curcumin and bisdemethoxycurcumin

Curcuminoids are turmeric-extracted phytochemicals with documented chemopreventive and anti-tumor activities against several types of malignancies. Curcuminoids can modulate several molecular pathways and cellular targets involved in different stages of tumor initiation, growth, and metastasis. Bisdemethoxycurcumin (BDMC) is a minor constituent (approximately 3%) of curcuminoids that has been shown to be more stable than the other two main curcuminoids, that is, curcumin and demthoxycurcumin. Recent studies have revealed that BDMC has anti-tumor effects exerted through a multimechanistic mode of action involving inhibition of cell proliferation, invasion and migration, metastasis and tumour growth, and induction of apoptotic death in cancer cells. The present review discusses the findings on the anti-tumor effects of BDMC, underlying mechanisms, and the relevance of finding for translational studies in human.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Diarylheptanoids; Humans; Neoplasms; Phytotherapy; Plants, Medicinal

Alzheimer's disease (AD) is the most common form of dementia. There is limited choice in modern therapeutics, and drugs available have limited success with multiple side effects in addition to high cost. Hence, newer and alternate treatment options are being explored for effective and safer therapeutic targets to address AD. Turmeric possesses multiple medicinal uses including treatment for AD. Curcuminoids, a mixture of curcumin, demethoxycurcumin, and bisdemethoxycurcumin, are vital constituents of turmeric. It is generally believed that curcumin is the most important constituent of the curcuminoid mixture that contributes to the pharmacological profile of parent curcuminoid mixture or turmeric. A careful literature study reveals that the other two constituents of the curcuminoid mixture also contribute significantly to the effectiveness of curcuminoids in AD. Therefore, it is emphasized in this review that each component of the curcuminoid mixture plays a distinct role in making curcuminoid mixture useful in AD, and hence, the curcuminoid mixture represents turmeric in its medicinal value better than curcumin alone. The progress in understanding the disease etiology demands a multiple-site-targeted therapy, and the curcuminoid mixture of all components, each with different merits, makes this mixture more promising in combating the challenging disease.

Topics: Alzheimer Disease; Animals; Curcuma; Curcumin; Diarylheptanoids; Humans; Molecular Structure; Phytotherapy

Curcuminoids are safe natural yellow pigments used as food coloring agents and traditional drugs with a variety of biological functions such as antitumor, anti-inflammatory and antioxidant activities. Poor oral bioavailability and the low plasma concentration of curcuminoids limited their clinical use, and one of the major reasons is their rapid metabolism in vivo. The predominant metabolic pathways are reduction and conjugation, and some drug metabolizing enzymes such as alcohol dehydrogenase, UDP-glucuronosyltransferases (UGTs) or sulfotransferases (SULTs) involved in the metabolic reactions. Besides the major metabolic pathways, dehydroxylation, cyclization and methylation can also occur in vivo. In addition, more than thirty metabolites of curcuminoids have been identified in biological matrices including the plasma, urine and bile from rats or humans by LC-MS/MS analysis and other methods. Some metabolites such as tetrahydro-curcuminoids have been reported to be active, which may explain how and why curcuminoids with poor oral bioavailability display their effectiveness in vivo. The present review mainly summarizes curcuminoid metabolism and its contribution to the pharmacological effects.

Topics: Animals; Biological Availability; Curcumin; Diarylheptanoids; Humans; Tissue Distribution

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of intracellular and extracellular aggregates. According to the amyloid beta (Abeta) hypothesis, amyloidosis occurring in the brain is a leading cause of neurodegeneration in AD. Defects in the innate immune system may decrease the clearance of Abeta in the brain. Macrophages of most AD patients do not transport Abeta into endosomes and lysosomes, and monocytes from AD patients do not efficiently clear Abeta from AD brain. After stimulation with Abeta, mononuclear cells of normal subjects display up-regulated transcription of MGAT3, which encodes beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase, and Toll-like receptor (TLR) genes. Monocytes of AD patients generally down-regulate these genes. A commonly used, naturally occurring material from a spice that enhances certain key functions defective in cells of innate immunity of many AD patients has shown epidemiologic rationale for use in AD treatment. Bisdemethoxycurcumin, a natural curcumin, is a minor constituent of turmeric (curry), and it enhances phagocytosis and clearance of Abeta in cells from most AD patients. We confirmed the effectiveness of a synthetic version of the same compound. In mononuclear cells of most AD patients, bisdemethoxycurcumin enhanced defective phagocytosis of Abeta and increased the transcription of MGAT3 and TLR genes. The potency of bisdemethoxycurcumin as a highly purified compound in facilitating the clearance of Abeta in mononuclear cells suggests the promise of enhanced effectiveness compared to curcuminoid mixtures. Bisdemethoxycurcumin appears to enhance immune function in mononuclear cells of AD patients and may provide a novel approach to AD immunotherapy.

Topics: Acyltransferases; Alzheimer Disease; Amyloid beta-Peptides; Animals; Curcumin; Diarylheptanoids; Humans; Immunity, Innate; Leukocytes, Mononuclear; Models, Biological; Toll-Like Receptors

The optimal health benefits of curcumin are limited by its low solubility in water and corresponding poor intestinal absorption. Cyclodextrins (CD) can form inclusion complexes on a molecular basis with lipophilic compounds, thereby improving aqueous solubility, dispersibility, and absorption. In this study, we investigated the bioavailability of a new γ-cyclodextrin curcumin formulation (CW8). This formulation was compared to a standardized unformulated curcumin extract (StdC) and two commercially available formulations with purported increased bioavailability: a curcumin phytosome formulation (CSL) and a formulation of curcumin with essential oils of turmeric extracted from the rhizome (CEO).. Twelve healthy human volunteers participated in a double-blinded, cross-over study. The plasma concentrations of the individual curcuminoids that are present in turmeric (namely curcumin, demethoxycurcumin, and bisdemethoxycurcumin) were determined at baseline and at various intervals after oral administration over a 12-h period.. CW8 showed the highest plasma concentrations of curcumin, demethoxycurcumin, and total curcuminoids, whereas CSL administration resulted in the highest levels of bisdemethoxycurcumin. CW8 (39-fold) showed significantly increased relative bioavailability of total curcuminoids (AUC. The data presented suggest that γ-cyclodextrin curcumin formulation (CW8) significantly improves the absorption of curcuminoids in healthy humans.

Topics: Adult; Antineoplastic Agents, Phytogenic; Antioxidants; Area Under Curve; Cohort Studies; Cross-Over Studies; Curcumin; Diarylheptanoids; Dietary Supplements; Double-Blind Method; Female; Food Additives; Food Handling; gamma-Cyclodextrins; Humans; Intestinal Absorption; Male; Nutritive Value; Young Adult

Pulmonary problems are among the most frequent chronic complications of sulfur mustard (SM) intoxication and are often accompanied by deregulated production of pro-inflammatory cytokines. Curcuminoids, comprising curcumin, demethoxycurcumin and bisdemethoxycurcumin, are phytochemicals with remarkable anti-inflammatory properties that are derived from dried rhizomes of the plant Curcuma longa L. (turmeric). The present pilot study aimed to investigate the clinical effects of supplementation with curcuminoids on markers of pulmonary function and systemic inflammation in SM-intoxicated subjects. In a randomized double-blind placebo-controlled trial, 89 male subjects who were suffering from chronic SM-induced pulmonary complications were recruited and assigned to either curcuminoids (500 mg TID per oral; n=45) or placebo (n=44) for a period of 4 weeks. Efficacy measures were changes in the spirometric parameters (FVC, FEV1, FEV1/FVC) and serum levels of inflammatory mediators including interleukins 6 (IL-6) and 8 (IL-8), tumor necrosis factor-α (TNFα), transforming growth factor-β (TGFβ), high-sensitivity C-reactive protein (hs-CRP), calcitonin gene related peptide (CGRP), substance P and monocyte chemotactic protein-1 (MCP-1). 78 subjects completed the trial. Although FEV1 and FVC remained comparable between the groups, there was a greater effect of curcuminoids vs. placebo in improving FEV1/FVC (p=0.002). Curcuminoids were also significantly more efficacious compared to placebo in modulating all assessed inflammatory mediators: IL-6 (p<0.001), IL-8 (p=0.035), TNFα (p<0.001), TGFβ (p<0.001), substance P (p=0.016), hs-CRP (p<0.001), CGRP (p<0.001) and MCP-1 (p<0.001). Curcuminoids were safe and well-tolerated throughout the trial. Short-term adjunctive therapy with curcuminoids can suppress systemic inflammation in patients suffering from SM-induced chronic pulmonary complications.

Topics: Adult; Anti-Inflammatory Agents; Chemical Warfare Agents; Chronic Disease; Curcumin; Cytokines; Diarylheptanoids; Double-Blind Method; Forced Expiratory Volume; Humans; Inflammation; Inflammation Mediators; Lung Diseases; Male; Middle Aged; Mustard Gas; Pilot Projects; Treatment Outcome; Vital Capacity

Curcumin revealed various health-beneficial properties in numerous studies. However its bioavailability is low due to its limited intestinal uptake and rapid metabolism. The aim of our project was to develop novel curcumin formulations with improved oral bioavailability and to study their safety as well as potential sex-differences.. In this crossover study, healthy subjects (13 women, 10 men) took, in random order, a single oral dose of 500 mg curcuminoids as native powder, micronized powder, or liquid micelles. Blood and urine samples were collected for 24 h and total curcuminoids and safety parameters were quantified. Based on the area under the plasma concentration-time curve (AUC), the micronized curcumin was 14-, 5-, and 9-fold and micellar curcumin 277-, 114-, and 185-fold better bioavailable than native curcumin in women, men, and all subjects, respectively. Thus, women absorbed curcumin more efficiently than men. All safety parameters remained within the reference ranges following the consumption of all formulations.. Both, the micronized powder and in particular the liquid micellar formulation of curcumin significantly improved its oral bioavailability without altering safety parameters and may thus be ideally suited to deliver curcumin in human intervention trials. The observed sex differences in curcumin absorption warrant further investigation.

Topics: Administration, Oral; Biological Availability; Cross-Over Studies; Curcumin; Diarylheptanoids; Female; Humans; Male; Micelles; Powders; Sex Factors; 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

It is well established that myocardial infarction (MI) associated with coronary artery bypass grafting (CABG) predicts a poor outcome. Nevertheless, cardioprotective therapies to limit myocardial injury after CABG are lacking. Previous studies have shown that curcuminoids decrease proinflammatory cytokines during cardiopulmonary bypass surgery and decrease the occurrence of cardiomyocytic apoptosis after cardiac ischemia/reperfusion injury in animal models. We aimed to evaluate whether curcuminoids prevent MI after CABG compared to placebo. The 121 consecutive patients undergoing CABG were randomly allocated to receive placebo or curcuminoids 4 g/day beginning 3 days before the scheduled surgery and continued until 5 days after surgery. The primary end point was incidence of in-hospital MI. The secondary end point was the effect of curcuminoids on C-reactive protein, plasma malondialdehyde, and N-terminal pro-B-type natriuretic peptide levels. Baseline characteristics were comparable between the curcuminoid and placebo groups. Mean age was 61 ± 9 years. On-pump CABG procedures were performed in 51.2% of patients. Incidence of in-hospital MI was decreased from 30.0% in the placebo group to 13.1% in the curcuminoid group (adjusted hazard ratio 0.35, 0.13 to 0.95, p = 0.038). Postoperative C-reactive protein, malondialdehyde, and N-terminal pro-B-type natriuretic peptide levels were also lower in the curcuminoid than in the placebo group. In conclusion, we demonstrated that curcuminoids significantly decreased MI associated with CABG. The antioxidant and anti-inflammatory effects of curcuminoids may account for their cardioprotective effects shown in this study.

Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Coronary Angiography; Coronary Artery Bypass; Coronary Artery Disease; Curcuma; Curcumin; Diarylheptanoids; Double-Blind Method; Drug Combinations; Follow-Up Studies; Humans; Incidence; Myocardial Infarction; Phytotherapy; Plant Preparations; Preoperative Care; Prospective Studies; Thailand; Treatment Outcome

The relative absorption of a standardized curcuminoid mixture and its corresponding lecithin formulation (Meriva) was investigated in a randomized, double-blind, crossover human study. Clinically validated dosages were used for both products, and plasma levels of all three major curcuminoids [curcumin (1a), demethoxycurcumin (1b), and bisdemethoxycurcumin (1c)] were evaluated. Total curcuminoid absorption was about 29-fold higher for Meriva than for its corresponding unformulated curcuminoid mixture, but only phase-2 metabolites could be detected, and plasma concentrations were still significantly lower than those required for the inhibition of most anti-inflammatory targets of curcumin. Remarkably, phospholipid formulation increased the absorption of demethoxylated curcuminoids much more than that of curcumin (1a), with significant differences in plasma curcuminoid profile between Meriva and its corresponding unformulated curcuminoid mixture. Thus, the major plasma curcuminoid after administration of Meriva was not curcumin (1a), but demethoxycurcumin (1b), a more potent analogue in many in vitro anti-inflammatory assays. The improved absorption, and possibly also a better plasma curcuminoid profile, might underlie the clinical efficacy of Meriva at doses significantly lower than unformulated curcuminoid mixtures.

Topics: Chemistry, Pharmaceutical; Curcumin; Diarylheptanoids; Humans; Lecithins; Molecular Structure; Reference Standards

Patients with Alzheimer's disease (AD) suffer from brain amyloidosis related to defective clearance of amyloid-beta (Abeta) by the innate immune system. To improve the innate immune system of AD patients, we studied immune stimulation of macrophages by 1alpha,25(OH)2-vitamin D3(1,25D3) in combination with curcuminoids. AD patients' macrophages segregate into Type I (positively stimulated by curcuminoids regarding MGAT-III transcription) and Type II (not stimulated). In both Type I and Type II macrophages, 1,25D3 strongly stimulated Abeta phagocytosis and clearance while protecting against apoptosis. Certain synthetic curcuminoids in combination with 1,25D3 had additive effects on phagocytosis in Type I but not Type II macrophages. In addition, we investigated the mechanisms of 1,25D3 and curcuminoids in macrophages. The 1,25D3 genomic antagonist analog MK inhibited 1,25D3 but not curcuminoid effects, suggesting that 1,25D3 acts through the genomic pathway. In silico, 1,25D3 showed preferential binding to the genomic pocket of the vitamin D receptor, whereas bisdemethoxycurcumin showed preference for the non-genomic pocket. 1,25D3 is a promising hormone for AD immunoprophylaxis because in Type I macrophages combined treatment with 1,25D3 and curcuminoids has additive effects, and in Type II macrophages 1,25D3 treatment is effective alone. Human macrophages are a new paradigm for testing immune therapies for AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cells, Cultured; Cholecalciferol; Cognition Disorders; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Drug Interactions; Female; Gene Expression Regulation; Humans; Liver; Macrophages; Male; Middle Aged; N-Acetylglucosaminyltransferases; Peptide Fragments; Phagocytosis; Protein Structure, Tertiary; Receptors, Calcitriol; Time Factors; Toll-Like Receptor 1; Transfection

Human glioblastoma (GBM) is one of the common cancer death in adults worldwide, and its metastasis will lead to difficult treatment. Finding compounds for future to develop treatment is urgent. Bisdemethoxycurcumin (BDMC), a natural product, was isolated from the rhizome of turmeric (Curcuma longa), which has been shown to against many human cancer cells. In the present study, we evaluated the antimetastasis activity of BDMC in human GBM cells. Cell proliferation, cell viability, cellular uptake, wound healing, migration and invasion, and western blotting were analyzed. Results indicated that BDMC at 1.5-3 μM significantly decreased the cell proliferation by MTT assay. BDMC showed the highest uptake by cells at 3 h. After treatment of BDMC at 12-48 h significantly inhibited cell motility in GBM 8401 cells by wound healing assay. BDMC suppressed cell migration and invasion at 24 and 48 h treatment by transwell chamber assay. BDMC significantly decreased the levels of proteins associated with PI3K/Akt, Ras/MEK/ERK pathways and resulted in the decrease in the expressions of NF-κB, MMP-2, MMP-9, and N-cadherin, leading to the inhibition of cell migration and invasion. These findings suggest that BDMC may be a potential candidate for the antimetastasis of human GBM cells in the future.

Topics: Brain; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Curcumin; Diarylheptanoids; Glioblastoma; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; NF-kappa B; Phosphatidylinositol 3-Kinases; Signal Transduction

Curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are the main components of turmeric that commonly used to treat neuropathic pain (NP). However, the mechanism of the therapy is not sufficiently clarified. Herein, network pharmacology, molecular docking and molecular dynamics (MD) approaches were used to investigate the mechanism of curcuminoids for NP treatment.. Active targets of curcuminoids were obtained from the Swiss Target database, and NP-related targets were retrieved from GeneCards, OMIM, Drugbank and TTD databases. A protein-protein interaction (PPI) network was built to screen the core targets. Furthermore, DAVID was used for GO and KEGG pathway enrichment analyses. Interactions between potential targets and curcuminoids were assessed by molecular docking and the MD simulations were run for 100ns to validate the docking results on the top six complexes.. CUR, DMC, and BDMC had 100, 99 and 100 targets respectively. After overlapping with NP there were 33, 33 and 31 targets respectively. PPI network analysis of TOP 10 core targets, TNF, GSK3β were common targets of curcuminoids. Molecular docking and MD results indicated that curcuminoids bind strongly with the core targets. The GO and KEGG showed that curcuminoids regulated nitrogen metabolism, the serotonergic synapse and ErbB signaling pathway to alleviate NP. Furthermore, specific targets in these three compounds were also analysed at the same time.. This study systematically explored and compared the anti-NP mechanism of curcuminoids, providing a novel perspective for their utilization.

Topics: Curcuma; Curcumin; Databases, Factual; Diarylheptanoids; ErbB Receptors; Glycogen Synthase Kinase 3 beta; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Targeted Therapy; Neuralgia; Nitrogen; Serotonin; Tumor Necrosis Factor-alpha

Turmeric (

Topics: Animals; Curcuma; Curcumin; Diarylheptanoids; Mice; Molecular Docking Simulation; Plant Extracts; Receptors, Histamine H1; Sleep Aids, Pharmaceutical; Sleep Latency; Sleep, REM

The natural bioactive compounds of Curcuma longa, known as curcuminoids, has been shown to exerts anticancer effects to diverse cancer cell line in vitro, including breast cancer cell line. These curcuminoids consist of curcumin (Cur), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC). Furthermore, there has never been a study to compare the extent of antiproliferative and apoptotic modulation potential between Cur, DMC and BDMC in the breast cancer cell, until now. In the present study, we explore the efficacy among Cur, DMC and BDMC to alters MCF-7 cell viability, which might lead to apoptotic modulation.. This kind of study was performed in vitro whereby the cells were maintained in an appropriate medium and the anticancer effect of curcuminoids (Cur, DMC and BDMC) was measured by using resazurin-based PrestoBlue cell viability assay. Later, MCF-7 breast cancer cells were cultured in 12 wells plate added with different concentrations of Cur, DMC and BDMC for western blotting analysis. Statistical analysis was performed with GraphPad 8, One-way ANOVA and Student's t-test.. The result showed that Cur, DMC and BDMC inhibiting the proliferation of MCF-7 cells. In the concentration dose of 31.25 μg mL-1, the cell viability in cells treated with Cur is 27%, DMC is 31.5% and BDMC is 46%. The IC50 dose of Cur, DMC and BDMC were 25.63, 29.94 and 36.91 μg mL-1.. Cur is more effective in inhibiting proliferation and apoptotic modulation in MCF-7 cells compare to DMC and BDMC. It represents the potential of Cur, DMC and BDMC as adjunctive therapy in treating breast cancer.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Proteins; Breast Neoplasms; Cell Proliferation; Curcuma; Curcumin; Diarylheptanoids; Female; Humans; MCF-7 Cells

Curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) - the class of natural compound derived from turmeric can exist as keto-enol and β-diketone tautomer form. The structure and dynamics of particular relevance CUR is reported in prior studies, whereas DMC and BDMC, by far, have not been scrutinized. In the present studies, we have investigated the detailed molecular structure of CUR, DMC and BDMC by employing NMR spectroscopy as a key tool. The bridging carbon as methylene in β-diketone form and methine in keto-enol form shows significant difference in NMR spectrum. The results justified that Curcuminoids (CC) has nearly 3% of β-diketone tautomer in DMSO solvent at 298 K. Further, results revealed that β-diketone form was favoured in alkaline pH condition whereas acidic and neutral pH conditions favour keto-enol tautomer. However, at higher temperature equilibrium shift towards β-diketone tautomer. Moreover, this is the first report by NMR for observing the presence of β-diketone tautomer.

Topics: Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Hydrogen-Ion Concentration; Ketones; Magnetic Resonance Spectroscopy; Molecular Conformation

The gastroprotective effect of a turmeric acetone extract (TAE) (

Topics: Acetone; Animals; Curcuma; Curcumin; Diarylheptanoids; Ethanol; Plant Extracts; Protective Agents; Rats, Wistar; Stomach

Curcumin, together with demethoxycurcumin and bisdemethoxycurcumin as a whole called curcuminoids, is an active phytochemical constituent present in the turmeric. When it comes to their analysis, most will rely on UV-Visible spectroscopy, HPLC and LC-MS methods. Looking to improve productivity, time and simplicity, we are proposing a

Topics: Chromatography, High Pressure Liquid; Curcuma; Diarylheptanoids; Limit of Detection; Plant Extracts; Proton Magnetic Resonance Spectroscopy; Reference Standards; Solvents

Curcuma longa and Azadirachta indica are traditionally used in Indian cuisine and Ayurvedic medicine as nutraceuticals against diabetes. The crude C. longa isopropanol extract, bisdemethoxycurcumin (BDMC), the purified bioactive component from C. longa, and limonoids azadiradione, gedunin from A. indica, are able to inhibit in vitro the antidiabetic target human pancreatic α-amylase independently. However, no reports on their in vivo efficacy in animal models exist. Thus, the antidiabetic effect of these orally administered human pancreatic α-amylase inhibitors was performed on streptozotocin-induced Sprague-Dawley rats. Initially, the normal rats were treated with test compounds (10-100 mg/kg of body weight) in corn oil (5 ml/kg), and as no lethality was observed in these doses, further studies were carried out with lowest concentration of 10 mg/kg of body weight. A reduction in area under curve (AUC) suggested glucose-lowering effect of these compounds in starch fed diabetic rats. The efficacy study showed a significant improvement in body weight, blood glucose levels, serum amylase, and fructosamine levels as well in other serum parameters associated with diabetes with respect to liver and renal functions. Hence, under in vivo conditions, inhibition of α-amylase activity by BDMC and limonoids affirms it as one of the mechanisms of action resulting in reduction of blood glucose levels. PRACTICAL APPLICATIONS: Bisdemethoxycurcumin from C. longa and limonoids, namely, azadiradione and gedunin, from A. indica are potent inhibitors of the antidiabetic target human pancreatic α-amylase. Oral Starch Tolerance Test (OSTT) and 28-day efficacy study to check the effect of these orally administered inhibitors in diabetic rat models showed significant improvements in serum blood glucose and amylase levels as well as in other diabetes related serum parameters, namely, bilirubin, lipids, lactate dehydrogenase, alkaline phosphatase, and urea. The study contributes to understanding the action and efficacy of these pancreatic α-amylase inhibitors and suggests a potential role for them as nutraceuticals/therapeutics in management of post-prandial hyperglycemia.

Topics: Administration, Oral; Amylases; Animals; Azadirachta; Blood Glucose; Curcuma; Diabetes Mellitus, Experimental; Diarylheptanoids; Limonins; Plant Extracts; Rats; Rats, Sprague-Dawley

Curcumin, a major bioactive component of turmeric (Curcuma longa), is known for its multiple health benefits. Curcumin as such is a mixture of its analogs: bisdemethoxycurcumin (BDMC)-3%, and demethoxycurcumin (DMC)-17%. Although the effect of curcumin on platelets is documented, the effect of BDMC and DMC on platelets is less studied. Considering the indispensable role played by platelets in hemostasis, thrombosis, inflammation, and immunity, the present study evaluates the effect of curcumin, DMC and BDMC on platelet apoptosis. The components of curcumin were purified by silica-gel column chromatography. The purity and mass analysis of the purified curcuminoids was determined by RP-HPLC and LC-MS respectively. When analyzed for platelet apoptotic markers, only BDMC demonstrated increased incidence of platelet apoptotic markers including increase in intracellular Ca

Topics: Apoptosis; Blood Platelets; Curcumin; Diarylheptanoids; Humans; MAP Kinase Signaling System

The effects of two-drug combination, all-trans retinoic acid (ATRA) and bisdemethoxycurcumin (BDMC), on apoptosis induction of liver cancer cells were investigated in human liver Hep 3B cells. Two-drug combination caused a more effective decrease in cell viability and in induction of S phase arrest, DNA damage, and cell apoptosis than that of ATRA or BDMC only. Also, the two-drug combination caused more cells to undergo significantly increased ROS productions when compared to that of ATRA or BDMC only. Results of Western blotting demonstrated that two-drug combination increased expressions of Fas, pro-apoptotic proteins, and active form of caspase-3 and -9, but decreased that of anti-apoptotic proteins and XIAP than that of ATRA or BDMC only in Hep 3B cells. In conclusion, ATRA combined with BDMC enhance cell apoptosis and associated protein expression in Hep 3B cells. PRACTICAL APPLICATIONS: Bisdemethoxycurcumin (BDMC) derived from natural plants, turmeric (Curcuma longa), which had been used for Asia food for thousands of years. All-trans retinoid acid (ATRA) is currently used as a primary treatment for patients with acute promyelocytic leukemia. In previous study, ATRA and BDMC were reported to have anti-inflammatory and anticancer effects. Our results showed that treatment of ATRA combined with BDMC showed more effectively apoptosis than that of ATRA or BDMC only in Hep 3B cells. The findings also provided possible pathways concerning the induction of liver cancer cell apoptosis. We conclude that ATRA combined with BDMC may be potent anticancer agents or adjuvants for liver cancer therapy in the future.

Topics: Apoptosis; Cell Line, Tumor; Curcumin; Diarylheptanoids; Humans; Liver Neoplasms; Tretinoin

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents and has also been associated with a high degree of malignancy and enhanced metastatic capacity. Curcumin (CUR) is well known for its anti-osteosarcoma activity. However, both demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are natural curcumin analogues/congeners from turmeric whose role in osteosarcoma development remains unknown.. To evaluate the growth inhibitory effects of CUR, DMC and BDMC on osteosarcoma (HOS and U2OS), breast (MDA-MB-231), and melanoma (A2058) cancer cells, we employed the MTT assay, annexin V-FITC /7-AAD staining, and clonogenic assay.. CUR,DMC, and BDMC all decreased the viability of HOS, U2OS, MDA-MB-231, and A2058 cancer cells. Additionally, CUR,DMC, and BDMC induced the apoptosis of HOS cells through activation of Smad 2/3 or repression of Akt signaling pathway. Furthermore, the combination of CUR,DMC, and BDMC synergistically reduced cell viability, colony formation and increased apoptosis than either two or a single agent in HOS cells.. The combination of these three compounds could be used as a novel target for the treatment of osteosarcoma.

Topics: Apoptosis; Caspases; Cell Line, Tumor; Curcumin; Diarylheptanoids; Drug Therapy, Combination; Humans; Molecular Structure; Proto-Oncogene Proteins c-akt; Signal Transduction; Smad Proteins

In a previous study, we evaluated the potential beneficial effect of nano-bubble curcumin extract (NCE) in reducing exercise-related injuries and improving performance.. In this study, we seek to investigate changes in the gut microbiota composition upon NCE supplementation in relation to health and exercise performance. Male ICR mice were divided into 3 groups (n = 8 per group) and orally administered NCE once daily for six weeks at 0 (vehicle), 3.075 (NCE-1X) and 15.375 g kg. NCE-5X did not appear to obviously cluster with the vehicle group, although NCE-5X groups showed an increased Firmicutes/Bacteroidetes ratio compared with the vehicle group. In addition, anti-fatigue activity and exercise performance were evaluated by investigating the exhaustive swimming time, forelimb grip strength and serum levels of lactate, ammonia, glucose, blood urea nitrogen (BUN), creatine kinase (CK) and lactate dehydrogenase (LDH) after swimming. The NCE-1X and NCE-5X groups showed a significantly longer exhaustive swimming time and higher relative forelimb grip strength than the vehicle group. Tissue glycogen content, an important energy source for exercise, increased significantly with NCE supplementation.. Taken together, our results indicate that NCE supplementation alters the gut microbiota composition and aids in overcoming physical fatigue. Curcumin may be acting on the gut microbiome to modulate the gut system towards improving exercise performance.

Topics: Animals; Curcumin; Diarylheptanoids; Dietary Supplements; Fatigue; Gastrointestinal Microbiome; Glycogen; Male; Mice; Mice, Inbred ICR; Plant Extracts; RNA, Ribosomal, 16S

The curcumin-C3 (cur-C3) complex obtained from Curcuma longa rhizome is a combination of three curcuminoids, namely, curcumin, dimethoxycurcumin, and bisdemethoxycurcumin. Cur and curcuminoids have been extensively researched for their wide range of therapeutic properties against inflammatory diseases, diabetes, and cancer.. In spite of their extensive medicinal properties, cur and curcuminoids have poor solubility and bioavailability due to their hydrophobicity. This limitation can be overcome by complexing cur-C3 with natural cyclic oligosaccharides, such as Cyclodextrin (CD).. In this study, cur-C3 and CD (α, β) inclusion complexes (ICs) were prepared with different molar ratios and characterized by nuclear magnetic resonance, Fourier transform infrared spectroscopy, X-ray diffraction, and transmission electron microscopy.. The cur-C3 cyclodextrin ICs showed an increased entrapment efficiency of 97.8% and improved antioxidant activity compared to cur and can be used as an antioxidant to reduce cancer-related oxidative stress. Additionally, α- CD ICs of curcumin-C3 caused an increase in growth inhibition of Staphylococcus aureus.. Our findings suggest that both α- and β-CDs are suitable carriers for cur-C3 and can be used as an effective treatment for cancer-associated oxidative stress and as a preventive treatment for nosocomial infections and pneumonia.

Topics: alpha-Cyclodextrins; Anti-Bacterial Agents; Antioxidants; beta-Cyclodextrins; Biological Availability; Curcumin; Diarylheptanoids; Drug Compounding; Escherichia coli; Hydrophobic and Hydrophilic Interactions; Solubility; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction

Renal fibrosis is the common final outcome of nearly all progressive chronic kidney diseases (CKD) that eventually develop into end-stage renal failure, which threatens the lives of patients. Currently, there are no effective drugs for the treatment of renal fibrosis. However, studies have shown that certain plant natural products have a fibrosis-alleviating effect. Thus, we have screened a large number of natural products for their ability to protect against renal fibrosis and found that bisdemethoxycurcumin has a good therapeutic effect in renal fibrosis according to the data obtained in a mouse model of unilateral ureteral obstruction (UUO). The results indicate that bisdemethoxycurcumin can efficiently attenuate renal fibrosis induced by UUO. Additional studies of the bisdemethoxycurcumin mechanism of action in the treatment of renal fibrosis demonstrated that the therapeutic effect of bisdemethoxycurcumin is mediated by the specific induction of fibroblast apoptosis at a concentration of 20 μM. bisdemethoxycurcumin can efficiently protect against renal fibrosis both in vitro and in vivo. This discovery will provide new ideas for renal fibrosis treatment in clinics and a new direction for the development of effective drug therapy of renal fibrosis.

Topics: Animals; Apoptosis; Biological Products; Cell Line; Curcumin; Diarylheptanoids; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Humans; Kidney; Male; Mice; Protective Agents; Renal Insufficiency, Chronic; Ureteral Obstruction; Urinary Tract

Excision repair cross-complementary 1 (ERCC1) overexpression in lung cancer cells is strongly correlated with its resistance to platinum-based chemotherapy. Overexpression of thymidine phosphorylase (TP) reverts platinum-induced cancer cell death.. Curcumin has been reported to enhance antitumor properties through the suppression of TP and ERCC1 in non-small cell lung carcinoma cells (NSCLC). Nevertheless, whether two other curcuminoids, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) from Curcuma longa demonstrate antitumor activity like that of curcumin remain unknown.. MTT assay was conducted to determine the cell cytotoxicity. Western blotting was used to determine the protein expressions. Docking is the virtual screening of a database of compounds and predicting the strongest binders based on various scoring functions. BIOVIA Discovery Studio 4.5 (D.S. 4.5) were used for docking.. Firstly, when compared with curcumin and BDMC, DMC exhibited the most potent cytotoxic effect on NSCLC, most importantly, MRC-5, a lung fetal fibroblast, was insensitive to DMC (under 30 µM). Secondly, DMC alone significantly inhibited on-target cisplatin (CDDP) resistance protein, ERCC1, via PI3K-Akt-snail pathways, and TP protein expression in A549 cells. Thirdly, DMC treatment markedly increased post-target CDDP resistance pathway including Bax and cytochrome c. DMC significantly decreased Bcl-2 protein expressions. Finally, MTT assay indicated that DMC significantly increased CDDP-induced cytotoxicity and was confirmed with an increased Bax/Bcl-2 ratio, indicating upregulation of caspase-3.. We concluded that enhancement of the cytotoxicity to CDDP by coadminstration with DMC was mediated by down-regulation of the expression of TP and ERCC1, regulated by PI3K-Akt-Snail pathway inactivation.

Topics: A549 Cells; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cisplatin; Curcuma; Curcumin; Diarylheptanoids; DNA-Binding Proteins; Down-Regulation; Endonucleases; Humans; Lung Neoplasms; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Thymidine Phosphorylase

An exploration of the antioxidant power of curcumin, demethoxycurcumin, and bisdemethoxycurcumin, three natural antioxidants found in Curcuma longa, is reported in this work. We exhaust all structural possibilities leading to intramolecular hydrogen bonding and evaluate 15 isomers in total. Calculations were carried out in the gas phase and in the presence of solvents (water, to mimic biological media, and ethanol, to reproduce experimental assays) following the hydrogen atom transfer (HAT) and single electron transfer (SET) mechanisms. CH3OH-O hydrogen bonds are directly related to the antioxidant power via both mechanisms. We provide evidence to explain the experimental observations and to understand the fundamental factors driving antioxidant activity from a molecular perspective. Noticeably, the solvent enhances the antioxidant power in every case. All structures considered here are predicted to have better antioxidant abilities than phenol, and come very close to or surpass vitamin E.

Topics: Antioxidants; Curcumin; Diarylheptanoids; Hydrogen Bonding

Leukemic cells remaining in the body is the main problem for cancer patients, and these cells are called Leukemic Stem Cells (LSCs). Many studies have revealed that the overexpression of the Wilms' tumor 1 (WT1) protein is related to leukemogenesis. Curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) from Thai turmeric (

Topics: Antigens, CD34; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Curcuma; Curcumin; Diarylheptanoids; Humans; K562 Cells; Leukemia; Leukocytes, Mononuclear; Microscopy, Fluorescence; Neoplastic Stem Cells; WT1 Proteins

Curcuminoids, mainly present in the plant rhizomes of turmeric (Curcuma longa), consist of mainly three forms (curcumin (CUR), bisdemethoxycurcumin (BDMC) and demethoxycurcumin (DMC)). It has been reported that different forms of curcuminoids possess different biological activities. However, the mechanisms associated with these differences are not well-understood. Recently, our laboratory found differences in the cellular uptake of these curcuminoids. Therefore, it has been inferred that these differences contribute to the different biological activities.. In this study, we investigated the mechanisms of differential cellular uptake of these curcuminoids.. Based on our previous study, we hypothesized the differential cellular uptake is caused by (I) polarity, (II) transporters, (III) metabolism rate of curcuminoids and (IV) medium components. These four hypotheses were each investigated by (I) neutralizing the polarities of curcuminoids by encapsulation into poly(lactic-co-glycolic) acid nanoparticles (PLGA-NPs), (II) inhibition of polyphenol-related absorption transporters, (III) analysis of the cellular curcuminoids and their metabolites by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and (IV) use of different mediums in cell study.. The differential cellular uptake was not affected by (I-III). However, when investigating (IV), not only CUR but also BDMC and DMC were incorporated into cells when serum free media was used. Furthermore, when we used the serum free medium containing bovine serum albumin (BSA), only CUR was taken up but BDMC and DMC were not. Therefore, we identified that the differential cellular uptake of curcuminoids is caused by the medium components, especially BSA. Also, the fluorescence quenching study suggested that differential cellular uptake is due to the different interaction between BSA and each curcuminoid.. The differential cellular uptake of curcuminoids was caused by the different interaction between curcuminoids and BSA. The results from this study might give clues on the mechanisms by which curcuminoids exhibit different physiological activities.

Topics: Albumins; Cell Line; Chromatography, Liquid; Curcuma; Curcumin; Diarylheptanoids; Humans; Monocytes; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Serum Albumin, Bovine; Tandem Mass Spectrometry

A fast and reliable ultra-performance liquid chromatography-diode array detection method was developed and validated for the quantitative assessment of turmeric extracts from different geographical locations. Acclaim RSLC PolarAdvantage II column (2.2 μm, 2.1 × 100 mm) was used to analyze individual curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) from turmeric samples. The detection was done on ultraviolet absorbance at 425 nm and the column temperature was maintained at 45 °C. A mobile phase consisting of acetonitrile and water was found to be suitable for separation, at a flow rate of 1 mL/min with linear gradient elution. Linearity, specificity, precision, recovery and robustness were measured to validate the method and instrument. Under the described conditions, curcuminoids were collected within one minute. The calibration curve of each curcuminoid showed good linearity (correlation coefficient > 0.999). The relative standard deviations (RSD) of intra-day, inter-day precision and repeatability were less than 0.73%, 2.47% and 2.47%, respectively. In the recovery test, the accuracy ranged from 98.54%-103.91% with RSD values of less than 2.79%. The developed method was used for quantification of individual curcuminoids of turmeric samples. Analysis of turmeric samples from Nepal and South Korea revealed that curcuminoid content was related to geographical location. Turmeric cultivated in warmer climates were found to have higher curcumionoid content than turmeric samples from cooler climates, the southern part of Nepal was found to have two times higher content of curcuminoids than turmeric from the north.

Topics: Calibration; Chromatography, High Pressure Liquid; Curcuma; Curcumin; Diarylheptanoids; Plant Extracts

Turmeric (Curcuma longa L, Zingiberaceae) rhizomes exhibit versatile biological activities including the significant anti-cancer property. As an herbal medicine, the therapeutic effects of turmeric may be expressed by multi-components which have complicated integration effects on multi-targets. Therefore, having previously found three A549 cell-binding curcuminoids (curcumin, Cur; demethoxycurcumin, DMcur; bisdemethoxycurcumin, BMcur) from turmeric, studies were undertaken in this paper to determine the anti-cancer mechanism and integration effects of these curcuminoids by using chemical markers' knockout and UHPLC-LTQ Orbitrap MS-based metabolomics. Four curcuminoid-containing fractions including a mixture of 3 cell-binding curcuminoids (CE), and three individual curcuminoids with natural proportion in turmeric were prepared by chemical markers' knockout method. CE, Cur, DMcur and BMcur fractions showed significant anti-cancer activity on A549 cells. The activities of CE, Cur and BMcur fractions were comparative with the turmeric crude extract (TcE). In the metabolomics study, CE and three individual curcuminoid fractions changed the expression of 25 metabolites in A549 cells, which were involved in glycerophospholipid catabolism, sphingolipid metabolism and fatty acid metabolism, etc. Among them, glycerophospholipid catabolism was disordered greatly in CE group, while sphingolipid metabolism was suggested to be closely related to DMcur and BMcur activity. Furthermore, the metabolomics data showed that three curcuminoids existed synergistic and antagonistic actions and the use of multi-curcuminoids is more powerful than use of single curcuminoid on the metabolic alterations of A549 cells.

Topics: A549 Cells; Antineoplastic Agents; Cell Line, Tumor; Chromatography, High Pressure Liquid; Curcuma; Curcumin; Diarylheptanoids; Humans; Lung Neoplasms; Metabolomics; Phytotherapy; Plant Extracts; Rhizome

The current study introduces a new idea of utilising several bio/chemoinformatics tools in comparing two bio-similar natural molecules viz. curcumin and bisdemethoxycurcumin (BDMC) in order to select a potential nose-to-brain remedy for Alzheimer disease. The comparison comprised several bio/chemo informatics tools. It encompassed all levels starting from loading the drug in a certain carrier; PLGA nanoparticles, to the biopharmaceutical level investigating the interaction with mucin and inhibition of P-gp blood-brain barrier efflux pumps. Finally, the therapeutic level was investigated by studying the interaction with pharmacological targets such as amyloid peptide plaques and cyclooxygenase2 enzyme responsible for the inflammatory reactions of the studied disease. The comparison revealed the superiority of curcumin over BDMC. Five new analogues were also hypothesised where diethoxybisdemethoxycurcumin was  recommended as a superior molecule. This work introduced the virtual utilisation of bio/chemo informatics tools as a reliable and economic alternative to the exhausting and resources-consuming wet-lab experimentation.

Topics: Alzheimer Disease; ATP Binding Cassette Transporter, Subfamily B; Brain; Computational Biology; Curcumin; Diarylheptanoids; Drug Carriers; Humans; Inflammation; Mucins; Nose

Inflammation‑associated damage may occur in any tissue following infection, exposure to toxins, following ischemia, and in allergic and auto‑immune reactions. Inflammation may also result from mast cell degranulation induced by the intracellular calcium concentration. The inflammatory process may be inhibited by compounds that affect mast cells. Bisdemethoxycurcumin [1,7‑bis(4‑hydroxyphenyl) hepta‑1,6‑diene‑3,5‑dione, BDCM] is the active component of turmeric. It has anticancer, antioxidant and antibacterial properties. To investigate the molecular mechanism associated with the anti‑inflammatory activity of BDCM, human mast cell line 1 (HMC‑1) cells were treated with phorbol‑12‑myristate‑13‑acetate (PMA) and calcium ionophore A23187 (A23187) to induce the inflammatory process. Various HMC‑1 cells were pretreated with BDCM prior to stimulation of inflammation. BDCM inhibited the inflammation‑triggered production of cytokines including interleukin (IL)‑6, IL‑8, and tumor necrosis factor (TNF)‑α. BDCM inhibition extended to the gene level. In activated HMC‑1 cells, phosphorylation levels of extracellular signal‑regulated kinase, c‑jun N‑terminal kinase and p38 mitogen‑activated protein kinase were decreased by treatment with BDCM. BDCM also inhibited nuclear factor‑(NF)‑κB activation and IκB degradation. In conclusion, BDCM suppresses the expression of TNF‑α, IL‑8, and IL‑6 by inhibiting the NF‑κB and mitogen activated protein kinase signaling pathways.

Topics: Calcimycin; Cell Line; Curcumin; Diarylheptanoids; Gene Expression Regulation; Humans; Inflammation; Mast Cells; Mitogen-Activated Protein Kinase Kinases; NF-kappa B; Signal Transduction; Tetradecanoylphorbol Acetate; Transcription Factor RelA

Curcuminoids (cus) have attracted increasing attention because of the antioxidant, anticancer, and antitumor activities while their production is limited because of its main source, turmeric plant, demonstrates extensive seasonal variation. In this study, we constructed Escherichia coli co-culture system for the rapid production of curcuminoids from glucose. Firstly, the overexpression of curcuminoid synthase and four different strategies related to increasing the intracellular malonyl-CoA pool were conducted in engineered E. coli. We found that bisdemethoxycurcumin (BDMC) is the main product and that high level of malonyl-CoA pool is essential for BDMC production. We also obtained the maximum titer (13.8 mg L

Topics: Coculture Techniques; Curcumin; Diarylheptanoids; Escherichia coli; Glucose; Metabolic Engineering

Three curcuminoids: bisdemethoxycurcumin, demethoxycurcumin, and curcumin from turmeric were successfully separated by a high capacity solvent system composed of heptane: chloroform: methanol: water mixture (5: 6: 3: 2 v/v/v/v) tailored for centrifugal partition chromatographs at K-values of 0.504, 1.057, 1.644, respectively. These three ferulic acid derivatives obtained at a purity rate exceeding 95% were analysed by an HPLC-MS spectrometer. Turmeric extract inhibited the proliferation/viability of A549 human lung cancer, HT29 colon cancer, and T98G glioblastoma cell lines in (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay (MTT). Single curcuminoids significantly decreased the viability/proliferation of lung cancer cells in a dose-dependent manner. However, total extract displayed the superior anticancer activity in the investigated cell lines. Crude extract in combination with cisplatin augmented the decrease in the viability of cancer cells compared with single compound treatment in A549 lung cancer cells. Total extract of Curcuma longa could be regarded as being more effective against lung cancer cells in vitro than its separated compounds.

Topics: A549 Cells; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Chemical Fractionation; Chromatography, High Pressure Liquid; Coumaric Acids; Curcuma; Curcumin; Diarylheptanoids; HT29 Cells; Humans; Mass Spectrometry; Neoplasms; Phytotherapy; Plant Extracts; Solvents

Amyloid deposition, arising from the fibrillogenesis of proteins in organs and tissues of the body, causes several neurodegenerative disorders. One therapeutic approach is based on the use of polyphenols and their derivatives for suppressing and inhibiting the accumulation of these toxic fibrils in tissues. In the present study, the anti-amyloidogenic activities of bisdemethoxycurcumin (BDMC), a natural polyphenolic compound, and diacetylbisdemethoxycurcumin (DABC), a synthetic derivative of curcumin, on the amyloid fibrillation of hen egg white lysozyme (HEWL) is studied in depth using thioflavin T (ThT) fluorescence, atomic force microscopy (AFM), circular dichroism spectroscopy (CD), molecular docking and Ligplot calculations. The binding parameters such as binding constants and the number of substantive binding sites were obtained experimentally. It could be shown from docking simulation that four hydrogen bonds via the two phenolic OH groups of BDMC and two β-diketone moiety of BDMC are formed with the Asp-101, Trp-63, Asn-59 and Glu-35 of HEWL, whereas, two hydrogen bonds formed via two β-diketone moiety of DABC with Asn-39 and Trp-63 of HEWL. The short Fӧrster's distance (r) between donor and acceptor, the binding constant values and also the nature of interaction, demonstrate strong interaction between these two curcuminoids and lysozyme. According to amyloid fibrillation and binding results, the interaction of BDMC with HEWL is stronger than that of DABC and amyloid fibrillation of HEWL was inhibited more effectively by BDMC than DABC. It can be suggested that the more inhibitory activity of BDMC than DABC is correlated to the stronger interaction of BDMC with HEWL. These natural polyphenolic compounds are thus good candidates for inhibiting of amyloid formation. The inhibitory activities of BDMC and DABC can be used in drug formulation against the dangerous amyloid-related diseases and provide health promotion for organs and tissues of the body.

Topics: Amyloid; Animals; Benzothiazoles; Chickens; Curcumin; Diarylheptanoids; Molecular Docking Simulation; Molecular Structure; Muramidase; Particle Size; Protein Aggregates; Thiazoles

Curcuminoids (Curs), oleoresins from

Topics: A549 Cells; Antineoplastic Agents, Phytogenic; Cell Death; Curcumin; Diarylheptanoids; Drug Carriers; Drug Delivery Systems; Drug Liberation; Dynamic Light Scattering; Emulsions; Humans; Hydrophobic and Hydrophilic Interactions; Microscopy, Electron, Transmission; Nanoparticles; Particle Size; Polymerization; Polymethyl Methacrylate; Spectroscopy, Fourier Transform Infrared

The natural compound, curcumin (CUR), possesses several pharmacological properties, including p300-specific histone acetyltransferase (HAT) inhibitory activity. In our previous study, we demonstrated that CUR could prevent the development of cardiac hypertrophy by inhibiting p300-HAT activity. Other major curcuminoids isolated from Curcuma longa including demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are structural analogs of CUR. In present study, we first confirmed the effect of these three curcuminoid analogs on p300-HAT activity and cardiomyocyte hypertrophy. Our results showed that DMC and BDMC inhibited p300-HAT activity and cardiomyocyte hypertrophy to almost the same extent as CUR. As the three compounds have structural differences in methoxy groups at the 3-position of their phenol rings, our results suggest that these methoxy groups are not involved in the inhibitory effects on p300-HAT activity and cardiac hypertrophy. These findings provide useful insights into the structure-activity relationship and biological activity of curcuminoids for p300-HAT activity and cardiomyocyte hypertrophy.

Topics: Animals; Cattle; Cells, Cultured; Curcuma; Curcumin; Diarylheptanoids; Heart Failure; Humans; Hypertrophy; Myocytes, Cardiac; p300-CBP Transcription Factors; Phytotherapy; Rabbits; Structure-Activity Relationship

Curcuminoids, the major bioactive constituents of traditional medicine known as turmeric, have exhibited extensive therapeutic benefits. Excited by violet-blue light, curcuminoids can emit native fluorescence, making them possible to be detected with high sensitivity and specificity by laser-induced native fluorescence (LINF). Here, a commercial 445 nm laser diode was used as an excitation source to construct a confocal laser-induced fluorescence (LIF) detector and then a complete capillary electrophoresis (CE) system coupled with LIF detection was established. With three major curcuminoids, curcumin, demethoxy curcumin (DMC) and bisdemethoxy curcumin (BDMC) as target analytes, a micellar electrokinetic chromatography (MEKC) method was proposed using mixed micelles consisting of Triton X-100 and SDS to sensitize the native fluorescence of curcuminoids and enhance their separation efficiency. Fluorescence spectra revealed that the mixed micelles induced fluorescence synergism could enhance the signals of three curcuminoids by 77-, 57-, and 47-fold for curcumin, DMC, and BDMC. After systematic investigation, the optimal separation buffer for curcuminoids was chosen as follows: 20 mM Triton X-100, 20 mM SDS, 30% (v/v) methanol in 10 mM borax solution at pH 10.0. Under these conditions, a baseline separation of three curcuminoids was achieved within 10 min and the detection limits were found to be 4.1, 2.6, and 0.4 ng/mL for curcumin, DMC, and BDMC, respectively. Furthermore, the developed MEKC-LINF method was validated in terms of precision, linearity, accuracy and successfully applied for the determination of three curcuminoids in turmeric, medicinal turmeric liniment, curry seasoning, and human urine samples.

Topics: Buffers; Calibration; Chromatography, Micellar Electrokinetic Capillary; Curcuma; Curcumin; Diarylheptanoids; Humans; Hydrogen-Ion Concentration; Lasers; Limit of Detection; Methanol; Micelles; Octoxynol; Reference Standards; Regression Analysis; Reproducibility of Results; Spectrometry, Fluorescence

Bisdemethoxycurcumin (BDMC) exhibits biological activities including anticancer and anti-metastasis in human cancer cell lines, but there is no available information to show whether BDMC suppresses cell migration and invasion of human cervical cancer cells.. Wound-healing, migration, invasion, zymography, and western blotting assays were used to investigate the effects of BDMC on HeLa cells in vitro.. BDMC reduced the total viable cell number in a dose-dependent manner. The wound-healing assay show BDMC suppressed the movement of HeLa cells. Furthermore, the trans-well chamber assays showed that BDMC suppressed the cell migration and invasion. Gelatin zymograph assay showed that BDMC did not inhibit matrix metalloproteinase-2 (MMP-2) and -9 activities in vitro. However, western blotting assay showed that BDMC significantly reduced protein levels of growth factor receptor-bound protein 2 (GRB2), Ras homolog gene family, member A (Rho A), urokinase-type plasminogen activator (uPA), RAS, MMP-2, and N-cadherin but increased those of phosphor-extracellular-signal related kinase (p-ERK1/2), E-cadherin and nuclear factor-ĸB (NF-ĸB) in HeLa cells. Confocal laser microscopy assay was used to further confirm BDMC increased NF-ĸB when compared to controls.. BDMC may have potential as a novel anti-metastasis agent for the treatment of human cervical cancer.

Topics: Blotting, Western; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Female; HeLa Cells; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Microscopy, Confocal; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B; Uterine Cervical Neoplasms

Most allergic reactions are induced by mast cell activation. Mast cells play vital roles in the pathogenesis of allergic diseases. Bisdemethoxycurcumin (BDMC), a natural curcuminoid, has potential anti-allergic effects. Hence, we explored the effect of BDMC on mast cell-mediated allergic diseases. The study proved that BDMC suppresses β-hexosaminidase release, granule release, and membrane ruffling in monoclonal anti-2,4,6-dinitrophenyl-immunoglobulin (Ig) E/human serum albumin (DNP-IgE/HSA)-stimulated rat basophilic leukaemia cells (RBL-2H3 cells), and BDMC suppressed ovalbumin (OVA)-induced allergic rhinitis (AR) symptoms and OVA-specific IgE levels in AR mice. Furthermore, BDMC increased the survival of compound 48/80 anaphylaxis shock mice and elevated the decreased rectal temperature in OVA-induced active systemic anaphylaxis mice. These findings indicate that BDMC regulates the degranulation of mast cells, demonstrating its potential in the treatment of mast cell-induced allergic reactions.

Topics: Anaphylaxis; Animals; Cell Line; Curcumin; Diarylheptanoids; Hypersensitivity; Male; Mast Cells; Mice; Mice, Inbred BALB C; Ovalbumin; p-Methoxy-N-methylphenethylamine; Rats; Rhinitis, Allergic

Iron overload disorders may be treated by chelation therapy. This study describes a novel method for isolating iron chelators from complex mixtures including plant extracts. We demonstrate the one-step isolation of curcuminoids from turmeric, the medicinal food spice derived from Curcuma longa. The method uses iron-nitrilotriacetic acid (NTA)-agarose, to which curcumin binds rapidly, specifically, and reversibly. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin each bound iron-NTA-agarose with comparable affinities and a stoichiometry near 1. Analyses of binding efficiencies and purity demonstrated that curcuminoids comprise the primary iron binding compounds recovered from a crude turmeric extract. Competition of curcuminoid binding to the iron resin was used to characterize the metal binding site on curcumin and to detect iron binding by added chelators. Curcumin-Iron-NTA-agarose binding was inhibited by other metals with relative potency: (>90% inhibition) Cu

Topics: Aluminum; Animals; Binding, Competitive; Calcium; Cell Line; Chromatography, Affinity; Copper; Curcuma; Curcumin; Deferoxamine; Diarylheptanoids; Edetic Acid; Epithelial Cells; Ferric Compounds; Iron; Iron Chelating Agents; Kinetics; Liver; Magnesium; Manganese; Nitrilotriacetic Acid; Plant Extracts; Rats; Zinc

This study aimed to investigate the absorption mechanism of three curcumin constituents in rat small intestines. Self-emulsification was used to solubilize the three curcumin constituents, and the rat in situ intestinal perfusion method was used to study factors on drug absorption, including drug mass concentration, absorption site, and the different types and concentrations of absorption inhibitors. Within the scope of experimental concentrations, three curcumin constituents were absorbed in rat small intestines through the active transport mechanism.

Topics: 2,4-Dinitrophenol; Adjuvants, Pharmaceutic; Animals; ATP-Binding Cassette Transporters; Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Emulsions; Enzyme Inhibitors; Female; Intestinal Absorption; Intestine, Small; Male; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Perfusion Imaging; Probenecid; Rats, Sprague-Dawley; Reference Values; Reproducibility of Results; Time Factors; Uncoupling Agents; Verapamil

Response surface methodology, coupled to a full factorial three-level experimental design, was applied to investigate the combined influence of pH (between 7.0 and 8.6) and composition of methanol-water mixtures (between 30 and 70% v/v of methanol content) on the stability of curcumin and its analogues demethoxycurcumin and bisdemethoxycurcumin. The response plots revealed that addition of methanol noticeably improved the stability of curcuminoids, this effect being both pH- and structure-dependent. In the central point of the experimental domain, half-life times of curcumin, demethoxycurcumin and bisdemethoxycurcumin were 3.8±0.2, 27±2 and 251±17h, respectively. Stability of curcuminoids increased at lower pH and higher methanol content and decreased in the opposite vertex of the experimental domain. These results can be interpreted by assuming that addition of methanol to water produces a different variation of pH of the medium and apparent pKa values of the ionisable groups of curcuminoids.

Topics: Curcumin; Diarylheptanoids; Hydrogen-Ion Concentration; Methanol; Water

It was reported that bovine α-lactalbumin (BLA) as an important whey protein can be utilized as valuable vehicle for metal ions. The goal of this study was to investigate the interaction of BLA with bisdemethoxycurcumin (BDMC), Diacetylcurcumin (DAC), and diacetylbisdemethoxycurcumin (DABC) as three bioactive compounds by fluorescence quenching measurements and docking studies. It was observed that these ligands come closer to tryptophan residues and quench their emission without any change in their micro region polarity. The Stern-Volmer equation which is the best model to provide information about the interaction between small bioactive molecules and proteins was used to obtain the binding constants and the binding stoichiometry. Information about the extent of resonance energy transfer and Förster's distance between donor and acceptor was estimated. Thermodynamic parameters confirmed that the final BDMC-BLA complex was stabilized by hydrogen bonds, whereas the final DABC-BLA and DAC-BLA complexes were stabilized by hydrophobic bonds which are in accordance with their chemical structures. Both the synchronous and docking studies verified that theTrp-26 which is the most exposed Tryptophan residue has the most contribution in the binding process. The Förster's distances between bound ligands and tryptophans were in agreement with the measured distances by docking studies. The obtained achievements confirmed that there are considerable binding interactions between these curcuminoids and BLA.

Topics: Amino Acid Motifs; Animals; Binding Sites; Cattle; Crystallography, X-Ray; Curcumin; Diarylheptanoids; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Kinetics; Lactalbumin; Molecular Docking Simulation; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Thermodynamics

Topics: Coated Materials, Biocompatible; Curcumin; Cytotoxins; Diarylheptanoids; Drug Carriers; Hep G2 Cells; Humans; Lactic Acid; Nanoparticles; Neoplasms; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer

Topics: Ammonia-Lyases; Arabidopsis; Biosynthetic Pathways; Culture Media; Curcumin; Diarylheptanoids; Escherichia coli; Gene Expression Regulation, Bacterial; Glucose; Industrial Microbiology; Ligases; Metabolic Engineering; Phenylalanine Ammonia-Lyase; Shikimic Acid; Tyrosine

Bisdemethoxycurcumin (BDMC), which is isolated from the rhizomes of Curcuma longa, has anti-inflammatory and anti-carcinogenic activities. Here we found that BDMC enhanced X-ray-induced apoptosis in human T-cell leukemia MOLT-4 cells. Knockdown of p53 significantly attenuated the radiosensitizing effect of BDMC. However, BDMC did not enhance X-ray-mediated activation of the p53 signaling pathway via p53's transactivation or mitochondrial translocation. On the other hand, BDMC promoted the X-ray-induced dephosphorylation at Ser 70 in Bcl-2's flexible loop regulatory domain and Bcl-2 binding to p53. Overexpressing Bcl-2 completely blocked the BDMC's radiosensitization effect. Our results indicate that BDMC stimulates the dephosphorylation and p53-binding activity of Bcl-2 and suggest that BDMC may induce a neutralization of Bcl-2's anti-apoptotic function, thereby enhancing X-ray-induced apoptosis.

Topics: Apoptosis; Cell Line, Tumor; Curcumin; Diarylheptanoids; Humans; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53; X-Rays

Antioxidant, anticholinesterase and antidiabetic activities of three curcuminoids isolated from the Curcuma longa were simultaneously tested and compared in this study. The highest antioxidant power was detected for curcumin with the applied methods. The drug potentials of curcuminoids for Alzheimer's disease were controlled. Bisdemethoxycurcumin (BDMC) showed substantial inhibitory activity. The activity of demethoxycurcumin (DMC) followed BDMC, whereas curcumin showed very little acetylcholinesterase inhibition activity. Antidiabetic activity of curcuminoids was evaluated by their α-glucosidase inhibitory activities. All curcuminoids show activities with decreasing order as BDMC > curcumin > DMC. The significant activities of BDMC compared to its isomers and examination of chemical structures of isomers might be a starting point in designing new drugs for Alzheimer's and Diabetes Mellitus.

Topics: Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Curcuma; Curcumin; Diarylheptanoids; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Plant Extracts

Curcumin, a natural compound extracted from the rhizomes of Curcuma Longa, is known to display pronounced anticancer activity but lacks good pharmacokinetic properties. In that respect, augmenting the water solubility by structural modification of the curcumin scaffold may result in improved bioavailability and pharmacokinetics. A possible scaffold modification, especially important for this study, concerns the imination of the labile β-diketone moiety in curcumin. Previous work revealed that novel N-alkyl β-enaminones showed a similar water solubility as compared to curcumin, accompanied by a stronger anti-proliferative activity. To extend this β-enaminone compound library, new analogues were prepared in this work using more polar amines (hydroxyalkylamines and methoxyalkylamines instead of alkylamines) with the main purpose to improve the water solubility without compromising the biological activity of the resulting curcuminoids. Compared to their respective parent compounds, i.e. curcumin and bisdemethoxycurcumin, the bisdemethoxycurcumin N-(hydroxy/methoxy)alkyl enaminone analogues showed better water solubility, antioxidant and anti-proliferative activities. In addition, the curcumin enaminones displayed activities comparable to or better than curcumin, and the water solubility was improved significantly. The constructed new analogues may thus be of interest for further exploration concerning their impact on oxidative stress related diseases such as cancer.

Topics: Amines; Antineoplastic Agents; Antioxidants; Cell Line, Tumor; Cell Proliferation; Curcuma; Curcumin; Diarylheptanoids; Humans; Neoplasms; Solubility; Water

To study the relationship between the component content of curcuminoids in Curcumae Longae Rhizoma and powder color indeces L*, a* and b* those were measured by chromaticity instrument, in order to provide scientific basis for quality assessment of Curcuma longa medicinal materials.. Detect the content of curcumin,demethoxycurcumin,bisdemethoxycurcumin,then detect the content of curcuminoids by the Chinese Pharmacopoeia method. Measure the color indeces L*, a* and b* of Curcumae Longae Rhizoma powder by colorimeter. Finally, the relationship between the content and the color was analyzed by using the Grey Relational Analysis, Pearson correlation coefficient and regression analysis.. There was positive correlation between the content of curcuminoids and a*. But there was no definitely relation between the content of curcuminoids and b* or L*.. The content of curcuminoids is closely related with the degree of the color red, the higher the content, the red is deeper. a* could be recognized as an important basis of Curcumae Longae Rhizoma medicinal materials quality.

Topics: Color; Colorimetry; Curcuma; Curcumin; Diarylheptanoids; Powders; Rhizome

Stroke is a one of the leading causes of disease and deaths worldwide, which causes irreversible deterioration of the central nervous system. Curcuminoids are reported to have a potential role in the amelioration of cerebral ischemia but they exhibit low serum and tissue levels due to low solubility and poor absorption. Curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)-loaded PNIPAM nanoparticles (NPs) were prepared by free radical polymerization and characterized for particles size, entrapment efficiency, zeta potential, in vitro release and ex vivo permeation study. Optimized CUR, DMC and BDMC-loaded NPs had the mean size of 92.46 ± 2.8, 91.23 ± 4.2 and 94.28 ± 1.91 nm; zeta potential of -16.2 ± 1.42, -15.6 ± 1.33 and -16.6 ± 1.21 mV; loading capacity of 39.31 ± 3.7, 38.91 ± 3.6 and 40.61 ± 3.6% and entrapment efficiency of 84.63 ± 4.2, 84.71 ± 3.99 and 85.73 ± 4.31%, respectively. Ultra-performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectroscopy based bioanalytical method was developed and validated for pharmacokinetics, biodistribution, brain-targeting efficiency and brain drug-targeting potential studies post-intranasal (i.n.) administration which showed enhanced bioavailability of curcuminoids in brain as compared to intravenous administration. Improved neurobehavioural activity (locomotor and grip strength) and reduced cytokines levels (TNF-α and IL-1β) was observed in middle cerebral artery occlusion induced cerebral ischemic rats after i.n. administration of curcuminoids NPs. Finally, the toxicity study was performed which revealed safe nature of developed NPs.

Topics: Acrylic Resins; Administration, Intranasal; Animals; Biological Availability; Brain; Brain Ischemia; Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Drug Delivery Systems; Nanoparticles; Nasal Mucosa; Particle Size; Rats; Rats, Wistar; Spectrometry, Mass, Electrospray Ionization; Stroke; Tandem Mass Spectrometry; Tissue Distribution

Nonsmall cell lung carcinoma (NSCLC) is a devastating primary lung tumor resistant to conventional therapies. Bisdemethoxycurcumin (BDMC) is one of curcumin derivate from Turmeric and has been shown to induce NSCLC cell death. Although there is one report to show BDMC induced DNA double strand breaks, however, no available information to show BDMC induced DNA damage action with inhibited DNA repair protein in lung cancer cells in detail. In this study, we tested BDMC-induced DNA damage and condensation in NCI-H460 cells by using Comet assay and DAPI staining examinations, respectively and we found BDMC induced DNA damage and condension. Western blotting was used to examine the effects of BDMC on protein expression associated with DNA damage and repair and results indicated that BDMC suppressed the protein levels associated with DNA damage and repair, such as 14-3-3σ (an important checkpoint keeper of DDR), O6-methylguanine-DNA methyltransferase, DNA repair proteins breast cancer 1, early onset, mediator of DNA damage checkpoint 1 but activate phosphorylated p53 and p-H2A.X (phospho Ser140) in NCI-H460 cells. Confocal laser systems microscopy was used for examining the protein translocation and results show that BDMC increased the translocation of p-p53 and p-H2A.X (phospho Ser140) from cytosol to nuclei in NCI-H460 cells. In conclusion, BDMC induced DNA damage and condension and affect DNA repair proteins in NCI-H460 cells in vitro. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1859-1868, 2016.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Diarylheptanoids; DNA Damage; DNA Repair; Histones; Humans; Lung Neoplasms; Phosphorylation; Protein Transport; Tumor Suppressor Protein p53

Curcuminoids are the major natural phenolic compounds found in the rhizome of many Curcuma species. Curcuminoids consist of a mixture of curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). Although numerous studies have shown that curcumin induced cell apoptosis in many human cancer cells, however, mechanisms of BDMC-inhibited cell growth and -induced apoptosis in human lung cancer cells still remain unclear. Herein, we investigated the effect of BDMC on the cell death via the cell cycle arrest and induction of apoptosis in NCI H460 human lung cancer cells. Flow cytometry assay was used to measure viable cells, cell cycle distribution, the productions of reactive oxygen species (ROS) and Ca

Topics: Antineoplastic Agents; Apoptosis; Caspases; cdc25 Phosphatases; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Curcumin; Cyclin A; Cyclin E; Diarylheptanoids; DNA Damage; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Reactive Oxygen Species; S Phase; Signal Transduction

Obesity is caused by excessive accumulation of body fat and is closely related to complex metabolic diseases. Adipogenesis is a key process that is required in adipocyte hypertrophy in the development of obesity. Curcumin (Cur) has been reported to inhibit adipocyte differentiation, but the inhibitory effects of other curcuminoids present in turmeric, such as demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), on adipogenesis have not been investigated. Here, we investigated the effects of curcuminoids on adipogenesis and the molecular mechanisms of adipocyte differentiation. Among three curcuminoids, BDMC was the most effective suppressor of lipid accumulation in adipocytes. BDMC suppressed adipogenesis in the early stage primarily through attenuation of mitotic clonal expansion (MCE). In BDMC-treated preadipocytes, cell cycle arrest at the G0/G1 phase was found after initiation of adipogenesis and was accompanied by downregulation of cyclin A, cyclin B, p21, and mitogen-activated protein kinase (MAPK) signaling. The protein levels of the adipogenic transcription factors peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding proteins (C/EBP)α were also reduced by BDMC treatment. Furthermore, 0.5% dietary BDMC (w/w) significantly lowered body weight gain and adipose tissue mass in high-fat diet (HFD)-fed mice. The results of H&E staining showed that dietary BDMC reduced hypertrophy in adipocytes. These results demonstrate for the first time that BDMC suppressed adipogenesis in 3T3-L1 adipocytes and prevented HFD-induced obesity. Our results suggest that BDMC has the potential to prevent obesity.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; Curcumin; Diarylheptanoids; Diet, High-Fat; Down-Regulation; Humans; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Obesity; PPAR gamma

The study aimed to investigate the synergistic activity of scopoletin and bisdemethoxycurcumin (BDMC) against the carmine spider mite Tetranychus cinnabarinus. The acaricidal activities of mixtures of scopoletin and BDMC against T. cinnabarinus female adults were measured via slide dipping and leaf disc dipping. A mathematical model was established by SPSS software. Bioassays for multiple effects including contact, ovicidal, cowpea root intake, repellency and oviposition inhibitory activity were carried out. The optimal mass ratio of the mixture of scopoletin and BDMC (at their respective LC(50)), the median lethal concentration (LC(50)) and the co-toxicity coefficient were 7:6, 0.19 mg/mL and 129, respectively. LC(50) values of contact activities of the mixture at optimal ratio against adults, nymphs, larvae, and eggs were 0.19, 0.18, 0.06, and 1.52 mg/mL, respectively. LC(50) values of cowpea root intake activity against adults and nymphs were 5.62 and 6.52 mg/mL, respectively. The highest repellent rates against adults and nymphs were 69.5% and 72.5%, respectively. The mixture of scopoletin and BDMC at the optimal mass ratio possessed strong acaricidal activity against T. cinnabarinus at various developmental stages.

Topics: Animals; Curcumin; Diarylheptanoids; Drug Synergism; Female; Lethal Dose 50; Models, Theoretical; Scopoletin; Tetranychidae

Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has become one of the most common causes of chronic liver disease over the last decade in developed countries. NAFLD includes a spectrum of pathological hepatic changes, such as steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Bisdemethoxycurcumin (BDMC) is polyphenolic compounds with a diarylheptanoid skeleton, curcumin close analogues, which is derived from the Curcumae Longae Rhizoma. While the rich bioavailability research of curcumin, BDMC is the poor studies. We investigated whether BDMC has the hepatoprotective effect and combinatory preventive effect with silymarin on methionine choline deficient (MCD)-diet-induced NAFLD in C57BL/6J mice. C57BL/6J mice were divided into five groups of normal (normal diet without any treatment), MCD diet (MCD diet only), MCD + silymarin (SIL) 100 mg/kg group, MCD + BDMC 100 mg/kg group, MCD + SIL 50 mg/kg + BDMC 50 mg/kg group. Body weight, liver weight, liver function tests, histological changes were assessed and quantitative real-time polymerase chain reaction and Western blot analyses were conducted after 4 weeks. Mice lost body weight on the MCD-diet, but BDMC did not lose less than the MCD-diet group. Liver weights decreased from BDMC, but they increased significantly in the MCD-diet groups. All liver function test values decreased from the MCD-diet, whereas those from the BDMC increased significantly. The MCD- diet induced severe hepatic fatty accumulation, but the fatty change was reduced in the BDMC. The BDMC showed an inhibitory effect on liver lipogenesis by reducing associated gene expression caused by the MCD-diet. In all experiments, the combinations of BDMC with SIL had a synergistic effect against MCD-diet models. In conclusion, our findings indicate that BDMC has a potential suppressive effect on NAFLD. Therefore, our data suggest that BDMC may act as a novel and potent therapeutic agent against NAFLD.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Cholesterol; Choline; Choline Deficiency; Curcuma; Curcumin; Diarylheptanoids; Drug Synergism; Food, Formulated; Lipogenesis; Liver; Liver Function Tests; Male; Methionine; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Organ Size; Protective Agents; Silymarin; Triglycerides

Turmeric, a rhizome of Curcumin longa L. is widely used as both a spice and an herbal medicine. The traditional use of turmeric in gastroenterology is mainly based on its choleretic activity. The aim of this study is to determine the effects of turmeric on bile flow (BF) and total bile acids (TBAs) excretion in a bile fistula rat model after acute duodenal administration. A significant dose-dependent enhancement in both BF and TBAs was detected after treatment with the turmeric decoctions which suggested the choleretic activity was bile acid-dependent secretion. In order to direct the active group of compounds, aqueous (AE), ethyl acetate (EtOAc), and petroleum ether (PE) extracts were investigated. The EtOAc and PE extracts showing high effects were purified to locate the active ingredients. Three curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) and 2 sesquiterpenes (bisacurone B and ar-turmerone) were isolated. It was found Bisacurone B was the most potent choleretic ingredient followed by ar-turmerone, bisdemethoxycurcumin demethoxycurcumin, and then curcumin. The amounts of the active ingredients were quantitatively analyzed by high-performance liquid chromatography. The EtOAc and PE extracts had high sesquiterpenes and curcuminoids content, while the AE extract had poor content of sesquiterpenes and curcuminoids which affected neither BF nor TBAs. Based on the results of multiple linear regression analysis, the content of BIS and TUR were dominant factors (P < 0.01) of controlling BL and TBAs in EtOAC and PE extracts.

Topics: Animals; Bile; Bile Acids and Salts; Cholagogues and Choleretics; Chromatography, High Pressure Liquid; Curcuma; Curcumin; Cyclohexanols; Diarylheptanoids; Ketones; Plant Extracts; Rats; Rhizome; Sesquiterpenes

As one main active compound of curcuminoids, Bisdemethoxycurcumin (BDMC) possesses several biological activities, such as anti-inflammation and anti-cancer activities. However, the detailed mechanism of BDMC's anti-metastasis activity in ovarian cancer has not been clearly elucidated yet. In the present study, cell proliferation, wound healing motility, cell adhesion and invasion with or without BDMC were determined. In addition, western blot was used to examine proteins expressions. The lucigenin-enhanced luminescence was introduced to assess cellular oxidative stress. The luciferase reporter gene assay was introduced to evaluate the transcriptional activity of NF-κB. Finally, BDMC significantly inhibited the adhesion, migration, invasion and metastasis of SKOV-3 cells. Moreover, BDMC inhibited expressions of several degradation-associated proteins, such as matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), CD147, urokinase plasminogen activator (uPA), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), whereas increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), in a dose-dependent manner. In addition, BDMC reduced generation of cellular superoxide in a dose-dependent manner. Furthermore, BDMC inhibited the phosphorylation levels of NF-κB p65 and IκB-α, and consequently reduced NF-κB-driven luciferase expression. Collectively, BDMC serves as a therapeutic medicine to suppress ovarian cancer, perhaps via inhibiting cellular oxidative stress and subsequently inactivating NF-κB pathway.

Topics: Animals; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Female; Humans; Matrix Metalloproteinases; Mice; NIH 3T3 Cells; Ovarian Neoplasms; Oxidative Stress; Time Factors

The presence of β-amyloid (Aβ) containing plaques in the brain is a hallmark of Alzheimer's disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Early diagnosis is of great importance for optimal treatment and for monitoring disease progression in the brain. Highly specific and sensitive biomarkers are thus greatly needed to assess therapeutic efficacy, not only clinically, but also in terms of clearance of histopathological lesions and decelerated neurodegeneration. The objective of the present study was to give more insight into the binding of curcumin analogues, curcuminoids, to Aβ containing plaques in postmortem tissue from AD patients. In vitro autoradiography was utilized to explore affinity and displacement of the curcuminoids; curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC) and dimethoxycurcumin (DIMC). We found that BDMC had the highest affinity for Aβ containing plaques in cortical AD brain tissue in comparison to other curcuminoids. Subsequently, [(3)H]BDMC showed significantly higher specific binding in cortical AD brain tissue compared to control subjects. These findings suggest that curcumin analogues, especially BDMC, may serve as a potential radioligands for Aβ plaque neuroimaging.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aminopyridines; Amyloid beta-Peptides; Autoradiography; Benzothiazoles; Curcumin; Diarylheptanoids; Female; Humans; Inhibitory Concentration 50; Male; Temporal Lobe

The B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) locus encodes a 37-kD protein that is a key regulatory component of the polycomb regulatory complex 1 (PRC1). When overexpressed in various cancer types, the BMI1 protein induces cell growth and promotes tumor growth in vitro and in vivo. Curcumin, a major phytochemical in turmeric (Curcuma longa), inhibits the proliferation and survival of many types of cancer cells, both in vitro and in vivo, and has been reported to reduce BMI1 expression in breast cancer cells. In this study, effects of curcumin and two analogs (bisdemethoxycurcumin and dimethoxycurcumin) on BMI1 expression were evaluated in DLD-1 colorectal cancer cells. Bisdemethoxycurcumin (BDMC) is naturally occurring in turmeric, whereas dimethoxycurcumin (DMC) is a synthetic analog of curcumin. All three compounds reduced cell survival, but only the natural compound downregulated BMI1 protein expression; curcumin significantly reduced BMI1 levels more than bisdemethoxycurcumin and dimethoxycurcumin. In addition, curcumin and BDMC inhibit survival of the DLD-1 colorectal cancer cells by inducing apoptosis, whereas DMC inhibits survival by a mechanism other than apoptosis.

Topics: Adult; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Diarylheptanoids; Down-Regulation; Humans; Male; Polycomb Repressive Complex 1

A novel stirrer-liquid/solid microextraction method was developed for the separation and enrichment of trace levels of curcumin, bisdemethoxycurcumin, and demethoxycurcumin in Rhizoma Curcumae Longae, Radix Curcumae, and Rhizoma Curcumae before their analysis by high-performance liquid chromatography with ultraviolet detection. In the proposed approach, a magnetic stirrer was immersed in decanol to coat its surface completely with decanol, which was used as an extraction platform. The stirrer coated with decanol is not only a power to agitate the sample solution to constantly update the sample on the stirrer surface but also it can adsorb and extract the target analytes. Some effective parameters, including suitable superficial area of stirrer, extraction solvent, sample phase pH, NaCl concentration, stirring rate, extraction time, sample phase volume, were analyzed and selected. Under the optimal conditions, the linearities are 0.0044-2.20 μg/mL, detection limits are 0.3-0.6 ng/mL, and the extraction content per unit length and enrichment factors of the target analytes are 6.24-9.71/mm and 589-917, respectively. Also, the stirrer-liquid/solid microextraction mechanism for the extraction and enrichment of the target analytes was analyzed and expounded. The results showed that stirrer-liquid/solid microextraction is a simple, rapid sample pretreatment approach with a high enrichment factor.

Topics: Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Drugs, Chinese Herbal; Limit of Detection; Liquid Phase Microextraction; Solid Phase Microextraction

Pancreatic cancer is a highly aggressive malignancy, which is intrinsically resistant to current chemotherapies. Herein, we investigate whether bisdemethoxycurcumin (BDMC), a derivative of curcumin, potentiates gemcitabine in human pancreatic cancer cells. The result suggests that BDMC sensitizes gemcitabine by inducing mitochondrial dysfunctions and apoptosis in PANC-1 and MiaPaCa-2 pancreatic cancer cells. Utilizing two-dimensional gel electrophoresis and mass spectrometry, we identify 13 essential proteins with significantly altered expressions in response to gemcitabine alone or combined with BDMC. Protein-protein interaction network analysis pinpoints glucose-regulated protein 78 (GRP78) as the key hub activated by BDMC. We then reveal that BDMC upregulates GRP78 and facilitates apoptosis through eIF2α/CHOP pathway. Moreover, DJ-1 and prohibitin, two identified markers of chemoresistance, are increased by gemcitabine in PANC-1 cells. This could be meaningfully reversed by BDMC, suggesting that BDMC partially offsets the chemoresistance induced by gemcitabine. In summary, these findings show that BDMC promotes apoptosis through a GRP78-dependent pathway and mitochondrial dysfunctions, and potentiates the antitumor effect of gemcitabine in human pancreatic cancer cells.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Deoxycytidine; Diarylheptanoids; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Endoplasmic Reticulum Chaperone BiP; Eukaryotic Initiation Factor-2; Gemcitabine; Heat-Shock Proteins; Humans; Mitochondria; Pancreatic Neoplasms; Prohibitins; Protein Deglycase DJ-1; Protein Interaction Maps; Repressor Proteins; RNA Interference; Signal Transduction; Transcription Factor CHOP; Transfection

This paper describes the synthesis of novel molecularly imprinted polymers (MIPs), prepared by a noncovalent imprinting approach, for cleanup and preconcentration of curcumin (CUR) and bisdemethoxycurcumin (BDMC) from medicinal herbal extracts and further analysis by high-performance liquid chromatography with fluorescence detection (HPLC-FLD). Two molecular mimics, a mixture of reduced BDMCs and 4-(4-hydroxyphenyl)-2-butanone (HPB), have been synthesized and applied as templates for MIP synthesis. The polymers were prepared using N-(2-aminoethyl) methacrylamide (EAMA) as functional monomer, ethylene glycol dimethacrylate (EDMA) as the cross-linker (in a 1:5 molar ratio), and a mixture of acetonitrile/dimethylsulfoxide (90%, v/v) as porogen. MIPs prepared using a mixture of reduced BDMCs as template showed higher selectivity for CUR and BDMC than those obtained with HPB, with imprinting factors of 3.5 and 2.7 for CUR and BDMC, respectively, using H2O/acetonitrile (65:35, v/v) as mobile phase. The adsorption isotherms for CUR in the MIP and the nonimprinted polymer (NIP) were fitted to the Freundlich isotherm model, and the calculated average binding affinities for CUR were (17 ± 2) and (8 ± 1) mM(-1) for the MIP and the NIP, respectively. The polymers were packed into solid-phase extraction (SPE) cartridges, and the optimized molecularly imprinted solid-phase extraction (MISPE-HPLC) with fluorescence detection (FLD) method allowed the extraction of both curcuminoids from aqueous samples (50 mM NH4Ac, pH 8.8) followed by a selective washing with acetonitrile/NH4Ac, 50 mM at pH 8.8 (30:70%, v/v), and elution with 3 × 1 mL of MeOH. Good recoveries and precision ranging between 87 and 92%, with relative standard deviation (RSD) of <5.3% (n = 3), were obtained after the preconcentration of 10-mL solutions containing both CUR and BDMC at concentrations in the range of 0-500 μg L(-1). The optimized method has been applied to the analysis of both curcuminoids in medicinal herbal extracts.

Topics: Binding Sites; Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Molecular Imprinting; Molecular Mimicry; Molecular Structure; Plant Extracts; Plant Preparations; Polymers; Solid Phase Extraction; Spectrophotometry, Ultraviolet

The therapeutic agents for dementia are limited due to the complex system underlying the mechanisms. Taking a preventive point of view, we focused on the inhibition of β-secretase and acetylcholinesterase (AChE). In addition, plant resources including herbs and spices have been widely consumed, and further, may be consumed for a long period over a lifetime. Considering this background, we screened β-secretase and AChE inhibitors from curry spices. Amongst them, curry leaf, black pepper, and turmeric extracts were effective to inhibit β-secretase. Furthermore, black pepper and turmeric extracts were also effective to inhibit AChE. Having these results in hand, we focused on the investigation of β-secretase inhibitors since the inhibitor of this enzyme has not previously been well investigated. As a result, α- and β-caryophyllene, β-caryophyllene oxide (from curry leaf), piperine (from black pepper), curcumin, demethoxycurcumin, and bisdemethoxycurcumin (from turmeric) were successfully identified as low molecular inhibitors. This is the first report to determine α- and β-caryophyllene, β-caryophyllene oxide, and piperine as β-secretase inhibitors. These compounds may pass through the blood brain barrier since their molecular weights are relatively low.

Topics: Acetylcholinesterase; Alkaloids; Amyloid Precursor Protein Secretases; Benzodioxoles; Cholinesterase Inhibitors; Curcuma; Curcumin; Diarylheptanoids; Murraya; Piper nigrum; Piperidines; Plant Extracts; Polycyclic Sesquiterpenes; Polyunsaturated Alkamides; Sesquiterpenes

Bisdemethoxycurcumin (BDCur) has been found widely in foods such as cheese, butter, etc., and in curry (powder) as a spice. It has been reported to possess anticancer activity. However, its poor absorption limited its application. Natural borneol (NB) has been used as a promoter of drug absorption and widely used in candies, beverages, baked goods, chewing gum and other foods. Thus, we investigated whether NB could potentiate the cellular uptake of BDCur, and elucidated the molecular mechanisms of their combined inhibitory effects on HepG2 cells. Our results demonstrate that NB significantly enhanced the cellular uptake of BDCur. Induction of cell cycle arrest in HepG2 cells by NB and BDCur in combination was evidenced by accumulation of the G2/M cell population. Further investigation on the molecular mechanism showed that NB and BDCur in combination resulted in a significant decrease in the expression level of Cdc2 and cyclin B. Moreover, studies also found that ROS acted as an upstream mediator in NB/BDCur-induced HepG2 cell growth inhibition and led to DNA damage with up-regulation of the expression level of phosphorylated ATM and p53. Our findings suggest that the strategy of using NB and BDCur in combination may have promising potential applications in cancer chemoprevention.

Topics: Absorption, Physiological; Antineoplastic Agents, Phytogenic; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Camphanes; Carcinoma, Hepatocellular; CDC2 Protein Kinase; Curcuma; Curcumin; Cyclin B; Diarylheptanoids; Drug Synergism; Food Additives; G2 Phase; Hep G2 Cells; Humans; Liver Neoplasms; Neoplasm Proteins; Phosphorylation; Protein Processing, Post-Translational; Reactive Oxygen Species; Rhizome; Tumor Suppressor Protein p53

Activated Hepatic Stellate Cells (HSCs), major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC in hepatic fibrosis has not been studied thus far in the context of the apoptosis in activated HSCs. In the current study, we compared the activities of BDMC and curcumin in the HSC-T6 cell line and demonstrated that BDMC relatively induced a potent apoptosis. BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl2 and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR) 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2. Additionally, incubation with BDMC increased the formation of death-induced signaling complex in HSC-T6 cells. Treatment with BDMC significantly diminished total intracellular ATP levels and upregulated ATP inhibitory factor-1. Collectively, the results demonstrate that BDMC induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2.

Topics: Adenosine Triphosphate; Apoptosis; Cell Line; Curcumin; Diarylheptanoids; Flow Cytometry; Hepatic Stellate Cells; Humans; Proteins; Receptor, Cannabinoid, CB2

The present study deals with the toxicity assessment of NBDMCA in vitro using red cell model and in vivo using rat model. Hemolysis was used as toxicity index in red blood cells. Different concentrations of NBDMCA viz., 20, 40, 60, 80, 100μg/ml in PBS were incubated with the red blood cells of rat. NBDMCA was found to induce less than 3% hemolysis in intact erythrocytes which was far lesser than the accepted threshold of 5%. Hematological cum biochemical parameters along with histopathological analysis and hemolysis were used as toxicity indices in rats. Whole blood of the NBDMCA-treated rats and control rats were analyzed for hematological parameters: erythrocyte count, leukocyte count, leukocyte differential count, hemoglobin, hematocrit, mean cell volume (MCV), mean corpuscular hemoglobin (MCH) using fully automated hematology analyzer. All hematological parameters analyzed were within the normal values in both the groups. Plasma samples were analyzed for biochemical parameters including glucose, blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatinine (Cre), albumin (Alb), total protein (TP), calcium (Ca) and phosphorus (P) using fully automated biochemistry analyzer. Invariably, all the biochemical parameters are significantly similar in both the groups. Gross examination of vital organs like lung, heart, kidney, spleen and brain reveals no detectable abnormalities in NBDMCA-treated animals. Internal organs like heart, brain, lung, liver, spleen and kidneys of the experimental animals were collected and fixed in 10% formalin, processed in vacuum infiltration tissue processor, embedded with paraffin wax and sectioned at approximately 5μm thick, stained with hematoxylin and eosin. The sections were examined and imaged through light microscopy. NBDMCA did not produce any significant changes in the histoarchitecture of all the organs studied. Heart, aorta, brain, lung, liver, kidney and spleen showed normal pathology report. The histopathological data correlated with the biochemical results indicating normal hepatocellular and nephrotic function. Our investigation clearly revealed that NBDMCA is hemocompatible in vitro and also safe to vital organs in vivo. We conclude that NBDMCA is non-toxic and safe and can be promoted as an ideal therapeutic tool for human use.

Topics: Administration, Intravenous; Animals; Cells, Cultured; Curcumin; Diarylheptanoids; Erythrocyte Count; Erythrocyte Indices; Erythrocytes; Hemolysis; Leukocyte Count; Male; Nanoparticles; Rats, Wistar

This study demonstrates the binding properties of bisdemethoxycurcumin (BDMC) and diacetylbisdemethoxycurcumin (DABC) as bioactive curcuminoids with bovine β-lactoglobulin (BLG) variant B using fluorescence and circular dichroism (CD) spectroscopy; molecular docking, and molecular dynamics simulation methods. The estimated binding constants for BLG-BDMC and BLG-DABC complexes were (8.99±0.10)×10(4) M(-1) and (1.87±0.10)×10(2) M(-1), respectively. The distances between BLG and these curcuminoids were obtained based on the Förster's theory of non-radiative energy transfer. Molecular docking studies revealed the binding of BDMC and DABC to the protein surface cleft of protein by formation of four and one hydrogen bonds, respectively. Finally, molecular dynamics simulation results represent the conformational changes of BLG due to its interaction with BDMC. Also, the profiles of atomic fluctuations signified the rigidity of ligand binding site during the simulation.

Topics: Acetylation; Animals; Cattle; Circular Dichroism; Curcuma; Curcumin; Diarylheptanoids; Lactoglobulins; Molecular Docking Simulation; Protein Binding

Curcuminoids are the main bioactive constituents of the rhizome of turmeric. Erythrocytes lesions in diabetes are probably related to hyperglycemia and protein glycation. It has been reported that curcumin prevent lipid peroxidation. However, reports on the effects of demethoxycurcumin and bis-demethoxycurcumin on human erythrocytes at high glucose levels are scarce. Our aim is to investigate the effect of curcuminoids on oxidative stress and membrane of erythrocytes exposed to hyperglycemic condition.. In this study, the different blood samples were treated with two doses of glucose (10 or 30 mM) to mimic hyperglycemia in the presence or absence of three kinds of curcuminoids (5 or 10 μM) in a medium at 37 °C for 24 h (Each experiment consists of 20 blood samples from 10 male and 10 female volunteers). The malondialdehyde was checked by HPLC, antioxidase (GSH and GSSG) were measured by LC/MS, SOD was checked by WST-1 kit, morphology and phospholipid symmetry were detected by flow cytometry, confocal scanning microscope and scanning electron microscope.. The results illustrated that all three curcuminoids reduce oxidative stress damage on the membrane and maintain a better profile for erythrocytes. Furthermore, three curcuminoids had benefit effects on antioxidase.. The three kinds of curcuminoids supplementation may prevent lipid peroxidation at different intensity and membrane dysfunction of human erythrocytes in hyperglycemia.

Topics: Cell Membrane; Cell Shape; Cells, Cultured; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Erythrocytes; Female; Glucose; Humans; Male; Oxidative Stress

Poor oral bioavailability of curcuminoids limited their various applications, and one of the main reasons is their rapid metabolism in vivo. Sulfonation via sulfotransferases (SULTs) is an important metabolic pathway for such compounds. The objective of this study is to determine the SULT-isoform-specific metabolic fingerprint, tissue-specific rate, and reaction kinetic profiles to describe the characterization and contribution of curcuminoids sulfonation.. Sulfonation of curcuminoids was investigated by using nine expressed SULT isoforms and four pooled human tissue S9 fractions. The results showed that human small intestine is the predominant tissue responsible for sulfonation of curcuminoids. SULT1A3 is a major isoform catalyzing sulfonation of curcumin and demethoxycurcumin, but not for bisdemethoxycurcumin. SULT1B1 is only responsible for sulfonation of curcumin. Although SULT1C4 and 1E1 could highly catalyze the sulfate conjugations toward all the three compounds, the correlativities with human small intestine S9 fractions were much weaker (R(2) = 0.100-0.482). Almost all the kinetic profiles of the SULT isoforms for curcuminoids exhibited substrate inhibition kinetics.. This investigation contributed to elucidate the SULT-mediated metabolism and detoxication of curcuminoids at molecular levels and in different organs.

Topics: Arylsulfotransferase; Biological Availability; Curcumin; Diarylheptanoids; Humans; Intestine, Small; Sulfotransferases; Tandem Mass Spectrometry

To investigate the effects of bisdemethoxycurcumin (BDMC) on non-small cell lung cancer (NSCLC) cell line, A549, and the highly metastatic lung cancer 95D cells.. CCK-8 assay was used to assess the effect of BDMC on cytotoxicity. Flow cytometry was used to evaluate apoptosis. Western blot analysis, electron microscopy, and quantification of GFP-LC3 punctuates were used to test the effect of BDMC on autophagy and apoptosis of lung cancer cells.. BDMC inhibited the viability of NSCLC cells, but had no cytotoxic effects on lung small airway epithelial cells (SAECs). The apoptotic cell death induced by BDMC was accompanied with the induction of autophagy in NSCLC cells. Blockage of autophagy by the autophagy inhibitor 3-methyladenine (3-MA) repressed the growth inhibitory effects and induction of apoptosis by BDMC. In addition, BDMC treatment significantly decreased smoothened (SMO) and the transcription factor glioma-associated oncogene 1 (Gli1) expression. Furthermore, depletion of Gli1 by siRNA and cyclopamine (a specific SMO inhibitor) induced autophagy.. Aberrant activation of Hedgehog (Hh) signaling has been implicated in several human cancers, including lung cancers. The present findings provide direct evidence that BDMC-induced autophagy plays a pro-death role in NSCLC, in part, by inhibiting Hedgehog signaling.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Diarylheptanoids; Down-Regulation; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Signal Transduction; Zinc Finger Protein GLI1

Extracts from the rhizome of the turmeric plant are widely consumed as anti-inflammatory dietary supplements. Turmeric extract contains the three curcuminoids, curcumin (≈80% relative abundance), demethoxycurcumin (DMC; ≈15%), and bisdemethoxycurcumin (BDMC; ≈5%). A distinct feature of pure curcumin is its instability at physiological pH, resulting in rapid autoxidation to a bicyclopentadione within 10-15 min. Here, we describe oxidative transformation of turmeric extract, DMC, and BDMC and the identification of their oxidation products using LC-MS and NMR analyses. DMC autoxidized over the course of 24 h to the expected bicyclopentadione diastereomers. BDMC was resistant to autoxidation, and oxidative transformation required catalysis by horseradish peroxidase and H2O2 or potassium ferricyanide. The product of BDMC oxidation was a stable spiroepoxide that was equivalent to a reaction intermediate in the autoxidation of curcumin. The ability of DMC and BDMC to poison recombinant human topoisomerase IIα was significantly increased in the presence of potassium ferricyanide, indicating that oxidative transformation was required to achieve full DNA cleavage activity. DMC and BDMC are less prone to autoxidation than curcumin and contribute to the enhanced stability of turmeric extract at physiological pH. Their oxidative metabolites may contribute to the biological effects of turmeric extract.

Topics: Antigens, Neoplasm; Curcuma; Curcumin; Diarylheptanoids; DNA Cleavage; DNA Topoisomerases, Type II; DNA-Binding Proteins; Epoxy Compounds; Humans; Oxidation-Reduction; Plant Extracts

Curcumin (Cur) and bisdemethoxycurcumin (BDMC), extracted from Curcuma longa, are poorly water-soluble polyphenol compounds that have shown anti-inflammatory potential for the treatment of osteoarthritis. To increase cellular uptake of Cur and BDMC in bone tissue, soybean phosphatidylcholines were used for liposome formulation. In this study, curcuminoid (Cur and BDMC)-loaded liposomes were characterized in terms of particle size, encapsulation efficiency, liposome stability, and cellular uptake. The results show that there is about 70% entrapment efficiency of Cur and BDMC in liposomes and that particle sizes are stable after liposome formation. Both types of liposome can inhibit macrophage inflammation and osteoclast differential activities. In comparison with free drugs (Cur and BDMC), curcuminoid-loaded liposomes were less cytotoxic and expressed high cellular uptake of the drugs. Of note is that Cur-loaded liposomes can prevent liposome-dependent inhibition of osteoblast differentiation and mineralization, but BDMC-loaded liposomes could not. With interleukin (IL)-1β stimulation, curcuminoid-loaded liposomes can successfully downregulate the expression of inflammatory markers on osteoblasts, and show a high osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL) ratio to prevent osteoclastogenesis. In the present study, we demonstrated that Cur and BDMC can be successfully encapsulated in liposomes and can reduce osteoclast activity and maintain osteoblast functions. Therefore, curcuminoid-loaded liposomes may slow osteoarthritis progression.

Topics: Alkaline Phosphatase; Animals; Biological Availability; Bone and Bones; Cell Differentiation; Cell Proliferation; Cell Survival; Chemistry, Pharmaceutical; Curcumin; Diarylheptanoids; Drug Compounding; Liposomes; Mice; Nanoparticles; Nitrites; Osteoarthritis; Osteoclasts; Particle Size

Curcuminoids consisted curcumin, demethoxycurcumin and bisdemethoxycurcumin, were extracted from turmeric using subcritical solvent by varying conditions of temperature (110-150 °C), time (1-10 min), pressure (5-100 atm), solid-to-solvent ratio, and mixing ratio of solvent. Preliminary lab-scale experiments were conducted to determine the optimum extraction temperature and mixing ratio of water and ethanol for the pilot-scale extraction. The maximum yield of curcuminoids in the pilot-scale system was 13.58% (curcumin 4.94%, demethoxycurcumin 4.73%, and bisdemethoxycurcumin 3.91% in dried extracts) at 135 °C/5 min with water/ethanol mixture (50:50, v/v) as a solvent. On the other hand, the extraction yields of curcuminoids were obtained as 10.49%, 13.71% and 13.96% using the 50%, 95% and 100% ethanol, respectively, at the atmospheric condition (60 °C/120 min). Overall results showed that the subcritical solvent extraction is much faster and efficient extraction method considering extracted curcuminoids contents and has a potential to develop a commercial process for the extraction of curcuminoids.

Topics: Chromatography, High Pressure Liquid; Cost-Benefit Analysis; Curcuma; Curcumin; Diarylheptanoids; Ethanol; Hot Temperature; Pilot Projects; Plant Extracts; Solvents; Water

Bisdemethoxycurcumin (BDMC) is an active component of curcumin and a chemotherapeutic agent, which has been suggested to inhibit tumor growth, invasion and metastasis in multiple cancers. But its contribution and mechanism of action in invasion and metastasis of non-small cell lung cancer (NSCLC) are not very clear. Therefore, we tried to study the effects of BDMC on regulation of epithelial-to-mesenchymal transition (EMT), which is closely linked to tumor cell invasion and metastasis.. In this study, we first induced transforming growth factor-β1 (TGF-β1) mediated EMT in highly metastatic lung cancer 95D cells. Thereafter, we studied the effects of BDMC on invasion and migration of 95D cells. In addition, EMT markers expressions were also analyzed by western blot and immunofluorescence assays. The contribution of Wnt inhibitory factor-1 (WIF-1) in regulating BDMC effects on TGF-β1 induced EMT were further analyzed by its overexpression and small interfering RNA knockdown studies.. It was observed that BDMC inhibited the TGF-β1 induced EMT in 95D cells. Furthermore, it also inhibited the Wnt signaling pathway by upregulating WIF-1 protein expression. In addition, WIF-1 manipulation studies further revealed that WIF-1 is a central molecule mediating BDMC response towards TGF-β1 induced EMT by regulating cell invasion and migration.. Our study concluded that BDMC effects on TGF-β1 induced EMT in NSCLC are mediated through WIF-1 and elucidated a novel mechanism of EMT regulation by BDMC.

Topics: Adaptor Proteins, Signal Transducing; Blotting, Western; Cell Line, Tumor; Cell Movement; Curcumin; Diarylheptanoids; Epithelial-Mesenchymal Transition; Humans; Lung Neoplasms; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction

In spite of the need for sensing bisdemethoxycurcumin analog (BDMCA), there is no detection system available so far. For the first time, we have demonstrated a sensing system for detecting BDMCA. Initially, chitosan thin films of three different molecular weights (low, average, high) were tested for the conductivity. The high molecular weight chitosan film was found to produce higher conductance and hence, used as the substrate. Addition of BDMCA to this substrate induced a significant conductance change (as revealed by impedance analyzer), making the detection system qualitative. Addition of increasing concentrations of BDMCA produced significantly concomitant increase in the conductivity (observed as decrease in current density as revealed by cyclic voltammetry) making the sensor quantitative. Our results show that this chitosan based electrochemical sensing system can be used for the rapid quantitative detection of BDMCA. As there is no BDMCA sensor available so far, this type of detection is very essential to monitor the pharmacokinetic behavior, the therapeutic dosage, bioavailability and related toxicity of BDMCA in different formulations and samples.

Topics: Chitosan; Curcumin; Diarylheptanoids; Electric Conductivity; Electrochemical Techniques; Microscopy, Electron, Scanning; X-Ray Diffraction

To study the in vitro anti-angiogenesis effect of three curcumin pigments (curcumin, demethoxycurcumin, bisdemethoxycurcumin). In the study, the inhibitory effect of the three curcumin pigments on proliferation of HUVEC cells induced by OX-LDL and the effect on migration of HUVEC cells were detected. The effect on neovascularization was observed by chorioallantoic membrane (CAM) test. The effect on cell adhesion factors ICAM-1 and VCAM-1 of HUVECs were tested by Real-time RT-PCR. It was found that the three curcumins could inhibit the proliferation of HUVEC cells induced by OX-LDL within the dosage range 4, 8, 16 mg x L(-1), with a dose-dependence. The proliferative effect of curcumins on HUVECs was greater than the other two derivatives (P < 0.01). All of the three curcumin pigments inhibited the migration of HUVEC cells and the angiogenesis of chick chorioallantoic membrane (CAM). The migration inhibition rate of curcumins at middle and high concentrations was greater than the other two (P < 0.01). All of the three curcumin could down-regulate the expression of VEGF and ICAM-1, and curcumins showed more obvious effect in down-regulating VEGF than demethoxycurcumin and bisdemethoxycurcumin(P < 0.01); Bisdemethoxycurcumin showed the most significant effect in down-regulating ICAM-1 (P < 0.01). All of the three showed no remarkable effect on expression of VCAM-1, and only bisdemethoxycurcumin showed the down-regulating effect (P < 0.05). According to the findings, all of the three curcumin pigments could resist angiogenesis by inhibiting proliferation and migration of endothelial cells and down-regulating the expression of VEGF and adhesion molecules ICAM-1.

Topics: Angiogenesis Inhibitors; Animals; Cell Movement; Cells, Cultured; Chorioallantoic Membrane; Curcumin; Diarylheptanoids; Humans; Intercellular Adhesion Molecule-1; RNA, Messenger; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Curcumin is the major constituent of turmeric (Curcuma longa L.). It has attracted widespread attention for its anticancer and anti-inflammatory activities. The separation of curcumin and its two close analogs, demethoxycurcumin and bisdemethoxycurcumin, has been challenging by conventional techniques. In this study, an environmentally friendly method based on supercritical fluid chromatography was established for the rapid and facile separation of the three curcuminoids directly from the methanol extract of turmeric. The method was first developed and optimized by ultra performance convergence chromatography, and was then scaled up to preparative supercritical fluid chromatography. Eluted with supercritical fluid CO2 containing 8-15% methanol (containing 10 mM oxalic acid) at a flow rate of 80 mL/min, curcumin, demethoxycurcumin and bisdemethoxycurcumin could be well separated on a Viridis BEH OBD column (Waters, 250 mm × 19 mm, 5 μm) within 6.5 min. As a result, 20.8 mg of curcumin (97.9% purity), 7.0 mg of demethoxycurcumin (91.1%), and 4.6 mg of bisdemethoxycurcumin (94.8%) were obtained after a single step of supercritical fluid chromatography separation with a mean recovery of 76.6%. Showing obvious advantages in low solvent consumption, large sample loading, and easy solvent removal, supercritical fluid chromatography was proved to be a superior technique for the efficient separation of natural products.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Chromatography, High Pressure Liquid; Chromatography, Supercritical Fluid; Curcuma; Curcumin; Diarylheptanoids; Humans; Solvents

The objectives of this study were to explore the inhibition mechanism of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus. In addition, human bronchus epithelial cell line BEAS-2B (normal cell) was selected for comparison. A high-performance liquid chromatography (HPLC) method was developed to separate and quantify the various curcuminoids in C. longa extract, including curcumin (1,714.5 μg/mL), demethoxycurcumin (1,147.4 μg/mL), and bisdemethoxycurcumin (190.2 μg/mL). A high-stability nanoemulsion composed of Tween 80, water, and curcuminoid extract was prepared, with mean particle size being 12.6 nm. The cell cycle was retarded at G2/M for both the curcuminoid extract and nanoemulsion treatments; however, the inhibition pathway may be different. H460 cells were more susceptible to apoptosis than A549 cells for both curcuminoid extract and nanoemulsion treatments. Growth of BEAS-2B remained unaffected for both the curcuminoid extract and nanoemulsion treatments, with a concentration range from 1 to 4 μg/mL. Also, the activities of caspase-3, caspase-8, and caspase-9 followed a dose-dependent increase for both A549 and H460 cells for both the treatments, accompanied by a dose-dependent increase in cytochrome C expression and a dose-dependent decrease in CDK1 expression. Interestingly, a dose-dependent increase in cyclin B expression was shown for A549 cells for both the treatments, while a reversed trend was found for H460 cells. Both mitochondria and death receptor pathways may be responsible for apoptosis of both A549 and H460 cells.

Topics: Apoptosis; Caspase 3; Caspase 8; Caspase 9; CDC2 Protein Kinase; Cell Cycle; Cell Line, Tumor; Chromatography, High Pressure Liquid; Curcuma; Curcumin; Cyclin B1; Cyclin-Dependent Kinases; Diarylheptanoids; Dose-Response Relationship, Drug; Emulsions; Humans; Lung Neoplasms; Mitochondria; Nanostructures; Plant Extracts

This study compared the ability of nine culinary plant extracts containing a wide array of phytochemicals to inhibit fructose uptake and then explored the involvement of intestinal fructose transporters and phytochemicals for selected samples. The chemical signature was characterized by high performance liquid chromatography with mass spectrometry. Inhibition of [(14)C]-fructose uptake was tested by using human intestinal Caco-2 cells. Then, the relative contribution of the two apical-facing intestinal fructose transporters, GLUT2 and GLUT5, and the signature components for fructose uptake inhibition was confirmed in naive, phloretin-treated and forskolin-treated Caco-2 cells. HPLC/MS analysis of the chemical signature revealed that guava leaf contained quercetin and catechin, and turmeric contained curcumin, bisdemethoxycurcumin and dimethoxycurcumin. Similar inhibition of fructose uptake (by ~50%) was observed with guava leaf and turmeric in Caco-2 cells, but with a higher contribution of GLUT2 for turmeric and that of GLUT5 for guava leaf. The data suggested that, in turmeric, demethoxycurcumin specifically contributed to GLUT2-mediated fructose uptake inhibition, and curcumin did the same to GLUT5-mediated fructose uptake inhibition, but GLUT2 inhibition was more potent. By contrast, in guava leaf, catechin specifically contributed to GLUT5-mediated fructose uptake inhibition, and quercetin affected both GLUT5- and GLUT2-mediated fructose uptake inhibition, resulting in the higher contribution of GLUT5. These results suggest that demethoxycurcumin is an important contributor to GLUT2-mediated fructose uptake inhibition for turmeric extract, and catechin is the same to GLUT5-mediated fructose uptake inhibition for guava leaf extract. Quercetin, curcumin and bisdemethoxycurcumin contributed to both GLUT5- and GLUT2-mediated fructose uptake inhibition, but the contribution to GLUT5 inhibition was higher than the contribution to GLUT2 inhibition.

Topics: Caco-2 Cells; Curcuma; Curcumin; Diarylheptanoids; Fructose; Gene Expression Regulation, Enzymologic; Glucose Transporter Type 2; Glucose Transporter Type 5; Humans; Phytochemicals; Plant Extracts; Psidium; Quercetin

Curcumin is an active component of the medicinal plant turmeric, which has been reported to have anti‑metastatic activities and induce autophagy in numerous cancer types. Bisdemethoxycurcumin (BDMC), one of the major active curcumin derivatives present in turmeric, was previously shown to trigger autophagy in highly metastatic large‑cell lung cancer 95D cells. However, the effects of the induction of autophagy by BDMC on the invasion and migration of 95D cells has remained elusive. Therefore, the present study investigated the effects of BDMC on the invasion and migration of highly metastatic large‑cell lung cancer 95D cells. Meanwhile we observed the effect of autophagy induced by BDMC on the migration and invasion in 95D cells. Transwell assays showed that BDMC exerted an inhibitory effect on the migration and invasion of 95D cells. Furthermore, the expression of vimentin was downregulated, while E‑cadherin expression was upregulated in 95D cells treated with BDMC. In addition, blockage of autophagy through Beclin1‑targeted small interfering RNA attenuated the inhibition of BDMC on 95D-cell migration and invasion. These findings provided direct evidence that BDMC inhibits 95D-cell migration and invasion. Furthermore, the inhibition of 95D-cell migration and invasion was associated with the downregulation of vimentin expression and the upregulation of E‑cadherin expression. Autophagy was involved in the anti‑cancer effects of BDMC on 95D cells. The present study provided novel insight into the underlying mechanisms of the anti-cancer effect of BDMC.

Topics: Antineoplastic Agents; Autophagy; Cadherins; Carcinoma, Large Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Diarylheptanoids; Humans; Lung; Lung Neoplasms; Neoplasm Invasiveness; Vimentin

A series of half-sandwich cyclopentadienyl rhodium(III) and iridium(III) complexes of the type [Cp*M(curc/bdcurc)Cl] and [Cp*M(curc/bdcurc)(PTA)][SO3CF3], in which Cp* = pentamethylcyclopentadienyl, curcH = curcumin and bdcurcH = bisdemethoxycurcumin as O^O-chelating ligands, and PTA = 1,3,5-triaza-7-phosphaadamantane, is described. The X-ray crystal structures of three of the complexes, i.e. [Cp*Rh(curc)(PTA)][SO3CF3] (5), [Cp*Rh(bdcurc)(PTA)][SO3CF3] (6) and [Cp*Ir(bdcurc)(PTA)][SO3CF3] (8), confirm the expected "piano-stool" geometry. With the exception of 5, the complexes are stable under pseudo-physiological conditions and are moderately cytotoxic to human ovarian carcinoma (A2780 and A2780cisR) cells and also to non-tumorigenic human embryonic kidney (HEK293) cells, but lack the cancer cell selectivity observed for related arene ruthenium(II) complexes.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Coordination Complexes; Curcumin; Diarylheptanoids; HEK293 Cells; Humans; Iridium; Ligands; Rhodium

To optimize the optimal microwave-assisted extraction method of curcuminoids from Curcuma longa.. On the base of single factor experiment, the ethanol concentration, the ratio of liquid to solid and the microwave time were selected for further optimization. Support Vector Regression (SVR) and Central Composite Design-Response Surface Methodology (CCD) algorithm were utilized to design and establish models respectively, while Particle Swarm Optimization (PSO) was introduced to optimize the parameters of SVR models and to search optimal points of models. The evaluation indicator, the sum of curcumin, demethoxycurcumin and bisdemethoxycurcumin by HPLC, were used.. The optimal parameters of microwave-assisted extraction were as follows: ethanol concentration of 69%, ratio of liquid to solid of 21 : 1, microwave time of 55 s. On those conditions, the sum of three curcuminoids was 28.97 mg/g (per gram of rhizomes powder).. Both the CCD model and the SVR model were credible, for they have predicted the similar process condition and the deviation of yield were less than 1.2%.

Topics: Curcuma; Curcumin; Diarylheptanoids; Microwaves; Phytochemicals; Plant Extracts; Rhizome; Support Vector Machine

An ultra high performance liquid chromatography-electrospray ionization-synapt mass spectrometric method (UHPLC/ESI-QTOF-MS/MS) for the analysis of curcumin (Cur), demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC) in Wistar rat brain homogenate was developed and validated. The chromatographic separation was achieved on a Waters ACQUITY UPLC™ BEH C18 (2.1mm × 100 mm; 1.7μm) column using isocratic mobile phase, consisting of acetonitrile: 10mM ammonium formate: formic acid (90:10:0.05v/v/v), at a flow rate of 0.2 ml min(-1) . The transitions occurred at m/z 367.0694/217.0598, 337.0717/173.0910, 307.0760/187.0844 for Cur, DMC, BDMC and m/z 307.0344/229.0677 for the IS (Nimesulide) respectively. The recovery of the analytes from Wistar rat brain homogenate was optimized using liquid-liquid extraction technique (LLE) in (ethyl acetate: chloform) mixture. The total run time was 3.0 min and the elution of Cur, DMC, BDMC occurred at 1.6, 1.75, 1.70 min, and for the IS 1.87 min, respectively. The linear dynamic range was established over the concentration range of 1.00 ng mL(-1) to 1000.0 ng mL(-1) (r(2) ; 0.9909 ± 0.0011, 0.9911 ± 0.003, and 0.9919 ± 0.0013) for Cur, DMC, and BDMC, respectively. The intra and inter-assay accuracy in terms of % CV for Cur, DMC, and BDMC was in the range 0.47-2.20, 0.47-1.65, and0.44-2.70, respectively. The lower limit of detection (LOD) and quantitation (LOQ) for Cur, DMC, and BDMC were 0.46, 0.05, 0.16 ng mL(-1) and 0.153, 0.015, 0.052 ng mL(-1) , respectively. Analytes were stable and the method proved to be accurate (recovery, >85%), specific and was applied to evaluate the Cur, DMC, BDMC loaded PNIPAM NPs as vehicles for nose to brain drug delivery.

Topics: Acrylic Resins; Administration, Intranasal; Animals; Antineoplastic Agents; Brain; Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Limit of Detection; Nanoparticles; Rats; Rats, Wistar; Tandem Mass Spectrometry

Curcuminoids are a group of compounds with a similar chemical backbone structure but containing different numbers of methoxy groups that have therapeutic potential due to their anti-inflammatory and anti-oxidant properties. They mainly bind to albumin in plasma. These findings influence their body disposition and biological activities. Spectroscopic analysis using site specific probes on human serum albumin (HSA) clearly indicated that curcumin (Cur), demethylcurcumin (Dmc) and bisdemethoxycurcumin (Bdmc) bind to both Site I (sub-site Ia and Ib) and Site II on HSA. At pH 7.4, the binding constants for Site I were relatively comparable between curcuminoids, while the binding constants for Site II at pH 7.4 were increased in order Cur < Dmc < Bdmc. Binding experiments using HSA mutants showed that Trp214 and Arg218 at Site I, and Tyr411 and Arg410 at Site II are involved in the binding of curcuminoids. The molecular docking of all curcuminoids to the Site I pocket showed that curcuminoids stacked with Phe211 and Trp214, and interacted with hydrophobic and aromatic amino acid residues. In contrast, each curcuminoid interacted with Site II in a different manner depending whether a methoxy group was present or absent. A detailed analysis of curcuminoids-albumin interactions would provide valuable information in terms of understanding the pharmacokinetics and the biological activities of this class of compounds.

Topics: Circular Dichroism; Curcumin; Diarylheptanoids; Fluorescent Dyes; Humans; Mutation; Oxidation-Reduction; Serum Albumin

Leukemia is a hematologic malignancy with a frequent incidence and high mortality rate. Previous studies have shown that the FLT3 gene is overexpressed in leukemic blast cells, especially in acute myeloid leukemia. In this study, a commercially available curcuminoid mixture (1), pure curcumin (2), pure demethoxycurcumin (3), and pure bisdemethoxycurcumin (4) were investigated for their inhibitory effects on cell growth, FLT3 expression, and cell cycle progression in an FLT3-overexpressing EoL-1 leukemic cell line using an MTT assay, Western blotting, and flow cytometry, respectively. The mixture (1) and compounds 2-4 demonstrated cytotoxic effects with IC50 values ranging from 6.5 to 22.5 μM. A significant decrease in FLT3 protein levels was found after curcuminoid treatment with IC20 doses, especially with mixture 1 and compound 2. In addition, mixture 1 and curcumin (2) showed activity on cell cycle arrest at the G0/G1 phase and decreased the FLT3 and STAT5A protein levels in a dose-dependent manner. Compound 2 demonstrated the greatest potential for inhibiting cell growth, cell cycle progression, and FLT3 expression in EoL-1 cells. This investigation has provided new findings regarding the effect of turmeric curcuminoids on FLT3 expression in leukemic cells.

Topics: Cell Cycle Checkpoints; Cell Proliferation; Curcuma; Curcumin; Diarylheptanoids; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Molecular Structure

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

We have optimized a protocol for the preparation of bisdemethoxy curcumin analog nanoparticles (BDMCA-NP) by the solvent assisted process. The structural similarities between bulk and nano BDMCA were determined by Co-TLC, NMR and F-TIR. This shows that our synthesis protocol enhanced the dispersibility and reduce the size of BDMCA without altering the integrity of functional moieties and structure, which is crucial for anticancer and antioxidant activities. The morphology and size of BDMCA-NP as determined by SEM, HRTEM and DLS was found to be around 80 nm. BDMCA-NP treated breast cancer cell lines (MCF 7) showed cell death as characterized by MTT assay. Flow cytometric analysis of BDMCA-NP treated MCF 7 cell lines showed an increase of cell count in G2/M phase indicates the cell cycle arrest. Western blot analysis revealed the presence of caspase 3, caspase 9, cleaved fragments of PARP and Bax proteins in the BDMCA-NP treated MCF 7 cell lines, but not in untreated cell lines. To recap, we have prepared BDMCA-NP by solvent assisted process, which exerted anticancer activity against breast cancer cells, which may be due to (i) enhanced dispersibility and surface: volume ratio, (ii) apoptosis (iii) mitochondrial pathway induced cell death, (iv) G2/M phase cell cycle arrest and (v) disassembly of mitotic spindle of the cancer cells. Thus, nano BDMCA can be used as a potent anticancer agent.

Topics: Animals; Antineoplastic Agents; Apoptosis; Chlorocebus aethiops; Crystallization; Curcumin; Diarylheptanoids; Diffusion; Drug Compounding; Humans; MCF-7 Cells; Nanoparticles; Neoplasms, Experimental; Particle Size; Surface Properties; Treatment Outcome; Vero Cells

Recent animal studies reported that curcumin, the active constituent of Curcuma longa, has several central actions and may attenuate morphine tolerance.. In the present study, we utilized the intracranial self-stimulation (ICSS) paradigm to examine the effects of the commercially available curcuminoid mixture and each one of its components, individually, on brain stimulation reward and on the reward-facilitating effect of morphine.. Male Sprague-Dawley rats were implanted with an electrode into the medial forebrain bundle and trained to respond for electrical stimulation using a rate-frequency paradigm. In the first study, rats were injected with graded doses either of the curcuminoid mixture, or curcumin I, or II, or III. In the second study, we examined whether a low dose of the curcuminoid mixture or each individual curcumin analogue composing it could counteract the reward-facilitating effect of morphine.. At low doses, both the curcuminoid mixture and curcumin I did not affect brain stimulation reward, whereas, higher doses increased ICSS thresholds. Curcumin II and curcumin III did not affect brain stimulation reward at any doses. Subthreshold doses of the curcuminoid mixture and curcumin I inhibited the reward-facilitating effect of morphine.. Both the curcuminoid mixture and curcumin I lack hedonic properties and moderate the reward-facilitating effect of morphine. Our data suggest that curcumin interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids and provide evidence that curcumin may be a promising adjuvant for attenuating morphine's rewarding effects in patients who are under long-term opioid therapy.

Topics: Analgesics, Opioid; Animals; Curcumin; Diarylheptanoids; Electric Stimulation; Male; Medial Forebrain Bundle; Morphine; Rats; Rats, Sprague-Dawley; Reward; Self Stimulation

The paper is aimed to study the dynamic accumulation regulation of curcumin (Cur), demethoxycurcumin (DMC) and bisdemethoxyeurcumin (BDMC) in three strains of Curcuma longa, and provide scientific references for formalized cultivation, timely harvesting, quality control and breeding cultivation of C. longa. The accumulation regulation of the three curcumin derivatives was basically the same in rhizome of three strains. The relative contents decreased along with plant development growing, while the accumulation per hectare increased with plant development growing. The accumulation of curcuminoids per hectare could be taken as the assessment standard for the best harvest time of C. longa. A3 was the best strain in terms of Cur and BDMC content.

Topics: Curcuma; Curcumin; Diarylheptanoids; Quality Control; Rhizome

Head and neck cancer is the sixth most frequently occurring cancer worldwide and accounts for about 2% of all cancer-related deaths annually. Curcumin is a well-known chemopreventive agent, and apoptosis induction by curcumin has been reported in many cancer cell types. We synthesized an ortho-hydroxy substituted analog of curcumin, bisdemethoxycurcumin analog (BDMC-A), and aimed to demarcate the apoptotic effects induced by BDMC-A on human laryngeal cancer Hep-2 cells and to compare these effects with those induced by curcumin.. We evaluated the apoptotic effects of BDMC-A in comparison to those of curcumin on Hep-2 cells by performing Western blotting, RT-PCR, fluorescent staining and DNA fragmentation assays. In addition, we carried out an in silico molecular docking study on the EGFR kinase domain.. We found that BDMC-A can induce apoptosis in Hep-2 cells by regulating the expression of both intrinsic and extrinsic apoptotic proteins, i.e., Bcl-2, Bax, apoptososme complex and death receptors, more efficiently than curcumin. We also observed increased nuclear fragmentation and chromatin condensation after BDMC-A treatment compared to curcumin treatment. Depolarized mitochondria and ROS generation was well pronounced in both BDMC-A and curcumin treated Hep-2 cells. Our in silico molecular docking study on the EGFR kinase domain revealed that BDMC-A may dock more efficiently than curcumin.. From our results we conclude that BDMC-A can induce apoptosis in Hep-2 laryngeal carcinoma cells more effectively than curcumin, and that this activity can be attributed to the presence of a hydroxyl group at the ortho position within this compound.

Topics: Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Cell Proliferation; Curcumin; Diarylheptanoids; Humans; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

While the chemotherapeutic effect of curcumin, one of three major curcuminoids derived from turmeric, has been reported, largely unexplored are the effects of complex turmeric extracts more analogous to traditional medicinal preparations, as well as the relative importance of the three curcuminoids and their metabolites as anti-cancer agents. These studies document the pharmacodynamic effects of chemically-complex turmeric extracts relative to curcuminoids on human breast cancer cell growth and tumor cell secretion of parathyroid hormone-related protein (PTHrP), an important driver of cancer bone metastasis. Finally, relative effects of structurallyrelated metabolites of curcuminoids were assessed on the same endpoints. We report that 3 curcuminoid-containing turmeric extracts differing with respect to the inclusion of additional naturally occurring chemicals (essential oils and/or polar compounds) were equipotent in inhibiting human breast cancer MDA-MB-231 cell growth (IC50=10-16µg/mL) and secretion of osteolytic PTHrP (IC50=2-3µg/mL) when concentrations were normalized to curcuminoid content. Moreover, these effects were curcuminoid-specific, as botanically-related gingerol containing extracts had no effect. While curcumin and bis-demethoxycurcumin were equipotent to each other and to the naturally occurring curcuminoid mixture (IC50=58µM), demethoxycurcumin did not have any effect on cell growth. However, each of the individual curcuminoids inhibited PTHrP secretion (IC50=22-31µM) to the same degree as the curcuminoid mixture (IC50=16µM). Degradative curcuminoid metabolites (vanillin and ferulic acid) did not inhibit cell growth or PTHrP, while reduced metabolites (tetrahydrocurcuminoids) had inhibitory effects on cell growth and PTHrP secretion but only at concentrations ≥10-fold higher than the curcuminoids. These studies emphasize the structural and biological importance of curcuminoids in the anti-breast cancer effects of turmeric and contradict recent assertions that certain of the curcuminoid metabolites studied here mediate these anti-cancer effects.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cell Culture Techniques; Cell Line, Tumor; Cell Survival; Curcuma; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Female; Humans; Parathyroid Hormone-Related Protein; Plant Extracts; Rhizome; Zingiber officinale

Curcuminoid, a dietary polyphenolic compound, has poor water solubility and low bioavailability following oral administration. The aim of this study was to develop a formulation of curcuminoid-loaded microemulsion (Cur-ME) to improve its oral bioavailability. The optimized Cur-ME formulation was prepared by using labrafac lipophile WL 1349, cremophor RH 40, and glycerine as the oil phase, the surfactant, and the cosurfactant, respectively. Pharmacokinetics and bioavailability of curcuminoid suspension and Cur-ME were evaluated and compared in rats. Plasma bisdemethoxycurcumin (BDMC), treated as the representing component of curcuminoid, was determined by high-performance liquid chromatography with fluorescence detector. After gavage administration of curcuminoid suspension, the plasma BDMC level was very low, below 5 ng/mL, whereas for Cur-ME, double peak of maximum concentrations were observed. The relative bioavailability of Cur-ME was enhanced in an average of 9.6-fold that of curcuminoid suspension. It was concluded that the bioavailbility of curcuminoid was enhanced greatly by the microemulsion.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Curcumin; Diarylheptanoids; Dietary Supplements; Emulsions; Glycerol; Intestinal Absorption; Male; Nutritive Value; Polyethylene Glycols; Random Allocation; Rats; Rats, Sprague-Dawley; Solubility; Surface-Active Agents; Triglycerides

A key event in the development of plaque in the arteries is the migration and proliferation of smooth muscle cells (SMCs) from the media to the intima of the blood vessel. This study was conducted to evaluate the effects of bisdemethoxycurcumin (BC), a naturally occurring structural analog of curcumin (CC), on platelet-derived growth factor (PDGF)-stimulated migration and proliferation of SMCs.. CC and BC were synthesized by condensing acetyl acetone with vanillin and 4-hydroxybenzaldehyde, respectively. SMCs isolated from adult rat aorta were stimulated with PDGF in the presence or absence of CC or BC following which, cell migration and proliferation were assessed by monolayer wound healing assay and [(3) H]-thymidine incorporation respectively. PDGF-stimulated phosphorylation of PDGF receptor-β and its downstream effectors Akt and ERK were assessed by Western blotting. Intracellular reactive oxygen species was assessed using the fluorescent dye 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. BC elicited a concentration-dependent inhibition of PDGF-stimulated phosphorylation of PDGF receptor-β, Akt and Erk as well as the PDGF-stimulated SMC migration and proliferation. BC was more potent than CC in inhibiting migration and proliferation and suppressing PDGF-signaling in SMCs. Both compounds were equipotent in inhibiting PDGF-stimulated generation of intracellular reactive oxygen species.. BC may be of potential use in the prevention or treatment of vascular disease.

Topics: Animals; Benzaldehydes; Cell Movement; Cell Proliferation; Curcumin; Diarylheptanoids; Electrophoresis, Polyacrylamide Gel; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction

By using slide-dip bioassay method under laboratory condition, an investigation was made on the lethal effects of scopoletin, bisdemethoxycurcumin (BDMC), and their combination at an optimal mass ratio (7:6) of scopoletin to BDMC against the adult females of Tetranychus cinnabarinus Boisd. A time-dose mortality model (TDM) was established, which passed the Hosmer-Lemeshow test. The sensitivity of the adult females to the concentration change of the acaricides was in the sequence of scopoletin > optimal mass ratio of scopoletin to BDMC > BDMC. The peak mortality of the female adults was found at 32, 28 and 32 h after treated with BDMC, scopoletin, and their combination at the optimal mass ratio, respectively. The values of the LC50 and LC90 at 48 h after treated with BDMC, scopoletin, and their combination at the optimal mass ratio were 0.3324, 0.2035 and 0.2195 mg x mL(-1), and 2.1198, 0.9521 and 1.1617 mg x mL(-1), and the median lethal time (LT50) of BDMC, scopoletin, and their combination at the optimal mass ratio was 7.4, 6.0 and 6.1 h at the concentration 1.0 mg x mL(-1), and 6.4, 4.8 and 5.0 h at the concentration 2.0 mg x mL(-1), respectively. The acaricidal activity and time-dose response of the optimal combination of scopoletin and BDMC were closer to those of scopoletin, suggesting a synergistic acaricidal activity of the combination of scopoletin and BDMC, which was worthy to be developed for application.

Topics: Acaricides; Animals; Curcumin; Diarylheptanoids; Drug Synergism; Female; Plant Extracts; Scopoletin; Tetranychidae

Oxidative stress and inflammatory damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. The present study examined the hypothesis that intranasal delivery of nanoformulation of curcuminoids would reduce oxidative stress-associated brain injury after middle cerebral artery occlusion (MCAO). The rats were subjected to 2 h of MCAO followed by 22 h reperfusion, after which the grip strength, locomotor activity was performed. The effects of treatment in the rats were assessed by grip strength, locomotor activity and biochemical studies (glutathione peroxidase, glutathione reductase, lipid peroxidation, superoxide dismutase, and catalase) in the brain. Pretreatment with polymeric N-isopropyl acryl amide (PNIPAM) nanoparticles formulation of all three curcuminoids (curcumin (Cur), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC)) at doses (100 μg/kg body weight) given intranasally was effective in bringing significant changes on all the parameters. While nanoformulation of curcumin at a dose of 100 μg/kg body weight was most active in the treatment of cerebral ischemia as compared to others nanoformulation of curcuminoids. The potency of antioxidant activity significantly decreased in the order of PNIPAM nanoformulation of Cur > DMC >> BDMC, thus suggesting the critical role of methoxy groups on the phenyl ring.

Topics: Acrylic Resins; Animals; Antioxidants; Biomarkers; Curcumin; Diarylheptanoids; Hand Strength; Light; Motor Activity; Nanoparticles; Oxidative Stress; Particle Size; Rats; Rats, Wistar; Scattering, Radiation; Stroke; Thiobarbituric Acid Reactive Substances

Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin present in the phenolic components extracted from the dried rhizome of Curcuma longa L. BDMC demonstrated potential chemotherapeutic activities but the underlying mechanisms have not been fully clarified. In the present study, the role of reactive oxidative species (ROS) in the anti-cancer effects of BDMC was investigated.. MCF-7 cells were exposed to BDMC, and then the cell proliferation, colony formation ability and cell cycle profile were analyzed. Cellular ROS level was determined by flow cytometry and fluorescent microscope observation using specific fluorescent probes. Mitochondrial membrane potential (ψm) was assessed using JC-1. In addition, effects of BDMC on senescence-related molecules were analyzed by western blot assay.. BDMC significantly inhibited MCF-7 breast cancer cell proliferation, while a rapid rise of the intracellular ROS level accompanied with a reduction of Dym were observed. In addition, BDMC activated the pro-apoptotic protein p53 and its downstream effector p21 as well as the cell cycle regulatory proteins p16 and its downstream effector retinoblastoma protein (Rb). All of these BDMC-induced effects were counteracted with the pre-incubation of the antioxidant N-acetylcysteine (NAC).. These results suggested that BDMC-induced ROS accumulation may contribute to its inhibitory effect on MCF-7 cell viability through regulation of p53/p21 and p16/Rb pathways.

Topics: Acetylcysteine; Antineoplastic Agents; Antioxidants; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Curcumin; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Diarylheptanoids; Humans; MCF-7 Cells; Membrane Potential, Mitochondrial; Nitrogen Oxides; Reactive Oxygen Species; Retinoblastoma Protein; Signal Transduction; Tumor Suppressor Protein p53

Two compounds, 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (BHPHTO) and bisdemethoxycurcumin (BDMC) they have been isolated from the rhizomes of Alpinia galangal, and the structures of both pure constituents were determined using spectroscopic analyses. The study examined the bioeffectivenesses of the two compounds on the human melanoma A2058 and showed that significantly inhibited the proliferation of melanoma cells in the cell viability assay. This research was also taken on the tests to B16-F10 cell line and showed minor inhibitory consequences of cellular tyrosinase activities and melanin contents. Our results revealed the anticancer effects of A. galangal compounds, and therefore, the target compounds could be potentially applied in the therapeutic application and the food industry.

Topics: Alpinia; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Curcumin; Diarylheptanoids; Humans; Melanins; Monophenol Monooxygenase; Phenols; Rhizome

Thalassemia is an inherited disorder of hemoglobin molecules that is characterized by an imbalance of α- and β-globin chain synthesis. Accumulation of unbound α-globin chains in erythroid cells is the major cause of pathology in β-thalassemia. Stimulation of γ-globin production can ameliorate disease severity as it combines with the α-globin to form fetal hemoglobin. We examined γ-globin-inducing effect of curcuminoids extracted from Curcuma longa L. and their metabolite reduced forms in erythroid leukemia K562 and human primary erythroid precursor cells. The results showed that curcuminoid compounds, especially bisdemethoxycurcumin are potential γ-globin enhancers. We also demonstrated that its reduced analog, hexahydrobisdemethoxycurcumin (HHBDMC), is most effective and leads to induction of γ-globin mRNA and HbF in primary erythroid precursor cells for 3.6 ± 0.4- and 2.0 ± 0.4-folds, respectively. This suggested that HHBDMC is the potential agent to be developed as a new therapeutic drug for β-thalassemia and related β-hemoglobinopathies.

Topics: Cell Differentiation; Cells, Cultured; Curcumin; Diarylheptanoids; Erythroid Cells; Fetal Hemoglobin; gamma-Globins; Humans; K562 Cells

Traditionally, active compounds were discovered from natural product extracts by bioassay-guided fractionation, which was with high cost and low efficiency. A well-trained support vector regression model based on mean impact value was used to identify lead active compounds on inhibiting the proliferation of the HeLa cells in curcuminoids from Curcuma longa L. Eight constituents possessing the high absolute mean impact value were identified to have significant cytotoxicity, and the cytotoxic effect of these constituents was partly confirmed by subsequent MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays and previous reports. In the dosage range of 0.2-211.2, 0.1-140.2, 0.2-149.9 μm, 50% inhibiting concentrations (IC50 ) of curcumin, demethoxycurcumin, and bisdemethoxycurcumin were 26.99 ± 1.11, 19.90 ± 1.22, and 35.51 ± 7.29 μm, respectively. It was demonstrated that our method could successfully identify lead active compounds in curcuminoids from Curcuma longa L. prior to bioassay-guided separation. The use of a support vector regression model combined with mean impact value analysis could provide an efficient and economical approach for drug discovery from natural products.

Topics: Antineoplastic Agents; Biological Assay; Curcuma; Curcumin; Cytotoxins; Diarylheptanoids; Drug Discovery; HeLa Cells; Humans; Support Vector Machine

Curcumin (CUR), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) have been demonstrated as having antioxidant, anticarcinogenic, and hypocholesterolemic activities. We report the diverse antiatherogenic effects and mechanisms of curcuminoids.. We found that CUR was the most potent antioxidant against copper-mediated LDL oxidation as measured by thiobarbituric acid-reactive substances assay, oxidized LDL (oxLDL) ELISA, and electrophoretic mobility. CUR upregulated heme oxygenase-1, modifier subunit of glutamate-cysteine ligase (GCLM), and CD36 expression in undifferentiated THP-1 cells, supporting the possible involvement of Nrf2 pathway in CD36 expression. Monocyte-to-macrophage differentiation plays a vital role in early atherogenesis. BDMC reduced oxLDL uptake most effectively, while CUR was the best inhibitor for CD36, scavenger receptor A, and lectin-like oxidized LDL receptor-1 expression during phorbol 12-myristate 13-acetate (PMA)-induced THP-1 differentiation. In PMA-differentiated THP-1 macrophages, CUR and DMC effectively induced heme oxygenase-1 expression, but attenuated oxLDL-induced CD36 expression, leading to decreased oxLDL uptake.. This result indicates curcuminoids, despite structural similarities, exert different atheroprotective effects. Curcuminoids, especially CUR and DMC, are hormetic compounds, which induce Phase II enzyme expression and confer resistance to PMA- and oxLDL-induced scavenger receptor expression and activity.

Topics: Antioxidants; Biomarkers; CD36 Antigens; Cell Differentiation; Cell Line, Tumor; Copper; Curcumin; Diarylheptanoids; Foam Cells; Gene Expression Regulation; Glutamate-Cysteine Ligase; Heme Oxygenase-1; Humans; Lipid Peroxidation; Lipoproteins, LDL; Monocytes; Scavenger Receptors, Class A; Scavenger Receptors, Class E; Tetradecanoylphorbol Acetate; Thiobarbituric Acid Reactive Substances; Up-Regulation

Neurodegenerative diseases are associated with accumulation of modified proteins or peptides including amyloid-β (Aβ) in Alzheimer's disease (AD), and misfolded superoxide dismutase-1 (SOD-1) in amyotrophic lateral sclerosis (ALS). Clearance of Aβ or SOD-1 by the innate immune system may be important for controlling or preventing disease onset. Curcumins restore Aβ phagocytosis by peripheral blood mononuclear cells (PBMCs) from AD patients and Aβ clearance with upregulation of key genes including MGAT3, vitamin D receptor (VDR) and Toll-like receptors (TLRs). Certain curcumins inhibit inflammatory processes of PBMCs from ALS patients. We developed an in vitro system using human monocytes from patients and monocytic cell lines (i.e. U-937, THP-1) for evaluating curcuminoid potency of innate immune cell stimulation. Bisdemethoxycurcumin and certain analogs potentiated MGAT3,VDR and TLR gene expression 3- to 300-fold in U-937 cells. The effect of curcumins on inflammation in monocytes from patients with ALS was examined. Recursive medicinal chemistry was applied to identify compounds that stimulate the innate immune system for use in the clearance of Aβ in AD and the reversal of neuroinflammation and defective SOD-1 accumulation in ALS.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Transformed; Cells, Cultured; Curcumin; Cytokines; Diarylheptanoids; Gene Expression Regulation; Humans; Monocytes; N-Acetylglucosaminyltransferases; Receptors, Calcitriol; RNA, Messenger; Superoxide Dismutase; Toll-Like Receptors

Curcumin, a poly-phenolic compound, possesses diverse pharmacologic activities. However, the barrier protective functions of curcumin or its derivative have not yet been studied. The objective of this study was to investigate the barrier protective activities of curcumin and its derivative (bisdemethoxycurcumin, BDMC) on lipopolysaccharide (LPS) barrier disruption in human umbilical vein endothelial cells (HUVECs) were investigated.. The barrier protective effects of curcumin and BDMC such as permeability, expression of cell adhesion molecules, monocytes adhesion and migration toward HUVECs were tested.. Curcumin and BDMC inhibited LPS-induced barrier permeability, monocyte adhesion and migration; inhibitory effects were significantly correlated with inhibitory functions of curcumin and BDMC on LPS-induced cell adhesion molecules (vascular cell adhesion molecules, intracellular cell adhesion molecule, E-selectin). Furthermore, LPS-induced nuclear factor-κB (NF-κB) activation and tumor necrosis factor-α (TNF-α) release from HUVECs were inhibited by curcumin and BDMC. Surprisingly, the barrier protective activities of BDMC were better than those of curcumin, indicating that the methoxy group in curcumin negatively regulated barrier protection function of curcumin.. Given these results, curcumin or its derivative, BDMC, showed barrier protective activities and they could be a therapeutic candidates for various systemic inflammatory diseases.

Topics: Cell Adhesion; Cells, Cultured; Curcumin; Diarylheptanoids; E-Selectin; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Lipopolysaccharides; NF-kappa B; Permeability; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

The first example of a ruthenium sensitizer (TUS-22) having a natural dye, bisdemethoxycurcumin, as a ligand has been synthesized. The dye-sensitized solar cell based on this novel dye showed 5.8% conversion efficiency under AM 1.5 (100 mW/cm(2)) irradiation.

Topics: Coloring Agents; Curcumin; Diarylheptanoids; Dielectric Spectroscopy; Ligands; Photochemistry; Ruthenium; Solar Energy

Curcumin, a polyphenol responsible for the yellow color of the curry spice turmeric, possesses antiinflammatory, antiproliferative and antiangiogenic activities. However, anticoagulant activities of curcumin have not been studied. Here, the anticoagulant properties of curcumin and its derivative (bisdemethoxycurcumin, BDMC) were determined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT) as well as cell-based thrombin and activated factor X (FXa) generation activities. Data showed that curcumin and BDMC prolonged aPTT and PT significantly and inhibited thrombin and FXa activities. They inhibited the generation of thrombin or FXa. In accordance with these anticoagulant activities, curcumin and BDMC showed anticoagulant effect in vivo. Surprisingly, these anticoagulant effects of curcumin were better than those of BDMC indicating that methoxy group in curcumin positively regulated anticoagulant function of curcumin. Therefore, these results suggest that curcumin and BDMC possess antithrombotic activities and daily consumption of the curry spice turmeric might help maintain anticoagulant status.

Topics: Animals; Anticoagulants; Bleeding Time; Blood Coagulation; Cells, Cultured; Curcumin; Diarylheptanoids; Factor Xa; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred C57BL; Partial Thromboplastin Time; Prothrombin Time; Thrombin

Curcuminoids are poorly water-soluble compounds with promising antimalarial activity. To overcome some of the drawbacks of curcuminoids, we explored the potential of liposomes for the intravenous delivery of curcuminoids in a model of mouse malaria. The curcuminoids-loaded liposomes were formulated from phosphatidylcholine (soy PC) by the thin-film hydration method. Antimalarial activity of curcuminoids-loaded liposomes alone and in combination with α/β arteether when administered intravenously, was evaluated in Plasmodium berghei infected mice. Animals treated with curcuminoids-loaded liposomes showed lower parasitemia and higher survival when compared to control group (no treatment). Importantly, the combination therapy of curcuminoids-loaded liposomes (40 mg/kg body wt) along with α/β arteether (30 mg/kg body wt) was able to not only cure infected mice but also prevented recrudescence. These data suggest that curcuminoids-loaded liposomes may show promise as a formulation for anti-malarial therapy.

Topics: Animals; Antimalarials; Artemisinins; Curcuma; Curcumin; Diarylheptanoids; Disease Models, Animal; Hemolysis; Humans; Liposomes; Malaria; Mice; Phytotherapy; Plant Extracts; Plant Roots; Plasmodium berghei; Polyphenols

Curcuminoids are natural food coloring additives with anti-inflammatory, antioxidant, and anticarcinogenic activity, which contain mainly three diarylheptanoids: curcumin, demethoxycurcumin, and bisdemethoxycurcumin. In this paper, the metabolites of curcuminoids in the feces and urine of rats after oral administration by gavage were investigated. Four new metabolites, 3-hydroxy-[1-(4-hydroxyphenyl)-7-(3-hydroxyphey)] heptane-A (M1), 3-hydroxy-[1-(4-hydroxyphenyl)-7-(3-hydroxyphey)] heptane-B (M2), 3-hydroxy-1,7-bis(3-hydroxyphenyl) heptane-A (M3) and 3-hydroxy-1,7-bis(3-hydroxyphenyl) heptane-B (M4), along with five known metabolites (M5-M9), were isolated from the feces of male Wistar-derived rats and nine known metabolites (M5-M8, M10-M14) were isolated from the urine. Their structures were elucidated by extensive spectroscopic analysis. The finding that the metabolites occurred as several pairs of enantiomers was confirmed by chiral column chromatography. Based on the metabolites' profiles, possible metabolic pathways of the curcuminoids in rats are proposed.

Topics: Animals; Biotransformation; Curcumin; Diarylheptanoids; Feces; Male; Metabolic Networks and Pathways; Molecular Structure; Rats; Rats, Wistar

Curcuma longa rhizome is used extensively in culinary preparations in Far East and South-East Asia. Health benefits of curcuminoids from C. longa as antioxidants, anti-cancer and anti-inflammatory molecules have been well documented. We report here for the first time that Bisdemethoxycurcumin (BDMC) from C. longa, acts as an inhibitor to inactivate human pancreatic α-amylase, a therapeutic target for oral hypoglycemic agents in type-2 diabetes. Bioactivity guided isolation of rhizome isopropanol extract led to the identification by HPLC and NMR of BDMC as a lead small molecule inhibitor of porcine and human pancreatic α-amylase with an IC(50) value of 0.026 and 0.025 mM, respectively. Kinetic analysis revealed that using starch as the substrate, HPA exhibited an uncompetitive mode of inhibition with an apparent K(i) of 3.0 μM. The study gains importance as BDMC could be a good drug candidate in development of new inhibitors of HPA and of functional foods for controlling starch digestion in order to reduce post-prandial hyperglycemia.

Topics: Curcuma; Curcumin; Diabetes Mellitus, Type 2; Diarylheptanoids; Enzyme Inhibitors; Humans; Kinetics; Molecular Weight; Pancreatic alpha-Amylases; Plant Extracts; Rhizome

Curcuminoids (including curcumin) are natural antioxidants demonstrating potent chemopreventive properties against several forms of cancer. This study investigated the antiproliferative and induced apoptotic effects of curcuminoids on three cell lines isolated from human breast adenocarcinoma and ductal carcinoma (MDA-MB-231, MDA-MB-435S, and MCF-7).. This study developed a highly sensitive, reproducible assay method using high-pressure liquid chromatography to quantify the cellular uptake of curcuminoids by breast cancer cells and quantitate its effect on inhibition of proliferation and activation of apoptosis in breast cancer cells.. Results indicate that curcuminoids inhibited cell proliferation and activation of apoptosis in the cell lines in this study. Both effects were observed to increase in proportion to the cellular uptake of curcuminoids; cellular uptake increased following an increase in the dosage of curcuminoids.. The inhibition of proliferation and increased apoptosis of breast cancer cells appears to be associated with the uptake of curcuminoids by cancer cells.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Biological Availability; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Female; Humans

The steady-state absorption and fluorescence, as well as the time-resolved fluorescence properties of bisdemethoxycurcumin dissolved in several solvents differing in polarity and H-bonding capability were measured. The photodegradation quantum yield of the compound in acetonitrile and methanol was determined. The bisdemethoxycurcumin decay mechanisms from the S(1) state were discussed and compared with those of curcumin. The differences in S(1) dynamics observed between bisdemethoxy-curcumin and curcumin could be ascribed to a difference in H-bond acceptor/donor properties of the phenolic OH and a difference in strength of the intramolecular H-bond in the keto-enol moiety within the two molecules.

Topics: Absorption; Curcumin; Diarylheptanoids; Photolysis; Solvents; Spectrometry, Fluorescence

Three curcumin analogues viz., bisdemethoxy curcumin, monodemethoxy curcumin, and dimethoxycurcumin that differ at the phenolic substitution were synthesized. These compounds have been subjected for free radical reactions with DPPH radicals, superoxide radicals (O(2)(•-)), singlet oxygen ((1)O(2)) and peroxyl radicals (CCl(3)O(2)(•)) and the bimolecular rate constants were determined. The DPPH radical reactions were followed by stopped-flow spectrometer, (1)O(2) reactions by transient luminescence spectrometer, and CCl(3)O(2)(•) reactions using pulse radiolysis technique. The rate constants indicate that the presence of o-methoxy phenolic OH increases its reactivity with DPPH and CCl(3)O(2)(•), while for molecules lacking phenolic OH, this reaction is very sluggish. Reaction of O(2)(•-) and (1)O(2) with curcumin analogues takes place preferably at β-diketone moiety. The studies thus suggested that both phenolic OH and the β-diketone moiety of curcumin are involved in neutralizing the free radicals and their relative scavenging ability depends on the nature of the free radicals.

Topics: Biphenyl Compounds; Carbon Tetrachloride; Curcumin; Diarylheptanoids; Free Radical Scavengers; Free Radicals; Hydroxyl Radical; Peroxides; Picrates; Pulse Radiolysis; Reactive Oxygen Species; Singlet Oxygen; Spectrum Analysis; Structure-Activity Relationship; Superoxides

Curcuminoids are the major active components extracted from Curcuma longa and are well known for their antioxidant effects. Previous studies have reported that the antioxidant properties of curcuminoids are mainly attributed to their free radical scavenging abilities. However, whether there are other mechanisms besides the non-enzymatic process and how they are involved, still remains unknown. In the present study, we explored the protective effects of bisdemethoxycurcumin (Cur3) against tert-butyl hydroperoxide (t-BHP)-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs), focusing on the effect of Cur3 on the regulation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the mitogen-activated protein kinase (MAPK) pathways. The pre-treatment with Cur3 inhibited t-BHP-induced cell damage dose-dependently, which was evident by the increased cell viability and the corresponding decrease in lactate dehydrogenase release. The pre-treatment with Cur3 also attenuated t-BHP-induced cell morphological changes and apoptosis. MAPKs, including p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase 1/2 (ERK1/2), as well as PI3K/Akt have been reported to be involved in proliferation, apoptosis and differentiation under various stress stimulations. The pre-treatment with Cur3 decreased t-BHP-induced ERK1/2 phosphorylation and increased t-BHP-induced Akt phosporylation but did not affect the phosphorylation of p38 or JNK. In addition, the Cur3-induced increase in cell viability was attenuated by the treatment with wortmannin or LY294002, the upstream inhibitors of Akt, and was enhanced by the treatment with 2-[2'-amino-3'-methoxyphenyl]-oxanaphthalen-4-one (PD98059), an upstream inhibitor of ERK1/2. These results suggest that the ERK1/2 and PI3K/Akt signaling pathways could be involved in the protective effects of Cur3 against t-BHP-induced damage in HUVECs.

Topics: Apoptosis; Curcumin; Diarylheptanoids; Endothelial Cells; Enzyme Activation; Enzyme Inhibitors; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; tert-Butylhydroperoxide

This paper aims to investigate the metabolism and pharmacokinetics of curcumin, demethoxycurcumin and bisdemethoxycurcumin in mice tumor. To improve water solubility, nanoparticle formulations were prepared as curcuminoids-loaded solid lipid nanoparticles (curcuminoids-SLNs) and curcumin-loaded solid lipid nanoparticles (curcumin-SLNs). After intragastric administration to tumor-bearing ICR mice, the plasma and tumor samples were analyzed by liquid chromatography with ion trap mass spectrometry. We discovered that curcuminoids were mainly present as glucuronides in plasma, whereas in free form in tumor tissue. A validated LC/MS/MS method was established to determine the three free curcuminoids in tumor homogenate. Samples were separated on a Zorbax SB-C(18) column, eluted with acetonitrile-water (containing 0.1% formic acid), and detected by TSQ Quantum triple quadrupole mass spectrometer in selected reaction monitoring mode. The method showed good linearity (r(2)=0.997-0.999) over wide dynamic ranges (2-6000 ng/mL). Variations within- and between-batch never exceeded 11.2% and 13.4%, respectively. The extraction recovery rates ranged from 78.3% to 87.7%. The pharmacokinetics of curcuminoids in mice tumor fit two-compartment model and first order elimination. For curcumin-SLNs group, the dosing of 250 mg/kg of curcumin resulted in AUC((0-48 h)) of 2285 ngh/mL and C(max) of 209 ng/mL. For curcuminoids-SLNs group, the dosing equivalent to 138 mg/kg of curcumin resulted in higher tumor concentrations (AUC=2811 ngh/mL, C(max)=285 ng/mL). It appeared that co-existing curcuminoids improved the bioavailability of curcumin.

Topics: Animals; Area Under Curve; Biphenyl Compounds; Chromatography, Liquid; Curcumin; Diarylheptanoids; Drug Delivery Systems; Drug Stability; Lignans; Linear Models; Lipids; Male; Mice; Mice, Inbred ICR; Nanoparticles; Neoplasm Transplantation; Neoplasms; Reproducibility of Results; Tandem Mass Spectrometry

Hypermethylation of the Wnt inhibitory factor-1 (WIF-1) promoter has been implicated in the overactivation of the Wnt pathway in human lung cancer. Curcuminoids exert anti-cancer effects and have been reported to act as hypomethylating agents. Previously, we have investigated and compared the demethylation effects of three curcuminoids and observed that bisdemethoxycurcumin exhibited the strongest demethylation potency. In this study, we used lung cancer cell lines with WIF-1 promoter hypermethylated as a model to study the demethylating effect of bisdemethoxycurcumin on WIF-1 restoration, Wnt signaling activity and cell death. Bisdemethoxycurcumin directly suppressed the activity of DNA methyltransferase-1 (DNMT1) but did not influence DNMT1 expression. In addition, it induced WIF-1 promoter demethylation and protein re-expression. WIF-1 restoration in lung cancer cells down-regulated nuclear β-catenin and the canonical Wnt cascade. Furthermore, we also showed that down-regulation of Wnt signaling by WIF-1 was required for bisdemethoxycurcumin-induced apoptosis in certain lung cancer cell types. This report is the first to show that bisdemethoxycurcumin induces apoptosis by reactivating WIF-1 from a silenced state. Our results provide new insights into the anti-cancer actions of bisdemethoxycurcumin.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Base Sequence; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Diarylheptanoids; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; Mice, SCID; Molecular Sequence Data; Promoter Regions, Genetic; Repressor Proteins; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

This paper determined the contact-killing and fumigant activities of natural plant product bisdemethoxycurcumin (BDMC) on the important phytophagous mite Tetranychus cinnabarinus (Acari:Tetranychidae) at its different life stages, and studied the repellency effects of BDMC on the mite larvae, nymphs, and adults, and the inhibition efficiency of BDMC on the female mite oviposition under the conditions of 26 degrees C +/- 1 degree C, 60%-80% RH, and light cycle 14L : 10D h. The median lethal concentration (LC50) of BDMC at 48 h against female adults determined by slide-dip method was 0.433 mg x mL(-1). At concentration 0.883 mg x mL(-1) (LC70), the contact-killing activity of BDMC against different life stage T. cinnabarinus was in the order of larva > nymph > adult > egg, and the corrected mortality of larvae at 24 h and 48 h was 60.0% and 83.3%, respectively. BDMC had no obvious fumigant activity against different life stage T. cinnabarinus, and the corrected mortality was all less than 3% after treatment 24 h and 48 h. BDMC had stronger repellency activity against the mite, with the repellency rate against larvae at different treatment times all above 85%, followed by against nymphs, and that against adults after 72 h being only 47.8%. BDMC had obvious oviposition inhibition activity against female adults, with the inhibition rate after 120 h reached 89.3%. All the results suggested that the main action modes of BDMC against T. cinnabarinus were contact-killing, repellency, and oviposition inhibition.

Topics: Acaricides; Animals; Crops, Agricultural; Curcumin; Diarylheptanoids; Female; Larva; Mites; Oviposition; Plant Extracts

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cholecalciferol; Curcumin; Diarylheptanoids; Disease Progression; Humans; Leukocytes, Mononuclear; N-Acetylglucosaminyltransferases; Phagocytosis; Precision Medicine; Prognosis

The natural curcuminoids curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) have been chemically modified to give 46 analogs and 8 pairs of 1:1 mixture of curcuminoid analogs and these parent curcuminoids and their analogs were assessed against protozoa of the Trypanosoma and Leishmania species. The parent curcuminoids exhibited low antitrypanosomal activity (EC(50) for our drug-sensitive Trypanosoma brucei brucei line (WT) of compounds 1, 2 and 3 are 2.5, 4.6 and 7.7 microM, respectively). Among 43 curcuminoid analogs and 8 pairs of 1:1 mixture of curcuminoid analogs tested, 8 pure analogs and 5 isomeric mixtures of analogs exhibited high antitrypanosomal activity in submicromolar order of magnitude. Among these highly active analogs, 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (40) was the most active compound, with an EC(50) value of 0.053+/-0.007 microM; it was about 2-fold more active than the standard veterinary drug diminazene aceturate (EC(50) 0.12+/-0.01 microM). Using a previously characterized diminazene-resistant T. b. brucei (TbAT1-KO) and a derived multi-drug resistant line (B48), no cross-resistance of curcuminoids was observed to the diamidine and melaminophenyl arsenical drugs that are the current treatments. Indeed, curcuminoids carrying a conjugated keto (enone) motif, including 40, were significantly more active against T. b. brucei B48. This enone motif was found to contribute to particularly high trypanocidal activity against all Trypanosoma species and strains tested. The parent curcuminoids showed low antileishmanial activity (EC(50) values of compounds 1 and 2 for Leishmania mexicana amastigotes are 16+/-3 and 37+/-6 microM, respectively) while the control drug, pentamidine, displayed an EC(50) of 16+/-2 microM. Among the active curcuminoid analogs, four compounds exhibited EC(50) values of less than 5 microM against Leishmania major promastigotes and four against L. mexicana amastigotes. No significant difference in sensitivity to curcuminoids between L. major promastigotes and L. mexicana amastigotes was observed. The parent curcuminoids and most of their analogs were also tested for their toxicity against human embryonic kidney (HEK) cells. All the curcuminoids exhibited lower toxicity to HEK cells than to T. b. brucei bloodstream forms and only one of the tested compounds showed significantly higher activity against HEK cells than curcumin (1). The selectivity index for T. b. brucei ranged from 3-fold to 15

Topics: Antimalarials; Cell Line; Curcumin; Diarylheptanoids; Humans; Inhibitory Concentration 50; Leishmania; Molecular Structure; Trypanocidal Agents; Trypanosoma

Glyoxalase I (GLOI) is a key metalloenzyme in glycolytic pathway by detoxifying reactive alpha-ketoaldehydes such as methylglyoxal. Recent studies demonstrate that the nature product curcumin is an efficient inhibitor of GLOI, but its binding mechanism towards GLOI is still unclear. In the present study, molecular docking and molecular dynamics (MD) simulations were performed to better understand the inhibitory mechanism of curcumin towards GLOI. The enol form of curcumin coordinates with the catalytic zinc ion of GLOI and forms a strong hydrogen bond with Glu 172, whereas its keto tautomer displays unfavorable electrostatic interactions with Glu 172 and Glu 99. The calculated binding free energies suggest that GLOI prefers the primary enol form (DeltaG=-30.38kcal/mol) to the keto tautomer (DeltaG=-24.16kcal/mol). The present work also reveals that bisdemethoxycurcumin binds to GLOI in a similar manner as curcumin and exhibits a slightly less negative predicted binding free energy, which is further validated by our comparative kinetics analysis (Ki=18.2 and 10.3muM for bisdemethoxycurcumin and curcumin, respectively). Results of the study can provide an insight into the development of novel and more effective GLOI inhibitors.

Topics: Crystallography, X-Ray; Curcumin; Diarylheptanoids; Glutamic Acid; Hydrogen Bonding; Kinetics; Lactoylglutathione Lyase; Models, Molecular; Molecular Dynamics Simulation; Protein Binding; Thermodynamics

We have identified a novel anti-inflammatory signaling pathway that leads to the expression of heme oxygenase-1 (HO-1) in response to bisdemethoxycurcumin (BDMC), an analog of curcumin. Treatment with BDMC suppressed inducible nitric oxide synthase expression and nitric oxide (NO) production by down-regulating NF-kappaB activity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. These effects were reversed by blocking HO-1 activity or expression. The signaling pathway involved in BDMC-mediated HO-1 induction included Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase 1/2 (ERK1/2). BDMC induced phosphorylation of ERK1/2 in a CaMKII-dependent manner. Pretreatment with the mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor, U0126, inhibited CaMKII-induced stimulation of HO-1 promoter activity, suggesting that ERK1/2 is a downstream mediator of CaMKII in BDMC signaling to HO-1 expression. Furthermore, the CaMKII-ERK1/2 cascade targets the transcription factor, NF-E2-related factor-2 (Nrf2). Finally, inhibition of the Ca(2+)-CaMKII-ERK1/2-linked cascade attenuated significantly suppression by BDMC of LPS-induced iNOS expression and subsequent NO production. Collectively, our findings identify a Ca(2+)/calmodulin-CaMKII-ERK1/2-Nrf2 cascade as a novel anti-inflammatory pathway mediating BDMC signaling to HO-1 expression in macrophages.

Topics: Animals; Butadienes; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Line; Curcumin; Diarylheptanoids; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Inflammation; Lipopolysaccharides; Macrophages; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-E2-Related Factor 2; NF-kappa B; Nitriles; Signal Transduction; Up-Regulation

Alzheimer's disease (AD) is a neurodegenerative disease. There are a limited number of therapeutic options available for the treatment of AD. Curcuminoids (a mixture of bisdemethoxycurcumin, demethoxycurcumin and curcumin) is the main chemical constituent found in turmeric, a well known curry spice, having potential in the treatment of AD. The objective of this study was to investigate the effects of curcuminoid mixture and individual constituents on spatial learning and memory in an amyloid-beta (Abeta) peptide-infused rat model of AD and on the expression of PSD-95, synaptophysin and camkIV. Curcuminoid mixture showed a memory-enhancing effect in rats displaying AD-like neuronal loss only at 30 mg/kg, whereas individual components were effective at 3-30 mg/kg. A shorter duration treatment with test compounds showed that the curcuminoid mixture and bisdemethoxycurcumin increased PSD-95 expression in the hippocampus at 3-30 mg/kg, with maximum effect at a lower dose (3 mg/kg) with respective values of 470.5 and 587.9%. However, after a longer duration treatment, two other compounds (demethoxycurcumin and curcumin) also increased PSD-95 to 331.7 and 226.2% respectively at 30 mg/kg. When studied for their effect on synaptophysin in the hippocampus after the longer duration treatment, the curcuminoid mixture and all three individual constituents increased synaptophysin expression. Of these, demethoxycurcumin was the most effective showing a 350.1% increase (P<0.01) at 30 mg/kg compared to the neurotoxin group. When studied for their effect on camkIV expression after longer treatment in the hippocampus, only demethoxycurcumin at 30 mg/kg increased levels to 421.2%. These compounds salvaged PSD-95, synaptophysin and camkIV expression levels in the hippocampus in the rat AD model, which suggests multiple target sites with the potential of curcuminoids in spatial memory enhancing and disease modifying in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Cell Count; Curcumin; Diarylheptanoids; Disks Large Homolog 4 Protein; Gene Expression Profiling; Hippocampus; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Memory; Neuronal Plasticity; Neurons; Peptide Fragments; Rats; Rats, Sprague-Dawley; Synaptophysin; Time Factors

Matrix metalloproteinase-3 (MMP-3) is a key enzyme with important implications in the invasion and metastasis of breast cancer cells. Curcumin (Cur), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are major forms of curcuminoids found in turmeric powder with reported anticancer activity. This study focuses on the comparative effect of Cur, DMC and BDMC on the modulation of MMP-3 activity and its secretion in MDA-MB-231 breast cancer cells. MMP-3 levels were determined by casein zymography, ELISA and western blotting. Analysis of MMP-3 expression by casein zymography revealed high expression in MDA-MB-231 invasive breast carcinoma cells, but not in MCF-7 non-invasive breast cancer cells. ELISA assays showed MMP-3 levels were significantly decreased in all curcuminoid treatments. Using zymography, treatment with non-toxic doses revealed that every curcuminoid compound except Cur reduced MMP-3 levels. Moreover, the result from western blot analysis confirmed that only DMC and BDMC reduced MMP-3 secretion in MDA-MB-231 cells, but Cur did not have any effect. MMP-3 activity revealed that none of the curcuminoids showed significant effects. However, treatment of the cells with Cur, DMC and BDMC exhibited a significant inhibition of cell invasion and motility with DMC and BDMC being more potent. These results suggest that Cur, DMC, and BDMC may be used as MMP-3 inhibitors to modulate MMP-3 expression.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Curcuma; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Female; Humans; Matrix Metalloproteinase 3; Matrix Metalloproteinase Inhibitors; Mice; Neoplasm Staging; NIH 3T3 Cells

The hallmark of Alzheimer's disease (AD) is the accumulation of β-amyloid protein (Aβ). Aβ is generated from the β-amyloid precursor protein (APP) through the proteolysis of β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Aβ(42) isoform is more easily aggregate and more toxic to neurons than any other Aβ isoforms, thus being regarded as the primary toxic specie in AD. Curcumin mix has potent anti-amyloidogenic effect and shows great promise for AD treatment and prevention. The present study was conducted to examine the effects of curcumin mix and its different curcuminoids including curcumin (Cur), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) on Aβ(42), APP and BACE1. We found that Cur was the most active curcuminoid fraction in suppressing Aβ(42) production and the order of inhibitory potency of other curcuminoids was DMC>curcumin mix>BDMC. Cur, but not other curcuminoids, could reduce APP protein expression and none of curcuminoids affected APP mRNA level. BDMC could reduce BACE1 mRNA and protein levels, while DMC only affected BACE1 mRNA expression. Our data indicate that the anti-amyloidogenic effect of Cur may be mediated through the modulation of APP, while the anti-amyloidogenic effect of BDMC may be mediated through the modulation of BACE1.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Cell Survival; Curcumin; Diarylheptanoids; HEK293 Cells; Humans; Mutation; Peptide Fragments

Curcuma mangga extract and its compounds were investigated for their anti-inflammatory mechanisms against nitric oxide (NO) and prostaglandin E2 (PGE2) release using RAW 264.7 cells. From bioassay-guided fractionation, demethoxycurcumin (1) was isolated from the chloroform fraction, whereas 15,16 bisnorlabda-8(17), 11-dien-13-one (2) and (E)-15,15-diethoxylabda-8(17),12-dien-16-al (3) were from the n-hexane fraction. Bisdemethoxycurcumin (4), the structure of which is similar to that of 1, was also tested. Of the tested compounds, 3 exhibited the highest activity against NO release with an IC50 value of 9.4 microM, followed by 1 (IC50 = 12.1 microM), 4 (IC50 = 16.9 microM) and 2 (IC50 = 30.3 microM). For the effect on PGE2 release, 1 possessed the highest activity (IC50 = 4.5 microM, followed by 4 (IC50 = 5.6 microM), 3 (IC50 = 35.3 microM) and 2 (IC50 = 42.5 microM). The mechanism at transcriptional level revealed that 1, 3 and 4 down-regulated the mRNA expressions of iNOS and COX-2 in a dose-dependent manner, whereas 2 had an effect only on iNOS mRNA. These results indicate that C. mangga and its compounds do exert anti-inflammatory activity. Moreover, this is the first report of the isolation of 3 from C. mangga rhizomes.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Curcuma; Curcumin; Diarylheptanoids; Dinoprostone; Drug Evaluation, Preclinical; Macrophages; Mice; Nitric Oxide; Rhizome

The antiulcer effect of bisdemethoxycurcumin, a yellow pigment found mainly in rhizomes of Curcuma longa, was compared with curcumin in gastric ulcer model systems to validate its clinical application as a remedy for peptic ulcer. Western blot analysis of mouse macrophage cell line RAW 264.7 activated with lipopolysaccharide showed that bisdemethoxycurcumin inhibited inducible nitric oxide synthase (iNOS) production significantly but had no effect on tumor necrosis factor-alpha (TNF-alpha) production, whereas curcumin showed stronger suppression of iNOS protein production and inhibited TNF-alpha protein production significantly. However, bisdemethoxycurcumin and curcumin possessed similar potency in scavenging nitric oxide generated from mouse macrophage cell line RAW 264.7. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed that both curcuminoids inhibited the induction of iNOS dose-dependently at the transcriptional level and curcumin also appeared to inhibit the induction of TNF-alpha at post-transcriptional level. In an animal model, intraduodenal administration of bisdemethoxycurcumin (5-80 mg/kg body wt.) showed a strong inhibitory effect on gastric acid secretion in pylorus-ligated rats whereas curcumin (5-20 mg/kg body wt.) showed a less inhibitory effect, with maximum potency at a dose of 20mg/kg body wt. Moreover, oral administration of bisdemethoxycurcumin at doses of 20-80 mg/kg body wt. twice daily for 10 days showed a significant curative efficacy in accelerating the healing of acetic acid-induced chronic gastric ulcer and promotion of mucosal regeneration in the ulcerated portion in a dose-related manner with potency equal to curcumin. In contrast, the curative potency of curcumin tended to decrease at doses over 160 mg/kg body wt./day. Western blot analysis in ulcerated gastric mucosa showed that bisdemethoxycurcumin dose-dependently reduced the increased protein expression level of iNOS but not TNF-alpha. These results indicated that bisdemethoxycurcumin directly accelerates gastric ulcer healing with potency equal to curcumin. Its antiulcer effect might be due to its properties of decreasing gastric acid secretion and enhancing the mucosal defensive mechanism through suppression of iNOS-mediated inflammation.

Topics: Animals; Anti-Ulcer Agents; Cell Line; Curcuma; Curcumin; Diarylheptanoids; Disease Models, Animal; Gastric Acid; Gastric Mucosa; Lipopolysaccharides; Macrophages; Male; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Phytotherapy; Plant Preparations; Rats; Rats, Wistar; Rhizome; RNA, Messenger; Stomach Ulcer; Tumor Necrosis Factor-alpha

An HPLC method using fluorescence detection for the quantitation of curcuminoids, such as curcumin (C), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) in turmeric products is described. This method involves a simple ultrasonic extraction with methanol as a pretreatment of turmeric products. The separation of curcuminoids and 2,5-xylenol (internal standard) was achieved within 30 min on a Cadenza CD-C(18) column (250 x 4.6 mm; i.d., 3 microm) with a mixture of acetate buffer and CH(3)CN. The calibration curves of standard curcuminoids showed good linearities of more than 0.993 of the correlation coefficient. The instrumental detection limits for C, DMC and BDMC (signal-to-noise ratio = 3) were 1.5, 0.9 and 0.09 ng mL(-1), respectively. The relative standard deviations of intra-and inter-day assays by curcuminoids spiked to turmeric powder were less than 6.1%. The proposed method was successfully applied to determine curcuminoids in commercial turmeric products, such as turmeric powders, a tablet, a dressing, a beverage, tea, and crude drugs.

Topics: Calibration; Chromatography, High Pressure Liquid; Curcuma; Curcumin; Diarylheptanoids; Fluorescence; Methanol; Molecular Structure; Plant Extracts; Reproducibility of Results; Sensitivity and Specificity; Stereoisomerism; Ultrasonics

The metabolic profile of polar (methanol) and non-polar (hexane) extracts of Curcuma domestica, a widely used medicinal plant, was established using various different analytical techniques, including GC-FID, GC-MS, HR-GC-MS and analytical HPLC-ESI-MS/MS by means of LTQ-Orbitrap technology. The major non-volatile curcuminoids curcumin, demethoxycurcumin and bisdemethoxycurcumin were identified when their chromatographic and precursor ion masses were compared with those of authentic standard compounds. In this paper we describe for the first time a GC/MS-based method for metabolic profiling of the hydrophilic extract. We also identified 61 polar metabolites as TMS derivatives.

Topics: Chromatography, High Pressure Liquid; Curcuma; Curcumin; Diarylheptanoids; Gas Chromatography-Mass Spectrometry; Hexanes; Methanol; Plant Extracts; Spectrometry, Mass, Electrospray Ionization

Curcumin, a phenolic compound from the plant Curcuma longa L., has shown a wide-spectrum of chemopreventive, antioxidant and antitumor properties. Although its promising chemotherapeutic activity, preclinical and clinical studies highlight Curcumin limited therapeutic application due to its instability in physiological conditions. To improve its stability and activity, many derivatives have been synthesized and studied, among which bis-DemethoxyCurcumin (bDMC) and diAcetylCurcumin (DAC). In this report, we show that both bDMC and DAC are more stable than Curcumin in physiological medium. To explore the mechanism of their chemotherapeutic effect, we studied their role in proliferation in the HCT116 human colon cancer cells. We correlated kinetic stability and cellular uptake data to their biological effects. Both bDMC and DAC impair correct spindles formation and induce a p53- and p21(CIP1/WAF1)-independent mitotic arrest, which is more stable and long-lasting for bDMC. A subsequent p53/p21(CIP1/WAF1)-dependent inhibition of G1 to S transition is triggered by Curcumin and DAC as a consequence of the mitotic slippage, preventing post-mitotic cells from re-entering the cell cycle. Conversely, the G1/S arrest induced by bDMC is a direct effect of the drug and concomitant to the mitotic block. Finally, we demonstrate that bDMC induces rapid DNA double-strand breaks, moving for its possible development in anti-cancer clinical applications.

Topics: Anticarcinogenic Agents; Cell Cycle; Cell Line, Tumor; Chromatin Immunoprecipitation; Curcumin; Diarylheptanoids; Drug Stability; Flow Cytometry; Humans; Immunoblotting; Microscopy, Fluorescence; Mitosis; Molecular Structure; Reverse Transcriptase Polymerase Chain Reaction; Structure-Activity Relationship

A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, shares high sequence identity with aldose reductase (AR), and was recently identified as a therapeutic target in the treatment of several types of cancer. We have compared the inhibitory effects of plant components on recombinant AKR1B10 and AR. AKR1B10 was inhibited by curcuminoids, magnolol, honokiol and resveratrol, with IC(50) values of 0.06-5 microM, which were lower than their values for AR. Among them, bisdemethoxycurcumin was the most potent competitive inhibitor (K(i)=22 nM) with the highest selectivity (85-fold versus AR), and acted as an effective inhibitor in cellular level. In contrast, demethoxycurcumin and curcumin showed >3-fold less potency and selectivity. Molecular docking studies of the curcuminoids in the AKR1B10-NADP(+) complex and site-directed mutagenesis of the putative binding residues suggest that Gln114, Val301 and Gln303 are important for determining the inhibitory potency and selectivity of the curcuminoids.

Topics: Aldehyde Reductase; Aldo-Keto Reductases; Amino Acid Substitution; Biomarkers, Tumor; Catalytic Domain; Curcumin; Diarylheptanoids; Enzyme Inhibitors; Flavonoids; Glutamine; HeLa Cells; Humans; Models, Molecular; Mutagenesis, Site-Directed; Phenols; Polyphenols; Valine

Curcumin (Cur), a component of turmeric (Curcuma longa), has been reported to exhibit antimetastatic activities, but the mechanisms remain unclear. Other curcuminoids present in turmeric, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) have not been investigated whether they exhibit antimetastatic activity to the same extent as curcumin. The regulation of matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA) play important role in cancer cell invasion by cleavage of extracellular matrix (ECM). In this line, we comparatively examined the influence of Cur, DMC and BDMC on the expressions of uPA, MMP-2, MMP-9, membrane Type 1 MMP (MT1-MMP), tissue inhibitor of metalloproteinases (TIMP-2), and in vitro invasiveness of human fibrosarcoma cells. The results indicate that the differential potency for inhibition of cancer cell invasion was BDMC> or =DMC>Cur, whereas the cell migration was not affected. Zymography analysis exhibited that curcumin, DMC and BDMC significantly decreased uPA, active-MMP-2 and MMP-9 but not pro-MMP-2 secretion from the cells in a dose-dependent manner, in which BDMC and DMC show higher potency than curcumin. The suppression of active MMP-2 level correlated with inhibition of MT1-MMP and TIMP-2 protein levels involved in pro-MMP-2 activation. Importantly, BDMC and DMC at 10 microM reduced MT1-MMP and TIMP-2 protein expression, but curcumin slightly reduced only MT1-MMP but not TIMP-2. In addition, three forms of curcuminoids significantly inhibited collagenase, MMP-2, and MMP-9 but not uPA activity. In summary, these data demonstrated that DMC and BDMC show higher antimetastasis potency than curcumin by the differentially down-regulation of ECM degradation enzymes.

Topics: 3T3 Cells; Animals; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Diarylheptanoids; Fibrosarcoma; Gene Expression Regulation, Enzymologic; Humans; Matrix Metalloproteinases; Mice; Neoplasm Invasiveness; Urokinase-Type Plasminogen Activator

The rhizomes of Curcuma phaeocaulis, Curcuma kwangsiensis, Curcuma wenyujin and Curcuma longa are used as Ezhu or Jianghuang in traditional Chinese medicine for a long time. Due to their similar morphological characters, it is difficult to distinguish their origins of raw materials used in clinic. In this study, a simple, rapid and reliable twice development TLC method was developed for qualitative and quantitative analysis of the four species of Curcuma rhizomes. The chromatography was performed on silica gel 60F(254) plate with chloroform-methanol-formic acid (80:4:0.8, v/v/v) and petroleum ether-ethyl acetate (90:10, v/v) as mobile phase for twice development. The TLC markers were colorized with 1% vanillin-H(2)SO(4) solution. The four species of Curcuma were easily discriminated based on their characteristic TLC profiles, and simultaneous quantification of eight compounds, including bisdemethoxycurcumin, demethoxycurcumin, curcumine, curcumenol, curcumol, curdione, furanodienone and curzerene, in Curcuma were also performed densitometrically at lambda(scan)=518nm and lambda(reference)=800 nm. The investigated compounds had good linearity (r(2)>0.9905) within test ranges. Therefore, the developed TLC method can be used for quality control of Curcuma rhizomes.

Topics: Acetates; Alkanes; Benzaldehydes; Chloroform; Chromatography, Thin Layer; Curcuma; Curcumin; Diarylheptanoids; Formates; Gels; Methanol; Plant Roots; Reference Standards; Reproducibility of Results; Sesquiterpenes; Sesquiterpenes, Germacrane; Silicon Dioxide; Solutions; Species Specificity; Sulfuric Acids; Time Factors

Microglia are the resident innate immune cells in the central nervous system. Evidence supports that the unregulated activation of microglia results in the production of pro-inflammatory cytokines and chemokines that propagate neuronal injury and finally cause neurodegenerative diseases. Curcuminn (Cur), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are curcuminoid pigments extracted from turmeric (Curcuma longa L.). Cur has been reported to suppress the activation of microglia by reducing toxic factors production, but little is known about whether the two natural demethoxy derivatives of Cur, DMC and BDMC, have the similar effects as Cur. In the present study, we found that all of the three curcuminoid pigments significantly suppressed nitric oxide (NO) production by LPS-activated microglia and the relative potency was DMC>BDMC>Cur. This result was verified by RT-PCR analysis of iNOS mRNA. The NO-scavenging abilities of three curcuminoid pigments are very weak, which suggested that the indirect effect may not be critical in inhibiting NO production by LPS-activated microglia. Moreover, these three curcuminoid pigments attenuated the expression of mRNA and proteins of tumor necrosis factor-alpha (TNF-alpha) in a concentration-dependent manner and the relative potency was also DMC>BDMC>Cur. In conclusion, Cur, DMC and BDMC were found as potent microglia-activation inhibitors, and DMC exhibited the strongest inhibitory activity on NO and TNF-alpha production. These results provided an interesting clue for designing new compounds which could have better potential therapeutic implications for various neurodegenerative diseases.

Topics: Animals; Animals, Newborn; Cells, Cultured; Cerebral Cortex; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Drug Interactions; Lipopolysaccharides; Microglia; Nitric Oxide; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

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

To investigate the stability of curcumin, demethoxycurcumin and bisdemethoxycurcumin in different buffer solution.. To determine concentration of curcumin by HPLC when added curcumin, demethoxycurcumin and bisdemethoxycurcumin into the buffer solution the equation of degradation was established.. The sequence of stability are bisdemethoxycurcumin > or = demethoxycurcumin > or =curcumin at the same condition.. The demethoxycurcumin can stabilize curcumin more strong than the others. The demethoxycurcumin is a nature stabilizing agent for curcumin.

Topics: Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Drug Stability; Hydrogen-Ion Concentration

In this study, molecularly imprinted poly (methacrylamide-co-methacrylic acid) composite membranes with different ratio of methacrylamide (MAM) versus methacrylic acid (MAA) were prepared via UV initiated photo-copolymerization on the commercial filter paper. Curcumin was chosen as the template molecule. Infra-red (IR) spectroscopy was used to study the binding mechanism between the imprinted sites and the templates. The morphology of the resultant membranes was visualized by scanning electron microscopy (SEM). Static equilibrium binding and recognition properties of the imprinted composite membranes to curcumin (cur-I) and its analogues demethoxycurcumin (cur-II) or bisdemethoxycurcumin (cur-III) were tested. The results showed that curcumin-imprinted membranes had the best recognition ability to curcumin compared to its analogues. From the results, the biggest selectivity factor of alpha(cur-I/cur-II) and alpha(cur-I/cur-III) were 1.50 and 5.94, and they were obtained from the composite membranes in which MAM/MAA were 1:4 and 0:1, respectively. The results of this study implied that the molecularly imprinted composite membranes could be used as separation membranes for curcumin enrichment.

Topics: Acrylamides; Curcumin; Diarylheptanoids; Membranes, Artificial; Methacrylates; Microscopy, Electron, Scanning; Molecular Imprinting; Particle Size; Polymers; Polymethacrylic Acids; Sensitivity and Specificity; Spectroscopy, Fourier Transform Infrared; Surface Properties; Ultraviolet Rays

Demethoxycurcumin and bisdemethoxycurcumin are the main active ingredients isolated from Curcumae Longae Radix. Recent studies demonstrated that both compounds exhibit antioxidative and anti-inflammatory effects as well as effects on cancer cell lines. In this study, we compared the activities of demethoxycurcumin and bisdemethoxycurcumin, and both compounds were evaluated on lipopolysaccharide (LPS)-induced nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), cycloxygenase-2 (COX-2) and nuclear factor-kappaB (NF-kappaB) activity in a RAW 264.7 macrophage cell line. The evaluation:results suggested that the anti-inflammatory properties of demethoxycurcumin and bisdemethoxycurcumin were attributed to the inhibition of iNOS and COX-2 expression, as initiated by the inhibition of NF-kappaB activity. Additionally, both of them significantly inhibited carrageenan-induced paw edema in mice. Taken together, all of the results showed that the suppressive effect of demethoxycurcumin was stronger than that of bisdemethoxycurcumin, indicating that the methoxy group had enhanced demethoxycurcumin's anti-inflammation effects.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Line; Curcumin; Cyclooxygenase 2; Diarylheptanoids; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Gene Expression Regulation, Enzymologic; I-kappa B Proteins; Inflammation Mediators; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; NF-KappaB Inhibitor alpha; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphorylation; 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

Curcuminoids loaded solid lipid nanoparticles (SLNs) have been successfully developed using a microemulsion technique at approximately 75 degrees C. It was found that variation in the amount of ingredients had profound effects on the curcuminoid loading capacity, the mean particle size, and size distribution. At optimized process conditions, lyophilized curcuminoids loaded SLNs showed spherical particles with a mean particle size of approximately 450nm and a polydispersity index of 0.4. Up to 70% (w/w) curcuminoids incorporation efficacy was achieved. In vitro release studies showed a prolonged release of the curcuminoids from the solid lipid nanoparticles up to 12h following the Higuchi's square root model. After 6-month storage at room temperature in the absence of sunlight, the physical and chemical stabilities of the lyophilized curcuminoids loaded SLNs could be maintained, i.e. the mean particle size and the amount of curcuminoids showed no significant changes (P>0.05) compared to the freshly prepared SLNs. In addition, the chemical stability of curcuminoids incorporated into SLNs was further investigated by dispersing them into a model cream base. The results revealed that after storage in the absence of sunlight for 6 months, the percentages of the remaining curcumin, bisdemethoxycurcumin and demethoxycurcumin were 91, 96 and 88, respectively.

Topics: Antioxidants; Chemistry, Pharmaceutical; Curcumin; Diarylheptanoids; Drug Carriers; Drug Compounding; Drug Stability; Drug Storage; Emulsions; Kinetics; Lipids; Models, Chemical; Nanoparticles; Ointments; Oxidation-Reduction; Oxygen; Particle Size; Photolysis; Solubility; Sunlight; Surface Properties; Technology, Pharmaceutical; Temperature

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

We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-beta (Abeta) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport Abeta into endosomes and lysosomes, and AD monocytes do not efficiently clear Abeta from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport Abeta to endosomes and lysosomes, and monocytes of these subjects clear Abeta in AD brain sections. Upon Abeta stimulation, mononuclear cells of normal subjects up-regulate the transcription of beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of Abeta may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon Abeta stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of Abeta, the transcription of MGAT3 and TLRs, and the translation of TLR2-4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.

Topics: Acyltransferases; Aged; Alzheimer Disease; Amyloid beta-Peptides; Cell Communication; Curcumin; Diarylheptanoids; Down-Regulation; Humans; Immunity, Innate; Immunotherapy; Lymphocytes; Macrophages; Phagocytosis; Protein Biosynthesis; Protein Transport; RNA, Small Interfering; Toll-Like Receptors; Transcription, Genetic

To investigate the anti-proliferation of three different structural curcumin pigmen monomers on the bovine VSMC stimulated by ox-LDL and the effect on the expression of LDL-R.. MTT and FCM were used to observe the anti-proliferation of three different on the bovine VSMC stimulated by ox-LDL and the effect on the expression of LDL-R.. ox-LDL(2.5,5, 10 mg x L(-1)) had obvious proliferative effect on VSMC, P < 0.05, curcumin (16.5,33,66 micromol x L(-1)), demethoxycurcumin (33,66 micromol x L(-1)) and bisdemethoxycurcumin (66 micromol x L(-1)) had obvious inhibition effect on the proliferation of VSMC stimulated by 10 mg x L(-1) ox-LDL (P < 0.05, curcumin > demethoxycurcumin > bisdemethoxycurcumin) . Three curcumin (16.5,33,66 micromol x L(-1)) could obviously activate the expression of LDLR of VSMC.. The three different structural curcumin pigmen monomers can not only inhibit the proliferation of bovine VSMC obviously stimulated by ox-LDL, but also promote the expression of LDL-R on bovine VSMC, that may be the mechanism of delaying the development of arteriosclerosis.

Topics: Animals; Aorta; Cattle; Cell Proliferation; Cells, Cultured; Curcuma; Curcumin; Diarylheptanoids; Lipoproteins, LDL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Plants, Medicinal; Receptors, LDL; Structure-Activity Relationship

Recently, it has been reported that curcumin, which is known as a potent antioxidant, acts as a non- stressful and non-cytotoxic inducer of the cytoprotective heme oxygenase (HO)-1. In this study, naturally occurring curcuminoids, such as pure curcumin, demethoxycurcumin (DMC) and bis-demethoxycurcumin (BDMC), were compared for their potential ability to modulate HO-1 expression and cytoprotective activity in human endothelial cells. All three curcuminoids could induce HO-1 expression and HO activity with differential levels. The rank order of HO activity was curcumin, DMC and BDMC. In comparison with endothelial protection against H2O2-induced cellular injury, cytoprotective capacity was found to be highest with curcumin, followed by DMC and BDMC. Interestingly, cytoprotective effects afforded by curcuminoids were considerably associated with their abilities to enhance HO activity. Considering that the main difference among the three curcuminoids is the number of methoxy groups (none for BDMC, one for DMC, and two for curcumin), the presence of methoxy groups in the ortho position on the aromatic ring was suggested to be essential to enhance HO-1 expression and cytoprotection in human endothelial cells. Our results may be useful in designing more efficacious HO-1 inducers which could be considered as promising pharmacological agents in the development of therapeutic approaches for the prevention or treatment of endothelial diseases caused by oxidative damages.

Topics: Curcumin; Cytoprotection; Diarylheptanoids; DNA Damage; Endothelial Cells; Heme Oxygenase-1; Humans; Hydrogen Peroxide; Models, Biological; Signal Transduction

A method to detect and quantify curcumin and two curcuminoid metabolites in biological matrices, including mouse serum and mouse lung cell cultures, was developed. Standard curves between 0.04 and 10.00 nmol curcumin were prepared in serum, giving correlation coefficients of 0.94-0.99. Alcoholic extraction, concentration, and addition of dilute hydrochloric acid to stabilize the curcumin were essential to the reproducibility of the protocol. Untreated and curcumin-treated mouse lung fibrotic and nonfibrotic cell cultures were analyzed by matrix-assisted laser desorption ionization time of flight mass spectrometry utilizing this method. Curcumin uptake was calculated to be 7.0-11.6% for the saline-treated cells and 7.4-11.9% for the bleomycin-treated cultures. Curcumin was not detected in untreated cells. Two additional peaks (m/z=399 and 429) were observed in the curcumin-treated cells. These may be curcumin-derived products resulting from HCl treatment of the tissue samples.

Topics: Animals; Bleomycin; Cells, Cultured; Curcumin; Diarylheptanoids; Lung; Mice; Mice, Inbred Strains; Pulmonary Fibrosis; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

We have evaluated the comparative effect of curcumin (diferuloyl methane) and its analogue [bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione] (BDMC-A) on carbon tetrachloride-induced hepatotoxicity in rats. Administration of carbon tetrachloride (3 ml/kg/week) for three months significantly (P<0.05) increased the levels of marker enzymes such as aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT). The levels of plasma thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides were also significantly (P<0.05) increased. We have observed a significant (P<0.05) decrease in the levels of plasma reduced glutathione (GSH), vitamin C and vitamin E. There was a significant (P<0.05) increase in the levels of TBARS and hydroperoxides in liver and kidney and a significant (P<0.05) decrease in the activities of enzymic antioxidants- superoxide dismutase (SOD), catalase and GSH peroxidase along with GSH in CCl(4)-treated rats. Oral administration of curcumin and BDMC-A to CCl(4)-induced rats for a period of three months significantly (P<0.05) decreased the levels of marker enzymes, plasma TBARS and hydroperoxides and increased the levels of plasma and tissue antioxidants. Histopathological studies of liver also showed protective effect of curcumin and BDMC-A. We have observed thickening of blood vessels and microvesicular fatty changes around the portal triad in CCl(4)-treated rat liver. Treatment with curcumin showed only mild sinusoidal dilatation while with BDMC-A there was only mild portal inflammation. The effect exerted by BDMC-A was found to be more promising than curcumin.

Topics: Animals; Carbon Tetrachloride; Curcumin; Diarylheptanoids; Free Radicals; Glutathione; Lipid Peroxidation; Liver; Male; Rats; Rats, Wistar

Multidrug resistance (MDR) is a phenomenon that is often associated with decreased intracellular drug accumulation in patient's tumor cells resulting from enhanced drug efflux. It is related to the overexpression of a membrane protein, P-glycoprotein (Pgp-170), thereby reducing drug cytotoxicity. A variety of studies have tried to find MDR modulators which increase drug accumulation in cancer cells.. In this study, natural curcuminoids, pure curcumin, demethoxycurcumin and bisdemethoxycurcumin, isolated from turmeric (Curcuma longa Linn), were compared for their potential ability to modulate the human MDR-1 gene expression in multidrug resistant human cervical carcinoma cell line, KB-V1 by Western blot analysis and RT-PCR.. Western blot analysis and RT-PCR showed that all the three curcuminoids inhibited MDR-1 gene expression, and bisdemethoxycurcumin produced maximum effect. In additional studies we found that commercial grade curcuminoid (approximately 77% curcumin, 17% demethoxycurcumin and 3% bisdemthoxycurcumin) decreased MDR-1 gene expression in a dose dependent manner and had about the same potent inhibitory effect on MDR-1 gene expression as our natural curcuminoid mixtures.. These results indicate that bisdemethoxycurcumin is the most active of the curcuminoids present in turmeric for modulation of MDR-1 gene. Treatment of drug resistant KB-V1 cells with curcumin increased their sensitivity to vinblastine, which was consistent with a decreased MDR-1 gene product, a P-glycoprotein, on the cell plasma membrane. Although many drugs that prevent the P-glycoprotein function have been reported, this report describes the inhibition of MDR-1 expression by a phytochemical. The modulation of MDR-1 expression may be an attractive target for new chemosensitizing agents.

Topics: Cell Line, Tumor; Curcumin; Diarylheptanoids; Gene Expression; Genes, MDR; Humans; Reverse Transcriptase Polymerase Chain Reaction

This study evaluates the effect of a Curcuma longa extract on the development of experimental atherosclerosis (fatty streak) in rabbits and its interaction with other plasmatic antioxidants.. Two experimental groups of male New Zealand White rabbits, a control group and a curcuma-extract (CU) group, were fed an atherogenic diet. Additionally, the CU group received an oral curcuma hydroalcoholic extract. Six animals from each experimental group were killed after 10, 20, and 30 days. Compared with the CU group, the control group showed significantly higher plasma lipid peroxide at all experimental times (10, 20, and 30 days) and significantly lower alpha-tocopherol and coenzyme Q levels at 20 and 30 days. Histological results for the fatty streak lesions revealed damage in the thoracic and abdominal aorta that was significantly lower in the CU group than in the control group at 30 days.. Supplementation with Curcuma longa reduces oxidative stress and attenuates the development of fatty streaks in rabbits fed a high cholesterol diet.

Topics: alpha-Tocopherol; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Aortic Diseases; Arteriosclerosis; Coenzymes; Coumaric Acids; Curcuma; Curcumin; Diarylheptanoids; Diet, Atherogenic; Dietary Supplements; Lipid Peroxides; Lipoproteins, LDL; Male; Oxidative Stress; Plant Extracts; Rabbits; Ubiquinone; Vitamin A

The protective effect of a curcumin analog [bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione] was investigated on hepatic lipid peroxidation (LPO) and antioxidant status during 1,2-dimethylhydrazine-induced colon carcinogenesis in male Wistar rats. The effects were compared with that of curcumin, a known antioxidant and anticarcinogen. Colon cancer was induced by sub-cutaneous injection of DMH at a dosage of 20mg/kg body weight (15 doses, at 1-week intervals). DMH administered rats developed gross tumours in the colon. Enhanced lipid peroxidation in the liver of colon tumour bearing rats was accompanied by a significant decrease in the activities of glutathione peroxidase (GPx), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT). Intragastric administration of curcumin (80mg/kg body weight) and curcumin analog (80mg/kg body weight) to DMH-injected rats significantly reduced the number and size of tumour in the colon, lowered lipid peroxidation and enhanced the activities of GPx, GST, SOD and CAT in the liver. We speculate that the curcumin analog used in the present study exerts chemoprevention against cancer development at extrahepatic sites by modulating hepatic biotransformation enzymes and antioxidant status. The effect is comparable with that of curcumin. This shows that the hydroxyl group in the aromatic ring is responsible for the protective effect rather than the methoxy group.

Topics: 1,2-Dimethylhydrazine; Animals; Carcinogens; Colonic Neoplasms; Curcumin; Diarylheptanoids; Liver; Male; Oxidative Stress; Rats; Rats, Wistar

From Curcuma longa, two novel compounds, 4' '-(3' "-methoxy-4' "-hydroxyphenyl)-2' '-oxo-3' '-enebutanyl 3-(3'-methoxy-4'hydroxyphenyl)propenoate (calebin-A, 1) and 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (2), and seven known compounds, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (curcumin, 3), 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (demethoxycurcumin, 4), 1,7-bis(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (bisdemethoxycurcumin, 5), 1-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-6-heptene-3,5-dione (6), 1,7-bis(4-hydroxyphenyl)-1-heptene-3,5-dione (7), 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (8), and 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one (9), were isolated following a bioassay-guided fractionation scheme utilizing an assay to detect protection of PC12 cells from beta-amyloid insult. Compounds 1, 3-5, and 7 were found to more effectively protect PC12 cells from betaA insult (ED(50) = 0.5-10 microg/mL) than Congo red (10) (ED(50) = 37-39 microg/mL).

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Biological Products; Cell Survival; Cinnamates; Curcuma; Curcumin; Diarylheptanoids; Diterpenes; Molecular Structure; Monoterpenes; PC12 Cells; Peptide Fragments; Plants, Medicinal; Rats

Commercially available curcumin, a bright orange-yellow color pigment of turmeric, consists of a mixture of three curcuminoids, namely, curcumin, demethoxycurcumin, and bisdemethoxycurcumin. These were isolated by column chromatography and identified by spectroscopic studies. The purity of the curcuminoids was analyzed by an improved HPLC method. HPLC separation was performed on a C(18) column using three solvents, methanol, 2% AcOH, and acetonitrile, with detection at 425 nm. Four different commercially available varieties of turmeric, namely, Salem, Erode, Balasore, and local market samples, were analyzed to detect the percentage of these three curcuminoids. The percentages of curcumin, demethoxycurcumin, and bisdemethoxycurcumin as estimated using their calibration curves were found to be 1.06 +/- 0.061 to 5.65 +/- 0.040, 0.83 +/- 0.047 to 3.36 +/- 0.040, and 0.42 +/- 0.036 to 2.16 +/- 0.06, respectively, in four different samples. The total percentages of curcuminoids are 2.34 +/- 0.171 to 9.18 +/- 0.232%.

Topics: Acetonitriles; Chromatography, High Pressure Liquid; Coumaric Acids; Curcuma; Curcumin; Diarylheptanoids; Magnetic Resonance Spectroscopy; Methanol; Solvents

beta-Amyloid (betaA) induced oxidative stress is a well-established pathway of neuronal cell death in Alzheimer's disease. From turmeric, Curcuma longa L. (Zingiberaceae), three curcuminoids, curcumin, demethoxycurcumin, and bisdemethoxycurcumin, were found to protect PC12 rat pheochromocytoma and normal human umbilical vein endothelial (HUVEC) cells from betaA(1-42) insult, as measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction assay. ED(50) values of curcumin, demethoxycurcumin, and bisdemethoxycurcumin toward PC12 and HUVEC cells were 7.1+/-0.3, 4.7+/-0.1, 3.5+/-0.2 microg/ml and 6.8+/-0.4, 4.2+/-0.3, and 3.0+/-0.3 microg/ml, respectively. These compounds were better antioxidants than alpha-tocopherol as determined by DPPH radical trapping experiment. alpha-Tocopherol did not protect the cells from betaA(1-42) insult even at>50 microg/ml concentration. The results suggest that these compounds may be protecting the cells from betaA(1-42) insult through antioxidant pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cell Survival; Coumaric Acids; Curcumin; Diarylheptanoids; Endothelium, Vascular; Humans; PC12 Cells; Peptide Fragments; Rats; Umbilical Veins; Zingiberales

Assay-guided fractionation of the EtOAc soluble fraction of the rhizomes of Curcuma longa furnished three DPPH free radical scavenging diarylheptanoids, curcumin (1), demethoxycurcumin (2), and bisdemethoxycurcumin (3). Compounds 1-3 showed the DPPH radical scavenging effects with IC(50) values of 2.8, 39.2, 308.7 microM, respectively. L-Ascorbic acid and resveratrol as positive controls exhibited IC(50) values of 22.5 and 25.0 microM, respectively. Compounds 1-3 showed significant hepatoprotective effects on tacrine-induced cytotoxicity in human liver-derived Hep G2 cells. The EC(50) values of 1-3 are 86.9, 70.7, and 50.2 microM, respectively. Silybin (EC(50) = 69.0 microM) and silychristin (EC(50) = 82.7 microM) were used as positive controls.

Topics: Coumaric Acids; Curcuma; Curcumin; Diarylheptanoids; Free Radical Scavengers; Humans; Inhibitory Concentration 50; Rhizome; Tumor Cells, Cultured

Curcumin I, curcumin II (monodemethoxycurcumin) and curcumin III (bisdemethoxycurcumin) from Curcuma longa were assayed for their cytotoxicity, antioxidant and anti-inflammatory activities. These compounds showed activity against leukemia, colon, CNS, melanoma, renal, and breast cancer cell lines. The inhibition of liposome peroxidation by curcumins I-III at 100 microg/ml were 58, 40 and 22%, respectively. The inhibition of COX-I and COX-II enzymes by the curcumins was observed. Curcumins I-III were active against COX-I enzyme at 125 microg/ml and showed 32, 38.5 and 39.2% inhibition of the enzyme, respectively. Curcumins I-III also showed good inhibition of the COX-II enzyme at 125 mg/ml with 89.7, 82.5 and 58.9% inhibition of the enzyme, respectively.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Antioxidants; Coumaric Acids; Curcumin; Cyclooxygenase Inhibitors; Diarylheptanoids; Humans; Tumor Cells, Cultured; Zingiberales

Curcuminoids, curcumin and its structurally related compounds, constitute the phenolic yellowish pigment of turmeric. We investigated the absorption and metabolism of orally administered curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) in rats. HPLC and LC-MS analyses after enzymatic hydrolyses showed that the predominant metabolites in plasma following administration were glucuronides and glucuronide/sulfates (conjugates with both glucuronide and sulfate) of curcuminoids. The plasma concentrations of conjugated curcuminoids reached a maximum one hour after administration. The conjugative enzyme activities for glucuronidation and sulfation of curcumin were found in liver, kidney and intestinal mucosa. These results indicate that orally administered curcuminoids are absorbed from the alimentary tract and present in the general blood circulation after largely being metabolized to the form of glucuronide and glucuronide/sulfate conjugates.

Topics: Administration, Oral; Animals; Coumaric Acids; Curcumin; Diarylheptanoids; Glucuronides; Glucuronosyltransferase; Organ Specificity; Rats; Sulfates; Sulfotransferases; Time Factors

To clarify the characteristics of genus Curcuma plants, we studied the properties of six strains of Curcuma longa L. and two strains of C. aromatica Salisb. preserved at Izu Experimental Station for Medicinal Plants of National Institute of Health Sciences. Six strains of C. longa were classified into three types according to morphological characteristics, rhizome production, and differences in curcuminoid content of rhizome. The curcuminoid content of the rhizomes in each strain ranged from 2.20 mg/g to 55.23 mg/g. Strains showing a high curcuminoid content had a low rhizome yield. No difference was observed between two strains of C. aromatica in terms of morphological characteristics. C. longa can be easily distinguished by differences in the development of tuberous roots and the color of the rhizome cross section.

Topics: Chromatography, High Pressure Liquid; Coumaric Acids; Curcumin; Diarylheptanoids; Government Agencies; Japan; Plants, Medicinal

Curcumin, a naturally occurring phytochemical responsible for the colour of turmeric shows a wide range of pharmacological properties including antioxidant, anti-inflammatory and anti-cancer effects. We have earlier shown that curcumin in the presence of Cu(II) causes strand cleavage in DNA through generation of reactive oxygen species, particularly the hydroxyl radical. Thus, curcumin shows both antioxidant as well as pro-oxidant effects. In order to understand the chemical basis of various biological properties of curcumin, we have studied the structure-activity relationship between curcumin and its two naturally occurring derivatives namely demethoxycurcumin (dmC) and bisdemethoxycurcumin (bdmC). Curcumin was found to be the most effective in the DNA cleavage reaction and a reducer of Cu(II) followed by dmC and bdmC. The rate of formation of hydroxyl radicals by the three curcuminoids also showed a similar pattern. The relative antioxidant activity was examined by studying the effect of these curcuminoids on cleavage of plasmid DNA by Fe(II)-EDTA system (hydroxyl radicals) and the generation of singlet oxygen by riboflavin. The results indicate that curcumin is considerably more active both as an antioxidant as well as an oxidative DNA cleaving agent. The DNA cleavage activity is the consequence of binding of Cu(II) to various sites on the curcumin molecule. Based on the present results, we propose three binding sites for Cu(II). Two of the sites are provided by the phenolic and methoxy groups on the two benzene rings and the third site is due to the presence of 1,3-diketone system between the rings. Furthermore, both the antioxidant as well as pro-oxidant effects of curcuminoids are determined by the same structural moieties.

Topics: Animals; Antioxidants; Cattle; Copper; Coumaric Acids; Curcumin; Diarylheptanoids; DNA, Superhelical; DNA, Viral; Electrophoresis, Agar Gel; Hydroxyl Radical; Oxidation-Reduction; Oxygen; Plasmids; Structure-Activity Relationship

Former studies have shown that curcumin, which can be extracted from different Curcuma species, is able to stimulate bile flow in rats, whereas bisdemethoxycurcumin, which is mainly found in rhizomes of Curcuma longa, is believed to inhibit bile flow. To reevaluate this observation we investigated the influence of both curcuminoids on bile flow, bile acid concentration and excretion over a time period of 180 min in the bile fistula model in rats. Furthermore, we tested the ability of both curcuminoids to reduce cyclosporin-induced cholestasis. 30 min after intravenous injection of 25 mg/kg of curcumin and bisdemethoxycurcumin bile flow was enhanced from 500 microliters/kg/15 min (100%) to 180% and to 220%, respectively. The choleretic effect of bisdemethoxycurcumin lasted longer than that of curcumin. Following intravenous injection of 30 mg/kg of cyclosporin, which reduced bile flow, bile acid concentration (15 mmol/l) and excretion (12.5 mumol/kg/15 min) to 40% of the initial value, administration of curcumin and bisdemethoxycurcumin transiently increased bile flow to 100% and to 125% of the starting value, respectively. However, only bisdemethoxycurcumin statistically significantly attenuated cyclosporin-induced reduction of bile acid excretion. We conclude that the beneficial properties of curcuminoids for the therapy of cyclosporin-induced cholestasis still remain to be proven.

Topics: Animals; Bile; Cholagogues and Choleretics; Cholestasis; Coumaric Acids; Curcumin; Cyclosporine; Diarylheptanoids; Immunosuppressive Agents; Male; Rats; Rats, Wistar

Curcumin, demethoxycurcumin and bisdemethoxycurcumin are the yellow coloring phenolic compounds isolated from the spice turmeric. This study was part of a program correlating the biological activity and molecular structure of antitumor agents; the effect of these curcuminoids and cyclocurcumin (Cyclocur) was examined on the proliferation of MCF-7 human breast tumor cells. Curcuminoids appeared to be potent inhibitors, whereas Cyclocur was less inhibitory. To contribute to our understanding of the mechanism of antiproliferative activity of curcumin, cell cycle analysis was performed by propidium iodide staining and a flow cytometry technique. Curcumin exerts a cytostatic effect at G2/M which explains its antiproliferative activity. The presence of the diketone moiety in the curcumin molecule seems to be essential for the inhibitory activity.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cell Cycle; Cell Division; Coumaric Acids; Curcumin; Diarylheptanoids; Humans; Structure-Activity Relationship; 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