curcumin and ferulic-acid

Substantial pre-clinical and human studies have shown that curcumin, a dietary compound from turmeric, has a variety of health-promoting biological activities. A better understanding of the biochemical mechanisms for the health-promoting effects of curcumin could facilitate the development of effective strategies for disease prevention. Recent studies have shown that in aqueous buffer, curcumin rapidly degrades and leads to formation of various degradation products. In this review, we summarized and discussed the biological activities of chemical degradation products of curcumin, including alkaline hydrolysis products (such as ferulic acid, vanillin, ferulaldehyde, and feruloyl methane), and autoxidation products (such as bicyclopentadione). Though many of these degradation products are biologically active, they are substantially less-active compared to curcumin, supporting that chemical degradation has a limited contribution to the biological activities of curcumin.

Topics: Animals; Benzaldehydes; Coumaric Acids; Curcumin; Humans; Hydrolysis; Oxidation-Reduction

Ferulic acid, a natural phytochemical has gained importance as a potential therapeutic agent by virtue of its easy commercial availability, low cost and minimal side-effects. It is a derivative of curcumin and possesses the necessary pharmacokinetic properties to be retained in the general circulation for several hours. The therapeutic effects of ferulic acid are mediated through its antioxidant and anti-inflammatory properties. It exhibits different biological activities such as anti-inflammatory, anti-apoptotic, anti-carcinogenic, anti-diabetic, hepatoprotective, cardioprotective, neuroprotective actions, etc. The current review addresses its therapeutic effects under different pathophysiological conditions (eg. cancer, cardiomyopathy, skin disorders, brain disorders, viral infections, diabetes etc.).

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Cardiomyopathies; Cell Differentiation; Coumaric Acids; Curcumin; Diabetes Complications; Humans; Inflammation; Parkinson Disease; Schwann Cells; Skin Diseases

Polyphenols are the most abundant components of our daily food, occupying the major portion of naturally occurring phytochemicals in plants. Currently, polyphenols have received a special attention from the scientific community against health risk because of their antioxidant capacity and the ability to scavenge the free radicals formed during the pathological process like cancer, cardiovascular diseases and neurodegenerative disorders. Alzheimer's disease, one of the common forms of dementia is an intricate, multifactorial mental illness which is characterized by age-dependent memory loss ultimately leading to a steady decline of cognitive function. Extracellular amyloid beta deposition and intracellular tau hyperphosphorylation are the two main alterations occurring in the cells reported to cause neuronal dysfunction during AD. Dietary intake of polyphenols is known to attenuate the progression of the disease by showing strong potential to tackle the alterations and reduce the risk of AD by reversing the cognitive deficits. A large number of polyphenolic compounds showing promising results against AD pathologies have been identified and described in the past decade. Many efforts have been made to unravel the molecular mechanisms and the specific interactions of polyphenols with their targets in the pathway. This review focuses on the therapeutic potential and promising role of dietary polyphenols as nutraceuticals to combat AD.

Topics: Alzheimer Disease; Animals; Coumaric Acids; Curcumin; Diet; Flavonoids; Humans; Research; Resveratrol; Stilbenes

In transdermal drug delivery systems, the physicochemical properties of the drug affect its percutaneous permeability. However, whether the physicochemical properties of drugs change their transdermal permeability in the presence of pores in the presence of solid microneedles (MNs) has been less studied in this area. In this project, cinnamaldehyde, curcumin, ferulic acid and geniposide were selected as model drugs for the study of their transdermal permeability under the action of MNs, and a combination of classical experiments and visualization means such as scanning electron microscopy and laser confocal was used to investigate the permeation-promoting mechanism of MNs. The results showed that the MNs had significant permeation-promoting effects on different properties of drugs, with the permeation-promoting effects on cinnamaldehyde, curcumin, ferulic acid and geniposide being 6.36, 17.43, 29.54 and 8.91 times, respectively, and the permeation-promoting effects were more pronounced for lipid-soluble and amphiphilic drugs. Using scanning electron microscopy, transmission electron microscopy and other means to confirm that MNs can promote the penetration by acting on the skin to produce pores, and their effect on skin structure is greater than that of drugs. In addition, the existence of pores increases the amount of drug transdermal, which may enhance the diffusion of drug on the skin, and has no effect on lipid exchange and transdermal route. Through the research, it has been found that MNs is equivalent to direct peeling of the stratum corneum (SC), but it is simpler and safer for the patient.

Topics: Administration, Cutaneous; Curcumin; Drug Delivery Systems; Humans; Lipids; Needles; Permeability; Pharmaceutical Preparations; Skin

Curcumin is a polyphenolic compound found in Curcuma longa. This bioactive molecule has several reported health-benefit effects, being the anticarcinogenic activity among the most promising ones. However, curcumin extraction from natural sources is hampered by impure products obtained from harsh chemicals and limited by plant seasonality and high prices. Therefore, curcumin heterologous production emerged as an interesting alternative. Escherichia coli has been explored as chassis but the implementation of the pathway in Saccharomyces cerevisiae can have several advantages, including its generally regarded as safe status. Hence, S. cerevisiae was engineered for the first time to produce curcumin from its precursor ferulic acid.. The enzymes 4-coumarate-CoA ligase (4CL1) from Arabidopsis thaliana or feruloyl-CoA synthetase (FerA) from Pseudomonas paucimobilis and type III polyketide synthases (PKSs) from Oryza sativa or C. longa were expressed in BY4741 strain. To avoid ferulic acid deviation, the gene FDC1 coding a ferulic acid decarboxylase was deleted. The maximum curcumin titer was obtained with FerA combined with C. longa PKSs (2.7 mg L. Up to our knowledge, this is the first work reporting the expression of a feruloyl-CoA synthase and also curcuminoid biosynthetic enzymes in S. cerevisiae, and consequently, curcumin production.

Topics: Coumaric Acids; Curcumin; Ligases; Saccharomyces cerevisiae

Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive cognitive decline. Several effective natural components have been identified for the treatment of AD. However, it is difficult to obtain conclusive evidence on the safety and effectiveness of natural components, because a variety of factors are associated with the progression of AD pathology. We hypothesized that a therapeutic effect could be achieved by combining multiple ingredients with different efficacies. The purpose of this study was thus to evaluate a combination treatment of curcumin (Cur) and ferulic acid (FA) for amyloid-β (Aβ)-induced neuronal cytotoxicity. The effect of Cur or FA on Aβ aggregation using thioflavin T assay was confirmed to be inhibited in a concentration-dependent manner by Cur single or Cur + FA combination treatment. The effects of Cur + FA on the cytotoxicity of human neuroblastoma (SH-SY5Y) cells induced by Aβ exposure were an increase in cell viability, a decrease in ROS and mitochondrial ROS, and repair of membrane damage. Combination treatment showed an overall higher protective effect than treatment with Cur or FA alone. These results suggest that the combined action mechanisms of Cur and FA may be effective in preventing and suppressing the progression of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Coumaric Acids; Curcumin; Humans; Neuroblastoma; Neurodegenerative Diseases; Neuroprotective Agents; Neurotoxicity Syndromes; Reactive Oxygen Species

Topics: Alzheimer Disease; Amides; Amyloid; Coumaric Acids; Dose-Response Relationship, Drug; Humans; Molecular Structure; Protein Aggregates; Structure-Activity Relationship

The polyphenols curcumin (CU) and ferulic acid (FA) are able to inhibit the aggregation of amyloid-β (Aβ) peptide with different strengths. CU is a strong inhibitor while FA is a weaker one. In the present study, we examine the effects of CU and FA on the folding process of an Aβ monomer by 1 µs molecular dynamics (MD) simulations. We found that both inhibitors increase the helical propensity and decrease the non-helical propensity of Aβ peptide. They prevent the formation of a dense bulk core and shorten the average lifetime of intramolecular hydrogen bonds in Aβ. CU makes more and longer-lived hydrogen bonds, hydrophobic, π-π, and cation-π interactions with Aβ peptide than FA does, which is in a good agreement with the observed stronger inhibitory activity of CU on Aβ aggregation.

Topics: Amyloid beta-Peptides; Coumaric Acids; Curcumin; Hydrogen Bonding; Ligands; Models, Molecular; Protein Folding; Protein Stability; Protein Structure, Secondary; Solvents; Static Electricity

Street-vended foods are cheap, readily available and have been currently identified as possible means for micronutrient fortification in an effort to prevent malnutrition in developing countries. The effect of enriching street-vended zobo drink (Hibiscus sabdariffa) with turmeric (Curcuma longa) was studied to assess the potential to increase health-supporting properties for its consumers. Two processing methods were tested: boiled turmeric root in zobo and addition of fresh turmeric paste to zobo in different concentrations. Vitamin C in turmeric-fortified zobo ranged from 496-725 μg per 100 mL, delphinidin-3-sambubioside from 52-69 mg per 100 mL, and cyanidin-3-sambubioside from 21-27 mg per 100 mL. Micronutrients ranged from 10.9-14 mg L

Topics: Anthocyanins; Beverages; Chlorogenic Acid; Coumaric Acids; Curcuma; Hibiscus; Hydrogen-Ion Concentration; Minerals; Proteins

Platinum-based agents, such as cisplatin, form the mainstay of currently used chemotherapeutic regimens for several malignancies; however, the main limitations are chemoresistance and ototoxic side effects. In this study we used two different polyphenols, curcumin and ferulic acid as adjuvant chemotherapeutics evaluating (1) in vivo their antioxidant effects in protecting against cisplatin ototoxicity and (2) in vitro the transcription factors involved in tumor progression and cisplatin resistance. We reported that both polyphenols show antioxidant and oto-protective activity in the cochlea by up-regulating Nrf-2/HO-1 pathway and downregulating p53 phosphorylation. However, only curcumin is able to influence inflammatory pathways counteracting NF-κB activation. In human cancer cells, curcumin converts the anti-oxidant effect into a pro-oxidant and anti-inflammatory one. Curcumin exerts permissive and chemosensitive properties by targeting the cisplatin chemoresistant factors Nrf-2, NF-κB and STAT-3 phosphorylation. Ferulic acid shows a biphasic response: it is pro-oxidant at lower concentrations and anti-oxidant at higher concentrations promoting chemoresistance. Thus, polyphenols, mainly curcumin, targeting ROS-modulated pathways may be a promising tool for cancer therapy. Thanks to their biphasic activity of antioxidant in normal cells undergoing stressful conditions and pro-oxidant in cancer cells, these polyphenols probably engage an interplay among the key factors Nrf-2, NF-κB, STAT-3 and p53.

Topics: Animals; Antineoplastic Agents; Cisplatin; Cochlea; Coumaric Acids; Curcumin; Drug Resistance, Neoplasm; Drug Synergism; Humans; Male; NF-kappa B; Nuclear Respiratory Factor 1; Ototoxicity; Phosphorylation; Rats; Rats, Wistar

The amyloid plaques are a key hallmark of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Amyloidogenesis is a complex long-lasting multiphase process starting with the formation of nuclei of amyloid peptides: a process assigned as a primary nucleation. Curcumin (CU) is a well-known inhibitor of the aggregation of amyloid-beta (Aβ) peptides. Even more, CU is able to disintegrate preformed Aβ firbils and amyloid plaques. Here, we simulate by molecular dynamics the primary nucleation process of 12 Aβ peptides and investigate the effects of CU on the process. We found that CU molecules intercalate among the Aβ chains and bind tightly to them by hydrogen bonds, hydrophobic, π-π, and cation-π interactions. In the presence of CU, the Aβ peptides form a primary nucleus of a bigger size. The peptide chains in the nucleus become less flexible and more disordered, and the number of non-native contacts and hydrogen bonds between them decreases. For comparison, the effects of the weaker Aβ inhibitor ferulic acid (FA) on the primary nucleation are also examined. Our study is in good agreement with the observation that taken regularly, CU is able to prevent or at least delay the onset of neurodegenerative disorders.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Binding Sites; Coumaric Acids; Curcumin; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Neuroprotective Agents; Protein Aggregates; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs

Alzheimer's disease (AD) is the most common form of dementia and its prevention and treatment is a worldwide issue. Many natural components considered to be effective against AD have been identified. However, almost all clinical trials of these components for AD reported inconclusive results. We thought that multiple factors such as amyloid β (Aβ) and tau progressed the pathology of AD and that a therapeutic effect would be obtained by using multiple active ingredients with different effects. Thus, in this study, we treated ferulic acid (FA), phosphatidylserine (PS) and curcumin (Cur) in combination or alone to APPswe/PS1dE9 transgenic mice and evaluated cognitive function by Y-maze test. Consequently, only the three-ingredient group exhibited a significant improvement in cognitive function compared to the control group. In addition, we determined the amounts of Aβ, brain-derived neurotrophic factor (BDNF), interleukin (IL)-1β, acetylcholine and phosphorylated tau in the mouse brains after the treatment. In the two-ingredient (FA and PS) group, a significant decrease in IL-1β and an increasing trend in acetylcholine were observed. In the Cur group, significant decreases in Aβ and phosphorylated tau and an increasing trend in BDNF were observed. In the three-ingredient group, all of them were observed. These results indicate that the intake of multiple active ingredients with different mechanisms of action for the prevention and treatment of AD.

Topics: Acetylcholine; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Brain-Derived Neurotrophic Factor; Cognition; Coumaric Acids; Curcumin; Drug Therapy, Combination; Interleukin-1beta; Mice, Transgenic; Neuroprotective Agents; Phosphatidylserines; Presenilin-1; tau Proteins

Curcumin is a phenolic compound produced by some plants, among which Curcuma longa is the reachest in this principal curcuminoid. At elevated temperature curcumin degrades to trans-6-(4'-hydroxy-3'-methoxyphenyl)-2,4-dioxo-5-hexenal, vanillin, ferulic acid and feruloylmethane, however, the formation of feruloyloacetone ((5E)-6-(4-hydroxy-3-methoxyphenyl)hex-5-ene-2,4-dione) in the curcumin degradation process has not been reported yet. As results from experiments, even 28.8% or 20.6% of the degraded curcumin is transformed to feruloyloacetone during 2 h heating of alkaline or acidic curcumin solution, respectively. The structure of the identified feruloyloacetone was confirmed by MS

Topics: Benzaldehydes; Coumaric Acids; Curcumin; Food Handling; Magnetic Resonance Spectroscopy; Styrenes

Aminopeptidase B (Ap-B) is a Zn

Topics: Aminopeptidases; Animals; Biological Products; Coumaric Acids; Coumarins; Curcumin; Kinetics; Molecular Docking Simulation; Protease Inhibitors; Rats; Recombinant Proteins; Resveratrol; Xanthones

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

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Coumaric Acids; Drug Design; Eels; Humans; Memory Disorders; Mice; PC12 Cells; Rats

This study aims to determine the potential protective effects of ferulic acid against cisplatin-induced nephrotoxicity and to compare its effect with curcumin, a well-known protective agent against cisplatin- induced toxicity in rats. Administration of cisplatin resulted in high BUN (Blood Urea Nitrogen), creatinine, MDA (Malondialdehyde), MPO (Myeloperoxidase), TOS (Total Oxidative Status), PtNT (Protein Nitrotyrosine) levels (p<0.05). Histological observations showed abnormal morphology of kidney; in addition with appearance of TUNEL positive cells indicating apoptosis in cisplatin administered group. HO-1 (Heme Oxygenase-1) levels measured by RT-PCR (Real Time Polymerase Chain Reaction), and TAS (Total Antioxidative Status) revealed antioxidant depletion due to cisplatin toxicity in animals (p<0.05). All parameters showed improvement in groups treated with ferulic acid (p<0.05). Ferulic acid treatment was found significant in preventing oxidative stress, increasing antioxidative status and regaining histological parameters to normal, indicating nephroprotective and antioxidant effects of this phenolic compound.

Topics: Animals; Blood Urea Nitrogen; Cisplatin; Coumaric Acids; Curcumin; Heme Oxygenase (Decyclizing); Kidney; Kidney Diseases; Male; Malondialdehyde; Peroxidase; Protective Agents; Rats, Wistar; RNA, Messenger; Tyrosine

The aim of this study was to evaluate the effect of different natural substances on SIRT1 expression and on AMPK and mTOR phosphorylation. Moreover, we investigated the presence of a synergistic effect between the substances.. Human cervical carcinoma cells were seeded in 12-well plates, then incubated with the nine tested substances (resveratrol, quercetin, berberine, catechin, tyrosol, ferulic acid, niclosamide, curcumin, and malvidin) at different concentrations and left in incubation for 3, 6, and 24 h. The targeting proteins' expression and phosphorylation were evaluated by immunoblotting, and cytotoxicity tests were performed by CellTiter-Blue Cell Viability Assay.. No statistically significant decrease (P > 0.05) in the number of viable cells was found. The expression of SIRT1 was significantly increased in all experimental groups compared with the control group (P < 0.001). Instead, the simultaneous administration involved a significant and synergistic increase in the expression of SIRT1 for some but not all of the tested compounds. Finally, the individual administration of berberine, quercetin, ferulic acid, and tyrosol resulted in a statistically significant increase in AMPK activation and mTOR inhibition, whereas their associated administration did not reveal a synergistic effect.. Our results provide evidence that all compounds have the potential to stimulate SIRT1 and sustain the stimulating action of resveratrol on SIRT1, already widely reported in the literature. In this regard, we confirm the interaction of these substances also with the pathway of AMPK and mTOR, in support of the studies that highlight the importance of SIRT1/AMPK and mTOR pathway in many diseases.

Topics: AMP-Activated Protein Kinases; Anthocyanins; Berberine; Catechin; Cell Line, Tumor; Cell Survival; Coumaric Acids; Curcumin; Dietary Supplements; Gene Expression Regulation; Humans; Niclosamide; Phenylethyl Alcohol; Phosphorylation; Quercetin; Resveratrol; Sirtuin 1; Stilbenes; TOR Serine-Threonine Kinases

A novel series of ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC50 of 3.2-34.7μM) and self-induced β-amyloid (Aβ1-42) aggregation (30.8-39.1%, 25μM), to act as potential antioxidants (ORAC-FL value of 0.9-1.3). In particular, compound 17d had the greatest ability to inhibit AChE (IC50=3.2μM), and Aβ1-42 aggregation (30.8%) was also an excellent antioxidant and neuroprotectant. Moreover, it is capable of disaggregating self-induced Aβ aggregation. Furthermore, 17d could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 17d is a potential multifunctional agent for the treatment of AD.

Topics: Alkanes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Chemistry Techniques, Synthetic; Cholinesterase Inhibitors; Coumaric Acids; Drug Design; Drug Evaluation, Preclinical; Ethylamines; Humans; Hydrogen Peroxide; Neuroprotective Agents; PC12 Cells; Rats

Ferulic acid has structural similarity with curcumin which is being reported for its monoamine oxidase (MAO) inhibitory activity. Based on this similarity, we designed a series of ferulic acid amides 6a-m and tested for their inhibitory activity on human MAO (hMAO) isoforms. All the compounds were found to inhibit the hMAO isoforms either selectively or non-selectively. Nine compounds (6a, 6b, 6g-m) were found to inhibit hMAO-B selectively, whereas the other four (6c-f) were found to be non-selective. There is a gradual shift from hMAO-B selectivity (6a,b) to non-selectivity (6c-f) as there is an increase in chain length at the amino terminus. In case of compounds having an aromatic nucleus at the amino terminus, increasing the carbon number between N and the aromatic ring increases the potency as well as selectivity toward hMAO-B. Compounds 6f, 6j, and 6k were subjected to membrane permeability and metabolic stability studies by in vitro assay methods. They were found to have a better pharmacokinetic profile than curcumin, ferulic acid, and selegiline. In order to understand the structural features responsible for the potency and selectivity of 6k, we carried out a molecular docking simulation study.

Topics: Amides; Animals; Cell Membrane Permeability; Coumaric Acids; Curcumin; Dogs; Humans; Isoenzymes; Madin Darby Canine Kidney Cells; Microsomes, Liver; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship

Feruloyl amylopectin (FAP) was synthesized by the N,N'-carbonyldiimidazole (CDI) activation method, and the enzymatically cross-linked feruloyl amylopectin (CL-FAP) was prepared via catalysis of horseradish peroxidase (HRP) with the presence of hydrogen peroxide (H2O2). RP-HPLC-DAD/ESI-TOF-MS measured ferulic acid and its derivatives in FAP and CL-FAP. FAP was primarily composed of two ferulate monomers, while CL-FAP was composed of two ferulate monomers and two ferulate dehydrodimers. The ester formation in the feruloyl group was confirmed by the presence of carbonyl and aromatic CC signal near 1,725 (1,723) and 1,510 cm(-1) in the FT-IR spectra. X-ray diffraction studies showed that the two modified amylopectins lost the ordered A-type crystalline structure, characteristic of maize amylopectin. The encapsulation capacity of curcumin (ECC) in 1mg/mL CL-FAP microemulsion was measured at 88.13 μg/mg by HPLC.

Topics: Amylopectin; Chromatography, High Pressure Liquid; Coumaric Acids; Curcumin; Drug Compounding; Oxidation-Reduction; Solubility; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction; Zea mays

Crystallographic structure determination of protein-ligand complexes of transthyretin (TTR) has been hindered by the low affinity of many compounds that bind to the central cavity of the tetramer. Because crystallization trials are carried out at protein and ligand concentration that approach the millimolar range, low affinity is less of a problem than the poor solubility of many compounds that have been shown to inhibit amyloid fibril formation. To achieve complete occupancy in co-crystallization experiments, the minimal requirement is one ligand for each of the two sites within the TTR tetramer. Here we present a new strategy for the co-crystallization of TTR using high molecular weight polyethylene glycol instead of high ionic strength precipitants, with ligands solubilized in multicomponent mixtures of compounds. This strategy is applied to the crystallization of TTR complexes with curcumin and 16α-bromo-estradiol. Here we report the crystal structures with these compounds and with the ferulic acid that results from curcumin degradation.

Topics: Coumaric Acids; Cryoprotective Agents; Crystallization; Crystallography, X-Ray; Curcumin; Estradiol; Humans; Hydrophobic and Hydrophilic Interactions; Ligands; Models, Molecular; Prealbumin; Solubility; Solutions; Static Electricity

Curcumin is a secondary plant metabolite present in Curcuma longa L. Since curcumin is widely used as a food colorant in thermally processed food it may undergo substantial chemical changes which in turn could affect its biological activity. In the current study, curcumin was roasted at 180 °C up to 70 minutes and its kinetic of degradation was analyzed by means of HPLC-PDA and LC-MS, respectively. Roasting of curcumin resulted in the formation of the degradation products vanillin, ferulic acid, and 4-vinyl guaiacol. In cultured hepatocytes roasted curcumin as well as 4-vinyl guaiacol enhanced the transactivation of the redox-regulated transcription factor Nrf2, known to be centrally involved in cellular stress response and antioxidant defense mechanisms. The antioxidant enzyme paraoxonase 1 was induced by roasted curcumin and 4-vinyl guaiacol. Furthermore, roasted curcumin and 4-vinyl guaiacol decreased interleukin-6 gene expression in lipopolysaccharide stimulated murine macrophages. Current data suggest that curcumin undergoes degradation due to roasting and its degradation product exhibit significant biological activity in cultured cells.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Aryldialkylphosphatase; Benzaldehydes; Cell Line, Tumor; Coumaric Acids; Curcuma; Curcumin; Food Coloring Agents; Guaiacol; Hepatocytes; Hot Temperature; Humans; Interleukin-6; Macrophage Activation; Macrophages; Mice; NF-E2-Related Factor 2; RAW 264.7 Cells; Rhizome; Transcriptional Activation

Charismatic therapeutic potential of curcumin in biological research have triggered an interest to explore the thermal degradation pattern of curcumin, formation of ferulic acid and vanillin as degraded metabolites at different temperatures in methanol and corn oil. The results revealed 47% w/w loss of curcumin along with formation of 17% w/w vanillin and 9% w/w ferulic acid at boiling temperature of methanol while oil samples show 38.9% w/w loss of curcumin but not confirming the formation of ferulic acid and vanillin. Findings of this study revealed that formation of vanillin in methanol starts around 50°C and its concentration goes on increasing up to 70°C and then further degraded at boiling temperature of methanol. Formation of ferulic acid begins around 60°C and initially increases with rise of temperature and then decreases approaching boiling point of methanol. Vanillin as well as ferulic acid was absent in corn oil samples though degradation of curcumin was observed by reduction in peak area of curcumin. The present study was done by applying a validated high-performance thin-layer chromatography method. The method involved glass-backed HPTLC plates precoated with silica gel 60F254 as the stationary phase and toluene: ethyl acetate: methanol (8:1:1, v/v/v) as mobile phase.

Topics: Benzaldehydes; Calibration; Chromatography, Thin Layer; Coumaric Acids; Curcumin; Drug Stability; Temperature

Lewy bodies, mainly composed of α-synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited αS fibrillation and destabilized preformed αS fibrils. Cumulative evidence suggests that low-order αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on αS oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited αS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of αS, whereas direct binding of RA to monomeric αS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated αS synaptic toxicity by inhibition of αS oligomerization. These results suggest that Myr and RA prevent the αS aggregation process, reducing the neurotoxicity of αS oligomers. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds on α-synuclein (αS) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited αS oligomerization and secondary structure conversion. Myr and RA ameliorated αS synaptic toxicity on the experiment of long-term potentiation. Our results suggest that Myr and RA prevent αS aggregation process and reduce the neurotoxicity of αS oligomers. Phenolic compounds are good candidates of disease modifying drugs for α-synucleinopathies.

Topics: alpha-Synuclein; Amyloid; Animals; Antioxidants; Cinnamates; Circular Dichroism; Coumaric Acids; Curcumin; Depsides; Drug Evaluation, Preclinical; Flavonoids; Hippocampus; Long-Term Potentiation; Masoprocol; Mice; Microscopy, Atomic Force; Models, Molecular; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Phenols; Polymerization; Protein Structure, Secondary; Rosmarinic Acid

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

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

Curcumin, a naturally occuring polyphenolic phytoconstituent, is isolated from the rhizomes of Curcuma longa Linn. (Zingiberaceae). It is water insoluble under acidic or neutral conditions but dissolves in alkaline environment. In neutral or alkaline conditions, curcumin is highly unstable undergoing rapid hydrolytic degradation to feruloyl methane and ferulic acid. Thus, the use of curcumin is limited by its poor aqueous solubility in acidic or neutral conditions and instability in alkaline pH. In the present study, curcumin nanocrystals were prepared using high-pressure homogenization, to improve its solubility. Five different stabilizers [polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), sodium dodecyl sulfate (SDS), carboxymethylcellulose sodium salt] possessing different stabilization mechanism were investigated. The nanoparticles were characterized with regard to size, surface charge, shape and morphology, thermal property, and crystallinity. A short-term stability study was performed storing the differently stabilized nanoparticles at 4°C and room temperature. PVA, PVP, TPGS, and SDS successfully produced curcumin nanoparticle with the particle size in the range of 500-700 nm. PVA, PVP, and TPGS showed similar performance in preserving the curcumin nanosuspension stability. However, PVP is the most efficient polymer to stabilize curcumin nanoparticle. This study illustrates that the developed curcumin nanoparticle held great potential as a possible approach to improve the curcumin solubility then enhancing bioavailability.

Topics: Carboxymethylcellulose Sodium; Chemistry, Pharmaceutical; Coumaric Acids; Curcumin; Drug Stability; Excipients; Hydrogen-Ion Concentration; Hydrolysis; Methane; Nanoparticles; Nanotechnology; Particle Size; Polyethylene Glycols; Polyvinyl Alcohol; Povidone; Pressure; Sodium Dodecyl Sulfate; Solubility; Surface Properties; Technology, Pharmaceutical; Temperature; Vitamin E

Aggregated β-amyloid (Aβ) plays crucial roles in Alzheimer's disease (AD) pathogenesis, therefore blockade of Aβ aggregation is considered as a potential therapeutic target. We designed and synthesized small molecules to reduce Aβ-induced cytotoxicity by inhibiting Aβ aggregation. The small molecules were screened via ThT, MTT, and cell-based cytotoxicity assay (Aβ burden assay). Selected compounds 1c, 1d, 1e, and 1f were then investigated by evaluating their effects on cognitive impairment of acute AD mice model. Learning and memory dysfunction by injection of Aβ(1-42) was recovered by administration of these molecules. Especially, 1d showed the best recovery activity in Y-maze task, object recognition task, and passive avoidance task with dose dependent manner. These results suggest that 1d has high potential as a therapeutic agent for AD.

Topics: Amyloid beta-Peptides; Animals; Benzene Derivatives; Benzothiazoles; Cells, Cultured; Coumaric Acids; Curcumin; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Molecular Structure; Molecular Weight; Peptide Fragments; Resveratrol; Stilbenes; Thiazoles

Curcumin, the most active compound of curcuminoids, has been shown to inhibit formation of advanced glycation end products (AGEs) in streptozotocin-induced diabetic rats. However, little is known on whether curcumin may trap methylglyoxal (MGO), a major reactive dicarbonyl compound, to inhibit AGE formation. We found that one molecule of curcumin effectively trapped one molecule of MGO at a 1:3 ratio at 24 h of incubation under physiological conditions (pH 7.4, 37 °C). Curcumin decreased N(ε)-(carboxymethyl)lysine (CML) expression in human umbilical vein endothelial cells. We further used two curcumin analogues, dimethoxycurcumin (DIMC) and ferulic acid, to investigate the possible MGO-trapping mechanism of curcumin. Results reveal that DIMC, but not ferulic acid, exhibited MGO-trapping capacity, indicating curcumin traps MGO at the electron-dense carbon atom (C10) between the two keto carbon groups. Thus, curcumin may prevent MGO-induced endothelial dysfunction by directly trapping MGO.

Topics: Animals; Blotting, Western; Cell Proliferation; Cell-Free System; Chromatography, High Pressure Liquid; Coumaric Acids; Curcumin; Diabetes Mellitus, Experimental; Glycation End Products, Advanced; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen-Ion Concentration; Pyruvaldehyde; Rats; Tandem Mass Spectrometry

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

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

Curcumin is known to be an antioxidant, as it can scavenge free radicals from biological media. A sequence of H-abstraction and addition reactions involving up to eight OH radicals and curcumin or its degradation products leading to the formation of two other antioxidants, namely, ferulic acid and vanillin, was studied. Single electron transfer from curcumin to an OH radical was also studied. All relevant extrema on the potential energy surfaces were located by optimizing geometries of the reactant and product complexes, as well as those of the transition states, at the BHandHLYP/6-31G(d,p) level of density functional theory in the gas phase. Single-point energy calculations were also performed in the gas phase at the BHandHLYP/aug-cc-pVDZ and B3LYP/aug-cc-pVDZ levels of theory. Solvent effects in aqueous media were treated by performing single-point energy calculations at all of the above-mentioned levels of theory employing the polarizable continuum model and the geometries optimized at the BHandHLYP/6-31G(d,p) level in the gas phase. A few reaction steps were also studied by geometry optimization in aqueous media, and the thus-obtained Gibbs free energy barriers were similar to those obtained by corresponding single-point energy calculations. Our calculations show that the hydrogen atom of the OH group attached to the phenol moiety of curcumin would be most efficiently abstracted by an OH radical, in agreement with experimental observations. Further, our study shows that OH addition would be most favored at the C10 site of the heptadiene chain. It was found that curcumin can serve as an effective antioxidant.

Topics: Benzaldehydes; Computer Simulation; Coumaric Acids; Curcumin; Electron Transport; Free Radical Scavengers; Free Radicals; Gases; Hydrogen; Hydroxyl Radical; Models, Chemical; Molecular Structure; Water

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

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

The modulating effect of curcumin and ferulic acid was investigated on expression pattern of apoptosis regulatory p53 and bcl-2 proteins in oral squamous cell carcinoma (OSCC). The OSCC was induced in the buccal pouch of golden Syrian hamster by painting with 0.5% 7,12-dimethylbenz[a]anthracene (DMBA) three-times a week for 14 weeks. The expression pattern of p53 and bcl-2 proteins was analyzed by immunohistochemical staining. We noticed 100% tumor formation in hamsters painted with DMBA alone for 14 weeks. Overexpression of p53 and bcl-2 proteins was observed in the buccal mucosa of tumor-bearing hamsters. Oral administration of curcumin (80 mg/kg body wt) and ferulic acid (40 mg/kg body wt) to DMBA painted hamsters on days alternate to DMBA painting for 14 weeks completely inhibited tumor formation and down-regulated the expression pattern of p53 and bcl-2 proteins. Our results thus demonstrated the protective role of curcumin and ferulic acid on DMBA-induced abnormal expression of p53 and bcl-2 proteins in the buccal mucosa of golden Syrian hamsters.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Coumaric Acids; Cricetinae; Curcumin; Immunohistochemistry; Male; Mesocricetus; Mouth Neoplasms; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

Adiponectin is positively correlated with insulin sensitivity. Hydroxycinnamic acid derivatives (HADs), observed ubiquitously in plants, have some physiological functions. In this study, we investigated the effect of HADs on serum adiponectin concentrations in mice and on adiponectin secretion of 3T3-L1 adipocytes. In mice, serum adiponectin concentrations were increased by gamma-oryzanol administration. CAPE, curcumin, and trans-ferulic acid markedly enhanced the adiponectin secretion of 3T3-L1 adipocytes, but not gamma-oryzanol. To clarify the effects of gamma-oryzanol in mice or the effects of HADs on the underlying mechanisms of adiponectin secretion, we further investigated the effect of HADs on adiponectin secretion in the NF-kappaB activation state. Although the adiponectin secretion was reduced in the presence of lipopolysaccharide plus TNF-alpha and IFN-gamma, only gamma-oryzanol supported the activity of adiponectin secretion under NF-kappaB activated condition. The results indicate that these HADs might regulate adiponectin secretion by the inhibition of NF-kappaB activation. HADs might be effective for ameliorating type 2 diabetes.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Caffeic Acids; Coumaric Acids; Curcumin; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Interferon-gamma; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Phenylethyl Alcohol; Phenylpropionates; Phytotherapy; Pioglitazone; Plant Extracts; Plant Oils; Rice Bran Oil; Thiazolidinediones; Tumor Necrosis Factor-alpha

Inhibition of amyloid-beta (Abeta) aggregation is an attractive therapeutic strategy for Alzheimer's disease (AD). Certain phenolic compounds have been reported to have anti-Abeta aggregation effects in vitro. This study systematically investigated the effects of phenolic compounds on AD model transgenic mice (Tg2576). Mice were fed five phenolic compounds (curcumin, ferulic acid, myricetin, nordihydroguaiaretic acid (NDGA), and rosmarinic acid (RA)) for 10 months from the age of 5 months. Immunohistochemically, in both the NDGA- and RA-treated groups, Abeta deposition was significantly decreased in the brain (P < 0.05). In the RA-treated group, the level of Tris-buffered saline (TBS)-soluble Abeta monomers was increased (P < 0.01), whereas that of oligomers, as probed with the A11 antibody (A11-positive oligomers), was decreased (P < 0.001). However, in the NDGA-treated group, the abundance of A11-positive oligomers was increased (P < 0.05) without any change in the levels of TBS-soluble or TBS-insoluble Abeta. In the curcumin- and myricetin-treated groups, changes in the Abeta profile were similar to those in the RA-treated group, but Abeta plaque deposition was not significantly decreased. In the ferulic acid-treated group, there was no significant difference in the Abeta profile. These results showed that oral administration of phenolic compounds prevented the development of AD pathology by affecting different Abeta aggregation pathways in vivo. Clinical trials with these compounds are necessary to confirm the anti-AD effects and safety in humans.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cinnamates; Coumaric Acids; Curcumin; Depsides; Disease Models, Animal; Female; Flavonoids; Humans; Immunohistochemistry; Masoprocol; Mice; Mice, Transgenic; Phenols; Rosmarinic Acid; Signal Transduction

Curcuminoids, which are produced specifically by plants of the order Zingiberales, have long been used as food additives because of their aromatic, stimulant and colouring properties and as traditional Asian medicines because of their anti-tumour, antioxidant and hepatoprotective activities. Curcuminoids are therefore attractive targets for metabolic engineering. An artificial curcuminoid biosynthetic pathway, including reactions of phenylalanine ammonia-lyase (PAL) from the yeast Rhodotorula rubra, 4-coumarate : CoA ligase (4CL) from Lithospermum erythrorhizon and curcuminoid synthase (CUS) from rice (Oryza sativa), a type III polyketide synthase, was constructed in Escherichia coli for the production of curcuminoids. Cultivation of the recombinant E. coli cells in the presence of tyrosine or phenylalanine, or both, led to production of bisdemethoxycurcumin, dicinnamoylmethane and cinnamoyl-p-coumaroylmethane. Another E. coli system carrying 4CL and CUS genes was also used for high-yield production of curcuminoids from exogenously supplemented phenylpropanoid acids: p-coumaric acid, cinnamic acid and ferulic acid. The yields of curucminoids were up to approximately 100 mg l(-1). Furthermore, this system gave approximately 60 mg curcumin l(-1) from 10 g rice bran pitch, an industrial waste discharged during rice edible oil production, as a source of ferulic acid.

Topics: Coenzyme A Ligases; Coumaric Acids; Culture Media; Curcumin; DNA, Recombinant; Escherichia coli; Genes, Plant; Genetic Engineering; Genetic Enhancement; Industrial Microbiology; Lithospermum; Oryza; Phenylalanine; Phenylalanine Ammonia-Lyase; Rhodotorula; Tyrosine

Curcumin (diferuloylmethane) is a major yellow pigment and dietary component derived from Curcuma longa. It has potent anti-inflammatory, anticarcinogenic, antioxidant and chemoprotective activities among others. We studied the interactions of curcumin, a mixture of its decomposition products, and four of its individually identified decomposition products (vanillin, vanillic acid, ferulic aldehyde and ferulic acid) on five major human drug-metabolizing cytochrome P450s (CYPs). Curcumin inhibited CYP1A2 (IC(50), 40.0 microM), CYP3A4 (IC(50), 16.3 microM), CYP2D6 (IC(50), 50.3 microM), CYP2C9 (IC(50), 4.3 microM) and CYP2B6 (IC(50), 24.5 microM). Curcumin showed a competitive type of inhibition towards CYP1A2, CYP3A4 and CYP2B6, whereas a non-competitive type of inhibition was observed with respect to CYP2D6 and CYP2C9. The inhibitory activity towards CYP3A4, shown by curcumin may have implications for drug-drug interactions in the intestines, in case of high exposure of the intestines to curcumin upon oral administration. In spite of the significant inhibitory activities shown towards the major CYPs in vitro, it remains to be established, whether curcumin will cause significant drug-drug interactions in the liver, given the reported low systemic exposure of the liver to curcumin. The decomposition products of curcumin showed no significant inhibitory activities towards the CYPs investigated, and therefore, are not likely to cause drug-drug interactions at the level of CYPs.

Topics: Aryl Hydrocarbon Hydroxylases; Benzaldehydes; Coumaric Acids; Curcumin; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Stability; Enzyme Inhibitors; Humans; In Vitro Techniques; Kinetics; Oxidoreductases, N-Demethylating; Vanillic Acid

We demonstrate that two hydroxycinnamic acids, (E )-ferulic acid and (E )-p-coumaric acid, have the ability to protect against oxidative stress and genotoxicity in cultured mammalian cells. They also show the ability to reduce the activity of the xenobiotic metabolising enzyme, cytochrome P450 1A, and downregulate the expression of the cyclooxygenase-2 enzyme. At equitoxic doses, their activities are equal to or superior to that of the known anticarcinogen, curcumin. The hydroxycinnamic acids are both important components of plant cell walls in certain plant foods. It is known that the action of microbial hydroxycinnamoyl esterases can lead to the release of hydroxycinnamic acids from ester-linkages to cell wall polysaccharides into the human colon. Thus, providing they can reach effective levels in the colon, they could provide an important mechanism by which dietary fibres of food plants, such as spinach or cereal, protect against colon cancer.

Topics: Antimutagenic Agents; Antioxidants; Cell Division; Cell Line; Cell Nucleus; Cell Wall; Coumaric Acids; Curcumin; Cyclooxygenase 2; Cytochrome P-450 Enzyme System; Dietary Fiber; DNA Damage; Glutathione Transferase; HT29 Cells; Humans; Membrane Proteins; Plants, Edible; Propionates; Prostaglandin-Endoperoxide Synthases

We have developed an in vitro assay system for the evaluation of the inhibitory effects of phenolic antioxidants on myeloperoxidase (MPO) activity. The formation of dityrosine from the MPO/H2O2/L-tyrosine system was used as an indicator of the MPO activity. Because the buffer system used does not include chloride ion, this assay has the advantage of exclusion of direct reaction between an antioxidant and HOCl. In this assay, ferulic acid, gallic acid, and quercetin strongly inhibited the dityrosine formation, and curcumin and caffeic acid were also effective.

Topics: Antioxidants; Buffers; Chromatography, High Pressure Liquid; Coumaric Acids; Curcumin; Enzyme Inhibitors; Gallic Acid; Peroxidase; Phenols; Quercetin; Spectrometry, Fluorescence; Tyrosine

The ability of the differentiation inducing agent sodium butyrate (NaB) alone or combined with plant-derived phenolic compounds to produce growth inhibition in human erythroleukemic cells was investigated. As a single agent, curcumin produced a marked inhibition of proliferation indicated by its low concentration used. The effect of phenolics on the cell cycle could probably contribute to the augmented antiproliferative activity of NaB. The present data show that quercetin produced synergistic effect in terms of cell killing in association with NaB. Both curcumin and ferulic acid potentiated NaB-induced reduction of cell number. When NaB was added before exposure to graded doses of quercetin it did induce a greater inhibitory effect. The combination of NaB and quercetin seems less effective on S180 ascites tumour cells. As a single agent quercetin was found to be the most efficacious on S180 tumour model.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Butyrates; Cell Division; Cell Survival; Coumaric Acids; Curcumin; Drug Synergism; Flow Cytometry; Humans; K562 Cells; Mice; Neoplasm Transplantation; Quercetin; Sarcoma 180

The effects of the phenolic compounds butylated hydroxytoluene (BHT), sesamin (S), curcumin (CU), and ferulic acid (FA) on plasma, liver, and lung concentrations of alpha- and gamma-tocopherols (T), on plasma and liver cholesterol, and on the fatty acid composition of liver lipids were studied in male Sprague-Dawley rats. Test compounds were given to rats ad libitum for 4 wk at 4 g/kg diet, in a diet low but adequate in vitamin E (36 mg/kg of gamma-T and 25 mg/kg of alpha-T) and containing 2 g/kg of cholesterol. BHT significantly reduced feed intake (P < 0.05) and body weight and increased feed conversion ratio; S and BHT caused a significant enlargement of the liver (P < 0.001), whereas CU and FA did not affect any of these parameters. The amount of liver lipids was significantly lowered by BHT (P < 0.01) while the other substances reduced liver lipid concentrations but not significantly. Regarding effects on tocopherol levels, (i) feeding of BHT resulted in a significant elevation (P< 0.001) of alpha-T in plasma, liver, and lung, while gamma-T values remained unchanged; (ii) rats provided with the S diet had substantially higher gamma-T levels (P < 0.001) in plasma, liver, and lung, whereas alpha-T levels were not affected; (iii) administration of CU raised the concentration of alpha-T in the lung (P < 0.01) but did not affect the plasma or liver values of any of the tocopherols; and (iv) FA had no effect on the levels of either homolog in the plasma, liver, or lung. The level of an unknown substance in the liver was significantly reduced by dietary BHT (P < 0.001). BHT was the only compound that tended to increase total cholesterol (TC) in plasma, due to an elevation of cholesterol in the very low density lipoprotein + low density lipoprotein (VLDL + LDL) fraction. S and FA tended to lower plasma total and VLDL + LDL cholesterol concentrations, but the effect for CU was statistically significant (P < 0.05). FA increased plasma high density lipoprotein cholesterol while the other compounds reduced it numerically, but not significantly. BHT, CU, and S reduced cholesterol levels in the liver TC (P < 0.001) and percentages of TC in liver lipids (P < 0.05). With regard to the fatty acid composition of liver lipids, S increased the n-6/n-3 and the 18:3/20:5 polyunsaturated fatty acids (PUFA) ratios, and BHT lowered total monounsaturated fatty acids and increased total PUFA (n-6 + n-3). The effects of CU and FA on fatty acids were not highly significant. Thes

Topics: Animals; Butylated Hydroxytoluene; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Coumaric Acids; Curcumin; Diet; Dioxoles; Fatty Acids; Lignans; Liver; Lung; Male; Phenols; Rats; Rats, Sprague-Dawley; Vitamin E

Previous studies have shown that an antisense phosphorothioate oligonucleotide to the Rel A subunit of NF- kappa B, as well as vitamin E and related antioxidants, significantly enhanced the differentiation of HL-60 leukemia cells when combined with low levels of 1 alpha, 25-dihydroxyvitamin D3 (vitamin D3) an effect accompanied by a marked inhibition of the transcription factor, NF-kappa B. Curcumin, a potent inhibitor of tumor promotion and of tumor cell growth, has also been shown to have antioxidant properties and to inhibit NF-kappa b. to ascertain whether curcumin would also enhance the differentiation of HL-60 leukemia cells produced by vitamin D3, presumably by interfering with NF- kappa B activity, the effects of curcumin on the differentiation of HL-60 cells produced by low levels of vitamin D3 were measured. Curcumin used alone did not produce a significant degree of differentiation of HL-60 cells; however, this agent markedly enhanced the expression of differentiation markers induced by low levels of vitamin D3. Curcumin also increased the differentiation of HL-60 cells when combined with vitamin D analogues (1,25-dihydroxy-16-ene-23-yne vitamin D3 and 1,25-dihydroxy-16-ene vitamin D3) that share the receptor binding properties of vitamin D3, whereas as vitamin D analogue (1,25-dihydroxy-16,23-diene vitamin D3) that caused significant calcium mobilization, but was less effective than vitamin d3 in binding the receptor, did not cause the differentiation of HL-60 cells in the presence or absence of curcumin. Several dietary compounds structurally related to curcumin (i.e., caffeic acid, chlorogenic acid, and ferulic acid) did not increase the differentiation of HL-60 cells produced by vitamin D3. However, the more lipophilic ethyl of ferulic and caffeic acid were capable of inducing the differentiation of HL-60 cells, as well as enhancing the maturation produced by vitamin D3. Curcumin caused a marked reduction in NF-kappa B activity in nuclear extracts of HL-60 cells exposed to this agent in the presence or absence of vitamin D3, supporting the possibility that NF-kappa B may be a factor in the regulation of the state of differentiation of leukemia cells.

Topics: Caffeic Acids; Calcitriol; Cell Differentiation; Cell Division; Chlorogenic Acid; Coumaric Acids; Curcumin; DNA-Binding Proteins; Drug Synergism; HL-60 Cells; Humans; Leukemia, Myeloid; Macrophage-1 Antigen; NF-kappa B; Oxidation-Reduction

The interaction between coffee (100 mg freeze-dried home brew/kg body weight) and dietary constituents was assessed for anti-genotoxic effects against cyclophosphamide, N-methyl-N-nitro-N- nitrosoguanidine (MNNG), N-nitroso-N-ethylurea, mitomycin C and urethane (URE) in the mouse bone marrow micronucleus test. Combinations of dietary constituents consisting of (1) chlorogenic acid, caffeic acid, ellagic acid and ferulic acid, (2) beta-carotene, curcumin and alpha-tocopherol, (3) chlorogenic acid, curcumin, alpha-tocopherol, anethole and eugenol, and (4) beta-carotene, curcumin, ellagic acid and chlorogenic acid were used in this study. Before the genotoxin was injected i.p., identical groups of mice were orally administered either vehicle control, coffee, dietary constituents, or coffee plus dietary constituents. Co-administration of coffee with the dietary constituents enhanced the anti-genotoxic effect compared with that of either coffee or the dietary constituents alone. Two-factor analysis of variance of the data suggests that there is a significant synergistic interaction between coffee and the dietary constituents for anti-genotoxic effects against MNNG (combination 1 and 2) and URE (combination 4).

Topics: Allylbenzene Derivatives; Animals; Anisoles; Antimutagenic Agents; Antioxidants; beta Carotene; Bone Marrow; Caffeic Acids; Carotenoids; Chlorogenic Acid; Coffee; Coumaric Acids; Curcumin; Diet; DNA Damage; Ellagic Acid; Eugenol; Flavoring Agents; Food-Drug Interactions; Male; Mice; Micronucleus Tests; Mutagens; Vitamin E

Topical application of curcumin, the yellow pigment in turmeric and curry, strongly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase activity, DNA synthesis, and tumor promotion in mouse skin (Huang et al., Cancer Res., 48: 5941-5946, 1988). Chlorogenic acid, caffeic acid, and ferulic acid (structurally related dietary compounds) were considerably less active. In the present study, topical application of curcumin markedly inhibited TPA- and arachidonic acid-induced epidermal inflammation (ear edema) in mice, but chlorogenic acid, caffeic acid, and ferulic acid were only weakly active or inactive. The in vitro addition of 3, 10, 30, or 100 microM curcumin to cytosol from homogenates of mouse epidermis inhibited the metabolism of arachidonic acid to 5-hydroxyeicosatetraenoic acid (5-HETE) by 40, 60, 66, or 83%, respectively, and the metabolism of arachidonic acid to 8-HETE was inhibited by 40, 51, 77, or 85%, respectively [IC50 (concentration needed for 50% inhibition) = 5-10 microM]. Chlorogenic acid, caffeic acid, or ferulic acid (100 microM) inhibited the metabolism of arachidonic acid to 5-HETE by 36, 10, or 16%, respectively, and these hydroxylated cinnamic acid derivatives inhibited the metabolism of arachidonic acid to 8-HETE by 37, 20, or 10%, respectively (IC50 greater than 100 microM). The metabolism of arachidonic acid to prostaglandin E2, prostaglandin F2 alpha, and prostaglandin D2 by epidermal microsomes was inhibited approximately 50% by the in vitro addition of 5-10 microM curcumin. Chlorogenic acid, caffeic acid, and ferulic acid (100 microM) were inactive. In vitro rat brain protein kinase C activity was not affected by 50-200 microM curcumin, chlorogenic acid, caffeic acid, or ferulic acid. The inhibitory effects of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on TPA-induced tumor promotion in mouse epidermis parallel their inhibitory effects on TPA-induced epidermal inflammation and epidermal lipoxygenase and cyclooxygenase activities.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Caffeic Acids; Chlorogenic Acid; Coumaric Acids; Curcumin; Dermatitis, Contact; Female; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Lipoxygenase; Mice; Peroxidases; Prostaglandin-Endoperoxide Synthases; Tetradecanoylphorbol Acetate

The effects of topically applied curcumin, chlorogenic acid, caffeic acid, and ferulic acid on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal ornithine decarboxylase activity, epidermal DNA synthesis, and the promotion of skin tumors were evaluated in female CD-1 mice. Topical application of 0.5, 1, 3, or 10 mumol of curcumin inhibited by 31, 46, 84, or 98%, respectively, the induction of epidermal ornithine decarboxylase activity by 5 nmol of TPA. In an additional study, the topical application of 10 mumol of curcumin, chlorogenic acid, caffeic acid, or ferulic acid inhibited by 91, 25, 42, or 46%, respectively, the induction of ornithine decarboxylase activity by 5 nmol of TPA. The topical application of 10 mumol of curcumin together with 2 or 5 nmol of TPA inhibited the TPA-dependent stimulation of the incorporation of [3H]-thymidine into epidermal DNA by 49 or 29%, respectively, whereas lower doses of curcumin had little or no effect. Chlorogenic acid, caffeic acid, and ferulic acid were less effective than curcumin as inhibitors of the TPA-dependent stimulation of DNA synthesis. Topical application of 1, 3, or 10 mumol of curcumin together with 5 nmol of TPA twice weekly for 20 weeks to mice previously initiated with 7,12-dimethylbenz[a]anthracene inhibited the number of TPA-induced tumors per mouse by 39, 77, or 98%, respectively. Similar treatment of mice with 10 mumol of chlorogenic acid, caffeic acid, or ferulic acid together with 5 nmol of TPA inhibited the number of TPA-induced tumors per mouse by 60, 28, or 35%, respectively, and higher doses of the phenolic acids caused a more pronounced inhibition of tumor promotion. The possibility that curcumin could inhibit the action of arachidonic acid was evaluated by studying the effect of curcumin on arachidonic acid-induced edema of mouse ears. The topical application of 3 or 10 mumol of curcumin 30 min before the application of 1 mumol of arachidonic acid inhibited arachidonic acid-induced edema by 33 or 80%, respectively.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Arachidonic Acid; Arachidonic Acids; Caffeic Acids; Catechols; Chlorogenic Acid; Cinnamates; Coumaric Acids; Curcumin; DNA; Edema; Female; Mice; Ornithine Decarboxylase; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate

The polycyclic aromatic hydrocarbon, benzo[a]pyrene, induced dose-related nuclear damage (micronuclei, pyknotic nuclei and karyorrhectic bodies) in colonic epithelial cells of C57BL/6J mice within 24 hr when administered intrarectally in single doses of 0-200 mg/kg body weight. This damage was reduced when mice ingested the plant phenols, caffeic, ferulic and ellagic acids, and quercetin at levels of 4% or BHA at 2% (w/w) in the diet for 1 wk prior to the benzo[a]pyrene challenge (100 mg/kg body weight). Benzo[a]pyrene-induced nuclear damage was not significantly inhibited by 4% curcumin under similar conditions. The inhibition of nuclear damage is consistent with reported antimutagenic effects for these agents in vitro and in longer term animal studies. The procedure described here may provide a rapid in vivo method for assessing the potential of natural products to inhibit the carcinogenic process.

Topics: Animals; Benzo(a)pyrene; Butylated Hydroxyanisole; Caffeic Acids; Cell Nucleus; Colon; Coumaric Acids; Curcumin; Dose-Response Relationship, Drug; Ellagic Acid; Epithelial Cells; Epithelium; Female; Mice; Mice, Inbred C57BL; Phenols; Quercetin

Topics: 1,2-Dimethylhydrazine; Acetylcysteine; Animals; Carcinogens; Cell Nucleus; Colon; Coumaric Acids; Curcumin; Dimethylhydrazines; Ellagic Acid; Epithelium; Female; Glutathione; Methylhydrazines; Mice; Mice, Inbred C57BL; Mutation; Quercetin