozotocin (45 mg/kg BW), 15 min after an i.p injection of nicotinamide (110 mg/kg BW). The levels of fasting plasma glucose and insulin were estimated. As an index of oxidative stress, the levels of enzymic antioxidants and lipid peroxidation products were analyzed in liver and kidney. Diabetic rats showed an increase in the levels of fasting plasma glucose, lipid peroxidative products such as thiobarbituric acid reactive substances and lipid hydroperoxides and a decrease in plasma insulin, and enzymic antioxidants viz., superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase. Combined administration of tetrahydrocurcumin (80 mg/kg BW) and chlorogenic acid (5 mg/kg BW) to diabetic rats for 45 days, reversed the biochemical changes to near normal. The above findings were supported by histological observations of the liver and kidney. Together the present study clearly reflects that combined dosage of tetrahydrocurcumin and chlorogenic acid augments enzymic antioxidants with a concomitant decrease in lipid peroxidation and protects against streptozotocin-nicotinamide-induced type 2 diabetes in experimental rats.

Topics: Animals; Antioxidants; Chlorogenic Acid; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Combinations; Kidney; Lipid Peroxidation; Liver; Niacinamide; Oxidative Stress; Oxidoreductases; Protective Agents; Rats; Streptozocin; Treatment Outcome

We have shown that separate dose of tetrahydrocurcumin (THC) at a dose of 80 mg/kg body weight (b.w.) and chlorogenic acid (CGA) at a dose of 5 mg/kg b.w. exerts antidiabetic potential in streptozotocin (STZ) (45 mg/kg b.w.) nicotinamide induced diabetic rats. In the present study we have attempted to compare the antihyperglycemic activity exerted by the combined treatment of THC/CGA with THC and CGA alone treated diabetic rats. After the experimental period of 45 days we observed that supplementation with combined dose of THC/CGA significantly decreased glycosylated hemoglobin (HbA(1C)) and increased the levels of plasma insulin, C-peptide, hemoglobin and glycogen which were decreased upon STZ treatment and also significantly reversed the altered activities of gluconeogenic enzymes such as glucose-6-phosphatase, fructose-1,6-bisphosphatase, and of glycolytic enzymes such as glucokinase and hexokinase in the tissues of experimental rats as compared to their individual supplementation. Thus our results substantiate that though THC and CGA alone found to exert hypoglycemic activity the maximum hypoglycemic effect was always observed in diabetic rats treated THC/CGA and this summed effect seems to have a promising value for the development of a potent phytomedicine for diabetes.

Topics: Animals; Chlorogenic Acid; Curcumin; Diabetes Mellitus, Experimental; Drug Combinations; Feasibility Studies; Glycogen; Hypoglycemic Agents; Insulin; Male; Niacinamide; Rats; Rats, Wistar; Signal Transduction; Streptozocin; Treatment Outcome

Curcuminoids exhibit anti-proliferative properties in many cell lines by modulating signalling pathways to inhibit cell growth. However, the specific effects of curcuminoids on human keratinocytes are not well defined, and this situation impairs mechanistic thinking regarding potential therapeutic uses. We hypothesized that curcuminoids would modulate key growth regulatory pathways in keratinocytes to inhibit cell proliferation. To test this hypothesis, the effects of curcumin and tetrahydrocurcumin (THC) on mitogen-activated protein (MAP) kinase signalling in keratinoctyes were determined. Primary human keratinocytes treated with curcumin or THC demonstrated decreased activation of p44/42 MAP kinases but increased levels of activated p38 MAP kinases. These data suggest that curcuminoids specifically activate stress-induced MAP kinases while inhibiting mitogen-induced MAP kinases. Curcuminoids also promote the phosphorylation of p53 on serine 15 in a dose-dependent and p38-dependent manner, suggesting that these compounds may activate p53. The effects of curcuminoids on keratinocytes mirrored some aspects of UVB and could be inhibited by N-acetylcysteine, suggesting that these compounds activate p38 through a mechanism that involves glutathione depletion. Both curcuminoids induced G2/M block and inhibited keratinocyte growth, and THC increased cellular levels of p21, a known p53 transcriptional target. These data demonstrate that curcuminoids can differentially regulate MAP kinases to inhibit keratinocyte growth while inducing p21. Curcuminoids also synergize with UVB to enhance p53 phosphorylation. The findings provide a rationale for testing curcuminoids in disorders associated with impaired p53 function or in which UVB-treatment is efficacious.

Topics: Acetylcysteine; Cell Division; Cell Proliferation; Cells, Cultured; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Glutathione; Humans; Imidazoles; Interphase; Keratinocytes; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Biological; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase Inhibitors; Pyridines; Signal Transduction; Tumor Suppressor Protein p53; Ultraviolet Rays

Smoking is associated with an increased risk of oral health and dental problems. The aim of this study is to address the hypothesis that nicotine impairs wound healing by increasing reactive oxygen species and inhibiting cell migration, and antioxidants (AOs) may counteract nicotine effects.. Primary human gingival fibroblasts (HGFs) and human periodontal ligament (HPDL) fibroblasts were grown to confluence, pretreated with 6 mM nicotine for 2 hours, and treated with AOs in the presence of nicotine. The pure AO compounds ferulic acid (F), phloretin (P), tetrahydrocurcuminoid Cockroft Gault (T), and resveratrol (R) were tested in single, double, or triple combinations (10(-5) M). The migratory behavior at a scratch-wound edge was recorded every 15 minutes for 10 hours by using live-cell imaging. The active form of the Rho-associated protein (Rac) and guanosine triphosphate (GTP) (RacGTP) was immunolabeled and analyzed using confocal microscopy.. Combinations of double and triple AOs had a greater effect than single AOs on migration rates and Rac activation. The triple combinations PFR and RFT clearly and unambiguously counteracted the effects of nicotine and significantly increased migration rates in HGF and HPDL fibroblast.. Treatment with AO combinations clearly counteracted the effects of nicotine by restoring and increasing cell-migration rates. We found the combination of PFR was the most effective in HGFs, whereas, RFT was the most effective combination in HPDL fibroblast. These results clearly demonstrate that PF, RFT, and PFR counteract the negative effects of nicotine on cultured oral fibroblasts via the RacGTP signal-transduction pathway.

Topics: Antioxidants; Cell Movement; Cell Survival; Cells, Cultured; Coumaric Acids; Curcumin; Enzyme Inhibitors; Fibroblasts; Free Radical Scavengers; Gingiva; Humans; Nicotine; Periodontal Ligament; Phenols; Phloretin; rac GTP-Binding Proteins; Reactive Oxygen Species; Resveratrol; Ribonucleotide Reductases; Signal Transduction; Stilbenes; Time Factors; Wound Healing

Diabetes mellitus is associated with dyslipidemia, which is a significant risk factor for cardiovascular complications. The present study was carried out to evaluate the effects of tetrahydrocurcumin (THC) and chlorogenic acid (CGA) alone and in combination on alterations in lipids, lipoproteins and enzymes involved in lipid metabolism in streptozotocin (STZ)-nicotinamide (NA)-induced type 2 diabetic rats. A significant (p<0.05) increase in the concentrations of plasma and tissue (liver and kidney) lipids (cholesterol, triglycerides (TGs), free fatty acids (FFAs) and phospholipids (PLs)) and low density and very low-density lipoproteins (LDL and VLDL), and a decrease in the concentration of high-density lipoproteins (HDL) were noticed in STZ administered diabetic rats. In addition, the activity of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase increased significantly (p<0.05) in the liver and kidney whereas the activities of lipoprotein lipase (LPL) and lecithin cholesterol acyl transferase (LCAT) were decreased significantly (p<0.05) in the plasma of diabetic rats. Combined administration of CGA (5mg/kg b.w.) and THC (80mg/kg b.w.) for 45 days remarkably reduced the STZ-induced changes in lipids, lipoproteins and lipid metabolising enzymes when compared to the effects of CGA or THC alone in diabetic rats. These results indicate that combination of THC and CGA can potentially ameliorate lipid abnormalities in experimental type 2 diabetes.

Topics: Animals; Chlorogenic Acid; Curcumin; Diabetes Mellitus, Experimental; Drug Combinations; Hydroxymethylglutaryl CoA Reductases; Hypolipidemic Agents; Lipoprotein Lipase; Lipoproteins; Liver; Male; Niacinamide; Phosphatidylcholine-Sterol O-Acyltransferase; Rats; Rats, Wistar

Molecular docking of the interaction of curcumin and DNMT1 suggested that curcumin covalently blocks the catalytic thiolate of C1226 of DNMT1 to exert its inhibitory effect. This was validated by showing that curcumin inhibits the activity of M. SssI with an IC(50) of 30 nM, but no inhibitory activity of hexahydrocurcumin up to 100 microM. In addition, curcumin can induce global DNA hypomethylation in a leukemia cell line.

Topics: Catalysis; Catalytic Domain; Cell Line, Tumor; Curcumin; Cytosine; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Dose-Response Relationship, Drug; Drug Design; Humans; Inhibitory Concentration 50; Leukemia; Models, Chemical; Molecular Conformation

The present study was undertaken to evaluate the cardioprotective potential of tetrahydrocurcumin (THC) and rutin in an in vivo rat ischemia-reperfusion (I/R) model of myocardial infarction (MI). Male wistar rats were divided into six groups receiving saline (control MI/R group), vehicle control MI/R group, THC (5 mg kg(-1) and 10 mg kg(-1)) and rutin (5 mg kg(-1) and 10 mg kg(-1)) i.p. injection respectively. At the day of the experiment, each group was subjected to acute ischemia for 30 min by occlusion of the left anterior descending coronary artery (LAD). Thereafter reperfusion was allowed for 4 h. MI/R resulted in significant cardiac necrosis, elevation in lipid peroxidation, elevation in cardiac marker enzymes AST, ALT and decline in antioxidant status catalase, reduced glutathione in the normal control MI/R group and vehicle control MI/R group. Myocardial infarction produced after MI/R was significantly reduced in tetrahydrocurcumin and rutin of the myocardial antioxidant status, infarct size reduction compared to control and vehicle control MI/R group. Furthermore, MI/R induced lipid peroxidation was significantly reduced by tetrahydrocurcumin and rutin. Cardioprotection in the treatment group was probably a result from suppression of oxidative stress. Histopathological examination further confirmed the protective effect of tetrahydrocurcumin and rutin on the MI/R heart.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Cardiotonic Agents; Catalase; Coronary Vessels; Curcumin; Glutathione; Ligation; Lipid Peroxidation; Male; Malondialdehyde; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Rats; Rats, Wistar; Rutin

Inhibition of beta-amyloid (A beta) accumulation and A beta fibril (fA beta) formation from A beta are attractive therapeutic targets for the treatment of Alzheimer's disease (AD). While previous studies have shown anti-amyloidogenic effects of curcumin in vitro and in vivo, no studies have examined optimized turmeric extracts enriched in curcuminoids or turmerones. Three standardized turmeric extracts, HSS-838, HSS-848, and HSS-888, were prepared with different chemical profiles to investigate their potential therapeutic benefits for AD. These extracts were fingerprinted by DART TOF-MS to reveal the significant chemical complexity. In addition four curcuminoids (curcumin, tetrahydrocurcumin, demethoxycurcumin and bisdemethoxycurcumin) were also examined. We measured the effects of the extracts and curcuminoids, on the aggregation of A beta by using a thioflavin T cell-free assay and the secretion of A beta from human neuronal cells (SweAPP N2A cells) in vitro. All three extracts and the curcuminoids showed dose-dependent inhibition of fA beta aggregation from A beta(1-42) in the cell-free assay, with IC(50) values of

Topics: Amyloid beta-Peptides; Anti-Inflammatory Agents; Cell Line; Culture Media, Conditioned; Curcuma; Curcumin; Diarylheptanoids; Enzyme-Linked Immunosorbent Assay; Humans; Mass Spectrometry; Phytotherapy; Plant Extracts

Tetrahydrocurcumin (THC) is an active metabolite of curcumin. It has been reported to have similar pharmacological activity to curcumin. The proteases that participate in extracellular matrix (ECM) degradation are involved in cancer cell metastasis. The present study investigates the effect of an ultimate metabolite of curcumin, THC, on the invasion and motility of highly-metastatic HT1080 human fibrosarcoma cells.. The effect of THC on HT1080 cell invasion and migration was determined using Boyden chamber assay. Cell-adhesion assay was used for examining the binding of cells to ECM molecules. Zymography assay was used to analyze the effect of THC on matrix metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) secretion from HT1080 cells. Tissue inhibitor of metalloproteinase (TIMP)-2 and membrane-type 1 matrix metalloproteinase (MT1-MMP) proteins levels were analyzed by Western blotting.. Treatment with THC reduced HT1080 cell invasion and migration in a dose-dependent manner. THC also decreased the cell adhesion to Matrigel and laminin-coated plates. Analysis by zymography demonstrated that treatment with THC reduced the levels of MMP-2, MMP-9, and uPA. THC also inhibited the levels of MT1-MMP and TIMP-2 proteins detected by Western blot analysis.. Our findings revealed that THC reduced HT1080 cell invasion and migration. The inhibition of cancer cell invasion is associated with the downregulation of ECM degradation enzymes and the inhibition of cell adhesion to ECM proteins.

Topics: Animals; Anticarcinogenic Agents; Cell Line, Tumor; Cell Movement; Curcumin; Down-Regulation; Humans; Matrix Metalloproteinases; Mice; Neoplasm Invasiveness; NIH 3T3 Cells; Urokinase-Type Plasminogen Activator

Curcumin, a component of turmeric (Curcuma longa), has been reported to suppress beta-catenin response transcription (CRT), which is aberrantly activated in colorectal cancer. However, the effects of its natural analogs (demethoxycurcumin [DMC] and bisdemethoxycurcumin [BDMC]) and metabolite (tetrahydrocurcumin [THC]) on the Wnt/beta-catenin pathway have not been investigated. Here, we show that DMC and BDMC suppressed CRT that was activated by Wnt3a conditioned-medium (Wnt3a-CM) without altering the level of intracellular beta-catenin, and inhibited the growth of various colon cancer cells, with comparable potency to curcumin. Additionally, DMC and BDMC down-regulated p300, which is a positive regulator of the Wnt/beta-catenin pathway. Notably, THC also inhibited CRT and cell proliferation, but to a much lesser degree than curcumin, DMC, or BDMC, indicating that the conjugated bonds in the central seven-carbon chain of curcuminoids are essential for the inhibition of Wnt/beta-catenin pathway and the anti-proliferative activity of curcuminoids. Thus, our findings suggest that curcumin derivatives inhibit the Wnt/beta-catenin pathway by decreasing the amount of the transcriptional coactivator p300.

Topics: Antineoplastic Agents; beta Catenin; Cell Line; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Curcumin; Diarylheptanoids; Down-Regulation; Humans; p300-CBP Transcription Factors; Wnt Proteins

Curcumin (diferuloymethane), a yellow colouring agent present in the rhizome of Curcuma longa Linn (Zingiberaceae), has been reported to possess anti-inflammatory, antioxidant, antimutagenic and anticarcinogenic activities. Curcumin exerts its chemoprotective and chemopreventive effects via multiple mechanisms. It has been reported to induce expression of the antioxidant enzymes in various cell lines. Heme oxygenase-1 (HO-1) is an important antioxidant enzyme that plays a pivotal role in cytoprotection against noxious stimuli of both endogenous and exogenous origin. In the present study, we found that oral administration of curcumin at 200mg/kg dose for four consecutive days not only protected against dimethylnitrosamine (DMN)-induced hepatic injury, but also resulted in more than three-fold induction of HO-1 protein expression as well as activity in rat liver. Inhibition of HO-1 activity by zinc protoporphyrin-IX abrogated the hepatoprotective effect of curcumin against DMN toxicity. NF-E2-related factor 2 (Nrf2) plays a role in the cellular protection against oxidative stress through antioxidant response element (ARE)-directed induction of several phase-2 detoxifying and antioxidant enzymes including HO-1. Curcumin administration resulted in enhanced nuclear translocation and ARE-binding of Nrf2. Taken together, these findings suggest that curcumin protects against DMN-induced hepatotoxicity, at least in part, through ARE-driven induction of HO-1 expression.

Topics: Animals; Anticarcinogenic Agents; Blotting, Western; Carcinogens; Curcumin; Dimethylnitrosamine; Electrophoretic Mobility Shift Assay; Enzyme Induction; Enzymes; Glutathione; Heme Oxygenase-1; Immunohistochemistry; Lipid Peroxidation; Male; NF-E2-Related Factor 2; Oxidation-Reduction; Rats; Rats, Wistar; Up-Regulation

Curcumin is the most active component of turmeric. It is believed that curcumin is a potent antioxidant and anti-inflammatory agent. Tetrahydrocurcumin (THC) is one of the major metabolites of curcumin, and exhibits many of the same physiological and pharmacological activities as curcumin and, in some systems, may exert greater antioxidant activity than curcumin. Using circulating erythrocytes as the cellular mode, the insulin-binding effect of THC and curcumin was investigated. Streptozotocin (STZ)-nicotinamide-induced male Wistar rats were used as the experimental models. THC (80 mg/kg body weight) was administered orally for 45 days. The effect of THC on blood glucose, plasma insulin and insulin binding to its receptor on the cell membrane of erythrocytes were studied. Mean specific binding of insulin was significantly lowered in diabetic rats with a decrease in plasma insulin. This was due to a significant decrease in mean insulin receptors. Erythrocytes from diabetic rats showed a decreased ability for insulin-receptor binding when compared with THC-treated diabetic rats. Scatchard analysis demonstrated that the decrease in insulin binding was accounted for by a decrease in insulin receptor sites per cell, with erythrocytes of diabetic rats having less insulin receptor sites per cell than THC-treated rats. High affinity (K d1), low affinity (K d2) and kinetic analyses revealed an increase in the average receptor affinity of erythrocytes from THC-treated rats compared with those of diabetic rats. These results suggest that acute alteration of the insulin receptor on the membranes of erythrocytes occurred in diabetic rats. Treatment with THC significantly improved specific insulin binding to the receptors, with receptor numbers and affinity binding reaching near-normal levels. Our study suggests the mechanism by which THC increases the number of total cellular insulin binding sites resulting in a significant increase in plasma insulin. The effect of THC is more prominent than that of curcumin.

Topics: Animals; Blood Glucose; Curcumin; Diabetes Mellitus, Experimental; Erythrocyte Membrane; Erythrocytes; Insulin; Kinetics; Male; Molecular Structure; Rats; Rats, Wistar; Receptor, Insulin

To determine the effect of tetrahydrocurcumin (THC) on tumor angiogenesis compared with curcumin (CUR) by using both in vitro and in vivo models of human hepatocellular carcinoma cell line (HepG2).. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used for testing the anti-proliferating activities of CUR and THC. In male BALB/c nude mice, 2 multiply 10(6) human HepG2 cells were inoculated onto a dorsal skin-fold chamber. One day after HepG2 inoculation, the experimental groups were fed oral daily with CUR or THC (300 mg/kg or 3000 mg/kg). On d 7, 14 and 21, the tumor microvasculature was observed using fluorescence videomicroscopy and capillary vascularity (CV) was measured.. Pathological angiogenic features including microvascular dilatation, tortuosity, and hyper-permeability were observed. CUR and THC could attenuate these pathologic features. In HepG2-groups, the CV were significantly increased on d 7 (52.43%), 14 (69.17%), and 21 (74.08%), as compared to controls (33.04%, P < 0.001). Treatment with CUR and THC resulted in significant decrease in the CV (P < 0.005 and P < 0.001, respectively). In particular, the anti-angiogenic effects of CUR and THC were dose-dependent manner. However, the beneficial effect of THC treatment than CUR was observed, in particular, from the 21 d CV (44.96% and 52.86%, P < 0.05).. THC expressed its anti-angiogenesis without any cytotoxic activities to HepG2 cells even at the highest doses. It is suggested that anti-angiogenic properties of CUR and THC represent a common potential mechanism for their anti-cancer actions.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation

We investigated the effects of the polyphenolic compound curcumin and its metabolite tetrahydrocurcumin (ThC), in the model of Parkinson's disease induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this model depletion of dopamine(DA) and DOPAC (3,4-dihydroxy phenyl acetic acid)) occurs with increased monoamine oxidase (MAO-B) activity. We used HPLC with electrochemical detection to measure DA and DOPAC respectively while MAO-B was assayed by spectroflourimetry using the conversion of the fluorogenic substrate, kyuramine. Systemic administration of curcumin (80 mg/kg i. p.) and tetrahydrocurcumin (60 mg/kg i. p.) significantly reversed the MPTP-induced depletion of DA and DOPAC. The MAO-B activity was also significantly inhibited by these compounds. The results showed that curcumin and tetrahydrocurcumin reversed the MPTP induced depletion of DA and DOPAC which may in part be due to inhibition of MAO-B activity. In conclusion, both curcumin and its metabolite ThC exert neuroprotection against MPTP induced neurotoxicity.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Animals; Curcumin; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Flavonoids; Male; Mice; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nerve Degeneration; Neurons; Parkinson Disease; Phenols; Polyphenols

Many studies have been performed with the aim of developing effective resistance modulators to overcome the multidrug resistance (MDR) of human cancers. Potent MDR modulators are being investigated in clinical trials. Many current studies are focused on dietary herbs due to the fact that these have been used for centuries without producing any harmful side effects. In this study, the effect of tetrahydrocurcumin (THC) on three ABC drug transporter proteins, P-glycoprotein (P-gp or ABCB1), mitoxantrone resistance protein (MXR or ABCG2) and multidrug resistance protein 1 (MRP1 or ABCC1) was investigated, to assess whether an ultimate metabolite form of curcuminoids (THC) is able to modulate MDR in cancer cells. Two different types of cell lines were used for P-gp study, human cervical carcinoma KB-3-1 (wild type) and KB-V-1 and human breast cancer MCF-7 (wild type) and MCF-7 MDR, whereas, pcDNA3.1 and pcDNA3.1-MRP1 transfected HEK 293 and MXR overexpressing MCF7AdrVp3000 or MCF7FL1000 and its parental MCF-7 were used for MRP1 and MXR study, respectively. We report here for the first time that THC is able to inhibit the function of P-gp, MXR and MRP1. The results of flow cytometry assay indicated that THC is able to inhibit the function of P-gp and thereby significantly increase the accumulation of rhodamine and calcein AM in KB-V-1 cells. The result was confirmed by the effect of THC on [(3)H]-vinblastine accumulation and efflux in MCF-7 and MCF-7MDR. THC significantly increased the accumulation and inhibited the efflux of [(3)H]-vinblastine in MCF-7 MDR in a concentration-dependent manner. This effect was not found in wild type MCF-7 cell line. The interaction of THC with the P-gp molecule was clearly indicated by ATPase assay and photoaffinity labeling of P-gp with transport substrate. THC stimulated P-gp ATPase activity and inhibited the incorporation of [(125)I]-iodoarylazidoprazosin (IAAP) into P-gp in a concentration-dependent manner. The binding of [(125)I]-IAAP to MXR was also inhibited by THC suggesting that THC interacted with drug binding site of the transporter. THC dose dependently inhibited the efflux of mitoxantrone and pheophorbide A from MXR expressing cells (MCF7AdrVp3000 and MCF7FL1000). Similarly with MRP1, the efflux of a fluorescent substrate calcein AM was inhibited effectively by THC thereby the accumulation of calcein was increased in MRP1-HEK 293 and not its parental pcDNA3.1-HEK 293 cells. The MDR reversing properties of THC on P-

Topics: Adenosine Triphosphate; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Beryllium; Cell Line, Tumor; Chlorophyll; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; Fluoresceins; Fluorescent Dyes; Fluorides; Humans; Mitoxantrone; Molecular Structure; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Organic Anion Transporters; Rhodamine 123; Vinblastine

Curcumin has been shown to induce apoptosis in many cancer cells. However, the molecular mechanism(s) responsible for curcumin-induced apoptosis is not well understood and most probably involves several pathways. In HL-60 cells, curcumin induced apoptosis and endoplasmic reticulum (ER) stress as evidenced by the survival molecules such as phosphorylated protein kinase-like ER-resident kinase, phosphorylated eukaryotic initiation factor-2alpha, glucose-regulated protein-78, and the apoptotic molecules such as caspase-4 and CAAT/enhancer binding protein homologous protein (CHOP). Inhibition of caspase-4 activity by z-LEVD-FMK, blockage of CHOP expression by small interfering RNA, and treatment with salubrinal, an ER inhibitor, significantly reduced curcumin-induced apoptosis. Removing two double bonds in curcumin, which was speculated to form Michael adducts with thiols in secretory proteins, resulted in a loss of the ability of curcumin to induce apoptosis as well as ER stress. Thus, the present study shows that curcumin-induced apoptosis is associated with its ability to cause ER stress.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Caspase Inhibitors; Caspases, Initiator; Curcumin; Dose-Response Relationship, Drug; Endoplasmic Reticulum; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Molecular Structure; RNA, Small Interfering; Transcription Factor CHOP; Transfection

The antioxidant activities of curcumin, its natural demethoxy derivatives (demethoxycurcumin, Dmc and bisdemethoxycurcumin, Bdmc) and metabolite hydrogenated derivatives (tetrahydrocurcumin, THC; hexahydrocurcumin, HHC; octahydrocurcumin; OHC) were comparatively studied using 2,2-diphenyl-1-picrylhydrazyl (DDPH) radical, 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH) induced linoleic oxidation and AAPH induced red blood cell hemolysis assays. Hydrogenated derivatives of curcumin exhibited stronger DPPH scavenging activity compared to curcumin and a reference antioxidant, trolox. The scavenging activity significantly decreased in the order THC>HHC=OHC>trolox>curcumin>Dmc>>>Bdmc. Stronger antioxidant activities toward lipid peroxidation and red blood cell hemolysis were also demonstrated in the hydrogenated derivatives. By the model of AAPH induced linoleic oxidation, the stoichiometric number of peroxyl radical that can be trapped per molecule (n) of hydrogenated derivatives were 3.4, 3.8 and 3.1 for THC, HHC and OHC, respectively. The number (n) of curcumin and Dmc were 2.7 and 2.0, respectively, which are comparable to trolox, while it was 1.4 for Bdmc. The inhibition of AAPH induced red blood cell hemolysis significantly decreased in the order OHC>THC=HHC>trolox>curcumin=Dmc. Results in all models demonstrated the lower antioxidant activity of the demethoxy derivatives, suggesting the ortho-methoxyphenolic groups of curcumin are involved in antioxidant activities. On the other hand, hydrogenation at conjugated double bonds of the central seven carbon chain and beta diketone of curcumin to THC, HHC and OHC remarkably enhance antioxidant activity.

Topics: Amidines; Antioxidants; Biphenyl Compounds; Chromans; Curcumin; Diarylheptanoids; Erythrocyte Membrane; Free Radical Scavengers; Free Radicals; Hemolysis; Humans; Hydrogenation; In Vitro Techniques; Linoleic Acid; Lipid Peroxidation; Molecular Structure; Oxidants; Picrates; Structure-Activity Relationship; Time Factors

Curcuma longa (Zingiberaceae) has been used traditionally as antidiabetic, and has been proven scientifically to possess high antioxidant activity and anticancer properties. The active components of Curcuma longa such as curcumin and tetrahydrocurcumin (THC), a major colourless metabolite of curcumin also possesses antidiabetic, antiinflammatory and antioxidant activity. The ethnopharmacological value of this plant, the effect of THC on glycoproteins was carried out in normal and streptozotocin-nicotiniamide induced type 2 hyperglycaemic rats for 45 days. Glucose, plasma insulin and glycoprotein components in plasma and tissues (hexose, hexosamine, fucose and sialic acid) were determined. Oral administration of THC to diabetic rats showed a decrease in the level of blood glucose and plasma glycoproteins. The levels of plasma insulin and tissue sialic acid were increased where as the levels of tissue hexose, hexosamine and fucose were near normal in diabetic rats treated with THC. The present study indicates that the THC possesses a significant beneficial effect on glycoprotein moiety in addition to its antidiabetic effect. The effect of THC is more prominent than curcumin.

Topics: Animals; Blood Glucose; Curcuma; Curcumin; Diabetes Mellitus, Experimental; Glycoproteins; Insulin; Male; Niacinamide; Plant Extracts; Random Allocation; Rats; Streptozocin

The effect of feeding of two different antioxidants, tetrahydrocurcumin (TC) and green tea polyphenols (PPs) on the survival of male C57BL/6 mice was examined. Mice that started to receive diets containing TC (0.2%) at the age of 13 months had significantly longer average life spans (days, mean +/- SD) than control mice (797.6 +/- 151.2 vs.882 +/- 154.6, both n = 50, controls vs. TC treated, plus 11.7%, P < 0.01). The 10% longest survival was also significantly greater in TC-treated mice (plus 6.5%, P < 0.01). In contrast, in mice that started to receive TC in their 19th month of life, no significant difference from the control mice was found for either the average life span or the 10% longest survival. In mice that received water containing PPs (80 mg/l), the average life span was also significantly longer than in the control mice (801 +/- 121.5 vs. 852.7 +/- 88.2, plus 6.4%, P < 0.05), although the 10% longest survival was not significantly different from that in the control mice (P > 0.05). The body weights of the TC (but not PP) fed mice, were slightly (2-4%) but significantly (P < 0.05) lower than the values for the corresponding ages in the control mice in the first six months of treatment. Thereafter, the difference in average body weight between the control and the TC-fed animals was totally lost. Although an additional contribution of an unintended slight decrease in food intake due to TC feeding (suspected due to the difference in body weight) is not excluded, we suggest that the feeding of nutritional antioxidants such as TC and PPs may have the potential to beneficially modify the life spans of animals.

Topics: Aging; Animals; Body Weight; Camellia sinensis; Curcumin; Flavonoids; Kaplan-Meier Estimate; Longevity; Male; Mice; Mice, Inbred C57BL; Phenols; Plant Extracts; Polyphenols; Tea

Curcumin, a component of turmeric (Curcuma longa), has been shown to exhibit chemopreventive activity. Whether analogs of curcumin (Cur), such as demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumin (THC) and turmerones, modulate inflammatory signaling and cell proliferation signaling to same extent as curcumin was investigated. The results indicate that the relative potency for suppression of tumor necrosis factor (TNF)-induced nuclear factor-kappaB (NF-kappaB) activation was Cur > DMC > BDMC; thus suggesting the critical role of methoxy groups on the phenyl ring. THC, which lacks the conjugated bonds in the central seven-carbon chain, was completely inactive for suppression of the transcription factor. Turmerones also failed to inhibit TNF-induced NF-kappaB activation. The suppression of NF-kappaB activity correlated with inhibition of NF-kappaB reporter activity and with down-regulation of cyclooxygenase-2, cyclin D1 and vascular endothelial growth factor, all regulated by NF-kappaB. In contrast to NF-kappaB activity, the suppression of proliferation of various tumor cell lines by Cur, DMC and BDMC was found to be comparable; indicating the methoxy groups play minimum role in the growth-modulatory effects of curcumin. THC and turmerones were also found to be active in suppression of cell growth but to a much lesser extent than curcumin, DMC and BDMC. Whether suppression of NF-kappaB or cell proliferation, no relationship of any of the curcuminoid was found with reactive oxygen species (ROS) production. Overall, our results demonstrated that different analogs of curcumin present in turmeric exhibit variable anti-inflammatory and anti-proliferative activities, which do not correlate with their ability to modulate the ROS status.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Tumor; Curcumin; Diarylheptanoids; Glutathione; Growth Inhibitors; Humans; Jurkat Cells; NF-kappa B; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction; Tumor Necrosis Factor-alpha; U937 Cells

In vascular smooth muscle cells (VSMCs), induction of the heme oxygenase-1 (HO-1) confers vascular protection against cellular proliferation mainly via its up-regulation of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) that is involved in negative regulation of cellular proliferation. In the present study, we investigated whether the phytochemical curcumin and its metabolite tetrahydrocurcumin could induce HO-1 expression and growth inhibition in rat VSMCs and, if so, whether their antiproliferative effect could be mediated via HO-1 expression. At non-toxic concentrations, curcumin possessing two Michael-reaction acceptors induced HO-1 expression by activating antioxidant response element (ARE) through translocation of the nuclear transcription factor E2-related factor-2 (Nrf2) into the nucleus and also inhibited VSMC growth triggered by 5% FBS in a dose-dependent manner. In contrast, tetrahydrocurcumin lacking Michael-reaction acceptor showed no effect on HO-1 expression, ARE activation and VSMC growth inhibition. The antiproliferative effect of curcumin in VSMCs was accompanied by the increased expression of p21(WAF1/CIP1). Inhibition of VSMC growth and expression of p21(WAF1/CIP1) by curcumin were partially, but not completely, abolished when the cells were co- incubated with the HO inhibitor tin protoporphyrin. In human aortic smooth muscle cells (HASMCs), curcumin also inhibited growth triggered by TNF-alpha and increased p21(WAF1/CIP1) expression via HO-1-dependent manner. Our findings suggest that curcumin has an ability to induce HO-1 expression, presumably through Nrf2-dependent ARE activation, in rat VSMCs and HASMCs, and provide evidence that the antiproliferative effect of curcumin is considerably linked to its ability to induce HO-1 expression.

Topics: Active Transport, Cell Nucleus; Animals; Aorta; Cell Nucleus; Cell Proliferation; Cells, Cultured; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Gene Expression Regulation; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Metalloporphyrins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-E2-Related Factor 2; Protoporphyrins; Rats; Regulatory Sequences, Nucleic Acid; Response Elements; Tumor Necrosis Factor-alpha

The Government Pharmaceutical Organization of Thailand (GPO) has developed many products using liposome nanotechnology and Thai herbal extracts.. Evaluate the irritation potential of GPO products on human skin using the single application closed patch test under occlusion. The authors also studied the moisturizing efficacy of a commercial curmin extract cream (GPO curmin cream).. Thirty-six female volunteers were tested with 12 test materials developed by GPO including liposome, curmin extract: tetrahydrocurcuminoids (THC), and commercial curmin cream. Two and a half percent sodium dodecyl sulfate (SDS) was used as positive control. Standard Finn chambers on Scanpor tape with webril cotton were used as occlusive patch test devices. Cutaneous irritation responses were graded after patch removal and the incidence of irritation compared to the positive control was used for evaluation. Corneometer was used to measure skin hydration before and after application of curmin cream.. All volunteers completed the present study. The skin irritation effects from the test materials were significantly lower (p-value < 0.001, McNemar statistic test) than the positive control. Measurement of skin hydration after twice daily application of GPO curmin cream was significantly higher (p-value < 0.001, paired t-test) than the control skin.. The test materials and finished products developed by the GPO are not likely to induce skin irritation under normal conditions of use. Furthermore, twice-daily application of the commercial GPO curmin cream can significantly increase skin hydration.

Topics: Adult; Curcumin; Dermatitis, Irritant; Exanthema; Female; Humans; Middle Aged; Pilot Projects; Plant Extracts; Skin Care; Skin Irritancy Tests; Thailand

Oxidative damage has been suggested to be a contributory factor in the development and complication of diabetes. To investigate the effect of tetrahydrocurcumin (THC) on the occurrence of oxidative stress in the brain of rats during diabetes, we investigated the extent of oxidative damage as well as the status of the antioxidant defense system. Oral administration of THC at 80 mg/kg of body weight to diabetic rats for 45 days resulted in a significant reduction in blood glucose and significant increase in plasma insulin levels. In addition, THC caused significant increases in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, and reduced glutathione in the brains of diabetic rats with significant decrease in the lipid peroxidative markers thiobarbituric acid-reactive substances and hydroperoxides in brain, suggesting efficacy for protection against lipid peroxidation-induced membrane damage. The effect of THC was greater than that of curcumin. Results of the present study suggest that THC showed antioxidant effects in addition to its antidiabetic effect in type 2 diabetic rats.

Topics: Animals; Antioxidants; Blood Glucose; Brain; Curcumin; Diabetes Mellitus, Experimental; Free Radicals; Insulin; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Wistar

Curcuma longa (Zingiberaceae) has been used traditionally as antidiabetic and has been proven scientifically to possess high antioxidant activity and anticancer properties. The active components of Curcuma longa such as curcumin and tetrahydrocurcumin (THC), a major colourless metabolite of curcumin also possesses antidiabetic, antiinflammatory and antioxidant activity. In the present study the effect of THC and curcumin on erythrocyte membrane bound enzymes and antioxidants activity in streptozotocin (STZ) and nicotinamide induced type 2 diabetic model was investigated. Oral administration of THC at 80 mg/kg body weight to diabetic rats for 45 days. The effect of THC and curcumin on glucose, insulin, haemoglobin, glycosylated haemoglobin, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), glutathione peroxide (Gpx), glutathione-S-transferase (GST), reduced glutathione (GSH) and membrane bound enzymes were studied. The effect of THC was compared with curcumin. The levels of blood glucose, glycosylated haemoglobin, erythrocyte TBARS, were increased significantly whereas the level of plasma insulin and haemoglobin, erythrocyte antioxidants (SOD, CAT, GPx, GST and GSH), membrane bound total ATPase, Na(+)/K(+)-ATPase, Ca(2+)-ATPase, Mg(2+)-ATPase were decreased significantly in diabetic rats. Administration of THC and curcumin to diabetic rats showed decreased level of blood glucose, glycosylated haemoglobin and erythrocyte TBARS. In addition the levels of plasma insulin, haemoglobin, erythrocyte antioxidants and the activities of membrane bound enzymes also were increased in THC and curcumin treated diabetic rats. These biochemical observations were supplemented by histopathological examination of pancreas section. The present study indicates that the THC possesses a significant beneficial effect on erythrocyte membrane bound enzymes and antioxidants defense in addition to its antidiabetic effect.

Topics: Adenosine Triphosphatases; Animals; Blood Glucose; Catalase; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Erythrocyte Membrane; Erythrocytes; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Glycosylation; Hemoglobins; Hypoglycemic Agents; Insulin; Male; Pancreas; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Curcumin is the most active component of turmeric. It is believed that curcumin is a potent antioxidant and anti-inflammatory agent. Tetrahydrocurcumin is one of the major metabolites of curcumin that exhibits many of the same physiologic and pharmacological activities as curcumin and in some systems may exert greater antioxidant activity than curcumin. Oral administration of tetrahydrocurcumin at 80 mg/kg body weight to diabetic rats for 45 days resulted in a significant reduction in blood glucose and significant increase in plasma insulin levels. In addition, the diabetic rats had decreased levels of plasma total protein, albumin, globulin and albumin/globulin ratio as compared to control rats. After treatment with tetrahydrocurcumin and curcumin total protein, albumin, globulin and albumin/globulin ratio were brought back to near normal. The activities of hepatic and renal markers were significantly elevated in diabetic rats as compared to control rats, and treatment with tetrahydrocurcumin and curcumin has reversed these parameters to near normal levels. In diabetic rats, the decreased levels of urea, uric acid and creatinine with increased levels of albumin and urine volume was observed, and treatment with tetrahydrocurcumin and curcumin reversed these parameters to near normal. Tetrahydrocurcumin appeared to have a better protective effect when compared to curcumin.

Topics: Animals; Antioxidants; Biomarkers; Chemoprevention; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Kidney; Liver; Male; Niacinamide; Rats; Rats, Wistar; Streptozocin

Hyperlipidemia is an associated complication of diabetes mellitus. In the present study, we investigated the effect of tetrahydrocurcumin (THC), one of the active metabolites of curcumin on lipid profile in streptozotocin (STZ)-nicotinamide-induced diabetic rats. THC 80 mg/kg body weight was orally administered to diabetic rats for 45 days, resulting in a significant reduction in blood glucose and a significant increase in plasma insulin in diabetic rats, which proved that THC possess an antidiabetic effect. THC also caused a significant reduction serum and liver cholesterol, triglycerides, free fatty acids, phospholipids, HMG CoA reductase activity, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol levels. The decreased serum high-density lipoprotein (HDL) cholesterol in diabetic rats was also reversed toward normalization after the treatment. These biochemical observations were supplemented by histopathological examination of liver section. The effect was compared with curcumin (80 mg/kg body weight). The results showed that THC had antihyperlipidemic action in control and experimental diabetic rats. The antidiabetic and antihyperlipidemic effects of THC are more potent than those of curcumin at the same dose.

Topics: Animals; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hydroxymethylglutaryl CoA Reductases; Hypolipidemic Agents; Lipid Metabolism; Liver; Male; Rats; Rats, Wistar; Streptozocin

Changes in the structural and functional properties of collagen caused by advanced glycation might be of importance for the etiology of late-stage complications in diabetics. Curcumin is the most active component of turmeric. It is believed that curcumin is a potent antioxidant and anti-inflammatory agent. Tetrahydrocurcumin (THC) is one of the major metabolites of curcumin, exhibiting many of the same physiological and pharmacological activities of curcumin and in some systems may exert greater antioxidant activity than curcumin. In diabetic rats, hydroxyproline and collagen content as well as its degree of cross-linking were increased, as shown by increased extent of glycation, collagen-linked fluorescence, neutral salt collagen, and decreased acid and pepsin solubility. Administration of THC for 45 days to diabetic rats significantly reduced the accumulation and cross-linking of collagen. The effects of THC were comparable with those of curcumin. In conclusion, administration of THC had a positive influence on the content of collagen and its properties in streptozotocin- and nicotinamide-induced diabetic rats. THC was found to be more effective than curcumin.

Topics: Animals; Collagen; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hydroxyproline; Male; Niacinamide; Rats; Rats, Wistar; Streptozocin; Tail; Tendons

To study pharmacokinetic properties of curcumin, a fast sensitive assay method was developed to determine curcumin and its metabolite tetrahydrocurcumin in rat plasma. The assay was based on tandem mass spectrometry detection (LC/MS/MS). Salbutamol was used as the internal standard (IS). The method had the lower limit of quantitation (LLOQ) of 0.5 ng/ml in rat plasma, which corresponds to 2.5 pg for the 5 microl injection volume. Good linearity was got to 500 ng/ml. The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Phospholipid complex of the natural compound curcumin was prepared in order to improve its bioavailability. Complex formation resulted in an obvious increase in bioavailability of curcumin in rat in vivo according to the assay by above LC/MS/MS method.

Topics: Animals; Biological Availability; Calibration; Chromatography, High Pressure Liquid; Curcumin; Male; Mass Spectrometry; Phospholipids; Rats; Rats, Sprague-Dawley; Reference Standards; Reproducibility of Results; Solutions

Oxidative stress has been suggested to be a contributory factor in development and complication of diabetes. In the present study, we have investigated the effect of tetrahydrocurcumin (THC), one of the active metabolites of curcumin on antioxidants status in streptozotocin-nicotinamide induced diabetic rats. Oral administration of THC at 80 mg/kg body weight of diabetic rats for 45 days resulted in significant reduction in blood glucose and significant increase in plasma insulin levels. In addition, THC caused significant increase in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, reduced glutathione, vitamin C and vitamin E in liver and kidney of diabetic rats with significant decrease in thiobarbituric acid reactive substances (TBARS) and hydroperoxides formation in liver and kidney, suggesting its role in protection against lipid peroxidation induced membrane damage. These biochemical observations were supplemented by histopathological examination of liver and kidney section. The antidiabetic and antioxidant effects of THC are more potent than those of curcumin at the same dose. Results of the present study indicated that THC showed antioxidant effect in addition to its antidiabetic effect in type 2 diabetic rats.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Glucose; Curcumin; Diabetes Mellitus, Experimental; Glutathione; Glutathione Transferase; Insulin; Kidney; Lipid Peroxidation; Liver; Male; Niacinamide; Oxidative Stress; Oxidoreductases; Rats; Rats, Wistar; Streptozocin; Thiobarbituric Acid Reactive Substances; Vitamin E

Hyperlipidaemia is an associated complication of diabetes mellitus. We recently reported that tetrahydrocurcumin lowered the blood glucose in diabetic rats. In the present study, we have investigated the effect of tetrahydrocurcumin, one of the active metabolites of curcumin on lipid profile and lipid peroxidation in streptozotocin-nicotinamide-induced diabetic rats. Tetrahydrocurcumin 80 mg/kg body weight was administered orally to diabetic rats for 45 days, resulted a significant reduction in blood glucose and significant increase in plasma insulin in diabetic rats, which proved its antidiabetic effect. Tetrahydrocurcumin also caused a significant reduction in lipid peroxidation (thiobarbituric acid reactive substances and hydroperoxides) and lipids (cholesterol, triglycerides, free fatty acids and phospholipids) in serum and tissues, suggesting its role in protection against lipid peroxidation and its antihyperlipidemic effect. Tetrahydrocurcumin showed a better effect when compared with curcumin. Results of the present study indicate that tetrahydrocurcumin showed antihyperlipidaemic effect in addition to its antidiabetic effect in type 2 diabetic rats.

Topics: Animals; Blood Glucose; Cholesterol; Curcumin; Diabetes Mellitus, Experimental; Fatty Acids, Nonesterified; Glycated Hemoglobin; Insulin; Intubation, Gastrointestinal; Kidney; Lipid Metabolism; Lipid Peroxidation; Lipid Peroxides; Liver; Male; Molecular Structure; Niacinamide; Phospholipids; Rats; Rats, Wistar; Streptozocin; Thiobarbiturates; Triglycerides

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.

Topics: Administration, Oral; Animals; Antioxidants; Chemoprevention; Chloroquine; Creatinine; Curcumin; Disease Models, Animal; Female; Kidney; Lipid Peroxidation; Nephritis; Oxidative Stress; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Urea

Clinical research has confirmed the efficacy of several photo-chemicals in modulating oxidative stress associated with diabetes mellitus. Here we investigate the effect of tetrahydrocurcumin (THC), an active metabolite of curcumin, on antioxidant status in streptozotocin-nicotinamide-induced diabetes in rats. A single dose of streptozotocin (65 mg kg(-1) bwt) resulted in decreased insulin, hyperglycemia, increased lipid peroxidation (thiobarbituric reactive substances, lipid hydroperoxides), and decreased antioxidant levels (vitamin C, vitamin E, reduced glutathione and ceruloplasmin). The oral administration of THC (80 mg kg(-1) bwt) for 45 days to diabetic rats significantly increased plasma insulin and plasma antioxidants and significantly decreased lipid peroxidation. The positive effects of THC were better that those achieved with curcumin. The results of the study indicate that in addition to its antidiabetic effect in type 2 diabetic rats, THC has an antioxidant effect.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Blood Glucose; Ceruloplasmin; Curcumin; Diabetes Mellitus, Experimental; Glutathione; Hyperglycemia; Insulin; Lipid Peroxidation; Male; Niacinamide; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Vitamin E

Tetrahydrocurcumin (THC) is an antioxidative substance, which is derived from curcumin, the component of turmeric. In the present investigation, the effect of THC and curcumin against chloroquine (CQ) induced hepatotoxicity were studied in female Wistar rats.. On single oral administration of CQ (970 mg/kg body weight) the activities of serum marker enzymes namely aspartate transaminase, alanine transaminase and alkaline phosphatase and the levels of bilirubin were significantly increased with significant alterations of lipids in serum and lipidperoxidation markers such as thiobarbituric acid reactive substances (TBARS) and hydroperoxides in plasma and liver were also elevated in CQ treated rats. The levels of non-enzymic antioxidants (vitamin C, vitamin E and reduced glutathione) and enzymic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) were also decreased in CQ treated rats. Administration of THC (80 mg/kg body weight) and curcumin (80 mg/kg body weight) for 8 days before and 7 days after single administration of CQ significantly decreased the activities of serum markers and lipids in serum. In addition, the level of TBARS and hydroperoxides were significantly decreased with significant increase in non-enzymic and enzymic antioxidants on treatment with THC and curcumin. The biochemical observation was supplemented by histopathological examination of liver section. The results of the study reveal that THC shows more pronounced protective effect than curcumin against CQ induced toxicity.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chloroquine; Curcuma; Curcumin; Female; Liver Diseases; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances

Curcumin is a well-known chemopreventive agent of oral cancers as well as stomach and intestinal cancers. The relationship between reactive oxygen species (ROS) production and cell membrane mobility was investigated to clarify the pro-oxidant mechanism of curcumin and tetrahydrocurcumin (TH-curcumin).. The intracellular ROS production and membrane mobility by curcumin or TH-curcumin were measured in human submandibular adenocarcinoma cells (HSGs) and human primary gingival fibroblasts (HGFs). ROS and mobility were measured by 5-(and -6)-carboxy-2',7'-dichlorofluorescein diacetate staining and fluorescence recovery after photo bleaching, respectively.. Curcumin produced ROS dose-dependently. ROS appeared in the region surrounding the cell membrane. The membrane mobility coefficient of the curcumin-treated cells was significantly lower than that of control cells. The lowered membrane mobility induced by curcumin was reversed by the addition of glutathione, an antioxidant. In contrast, TH-curcumin did not affect the ROS production or the membrane mobility coefficient. The alternations induced by curcumin treated HSG cells were greater than those by HGF cells.. The reduction in membrane mobility induced by curcumin was attributed to ROS production. The oxidative effects of curcumin may be related to the structure of the alpha, beta-unsaturated carbonyl moiety as well as the phenolic OH group of this compound.

Topics: Adenocarcinoma; Anticarcinogenic Agents; Antioxidants; Cell Line, Tumor; Cells, Cultured; Curcumin; Dose-Response Relationship, Drug; Fibroblasts; Fluorescence Recovery After Photobleaching; Gingiva; Humans; Membrane Fluidity; Molecular Structure; Oxidants; Reactive Oxygen Species; Submandibular Gland Neoplasms

Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, exhibits many of the same physiologic and pharmacological activities as curcumin and in some systems may exert greater antioxidant activity than curcumin. However, evaluation of clinical efficacy is limited by lack of sensitive methods for quantifying intake/absorption in blood or urine. We have developed a sensitive high performance liquid chromatography (HPLC) analytical method for detection of THC in plasma and urine. The method involves extracting the THC from 0.2 mL samples with 95% ethyl acetate/5% methanol, and beta-17-estradiol acetate as an internal standard. Analysis with a reversed-phase C18 column and UV detection at 280 nm demonstrates linear performance from 0.050 to 6.0 microg/mL in plasma, and 0.060 to 6.0 microg/mL in urine. The coefficients of variation for intra- and inter-assays were each<8.6%. The average recovery of THC from plasma and urine was greater than 98.5%. These data demonstrate a rapid, sensitive and accurate method for HPLC quantification of THC in plasma and urine.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, High Pressure Liquid; Curcumin; Female; Humans; Male; Mice; Mice, Inbred C57BL; Reference Standards; Reproducibility of Results

Erythromycin estolate (EME), a potent macrolide antibiotic, generates free radicals, but their role in the development of liver toxicity is not yet well understood. The present study was carried out to investigate the effect of the antioxidant drug tetrahydrocurcumin (a metabolite of curcumin, the main component of turmeric) against EME-induced lipid peroxidation in rats. The oral administration of combined THC (80 mg/kg body weight) and EME (800 mg/kg body weight) for 15 days significantly decreased lipid peroxidation and enhanced cellular antioxidant defenses when compared with the group treated with EME alone. Supplemental histopathological examination of liver sections revealed that THC had a better antioxidant effect than Silymarin (200 mg/kg body weight), a reference drug. The results of this study indicate that THC affords significant protection against EME-induced lipid peroxidation.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Catalase; Curcumin; Erythromycin Estolate; Female; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Hydrogen Peroxide; Kidney; Lipid Peroxidation; Liver; Oxidants; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

The enzymes of glucose and lipid metabolism are markedly altered in experimental diabetes. In the present study, we investigated the effect of tetrahydrocurcumin (THC), one of the active metabolites in curcumin, on the key hepatic metabolic enzymes involved in carbohydrate metabolism in streptozotocin-induced diabetic rats. Different doses of THC (20, 40, and 80 mg\\kg body weight) were orally administered to diabetic rats for 45 days. The activities of hexokinase, glucose-6-phosphate dehydrogenase (G6PD), glucose-6-phosphatase, fructose-1,6-bisphosphatase, and sorbitol dehydrogenase in liver, and glycogen content in liver and muscle were assayed. In untreated diabetic control rats, the activities of the gluconeogenic enzymes were significantly increased, whereas hexokinase and G6PD activity and glycogen levels were significantly decreased. Both THC and curcumin were able to restore the altered enzyme activities to near normal levels. Tetrahydrocurcumin was more effective than curcumin. Our results indicate that the administration of THC to diabetic animals normalizes blood glucose and causes a marked improvement of altered carbohydrate metabolic enzymes.

Topics: Animals; Blood Glucose; Body Weight; Carbohydrate Metabolism; Curcumin; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Glycated Hemoglobin; Glycogen; Hemoglobins; Insulin; Liver; Male; Rats; Rats, Wistar

Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, was investigated for its possible hepatoprotective effect in Wistar rats against erythromycin estolate-induced toxicity. Oral administration of THC significantly prevented the occurrence of erythromycin estolate-induced liver damage. The increased level of serum enzymes (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP)), bilirubin, cholesterol, triglycerides, phospholipids, free fatty acids and plasma thiobarbituric acid reactive substances (TBARS) and hydroperoxides observed in rats treated with erythromycin estolate were very much reduced in rats treated with THC and erythromycin estolate. This biochemical observation were supplemented by histopathological examination of liver section. Results of this study revealed that THC could afford a significant protection against erthromycin estolate-induced hepatocellular damage. Tetrahydrocurcumin had a better protective effect when compared with Silymarin, a reference drug.

Topics: Administration, Oral; Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Butylated Hydroxytoluene; Chemical and Drug Induced Liver Injury; Cholesterol; Curcumin; Erythromycin Estolate; Fatty Acids, Nonesterified; Female; Glutathione; Lipid Peroxides; Phospholipids; Rats; Rats, Wistar; Silymarin; Thiobarbiturates; Triglycerides

So-called antioxidant strategies have not been shown convincingly to be effective in increasing life spans of animals. Thus, the general consensus of experimental gerontology in the last century was that the only reproducible means of prolonging survivals of animals is the calorie restriction paradigm. As a challenge against this dogma, we attempted to examine the effect of two potent antioxidants, one tetrahydrocurcumin (a biotransformed metabolite of curcumin contained in turmeric of Indian curry) and the other green tea polyphenols.

Topics: Aging; Animal Nutritional Physiological Phenomena; Animals; Antioxidants; Arteriosclerosis; Curcumin; Flavonoids; Longevity; Male; Mice; Mice, Inbred C57BL; Nutritional Physiological Phenomena; Phenols; Polyphenols; Tea

In this study, some of the synthetic curcuminoid derivatives are analyzed for their anti-angiogenic activity. Intraperitoneal administration of the compounds tetrahydrocurcumin (THC), salicyl curcumin (SC) and curcuminIII (C-III) reduced the number of tumour directed capillaries induced by injecting B16F-10 melanoma cells on the ventral side of C57BL/6 mice. THC (14.5 +/- 2.5 capillaries) and SC (16 +/- 2.5 capillaries) were more significant (P < 0.001) than C-III (19 +/- 1.8 capillaries) compared to the untreated control (30.8 +/- 2.1 capillaries). Treatment with these curcuminoids reduced the serum NO as well as TNF-alpha levels of the angiogenesis-induced animals. In vitro NO and TNF-alpha production by the activated MOs were reduced in a concentration dependent manner by the treatment of the curcuminoid compounds.

Topics: Angiogenesis Inhibitors; Animals; Capillaries; Curcumin; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Nitric Oxide; Phytotherapy; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Topics: Allergens; Curcuma; Curcumin; Dermatitis, Allergic Contact; Diagnosis, Differential; Female; Humans; Middle Aged; Patch Tests; Sunscreening Agents

Tetrahydrocurcumin (THC) is an antioxidative substance which is derived from curcumin by hydrogenation. Curcumin is the main component of turmeric and is responsible for the yellow color of curried foods.First, LDL derived from a normal human volunteer was incubated in the presence of an antioxidant with 10 microM CuSO(4) at 37 degrees C for 2 hours.All antioxidants tested (THC, curcumin, probucol, and alpha-tocopherol) dose-dependently (1-10 microM) inhibited the oxidative modification of LDL. Probucol was the strongest, followed by THC, alpha-tocopherol, and curcumin.Next, in order to evaluate the antioxidative activity of THC in vivo, we fed rabbits diets containing 1% cholesterol with or without 0.5% THC and examined their effects on oxidative stress and atherosclerosis. Animals were divided into two groups: the control group rabbits (n = 12) were fed a normal chow diet and the experimental group (n = 12) was fed a diet containing 0.5% THC for one week.Then, 1% cholesterol was added to the diets and the animals were allowed to feed further for either 6 (n = 4 for each group) or 12 weeks (n = 8 for each group). Although serum cholesterol levels rapidly increased after starting the high cholesterol diet, no difference was observed between the control and THC groups.TBARS formation in the absence of added copper ion was inhibited in the LDL separated from THC-treated animals compared with that from control animals.THC treatment tended to inhibit the area covered with atherosclerotic lesions compared with the control, although this was not significant (28.8 +/- 17.5% vs. 40.0 +/- 23.7%, p = 0.2). Formation of N(epsilon)-(hexanoyl) lysine, 4-hydroxynonenal and dityrosine in liver and kidney also had a tendency to be inhibited by THC treatment. Although free THC was not detected in serum and liver, THC was detected in samples treated with beta-glucuronidase and sulfatase, suggesting that THC is present as a conjugate with glucuronic acid or sulfate. In conclusion, the present results suggest that curcuminoids, particularly THC, which are contained in turmeric, may be useful as a functional food factor.

Topics: alpha-Tocopherol; Animals; Antioxidants; Body Weight; Cholesterol, Dietary; Curcumin; Enzyme-Linked Immunosorbent Assay; Humans; Kidney; Lipoproteins, LDL; Liver; Male; Organ Size; Oxidative Stress; Rabbits; Thiobarbituric Acid Reactive Substances; Tyrosine

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

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

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.

Topics: Animals; Antioxidants; Curcumin; Gamma Rays; Lipid Peroxidation; Male; Microsomes, Liver; Molecular Structure; Pulse Radiolysis; Rats; Rats, Wistar

Nitric oxide (NO) plays an important role in inflammation and in the multiple stages of carcinogenesis. In this study, we investigated the inhibitory effects of curcumin and its metabolites, tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin, on the induction of NO synthase (NOS) in RAW 264.7 cells activated with lipopolysaccharide (LPS). Western blotting and northern blotting analyses demonstrated that curcumin strongly reduced 130-kDa protein and 4.5-kb mRNA levels of iNOS in LPS-activated macrophages compared with its metabolites, tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin. Moreover, electrophoretic mobility shift assay (EMSA) experiments indicated that curcumin blocked the LPS-induced binding of nuclear factor-kappaB (NFkappaB), a transcription factor necessary for iNOS induction to its (32)P-labeled double-stranded oligonucleotide probe. The inhibition of NFkappaB activation occurred through the prevention of inhibitor kappaB (IkappaB) degradation. Transient transfection experiments also showed that curcumin inhibited NFkappaB-dependent transcriptional activity. Curcumin blocked the disappearance of inhibitory kappaBalpha (IkappaBalpha) and p65 from the cytosolic fraction, and inhibited the phosphorylation of IkappaBalpha. Furthermore, we showed that curcumin could inhibit the IkappaB kinase 1 (IKK1) and IkappaB kinase 2 (IKK2) activities induced by LPS, but tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin were less active. These results suggest that curcumin may exert its anti-inflammatory and anti-carcinogenic properties by suppressing the activation of NFkappaB through inhibition of IKK activity.

Topics: Animals; Cells, Cultured; Curcumin; Down-Regulation; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Hydrogenation; I-kappa B Kinase; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phosphorylation; Protein Serine-Threonine Kinases; RNA, Messenger

Curcumin, the yellow pigment in turmeric and curry, has antioxidative and anticarcinogenic activities. In this study, we investigated the pharmacokinetic properties of curcumin in mice. After i.p. administration of curcumin (0.1 g/kg) to mice, about 2.25 microg/ml of curcumin appeared in the plasma in the first 15 min. One hour after administration, the levels of curcumin in the intestines, spleen, liver, and kidneys were 177.04, 26.06, 26.90, and 7.51 microg/g, respectively. Only traces (0.41 microg/g) were observed in the brain at 1 h. To clarify the nature of the metabolites of curcumin, the plasma was analyzed by reversed-phase HPLC, and two putative conjugates were observed. Treatment of the plasma with beta-glucuronidase resulted in a decrease in the concentrations of these two putative conjugates and the concomitant appearance of tetrahydrocurcumin (THC) and curcumin, respectively. To investigate the nature of these glucuronide conjugates in vivo, the plasma was analyzed by electrospray. The chemical structures of these metabolites, determined by mass spectrometry/mass spectrometry analysis, suggested that curcumin was first biotransformed to dihydrocurcumin and THC and that these compounds subsequently were converted to monoglucuronide conjugates. Because THC is one of the major metabolites of curcumin, we studied its stability at different pH values. THC was very stable in 0.1 M phosphate buffers of various pH values. Moreover, THC was more stable than curcumin in 0.1 M phosphate buffer, pH 7.2 (37 degrees C). These results, together with previous findings, suggest that curcumin-glucuronoside, dihydrocurcumin-glucuronoside, THC-glucuronoside, and THC are major metabolites of curcumin in vivo.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Biotransformation; Chromatography, High Pressure Liquid; Curcumin; Female; Glucuronates; Glucuronidase; Hydrolysis; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Oxidation-Reduction; Tissue Distribution

The inhibitory effects of curcumin and two tetrahydrocurcuminoids on tumor promoter-induced oxidative stress in vitro and in vivo were investigated. Curcumin, tetrahydrocurcumin (THC) and dihydroxytetrahydrocurcumin (DHTHC) exhibited significant inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced O2-generation in differentiated HL-60 cells. The inhibitory activity of THC was weaker than that of curcumin. This tendency was the inverse of the results of previous studies on in vitro antioxidative activity against lipid peroxidation. The curcuminoids inhibited TPA-induced intracellular peroxide formation in differentiated HL-60 cells. THC exhibited much weaker inhibition of intracellular peroxide formation than curcumin, suggesting that this inhibition might be attributable to the inhibition of O2-generation. The inhibitory effects of curcuminoids on TPA-induced H2O2 formation in female ICR mouse skin were further examined using the double-TPA-application model. Each TPA application induces two distinct biochemical events, 1) recruitment of inflammatory cells to the inflammatory regions and 2) activation of oxidant-producing cells. Double pretreatment of mice with curcuminoids before each TPA treatment significantly suppressed double TPA application-induced H2O2 formation in the mouse skin. Coadministrations of curcumin with either first or second TPA treatment significantly inhibited H2O2 formation. In addition, THC tends to show weaker inhibitory activities than curcumin in bioassays related to tumor promotion, i.e., inhibition of tumor promoter-induced inflammation in mouse skin and Epstein-Barr virus activation. These tendencies were parallel to those in the tumor-suppressive potential of curcumin and THC in mouse skin, as previously reported. Thus, we concluded that curcuminoids significantly suppress TPA-induced oxidative stress via both interference with infiltration of leukocytes into the inflammatory regions and inhibition of their activation.

Topics: Animals; Anticarcinogenic Agents; Antigens, Viral; Curcumin; Edema; Female; Fluorescent Antibody Technique, Indirect; Hydrogen Peroxide; Leukocytes; Mice; Mice, Inbred ICR; Oxidative Stress; Reactive Oxygen Species; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Commercial grade curcumin (approximately 77% curcumin, 17% demethoxycurcumin and 3% bisdemethoxycurcumin) is widely used as a yellow coloring agent and spice in foods. In the present study topical application of commercial grade curcumin, pure curcumin or demethoxycurcumin had an equally potent inhibitory effect on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases in ornithine decarboxylase activity and TPA-induced tumor promotion in 7,12-dimethylbenz[a]anthracene-initiated mouse skin. Bisdemethoxycurcumin and tetrahydrocurcumin were less active. In additional studies we found that commercial grade curcumin, pure curcumin, demethoxycurcumin and bisdemethoxycurcumin had about the same potent inhibitory effect on TPA-induced inflammation of mouse ears, as well as TPA-induced transformation of cultured JB6 (P+) cells. Tetrahydrocurcumin was less active. The results indicate that pure curcumin and demethoxycurcumin (the major constituents of commercial grade curcumin) have the same potent inhibitory effects as commercial grade curcumin for inhibition of TPA-induced tumor promotion, but bisdemethoxycurcumin and tetrahydrocurcumin are less active.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Cell Line; Cell Transformation, Neoplastic; Coumaric Acids; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Enzyme Induction; Female; Mice; Mice, Inbred Strains; Ornithine Decarboxylase; Skin; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Time Factors