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Sample records for caffeic acid o-methyltransferase

  1. Functional characterization of cinnamyl alcohol dehydrogenase and caffeic acid O-methyltransferase in Brachypodium distachyon.

    Science.gov (United States)

    Lignin is a significant recalcitrant in the conversion of plant biomass to bioethanol. Cinnamyl alcohol dehydrogenase (CAD) and caffeic acid O-methyltransferase (COMT) catalyze key steps in the pathway of lignin monomer biosynthesis. Brown midrib mutants in Zea mays and Sorghum bicolor with impaired...

  2. Functional characterization of cinnamyl alcohol dehydrogenase and caffeic acid O-methyltransferase in Brachypodium distachyon

    Science.gov (United States)

    2013-01-01

    Background Lignin is a significant barrier in the conversion of plant biomass to bioethanol. Cinnamyl alcohol dehydrogenase (CAD) and caffeic acid O-methyltransferase (COMT) catalyze key steps in the pathway of lignin monomer biosynthesis. Brown midrib mutants in Zea mays and Sorghum bicolor with impaired CAD or COMT activity have attracted considerable agronomic interest for their altered lignin composition and improved digestibility. Here, we identified and functionally characterized candidate genes encoding CAD and COMT enzymes in the grass model species Brachypodium distachyon with the aim of improving crops for efficient biofuel production. Results We developed transgenic plants overexpressing artificial microRNA designed to silence BdCAD1 or BdCOMT4. Both transgenes caused altered flowering time and increased stem count and weight. Downregulation of BdCAD1 caused a leaf brown midrib phenotype, the first time this phenotype has been observed in a C3 plant. While acetyl bromide soluble lignin measurements were equivalent in BdCAD1 downregulated and control plants, histochemical staining and thioacidolysis indicated a decrease in lignin syringyl units and reduced syringyl/guaiacyl ratio in the transgenic plants. BdCOMT4 downregulated plants exhibited a reduction in total lignin content and decreased Maule staining of syringyl units in stem. Ethanol yield by microbial fermentation was enhanced in amiR-cad1-8 plants. Conclusion These results have elucidated two key genes in the lignin biosynthetic pathway in B. distachyon that, when perturbed, may result in greater stem biomass yield and bioconversion efficiency. PMID:23902793

  3. Down-regulation of the caffeic acid O-methyltransferase gene in switchgrass reveals a novel monolignol analog

    Directory of Open Access Journals (Sweden)

    Tschaplinski Timothy J

    2012-09-01

    Full Text Available Abstract Background Down-regulation of the caffeic acid 3-O-methyltransferase EC 2.1.1.68 (COMT gene in the lignin biosynthetic pathway of switchgrass (Panicum virgatum resulted in cell walls of transgenic plants releasing more constituent sugars after pretreatment by dilute acid and treatment with glycosyl hydrolases from an added enzyme preparation and from Clostridium thermocellum. Fermentation of both wild-type and transgenic switchgrass after milder hot water pretreatment with no water washing showed that only the transgenic switchgrass inhibited C. thermocellum. Gas chromatography–mass spectrometry (GCMS-based metabolomics were undertaken on cell wall aqueous extracts to determine the nature of the microbial inhibitors. Results GCMS confirmed the increased concentration of a number of phenolic acids and aldehydes that are known inhibitors of microbial fermentation. Metabolomic analyses of the transgenic biomass additionally revealed the presence of a novel monolignol-like metabolite, identified as trans-3, 4-dimethoxy-5-hydroxycinnamyl alcohol (iso-sinapyl alcohol in both non-pretreated, as well as hot water pretreated samples. iso-Sinapyl alcohol and its glucoside were subsequently generated by organic synthesis and the identity of natural and synthetic materials were confirmed by mass spectrometric and NMR analyses. The additional novel presence of iso-sinapic acid, iso-sinapyl aldehyde, and iso-syringin suggest the increased activity of a para-methyltransferase, concomitant with the reduced COMT activity, a strict meta-methyltransferase. Quantum chemical calculations were used to predict the most likely homodimeric lignans generated from dehydration reactions, but these products were not evident in plant samples. Conclusions Down-regulation of COMT activity in switchgrass resulted in the accumulation of previously undetected metabolites resembling sinapyl alcohol and its related metabolites, but that are derived from para

  4. Activity of chalcones derived from 2,4,5-trimethoxybenzaldehyde against Meloidogyne exigua and in silico interaction of one chalcone with a putative caffeic acid 3-O-methyltransferase from Meloidogyne incognita.

    Science.gov (United States)

    Nunes, Alexandro Silva; Campos, Vicente Paulo; Mascarello, Alessandra; Stumpf, Taisa Regina; Chiaradia-Delatorre, Louise Domenghini; Machado, Alan Rodrigues Teixeira; Santos Júnior, Helvécio Martins; Yunes, Rosendo Augusto; Nunes, Ricardo José; Oliveira, Denilson Ferreira

    2013-12-01

    Meloidogyne exigua is a parasitic nematode of plants that causes great losses to coffee farmers. In an effort to develop parasitic controls, 154 chalcones were synthesized and screened for activity against this nematode. The best results were obtained with (2E)-1-(4'-nitrophenyl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one (6) with a 50% lethal concentration (LC50) of 171 μg/ml against M. exigua second-stage juveniles, in comparison to the commercially-available nematicide carbofuran which had an LC50 of 260 μg/ml under the same conditions. When coffee plants were used, 6 reduced the nematode population to ~50% of that observed in control plants. To investigate the mechanism of action of 6, an in silico study was carried out, which indicated that 6 may act against M. exigua through inhibition of a putative caffeic acid 3-O-methyltransferase homodimer, the amino acid sequence of which was determined by examining the genome of Meloidogyne incognita. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Butylated caffeic acid: An efficient novel antioxidant

    Directory of Open Access Journals (Sweden)

    G. Shi

    2017-09-01

    Full Text Available A novel antioxidant, butylated caffeic acid (BCA was rationally designed by adding a tert-butyl group to caffeic acid, which was synthesized at a high yield (36.2% from 2-methoxy-4-methylphenol by a four-step reaction including Friedel-Crafts alkylation, bromine oxidation, ether bond hydrolysis and Knoevenagel condensation. Its antioxidant capacity was much stronger than common commercial antioxidant tert-butyl hydroquinone (TBHQ and its mother compound, caffeic acid, in both rancimat and deep frying tests. When investigated via the DPPH method, the antioxidant capacity of BCA was almost equal to TBHQ, but lower than caffeic acid. BCA could be a potentially strong antioxidant, especially for food processing at high temperatures such as deep frying and baking.

  6. Chlorogenic acid and caffeic acid are absorbed in humans

    NARCIS (Netherlands)

    Olthof, M.R.; Hollman, P.C.H.; Katan, M.B.

    2001-01-01

    Chlorogenic acid, an ester of caffeic acid and quinic acid, is a major phenolic compound in coffee; daily intake in coffee drinkers is 0.5-1 g. Chlorogenic acid and caffeic acid are antioxidants in vitro and might therefore contribute to the prevention of cardiovascular disease. However, data on the

  7. Salvianolic acid B as a substrate and weak catechol-O-methyltransferase inhibitor in rats.

    Science.gov (United States)

    Qi, Qu; Cao, Lijuan; Li, Feiyan; Wang, Hong; Liu, Huiying; Hao, Haiping; Hao, Kun

    2015-01-01

    1. The aim of this study was to investigate the biotransformation of salvianolic acid B (SAB) by catechol-O-methyltransferase (COMT) and its interaction with levodopa (l-DOPA) methylation in rats. 2. The enzyme kinetics of SAB were studied after incubation with rat COMT. The in vivo SAB and 3-monomethyl-SAB (3-MMS) levels were determined after a single dose of tolcapone with or without SAB administration. For l-DOPA, the effect of SAB inhibition on l-DOPA methylation was studied in vitro. The l-DOPA and 3-O-methyldopa (3-OMD) levels were determined after single and multiple doses of SAB with or without l-DOPA administration. 3. After incubation, we found that SAB was methylated mainly by rat liver and kidney COMT. Tolcapone strongly inhibited the formation of 3-MMS in vitro and in vivo, without any change in the plasma concentration of SAB. Moreover, tolcapone significantly increased the cumulative bile excretion of SAB from 3% to 40% in the rat. SAB inhibited the methylation of l-DOPA with an IC50 value of 2.08 μM in vitro. In vivo, a single intravenous dose of SAB decreased the plasma concentration of 3-OMD, with no obvious effect on the pharmacokinetics of l-DOPA. Multiple doses of SAB given to rats also decreased the plasma concentration of 3-OMD, while SAB increased the plasma concentration of l-DOPA.

  8. Toxicity and biodegradability of caffeic acid in anaerobic digesting ...

    African Journals Online (AJOL)

    ... to treat waste caffeic acid by anaerobic digestion and adsorption of its derivates, in order to reduce the contribution to global warming and to protect the environment. Keywords: anaerobes, anaerobic digestion, biogas, biomass, caffeic acid, graphene, inhibition, polyphenols, renewable energy, toxicity, wastewater ...

  9. Pharmacokinetics of Caffeic Acid from Methanol Seed Extract of ...

    African Journals Online (AJOL)

    Purpose: To describe caffeic acid-based pharmacokinetics of methanol extract of seed of Syzygium cumini L. in rats. Methods: A dose of the extract (500 mg, equivalent to 37.135 mg caffeic acid) was administered orally to 6 male Wister rats, weighing 200 ± 10 g. Blood samples (0.5 mL), collected from the tail vein at 0, 15,.

  10. Toxicity and biodegradability of caffeic acid in anaerobic digesting ...

    African Journals Online (AJOL)

    ABSTRACT. Caffeic acid in waste comes from a variety of industries, and its disposal is likely to increase due to emerging processes such as graphene production and use in healthcare products. The current sustainable option to treat waste caffeic acid and prevent its natural transformation in soil to greenhouse gases, ...

  11. Inhibition of multiplication of herpes simplex virus by caffeic acid.

    Science.gov (United States)

    Ikeda, Keiko; Tsujimoto, Kazuko; Uozaki, Misao; Nishide, Mitsunori; Suzuki, Yukiko; Koyama, A Hajime; Yamasaki, Hisashi

    2011-10-01

    Hot water extracts of coffee grinds and commercial instant coffee solutions have been shown to exhibit marked antiviral and virucidal activities against herpes simplex virus type 1 (HSV-1). Specifically, it has been shown that caffeine and N-methyl-pyridinium formate inhibit the multiplication of HSV-1 in HEp-2 cells. The present study examined the virological properties and the antiviral activity of caffeic acid against HSV-1. Caffeic acid inhibited the multiplication of HSV-1 in vitro, while chlorogenic acid, a caffeic acid ester with quinic acid, did not. These reagents did not have a direct virucidal effect. The one-step growth curve of HSV-1 showed that the addition of caffeic acid at 8 h post infection (h p.i.) did not significantly affect the formation of progeny viruses. An analysis of the influence of the time of caffeic acid addition, revealed that addition at an early time post infection remarkably inhibited the formation of progeny infectious virus in the infected cells, but its addition after 6 h p.i. (i.e., the time of the completion of viral genome replication) did not efficiently inhibit this process. These results indicate that caffeic acid inhibits HSV-1 multiplication mainly before the completion of viral DNA replication, but not thereafter. Although caffeic acid showed some cytotoxicity by prolonged incubation, the observed antiviral activity is likely not the secondary result of the cytotoxic effect of the reagent, because the inhibition of the virus multiplication was observed before appearance of the notable cytotoxicity.

  12. Pharmacokinetics of Caffeic Acid from Methanol Seed Extract of ...

    African Journals Online (AJOL)

    Purpose: To describe caffeic acid-based pharmacokinetics of methanol extract of seed of Syzygium cumini L. in rats. Methods: A dose of the extract (500 mg, equivalent to 37.135 mg caffeic acid) was administered orally to 6 male Wister rats, weighing 200 ± 10 g. Blood samples (0.5 mL), collected from the tail vein at 0, 15, ...

  13. Novel Caffeic Acid Nanocarrier: Production, Characterization, and Release Modeling

    Directory of Open Access Journals (Sweden)

    Milad Fathi

    2013-01-01

    Full Text Available This paper deals with the development of novel nanocarriers using layer by layer carbohydrate coating of caffeic acid loaded solid lipid nanoparticles (SLNs to improve stability and colon delivery of the poorly water-soluble caffeic acid. Three biopolymers (chitosan, alginate, and pectin in different concentrations (0.1, 0.25, and 0.5% were electrostatically coated over the SLN surface. The size and zeta potential of produced nanocarriers were measured using photon correlation spectroscopy. Mathematical models (i.e., zero-order, first-order, Higuchi, Ritger-Peppas, reciprocal powered time, Weibull, and quadratic models were used to describe the release and kinetic modeling in gastrointestinal solution (GIS. Also, antioxidant activity of caffeic acid during the release in GIS was investigated using DPPH and reducing activity methods. The prepared treatments coated by alginate-chitosan as well as pectin-chitosan coated SLN at the concentration of 0.1% showed nanosized bead; the latter efficiently retarded the release of caffeic acid in gastric media up to 2.5 times higher than that of SLN. Zeta potential values of coated samples were found to significantly increase in comparison to SLN indicating the higher stability of produced nanocarriers. Antioxidant activity of caffeic acid after gastric release did not result in the same trend as observed for caffeic acid release from different treatments; however, in line with less caffeic acid release in the intestine solution by the effect of coating, lower antioxidant activity was determined at the end stage of the experiment.

  14. Caffeic Acid Derivatives in Dried Lamiaceae and Echinacea purpurea Products

    Science.gov (United States)

    The concentrations of caffeic acid derivatives within Lamiaceae and Echinacea (herb, spice, tea, and dietary supplement forms) readily available in the U.S. marketplace (n=72) were determined. After the first identification of chicoric acid in Ocimum basilicum (basil), the extent to which chicoric a...

  15. Caffeic acid ethanolamide prevents cardiac dysfunction through sirtuin dependent cardiac bioenergetics preservation

    National Research Council Canada - National Science Library

    Lee, Shih-Yi; Ku, Hui-Chun; Kuo, Yueh-Hsiung; Yang, Kai-Chien; Tu, Ping-Chen; Chiu, His-Lin; Su, Ming-Jai

    2015-01-01

    .... Caffeic acid ethanolamide (CAEA), a synthesized derivative from caffeic acid that exerted antioxidative properties, was thus applied in this study to explore its effects on the pathogenesis of heart failure...

  16. Caffeic Acid Induces Apoptosis in Human Cervical Cancer Cells Through the Mitochondrial Pathway

    Directory of Open Access Journals (Sweden)

    Wei-Chun Chang

    2010-12-01

    Conclusion: Caffeic acid induces apoptosis by inhibiting Bcl-2 activity, leading to release of cytochrome c and subsequent activation of caspase-3, indicating that caffeic acid induces apoptosis via the mitochondrial apoptotic pathway. This also suggests that caffeic acid has a strong anti-tumor effect and may be a promising chemopreventive or chemotherapeutic agent.

  17. Separation and purification of the antioxidant compounds, caffeic acid phenethyl ester and caffeic acid from mushrooms by molecularly imprinted polymer.

    Science.gov (United States)

    Li, Ning; Ng, Tzi Bun; Wong, Jack Ho; Qiao, Ji Xuan; Zhang, Ye Ni; Zhou, Rong; Chen, Rong Rong; Liu, Fang

    2013-08-15

    Caffeic acid phenethyl ester (CAPE) and caffeic acid (CA), two naturally occurring phenolic antioxidants, have been reported to have a diversity of biological activities. In this investigation, a novel approach to separate and enrich CAPE and CA from 25 species of mushrooms using molecularly imprinted polymers (MIPs) as the sorbent material is reported. The MIPs were synthesized using CAPE as the template, and its adsorption behavior was investigated in detail. In comparison with C18-solid phase extraction (SPE), MIP-SPE displayed high selectivity and good affinity for CAPE and CA. The antioxidant potential of the mushroom extracts, before and after preconcentration using MIPs, was assayed by inhibition of erythrocyte hemolysis and lipid peroxidation. Application of MIPs with a high affinity toward CAPE and CA provides a novel method for obtaining active compounds from natural products. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Induction of HDMBOA-Glc accumulation and DIMBOA-Glc 4-O-methyltransferase by jasmonic acid in poaceous plants.

    Science.gov (United States)

    Oikawa, Akira; Ishihara, Atsushi; Iwamura, Hajime

    2002-10-01

    Induction of the accumulation of 2-(2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one)-beta-D-glucopyranose (HDMBOA-Glc) by jasmonic acid (JA) was investigated in wheat, Job's tears (Coix lacryma-jobi), and rye. An increase in HDMBOA-Glc and a corresponding decrease in 2-(2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one)-beta-D-glucopyranose (DIMBOA-Glc) were found in wheat and Job's tears, whereas no such changes were observed in rye. The activity of S-adenosyl-L-methionine:DIMBOA-Glc 4-O-methyltransferase which catalyzes the conversion of DIMBOA-Glc to HDMBOA-Glc was detected in wheat leaves treated with 50 micro M JA. The activity started to increase 3 h after treatment with JA, reached a maximum after 9 h, and then decreased gradually. This mode of induction was well correlated with that for the accumulation of HDMBOA-Glc, indicating the induction of enzyme activity was responsible for the accumulation of HDMBOA-Glc. The enzyme was purified from JA-treated wheat leaves by three steps of chromatography, resulting in 95-fold purification. The enzyme showed strict substrate specificity for DIMBOA-Glc with a K(m) value of 0.12 mM. DIBOA-Glc was also accepted as substrate, but the K(m) value was 10 times larger than that for DIMBOA-Glc. The aglycones, DIMBOA and DIBOA, were not methylated by the enzyme. The K(m) value for S-adenosyl-L-methionine was 0.06 mM. The optimum pH and temperature were 7.5 and 35 degrees C, respectively. The activity was slightly enhanced by the presence of 1 mM EDTA, while heavy metal ions at 5 mM completely inhibited the activity.

  19. Independent Recruitment of an O-Methyltransferase for Syringyl Lignin Biosynthesis in Selaginella moellendorffii[W

    Science.gov (United States)

    Weng, Jing-Ke; Akiyama, Takuya; Ralph, John; Chapple, Clint

    2011-01-01

    Syringyl lignin, an important component of the secondary cell wall, has traditionally been considered to be a hallmark of angiosperms because ferns and gymnosperms in general lack lignin of this type. Interestingly, syringyl lignin was also detected in Selaginella, a genus that represents an extant lineage of the most basal of the vascular plants, the lycophytes. In angiosperms, syringyl lignin biosynthesis requires the activity of ferulate 5-hydroxylase (F5H), a cytochrome P450-dependent monooxygenase, and caffeic acid/5-hydroxyferulic acid O-methyltransferase (COMT). Together, these two enzymes divert metabolic flux from the biosynthesis of guaiacyl lignin, a lignin type common to all vascular plants, toward syringyl lignin. Selaginella has independently evolved an alternative lignin biosynthetic pathway in which syringyl subunits are directly derived from the precursors of p-hydroxyphenyl lignin, through the action of a dual specificity phenylpropanoid meta-hydroxylase, Sm F5H. Here, we report the characterization of an O-methyltransferase from Selaginella moellendorffii, COMT, the coding sequence of which is clustered together with F5H at the adjacent genomic locus. COMT is a bifunctional phenylpropanoid O-methyltransferase that can methylate phenylpropanoid meta-hydroxyls at both the 3- and 5-position and function in concert with F5H in syringyl lignin biosynthesis in S. moellendorffii. Phylogenetic analysis reveals that Sm COMT, like F5H, evolved independently from its angiosperm counterparts. PMID:21742988

  20. Synthesis, Preliminary Bioevaluation and Computational Analysis of Caffeic Acid Analogues

    Directory of Open Access Journals (Sweden)

    Zhiqian Liu

    2014-05-01

    Full Text Available A series of caffeic acid amides were designed, synthesized and evaluated for anti-inflammatory activity. Most of them exhibited promising anti-inflammatory activity against nitric oxide (NO generation in murine macrophage RAW264.7 cells. A 3D pharmacophore model was created based on the biological results for further structural optimization. Moreover, predication of the potential targets was also carried out by the PharmMapper server. These amide analogues represent a promising class of anti-inflammatory scaffold for further exploration and target identification.

  1. Synthesis and Functional Characterization of Caffeic Acid Glucoside Using Leuconostoc mesenteroides Dextransucrase.

    Science.gov (United States)

    Nam, Seung-Hee; Kim, Young-Min; Walsh, Marie K; Wee, Young-Jung; Yang, Kwang-Yeol; Ko, Jin-A; Han, Songhee; Thanh Hanh Nguyen, Thi; Kim, Ji Young; Kim, Doman

    2017-04-05

    Caffeic acid was modified via transglucosylation using sucrose and dextransucrase from Leuconostoc mesenteroides B-512FMCM. Following enzymatic modification, a caffeic acid glucoside was isolated by butanol separation, silica gel chromatography, and preparative HPLC. The synthesized caffeic acid glucoside had a molecular mass-to-charge ratio of 365 m/z, and its structure was identified as caffeic acid-3-O-α-d-glucopyranoside. The production of this caffeic acid-3-O-α-d-glucopyranoside at a concentration of 153 mM was optimized using 325 mM caffeic acid, 355 mM sucrose, and 650 mU mL-1 dextransucrase in the synthesis reaction. In comparison with the caffeic acid, the caffeic acid-3-O-α-d-glucopyranoside displayed 3-fold higher water solubility, 1.66-fold higher antilipid peroxidation effect, 15% stronger inhibition of colon cancer cell growth, and 11.5-fold higher browning resistance. These results indicate that this caffeic acid-3-O-α-d-glucopyranoside may be a suitable functional component of food and pharmaceutical products.

  2. Antioxidative effect of lipophilized caffeic acid in fish oil enriched mayonnaise and milk

    DEFF Research Database (Denmark)

    Alemán, Mercedes; Bou, Ricard; Guardiola, Francesc

    2015-01-01

    The antioxidative effect of lipophilized caffeic acid was assessed in two different fish oil enriched food products: mayonnaise and milk. In both emulsion systems, caffeic acid esterified with fatty alcohols of different chain lengths (C1–C20) were better antioxidants than the original phenolic c...

  3. Caffeic Acid Inhibits NFkappaB Activation of Osteoclastogenesis Signaling Pathway

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    Ferry Sandra

    2011-12-01

    Full Text Available BACKGROUND: Caffeic acid (3,4-dihydroxycinnamic acids is involved in various green plants. Based on our previous report, a major component of sweet potato extracts, possibly caffeic acid, was shown as a promising inhibitor of osteoclastogenesis. However, the effect of caffeic acid in inhibiting osteoclastogenesis needs to be confirmed. The underlying mechanism needs to be disclosed as well. METHODS: Caffeic acid in various concentrations was added to in vitro osteoclastogenesis of receptor activator nuclear factor kB ligand (RANKL-tumor necrosis factor alpha (TNF-α-macrophage colony stimulating factor (M-CSF-induced bone marrow-derived monocyte/macrophage precursor cells (BMMs and RANKL-TNF-α-induced RAW264 cells D-Clone (RAW-D cells. Tartrate resistant acid phosphatase (TRAP staining was performed and TRAP-positive polynucleated cells (PNCs were counted. For apoptosis analysis, caffeic acid-treated BMMs, RAW-D cells and osteoclast-like PNCs were subjected to Sub-G1 Apoptosis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL assays. To measure NFkB activity, RAW-D cells were transfected with pNFkB-TA-Luc and subjected to Dual Luciferase Reporter Assay System. RESULTS: Caffeic acid inhibited osteoclastogenesis of RANKL-TNF-α-M-CSF-induced BMMs as well as RANKL-TNF-α-induced RAW-D cells in a dose dependent manner. Caffeic acid did not induce apoptosis in BMMs, RAW-D cells and osteoclast-like PNCs. RANKL-TNF-α-induced NFkB activity in RAW-D was diminished by caffeic acid in a dose dependent manner. Significant NFkB activity inhibtion was observed starting from 1µg/mL caffeic acid. CONCLUSIONS: Caffeic acid could be a potent osteoclastogenesis inhibitor through inhibition of NFkB activity. Our present study should be further followed up to disclose caffeic acid's possible overlying signaling pathways in inhibiting osteoclastogenesis. KEYWORDS: caffeic acid, osteoclastogenesis, NFkB, RANKL, TNF-α.

  4. Modulatory effect of caffeic acid on cholinesterases inhibitory properties of donepezil.

    Science.gov (United States)

    Agunloye, Odunayo Michael; Oboh, Ganiyu

    2017-09-22

    Background Donepezil hydrochloride commonly used in the management of Alzheimer's disease (AD), exhibiting its inhibitory effects on acetylcholinesterase and butyrylcholinesterase activity thereby enhance cognitive function. Caffeic acid member of hydroxycinnamic acid is widely present in human diet. This study aims to investigate influence of caffeic acid on acetylcholinesterase and butyrylcholinesterase inhibitory properties of donepezil (in vitro). Methods 5 mg of donepezil was dissolved in 50 mL distilled water while 10 mg of caffeic acid was dissolved in 100 mL distilled water. Therefore, mixtures of samples were prepared as follows: A2=donepezil 0.075 mg/mL+caffeic acid 0.025 mg/mL; A3=donepezil 0.050 mg/mL+caffeic acid 0.050 mg/mL; A4=donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL. All samples were kept in the refrigerator at 4 °C for subsequent analysis. Results The result showed that all the combinations show an inhibitory effect on acetylcholinesterase and butyrylcholinesterase activity in vitro, with the combination A4=donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL had significant (pdonepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL and A3=donepezil 0.050 mg/mL+caffeic acid 0.050 mg/mL had highest inhibitory effect against FeSO4 and SNP induced lipid peroxidation in rat brain homogenate in vitro respectively. Moreover, all the samples exhibit antioxidant properties as typified by their ability to chelate iron (II) ion (Fe2+), hydroxyl radical (OH٭) radical scavenging ability and ferric reducing property (FRAP). Conclusions Therefore, the combination of caffeic acid with donepezil enhances the antioxidant properties of donepezil. The combination of caffeic acid with donepezil could be a therapeutic aid in the management of AD, possibly with fewer side effects of donepezil. Nevertheless, the combination donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL acid look promising.

  5. Activity of caffeic acid in different fish lipid matrices: A review

    DEFF Research Database (Denmark)

    Medina, Isabel; Undeland, Ingrid; Larsson, Karin

    2012-01-01

    was however clearly dependent on the lipid to antioxidant ratio. In these systems, an important redox cycle between caffeic acid and the endogenous reducing agents ascorbic acid and tocopherol were further thought to play an important role for the protective effects. The effect of caffeic acid was also highly......Caffeic acid, a hydroxycinnamic acid common in different vegetable sources, has been employed as a natural antioxidant for inhibiting oxidation of fish lipids present in different food matrices. The aim of this review is to discuss the mechanisms involved in the antioxidative and prooxidative...... effects of caffeic acid found in different model systems containing fish lipids. These model systems include bulk fish oils, liposomes from cod roe phospholipids, fish oil emulsions, washed cod mince, regular horse mackerel mince and a fish oil fortified fitness bar. The data reported show...

  6. Formation of volatile chemicals from thermal degradation of less volatile coffee components: quinic acid, caffeic acid, and chlorogenic acid.

    Science.gov (United States)

    Moon, Joon-Kwan; Shibamoto, Takayuki

    2010-05-12

    The less volatile constituents of coffee beans (quinic acid, caffeic acid, and chlorogenic acid) were roasted under a stream of nitrogen, air, or helium. The volatile degradation compounds formed were analyzed by gas chromatography and gas chromatography-mass spectrometry. Caffeic acid produced the greatest amount of total volatiles. Quinic acid and chlorogenic acid produced a greater number of volatiles under the nitrogen stream than under the air stream. These results suggest that the presence of oxygen does not play an important role in the formation of volatile compounds by the heat degradation of these chemicals. 2,5-Dimethylfuran formed in relatively large amounts (59.8-2231.0 microg/g) in the samples obtained from quinic acid and chlorogenic acid but was not found in the samples from caffeic acid. Furfuryl alcohol was found in the quinic acid (259.9 microg/g) and caffeic acid (174.4 microg/g) samples roasted under a nitrogen stream but not in the chlorogenic sample. The three acids used in the present study do not contain a nitrogen atom, yet nitrogen-containing heterocyclic compounds, pyridine, pyrrole, and pyrazines, were recovered. Phenol and its derivatives were identified in the largest quantities. The amounts of total phenols ranged from 60.6 microg/g (quinic acid under helium) to 89893.7 microg/g (caffeic acid under helium). It was proposed that phenol was formed mainly from quinic acid and that catechols were formed from caffeic acid. Formation of catechol from caffeic acid under anaerobic condition indicates that the reaction participating in catechol formation was not oxidative degradation.

  7. Caffeic acid production by simultaneous saccharification and fermentation of kraft pulp using recombinant Escherichia coli.

    Science.gov (United States)

    Kawaguchi, Hideo; Katsuyama, Yohei; Danyao, Du; Kahar, Prihardi; Nakamura-Tsuruta, Sachiko; Teramura, Hiroshi; Wakai, Keiko; Yoshihara, Kumiko; Minami, Hiromichi; Ogino, Chiaki; Ohnishi, Yasuo; Kondo, Ahikiko

    2017-07-01

    Caffeic acid (3,4-dihydroxycinnamic acid) serves as a building block for thermoplastics and a precursor for biologically active compounds and was recently produced from glucose by microbial fermentation. To produce caffeic acid from inedible cellulose, separate hydrolysis and fermentation (SHF) and simultaneous saccharification and fermentation (SSF) reactions were compared using kraft pulp as lignocellulosic feedstock. Here, a tyrosine-overproducing Escherichia coli strain was metabolically engineered to produce caffeic acid from glucose by introducing the genes encoding a 4-hydroxyphenyllactate 3-hydroxylase (hpaBC) from Pseudomonas aeruginosa and tyrosine ammonia lyase (fevV) from Streptomyces sp. WK-5344. Using the resulting recombinant strain, the maximum yield of caffeic acid in SSF (233 mg/L) far exceeded that by SHF (37.9 mg/L). In the SSF with low cellulase loads (≤2.5 filter paper unit/g glucan), caffeic acid production was markedly increased, while almost no glucose accumulation was detected, indicating that the E. coli cells experienced glucose limitation in this culture condition. Caffeic acid yield was also negatively correlated with the glucose concentration in the fermentation medium. In SHF, the formation of by-product acetate and the accumulation of potential fermentation inhibitors increased significantly with kraft pulp hydrolysate than filter paper hydrolysate. The combination of these inhibitors had synergistic effects on caffeic acid fermentation at low concentrations. With lower loads of cellulase in SSF, less potential fermentation inhibitors (furfural, 5-hydroxymethyfurfural, and 4-hydroxylbenzoic acid) accumulated in the medium. These observations suggest that glucose limitation in SSF is crucial for improving caffeic acid yield, owing to reduced by-product formation and fermentation inhibitor accumulation.

  8. Preparation and characterization of SPION functionalized via caffeic acid

    Energy Technology Data Exchange (ETDEWEB)

    Baykal, A. [Department of Chemistry, Fatih University, B.Çekmece, 34500 Istanbul (Turkey); Amir, Md., E-mail: mda.fatih@gmail.com [Department of Chemistry, Fatih University, B.Çekmece, 34500 Istanbul (Turkey); Günerb, S. [Department of Physics, Fatih University, B.Çekmece, 34500 Istanbul (Turkey); Sözeri, H. [TUBITAK-UME, National Metrology Institute, 41470 Gebze, Kocaeli (Turkey)

    2015-12-01

    Caffeic acid coated superparamagnetic iron oxide nanoparticles (SPION-CFA) was synthesized by reflux method. The structural, spectroscopic and magnetic properties were studied by X-ray diffraction (XRD), Transmission electron microscopy (TEM), Scanning electron microscopy (SEM), and Vibrating sample magnetometer (VSM) techniques. Thermal gravimetric analysis (TG) and Fourier transform infrared spectroscopy (FT-IR) confirmed the presence of CA on the surface of SPION. The theoretical analyzes performed on recorded room temperature VSM spectrum confirmed the formation of superparamagnetic nature of SPION-CFA. The particle size dependent Langevin function was applied to determine the average magnetic particle dimension (D{sub mag}) around 11.93 nm. In accordance, the average crystallite and particle sizes were obtained as 11.40 nm and ~12.00 nm from XRD and TEM measurements. The extrapolated specific saturation magnetization (σ{sub s}) is 44.11 emu/g and measured magnetic moment is 1.83 µ{sub B}. These parameters assign small order of magnetization for NPs with respect to bulk Fe{sub 3}O{sub 4}. Magnetic anisotropy was offered as uniaxial and calculated effective anisotropy constant (K{sub eff}) is 34.82×10{sup 4} Erg/g. The size-dependent saturation magnetization suggests the existence of a magnetically inactive layer as 1.035 nm for SPION-CFA. - Highlights: • The effects of CFA on the microstructure and magnetic properties of SPION have been investigated. • Product was structurally and magnetically characterized. • Product presented superparamagnetic behavior at room temperature.

  9. Quantitative analysis of caffeic and ferulic acids in oatmeal. Comparison of a conventional method with a stable isotope dilution assay.

    Science.gov (United States)

    Guth, H; Grosch, W

    1994-09-01

    [13C]Caffeic acid and [13C]ferulic acid were synthesized and then used as internal standards for the determination of these acids (free and esterified) in oatmeal. A comparative study indicated that 84% of the ferulic acid, but only 32% of the caffeic acid, which is more susceptible to oxidation than the former, could be found by a conventional analytical approach.

  10. Nanomolar Caffeic Acid Decreases Glucose Uptake and the Effects of High Glucose in Endothelial Cells.

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    Lucia Natarelli

    Full Text Available Epidemiological studies suggest that moderate and prolonged consumption of coffee is associated with a reduced risk of developing type 2 diabetes but the molecular mechanisms underlying this effect are not known. In this study, we report the effects of physiological concentrations of caffeic acid, easily achievable by normal dietary habits, in endothelial cells cultured in 25 mM of glucose (high glucose, HG. In HG, the presence of 10 nM caffeic acid was associated with a decrease of glucose uptake but not to changes of GLUT-1 membrane localization or mRNA levels. Moreover, caffeic acid countered HG-induced loss of barrier integrity, reducing actin rearrangement and FITC-dextran passage. The decreased flux of glucose associated to caffeic acid affected HG induced apoptosis by down-regulating the expression of initiator (caspase 8 and 9 and effector caspases (caspase 7 and 3 and by increasing the levels of phosphorylated Bcl-2. We also observed that caffeic acid in HG condition was associated to a reduction of p65 subunit nuclear levels with respect to HG alone. NF-κB activation has been shown to lead to apoptosis in HG treated cells and the analysis of the expression of a panel of about 90 genes related to NF-κB signaling pathway revealed that caffeic acid significantly influenced gene expression changes induced by HG. In conclusion, our results suggest that caffeic acid, decreasing the metabolic stress induced by HG, allows the activation of survival mechanisms mediated by a different modulation of NF-κB-related signaling pathways and to the activation of anti-apoptotic proteins.

  11. Biosynthesis of caffeic acid in Escherichia coli using its endogenous hydroxylase complex

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    Lin Yuheng

    2012-04-01

    Full Text Available Abstract Background Caffeic acid (3,4-dihydroxycinnamic acid is a natural phenolic compound derived from the plant phenylpropanoid pathway. Caffeic acid and its phenethyl ester (CAPE have attracted increasing attention for their various pharmaceutical properties and health-promoting effects. Nowadays, large-scale production of drugs or drug precursors via microbial approaches provides a promising alternative to chemical synthesis and extraction from plant sources. Results We first identified that an Escherichia coli native hydroxylase complex previously characterized as the 4-hydroxyphenylacetate 3-hydroxylase (4HPA3H was able to convert p-coumaric acid to caffeic acid efficiently. This critical enzymatic step catalyzed in plants by a membrane-associated cytochrome P450 enzyme, p-coumarate 3-hydroxylase (C3H, is difficult to be functionally expressed in prokaryotic systems. Moreover, the performances of two tyrosine ammonia lyases (TALs from Rhodobacter species were compared after overexpression in E. coli. The results indicated that the TAL from R. capsulatus (Rc possesses higher activity towards both tyrosine and L-dopa. Based on these findings, we further designed a dual pathway leading from tyrosine to caffeic acid consisting of the enzymes 4HPA3H and RcTAL. This heterologous pathway extended E. coli native tyrosine biosynthesis machinery and was able to produce caffeic acid (12.1 mg/L in minimal salt medium. Further improvement in production was accomplished by boosting tyrosine biosynthesis in E. coli, which involved the alleviation of tyrosine-induced feedback inhibition and carbon flux redirection. Finally, the titer of caffeic acid reached 50.2 mg/L in shake flasks after 48-hour cultivation. Conclusion We have successfully established a novel pathway and constructed an E. coli strain for the production of caffeic acid. This work forms a basis for further improvement in production, as well as opens the possibility of microbial synthesis

  12. Inhibitory effects of caffeic acid phenethyl ester derivatives on replication of hepatitis C virus.

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    Hui Shen

    Full Text Available Caffeic acid phenethyl ester (CAPE has been reported as a multifunctional compound. In this report, we tested the effect of CAPE and its derivatives on hepatitis C virus (HCV replication in order to develop an effective anti-HCV compound. CAPE and CAPE derivatives exhibited anti-HCV activity against an HCV replicon cell line of genotype 1b with EC50 values in a range from 1.0 to 109.6 µM. Analyses of chemical structure and antiviral activity suggested that the length of the n-alkyl side chain and catechol moiety are responsible for the anti-HCV activity of these compounds. Caffeic acid n-octyl ester exhibited the highest anti-HCV activity among the tested derivatives with an EC50 value of 1.0 µM and an SI value of 63.1 by using the replicon cell line derived from genotype 1b strain Con1. Treatment with caffeic acid n-octyl ester inhibited HCV replication of genotype 2a at a similar level to that of genotype 1b irrespectively of interferon signaling. Caffeic acid n-octyl ester could synergistically enhance the anti-HCV activities of interferon-alpha 2b, daclatasvir, and VX-222, but neither telaprevir nor danoprevir. These results suggest that caffeic acid n-octyl ester is a potential candidate for novel anti-HCV chemotherapy drugs.

  13. Anti-inflammatory activity of caffeic acid derivatives isolated from the roots of Salvia miltiorrhiza Bunge.

    Science.gov (United States)

    Choi, Hyun Gyu; Tran, Phuong Thao; Lee, Jeong-Hyung; Min, Byung Sun; Kim, Jeong Ah

    2017-11-09

    Ten caffeic acid derivatives (1-10) were isolated from the roots of Salvia miltiorrhiza by using various chromatographic methods and their chemical structures were spectroscopically elucidated. The absolute configurations of chiral centers were determined by comparison with reported coupling constants, optical rotation values, and CD techniques. Anti-inflammatory activities were evaluated using nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 inhibition assays, and by determining the expression of heme oxygenase (HO)-1. Two new caffeic acid derivatives, 8-epiblechnic acid 9-methyl ester (4) and 8-epiblechnic acid 9'-methyl ester (5), and eight known derivatives, caffeic acid methyl ester (1), shimobashiric acid B (2), rosmarinic acid methyl ester (3), salvianolic acid C (6), methyl salvianolate C (7), lithospermic acid monomethyl ester (8), lithospermic acid dimethyl ester (9), and dimethyl lithospermate B (10), were isolated from the ethyl acetate fraction of S. miltiorrhiza. All caffeic acid derivatives were evaluated for their inhibitory effect on NO production. Compounds 2 and 3 inhibited NO production with IC50 values of 1.4 and 0.6 μM, respectively. These compounds also strongly inhibited the production of iNOS and COX-2. In addition, compound 3 induced the expression HO-1 in a concentration-dependent manner at 0.1, 0.3, and 1.0 μM.

  14. [Anti-inflammatory effect of Urtica dioica folia extract in comparison to caffeic malic acid].

    Science.gov (United States)

    Obertreis, B; Giller, K; Teucher, T; Behnke, B; Schmitz, H

    1996-01-01

    Urtica dioica extract is a traditionary used adjuvant therapeutic in rheumatoid arthritis. The antiphlogistic effects of the urtica dioica folia extract IDS 23 (Extractum Urticae dioicae foliorum) and the main phenolic ingredient caffeic malic acid were tested concerning the inhibitory potential on biosynthesis of arachidonic acid metabolites in vitro. The caffeic malic acid was isolated from Urtica folia extract using gel exclusion- and high performance liquid chromatography and identified by mass spectroscopy and nuclear magnetic resonance. Concerning the 5-lipoxygenase products IDS 23 showed a partial inhibitory effect. The isolated phenolic acid inhibited the synthesis of the leukotriene B4 in a concentration dependent manner. The concentration for halfmaximal inhibition (IC50) was 83 microns/ml in the used assay. IDS 23 showed a strong concentration dependent inhibition of the synthesis of cyclooxygenase derived reactions. The IC50 were 92 micrograms/ml for IDS 23 and 38 micrograms/ml for the caffeic malic acid. Calculating the content in IDS 23 the caffeic malic acid is a possible but not the only active ingredient of the plant extract in the tested assay systems. It is demonstrated that the phenolic component showed a different enzymatic target compared with IDS 23. The antiphlogistic effects observed in vitro may give an explanation for the pharmacological and clinical effects of IDS 23 in therapie of rheumatoid diseases.

  15. The timing of caffeic acid treatment with cisplatin determines sensitization or resistance of ovarian carcinoma cell lines

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    R. Sirota

    2017-04-01

    The use of caffeic acid as adjuvant for cisplatin should be carefully examined due to different pharmacokinetic profiles of caffeic acid and cisplatin. Thus, it is questionable if the two agents can reach the tumors at the right time frame in vivo.

  16. Antimicrobial and enhancement of the antibiotic activity by phenolic compounds: Gallic acid, caffeic acid and pyrogallol.

    Science.gov (United States)

    Lima, Valéria N; Oliveira-Tintino, Cícera D M; Santos, Enaide S; Morais, Luís P; Tintino, Saulo R; Freitas, Thiago S; Geraldo, Yuri S; Pereira, Raimundo L S; Cruz, Rafael P; Menezes, Irwin R A; Coutinho, Henrique D M

    2016-10-01

    The indiscriminate use of antimicrobial drugs has increased the spectrum of exposure of these organisms. In our studies, these phenolic compounds were evaluated: gallic acid, caffeic acid and pyrogallol. The antibacterial, antifungal and modulatory of antibiotic activities of these compounds were assayed using microdilution method of Minimum Inhibitory Concentration (MIC) to bacteria and Minimum Fungicide Concentration (MFC) to fungi. The modulation was made by comparisons of the MIC and MFC of the compounds alone and combined with drugs against bacteria and fungi respectively, using a sub-inhibitory concentration of 128 μg/mL of substances (MIC/8). All substances not demonstrated clinically relevant antibacterial activity with a MIC above ≥1024 μg/mL. As a result, we observed that the caffeic acid presented a potentiating antibacterial effect over the 3 groups of bacteria studied. Pyrogallol showed a synergistic effect with two of the antibiotics tested, but only against Staphylococcus aureus. In general, caffeic acid was the substance that presented with the greatest number of antibiotics and with the greatest number of bacteria. In relation to the antifungal activity of all the compounds, the verified results were ≥1024 μg/mL, not demonstrating significant activity. Regarding potentiation of the effect of fluconazole, was observed synergistic effect only when assayed against Candida tropicalis, with all substances. Therefore, as can be seen, the compounds presented as substances that can be promising potentiating agents of antimicrobial drugs, even though they do not have direct antibacterial and antifungal action. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Determination of caffeic acid in root and rhizome of Black cohosh (Cimicifuga racemosa (L. Nutt.

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    Zapala Karolina

    2014-06-01

    Full Text Available Cimicifuga racemosa, is a plant with a diverse and long history of medicinal use. Caffeic acid, bioactive compound, which often occurs with other polyphenols can influence the biological activity of this plant. The aim of our work was quantitative analysis of caffeic acid in roots and rhizomes of two varieties of C. racemosa. Analysis was performed by HPLC method. The extracts were separated on C18 reversed-phase column using mixture of methanol, water and formic acid (25:75:0.5 v/v/v as a mobile phase. The flow rate of eluent was 1.0 ml·min-1. The obtained validation parameters such as linearity, linear regression equation and precision expressed as a relative standard deviation were adequate for quantitative determination. Caffeic acid was found in all tested extracts. The highest total amount of caffeic acid was determined in C. racemosa var. racemosa (255.3 μg·g-1 while its concentration in C. racemosa var. cordifolia was significantly lower (213.0 μg·g-1.

  18. Effect of high pressure on peanut allergens in the presence of polyphenol oxidase and caffeic acid

    Science.gov (United States)

    High pressure (HP) enhances enzymatic reactions. Because polyphenol oxidase (PPO) is an enzyme, and reduces IgE binding of peanut allergens in presence of caffeic acid (CA), we postulated that a further reduction in IgE binding can be achieved, using HP together with PPO and CA. Peanut extracts cont...

  19. Grape skins (Vitis vinifera L.) catalyze the in vitro enzymatic hydroxylation of p-coumaric acid to caffeic acid

    DEFF Research Database (Denmark)

    Arnous, Anis; Meyer, Anne S.

    2009-01-01

    The ability of grape skins to catalyze in vitro conversion of p-coumaric acid to the more potent antioxidant caffeic acid was studied. Addition of different concentrations of p-coumaric to red grape skins (Cabernet Sauvignon) resulted in formation of caffeic acid. This caffeic acid formation (Y......) correlated positively and linearly to p-coumaric acid consumption (X): Y = 0.5 X + 9.5; R 2 = 0.96, P skin concentrations, indicated that the grape skins harboured an o......-hydroxylation activity, proposedly a monophenol- or a flavonoid 3′-monooxygenase activity (EC 1.14.18.1 or EC 1.14.13.21). The K m of this crude o-hydroxylation activity in the red grape skin was 0.5 mM with p-coumaric acid....

  20. HIGH PERFORMANCE THIN LAYER CHROMATOGRAPHIC DETERMINATION OF CAFFEIC ACID AND ROSMARINIC ACID FROM THE LEAVES OF Orthosiphon stamineus

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    M. Amzad Hossain

    2010-06-01

    Full Text Available This paper presents the studies performed on extraction of Orthosiphon stamineus, Benth by using different solvent for the identification and quantification of the caffeic acid derivatives such as caffeic acid  and rosmarinic acid which confers to the leaves of this plant with remarkable pharmaceutical properties. High performance thin-layer chromatographic (HPTLC allows the identification and the quantification of more than 20 samples in the same chromatographic run. The analysis of the samples requires 15-30 min compared with more than 2 h using a typical HPLC method. Using the techniques of the HPTLC and the UV-VIS spectra we have found that the extraction of this herb plant contain, the caffeic acid and rosmarinic acid ranging between 0.029% up to 0.506% and up to 0.24% to 2.24% respectively.     Keywords: Caffice acid derivatives, quantification, Malaysian Orthosiphon stamineus, HPTLC

  1. Ameliorative Effects of Caffeic Acid on Lead Accumulation and Oxidative Stress in Lead-Exposed Mice

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    Maryam Lotfi-Ghahramanloo

    2016-05-01

    Full Text Available Background The currently approved treatment for lead toxicity is chelation therapy to reduce the burden of the toxic effects of lead, but the safety and efficacy of the various chelating agents may be questioned. Objectives This study was aimed to evaluate the effects of caffeic acid, a dietary non-flavonoid phenolic acid, on lead accumulation and lead-induced oxidative stress in mice. Materials and Methods In this experimental study, 24 mice were divided into four groups. Group 1 served as control. Mice in group 2 received water containing 1000 ppm lead acetate. Group 3 animals received caffeic acid (60 mg/kg body weight i.p. during lead treatment. Mice in group 4 only received caffeic acid. At the end of the experiment (18 days, blood samples were drawn and the levels of lead and some oxidative-stress related parameters were measured. Results Blood Pb concentration increased significantly in group 2 as compared to control group. Lead exposure caused significant increase of malondialdehyde and decrease of glutathione concentrations in erythrocyte haemolysate as compared to control group. Although caffeic acid was effective in normalization of the attenuated levels of erythrocytic glutathione, its administration had no significant effect in decreasing the augmented levels of erythrocytic malondialdehyde in group 3. Values of other measured parameters including erythrocytic activities of glutathione peroxidase and superoxide dismutase did not change significantly among experimental groups. Conclusions Present results show some beneficial effects of caffeic acid against lead poisoning and it can be thus proposed as a potential prophylactic treatment for amelioration of lead toxicity.

  2. Function Analysis of Caffeoyl-CoA O-Methyltransferase for Biosynthesis of Lignin and Phenolic Acid in Salvia miltiorrhiza.

    Science.gov (United States)

    Wang, Zhengjun; Ge, Qian; Chen, Chen; Jin, Xinxin; Cao, Xiaoyan; Wang, Zhezhi

    2017-02-01

    In this study, we cloned a full-length cDNA and the genomic DNA sequence of SmCCoAOMT (GenBank ID JQ007585) from Salvia miltiorrhiza. The 744-bp open-reading frame encodes a protein of 247 amino acids that shares 95 % similarity with one in Vitis vinifera. Real-time quantitative PCR analysis revealed that SmCCoAOMT is most highly expressed in the stems and can be induced by methyl jasmonate (MeJA) and XC-1 treatment. To evaluate its function in vivo, we generated RNA interference transgenic plants through Agrobacterium tumefaciens-mediated gene transfer. Compared with untransformed control plants, the transgenics had significantly less lignin and the expression of lignin-biosynthetic genes SmCCR and SmCOMT was depressed. In 90-day-old roots from plants of transgenic line M5, accumulations of rosmarinic acid and salvianolic acid B (Sal B) were greatly reduced by 0.89- and 0.69-fold, respectively. This low-Sal B phenotype was stable in the roots, with the level of accumulation being approximately 43.58 mg g(-1) dry weight, which was 52 % of the amount measured in the untransformed control. Our results suggest that SmCCoAOMT is involved in lignin biosynthesis and affects the accumulation of phenolic acids. This study also provides potential guidance for using lignin-related genes to genetically engineer Salvia miltiorrhiza.

  3. Protective effect of dietary polyphenol caffeic acid on ethylene glycol-induced kidney stones in rats.

    Science.gov (United States)

    Yasir, Fauzia; Wahab, Atia-Tul-; Choudhary, M Iqbal

    2017-06-14

    Dietary polyphenol caffeic acid (1) has been reported for various pharmacological activities. The aim of the current study was to investigate the effect of caffeic acid (1) on ethylene glycol-induced renal stones in rats. For the study, male Wistar rats were divided into seven groups; normal, pathological, and standard drug controls, and preventive and curative groups. Normal control group received drinking water for 8 weeks. Pathological, standard drug, preventive, and curative groups received 0.75% ethylene glycol in drinking water for the induction of calcium oxalate stone formation, along with the regular diet. Standard drug group received Urocit-K by gavage from day 1, while preventive and curative groups received caffeic acid (1) by gavage at doses of 20 and 40 mg/kg on day 1 and day 14, respectively. At the end of the experiment, urine analysis and kidney histopathology were performed. Real-time PCR was performed to evaluate the renal expression of the most important genes involved in urolithiasis, i.e., osteopontin, Tamm-Horsfall, prothrombin fragment 1, and bikunin genes. The results indicated that in both the preventive and curative groups, treatment of rats with caffeic acid (1) significantly regulated the altered biochemical parameters, along with the remarkable reduction of calcium oxalate deposits in the kidneys, as compared to the pathological group. Treatment with compound 1 also resulted in down-regulation of the osteopontin gene, and up-regulation of the prothrombin fragment 1, Tamm-Horsfall, and bikunin genes. These results suggest that caffeic acid (1) can be further investigated for the prevention, and treatment of kidney stones.

  4. Inhibitory Effects of Caffeic Acid, a Coffee-Related Organic Acid, on the Propagation of Hepatitis C Virus.

    Science.gov (United States)

    Tanida, Isei; Shirasago, Yoshitaka; Suzuki, Ryosuke; Abe, Ryo; Wakita, Takaji; Hanada, Kentaro; Fukasawa, Masayoshi

    2015-01-01

    Multipurpose cohort studies have demonstrated that coffee consumption reduces the risk of hepatocellular carcinoma (HCC). Given that one of the main causes of HCC is hepatitis C virus (HCV) infection, we examined the effect of caffeic acid, a major organic acid derived from coffee, on the propagation of HCV using an in vitro naïve HCV particle-infection and production system within human hepatoma-derived Huh-7.5.1-8 cells. When cells were treated with 1% coffee extract or 0.1% caffeic acid for 1-h post HCV infection, the amount of HCV particles released into the medium at 3 and 4 days post-infection considerably decreased. In addition, HCV-infected cells cultured with 0.001% caffeic acid for 4 days, also released less HCV particles into the medium. Caffeic acid treatment inhibited the initial stage of HCV infection (i.e., between virion entry and the translation of the RNA genome) in both HCV genotypes 1b and 2a. These results suggest that the treatment of cells with caffeic acid may inhibit HCV propagation.

  5. Caffeic acid attenuates oxidative stress, learning and memory deficit in intra-cerebroventricular streptozotocin induced experimental dementia in rats.

    Science.gov (United States)

    Deshmukh, Rahul; Kaundal, Madhu; Bansal, Vikas; Samardeep

    2016-07-01

    Oxidative stress has been implicated in cognitive decline as seen during normal aging and in sporadic Alzheimer's disease (AD). Caffeic acid, a polyphenolic compound, has been reported to possess potent antioxidant and neuroprotective properties. The role of caffeic acid in experimental dementia is not fully understood. Thus the present study was designed to investigate the therapeutic potential of caffeic acid in streptozotocin (STZ)-induced experimental dementia of Alzheimer's type in rats. Streptozotocin (STZ) was administered intracerebroventrically (ICV) on day 1 and 3 (3mg/kg, ICV bilaterally) in Wistar rats. Caffeic acid was administered (10, 20 and 40mg/kg/day p.o.) 1h following STZ infusion upto 21st day. Morris water maze and object recognition task were used to assess learning and memory in rats. Terminally, acetylcholinesterase (AChE) activity and the levels of oxido-nitrosative stress markers were determined in cortical and hippocampal brain regions of rats. STZ produced significant (plearning and memory impairment, oxido-nitrosative stress and cholinergic deficit in rats. Whereas, caffeic acid treatment significantly (p<0.001) and dose dependently attenuated STZ induced behavioral and biochemical abnormalities in rats. The observed cognitive improvement following caffeic acid in STZ treated rats may be due to its antioxidant activity and restoration of cholinergic functions. Our results suggest the therapeutic potential of caffeic acid in cognitive disorders such as AD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  6. Development and validation of an LCMS method to determine the pharmacokinetic profiles of caffeic acid phenethyl amide and caffeic acid phenethyl ester in male Sprague-Dawley rats.

    Science.gov (United States)

    Yang, John; Bowman, Phillip D; Kerwin, Sean M; Stavchansky, Salomon

    2014-02-01

    A validated LCMS method was developed for the quantitative determination of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) from rat plasma. Separation was achieved using a reverse-phase C12 HPLC column (150 × 2.00 mm, 4 µm) with gradient elution running water (A) and acetonitrile (B). Mass spectrometry was performed with electrospray ionization in negative mode. This method was used to determine the pharmacokinetic profiles of CAPA and CAPE in male Sprague-Dawley rats following intravenous bolus administration of 5, 10 and 20 mg/kg of CAPA and 20 mg/kg of CAPE. The pharmacokinetic analysis suggests the lack of dose proportionality in the dose range of 5-20 mg/kg of CAPA. Total clearance values for CAPA ranged from 45 to 156 mL/min and decreased with increasing dose of CAPA. The volume of distribution for CAPA ranged from 17,750 to 52,420 mL, decreasing with increasing dose. The elimination half-life for CAPA ranged from 243.1 to 295.8 min and no statistically significant differences were observed between dose groups in the range of 5-20 mg/kg (p > 0.05). The elimination half-life for CAPE was found to be 92.26 min. Copyright © 2013 John Wiley & Sons, Ltd.

  7. Possible molecular targets for therapeutic applications of caffeic acid phenethyl ester in inflammation and cancer

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    Ghulam Murtaza

    2015-03-01

    Full Text Available Of the various derivatives of caffeic acid, caffeic acid phenethyl ester (CAPE is a hydrophobic, bioactive polyphenolic ester obtained from propolis extract. The objective in writing this review article was to summarize all published studies on therapeutics of CAPE in inflammation and cancer to extract direction for future research. The possible molecular targets for the action of CAPE, include various transcription factors such as nuclear factor-κB, tissue necrosis factor-α, interleukin-6, cyclooxygenase-2, Nrf2, inducible nitric oxide synthase, nuclear factor of activated T cells, hypoxia-inducible factor-1α, and signal transducers and activators of transcription. Based on the valuable data on its therapeutics in inflammation and cancer, clinical studies of CAPE should also be conducted to explore its toxicities, if any.

  8. Binding of caffeic acid to human serum albumin by the retention data and frontal analysis.

    Science.gov (United States)

    An, Yuxin; Li, Qian; Chen, Jiejun; Gao, Xiaokang; Chen, Hongwei; Xiao, Chaoni; Bian, Liujiao; Zheng, Jianbin; Zhao, Xinfeng; Zheng, Xiaohui

    2014-12-01

    A new mathematical model and frontal analysis were used to characterize the binding behavior of caffeic acid to human serum albumin (HSA) based on high-performance affinity chromatography. The experiments were carried out by injecting various mole amounts of the drug onto an immobilized HSA column. They indicated that caffeic acid has only one type of binding site to HSA on which the association constant was 2.75 × 10(4) /m. The number of the binding site involving the interaction between caffeic acid and HSA was 69 nm. The data obtained by the frontal analysis appeared to present the same results for both the association constant and the number of binding sites. This new model based on the relationship between the mole amounts of injection and capacity factors assists understanding of drug-protein interaction. The proposed model also has the advantages of ligand saving and rapid operation. Copyright © 2014 John Wiley & Sons, Ltd.

  9. Molecularly imprinted polymer for caffeic acid by precipitation polymerization and its application to extraction of caffeic acid and chlorogenic acid from Eucommia ulmodies leaves.

    Science.gov (United States)

    Miura, Chitose; Matsunaga, Hisami; Haginaka, Jun

    2016-08-05

    Molecularly imprinted polymers (MIPs) for caffeic acid (CA) were prepared using 4-vinylpyridine and methacrylamide (MAM) as functional monomers, divinylbenzene as a crosslinker and acetonitrile-toluene (3:1, v/v) as a porogen by precipitation polymerization. The use of MAM as the co-monomer resulted in the formation of microsphere MIPs and non-imprinted polymers (NIPs) with ca. 3- and 5-μm particle diameters, respectively. Binding experiments and Scatchard analyses revealed that the binding capacity and affinity of the MIP to CA are higher than those of the NIP. The retention and molecular-recognition properties of the prepared MIPs were evaluated using water-acetonitrile and sodium phosphate buffer-acetonitrile as mobile phases in hydrophilic interaction chromatography (HILIC) and reversed-phase chromatography, respectively. In HILIC mode, the MIP showed higher molecular-recognition ability for CA than in reversed-phase mode. In addition to shape recognition, hydrophilic interactions seem to work for the recognition of CA on the MIP in HILIC mode, while hydrogen bonding and hydrophobic interactions seem to work for the recognition of CA in reversed-phase mode. The MIP had a specific molecular-recognition ability for CA in HILIC mode, while other structurally related compounds, such as chlorogenic acid (CGA), gallic acid, protocatechuic acid and vanillic acid, could not be recognized by the MIP. Furthermore, the MIP was successfully applied for extraction of CA and CGA in the leaves of Eucommia ulmodies in HILIC mode. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Mechanism and kinetics in reactions of caffeic acid with radicals by pulse radiolysis and calculation

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    Li, Xifeng; Cai, Zhongli; Katsumura, Yosuke [Tokyo Univ., Tokai, Ibaraki (Japan). Nuclear Engineering Research Lab

    2000-03-01

    The interaction of caffeic acid with e{sub aq}{sup -}, (CH{sub 3}){sub 2}(OH) CCH{sub 2}{sup {center_dot}}, CO{sub 2}{sup {center_dot}}{sup -}, H{sup {center_dot}}, {center_dot}OH and N{sub 3}{sup {center_dot}} radicals were studied by {gamma}-, pulse radiolysis and molecular orbital calculation. UV-visible spectra of electron/{center_dot}OH adducts, semi-quinone radicals of caffeic ions, and the stable products from the reactions were derived. The rate constants were determined. The attacked sites and the most favorable structures of the transient radicals were predicted. Reaction mechanisms were proposed. (author)

  11. Green synthesis of gold-chitosan nanocomposites for caffeic acid sensing.

    Science.gov (United States)

    Di Carlo, Gabriella; Curulli, Antonella; Toro, Roberta G; Bianchini, Chiara; De Caro, Tilde; Padeletti, Giuseppina; Zane, Daniela; Ingo, Gabriel M

    2012-03-27

    In this work, colloidal gold nanoparticles (AuNPs) stabilized into a chitosan matrix were prepared using a green route. The synthesis was carried out by reducing Au(III) to Au(0) in an aqueous solution of chitosan and different organic acids (i.e., acetic, malonic, or oxalic acid). We have demonstrated that by varying the nature of the acid it is possible to tune the reduction rate of the gold precursor (HAuCl(4)) and to modify the morphology of the resulting metal nanoparticles. The use of chitosan, a biocompatible and biodegradable polymer with a large number of amino and hydroxyl functional groups, enables the simultaneous synthesis and surface modification of AuNPs in one pot. Because of the excellent film-forming capability of this polymer, AuNPs-chitosan solutions were used to obtain hybrid nanocomposite films that combine highly conductive AuNPs with a large number of organic functional groups. Herein, Au-chitosan nanocomposites are successfully proposed as sensitive and selective electrochemical sensors for the determination of caffeic acid, an antioxidant that has recently attracted much attention because of its benefits to human health. A linear response was obtained over a wide range of concentration from 5.00 × 10(-8) M to 2.00 × 10(-3) M, and the limit of detection (LOD) was estimated to be 2.50 × 10(-8) M. Moreover, further analyses have demonstrated that a high selectivity toward caffeic acid can be achieved without interference from catechin or ascorbic acid (flavonoid and nonphenolic antioxidants, respectively). This novel synthesis approach and the high performances of Au-chitosan hybrid materials in the determination of caffeic acid open up new routes in the design of highly efficient sensors, which are of great interest for the analysis of complex matrices such as wine, soft drinks, and fruit beverages. © 2012 American Chemical Society

  12. Migration Rate Inhibition of Breast Cancer Cells Treated by Caffeic Acid and Caffeic Acid Phenethyl Ester: An In Vitro Comparison Study

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    Agata Kabała-Dzik

    2017-10-01

    Full Text Available One of the deadliest cancers among women is a breast cancer. Research has shown that two natural substances occurring in propolis, caffeic acid (CA and caffeic acid phenethyl ester (CAPE, have significant anticancer effects. The purpose of our in vitro study was to compare cytotoxic activity and migration rate inhibition using CA and CAPE (doses of 50 and 100 µm against triple-negative, MDA-MB-231 breast adenocarcinoma line cells, drawn from Caucasian women. Viability was measured by XTT-NR-SRB assay (Tetrazolium hydroxide-Neutral Red-Sulforhodamine B for 24 h and 48 h periods. Cell migration for wound healing assay was taken for 0 h, 8 h, 16 h, and 24 h periods. CAPE displayed more than two times higher cytotoxicity against MDA-MB-231 cells. IC50 values for the XTT assay were as follows: CA for 24 h and 48 h were 150.94 µM and 108.42 µM, respectively, while CAPE was 68.82 µM for 24 h and 55.79 µM for 48 h. For the NR assay: CA was 135.85 µM at 24 h and 103.23 µM at 48 h, while CAPE was 64.04 µM at 24 h and 53.25 µM at 48 h. For the SRB assay: CA at 24 h was 139.80 µM and at 48 h 103.98 µM, while CAPE was 66.86 µM at 24 h and 47.73 µM at 48 h. Both agents suspended the migration rate; however, CAPE displayed better activity. Notably, for the 100 µM CAPE dose, motility of the tested breast carcinoma cells was halted.

  13. Migration Rate Inhibition of Breast Cancer Cells Treated by Caffeic Acid and Caffeic Acid Phenethyl Ester: An In Vitro Comparison Study

    Science.gov (United States)

    Rzepecka-Stojko, Anna; Kubina, Robert; Jastrzębska-Stojko, Żaneta; Stojko, Rafał; Wojtyczka, Robert Dariusz; Stojko, Jerzy

    2017-01-01

    One of the deadliest cancers among women is a breast cancer. Research has shown that two natural substances occurring in propolis, caffeic acid (CA) and caffeic acid phenethyl ester (CAPE), have significant anticancer effects. The purpose of our in vitro study was to compare cytotoxic activity and migration rate inhibition using CA and CAPE (doses of 50 and 100 µm) against triple-negative, MDA-MB-231 breast adenocarcinoma line cells, drawn from Caucasian women. Viability was measured by XTT-NR-SRB assay (Tetrazolium hydroxide-Neutral Red-Sulforhodamine B) for 24 h and 48 h periods. Cell migration for wound healing assay was taken for 0 h, 8 h, 16 h, and 24 h periods. CAPE displayed more than two times higher cytotoxicity against MDA-MB-231 cells. IC50 values for the XTT assay were as follows: CA for 24 h and 48 h were 150.94 µM and 108.42 µM, respectively, while CAPE was 68.82 µM for 24 h and 55.79 µM for 48 h. For the NR assay: CA was 135.85 µM at 24 h and 103.23 µM at 48 h, while CAPE was 64.04 µM at 24 h and 53.25 µM at 48 h. For the SRB assay: CA at 24 h was 139.80 µM and at 48 h 103.98 µM, while CAPE was 66.86 µM at 24 h and 47.73 µM at 48 h. Both agents suspended the migration rate; however, CAPE displayed better activity. Notably, for the 100 µM CAPE dose, motility of the tested breast carcinoma cells was halted. PMID:29048370

  14. Adsorption of Acid Red 114 onto Fe3O4@Caffeic acid recycable magnetic nanocomposite

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    Aylin YILDIZ

    2016-11-01

    Full Text Available In this study, the adsorption capacity of caffeic acid (CFA functionalized Fe3O4 magnetic recyclable nanocomposite (Fe3O4@CFA MNCs for removal of industrial dye Acid Red 114 (AR 114 was investigated. The max. adsorption (qm of the Fe3O4@CFA MNCs for AR114 was 333 mg/g without pH correction of the solution. Compared with other studies these adsorbent possess very adsorption capacity for AR114 dye. The adsorption isotherm data and the process of adsorption kinetics were fitted using the Langmuir equation and a pseudo-second-order kinetic model that showed chemisorption may be the rate controlling step in the adsorption processes. It was proved which the magnetic NMs technology was contributed by this study which can be a new and covetable alternative for organic contaminant adsorption. Furthermore, the reusability of the Fe3O4@CFA MNCs was investigated and significant removal of AR114 obtained even after five cycles

  15. The effects of gallic/ferulic/caffeic acids on colour intensification and anthocyanin stability.

    Science.gov (United States)

    Qian, Bing-Jun; Liu, Jian-Hua; Zhao, Shu-Juan; Cai, Jian-Xiong; Jing, Pu

    2017-08-01

    The mechanism by which copigments stabilize colour, by protecting anthocyanin chromophores from nucleophilic attack, seems well accepted. This study was to determine effects of gallic/ferulic/caffeic acids on colour intensification and anthocyanin stability. Molecular dynamics simulations were applied to explore molecular interactions. Phenolic acids intensified the colour by 19%∼27%. Colour fading during heating followed first-order reactions with half-lives of 3.66, 9.64, 3.50, and 3.39h, whereas anthocyanin degradation, determined by the pH differential method (or HPLC-PDA), followed second-order reactions with half-lives of 3.29 (3.40), 3.43 (3.39), 2.29 (0.39), and 2.72 (0.32)h alone or with gallic/ferulic/caffeic acids, respectively, suggesting that anthocyanin degradation was faster than the colour fading. The strongest protection of gallic acids might be attributed to the shortest distance (4.37Å) of its aromatic ring to the anthocyanin (AC) panel. Hyperchromic effects induced by phenolic acids were pronounced and they obscured the accelerated anthocyanin degradation due to self-association interruption. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Protective Effects of Caffeic Acid Phenethyl Ester on Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats.

    Science.gov (United States)

    Uysal, Ersin; Yılmaz, H Ramazan; Ugan, Yunus; Altuntas, Atila; Dogru, Atalay; Kutlucan, Ali; Tunc, Sevket Ercan

    2015-12-01

    We investigated the protective effect of caffeic acid phenethyl ester (CAPE) on cyclophosphamide-induced hemorrhagic cystitis in rats in comparison with 2-mercaptoethane sulfonate (MESNA). Forty male rats were randomized into four groups: group 1 (control), group 2 (cyclophosphamide), group 3 (cyclophosphamide + MESNA), group 4 (cyclophosphamide + CAPE). Cyclophosphamide injection increased malondialdehyde levels indicating oxidative stress, whereas CAPE and MESNA ameliorated malondialdehyde levels in the bladder (p hemorrhagic cystitis, we suggest that it would be more beneficial to use MESNA with CAPE to prevent histological damage. © 2015 Wiley Periodicals, Inc.

  17. Can propolis and caffeic acid phenethyl ester (CAPE be promising agents against cyclophosphamide toxicity?

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    Sumeyya Akyol

    2016-03-01

    Full Text Available Propolis is a mixture having hundreds of polyphenols including caffeic acid phenethyl ester (CAPE. They have been using in several medical conditions/diseases in both in vitro and in vivo experimental setup. Cyclophosphamide has been used to treat a broad of malignancies including Hodgkin's and non-Hodgking's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, Ewing's sarcoma, breast cancer, testicular cancer, etc. It may cause several side effects after treatment. In this mini review, the protective effects of propolis and CAPE were compared each other in terms of effectiveness against cyclophosphamide-induced injuries. [J Intercult Ethnopharmacol 2016; 5(1.000: 105-107

  18. Protective role of caffeic acid in an Aβ25-35-induced Alzheimer's disease model

    OpenAIRE

    Kim, Ji Hyun; Wang, Qian; Choi, Ji Myung; Lee, Sanghyun; Cho, Eun Ju

    2015-01-01

    BACKGROUND/OBJECTIVES Alzheimer's disease (AD) is characterized by deficits in memory and cognitive functions. The accumulation of amyloid beta peptide (Aβ) and oxidative stress in the brain are the most common causes of AD. MATERIALS/METHODS Caffeic acid (CA) is an active phenolic compound that has a variety of pharmacological actions. We studied the protective abilities of CA in an Aβ25-35-injected AD mouse model. CA was administered at an oral dose of 10 or 50 mg/kg/day for 2 weeks. Behavi...

  19. Synthesis and Biological Activity of Arylspiroborate Salts Derived from Caffeic Acid Phenethyl Ester

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    Martin J. G. Hébert

    2015-01-01

    Full Text Available Two novel boron compounds containing caffeic acid phenethyl ester (CAPE derivatives have been prepared and characterized fully. These new compounds and CAPE have been investigated for potential antioxidant and antimicrobial properties and their ability to inhibit 5-lipoxygenase and whether chelation to boron improves their biological activity. Sodium salt 4 was generally more active than ammonium salt 5 in the biological assays and surpassed the radical scavenging ability of CAPE. Compounds 4 and 5 were more active than CAPE and Zileuton in human polymorphonuclear leukocytes. These results clearly show the effectiveness of the synthesized salts as transporter of CAPE.

  20. Polydopamine-coated magnetic molecularly imprinted polymer for the selective solid-phase extraction of cinnamic acid, ferulic acid and caffeic acid from radix scrophulariae sample.

    Science.gov (United States)

    Yin, Yuli; Yan, Liang; Zhang, Zhaohui; Wang, Jing; Luo, Ningjing

    2016-04-01

    We describe novel cinnamic acid polydopamine-coated magnetic imprinted polymers for the simultaneous selective extraction of cinnamic acid, ferulic acid and caffeic acid from radix scrophulariae sample. The novel magnetic imprinted polymers were synthesized by surface imprinting polymerization using magnetic multi-walled carbon nanotubes as the support material, cinnamic acid as the template and dopamine as the functional monomer. The magnetic imprinted polymers were characterized by transmission electron microscopy, scanning electron microscopy, Fourier transform infrared spectroscopy and vibrating sample magnetometry. The results revealed that the magnetic imprinted polymers had outstanding magnetic properties, high adsorption capacity, selectivity and fast kinetic binding toward cinnamic acid, ferulic acid and caffeic acid. Coupled with high-performance liquid chromatography, the extraction conditions of the magnetic imprinted polymers as a magnetic solid-phase extraction sorbent were investigated in detail. The proposed imprinted magnetic solid phase extraction procedure has been used for the purification and enrichment of cinnamic acid, ferulic acid and caffeic acid successfully from radix scrophulariae extraction sample with recoveries of 92.4-115.0% for cinnamic acid, 89.4-103.0% for ferulic acid and 86.6-96.0% for caffeic acid. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Synthesis and Antiradical/Antioxidant Activities of Caffeic Acid Phenethyl Ester and Its Related Propionic, Acetic, and Benzoic Acid Analoguesc

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    Mohamed Touaibia

    2012-12-01

    Full Text Available Caffeic acid phenethyl ester (CAPE is a bioactive component isolated from propolis. A series of CAPE analogues was synthesized and their antiradical/antioxidant effects analyzed. The effect of the presence of the double bond and of the conjugated system on the antioxidant effect is evaluated with the analogues obtained from 3-(3,4-dihydroxyphenyl propanoic acid. Those obtained from 2-(3,4-dihydroxyphenyl acetic acid and 3,4-dihydroxybenzoic acid allow the evaluation of the effect of the presence of two carbons between the carbonyl and aromatic system.

  2. Synthesis and antiradical/antioxidant activities of caffeic acid phenethyl ester and its related propionic, acetic, and benzoic acid analogues.

    Science.gov (United States)

    LeBlanc, Luc M; Paré, Aurélie F; Jean-François, Jacques; Hébert, Martin J G; Surette, Marc E; Touaibia, Mohamed

    2012-12-10

    Caffeic acid phenethyl ester (CAPE) is a bioactive component isolated from propolis. A series of CAPE analogues was synthesized and their antiradical/antioxidant effects analyzed. The effect of the presence of the double bond and of the conjugated system on the antioxidant effect is evaluated with the analogues obtained from 3-(3,4-dihydroxyphenyl) propanoic acid. Those obtained from 2-(3,4-dihydroxyphenyl) acetic acid and 3,4-dihydroxybenzoic acid allow the evaluation of the effect of the presence of two carbons between the carbonyl and aromatic system.

  3. Regulatory Effects of Caffeic Acid Phenethyl Ester on Neuroinflammation in Microglial Cells

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    Cheng-Fang Tsai

    2015-03-01

    Full Text Available Microglial activation has been widely demonstrated to mediate inflammatory processes that are crucial in several neurodegenerative disorders. Pharmaceuticals that can deliver direct inhibitory effects on microglia are therefore considered as a potential strategy to counter balance neurodegenerative progression. Caffeic acid phenethyl ester (CAPE, a natural phenol in honeybee propolis, is known to possess antioxidant, anti-inflammatory and anti-microbial properties. Accordingly, the current study intended to probe the effects of CAPE on microglia activation by using in vitro and in vivo models. Western blot and Griess reaction assay revealed CAPE significantly inhibited the expressions of inducible nitric oxide synthase (NOS, cyclooxygenase (COX-2 and the production of nitric oxide (NO. Administration of CAPE resulted in increased expressions of hemeoxygenase (HO-1and erythropoietin (EPO in microglia. The phosphorylated adenosine monophosphate-activated protein kinase (AMPK-α was further found to regulate the anti-inflammatory effects of caffeic acid. In vivo results from immunohistochemistry along with rotarod test also revealed the anti-neuroinflammatory effects of CAPE in microglia activation. The current study has evidenced several possible molecular determinants, AMPKα, EPO, and HO-1, in mediating anti-neuroinflammatory responses in microglial cells.

  4. Choline chloride-based deep eutectic solvents as additives for optimizing chromatographic behavior of caffeic acid

    Energy Technology Data Exchange (ETDEWEB)

    Li, Guizhen; Zhu, Tao; Lei, Yingjie [Tianjin University of Technology, Tianjin (China)

    2015-10-15

    A series of deep eutectic solvents (DESs) were prepared using glycerol and choline chloride (ChCl), and Fourier transform infrared spectrometer (FT-IR) was used to analyze the spectra of glycerol, choline chloride and DESs based on glycerol and choline chloride. Then DESs were used as the additives of mobile phase to optimize chromatographic behavior of caffeic acid in high performance liquid chromatography (HPLC). A 17-run Box-Behnken design (BBD) was employed to evaluate effect of DESs as additives by analyzing the maximum theoretical plate number. Three factors, reaction temperature (60 .deg. C, 80 .deg. C, 100 .deg. C), molar ratio of glycerol and choline chloride (2 : 1, 3 : 1, 4 : 1, n/n), and volume percent of additives (0.05%, 0.10%, 0.15%, v/v), were investigated in BBD. The optimum experiment condition was that of reaction temperature (80 .deg. C), molar ratio of glycerol and ChCl (3 : 1, n/n), and volume percent of additive (0.10%, v/v). The mean chromatographic theoretical plate number of the caffeic acid this condition was 1567.5, and DESs as additives shorten the retention time and modify the chromatogram shape, proving DESs as additives for effective theoretical plate number and column efficiency in HPLC.

  5. Radio-Modulatory Potential ofCaffeic Acid Phenethyl Ester: A Therapeutic Perspective.

    Science.gov (United States)

    Anjaly, Km; Tiku, Ashu

    2017-11-13

    Use of natural agents is an upcoming area of research in cancer biology. Caffeic acid phenethyl ester has received great attention because of its therapeutic potential in various conditions including cancer. It is an active/abundant component of propolis. Propolis is a honey bee hive product produced by bees using their enzyme-rich digestive secretions on resinous mix, bee wax and pollen from plants. It is used to protect the beehive against bacteria and other infections.Although a lot of work has been done on chemotherapeutic aspects of CAPE, its role as a radiomodulator is yet to be delineated. It can act both as radioprotector and radiosensitizer. Depending on the tissue type it can modulate the radiation response by following different mechanisms. This review will focus on the differential radiomodulatory effects of Caffeic Acid Phenethyl Ester in normal and cancer cells.Besides chemistry and bioavailability,it's potential as a therapeutic agent against radiation induced damage will also be discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Thermal transformation of bioactive caffeic acid on fumed silica seen by UV-Vis spectroscopy, thermogravimetric analysis, temperature programmed desorption mass spectrometry and quantum chemical methods.

    Science.gov (United States)

    Kulik, Tetiana V; Lipkovska, Natalia O; Barvinchenko, Valentyna M; Palyanytsya, Borys B; Kazakova, Olga A; Dudik, Olesia O; Menyhárd, Alfréd; László, Krisztina

    2016-05-15

    Thermochemical studies of hydroxycinnamic acid derivatives and their surface complexes are important for the pharmaceutical industry, medicine and for the development of technologies of heterogeneous biomass pyrolysis. In this study, structural and thermal transformations of caffeic acid complexes on silica surfaces were studied by UV-Vis spectroscopy, thermogravimetric analysis, temperature programmed desorption mass spectrometry (TPD MS) and quantum chemical methods. Two types of caffeic acid surface complexes are found to form through phenolic or carboxyl groups. The kinetic parameters of the chemical reactions of caffeic acid on silica surface are calculated. The mechanisms of thermal transformations of the caffeic chemisorbed surface complexes are proposed. Thermal decomposition of caffeic acid complex chemisorbed through grafted ester group proceeds via three parallel reactions, producing ketene, vinyl and acetylene derivatives of 1,2-dihydroxybenzene. Immobilization of phenolic acids on the silica surface improves greatly their thermal stability. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Analysis of Caffeic Acid Extraction From Ocimum gratissimum Linn. by High Performance Liquid Chromatography and its Effects on a Cervical Cancer Cell Line

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    Je-Chiuan Ye

    2010-09-01

    Conclusion: This paper shows that high performance liquid chromatography is a suitable analytical method for determining caffeic acid levels in O. gratissimum, Ju ZenTa, and several vegetable oils. Caffeic acid can suppress the proliferation of HeLa cells.

  8. Product analysis of caffeic acid oxidation by on-line electrochemistry/electrospray ionization mass spectrometry.

    Science.gov (United States)

    Arakawa, Ryuichi; Yamaguchi, Masashi; Hotta, Hiroki; Osakai, Toshiyuki; Kimoto, Takashi

    2004-08-01

    On-line electrochemistry/electrospray ionization mass spectrometry (EC/ESI-MS) was developed using a microflow electrolytic cell. This technique was applied to electrochemical oxidation of caffeic acid (CAF) which is known to be a highly antioxidative agent. Effects of electrolytic potentials on ion intensities of product ions and on electrolytic currents were examined at different pHs. Dimer products were detected at electrolytic potentials of E = 0.7 V (vs. Ag/AgCl) and trimer products at 1.0 V at pH 9. Dimer products were distinguished from hydrogen-bonded complexes by MS/MS experiments. Hydrogen/deuterium exchange experiments determined the number of hydroxyl and carboxyl groups in the Dimers formed by electrolysis. The mechanism of oxidative polymerization of CAF is discussed with speculation as to the structure of the dimer product.

  9. Antiviral Properties of Caffeic Acid Phenethyl Ester and Its Potential Application

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    Haci Kemal Erdemli

    2015-12-01

    Full Text Available Caffeic acid phenethyl ester (CAPE is found in variety of plants and well known active ingredient of the honeybee propolis. CAPE showed anti-inflammatory, anticarcinogenic, antimitogenic, antiviral and immunomodulatory properties in several studies. The beneficial effects of CAPE on different health issues attracted scientists to make more studies on CAPE. Specifically, the anti-viral effects of CAPE and its molecular mechanisms may reveal the important properties of virus-induced diseases. CAPE and its targets may have important roles to design new therapeutics and understand the molecular mechanisms of virus related diseases. In this mini-review, we summarize the antiviral effects of CAPE under the light of medical and chemical literature. [J Intercult Ethnopharmacol 2015; 4(4.000: 344-347

  10. Caffeic acid phenethyl ester attenuates IgE-induced immediate allergic reaction.

    Science.gov (United States)

    Nader, Manar A

    2013-04-01

    Caffeic acid phenethyl ester (CAPE) is the active component of honey bee propolis extracts. The results of the current study demonstrate that CAPE attenuated immunoglobulin (Ig)E-mediated allergic response in mast cells. Oral administration of CAPE inhibited IgE-mediated passive cutaneous anaphylaxis. CAPE effectively reduced both histamine and serotonin (5-HT)-induced vascular permeability in rats. CAPE also reduced histamine and leukotrienes (LTs) release from isolated rat peritoneal mast cells. Moreover, CAPE suppressed contraction induced by histamine (3 × 10(-8)-3 × 10(-5) M), 5-HT (3 × 10(-9)-10(-6) M) and adenosine (3 × 10(-8)-10(-5) M) in guinea pig tracheal zigzag. These findings provide evidence that CAPE may serve as an effective therapeutic agent for allergic diseases.

  11. Engineering alfalfa to accumulate useful caffeic acid derivatives and characterization of hydroxycinnamoyl-CoA transferases from legumes

    Science.gov (United States)

    Some forages crops, such as red clover, accumulate high levels of caffeic acid derivatives. Oxidation of these o-diphenols to quinones by endogenous polyphenol oxidases (PPOs) and the subsequent reactions of these quinones (probably with endogenous plant proteases) result in a significant reduction ...

  12. Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL-induced EGF-receptor activation

    Science.gov (United States)

    Vacaresse, Nathalie; Vieira, Otília; Robbesyn, Fanny; Jürgens, Günther; Salvayre, Robert; Negre-Salvayre, Anne

    2001-01-01

    Oxidized low density lipoproteins (oxLDL) are thought to play a major role in atherosclerosis. OxLDL act in part through alteration of intracellular signalling pathways in cells of the vascular wall. We recently reported that the EGF receptor (EGFR) signalling pathway is activated by lipid peroxidation products (among them 4-hydroxynonenal, 4-HNE) contained in oxLDL.The use of phenolic antioxidants, such as trolox, alpha-tocopherol, caffeic acid and tyrphostins A-25, A-46 or A-1478, showed that the oxLDL-induced EGFR activation is constituted by two separate components, the first (early) one being antioxidant-insensitive, the second (late) being antioxidant-sensitive.4-HNE derivatization of EGFR and EGFR activation induced by exogenous 4-HNE, suggest that the early (0.5 – 3 h) component of oxLDL-induced EGFR activation is mediated (at least in part) by 4-HNE (and possibly by other oxidized lipids). This early component is antioxidant-insensitive.The second component (4 – 5 h) of the oxLDL-induced EGFR activation is antioxidant-sensitive, since it is blocked by antioxidants such as trolox, caffeic acid or PDTC, which act by blocking the cellular oxidative stress (H2O2 generation) evoked by oxLDL. Conversely, exogenous H2O2 induced EGFR autophosphorylation (thus mimicking the second component) and was also inhibited by antioxidants. This effect is mediated in part through inhibition by oxidative stress of protein tyrosine phosphatases involved in EGFR dephosphorylation. PMID:11309250

  13. Effect of caffeic acid phenethyl ester on bone formation in the expanded inter-premaxillary suture

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    Kazancioglu HO

    2015-12-01

    Full Text Available Hakki Oguz Kazancioglu,1 Sertac Aksakalli,2 Seref Ezirganli,1 Muhammet Birlik,2 Mukaddes Esrefoglu,3 Ahmet Hüseyin Acar1 1Department of Oral and Maxillofacial Surgery, 2Department of Orthodontics, Faculty of Dentistry, 3Department of Histology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey Background: Narrow maxilla is a common problem in orthodontics and dentofacial orthopedics. To solve this problem, a procedure called rapid maxillary expansion (RME has been used. However, relapse tendency is a major problem of RME. Although relapse tendency is not clearly understood, various treatment procedures and new application has been investigated. The present study aimed to investigate the possible effectiveness of caffeic acid phenethyl ester (CAPE on new bone formation in rat midpalatal suture after RME.Materials and methods: Twenty male Sprague Dawley rats were used in this study. The animals were randomly divided into two groups as control and CAPE group. In CAPE group, CAPE was administered systemically via intraperitoneal injection. RME procedure was performed on all animals. For this purpose, the springs were placed on the maxillary incisors of rats and activated for 5 days. After then, the springs were removed and replaced with short lengths of rectangular retaining wire for consolidation period of 15 days. At the end of the study, histomorphometric analysis was carried out to assess of new bone formation.Results: New bone formation was significantly greater in CAPE group than the control group (P<0.05. CAPE enhances new bone formation in midpalatal suture after RME.Conclusion: These results show that CAPE may decrease the time needed for retention. Keywords: rapid maxillary expansion, bone formation, caffeic acid phenethyl ester, midpalatal suture, histopathology

  14. Inhibitory effect of caffeic acid on human organic anion transporters hOAT1 and hOAT3: a novel candidate for food-drug interaction.

    Science.gov (United States)

    Uwai, Yuichi; Ozeki, Yukihiro; Isaka, Tomonori; Honjo, Hiroaki; Iwamoto, Kikuo

    2011-01-01

    Several kinds of food have been shown to influence the absorption and metabolism of drugs, although there is little information about their effect on the renal excretion of drugs. In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effects of chlorogenic acid, caffeic acid and quinic acid, which are contained in coffee, fruits and vegetables, on human organic anion transporters hOAT1 and hOAT3; these transporters mediate renal tubular uptake of anionic drugs from blood. Injection of hOAT1 and hOAT3 cRNA into oocytes stimulated uptake of typical substrates of hOAT1 and hOAT3 (p-aminohippurate and estrone sulfate, respectively); among the three compounds tested, caffeic acid most strongly inhibited these transporters. The apparent 50% inhibitory concentrations of caffeic acid were estimated to be 16.6 µM for hOAT1 and 5.4 µM for hOAT3. Eadie-Hofstee plot analysis showed that caffeic acid inhibited both transporters in a competitive manner. In addition to the transport of p-aminohippurate and estrone sulfate, that of antifolates and antivirals was inhibited by caffeic acid. These findings show that caffeic acid has inhibitory potential against hOAT1 and hOAT3, suggesting that renal excretion of their substrates could be affected in patients consuming a diet including caffeic acid.

  15. Fungal biotransformation of chlorogenic and caffeic acids by Fusarium graminearum: New insights in the contribution of phenolic acids to resistance to deoxynivalenol accumulation in cereals.

    Science.gov (United States)

    Gauthier, Léa; Bonnin-Verdal, Marie-Noelle; Marchegay, Gisèle; Pinson-Gadais, Laetitia; Ducos, Christine; Richard-Forget, Florence; Atanasova-Penichon, Vessela

    2016-03-16

    Fusarium Head Blight and Gibberella Ear Rot, mainly caused by the fungi Fusarium graminearum and Fusarium culmorum, are two of the most devastating diseases of small-grain cereals and maize. In addition to yield loss, these diseases frequently result in contamination of kernels with toxic type B trichothecenes. The potential involvement of chlorogenic acid in cereal resistance to Fusarium Head Blight and Gibberella Ear Rot and to trichothecene accumulation was the focus of this study. The effects of chlorogenic acid and one of its hydrolyzed products, caffeic acid, on fungal growth and type B trichothecenes biosynthesis were studied using concentrations close to physiological amounts quantified in kernels and a set of F. graminearum and F. culmorum strains. Both chlorogenic and caffeic acids negatively impact fungal growth and mycotoxin production, with caffeic acid being significantly more toxic. Inhibitory efficiencies of both phenolic acids were strain-dependent. To further investigate the antifungal and anti "mycotoxin" effect of chlorogenic and caffeic acids, the metabolic fate of these two phenolic acids was characterized in supplemented F. graminearum broths. For the first time, our results demonstrated the ability of F. graminearum to degrade chlorogenic acid into caffeic, hydroxychlorogenic and protocatechuic acids and caffeic acid into protocatechuic and hydroxycaffeic acids. Some of these metabolic products can contribute to the inhibitory efficiency of chlorogenic acid that, therefore, can be compared as a "pro-drug". As a whole, our data corroborate the contribution of chlorogenic acid to the chemical defense that cereals employ to counteract F. graminearum and its production of mycotoxins. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Caffeic Acid-PLGA Conjugate to Design Protein Drug Delivery Systems Stable to Irradiation

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    Francesca Selmin

    2015-01-01

    Full Text Available This work reports the feasibility of caffeic acid grafted PLGA (g-CA-PLGA to design biodegradable sterile microspheres for the delivery of proteins. Ovalbumin (OVA was selected as model compound because of its sensitiveness of γ-radiation. The adopted grafting procedure allowed us to obtain a material with good free radical scavenging properties, without a significant modification of Mw and Tg of the starting PLGA (Mw PLGA = 26.3 ± 1.3 kDa vs. Mw g-CA-PLGA = 22.8 ± 0.7 kDa; Tg PLGA = 47.7 ± 0.8 °C vs. Tg g-CA-PLGA = 47.4 ± 0.2 °C. By using a W1/O/W2 technique, g-CA-PLGA improved the encapsulation efficiency (EE, suggesting that the presence of caffeic residues improved the compatibility between components (EEPLGA = 35.0% ± 0.7% vs. EEg-CA-PLGA = 95.6% ± 2.7%. Microspheres particle size distribution ranged from 15 to 50 µm. The zeta-potential values of placebo and loaded microspheres were −25 mV and −15 mV, respectively. The irradiation of g-CA-PLGA at the dose of 25 kGy caused a less than 1% variation of Mw and the degradation patterns of the non-irradiated and irradiated microspheres were superimposable. The OVA content in g-CA-PLGA microspheres decreased to a lower extent with respect to PLGA microspheres. These results suggest that g-CA-PLGA is a promising biodegradable material to microencapsulate biological drugs.

  17. Impact of caffeic acid addition on phenolic composition of tempranillo wines from different winemaking techniques.

    Science.gov (United States)

    Aleixandre-Tudó, José Luis; Alvarez, I; Lizama, Victoria; García, María José; Aleixandre, José Luis; Du Toit, Wessel J

    2013-12-11

    The effect of prefermentative and postfermentative caffeic acid (CFA) addition, prefermentative cold maceration, and a simulation of the micro-oxygenation technique through acetaldehyde addition on the phenolic and color composition of Tempranillo wines was investigated. Cold soaking and dry ice addition were performed as prefermentative techniques. Wines were analyzed after the end of the malolactic fermentation and after 6 and 12 months' storage. The results showed an important effect in wines to which CFA had been added, suggesting intramolecular copigmentation reactions through direct interaction between anthocyanins and free phenolic acids, thereby increasing the acylated anthocyanin fraction with an increase in color stability. The higher concentration of total phenols and lower hue values in CFA-added wines also contributed to the stability of these compounds during storage. Prefermentative cold maceration was shown to be influenced by the vintage. Phenolic acids, the acylated anthocyanin fraction, and total phenolics showed higher values in CFA-added and acetaldehyde-added wines. No differences were found in color density between the control wines and both the prefermentative and postfermentative CFA-added wines. However, a higher anthocyanin polymeric fraction and higher acylated anthocyanins, phenolic acids, and total phenols were observed in the CFA-added wines. The implications of this for the color stability of Tempranillo are also discussed.

  18. Chlorogenic acid versus amaranth's caffeoylisocitric acid - Gut microbial degradation of caffeic acid derivatives.

    Science.gov (United States)

    Vollmer, Maren; Schröter, David; Esders, Selma; Neugart, Susanne; Farquharson, Freda M; Duncan, Sylvia H; Schreiner, Monika; Louis, Petra; Maul, Ronald; Rohn, Sascha

    2017-10-01

    The almost forgotten crop amaranth has gained renewed interest in recent years due to its immense nutritive potential. Health beneficial effects of certain plants are often attributed to secondary plant metabolites such as phenolic compounds. As these compounds undergo significant metabolism after consumption and are in most cases not absorbed very well, it is important to gain knowledge about absorption, biotransformation, and further metabolism in the human body. Whilst being hardly found in other edible plants, caffeoylisocitric acid represents the most abundant low molecular weight phenolic compound in many leafy amaranth species. Given that this may be a potentially bioactive compound, gastrointestinal microbial degradation of this substance was investigated in the present study by performing in vitro fermentation tests using three different fecal samples as inocula. The (phenolic) metabolites were analyzed using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Furthermore, quantitative polymerase chain reaction (qPCR) analyses were carried out to study the influence on the microbiome and its composition. The in vitro fermentations led to different metabolite profiles depending on the specific donor. For example, the metabolite 3-(4-hydroxyphenyl)propionic acid was observed in one fermentation as the main metabolite, whereas 3-(3-hydroxyphenyl)propionic acid was identified in the other fermentations as important. A significant change in selected microorganisms of the gut microbiota however was not detected. In conclusion, caffeoylisocitric acid from amaranth, which is a source of several esterified phenolic acids in addition to chlorogenic acid, can be metabolized by the human gut microbiota, but the metabolites produced vary between individuals. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Caffeic Acid Phenethyl Ester from the Twigs of Cinnamomum cassia Inhibits Malignant Cell Transformation by Inducing c-Fos Degradation.

    Science.gov (United States)

    Shin, Seung Ho; Lee, Seoung Rak; Lee, Eunjung; Kim, Ki Hyun; Byun, Sanguine

    2017-07-28

    The twigs of Cinnamomum cassia, commonly referred to as Cinnamomi Ramulus, are widely used as one of the primary ingredients in Chinese/Korean traditional medicines that have anticancer effects. However, the active constituents responsible for its anticancer effects and their molecular mechanisms still remain to be elucidated. Caffeic acid phenethyl ester (CAPE) and caffeic acid (CA) were isolated for the first time from C. cassia using LC-MS-guided phytochemical isolation methods. CAPE significantly suppressed EGF- and TPA-induced cell transformation of JB6 P+ cells at sub-micromolar concentrations, whereas CA, a structurally similar compound to CAPE, had no such effect. The antiproliferative and chemopreventive activity of CAPE was found to arise through the inhibition of AP-1 transcriptional activity via the promotion of c-Fos degradation. These findings demonstrate that CAPE may contribute to the chemopreventive/chemotherapeutic effects of C. cassia through downregulating c-Fos.

  20. Protective Effects of Intralipid and Caffeic Acid Phenethyl Ester on Nephrotoxicity Caused by Dichlorvos in Rats

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    Muhammet Murat Celik

    2015-01-01

    Full Text Available The protective effects of Caffeic Acid Phenethyl Ester (CAPE and intralipid (IL on nephrotoxicity caused by acute Dichlorvos (D toxicity were investigated in this study. Forty-eight Wistar Albino rats were divided into 7 groups as follows: Control, D, CAPE, intralipid, D + CAPE, D + IL, and D + CAPE + IL. When compared to D group, the oxidative stress index (OSI values were significantly lower in Control, CAPE, and D + IL + CAPE groups. When compared to D + IL + CAPE group, the TOS and OSI values were significantly higher in D group (P<0.05. When mitotic cell counts were assessed in the renal tissues, it was found that mitotic cell count was significantly higher in the D group while it was lower in the D + CAPE, D + IL, and D + IL + CAPE groups when compared to the control group (P<0.05. Also, immune reactivity showed increased apoptosis in D group and low profile of apoptosis in the D + CAPE group when compared to the Control group. The apoptosis level was significantly lower in D + IL + CAPE compared to D group (P<0.05 in the kidneys. As a result, we concluded that Dichlorvos can be used either alone or in combination with CAPE and IL as supportive therapy or as facilitator for the therapeutic effect of the routine treatment in the patients presenting with pesticide poisoning.

  1. Caffeic Acid Phenethyl Ester Is a Potential Therapeutic Agent for Oral Cancer

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    Ying-Yu Kuo

    2015-05-01

    Full Text Available Head and neck cancers, which affect 650,000 people and cause 350,000 deaths per year, is the sixth leading cancer by cancer incidence and eighth by cancer-related death worldwide. Oral cancer is the most common type of head and neck cancer. More than 90% of oral cancers are oral and oropharyngeal squamous cell carcinoma (OSCC. The overall five-year survival rate of OSCC patients is approximately 63%, which is due to the low response rate to current therapeutic drugs. In this review we discuss the possibility of using caffeic acid phenethyl ester (CAPE as an alternative treatment for oral cancer. CAPE is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment can effectively suppress the proliferation, survival, and metastasis of oral cancer cells. CAPE treatment inhibits Akt signaling, cell cycle regulatory proteins, NF-κB function, as well as activity of matrix metalloproteinase (MMPs, epidermal growth factor receptor (EGFR, and Cyclooxygenase-2 (COX-2. Therefore, CAPE treatment induces cell cycle arrest and apoptosis in oral cancer cells. According to the evidence that aberrations in the EGFR/phosphoinositide 3-kinase (PI3K/protein kinase B (Akt signaling, NF-κB function, COX-2 activity, and MMPs activity are frequently found in oral cancers, and that the phosphorylation of Akt, EGFR, and COX-2 correlates to oral cancer patient survival and clinical progression, we believe that CAPE treatment will be useful for treatment of advanced oral cancer patients.

  2. Modulation of Tamoxifen Cytotoxicity by Caffeic Acid Phenethyl Ester in MCF-7 Breast Cancer Cells

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    Tarek K. Motawi

    2016-01-01

    Full Text Available Although Tamoxifen (TAM is one of the most widely used drugs in managing breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE is a polyphenolic compound present in many medicinal plants and in propolis. The present study examined the effect of CAPE on TAM cytotoxicity in MCF-7 cells. MCF-7 cells were treated with different concentrations of TAM and/or CAPE for 48 h. This novel combination exerted synergistic cytotoxic effects against MCF-7 cells via induction of apoptotic machinery with activation of caspases and DNA fragmentation, along with downregulation of Bcl-2 and Beclin 1 expression levels. However, the mammalian microtubule-associated protein light chain LC 3-II level was unchanged. Vascular endothelial growth factor level was also decreased, whereas levels of glutathione and nitric oxide were increased. In conclusion, CAPE augmented TAM cytotoxicity via multiple mechanisms, providing a novel therapeutic approach for breast cancer treatment that can overcome resistance and lower toxicity. This effect provides a rationale for further investigation of this combination.

  3. Caffeic acid and hydroxytyrosol have anti-obesogenic properties in zebrafish and rainbow trout models.

    Science.gov (United States)

    Lutfi, Esmail; Babin, Patrick J; Gutiérrez, Joaquim; Capilla, Encarnación; Navarro, Isabel

    2017-01-01

    Some natural products, known sources of bioactive compounds with a wide range of properties, may have therapeutic values in human health and diseases, as well as agronomic applications. The effect of three compounds of plant origin with well-known dietary antioxidant properties, astaxanthin (ATX), caffeic acid (CA) and hydroxytyrosol (HT), on zebrafish (Danio rerio) larval adiposity and rainbow trout (Onchorynchus mykiss) adipocytes was assessed. The zebrafish obesogenic test (ZOT) demonstrated the anti-obesogenic activity of CA and HT. These compounds were able to counteract the obesogenic effect produced by the peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (RGZ). CA and HT suppressed RGZ-increased PPARγ protein expression and lipid accumulation in primary-cultured rainbow trout adipocytes. HT also significantly reduced plasma triacylglycerol concentrations, as well as mRNA levels of the fasn adipogenic gene in the adipose tissue of HT-injected rainbow trout. In conclusion, in vitro and in vivo approaches demonstrated the anti-obesogenic potential of CA and HT on teleost fish models that may be relevant for studying their molecular mode of action. Further studies are required to evaluate the effect of these bioactive components as food supplements for modulating adiposity in farmed fish.

  4. Caffeic Acid Phenethyl Ester Regulates PPAR’s Levels in Stem Cells-Derived Adipocytes

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    Luca Vanella

    2016-01-01

    Full Text Available Hypertrophic obesity inhibits activation of peroxisome proliferators-activated receptor gamma (PPARγ, considered the key mediator of the fully differentiated and insulin sensitive adipocyte phenotype. We examined the effects of Caffeic Acid Phenethyl Ester (Cape, isolated from propolis, a honeybee hive product, on Adipose Stem Cells (ASCs differentiation to the adipocyte lineage. Finally we tested the effects of Cape on insulin-resistant adipocytes. Quantification of Oil Red O-stained cells showed that lipid droplets decreased following Cape treatment as well as radical oxygen species formation. Additionally, exposure of ASC to high glucose levels decreased adiponectin and increased proinflammatory cytokines mRNA levels, which were reversed by Cape-mediated increase of insulin sensitivity. Cape treatment resulted in decreased triglycerides synthesis and increased beta-oxidation. Exposure of ASCs to Lipopolysaccharide (LPS induced a reduction of PPARγ, an increase of IL-6 levels associated with a well-known stimulation of lipolysis; Cape partially attenuated the LPS-mediated effects. These observations reveal the main role of PPARγ in the adipocyte function and during ASC differentiation. As there is now substantial interest in functional food and nutraceutical products, the observed therapeutic value of Cape in insulin-resistance related diseases should be taken into consideration.

  5. Caffeic acid and quercetin exert caspases-independent apoptotic effects on Leishmania major promastigotes, and reactivate the death of infected phagocytes derived from BALB/c mice

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    Radia Belkhelfa-Slimani

    2017-04-01

    Conclusions: The leishmanicidal effect of caffeic acid and quercetin on promastigotes and amastigotes, as well as reactivation of infected phagocytes apoptosis, suggested a potential therapeutic role against cutaneous leishmaniasis.

  6. Terpenoids, flavonoids and caffeic acid derivatives from Salvia viridis L. cvar. Blue Jeans.

    Science.gov (United States)

    Rungsimakan, Supattra; Rowan, Michael G

    2014-12-01

    Three diterpenoids, 1-oxomicrostegiol (1), viroxocin (2), viridoquinone (3), were isolated from the roots of Salvia viridis L. cvar. Blue Jeans. Five known diterpenoids, microstegiol (4), 7α-acetoxy-14-hydroxy-8,13-abietadiene-11,12-dione (5; 7-O-acetylhorminone tautomer), 7α,14-dihydroxy-8,13-abietadiene-11,12-dione (6; horminone tautomer), ferruginol and salvinolonyl 12-methyl ether (7) were also found in the roots together with 1-docosyl ferulate (8), and a mixture of 2-(4'-alkoxyphenyl) ethyl alkanoates (9). Two lupane triterpenoids, 2α-acetoxy-lup-20(29)-en-3β-ol (10), and 3β-acetoxy-lup-20(29)-en-2α-ol (11) were found in the aerial parts together with known compounds, lup-20(29)-ene-2α,3β-diol (12), ursolic acid, oleanolic acid, β-sitosterol and β-sitosterol glucoside. A known phenylpropanoid, trans-verbascoside (or acteoside; 13), was the main constituent in the polar fraction of the aerial part, and it is now reported in the genus Salvia for the first time. Other polyphenolic compounds were cis-verbascoside (14), leucosceptoside A (15), martynoside (16), caffeic acid, 6-O-caffeoyl-glucose (18), rosmarinic acid, salidroside, luteolin-7-O-α-rhamnopyranosyl-(1→6)-β-galactopyranoside, luteolin-7-O-β-galactopyranoside, luteolin-7-O-α-rhamnopyranosyl-(1→6)-β-glucopyranoside, luteolin-7-O-β-glucopyranoside, and apigenin-7-O-β-glucopyranoside. The structures were determined by 1D-, 2D-NMR and HR-ESI-MS techniques. Compounds 6, 10, ferruginol, ursolic acid and oleanolic acid exhibited antibacterial activity against Enterococcus faecalis (ATCC 775) with MIC 50 μM, 25 μM, 50 μM, 12.5 μM, 12.5 μM respectively. Ferruginol, ursolic acid and oleanolic acid were also active against Staphylococcus aureus (ATCC 6571), and Bacillus cereus (ATCC 2599) with MIC 12.5-50 μM. 4 was also active against S.aureus (ATCC 6571) with MIC 50 μM. These values are consistent with previous studies on the antimicrobial activity of Salvia diterpenoids. Copyright

  7. Structural characterization of the mitomycin 7-O-methyltransferase.

    Science.gov (United States)

    Singh, Shanteri; Chang, Aram; Goff, Randal D; Bingman, Craig A; Grüschow, Sabine; Sherman, David H; Phillips, George N; Thorson, Jon S

    2011-07-01

    Mitomycins are quinone-containing antibiotics, widely used as antitumor drugs in chemotherapy. Mitomycin-7-O-methyltransferase (MmcR), a key tailoring enzyme involved in the biosynthesis of mitomycin in Streptomyces lavendulae, catalyzes the 7-O-methylation of both C9β- and C9α-configured 7-hydroxymitomycins. We have determined the crystal structures of the MmcR-S-adenosylhomocysteine (SAH) binary complex and MmcR-SAH-mitomycin A (MMA) ternary complex at resolutions of 1.9and 2.3 Å, respectively. The study revealed MmcR to adopt a common S-adenosyl-L-methionine-dependent O-methyltransferase fold and the presence of a structurally conserved active site general acid-base pair is consistent with a proton-assisted methyltransfer common to most methyltransferases. Given the importance of C7 alkylation to modulate mitomycin redox potential, this study may also present a template toward the future engineering of catalysts to generate uniquely bioactive mitomycins. Copyright © 2011 Wiley-Liss, Inc.

  8. Structural characterization of the mitomycin 7-O-methyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Shanteri; Chang, Aram; Goff, Randal D.; Bingman, Craig A.; Grüschow, Sabine; Sherman, David H.; Phillips, Jr., George N.; Thorson, Jon S. (Michigan); (UW)

    2014-10-02

    Mitomycins are quinone-containing antibiotics, widely used as antitumor drugs in chemotherapy. Mitomycin-7-O-methyltransferase (MmcR), a key tailoring enzyme involved in the biosynthesis of mitomycin in Streptomyces lavendulae, catalyzes the 7-O-methylation of both C9{beta}- and C9{alpha}-configured 7-hydroxymitomycins. We have determined the crystal structures of the MmcR-S-adenosylhomocysteine (SAH) binary complex and MmcR-SAH-mitomycin A (MMA) ternary complex at resolutions of 1.9 and 2.3 {angstrom}, respectively. The study revealed MmcR to adopt a common S-adenosyl-L-methionine-dependent O-methyltransferase fold and the presence of a structurally conserved active site general acid-base pair is consistent with a proton-assisted methyltransfer common to most methyltransferases. Given the importance of C7 alkylation to modulate mitomycin redox potential, this study may also present a template toward the future engineering of catalysts to generate uniquely bioactive mitomycins.

  9. Detoxification Processes from Vanadate at the Root Apoplasm Activated by Caffeic and Polygalacturonic Acids.

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    Giovanni Garau

    Full Text Available In the root apoplasm, V(V and V(IV toxicity can be alleviated through redox and complexation reactions involving phenolic substances and the polyuronic components. In such context we report the role of polygalacturonic acid (PGA on the reducing activity of caffeic acid (CAF towards V(V. The redox reaction was particularly effective at pH 2.8 leading to the formation of oxidation products with redox activity towards V(V. An o-quinone was identified as the first product of the reaction which is further involved in the formation of CAF dimers. At pH ≥ 3.6 the redox activity decreased and a yield in V(IV equal to 38, 31, 21 and 14% was found at pH 3.6, 4.0. 5.0 and 6.0 respectively compared with that obtained at pH 2.8. The redox reaction was faster in the presence of PGA and a higher yield of V(IV was found in the 4.0-6.0 pH range with respect to the CAF-V(V binary system. The higher efficiency of the redox reaction in the presence of PGA was related with the ability of PGA to bind V(IV. The biological significance of the redox reaction between CAF and V(V, as well as the role of PGA in such reaction, was established "in vivo" using triticale plants. Results showed that PGA reduced significantly the phytotoxic effects of the V(V-CAF system.

  10. Caffeic Acid Phenethyl Ester Protects against Amphotericin B Induced Nephrotoxicity in Rat Model

    Science.gov (United States)

    Altuntaş, Atila; Yılmaz, H. Ramazan; Altuntaş, Ayşegül; Uz, Efkan; Demir, Murat; Gökçimen, Alparslan; Aksu, Oğuzhan; Bayram, Dilek Şenol; Sezer, Mehmet Tuğrul

    2014-01-01

    The present study was conducted to investigate whether caffeic acid phenethyl ester (CAPE), an active component of propolis extract, has a protective effect on amphotericin B induced nephrotoxicity in rat models. Male Wistar-Albino rats were randomly divided into four groups: (I) control group (n = 10), (II) CAPE group (n = 9) which received 10 μmol/kg CAPE intraperitoneally (i.p.), (III) amphotericin B group (n = 7) which received one dose of 50 mg/kg amphotericin B, and (IV) amphotericin B plus CAPE group (n = 7) which received 10 μmol/kg CAPE i.p. and one dose of 50 mg/kg amphotericin B. The left kidney was evaluated histopathologically for nephrotoxicity. Levels of malondialdehyde (MDA), nitric oxide (NO), enzyme activities including catalase (CAT), and superoxide dismutase (SOD) were measured in the right kidney. Histopathological damage was prominent in the amphotericin B group compared to controls, and the severity of damage was lowered by CAPE administration. The activity of SOD, MDA, and NO levels increased and catalase activity decreased in the amphotericin B group compared to the control group (P = 0.0001, P = 0.003, P = 0.0001, and P = 0.0001, resp.). Amphotericin B plus CAPE treatment caused a significant decrease in MDA, NO levels, and SOD activity (P = 0.04, P = 0.02, and P = 0.0001, resp.) and caused an increase in CAT activity compared with amphotericin B treatment alone (P = 0.005). CAPE treatment seems to be an effective adjuvant agent for the prevention of amphotericin B nephrotoxicity in rat models. PMID:25032223

  11. The protective effects of caffeic acid phenethyl ester against toluene-induced nephrotoxicity in rats.

    Science.gov (United States)

    Meydan, Sedat; Nacar, Ahmet; Oztürk, Hasan Oktay; Tas, Ufuk; Köse, Evren; Zararsiz, Ismail; Yılmaz, Nigar; Kus, Ilter

    2016-01-01

    Caffeic acid phenethyl ester (CAPE) has antioxidant and anti-inflammatory properties. The aim of this study is to examine the negative effects of toluene on kidney tissues and functions and to investigate the protective effects of CAPE against toluene-induced nephrotoxicity in rats. A total of 21 male Wistar rats were divided into three groups of equal number in each. The rats in group I were the controls. Toluene was intraperitoneally injected into the rats in group II with a dose of 500 mg/kg. Rats in group III received CAPE daily while exposed to toluene. After 14 days of experimental period, all rats were killed by decapitation. Enzymatic activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) and malondialdehyde (MDA) levels were studied in the rat kidneys. Blood urea nitrogen (BUN) and serum creatinine levels were measured for renal function. The CAT and SOD enzyme activities and serum creatinine levels were significantly increased in rats treated with toluene when compared with the controls. But GSH-Px activity, MDA, and BUN levels showed statistically nonsignificant changes. However, increased CAT and SOD enzyme activities and decreased serum creatinine levels were detected in the rats that received CAPE while exposed to toluene. The GSH-Px activity and MDA and BUN levels in the same group did not show statistically significant changes. The results of our study demonstrated that toluene damages kidney tissue and is a nephrotoxic substance. CAPE was able to prevent the renal damage as antioxidant, antitoxic, and nephroprotective agent. © The Author(s) 2013.

  12. Antioxidant Activity of Caffeic Acid against Iron-Induced Free Radical Generation--A Chemical Approach.

    Science.gov (United States)

    Genaro-Mattos, Thiago C; Maurício, Ângelo Q; Rettori, Daniel; Alonso, Antonio; Hermes-Lima, Marcelo

    2015-01-01

    Caffeic acid (CA) is a phenolic compound widely found in coffee beans with known beneficial effects in vivo. Many studies showed that CA has anti-inflammatory, anti-mutagenic, antibacterial and anti-carcinogenic properties, which could be linked to its antioxidant activity. Taking in consideration the reported in vitro antioxidant mechanism of other polyphenols, our working hypothesis was that the CA antioxidant activity could be related to its metal-chelating property. With that in mind, we sought to investigate the chemical antioxidant mechanism of CA against in vitro iron-induced oxidative damage under different assay conditions. CA was able to prevent hydroxyl radical formation promoted by the classical Fenton reaction, as determined by 2-deoxyribose (2-DR) oxidative degradation and DMPO hydroxylation. In addition to its ability to prevent hydroxyl radical formation, CA had a great inhibition of membrane lipid peroxidation. In the lipid peroxidation assays CA acted as both metal-chelator and as hydrogen donor, preventing the deleterious action promoted by lipid-derived peroxyl and alkoxyl radicals. Our results indicate that the observed antioxidant effects were mostly due to the formation of iron-CA complexes, which are able to prevent 2-DR oxidation and DMPO hydroxylation. Noteworthy, the formation of iron-CA complexes and prevention of oxidative damage was directly related to the pH of the medium, showing better antioxidant activity at higher pH values. Moreover, in the presence of lipid membranes the antioxidant potency of CA was much higher, indicating its enhanced effectiveness in a hydrophobic environment. Overall, our results show that CA acts as an antioxidant through an iron chelating mechanism, preventing the formation of free hydroxyl radicals and, therefore, inhibiting Fenton-induced oxidative damage. The chemical properties of CA described here--in association with its reported signaling effects--could be an explanation to its beneficial effects

  13. Antioxidant Activity of Caffeic Acid against Iron-Induced Free Radical Generation—A Chemical Approach

    Science.gov (United States)

    Genaro-Mattos, Thiago C.; Maurício, Ângelo Q.; Rettori, Daniel; Alonso, Antonio; Hermes-Lima, Marcelo

    2015-01-01

    Caffeic acid (CA) is a phenolic compound widely found in coffee beans with known beneficial effects in vivo. Many studies showed that CA has anti-inflammatory, anti-mutagenic, antibacterial and anti-carcinogenic properties, which could be linked to its antioxidant activity. Taking in consideration the reported in vitro antioxidant mechanism of other polyphenols, our working hypothesis was that the CA antioxidant activity could be related to its metal-chelating property. With that in mind, we sought to investigate the chemical antioxidant mechanism of CA against in vitro iron-induced oxidative damage under different assay conditions. CA was able to prevent hydroxyl radical formation promoted by the classical Fenton reaction, as determined by 2-deoxyribose (2-DR) oxidative degradation and DMPO hydroxylation. In addition to its ability to prevent hydroxyl radical formation, CA had a great inhibition of membrane lipid peroxidation. In the lipid peroxidation assays CA acted as both metal-chelator and as hydrogen donor, preventing the deleterious action promoted by lipid-derived peroxyl and alkoxyl radicals. Our results indicate that the observed antioxidant effects were mostly due to the formation of iron-CA complexes, which are able to prevent 2-DR oxidation and DMPO hydroxylation. Noteworthy, the formation of iron-CA complexes and prevention of oxidative damage was directly related to the pH of the medium, showing better antioxidant activity at higher pH values. Moreover, in the presence of lipid membranes the antioxidant potency of CA was much higher, indicating its enhanced effectiveness in a hydrophobic environment. Overall, our results show that CA acts as an antioxidant through an iron chelating mechanism, preventing the formation of free hydroxyl radicals and, therefore, inhibiting Fenton-induced oxidative damage. The chemical properties of CA described here—in association with its reported signaling effects—could be an explanation to its beneficial effects

  14. Antioxidant Activity of Caffeic Acid against Iron-Induced Free Radical Generation--A Chemical Approach.

    Directory of Open Access Journals (Sweden)

    Thiago C Genaro-Mattos

    Full Text Available Caffeic acid (CA is a phenolic compound widely found in coffee beans with known beneficial effects in vivo. Many studies showed that CA has anti-inflammatory, anti-mutagenic, antibacterial and anti-carcinogenic properties, which could be linked to its antioxidant activity. Taking in consideration the reported in vitro antioxidant mechanism of other polyphenols, our working hypothesis was that the CA antioxidant activity could be related to its metal-chelating property. With that in mind, we sought to investigate the chemical antioxidant mechanism of CA against in vitro iron-induced oxidative damage under different assay conditions. CA was able to prevent hydroxyl radical formation promoted by the classical Fenton reaction, as determined by 2-deoxyribose (2-DR oxidative degradation and DMPO hydroxylation. In addition to its ability to prevent hydroxyl radical formation, CA had a great inhibition of membrane lipid peroxidation. In the lipid peroxidation assays CA acted as both metal-chelator and as hydrogen donor, preventing the deleterious action promoted by lipid-derived peroxyl and alkoxyl radicals. Our results indicate that the observed antioxidant effects were mostly due to the formation of iron-CA complexes, which are able to prevent 2-DR oxidation and DMPO hydroxylation. Noteworthy, the formation of iron-CA complexes and prevention of oxidative damage was directly related to the pH of the medium, showing better antioxidant activity at higher pH values. Moreover, in the presence of lipid membranes the antioxidant potency of CA was much higher, indicating its enhanced effectiveness in a hydrophobic environment. Overall, our results show that CA acts as an antioxidant through an iron chelating mechanism, preventing the formation of free hydroxyl radicals and, therefore, inhibiting Fenton-induced oxidative damage. The chemical properties of CA described here--in association with its reported signaling effects--could be an explanation to its

  15. Cloning and expressing a highly functional and substrate specific farnesoic acid o-methyltransferase from the Asian citrus psyllid (Diaphorina citri Kuwayama)

    Science.gov (United States)

    Van Ekert, Evelien; Shatters, Robert G.; Rougé, Pierre; Powell, Charles A.; Smagghe, Guy; Borovsky, Dov

    2015-01-01

    The Asian citrus psyllid, Diaphorina citri, transmits a phloem-limited bacterium, Candidatus ‘Liberibacter’ asiaticus that causes citrus greening disease. Because juvenile hormone (JH) plays an important role in adult and nymphal development, we studied the final steps in JH biosynthesis in D. citri. A putative JH acid methyltransferase ortholog gene (jmtD) and its cognate cDNA were identified by searching D. citri genome database. Expression analysis shows expression in all life stages. In adults, it is expressed in the head-thorax, (containing the corpora allata), and the abdomen (containing ovaries and male accessory glands). A 3D protein model identified the catalytic groove with catalytically active amino acids and the S-adenosyl methionine (SAM)-binding loop. The cDNA was expressed in Escherichia coli cells and the purified enzyme showed high preference for farnesoic acid (FA) and homoFA (kcat of 0.752 × 10−3 and 0.217 × 10−3 s−1, respectively) as compared to JH acid I (JHA I) (cis/trans/cis; 2Z, 6E, 10cis), JHA III (2E, 6E, 10cis), and JHA I (trans/cis/cis; 2E, 2Z, 10cis) (kcat of 0.081 × 10−3, 0.013 × 10−3, and 0.003 × 10−3 s−1, respectively). This suggests that this ortholog is a DcFA-o-methyl transferase gene (fmtD), not a jmtD, and that JH biosynthesis in D. citri proceeds from FA to JH III through methyl farnesoate (MF). DcFA-o-MT does not require Ca2+, Mg2+ or Zn2+, however, Zn2+ (1 mM) completely inhibits the enzyme probably by binding H115 at the active groove. This represents the first purified FA-o-MT from Hemiptera with preferred biological activity for FA and not JHA. PMID:25893162

  16. Methyl farnesoate synthesis in the lobster mandibular organ: The roles of HMG-CoA reductase and farnesoic acid-O-methyltransferase

    Science.gov (United States)

    Li, Sheng; Friesen, Jon A.; Holford, Kenneth C.; Borst, David W.

    2009-01-01

    Eyestalk ablation (ESA) increases crustacean production of methyl farnesoate (MF), a juvenile hormone-like compound, but the biochemical steps involved are not completely understood. We measured the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) and farnesoic acid-O-methyl transferase (FAOMeT), an early step and the last step in MF synthesis. ESA elevated hemolymph levels of MF in male lobsters. Enzyme activity suggested that increased MF production on day one was due largely to elevated HMGR activity while changes in FAOMeT activity closely paralleled changes in MF levels on day 14. Transcript levels for HMGR and FAOMeT changed little on day one, but both increased substantially on day 14. We treated ESA males with a partially purified mandibular organ inhibiting hormone (MOIH) and observed a significant decline in MF levels, FAOMeT activity, and FAOMeT-mRNA levels after 5 hours. However, no effect was observed on HMGR activity or its mRNA indicating that they must be regulated by a separate sinus gland peptide. We confirmed that lobster HMGR was not a phosphoprotein and was not regulated by reversible phosphorylation, an important mechanism for regulating other HMGRs. Nevertheless, molecular modeling indicated that the catalytic mechanisms of lobster and mammalian HMGR were similar. PMID:19778626

  17. Pharmacokinetics of Caffeic Acid, Ferulic Acid, Formononetin, Cryptotanshinone, and Tanshinone IIA after Oral Administration of Naoxintong Capsule in Rat by HPLC-MS/MS

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    Jin Li

    2017-01-01

    Full Text Available Naoxintong capsule (NXTC was a famous patent medicine of Traditional Chinese Medicine (TCM to treat cerebrovascular diseases in China. An LC-MS/MS method was developed for simultaneous determination of 11 major ingredients (paeoniflorin, ecdysterone, amygdalin, mulberroside A, caffeic acid, ferulic acid, salvianolic acid B, astragaloside IV, formononetin, cryptotanshinone, and tanshinone IIA in NXTC in rat plasma. All analytes were separated on an Eclipse plus C18 column using a gradient mobile phase system of acetonitrile-0.1% formic acid aqueous solution. The lower limits of quantification of 11 ingredients were between 0.075 and 10 ng mL−1. The precision was less than 15% and the accuracies were between 85% and 115%. The results showed that caffeic acid, ferulic acid, formononetin, cryptotanshinone, and tanshinone IIA could be detected after oral administration of NXTC. The validated method was successfully applied to pharmacokinetic study of the caffeic acid, ferulic acid, formononetin, cryptotanshinone, and tanshinone IIA in rats after oral administration of NXTC at single and triple dose.

  18. Ternary choline chloride/caffeic acid/ethylene glycol deep eutectic solvent as both a monomer and template in a molecularly imprinted polymer.

    Science.gov (United States)

    Fu, Najing; Liu, Xiao; Li, Liteng; Tang, Baokun; Row, Kyung Ho

    2017-05-01

    A molecularly imprinted polymer based on a ternary deep eutectic solvent comprised of choline chloride/caffeic acid/ethylene glycol was prepared. The caffeic acid in the ternary deep eutectic solvent was used as both a monomer and template. The molecularly imprinted polymer based on the ternary deep eutectic solvent was characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, field-emission scanning electron microscopy, Brunauer-Emmett-Teller surface area analysis, atomic force microscopy, and elemental analysis. A series of molecularly imprinted polymers based on choline chloride/caffeic acid/ethylene glycol with different molar ratios was prepared and applied to the molecular recognition of polyphenols. A comparison of the recognition ability of molecularly imprinted polymers to polyphenols revealed that the choline chloride/caffeic acid/ethylene glycol (1:0.4:1, molar ratio) molecularly imprinted polymer had the best molecular recognition effect with 132 μg/g of protocatechuic acid, 104 μg/g of catechins, 80 μg/g of epicatechin, and 123 μg/g of caffeic acid in 6 h, as well as good molecular recognition ability for polyphenols from a Radix Asteris sample. These results show that the ternary deep eutectic solvent based molecularly imprinted polymer is a potential medium that can be applied to drug purification, drug delivery, and drug analysis. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Lithium-induced renal toxicity in rats: protection by a novel antioxidant caffeic acid phenethyl ester.

    Science.gov (United States)

    Oktem, Faruk; Ozguner, Fehmi; Sulak, Osman; Olgar, Seref; Akturk, Onur; Yilmaz, H Ramazan; Altuntas, Irfan

    2005-09-01

    Lithium carbonate used in the long-term treatment of manic-depressive illness has been reported to lead to progressive renal impairment in rats and humans. Caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, protects tissues from reactive oxygene species mediated oxidative stress in ischemia-reperfusion and toxic injuries. The beneficial effect CAPE on lithium-induced nephrotoxicity has not been reported yet. The purpose of this study was to examine a possible renoprotective effect of CAPE against lithium-induced nephrotoxicity in a rat model. Twenty-two adult male rats were randomly divided into three experimental groups, as follows: control group, lithium-treated group (Li), and lithium plus CAPE-treated group (Li+CAPE). Li were treated intraperitoneally (i.p.) with 25 mg/kg Li2CO3 solution in 0.9% NaCl twice daily for 4 weeks. CAPE was co-administered i.p. with a dose of 10 microM/kg/day for 4 weeks. Serum Li, blood urea nitrogen and plasma creatinine, urinary N-acetyl-beta-D-glucosaminidase (NAG, a marker of renal tubular injury), and malondialdehyde (MDA, an index of lipid peroxidation), were used as markers of oxidative stress-induced renal impairment in Li-treated rats. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in renal tissue. Serum Li levels were found high in the Li and Li+CAPE groups. In Li-administrated rats, urinary NAG and renal MDA levels were increased according to control and Li+CAPE groups (p < 0.05). CAPE caused a significant reduction in the levels of these parameters. Likewise, renal SOD, CAT and GSH-Px activities were decreased in Li-administrated animals; CAPE caused a significant increase in the activities of these antioxidant enzymes. In conclusion, CAPE treatment has a protective effect against Li-induced renal tubular damage and oxidative stress in a rat model.

  20. Development of an Electrochemical Sensor for NADH Determination Based on a Caffeic Acid Redox Mediator Supported on Carbon Black

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    Chiara Zanardi

    2015-04-01

    Full Text Available Screen-printed electrode (SPE modified with carbon black nanoparticles (CB has been tested as a new platform for the stable deposition of caffeic acid (CFA on the electrode surface. The electrochemical performance from varying the amount of CFA/CB composite has been tested with respect to NADH determination. The electrocatalytic activity of CFA/CB has also been compared with that of SPEs modified by a single component of the coating, i.e., either CFA or CB. Finally, glycerol dehydrogenase, a typical NADH-dependent enzyme, was deposited on the CFA/CB coating in order to test the applicability of the sensor in glycerol determination.

  1. Caffeic acid: potential applications in nanotechnology as a green reducing agent for sustainable synthesis of gold nanoparticles.

    Science.gov (United States)

    Seo, Yu Seon; Cha, Song-Hyun; Yoon, Hye-Ran; Kang, Young-Hwa; Park, Youmie

    2015-04-01

    The sustainable synthesis of gold nanoparticles from gold ions was conducted with caffeic acid as a green reducing agent. The formation of gold nanoparticles was confirmed by spectroscopic and microscopic methods. Spherical nanoparticles with an average diameter of 29.99 ± 7.43 nm were observed in high- resolution transmission electron microscopy and atomic force microscopy images. The newly prepared gold nanoparticles exhibited catalytic activity toward the reduction of 4-nitrophenol to 4-aminophenol in the presence of sodium borohydride. This system enables the preparation of green catalysts using plant natural products as reducing agents, which fulfills the growing need for sustainability initiatives.

  2. Effect of pH on the antimicrobial activity and oxidative stability of oil-in-water emulsions containing caffeic acid.

    Science.gov (United States)

    Almajano, M P; Carbó, R; Delgado, M E; Gordon, M H

    2007-06-01

    Antioxidant properties in food are dependent on various parameters. These include the pH value and interactions with food components, including proteins or metal ions. Food components affect antioxidant stability and also influence the properties of microorganisms and their viability. This paper describes an investigation of the effect of pH on the antioxidant and antibacterial properties of caffeic acid in different media. The pH values studied, using an oil-in-water emulsion as model system, were 3, 5 (with and without phosphate buffer), and 9. Effects of mixtures of caffeic acid, bovine serum albumin (BSA), and Fe (III) on oxidative deterioration in the emulsion samples were studied. The results show that the antioxidant activity of caffeic acid was increased by the presence of BSA. This effect was pH dependent and was affected by the presence of iron ions. Antibacterial properties were also pH dependent. The minimum concentration of caffeic acid required to inhibit some microorganisms in the pH range of 5 to 7 was determined. A concentration of 0.4% (w/w) caffeic acid was enough to inhibit the growth of some of the studied microorganisms in the pH range of 5 to 7. However, near-neutral pH concentrations higher than 0.4% were needed to inhibit some microorganisms, including Listeria monocytogenes, E. coli, and Staphylococcus aureus, in the medium.

  3. Comparison of Two Components of Propolis: Caffeic Acid (CA and Caffeic Acid Phenethyl Ester (CAPE Induce Apoptosis and Cell Cycle Arrest of Breast Cancer Cells MDA-MB-231

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    Agata Kabała-Dzik

    2017-09-01

    Full Text Available Studies show that caffeic acid (CA and caffeic acid phenethyl ester (CAPE are compounds with potent chemopreventive effects. Breast cancer is a common form of aggressive cancer among women worldwide. This study shows a comparison of CA and CAPE activity on triple-negative human caucasian breast adenocarcinoma line cells (MDA-MB-231. MDA-MB-231 cells were treated by CA and CAPE with doses of from 10 to 100 µM, for periods of 24 h and 48 h. Cytotoxicity MTT tests, apoptosis by Annexin V, and cell cycle with Dead Cell Assays were performed. Cytotoxic activity was greater for CAPE compared to CA (both incubation times, same dosage. IC50 values for CAPE were 27.84 µM (24 h and 15.83 µM (48 h and for CA > 10,000 µM (24 h and > 1000 µM (48 h. Polyphenols induced apoptosis, while CAPE (dose dependently, induced a higher apoptotic effect. CAPE also induced cell cycle arrest in S phase (time and dose dependently, CA did it only for 50 and 100 µM. A dose dependent decline was seen for the G0/G1 phase (CAPE, 48 h, as well as elimination of phase G2/M by 100 µM of CAPE (only mild effect for CA. Comparing CA and CAPE activity on MDA-MB-231, CAPE clearly showed better activity for the same dosages and experiment times.

  4. A novel Mg(2+)-dependent O-methyltransferase in the phenylpropanoid metabolism of Mesembryanthemum crystallinum.

    Science.gov (United States)

    Ibdah, Mwafaq; Zhang, Xing-Hai; Schmidt, Jürgen; Vogt, Thomas

    2003-11-07

    Upon irradiation with elevated light intensities, the ice plant (Mesembryanthemum crystallinum) accumulates a complex pattern of methylated and glycosylated flavonol conjugates in the upper epidermal layer. Identification of a flavonol methylating activity, partial purification of the enzyme, and sequencing of the corresponding peptide fragments revealed a novel S-adenosyl-l-methionine-dependent O-methyltransferase that was specific for flavonoids and caffeoyl-CoA. Cloning and functional expression of the corresponding cDNA verified that the new methyltransferase is a multifunctional 26.6-kDa Mg(2+)-dependent enzyme, which shows a significant sequence similarity to the cluster of caffeoyl coenzyme A-methylating enzymes. Functional analysis of highly homologous members from chickweed (Stellaria longipes), Arabidopsis thaliana, and tobacco (Nicotiana tabacum) demonstrated that the enzymes from the ice plant, chickweed, and A. thaliana possess a broader substrate specificity toward o-hydroquinone-like structures than previously anticipated for Mg(2+)-dependent O-methyltransferases, and are distinctly different from the tobacco enzyme. Besides caffeoyl-CoA and flavonols, a high specificity was also observed for caffeoylglucose, a compound never before reported to be methylated by any plant O-methyltransferase. Based on phylogenetic analysis of the amino acid sequence and differences in acceptor specificities among both animal and plant O-methyltransferases, we propose that the enzymes from the Centrospermae, along with the predicted gene product from A. thaliana, form a novel subclass within the caffeoyl coenzyme A-dependent O-methyltransferases, with potential divergent functions not restricted to lignin monomer biosynthesis.

  5. Enzymatic Browning in Sugar Beet Leaves (Beta vulgaris L.): Influence of Caffeic Acid Derivatives, Oxidative Coupling, and Coupled Oxidation.

    Science.gov (United States)

    Vissers, Anne; Kiskini, Alexandra; Hilgers, Roelant; Marinea, Marina; Wierenga, Peter Alexander; Gruppen, Harry; Vincken, Jean-Paul

    2017-06-21

    Sugar beet (Beta vulgaris L.) leaves of 8 month (8m) plants showed more enzymatic browning than those of 3 month (3m). Total phenolic content increased from 4.6 to 9.4 mg/g FW in 3m and 8m, respectively, quantitated by reverse-phase-ultrahigh-performance liquid chromatography-ultraviolet-mass spectrometry (RP-UHPLC-UV-MS). The PPO activity was 6.7 times higher in extracts from 8m than from 3m leaves. Substrate content increased from 0.53 to 2.45 mg/g FW in 3m and 8m, respectively, of which caffeic acid glycosyl esters were most important, increasing 10-fold with age. Caffeic acid glycosides and vitexin derivatives were no substrates. In 3m and 8m, nonsubstrate-to-substrate ratios were 8:1 and 3:1, respectively. A model system showed browning at 3:1 ratio due to formation of products with extensive conjugated systems through oxidative coupling and coupled oxidation. The 8:1 ratio did not turn brown as oxidative coupling occurred without much coupled oxidation. We postulate that differences in nonsubstrate-to-substrate ratio and therewith extent of coupled oxidation explain browning.

  6. Modulation of phenytoin teratogenicity and embryonic covalent binding by acetylsalicylic acid, caffeic acid, and alpha-phenyl-N-t-butylnitrone: implications for bioactivation by prostaglandin synthetase

    Energy Technology Data Exchange (ETDEWEB)

    Wells, P.G.; Zubovits, J.T.; Wong, S.T.; Molinari, L.M.; Ali, S.

    1989-02-01

    Teratogenicity of the anticonvulsant drug phenytoin is thought to involve its bioactivation by cytochromes P-450 to a reactive arene oxide intermediate. We hypothesized that phenytoin also may be bioactivated to a teratogenic free radical intermediate by another enzymatic system, prostaglandin synthetase. To evaluate the teratogenic contribution of this latter pathway, an irreversible inhibitor of prostaglandin synthetase, acetylsalicylic acid (ASA), 10 mg/kg intraperitoneally (ip), was administered to pregnant CD-1 mice at 9:00 AM on Gestational Days 12 and 13, 2 hr before phenytoin, 65 mg/kg ip. Other groups were pretreated 2 hr prior to phenytoin administration with either the antioxidant caffeic acid or the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). Caffeic acid and PBN were given ip in doses that respectively were up to 1.0 to 0.05 molar equivalents to the dose of phenytoin. Dams were killed on Day 19 and the fetuses were assessed for teratologic anomalies. A similar study evaluated the effect of ASA on the in vivo covalent binding of radiolabeled phenytoin administered on Day 12, in which case dams were killed 24 hr later on Day 13. ASA pretreatment produced a 50% reduction in the incidence of fetal cleft palates induced by phenytoin (p less than 0.05), without significantly altering the incidence of resorptions or mean fetal body weight. Pretreatment with either caffeic acid or PBN resulted in dose-related decreases in the incidence of fetal cleft palates produced by phenytoin, with maximal respective reductions of 71 and 82% at the highest doses of caffeic acid and PBN (p less than 0.05).

  7. A Comparative Study of the Radical-scavenging Activity of the Phenolcarboxylic Acids Caffeic Acid, p-Coumaric Acid, Chlorogenic Acid and Ferulic Acid, With or Without 2-Mercaptoethanol, a Thiol, Using the Induction Period Method

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    Seiichiro Fujisawa

    2008-10-01

    Full Text Available Phenolcarboxylic acid antioxidants do not act in vivo as radical-scavengers in isolation, but rather together with GSH (glutathione, a coantioxidant, they constitute an intricate antioxidant network. Caffeic acid, p-coumaric acid, ferulic acid and chlorogenic acid with or without 2-mercaptoethanol (ME, as a substitute for GSH, was investigated by the induction period (IP method for polymerization of methyl methacrylate (MMA initiated by thermal decomposition of 2,2'-azobisisobutyronitrile (AIBN, a source of alkyl radicals, R. and benzoyl peroxide (BPO, a source of peroxy radicals, PhCOO. using differential scanning calorimetry (DSC. Upon PhCOO. radical scavenging, the stoichiometric factors (n, number of free radical trapped by one mole of antioxidant for caffeic acid, ferulic acid, p-coumaric acid and chlorogenic acid were 2.4, 1.8, 1.7 and 0.9, whereas upon R. radical scavenging, the corresponding values were 1.3, 1.2, 1.0 and 0.8, respectively. Antioxidants with n values close to 2 suggest the stepwise formation of semiquinone radicals and quinones. By contrast, those with n values close to 1 suggest the formation of dimers after single-electron oxidation, possibly due to recombination of corresponding aryloxy radicals. The ratio of the rate constant of inhibition to that of propagation (kinh/kp declined in the order chlorogenic acid > p-coumaric acid > ferulic acid > caffeic acid. The ratio of the observed IP for the phenolcarboxylic acid/2-mercapto-ethanol (ME mixture (1:1 molar ratio (A to the calculated IP (the simple sum of phenol acid antioxidant and ME (B was investigated. Upon R. scavenging, the caffeic acid or p-coumaric acid/ME mixture was A/B > 1, particularly the former was 1.2, suggesting a synergic effect. By contrast, upon PhCOO. scavenging, the corresponding mixture was A/B < 1, particularly the latter was 0.7, suggesting an antagonistic effect. Upon both radicals scavenging, the A/B for the ferulic acid or chlorogenic acid

  8. Reduction of the DNA damages, Hepatoprotective Effect and Antioxidant Potential of the Coconut Water, ascorbic and Caffeic Acids in Oxidative Stress Mediated by Ethanol

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    VANDERSON S. BISPO

    Full Text Available ABSTRACT Hepatic disorders such as steatosis and alcoholic steatohepatitis are common diseases that affect thousands of people around the globe. This study aims to identify the main phenol compounds using a new HPLC-ESI+-MS/MS method, to evaluate some oxidative stress parameters and the hepatoprotective action of green dwarf coconut water, caffeic and ascorbic acids on the liver and serum of rats treated with ethanol. The results showed five polyphenols in the lyophilized coconut water spiked with standards: chlorogenic acid (0.18 µM, caffeic acid (1.1 µM, methyl caffeate (0.03 µM, quercetin (0.08 µM and ferulic acid (0.02 µM isomers. In the animals, the activity of the serum γ-glutamyltranspeptidase (γ-GT was reduced to 1.8 I.U/L in the coconut water group, 3.6 I.U/L in the ascorbic acid group and 2.9 I.U/L in the caffeic acid groups, when compared with the ethanol group (5.1 I.U/L, p<0.05. Still in liver, the DNA analysis demonstrated a decrease of oxidized bases compared to ethanol group of 36.2% and 48.0% for pretreated and post treated coconut water group respectively, 42.5% for the caffeic acid group, and 34.5% for the ascorbic acid group. The ascorbic acid was efficient in inhibiting the thiobarbituric acid reactive substances (TBARS in the liver by 16.5% in comparison with the ethanol group. These data indicate that the green dwarf coconut water, caffeic and ascorbic acids have antioxidant, hepatoprotective and reduced DNA damage properties, thus decreasing the oxidative stress induced by ethanol metabolism.

  9. Monolignol 4-O-methyltransferases and uses thereof

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Chang-Jun; Bhuiya, Mohammad-Wadud; Zhang, Kewei

    2014-11-18

    Modified (iso)eugenol 4-O-methyltransferase enzymes having novel capacity for methylation of monolignols and reduction of lignin polymerization in plant cell wall are disclosed. Sequences encoding the modified enzymes are disclosed.

  10. Efficacy of various naturally occurring caffeic acid derivatives in preventing post-harvest protein losses in forages.

    Science.gov (United States)

    Sullivan, Michael L; Zeller, Wayne E

    2013-01-01

    In red clover, oxidation of endogenous o-diphenols by polyphenol oxidase (PPO) inhibits post-harvest proteolyis. This system is transferable to alfalfa by providing PPO (via a transgene) and o-diphenol PPO substrates (via exogenous application). To exploit the PPO system for protein protection, it would be advantageous to produce PPO substrates in alfalfa, which lacks them. We assessed the extent of PPO-mediated proteolytic inhibition by phenolic compounds, especially those whose biosynthesis could be engineered into alfalfa. Tested compounds included o-diphenols (caffeic acid, phaselic acid, chlorogenic acid, clovamide) and monophenols (p-coumaric acid, p-coumaroyl-malic acid). In the presence of PPO, 2 mmol o-diphenol g⁻¹ protein reduced 24 h proteolysis 68-87% (P < 0.001) and as little as 0.25 mmol g⁻¹ protein still decreased 24 h proteolysis 43-60% (P < 0.001). At high concentrations, clovamide inhibited 24 h proteolysis 50% (P < 0.001) in the absence of PPO, likely due to non-PPO oxidation. Monophenol p-coumaric acid did not inhibit 24 h proteolyis, although high levels of its malate ester did exhibit PPO- and oxygen-independent inhibition (37%, P < 0.001). For PPO-mediated proteolytic inhibition, pathways for both phaselic acid and chlorogenic acid may be good targets for engineering into alfalfa. Clovamide may be useful for inhibiting proteolysis without PPO. Published 2012 by John Wiley & Sons, Ltd.

  11. Methylation of sulfhydryl groups: a new function for a family of small molecule plant O-methyltransferases

    Science.gov (United States)

    Coiner, Heather; Schröder, Gudrun; Wehinger, Elke; Liu, Chang-Jun; Noel, Joseph P.; Schwab, Wilfried; Schröder, Joachim

    2010-01-01

    Summary In plants, type I and II S-adenosyl-L-methionine-dependent O-methyltransferases (OMTs) catalyze most hydroxyl group methylations of small molecules. A homology-based RT-PCR strategy using Catharanthus roseus (Madagascar periwinkle) RNA previously identified six new type I plant OMT family members. We now describe the molecular and biochemical characterization of a seventh protein. It shares 56–58% identity with caffeic acid OMTs (COMTs), but it failed to methylate COMT substrates, and had no activity with flavonoids. However, the in vitro incubations revealed unusually high background levels without added substrates. A search for the responsible component revealed that the enzyme methylated dithiothreitol (DTT), the reducing agent added for enzyme stabilization. Unexpectedly, product analysis revealed that the methylation occurred on a sulfhydryl moiety, not on a hydroxyl group. Analysis of 34 compounds indicated a broad substrate range, with a preference for small hydrophobic molecules. Benzene thiol (Km 220 μM) and furfuryl thiol (Km 60 μM) were the best substrates (6–7-fold better than DTT). Small isosteric hydrophobic substrates with hydroxyl groups, like phenol and guaiacol, were also methylated, but the activities were at least 5-fold lower than with thiols. The enzyme was named C. roseus S-methyltransferase 1 (CrSMT1). Models based on the COMT crystal structure suggest that S-methylation is mechanistically identical to O-methylation. CrSMT1 so far is the only recognized example of an S-methyltransferase in this protein family. Its properties indicate that a few changes in key residues are sufficient to convert an OMT into a S-methyltransferase (SMT). Future functional investigations of plant methyltransferases should consider the possibility that the enzymes may direct methylation at sulfhydryl groups. PMID:16623883

  12. Caffeic Acid Phenethyl Ester as a Protective Agent against Nephrotoxicity and/or Oxidative Kidney Damage: A Detailed Systematic Review

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    Sumeyya Akyol

    2014-01-01

    Full Text Available Caffeic acid phenethyl ester (CAPE, an active component of propolis, has been attracting the attention of different medical and pharmaceutical disciplines in recent years because of its antioxidant, anti-inflammatory, antiproliferative, cytotoxic, antiviral, antifungal, and antineoplastic properties. One of the most studied organs for the effects of CAPE is the kidney, particularly in the capacity of this ester to decrease the nephrotoxicity induced by several drugs and the oxidative injury after ischemia/reperfusion (I/R. In this review, we summarized and critically evaluated the current knowledge regarding the protective effect of CAPE in nephrotoxicity induced by several special medicines such as cisplatin, doxorubicin, cyclosporine, gentamycin, methotrexate, and other causes leading to oxidative renal injury, namely, I/R models and senility.

  13. Effects of propolis, caffeic acid phenethyl ester, and pollen on renal injury in hypertensive rat: An experimental and theoretical approach.

    Science.gov (United States)

    Salmas, Ramin Ekhteiari; Gulhan, Mehmet Fuat; Durdagi, Serdar; Sahna, Engin; Abdullah, Huda I; Selamoglu, Zeliha

    2017-08-01

    The objective of this study was to evaluate the antioxidant effects of propolis, caffeic acid phenethyl ester (CAPE; active compound in propolis), and pollen on biochemical oxidative stress biomarkers in rat kidney tissue inhibited by Nω -nitro-L-arginine methyl ester (L-NAME). The biomarkers evaluated were paraoxonase (PON1), oxidative stress index (OSI), total antioxidant status (TAS), total oxidant status (TOS), asymmetric dimethylarginine (ADMA), and nuclear factor kappa B (NF-κB). TAS levels and PON1 activity were significantly decreased in kidney tissue samples in the L-NAME-treated group (P propolis, CAPE, and pollen groups compared with the L-NAME-treated group. TOS, ADMA, and NF-κB levels were significantly increased in the kidney tissue samples of the L-NAME-treated group (P propolis, CAPE, and pollen groups (P propolis, CAPE administration. Copyright © 2017 John Wiley & Sons, Ltd.

  14. Amine-modified SBA-15 and MCF mesoporous molecular sieves as promising sorbents for natural antioxidant. Modeling of caffeic acid adsorption.

    Science.gov (United States)

    Moritz, Michał; Geszke-Moritz, Małgorzata

    2016-04-01

    This work presents a detailed study of caffeic acid adsorption on mesoporous SBA-15 and MCF silicas functionalized with (3-aminopropyl)triethoxysilane (APTES) and 3-[2-(aminoethylamino)propyl]trimethoxysilane (AEAPTMS). Synthesized mesoporous adsorbents were characterized using different analytical techniques such as N2 sorption, XRD, TEM, SEM and FT-IR. The adsorption studies of caffeic acid were conducted in various organic solvents. Moreover, the effect of water content in 2-propanol-water mixture on adsorption efficiency was investigated. The experimental data were best fitted to the Langmuir equation, followed by the Temkin, Dubinin-Radushkevich and Freundlich models. The maximum adsorption capacity values calculated from the Langmuir model demonstrated that SBA-15 and MCF silicas modified with AEAPTMS revealed better adsorption properties toward caffeic acid (192.3 and 161.3mg/g, respectively) as compared to the materials modified with APTES (125.0 and 113.6 mg/g, respectively). The obtained results indicate that both SBA-15 and MCF silicas functionalized with AEAPTMS and APTES are promising materials for the entrapment of caffeic acid. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Caffeic Acid Reduces the Viability and Migration Rate of Oral Carcinoma Cells (SCC-25 Exposed to Low Concentrations of Ethanol

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    Arkadiusz Dziedzic

    2014-10-01

    Full Text Available Alcohol increases the risk of carcinoma originated from oral epithelium, but the biological effects of ultra-low doses of ethanol on existing carcinoma cells in combination with natural substances are still unclear. A role for ethanol (EtOH, taken in small amounts as an ingredient of some beverages or mouthwashes to change the growth behavior of established squamous cell carcinoma, has still not been examined sufficiently. We designed an in vitro study to determine the effect of caffeic acid (CFA on viability and migration ability of malignant oral epithelial keratinocytes, exposed to ultra-low concentrations (maximum 100 mmol/L EtOH. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-dimethyltetrazolium bromide and LDH (lactate dehydrogenase assays were used to assess the cytotoxic effect of EtOH/CFA and the viability of squamous carcinoma SCC-25 cells (ATCC CRL-1628, mobile part of the tongue. Tested EtOH concentrations were: 2.5, 5, 10, 25, 50, and 100 mmol/L, along with an equal CFA concentration of 50 μmol/L. Carcinoma cells’ migration was investigated by monolayer “wound” healing assay. We demonstrated that very low concentrations of EtOH ranging between 2.5 and 10 mmol/L may induce the viability of oral squamous cell carcinoma cells, while the results following addition of CFA reveal an antagonistic effect, attenuating pro-proliferative EtOH activity. The migration rate of oral squamous carcinoma cells can be significantly inhibited by the biological activity of caffeic acid.

  16. Comparison of chicoric acid, and its metabolites caffeic acid and caftaric acid: In vitro protection of biological macromolecules and inflammatory responses in BV2 microglial cells

    Directory of Open Access Journals (Sweden)

    Qian Liu

    2017-12-01

    Full Text Available Chicoric acid (CA, a natural phenolic acid, has been used as a nutraceutical food ingredient due to its powerful antioxidant, anti-HIV and anti-diabetic bioactivities. CA could be partly metabolized into caffeic acid (CFA and caftaric acid (CTA on cytochrome P450s in rat liver microsomes. To compare the protective effects of CA and its metabolites on biomolecules and inflammatory responses, oxidative damage induced by free radicals in vitro and microglial inflammation triggered by lipopolysaccharide in BV2 cells were constructed. Results showed that CA, CTA and CFA all significantly inhibited protein degradation and carbonylation induced by hydroxyl radicals and alcoxyl radicals, and suppressed hemin/nitrite/H2O2 triggered-nitration. Moreover, CA, CTA and CFA all exerted remarkable inhibition capacities on linoleic acid and soybean lecithin liposomes peroxidation in a dose-dependent manner, and restrained the oxidation of herring sperm DNA, as well as the breakage of pBR322 plasmid DNA. Furthermore, CA and its metabolites suppressed lipopolysaccharide-induced decline of BV2 cell viability and the production of NO and ROS. However, bioactivities of CA were significantly stronger than those of its metabolites within a certain concentration range. This study provides scientific basis for the application of CA and its metabolites as nutrition and natural antioxidants. Keywords: Chicoric acid and its metabolites, Oxidative damage, Biomolecules, Microglia, Inflammation

  17. Evaluation of Chemical Constituents and Antioxidant Activity of Coconut Water (Cocus nucifera L. and Caffeic Acid in Cell Culture

    Directory of Open Access Journals (Sweden)

    JOAO L.A. SANTOS

    2013-09-01

    Full Text Available Coconut water contains several uncharacterized substances and is widely used in the human consumption. In this paper we detected and quantified ascorbic acid and caffeic acid and total phenolics in several varieties of coconut using HPLS/MS/MS (25.8 ± 0.6 µg/mL and 1.078 ± 0.013 µg/mL and 99.7 µg/mL, respectively, in the green dwarf coconut water, or 10 mg and 539 µg and 39.8 mg for units of coconut consumed, 500 ± 50 mL. The antioxidant potential of four coconut varieties (green dwarf, yellow dwarf, red dwarf and yellow Malaysian was compared with two industrialized coconut waters and the lyophilized water of the green dwarf variety. All varieties were effective in scavenging the DPPH radical (IC50=73 µL and oxide nitric (0.1 mL with an IP of 29.9% as well as in inhibiting the in vitro production of thiobarbituric acid reactive substances (1 mL with an IP of 34.4%, highlighting the antioxidant properties of the green dwarf which it is the most common used. In cell culture, the green dwarf water was efficient in protecting against oxidative damages induced by hydrogen peroxide.

  18. Dietary phenolic antioxidants, caffeic acid and Trolox, protect rainbow trout gill cells from nitric oxide-induced apoptosis.

    Science.gov (United States)

    Chung, Mi Ja; Walker, Paul A; Hogstrand, Christer

    2006-12-30

    Caffeic acid (CA) and Trolox are phenolic acids that have beneficial antioxidant effect, but the underlying mechanisms involved are not fully understood. The extent to which CA and Trolox protect against sodium nitroprusside (SNP)-induced oxidative cell injury was investigated in cultured rainbow trout gill cells. The cells exposed to SNP for 24 h displayed a dose-dependent leakage of lactate dehydrogenase (LDH) and decreased cell viability as indicated by the MTT assay (mitochondrial dehydrogenase activity). Both effects were prevented by treatment with 50 microM CA or Trolox. CA or Trolox, protected against SNP-induced caspase-3 activation and DNA fragmentation, indicating a reduction of apoptosis. Thus, the results indicate that SNP induced cell death is caspase-3 related apoptosis and the treatment with CA inhibited the apoptotic pathway. In addition, we studied the effect of CA and Trolox on expression of zinc-responsive antioxidant genes such as metallothioneins (MT), glutathione-S-transferase (GST Class pi) and glucose-6-phosphate dehydrogenase (G6PD) in cultured gill cells. CA, 100 microM, increased accumulation of mRNA for MTA, MTB, GST and G6PD in cells. Thus, in addition to its ability to sequester free radicals, CA may protect against oxidative stress through expression of zinc-induced antioxidant proteins. Because of these properties we suggest that CA could be a beneficial additive to fish feeds in aquaculture.

  19. Caffeic acid phenethyl ester downregulates phospholipase D1 via direct binding and inhibition of NFκB transactivation

    Energy Technology Data Exchange (ETDEWEB)

    Park, Mi Hee; Kang, Dong Woo [Department of Molecular Biology, Pusan National University, Busan 609-735 (Korea, Republic of); Jung, Yunjin [College of Pharmacy, Pusan National University, Busan 609-735 (Korea, Republic of); Choi, Kang-Yell [Translational Research Center for Protein Function Control, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul (Korea, Republic of); Min, Do Sik, E-mail: minds@pusan.ac.kr [Department of Molecular Biology, Pusan National University, Busan 609-735 (Korea, Republic of)

    2013-12-06

    Highlights: •We found CAFÉ, a natural product that suppresses expression and activity of PLD1. •CAPE decreased PLD1 expression by inhibiting NFκB transactivation. •CAPE rapidly inhibited PLD activity via its binding to a Cys837 of PLD1. •PLD1 downregulation by CAPE inhibited invasion and proliferation of glioma cells. -- Abstract: Upregulation of phospholipase D (PLD) is functionally linked with oncogenic signals and tumorigenesis. Caffeic acid phenethyl ester (CAPE) is an active compound of propolis extract that exhibits anti-proliferative, anti-inflammatory, anti-oxidant, and antineoplastic properties. In this study, we demonstrated that CAPE suppressed the expression of PLD1 at the transcriptional level via inhibition of binding of NFκB to PLD1 promoter. Moreover, CAPE, but not its analogs, bound to a Cys837 residue of PLD1 and inhibited enzymatic activity of PLD. CAPE also decreased activation of matrix metalloproteinases-2 induced by phosphatidic acid, a product of PLD activity. Ultimately, CAPE-induced downregulation of PLD1 suppressed invasion and proliferation of glioma cells. Taken together, the results of this study indicate that CAPE might contribute to anti-neoplastic effect by targeting PLD1.

  20. Synthesis and optimization of N-heterocyclic pyridinones as catechol-O-methyltransferase (COMT) inhibitors.

    Science.gov (United States)

    Zhao, Zhijian; Harrison, Scott T; Schubert, Jeffrey W; Sanders, John M; Polsky-Fisher, Stacey; Zhang, Nanyan Rena; McLoughlin, Debra; Gibson, Christopher R; Robinson, Ronald G; Sachs, Nancy A; Kandebo, Monika; Yao, Lihang; Smith, Sean M; Hutson, Pete H; Wolkenberg, Scott E; Barrow, James C

    2016-06-15

    A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Caffeic Acid Derivatives in Market Available Lamiaceae and Echinacea purpurea Products

    Science.gov (United States)

    Fresh basil leaves contain chicoric acid, the principal phenolic compound of Echinacea purpurea and purportedly the active ingredient in its dietary supplements. Our group discovered and first reported chicoric acid in basil. This following study examined the distribution of chicoric acid within the...

  2. Additions of caffeic acid, ascorbyl palmitate or gamma-tocopherol to fish oil-enriched energy bars affect lipid oxidation differently

    DEFF Research Database (Denmark)

    Horn, Anna Frisenfeldt; Nielsen, Nina Skall; Jacobsen, Charlotte

    2009-01-01

    The objectives of the study were to investigate the effects of caffeic acid, ascorbyl palmitate and gamma-tocopherol on protection of fish oil-enriched energy bars against lipid oxidation during storage for 10 weeks at room temperature. The lipophilic gamma-tocopherol reduced lipid oxidation during......, or the hydrophilic caffeic acid, or the amphiphilic ascorbyl palmitate at concentrations of 75, 150 and 300 mu g/g fish oil. Prooxidative effects were observed as an increase in the formation of lipid hydroperoxides and volatile secondary oxidation products, as well as the development of rancid off...... storage when added at a concentration above 440 mu g/g fish oil. However, the best antioxidative effect was observed when it was added at a concentration of 660 mu g/g fish oil. In contrast, prooxidative effects were observed when using either gamma-tocopherol at concentrations below 220 mu g/g fish oil...

  3. Protective Effects of Intralipid and Caffeic Acid Phenyl Esther (CAPE) on Neurotoxicity Induced by Ethanol in Rats.

    Science.gov (United States)

    Basarslan, Seyit Kagan; Osun, Arif; Senol, Serkan; Korkmaz, Murat; Ozkan, Umit; Kaplan, Ibrahim

    2017-01-01

    Ethanol causes oxidative degradation of the mitochondrial genome in the brain. This effect could contribute to the development of brain injury in some alcoholic patients. We investigated the protective effect of caffeic acid phenyl esther (CAPE) and intralipid (IL) on oxidative stress and neurotoxicity induced by ethanol intake. The forty-eight rats were randomly divided into seven groups. Ethanol was administered for acute toxicity. IL and CAPE were administered immediately after ethanol intake. Total oxidant status (TOS), total antioxidant status (TAS), and oxidative status index (OSi) were evaluated and histologic examination of cerebellum and brain tissue with Hematoxylin-Eosin and immuno-histochemical dyes was performed. In the ethanol group, TAS levels were significantly lower than the other groups and this finding indicates that the toxic effect of ethanol reduces antioxidant levels. In the ethanol group, TOS levels were significantly higher than the other groups. These results showed that ethanol induced oxidative stress. IL treatment increased TAS levels, and CAPE decreased TOS levels against ethanol toxicity. There was correlation between TAS and TOS levels. Also, histopathologic results confirmed these biochemical results. CAPE and IL treatment could be effective course of therapy to enhance therapeutic efficacy and may provide a promising approach for the treatment of neurotoxicity and oxidative stress induced by ethanol in clinic.

  4. Enhanced antioxidant effect of caffeic acid phenethyl ester and Trolox in combination against radiation induced-oxidative stress.

    Science.gov (United States)

    Bai, Hua; Liu, Rui; Chen, Hong-Li; Zhang, Wei; Wang, Xin; Zhang, Xiao-Di; Li, Wen-Li; Hai, Chun-Xu

    2014-01-25

    Combinations of antioxidants are believed to be more effective than single antioxidant because when antioxidants are combined they support each other synergistically to create a magnified effect. Discovering the enhancer effects or synergies between bioactive components is valuable for resisting oxidative stress and improving health benefits. The aim of this study was to investigate a possible cooperation of natural antioxidant caffeic acid phenethyl ester (CAPE) with synthetic antioxidant Trolox in the model systems of chemical generation of free radicals, lipid peroxidation of microsomes and radiation-induced oxidative injury in L929 cells. Based on the intermolecular interaction between CAPE and Trolox, the present study shows a synergistic effect of CAPE and Trolox in combination on elimination of three different free radicals and inhibition of lipid peroxidation initiated by three different systems. CAPE and Trolox added simultaneously to the L929 cells exerted an enhanced preventive effect on the oxidative injury induced by radiation through decreasing ROS generation, protecting plasma membrane and increasing the ratios of reduced glutathione/oxidized glutathione and the expression of key antioxidant enzymes mediated by nuclear factor erythroid 2 p45-related factor 2 (Nrf2). Our results showed for the first time that administration of CAPE and Trolox in combination may exert synergistic antioxidant effects, and further indicate that CAPE and Trolox combination functions mainly through scavenging ROS directly, inhibiting lipid peroxidation and promoting redox cycle of GSH mediated by Nrf2-regulated glutathione peroxidase and glutathione reductase expression. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Novel Antidepressant-Like Activity of Caffeic Acid Phenethyl Ester Is Mediated by Enhanced Glucocorticoid Receptor Function in the Hippocampus

    Directory of Open Access Journals (Sweden)

    Mi-Sook Lee

    2014-01-01

    Full Text Available Caffeic acid phenethyl ester (CAPE is an active component of propolis that has a variety of potential pharmacological effects. Although we previously demonstrated that propolis has antidepressant-like activity, the effect of CAPE on this activity remains unknown. The present study assessed whether treatment with CAPE (5, 10, and 20 µmol/kg for 21 days has an antidepressant-like effect in mice subjected to chronic unpredictable stress via tail suspension (TST and forced swim (FST tests. CAPE administration induced behaviors consistent with an antidepressant effect, evidenced by decreased immobility in the TST and FST independent of any effect on serum corticosterone secretion. Western blots, conducted subsequent to behavioral assessment, revealed that CAPE significantly decreased glucocorticoid receptor phosphorylation at S234 (pGR(S234, resulting in an increased pGR(S220/S234 ratio. We also observed negative correlations between pGR(S220/(S234 and p38 mitogen-activated protein kinase (p38MAPK phosphorylation, which was decreased by CAPE treatment. These findings suggest that CAPE treatment exerts an antidepressant-like effect via downregulation of p38MAPK phosphorylation, thereby contributing to enhanced GR function.

  6. Fibrinolytic Activity and Dose-Dependent Effect of Incubating Human Blood Clots in Caffeic Acid Phenethyl Ester: In Vitro Assays

    Directory of Open Access Journals (Sweden)

    Abuzar Elnager

    2015-01-01

    Full Text Available Background. Caffeic acid phenethyl ester (CAPE has been reported to possess time-dependent fibrinolytic activity by in vitro assay. This study is aimed at investigating fibrinolytic dose-dependent activity of CAPE using in vitro assays. Methods. Standardized human whole blood (WB clots were incubated in either blank controls or different concentrations of CAPE (3.75, 7.50, 15.00, 22.50, and 30.00 mM. After 3 hours, D-dimer (DD levels and WB clot weights were measured for each concentration. Thromboelastography (TEG parameters were recorded following CAPE incubation, and fibrin morphology was examined under a confocal microscope. Results. Overall, mean DD (μg/mL levels were significantly different across samples incubated with different CAPE concentrations, and the median pre- and postincubation WB clot weights (grams were significantly decreased for each CAPE concentration. Fibrin removal was observed microscopically and indicated dose-dependent effects. Based on the TEG test, the Ly30 fibrinolytic parameter was significantly different between samples incubated with two different CAPE concentrations (15.0 and 22.50 mM. The 50% effective dose (ED50 of CAPE (based on DD was 1.99 mg/mL. Conclusions. This study suggests that CAPE possesses fibrinolytic activity following in vitro incubation and that it has dose-dependent activities. Therefore, further investigation into CAPE as a potential alternative thrombolytic agent should be conducted.

  7. Effect of Caffeic Acid Phenethyl Ester on Vascular Damage Caused by Consumption of High Fructose Corn Syrup in Rats

    Directory of Open Access Journals (Sweden)

    Aburrahman Gun

    2016-01-01

    Full Text Available Fructose corn syrup is cheap sweetener and prolongs the shelf life of products, but fructose intake causes hyperinsulinemia, hypertriglyceridemia, and hypertension. All of them are referred to as metabolic syndrome and they are risk factors for cardiovascular diseases. Hence, the harmful effects of increased fructose intake on health and their prevention should take greater consideration. Caffeic Acid Phenethyl Ester (CAPE has beneficial effects on metabolic syndrome and vascular function which is important in the prevention of cardiovascular disease. However, there are no known studies about the effect of CAPE on fructose-induced vascular dysfunction. In this study, we examined the effect of CAPE on vascular dysfunction due to high fructose corn syrup (HFCS. HFCS (6 weeks, 30% fed with drinking water caused vascular dysfunction, but treatment with CAPE (50 micromol/kg i.p. for the last two weeks effectively restored this problem. Additionally, hypertension in HFCS-fed rats was also decreased in CAPE supplemented rats. CAPE supplements lowered HFCS consumption-induced raise in blood glucose, homocysteine, and cholesterol levels. The aorta tissue endothelial nitric oxide synthase (eNOS production was decreased in rats given HFCS and in contrast CAPE supplementation efficiently increased its production. The presented results showed that HFCS-induced cardiovascular abnormalities could be prevented by CAPE treatment.

  8. Development of a Mitochondriotropic Antioxidant Based on Caffeic Acid: Proof of Concept on Cellular and Mitochondrial Oxidative Stress Models.

    Science.gov (United States)

    Teixeira, José; Cagide, Fernando; Benfeito, Sofia; Soares, Pedro; Garrido, Jorge; Baldeiras, Inês; Ribeiro, José A; Pereira, Carlos M; Silva, António F; Andrade, Paula B; Oliveira, Paulo J; Borges, Fernanda

    2017-08-24

    Targeting mitochondrial oxidative stress is an effective therapeutic strategy. In this context, a rational design of mitochondriotropic antioxidants (compounds 22-27) based on a dietary antioxidant (caffeic acid) was performed. Jointly named as AntiOxCINs, these molecules take advantage of the known ability of the triphenylphosphonium cation to target active molecules to mitochondria. The study was guided by structure-activity-toxicity-property relationships, and we demonstrate in this work that the novel AntiOxCINs act as mitochondriotropic antioxidants. In general, AntiOxCINs derivatives prevented lipid peroxidation and acted as inhibitors of the mitochondrial permeability transition pore. AntiOxCINs toxicity profile was found to be dependent on the structural modifications performed on the dietary antioxidant. On the basis of mitochondrial and cytotoxicity/antioxidant cellular data, compound 25 emerged as a potential candidate for the development of a drug candidate with therapeutic application in mitochondrial oxidative stress-related diseases. Compound 25 increased GSH intracellular levels and showed no toxicity on mitochondrial morphology and function.

  9. Poly(3-hydroxybutyrate)/caffeic acid electrospun fibrous materials coated with polyelectrolyte complex and their antibacterial activity and in vitro antitumor effect against HeLa cells

    Energy Technology Data Exchange (ETDEWEB)

    Ignatova, Milena G. [Laboratory of Bioactive Polymers, Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev St, Bl. 103A, BG-1113 Sofia (Bulgaria); Manolova, Nevena E., E-mail: manolova@polymer.bas.bg [Laboratory of Bioactive Polymers, Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev St, Bl. 103A, BG-1113 Sofia (Bulgaria); Rashkov, Iliya B. [Laboratory of Bioactive Polymers, Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev St, Bl. 103A, BG-1113 Sofia (Bulgaria); Markova, Nadya D. [Institute of Microbiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Bl. 26, BG-1113 Sofia (Bulgaria); Toshkova, Reneta A.; Georgieva, Ani K.; Nikolova, Elena B. [Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Acad. G. Bonchev St, bl. 25, BG-1113 Sofia (Bulgaria)

    2016-08-01

    The purpose of this work was to investigate the possibility for the preparation of new poly(3-hydroxybutyrate) (PHB)/poly(ethylene glycol) (PEG)-based fibrous materials containing natural phenolic compound caffeic acid (CA) of diverse architectures, as well as to study the impact of the fiber composition on the in vitro CA release profile and on the biological properties of the fibrous materials. The application of the one-pot electrospinning enabled the fabrication of nanofibrous materials from PHB and PEG loaded with the CA. Materials with targeted design were obtained by coating with polyelectrolyte complex of alginate (Alg) and N,N,N-trimethylchitosan (TMCh). Three different processing paths were used to obtain coated mats: (i) with CA incorporated in the PHB/PEG core; (ii) with CA embedded in the Alg layer; and (iii) with CA included in the TMCh layer. The in vitro release of CA was modulated by controlling the composition and the architecture of the nanofibrous mats. The performed microbiological screening and MTT cell viability studies revealed that in contrast to the bare mats, the CA-containing nanofibrous materials were effective in suppressing the growth of the Gram-positive bacteria Staphylococcus aureus and the Gram-negative bacteria Escherichia coli and displayed good cytotoxicity against human cervical HeLa tumor cells. In addition, the proliferation of murine spleen lymphocytes and peritoneal macrophages was increased by the prepared CA-containing nanofibrous materials. The obtained materials are promising for antibacterial wound dressing applications as well as for application in local treatment of cervical tumors. - Highlights: • New caffeic acid-loaded materials from PHB and PEG were prepared by electrospinning. • Different design is achieved by coating and formation of polyelectrolyte complexes. • The control on the architecture of the mats enables modulating caffeic acid release. • The caffeic acid-loaded mats suppress the growth of

  10. Effect of propolis and caffeic acid phenethyl ester (CAPE) on NFκB activation by HTLV-1 Tax.

    Science.gov (United States)

    Shvarzbeyn, Jenny; Huleihel, Mahmoud

    2011-06-01

    HTLV-1 is the etiological agent of aggressive malignancy of the CD4(+) T-cells, adult T-cell leukemia (ATL), and other severe clinical disorders. The viral Tax protein is a key factor in HTLV-1 pathogenicity. A major part of Tax oncogenic potential is accounted for by its capacity of inducing the transcriptional activity of the NFκB factors, which regulate the expression of numerous cellular genes. Propolis (PE), a natural product produced by honeybees, has been used for a long time in folk medicine. One of PE active components, caffeic acid phenylethyl ester (CAPE), was well characterized and found to be a potent inhibitor of NFκB activation. Therefore, the aim of this study was to pursue the possibility of blocking Tax oncogenic effects by treatment with these natural products. Human T-cell lines were used in this study since these cells are the main targets of HTLV-1 infections. We tried to determine which step of Tax-induced NFκB activation is blocked by these products. Our results showed that both tested products substantially inhibited the activation of NFκB-dependent promoter by Tax. However, only PE could efficiently inhibit also the Tax-induced activation of SRF- and CREB-dependent promoters. Our results showed also that PE and CAPE strongly prevented both Tax binding to IκBα and its induced degradation by Tax. However, both products did not interfere in the nuclear transport of Tax or NFκB proteins. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Human catechol-O-methyltransferase: Cloning and expression of the membrane-associated form

    Energy Technology Data Exchange (ETDEWEB)

    Bertocci, B.; Miggiano, V.; Da Prada, M.; Dembic, Z.; Lahm, H.W.; Malherbe, P. (F. Hoffmann-La Roche Ltd., Basel (Switzerland))

    1991-02-15

    A cDNA clone for human catechol-O-methyltransferase was isolated from a human hepatoma cell line (Hep G2) cDNA library by hybridization screening with a porcine cDNA probe. The cDNA clone was sequenced and found to have an insert of 1226 nucleotides. The deduced primary structure of hCOMT is composed of 271 amino acid residues with the predicted molecular mass of 30 kDa. At its N terminus it has a hydrophobic segment of 21 amino acid residues that may be responsible for insertion of hCOMT into the endoplasmic reticulum membrane. The primary structure of hCOMT exhibits high homology to the porcine partial cDNA sequence (93%). The deduced amino acid sequence contains two tryptic peptide sequences (T-22, T-33) found in porcine liver catechol-O-methyltransferase (CEMT). The coding region of hCOMT cDNA was placed under the control of the cytomegalovirus promoter to transfect human kidney 293 cells. The recombinant hCOMT was shown by immunoblot analysis to be mainly associated with the membrane fraction. RNA blot analysis revealed one COMT mRNA transcript of 1.4 kilobases in Hep G2 poly(A){sup +} RNA.

  12. Behavioral and genotoxic evaluation of rosmarinic and caffeic acid in acute seizure models induced by pentylenetetrazole and pilocarpine in mice.

    Science.gov (United States)

    Coelho, Vanessa Rodrigues; Vieira, Caroline Gonçalves; de Souza, Luana Pereira; da Silva, Lucas Lima; Pflüger, Pricila; Regner, Gabriela Gregory; Papke, Débora Kuck Mausolff; Picada, Jaqueline Nascimento; Pereira, Patrícia

    2016-11-01

    The goal of this study was to investigate the effects of rosmarinic acid (RA) and caffeic acid (CA) in the acute pentylenetetrazole (PTZ) and pilocarpine (PIL) seizure models. We also evaluated the effect of RA and CA on the diazepam (DZP)-induced sleeping time test and its possible neuroprotective effect against the genotoxic damage induced by PTZ and PIL. Mice were treated intraperitoneally (i.p.) with saline, RA (2 or 4 mg/kg), or CA (4 or 8 mg/kg) alone or associated to low-dose DZP. After, mice received a single dose of PTZ (88 mg/kg) or PIL (250 mg/kg) and were monitored for the percentage of seizures and the latency to first seizure (LFS) >3 s. Vigabatrin and DZP were used as positive controls. In the DZP-induced sleeping time test, mice were treated with RA and CA and 30 min after receiving DZP (25 mg/kg, i.p.). The alkaline comet assay was performed after acute seizure tests to evaluate the antigenotoxic profiles of RA and CA. The doses of RA and CA tested alone did not reduce the occurrence of seizures induced by PTZ or PIL. The association of 4 mg/kg RA + low-dose DZP was shown to increase LFS in the PTZ model, compared to the group that received only the DZP. In the DZP-induced sleeping time test, the latency to sleep was reduced by 4 mg/kg RA and 8 mg/kg CA. The PTZ-induced genotoxic damage was not prevented by RA or CA, but the PIL-induced genotoxic damage was decreased by pretreatment with 4 mg/kg RA (in cortex) and 4 mg/kg CA (in hippocampus). In conclusion, RA and CA presented neuroprotective effect against PIL-induced genotoxic damage and reduced the latency to DZP-induced sleep. Of the rosmarinic acid, 4 mg/kg enhanced the DZP effect in the increase of latency to clonic PTZ-induced seizures.

  13. Specialized (iso)eugenol-4-O-methyltransferases (s-IEMTs) and methods of making and using the same

    Science.gov (United States)

    Liu, Chang-Jun; Cai, Yuanheng

    2017-01-31

    Specialized (iso)eugenol 4-O-methyltransferase (s-IEMT) enzymes having increased capacity for methylation of monolignols are disclosed. The s-IEMTs have unique activity favoring methylation of coniferyl alcohol versus sinapyl alcohol. Various s-IEMTs methylate ferulic acid. Means for producing the various s-IEMTs are provided. The s-IEMTs are useful for modification of lignin content and production of aromatic compounds.

  14. Plant isoflavone and isoflavanone O-methyltransferase genes

    Science.gov (United States)

    Broeckling, Bettina E.; Liu, Chang-Jun; Dixon, Richard A.

    2014-08-19

    The invention provides enzymes that encode O-methyltransferases (OMTs) from Medicago truncatula that allow modification to plant (iso)flavonoid biosynthetic pathways. In certain aspects of the invention, the genes encoding these enzymes are provided. The invention therefore allows the modification of plants for isoflavonoid content. Transgenic plants comprising such enzymes are also provided, as well as methods for improving disease resistance in plants. Methods for producing food and nutraceuticals, and the resulting compositions, are also provided.

  15. Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin-like Growth Factor I Receptor Levels in Human Breast Cancer.

    Science.gov (United States)

    Rosendahl, Ann H; Perks, Claire M; Zeng, Li; Markkula, Andrea; Simonsson, Maria; Rose, Carsten; Ingvar, Christian; Holly, Jeff M P; Jernström, Helena

    2015-04-15

    Epidemiologic studies indicate that dietary factors, such as coffee, may influence breast cancer and modulate hormone receptor status. The purpose of this translational study was to investigate how coffee may affect breast cancer growth in relation to estrogen receptor-α (ER) status. The influence of coffee consumption on patient and tumor characteristics and disease-free survival was assessed in a population-based cohort of 1,090 patients with invasive primary breast cancer in Sweden. Cellular and molecular effects by the coffee constituents caffeine and caffeic acid were evaluated in ER(+) (MCF-7) and ER(-) (MDA-MB-231) breast cancer cells. Moderate (2-4 cups/day) to high (≥5 cups/day) coffee intake was associated with smaller invasive primary tumors (Ptrend = 0.013) and lower proportion of ER(+) tumors (Ptrend = 0.018), compared with patients with low consumption (≤1 cup/day). Moderate to high consumption was associated with lower risk for breast cancer events in tamoxifen-treated patients with ER(+) tumors (adjusted HR, 0.51; 95% confidence interval, 0.26-0.97). Caffeine and caffeic acid suppressed the growth of ER(+) (P ≤ 0.01) and ER(-) (P ≤ 0.03) cells. Caffeine significantly reduced ER and cyclin D1 abundance in ER(+) cells. Caffeine also reduced the insulin-like growth factor-I receptor (IGFIR) and pAkt levels in both ER(+) and ER(-) cells. Together, these effects resulted in impaired cell-cycle progression and enhanced cell death. The clinical and experimental findings demonstrate various anticancer properties of caffeine and caffeic acid against both ER(+) and ER(-) breast cancer that may sensitize tumor cells to tamoxifen and reduce breast cancer growth. ©2015 American Association for Cancer Research.

  16. Synthesis of caffeic acid molecularly imprinted polymer microspheres and high-performance liquid chromatography evaluation of their sorption properties.

    Science.gov (United States)

    Valero-Navarro, Angel; Gómez-Romero, María; Fernández-Sánchez, Jorge F; Cormack, Peter A G; Segura-Carretero, Antonio; Fernández-Gutiérrez, Alberto

    2011-10-14

    In the current work, a molecularly imprinted polymer (MIP) has been synthesised and used to enable the extraction of a naturally-occurring antioxidant from complex media. More specifically, we describe the first example of a caffeic acid (CA) MIP which has been synthesised in the form of well-defined polymer microspheres, and its use for the extraction of CA from fruit juice sample. The CA MIP was synthesised by precipitation polymerisation using 4-vinylpyridine as functional monomer, divinylbenzene-80 as crosslinker and acetonitrile:toluene (75/25, v/v) as porogen. The particle sizing and morphological characterisation of the polymers was carried out by means of scanning electron microscopy (narrow particle size distribution; ∼5 and 1.5 μm particle diameters for the MIP and NIP [non-imprinted polymer], respectively) and nitrogen sorption porosimetry (specific surface areas of 340 and 350 m(2)g(-1), and specific pore volumes of 0.17 and 0.19 cm(3)g(-1) for the MIP and NIP, respectively). The polymers were evaluated further by batch rebinding experiments, and from the derived isotherms their binding capacity and binding strength were determined (number of binding sites (N(K))=0.6 and 0.3 mmol g(-1) for the MIP and NIP, respectively, and apparent average adsorption constant (K(N))=10.0 and 1.6L mmol(-1) for the MIP and NIP, respectively). To evaluate the molecular recognition character of the MIP it was packed into a stainless steel column (50 mm × 4.6 mm i.d.) and evaluated as an HPLC-stationary phase. The mobile phase composition, flow rate, and the elution profile were then optimised in order to improve the peak shape without negatively affecting the imprinting factor (IF). Very interesting, promising properties were revealed. The imprinting factor (IF) under the optimised conditions was 11.9. Finally, when the imprinted LC column was used for the selective recognition of CA over eight related compounds, very good selectivity was obtained. This outcome enabled

  17. Determination of catechol O-methyltransferase activity in relation to melanin metabolism using high-performance liquid chromatography with fluorimetric detection

    NARCIS (Netherlands)

    Smit, N. P.; Pavel, S.; Kammeyer, A.; Westerhof, W.

    1990-01-01

    A new sensitive method for the determination of catechol O-methyltransferase activity has been developed. The method is based on the O-methylation of the indolic intermediates of melanin metabolism. The substrate, 5,6-dihydroxyindole-2-carboxylic acid, is converted by the enzyme to two O-methylated

  18. Structure and Mechanism of the Rebeccamycin Sugar 4'-O-Methyltransferase RebM

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Shanteri; McCoy, Jason G.; Zhang, Changsheng; Bingman, Craig A.; Phillips, Jr., George N.; Thorson, Jon S. (UW)

    2008-12-12

    The 2.65-{angstrom} crystal structure of the rebeccamycin 4'-O-methyltransferase RebM in complex with S-adenosyl-l-homocysteine revealed RebM to adopt a typical S-adenosylmethionine-binding fold of small molecule O-methyltransferases (O-MTases) and display a weak dimerization domain unique to MTases. Using this structure as a basis, the RebM substrate binding model implicated a predominance of nonspecific hydrophobic interactions consistent with the reported ability of RebM to methylate a wide range of indolocarbazole surrogates. This model also illuminated the three putative RebM catalytic residues (His{sup 140/141} and Asp{sup 166}) subsequently found to be highly conserved among sequence-related natural product O-MTases from GC-rich bacteria. Interrogation of these residues via site-directed mutagenesis in RebM demonstrated His{sup 140} and Asp{sup 166} to be most important for catalysis. This study reveals RebM to be a member of the general acid/base-dependent O-MTases and, as the first crystal structure for a sugar O-MTase, may also present a template toward the future engineering of natural product MTases for combinatorial applications.

  19. Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid

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    Burgos-Morón, Estefanía; Calderón-Montaño, José Manuel; Orta, Manuel Luis; Guillén-Mancina, Emilio; Mateos, Santiago; López-Lázaro, Miguel

    2016-01-01

    Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee. PMID:27399778

  20. Regulation of Catechol-O-Methyltransferase Expression in Human Myometrial Cells

    Science.gov (United States)

    Wentz, Melissa J.; Jamaluddin, Mohammad; Garfield, Robert E.; Al-Hendy, Ayman

    2014-01-01

    OBJECTIVE The catechol-O-methyltransferase enzyme catalyzes the methylation of the catechol estrogens, 2- or 4-hydroxyestrogen, to 2- or 4-methoxyestrogen. Both the hydroxy estrogens and methoxy estrogens were shown to modulate the effects of estrogen. Because catechol-O-methyltransferase activity controls levels of these metabolites, it may help regulate the cellular estrogenic milieu. In this study, we examined the regulation of catechol-O-methyltransferase expression in human myometrial cells. METHODS Catechol-O-methyltransferase expression was assessed by reverse transcription–polymerase chain reaction, Western blot, and luciferase assays in human myometrial cells after treatment with estrogen or progesterone. Catechol-O-methyltransferase expression was measured in cells after treatment with tumor necrosis factor alpha (TNFα) alone or with lactacystin, a protea-some inhibitor. Luciferase assays were also conducted using human myometrial cells containing an estrogen response element–luciferase reporter gene to measure levels of estrogen-mediated transactivation after treatment with estrogen and increasing concentrations of 2-hydroxestrogen. RESULTS Catechol-O-methyltransferase expression was down-regulated by progesterone or estrogen. Tumor necrosis factor alpha upregulated catechol-O-methyltransferase expression, whereas cotreatment with lactacystin attenuated this response, suggesting that TNFα activated nuclear factor kappa B to induce catechol-O-methyltransferase expression. Increased concentrations of 2-hydroxyestrogen attenuated estrogen-mediated transcription in the myometrial cells. CONCLUSION Catechol-O-methyltransferase expression may be regulated in the myometrium to control the local action of estrogen. Low levels of catechol-O-methyltransferase in the myometrium would result in an accumulation of 2-hydroxyestrogen and may antagonize the local effect of estrogen. High levels of catechol-O-methyltransferase in the myometrium would result in

  1. Hypnotizability and Catechol-O-Methyltransferase (COMT polymorphysms in Italians

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    Silvano ePresciuttini

    2014-01-01

    Full Text Available Higher brain dopamine content depending on lower activity of Catechol-O-Methyltransferase (COMT in subjects with high hypnotisability scores (highs has been considered responsible for their attentional characteristics. However, the results of the previous genetic studies on association between hypnotisability and the Catechol-O-Methyltransferase (COMT single nucleotide polymorphism (SNP rs4680 (Val158Met were inconsistent. Here, we used a selective genotyping approach to re-evaluate the association between hypnotisability and COMT in the context of a two-SNP haplotype analysis, considering not only the Val158Met polymorphism, but also the closely located rs4818 SNP. An Italian sample of 53 highs, 49 low hypnotizable subjects (lows and 57 controls, were genotyped for a segment of 805 bp of the COMT gene, including Val158Met and the closely located rs4818 SNP. Our selective genotyping approach had 97.1% power to detect the previously reported strongest association at the significance level of 5%. We found no evidence of association at the SNP, haplotype and diplotype levels. Thus, our results challenge the dopamine-based theory of hypnosis and indirectly support recent neuropsychological and neurophysiological findings reporting the lack of any association between hypnotisability and focused attention abilities.

  2. Caffeic acid phenethyl ester, a promising component of propolis with a plethora of biological activities: a review on its anti-inflammatory, neuroprotective, hepatoprotective, and cardioprotective effects.

    Science.gov (United States)

    Tolba, Mai F; Azab, Samar S; Khalifa, Amani E; Abdel-Rahman, Sherif Z; Abdel-Naim, Ashraf B

    2013-08-01

    Caffeic acid phenethyl ester (CAPE) is an important active component of honey bee propolis that possesses a plethora of biological activities. Propolis is used safely in traditional medicine as a dietary supplement for its therapeutic benefits. This review highlights the recently published data about CAPE bioavailability, anti-inflammatory, neuroprotective; hepatoprotective and cardioprotective activities. CAPE showed promising efficacy both in vitro and in vivo studies in animal models with minimum adverse effects. Its effectiveness was demonstrated in multiple target organs. Despite this fact, it has not been yet investigated as a protective agent or a potential therapy in humans. Investigation of CAPE efficacy in clinical trials is strongly encouraged to elucidate its therapeutic benefit for different human diseases after performing full preclinical toxicological studies and gaining more insights into its pharmacokinetics. © 2013 International Union of Biochemistry and Molecular Biology.

  3. Inhibition of Procarcinogen Activating Enzyme CYP1A2 Activity and Free Radical Formation by Caffeic Acid and its Amide Analogues.

    Science.gov (United States)

    Narongchai, Paitoon; Niwatananun, Kanokporn; Narongchai, Siripun; Kusirisin, Winthana; Jaikang, Churdsak

    2016-01-01

    Caffeic acid (CAF) and its amide analogues, ethyl 1-(3',4'-dihydroxyphenyl) propen amide (EDPA), phenethyl 1-(3',4'-dihydroxyphenyl) propen amide (PEDPA), phenmethyl 1- (3',4'-dihydroxyphenyl) propen amide (PMDPA) and octyl 1-(3',4'-dihydroxyphenyl) propen amide (ODPA) were investigated for the inhibition of procarcinogen activating enzyme. CYP1A2 and scavenging activity on formation of nitric oxide, superoxide anion, DPPH radical and hydroxyl radical. It was found that they inhibited CYP1A2 enzyme by uncompetitive inhibition. Apparent Ki values of CAF, EDPA, PEDPA, PMDPA and ODPA were 0.59, 0.39, 0.45, 0.75 and 0.80 µM, respectively suggesting potent inhibitors of CYP1A2. Moreover, they potentially scavenged nitric oxide radical with IC 50 values of 0.12, 0.22, 0.28, 0.22 and 0.51 mM, respectively. The IC50 values of superoxide anion scavenging were 0.20, 0.22, 0.44, 2.18 and 2.50 mM, respectively. 1, 1- diphenyl-2- picrylhydrazyl (DPPH) radical-scavenging ability, shown as IC50 values, were 0.41, 0.29, 0.30, 0.89 and 0.84 mM, respectively. Moreover, the hydroxyl radical scavenging in vitro model was shown as IC50 values of 23.22, 21.06, 17.10, 17.21 and 15.81 µM, respectively. From our results, caffeic acid and its amide analogues are in vitro inhibitors of human CYP1A2 catalytic activity and free radical formation. They may be useful to be developed as potential chemopreventive agents that block CYP1A2-mediated chemical carcinogenesis.

  4. Preventative Effects of Caffeic Acid Phenyl Ester on Cadmium Intoxication Induced Hematological and Blood Coagulation Disturbances and Hepatorenal Damage in Rats

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    Ashour, Tariq Helal

    2014-01-01

    The preventative effect of caffeic acid phenyl ester (CAPE) against hematological, blood coagulation, and hepatorenal disturbances in cadmium (Cd) intoxication was investigated in rats. Male Wistar rats were randomly assigned into control group, Cd-group, and Cd + CAPE group. Cd intoxication was induced by intraperitoneal injection (i.p.) of CdCl2 (1 mg/kg/day) for 21 days, and CAPE was daily given (10 micromol/kg; i.p.) for also 21 days. The results showed that Cd intoxication impaired hepatorenal function and significantly prolonged prothrombin time and activated partial thromboplastin time and decreased fibrinogen level, red blood cells and platelets counts, hemoglobin concentration, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. Interestingly, all these hematological, blood coagulation, and hepatorenal deteriorations of Cd toxicity were significantly prevented by CAPE. Additionally, CAPE significantly reversed the significant decreases in levels of total reduced glutathione and superoxide dismutase and increases in levels of thiobarbituric acid reactive substances that were observed in the sera and liver and kidney homogenates of Cd group. It is concluded that CAPE is a promising compound that can counteract the hematological and blood coagulation disturbances, oxidative stress, and hepatorenal damages in Cd intoxication. However, further studies are crucially needed to improve this treatment in patients. PMID:25006475

  5. Catechol Groups Enable Reactive Oxygen Species Scavenging-Mediated Suppression of PKD-NFkappaB-IL-8 Signaling Pathway by Chlorogenic and Caffeic Acids in Human Intestinal Cells

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    Hee Soon Shin

    2017-02-01

    Full Text Available Chlorogenic acid (CHA and caffeic acid (CA are phenolic compounds found in coffee, which inhibit oxidative stress-induced interleukin (IL-8 production in intestinal epithelial cells, thereby suppressing serious cellular injury and inflammatory intestinal diseases. Therefore, we investigated the anti-inflammatory mechanism of CHA and CA, both of which inhibited hydrogen peroxide (H2O2-induced IL-8 transcriptional activity. They also significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB transcriptional activity, nuclear translocation of the p65 subunit, and phosphorylation of IκB kinase (IKK. Additionally, upstream of IKK, protein kinase D (PKD was also suppressed. Finally, we found that they scavenged H2O2-induced reactive oxygen species (ROS and the functional moiety responsible for the anti-inflammatory effects of CHA and CA was the catechol group. Therefore, we conclude that the presence of catechol groups in CHA and CA allows scavenging of intracellular ROS, thereby inhibiting H2O2-induced IL-8 production via suppression of PKD-NF-κB signaling in human intestinal epithelial cells.

  6. Absorption properties and effects of caffeic acid phenethyl ester and its p-nitro-derivative on P-glycoprotein in Caco-2 cells and rats.

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    Gou, Jing; Yao, Xiaofang; Tang, Hao; Zou, Kaili; Liu, Yujia; Zuo, Hua; Zhao, Xiaoyan; Li, Zhubo

    2016-12-01

    Caffeic acid phenethyl ester (CAPE), isolated from honeybee propolis, has pharmacological applications. A synthesized CAPE derivative, p-nitro-caffeic acid phenethyl ester (CAPE-NO2), showed similar activities with CAPE. The pharmacological activities of CAPE and CAPE-NO2 are related to their absorption properties. To understand the pharmacokinetic profiles of CAPE and CAPE-NO2 in rats and investigate the absorption mechanisms and effects on P-glycoprotein in Caco-2 cells. The pharmacokinetic profiles of CAPE and CAPE-NO2 were obtained after oral administration (10 mg/kg) to rats. Transport studies of CAPE and CAPE-NO2 (5, 10, 20 μM) were performed in Caco-2 cell model. P-gp activities were assayed by rhodamine 123 cellular retention. Expression of P-gp was determined after the cells were administrated with CAPE and CAPE-NO2 (5, 20 μM) for 48 and 72 h. The AUC(0-t) of CAPE-NO2 (3239.9 ± 352 ng × h/mL) was two-time greater than CAPE (1659.6 ± 152 ng × h/mL) in rats. The Papp values of CAPE and CAPE-NO2 were (4.86 ± 0.90) × 10(-6 )cm/s and (12.34 ± 1.6) × 10(-6 )cm/s, respectively. The accumulation of rhodamine 123 was increased by 1.3- to 1.9-fold and 1.4- to 2.3-fold in CAPE and CAPE-NO2 groups after 1 h administration, respectively. However, CAPE and CAPE-NO2 increased the P-gp levels by 2.1- and 1.7-fold, respectively. The absorption of CAPE-NO2 can be enhanced in rats and Caco-2 cells compared with CAPE. The two compounds are potential inhibitors of P-gp. The increased P-gp levels generated by CAPE and CAPE-NO2 played a role as a defense mechanism by limiting intracellular xenobiotic levels.

  7. Cloning and expression of a novel catechol-O-methyltransferase in common marmosets.

    Science.gov (United States)

    Uehara, Shotaro; Uno, Yasuhiro; Inoue, Takashi; Sasaki, Erika; Yamazaki, Hiroshi

    2017-02-04

    Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of endogenous catechol amines and estrogens and exogenous catechol-type of drugs. A Parkinson's disease model of common marmoset (Callithrix jacchus) has been widely used in preclinical studies to evaluate inhibitory potential of new drug candidates on marmoset COMT. Despite COMT inhibitors could potentiate the pharmacological action of levodopa on Parkinson's disease in animal models, marmoset COMT cDNA has not yet been identified and characterized. In this study, a cDNA highly homologous to human COMT was cloned from marmoset livers. This cDNA encoded 268 amino acids containing a transmembrane region and critical amino acid residues for catalytic function. The amino acid sequences of marmoset COMT shared high sequence identity (90%) with human COMT. COMT mRNA was expressed in all five tissues tested, including brain, lung, liver, kidney and small intestine, and was more abundant in marmoset liver and kidney. Membrane-bound COMT was immunochemically detected in livers and kidneys, whereas soluble COMT was detected in livers, similar to humans. These results indicated that the molecular characteristics of marmoset COMT were generally similar to the human ortholog.

  8. Mapping the conformational space accessible to catechol-O-methyltransferase.

    Science.gov (United States)

    Ehler, Andreas; Benz, Jörg; Schlatter, Daniel; Rudolph, Markus G

    2014-08-01

    Methylation catalysed by catechol-O-methyltransferase (COMT) is the main pathway of catechol neurotransmitter deactivation in the prefrontal cortex. Low levels of this class of neurotransmitters are held to be causative of diseases such as schizophrenia, depression and Parkinson's disease. Inhibition of COMT may increase neurotransmitter levels, thus offering a route for treatment. Structure-based drug design hitherto seems to be based on the closed enzyme conformation. Here, a set of apo, semi-holo, holo and Michaelis form crystal structures are described that define the conformational space available to COMT and that include likely intermediates along the catalytic pathway. Domain swaps and sizeable loop movements around the active site testify to the flexibility of this enzyme, rendering COMT a difficult drug target. The low affinity of the co-substrate S-adenosylmethionine and the large conformational changes involved during catalysis highlight significant energetic investment to achieve the closed conformation. Since each conformation of COMT is a bona fide target for inhibitors, other states than the closed conformation may be promising to address. Crystallographic data for an alternative avenue of COMT inhibition, i.e. locking of the apo state by an inhibitor, are presented. The set of COMT structures may prove to be useful for the development of novel classes of inhibitors.

  9. Catechol-O-methyltransferase inhibitors in Parkinson's disease.

    Science.gov (United States)

    Müller, Thomas

    2015-02-01

    Inhibitors of catechol-O-methyltransferase (COMT) are commonly used as an adjunct to levodopa in patients with Parkinson's disease (PD) for the amelioration of wearing-off symptoms. This narrative review aims to discuss the role of COMT inhibitors on peripheral levodopa metabolism and continuous brain delivery of levodopa, and to describe their metabolic properties. Oral application of levodopa formulations with a dopa decarboxylase inhibitor (DDI) results in fluctuating levodopa plasma concentrations, predominantly due to the short half-life of levodopa and its slowing of gastric emptying. Following transport across the blood-brain barrier and its metabolic conversion to dopamine, these peripheral 'ups and downs' of levodopa are reflected in fluctuating dopamine levels in the synaptic cleft between presynaptic and postsynaptic dopaminergic neurons of the nigrostriatal system. As a result, pulsatile postsynaptic dopaminergic stimulation takes place and results in the occurrence of motor complications, such as wearing-off and dyskinesia. More continuous plasma behaviour was observed after the combination of levodopa/DDI formulations with COMT inhibitors. These compounds also weaken a levodopa/DDI-related homocysteine increase, as biomarker for an impaired methylation capacity, which is involved in an elevated oxidative stress exposure. These findings favour the concept of chronic levodopa/DDI application with concomitant inhibition of COMT and monoamine oxidase, since deamination of dopamine via this enzyme also generates free radicals. This triple combination is suggested as standard levodopa application in patients with PD who need levodopa, if they will tolerate it.

  10. Caffeic Acid Phenylethyl Ester and MG-132 Have Apoptotic and Antiproliferative Effects on Leukemic Cells But Not on Normal Mononuclear Cells12

    Science.gov (United States)

    Cavaliere, Victoria; Papademetrio, Daniela L; Lorenzetti, Mario; Valva, Pamela; Preciado, María Victoria; Gargallo, Patricia; Larripa, Irene; Monreal, Mariela B; Pardo, María Laura; Hajos, Silvia E; Blanco, Guillermo AC; Álvarez, Élida MC

    2009-01-01

    Chemotherapy aims to limit proliferation and induce apoptotic cell death in tumor cells. Owing to blockade of signaling pathways involved in cell survival and proliferation, nuclear factor κB (NF-κB) inhibitors can induce apoptosis in a number of hematological malignancies. The efficacy of conventional chemotherapeutic drugs, such as vincristine (VCR) and doxorubicine (DOX), may be enhanced with combined therapy based on NF-κB modulation. In this study, we evaluated the effect of caffeic acid phenylethyl ester (CAPE) and MG-132, two nonspecific NF-κB inhibitors, and conventional chemotherapeutics drugs DOX and VCR on cell proliferation and apoptosis induction on a lymphoblastoid B-cell line, PL104, established and characterized in our laboratory. CAPE and MG-132 treatment showed a strong antiproliferative effect accompanied by clear cell cycle deregulation and apoptosis induction. Doxorubicine and VCR showed antiproliferative effects similar to those of CAPE and MG-132, although the latter drugs showed an apoptotic rate two-fold higher than DOX and VCR. None of the four compounds showed cytotoxic effect on peripheral mononuclear cells from healthy volunteers. CAPE- and MG-132-treated bone marrow cells from patients with myeloid and lymphoid leukemias showed 69% (P < .001) and 25% decrease (P < .01) in cell proliferation and 42% and 34% (P < .01) apoptosis induction, respectively. Overall, our results indicate that CAPE and MG-132 had a strong and selective apoptotic effect on tumor cells that may be useful in future treatment of hematological neoplasias. PMID:19252751

  11. Caffeic Acid Phenethyl Ester and Ethanol Extract of Propolis Induce the Complementary Cytotoxic Effect on Triple-Negative Breast Cancer Cell Lines

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    Anna Rzepecka-Stojko

    2015-05-01

    Full Text Available Chemotherapy of breast cancer could be improved by bioactive natural substances, which may potentially sensitize the carcinoma cells’ susceptibility to drugs. Numerous phytochemicals, including propolis, have been reported to interfere with the viability of carcinoma cells. We evaluated the in vitro cytotoxic activity of ethanol extract of propolis (EEP and its derivative caffeic acid phenethyl ester (CAPE towards two triple-negative breast cancer (TNBC cell lines, MDA-MB-231 and Hs578T, by implementation of the MTT and lactate dehydrogenase (LDH assays. The morphological changes of breast carcinoma cells were observed following exposure to EEP and CAPE. The IC50 of EEP was 48.35 µg∙mL−1 for MDA-MB-23 cells and 33.68 µg∙mL−1 for Hs578T cells, whereas the CAPE IC50 was 14.08 µM and 8.01 µM for the MDA-MB-231 and Hs578T cell line, respectively. Here, we report that propolis and CAPE inhibited the growth of the MDA-MB-231 and Hs578T lines in a dose-dependent and exposure time-dependent manner. EEP showed less cytotoxic activity against both types of TNBC cells. EEP and, particularly, CAPE may markedly affect the viability of breast cancer cells, suggesting the potential role of bioactive compounds in chemoprevention/chemotherapy by potentiating the action of standard anti-cancer drugs.

  12. In vitro effect of caffeic acid phenethyl ester on matrix metalloproteinases (MMP-1 and MMP-9) and their inhibitor (TIMP-1) in lipopolysaccharide-activated human monocytes.

    Science.gov (United States)

    Vilela, Polyana das Graças Figueiredo; de Oliveira, Jonatas Rafael; de Barros, Patrícia Pimentel; Leão, Mariella Vieira Pereira; de Oliveira, Luciane Dias; Jorge, Antonio Olavo Cardoso

    2015-09-01

    The role of matrix metalloproteinases (MMPs) in tissue degradation has become evident in many diseases and great interest therefore exists in the pharmacological control of the activity of these enzymes. This study evaluated the effect of caffeic acid phenethyl ester (CAPE) on the production of MMPs and their inhibitor (TIMP) in monocytes activated by lipopolysaccharide (LPS). The human monocytic cell line (THP-1) was treated with non-cytotoxic concentrations of CAPE (10 and 60μM) combined with 1μg/mL of LPS. The gene expression of MMP-1, MMP-9 and TIMP-1 was evaluated by quantitative real-time polymerase chain reaction. The protein secretion into the culture medium was assessed via enzyme-linked immunosorbent assay and the gelatinolytic activity of MMP-9 by zymography. CAPE, especially at the highest concentration, down-regulated MMP-1 and MMP-9 gene expression but up-regulated the gene expression of TIMP-1. Furthermore, CAPE reduced the secreted protein level of MMP-1 and MMP-9 as well as the gelatinolytic activity of MMP-9. CAPE was able to inhibit the gene expression, production and the activity of MMPs induced by LPS and also increased the gene expression of TIMP-1. The present observations suggest that CAPE exerted a positive effect on the regulatory mechanism between MMPs and TIMP, which is important for the control of different diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer.

    Science.gov (United States)

    Wu, Jing; Omene, Coral; Karkoszka, Jerzy; Bosland, Maarten; Eckard, Jonathan; Klein, Catherine B; Frenkel, Krystyna

    2011-09-01

    Breast cancer (BC) patients use alternative and natural remedies more than patients with other malignancies. Specifically, 63-83% use at least one type of alternative medicine and 25-63% use herbals and vitamins. Propolis is a naturopathic honeybee product, and CAPE (caffeic acid phenethyl ester), is a major medicinal component of propolis. CAPE, in a concentration dependent fashion, inhibits MCF-7 (hormone receptor positive, HR+) and MDA-231 (a model of triple negative BC (TNBC) tumor growth, both in vitro and in vivo without much effect on normal mammary cells and strongly influences gene and protein expression. It induces cell cycle arrest, apoptosis and reduces expression of growth and transcription factors, including NF-κB. Notably, CAPE down-regulates mdr-1 gene, considered responsible for the resistance of cancer cells to chemotherapeutic agents. Further, CAPE dose-dependently suppresses VEGF formation by MDA-231 cells and formation of capillary-like tubes by endothelial cells, implicating inhibitory effects on angiogenesis. In conclusion, our results strongly suggest that CAPE inhibits MDA-231 and MCF-7 human breast cancer growth via its apoptotic effects, and modulation of NF-κB, the cell cycle, and angiogenesis. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  14. Effect of caffeic acid phenethyl ester on oxidant and anti-oxidant status of liver and serum in a rat model with acute methanol intoxication.

    Science.gov (United States)

    Yazgan, Ü C; Elbey, B; Kuş, S; Baykal, B; Keskin, I; Yılmaz, A; Şahin, A

    2017-05-01

    Methanol toxicity is one of the major public health problems because it can cause severe morbidity and mortality. Methanol intoxication causes changes in the balance between the production of free radicals and antioxidant capacity. We aimed to investigate the effects of caffeic acid phenethyl ester (CAPE) on the total oxidant status, total antioxidant status (TAS), and oxidative stress index (OSI) parameters of the liver and the serum in a rat model of acute methanol intoxication. Rats were treated with intraperitoneal (i.p.) Methotrexate (MTX) for 7 days. On the 8th day, i.p. Methanol was administered in the methanol, ethanol and CAPE groups. Four hours after methanol treatment, ethanol was injected i.p. in the ethanol group; CAPE (i.p.) in the CAPE group; serum physiologic i.p. in other groups. After 8 hours, rats were killed and the serum and the liver samples were obtained for biochemical analyses. The OSI value was significantly higher in the methanol group compared to the ethanol and CAPE groups. Serum TAS levels of the methanol group were significantly different compared to the control group, but not compared to the MTX group. The amelioration of oxidative stress was greater in the CAPE group compared to the ethanol group but was not statistically significant. This study demonstrates that CAPE treatment ameliorates oxidative stress in the serum and liver in a rat model of acute methanol intoxication.

  15. Development of novel antibacterial active, HaCaT biocompatible and biodegradable CA-g-P(3HB-EC biocomposites with caffeic acid as a functional entity

    Directory of Open Access Journals (Sweden)

    H. M. N. Iqbal

    2015-09-01

    Full Text Available We have developed novel composites by grafting caffeic acid (CA onto the P(3HB-EC based material and laccase from Trametes versicolor was used for grafting purposes. The resulting composites were designated as CA-g-P(3HB-EC i.e., P(3HB-EC (control, 5CA-g-P(3HB-EC, 10CA-g-P(3HB-EC, 15CA-g-P(3HB-EC and 20CA-g-P(3HB-EC. FT-IR (Fourier-transform infrared spectroscopy was used to examine the functional and elemental groups of the control and laccase-assisted graft composites. Evidently, 15CA-g-P(3HB-EC composite exhibited resilient antibacterial activity against Gram-positive and Gram-negative bacterial strains. Moreover, a significant level of biocompatibility and biodegradability of the CA-g-P(3HB-EC composites was also achieved with the human keratinocytes-like HaCaT cells and soil burial evaluation, respectively. In conclusion, the newly developed novel composites with multi characteristics could well represent the new wave of biomaterials for medical applications, and more specifically have promising future in the infection free would dressings, burn and/or skin regeneration field due to their sophisticated characteristics.

  16. Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α

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    Kim, Hyung Gyun [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Han, Eun Hee [Division of Life Science, Korea Basic Science Institute, Daejeon (Korea, Republic of); Im, Ji Hye; Lee, Eun Ji; Jin, Sun Woo [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2015-09-25

    Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. Moreover, CAPE inhibited 3-MC-induced CYP1A1 activity, mRNA expression, protein level, and promoter activity. CAPE treatment also decreased 3-MC-inducible xenobiotic-response element (XRE)-linked luciferase, aryl hydrocarbons receptor (AhR) transactivation and nuclear localization. CAPE induced hypoxia inducible factor-1α (HIF-1α) protein level and HIF-1α responsible element (HRE) transcriptional activity. CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 protein expression. Taken together, CAPE decreases 3-MC-mediated CYP1A1 expression, and this inhibitory response is associated with inhibition of AhR and HIF-1α induction. - Highlights: • CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. • CAPE inhibited 3-MC-induced CYP1A1 expression. • CAPE induced HIF-1α induction. • CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 expression.

  17. Biotechnological Production of Dimethoxyflavonoids Using a Fusion Flavonoid O-Methyltransferase Possessing Both 3'- and 7-O-Methyltransferase Activities.

    Science.gov (United States)

    Lee, Danbi; Park, Hye Lin; Lee, Sang-Won; Bhoo, Seong Hee; Cho, Man-Ho

    2017-05-26

    Although they are less abundant in nature, methoxyflavonoids have distinct physicochemical and pharmacological properties compared to common nonmethylated flavonoids. Thus, enzymatic conversion and biotransformation using genetically engineered microorganisms of flavonoids have been attempted for the efficient production of methoxyflavonoids. Because of their regiospecificity, more than two flavonoid O-methyltransferases (FOMTs) and enzyme reactions are required to biosynthesize di(or poly)-methoxyflavonoids. For the one-step biotechnological production of bioactive di-O-methylflavonoids, we generated a multifunctional FOMT fusing a 3'-OMT (SlOMT3) and a 7-OMT (OsNOMT). The SlOMT3/OsNOMT fusion enzyme possessed both 3'- and 7-OMT activities to diverse flavonoid substrates, which were comparable to those of individual SlOMT3 and OsNOMT. The SlOMT3/OsNOMT enzyme also showed 3'- and 7-OMT activity for 7- or 3'-O-methylflavonoids, respectively, suggesting that the fusion enzyme can sequentially methylate flavonoids into di-O-methylflavonoids. The biotransformation of the flavonoids quercetin, luteolin, eriodictyol, and taxifolin using SlOMT3/OsNOMT-transformed Escherichia coli generated corresponding di-O-methylflavonoids, rhamnazin, velutin, 3',7-di-O-methyleriodictyol, and 3',7-di-O-methyltaxifolin, respectively. These results indicate that dimethoxyflavonoids may be efficiently produced from nonmethylated flavonoid precursors through a one-step biotransformation using the engineered E. coli harboring the SlOMT3/OsNOMT fusion gene.

  18. Catechol-O-methyltransferase association with hemoglobin A1c.

    Science.gov (United States)

    Hall, Kathryn T; Jablonski, Kathleen A; Chen, Ling; Harden, Maegan; Tolkin, Benjamin R; Kaptchuk, Ted J; Bray, George A; Ridker, Paul M; Florez, Jose C; Mukamal, Kenneth J; Chasman, Daniel I

    2016-07-01

    Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes. We tested whether COMT polymorphisms were associated with baseline HbA1c in the Women's Genome Health Study (WGHS), and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and with susceptibility to type 2 diabetes in WGHS, DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM), and the Diabetes Prevention Program (DPP). Given evidence that COMT modifies some drug responses, we examined association with type 2 diabetes and randomized metformin and aspirin treatment. COMT rs4680 high-activity G-allele was associated with lower HbA1c in WGHS (β=-0.032% [0.012], p=0.008) and borderline significant in MAGIC (β=-0.006% [0.003], p=0.07). Combined COMT per val allele effects on type 2 diabetes were significant (OR=0.98 [0.96-0.998], p=0.03) in fixed-effects analyses across WGHS, DIAGRAM, and DPP. Similar results were obtained for 2 other COMT SNPs rs4818 and rs4633. In the DPP, the rs4680 val allele was borderline associated with lower diabetes incidence among participants randomized to metformin (HR=0.81 [0.65-1.00], p=0.05). COMT rs4680 high-activity G-allele was associated with lower HbA1c and modest protection from type 2 diabetes. The directionality of COMT associations was concordant with those previously observed for cardiometabolic risk factors and CVD. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Catechol-O-methyltransferase, dopamine, and sleep-wake regulation.

    Science.gov (United States)

    Dauvilliers, Yves; Tafti, Mehdi; Landolt, Hans Peter

    2015-08-01

    Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and environment. The catechol-O-methyltransferase (COMT) gene is an interesting candidate, being one of the major mammalian enzymes involved in the catabolism of catecholamines. The activity of COMT enzyme is genetically polymorphic due to a guanine-to-adenine transition at codon 158, resulting in a valine (Val) to methionine (Met) substitution. Individuals homozygous for the Val allele show higher COMT activity, and lower dopaminergic signaling in prefrontal cortex (PFC) than subjects homozygous for the Met allele. Since COMT has a crucial role in metabolising dopamine, it was suggested that the common functional polymorphism in the COMT gene impacts on cognitive function related to PFC, sleep-wake regulation, and potentially on sleep pathologies. The COMT Val158Met polymorphism may predict inter-individual differences in brain electroencephalography (EEG) alpha oscillations and recovery processes resulting from partial sleep loss in healthy individuals. The Val158Met polymorphism also exerts a sexual dimorphism and has a strong effect on objective daytime sleepiness in patients with narcolepsy-cataplexy. Since the COMT enzyme inactivates catecholamines, it was hypothesized that the response to stimulant drugs differs between COMT genotypes. Modafinil maintained executive functioning performance and vigilant attention throughout sleep deprivation in subjects with Val/Val genotype, but less in those with Met/Met genotype. Also, homozygous Met/Met patients with narcolepsy responded to lower doses of modafinil compared to Val/Val carriers. We review here the critical role of the common functional COMT gene polymorphism, COMT enzyme activity, and the prefrontal dopamine levels in the regulation of sleep and wakefulness in normal subjects, in narcolepsy and other sleep-related disorders, and its impact on the response to psychostimulants. Copyright © 2014 Elsevier Ltd. All

  20. Inhibitors of catechol-O-methyltransferase sensitize mice to pain

    Science.gov (United States)

    Kambur, O; Talka, R; Ansah, OB; Kontinen, VK; Pertovaara, A; Kalso, E; Männistö, PT

    2010-01-01

    BACKGROUND AND PURPOSE Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson's disease in which pain is an important symptom. COMT polymorphisms modulate pain and opioid analgesia in humans. In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodynia and hyperalgesia in a model of diabetic neuropathy. Here, we have assessed the effects of acute and repeated administrations of COMT inhibitors on mechanical, thermal and carrageenan-induced nociception in male mice. EXPERIMENTAL APPROACH We used single and repeated administration of a peripherally restricted, short-acting (nitecapone) and also a centrally acting (3,5-dinitrocatechol, OR-486) COMT inhibitor. We also tested CGP 28014, an indirect inhibitor of COMT enzyme. Effects of OR-486 on thermal nociception were also studied in COMT deficient mice. Effects on spinal pathways were assessed in rats given intrathecal nitecapone. KEY RESULTS After single administration, both nitecapone and OR-486 reduced mechanical nociceptive thresholds and thermal nociceptive latencies (hot plate test) at 2 and 3 h, regardless of their brain penetration. These effects were still present after chronic treatment with COMT inhibitors for 5 days. Intraplantar injection of carrageenan reduced nociceptive latencies and both COMT inhibitors potentiated this reduction without modifying inflammation. CGP 28014 shortened paw flick latencies. OR-486 did not modify hot plate times in Comt gene deficient mice. Intrathecal nitecapone modified neither thermal nor mechanical nociception. CONCLUSIONS AND IMPLICATIONS Pro-nociceptive effects of COMT inhibitors were confirmed. The pro-nociceptive effects were primarily mediated via mechanisms acting outside the brain and spinal cord. COMT protein was required for these actions. PMID:20726980

  1. Catechol-o-methyltransferase and 3,4-({+/-})-methylenedioxymethamphetamine toxicity.

    Science.gov (United States)

    Herndon, Joseph M; Cholanians, Aram B; Lizarraga, Lucina E; Lau, Serrine S; Monks, Terrence J

    2014-05-01

    Metabolism of 3,4-(±)-methylenedioxymethamphetamine (MDMA) is necessary to elicit its neurotoxic effects. Perturbations in phase I and phase II hepatic enzymes can alter the neurotoxic profile of systemically administered MDMA. In particular, catechol-O-methyltransferase (COMT) plays a critical role in determining the fraction of MDMA that is converted to potentially neurotoxic metabolites. Thus, cytochrome P450 mediated demethylenation of MDMA, or its N-demethylated metabolite, 3,4-(±)-methylenedioxyamphetamine, give rise to the catechols, N-methyl-α-methyldopamine and α-methyldopamine, respectively. Methylation of these catechols by COMT limits their oxidation and conjugation to glutathione, a process that ultimately gives rise to neurotoxic metabolites. We therefore determined the effects of modulating COMT, a critical enzyme involved in determining the fraction of MDMA that is converted to potentially neurotoxic metabolites, on MDMA-induced toxicity. Pharmacological inhibition of COMT in the rat potentiated MDMA-induced serotonin deficits and exacerbated the acute MDMA-induced hyperthermic response. Using a genetic mouse model of COMT deficiency, in which mice lack a functional COMT gene, such mice displayed greater reductions in dopamine concentrations relative to their wild-type (WT) counterparts. Neither WT nor COMT deficient mice were susceptible to MDMA-induced decreases in serotonin concentrations. Interestingly, mice devoid of COMT were far more susceptible to the acute hyperthermic effects of MDMA, exhibiting greater increases in body temperature that ultimately resulted in death. Our findings support the view that COMT plays a pivotal role in determining the toxic response to MDMA.

  2. Establishment of hairy root cultures of Rhaponticum carthamoides (Willd.) Iljin for the production of biomass and caffeic acid derivatives.

    Science.gov (United States)

    Skała, Ewa; Kicel, Agnieszka; Olszewska, Monika A; Kiss, Anna K; Wysokińska, Halina

    2015-01-01

    The aim of the study was to obtain transformed roots of Rhaponticum carthamoides and evaluate their phytochemical profile. Hairy roots were induced from leaf explants by the transformation of Agrobacterium rhizogenes strains A4 and ATCC 15834. The best response (43%) was achieved by infection with A4 strain. The effects of different liquid media (WPM, B5, SH) with full and half-strength concentrations of macro- and micronutrients on biomass accumulation of the best grown hairy root line (RC3) at two different lighting conditions (light or dark) were investigated. The highest biomass (93 g L(-1) of the fresh weight after 35 days) was obtained in WPM medium under periodic light. UPLC-PDA-ESI-MS(3) and HPLC-PDA analyses of 80% aqueous methanol extracts from the obtained hairy roots revealed the presence of eleven caffeoylquinic acids and their derivatives and five flavonoid glycosides. The production of caffeoylquinic acids and their derivatives was elevated in hairy roots grown in the light. Only light-grown hairy roots demonstrated the capability for the biosynthesis of such flavonoid glycosides as quercetagetin, quercetin, luteolin, and patuletin hexosides. Chlorogenic acid, 3,5-di-O-caffeoylquinic acid and a tentatively identified tricaffeoylquinic acid derivative were detected as the major compounds present in the transformed roots.

  3. Establishment of Hairy Root Cultures of Rhaponticum carthamoides (Willd. Iljin for the Production of Biomass and Caffeic Acid Derivatives

    Directory of Open Access Journals (Sweden)

    Ewa Skała

    2015-01-01

    Full Text Available The aim of the study was to obtain transformed roots of Rhaponticum carthamoides and evaluate their phytochemical profile. Hairy roots were induced from leaf explants by the transformation of Agrobacterium rhizogenes strains A4 and ATCC 15834. The best response (43% was achieved by infection with A4 strain. The effects of different liquid media (WPM, B5, SH with full and half-strength concentrations of macro- and micronutrients on biomass accumulation of the best grown hairy root line (RC3 at two different lighting conditions (light or dark were investigated. The highest biomass (93 g L−1 of the fresh weight after 35 days was obtained in WPM medium under periodic light. UPLC-PDA-ESI-MS3 and HPLC-PDA analyses of 80% aqueous methanol extracts from the obtained hairy roots revealed the presence of eleven caffeoylquinic acids and their derivatives and five flavonoid glycosides. The production of caffeoylquinic acids and their derivatives was elevated in hairy roots grown in the light. Only light-grown hairy roots demonstrated the capability for the biosynthesis of such flavonoid glycosides as quercetagetin, quercetin, luteolin, and patuletin hexosides. Chlorogenic acid, 3,5-di-O-caffeoylquinic acid and a tentatively identified tricaffeoylquinic acid derivative were detected as the major compounds present in the transformed roots.

  4. Catechol-O-methyltransferase gene polymorphism and vulvar pain in women with vulvodynia.

    Science.gov (United States)

    Patanwala, Insiyyah Y; Lamvu, Georgine; Ledger, William J; Witzeman, Kathryn; Marvel, Richard; Rapkin, Andrea; Bongiovanni, Ann Marie; Feranec, Jessica; Witkin, Steven S

    2017-04-01

    The underlying causes of vulvar pain in women with vulvodynia remain poorly understood. Catechol-O-methyltransferase, an enzyme that metabolizes catecholamines, is a neuromodulator that is involved with perception and sensitivity to pain. The catechol-O-methyltransferase gene is polymorphic, and a single nucleotide polymorphism is associated with low activity and heightened pain sensitivity. The variant allele that encodes this polymorphism commonly is called the "L allele" because of its low enzyme activity as opposed to the normal H (high activity) allele. The methionine-containing catechol-O-methyltransferase protein coded by the L allele results in elevated catecholamine levels, reduced inactivation of the dopaminergic and adrenergic systems, and increased sensitivity to pain. This polymorphism not only may decrease the pain threshold in response to acute pain but also may facilitate the development of chronic pain. Therefore, the objective of our study was to assess whether a variation in the catechol-O-methyltransferase genotype is involved in increased pain sensitivity in women with vulvodynia. We conducted a prospective cohort study. Buccal swabs were collected from 167 white women with vulvodynia and 107 control subjects; the DNA was tested for a single nucleotide polymorphism at position 158 (rs4680) in the catechol-O-methyltransferase gene. Women with vulvodynia had a marginally increased, yet not significant, prevalence of the catechol-O-methyltransferase genotype that is associated with high activity of the coded protein: 32.9% in the women with vulvodynia, as opposed to 21.5% in the control subjects (odds ratio, 1.80; 95% confidence interval, 1.02-3.15). Subgrouping the cases based on pain frequency revealed that the elevated occurrence of this catechol-O-methyltransferase genotype was present in 40.6% of the subset of women who experienced pain only with sexual intercourse vs only 21.5% of control subjects (odds ratio, 2.50; 95% confidence interval

  5. Analysis of the Association between Catechol-O-Methyltransferase Val158Met and Male Sexual Orientation.

    Science.gov (United States)

    Yu, Wei; Tu, Dan; Hong, Fuchang; Wang, Jing; Liu, Xiaoli; Cai, Yumao; Xu, Ruiwei; Zhao, Guanglu; Wang, Feng; Pan, Hong; Wu, Shinan; Feng, Tiejian; Wang, Binbin

    2015-09-01

    Male sexual orientation is thought to have a genetic component. However, previous studies have failed to generate positive results from among candidate genes. Catechol-O-methyltransferase (COMT), located on chromosome 22, has six exons, spans 27 kb, and encodes a protein of 271 amino acids. COMT has an important role in regulating the embryonic levels of catecholamine neurotransmitters (such as dopamine, norepinephrine, and epinephrine) and estrogens. COMT is also thought to be related to sexual orientation. This study aimed to investigate the relationship between the COMT Val158Met variant and male sexual orientation. We performed association analysis of the COMT gene single nucleotide polymorphism, Val158Met, in 409 homosexual cases and 387 heterosexual control Chinese men. COMT polymorphism status was determined using a polymerase chain reaction-based assay. Polymerase chain reaction was performed to genotype the COMT Val158Met polymorphism. The frequency differences of the genotype and alleles distribution between the male homosexual and control groups. Significant differences, both in genotype and alleles, between male homosexual individuals and controls indicated a genetic component related to male homosexuality. The Val allele recessive model could be an interrelated genetic model of the cause of male homosexuality. The COMT Val158Met variant might be associated with male sexual orientation and a recessive model was suggested. © 2015 International Society for Sexual Medicine.

  6. Structural Characterization of the Mitomycin 7-O-Methyltransferase MmcR

    Science.gov (United States)

    Singh, Shanteri; Chang, Aram; Goff, Randal D.; Bingman, Craig A.; Grüschow, Sabine; Sherman, David H.; Phillips, George N.; Thorson, Jon S.

    2011-01-01

    Mitomycins are quinone-containing antibiotics, widely used as anti-tumor drugs in chemotherapy. Mitomycin-7-O-methyltransferase (MmcR), a key tailoring enzyme involved in the biosynthesis of mitomycin in Streptomyces lavendulae, catalyzes the 7-O-methylation of both C9β- and C9α-configured 7-hydroxymitomycins. We have determined the crystal structures of the MmcR–S-adenosylhomocysteine (SAH) binary complex and MmcR–SAH-Mitomycin A (MMA) ternary complex at resolutions of 1.9 and 2.3 Å, respectively. The study revealed MmcR to adopt a common SAM-dependent O-MTase fold and the presence of a structurally-conserved active site general acid-base pair is consistent with a proton assisted methyltransfer common to most methyltransferases. Given the importance of C7 alkylation to modulate mitomycin redox potential this study may also present a template toward the future engineering of catalysts to generate uniquely bioactive mitomycins. PMID:21538548

  7. An unusual caffeic acid derived bicyclic [2.2.2] octane lignan and other constituents from Cordia rufescens.

    Science.gov (United States)

    do Vale, Ademir E; David, Jorge M; dos Santos, Edlene O; David, Juceni P; e Silva, Lidercia C R C; Bahia, Marcus V; Brandão, Hugo N

    2012-04-01

    This work reports isolation of an unusual lignan with a bicyclic [2.2.2] octene skeleton, named rufescenolide (1), from stems of Cordia rufescens, along with β-sitosterol, stigmasterol, syringaldehyde, 3-β-O-D-glucopyranosyl-sitosterol, methyl caffeate, 4-methoxy-protocatechuic acid and methyl rosmarinate. Structural characterizations employed IR spectroscopic, ESIHRMS and mono and dimensional NMR spectroscopy. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Nitrogen Limited Red and Green Leaf Lettuce Accumulate Flavonoid Glycosides, Caffeic Acid Derivatives, and Sucrose while Losing Chlorophylls, Β-Carotene and Xanthophylls.

    Directory of Open Access Journals (Sweden)

    Christine Becker

    Full Text Available Reduction of nitrogen application in crop production is desirable for ecological and health-related reasons. Interestingly, nitrogen deficiency can lead to enhanced concentrations of polyphenols in plants. The reason for this is still under discussion. The plants' response to low nitrogen concentration can interact with other factors, for example radiation intensity. We cultivated red and green leaf lettuce hydroponically in a Mediterranean greenhouse, supplying three different levels of nitrogen (12 mM, 3 mM, 0.75 mM, either in full or reduced (-50% radiation intensity. In both red and green lettuce, we found clear effects of the nitrogen treatments on growth characteristics, phenolic and photosynthetic compounds, nitrogen, nitrate and carbon concentration of the plants. Interestingly, the concentrations of all main flavonoid glycosides, caffeic acid derivatives, and sucrose increased with decreasing nitrogen concentration, whereas those of chlorophylls, β-carotene, neoxanthin, lactucaxanthin, all trans- and cis-violaxanthin decreased. The constitutive concentrations of polyphenols were lower in the green cultivar, but their relative increase was more pronounced than in the red cultivar. The constitutive concentrations of chlorophylls, β-carotene, neoxanthin, all trans- and cis-violaxanthin were similar in red and green lettuce and with decreasing nitrogen concentration they declined to a similar extent in both cultivars. We only detected little influence of the radiation treatments, e.g. on anthocyanin concentration, and hardly any interaction between radiation and nitrogen concentration. Our results imply a greater physiological plasticity of green compared to the red lettuce regarding its phenolic compounds. They support the photoprotection theory regarding anthocyanins as well as the theory that the deamination activity of phenylalanine ammonia-lyase drives phenylpropanoid synthesis.

  9. Nitrogen Limited Red and Green Leaf Lettuce Accumulate Flavonoid Glycosides, Caffeic Acid Derivatives, and Sucrose while Losing Chlorophylls, Β-Carotene and Xanthophylls

    Science.gov (United States)

    Becker, Christine; Urlić, Branimir; Jukić Špika, Maja; Kläring, Hans-Peter; Krumbein, Angelika; Baldermann, Susanne; Goreta Ban, Smiljana; Perica, Slavko; Schwarz, Dietmar

    2015-01-01

    Reduction of nitrogen application in crop production is desirable for ecological and health-related reasons. Interestingly, nitrogen deficiency can lead to enhanced concentrations of polyphenols in plants. The reason for this is still under discussion. The plants’ response to low nitrogen concentration can interact with other factors, for example radiation intensity. We cultivated red and green leaf lettuce hydroponically in a Mediterranean greenhouse, supplying three different levels of nitrogen (12 mM, 3 mM, 0.75 mM), either in full or reduced (-50%) radiation intensity. In both red and green lettuce, we found clear effects of the nitrogen treatments on growth characteristics, phenolic and photosynthetic compounds, nitrogen, nitrate and carbon concentration of the plants. Interestingly, the concentrations of all main flavonoid glycosides, caffeic acid derivatives, and sucrose increased with decreasing nitrogen concentration, whereas those of chlorophylls, β-carotene, neoxanthin, lactucaxanthin, all trans- and cis-violaxanthin decreased. The constitutive concentrations of polyphenols were lower in the green cultivar, but their relative increase was more pronounced than in the red cultivar. The constitutive concentrations of chlorophylls, β-carotene, neoxanthin, all trans- and cis-violaxanthin were similar in red and green lettuce and with decreasing nitrogen concentration they declined to a similar extent in both cultivars. We only detected little influence of the radiation treatments, e.g. on anthocyanin concentration, and hardly any interaction between radiation and nitrogen concentration. Our results imply a greater physiological plasticity of green compared to the red lettuce regarding its phenolic compounds. They support the photoprotection theory regarding anthocyanins as well as the theory that the deamination activity of phenylalanine ammonia-lyase drives phenylpropanoid synthesis. PMID:26569488

  10. Cooperative Reinforcement of Ionic Liquid and Reactive Solvent on Enzymatic Synthesis of Caffeic Acid Phenethyl Ester as an In Vitro Inhibitor of Plant Pathogenic Bacteria

    Directory of Open Access Journals (Sweden)

    Yan Xu

    2017-01-01

    Full Text Available It is widely believed that lipases in ionic liquids (ILs possess higher enzyme activity, stability and selectivity; however, reaction equilibrium is always limited by product inhibition, and the product is difficult to separate from non-volatile ILs using distillation. To solve this problem, using trialkylphosphine oxide (TOPO as a complexing agent, a novel biphase of reactive solvent and IL was firstly reported for caffeic acid phenethyl ester (CAPE production from methyl caffeate (MC and 2-phenylethanol (PE catalyzed by lipase via transesterification. The effects of the reaction parameters and their action mechanism were investigated, and the inhibition of CAPE against bacterial wilt pathogen Ralstonia solanacearum was firstly measured. The MC conversion of 98.83% ± 0.76% and CAPE yield of 96.29% ± 0.07% were obtained by response surface methodology in the 25 g/L TOPO-cyclohexane/[Bmim][Tf2N] (1:1, v/v; the complex stoichiometry calculation and FTIR spectrum confirmed that the reversible hydrogen-bond complexation between TOPO and caffeates significantly enhances the cooperative effect of two phases on the lipase-catalyzed reaction. The temperature was reduced by 14 °C; the MC concentration increased by 3.33-fold; the ratio of catalyst to donor decreased by 4.5-fold; and Km decreased 1.08-fold. The EC50 of CAPE against R. solanacearum was 0.17–0.75 mg/mL, suggesting that CAPE is a potential in vitro inhibitor of plant pathogenic bacteria.

  11. Anti-Apoptotic and Anti-Oxidant Effects of Caffeic Acid Phenethyl Ester on Cadmium-Induced Testicular Toxicity in Rats.

    Science.gov (United States)

    Erboga, Mustafa; Kanter, Mehmet; Aktas, Cevat; Bozdemir Donmez, Yeliz; Fidanol Erboga, Zeynep; Aktas, Emel; Gurel, Ahmet

    2016-05-01

    Cadmium (Cd) is a serious environmental and occupational contaminant and may represent a serious health hazard to humans and other animals. Cd is reported to induce the generation of reactive oxygen species, and induces testicular damage in many species of animals. The goal of our study was to examine the anti-apoptotic and anti-oxidant effects of caffeic acid phenethyl ester (CAPE) on Cd-induced oxidative stress, apoptosis, and testicular injury in rats. A total of 40 male Wistar albino rats were divided into four groups: control, CAPE alone, Cd-treated, and Cd-treated with CAPE; each group consisted of 10 animals. To induce toxicity, Cd (1 mg/kg body weight) was dissolved in normal saline and subcutaneously injected into rats for 30 days. The rats in CAPE-treated group were given a daily dose of 10 μmol/kg body weight of CAPE by using intraperitoneal injection. This application was continued daily for a total of 30 days. To date, no examinations of the anti-apoptotic and anti-oxidant properties of CAPE on Cd-induced apoptosis, oxidative damage, and testicular injury in rat testes have been reported. CAPE-treated animals showed an improved histological appearance and serum testosterone levels in Cd-treated group. Our data indicate a significant reduction in the number of apoptotic cells in testis tissues of the Cd-treated group with CAPE treatment. Moreover, CAPE significantly suppressed lipid peroxidation, compensated deficits in the anti-oxidant defenses in testes tissue resulted from Cd administration. These findings suggest that the protective potential of CAPE in Cd toxicity might be due to its anti-oxidant and anti-apoptotic properties, which could be useful for achieving optimum effects in Cd-induced testicular injury.

  12. Rapid and sensitive single-step radiochemical assay for catechol-O-methyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Zuercher, G.; Da Prada, M. (Hoffmann-La Roche (F.) and Co., Basel (Switzerland))

    1982-01-01

    A simple, rapid and reliable radiometric assay for the determination of catechol-O-methyltransferase activity is described. The method is based on the conversion of catechol to (/sup 3/H)guaiacol by catechol-O-methyltransferase in the presence of Mg/sup 2 +/, adenosine deaminase and S-adenosyl L-(methyl-/sup 3/H)methionine. Incubation and direct extraction of (/sup 3/H)guaiacol into organic scintillation fluid, as well as counting, are performed in the same standard scintillation vial. The assay is easy to perform and more sensitive than previous analogous procedures. The method has been applied to the assay of catechol-O-methyltransferase activity in discrete brain areas and also peripheral organs of rat and in human erythrocytes.

  13. Identification of white campion (Silene latifolia guaiacol O-methyltransferase involved in the biosynthesis of veratrole, a key volatile for pollinator attraction

    Directory of Open Access Journals (Sweden)

    Gupta Alok K

    2012-08-01

    Full Text Available Abstract Background Silene latifolia and its pollinator, the noctuid moth Hadena bicruris, represent an open nursery pollination system wherein floral volatiles, especially veratrole (1, 2-dimethoxybenzene, lilac aldehydes, and phenylacetaldehyde are of key importance for floral signaling. Despite the important role of floral scent in ensuring reproductive success in S. latifolia, the molecular basis of scent biosynthesis in this species has not yet been investigated. Results We isolated two full-length cDNAs from S. latifolia that show similarity to rose orcinol O-methyltransferase. Biochemical analysis showed that both S. latifolia guaiacol O-methyltransferase1 (SlGOMT1 &S. latifolia guaiacol O-methyltransferase2 (SlGOMT2 encode proteins that catalyze the methylation of guaiacol to form veratrole. A large Km value difference between SlGOMT1 (~10 μM and SlGOMT2 (~501 μM resulted that SlGOMT1 is 31-fold more catalytically efficient than SlGOMT2. qRT-PCR expression analysis showed that the SlGOMT genes are specifically expressed in flowers and male S. latifolia flowers had 3- to 4-folds higher level of GOMT gene transcripts than female flower tissues. Two related cDNAs, S. dioica O-methyltransferase1 (SdOMT1 and S. dioica O-methyltransferase2 (SdOMT2, were also obtained from the sister species Silene dioica, but the proteins they encode did not methylate guaiacol, consistent with the lack of veratrole emission in the flowers of this species. Our evolutionary analysis uncovered that SlGOMT1 and SlGOMT2 genes evolved under positive selection, whereas SdOMT1 and SdOMT2 genes show no evidence for selection. Conclusions Altogether, we report the identification and functional characterization of the gene, SlGOMT1 that efficiently catalyzes veratrole formation, whereas another copy of this gene with only one amino acid difference, SlGOMT2 was found to be less efficient for veratrole synthesis in S. latifolia.

  14. Cloning, functional characterization and catalytic mechanism of a bergaptol O-methyltransferase from Peucedanum praeruptorum Dunn

    Directory of Open Access Journals (Sweden)

    Yucheng eZhao

    2016-05-01

    Full Text Available Coumarins are main active components of Peucedanum praeruptorum Dunn. Among them, methoxylated coumarin compound, such as bergapten, xanthotoxin and isopimpinellin, has high officinal value and plays an important role in medicinal field. However, major issues associated with the biosynthesis mechanism of coumarins remain unsolved and no corresponding enzyme has been cloned from P. praeruptorum. In this study, a local BLASTN program was conducted to find the candidate genes from P. praeruptorum transcriptome database using the nucleotide sequence of Ammi majus bergaptol O-methyltransferase (AmBMT, GenBank accession No: AY443006 as a template. As a result, a 1335 bp full-length of cDNA sequence which contains an open reading frame of 1080 bp encoding a BMT polypeptide of 359 amino acids was obtained. The recombinant protein was functionally expressed in Escherichia coli and displayed an observed activity to bergaptol. In vitro experiments show that the protein has narrow substrate specificity for bergaptol. Expression profile indicated that the cloned gene had a higher expression level in roots and can be induced by methyl jasmonate (MeJA. Subcellular localization analysis showed that the BMT protein was located in cytoplasm in planta. Homology modeling and docking based site-directed mutagenesis have been employed to investigate the amino acid residues in BMT required for substrate binding and catalysis. Conservative amino acid substitutions at residue H264 affected BMT catalysis, whereas substitutions at residues F171, M175, D226 and L312 affected substrate binding. The systemic study summarized here will enlarge our knowledge on OMTs and provide useful information in investigating the coumarins biosynthesis mechanism in P. praeruptorum.

  15. Catechol-O-methyltransferase gene methylation and substance use in adolescents: The TRAILS study

    NARCIS (Netherlands)

    L.J. van der Knaap (Lisette); J.M. Schäfer (Johanna); I.H.A. Franken (Ingmar); F.C. Verhulst (Frank); F.V.A. van Oort (Floor); H. Riese (Harriëtte)

    2014-01-01

    textabstractSubstance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol-O-methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val108/158Met polymorphism

  16. Catechol-O-methyltransferase gene methylation and substance use in adolescents : the TRAILS study

    NARCIS (Netherlands)

    van der Knaap, L. J.; Schaefer, J. M.; Franken, I. H. A.; Verhulst, F. C.; van Oort, F. V. A.; Riese, H.

    Substance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol-O-methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val(108/158)Met polymorphism modulates COMT activity

  17. Polymorphisms in the catechol-o-methyltransferase gene and delirium in the elderly

    NARCIS (Netherlands)

    van Munster, Barbara C.; Baas, Frank; Tanck, Michael W.; de Rooij, Sophia E. J. A.

    2011-01-01

    Catechol-O-methyltransferase, encoded by the COMT gene, is one of the enzymes that degrade dopamine. The aim of this study was to investigate whether polymorphisms in the COMT gene were associated with delirium. Patients aged 65 years and older, acutely admitted to the medical department or to the

  18. Catechol-O-methyltransferase Val158Met and Cognitive Function in Parkinson's Disease

    NARCIS (Netherlands)

    Hoogland, Jeroen; de Bie, Rob M. A.; Williams-Gray, Caroline H.; Muslimović, Dino; Schmand, Ben; Post, Bart

    2010-01-01

    Cognitive dysfunction is one of the most incapacitating non-motor symptoms of Parkinson's disease (PD). Some cognitive deficits are thought to be related to abnormal dopamine homeostasis. The latter is influenced by catechol-O-methyltransferase (COMT), an enzyme that degrades dopamine. Previous

  19. Polymorphisms in catechol-O-methyltransferase and methylenetetrahydrofolate reductase in relation to the risk of schizophrenia.

    NARCIS (Netherlands)

    Muntjewerff, J.W.; Gellekink, H.; Heijer, M. den; Hoogendoorn, M.L.; Kahn, R.S.; Sinke, R.J.; Blom, H.J.

    2008-01-01

    BACKGROUND: Evidence is emerging for the association of aberrant homocysteine-methylation cycle and increased risk of schizophrenia. METHODS: We examined the prevalence of the catechol-O-methyltransferase (COMT) 324G>A (Val108/158Met) and methylenetetrahydrofolate reductase (MTHFR) 677C>T

  20. Association of Catechol-O-Methyltransferase (COMT) Polymorphism and Academic Achievement in a Chinese Cohort

    Science.gov (United States)

    Yeh, Ting-Kuang; Chang, Chun-Yen; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Ming-Yeh

    2009-01-01

    Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes the degradation pathway and inactivation of dopamine. It is accepted widely as being involved in the modulation of dopaminergic physiology and prefrontal cortex (PFC) function. The COMT Val158Met polymorphism is associated with variation in COMT activity. COMT 158Met allele…

  1. Catechol-O-methyltransferase val158met and cognitive function in Parkinson's disease

    NARCIS (Netherlands)

    Hoogland, J.; de Bie, R.M.A.; Williams-Gray, C.H.; Muslimovic, D.; Schmand, B.; Post, B.

    2010-01-01

    Cognitive dysfunction is one of the most incapacitating non-motor symptoms of Parkinson's disease (PD). Some cognitive deficits are thought to be related to abnormal dopamine homeostasis. The latter is influenced by catechol-O-methyltransferase (COMT), an enzyme that degrades dopamine. Previous

  2. Catechol-O-methyltransferase: a method for autoradiographic visualization of isozymes in cellogel

    Energy Technology Data Exchange (ETDEWEB)

    Brahe, C.; Crosti, N.; Meera Khan, P.; Serra, A.

    1984-02-01

    An electrophoretic procedure for separating the molecular forms of catechol-O-methyltransferase in cellulose acetate gel is described; the zones of enzyme activity were revealed by autoradiography. The electrophoretic patterns of the enzyme in several tissues and cell lines derived from four different species are presented.

  3. Catechol-O-methyltransferase Val158Met and the Risk of Dyskinesias in Parkinson's Disease

    NARCIS (Netherlands)

    De Lau, L.M.L.; Verbaan, D.; Marinus, J.; Heutink, P.; van Hilten, J.J.

    2012-01-01

    Background:: The A-allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with decreased enzymatic activity and higher dopamine availability. Methods:: We studied 219 patients with PD who were free of dyskinesias at baseline and underwent thorough annual examinations.

  4. Catechol-O-methyltransferase val158met and cognitive function in Parkinson's disease.

    NARCIS (Netherlands)

    Hoogland, J.; Bie, R.M. de; Williams-Gray, C.H.; Muslimovic, D.; Schmand, B.A.; Post, B.

    2010-01-01

    Cognitive dysfunction is one of the most incapacitating non-motor symptoms of Parkinson's disease (PD). Some cognitive deficits are thought to be related to abnormal dopamine homeostasis. The latter is influenced by catechol-O-methyltransferase (COMT), an enzyme that degrades dopamine. Previous

  5. Catechol-O-methyltransferase (COMT) gene variants and pain in chronic pancreatitis

    NARCIS (Netherlands)

    Esch, A.A.J.; Vries, E. De; Morsche, R.H.M. te; Oijen, M.G.H. van; Jansen, J.B.M.J.; Drenth, J.P.H.

    2011-01-01

    BACKGROUND: Pain is the major symptom of chronic pancreatitis. The role of genetics in pancreatic pain is unclear. Catechol-O-methyltransferase (COMT) regulates enkephalin levels and influences pain perception. The COMT gene contains functional polymorphisms that have been found to influence human

  6. Reuse of Organomineral Substrate Waste from Hydroponic Systems as Fertilizer in Open-Field Production Increases Yields, Flavonoid Glycosides, and Caffeic Acid Derivatives of Red Oak Leaf Lettuce (Lactuca sativa L.) Much More than Synthetic Fertilizer.

    Science.gov (United States)

    Dannehl, Dennis; Becker, Christine; Suhl, Johanna; Josuttis, Melanie; Schmidt, Uwe

    2016-09-28

    Effects of organic waste from a hydroponic system added with minerals (organomineral fertilizer) and synthetic fertilizer on major polyphenols of red oak leaf lettuce using HPLC-DAD-ESI-MS(3) were investigated. Interestingly, contents of the main flavonoid glycosides and caffeic acid derivatives of lettuce treated with organomineral fertilizer were equal to those synthesized without soil additives. This was found although soil nutrient concentrations, including that of nitrogen, were much lower without additives. However, lettuce treated with synthetic fertilizer showed a significant decrease in contents of caffeic acid derivatives and flavonoid glycosides up to 78.3 and 54.2%, respectively. It is assumed that a negative effect of a high yield on polyphenols as described in the growth-differentiation balance hypothesis can be counteracted by (i) a higher concentration of Mg or (ii) optimal physical properties of the soil structure. Finally, the organomineral substrate waste reused as fertilizer and soil improver resulted in the highest yield (+78.7%), a total fertilizer saving of 322 kg ha(-1) and waste reduction in greenhouses.

  7. Crystallization and preliminary X-ray diffraction studies of a catechol-O-methyltransferase/inhibitor complex

    Energy Technology Data Exchange (ETDEWEB)

    Rodrigues, M. L. [Instituto de Tecnologia Química e Biológica (ITQB), Universidade Nova de Lisboa, Av. República, Apt. 127, 2781-901 Oeiras (Portugal); Bonifácio, M. J.; Soares-da-Silva, P. [Department of Research and Development, BIAL, 4785 S. Mamede do Coronado (Portugal); Carrondo, M. A.; Archer, M., E-mail: archer@itqb.unl.pt [Instituto de Tecnologia Química e Biológica (ITQB), Universidade Nova de Lisboa, Av. República, Apt. 127, 2781-901 Oeiras (Portugal)

    2005-01-01

    Catechol-O-methyltransferase has been co-crystallized with a novel inhibitor, which has potential therapeutic application in the Parkinson’s disease therapy. Inhibitors of the enzyme catechol-O-methyltransferase (COMT) are used as co-adjuvants in the therapy of Parkinson’s disease. A recombinant form of the soluble cytosolic COMT from rat has been co-crystallized with a new potent inhibitor, BIA 8-176 [(3,4-dihydroxy-2-nitrophenyl)phenylmethanone], by the vapour-diffusion method using PEG 6K as precipitant. Crystals diffract to 1.6 Å resolution on a synchrotron-radiation source and belong to the monoclinic space group P2{sub 1}, with unit-cell parameters a = 52.77, b = 79.63, c = 61.54 Å, β = 91.14°.

  8. Catecholamine-o-methyltransferase polymorphisms are associated with postoperative pain intensity.

    LENUS (Irish Health Repository)

    Lee, Peter J

    2011-02-01

    single nucleotide polymorphisms (SNPs) in the genes for catecholamine-O-methyltransferase (COMT), μ-opioid receptor and GTP cyclohydrolase (GCH1) have been linked to acute and chronic pain states. COMT polymorphisms are associated with experimental pain sensitivity and a chronic pain state. No such association has been identified perioperatively. We carried out a prospective observational clinical trial to examine associations between these parameters and the development of postoperative pain in patients undergoing third molar (M3) extraction.

  9. Cloning and characterization of a norbelladine 4'-O-methyltransferase involved in the biosynthesis of the Alzheimer's drug galanthamine in Narcissus sp. aff. pseudonarcissus.

    Directory of Open Access Journals (Sweden)

    Matthew B Kilgore

    Full Text Available Galanthamine is an Amaryllidaceae alkaloid used to treat the symptoms of Alzheimer's disease. This compound is primarily isolated from daffodil (Narcissus spp., snowdrop (Galanthus spp., and summer snowflake (Leucojum aestivum. Despite its importance as a medicine, no genes involved in the biosynthetic pathway of galanthamine have been identified. This absence of genetic information on biosynthetic pathways is a limiting factor in the development of synthetic biology platforms for many important botanical medicines. The paucity of information is largely due to the limitations of traditional methods for finding biochemical pathway enzymes and genes in non-model organisms. A new bioinformatic approach using several recent technological improvements was applied to search for genes in the proposed galanthamine biosynthetic pathway, first targeting methyltransferases due to strong signature amino acid sequences in the proteins. Using Illumina sequencing, a de novo transcriptome assembly was constructed for daffodil. BLAST was used to identify sequences that contain signatures for plant O-methyltransferases in this transcriptome. The program HAYSTACK was then used to identify methyltransferases that fit a model for galanthamine biosynthesis in leaf, bulb and inflorescence tissues. One candidate gene for the methylation of norbelladine to 4'-O-methylnorbelladine in the proposed galanthamine biosynthetic pathway was identified. This methyltransferase cDNA was expressed in E. coli and the protein purified by affinity chromatography. The resulting protein was found to be a norbelladine 4'-O-methyltransferase (NpN4OMT of the proposed galanthamine biosynthetic pathway.

  10. Cloning and Characterization of a Norbelladine 4′-O-Methyltransferase Involved in the Biosynthesis of the Alzheimer’s Drug Galanthamine in Narcissus sp. aff. pseudonarcissus

    Science.gov (United States)

    Kilgore, Matthew B.; Augustin, Megan M.; Starks, Courtney M.; O’Neil-Johnson, Mark; May, Gregory D.; Crow, John A.; Kutchan, Toni M.

    2014-01-01

    Galanthamine is an Amaryllidaceae alkaloid used to treat the symptoms of Alzheimer’s disease. This compound is primarily isolated from daffodil (Narcissus spp.), snowdrop (Galanthus spp.), and summer snowflake (Leucojum aestivum). Despite its importance as a medicine, no genes involved in the biosynthetic pathway of galanthamine have been identified. This absence of genetic information on biosynthetic pathways is a limiting factor in the development of synthetic biology platforms for many important botanical medicines. The paucity of information is largely due to the limitations of traditional methods for finding biochemical pathway enzymes and genes in non-model organisms. A new bioinformatic approach using several recent technological improvements was applied to search for genes in the proposed galanthamine biosynthetic pathway, first targeting methyltransferases due to strong signature amino acid sequences in the proteins. Using Illumina sequencing, a de novo transcriptome assembly was constructed for daffodil. BLAST was used to identify sequences that contain signatures for plant O-methyltransferases in this transcriptome. The program HAYSTACK was then used to identify methyltransferases that fit a model for galanthamine biosynthesis in leaf, bulb and inflorescence tissues. One candidate gene for the methylation of norbelladine to 4′-O-methylnorbelladine in the proposed galanthamine biosynthetic pathway was identified. This methyltransferase cDNA was expressed in E. coli and the protein purified by affinity chromatography. The resulting protein was found to be a norbelladine 4′-O-methyltransferase (NpN4OMT) of the proposed galanthamine biosynthetic pathway. PMID:25061748

  11. Cloning and characterization of a norbelladine 4'-O-methyltransferase involved in the biosynthesis of the Alzheimer's drug galanthamine in Narcissus sp. aff. pseudonarcissus.

    Science.gov (United States)

    Kilgore, Matthew B; Augustin, Megan M; Starks, Courtney M; O'Neil-Johnson, Mark; May, Gregory D; Crow, John A; Kutchan, Toni M

    2014-01-01

    Galanthamine is an Amaryllidaceae alkaloid used to treat the symptoms of Alzheimer's disease. This compound is primarily isolated from daffodil (Narcissus spp.), snowdrop (Galanthus spp.), and summer snowflake (Leucojum aestivum). Despite its importance as a medicine, no genes involved in the biosynthetic pathway of galanthamine have been identified. This absence of genetic information on biosynthetic pathways is a limiting factor in the development of synthetic biology platforms for many important botanical medicines. The paucity of information is largely due to the limitations of traditional methods for finding biochemical pathway enzymes and genes in non-model organisms. A new bioinformatic approach using several recent technological improvements was applied to search for genes in the proposed galanthamine biosynthetic pathway, first targeting methyltransferases due to strong signature amino acid sequences in the proteins. Using Illumina sequencing, a de novo transcriptome assembly was constructed for daffodil. BLAST was used to identify sequences that contain signatures for plant O-methyltransferases in this transcriptome. The program HAYSTACK was then used to identify methyltransferases that fit a model for galanthamine biosynthesis in leaf, bulb and inflorescence tissues. One candidate gene for the methylation of norbelladine to 4'-O-methylnorbelladine in the proposed galanthamine biosynthetic pathway was identified. This methyltransferase cDNA was expressed in E. coli and the protein purified by affinity chromatography. The resulting protein was found to be a norbelladine 4'-O-methyltransferase (NpN4OMT) of the proposed galanthamine biosynthetic pathway.

  12. Synthesis and characterization of MnO2/NiO nanocomposites for photocatalysis of tetracycline antibiotic and modification with guanidine for carriers of Caffeic acid phenethyl ester-an anticancer drug.

    Science.gov (United States)

    Gupta, Vinod Kumar; Fakhri, Ali; Agarwal, Shilpi; Ahmadi, Elham; Nejad, Pedram Afshar

    2017-09-01

    In the present studies, modified NiO nanoparticles and MnO 2 /NiO nanocomposites with guanidine were synthesized by anchoring method for carriers of anticancer drug "Caffeic acid phenethyl ester". The prepared nanocomposites were characterized by using Scanning Electron Microscopy, Raman and Fourier transform infrared spectroscopy, X-ray diffraction, Vibrating sample magnetometer. The results from XRD indicated that the crystalline size of NiO nanoparticles and MnO 2 /NiO nanocomposites are 12 and 15nm, respectively. Saturation magnetization (Ms) for NiO NPs and MnO 2 /NiO nanocomposites was to be 0.60, and 0.68emu/g indicating that these are superparamagnetic and ferromagnetic properties in nature. The prepared nanocomposites were evaluated as catalyst for degradation of antibiotics in photocatalysis process. Particularly, the MnO 2 /NiO composite demonstrated the higher degradation rate (89.55%) of tetracycline antibiotic under UV light irradiation than the NiO (67.80%). Drug load on and release from nanopowders was investigated by using UV-Vis spectroscopy method. Time of drug loading was 100min and the drug release in 1-10h with 20-80% drug release were found, and then, it's applicable to in-vivo drug delivery. Therefore, the NiO nanoparticles and MnO 2 /NiO nanocomposites are promising for targeted Caffeic acid phenethyl ester anticancer drug delivery applications. The anticancer drug loaded on guanidine-NiO and guanidine-MnO 2 /NiO in high concentration has an antioxidant property. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. From the X-rays to a reliable “low cost” computational structure of caffeic acid: DFT, MP2, HF and integrated molecular dynamics-X-ray diffraction approach to condensed phases

    Science.gov (United States)

    Lombardo, Giuseppe M.; Portalone, Gustavo; Colapietro, Marcello; Rescifina, Antonio; Punzo, Francesco

    2011-05-01

    The ability of caffeic acid to act as antioxidant against hyperoxo-radicals as well as its recently found therapeutic properties in the treatment of hepatocarcinoma, still make this compound, more than 20 years later the refinement of its crystal structure, object of study. It belongs to the vast family of humic substances, which play a key role in the biodegradation processes and easily form complexes with ions widely diffused in the environment. This class of compounds is therefore interesting for potential environmental chemistry applications concerning the possible complexation of heavy metals. Our study focused on the characterization of caffeic acid as a starting necessary step, which will be followed in the future by the application of our findings on the study of the properties of caffeate anion interaction with heavy metal ions. To reach this goal, we applied a low cost approach - in terms of computational time and resources - aimed at the achievement of a high resolution, robust and trustable structure using the X-ray single crystal data, recollected with a higher resolution, as touchstone for a detailed check. A comparison between the calculations carried out with density functional theory (DFT), Hartree-Fock (HF) method and post SCF second order Møller-Plesset perturbation method (MP2), at the 6-31G ** level of the theory, molecular mechanics (MM) and molecular dynamics (MD) was performed. As a consequence we explained on one hand the possible reasons for the pitfalls of the DFT approach and on the other the benefits of using a good and robust force field developed for condensed phases, as AMBER, with MM and MD. The reliability of the latter, highlighted by the overall agreement extended up to the anisotropic displacement parameters calculated by means of MD and the ones gathered by X-ray measurements, makes it very promising for the above-mentioned goals.

  14. The catechol-O-methyltransferase inhibitory potential of Z-vallesiachotamine by in silicoand in vitro approaches

    Directory of Open Access Journals (Sweden)

    Carolina dos Santos Passos

    Full Text Available AbstractZ-Vallesiachotamine is a monoterpene indole alkaloid that has a β-N-acrylate group in its structure. This class of compounds has already been described in different Psychotriaspecies. Our research group observed that E/Z-vallesiachotamine exhibits a multifunctional feature, being able to inhibit targets related to neurodegeneration, such as monoamine oxidase A, sirtuins 1 and 2, and butyrylcholinesterase enzymes. Aiming at better characterizing the multifunctional profile of this compound, its effect on cathecol-O-methyltransferase activity was investigated. The cathecol-O-methyltransferase activity was evaluated in vitro by a fluorescence-based method, using S-(5′-adenosyl-l-methionine as methyl donor and aesculetin as substrate. The assay optimization was performed varying the concentrations of methyl donor (S-(5′-adenosyl-l-methionine and enzyme. It was observed that the highest concentrations of both factors (2.25 U of the enzyme and 100 µM of S-(5′-adenosyl-l-methionine afforded the more reproducible results. The in vitro assay demonstrated that Z-vallesiachotamine was able to inhibit the cathecol-O-methyltransferase activity with an IC50 close to 200 µM. Molecular docking studies indicated that Z-vallesiachotamine can bind the catechol pocket of catechol-O-methyltransferase enzyme. The present work demonstrated for the first time the inhibitory properties of Z-vallesiachotamine on cathecol-O-methyltransferase enzyme, affording additional evidence regarding its multifunctional effects in targets related to neurodegenerative diseases.

  15. Recovery of biological active catechol-O-methyltransferase isoforms from Q-sepharose.

    Science.gov (United States)

    Correia, F F; Santos, F M; Pedro, A Q; Bonifácio, M J; Queiroz, J A; Passarinha, L A

    2014-01-01

    The development of new catechol-O-methyltransferase inhibitors has led to an improvement in the treatment of Parkinson's disease. However, despite the fact that the soluble isoform has been extensively investigated, few studies have been published concerning membrane isoform chromatographic recovery and bioactivity levels. In this work, chromatographic profiles of both catechol-O-methyltransferase isoforms were compared using quaternary amine as a ligand to evaluate its activity levels and recovery rates. Results show that both proteins required different conditions for adsorption; the soluble isoform adsorption was performed at low ionic strength, while the membrane isoform required increasing linear salt gradient. However, the application of 0.5% Triton X-100 promoted membrane isoform adsorption even at low ionic strength. Indeed, chromatographic conditions of both isoforms became similar when detergents were applied. The developed methods also appear to be highly effective in bioactivity recovery, presenting rates of 107% for soluble protein and 67 and 91% for membrane isoform without and with detergents, respectively. The chromatographic strategies with and without detergents resulted in a 4.3- and sevenfold purification, respectively, corresponding to specific activity values of 331 and 496 nmol/h/mg. Thus, the use of Q-sepharose as anion exchanger was effective in the recovery of both enzymes, which is a requirement for further kinetic and pharmacological trials. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Sexually dimorphic effects of catechol-O-methyltransferase (COMT inhibition on dopamine metabolism in multiple brain regions.

    Directory of Open Access Journals (Sweden)

    Linda M Laatikainen

    Full Text Available The catechol-O-methyltransferase (COMT enzyme metabolises catecholamines. COMT inhibitors are licensed for the adjunctive treatment of Parkinson's disease and are attractive therapeutic candidates for other neuropsychiatric conditions. COMT regulates dopamine levels in the prefrontal cortex (PFC but plays a lesser role in the striatum. However, its significance in other brain regions is largely unknown, despite its links with a broad range of behavioural phenotypes hinting at more widespread effects. Here, we investigated the effect of acute systemic administration of the brain-penetrant COMT inhibitor tolcapone on tissue levels of dopamine, noradrenaline, and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC and homovanillic acid (HVA. We examined PFC, striatum, hippocampus and cerebellum in the rat. We studied both males and females, given sexual dimorphisms in several aspects of COMT's function. Compared with vehicle, tolcapone significantly increased dopamine levels in the ventral hippocampus, but did not affect dopamine in other regions, nor noradrenaline in any region investigated. Tolcapone increased DOPAC and/or decreased HVA in all brain regions studied. Notably, several of the changes in DOPAC and HVA, particularly those in PFC, were more prominent in females than males. These data demonstrate that COMT alters ventral hippocampal dopamine levels, as well as regulating dopamine metabolism in all brain regions studied. They demonstrate that COMT is of significance beyond the PFC, consistent with its links with a broad range of behavioural phenotypes. Furthermore, they suggest that the impact of tolcapone may be greater in females than males, a finding which may be of clinical significance in terms of the efficacy and dosing of COMT inhibitors.

  17. Sexually Dimorphic Effects of Catechol-O-Methyltransferase (COMT) Inhibition on Dopamine Metabolism in Multiple Brain Regions

    Science.gov (United States)

    Laatikainen, Linda M.; Sharp, Trevor; Harrison, Paul J.; Tunbridge, Elizabeth M.

    2013-01-01

    The catechol-O-methyltransferase (COMT) enzyme metabolises catecholamines. COMT inhibitors are licensed for the adjunctive treatment of Parkinson's disease and are attractive therapeutic candidates for other neuropsychiatric conditions. COMT regulates dopamine levels in the prefrontal cortex (PFC) but plays a lesser role in the striatum. However, its significance in other brain regions is largely unknown, despite its links with a broad range of behavioural phenotypes hinting at more widespread effects. Here, we investigated the effect of acute systemic administration of the brain-penetrant COMT inhibitor tolcapone on tissue levels of dopamine, noradrenaline, and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). We examined PFC, striatum, hippocampus and cerebellum in the rat. We studied both males and females, given sexual dimorphisms in several aspects of COMT's function. Compared with vehicle, tolcapone significantly increased dopamine levels in the ventral hippocampus, but did not affect dopamine in other regions, nor noradrenaline in any region investigated. Tolcapone increased DOPAC and/or decreased HVA in all brain regions studied. Notably, several of the changes in DOPAC and HVA, particularly those in PFC, were more prominent in females than males. These data demonstrate that COMT alters ventral hippocampal dopamine levels, as well as regulating dopamine metabolism in all brain regions studied. They demonstrate that COMT is of significance beyond the PFC, consistent with its links with a broad range of behavioural phenotypes. Furthermore, they suggest that the impact of tolcapone may be greater in females than males, a finding which may be of clinical significance in terms of the efficacy and dosing of COMT inhibitors. PMID:23613951

  18. Polymorphisms in O-methyltransferase genes are associated with stover cell wall digestibility in European maize (Zea mays L.)

    DEFF Research Database (Denmark)

    Brenner, Everton A; Zein, Imad; Chen, Yongsheng

    2010-01-01

    Background OMT (O-methyltransferase) genes are involved in lignin biosynthesis, which relates to stover cell wall digestibility. Reduced lignin content is an important determinant of both forage quality and ethanol conversion efficiency of maize stover. Results Variation in genomic sequences codi...

  19. Catechol-O-methyltransferase gene and obsessive-compulsive symptoms in patients with recent-onset schizophrenia: Preliminary results

    NARCIS (Netherlands)

    Zinkstok, Janneke; van Nimwegen, Lonneke; van Amelsvoort, Therese; de Haan, Lieuwe; Yusuf, Maryan Abdulkadir; Baas, Frank; Linszen, Don

    2008-01-01

    The catechol-O-methyltransferase (COMT) gene is a candidate gene for schizophrenia because of its role in the breakdown of dopamine in the prefrontal cortex. The COMT gene contains a functional polymorphism changing enzyme activity that has been associated with some neuropsychiatric

  20. Properties of the Membrane Binding Component of Catechol-O-methyltransferase Revealed by Atomistic Molecular Dynamics Simulations

    DEFF Research Database (Denmark)

    Orlowski, A.; St-Pierre, J. F.; Magarkar, A.

    2011-01-01

    We used atomistic simulations to study the membrane-bound form of catechol-O-methyltransferase (MB-COMT). In particular we investigated the 26-residue transmembrane a-helical segment of MB-COMT together with the 24-residue fragment that links the transmembrane component to the main protein unit...

  1. A direct correlation between the antioxidant efficiencies of caffeic acid and its alkyl esters and their concentrations in the interfacial region of olive oil emulsions. The pseudophase model interpretation of the "cut-off" effect.

    Science.gov (United States)

    Costa, Marlene; Losada-Barreiro, Sonia; Paiva-Martins, Fátima; Bravo-Díaz, Carlos; Romsted, Laurence S

    2015-05-15

    Recently published results for a series of homologous antioxidants, AOs, of increasing alkyl chain length show a maximum in AO efficiency followed by a significant decrease for the more hydrophobic AOs, typically called the "cut-off" effect. Here we demonstrate that in olive oil emulsions both antioxidant efficiencies and partition constants for distributions of AOs between the oil and interfacial regions, PO(I), show a maximum at the C8 ester. A reaction between caffeic acid, CA, and its specially synthesised C1-C16 alkyl esters, and a chemical probe is used to estimate partition constants for AO distributions and interfacial rate constants, kI, in intact emulsions based on the pseudophase kinetic model. The model provides a natural interpretation for both the maximum and the "cut-off" effect. More than 70% of the CA esters are in the interfacial region even at low surfactant volume fraction, ΦI=0.005. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Caffeic Acid Phenethyl Ester (Propolis Extract) Ameliorates Insulin Resistance by Inhibiting JNK and NF-κB Inflammatory Pathways in Diabetic Mice and HepG2 Cell Models.

    Science.gov (United States)

    Nie, Jiarui; Chang, Yaning; Li, Yujia; Zhou, Yingjun; Qin, Jiawen; Sun, Zhen; Li, Haibin

    2017-10-18

    Caffeic acid phenethyl ester (CAPE), extracted from propolis, was evaluated for the ameliorative effects on insulin resistance and the mechanisms were identified, using non-insulin-dependent diabetes mellitus (NIDDM) model mice and insulin resistance (IR) model cells. After 5 weeks of CAPE supplementation, insulin sensitivity, hyperlipidemia, and peroxisome proliferator-activated receptor-α (PPAR-α) levels were improved in mice. Proinflammatory cytokines in serum and the expressions of tumor necrosis factor-alpha (TNF-α) mRNA in tissues were markedly downregulated from CAPE-treated mice. In vitro, CAPE supplement significantly improved glucose consumption, glucose uptake, glycogen content, and oxidative stress and decreased expression of glucose-6-phosphatase (G6Pase) mRNA in cells. Both in vivo and in vitro, CAPE enhanced p-Akt (Ser473) and p-insulin receptor substrate (IRS)-1 (Tyr612), but inhibited p-JNK (Thr183/Tyr185), p-NF-κB p65 (Ser536), and nuclear translocation of p-NF-κB p65 (Ser536). In summary, CAPE can ameliorate insulin resistance through modulation of JNK and NF-κB signaling pathway in mice and HepG2 cells.

  3. Verbascoside is not genotoxic in the ST and HB crosses of the Drosophila wing spot test, and its constituent, caffeic acid, decreases the spontaneous mutation rate in the ST cross.

    Science.gov (United States)

    Santos-Cruz, Luis Felipe; Ávila-Acevedo, José Guillermo; Ortega-Capitaine, Diego; Ojeda-Duplancher, Jesús Clemente; Perdigón-Moya, Juana Laura; Hernández-Portilla, Luis Barbo; López-Dionicio, Héctor; Durán-Díaz, Angel; Dueñas-García, Irma Elena; Castañeda-Partida, Laura; García-Bores, Ana María; Heres-Pulido, María Eugenia

    2012-03-01

    Verbascoside (VB) is a phenylpropanoid isolated from Buddleja species, some of which originate in Mexico, and was first described in the sixteenth century in the codices of Mexican traditional medicine. VB is present in alcohol extracts and is widely used in the north of Mexico as a sunscreen. VB absorbs UV-A and UV-B radiation and has high antioxidant and anti-inflammatory capacities. VB and its constituent caffeic acid (CA) were screened to determine their genotoxic activity using the Drosophila wing spot test. Third instar larvae (72±4 h) of the standard (ST) and high bioactivation (HB) crosses, with regulated and high levels of cytochrome P450s (Cyp450s), respectively, were exposed to VB or CA (0, 27, 57, 81, 135, and 173 mM). VB was not genotoxic at any of the concentrations tested in both crosses. The amount of VB residue as determined by HPLC in the adult flies that were fed with VB indicated a low metabolism of this compound, which explains the absence of genotoxicity. CA decreased the spontaneous frequencies of small and total spots and showed putative toxicity in the ST cross. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. Cloning of a caffeoyl-coenzyme A O-methyltransferase from Camellia sinensis and analysis of its catalytic activity.

    Science.gov (United States)

    Zhang, Yue; Lv, Hai-peng; Ma, Cheng-ying; Guo, Li; Tan, Jun-feng; Peng, Qun-hua; Lin, Zhi

    2015-02-01

    Epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3"Me) present in leaves of Camellia sinensis has many beneficial biological activities for human health. However, EGCG3"Me occurs naturally in tea leaves in extremely limited quantities. Finding an enzyme from C. sinensis to catalyze the synthesis of EGCG3"Me is an alternative method to make up for the scarcity of EGCG3"Me in natural situations. In the present study, a complementary DNA (cDNA) encoding region and genomic DNA of the caffeoyl-coenzyme A O-methyltransferase (CCoAOMT) gene were isolated from C. sinensis (designated CsCCoAOMT). Nucleotide sequence analysis of CsCCoAOMT revealed an open reading frame of 738 bp that encodes a polypeptide with a predicted molecular weight of 28 kDa, which correlated well with the results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The full-length DNA sequence (2678 bp) contained five exons and four introns. The deduced amino acid sequence of CsCCoAOMT shared 92% identity with CCoAOMTs from Codonopsis lanceolata and Betula luminifera. The catalytic activity of CsCCoAOMT was analyzed. Three monomethylated epigallocatechin-3-O-gallate (EGCG) compounds (EGCG4"Me, EGCG3"Me, and EGCG3'Me) were produced by CsCCoAOMT with K(m) in the micromolar range. Real-time polymerase chain reaction (RT-PCR) experiments indicated that the CsCCoAOMT transcript was present at low levels during the early stages of leaf maturity (the first leaf and bud on a shoot) but the relative expression was augmented at advanced stages of leaf maturity (the third or fourth leaf on a shoot), which accorded well with changes in EGCG3"Me content in fresh leaves. Hence, we concluded that CsCCoAOMT catalyzes the syntheses of methylated EGCGs.

  5. Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders.

    Science.gov (United States)

    Ma, Zhiguo; Liu, Hongming; Wu, Baojian

    2014-03-01

    Catechol-O-methyltransferase (COMT) is of great importance in pharmacology because it catalyzes the metabolism (methylation) of endogenous and xenobiotic catechols. Moreover, inhibition of COMT is the drug target in the management of central nervous system (CNS) disorders such as Parkinson's disease due to its role in regulation of the dopamine level in the brain. The X-ray crystal structures for COMT have been available since 1994. The active sites for cofactor and substrate/inhibitor binding are well resolved to an atomic level, providing valuable insights into the catalytic mechanisms as well as the role of magnesium ions in catalysis. Determination of how the substrates/inhibitors bind to the protein leads to a structure-based approach that has resulted in potent and selective inhibitors. This review focuses on the design of two types of inhibitors (nitrocatechol-type and bisubstrate inhibitors) for COMT using the protein structures. © 2013 The British Pharmacological Society.

  6. Catechol-O-methyltransferase inhibits colorectal cancer cell proliferation and invasion.

    Science.gov (United States)

    Wu, Wenming; Wu, Qiao; Hong, Xiafei; Xiong, Guangbing; Xiao, Yi; Zhou, Jiaolin; Wang, Wenze; Wu, Huanwen; Zhou, Li; Song, Wei; Dai, Hongmei; Qiu, Huizhong; Zhao, Yupei

    2015-01-01

    Catechol-O-methyltransferase (COMT) has been reported as an important molecule in various types of cancers. The biological function of COMT in colorectal cancer (CRC) has not yet been fully investigated. We constructed a transient transfection of a CRC cell lines to up- and downregulate COMT expression level and tested the proliferative, invasion ability in vitro. We also constructed a stable transduced CRC cell line and conducted tumor-forming capacity experiment in mouse xenograft model in vivo. In vitro experiment showed that COMT inhibited the cell proliferation by regulating p-Akt, PTEN and inhibited G1 to S phase transition by regulating p53, p27, and cyclinD1. COMT inhibited invasion by regulating E-cadherin. In vivo experiment showed decreased tumor growth in COMT overexpressing cell line. COMT has tumor-suppressive functions for CRC cell lines in vitro and in vivo experiments. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

  7. Catechol-O-methyltransferase genotype and response to Compensatory Cognitive Training in outpatients with schizophrenia.

    Science.gov (United States)

    Burton, Cynthia Z; Vella, Lea; Kelsoe, John R; Bilder, Robert M; Twamley, Elizabeth W

    2015-06-01

    The catechol-O-methyltransferase (COMT) ValMet polymorphism is associated with cognitive functioning in schizophrenia and may predict cognitive training outcomes. This study aimed to explore the contribution of COMT genotype in predicting improvement following Compensatory Cognitive Training (CCT). We conducted mixed factorial analysis of variance to examine COMT genotype as a predictor of response to CCT (i.e. improved cognitive performance) in 41 participants with schizophrenia-spectrum disorders. We also explored the effect of CCT treatment and COMT genotype on psychiatric symptom severity, functional capacity, and subjective quality of life. Met carrier status did not predict CCT treatment outcomes. COMT genotype may exert only modest effects on cognitive training response. Further research with larger samples is needed to establish genetic predictors of response to cognitive training.

  8. Caffeic Acid Phenethyl Ester Induces Adrenoleukodystrophy (Abcd2) Gene in Human X-ALD Fibroblasts and Inhibits the Proinflammatory Response in Abcd1/2 Silenced Mouse Primary Astrocytes

    Science.gov (United States)

    Singh, Jaspreet; Khan, Mushfiquddin; Singh, Inderjit

    2013-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene. Accumulation of very long chain fatty acids (VLCFA) that have been attributed to reduced peroxisomal VLCFA β-oxidation activity are the hallmark of the disease. Overexpression of ABCD2 gene, the closest homolog of ABCD1, has been shown to compensate for ABCD1, thus correcting the VLCFA derrangement. The accumulation of VLCFA leads to a neuroinflammatory disease process associated with demyelination of the cerebral white matter. The present study underlines the importance of caffeic acid phenethyl ester (CAPE) in inducing the expression of ABCD2 (ALDRP), and normalizing the peroxisomal β-oxidation as well as the levels of saturated and monounsaturated VLCFAs in cultured human skin fibroblasts of X-ALD patients. The expression of ELOVL1, the single elongase catalyzing the synthesis of both saturated VLCFA (C26:0) and mono-unsaturated VLCFA (C26:1), was also reduced by CAPE treatment. Importantly, CAPE upregulated Abcd2 expression and peroxisomal β-oxidation and lowered the VLCFA levels in Abcd1-deficient U87 astrocytes and B12 oligodendrocytes. In addition, using Abcd1/Abcd2-silenced mouse primary astrocytes we examined the effects of CAPE in VLCFA-induced inflammatory response. CAPE treatment decreased the inflammatory response as the expression of inducible nitric oxide synthase, inflammatory cytokine, and activation of NF-κB in Abcd1/Abcd2-silenced mouse primary astrocytes was reduced. The observations indicate that CAPE corrects both the metabolic disease of VLCFA as well as secondary inflammatory disease; therefore, it may be a potential drug candidate to be tested for X-ALD therapy in humans. PMID:23318275

  9. Carbon nanotube reinforced hollow fiber solid/liquid phase microextraction: a novel extraction technique for the measurement of caffeic acid in Echinacea purpurea herbal extracts combined with high-performance liquid chromatography.

    Science.gov (United States)

    Es'haghi, Zarrin; Golsefidi, Mazyar Ahmadi; Saify, Ali; Tanha, Ali Akbar; Rezaeifar, Zohre; Alian-Nezhadi, Zahra

    2010-04-23

    A new design of hollow fiber solid-liquid phase microextraction (HF-SLPME) was developed for the determination of caffeic acid in medicinal plants samples as Echinacea purpure. The membrane extraction with sorbent interface used in this research is a three-phase supported liquid membrane consisting of an aqueous (donor phase), organic solvent/nano sorbent (membrane) and aqueous (acceptor phase) system operated in direct immersion sampling mode. The multi-walled carbon nanotube dispersed in the organic solvent is held in the pores of a porous membrane supported by capillary forces and sonification. It is in contact with two aqueous phases: the donor phase, which is the aqueous sample, and the acceptor phase, usually an aqueous buffer. All microextraction experiments were supported using an Accurel Q3/2 polypropylene hollow fiber membrane (600 microm I.D., 200 microm wall thicknesses, and 0.2 microm pore size). The experimental setup is very simple and highly affordable. The hollow fiber is disposable, so single use of the fiber reduces the risk of cross-contamination and carry-over problems. The proposed method allows the very effective and enriched recuperation of an acidic analyte into one single extract. In order to obtain high enrichment and extraction efficiency of the analyte using this novel technique, the main parameters were optimized. Under the optimized extraction conditions, the method showed good linearity (0.0001-50 microg/L), repeatability, low limits of detection (0.00005 microg/L) and excellent enrichment (EF=2108). Copyright 2010 Elsevier B.V. All rights reserved.

  10. 1,2,3-Triazolyl esterization of PAK1-blocking propolis ingredients, artepillin C (ARC) and caffeic acid (CA), for boosting their anti-cancer/anti-PAK1 activities along with cell-permeability.

    Science.gov (United States)

    Takahashi, Hideaki; Nguyen, Binh Cao Quan; Uto, Yoshihiro; Shahinozzaman, Md; Tawata, Shinkichi; Maruta, Hiroshi

    2017-05-30

    Artepillin C (ARC) and caffeic acid (CA) are among the major anti-cancer ingredients of propolis, and block the oncogenic/melanogenic/ageing kinase PAK1. However, mainly due to their COOH moiety, cell-permeability of these herbal compounds is rather limited. Thus, in this study, in an attempt to increase their cell-permeability without any significant loss of their water-solubility, we have esterized both ARC and CA with the water-soluble 1,2,3-triazolyl alcohol through Click Chemistry. We found that this esterization boosts the anti-cancer activity of ARC and CA by 100 and over 400 folds, respectively, against the PAK-dependent growth of A549 lung cells, but show no effect on the PAK1-independent growth of B16F10 melanoma cells. Confirming this "selective" toxicity, these esters are still capable of blocking the kinase PAK1 strongly in cell culture (with IC 50 around 5 µM), and the anti-PAK1 activity of 15A (ARC ester) and 15C (CA ester) appears to be 30-fold and 140-fold higher than ARC and CA, respectively. The 15A and 15C are 8-fold and 70-fold more cell-permeable (through the multi-drug resistant cell line EMT6) than ARC and CA, respectively. These data altogether suggest that both 15A and 15C would be far more useful than propolis for the treatment of a wide variety of PAK1-dependent diseases/disorders such as cancers, Alzheimer's diseases (AD), hypertension, diabetes (type 2), and hyper-pigmentation.

  11. Catechol-O-methyltransferase activity in erythrocytes from patients with eating disorders.

    Science.gov (United States)

    Amorim-Barbosa, T; Serrão, M P; Brandão, I; Vieira-Coelho, M A

    2016-06-01

    Abnormal feeding has been linked to disruptions in brain dopaminergic activity and recent studies have assessed the role of catechol-O-methyltransferase (COMT) in eating disorders. This is the first study to quantify the soluble catechol-O-methyltransferase (S-COMT) activity in erythrocytes from patients with anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED) and the first study at all to evaluate the COMT on patients with BED. Forty blood samples from patients with AN, BN and BED and healthy controls were drawn to evaluate S-COMT activity in erythrocytes by high-performance liquid chromatography and mass spectrometry. Since several patients were being treated with fluoxetine 20 mg, they were included in a different group (BN MED and BED MED). Liver homogenates from rats were used to evaluate baseline S-COMT activity in the presence of fluoxetine by the same in vitro procedures and assays. Erythrocyte S-COMT activity (pmol/mg prt/h) was significantly increased in patients with BN and BED (41.3 ± 6.8 and 41.4 ± 14, respectively) compared to control group (25.3 ± 9.7). In fluoxetine-treated patients with BN, S-COMT activity (15.9 ± 8.8) was decreased compared to the other BN group; however, in BED group, the difference between BED MED and BED was not observed. In patients with AN, no significant difference was found compared to controls. Patients with BN and BED presented higher S-COMT activity in erythrocytes, which is in agreement with previous studies on the literature addressing the high-activity COMT allele, Val158, as risk factor for eating disorders. Although in fluoxetine-treated patients with BN the activity of S-COMT was similar to the controls, this is not explained by a direct interaction between fluoxetine and S-COMT as verified in in vitro assays.

  12. Pharmacogenetics of Modafinil after sleep loss: Catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep

    OpenAIRE

    Bodenmann, S; Xu, S; Luhmann, U; Arand, M.; Berger, W.; Jung, H; Landolt, H P

    2009-01-01

    Sleep loss impairs waking functions and is homeostatically compensated in recovery sleep. The mechanisms underlying the consequences of prolonged wakefulness are unknown. The stimulant modafinil may promote primarily dopaminergic neurotransmission. Catechol-O-methyltransferase (COMT) catalyzes the breakdown of cerebral dopamine. A functional Val158Met polymorphism reduces COMT activity, and Val/Val homozygous individuals presumably have lower dopaminergic signaling in the prefrontal cortex th...

  13. Inhibition of low-density lipoprotein oxidation and oxidative burst in polymorphonuclear neutrophils by caffeic acid and hispidin derivatives isolated from sword brake fern (Pteris ensiformis Burm.).

    Science.gov (United States)

    Wei, Hsiu-An; Lian, Tzi-Wei; Tu, Yi-Chen; Hong, Jing-Ting; Kou, Mei-Chun; Wu, Ming-Jiuan

    2007-12-26

    Several antioxidant compounds have been previously identified from sword brake fern (Pteris ensiformis Burm.) by DPPH bleaching and Trolox equivalent antioxidant capacity (TEAC) analyses. Among the isolates, 7-O-caffeoylhydroxymaltol 3-O-beta-D-glucopyranoside and hispidin 4-O-beta- D-glucopyranoside [6-(3,4-dihydroxystyryl)-4-O-beta-D-glucopyranoside-2-pyrone] were two new compounds. The aim of this study is to elucidate the possible effect of the aqueous extract of sword brake fern (SBF) and these two compounds in preventing atherosclerosis. The results demonstrated that SBF and these two compounds strongly inhibited Cu2+-mediated low-density lipoprotein (LDL) oxidation measured by thiobarbituric acid-reactive substances assay (TBARS), conjugated diene production, and relative electrophoretic mobility. The commercial antioxidant dl-alpha-tocopherol showed lower antioxidant activity than these two compounds at the same molecular concentration. SBF and these two compounds also suppressed N-formylmethionyl-leucylphenylalanine (fMLP)-stimulated reactive oxygen species (ROS) production in human polymorphonuclear neutrophils (PMN). These findings indicate that sword brake fern may prevent atherosclerosis via inhibition of both LDL oxidation and ROS production.

  14. Variations in the catechol O-methyltransferase polymorphism and prefrontally guided behaviors in adolescents.

    Science.gov (United States)

    Wahlstrom, Dustin; White, Tonya; Hooper, Catalina J; Vrshek-Schallhorn, Suzanne; Oetting, William S; Brott, Marcia J; Luciana, Monica

    2007-03-01

    The catechol-O-methyltransferase (COMT) gene codes for an enzyme that degrades prefrontal cortex (PFC) synaptic dopamine. Of two identified alleles (Met and Val), the Met allele results in COMT activity that is up to 4 times less pronounced than that conferred by the Val allele, resulting in greater PFC dopamine concentrations. Met-Met homozygotes perform better than individuals who possess the Val allele on PFC-mediated cognitive tasks. These genotypic variations and their associations with executive functions have been described in adults and prepubescent children, but there is a paucity of research assessing these relations in adolescent samples. In this study, 70 children aged 9-17 were genotyped for COMT and completed measures of working memory, attention, fine motor coordination, and motor speed. COMT genotype modulated all but the motor speed measures. The Val-Met genotype was optimal for performance in this adolescent sample. Results are discussed within the context of developmental changes in the dopaminergic system during adolescence.

  15. Role of Petal-Specific Orcinol O-Methyltransferases in the Evolution of Rose Scent1

    Science.gov (United States)

    Scalliet, Gabriel; Lionnet, Claire; Le Bechec, Mickaël; Dutron, Laurence; Magnard, Jean-Louis; Baudino, Sylvie; Bergougnoux, Véronique; Jullien, Frédéric; Chambrier, Pierre; Vergne, Philippe; Dumas, Christian; Cock, J. Mark; Hugueney, Philippe

    2006-01-01

    Orcinol O-methyltransferase (OOMT) 1 and 2 catalyze the last two steps of the biosynthetic pathway leading to the phenolic methyl ether 3,5-dimethoxytoluene (DMT), the major scent compound of many rose (Rosa x hybrida) varieties. Modern roses are descended from both European and Chinese species, the latter being producers of phenolic methyl ethers but not the former. Here we investigated why phenolic methyl ether production occurs in some but not all rose varieties. In DMT-producing varieties, OOMTs were shown to be localized specifically in the petal, predominanty in the adaxial epidermal cells. In these cells, OOMTs become increasingly associated with membranes during petal development, suggesting that the scent biosynthesis pathway catalyzed by these enzymes may be directly linked to the cells' secretory machinery. OOMT gene sequences were detected in two non-DMT-producing rose species of European origin, but no mRNA transcripts were detected, and these varieties lacked both OOMT protein and enzyme activity. These data indicate that up-regulation of OOMT gene expression may have been a critical step in the evolution of scent production in roses. PMID:16361520

  16. Serotonin-Induced Hypersensitivity via Inhibition of Catechol O-Methyltransferase Activity

    Science.gov (United States)

    2012-01-01

    The subcutaneous and systemic injection of serotonin reduces cutaneous and visceral pain thresholds and increases responses to noxious stimuli. Different subtypes of 5-hydroxytryptamine (5-HT) receptors are suggested to be associated with different types of pain responses. Here we show that serotonin also inhibits catechol O-methyltransferase (COMT), an enzyme that contributes to modultion the perception of pain, via non-competitive binding to the site bound by catechol substrates with a binding affinity comparable to the binding affinity of catechol itself (Ki = 44 μM). Using computational modeling, biochemical tests and cellular assays we show that serotonin actively competes with the methyl donor S-adenosyl-L-methionine (SAM) within the catalytic site. Binding of serotonin to the catalytic site inhibits the access of SAM, thus preventing methylation of COMT substrates. The results of in vivo animal studies show that serotonin-induced pain hypersensitivity in mice is reduced by either SAM pretreatment or by the combined administration of selective antagonists for β2- and β3-adrenergic receptors, which have been previously shown to mediate COMT-dependent pain signaling. Our results suggest that inhibition of COMT via serotonin binding contributes to pain hypersensitivity, providing additional strategies for the treatment of clinical pain conditions. PMID:22500608

  17. Analysis of Oxidative Stress Status, Catalase and Catechol-O-Methyltransferase Polymorphisms in Egyptian Vitiligo Patients

    Science.gov (United States)

    Mehaney, Dina A.; Darwish, Hebatallah A.; Hegazy, Rehab A.; Nooh, Mohammed M.; Tawdy, Amira M.; Gawdat, Heba I.; El-Sawalhi, Maha M.

    2014-01-01

    Vitiligo is the most common depigmentation disorder of the skin. Oxidative stress is implicated as one of the probable events involved in vitiligo pathogenesis possibly contributing to melanocyte destruction. Evidence indicates that certain genes including those involved in oxidative stress and melanin synthesis are crucial for development of vitiligo. This study evaluates the oxidative stress status, the role of catalase (CAT) and catechol-O-Methyltransferase (COMT) gene polymorphisms in the etiology of generalized vitiligo in Egyptians. Total antioxidant capacity (TAC) and malondialdehyde (MDA) levels as well as CAT exon 9 T/C and COMT 158 G/A polymorphisms were determined in 89 patients and 90 age and sex-matched controls. Our results showed significantly lower TAC along with higher MDA levels in vitiligo patients compared with controls. Meanwhile, genotype and allele distributions of CAT and COMT polymorphisms in cases were not significantly different from those of controls. Moreover, we found no association between both polymorphisms and vitiligo susceptibility. In conclusion, the enhanced oxidative stress with the lack of association between CAT and COMT polymorphisms and susceptibility to vitiligo in our patients suggest that mutations in other genes related to the oxidative pathway might contribute to the etiology of generalized vitiligo in Egyptian population. PMID:24915010

  18. Molecular Cloning and Characterization of O-Methyltransferase from Mango Fruit (Mangifera indica cv. Alphonso).

    Science.gov (United States)

    Chidley, Hemangi G; Oak, Pranjali S; Deshpande, Ashish B; Pujari, Keshav H; Giri, Ashok P; Gupta, Vidya S

    2016-05-01

    Flavour of ripe Alphonso mango is invariably dominated by the de novo appearance of lactones and furanones during ripening. Of these, furanones comprising furaneol (4-hydroxy-2,5-dimethyl-3(2H)-furanone) and mesifuran (2,5-dimethyl-4-methoxy-3(2H)-furanone) are of particular importance due to their sweet, fruity caramel-like flavour characters and low odour detection thresholds. We isolated a 1056 bp complete open reading frame of a cDNA encoding S-adenosyl-L-methionine-dependent O-methyltransferase from Alphonso mango. The recombinantly expressed enzyme, MiOMTS showed substrate specificity towards furaneol and protocatechuic aldehyde synthesizing mesifuran and vanillin, respectively, in an in vitro assay reaction. A semi-quantitative PCR analysis showed fruit-specific expression of MiOMTS transcripts. Quantitative real-time PCR displayed ripening-related expression pattern of MiOMTS in both pulp and skin of Alphonso mango. Also, early and significantly enhanced accumulation of its transcripts was detected in pulp and skin of ethylene-treated fruits. Ripening-related and fruit-specific expression profile of MiOMTS and substrate specificity towards furaneol is a suggestive of its involvement in the synthesis of mesifuran in Alphonso mango. Moreover, a significant trigger in the expression of MiOMTS transcripts in ethylene-treated fruits point towards the transcriptional regulation of mesifuran biosynthesis by ethylene.

  19. Genetic influences on insight problem solving: the role of catechol-O-methyltransferase (COMT) gene polymorphisms.

    Science.gov (United States)

    Jiang, Weili; Shang, Siyuan; Su, Yanjie

    2015-01-01

    People may experience an "aha" moment, when suddenly realizing a solution of a puzzling problem. This experience is called insight problem solving. Several findings suggest that catecholamine-related genes may contribute to insight problem solving, among which the catechol-O-methyltransferase (COMT) gene is the most promising candidate. The current study examined 753 healthy individuals to determine the associations between 7 candidate single nucleotide polymorphisms on the COMT gene and insight problem-solving performance, while considering gender differences. The results showed that individuals carrying A allele of rs4680 or T allele of rs4633 scored significantly higher on insight problem-solving tasks, and the COMT gene rs5993883 combined with gender interacted with correct solutions of insight problems, specifically showing that this gene only influenced insight problem-solving performance in males. This study presents the first investigation of the genetic impact on insight problem solving and provides evidence that highlights the role that the COMT gene plays in insight problem solving.

  20. Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome.

    Science.gov (United States)

    Hall, Kathryn T; Lembo, Anthony J; Kirsch, Irving; Ziogas, Dimitrios C; Douaiher, Jeffrey; Jensen, Karin B; Conboy, Lisa A; Kelley, John M; Kokkotou, Efi; Kaptchuk, Ted J

    2012-01-01

    Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment ("waitlist"), placebo treatment alone ("limited") and, placebo treatment "augmented" with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.

  1. Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome.

    Science.gov (United States)

    Hall, K T; Kossowsky, J; Oberlander, T F; Kaptchuk, T J; Saul, J P; Wyller, V B; Fagermoen, E; Sulheim, D; Gjerstad, J; Winger, A; Mukamal, K J

    2016-10-01

    Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2500 fewer steps compared with placebo (Pinteraction=0.04). There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions.

  2. Catechol-O-Methyltransferase Gene Polymorphisms in Specific Obsessive-Compulsive Disorder Patients' Subgroups.

    Science.gov (United States)

    Melo-Felippe, Fernanda Brito; de Salles Andrade, Juliana Braga; Giori, Isabele Gomes; Vieira-Fonseca, Tamiris; Fontenelle, Leonardo Franklin; Kohlrausch, Fabiana Barzotti

    2016-01-01

    Pharmacological data and animal models support the hypothesis that the dopaminergic (DA) system is implicated in obsessive-compulsive disorder (OCD). Therefore, this case-control study assessed whether genetics variations in catechol-O-methyltransferase gene (COMT) could influence susceptibility to OCD and OCD features in a Brazilian sample. A sample of 199 patients with OCD and 200 healthy individuals was genotyped for -287A > G (rs2075507) and Val158Met (rs4680) single nucleotide polymorphisms (SNPs) by TaqMan(®) or restriction mapping. We observed a statistically significant predominance of the Met low-activity allele in the male patient group as compared to the male healthy control group. The -287A > G polymorphism's genotypes and alleles were significantly overrepresented among male individuals with ordering and female subjects with washing symptoms. We also found female hoarders to exhibit a significant higher frequency of the low activity Met/Met genotype of Val158Met polymorphism compared to female patients who did not express this dimension. Our data suggest an influence of COMT polymorphisms on OCD and OCD patients' features, such as gender, and ordering, washing, and hoarding symptom dimensions. Further studies to confirm the clinical importance of COMT SNPs in OCD are warranted.

  3. Catechol-O-methyltransferase (COMT) polymorphisms modulate working memory in individuals with schizophrenia and healthy controls.

    Science.gov (United States)

    Matsuzaka, Camila T; Christofolini, Denise; Ota, Vanessa K; Gadelha, Ary; Berberian, Arthur A; Noto, Cristiano; Mazzotti, Diego R; Spindola, Leticia M; Moretti, Patricia N; Smith, Marilia A C; Melaragno, Maria I; Belangero, Sintia I; Bressan, Rodrigo A

    2017-01-01

    Cognitive impairment is a core feature of schizophrenia, related to dopaminergic dysfunction in the prefrontal cortex (PFC). It is hypothesized that functional single nucleotide polymorphism (SNP) rs4680 of the catechol-O-methyltransferase (COMT) gene could mediate the relationship between cognition and dopamine activity in the PFC. Other COMT SNPs could also play a role. We evaluated the role of three COMT SNPs (rs737865, rs165599, and rs4680) in schizophrenia and their impact on three working memory tasks. For genetic association analyses, 212 individuals with schizophrenia and 257 healthy controls (HCs) were selected. The Visual Working Memory (VWM) Task, Keep Track Task, and Letter Memory Task were administered to 133 schizophrenics and 93 HCs. We found a significant association of rs737865, with the GG genotype exerting a protective effect and the GA haplotype (rs4680/rs165599) exerting a risk effect for schizophrenia. COMT rs4680 AA carriers and rs737865 AA carriers scored lowest on the Keep Track Task. When the genotype*group interaction effect was evaluated, rs165599 exerted opposite effects for VWM and Keep Track task performance in patients and controls, with AA carriers scoring lowest on both tests among controls, but highest among patients. These data support the hypothesis that COMT polymorphisms may be associated with schizophrenia and modulate cognition in patients and controls.

  4. Catechol-O-methyltransferase (COMT polymorphisms modulate working memory in individuals with schizophrenia and healthy controls

    Directory of Open Access Journals (Sweden)

    Camila T. Matsuzaka

    2017-03-01

    Full Text Available Objective: Cognitive impairment is a core feature of schizophrenia, related to dopaminergic dysfunction in the prefrontal cortex (PFC. It is hypothesized that functional single nucleotide polymorphism (SNP rs4680 of the catechol-O-methyltransferase (COMT gene could mediate the relationship between cognition and dopamine activity in the PFC. Other COMT SNPs could also play a role. Methods: We evaluated the role of three COMT SNPs (rs737865, rs165599, and rs4680 in schizophrenia and their impact on three working memory tasks. For genetic association analyses, 212 individuals with schizophrenia and 257 healthy controls (HCs were selected. The Visual Working Memory (VWM Task, Keep Track Task, and Letter Memory Task were administered to 133 schizophrenics and 93 HCs. Results: We found a significant association of rs737865, with the GG genotype exerting a protective effect and the GA haplotype (rs4680/rs165599 exerting a risk effect for schizophrenia. COMT rs4680 AA carriers and rs737865 AA carriers scored lowest on the Keep Track Task. When the genotype*group interaction effect was evaluated, rs165599 exerted opposite effects for VWM and Keep Track task performance in patients and controls, with AA carriers scoring lowest on both tests among controls, but highest among patients. Conclusion: These data support the hypothesis that COMT polymorphisms may be associated with schizophrenia and modulate cognition in patients and controls.

  5. Characterization of Non-Nitrocatechol Pan and Isoform Specific Catechol-O-methyltransferase Inhibitors and Substrates

    Science.gov (United States)

    2011-01-01

    Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since membrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial membrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity. PMID:22860182

  6. Catechol-O-methyltransferase, a new target for pancreatic cancer therapy.

    Science.gov (United States)

    Wu, Wenming; Wu, Qiao; Hong, Xiafei; Zhou, Li; Zhang, Jie; You, Lei; Wang, Wenze; Wu, Huanwen; Dai, Hongmei; Zhao, Yupei

    2015-05-01

    Catechol-O-methyltransferase (COMT) is an important molecule in different types of cancers. Its biological effect and therapeutic significance, however, rarely been investigated fully in pancreatic cancer. Immunohistologically, high COMT expression was significantly correlated with the longer overall survival of patients (P < 0.05), indicating its protective nature. The effects of COMT on cell growth, apoptosis, and invasion were evaluated using overexpression and silencing methods. In detail, we carried out experiments using one stably transduced and two transiently transfected pancreatic cancer cell lines in vitro, and one stably transduced cell line in vivo mice xenograft models. In vitro experiments showed that COMT inhibited cell proliferation, enhanced gemcitabine-induced apoptosis, and inhibited cell invasion in stably transduced and transiently transfected cell lines by regulating the PI3K/Akt pathway, p53, and E-cadherin. The COMT overexpressed and silenced cell lines showed significantly inhibited and enhanced growth capacities in in vivo xenograft models, respectively. In conclusion, COMT suppressed pancreatic cancer and its high expression predicted longer survival time. The interaction of COMT with the PI3K/Akt pathway makes it a potential target for therapy. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  7. Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome.

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    Kathryn T Hall

    Full Text Available Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT, an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS. The three treatment arms from this study were: no-treatment ("waitlist", placebo treatment alone ("limited" and, placebo treatment "augmented" with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035. The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.

  8. Serotonin-Induced Hypersensitivity via Inhibition of Catechol O-Methyltransferase Activity

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    Tsao Douglas

    2012-04-01

    Full Text Available Abstract The subcutaneous and systemic injection of serotonin reduces cutaneous and visceral pain thresholds and increases responses to noxious stimuli. Different subtypes of 5-hydroxytryptamine (5-HT receptors are suggested to be associated with different types of pain responses. Here we show that serotonin also inhibits catechol O-methyltransferase (COMT, an enzyme that contributes to modultion the perception of pain, via non-competitive binding to the site bound by catechol substrates with a binding affinity comparable to the binding affinity of catechol itself (Ki = 44 μM. Using computational modeling, biochemical tests and cellular assays we show that serotonin actively competes with the methyl donor S-adenosyl-L-methionine (SAM within the catalytic site. Binding of serotonin to the catalytic site inhibits the access of SAM, thus preventing methylation of COMT substrates. The results of in vivo animal studies show that serotonin-induced pain hypersensitivity in mice is reduced by either SAM pretreatment or by the combined administration of selective antagonists for β2- and β3-adrenergic receptors, which have been previously shown to mediate COMT-dependent pain signaling. Our results suggest that inhibition of COMT via serotonin binding contributes to pain hypersensitivity, providing additional strategies for the treatment of clinical pain conditions.

  9. Catechol-O-methyltransferase (COMT) gene modulates private self-consciousness and self-flexibility.

    Science.gov (United States)

    Wang, Bei; Ru, Wenzhao; Yang, Xing; Yang, Lu; Fang, Pengpeng; Zhu, Xu; Shen, Guomin; Gao, Xiaocai; Gong, Pingyuan

    2016-08-01

    Dopamine levels in the brain influence human consciousness. Inspired by the role of Catechol-O-methyltransferase (COMT) in inactivating dopamine in the brain, we investigated to what extent COMT could modulate individual's self-consciousness dispositions and self-consistency by genotyping the COMT Val158Met (rs4680) polymorphism and measuring self-consciousness and self-consistency and congruence in a college student population. The results indicated that COMT Val158Met polymorphism significantly modulated the private self-consciousness. The individuals with Val/Val genotype, corresponding to lower dopamine levels in the brain, were more likely to be aware of their feelings and beliefs. The results also indicated that this polymorphism modulated one's self-flexibility. The individuals with Val/Val genotype showed higher levels of stereotype in self-concept compared with those with Met/Met genotype. These findings suggest that COMT is a predictor of the individual differences in self-consciousness and self-flexibility. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Structural mechanism of S-adenosyl methionine binding to catechol O-methyltransferase.

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    Douglas Tsao

    Full Text Available Methyltransferases possess a homologous domain that requires both a divalent metal cation and S-adenosyl-L-methionine (SAM to catalyze its reactions. The kinetics of several methyltransferases has been well characterized; however, the details regarding their structural mechanisms have remained unclear to date. Using catechol O-methyltransferase (COMT as a model, we perform discrete molecular dynamics and computational docking simulations to elucidate the initial stages of cofactor binding. We find that COMT binds SAM via an induced-fit mechanism, where SAM adopts a different docking pose in the absence of metal and substrate in comparison to the holoenzyme. Flexible modeling of the active site side-chains is essential for observing the lowest energy state in the apoenzyme; rigid docking tools are unable to recapitulate the pose unless the appropriate side-chain conformations are given a priori. From our docking results, we hypothesize that the metal reorients SAM in a conformation suitable for donating its methyl substituent to the recipient ligand. The proposed mechanism enables a general understanding of how divalent metal cations contribute to methyltransferase function.

  11. Aberrant endometrial DNA methylome of homeobox A10 and catechol-O-methyltransferase in endometriosis.

    Science.gov (United States)

    Ji, Fei; Yang, Xinhua; He, Yan; Wang, Hui; Aili, Aixingzi; Ding, Yan

    2017-03-01

    Differential methylation of both HOXA10 and catechol-O-methyltransferase (COMT) has been reported in different endometrium disorders, and the two genes are linked through the estrogen pathway. The current study investigates the DNA methylation of HOXA10 and COMT in ectopic and eutopic endometrial tissues and its correlation with and the occurrence of endometriosis in women from Xinjiang province in China. In the current study, 120 patients with endometriosis were recruited from our hospital between January 2011 and June 2014. The DNA methylation sites of HOXA10 and COMT were detected using a DNA methylation array. The methylation levels of specific sites were compared between ectopic and eutopic endometrial tissues via pyrosequencing. Five differentially expressed CpGs were localized in the promoter region of the COMT gene and expressed significantly higher in the ectopic endometrium than the eutopic endometrium (P < 0.001). Two out of the five differentially expressed CpGs in the HOXA10 gene located in the promoter region were both significantly lower (nearly half) in the ectopic endometrium than the eutopic endometrium (P < 0.001). To summarize, significant differential methylation of HOXA10 and COMT promoter regions was found between the ectopic and eutopic endometrial tissues. This is the first study investigating the methylation of HOXA10 and COMT genes and their linkage to endometriosis in Chinese patients.

  12. Development of fed-batch profiles for efficient biosynthesis of catechol-O-methyltransferase

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    G.M. Espírito Santo

    2014-09-01

    Full Text Available Catechol-O-methyltransferase (COMT, EC 2.1.1.6 plays a crucial role in dopamine metabolism which has intimately linked this enzyme to some neurodegenerative diseases, such as Parkinson's disease. In recent years, in the attempt of developing new therapeutic strategies for Parkinson's disease, there has been a growing interest in the search for effective COMT inhibitors. In order to do so, large amounts of COMT in an active form are needed, and the best way to achieve this is by up-scaling its production through biotechnological processes. In this work, a fed-batch process for the biosynthesis of the soluble isoform of COMT in Escherichia coli is proposed. This final process was selected through the evaluation of the effect of different dissolved oxygen concentrations, carbon and nitrogen source concentrations and feeding profiles on enzymatic production and cell viability, while controlling various parameters (pH, temperature, starting time of the feeding and induction phases and carbon source concentration during the process. After several batch and fed-batch experiments, a final specific COMT activity of 442.34 nmol/h/mg with approximately 80% of viable cells at the end of the fermentation were achieved. Overall, the results described herein provide a great improvement on hSCOMT production in recombinant bacteria and provide a new and viable option for the use of a fed-batch fermentation with a constant feeding profile to the large scale production of this enzyme.

  13. Analysis of oxidative stress status, catalase and catechol-O-methyltransferase polymorphisms in Egyptian vitiligo patients.

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    Dina A Mehaney

    Full Text Available Vitiligo is the most common depigmentation disorder of the skin. Oxidative stress is implicated as one of the probable events involved in vitiligo pathogenesis possibly contributing to melanocyte destruction. Evidence indicates that certain genes including those involved in oxidative stress and melanin synthesis are crucial for development of vitiligo. This study evaluates the oxidative stress status, the role of catalase (CAT and catechol-O-Methyltransferase (COMT gene polymorphisms in the etiology of generalized vitiligo in Egyptians. Total antioxidant capacity (TAC and malondialdehyde (MDA levels as well as CAT exon 9 T/C and COMT 158 G/A polymorphisms were determined in 89 patients and 90 age and sex-matched controls. Our results showed significantly lower TAC along with higher MDA levels in vitiligo patients compared with controls. Meanwhile, genotype and allele distributions of CAT and COMT polymorphisms in cases were not significantly different from those of controls. Moreover, we found no association between both polymorphisms and vitiligo susceptibility. In conclusion, the enhanced oxidative stress with the lack of association between CAT and COMT polymorphisms and susceptibility to vitiligo in our patients suggest that mutations in other genes related to the oxidative pathway might contribute to the etiology of generalized vitiligo in Egyptian population.

  14. Catechol-O-methyltransferase Val158Met polymorphism is associated with somatosensory amplification and nocebo responses.

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    Laura Wendt

    Full Text Available A large number of unwanted adverse events and symptoms reported by patients in clinical trials are not caused by the drug provided, since most of adverse events also occur in corresponding placebo groups. These nocebo effects also play a major role in drug discontinuation in clinical practice, negatively affecting treatment efficacy as well as patient adherence and compliance. Experimental and clinical data document a large interindividual variability in nocebo responses, however, data on psychological, biological or genetic predictors of nocebo responses are lacking. Thus, with an established paradigm of behaviorally conditioned immunosuppressive effects we analyzed possible genetic predictors for nocebo responses. We focused on the genetic polymorphisms in the catechol-O-methyltransferase (COMT gene (Val158Met and analyzed drug specific and general side effects before and after immunosuppressive medication and subsequent placebo intake in 62 healthy male subjects. Significantly more drug-specific as well as general side effects were reported from homozygous carriers of the Val158 variant during medication as well as placebo treatment compared to the other genotype groups. Val158/Val158 carriers also had significantly higher scores in the somatosensory amplification scale (SSAS and the BMQ (beliefs about medicine questionnaire. Together these data demonstrate potential genetic and psychological variables predicting nocebo responses after drug and placebo intake, which might be utilized to minimize nocebo effects in clinical trials and medical practice.

  15. Attention-deficit/hyperactivity disorder phenotype is influenced by a functional catechol-O-methyltransferase variant.

    Science.gov (United States)

    Pálmason, Haukur; Moser, Dirk; Sigmund, Jessica; Vogler, Christian; Hänig, Susann; Schneider, Anna; Seitz, Christiane; Marcus, Alexander; Meyer, Jobst; Freitag, Christine M

    2010-02-01

    The catechol-O-methyltransferase gene (COMT) plays a crucial role in the metabolism of catecholamines in the frontal cortex. A single nucleotide polymorphism (Val(158)Met SNP, rs4680) leads to either methionine (Met) or valine (Val) at codon 158, resulting in a three- to fourfold reduction in COMT activity. The aim of the present study was to assess the COMT Val(158)Met SNP as a risk factor for attention-deficit/hyperactivity disorder (ADHD), ADHD symptom severity and co-morbid conduct disorder (CD) in 166 children with ADHD. The main finding of the present study is that the Met allele of the COMT Val(158)Met SNP was associated with ADHD and increased ADHD symptom severity. No association with co-morbid CD was observed. In addition, ADHD symptom severity and early adverse familial environment were positive predictors of lifetime CD. These findings support previous results implicating COMT in ADHD symptom severity and early adverse familial environment as risk factors for co-morbid CD, emphasizing the need for early intervention to prevent aggressive and maladaptive behavior progressing into CD, reducing the overall severity of the disease burden in children with ADHD.

  16. Catechol-O-methyltransferase (COMT)-mediated metabolism of catechol estrogens: comparison of wild-type and variant COMT isoforms.

    Science.gov (United States)

    Dawling, S; Roodi, N; Mernaugh, R L; Wang, X; Parl, F F

    2001-09-15

    The oxidative metabolism of 17beta-estradiol (E2) and estrone (E1) to catechol estrogens (2-OHE2, 4-OHE2, 2-OHE1, and 4-OHE1) and estrogen quinones has been postulated to be a factor in mammary carcinogenesis. Catechol-O-methyltransferase (COMT) catalyzes the methylation of catechol estrogens to methoxy estrogens, which simultaneously lowers the potential for DNA damage and increases the concentration of 2-methoxyestradiol (2-MeOE2), an antiproliferative metabolite. We expressed two recombinant forms of COMT, the wild-type (108Val) and a common variant (108Met), to determine whether their catalytic efficiencies differ with respect to catechol estrogen inactivation. The His-tagged proteins were purified by nickel-nitrilo-triacetic acid chromatography and analyzed by electrophoresis and Western immunoblot. COMT activity was assessed by determining the methylation of 2-OHE2, 4-OHE2, 2-OHE1, and 4-OHE1, using gas chromatography/mass spectrometry for quantitation of the respective methoxy products. In the case of 2-OHE2 and 2-OHE1, methylation occurred at 2-OH and 3-OH groups, resulting in the formation of 2-MeOE2 and 2-OH-3-MeOE2, and 2-MeOE1 and 2-OH-3-MeOE1, respectively. In contrast, in the case of 4-OHE2 and 4-OHE1, methylation occurred only at the 4-OH group, yielding 4-MeOE2 and 4-MeOE1, respectively. Individual and competition experiments revealed the following order of product formation: 4-MeOE2 > 4-MeOE1 > 2-MeOE2 > 2-MeOE1 > 2-OH-3-MeOE1 > 2-OH-3-MeOE2. The variant isoform differed from wild-type COMT by being thermolabile, leading to 2-3-fold lower levels of product formation. MCF-7 breast cancer cells with the variant COMT 108Met/Met genotype also displayed 2-3-fold lower catalytic activity than ZR-75 breast cancer cells with the wild-type COMT 108Val/Val genotype. Thus, inherited alterations in COMT catalytic activity are associated with significant differences in catechol estrogen and methoxy estrogen levels and, thereby, may contribute to interindividual

  17. Metabolism of (/sup 3/H)noradrenaline in different compartments of rat brain with respect to the role of catechol-O-methyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Koester, G.; Goede, E.; Breuer, H.

    1984-03-01

    Rats were pretreated with either reserpine or desmethylimipramine, either alone or in combination with tropolone. At either 10 min or 1 h after the intraventricular injection of (/sup 3/H)noradrenaline, in several brain regions the complete metabolic patterns were determined: normetanephrine; the glycol metabolites (methylated and nonmethylated) and their sulfate conjugates; and the acidic metabolites (methylated and non-methylated). A reserpine-induced increase in the turnover of (/sup 3/H)noradrenaline caused a transient increase of the catechol glycol followed by elevated levels of the two glycol sulfates. The stimulated (/sup 3/H)noradrenaline turnover if achieved by desmethylimipramine caused a transient increase of normetanephrine and initially lowered values of catechol glycols (both free and sulfated), which were followed by elevated levels. Drug-pretreated rats compensated for the inhibition of catechol-O-methyl-transferase by tropolone in different ways: Reserpine caused an early increase of the catechol glycol beyond the measurements in other treatment groups, whereas desmethylimipramine increased the nonmethylated carboxylic acid and glycol sulfates rather slowly to levels beyond those of other groups. The results support the existence of two compartments with a fast metabolism (an intraneuronal monoamine oxidase compartment and an extraneuronal catechol-O-methyltransferase compartment). In addition, there seems to exist another extra-neuronal space with a slow, monoamine oxidase-dependent noradrenaline turnover.

  18. Molecular Basis of Substrate Promiscuity for the SAM-Dependent O-Methyltransferase NcsB1, Involved in the Biosynthesis of the Enediyne Antitumor Antibiotic Neocarzinostatin

    Energy Technology Data Exchange (ETDEWEB)

    Cooke, H.; Guenther, E; Luo, Y; Shen, B; Bruner, S

    2009-01-01

    The small molecule component of chromoprotein enediyne antitumor antibiotics is biosynthesized through a convergent route, incorporating amino acid, polyketide, and carbohydrate building blocks around a central enediyne hydrocarbon core. The naphthoic acid moiety of the enediyne neocarzinostatin plays key roles in the biological activity of the natural product by interacting with both the carrier protein and duplex DNA at the site of action. We have previously described the in vitro characterization of an S-adenosylmethionine-dependent O-methyltransferase (NcsB1) in the neocarzinostatin biosynthetic pathway [Luo, Y., Lin, S., Zhang, J., Cooke, H. A., Bruner, S. D., and Shen, B. (2008) J. Biol. Chem. 283, 14694-14702]. Here we provide a structural basis for NcsB1 activity, illustrating that the enzyme shares an overall architecture with a large family of S-adenosylmethionine-dependent proteins. In addition, NcsB1 represents the first enzyme to be structurally characterized in the biosynthetic pathway of neocarzinostatin. By cocrystallizing the enzyme with various combinations of the cofactor and substrate analogues, details of the active site structure have been established. Changes in subdomain orientation were observed via comparison of structures in the presence and absence of substrate, suggesting that reorientation of the enzyme is involved in binding of the substrate. In addition, residues important for substrate discrimination were predicted and probed through site-directed mutagenesis and in vitro biochemical characterization.

  19. Ethanol extract of propolis and its constituent caffeic acid phenethyl ester inhibit breast cancer cells proliferation in inflammatory microenvironment by inhibiting TLR4 signal pathway and inducing apoptosis and autophagy.

    Science.gov (United States)

    Chang, Huasong; Wang, Yuehua; Yin, Xusheng; Liu, Xinying; Xuan, Hongzhuan

    2017-09-26

    Propolis and its major constituent - caffeic acid phenethyl ester (CAPE) have good abilities on antitumor and anti-inflammation. However, little is known about the actions of propolis and CAPE on tumor in inflammatory microenvironment, and inflammatory responses play decisive roles at different stages of tumor development. To understand the effects and mechanisms of ethanol-extracted Chinese propolis (EECP) and its major constituent - CAPE in inflammation-stimulated tumor, we investigated their effects on Toll-like receptor 4 (TLR4) signaling pathway which plays a crucial role in breast cancer MDA-MB-231 cell line. 80% confluent breast cancer MDA-MB-231 cells were stimulated with 1 μg/mL lipopolysaccaride (LPS). Then the cells were divided for treatment by CAPE (25 μg/mL) and EECP (25, 50 and 100 μg/mL), respectively. Cell viability, nitric oxide (NO) production and cell migration were measured by sulforhodamine B assay, chemical method and scratch assay. The levels of TLR4, MyD88, IRAK4, TRIF, caspase 3, PARP, LC3B and p62 were investigated through western blotting. The expression of TLR4, LC3B and nuclear factor-κB p65 (NF-κB p65) were tested by immunofluorescence microscopy assay. Treatment of different concentrations of EECP (25, 50 and 100 μg/mL) and CAPE (25 μg/mL) significantly inhibited LPS-stimulated MDA-MB-231 cell line proliferation, migration and NO production. Furthermore, EECP and CAPE activated caspase3 and PARP to induce cell apoptosis, and also upregulated LC3-II and decreased p62 level to induce autophagy during the process. TLR4 signaling pathway molecules such as TLR4, MyD88, IRAK4, TRIF and NF-κB p65 were all down-regulated after EECP and CAPE treatment in LPS-stimulated MDA-MB-231 cells. These findings indicated that EECP and its major constituent - CAPE inhibited breast cancer MDA-MB-231 cells proliferation in inflammatory microenvironment through activating apoptosis, autophagy and inhibiting TLR4 signaling pathway. EECP and

  20. The association of catechol-O-methyltransferase genotype with the phenotype of women with eating disorders.

    Science.gov (United States)

    Mikołajczyk, Elzbieta; Grzywacz, Anna; Samochowiec, Jerzy

    2010-01-11

    The modern brain imaging studies in patients with eating disorders have shown that neurotransmitting regulation differs distinctly from control groups. These disturbances have involved serotonin and dopamine system can be inherited and conditioned by genes. The aim of this work has been the analysis of association between eating disorders of anorexia or bulimia type and two polymorphisms of COMT gene. The additional goal has been the analysis of correlation among chosen personality and psychological features of ED women with the research gene variations. The group taken as research sample consisted of adult 103 women (mean age=22.45+/-3.8 years) suffered from serious ED with illness lasting minimum 12 months. According to ICD-10 criteria, 61 women were diagnosed as anorexia nervosa while as 42 bulimia nervosa. The control group consisted of 108 ethnically and age-matched women with excluded major psychiatric disorders. The study groups were filling up the Eating Disorders Inventory and the Temperament and Character Inventory. The genotype of catechol-O-methyltransferase in two polymorphisms rs4633 (his102his) and rs4680 (val158met) was determined. The joined GGCT genotype increased the risk of having ED over fivefold and over sevenfold the risk of having bulimia. Also haplotype CT was found three times more often in ED women than in controls. Besides the homozygous genotypes, AACC and GGCC reduced substantially the relative risk of ED. The patients with the low activity COMT genotype scored higher in EDI scales ineffectiveness, drive for thinness and perfectionism. The high activity genotype was connected with underdeveloped features of character marked in the poor cooperativeness and the poor self-directedness. These connections among genotypes and character scales were more expressed in bulimia group.

  1. Impact of physical exercise on catechol-O-methyltransferase activity in depressive patients: A preliminary communication.

    Science.gov (United States)

    Carneiro, Lara S F; Fonseca, António Manuel; Serrão, Paula; Mota, Maria Paula; Vasconcelos-Raposo, José; Vieira-Coelho, Maria Augusta

    2016-03-15

    Catechol-O-methyltransferase (COMT) is a catabolic enzyme involved in the degradation of bioactive molecules including the neurotransmitters epinephrine, norepinephrine, and dopamine. Higher COMT activity in depressive patients in comparison to non-depressed individuals has been reported. The effect of aerobic exercise on depressive patients has been studied and a number of researchers and clinicians believe it to be effective in the treatment of depression and to be involved in several molecular underlying mechanisms. However, the effect of physical exercise on this enzyme activity is unknown, and it remains to be elucidated if chronic exercise changes COMT activity. This randomized control trial evaluates the effects of chronic exercise on peripheral COMT (S-COMT) activity in women with depressive disorder. Fourteen women (aged: 51.4±10.5 years) diagnosed with depression (according to International Classification of Diseases-10) were randomized to one of two groups: pharmacotherapy plus physical exercise (n=7) or only pharmacotherapy (n=7). The aerobic exercise program was supervised, lasting between 45-50min/session, three times/week for 16 weeks. Erythrocyte soluble COMT were assessed prior to and after the exercise program. Exercise group when compared to a control group presented a significant decrease (p=0.02, r=-0.535) in S-COMT activity between baseline and post-intervention. These data are preliminary outcomes from a small sample and should be replicated. Chronic exercise therapy combined with pharmacotherapy leads to significant decrease in S-COMT activity. Our results provide evidence that exercise interferes with S-COMT activity, a molecular mechanism involved in depression. Copyright © 2016. Published by Elsevier B.V.

  2. Haplotypes of catechol-O-methyltransferase modulate intelligence-related brain white matter integrity.

    Science.gov (United States)

    Liu, Bing; Li, Jun; Yu, Chunshui; Li, Yonghui; Liu, Yong; Song, Ming; Fan, Ming; Li, Kuncheng; Jiang, Tianzi

    2010-03-01

    Twin studies have indicated a common genetic origin for intelligence and for variations in brain morphology. Our previous diffusion tensor imaging studies found an association between intelligence and white matter integrity of specific brain regions or tracts. However, specific genetic determinants of the white matter integrity of these brain regions and tracts are still unclear. In this study, we assess whether and how catechol-O-methyltransferase (COMT) gene polymorphisms affect brain white matter integrity. We genotyped twelve single nucleotide polymorphisms (SNPs) within the COMT gene and performed haplotype analyses on data from 79 healthy subjects. Our subjects had the same three major COMT haplotypes (termed the HPS, APS and LPS haplotypes) as previous studies have reported as regulating significantly different levels of enzymatic activity and dopamine. We used the mean fractional anisotropy (FA) values from four regions and five tracts of interest to assess the effect of COMT polymorphisms, including the well-studied val158met SNP and the three main haplotypes that we had identified, on intelligence-related white matter integrity. We identified an association between the mean FA values of two regions in the bilateral prefrontal lobes and the COMT haplotypes, rather than between them and val158met. The haplotype-FA value associations modulated nonlinearly and fit an inverted U-model. Our findings suggest that COMT haplotypes can nonlinearly modulate the intelligence-related white matter integrity of the prefrontal lobes by more significantly influencing prefrontal dopamine variations than does val158met. Copyright (c) 2009 Elsevier Inc. All rights reserved.

  3. Influence of catechol-O-methyltransferase (COMT) gene polymorphisms in pain sensibility of Brazilian fibromialgia patients.

    Science.gov (United States)

    Barbosa, Flávia Regina; Matsuda, Josie Budag; Mazucato, Mendelson; de Castro França, Suzelei; Zingaretti, Sônia Marli; da Silva, Lucienir Maria; Martinez-Rossi, Nilce Maria; Júnior, Milton Faria; Marins, Mozart; Fachin, Ana Lúcia

    2012-02-01

    Fibromyalgia syndrome (FS) is a rheumatic syndrome affecting to 2-3% of individuals of productive age, mainly women. Neuroendocrine and genetic factors may play a significant role in development of the disease which is characterized by diffuse chronic pain and presence of tender points. Several studies have suggested an association between FS, especially pain sensitivity, and polymorphism of the catechol-O-methyltransferase (COMT) gene. The aim of the present study was to characterize the SNPs rs4680 and rs4818 of the COMT gene and assess its influence in pain sensitivity of patients with fibromyalgia screened by the Fibromyalgia Impact Questionnaire (FIQ). DNA was extracted from peripheral blood of 112 patients with fibromyalgia and 110 healthy individuals and was used as template in PCR for amplification of a 185-bp fragment of the COMT gene. The amplified fragment was sequenced for analyses of the SNPs rs4680 and rs4818. The frequency of mutant genotype AA of SNP rs6860 was 77.67% in patients with FS and 28.18% for the control group. For the SNP rs4818, the frequency of mutant genotype CC was 73.21 and 39.09% for patients with FS and controls, respectively. Moreover, the FIQ score was higher in patients with the homozygous mutant genotype for SNPs rs4680 (87.92 points) and rs4818 (86.14 points). These results suggest that SNPs rs4680 and rs4818 of the COMT gene may be associated with fibromyalgia and pain sensitivity in FS Brazilian patients.

  4. Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia

    Science.gov (United States)

    Vargas-Alarcón, Gilberto; Fragoso, José-Manuel; Cruz-Robles, David; Vargas, Angélica; Vargas, Alfonso; Lao-Villadóniga, José-Ignacio; García-Fructuoso, Ferrán; Ramos-Kuri, Manuel; Hernández, Fernando; Springall, Rashidi; Bojalil, Rafael; Vallejo, Maite; Martínez-Lavín, Manuel

    2007-01-01

    Autonomic dysfunction is frequent in patients with fibromyalgia (FM). Heart rate variability analyses have demonstrated signs of ongoing sympathetic hyperactivity. Catecholamines are sympathetic neurotransmitters. Catechol-O-methyltransferase (COMT), an enzyme, is the major catecholamine-clearing pathway. There are several single-nucleotide polymorphisms (SNPs) in the COMT gene associated with the different catecholamine-clearing abilities of the COMT enzyme. These SNPs are in linkage disequilibrium and segregate as 'haplotypes'. Healthy females with a particular COMT gene haplotype (ACCG) producing a defective enzyme are more sensitive to painful stimuli. The objective of our study was to define whether women with FM, from two different countries (Mexico and Spain), have the COMT gene haplotypes that have been previously associated with greater sensitivity to pain. All the individuals in the study were female. Fifty-seven Mexican patients and 78 Spanish patients were compared with their respective healthy control groups. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Six COMT SNPs (rs2097903, rs6269, rs4633, rs4818, rs4680, and rs165599) were genotyped from peripheral blood DNA. In Spanish patients, there was a significant association between three SNPs (rs6269, rs4818, and rs4680) and the presence of FM when compared with healthy controls. Moreover, in Spanish patients with the 'high pain sensitivity' haplotype (ACCG), the disease, as assessed by the FIQ, was more severe. By contrast, Mexican patients displayed only a weak association between rs6269 and rs165599, and some FIQ subscales. In our group of Spanish patients, there was an association between FM and the COMT haplotype previously associated with high pain sensitivity. This association was not observed in Mexican patients. Studies with a larger sample size are needed in order to verify or amend these preliminary results. PMID:17961261

  5. Genetic polymorphisms of catechol-O-methyltransferase modify the neurobehavioral effects of mercury in children.

    Science.gov (United States)

    Woods, James S; Heyer, Nicholas J; Russo, Joan E; Martin, Michael D; Pillai, Pradeep B; Bammler, Theodor K; Farin, Federico M

    2014-01-01

    Mercury (Hg) is neurotoxic and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. This study examined the hypothesis that genetic variants of catechol-O-methyltransferase (COMT) that are reported to alter neurobehavioral functions that are also affected by Hg in adults might modify the adverse neurobehavioral effects of Hg exposure in children. Five hundred and seven children, 8-12 yr of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at seven subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the clinical trial, genotyping assays were performed for single-nucleotide polymorphisms (SNPs) of COMT rs4680, rs4633, rs4818, and rs6269 on biological samples provided by 330 of the trial participants. Regression-modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Similar analysis was performed using haplotypes of COMT SNPs. Among girls, few interactions for Hg exposure and COMT variants were found. In contrast, among boys, numerous gene-Hg interactions were observed between individual COMT SNPs, as well as with a common COMT haplotype affecting multiple domains of neurobehavioral function. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with common genetic variants of COMT, and may have important implications for strategies aimed at protecting children from the potential health risks associated with Hg exposure.

  6. Catechol-O-Methyltransferase Deficiency Leads to Hypersensitivity of the Pressor Response Against Angiotensin II.

    Science.gov (United States)

    Ueki, Norikazu; Kanasaki, Keizo; Kanasaki, Megumi; Takeda, Satoru; Koya, Daisuke

    2017-06-01

    Catechol-O-methyltransferase (COMT) metabolizes 2-hydroxyestradiol into 2-methoxyestradiol (2-ME); COMT deficiency has shown to be associated with hypertension in men and preeclampsia, the disease associated with hypersensitivity of pressor response against angiotensin II (Ang II). Here, we found that COMT deficiency could explain the hypersensitivity of pressor response against Ang II in mice because of the lack of 2-ME-dependent suppression of angiotensin II receptor type 1 (AT1R). Male C57BL/6 mice were subjected to COMT inhibitor (COMTi: 25 mg/kg per day) or oil (control) for 4 weeks, with or without low-dose Ang II infusion (ANGII: 70 ng/kg per minute) for the last 3 weeks. The Ang II-infused mice were treated with 2-ME (10 ng/d) or vehicle for the last 1 week. We obtained the following experimental groups: control, ANGII, COMTi, COMTi+ANGII, and COMTi+ANGII+2-ME. We performed similar experiments using the in vivo administration of small interfering RNA of COMT instead of COMTi. Neither ANGII nor COMTi exhibited significant alterations in systolic blood pressure. Compared with ANGII or COMTi, COMTi+ANGII displayed significantly higher systolic blood pressure, albuminuria, and glomerular endotheliosis; 2-ME normalized such alterations. Similar phenotypes were observed in COMT small interfering RNA-treated mice. In the aorta of COMT-deficient mice, AT1R expression was increased; 2-ME suppressed AT1R expression. The 2-ME exhibited peroxisome proliferator-activated receptor γ agonistic activity in vitro and ex vivo plasma from pregnant female mice as well. In vitro, 2-ME suppressed both basal and Ang II-induced AT1R levels in a peroxisome proliferator-activated receptor γ-dependent manner. The 2-ME is relevant to combat COMT deficiency-associated hypertensive disorders via suppression of AT1R by its peroxisome proliferator-activated receptor γ activity. © 2017 American Heart Association, Inc.

  7. How metal substitution affects the enzymatic activity of catechol-o-methyltransferase.

    Directory of Open Access Journals (Sweden)

    Manuel Sparta

    Full Text Available Catechol-O-methyltransferase (COMT degrades catecholamines, such as dopamine and epinephrine, by methylating them in the presence of a divalent metal cation (usually Mg(II, and S-adenosyl-L-methionine. The enzymatic activity of COMT is known to be vitally dependent on the nature of the bound metal: replacement of Mg(II with Ca(II leads to a complete deactivation of COMT; Fe(II is slightly less than potent Mg(II, and Fe(III is again an inhibitor. Considering the fairly modest role that the metal plays in the catalyzed reaction, this dependence is puzzling, and to date remains an enigma. Using a quantum mechanical / molecular mechanical dynamics method for extensive sampling of protein structure, and first principle quantum mechanical calculations for the subsequent mechanistic study, we explicate the effect of metal substitution on the rate determining step in the catalytic cycle of COMT, the methyl transfer. In full accord with experimental data, Mg(II bound to COMT is the most potent of the studied cations and it is closely followed by Fe(II, whereas Fe(III is unable to promote catalysis. In the case of Ca(II, a repacking of the protein binding site is observed, leading to a significant increase in the activation barrier and higher energy of reaction. Importantly, the origin of the effect of metal substitution is different for different metals: for Fe(III it is the electronic effect, whereas in the case of Ca(II it is instead the effect of suboptimal protein structure.

  8. Catechol-O-methyltransferase Val158Met polymorphism influences prefrontal executive function in early Parkinson's disease.

    Science.gov (United States)

    Zhang, Youwen; Feng, Shujun; Nie, Kun; Zhao, Xin; Gan, Rong; Wang, Limin; Zhao, Jiehao; Tang, Hongmei; Gao, Liang; Zhu, Ruiming; Wang, Lijuan; Zhang, Yuhu

    2016-10-15

    The catechol-O-methyltransferase (COMT) Val158Met polymorphism has been proposed to be associated with increased risk of Parkinson's disease (PD) and have a specific impact on dopamine-mediated prefrontal executive function in an inverted-U curve manner. We explored the influence of this genetic polymorphism on prefrontal executive function in a well-established Chinese cohort of early PD patients with no current or past history of motor fluctuations or dyskinesias. Cognitive functions were assessed in 250 patients with early PD using Wechsler Adult Intelligence Scale-Chinese Revision (WAIS-RC) and Wechsler Memory Scale-Chinese Revision (WMS-RC). These patients and 300 healthy controls were subsequently genotyped for the COMT gene Val158Met polymorphism. We employed analysis of covariance (ANCOVA) and a stratified analysis to determine the associations between the COMT Val158Met genotype and cognitive functions. The COMT Val158Met allele frequency and genotype distributions showed no statistically significant differences between PD patients and controls. However, patients with met/met genotype performed significantly worse on WAIS-RC similarities, a measure of executive function, compared to individuals with val/val genotype. Subsequent ANCOVA analysis revealed that COMT genotype interacted with sex and daily levodopa equivalent dose (LED) to influence executive function. Further stratified analysis showed that the lower-activity COMT met/met genotype has a detrimental effect on executive function among women. Our results demonstrate that COMT Val158Met polymorphism is probably not associated with increased risk of PD, but has an effect on prefrontal executive function interacting with gender and dopaminergic medication. Copyright © 2016. Published by Elsevier B.V.

  9. Genetic Polymorphisms of Catechol-O-Methyltransferase: Association with Temporomandibular Disorders and Postoperative Pain.

    Science.gov (United States)

    Mladenovic, Irena; Supic, Gordana; Kozomara, Ruzica; Dodic, Slobodan; Ivkovic, Nedeljka; Milicevic, Bojana; Simic, Ivana; Magic, Zvonko

    2016-01-01

    To evaluate the association between catechol-O-methyltransferase (COMT) gene polymorphisms and temporomandibular disorders (TMD), TMD pain, psychosocial impairment related to TMD, and postoperative pain. A total of 90 patients with a diagnosis of painful TMD and 92 matched controls were investigated for the presence of TMD, TMD pain, and psychosocial variables by the Research Diagnostic Criteria for TMD. In a prospective cohort study of 40 subjects who underwent extraction of at least one fully impacted mandibular third molar, subjects had 6 months post-surgery follow-up of postoperative pain. DNA extracted from peripheral blood was genotyped for three COMT polymorphisms (rs4680, rs6269, and rs165774) by real-time TaqMan method. The association between COMT polymorphisms and clinical variables was determined by calculating odds ratios (OR) and their 95% confidence intervals (CI). Homozygous AA genotype and heterozygous variant A allele carriers (genotype AG/AA) for rs165774 polymorphism were associated with increased risk of TMD compared to wild type (wt) GG genotype (OR = 9.448, P = .006; OR = 2.088, P = .017, respectively). In addition, AA genotype was associated with increased risk of arthralgia (OR = 4.448, P = .011), myofascial pain (OR = 3.543, P = .035), and chronic TMD pain (OR = 6.173, P = .006), compared to wt genotype. AA genotype for rs6269 polymorphism was related to less postoperative chronic TMD pain (P = .025) and lower postoperative acute pain at the extraction site (P = .030). No associations with depression and somatization were observed. AA genotype of rs165774 could be a significant risk factor for the development of TMD and TMD pain, while AA genotype of rs6269 presents less postoperative chronic TMD pain and acute pain at a dental extraction site.

  10. Catechol-O-Methyltransferase Genotype and Gait Speed Changes over 10 Years in Older Adults.

    Science.gov (United States)

    Metti, Andrea L; Rosano, Caterina; Boudreau, Robert; Massa, Robyn; Yaffe, Kristine; Satterfield, Suzanne; Harris, Tamara; Rosso, Andrea L

    2017-09-01

    To determine the association between catechol-O-methyltransferase (COMT) genotype and 6-m walk time and to determine whether these associations are quadratic in nature, similar to previously reported U-shaped associations between dopamine and gait and cognition. Prospective cohort study. Health, Aging and Body Composition Study. Black (n = 850) and white (n = 1,352) men and women with a mean age of 73.5 ± 2.85 at baseline. Mixed models were used to assess the association between the COMT genotype and 6-m walk time, cross-sectionally and longitudinally over 10 years. Models were assessed unstratified and stratified according to race because allele distributions were different between white and black participants. There was a significant U-shaped association between COMT genotype and 6-m walk time: those with higher (Val/Val) and lower (Met/Met) dopamine slowed more over 10 years (0.22 ± 0.02 seconds per visit and 0.23 ± 0.02 seconds per visit, respectively) than those with the intermediate (Met/Val) dopamine (0.20 ± 0.02 seconds per visit) (P = .005). Stratified results showed a significant relationship in black (P = .01) but not white (P = .15) participants. These findings indicate a role of dopaminergic regulation of gait speed in community-dwelling older adults and of prefrontal cortex involvement in gait performance. Future work should investigate the molecular integrity of dopaminergic networks and gait changes over time and structural changes in the brain with COMT and gait decline in older adults. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

  11. A novel catechol-O-methyltransferase variant associated with human disc degeneration.

    Science.gov (United States)

    Gruber, Helen E; Sha, Wei; Brouwer, Cory R; Steuerwald, Nury; Hoelscher, Gretchen L; Hanley, Edward N

    2014-01-01

    Disc degeneration and its associated low back pain are a major health care concern causing disability with a prominent role in this country's medical, social and economic structure. Low back pain is devastating and influences the quality of life for millions. Low back pain lifetime prevalence approximates 80% with an estimated direct cost burden of $86 billion per year. Back pain patients incur higher costs, greater health care utilization, and greater work loss than patients without back pain. Research was performed following approval of our Institutional Review Board. DNA was isolated, processed and amplified using routine techniques. Amplified DNA was hybridized to Affymetrix Genome-Wide Human SNP Arrays. Quality control and genotyping analysis were performed using Affymetrix Genotyping Console. The Birdseed v2 algorithm was used for genotyping analysis. 2589 SNPs were selected a priori to enter statistical analysis using lotistic regression in SAS. Our objective was to search for novel single nucleotide polymorphisms (SNPs) associated with disc degeneration. Four SNPs were found to have a significant relationship to disc degeneration; three are novel. Rs165656, a new SNP found to be associated with disc degeneration, was in catechol-O-methyltransferase (COMT), a gene with well-recognized pain involvement, especially in female subjects (p=0.01). Analysis confirmed the previously association between COMT SNP rs4633 and disc degeneration. We also report two novel disc degeneration-related SNPs (rs2095019 and rs470859) located in intergenic regions upstream to thrombospondin 2. Findings contribute to the challenging field of disc degeneration and pain, and are important in light of the high clinical relevance of low back pain and the need for improved understanding of its fundamental basis.

  12. Catechol-O-methyltransferase Gene Polymorphism (Val158Met) and Development of Pre-eclampsia.

    Science.gov (United States)

    Taravati, Ali; Tohidi, Fatemeh; Moniri, Mehrnaz; Kamali, Kasra

    2017-02-01

    Catechol-O-methyltransferase (COMT) is a key enzyme in degradation pathways of estrogens and catecholamines. The present meta-analysis was done to elucidate the association of COMT Val158Met polymorphism with pre-eclampsia among pregnant women. A literature search was conducted in electronic databases including PubMed, Scopus, Elsevier, Springer and Google Scholar to find eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals were calculated under dominant, recessive, co-dominant, and allelic models. This meta-analysis included 6 eligible studies consisting 2596 cases and 4223 controls. The ORs for the COMT G472A polymorphism and pre-eclampsia were indicative of positive association under several genetic models. The results indicated that COMT Val158Met polymorphism was significantly associated with the increased risk of pre-eclampsia in recessive model (AA vs. AG + GG: OR = 1.522 [95% CI: 1.089-2.127]; p = 0.014), co-dominant model (AA vs. GG: OR = 1.605 [95% CI: 1.102-2.336]; p = 0.014), and allelic model (A vs. T: OR = 1.200 [95% CI: 1.021-1.402]; p = 0.021). In summary, COMT Val158Met polymorphism is positively associated with the increased risk of pre-eclampsia among pregnant women, especially the homozygous carriers. It could be of value to investigate its association with pre-eclampsia in combination with additional risk factors. However, very large studies with different ethnic population are required to accurately demonstrate the role of this candidate gene in development of pre-eclampsia. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

  13. Effect of a natural mineral-rich water on catechol-O-methyltransferase function.

    Science.gov (United States)

    Bastos, Pedro; Araújo, João Ricardo; Azevedo, Isabel; Martins, Maria João; Ribeiro, Laura

    2014-01-01

    Catechol-O-methyltransferase (COMT) is a magnesium-dependent, catecholamine-metabolizing enzyme, whose impaired activity has been positively associated with cardiovascular diseases, particularly hypertension. Consumption of some natural mineral-rich waters has been shown to exert protective effects on cardiovascular risk factors, eg. by decreasing arterial blood pressure and blood lipids. However, the molecular mechanisms underlying these effects are still poorly understood. So, the aim of this work was to investigate the effect of natural mineral-rich water ingestion upon liver and adrenal glands COMT expression and activity in Wistar Han rats. Over a seven-week period, animals had access to one of the following three drinking solutions: 1) tap water (control group; TW), 2) tap water with added Na(+) (to make the same concentration as in the MW group (TWNaCl group), or 3) natural mineral-rich water [Pedras Salgadas(®), which is very rich in bicarbonate, and with higher sodium, calcium and magnesium content than control tap water (MW group)]. COMT expression and activity were determined by RT-PCR and HPLC-ED, respectively. A higher hepatic COMT activity was found in the MW group compared with the TW and TWNaCl groups. On the other hand, adrenal gland COMT mRNA expression decreased in the MW group compared to TW group. In conclusion, the ability of natural mineral-rich waters to increase hepatic COMT activity may eventually explain the positive cardiovascular effects associated with the consumption of some natural mineral-rich waters.

  14. The Role of Catechol-O-Methyltransferase (COMT Gene in the Etiopathogenesis of Schizophrenia

    Directory of Open Access Journals (Sweden)

    Ceren Acar

    2014-09-01

    Full Text Available Genetic factors in the risk of developing schizophrenia is of great importance. With the help of the advances in the field of genetics in recent years by using linkage analysis several genes have been identified that may be a risk factor in schizophrenia. Several association studies have been performed in many different populations on the candidate susceptibility genes that were defined in previous studies. However, these studies give controversial results in different countries with different populations, and there are problems in obtaining replicable results. In this review we aimed to focus on the genetic basis of schizophrenia and the relationship between schizophrenia and catechol-O-methyltransferase (COMT gene. COMT encodes an enzyme molecule which has an important function in dopamine pathways. It has great importance in catecholamine metabolism and pharmacology and genetic mechanism of catechol metabolism variations and their clinical consequences. COMT transfers the methyl group from S-adenosyl-methionine to the hydroxyl group of catechol nucleus (such as dopamine, norepinephrine or catechol estrogen. Genetic variations found in COMT gene are associated with a broad spectrum of clinical phenotype including psychiatric disorders or estrogen related cancers. Several groups have performed studies on the relationship between schizophrenia and COMT. The most commonly studied polymorphism in COMT gene is rs4680 and it causes a valine methionine conversion at codon 158. The association studies on this polymorphism in different populations gave both positive and negative results. Schizoprenia is a complex disease caused by the interaction of environmental and genetic factors, while interpreting the genetic data, this fact and the possibility of the presence of different gene products should be taken into account. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2014; 6(3.000: 217-226

  15. Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs.

    Directory of Open Access Journals (Sweden)

    Andrea G Nackley

    Full Text Available Catechol-O-methyltransferase (COMT is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val(158met position, designated as low (LPS, average (APS, and high pain sensitive (HPS, are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions. APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively. In the present study, we investigated whether additional minor single nucleotide polymorphisms (SNPs, accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity. Computer analysis of COMT ESTs showed that one synonymous minor SNP (rs769224 is linked to the APS haplotype and three minor SNPs (two synonymous: rs6267, rs740602 and one nonsynonymous: rs8192488 are linked to the HPS haplotype. Results from in silico and in vitro experiments revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzymatic activity. These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation. Thus, both minor synonymous and nonsynonymous SNPs in the coding region are markers of functional APS and HPS haplotypes rather than independent contributors to COMT activity.

  16. How Metal Substitution Affects the Enzymatic Activity of Catechol-O-Methyltransferase

    Science.gov (United States)

    Sparta, Manuel; Alexandrova, Anastassia N.

    2012-01-01

    Catechol-O-methyltransferase (COMT) degrades catecholamines, such as dopamine and epinephrine, by methylating them in the presence of a divalent metal cation (usually Mg(II)), and S-adenosyl-L-methionine. The enzymatic activity of COMT is known to be vitally dependent on the nature of the bound metal: replacement of Mg(II) with Ca(II) leads to a complete deactivation of COMT; Fe(II) is slightly less than potent Mg(II), and Fe(III) is again an inhibitor. Considering the fairly modest role that the metal plays in the catalyzed reaction, this dependence is puzzling, and to date remains an enigma. Using a quantum mechanical / molecular mechanical dynamics method for extensive sampling of protein structure, and first principle quantum mechanical calculations for the subsequent mechanistic study, we explicate the effect of metal substitution on the rate determining step in the catalytic cycle of COMT, the methyl transfer. In full accord with experimental data, Mg(II) bound to COMT is the most potent of the studied cations and it is closely followed by Fe(II), whereas Fe(III) is unable to promote catalysis. In the case of Ca(II), a repacking of the protein binding site is observed, leading to a significant increase in the activation barrier and higher energy of reaction. Importantly, the origin of the effect of metal substitution is different for different metals: for Fe(III) it is the electronic effect, whereas in the case of Ca(II) it is instead the effect of suboptimal protein structure. PMID:23056605

  17. Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Lachman, H.M.; Papolos, D.F.; Veit, S. [Albert Einstein College of Medicine, Bronx, NY (United States)] [and others

    1996-09-20

    Velo-cardio-facial-syndrome (VCFS) is a common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. The majority of patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. The psychiatric manifestations of VCFS could be due to haploinsufficiency of a gene(s) within 22q11. One candidate that has been mapped to this region is catechol-O-methyltransferase (COMT). We recently identified a polymorphism in the COMT gene that leads to a valine{r_arrow}methionine substitution at amino acid 158 of the membrane-bound form of the enzyme. Homozygosity for COMT158{sup met} leads to a 3- to 4-fold reduction in enzymatic activity, compared with homozygotes for COMT158{sup met}. We now report that in a population of patients with VCFS, there is an apparent association between the low-activity allele, COMT158{sup met}, and the development of bipolar spectrum disorder, and in particular, a rapid-cycling form. 33 refs., 3 tabs.

  18. Crystal Structure and Functional Analysis of the SARS-Coronavirus RNA Cap 2′-O-Methyltransferase nsp10/nsp16 Complex

    Science.gov (United States)

    Decroly, Etienne; Debarnot, Claire; Ferron, François; Bouvet, Mickael; Coutard, Bruno; Imbert, Isabelle; Gluais, Laure; Papageorgiou, Nicolas; Sharff, Andrew; Bricogne, Gérard; Ortiz-Lombardia, Miguel; Lescar, Julien; Canard, Bruno

    2011-01-01

    Cellular and viral S-adenosylmethionine-dependent methyltransferases are involved in many regulated processes such as metabolism, detoxification, signal transduction, chromatin remodeling, nucleic acid processing, and mRNA capping. The Severe Acute Respiratory Syndrome coronavirus nsp16 protein is a S-adenosylmethionine-dependent (nucleoside-2′-O)-methyltransferase only active in the presence of its activating partner nsp10. We report the nsp10/nsp16 complex structure at 2.0 Å resolution, which shows nsp10 bound to nsp16 through a ∼930 Å2 surface area in nsp10. Functional assays identify key residues involved in nsp10/nsp16 association, and in RNA binding or catalysis, the latter likely through a SN2-like mechanism. We present two other crystal structures, the inhibitor Sinefungin bound in the S-adenosylmethionine binding pocket and the tighter complex nsp10(Y96F)/nsp16, providing the first structural insight into the regulation of RNA capping enzymes in (+)RNA viruses. PMID:21637813

  19. Molecular Mapping of the RNA Cap 2′-O-Methyltransferase Activation Interface between Severe Acute Respiratory Syndrome Coronavirus nsp10 and nsp16*

    Science.gov (United States)

    Lugari, Adrien; Betzi, Stephane; Decroly, Etienne; Bonnaud, Emmanuel; Hermant, Aurélie; Guillemot, Jean-Claude; Debarnot, Claire; Borg, Jean-Paul; Bouvet, Mickaël; Canard, Bruno; Morelli, Xavier; Lécine, Patrick

    2010-01-01

    Several protein-protein interactions within the SARS-CoV proteome have been identified, one of them being between non-structural proteins nsp10 and nsp16. In this work, we have mapped key residues on the nsp10 surface involved in this interaction. Alanine-scanning mutagenesis, bioinformatics, and molecular modeling were used to identify several “hot spots,” such as Val42, Met44, Ala71, Lys93, Gly94, and Tyr96, forming a continuous protein-protein surface of about 830 Å2, bearing very conserved amino acids among coronaviruses. Because nsp16 carries RNA cap 2′-O-methyltransferase (2′O-MTase) activity only in the presence of its interacting partner nsp10 (Bouvet, M., Debarnot, C., Imbert, I., Selisko, B., Snijder, E. J., Canard, B., and Decroly, E. (2010) PLoS Pathog. 6, e1000863), functional consequences of mutations on this surface were evaluated biochemically. Most changes that disrupted the nsp10-nsp16 interaction without structural perturbations were shown to abrogate stimulation of nsp16 RNA cap 2′O-MTase activity. More strikingly, the Y96A mutation abrogates stimulation of nsp16 2′O-MTase activity, whereas Y96F overstimulates it. Thus, the nsp10-nsp16 interface may represent an attractive target for antivirals against human and animal pathogenic coronaviruses. PMID:20699222

  20. Molecular mapping of the RNA Cap 2'-O-methyltransferase activation interface between severe acute respiratory syndrome coronavirus nsp10 and nsp16.

    Science.gov (United States)

    Lugari, Adrien; Betzi, Stephane; Decroly, Etienne; Bonnaud, Emmanuel; Hermant, Aurélie; Guillemot, Jean-Claude; Debarnot, Claire; Borg, Jean-Paul; Bouvet, Mickaël; Canard, Bruno; Morelli, Xavier; Lécine, Patrick

    2010-10-22

    Several protein-protein interactions within the SARS-CoV proteome have been identified, one of them being between non-structural proteins nsp10 and nsp16. In this work, we have mapped key residues on the nsp10 surface involved in this interaction. Alanine-scanning mutagenesis, bioinformatics, and molecular modeling were used to identify several "hot spots," such as Val(42), Met(44), Ala(71), Lys(93), Gly(94), and Tyr(96), forming a continuous protein-protein surface of about 830 Å(2), bearing very conserved amino acids among coronaviruses. Because nsp16 carries RNA cap 2'-O-methyltransferase (2'O-MTase) activity only in the presence of its interacting partner nsp10 (Bouvet, M., Debarnot, C., Imbert, I., Selisko, B., Snijder, E. J., Canard, B., and Decroly, E. (2010) PLoS Pathog. 6, e1000863), functional consequences of mutations on this surface were evaluated biochemically. Most changes that disrupted the nsp10-nsp16 interaction without structural perturbations were shown to abrogate stimulation of nsp16 RNA cap 2'O-MTase activity. More strikingly, the Y96A mutation abrogates stimulation of nsp16 2'O-MTase activity, whereas Y96F overstimulates it. Thus, the nsp10-nsp16 interface may represent an attractive target for antivirals against human and animal pathogenic coronaviruses.

  1. Crystal structure and functional analysis of the SARS-coronavirus RNA cap 2'-O-methyltransferase nsp10/nsp16 complex.

    Directory of Open Access Journals (Sweden)

    Etienne Decroly

    2011-05-01

    Full Text Available Cellular and viral S-adenosylmethionine-dependent methyltransferases are involved in many regulated processes such as metabolism, detoxification, signal transduction, chromatin remodeling, nucleic acid processing, and mRNA capping. The Severe Acute Respiratory Syndrome coronavirus nsp16 protein is a S-adenosylmethionine-dependent (nucleoside-2'-O-methyltransferase only active in the presence of its activating partner nsp10. We report the nsp10/nsp16 complex structure at 2.0 Å resolution, which shows nsp10 bound to nsp16 through a ∼930 Ų surface area in nsp10. Functional assays identify key residues involved in nsp10/nsp16 association, and in RNA binding or catalysis, the latter likely through a SN2-like mechanism. We present two other crystal structures, the inhibitor Sinefungin bound in the S-adenosylmethionine binding pocket and the tighter complex nsp10(Y96F/nsp16, providing the first structural insight into the regulation of RNA capping enzymes in +RNA viruses.

  2. Crystal structure and functional analysis of the SARS-coronavirus RNA cap 2'-O-methyltransferase nsp10/nsp16 complex.

    Science.gov (United States)

    Decroly, Etienne; Debarnot, Claire; Ferron, François; Bouvet, Mickael; Coutard, Bruno; Imbert, Isabelle; Gluais, Laure; Papageorgiou, Nicolas; Sharff, Andrew; Bricogne, Gérard; Ortiz-Lombardia, Miguel; Lescar, Julien; Canard, Bruno

    2011-05-01

    Cellular and viral S-adenosylmethionine-dependent methyltransferases are involved in many regulated processes such as metabolism, detoxification, signal transduction, chromatin remodeling, nucleic acid processing, and mRNA capping. The Severe Acute Respiratory Syndrome coronavirus nsp16 protein is a S-adenosylmethionine-dependent (nucleoside-2'-O)-methyltransferase only active in the presence of its activating partner nsp10. We report the nsp10/nsp16 complex structure at 2.0 Å resolution, which shows nsp10 bound to nsp16 through a ∼930 Ų surface area in nsp10. Functional assays identify key residues involved in nsp10/nsp16 association, and in RNA binding or catalysis, the latter likely through a SN2-like mechanism. We present two other crystal structures, the inhibitor Sinefungin bound in the S-adenosylmethionine binding pocket and the tighter complex nsp10(Y96F)/nsp16, providing the first structural insight into the regulation of RNA capping enzymes in +RNA viruses.

  3. Determination of catechol-O-methyltransferase activity in brain tissue by high-performance liquid chromatography with on-line radiochemical detection

    Energy Technology Data Exchange (ETDEWEB)

    Nissinen, E.

    1985-01-01

    A sensitive assay for catechol-O-methyltransferase (COMT) activity by high-performance liquid chromatography with on-line radiochemical detection was described. The method was based on the measurement of /sup 3/H- labeled 3-O- and 4-O-methylated products of the substrate, 3,4- dihydroxybenzoic acid, using S-adenosyl-L-(methyl-/sup 3/H)methionine as the methyl donor, or the measurement of /sup 14/C-labeled 3-O- and 4-O-methylated products of the substrate, (7-/sup 14/C)dopamine. The reaction products were determined from the incubation mixture after removal of protein by injecting an aliquot into the liquid chromatograph. The detection limit with counting efficiency of 40% was 0.45 pmol /sup 3/H-labeled product, and 0. 04 pmol /sup 14/C-labeled product with 61% counting efficiency. The method is suitable for assaying membrane-bound and soluble COMT activities in the brain tissue and for calculation of meta/para product ratios.

  4. Current understanding of the interplay between catechol-O-methyltransferase genetic variants, sleep, brain development and cognitive performance in schizophrenia.

    Science.gov (United States)

    Tucci, Valter; Lassi, Glenda; Kas, Martien J

    2012-05-01

    Abnormal sleep is an endophenotype of schizophrenia. Here we provide an overview of the genetic mechanisms that link specific sleep physiological processes to schizophrenia-related cognitive defects. In particular, we will review the possible relationships between catechol-O-methyltransferase (COMT), sleep regulation and schizophrenia development. Recent studies validate the hypothesis that COMT mutations may trigger disturbances during adolescence that affect sleep and cortical development. Anomalies in cortical development during this critical developmental phase may increase the susceptibility for schizophrenia. In conclusion, in view of therapeutic efficacy, we can envisage indications for future investigations into the role of COMT for sleep regulation, cognitive performance and sleep-related cognitive deficits.

  5. Effects of Active-Site Modification and Quaternary Structure on the Regioselectivity of Catechol-O-Methyltransferase.

    Science.gov (United States)

    Law, Brian J C; Bennett, Matthew R; Thompson, Mark L; Levy, Colin; Shepherd, Sarah A; Leys, David; Micklefield, Jason

    2016-02-18

    Catechol-O-methyltransferase (COMT), an important therapeutic target in the treatment of Parkinson's disease, is also being developed for biocatalytic processes, including vanillin production, although lack of regioselectivity has precluded its more widespread application. By using structural and mechanistic information, regiocomplementary COMT variants were engineered that deliver either meta- or para-methylated catechols. X-ray crystallography further revealed how the active-site residues and quaternary structure govern regioselectivity. Finally, analogues of AdoMet are accepted by the regiocomplementary COMT mutants and can be used to prepare alkylated catechols, including ethyl vanillin. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  6. Attenuation and Restoration of Severe Acute Respiratory Syndrome Coronavirus Mutant Lacking 2′-O-Methyltransferase Activity

    OpenAIRE

    Menachery, Vineet D.; Yount, Boyd L.; Josset, Laurence; Gralinski, Lisa E.; Scobey, Trevor; Agnihothram, Sudhakar; Katze, Michael G.; Baric, Ralph S.

    2014-01-01

    The sudden emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and, more recently, Middle Eastern respiratory syndrome CoV (MERS-CoV) underscores the importance of understanding critical aspects of CoV infection and pathogenesis. Despite significant insights into CoV cross-species transmission, replication, and virus-host interactions, successful therapeutic options for CoVs do not yet exist. Recent identification of SARS-CoV NSP16 as a viral 2′-O-methyltransferase (...

  7. Crystal structures of human 108V and 108M catechol O-methyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Rutherford, K.; Le Trong, I.; Stenkamp, R.E.; Parson, W.W. (UWASH)

    2008-08-01

    Catechol O-methyltransferase (COMT) plays important roles in the metabolism of catecholamine neurotransmitters and catechol estrogens. The development of COMT inhibitors for use in the treatment of Parkinson's disease has been aided by crystallographic structures of the rat enzyme. However, the human and rat proteins have significantly different substrate specificities. Additionally, human COMT contains a common valine-methionine polymorphism at position 108. The methionine protein is less stable than the valine polymorph, resulting in decreased enzyme activity and protein levels in vivo. Here we describe the crystal structures of the 108V and 108M variants of the soluble form of human COMT bound with S-adenosylmethionine (SAM) and a substrate analog, 3,5-dinitrocatechol. The polymorphic residue 108 is located in the {alpha}5-{beta}3 loop, buried in a hydrophobic pocket {approx}16 {angstrom} from the SAM-binding site. The 108V and 108M structures are very similar overall [RMSD of C{sup {alpha}} atoms between two structures (C{sup {alpha}} RMSD) = 0.2 {angstrom}], and the active-site residues are superposable, in accord with the observation that SAM stabilizes 108M COMT. However, the methionine side chain is packed more tightly within the polymorphic site and, consequently, interacts more closely with residues A22 ({alpha}2) and R78 ({alpha}4) than does valine. These interactions of the larger methionine result in a 0.7-{angstrom} displacement in the backbone structure near residue 108, which propagates along {alpha}1 and {alpha}5 toward the SAM-binding site. Although the overall secondary structures of the human and rat proteins are very similar (C{sup {alpha}} RMSD = 0.4 {angstrom}), several nonconserved residues are present in the SAM-(I89M, I91M, C95Y) and catechol- (C173V, R201M, E202K) binding sites. The human protein also contains three additional solvent-exposed cysteine residues (C95, C173, C188) that may contribute to intermolecular disulfide bond

  8. Persistent Catechol-O-methyltransferase-dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors.

    Science.gov (United States)

    Ciszek, Brittney P; O'Buckley, Sandra C; Nackley, Andrea G

    2016-05-01

    Patients with chronic pain disorders exhibit increased levels of catecholamines alongside diminished activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. The authors found that acute pharmacologic inhibition of COMT in rodents produces hypersensitivity to mechanical and thermal stimuli via β-adrenergic receptor (βAR) activation. The contribution of distinct βAR populations to the development of persistent pain linked to abnormalities in catecholamine signaling requires further investigation. Here, the authors sought to determine the contribution of peripheral, spinal, and supraspinal βARs to persistent COMT-dependent pain. They implanted osmotic pumps to deliver the COMT inhibitor OR486 (Tocris, USA) for 2 weeks. Behavioral responses to mechanical and thermal stimuli were evaluated before and every other day after pump implantation. The site of action was evaluated in adrenalectomized rats receiving sustained OR486 or in intact rats receiving sustained βAR antagonists peripherally, spinally, or supraspinally alongside OR486. The authors found that male (N = 6) and female (N = 6) rats receiving sustained OR486 exhibited decreased paw withdrawal thresholds (control 5.74 ± 0.24 vs. OR486 1.54 ± 0.08, mean ± SEM) and increased paw withdrawal frequency to mechanical stimuli (control 4.80 ± 0.22 vs. OR486 8.10 ± 0.13) and decreased paw withdrawal latency to thermal heat (control 9.69 ± 0.23 vs. OR486 5.91 ± 0.11). In contrast, adrenalectomized rats (N = 12) failed to develop OR486-induced hypersensitivity. Furthermore, peripheral (N = 9), but not spinal (N = 4) or supraspinal (N = 4), administration of the nonselective βAR antagonist propranolol, the β2AR antagonist ICI-118,511, or the β3AR antagonist SR59230A blocked the development of OR486-induced hypersensitivity. Peripheral adrenergic input is necessary for the development of persistent COMT-dependent pain, and peripherally-acting βAR antagonists may benefit

  9. Molecular cloning and functional characterization of a novel isoflavone 3′-O-methyltransferase from Pueraria lobata

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    Jia eLi

    2016-06-01

    Full Text Available Pueraria lobata roots accumulate 3′-, 4′- and 7-O-methylated isoflavones and many of these methylated compounds exhibit various pharmacological activities. Either the 4′- or 7-O-methylation activity has been investigated at molecular levels in several legume species. However, the gene encoding the isoflavone 3′-O-methyltransferase has not yet been isolated from any plant species. In this study, we reported the first cDNA encoding the isoflavone 3′-O-methyltransferase from P. lobata (designated PlOMT4. Heterologous expressions in yeast and Escherichia coli cells showed that the gene product exhibits an enzyme activity to methylate the 3′-hydroxy group of the isoflavone substrate. The transcript abundance of PlOMT4 matches well with its enzymatic product in different organs of P. lobata and in the plant roots in response to methyl jasmonate elicitation. Integration of the biochemical with metabolic and transcript data supported the proposed function of PlOMT4. The identification of PlOMT4 would not only help to understand the isoflavonoid metabolism in P. lobata but also potentially provide an enzyme catalyst for methylating existing drug candidates to improve their hydrophobicity.

  10. Inactivation of pea genes by RNAi supports the involvement of two similar O-methyltransferases in the biosynthesis of (+)-pisatin and of chiral intermediates with a configuration opposite that found in (+)-pisatin.

    Science.gov (United States)

    Kaimoyo, Evans; VanEtten, Hans D

    2008-01-01

    (+)-Pisatin, the major phytoalexin of pea (Pisum sativum L.), is believed to be synthesized via two chiral intermediates, (-)-7,2'-dihydroxy-4',5'-methylenedioxyisoflavanone [(-)-sophorol] and (-)-7,2'-dihydroxy-4',5'-methylenedioxyisoflavanol [(-)-DMDI]; both have an opposite C-3 absolute configuration to that found at C-6a in (+)-pisatin. The expression of isoflavone reductase (IFR), which converts 7,2'-dihydroxy-4',5'-methylenedioxyisoflavone (DMD) to (-)-sophorol, sophorol reductase (SOR), which converts (-)-sophorol to (-)-DMDI, and hydroxymaackiain-3-O-methyltransferase (HMM), believed to be the last step of (+)-pisatin biosynthesis, were inactivated by RNA-mediated genetic interference (RNAi) in pea hairy roots. Some hairy root lines containing RNAi constructs of IFR and SOR accumulated DMD or (-)-sophorol, respectively, and were deficient in (+)-pisatin biosynthesis supporting the involvement of chiral intermediates with a configuration opposite to that found in (+)-pisatin in the biosynthesis of (+)-pisatin. Pea proteins also converted (-)-DMDI to an achiral isoflavene suggesting that an isoflavene might be the intermediate through which the configuration is changed to that found in (+)-pisatin. Hairy roots containing RNAi constructs of HMM also were deficient in (+)-pisatin biosynthesis, but did not accumulate (+)-6a-hydroxymaackiain, the proposed precursor to (+)-pisatin. Instead, 2,7,4'-trihydroxyisoflavanone (TIF), daidzein, isoformononetin, and liquiritigenin accumulated. HMM has a high amino acid similarity to hydroxyisoflavanone-4'-O-methyltransferase (HI4'OMT), an enzyme that methylates TIF, an early intermediate in the isoflavonoid pathway. The accumulation of these four compounds is consistent with the blockage of the synthesis of (+)-pisatin at the HI4'OMT catalyzed step resulting in the accumulation of liquiritigenin and TIF and the diversion of the pathway to produce daidzein and isoformononetin, compounds not normally made by pea. Previous

  11. Pathway engineering for phenolic acid accumulations in Salvia miltiorrhiza by combinational genetic manipulation.

    Science.gov (United States)

    Zhang, Yuan; Yan, Ya-Ping; Wu, Yu-Cui; Hua, Wen-Ping; Chen, Chen; Ge, Qian; Wang, Zhe-Zhi

    2014-01-01

    To produce beneficial phenolic acids for medical and commercial purposes, researchers are interested in improving the normally low levels of salvianolic acid B (Sal B) produced by Salvia miltiorrhiza. Here, we present a strategy of combinational genetic manipulation to enrich the precursors available for Sal B biosynthesis. This approach, involving the lignin pathway, requires simultaneous, ectopic expression of an Arabidopsis Production of Anthocyanin Pigment 1 transcription factor (AtPAP1) plus co-suppression of two endogenous, key enzyme genes: cinnamoyl-CoA reductase (SmCCR) and caffeic acid O-methyltransferase (SmCOMT). Compared with the untransformed control, we achieved a greater accumulation of Sal B (up to 3-fold higher) along with a reduced lignin concentration. This high-Sal B phenotype was stable in roots during vegetative growth and was closely correlated with increased antioxidant capacity for the corresponding plant extracts. Although no outward change in phenotype was apparent, we characterized the molecular phenotype through integrated analysis of transcriptome and metabolome profiling. Our results demonstrated the far-reaching consequences of phenolic pathway perturbations on carbohydrate metabolism, respiration, photo-respiration, and stress responses. This report is the first to describe the production of valuable end products through combinational genetic manipulation in S. miltiorrhiza plants. Our strategy will be effective in efforts to metabolically engineer multi-branch pathway(s), such as the phenylpropanoid pathway, in economically significant medicinal plants. © 2013 International Metabolic Engineering Society Published by International Metabolic Engineering Society All rights reserved.

  12. Short peptides derived from the interaction domain of SARS coronavirus nonstructural protein nsp10 can suppress the 2'-O-methyltransferase activity of nsp10/nsp16 complex.

    Science.gov (United States)

    Ke, Min; Chen, Yu; Wu, Andong; Sun, Ying; Su, Ceyang; Wu, Hao; Jin, Xu; Tao, Jiali; Wang, Yi; Ma, Xiao; Pan, Ji-An; Guo, Deyin

    2012-08-01

    Coronaviruses are the etiological agents of respiratory and enteric diseases in humans and livestock, exemplified by the life-threatening severe acute respiratory syndrome (SARS) caused by SARS coronavirus (SARS-CoV). However, effective means for combating coronaviruses are still lacking. The interaction between nonstructural protein (nsp) 10 and nsp16 has been demonstrated and the crystal structure of SARS-CoV nsp16/10 complex has been revealed. As nsp10 acts as an essential trigger to activate the 2'-O-methyltransferase activity of nsp16, short peptides derived from nsp10 may have inhibitory effect on viral 2'-O-methyltransferase activity. In this study, we revealed that the domain of aa 65-107 of nsp10 was sufficient for its interaction with nsp16 and the region of aa 42-120 in nsp10, which is larger than the interaction domain, was needed for stimulating the nsp16 2'-O-methyltransferase activity. We further showed that two short peptides derived from the interaction domain of nsp10 could inhibit the 2'-O-methyltransferase activity of SARS-CoV nsp16/10 complex, thus providing a novel strategy and proof-of-principle study for developing peptide inhibitors against SARS-CoV. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Catechol-O-Methyltransferase "Val[superscript 158]Met" Genotype, Parenting Practices and Adolescent Alcohol Use: Testing the Differential Susceptibility Hypothesis

    Science.gov (United States)

    Laucht, Manfred; Blomeyer, Dorothea; Buchmann, Arlette F.; Treutlein, Jens; Schmidt, Martin H.; Esser, Gunter; Jennen-Steinmetz, Christine; Rietschel, Marcella; Zimmermann, Ulrich S.; Banaschewski, Tobias

    2012-01-01

    Background: Recently, first evidence has been reported for a gene-parenting interaction (G x E) with regard to adolescent alcohol use. The present investigation set out to extend this research using the catechol-O-methyltransferase ("COMT") "Val[superscript 158]Met" polymorphism as a genetic susceptibility factor. Moreover, the current study…

  14. Catechol-O-methyltransferase Val 108/158 Met polymorphism and breast cancer risk: a case control study in Syria.

    Science.gov (United States)

    Lajin, Bassam; Hamzeh, Abdul Rezzak; Ghabreau, Lina; Mohamed, Ali; Al Moustafa, Ala-Eddin; Alachkar, Amal

    2013-01-01

    Catechol-O-methyltransferase (COMT) inactivates catechol estrogens by methylation and thus may play a protective role against mutations induced by estrogen metabolites. In this study we investigated the relationship between the Vall58Met polymorphism in the COMT gene and breast cancer risk in a population-based case control study in Syria. We examined 135 breast cancer patients and 107 healthy controls in North Syria to determine the association between the functional genetic Val158Met polymorphism in the COMT gene and female breast cancer risk. There was no significant overall association between the COMT genotype and individual susceptibility to breast cancer. Our data suggest that there may be no overall association between the COMT genotype and breast cancer.

  15. Virtual screening and bioassay study of novel inhibitors for dengue virus mRNA cap (nucleoside-2'O)-methyltransferase.

    Science.gov (United States)

    Luzhkov, Victor B; Selisko, Barbara; Nordqvist, Anneli; Peyrane, Frédéric; Decroly, Etienne; Alvarez, Karine; Karlen, Anders; Canard, Bruno; Qvist, Johan

    2007-12-15

    We report high-throughput structure-based virtual screening of putative Flavivirus 2'-O-methyltransferase inhibitors together with results from subsequent bioassay tests of selected compounds. Potential inhibitors for the S-adenosylmethionine binding site were explored using 2D similarity searching, pharmacophore filtering and docking. The inhibitory activities of 15 top-ranking compounds from the docking calculations were tested on a recombinant methyltransferase with the RNA substrate (7Me)GpppAC(5). Local and global docking simulations were combined to estimate the ligand selectivity for the target site. The results of the combined computational and experimental screening identified a novel inhibitor, with a previously unknown scaffold, that has an IC(50) value of 60 microM.

  16. Interactions Between Early Trauma and Catechol-O-Methyltransferase Genes on Inhibitory Deficits in Children With ADHD.

    Science.gov (United States)

    Park, Subin; Kim, Bung-Nyun; Kim, Jae-Won; Shin, Min-Sup; Yoo, Hee Jeong; Cho, Soo-Churl

    2017-02-01

    To investigate the interaction between childhood trauma exposure with the catechol-O-methyltransferase (COMT) and dopamine receptor D4 (DRD4) polymorphisms in relation to neuropsychological measures in children with ADHD. A cross-sectional examination of early traumatic experiences and the continuous performance test (CPT) were performed in 55 children with ADHD. Participants were also genotyped for the DRD4 exon III 48-bp variable number of tandem repeats (VNTR) polymorphism and the COMT Val158-Met (rs4680) polymorphism. There was significant interaction between the effects of the COMT genotype and trauma in commission errors. In participants with ADHD carrying the COMT Val/Val genotype, the group exposed to trauma showed significantly higher commission errors than the non-traumatized group. However, for the participants with other genotypes, no significant differences were found. This study suggests that there exists a genetic influence on the association between childhood trauma and the severity of inhibitory deficits in children with ADHD.

  17. Synthesis of [{sup 18}F]RO41-0960, a potent catechol-O-methyltransferase inhibitor, for PET studies

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Y.-S.; Sugano, Y.; Koomen, J.; Aggarwal, D. [Brookhaven National Lab., Upton, NY (United States). Dept. of Chemistry

    1997-04-01

    Ro41-0960 (3,4-dihydroxy-5-nitro-2`-fluorobenzophenone) is a potent, fluorine containing COMT inhibitor. In order to map catechol-O-methyltransferase (COMT) in vivo with PET, no-carrier-added [{sup 18}F]Ro41-0960 was synthesized by the nucleophilic aromatic substitution of [{sup 18}F]fluoride for 2`-nitro on 3,4-dimethoxy-5,2`-dimethoxy-5,2`-dinitrobenzophenone, followed by hydrolysis with HBr. During the course of this study it was found that [{sup 18}F]fluoromethane ([{sup 18}F]CH{sub 3}F) was generated as the side product of nucleophilic aromatic substitution reaction. Various precursors with different hydroxyl protecting groups were then investigated for the effects on this side reaction. (Author).

  18. Potential link between genetic polymorphisms of catechol-O-methyltransferase and dopamine receptors and treatment efficacy of risperidone on schizophrenia

    Directory of Open Access Journals (Sweden)

    Han JY

    2017-12-01

    Full Text Available Jiyang Han,1 Yan Li,2 Xumei Wang1 1Department of Psychiatry, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China; 2Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, Liaoning, China Objective: The current study aimed to explore the association of single nucleotide polymorphisms (SNPs within catechol-O-methyltransferase (COMT and dopamine receptors with schizophrenia and genetic association with risperidone treatment response.Methods: A total of 690 schizophrenic patients (case group were selected and 430 healthy people were included as the controls. All patients received risperidone treatment continuously for 8 weeks. Next, peripheral venous blood samples were collected and were subjected to polymerase chain reaction-restriction fragment length polymorphism to amplify and genotype the SNPs within COMT and dopamine receptors. Then, correlation analysis was conducted between Positive and Negative Syndrome Scale improvement rates and SNPs within COMT and the dopamine receptor gene.Results: The allele of DRD1 rs11749676 (A emerged as a key element in reducing schizophrenia risk with statistical significance (P<0.001. Remarkably, alleles of COMT rs165774 (G, DRD2 rs6277 (T, and DRD3 rs6280 (C were associated with raised predisposition to schizophrenia (all P<0.001. Regarding DRD1 rs11746641, DRD1 rs11749676, DRD2 rs6277, and DRD3 rs6280, the case group exhibited a lesser frequency of heterozygotes in comparison with wild homozygotes genotype (all P<0.001. SNPs (COMT rs4680, DRD2 rs6275, DRD2 rs1801028, and DRD2 rs6277 were remarkably associated with improvement rates of PANSS total scores (P<0.05. SNPs (COMT rs165599 and DRD2 rs1801028 were significantly associated with risperidone efficacy on negative symptoms (P<0.05.Conclusion: COMT SNPs and dopamine receptor SNPs were correlated with prevalence of schizophrenia and risperidone treatment efficacy of

  19. Preliminary Evidence for an Association Between Variants of the Catechol-O-Methyltransferase (COMT) Gene and Premature Ejaculation.

    Science.gov (United States)

    Jern, Patrick; Johansson, Ada; Strohmaier, Jana; Treutlein, Jens; Piha, Juhana; Rietschel, Marcella

    2017-12-01

    Studies have suggested that dopamine plays a role in the neurobiological mechanism that triggers ejaculation, leading scientists to hypothesize that dopamine-related genetic polymorphisms could contribute to symptoms of premature ejaculation (PE). To investigate associations between dopamine receptor and catechol-O-methyltransferase (COMT; an enzyme involved in the catabolism of dopamine) gene-linked polymorphisms and PE. PE status in patient groups was determined by clinical diagnosis performed by a physician specializing in sexual medicine. Self-reported PE symptoms from a validated questionnaire also were reported. Saliva samples were collected from 149 patients with PE and 1,022 controls from a population-based sample. In total, we tested associations between PE and 11 single-nucleotide polymorphisms in the dopamine receptor D1, D2, and D3 genes and in the COMT gene. We found no associations between dopamine receptor gene polymorphisms and PE, but 2 COMT-linked loci (rs4680 and rs4818) had significant associations after correction for multiple testing. 1 COMT gene-linked locus that was associated with PE symptoms in the present study, rs4680, is a well-documented functional polymorphism that causes a valine-to-methionine substitution. The other polymorphism, rs4818, is in high linkage disequilibrium with the rs4680 locus, indicating that they capture the same effect. Surprisingly, the rs4680 variant that was statistically significantly more prevalent in the PE group (ie, the valine-encoding allele) has been associated with higher enzymatic activity and therefore lower synaptic dopamine levels. Drugs targeting the dopaminergic system could affect PE symptoms. No replication sample was available for the present study; thus, our findings should be interpreted with caution. Moreover, a limitation of our study is the small sample in the context of genetic association studies (although it should be mentioned that genetically informative samples with phenotypic

  20. Protective Role of Maternal P.VAL158MET Catechol-O-methyltransferase Polymorphism against Early-Onset Preeclampsia and its Complications

    Directory of Open Access Journals (Sweden)

    Krnjeta Tijana

    2016-09-01

    Full Text Available Background: Up until now there have been contradictory data about the association between p.Val158Met catechol-O-methyltransferase (COMT polymorphism and risk of preeclampsia (PE. The goal of this study was to assess the potential correlation between p.Val158Met COMT polymorphism and risk of early-onset PE, risk of a severe form of early-onset PE, as well as risk of small-for-gestationalage (SGA complicating PE.

  1. Rational design of a live attenuated dengue vaccine: 2'-o-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques.

    Directory of Open Access Journals (Sweden)

    Roland Züst

    Full Text Available Dengue virus is transmitted by Aedes mosquitoes and infects at least 100 million people every year. Progressive urbanization in Asia and South-Central America and the geographic expansion of Aedes mosquito habitats have accelerated the global spread of dengue, resulting in a continuously increasing number of cases. A cost-effective, safe vaccine conferring protection with ideally a single injection could stop dengue transmission. Current vaccine candidates require several booster injections or do not provide protection against all four serotypes. Here we demonstrate that dengue virus mutants lacking 2'-O-methyltransferase activity are highly sensitive to type I IFN inhibition. The mutant viruses are attenuated in mice and rhesus monkeys and elicit a strong adaptive immune response. Monkeys immunized with a single dose of 2'-O-methyltransferase mutant virus showed 100% sero-conversion even when a dose as low as 1,000 plaque forming units was administrated. Animals were fully protected against a homologous challenge. Furthermore, mosquitoes feeding on blood containing the mutant virus were not infected, whereas those feeding on blood containing wild-type virus were infected and thus able to transmit it. These results show the potential of 2'-O-methyltransferase mutant virus as a safe, rationally designed dengue vaccine that restrains itself due to the increased susceptibility to the host's innate immune response.

  2. Linking electrostatic effects and protein motions in enzymatic catalysis. A theoretical analysis of catechol o-methyltransferase.

    Science.gov (United States)

    García-Meseguer, Rafael; Zinovjev, Kirill; Roca, Maite; Ruiz-Pernía, Javier J; Tuñón, Iñaki

    2015-01-22

    The role of protein motions in enzymatic catalysis is the subject of a hot scientific debate. We here propose the use of an explicit solvent coordinate to analyze the impact of environmental motions during the reaction process. The example analyzed here is the reaction catalyzed by catechol O-methyltransferase, a methyl transfer reaction from S-adenosylmethionine (SAM) to the nucleophilic oxygen atom of catecholate. This reaction proceeds from a charged reactant to a neutral product, and then a large electrostatic coupling with the environment could be expected. By means of a two-dimensional free energy surface, we show that a large fraction of the environmental motions needed to attain the transition state happens during the first stages of the reaction because most of the environmental motions are slower than changes in the substrate. The incorporation of the solvent coordinate in the definition of the transition state improves the transmission coefficient and the committor histogram in solution, while the changes are much less significant in the enzyme. The equilibrium solvation approach seems then to work better in the enzyme than in aqueous solution because the enzyme provides a preorganized environment where the reaction takes place.

  3. Genetic contribution of catechol-O-methyltransferase polymorphism (Val158Met) in children with chronic tension-type headache.

    Science.gov (United States)

    Fernández-de-las-Peñas, César; Ambite-Quesada, Silvia; Rivas-Martínez, Inés; Ortega-Santiago, Ricardo; de-la-Llave-Rincón, Ana Isabel; Fernández-Mayoralas, Daniel M; Pareja, Juan A

    2011-10-01

    Our aim was to investigate the relationship between Val158Met polymorphisms, headache, and pressure hypersensitivity in children with chronic tension-type headache (CTTH). A case-control study with blinded assessor was conducted. Seventy children with CTTH associated with pericranial tenderness and 70 healthy children participated. After amplifying Val158Met polymorphism by polymerase chain reactions, we assessed genotype frequencies and allele distributions. We classified children according to their Val158Met polymorphism: Val/Val, Val/Met, Met/Met. Pressure pain thresholds (PPT) were bilaterally assessed over the temporalis, upper trapezius, second metacarpal, and tibialis anterior muscles. The distribution of Val158Met genotypes was not significantly different (p = 0.335), between children with CTTH and healthy children, and between boys and girls (p = 0.872). Children with CTTH with the Met/Met genotype showed a longer headache history compared with those with Met/Val (p = 0.001) or Val/Val (p = 0.002) genotype. Children with CTTH with Met/Met genotype showed lower PPT over upper trapezius and temporalis muscles than children with CTTH with Met/Val or Val/Val genotype (p < 0.01). The Val158Met catechol-O-methyltransferase (COMT) polymorphism does not appear to be involved in predisposition to suffer from CTTH in children; nevertheless, this genetic factor may be involved in the phenotypic expression, as pressure hypersensitivity was greater in those CTTH children with the Met/Met genotype.

  4. Catechol-o-methyltransferase gene polymorphism modifies the effect of coffee intake on incidence of acute coronary events.

    Directory of Open Access Journals (Sweden)

    Pertti Happonen

    Full Text Available BACKGROUND: The role of coffee intake as a risk factor for coronary heart disease (CHD has been debated for decades. We examined whether the relationship between coffee intake and incidence of CHD events is dependent on the metabolism of circulating catecholamines, as determined by functional polymorphism of the catechol-O-methyltransferase (COMT gene. METHODOLOGY/PRINCIPAL FINDINGS: In a cohort of 773 men who were 42 to 60 years old and free of symptomatic CHD at baseline in 1984-89, 78 participants experienced an acute coronary event during an average follow-up of 13 years. In logistic regression adjusting for age, smoking, family history of CHD, vitamin C deficiency, blood pressure, plasma cholesterol concentration, and diabetes, the odds ratio (90% confidence interval comparing heavy coffee drinkers with the low activity COMT genotype with those with the high activity or heterozygotic genotypes was 3.2 (1.2-8.4. Urinary adrenaline excretion increased with increasing coffee intake, being over two-fold in heavy drinkers compared with nondrinkers (p = 0.008 for trend. CONCLUSIONS/SIGNIFICANCE: Heavy coffee consumption increases the incidence of acute coronary events in men with low but not high COMT activity. Further studies are required to determine to which extent circulating catecholamines mediate the relationship between coffee intake and CHD.

  5. In planta production of the highly potent resveratrol analogue pterostilbene via stilbene synthase and O-methyltransferase co-expression

    Energy Technology Data Exchange (ETDEWEB)

    Rimando A. M.; Liu C.; Pan, Z.; Polashock, J. J.; Dayan, F. E., Mizuno, C. S.; Snook, M. E.; Baerson, S. R.

    2012-04-01

    Resveratrol and related stilbenes are thought to play important roles in defence responses in several plant species and have also generated considerable interest as nutraceuticals owing to their diverse health-promoting properties. Pterostilbene, a 3,5-dimethylether derivative of resveratrol, possesses properties similar to its parent compound and, additionally, exhibits significantly higher fungicidal activity in vitro and superior pharmacokinetic properties in vivo. Recombinant enzyme studies carried out using a previously characterized O-methyltransferase sequence from Sorghum bicolor (SbOMT3) demonstrated its ability to catalyse the A ring-specific 3,5-bis-O-methylation of resveratrol, yielding pterostilbene. A binary vector was constructed for the constitutive co-expression of SbOMT3 with a stilbene synthase sequence from peanut (AhSTS3) and used for the generation of stably transformed tobacco and Arabidopsis plants, resulting in the accumulation of pterostilbene in both species. A reduced floral pigmentation phenotype observed in multiple tobacco transformants was further investigated by reversed-phase HPLC analysis, revealing substantial decreases in both dihydroquercetin-derived flavonoids and phenylpropanoid-conjugated polyamines in pterostilbene-producing SbOMT3/AhSTS3 events. These results demonstrate the potential utility of this strategy for the generation of pterostilbene-producing crops and also underscore the need for the development of additional approaches for minimizing concomitant reductions in key phenylpropanoid-derived metabolites.

  6. Association between the catechol-o-methyltransferase val158met polymorphism with susceptibility and severity of carpal tunnel syndrome

    Directory of Open Access Journals (Sweden)

    Erkol İnal E

    2015-12-01

    Full Text Available Carpal tunnel syndrome (CTS is the most common entrapment neuropathy of the upper extremity. In this study, we aimed to clarify the relationships between the catechol-O-methyltransferase (COMT gene Val158Met (rs4680 polymorphism and development, functional and clinical status of CTS. Ninety-five women with electro diagnostically confirmed CTS and 95 healthy controls were enrolled in the study. The functional and clinical status of the patients was measured by the Turkish version of the Boston Questionnaire and intensity of pain related to the past 2 weeks was evaluated on a visual analog scale (VAS. The Val158Met polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP, method. We divided patients according to the genotypes of the Val158Met polymorphism as Val/Val, Val/Met and Met/Met. There were not any significant differences in terms of Val158Met polymorphisms between patients and healthy controls (p >0.05. We also did not find any relationships between the Val158Met polymorphism and CTS (p >0.05. In conclusion, although we did not find any relationships between CTS and the Val158Met polymorphism, we could not generalize this result to the general population. Future studies are warranted to conclude precise associations.

  7. No association between catechol-O-methyltransferase (COMT) genotype and attention deficit hyperactivity disorder (ADHD) in Japanese children.

    Science.gov (United States)

    Yatsuga, Chiho; Toyohisa, Daiki; Fujisawa, Takashi X; Nishitani, Shota; Shinohara, Kazuyuki; Matsuura, Naomi; Ikeda, Shinobu; Muramatsu, Masaaki; Hamada, Akinobu; Tomoda, Akemi

    2014-08-01

    This study ascertained the association between attention deficit/hyperactivity disorder (ADHD) in Japanese children and a polymorphism of catechol-O-methyltransferase (COMT), a dopamine-control gene. The secondary aim of the study was the evaluation of a putative association between methylphenidate (MPH) effect/adverse effects and the COMT genotype. To ascertain the distribution of the Val158Met variant of COMT, 50 children meeting ADHD inclusion criteria were compared with 32 healthy children. Clinical improvement and the occurrence of adverse effects were measured before and 3 months after MPH administration in children with ADHD, and analyzed for genotype association. Wechsler Intelligence Scale for Children-Third Edition (WISC-III), age, MPH dose were included as co-variables. The occurrence of the COMT Val/Val genotype was significantly higher in children with ADHD (χ(2)(1)=7.13, pADHD rating scale scores, after correcting for the interaction between disorder and COMT genotype. Furthermore, no significant difference in MPH effect/adverse effects was observed in association with the COMT genotype in the ADHD group. These results showed a lack of association between the COMT Val/Val genotype and ADHD in Japan. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  8. Up- and down-regulation of Fragaria x ananassa O-methyltransferase: impacts on furanone and phenylpropanoid metabolism.

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    Lunkenbein, Stefan; Salentijn, Elma M J; Coiner, Heather A; Boone, Marjan J; Krens, Frans A; Schwab, Wilfried

    2006-01-01

    A complex mixture of hundreds of substances determines strawberry (Fragaria x ananassa) aroma, but only approximately 15 volatiles are considered as key flavour compounds. Of these, 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF) is regarded as the most important, but it is methylated further by FaOMT (Fragaria x ananassa O-methyltransferase) to 2,5-dimethyl-4-methoxy-3(2H)-furanone (DMMF) during the ripening process. It is shown here that transformation of strawberry with the FaOMT sequence in sense and antisense orientation, under the control of the cauliflower mosaic virus 35S promoter, resulted in a near total loss of DMMF, whereas the levels of the other volatiles remained unchanged. FaOMT repression also affected the ratio of feruloyl 1-O-beta-D-glucose and caffeoyl 1-O-beta-D-glucose, indicating a dual function of the enzyme in planta. Thus, FaOMT is involved in at least two different biochemical pathways in ripe strawberry fruit.

  9. Catechol-O-methyltransferase Val158met polymorphism interacts with early experience to predict executive functions in early childhood.

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    Blair, Clancy; Sulik, Michael; Willoughby, Michael; Mills-Koonce, Roger; Petrill, Stephen; Bartlett, Christopher; Greenberg, Mark

    2015-11-01

    Numerous studies demonstrate that the Methionine variant of the catechol-O-methyltransferase Val158Met polymorphism, which confers less efficient catabolism of catecholamines, is associated with increased focal activation of prefrontal cortex (PFC) and higher levels of executive function abilities. By and large, however, studies of COMT Val158Met have been conducted with adult samples and do not account for the context in which development is occurring. Effects of early adversity on stress response physiology and the inverted U shape relating catecholamine levels to neural activity in PFC indicate the need to take into account early experience when considering relations between genes such as COMT and executive cognitive ability. Consistent with this neurobiology, we find in a prospective longitudinal sample of children and families (N = 1292) that COMT Val158Met interacts with early experience to predict executive function abilities in early childhood. Specifically, the Valine variant of the COMT Val158Met polymorphism, which confers more rather than less efficient catabolism of catecholamines is associated with higher executive function abilities at child ages 48 and 60 months and with faster growth of executive function for children experiencing early adversity, as indexed by cumulative risk factors in the home at child ages 7, 15, 24, and 36 months. Findings indicate the importance of the early environment for the relation between catecholamine genes and developmental outcomes and demonstrate that the genetic moderation of environmental risk is detectable in early childhood. © 2015 Wiley Periodicals, Inc.

  10. [Polymorphisms of catechol-O-methyltransferase and monoamine oxidase B genes among Chinese patients with Parkinson's disease].

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    Hao, Hongying; Shao, Ming; An, Jing; Chen, Chushuang; Feng, Xiuli; Xie, Shu; Gu, Zhuqin; Chen, Biao

    2015-02-01

    To study polymorphisms of catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) genes among Chinese patients with Parkinson's disease. Genotypes of the COMT and MAO-B genes of 1408 patients with Parkinson's disease was sequenced using Sanger method. And these patients were recruited by Chinese Parkinson Study Group from 29 research centers throughout the country. The genotypic frequencies of COMT rs4680 AA, AG, GG were 8.9%, 42.0% and 49.1%. Those of rs4818 CC, CG, GG were 42.5%, 45.6% and 11.9%, respectively. The genotype frequencies of MAO-B rs1799836 A/AA, AG, G/GG were 74.4%, 14.1% and 11.5%, respectively. The haplotype formed by COMT rs4680 (GG) and MAO-B rs1799836 (A/AA) genotype has a frequency of 36.86%. Polymorphisms of COMT and MAO-B genes has a unique characteristics among Chinese patients with Parkinson's disease. They may be related with differences in drug response in such patients.

  11. Association between catechol-O-methyltransferase Val¹⁵⁸Met polymorphism and configural mode of face processing.

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    Doi, Hirokazu; Nishitani, Shota; Shinohara, Kazuyuki

    2015-01-23

    Human visual system heavily relies on the spatial configuration among facial parts in discriminating faces. There are individual differences in the ability of configural face processing, which are supposed to be partly attributable to genetic predispositions. However, few studies have identified a specific gene linked to configural face processing ability. The present study investigated an association between configural mode of face processing and a single-nucleotide polymorphism in codon 158 of catechol-O-methyltransferase gene (COMT Val(158)Met polymorphism) using part-spacing paradigm. The results have revealed superior sensitivity to the changes in facial configuration in participants with Met/Met genotype of COMT Val(158)Met polymorphism compared to the other genotypes. This effect was virtually eliminated when the faces were presented upside-down. There was no group-difference in the ability to detect the change in morphological features of individual facial parts. These results indicate that COMT Val(158)Met polymorphism partly explains the individual differences in the ability of configural face processing. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. Association between the Catechol O-Methyltransferase (COMT) Val158met Polymorphism and Different Dimensions of Impulsivity

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    Malloy-Diniz, Leandro Fernandes; Lage, Guilherme Menezes; Campos, Simone Becho; de Paula, Jonas Jardim; de Souza Costa, Danielle; Romano-Silva, Marco Aurélio; de Miranda, Débora Marques; Correa, Humberto

    2013-01-01

    Background Impulsivity is a multidimensional construct which has been associated with dopaminergic neurotransmission. Nonetheless, until this moment, few studies addressed the relationship between different types of impulsivity and the single nucleotide polymorphism caused by a substitution of valine (val) with methionine (met) in the 158 codon of the Catechol-o-Methyltransferase gene (COMT-val158met). The present study aimed to investigate the association between val158met COMT polymorphism and impulsive behavior measured by two neuropsychological tests. Methodology/Principal Findings We administered two neuropsychological tests, a Continuous Performance Task and the Iowa Gambling Task were applied to 195 healthy participants to characterize their levels of motor, attentional and non-planning impulsivity. Then, subjects were grouped by genotype, and their scores on impulsivity measures were compared. There were no significant differences between group scores on attentional and motor impulsivity. Those participants who were homozygous for the met allele performed worse in the Iowa Gambling Task than val/val and val/met subjects. Conclusions/Significance Our results suggest that met allele of val158met COMT polymorphism is associated with poor performance in decision-making/cognitive impulsivity task. The results reinforce the hypothesis that val and met alleles of the val158met polymorphism show functional dissociation and are related to different prefrontal processes. PMID:24039968

  13. Catechol-O-Methyltransferase (COMT Val108/158 Met polymorphism does not modulate executive function in children with ADHD

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    Stepanian Marina

    2004-12-01

    Full Text Available Abstract Background An association has been observed between the catechol-O-methyltransferase (COMT gene, the predominant means of catecholamine catabolism within the prefrontal cortex (PFC, and neuropsychological task performance in healthy and schizophrenic adults. Since several of the cognitive functions typically deficient in children with Attention Deficit Hyperactivity Disorder (ADHD are mediated by prefrontal dopamine (DA mechanisms, we investigated the relationship between a functional polymorphism of the COMT gene and neuropsychological task performance in these children. Methods The Val108/158 Met polymorphism of the COMT gene was genotyped in 118 children with ADHD (DSM-IV. The Wisconsin Card Sorting Test (WCST, Tower of London (TOL, and Self-Ordered Pointing Task (SOPT were employed to evaluate executive functions. Neuropsychological task performance was compared across genotype groups using analysis of variance. Results ADHD children with the Val/Val, Val/Met and Met/Met genotypes were similar with regard to demographic and clinical characteristics. No genotype effects were observed for WCST standardized perseverative error scores [F2,97 = 0.67; p > 0.05], TOL standardized scores [F2,99 = 0.97; p > 0.05], and SOPT error scores [F2,108 = 0.62; p > 0.05]. Conclusions Contrary to the observed association between WCST performance and the Val108/158 Met polymorphism of the COMT gene in both healthy and schizophrenic adults, this polymorphism does not appear to modulate executive functions in children with ADHD.

  14. No association between germline variation in catechol-O-methyltransferase and colorectal cancer survival in postmenopausal women

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    Passarelli, Michael N.; Newcomb, Polly A.; Makar, Karen W.; Burnett-Hartman, Andrea N.; Phipps, Amanda I.; David, Sean P.; Hsu, Li; Harrison, Tabitha A.; Hutter, Carolyn M.; Duggan, David J.; White, Emily; Chan, Andrew T.; Peters, Ulrike

    2013-01-01

    Objective Sex-steroid hormones play a role in colorectal cancer (CRC) development, but little is known about their influence on tumor progression and metastasis. Because catechol-O-methyltransferase activity (COMT; 22q11.21) is an important component of estrogen-mediated carcinogenesis, we hypothesized that germline variation in COMT may be associated with CRC survival. Methods We identified 10 single-nucleotide polymorphisms (SNPs) that tagged variation across both isoforms of COMT in 2,458 women with CRC from the Nurses’ Health Study (NHS), Postmenopausal Hormones Supplementary Study to the Colon Cancer Family Registry (PMH-CCFR), VITamins And Lifestyle (VITAL) Study, and Women’s Health Initiative (WHI). All four studies participate in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Results Over a median follow-up of 7 years across all studies, there were 799 deaths, including 566 from CRC. Accounting for multiple comparisons, no associations between the SNPs and CRC-specific or overall survival reached statistical significance, including the well-characterized Val108/158Met polymorphism (rs4680; hazard ratio per minor allele [HR], 1.04; 95% confidence interval [CI], 0.92–1.17 for CRC-specific survival and 1.01; 0.90–1.14 for overall survival). Conclusions In this large study of women with CRC, we found no evidence that common inherited variation in COMT is associated with survival-time after diagnosis. PMID:23880798

  15. Catechol-O-methyltransferase (COMT Genotype Affects Age-Related Changes in Plasticity in Working Memory: A Pilot Study

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    Stephan Heinzel

    2014-01-01

    Full Text Available Objectives. Recent work suggests that a genetic variation associated with increased dopamine metabolism in the prefrontal cortex (catechol-O-methyltransferase Val158Met; COMT amplifies age-related changes in working memory performance. Research on younger adults indicates that the influence of dopamine-related genetic polymorphisms on working memory performance increases when testing the cognitive limits through training. To date, this has not been studied in older adults. Method. Here we investigate the effect of COMT genotype on plasticity in working memory in a sample of 14 younger (aged 24–30 years and 25 older (aged 60–75 years healthy adults. Participants underwent adaptive training in the n-back working memory task over 12 sessions under increasing difficulty conditions. Results. Both younger and older adults exhibited sizeable behavioral plasticity through training (P<.001, which was larger in younger as compared to older adults (P<.001. Age-related differences were qualified by an interaction with COMT genotype (P<.001, and this interaction was due to decreased behavioral plasticity in older adults carrying the Val/Val genotype, while there was no effect of genotype in younger adults. Discussion. Our findings indicate that age-related changes in plasticity in working memory are critically affected by genetic variation in prefrontal dopamine metabolism.

  16. Association study between the rs165599 catechol-O-methyltransferase genetic polymorphism and schizophrenia in a Brazilian sample

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    Quirino Cordeiro

    2012-12-01

    Full Text Available Schizophrenia is a severe psychiatric disorder with frequent recurrent psychotic relapses and progressive functional impairment. It results from a poorly understood gene-environment interaction. The gene encoding catechol-O-methyltransferase (COMT is a likely candidate for schizophrenia. Its rs165599 (A/G polymorphism has been shown to be associated with alteration of COMT gene expression. Therefore, the present study aimed to investigate a possible association between schizophrenia and this polymorphism. The distribution of the alleles and genotypes of this polymorphism was investigated in a Brazilian sample of 245 patients and 834 controls. The genotypic frequencies were in Hardy-Weinberg equilibrium and no statistically significant differences were found between cases and controls when analyzed according to gender or schizophrenia subtypes. There was also no difference in homozygosis between cases and controls. Thus, in the sample studied, there was no evidence of any association between schizophrenia and rs165599 (A/G polymorphism in the non-coding region 3' of the COMT gene.

  17. Clinical symptoms in fibromyalgia are associated to catechol-O-methyltransferase (COMT) gene Val158Met polymorphism.

    Science.gov (United States)

    Inanir, Ahmet; Karakus, Nevin; Ates, Omer; Sezer, Saime; Bozkurt, Nihan; Inanir, Sema; Yigit, Serbulent

    2014-10-01

    1. Fibromyalgia syndrome (FMS) is a common chronic widespread pain syndrome mainly affecting women. The aim of this study was to explore the frequency and clinical significance of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism in a large cohort of Turkish patients with FMS. 2. The study included 379 FMS patients and 290 controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses. 3. The genotype frequencies of Val158Met polymorphism showed a small difference between FMS patients and healthy controls (p = 0.047), however, the Met/Met genotype was significantly higher in FMS patients than healthy controls (p = 0.016). No difference was observed for allele frequencies between two groups. Stratification analysis according to clinical features for this disease reveals that weight, FMS Impact Questionnaire score, algometry and Raynaud's syndrome, were detected to have statistically significant associations with Val158Met polymorphism (p = 0.037, p = 0.042, p = 0.039 and p = 0.033, respectively). Pain sensitivity, measured by algometry, was statistically higher in patients with Met/Met genotype than the patients with Val/Val and Val/Met genotypes (p = 0.017). 4. The results of this study suggested that COMT gene Val158Met polymorphism is positively associated with FMS and play a relevant role in the clinical symptoms of the disease.

  18. The impact of Val108/158Met polymorphism of catechol-O-methyltransferase on brain oscillations during working memory.

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    Altamura, Mario; Elvevåg, Brita; Goldberg, Terry E; Carver, Frederick W; Weinberger, Daniel R; Coppola, Richard

    2016-01-01

    This study investigated whether catechol-O-methyltransferase (COMT) Val/Met polymorphism was associated with variation in event-related desynchronization/synchronization (ERD/ERS) of responses during working memory (WM). 11 Val/Val and 11 Met/Met homozygous participants underwent magnetoencephalography (MEG) while performing a WM task. In contrast to small effects behaviourally, during the delay period Val/Val individuals showed lower ERS in the gamma band (Hz 30-50) in frontal regions, increased ERS in the alpha band (Hz 8-12) in the right frontal and parietal regions and increased ERD in the beta band (Hz 14-30) in the left fronto-temporal regions as compared with Met/Met homozygous individuals. During the response period Val/Val participants showed greater beta ERD in the prefrontal and parietotemporal regions. These results demonstrate that COMT genotype has a strong impact on brain responses (oscillatory activity) during WM performance likely a consequence of compensatory activity during the delay and response periods. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Association between the Catechol O-methyltransferase (COMT Val158met polymorphism and different dimensions of impulsivity.

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    Leandro Fernandes Malloy-Diniz

    Full Text Available BACKGROUND: Impulsivity is a multidimensional construct which has been associated with dopaminergic neurotransmission. Nonetheless, until this moment, few studies addressed the relationship between different types of impulsivity and the single nucleotide polymorphism caused by a substitution of valine (val with methionine (met in the 158 codon of the Catechol-o-Methyltransferase gene (COMT-val158met. The present study aimed to investigate the association between val158met COMT polymorphism and impulsive behavior measured by two neuropsychological tests. METHODOLOGY/PRINCIPAL FINDINGS: We administered two neuropsychological tests, a Continuous Performance Task and the Iowa Gambling Task were applied to 195 healthy participants to characterize their levels of motor, attentional and non-planning impulsivity. Then, subjects were grouped by genotype, and their scores on impulsivity measures were compared. There were no significant differences between group scores on attentional and motor impulsivity. Those participants who were homozygous for the met allele performed worse in the Iowa Gambling Task than val/val and val/met subjects. CONCLUSIONS/SIGNIFICANCE: Our results suggest that met allele of val158met COMT polymorphism is associated with poor performance in decision-making/cognitive impulsivity task. The results reinforce the hypothesis that val and met alleles of the val158met polymorphism show functional dissociation and are related to different prefrontal processes.

  20. Complex multilocus effects of catechol-O-methyltransferase haplotypes predict pain and pain interference 6 weeks after motor vehicle collision

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    Bortsov, Andrey V.; Diatchenko, Luda; McLean, Samuel A.

    2013-01-01

    Catechol-O-methyltransferase, encoded by COMT gene, is the primary enzyme that metabolizes catecholamines. COMT haplotypes have been associated with vulnerability to persistent non-traumatic pain. In this prospective observational study, we investigated the influence of COMT on persistent pain and pain interference with life functions after motor vehicle collision (MVC) in 859 European American adults for whom overall pain (0–10 numeric rating scale) and pain interference (Brief Pain Inventory) were assessed at week 6 after MVC. Ten single nucleotide polymorphisms (SNPs) spanning the COMT gene were successfully genotyped, nine were present in three haploblocks: block 1 (rs2020917, rs737865, rs1544325), block 2 (rs4633, rs4818, rs4680, rs165774) and block 3 (rs174697, rs165599). After adjustment for multiple comparisons, haplotype TCG from block 1 predicted decreased pain interference (p =.004). The pain-protective effect of the low pain sensitivity (LPS, CGGG) haplotype from block 2 was only observed if at least one TCG haplotype was present in block 1 (haplotype × haplotype interaction p=.002 and <.0001 for pain and pain interference, respectively). Haplotype AG from block 3 was associated with pain and interference in males only (sex × haplotype interaction p=.005 and .0005, respectively). These results suggest that genetic variants in the distal promoter are important contributors to the development of persistent pain after MVC, directly and via the interaction with haplotypes in the coding region of the gene. PMID:23963787

  1. Development of an HTRF Assay for the Detection and Characterization of Inhibitors of Catechol-O-Methyltransferase.

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    Kimos, Martha; Burton, Maggi; Urbain, David; Caudron, Didier; Martini, Murielle; Famelart, Michel; Gillard, Michel; Barrow, James; Wood, Martyn

    2016-06-01

    Catechol-O-methyltransferase (COMT) plays an important role in the deactivation of catecholamine neurotransmitters and hormones. Inhibitors of COMT, such as tolcapone and entacapone, are used clinically in the treatment of Parkinson's disease. Discovery of novel inhibitors has been hampered by a lack of suitable assays for high-throughput screening (HTS). Although assays using esculetin have been developed, these are affected by fluorescence, a common property of catechol-type compounds. We have therefore evaluated a new homogenous time-resolved fluorescence (HTRF)-based assay from CisBio (Codolet, France), which measures the production of S-adenosyl-L-homocysteine (SAH). The assay has been run in both HTS and medium-throughput screening (MTS) modes. The assay was established using membranes expressing human membrane-bound COMT and was optimized for protein and time to give an acceptable signal window, good potency for tolcapone, and a high degree of translation between data in fluorescence ratio and data in terms of [SAH] produced. pIC50 values for the hits from the HTS mode were determined in the MTS mode. The assay also proved suitable for kinetic studies such as Km,app determination. © 2015 Society for Laboratory Automation and Screening.

  2. Association of catechol-O-methyltransferase gene polymorphisms with schizophrenia and negative symptoms in a Chinese population

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    Li, Wen Jun; Kou, Chang Gui; Yu, Yaqin; Sun, Shilong; Zhang, Xuan; Kosten, Thomas R; Zhang, Xiang Yang

    2014-01-01

    The gene encoding Catechol O-methyltransferase (COMT), a dopamine catabolic enzyme, has been associated inconsistently with schizophrenia in spite of consistent evidence for dopaminergic dysfunction in the prefrontal cortex (PFC) of schizophrenia. Since one contribution to this inconsistency might be genetic heterogeneity, this study investigated whether the COMT gene was associated with the development and symptoms of schizophrenia in relatively genetically homogeneous Chinese schizophrenic patients. We analyzed two polymorphisms (rs740603 and rs4818) of the COMT gene in a case–control study of 604 Han Chinese (284 patients and 320 controls). The patients’ psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). We found no significant differences in the rs740603 and rs4818 genotype and allele distributions between the patient and control groups. Quantitative trait analysis by the UNPHASED program showed that the rs740603 and rs740603(G)-rs4818(G) haplotypes were associated with negative symptoms in the schizophrenic patients, particularly among female patients. Thus, the COMT gene polymorphisms may not contribute to the susceptibility to schizophrenia, but may contribute to the negative symptoms of schizophrenia among Han Chinese. PMID:22354729

  3. Association of Catechol-O-methyltransferase val/met polymorphism with cognitive function in Gilles de la Tourette syndrome patients.

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    Ji, Weidong; Li, Ning; Ju, Kang; Zheng, Hong; Yang, Chuang; Xu, Ping; Chen, Silu; Cao, Aiai; Chen, Xue; Guo, Lanting

    2015-04-01

    Gilles de la Tourette syndrome (GTS) is a kind of neuropsychiatric disorder with childhood onset. The cognitive dysfunction caused by GTS could affect the growth and learning of children and adolescents. The mechanism of cognitive functions was associated with dopaminergic system, thus we access the associations between polymorphism of some dopaminergic system-related genes including Catechol-O-methyltransferase (COMT) met/val, Dopamine receptor D4 (DRD4) exon III 48 bp VNTR (variable number of tandem repeats), Interleukin 1 (IL-1) Ra 86 bp and IL-1β exon 5, and cognitive functions in GTS patients. Genotyping analysis was performed through polymerase chain reaction (PCR). Test for cognitive functions of GTS patients included modified wisconsin card sorting test (WCST), trail making test, visual reproduction test, stroop test and verbal fluency test. The patients with COMT met/met genotype showed less perseverative errors in modified WCST test compared with patients with COMT val/val genotype (P 0.05). Polymorphism of COMT met/val was correlated with cognitive functions in GTS patients. This study provided basis for the analysis of molecular genetic pathology of cognitive dysfunctions in GTS.

  4. Association between the Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism and Manual Aiming Control in Healthy Subjects

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    Lage, Guilherme M.; Miranda, Débora M.; Romano-Silva, Marco A.; Campos, Simone B.; Albuquerque, Maicon R.; Corrêa, Humberto; Malloy-Diniz, Leandro F.

    2014-01-01

    Background Prefrontal dopamine is catabolized by the catechol-O-methyltransferase (COMT) enzyme. Current evidence suggests that the val/met single nucleotide polymorphism in the COMT gene can predict the efficiency of executive cognition in humans. Individuals carrying the val allele perform more poorly because less synaptic dopamine is available. Methodology/Principal Findings We investigated the influence of the COMT polymorphism on motor performance in a task that requires different executive functions. We administered a manual aiming motor task that was performed under four different conditions of execution by 111 healthy participants. Participants were grouped according to genotype (met/met, met/val, val/val), and the motor performance among groups was compared. Overall, the results indicate that met/met carriers presented lower levels of peak velocity during the movement trajectory than the val carriers, but met/met carriers displayed higher accuracy than the val carriers. Conclusions/Significance This study found a significant association between the COMT polymorphism and manual aiming control. Few studies have investigated the genetics of motor control, and these findings indicate that individual differences in motor control require further investigation using genetic studies. PMID:24956262

  5. Catechol-O-methyltransferase genotype modifies executive functioning and prefrontal functional connectivity in women with anorexia nervosa.

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    Favaro, Angela; Clementi, Maurizio; Manara, Renzo; Bosello, Romina; Forzan, Monica; Bruson, Alice; Tenconi, Elena; Degortes, Daniela; Titton, Francesca; Di Salle, Francesco; Santonastaso, Paolo

    2013-07-01

    Anorexia nervosa is characterized by high levels of perseveration and inflexibility, which interfere with successful treatments. Dopamine (DA) signalling seems to play a key role in modulating the prefrontal cortex, since both DA deficiency and excess nega tively influence the efficiency of cognitive functions. The present study explores the effect of a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene on the set-shifting abilities and prefrontal functional connectivity of patients with anorexia nervosa. All participants performed the Wisconsin Card Sorting Task, and a subsample underwent resting-state functional magnetic resonance imaging. We included 166 patients with DSM-IV lifetime anorexia nervosa and 140 healthy women in our study. Both underweight and weight-recovered patients with anorexia nervosa showed high levels of perseveration, but only in the underweight group did the Val158Met polymorphism affect cognitive performance, showing the U-shaped curve characteristic of increased DA signalling in the prefrontal cortex. Underweight patients with anorexia nervosa who are Met homozygotes had significantly higher levels of perseveration and increased prefrontal functional connectivity than underweight patients in the other genotype groups, indicating abnormal regional cortical processing. Although our data show that grey matter reduction in starving patients with anorexia nervosa did not explain our findings, the cross-sectional design of the present study did not allow us to distinguish between the effects of starvation and those of low estrogen levels. Starvation affects DA release in the prefrontal cortex of patients with anorexia nervosa with different effects on executive functioning and prefrontal functional connectivity according to the COMT genotype. This observation has several therapeutic implications that need to be addressed by future studies.

  6. Impact of Catechol-O-Methyltransferase Val 158Met (rs4680) Polymorphism on Breast Cancer Susceptibility in Asian Population

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    Rai, Vandana; Yadav, Upendra; Kumar, Pradeep

    2017-05-01

    Background: Catechol-O-methyltransferase (COMT) is an important estrogen-metabolizing enzyme. Numerous case-control studies have evaluated the role COMT Val 158Met (rs4680;472G->A) polymorphism in the risk of breast cancer and provided inconclusive results, hence present meta-analysis was designed to get a more reliable assessment in Asian population. Methods: A total of 26 articles were identified through a search of four electronic databases- PubMed, Google Scholar, Science Direct and Springer link, up to March, 2016. Pooled odds ratios (ORs) with 95% con¬fidence intervals (CIs) were used as association measure to find out relationship between COMT Val158Metpolymorphism and the risk of breast cancer. We also assessed between study heterogeneity and publication bias. All statistical analyses were done by Open Meta-Analyst. Results: Twenty six case-control studies involving 5,971 breast cancer patients and 7,253 controls were included in the present meta-analysis. The results showed that the COMT Val158Met polymorphism was significantly associated with breast cancer risk except heterozygote model(allele contrast odds ratio (ORAvsG)= 1.13, 95%CI=1.02-1.24,p=0.01; heterozygote/co-dominant ORGAvsGG= 1.03, 95%CI=0.96-1.11,p=0.34; homozygote ORAAvsGG= 1.38, 95%CI= 1.08-1.76,p=0.009; dominant model ORAA+GAvsGG= 1.08, 95%CI=1.01-1.16,p=0.02; and recessive model ORAAvsGA+GG= 1.35, 95%CI=1.07-1.71,p=0.01). In addition, we also performed subgroup analysis based on source of controls and menopausal state of patients. Conclusions: In conclusion, the COMT Val158Met polymorphism was related to increased breast cancer susceptibility in the Asian population. Creative Commons Attribution License

  7. Meta-analysis of association between a catechol-O-methyltransferase gene polymorphism and attention deficit hyperactivity disorder.

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    Cheuk, Daniel Ka Leung; Wong, Virginia

    2006-09-01

    There have been conflicting reports on the association between the Val158/108Met polymorphism of the catechol-O-methyltransferase (COMT) gene and attention deficit hyperactivity disorder (ADHD). Therefore we would like to perform a meta-analysis of previous studies to assess the overall magnitude and significance of the association. Family-based and case-control studies of the association between the COMT gene polymorphism and ADHD were searched systematically and comprehensively. Odds ratios (OR) of association were pooled by the fixed effects model if no significant heterogeneity was present among different studies. Subgroup analysis by gender and ADHD subtypes were also performed. Eleven family-based and two case-control studies were identified. After pooling the results, no significant association between the COMT Vall58/108Met polymorphism and ADHD was found (OR 0.99 (95% CI: 0.88-1.12), P = 0.87). There was also no significant association when the results were stratified by gender or ADHD subtype. There was no significant statistical heterogeneity (chi2 = 12.27, P = 0.2) although clinical heterogeneity was present in the studies, especially the ethnicity of subjects. Sensitivity analysis demonstrated absence of undue influence of any single study. Standard regression analysis showed no significant publication bias. We concluded that no significant association was present between the most common COMT gene polymorphism and ADHD. Further studies should employ larger sample size in more homogeneous subjects. Further investigations in moderator variables and gene-gene and gene-environment interactions are also warranted.

  8. Catechol-O-methyltransferase Val158Met polymorphism on the relationship between white matter hyperintensity and cognition in healthy people.

    Directory of Open Access Journals (Sweden)

    Mu-En Liu

    Full Text Available BACKGROUND: White matter lesions can be easily observed on T2-weighted MR images, and are termed white matter hyperintensities (WMH. Their presence may be correlated with cognitive impairment; however, the relationship between regional WMH volume and catechol-O-methyltransferase (COMT Val158Met polymorphism in healthy populations remains unclear. METHODS: We recruited 315 ethnic Chinese adults with a mean age of 54.9 ± 21.8 years (range: 21-89 y to examine the genetic effect of COMT on regional WMH and the manner in which they interact to affect cognitive function in a healthy adult population. Cognitive tests, structural MRI scans, and genotyping of COMT were conducted for each participant. RESULTS: Negative correlations between the Digit Span Forward (DSF score and frontal WMH volumes (r = -.123, P = .032, uncorrected were noted. For the genetic effect of COMT, no significant difference in cognitive performance was observed among 3 genotypic groups. However, differences in WMH volumes over the subcortical region (P = .016, uncorrected, whole brain (P = .047, uncorrected, and a trend over the frontal region (P = .050, uncorrected were observed among 3 COMT genotypic groups. Met homozygotes and Met/Val heterozygotes exhibited larger WMH volumes in these brain regions than the Val homozygotes. Furthermore, a correlation between the DSF and regional WMH volume was observed only in Met homozygotes. The effect size (cohen's f revealed a small effect. CONCLUSIONS: The results indicate that COMT might modulate WMH volumes and the effects of WMH on cognition.

  9. The O-methyltransferase gene MdoOMT1 is required for biosynthesis of methylated phenylpropenes in ripe apple fruit.

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    Yauk, Yar-Khing; Chagné, David; Tomes, Sumathi; Matich, Adam J; Wang, Mindy Y; Chen, Xiuyin; Maddumage, Ratnasiri; Hunt, Martin B; Rowan, Daryl D; Atkinson, Ross G

    2015-06-01

    Phenylpropenes, such as eugenol and trans-anethole, are important aromatic compounds that determine flavour and aroma in many herbs and spices. Some apple varieties produce fruit with a highly desirable spicy/aromatic flavour that has been attributed to the production of estragole, a methylated phenylpropene. To elucidate the molecular basis for estragole production and its contribution to ripe apple flavour and aroma we characterised a segregating population from a Royal Gala (RG, estragole producer) × Granny Smith (GS, non-producer) apple cross. Two quantitative trait loci (QTLs; accounting for 9.2 and 24.8% of the variation) on linkage group (LG) 1 and LG2 were identified that co-located with seven candidate genes for phenylpropene O-methyltransferases (MdoOMT1-7). Of these genes, only expression of MdoOMT1 on LG1 increased strongly with ethylene and could be correlated with increasing estragole production in ripening RG fruit. Transient over-expression in tobacco showed that MdoOMT1 utilised a range of phenylpropene substrates and catalysed the conversion of chavicol to estragole. Royal Gala carried two alleles (MdoOMT1a, MdoOMT1b) whilst GS appeared to be homozygous for MdoOMT1b. MdoOMT1a showed a higher affinity and catalytic efficiency towards chavicol than MdoOMT1b, which could account for the phenotypic variation at the LG1 QTL. Multiple transgenic RG lines with reduced MdoOMT1 expression produced lower levels of methylated phenylpropenes, including estragole and methyleugenol. Differences in fruit aroma could be perceived in these fruit, compared with controls, by sensory analysis. Together these results indicate that MdoOMT1 is required for the production of methylated phenylpropenes in apple and that phenylpropenes including estragole may contribute to ripe apple fruit aroma. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

  10. Catechol-o-methyltransferase gene modulation on suicidal behavior and personality traits: review, meta-analysis and association study.

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    Calati, Raffaella; Porcelli, Stefano; Giegling, Ina; Hartmann, Annette M; Möller, Hans-Jürgen; De Ronchi, Diana; Serretti, Alessandro; Rujescu, Dan

    2011-03-01

    Suicide is one of the leading causes of death among young adults. Both genetic and personality factors plausibly have a role on suicidal behavior. We focused on the catechol-O-methyltransferase gene (COMT) and we performed: a review of studies investigating the association between COMT and both suicidal behavior and personality; a meta-analysis of studies investigating the association between suicidal behavior and COMT rs4680 polymorphism; an association study investigating the link between seven COMT polymorphisms (rs737865, rs5844402, rs5993883, rs4680, rs4633, rs165599 and rs9332377) and both personality traits and suicidal behavior. For the review and the meta-analysis we performed an electronic search to identify studies focused on the association between COMT and both suicidal behavior and personality. The sample of the association study was composed of three groups: 289 German healthy controls, 111 German suicide attempters and 70 Italian mood disorder patients. From the review, the meta-analysis and the association study no relationship emerged between COMT and suicidal behavior. Nevertheless, from both review and association study several links were found between COMT and personality traits. In particular, in the association study we found a significant correlation between rs4633 and Reward Dependence (Temperament and Character Inventory). As secondary results we found an association between rs737865 and Angry Reaction (State-Trait Anger Expression Inventory) and between rs9332377 and Irritability (Questionnaire for Measuring Factors of Aggression). Our findings suggested that COMT variants may not be directly implicated in suicidal behavior, however evidence of a COMT role in the modulation of personality traits has been found. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. Association of Catechol-O-methyltransferase polymorphism Val158Met and mammographic density: A meta-analysis.

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    Kallionpää, Roope A; Uusitalo, Elina; Peltonen, Juha

    2017-08-15

    The Val158Met polymorphism in catechol-O-methyltransferase (COMT) enzyme reduces the methylation of catechol estrogens, which may affect mammographic density. High mammographic density is a known risk factor of breast cancer. Our aim was to perform meta-analysis of the effect of COMT Val158Met polymorphism on mammographic density. Original studies reporting data on mammographic density, stratified by the presence of COMT Val158Met polymorphism, were identified and combined using genetic models Met/Val vs. Val/Val, Met/Met vs. Val/Val, Val/Met+Met/Met vs. Val/Val (dominant model) and Met/Met vs. Val/Met+Val/Val (recessive model). Subgroup analyses by breast cancer status, menopausal status and use of hormone replacement therapy (HRT) were also performed. Eight studies were included in the meta-analysis. The overall effect in percent mammographic density was -1.41 (CI -2.86 to 0.05; P=0.06) in the recessive model. Exclusion of breast cancer patients increased the effect size to -1.93 (CI -3.49 to -0.37; P=0.02). The results suggested opposite effect of COMT Val158Met for postmenopausal users of HRT versus premenopausal women or postmenopausal non-users of HRT. COMT Val158Met polymorphism may be associated with mammographic density at least in healthy women. Menopausal status and HRT should be taken into account in future studies to avoid masking of the underlying effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Affect-modulated startle: interactive influence of catechol-O-methyltransferase Val158Met genotype and childhood trauma.

    Directory of Open Access Journals (Sweden)

    Benedikt Klauke

    Full Text Available The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system--partly conferred by catechol-O-methyltransferase (COMT gene variation--for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design and childhood maltreatment (CTQ as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.

  13. Inhibition of human catechol-O-methyltransferase-mediated dopamine O-methylation by daphnetin and its Phase II metabolites.

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    Liang, Si-Cheng; Ge, Guang-Bo; Xia, Yang-Liu; Pei-Pei, Dong; Ping, Wang; Qi, Xiao-Yi; Cai-Xia, Tu; Ling, Yang

    2017-06-01

    1. Finding and developing inhibitors of catechol-O-methyltransferase (COMT) from natural products is highly recommended. Daphnetin, a naturally occurring catechol from the family thymelaeaceae, has a chemical structure similar to several potent COMT inhibitors reported previously. Here the potential of daphnetin and its Phase II metabolites as inhibitors of COMT was investigated with human liver cytosol (HLC). 2. Daphnetin and its methylated metabolite (8-O-methyldaphnetin) were found to inhibit COMT-mediated dopamine O-methylation in a dose-dependent manner. The IC50 values for daphnetin (0.51∼0.53 μM) and 8-O-methyldaphnetin (22.5∼24.3 μM) were little affected by changes in HLC concentrations. Further kinetic analysis showed the differences in inhibition type and parameters (Ki) between daphnetin (competitive, 0.37 μM) and 8-O-methyldaphnetin (noncompetitive, 25.7 μM). Other metabolites, including glucuronidated and sulfated species, showed negligible inhibition against COMT. By using in vitro-in vivo extrapolation (IV-IVE), a 24.3-fold increase in the exposure of the COMT substrates was predicted when they are co-administrated with daphnetin. 3. With high COMT-inhibiting activity, daphnetin could serve as a lead compound for the design and development of new COMT inhibitors. Also, much attention should be paid to the clinical impact of combination of daphnetin and herbal preparations containing daphnetin with the drugs primarily cleared by COMT.

  14. Association analysis of the catechol-O-methyltransferase /methylenetetrahydrofolate reductase genes and cognition in late-onset depression.

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    Wang, Xiaoquan; Wang, Zusen; Wu, Yanfeng; Yuan, Yonggui; Hou, Zhenghua; Hou, Gang

    2014-05-01

    Increasing evidence suggests that the catechol-O-methyltransferase (COMT) gene might be associated with cognition in patients with mental disorders and healthy people. The metabolic pathways of COMT and methylenetetrahydrofolate reductase (MTHFR) are closely interconnected. In this study, we aimed to examine whether the COMT-MTHFR genotype interacted with cognitive function in late-onset depression (LOD) patients and COMT Val/Val homozygous individuals who also carried the MTHFR T allele and had poor neuropsychological test performance. Ninety-seven unrelated LOD patients who met DSM-IV criteria for major depressive disorder were recruited for the study and 103 normal controls were recruited from the local community. All of these patients and 44 normal controls completed a series of neuropsychological tests. Patients and normal controls were genotyped for COMT (rs4680) and MTHFR (rs1801133) variants using polymerase chain reaction-restriction fragment length polymorphism. There were no significant differences in the frequencies of the single alleles and genotypes of two polymorphisms between LOD patients and normal controls. No main effects of COMT or MTHFR genotype on any neuropsychological test performance were observed. There was a significant interactive effect of COMT Val158Met and MTHFR C677T polymorphisms on the Symbol Digit Modalities Test independent of diagnosis (P < 0.05). After controlling for covariates, the subjects with COMT Met/ Met and MTHFR C/C genotype had better Symbol Digit Modalities Test performance. The results suggest no major effect of COMT or MTHFR on cognitive function alone. However, an interaction of COMT Val158Met and MTHFR C677T polymorphisms may be associated with cognitive function. Further studies in a large sample are needed to replicate the genetic role in the LOD patients. © 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.

  15. Catechol-O-methyltransferase val158met genotype determines effect of reboxetine on emotional memory in healthy male volunteers

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    Gibbs, Ayana A.; Bautista, Carla E.; Mowlem, Florence D.; Naudts, Kris H.; Duka, Dora T.

    2014-01-01

    Background Catechol-O-methyltransferase (COMT) metabolizes catecholamines in the prefrontal cortex (PFC). A common polymorphism in the COMT gene (COMT val158met) has pleiotropic effects on cognitive and emotional processing. The met allele has been associated with enhanced cognitive processing but impaired emotional processing relative to the val allele. Methods We genotyped healthy, white men in relation to the COMT val158met polymorphism. They were given a single 4 mg dose of the selective noradrenaline reuptake inhibitor (NRI) reboxetine or placebo in a randomized, double-blind between-subjects model and then completed an emotional memory task 2 hours later. Results We included 75 men in the study; 41 received reboxetine and 34 received placebo. In the placebo group, met/met carriers did not demonstrate the usual memory advantage for emotional stimuli that was observed in val carriers. Reboxetine restored this emotional enhancement of memory in met/met carriers, but had no significant effect in val carriers. Limitations We studied only men, thus limiting the generalizability of our findings. We also relied on self-reported responses to screening questions to establish healthy volunteer status, and in spite of the double-blind design, participants were significantly better than chance at identifying their intervention allocation. Conclusion Emotional memory is impaired in healthy met homozygotes and selectively improved in this group by reboxetine. This has potential translational implications for the use of reboxetine, which is currently licensed as an antidepressant in several countries, and edivoxetine, a new selective NRI currently in development. PMID:24467942

  16. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene corresponds with desirability of "unhealthy" foods.

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    Wallace, Deanna L; Aarts, Esther; d'Oleire Uquillas, Federico; Dang, Linh C; Greer, Stephanie M; Jagust, William J; D'Esposito, Mark

    2015-09-01

    The role of dopamine is extensively documented in weight regulation and food intake in both animal models and humans. Yet the role of dopamine has not been well studied in individual differences for food desirability. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene has been shown to influence dopamine levels, with greater COMT enzymatic activity in val/val individuals corresponding to greater degradation of dopamine. Decreased dopamine has been associated with poorer cognitive control and diminished goal-directed behavior in various behavioral paradigms. Additionally, dopaminergic-rich regions such as the frontal cortex and dorsal striatum have been shown to be important for supporting food-related decision-making. However, the role of dopamine, as assessed by COMT genotype status, in food desirability has not been fully explored. Therefore, we utilized an individual's COMT genotype status (n = 61) and investigated food desirability based on self-rated "healthy" and "unhealthy" food perceptions. Here we found val/val individuals (n = 19) have greater desirability for self-rated "unhealthy" food items, but not self-rated "healthy" food items, as compared to val/met (n = 24) and met/met (n = 18) individuals (p < 0.005). Utilizing an objective health measure for the food items, we also found val/val and val/met individuals have greater desirability for objectively defined "unhealthy" food items, as compared to met/met individuals (p < 0.01). This work further substantiates the role of dopamine in food-related behaviors and more specifically in relationship to food desirability for "unhealthy" food items. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Catechol-O-methyltransferase (COMT) genotype moderates the effects of childhood trauma on cognition and symptoms in schizophrenia.

    Science.gov (United States)

    Green, Melissa J; Chia, T-Yunn; Cairns, Murray J; Wu, Jingqin; Tooney, Paul A; Scott, Rodney J; Carr, Vaughan J

    2014-02-01

    The interaction of genetic and environmental factors may affect the course and development of psychotic disorders. We examined whether the effects of childhood trauma on cognition and symptoms in schizophrenia were moderated by the Catechol-O-methyltransferase (COMT) Val(158)Met polymorphism, a common genetic variant known to affect cognition and prefrontal dopamine levels. Participants were 429 schizophrenia/schizoaffective cases from the Australian Schizophrenia Research Bank (ASRB). Cognitive performance was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Controlled Oral Word Association Test (COWAT), Letter Number Sequencing (LNS) test, and the Wechsler Test of Adult Reading (WTAR). Hierarchical regression was used to test the main effects and additive interaction effects of genotype and childhood trauma in the domains of physical abuse, emotional abuse, and emotional neglect, on cognition and symptom profiles of clinical cases. Consistent with previous findings, COMT Val homozygotes performed worse on cognitive measures in the absence of childhood adversity. In addition, a significant interaction between COMT genotype and physical abuse was associated with better executive function in Val homozygotes, relative to those of the same genotype with no history of abuse. Finally, the severity of positive symptoms was greater in Met carriers who had experienced physical abuse, and the severity of negative symptoms in Met carriers was greater in the presence of emotional neglect. These results suggest that the possible epigenetic modulation of the expression of the COMT Val(158)Met polymorphism and consequent effects on cognition and symptoms in schizophrenia, with worse outcomes associated with adverse childhood experiences in Met carriers. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Genetic contribution of catechol-O-methyltransferase in hippocampal structural and functional changes of female migraine sufferers.

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    Liu, Jixin; Lan, Lei; Mu, Junya; Zhao, Ling; Yuan, Kai; Zhang, Yi; Huang, Liyu; Liang, Fanrong; Tian, Jie

    2015-05-01

    Physiological and emotional stressors are associated with or provoke each migraine attack and cause structural and functional changes in the central nervous system. The hippocampus, a limbic structure important in anxiety-related behavior, is vulnerable to long-term stress. Given that catechol-O-methyltransferase (COMT) is widely distributed in the hippocampus and its genetic variation is thought to contribute to the interindividual variability in pain perception and anxiety regulation, whether or not migraine and COMT val(158) met genotype have an interactive effect in the key brain area related to maladaptive stress, the hippocampus, is still poorly understood. Using T1-weighted and resting functional MRI, we evaluated the effect of COMT genetic variations on migraine and possible interactions between COMT and the disease in brain structure and function in 135 females with migraine without aura (MWoA) and 111 matched health controls (HC). Optimized voxel-based morphometry (VBM) and functional connectivity (FC) analyses were applied. From the whole brain VBM analysis, we found a significant disease × genotype interaction in the hippocampus, which overlapped with disease-related increase of gray matter (GM) in val homozygote migraineurs. In our results, increased GM in the hippocampus was only found in val homozygote MWoA compared to val homozygote HC. Moreover, FC between the hippocampus and the medial prefrontal cortex was significantly decreased in val homozygotes, and it was negatively correlated with self-rating anxiety scale values.Our results indicated that brain structure and function of the hippocampus are differentially affected by migraine in val homozygotes compared with met carriers. © 2015 Wiley Periodicals, Inc.

  19. Association between the catechol-O-methyltransferase polymorphism Val158Met and Alzheimer's disease in a Japanese population.

    Science.gov (United States)

    Shibata, Nobuto; Nagata, Tomoyuki; Tagai, Kenji; Shinagawa, Shunichiro; Ohnuma, Tohru; Kawai, Eri; Kasanuki, Koji; Shimazaki, Hiromi; Toda, Aiko; Tagata, Yuko; Nakada, Tomoko; Nakayama, Kazuhiko; Yamada, Hisashi; Arai, Heii

    2015-09-01

    Catechol-O-methyltransferase (COMT) plays an important role in dopamine degradation, which is associated with the pathophysiology of Alzheimer's disease (AD) and alcoholism. A functional COMT polymorphism, Val158Met (rs4680 G > A), affects the onset of AD and is associated with alcohol dependence through dopamine receptor sensitivity in the prefrontal cortex. The aim of this case-control study (398 cases and 149 controls) was to investigate whether Val158Met polymorphism influences the onset of AD stratified according to alcohol consumption and apolipoprotein E (APOE) status. We also used single photon-emission computed tomography (SPECT) to analyse 26 patients with AD with the polymorphism. As a function of APOE status, the genotypic frequencies of rs4680 in patients with AD did not differ from those in controls. We detected a significant association between high alcohol consumption in patients with AD (HAC-AD group) and the polymorphism in genotypic and allelic frequencies. Logistic regression analyses demonstrated that the presence of the APOE genotype with rs4680 increased the risk for HAC-AD synergistically. Hyperperfusion in the right sub-lobar insula of patients with the G/G genotype was found compared with that of patients with the G/A genotype. SPECT studies showed a relationship between the polymorphism and compensatory reactions for dysfunctions of dopaminergic neurotransmission in AD pathophysiology. Although genetic association between the polymorphism and the onset of AD in a Japanese population were not observed, the polymorphism affected the risk for HAC-AD. Copyright © 2014 John Wiley & Sons, Ltd.

  20. Impaired Dopamine-Dependent Locomotory Behavior of C. elegans Neuroligin Mutants Depends on the Catechol-O-Methyltransferase COMT-4.

    Science.gov (United States)

    Rodríguez-Ramos, Ángel; Gámez-Del-Estal, M Mar; Porta-de-la-Riva, Montserrat; Cerón, Julián; Ruiz-Rubio, Manuel

    2017-11-01

    Neurexins and neuroligins are neuronal membrane adhesion molecules that have been involved in neuropsychiatric and neurodevelopmental disorders. The nrx-1 and nlg-1 genes of Caenorhabditis elegans encode NRX-1 and NLG-1, orthologue proteins of human neurexins and neuroligins, respectively. Dopaminergic and serotoninergic signalling control the locomotory rate of the nematode. When well-fed animals are transferred to a plate with food (bacterial lawn), they reduce the locomotory rate. This behavior, which depends on dopamine, is known as basal slowing response (BSR). Alternatively, when food-deprived animals are moved to a plate with a bacterial lawn, further decrease their locomotory rate. This behavior, known as enhanced slowing response (ESR), is serotonin dependent. C. elegans nlg-1-deficient mutants are impaired in BSR and ESR. Here we report that nrx-1-deficient mutants were defective in ESR, but not in BSR. The nrx-1;nlg-1 double mutant was impaired in both behaviors. Interestingly, the nlg-1 mutants upregulate the expression of comt-4 which encodes an enzyme with putative catechol-O-methyltransferase activity involved in dopamine degradation. Our study also shows that comt-4(RNAi) in nlg-1-deficient mutants rescues the wild type phenotypes of BSR and ESR. On the other hand, comt-4(RNAi) in nlg-1-deficient mutants also recovers, at least partially, the gentle touch response and the pharyngeal pumping rate that were impaired in these mutants. These latter behaviors are dopamine and serotonin dependent, respectively. Based on these results we propose a model for the neuroligin function in modulating the dopamine-dependent locomotory behavior in the nematode.

  1. Effect of opicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity and motor fluctuations in patients with Parkinson's disease.

    Science.gov (United States)

    Ferreira, J J; Rocha, J-F; Falcão, A; Santos, A; Pinto, R; Nunes, T; Soares-da-Silva, P

    2015-05-01

    Opicapone (OPC) is a novel third generation catechol-O-methyltransferase (COMT) inhibitor that enhances levodopa availability. This study investigated the effects of OPC in comparison with placebo on levodopa pharmacokinetics, tolerability and safety, COMT activity and motor response to levodopa in Parkinson's disease (PD) patients with motor fluctuations. This was a randomized, multicentre, double-blind and placebo-controlled study in four parallel groups of PD patients treated with standard-release 100/25 mg levodopa/carbidopa or levodopa/benserazide and with motor fluctuations (wearing-OFF phenomenon). Subjects were sequentially assigned to be administered, once-daily, up to 28 days (maintenance phase), placebo (n = 10) or 5 (n = 10), 15 (n = 10) and 30 mg (n = 10) OPC. Two levodopa tests were performed, one at baseline and another following the maintenance phase. Subjects kept a diary to record motor fluctuations (ON/OFF periods) throughout the study. In relation to placebo, levodopa exposure (AUC0-6) increased 24.7%, 53.9% and 65.6% following 5, 15 and 30 mg OPC, respectively. Maximum COMT inhibition (Emax) ranged from 52% (5 mg OPC) to 80% (30 mg OPC). The study was not designed to detect any significant differences in motor performance, but the exploratory analysis performed shows improvement in various motor outcomes, including a dose-dependent change in absolute OFF time corresponding to a percentage decrease of 4.16% (P > 0.05), 29.55% (P > 0.05) and 32.71% (P < 0.05) with 5, 15 and 30 mg OPC, respectively. Treatments were generally well tolerated and safe. OPC is a promising new COMT inhibitor that significantly decreased COMT activity, increased systemic exposure to levodopa and improved motor response. © 2015 EAN.

  2. Analysis of catechol-O-methyltransferase gene mutation and identification of new pathogenic gene for paroxysmal kinesigenic dyskinesia.

    Science.gov (United States)

    Gu, Chengzhi; Li, Jia; Zhu, Lianhai; Lu, Zhenhui; Huang, Huaiyu

    2016-03-01

    We aimed to analyze the mutation site and frequency of catechol-O-methyltransferase (COMT) gene, to explore the relationship between COMT genotype and phenotype, and to find new pathogenic genes for paroxysmal kinesigenic dyskinesia (PKD). PKD patients who were treated from December 2011 to January 2014 were selected and subjected to genetic testing in the exon region of COMT. Two patients and one intrafamilial healthy control were subjected to exome sequencing using whole exome capture in combination with high-throughput sequencing to find candidate pathogenic gene sites. The results were verified by Sanger sequencing. A total of 11 familial PKD patients from 4 families and 9 sporadic patients without family history were included. Pathogenic c.634dupC(p.P220fsX7) mutation of COMT gene was found in 7 familial PKD patients and3 sporadic patients. Mutated COMT gene carriers suffered from PKD earlier (average age of onset: 11.61 ± 2.33 vs 16.21 ± 2.58, P = 0.001) with symmetric symptoms in most cases, while the mutation-negative group only showed unilateral symptoms (P = 0.001). The mutation-positive group also had more daily attacks (P = 0.038). Carbamazepine worked for all mutation-positive patients (10/10, 100%), but only for a part of mutation-negative patients (3/10, 30.0%). About 90000 single nucleotide polymorphisms and 2000 insertion-deletion polymorphisms were detected in each of the three samples. c.737C → T(p.T246 M) mutation of POC1B gene was a new pathogenic site for a selected family. COMT gene mutation, which was the pathogenesis of most familial PKD patients and a part of sporadic patients, predicted the response to carbamazepine. POC1B may be a novel pathogenic gene for PKD.

  3. The role of catechol-O-methyltransferase in catechol-enhanced erythroid differentiation of K562 cells.

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    Suriguga; Li, Xiao-Fei; Li, Yang; Yu, Chun-Hong; Li, Yi-Ran; Yi, Zong-Chun

    2013-12-15

    Catechol is widely used in pharmaceutical and chemical industries. Catechol is also one of phenolic metabolites of benzene in vivo. Our previous study showed that catechol improved erythroid differentiation potency of K562 cells, which was associated with decreased DNA methylation in erythroid specific genes. Catechol is a substrate for the catechol-O-methyltransferase (COMT)-mediated methylation. In the present study, the role of COMT in catechol-enhanced erythroid differentiation of K562 cells was investigated. Benzidine staining showed that exposure to catechol enhanced hemin-induced hemoglobin accumulation and induced mRNA expression of erythroid specific genes in K562 cells. Treatment with catechol caused a time- and concentration-dependent increase in guaiacol concentration in the medium of cultured K562 cells. When COMT expression was knocked down by COMT shRNA expression in K562 cells, the production of guaiacol significantly reduced, and the sensitivity of K562 cells to cytotoxicity of catechol significantly increased. Knockdown of COMT expression by COMT shRNA expression also eliminated catechol-enhanced erythroid differentiation of K562 cells. In addition, the pre-treatment with methyl donor S-adenosyl-L-methionine or its demethylated product S-adenosyl-L-homocysteine induced a significant increase in hemin-induced Hb synthesis in K562 cells and the mRNA expression of erythroid specific genes. These findings indicated that O-methylation catalyzed by COMT acted as detoxication of catechol and involved in catechol-enhanced erythroid differentiation of K562 cells, and the production of S-adenosyl-L-homocysteine partly explained catechol-enhanced erythroid differentiation. © 2013.

  4. COMT Val158Met Genotype Determines the Direction of Cognitive Effects Produced by Catechol-O-Methyltransferase Inhibition

    Science.gov (United States)

    Farrell, Sarah M.; Tunbridge, Elizabeth M.; Braeutigam, Sven; Harrison, Paul J.

    2012-01-01

    Background Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val158Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype. Methods Thirty-four COMT Met158Met (Met-COMT) and 33 COMT Val158Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task. Results In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences. Conclusions Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders. PMID:22364739

  5. Catechol-O-Methyltransferase Val158Met Polymorphism Modulates Gray Matter Volume and Functional Connectivity of the Default Mode Network

    Science.gov (United States)

    Tian, Tian; Qin, Wen; Liu, Bing; Wang, Dawei; Wang, Junping; Jiang, Tianzi; Yu, Chunshui

    2013-01-01

    The effect of catechol-O-methyltransferase (COMT) Val158Met polymorphism on brain structure and function has been previously investigated separately and regionally; this prevents us from obtaining a full picture of the effect of this gene variant. Additionally, gender difference must not be overlooked because estrogen exerts an interfering effect on COMT activity. We examined 323 young healthy Chinese Han subjects and analyzed the gray matter volume (GMV) differences between Val/Val individuals and Met carriers in a voxel-wise manner throughout the whole brain. We were interested in genotype effects and genotype × gender interactions. We then extracted these brain regions with GMV differences as seeds to compute resting-state functional connectivity (rsFC) with the rest of the brain; we also tested the genotypic differences and gender interactions in the rsFCs. Val/Val individuals showed decreased GMV in the posterior cingulate cortex (PCC) compared with Met carriers; decreased GMV in the medial superior frontal gyrus (mSFG) was found only in male Val/Val subjects. The rsFC analysis revealed that both the PCC and mSFG were functionally correlated with brain regions of the default mode network (DMN). Both of these regions showed decreased rsFCs with different parts of the frontopolar cortex of the DMN in Val/Val individuals than Met carriers. Our findings suggest that the COMT Val158Met polymorphism modulates both the structure and functional connectivity within the DMN and that gender interactions should be considered in studies of the effect of this genetic variant, especially those involving prefrontal morphology. PMID:24147141

  6. Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma

    Science.gov (United States)

    Klauke, Benedikt; Winter, Bernward; Gajewska, Agnes; Zwanzger, Peter; Reif, Andreas; Herrmann, Martin J.; Dlugos, Andrea; Warrings, Bodo; Jacob, Christian; Mühlberger, Andreas; Arolt, Volker; Pauli, Paul; Deckert, Jürgen; Domschke, Katharina

    2012-01-01

    The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system – partly conferred by catechol-O-methyltransferase (COMT) gene variation – for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders. PMID:22745815

  7. The role of catechol-O-methyltransferase in catechol-enhanced erythroid differentiation of K562 cells

    Energy Technology Data Exchange (ETDEWEB)

    Suriguga,; Li, Xiao-Fei; Li, Yang; Yu, Chun-Hong; Li, Yi-Ran; Yi, Zong-Chun, E-mail: yizc@buaa.edu.cn

    2013-12-15

    Catechol is widely used in pharmaceutical and chemical industries. Catechol is also one of phenolic metabolites of benzene in vivo. Our previous study showed that catechol improved erythroid differentiation potency of K562 cells, which was associated with decreased DNA methylation in erythroid specific genes. Catechol is a substrate for the catechol-O-methyltransferase (COMT)-mediated methylation. In the present study, the role of COMT in catechol-enhanced erythroid differentiation of K562 cells was investigated. Benzidine staining showed that exposure to catechol enhanced hemin-induced hemoglobin accumulation and induced mRNA expression of erythroid specific genes in K562 cells. Treatment with catechol caused a time- and concentration-dependent increase in guaiacol concentration in the medium of cultured K562 cells. When COMT expression was knocked down by COMT shRNA expression in K562 cells, the production of guaiacol significantly reduced, and the sensitivity of K562 cells to cytotoxicity of catechol significantly increased. Knockdown of COMT expression by COMT shRNA expression also eliminated catechol-enhanced erythroid differentiation of K562 cells. In addition, the pre-treatment with methyl donor S-adenosyl-L-methionine or its demethylated product S-adenosyl-L-homocysteine induced a significant increase in hemin-induced Hb synthesis in K562 cells and the mRNA expression of erythroid specific genes. These findings indicated that O-methylation catalyzed by COMT acted as detoxication of catechol and involved in catechol-enhanced erythroid differentiation of K562 cells, and the production of S-adenosyl-L-homocysteine partly explained catechol-enhanced erythroid differentiation. - Highlights: • Catechol enhanced hemin-induced hemoglobin accumulation. • COMT-catalyzed methylation acted as detoxication of catechol. • COMT involved in catechol-enhanced erythroid differentiation.

  8. Association study of a functional catechol-o-methyltransferase polymorphism and cognitive function in patients with dementia.

    Science.gov (United States)

    Nedić, Gordana; Borovecki, Fran; Klepac, Natasa; Mubrin, Zdenko; Hajnsek, Sanja; Nikolac, Matea; Muck-Seler, Dorotea; Pivac, Nela

    2011-01-01

    A functional catechol-o-methyltransferase (COMT Val158/108Met) polymorphism, a valine (Val) to methionine (Met) substitution, has been associated with cognitive processing in the normal brain, older age, mild cognitive impairment and in various dementias. COMT is involved in the breakdown of dopamine and other catecholamines, especially in the frontal cortex; hence the carriers of Met allele, with the lower enzymatic activity, are expected to perform better on particular neuro-cognitive tests. The study included 46 patients with dementia and 65 healthy older subjects. The neurological status was assessed, using the Mini Mental Status Examination (MMSE), and the batery of different neurological tests. In DNA samples COMT polymorphism was genotyped. Patients with dementia exhibited significant genotype-induced differences in scores for MMSE, Visual Association Test (VAT) duration of numbers test, VAT time of response to numbers test, VAT average response to numbers test and WPLCR/PPLR unanswered. Carriers of Met/Met genotype had significantly lower scores of MMSE, significantly longer time to respond to VAT duration of numbers test, VAT time of response to numbers test and VAT average response to numbers test, and significantly greater number of unanswered questions to WPLCR/PPLR when compared to Met/Val or Val/Val genotypes. Our preliminary data showed significantly impaired performance in several neuro-cognitive tests in carriers of Met/Met genotype in patients with dementia compared to either Met/Val or Val/Val genotype carriers. Although Met/Met genotype with more dopamine available in the frontal cortex should be associated with better neuro-cognitive test results than Met/Val or Val/Val genotype, our data on patients with dementia did not confirm this hypothesis. Further study on larger sample of patients is needed to clarify the role of COMT polymorphism in cognitive functions.

  9. Structural Basis for Dual Functionality of Isoflavonoid O-Methyltransferases in the Evolution of Plant Defense Responses

    Energy Technology Data Exchange (ETDEWEB)

    Liu, C.-J.; Deavours, B.E.; Richard, S.B.; Ferrer, J.-L.; Blount, J.W.; Huhman, D.; Dixon, R.A.; Noel, J.

    2007-07-10

    In leguminous plants such as pea (Pisum sativum), alfalfa (Medicago sativa), barrel medic (Medicago truncatula), and chickpea (Cicer arietinum), 4'-O-methylation of isoflavonoid natural products occurs early in the biosynthesis of defense chemicals known as phytoalexins. However, among these four species, only pea catalyzes 3-O-methylation that converts the pterocarpanoid isoflavonoid 6a-hydroxymaackiain to pisatin. In pea, pisatin is important for chemical resistance to the pathogenic fungus Nectria hematococca. While barrel medic does not biosynthesize 6a-hydroxymaackiain, when cell suspension cultures are fed 6a-hydroxymaackiain, they accumulate pisatin. In vitro, hydroxyisoflavanone 4'-O-methyltransferase (HI4'OMT) from barrel medic exhibits nearly identical steady state kinetic parameters for the 4'-O-methylation of the isoflavonoid intermediate 2,7,4'-trihydroxyisoflavanone and for the 3-O-methylation of the 6a-hydroxymaackiain isoflavonoid-derived pterocarpanoid intermediate found in pea. Protein x-ray crystal structures of HI4'OMT substrate complexes revealed identically bound conformations for the 2S,3R-stereoisomer of 2,7,4'-trihydroxyisoflavanone and the 6aR,11aR-stereoisomer of 6a-hydroxymaackiain. These results suggest how similar conformations intrinsic to seemingly distinct chemical substrates allowed leguminous plants to use homologous enzymes for two different biosynthetic reactions. The three-dimensional similarity of natural small molecules represents one explanation for how plants may rapidly recruit enzymes for new biosynthetic reactions in response to changing physiological and ecological pressures.

  10. Structural Basis for Dual Functionality of Isoflavonoid O-Methyltransferases in the Evolution of Plant Defense Responses

    Energy Technology Data Exchange (ETDEWEB)

    Liu, C.; Deavours, B; Richard, S; Ferrer, J; Blount, J; Huhman, D; Dixon, R; Noel, J

    2006-01-01

    In leguminous plants such as pea (Pisum sativum), alfalfa (Medicago sativa), barrel medic (Medicago truncatula), and chickpea (Cicer arietinum), 4'-O-methylation of isoflavonoid natural products occurs early in the biosynthesis of defense chemicals known as phytoalexins. However, among these four species, only pea catalyzes 3-O-methylation that converts the pterocarpanoid isoflavonoid 6a-hydroxymaackiain to pisatin. In pea, pisatin is important for chemical resistance to the pathogenic fungus Nectria hematococca. While barrel medic does not biosynthesize 6a-hydroxymaackiain, when cell suspension cultures are fed 6a-hydroxymaackiain, they accumulate pisatin. In vitro, hydroxyisoflavanone 4'-O-methyltransferase (HI4'OMT) from barrel medic exhibits nearly identical steady state kinetic parameters for the 4'-O-methylation of the isoflavonoid intermediate 2,7,4'-trihydroxyisoflavanone and for the 3-O-methylation of the 6a-hydroxymaackiain isoflavonoid-derived pterocarpanoid intermediate found in pea. Protein x-ray crystal structures of HI4'OMT substrate complexes revealed identically bound conformations for the 2S,3R-stereoisomer of 2,7,4'-trihydroxyisoflavanone and the 6aR,11aR-stereoisomer of 6a-hydroxymaackiain. These results suggest how similar conformations intrinsic to seemingly distinct chemical substrates allowed leguminous plants to use homologous enzymes for two different biosynthetic reactions. The three-dimensional similarity of natural small molecules represents one explanation for how plants may rapidly recruit enzymes for new biosynthetic reactions in response to changing physiological and ecological pressures.

  11. Methyl transfer in glucosinolate biosynthesis mediated by indole glucosinolate O-Methyltransferase 5

    DEFF Research Database (Denmark)

    Pfalz, Marina; Mukhaimar, Maisara; Perreau, François

    2016-01-01

    Indole glucosinolates (IGs) are plant secondary metabolites that are derived from the amino acid tryptophan. The product of Arabidopsis (Arabidopsis thaliana) IG core biosynthesis, indol-3-ylmethyl glucosinolate (I3M), can be modified by hydroxylation and subsequent methoxylation of the indole ring...... in position 1 (1-IG modification) or 4 (4-IG modification). Products of the 4-IG modification pathway mediate plant-enemy interactions and are particularly important for Arabidopsis innate immunity. While CYP81Fs encoding cytochrome P450 monooxygenases and IGMTs encoding indole glucosinolate O...... modification. Here, we analyze two Arabidopsis transfer DNA insertion lines with targeted metabolomics. We show that biosynthesis of 1-methoxyindol-3-ylmethyl glucosinolate (1MOI3M) from I3M involves the predicted unstable intermediate 1-hydroxyindol-3-ylmethyl glucosinolate (1OHI3M) and that IGMT5, a gene...

  12. Recovery of (/sup 3/H)noradrenaline from different metabolic compartments of rat brain with respect to the role of catechol-O-methyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Koester, G.; Goede, E.; Breuer, H.

    1984-03-01

    Rats were treated with reserpine, desmethyl-imipramine, or carrier, either alone or in combination with tropolone. Either 10 min (t1) or 1 h (t2) after intraventricular injection of (/sup 3/H)noradrenaline, they were decapitated. The total /sup 3/H activity and the recovery of (/sup 3/H)noradrenaline were determined in tissue extracts from various brain regions. Maximum total /sup 3/H activity was measured at t1 in all tropolone-treated rats; the mean sum of these results served as an estimate of the initial tissue concentration of (/sup 3/H)noradrenaline. At t1, 40-50% of the sum of (/sup 3/H)noradrenaline and its metabolites was recovered unchanged in normal rats; reserpine and DMI reduced the recovery to 18-27%. In all groups, the decline of (/sup 3/H)noradrenaline was retarded after t1. Inhibition of catechol-O-methyltransferase by tropolone caused consistently elevated (/sup 3/H)noradrenaline levels, but did not affect the metabolic rate after t1 when compared with similarly pretreated, but tropolone-free rats. Thus, if catechol-O-methyltransferase was inhibited during the injection of (/sup 3/H)noradrenaline, a higher percentage of the amine had been taken up into spaces with a slow noradrenaline turnover. The maximum increase was seen when the neuronal uptake1 was inhibited by desmethylimipramine. This supported the hypothesis that an additional extraneuronal space exists, in addition to the known intraneuronal and extraneuronal compartments, which has a slow noradrenaline turnover. The tropolone effect on the noradrenaline recovery possibly shows that there might be a saturable ''methylating system,'' similar to that described for the periphery, in which catechol-O-methyltransferase is linked to the extraneuronal uptake.

  13. Coronavirus Nonstructural Protein 16 Is a Cap-0 Binding Enzyme Possessing (Nucleoside-2′O)-Methyltransferase Activity▿

    Science.gov (United States)

    Decroly, Etienne; Imbert, Isabelle; Coutard, Bruno; Bouvet, Mickaël; Selisko, Barbara; Alvarez, Karine; Gorbalenya, Alexander E.; Snijder, Eric J.; Canard, Bruno

    2008-01-01

    The coronavirus family of positive-strand RNA viruses includes important pathogens of livestock, companion animals, and humans, including the severe acute respiratory syndrome coronavirus that was responsible for a worldwide outbreak in 2003. The unusually complex coronavirus replicase/transcriptase is comprised of 15 or 16 virus-specific subunits that are autoproteolytically derived from two large polyproteins. In line with bioinformatics predictions, we now show that feline coronavirus (FCoV) nonstructural protein 16 (nsp16) possesses an S-adenosyl-l-methionine (AdoMet)-dependent RNA (nucleoside-2′O)-methyltransferase (2′O-MTase) activity that is capable of cap-1 formation. Purified recombinant FCoV nsp16 selectively binds to short capped RNAs. Remarkably, an N7-methyl guanosine cap (7MeGpppAC3-6) is a prerequisite for binding. High-performance liquid chromatography analysis demonstrated that nsp16 mediates methyl transfer from AdoMet to the 2′O position of the first transcribed nucleotide, thus converting 7MeGpppAC3-6 into 7MeGpppA2′OMeC3-6. The characterization of 11 nsp16 mutants supported the previous identification of residues K45, D129, K169, and E202 as the putative K-D-K-E catalytic tetrad of the enzyme. Furthermore, residues Y29 and F173 of FCoV nsp16, which may be the functional counterparts of aromatic residues involved in substrate recognition by the vaccinia virus MTase VP39, were found to be essential for both substrate binding and 2′O-MTase activity. Finally, the weak inhibition profile of different AdoMet analogues indicates that nsp16 has evolved an atypical AdoMet binding site. Our results suggest that coronavirus mRNA carries a cap-1, onto which 2′O methylation follows an order of events in which 2′O-methyl transfer must be preceded by guanine N7 methylation, with the latter step being performed by a yet-unknown N7-specific MTase. PMID:18417574

  14. Coronavirus nonstructural protein 16 is a cap-0 binding enzyme possessing (nucleoside-2'O)-methyltransferase activity.

    Science.gov (United States)

    Decroly, Etienne; Imbert, Isabelle; Coutard, Bruno; Bouvet, Mickaël; Selisko, Barbara; Alvarez, Karine; Gorbalenya, Alexander E; Snijder, Eric J; Canard, Bruno

    2008-08-01

    The coronavirus family of positive-strand RNA viruses includes important pathogens of livestock, companion animals, and humans, including the severe acute respiratory syndrome coronavirus that was responsible for a worldwide outbreak in 2003. The unusually complex coronavirus replicase/transcriptase is comprised of 15 or 16 virus-specific subunits that are autoproteolytically derived from two large polyproteins. In line with bioinformatics predictions, we now show that feline coronavirus (FCoV) nonstructural protein 16 (nsp16) possesses an S-adenosyl-L-methionine (AdoMet)-dependent RNA (nucleoside-2'O)-methyltransferase (2'O-MTase) activity that is capable of cap-1 formation. Purified recombinant FCoV nsp16 selectively binds to short capped RNAs. Remarkably, an N7-methyl guanosine cap ((7Me)GpppAC(3-6)) is a prerequisite for binding. High-performance liquid chromatography analysis demonstrated that nsp16 mediates methyl transfer from AdoMet to the 2'O position of the first transcribed nucleotide, thus converting (7Me)GpppAC(3-6) into (7Me)GpppA(2')(O)(Me)C(3-6). The characterization of 11 nsp16 mutants supported the previous identification of residues K45, D129, K169, and E202 as the putative K-D-K-E catalytic tetrad of the enzyme. Furthermore, residues Y29 and F173 of FCoV nsp16, which may be the functional counterparts of aromatic residues involved in substrate recognition by the vaccinia virus MTase VP39, were found to be essential for both substrate binding and 2'O-MTase activity. Finally, the weak inhibition profile of different AdoMet analogues indicates that nsp16 has evolved an atypical AdoMet binding site. Our results suggest that coronavirus mRNA carries a cap-1, onto which 2'O methylation follows an order of events in which 2'O-methyl transfer must be preceded by guanine N7 methylation, with the latter step being performed by a yet-unknown N7-specific MTase.

  15. An artificial neural network for membrane-bound catechol-O-methyltransferase biosynthesis with Pichia pastoris methanol-induced cultures.

    Science.gov (United States)

    Pedro, Augusto Q; Martins, Luís M; Dias, João M L; Bonifácio, Maria J; Queiroz, João A; Passarinha, Luís A

    2015-08-07

    Membrane proteins are important drug targets in many human diseases and gathering structural information regarding these proteins encourages the pharmaceutical industry to develop new molecules using structure-based drug design studies. Specifically, membrane-bound catechol-O-methyltransferase (MBCOMT) is an integral membrane protein that catalyzes the methylation of catechol substrates and has been linked to several diseases such as Parkinson's disease and Schizophrenia. Thereby, improvements in the clinical outcome of the therapy to these diseases may come from structure-based drug design where reaching MBCOMT samples in milligram quantities are crucial for acquiring structural information regarding this target protein. Therefore, the main aim of this work was to optimize the temperature, dimethylsulfoxide (DMSO) concentration and the methanol flow-rate for the biosynthesis of recombinant MBCOMT by Pichia pastoris bioreactor methanol-induced cultures using artificial neural networks (ANN). The optimization trials intended to evaluate MBCOMT expression by P. pastoris bioreactor cultures led to the development of a first standard strategy for MBCOMT bioreactor biosynthesis with a batch growth on glycerol until the dissolved oxygen spike, 3 h of glycerol feeding and 12 h of methanol induction. The ANN modeling of the aforementioned fermentation parameters predicted a maximum MBCOMT specific activity of 384.8 nmol/h/mg of protein at 30°C, 2.9 mL/L/H methanol constant flow-rate and with the addition of 6% (v/v) DMSO with almost 90% of healthy cells at the end of the induction phase. These results allowed an improvement of MBCOMT specific activity of 6.4-fold in comparison to that from the small-scale biosynthesis in baffled shake-flasks. The ANN model was able to describe the effects of temperature, DMSO concentration and methanol flow-rate on MBCOMT specific activity, as shown by the good fitness between predicted and observed values. This experimental procedure

  16. Conscientiousness is modified by genetic variation in catechol-O-methyltransferase to reduce symptom complaints in IBS patients.

    Science.gov (United States)

    Hall, Kathryn T; Tolkin, Benjamin R; Chinn, Garrett M; Kirsch, Irving; Kelley, John M; Lembo, Anthony J; Kaptchuk, Ted J; Kokkotou, Efi; Davis, Roger B; Conboy, Lisa A

    2015-01-01

    Attention to and perception of physical sensations and somatic states can significantly influence reporting of complaints and symptoms in the context of clinical care and randomized trials. Although anxiety and high neuroticism are known to increase the frequency and severity of complaints, it is not known if other personality dimensions or genes associated with cognitive function or sympathetic tone can influence complaints. Genetic variation in catechol-O-methyltransferase (COMT) is associated with anxiety, personality, pain, and response to placebo treatment. We hypothesized that the association of complaint reporting with personality might be modified by variation in the COMT val158met genotype. We administered a standard 25-item complaint survey weekly over 3-weeks to a convenience sample of 187 irritable bowel syndrome patients enrolled in a placebo intervention trial and conducted a repeated measures analysis. We found that complaint severity rating, our primary outcome, was negatively associated with the personality measures of conscientiousness (β = -0.31 SE 0.11, P = 0.003) and agreeableness (β = -0.38 SE 0.12, P = 0.002) and was positively associated with neuroticism (β = 0.24 SE 0.09, P = 0.005) and anxiety (β = 0.48 SE 0.09, P < 0.0001). We also found a significant interaction effect of COMT met alleles (β = -32.5 SE 14.1, P = 0.021). in patients genotyped for COMT val158met (N  = 87) specifically COMT × conscientiousness (β = 0.73 SE 0.26, P = 0.0042) and COMT × anxiety (β = -0.42 SE 0.16, P = 0.0078) interaction effects. These findings potentially broaden our understanding of the factors underlying clinical complaints to include the personality dimension of conscientiousness and its modification by COMT.

  17. Significant association of catechol-O-methyltransferase Val158Met polymorphism with bladder cancer instead of prostate and kidney cancer.

    Science.gov (United States)

    Chen, Yang; Yu, Xiaoxiang; Li, Tianyu; Yan, Haibiao; Mo, Zengnan

    2016-05-28

    Urological cancers occur worldwide. Many factors, among which the catechol-O-methyltransferase (COMT) Val158Met polymorphism, are said to be associated with the cancer risk. We conducted a meta-analysis to investigate the association between urological cancer susceptibility and COMT Val158Met in different genetic models. This study was based on material obtained from the PubMed, HuGENet and Embase databases. Four models including dominant (AA + AG vs. GG), recessive (AA vs. AG + GG), codominant (AA vs. AG, AA vs. GG) and per-allele analysis (A vs. G) were applied. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were used to evaluate the power of the associations. Fourteen eligible studies comprising 3,285 cases and 3,594 controls were included. Although we could not detect a positive function of the COMT Val158Met polymorphism in urological cancers, the polymorphism might be significantly associated with bladder cancer risk (dominant model [AA + AG vs. GG]: OR = 0.736, 95% CI = 0.586-0.925, I2 = 0.00%; recessive model [AA vs. AG + GG]: OR = 0.822, 95%CI = 0.653-1.035, I2 = 6.30%; codominant model [AA vs. AG]: OR = 0.908, 95% CI = 0.710-1.161, I2 = 0.00%; codominant model [AA vs. GG]: OR = 0.693, 95% CI = 0.524-0.917, I2 = 30.20%; allele analysis [A vs. G]: OR = 0.826, 95%CI = 0.717-0.951, I2 = 30.20%). The same significant associations were not found for kidney cancer and prostate cancer risk in different ethnicities. There also seemed to be no distinct effect of the polymorphism on benign prostatic hyperplasia. We suggest that bladder cancer but not prostate cancer and kidney cancer could be significantly associated with the Val158Met polymorphism. Interaction of COMT genetic and related environmental factors for urological cancers should not be ignored in future.

  18. Genetic contribution of catechol-O-methyltransferase variants in treatment outcome of low back pain: a prospective genetic association study

    Directory of Open Access Journals (Sweden)

    Omair Ahmad

    2012-05-01

    Full Text Available Abstract Background Treatment outcome of low back pain (LBP is associated with inter-individual variations in pain relief and functional disability. Genetic variants of catechol-O-methyltransferase (COMT gene have previously been shown to be associated with pain sensitivity and pain medication. This study examines the association between COMT polymorphisms and 7–11 year change in Oswestry Disability Index (ODI and Visual Analog Score (VAS for LBP as clinical outcome variables in patients treated with surgical instrumented lumbar fusion or cognitive intervention and exercise. Methods 93 unrelated patients with chronic LBP for duration of >1 year and lumbar disc degeneration (LDD were treated with lumbar fusion (N = 60 or cognitive therapy and exercises (N = 33. Standardised questionnaires assessing the ODI, VAS LBP, psychological factors and use of analgesics, were answered by patients both at baseline and at 7–11 years follow-up. Four SNPs in the COMT gene were successfully genotyped. Single marker as well as haplotype association with change in ODI and VAS LBP, were analyzed using Haploview, linear regression and R-package Haplostats. P-values were not formally corrected for multiple testing as this was an explorative study. Results Association analysis of individual SNPs adjusted for covariates revealed association of rs4633 and rs4680 with post treatment improvement in VAS LBP (p = 0.02, mean difference (β = 13.5 and p = 0.02, β = 14.2 respectively. SNPs, rs4633 and rs4680 were found to be genotypically similar and in strong linkage disequilibrium (LD. A significant association was found with covariates, analgesics (p = 0.001, β = 18.6; anxiety and depression (p = 0.008, β = 15.4 and age (p = 0.03, mean difference per year (β = 0.7 at follow-up. There was a tendency for better improvement among heterozygous patients compared to the homozygous. No association was observed for the

  19. Interactions among catechol-O-methyltransferase genotype, parenting, and sex predict children's internalizing symptoms and inhibitory control: Evidence for differential susceptibility.

    Science.gov (United States)

    Sulik, Michael J; Eisenberg, Nancy; Spinrad, Tracy L; Lemery-Chalfant, Kathryn; Swann, Gregory; Silva, Kassondra M; Reiser, Mark; Stover, Daryn A; Verrelli, Brian C

    2015-08-01

    We used sex, observed parenting quality at 18 months, and three variants of the catechol-O-methyltransferase gene (Val158Met [rs4680], intron1 [rs737865], and 3'-untranslated region [rs165599]) to predict mothers' reports of inhibitory and attentional control (assessed at 42, 54, 72, and 84 months) and internalizing symptoms (assessed at 24, 30, 42, 48, and 54 months) in a sample of 146 children (79 male). Although the pattern for all three variants was very similar, Val158Met explained more variance in both outcomes than did intron1, the 3'-untranslated region, or a haplotype that combined all three catechol-O-methyltransferase variants. In separate models, there were significant three-way interactions among each of the variants, parenting, and sex, predicting the intercepts of inhibitory control and internalizing symptoms. Results suggested that Val158Met indexes plasticity, although this effect was moderated by sex. Parenting was positively associated with inhibitory control for methionine-methionine boys and for valine-valine/valine-methionine girls, and was negatively associated with internalizing symptoms for methionine-methionine boys. Using the "regions of significance" technique, genetic differences in inhibitory control were found for children exposed to high-quality parenting, whereas genetic differences in internalizing were found for children exposed to low-quality parenting. These findings provide evidence in support of testing for differential susceptibility across multiple outcomes.

  20. The Flexible Mind Is Associated with the Catechol-O-Methyltransferase (COMT) Val[superscript 158]Met Polymorphism: Evidence for a Role of Dopamine in the Control of Task-Switching

    Science.gov (United States)

    Colzato, Lorenza S.; Waszak, Florian; Nieuwenhuis, Sander; Posthuma, Danielle; Hommel, Bernhard

    2010-01-01

    Genetic variability related to the catechol-O-methyltransferase (COMT) gene Val[superscript 128]Met polymorphism) has received increasing attention as a possible modulator of cognitive control functions. Recent evidence suggests that the Val[superscript 128]Met genotype may differentially affect cognitive stability and flexibility, in such a way…

  1. The Role of the Catechol-o-methyltransferase (COMT) Gene Val158Met in Aggressive Behavior, A Review of Genetic Studies

    Science.gov (United States)

    Qayyum, Arqam; Zai, Clement C.; Hirata, Yuko; Tiwari, Arun K.; Cheema, Sheraz; Nowrouzi, Behdin; Beitchman, Joseph H.; Kennedy, James L.

    2015-01-01

    Aggressive behaviors have become a major public health problem, and early-onset aggression can lead to outcomes such as substance abuse, antisocial personality disorder among other issues. In recent years, there has been an increase in research in the molecular and genetic underpinnings of aggressive behavior, and one of the candidate genes codes for the catechol-O-methyltransferase (COMT). COMT is involved in catabolizing catecholamines such as dopamine. These neurotransmitters appear to be involved in regulating mood which can contribute to aggression. The most common gene variant studied in the COMT gene is the Valine (Val) to Methionine (Met) substitution at codon 158. We will be reviewing the current literature on this gene variant in aggressive behavior. PMID:26630958

  2. Melatonin synthesis: Acetylserotonin O-methyltransferase (ASMT) is strongly expressed in a subpopulation of pinealocytes in the male rat pineal gland

    DEFF Research Database (Denmark)

    Rath, Martin Fredensborg; Coon, Steven L.; Amaral, Fernanda G.

    2016-01-01

    The rat pineal gland has been extensively used in studies of melatonin synthesis. However, the cellular localization of melatonin synthesis in this species has not been investigated. Here we focus on the localization of melatonin synthesis using immunohistochemical methods to detect the last enzyme...... in melatonin synthesis, acetylserotonin O-methyltransferase (ASMT), and in situ hybridization techniques to study transcripts encoding ASMT and two other enzymes in melatonin synthesis, tryptophan hydroxylase (TPH)-1 and aralkylamine N-acetyltransferase. In sections of the rat pineal gland, marked cell......-to-cell differences were found in ASMT immunostaining intensity and in the abundance of Tph1, Aanat, and Asmt transcripts. ASMT immunoreactivity was localized to the cytoplasm in pinealocytes in the parenchyma of the superficial pineal gland, and immunopositive pinealocytes were also detected in the pineal stalk...

  3. The catechol-O-methyltransferase (COMT) Val158Met genotype modulates working memory-related dorsolateral prefrontal response and performance in bipolar disorder

    DEFF Research Database (Denmark)

    Miskowiak, K. W.; Kjærstad, H. L.; Støttrup, M. M.

    2017-01-01

    -O-methyltransferase (COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity. This functional magnetic resonance imaging (fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working...... memory in BD. METHODS: Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test...... Automated Battery (CANTAB) Spatial Working Memory test outside the scanner. RESULTS: During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral...

  4. Radiometric assay for phenylethanolamine N-methyltransferase and catechol O-methyltransferase in a single tissue sample: application to rat hypothalamic nuclei, pineal gland, and heart

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    Culman, J.; Torda, T.; Weise, V.K.

    1987-08-01

    A simple and highly sensitive method for simultaneous assay of phenylethanolamine N-methyltransferase (PNMT) and catechol O-methyltransferase (COMT) is described. These enzymes are determined in a single tissue homogenate using S-(methyl-/sup 3/H) adenosyl-L-methionine as methyl donor and sequentially incubating with the substrates phenylethanolamine and epinephrine. The radioactive products of the enzymatic reactions, N-methylphenylethanolamine and metanephrine, are extracted and then separated by thin-layer chromatography. The identity of the reaction products has been established chromatographically and the conditions for both enzymatic reactions in the assay procedure have been defined. Measurement of PNMT activity in the rat pineal gland or in minute fragments of other tissues (e.g., brain nuclei) has not been possible using previously described methods. Activities of PNMT and COMT in the rat pineal gland, various hypothalamic nuclei, and the auricular and ventricular myocardia are herein reported.

  5. cap alpha. -deuterium and carbon-13 isotope effects for methyl transfer catalyzed by catechol O-methyltransferase. S/sub N/2-like transition state

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    Hegazi, M.F.; Borchardt, R.T.; Schowen, R.L.

    1979-07-18

    The rate at near saturation of methylation of 3,4-dihydroxyacetophenone by S-adenosyl-L-methionine, catalyzed by rat-liver catechol O-methyltransferase at pH 7.58 and 37.00 +- 0.05/sup 0/C, is increased by deuteration of the methyl group (V/sub CH/sub 3///V/sub CD/sub 3// = 0.83 +- 0.05) and decreased by introduction of /sup 13/C to the methyl group (V/sub 12//V/sub 13/ = 1.09 +- 0.05). This shows the rate-determining step to be transfer of the methyl group, with an S/sub N/2-like transition state in which the methyl is located symmetrically and tightly between leaving group and nucleophile.

  6. No evidence of association between Catechol-O-Methyltransferase (COMT Val158Met genotype and performance on neuropsychological tasks in children with ADHD: A case-control study

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    O'Donovan Michael C

    2004-06-01

    Full Text Available Abstract Background Several studies have suggested an association between the functional Val158Met polymorphism in the Catechol-O-Methyltransferase (COMT gene and neurocognitive performance. Two studies showed that subjects with the low activity Met allele performed better on the Wisconsin Card Sorting Test (WCST and another study found an effect on processing speed and attention. Methods We set out to examine the association between the Val158Met polymorphism and performance on neurocognitive tasks including those tapping working memory, attention and speed, impulsiveness and response inhibition in a sample of 124 children with ADHD. Task performance for each genotypic group was compared using analysis of variance. Results There was no evidence of association with performance on any of the neurocognitive tasks. Conclusions We conclude that Val158Met COMT genotype is not associated with neurocognitive performance in our sample.

  7. Synergistic associations of catechol-O-methyltransferase and brain-derived neurotrophic factor with executive function in aging are selective and modified by apolipoprotein E.

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    Sapkota, Shraddha; Vergote, David; Westaway, David; Jhamandas, Jack; Dixon, Roger A

    2015-01-01

    Genetic polymorphisms of catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) have shown promising but inconsistent linkages with executive function (EF) in normal aging. We tested (1) independent contributions of COMT and BDNF risk; (2) potential magnification by risk-related interactions or additive effects with age; and (3) effect modification through stratification by apolipoprotein E (APOE) (risk: ε4+). Multiple linear regression models were applied with nondemented older adults (N = 634; range: 53-95 years) for an EF latent variable. No independent effects of BDNF or COMT on EF were observed. Additive (but not interactive) effects of COMT, BDNF, and age showed that older adults with a high-risk allelic combination performed differentially worse. Of 2 tested models of synergistic effects, the additive approach selectively supported a magnification hypothesis, which was qualified by the presence or the absence of APOE ε4. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. The Role of the Catechol-o-Methyltransferase (COMT) GeneVal158Met in Aggressive Behavior, a Review of Genetic Studies.

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    Qayyum, Arqam; Zai, Clement C; Hirata, Yuko; Tiwari, Arun K; Cheema, Sheraz; Nowrouzi, Behdin; Beitchman, Joseph H; Kennedy, James L

    2015-01-01

    Aggressive behaviors have become a major public health problem, and early-onset aggression can lead to outcomes such as substance abuse, antisocial personality disorder among other issues. In recent years, there has been an increase in research in the molecular and genetic underpinnings of aggressive behavior, and one of the candidate genes codes for the catechol-O-methyltransferase (COMT). COMT is involved in catabolizing catecholamines such as dopamine. These neurotransmitters appear to be involved in regulating mood which can contribute to aggression. The most common gene variant studied in the COMT gene is the Valine (Val) to Methionine (Met) substitution at codon 158. We will be reviewing the current literature on this gene variant in aggressive behavior.

  9. Systematic analysis of O-methyltransferase gene family and identification of potential members involved in the formation of O-methylated flavonoids in Citrus.

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    Liu, Xiaogang; Luo, Yan; Wu, Hongkun; Xi, Wanpeng; Yu, Jie; Zhang, Qiuyun; Zhou, Zhiqin

    2016-01-10

    The O-methylation of various secondary metabolites is mainly catalyzed by S-adenosyl-l-methionine (SAM)-dependent O-methyltransferase (OMT) proteins that are encoded by the O-methyltransferase gene family. Citrus fruits are a rich source of O-methylated flavonoids that have a broad spectrum of biological activities, including anti-inflammatory, anticarcinogenic, and antiatherogenic properties. However, little is known about this gene family and its members that are involved in the O-methylation of flavonoids and their regulation in Citrus. In this study, 58 OMT genes were identified from the entire Citrus sinensis genome and compared with those from 3 other representative dicot plants. A comprehensive analysis was performed, including functional/substrate predictions, identification of chromosomal locations, phylogenetic relationships, gene structures, and conserved motifs. Distribution mapping revealed that the 58 OMT genes were unevenly distributed on the 9 citrus chromosomes. Phylogenetic analysis of 164 OMT proteins from C.sinensis, Arabidopsis thaliana, Populus trichocarpa, and Vitis vinifera showed that these proteins were categorized into group I (COMT subfamily) and group II (CCoAOMT subfamily), which were further divided into 10 and 2 subgroups, respectively. Finally, digital gene expression and quantitative real-time polymerase chain reaction analyses revealed that citrus OMT genes had distinct temporal and spatial expression patterns in different tissues and developmental stages. Interestingly, 18 and 11 of the 27 genes predicted to be involved in O-methylation of flavonoids had higher expression in the peel and pulp during fruit development, respectively. The citrus OMT gene family identified in this study might help in the selection of appropriate candidate genes and facilitate functional studies in Citrus. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Positron emission tomography in drug evaluation: Influence of three different catechol-O-methyltransferase inhibitors on metabolism of [NCA] 6-[{sup 18}F]fluoro-l-dopa in Rhesus monkey

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    Guenther, I.; Psylla, M.; Reddy, G.N.; Antonini, A.; Vontobel, P.; Reist, H.W.; Zollinger, A.; Nickles, R.J.; Beer, H.-F.; Schubiger, P.A.; Leenders, K.L

    1995-10-01

    We compared the influence of three different catechol-O-methyltransferase (COMT) inhibitors (CGP 28014, OR-611 and Ro 40-7592) on the metabolism of no-carrier-added (NCA) 6-[{sup 18}F]fluoro-l-dopa (6-FDOPA) in one Rhesus monkey. All three COMT inhibitors improved 6-FDOPA availability in plasma, increased the specific uptake in the brain and thus improved 6-FDOPA uptake measurements using positron emission tomography (PET). Best results were obtained with Ro 40-7592.

  11. Look beyond Catechol-O-Methyltransferase genotype for cathecolamines derangement in migraine: the BioBIM rs4818 and rs4680 polymorphisms study.

    Science.gov (United States)

    De Marchis, Maria Laura; Barbanti, Piero; Palmirotta, Raffaele; Egeo, Gabriella; Aurilia, Cinzia; Fofi, Luisa; Piroso, Serena; Ialongo, Cristiano; Della-Morte, David; D'Andrea, Giovanni; Ferroni, Patrizia; Guadagni, Fiorella

    2015-01-01

    The study of COMT gene polymorphisms in migraine could be of particular interest since impaired catecholaminergic neurotransmission, namely chronic dopaminergic and noradrenergic hypofunction, is a peculiar migraine trait. In this study, for the first time, we focused on the role of COMT rs4818 genetic variant, the polymorphism most strongly affecting COMT activity, in migraine. This study was conducted in a cohort of carefully clinical characterized Caucasian migraineurs recruited in a specifically dedicated migraine biobank, providing also a replication study on rs4680 polymorphism. Genotyping of rs4680 and rs4818 Catechol-O-Methyltransferase gene polymorphisms was performed on 380 unrelated migraine patients, and 132 healthy subjects matched for age, gender and race-ethnicity, with no clinical evidence or family history of migraine or other neurological diseases. The rs4680 and rs4818 genotypic frequencies did not deviate from those expected for a population in Hardy-Weinberg equilibrium and did not correlate with demographics or clinical migraine features, even when considering migraine subtypes such as dopaminergic migraine, menstrual migraine, and menstrually related migraine . COMT genotype does not influence migraine susceptibility or phenotype, even considering rs4818 polymorphism and peculiar clinical subtypes. This finding prompts to go over COMT to explain catecholamine derangement in migraine, exploring enzymes involved in catecholamines synthesis and catabolism, such as monoamine-oxidase, dopamine beta-hydroxylase, tyrosine-hydroxylase or tyrosine-decarboxylase, among others.

  12. Catechol-O-methyltransferase polymorphism is associated with the cortico-cerebellar functional connectivity of executive function in children with attention-deficit/hyperactivity disorder.

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    Mizuno, Yoshifumi; Jung, Minyoung; Fujisawa, Takashi X; Takiguchi, Shinichiro; Shimada, Koji; Saito, Daisuke N; Kosaka, Hirotaka; Tomoda, Akemi

    2017-07-07

    The cerebellum, although traditionally considered a motor structure, has been increasingly recognized to play a role in regulating executive function, the dysfunction of which is a factor in attention-deficit/hyperactivity disorder (ADHD). Additionally, catechol-O-methyltransferase (COMT) polymorphism has been reported to be associated with executive function. We examined whether the cortico-cerebellar executive function network is altered in children with ADHD and whether COMT polymorphism is associated with the altered network. Thirty-one children with ADHD and thirty age- and IQ-matched typically developing (TD) controls underwent resting-state functional MRI, and functional connectivity of executive function-related Crus I/II in the cerebellum was analysed. COMT Val158Met genotype data were also obtained from children with ADHD. Relative to TD controls, children with ADHD showed significantly lower functional connectivity of the right Crus I/II with the left dorsolateral prefrontal cortex. Additionally, the functional connectivity of children with ADHD was modulated by COMT polymorphism, with Met-carriers exhibiting significantly lower functional connectivity than the Val/Val genotype. These results suggest the existence of variations, such as ethnic differences, in COMT genetic effects on the cortico-cerebellar executive function network. These variations contribute to heterogeneity in ADHD. Further neuroimaging genetics study might lead to the development of fundamental therapies that target ADHD pathophysiology.

  13. Polymorphisms in catechol-O-methyltransferase and cytochrome p450 subfamily 19 genes predispose towards Madurella mycetomatis-induced mycetoma susceptibility.

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    van de Sande, Wendy W J; Fahal, Ahmed; Tavakol, Mehri; van Belkum, Alex

    2010-11-01

    Mycetoma caused by Madurella mycetomatis is a devastating and neglected disease which primarily affects males. Since this predominance cannot be easily explained by behaviour differences between men and women, other factors, including sex hormones, could be the cause. To monitor for possible deficiencies in hormone synthesis among mycetoma patients, we investigated the types and allele frequencies of the genes encoding for catechol-O-methyltransferase (COMT), cytochrome p450 subfamily 1 (CYP1B1), cytochrome p450 subfamily 17 (CYP17), cytochrome p450 subfamily 19 (CYP19) and hydroxysteroid dehydrogenase 3B (HSD3B). Significant differences in allele distribution were demonstrated for CYP19 (P=0.004) and COMT (P=0.005), as well as gender dimorphism for both CYP19 and COMT polymorphisms. The COMT polymorphism was associated with lesion size. The genotypes obtained for COMT and CYP19 were connected with higher 17β-estradiol production, which was confirmed by significantly elevated serum levels of 17β-estradiol in male patients. In contrast, lowered levels of dehydroepiandrosteron (DHEA) were found in mycetoma patients. The in vitro growth of M. mycetomatis was not influenced by 17β-estradiol, progesterone, DHEA and testosterone. The differences in hormone levels we noted between mycetoma patients and healthy controls did not directly affect the fungus itself. Indirect effects on the patients' hormone regulated immune states are the more likely explanations for mycetoma susceptibility.

  14. Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt)

    Science.gov (United States)

    Erickson, Timothy; Morgan, Clive P; Olt, Jennifer; Hardy, Katherine; Busch-Nentwich, Elisabeth; Maeda, Reo; Clemens, Rachel; Krey, Jocelyn F; Nechiporuk, Alex; Barr-Gillespie, Peter G; Marcotti, Walter; Nicolson, Teresa

    2017-01-01

    Transmembrane O-methyltransferase (TOMT/LRTOMT) is responsible for non-syndromic deafness DFNB63. However, the specific defects that lead to hearing loss have not been described. Using a zebrafish model of DFNB63, we show that the auditory and vestibular phenotypes are due to a lack of mechanotransduction (MET) in Tomt-deficient hair cells. GFP-tagged Tomt is enriched in the Golgi of hair cells, suggesting that Tomt might regulate the trafficking of other MET components to the hair bundle. We found that Tmc1/2 proteins are specifically excluded from the hair bundle in tomt mutants, whereas other MET complex proteins can still localize to the bundle. Furthermore, mouse TOMT and TMC1 can directly interact in HEK 293 cells, and this interaction is modulated by His183 in TOMT. Thus, we propose a model of MET complex assembly where Tomt and the Tmcs interact within the secretory pathway to traffic Tmc proteins to the hair bundle. DOI: http://dx.doi.org/10.7554/eLife.28474.001 PMID:28534737

  15. Elicitor-Induced Association of Isoflavone O-Methyltransferase with Endomembranes Prevents the Formation and 7-O-Methylation of Daidzein during Isoflavonoid Phytoalexin Biosynthesis

    Science.gov (United States)

    Liu, Chang-Jun; Dixon, Richard A.

    2001-01-01

    The bioactive isoflavonoids of the Leguminosae often are methylated on the 4′-position of their B-rings. Paradoxically, reverse genetic evidence implicates alfalfa isoflavone O-methyltransferase (IOMT) in the biosynthesis of 4′-O-methylated isoflavonoids such as the phytoalexin medicarpin in vivo, whereas biochemical studies indicate that IOMT has strict specificity for methylation of the A-ring 7-hydroxyl of daidzein, the presumed substrate for O-methylation, in vitro. Radiolabeling and isotope dilution studies now confirm that daidzein is not an intermediate in isoflavonoid phytoalexin biosynthesis in alfalfa. Furthermore, protein gel blot analysis and confocal microscopy of a transiently expressed IOMT–green fluorescent protein fusion in alfalfa leaves show that the operationally soluble IOMT localizes to endomembranes after elicitation of the isoflavonoid pathway. We propose that IOMT colocalizes with the endoplasmic reticulum–associated isoflavone synthase cytochrome P450 to ensure rapid B-ring methylation of the unstable 2,4′,7-trihydroxyisoflavanone product of isoflavone synthase, thereby preventing its dehydration to daidzein and subsequent A-ring methylation by free IOMT. In this way, metabolic channeling at the entry point into isoflavonoid phytoalexin biosynthesis protects an unstable intermediate from an unproductive metabolic conversion. PMID:11752378

  16. Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders.

    Science.gov (United States)

    Harrison, Paul J; Tunbridge, Elizabeth M

    2008-12-01

    Sex differences in the genetic epidemiology and clinical features of psychiatric disorders are well recognized, but the individual genes contributing to these effects have rarely been identified. Catechol-O-methyltransferase (COMT), which metabolizes catechol compounds, notably dopamine, is a leading candidate. COMT enzyme activity, and the neurochemistry and behavior of COMT null mice, are both markedly sexually dimorphic. Genetic associations between COMT and various psychiatric phenotypes frequently show differences between men and women. Many of these differences are unconfirmed or minor, but some appear to be of reasonable robustness and magnitude; eg the functional Val(158)Met polymorphism in COMT is associated with obsessive-compulsive disorder in men, with anxiety phenotypes in women, and has a greater impact on cognitive function in boys than girls. Sex-specific effects of COMT are usually attributed to transcriptional regulation by estrogens; however, additional mechanisms are likely to be at least as important. Here we review the evidence for a sexually dimorphic influence of COMT upon psychiatric phenotypes, and discuss its potential basis. We conclude that despite the evidence being incomplete, and lacking a unifying explanation, there are accumulating and in places compelling data showing that COMT differentially impacts on brain function and dysfunction in men and women. Since sex differences in the genetic architecture of quantitative traits are the rule not the exception, we anticipate that additional evidence will emerge for sexual dimorphisms, not only in COMT but also in many other autosomal genes.

  17. Production of Two Novel Methoxy-Isoflavones from Biotransformation of 8-Hydroxydaidzein by Recombinant Escherichia coli Expressing O-Methyltransferase SpOMT2884 from Streptomyces peucetius

    Directory of Open Access Journals (Sweden)

    Chien-Min Chiang

    2015-11-01

    Full Text Available Biotransformation of 8-hydroxydaidzein by recombinant Escherichia coli expressing O-methyltransferase (OMT SpOMT2884 from Streptomyces peucetius was investigated. Two metabolites were isolated and identified as 7,4′-dihydroxy-8-methoxy-isoflavone (1 and 8,4′-dihydroxy-7-methoxy-isoflavone (2, based on mass, 1H-nuclear magnetic resonance (NMR and 13C-NMR spectrophotometric analysis. The maximum production yields of compound (1 and (2 in a 5-L fermenter were 9.3 mg/L and 6.0 mg/L, respectively. The two methoxy-isoflavones showed dose-dependent inhibitory effects on melanogenesis in cultured B16 melanoma cells under non-toxic conditions. Among the effects, compound (1 decreased melanogenesis to 63.5% of the control at 25 μM. This is the first report on the 8-O-methylation activity of OMT toward isoflavones. In addition, the present study also first identified compound (1 with potent melanogenesis inhibitory activity.

  18. [Association study of the Val158Met polymorphism of the catechol-O-methyltransferase gene and alcoholism and heroin dependence: the role of a family history].

    Science.gov (United States)

    Kibitov, A O; Voskoboeva, E Iu; Brodianskiĭ, V M; Chuprova, N A; Smirnova, E V

    2010-01-01

    The aim of this study was to investigate the association the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene and predisposition to alcoholism and heroin dependence. The authors genotyped DNA samples from 964 Russian males (395 alcoholics, 243 heroin addicts and 326 healthy controls). The association between the Val158Met COMT polymorphism and alcoholism was found in males with high density of family history (two or more blood relatives with alcoholism within the family). In this group, the frequency of a L (Met) allele was significantly higher in comparison with controls (p=0,001), patients without family history (p=0,034) and patients with the mild density of family history (p=0,0005). The frequency of the HH (ValVal) genotype was reduced as well compared to the controls (p=0,003). In the group of heroin addicts with the mild density of family history, there was a trend to lower frequency of the HH genotype (p=0,058) compared to patients without family history. The results suggest that the functional Val158Met COMT polymorphism is one of the significant markers of genetic predisposition to addiction diseases.

  19. The catechol-o-methyltransferase Val158Met polymorphism modulates the intrinsic functional network centrality of the parahippocampal cortex in healthy subjects

    Science.gov (United States)

    Zhang, Xiaolong; Li, Jin; Qin, Wen; Yu, Chunshui; Liu, Bing; Jiang, Tianzi

    2015-01-01

    The influence of catechol-o-methyltransferase (COMT) Val158Met on brain activation and functional connectivity has been widely reported. However, voxel-wise effects of this genotype on resting-state brain networks remain unclear. Here, we used resting-state fMRI and eigenvector centrality to examine the effects of COMT Val158Met genotypes on the connection patterns of the brain network and working memory (WM) in healthy, young Val/Val and Met carrier subjects. There were significant differences in the performance level on the 2-back WM task between the different COMT genotypes: Val/Val individuals exhibited a higher correct rate compared to the Met carriers. A two-sample t test was used to examine the differences in the eigenvector centrality maps, using age and gender as covariates of no interest, between the Val/Val and Met carriers. We found that the Val/Val individuals exhibited significantly higher eigenvector centrality compared to the Met carriers in the left parahippocampal cortex. Furthermore, a significantly positive correlation between the mean eigenvector centrality of the significant cluster and the correct rate of the 2-back WM task was observed. By using a voxel-wise data-driven method, our findings may provide plausible implications regarding individual differences in the genetic contribution of COMT Val158Met to the brain network and cognition. PMID:26054510

  20. Determination of methylated CpG sites in the promoter region of catechol-O-methyltransferase (COMT and their involvement in the etiology of tobacco smoking

    Directory of Open Access Journals (Sweden)

    Qing Xu

    2010-06-01

    Full Text Available We previously reported that catechol-O-methyltransferase (COMT is significantly associated with nicotine dependence (ND in humans. In this study, we examined whether there exists any difference in the extent of methylation of CpG dinucleotides in the promoter region of COMT in smokers and nonsmokers by analyzing the methylation status of cytosines at 33 CpG sites through direct sequencing of bisulfite-treated DNA (N = 50 per group. The cytosine was methylated at 13 of 33 CpG sites, and two of these sites showed significant differences between smokers and matched nonsmoker controls. Specifically, in the -193 CpG site, the degree of methylation was 19.1% in smokers and 13.2% in nonsmokers (P < 0.01. This finding was confirmed by methylation-specific PCR using an additional 100 smoker and 100 nonsmoker control samples, which showed the degree of methylation to be 22.2% in smokers and 18.3% in nonsmokers (P < 0.01. For the -39 CpG site, the degree of methylation was 9.2% in smokers, whereas no methylation was found in nonsmoker controls. Together, our findings provide the first molecular explanation at the epigenetic level for the association of ND with methylation of the COMT promoter, implying that methylation plays a role in smoking dependence.

  1. Optimization of fermentation conditions for the production of human soluble catechol-O-methyltransferase by Escherichia coli using artificial neural network.

    Science.gov (United States)

    Silva, R; Ferreira, S; Bonifácio, M J; Dias, J M L; Queiroz, J A; Passarinha, L A

    2012-08-31

    The aim of this work was to optimize the temperature, pH and stirring rate of the production of human soluble catechol-O-methyltransferase (hSCOMT) in a batch Escherichia coli culture process. A central composite design (CCD) was firstly employed to design the experimental assays used in the evaluation of these operational parameters on the hSCOMT activity for a semi-defined and complex medium. Predictive artificial neural network (ANN) models of the hSCOMT activity as function of the combined effects of these variables was proposed based on this exploratory experiments performed for the two culture media. The regression coefficients (R(2)) for the final models were 0.980 and 0.983 for the semi-defined and complex medium, respectively. The ANN models predicted a maximum hSCOMT activity of 183.73 nmol/h, at 40 °C, pH 6.5 and stirring rate of 351 rpm, and 132.90 nmol/h, at 35 °C, pH 6.2 and stirring rate of 351 rpm, for semi-defined and complex medium, respectively. These results represent a 4-fold increase in total hSCOMT activity by comparison to the standard operational conditions used for this bioprocess at slight scale. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Melatonin Synthesis: Acetylserotonin O-Methyltransferase (ASMT) Is Strongly Expressed in a Subpopulation of Pinealocytes in the Male Rat Pineal Gland.

    Science.gov (United States)

    Rath, Martin F; Coon, Steven L; Amaral, Fernanda G; Weller, Joan L; Møller, Morten; Klein, David C

    2016-05-01

    The rat pineal gland has been extensively used in studies of melatonin synthesis. However, the cellular localization of melatonin synthesis in this species has not been investigated. Here we focus on the localization of melatonin synthesis using immunohistochemical methods to detect the last enzyme in melatonin synthesis, acetylserotonin O-methyltransferase (ASMT), and in situ hybridization techniques to study transcripts encoding ASMT and two other enzymes in melatonin synthesis, tryptophan hydroxylase (TPH)-1 and aralkylamine N-acetyltransferase. In sections of the rat pineal gland, marked cell-to-cell differences were found in ASMT immunostaining intensity and in the abundance of Tph1, Aanat, and Asmt transcripts. ASMT immunoreactivity was localized to the cytoplasm in pinealocytes in the parenchyma of the superficial pineal gland, and immunopositive pinealocytes were also detected in the pineal stalk and in the deep pineal gland. ASMT was found to inconsistently colocalize with S-antigen, a widely used pinealocyte marker; this colocalization was seen in cells throughout the pineal complex and also in displaced pinealocyte-like cells of the medial habenular nucleus. Inconsistent colocalization between ASMT and TPH protein was also detected in the pineal gland. ASMT protein was not detected in extraepithalamic parts of the central nervous system or in peripheral tissues. The findings in this report are of special interest because they provide reason to suspect that melatonin synthesis varies significantly among individual pinealocytes.

  3. Abiotic stresses differentially affect the expression of O-methyltransferase genes related to methoxypyrazine biosynthesis in seeded and parthenocarpic fruits of Vitis vinifera (L.).

    Science.gov (United States)

    Vallarino, José G; Gainza-Cortés, Felipe; Verdugo-Alegría, Claudio; González, Enrique; Moreno, Yerko M

    2014-07-01

    MPs (3-alkyl-2-methoxypyrazines) are grape-derived aroma compounds that are associated with detrimental herbaceous flavours in some wines. It is well known that several viticultural and environmental parameters can modulate MP concentrations in grapes, although comprehensive molecular studies have not been conducted in this field. Although the biosynthesis pathway of MPs has not been fully elucidated, four Vitis vinifera O-methyltransferase genes (VvOMT1-4) have been related to be involved in MP biosynthesis. We assessed whether different abiotic stresses induction have an impact on MP levels in grapes and wines from seeded and parthenocarpic fruits. Our results show that the timing of VvOMT3 expression is associated with the period of MPs accumulation in seeded fruits during both abiotic stresses, whereas no association was found in parthenocarpic fruits. These results are discussed in the context of how different viticultural practices can modulate VvOMT gene expression, which has a direct impact on MPs levels in wines. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Interaction between the Val158Met catechol-O-methyltransferase gene variant and second-generation antipsychotic treatment on blood pressure in children.

    Science.gov (United States)

    Cote, A T; Panagiotopoulos, C; Devlin, A M

    2015-02-01

    Second-generation antipsychotic (SGA) medications are associated with cardiometabolic risk factors such as obesity and elevated blood pressure (BP) in some individuals. The goal of this study is to determine whether the Val158Met variant (rs4680) in the catechol-O-methyltransferase (COMT) gene, associated with BP in adults, is associated with elevated BP in SGA-treated children. A cross-sectional population of SGA-treated (n=134) and SGA-naive (n=168) children, ⩽18 years of age, were genotyped and assessed for markers of cardiometabolic health. An interaction was found between SGA treatment and COMT genotype for BP. After adjusting for covariates, SGA-treated children with the Met allele had higher systolic and diastolic BP (P=0.014 and P=0.034, respectively), and higher fasting glucose concentrations (P=0.030) compared with children with the Val/Val genotype. This was not observed in SGA-naive children. The Met allele of the COMT Val158Met variant may identify SGA-treated children at risk for elevated BP and fasting blood glucose concentrations.

  5. Association between catechol-O-methyltransferase (COMT) Val/Met genotype and smoking cessation treatment with nicotine: a meta-analysis.

    Science.gov (United States)

    Choi, Hye Duck; Shin, Wan Gyoon

    2015-11-01

    Catechol-O-methyltransferase (COMT) is one of the major degradative pathways of dopamine and COMT Val/Met polymorphisms are associated with the enzyme activity, which is related to dopamine involvement in the nicotine addiction process. However, the reported results of several genetic studies are not consistent. We reviewed the smoking cessation outcomes among previously reported studies by comparing COMT polymorphism. A total of five studies were assessed in the present meta-analysis and the Met/Met, Val/Met or Val/Val genotype were compared with respect to smoking cessation outcomes. As the results, any significant association between COMT polymorphism and smoking cessation were not observed. In the subgroup analysis for evaluating the association between COMT polymorphism and smoking cessation therapy, three studies were assessed by comparing two groups (Met/Met vs Val/Met plus Val/Val). A significant association between COMT polymorphism and smoking cessation was observed (odds ratio: 1.871 and 95% CI: 1.382-2.534). The COMT polymorphisms are associated with the outcomes following smoking cessation treatment with nicotine.

  6. The catechol-o-methyltransferase Val158 Met polymorphism modulates organization of regional cerebral blood flow response to working memory in adults.

    Science.gov (United States)

    Heim, Alicia F; Coyne, Melissa J; Kamboh, M Ilyas; Ryan, Christopher; Jennings, J Richard

    2013-11-01

    This study examined the effect of catechol-o-methyltransferase (COMT) Val(158)Met genotypes on the co-activation of brain areas involved in cognition during a working memory (WM) task. The pattern of concomitant region of interest (ROI) activation during WM performance varied by genotype: Val/Val showing the least and Met/Met the most covariance. There were no differences of performance on the WM task between the COMT genotypes. However, relatively better performance was associated with less concomitance of dorsolateral prefrontal cortex (DLPFC) and cingulate cortex for Val/Val, but more concomitance of DLPFC with AH for Met/Met. Within genotypes WM performance was significantly correlated with rCBF to the amygdala/hippocampus (AH) for Val/Val (r = 0.44, p = 0.009), to the parietal lobe for Val/Met (r = 0.29, p = 0.03), and to the thalamus for Met/Met (r = 0.32, p = 0.04). Different genotypes showed different regional specificity and concomitant activation patterns suggesting that varying dopamine availability induces different brain processing pathways to achieve similar WM performance. © 2013.

  7. Association between the Catechol-O-Methyltransferase (COMT) Val¹⁵⁸Met Polymorphism and Alexithymia in Patients with Obsessive-Compulsive Disorder.

    Science.gov (United States)

    Koh, Min Jung; Kang, Jee In; Namkoong, Kee; Lee, Su Young; Kim, Se Joo

    2016-05-01

    Alexithymia, defined as a deficit in the ability to recognize and describe one's own feelings, may be related to the development and maintenance of obsessive-compulsive symptoms. The aim of this study was to evaluate the association between the catechol-O-methyltransferase (COMT) Val¹⁵⁸Met polymorphism and alexithymia in patients with obsessive-compulsive disorder (OCD). We recruited 244 patients with OCD (169 males, 75 females). Alexithymia was assessed using the 20-item Toronto Alexithymia Scale (TAS-20), and genotyping of the COMT Val¹⁵⁸Met polymorphism was evaluated. Patients with the COMT Val/Val genotype had significantly higher total and "difficulty identifying feelings" (DIF) subdimension scores than those with the Val/Met or Met/Met genotypes. Patients with the COMT Val/Val genotype had significantly higher "difficulty describing feelings" (DDF) subdimension scores than those with the COMT Val/Met genotype. However, there were no differences in the scores for the "externally oriented thinking" (EOT) subdimension among the three genotypes. These results indicate that the high-activity Val allele of the COMT Val¹⁵⁸Met polymorphism is associated with increased alexithymic traits in patients with OCD. The present finding suggests that alexithymia is an endophenotype of OCD that is mediated by the COMT Val¹⁵⁸Met polymorphism.

  8. Structure related effects of flavonoid aglycones on cell cycle progression of HepG2 cells: Metabolic activation of fisetin and quercetin by catechol-O-methyltransferase (COMT).

    Science.gov (United States)

    Poór, Miklós; Zrínyi, Zita; Kőszegi, Tamás

    2016-10-01

    Dietary flavonoids are abundant in the Plant Kingdom and they are extensively studied because of their manifold pharmacological activities. Recent studies highlighted that cell cycle arrest plays a key role in their antiproliferative effect in different tumor cells. However, structure-activity relationship of flavonoids is poorly characterized. In our study the influence of 18 flavonoid aglycones (as well as two metabolites) on cell cycle distribution was investigated. Since flavonoids are extensively metabolized by liver cells, HepG2 tumor cell line was applied, considering the potential metabolic activation/inactivation of flavonoids. Our major observations are the followings: (1) Among the tested compounds diosmetin, fisetin, apigenin, lutelin, and quercetin provoked spectacular extent of G2/M phase cell cycle arrest. (2) Inhibition of catechol-O-methyltransferase enzyme by entacapone decreased the antiproliferative effects of fisetin and quercetin. (3) Geraldol and isorhamnetin (3'-O-methylated metabolites of fisetin and quercetin, respectively) demonstrated significantly higher antiproliferative effect on HepG2 cells compared to the parent compounds. Based on these results, O-methylated flavonoid metabolites or their chemically modified derivatives may be suitable candidates of tumor therapy in the future. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Investigating the genetic basis of theory of mind (ToM: the role of catechol-O-methyltransferase (COMT gene polymorphisms.

    Directory of Open Access Journals (Sweden)

    Haiwei Xia

    Full Text Available The ability to deduce other persons' mental states and emotions which has been termed 'theory of mind (ToM' is highly heritable. First molecular genetic studies focused on some dopamine-related genes, while the genetic basis underlying different components of ToM (affective ToM and cognitive ToM remain unknown. The current study tested 7 candidate polymorphisms (rs4680, rs4633, rs2020917, rs2239393, rs737865, rs174699 and rs59938883 on the catechol-O-methyltransferase (COMT gene. We investigated how these polymorphisms relate to different components of ToM. 101 adults participated in our study; all were genetically unrelated, non-clinical and healthy Chinese subjects. Different ToM tasks were applied to detect their theory of mind ability. The results showed that the COMT gene rs2020917 and rs737865 SNPs were associated with cognitive ToM performance, while the COMT gene rs5993883 SNP was related to affective ToM, in which a significant gender-genotype interaction was found (p = 0.039. Our results highlighted the contribution of DA-related COMT gene on ToM performance. Moreover, we found out that the different SNP at the same gene relates to the discriminative aspect of ToM. Our research provides some preliminary evidence to the genetic basis of theory of mind which still awaits further studies.

  10. Age-Dependent Effects of Catechol-O-Methyltransferase (COMT) Gene Val158Met Polymorphism on Language Function in Developing Children.

    Science.gov (United States)

    Sugiura, Lisa; Toyota, Tomoko; Matsuba-Kurita, Hiroko; Iwayama, Yoshimi; Mazuka, Reiko; Yoshikawa, Takeo; Hagiwara, Hiroko

    2017-01-01

    The genetic basis controlling language development remains elusive. Previous studies of the catechol-O-methyltransferase (COMT) Val158Met genotype and cognition have focused on prefrontally guided executive functions involving dopamine. However, COMT may further influence posterior cortical regions implicated in language perception. We investigated whether COMT influences language ability and cortical language processing involving the posterior language regions in 246 children aged 6-10 years. We assessed language ability using a language test and cortical responses recorded during language processing using a word repetition task and functional near-infrared spectroscopy. The COMT genotype had significant effects on language performance and processing. Importantly, Met carriers outperformed Val homozygotes in language ability during the early elementary school years (6-8 years), whereas Val homozygotes exhibited significant language development during the later elementary school years. Both genotype groups exhibited equal language performance at approximately 10 years of age. Val homozygotes exhibited significantly less cortical activation compared with Met carriers during word processing, particularly at older ages. These findings regarding dopamine transmission efficacy may be explained by a hypothetical inverted U-shaped curve. Our findings indicate that the effects of the COMT genotype on language ability and cortical language processing may change in a narrow age window of 6-10 years. © The Author 2016. Published by Oxford University Press.

  11. A Single-Nucleotide Polymorphism in the Fetal Catechol-O-methyltransferase Gene is Associated With Spontaneous Preterm Birth in African Americans

    Science.gov (United States)

    Thota, Chandrasekhar; Menon, Ramkumar; Wentz, Melissa J.; Fortunato, Stephen J.; Bartlett, Jackie; Drobek, Cayce O.; Nair, Sangeeta; Al-Hendy, Ayman

    2012-01-01

    Catechol-O-methyltransferase (COMT) activity has been reported to be higher in African Americans (AA) than Caucasians (Cau). COMT converts 2- and 4-hydroxy (OH) estrogens to 2- and 4-methoxyestrogens, respectively, and can increase estrogenic milieu locally in tissues. To assess whether the increased incidence of preterm birth (PTB) among AA women is associated with single-nucleotide polymorphism (SNP) in the COMT gene, we examined variations in maternal and fetal COMT genes and their association with pregnancy outcomes (term vs preterm pregnancies) using 4 functional SNPs: rs4633, rs4680, rs4818, and rs6269 in both AA and Cau. We analyzed samples from 267 AA women (191 term and 76 preterm pregnancies) and 339 Cau (194 term and 145 preterm pregnancies) in this study. The results showed a significant difference (P < .05) in allele and genotype frequencies between term and preterm AA and Cau women in 3 SNPs in both maternal and fetal DNA. The analysis revealed that in AA fetal COMT genes, SNP rs4818 is associated with PTB at the allele (C; P < .001), genotype (C/C; P < .01), and 2- (P < .03) and 3 (P < .04)-window haplotype levels. Multidimensionality reduction analysis also showed a significant (P < .01) association between rs4818 and PTB. In conclusion, our study demonstrated that a synonymous polymorphism, rs4818 in the fetal COMT gene, is associated with PTB in AA. PMID:22158829

  12. Effect of 3 Single-Dose Regimens of Opicapone on Levodopa Pharmacokinetics, Catechol-O-Methyltransferase Activity and Motor Response in Patients With Parkinson Disease.

    Science.gov (United States)

    Rocha, José-Francisco; Ferreira, Joaquim J; Falcão, Amílcar; Santos, Ana; Pinto, Roberto; Nunes, Teresa; Almeida, Luis; Soares-da-Silva, Patrício

    2016-05-01

    This study determined the effects of single doses of opicapone (OPC), a novel third-generation catechol-O-methyltransferase (COMT) inhibitor, on levodopa and 3-O-methyl-levodopa (3-OMD) pharmacokinetics (PK), COMT activity and motor fluctuations in patients with Parkinson disease (PD). Subjects received, in a double-blind manner, 25, 50, and 100 mg OPC or placebo (PLC) in 4 separate treatment periods. The washout period between doses was at least 10 days. During each period, the OPC/PLC capsules were to be coadministered with the morning dose of 100/25 mg levodopa/carbidopa (LC) or levodopa/benserazide (LB) on day 3. In relation to PLC, levodopa exposure increased 3.7%, 16.4%, and 34.8% following 25, 50, or 100 mg OPC, respectively. Maximum S-COMT inhibition (Emax ) ranged from 67.8% (25 mg OPC) to 100% (100 mg OPC). Peak and extent of S-COMT inhibition were dose-dependent. Maximum decrease in the plasma 3-OMD was observed following administration of 100 mg OPC. Opicapone administered concomitantly with standard-release 100/25 mg LC or LB improved motor performance. Treatments were generally well tolerated and safe. It was concluded that OPC is a new COMT inhibitor that significantly decreased COMT activity and increased systemic exposure to levodopa in PD patients with motor fluctuations. © 2015, The American College of Clinical Pharmacology.

  13. The enzymatic activities of brain catechol-O-methyltransferase (COMT) and methionine sulphoxide reductase are correlated in a COMT Val/Met allele-dependent fashion.

    Science.gov (United States)

    Moskovitz, Jackob; Walss-Bass, Consuelo; Cruz, Dianne A; Thompson, Peter M; Hairston, Jenaqua; Bortolato, Marco

    2015-12-01

    The enzyme catechol-O-methyltransferase (COMT) plays a primary role in the metabolism of catecholamine neurotransmitters and is implicated in the modulation of cognitive and emotional responses. The best characterized single nucleotide polymorphism (SNP) of the COMT gene consists of a valine (Val)-to-methionine (Met) substitution at codon 108/158. The Met-containing variant confers a marked reduction in COMT catalytic activity. We recently showed that the activity of recombinant COMT is positively regulated by the enzyme Met sulphoxide reductase (MSR), which counters the oxidation of Met residues of proteins. The current study was designed to assess whether brain COMT activity may be correlated to MSR in an allele-dependent fashion. COMT and MSR activities were measured from post-mortem samples of prefrontal cortices, striata and cerebella of 32 subjects by using catechol and dabsyl-Met sulphoxide as substrates, respectively. Allelic discrimination of COMT Val(108/185) Met SNP was performed using the Taqman 5'nuclease assay. Our studies revealed that, in homozygous carriers of Met, but not Val alleles, the activity of COMT and MSR was significantly correlated throughout all tested brain regions. These results suggest that the reduced enzymatic activity of Met-containing COMT may be secondary to Met sulphoxidation and point to MSR as a key molecular determinant for the modulation of COMT activity. © 2015 British Neuropathological Society.

  14. Association of catechol-O-methyltransferase Val(108/158) Met genetic polymorphism with schizophrenia, P50 sensory gating, and negative symptoms in a Chinese population.

    Science.gov (United States)

    Mao, Qiao; Tan, Yun-Long; Luo, Xing-Guang; Tian, Li; Wang, Zhi-Ren; Tan, Shu-Ping; Chen, Song; Yang, Gui-Gang; An, Hui-Mei; Yang, Fu-De; Zhang, Xiang-Yang

    2016-08-30

    Catechol-O-methyltransferase (COMT), an enzyme involved in the degradation and inactivation of the neurotransmitter dopamine, is associated with the sensory gating phenomenon, protecting the cerebral cortex from information overload. The COMT Val(108/158)Met polymorphism is essential for prefrontal cortex processing capacity and efficiency. The current study was designed to investigate the role of COMT Val(108/158)Met polymorphism in development, sensory gating deficit, and symptoms of schizophrenia in Han Chinese population. P50 gating was determined in 139 schizophrenic patients and 165 healthy controls. Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptomatology in 370 schizophrenic subjects. COMT Val(108/158)Met polymorphism was genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP). No significant differences in COMT allele and genotype distributions were observed between schizophrenic patients and control groups. Although P50 deficits were present in patients, there was no evidence for an association between COMT Val(108/158)Met polymorphism and the P50 biomarker. Moreover, PANSS negative subscore was significantly higher in Val allele carriers than in Met/Met individuals. The present findings suggest that COMT Val(108/158)Met polymorphism may not contribute to the risk of schizophrenia and to the P50 deficits, but may contribute to the negative symptoms of schizophrenia among Han Chinese. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Evaluation of Mut(S) and Mut⁺ Pichia pastoris strains for membrane-bound catechol-O-methyltransferase biosynthesis.

    Science.gov (United States)

    Pedro, A Q; Oppolzer, D; Bonifácio, M J; Maia, C J; Queiroz, J A; Passarinha, L A

    2015-04-01

    Catechol-O-methyltransferase (COMT, EC 2.1.1.6) is an enzyme that catalyzes the methylation of catechol substrates, and while structural and functional studies of its membrane-bound isoform (MBCOMT) are still hampered by low recombinant production, Pichia pastoris has been described as an attractive host for the production of correctly folded and inserted membrane proteins. Hence, in this work, MBCOMT biosynthesis was developed using P. pastoris X33 and KM71H cells in shake flasks containing a semidefined medium with different methanol concentrations. Moreover, after P. pastoris glass beads lysis, biologically and immunologically active hMBCOMT was found mainly in the solubilized membrane fraction whose kinetic parameters were identical to its correspondent native enzyme. In addition, mixed feeds of methanol and glycerol or sorbitol were also employed, and its levels quantified using liquid chromatography coupled to refractive index detection. Overall, for the first time, two P. pastoris strains with opposite phenotypes were applied for MBCOMT biosynthesis under the control of the strongly methanol-inducible alcohol oxidase (AOX) promoter. Moreover, this eukaryotic system seems to be a promising approach to deliver MBCOMT in high quantities from fermentor cultures with a lower cost-benefit due to the cheaper cultivation media coupled with the higher titers tipically achieved in biorreactors, when compared with previously reported mammallian cell cultures.

  16. Catechol-O-methyltransferase inhibition alters pain and anxiety-related volitional behaviors through activation of β-adrenergic receptors in the rat.

    Science.gov (United States)

    Kline, R H; Exposto, F G; O'Buckley, S C; Westlund, K N; Nackley, A G

    2015-04-02

    Reduced catechol-O-methyltransferase (COMT) activity resulting from genetic variation or pharmacological depletion results in enhanced pain perception in humans and nociceptive behaviors in animals. Using phasic mechanical and thermal reflex tests (e.g. von Frey, Hargreaves), recent studies show that acute COMT-dependent pain in rats is mediated by β-adrenergic receptors (βARs). In order to more closely mimic the characteristics of human chronic pain conditions associated with prolonged reductions in COMT, the present study sought to determine volitional pain-related and anxiety-like behavioral responses following sustained as well as acute COMT inhibition using an operant 10-45°C thermal place preference task and a light/dark preference test. In addition, we sought to evaluate the effects of sustained COMT inhibition on generalized body pain by measuring tactile sensory thresholds of the abdominal region. Results demonstrated that acute and sustained administration of the COMT inhibitor OR486 increased pain behavior in response to thermal heat. Further, sustained administration of OR486 increased anxiety behavior in response to bright light, as well as abdominal mechanosensation. Finally, all pain-related behaviors were blocked by the non-selective βAR antagonist propranolol. Collectively, these findings provide the first evidence that stimulation of βARs following acute or chronic COMT inhibition drives cognitive-affective behaviors associated with heightened pain that affects multiple body sites. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. The impact of the Catechol-O-methyltransferase Val158Met polymorphism on survival in the general population – the HUNT study

    Directory of Open Access Journals (Sweden)

    Skorpen Frank

    2007-06-01

    Full Text Available Abstract Background The catechol-O-methyltransferase (COMT gene contains a functional polymorphism, Val158Met which has been related to common diseases like cancer, psychiatric illness and myocardial infarction. Whether the Val158Met polymorphism is associated with survival has not been evaluated in the general population. The aim of this prospective study was to evaluate the impact of codon 158 COMT gene polymorphism on survival in a population-based cohort. Methods The sample comprised 2979 non-diabetic individuals who participated in the Nord-Trøndelag Health Study (HUNT in the period 1995–97. The subjects were followed up with respect to mortality throughout year 2004. Results 212 men and 183 women died during the follow up. No association between codon 158 COMT gene polymorphism and survival was found. The unadjusted relative risk of death by non-ischemic heart diseases with Met/Met or Met/Val genotypes was 3.27 (95% confidence interval, 1.19–9.00 compared to Val/Val genotype. When we adjusted for age, gender, smoking, coffee intake and body mass index the relative risk decreased to 2.89 (95% confidence interval, 1.04–8.00. Conclusion During 10 year of follow-up, the Val158Met polymorphism had no impact on survival in a general population. Difference in mortality rates from non-ischemic heart diseases may be incidental and should be evaluated in other studies.

  18. Catechol-O-methyltransferase Val(108/158)Met polymorphism affects fronto-limbic connectivity during emotional processing in bipolar disorder.

    Science.gov (United States)

    Vai, B; Riberto, M; Poletti, S; Bollettini, I; Lorenzi, C; Colombo, C; Benedetti, F

    2017-03-01

    Catechol-O-methyltransferase (COMT) inactivates catecholamines, Val/Val genotype was associated to an increased amygdala (Amy) response to negative stimuli and can influence the symptoms severity and the outcome of bipolar disorder, probably mediated by the COMT polymorphism (rs4680) interaction between cortical and subcortical dopaminergic neurotransmission. The aim of this study is to explore how rs4680 and implicit emotional processing of negative emotional stimuli could interact in affecting the Amy connectivity in bipolar depression. Forty-five BD patients (34 Met carriers vs. 11 Val/Val) underwent fMRI scanning during implicit processing of fearful and angry faces. We explore the effect of rs4680 on the strength of functional connectivity from the amygdalae to whole brain. Val/Val and Met carriers significantly differed for the connectivity between Amy and dorsolateral prefrontal cortex (DLPFC) and supramarginal gyrus. Val/Val patients showed a significant positive connectivity for all of these areas, where Met carriers presented a significant negative one for the connection between DLPFC and Amy. Our findings reveal a COMT genotype-dependent difference in corticolimbic connectivity during affective regulation, possibly identifying a neurobiological underpinning of clinical and prognostic outcome of BD. Specifically, a worse antidepressant recovery and clinical outcome previously detected in Val/Val patients could be associated to a specific increased sensitivity to negative emotional stimuli. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  19. The catechol-o-methyltransferase Val¹⁵⁸Met polymorphism modulates the intrinsic functional network centrality of the parahippocampal cortex in healthy subjects.

    Science.gov (United States)

    Zhang, Xiaolong; Li, Jin; Qin, Wen; Yu, Chunshui; Liu, Bing; Jiang, Tianzi

    2015-06-09

    The influence of catechol-o-methyltransferase (COMT) Val(158)Met on brain activation and functional connectivity has been widely reported. However, voxel-wise effects of this genotype on resting-state brain networks remain unclear. Here, we used resting-state fMRI and eigenvector centrality to examine the effects of COMT Val(158)Met genotypes on the connection patterns of the brain network and working memory (WM) in healthy, young Val/Val and Met carrier subjects. There were significant differences in the performance level on the 2-back WM task between the different COMT genotypes: Val/Val individuals exhibited a higher correct rate compared to the Met carriers. A two-sample t test was used to examine the differences in the eigenvector centrality maps, using age and gender as covariates of no interest, between the Val/Val and Met carriers. We found that the Val/Val individuals exhibited significantly higher eigenvector centrality compared to the Met carriers in the left parahippocampal cortex. Furthermore, a significantly positive correlation between the mean eigenvector centrality of the significant cluster and the correct rate of the 2-back WM task was observed. By using a voxel-wise data-driven method, our findings may provide plausible implications regarding individual differences in the genetic contribution of COMT Val158Met to the brain network and cognition.

  20. Common variants of catechol-O-methyltransferase influence patient-controlled analgesia usage and postoperative pain in patients undergoing total hysterectomy.

    Science.gov (United States)

    Tan, E-C; Lim, E C P; Ocampo, C E; Allen, J C; Sng, B-L; Sia, A T

    2016-04-01

    Catechol-O-methyltransferase (COMT) gene polymorphisms and haplotypes have been associated with both experimental and clinical pain phenotypes. In this prospective study, we investigated the association of three common polymorphisms with experimentally induced pressure pain, postoperative pain and amount of self-administered morphine in 973 patients who underwent scheduled total hysterectomy. DNA extracted from peripheral blood was genotyped for three COMT polymorphisms by Taqman assay or a PCR-based method. In the overall sample, rs4633 and rs4680 were significantly associated with morphine use, whereas rs4818 was associated with time-averaged pain scores. Statistically significant associations were found between COMT rs4633 and rs4680 genotypes and the amount of morphine self-administered through a patient-controlled analgesia pump. For rs4818, the only statistically significant association was with time-averaged pain scores. Haplotype analysis showed statistically significant association of the low pain sensitivity haplotype with time-averaged pain scores; and average pain sensitivity haplotype with total morphine and weight-adjusted morphine.

  1. Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism and Eating Disorders: Data From a New Biobank and Meta-Analysis of Previously Published Studies.

    Science.gov (United States)

    Collantoni, Enrico; Solmi, Marco; Gallicchio, Davide; Santonastaso, Paolo; Meneguzzo, Paolo; Carvalho, Andrè F; Stubbs, Brendon; Clementi, Maurizio; Pinato, Claudia; Forzan, Monica; Cassina, Matteo; Fontana, Francesca; Piva, Ivana; Siani, Roberta; Salvo, Pierandrea; Tenconi, Elena; Veronese, Nicola; Correll, Christoph U; Favaro, Angela

    2017-11-01

    We investigated whether catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with eating disorders (EDs). We conducted a systematic literature search of studies published until 15 January 2017 and added data from the Italian 'Biobanca Veneta per i Disturbi Alimentari' biobank, performing a meta-analysis comparing COMT Val158Met genotype and allele frequencies in EDs and anorexia nervosa (AN) or bulimia nervosa (BN) patients versus controls. Ten studies plus Biobanca Veneta per i Disturbi Alimentari (ED: n = 920, controls: n = 261 controls) with 3541 ED patients (AN = 2388; BN = 233) and 3684 controls were included. There were no significant group differences in COMT Val158Met alleles and genotype frequencies between patients and controls, for all EDs pooled together [range of odds ratios (ORs): 0.96-1.04, p-values: 0.46-0.97, I2  = 0%] and when analysing separately patients with AN (ORs: 0.94-1.04, p-values: 0.31-0.61, I2  = 0%) or BN (ORs: 0.80-1.09, p-values: 0.28-0.64, I2  = 0-44%). Meta-analysing data results from 11 studies and 7225 subjects show that COMT Val158Met polymorphism is not associated with EDs. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

  2. The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase Val(158)Met polymorphism.

    Science.gov (United States)

    Kolassa, Iris-Tatjana; Kolassa, Stephan; Ertl, Verena; Papassotiropoulos, Andreas; De Quervain, Dominique J-F

    2010-02-15

    The risk for posttraumatic stress disorder (PTSD) depends on the number of traumatic event types experienced in a dose-response relationship, but genetic factors are known to also influence the risk of PTSD. The catechol-O-methyltransferase (COMT) Val158Met polymorphism has been found to affect fear extinction and might play a role in the etiology of anxiety disorders. Traumatic load and lifetime and current diagnosis of PTSD and COMT genotype were assessed in a sample of 424 survivors of the Rwandan Genocide living in the Nakivale refugee camp in southwestern Uganda. Higher numbers of different lifetime traumatic event types led to a higher prevalence of lifetime PTSD in a dose-response relationship. However, this effect was modulated by the COMT genotype: whereas Val allele carriers showed the typical dose-response relationship, Met/Met homozygotes exhibited a high risk for PTSD independently of the severity of traumatic load. The present findings indicate a gene-environment interaction between the human COMT Val158Met polymorphism and the number of traumatic event types experienced in the risk of developing PTSD. 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  3. Identification and characterization of a catechol-o-methyltransferase cDNA in the catfish Heteropneustes fossilis: Tissue, sex and seasonal variations, and effects of gonadotropin and 2-hydroxyestradiol-17β on mRNA expression.

    Science.gov (United States)

    Chaube, R; Rawat, A; Inbaraj, R M; Bobe, J; Guiguen, Y; Fostier, A; Joy, K P

    2017-05-15

    Catechol-O-methyltransferase (COMT) is involved in the methylation and inactivation of endogenous and xenobiotic catechol compounds, and serves as a common biochemical link in the catecholamine and catecholestrogen metabolism. Studies on cloning, sequencing and function characterization comt gene in lower vertebrates like fish are fewer. In the present study, a full-length comt cDNA of 1442bp with an open-reading frame (ORF) of 792bp, and start codon (ATG) at nucleotide 162 and stop codon (TAG) at nucleotide 953 was isolated and characterized in the stinging catfish Heteropneustes fossilis (accession No. KT597925). The ORF codes for a protein of 263 amino acid residues, which is also validated by the catfish transcriptome data analysis. The catfish Comt shared conserved putative structural regions important for S-adenosyl methionine (AdoMet)- and catechol-binding, transmembrane regions, two glycosylation sites (N-65 and N-91) at the N-terminus and two phosphorylation sites (Ser-235 and Thr-240) at the C-terminus. The gene was expressed in all tissues examined and the expression showed significant sex dimorphic distribution with high levels in females. The transcript was abundant in the liver, brain and gonads and low in muscles. The transcripts showed significant seasonal variations in the brain and ovary, increased progressively to the peak levels in spawning phase and then declined. The brain and ovarian comt mRNA levels showed periovulatory changes after in vivo and in vitro human chorionic gonadotropin (hCG) treatments with high fold increases at 16 and 24h in the brain and at 16h in the ovary. The catecholestrogen 2-hydroxyE2 up regulated ovarian comt expression in vitro with the highest fold increase at 16h. The mRNA and protein was localized in the follicular layer of the vitellogenic follicles and in the cytoplasm of primary follicles. The data were discussed in relation to catecholamine and catecholestrogen-mediated functions in the brain and ovary of the

  4. Integrated metagenomics and metatranscriptomics analyses of root-associated soil from transgenic switchgrass.

    Science.gov (United States)

    Chauhan, Archana; Smartt, Abby; Wang, Jun; Utturkar, Sagar; Frank, Ashley; Bi, Meng; Liu, Jiang; Williams, Daniel; Xu, Tingting; Eldridge, Melanie; Arreaza, Andres; Rogers, Alexandra; Gonzalez, Hector Castro; Layton, Alice C; Baxter, Holly L; Mazarei, Mitra; DeBruyn, Jennifer M; Stewart, C Neal; Brown, Steven D; Hauser, Loren J; Sayler, Gary S

    2014-08-14

    The benefits of using transgenic switchgrass with decreased levels of caffeic acid 3-O-methyltransferase (COMT) as biomass feedstock have been clearly demonstrated. However, its effect on the soil microbial community has not been assessed. Here we report metagenomic and metatranscriptomic analyses of root-associated soil from COMT switchgrass compared with nontransgenic counterparts. Copyright © 2014 Chauhan et al.

  5. Identification and characterization of PaMTH1, a putative O-methyltransferase accumulating during senescence of Podospora anserina cultures

    DEFF Research Database (Denmark)

    Averbeck, N B; Jensen, Ole Nørregaard; Mann, M

    2000-01-01

    A differential protein display screen resulted in the identification of a 27-kDa protein which strongly accumulates during the senescence of Podospora anserina cultures grown under standard conditions. After partial determination of the amino-acid sequence by mass-spectrometry analysis of trypsin...

  6. Apolipoprotein E epsilon4 and catechol-O-methyltransferase alleles in autopsy-proven Parkinson's disease: relationship to dementia and hallucinations.

    Science.gov (United States)

    Camicioli, Richard; Rajput, Ali; Rajput, Michelle; Reece, Christian; Payami, Haydeh; Hao, Chunhai; Rajput, Alex

    2005-08-01

    We determined whether apolipoprotein E epsilon4 (ApoE4) or catechol-O-methyltransferase (COMT) genotypes were associated with dementia, hallucinations, Alzheimer's disease pathological findings (AP), or cortical Lewy bodies (CLBs) in autopsy-confirmed cases of Parkinson's disease (PD). Outcomes were obtained from medical records. Pathology reports identified AP and CLBs. Brain tissue was genotyped. A total of 47 subjects (33 men, 14 women) had PD onset at 62.4 +/- 8.7 years of age and died at 77.8 +/- 5.6 years of age. Demented and hallucinating patients did not differ in age at onset (AO) of PD or age at death, or the proportion ApoE4+, AP+, or CLB+ compared to nondemented patients or non-hallucinating patients. ApoE4 and COMT (low metabolizer [LH], intermediate metabolizer [HL], or high metabolizer [HH]) did not influence AO, death, or dementia- or hallucination-free survival, based on age or duration of treatment. All seven subjects with AP were demented and had hallucinations. CLBs were associated with dementia but not hallucinations. In Cox regression models adjusting for AO and duration of treatment, increased risk of dementia was associated with male sex but not significantly with ApoE4; inclusion of AP in the model did not affect the results; COMT was not a risk factor for dementia. Psychosis risk was not associated with ApoE4, COMT, or sex. The observation that males have increased dementia risk and the trend for ApoE4 requires confirmation in larger prospective autopsy studies. Copyright 2005 Movement Disorder Society

  7. The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives.

    Science.gov (United States)

    Lelli-Chiesa, G; Kempton, M J; Jogia, J; Tatarelli, R; Girardi, P; Powell, J; Collier, D A; Frangou, S

    2011-04-01

    The Met allele of the catechol-O-methyltransferase (COMT) valine-to-methionine (Val158Met) polymorphism is known to affect dopamine-dependent affective regulation within amygdala-prefrontal cortical (PFC) networks. It is also thought to increase the risk of a number of disorders characterized by affective morbidity including bipolar disorder (BD), major depressive disorder (MDD) and anxiety disorders. The disease risk conferred is small, suggesting that this polymorphism represents a modifier locus. Therefore our aim was to investigate how the COMT Val158Met may contribute to phenotypic variation in clinical diagnosis using sad facial affect processing as a probe for its neural action. We employed functional magnetic resonance imaging to measure activation in the amygdala, ventromedial PFC (vmPFC) and ventrolateral PFC (vlPFC) during sad facial affect processing in family members with BD (n=40), MDD and anxiety disorders (n=22) or no psychiatric diagnosis (n=25) and 50 healthy controls. Irrespective of clinical phenotype, the Val158 allele was associated with greater amygdala activation and the Met158 allele with greater signal change in the vmPFC and vlPFC. Signal changes in the amygdala and vmPFC were not associated with disease expression. However, in the right vlPFC the Met158 allele was associated with greater activation in all family members with affective morbidity compared with relatives without a psychiatric diagnosis and healthy controls. Our results suggest that the COMT Val158Met polymorphism has a pleiotropic effect within the neural networks subserving emotional processing. Furthermore the Met158 allele further reduces cortical efficiency in the vlPFC in individuals with affective morbidity.

  8. Catechol-O-Methyltransferase Genotypes and Parenting Influence on Long-Term Executive Functioning After Moderate to Severe Early Childhood Traumatic Brain Injury: An Exploratory Study.

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    Kurowski, Brad G; Treble-Barna, Amery; Zang, Huaiyu; Zhang, Nanhua; Martin, Lisa J; Yeates, Keith Owen; Taylor, H Gerry; Wade, Shari L

    To examine catechol-O-methyltransferase (COMT) rs4680 genotypes as moderators of the effects of parenting style on postinjury changes in parent behavior ratings of executive dysfunction following moderate to severe early childhood traumatic brain injury. Research was conducted in an outpatient setting. Participants included children admitted to hospital with moderate to severe traumatic brain injury (n = 55) or orthopedic injuries (n = 70) between ages 3 and 7 years. Prospective cohort followed over 7 years postinjury. Parenting Practices Questionnaire and the Behavior Rating Inventory of Executive Functioning obtained at baseline, 6, 12, and 18 months, and 3.5 and 6.8 years postinjury. DNA was collected from saliva samples, purified using the Oragene (DNA Genotek, Ottawa, Ontario, Canada) OG-500 self-collection tubes, and analyzed using TaqMan (Applied Biosystems, Thermo Fisher Scientific, Waltham, Massachusetts) assay protocols to identify the COMT rs4680 polymorphism. Linear mixed models revealed a significant genotype × parenting style × time interaction (F = 5.72, P = .02), which suggested that the adverse effects of authoritarian parenting on postinjury development of executive functioning were buffered by the presence of the COMT AA genotype (lower enzyme activity, higher dopamine levels). There were no significant associations of executive functioning with the interaction between genotype and authoritative or permissive parenting ratings. The lower activity COMT rs4680 genotype may buffer the negative effect of authoritarian parenting on long-term executive functioning following injury in early childhood. The findings provide preliminary evidence for associations of parenting style with executive dysfunction in children and for a complex interplay of genetic and environmental factors as contributors to decreases in these problems after traumatic injuries in children. Further investigation is warranted to understand the interplay among genetic and

  9. CYP17, catechol-o-methyltransferase, and glutathione transferase M1 genetic polymorphisms, lifestyle factors, and breast cancer risk in women on Prince Edward Island.

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    Cribb, Alastair E; Joy Knight, Marion; Guernsey, Judy; Dryer, Dagny; Hender, Kimberly; Shawwa, Allam; Tesch, Marvin; Saleh, Tarek M

    2011-01-01

    Genetic polymorphisms in enzymes controlling the formation and disposition of estrogens and their metabolites have been shown to influence breast cancer risk. Environmental and lifestyle factors may interact with estrogen metabolism polymorphisms to influence breast cancer risk. We studied the role of lifestyle factors and genetic polymorphisms in estrogen metabolism in women from Prince Edward Island (PEI), a small province of 135,000 people on the east coast of Canada. Women (207 cases; 621 controls) were matched on age, menopausal status, and family history of breast cancer. The predominant lifestyle risk factors previously reported to influence breast cancer risk such as body mass index (BMI), parity, and smoking had similar influences in the PEI population. Genetic polymorphisms in CYP17, GSTM1, and catechol-O-methyltransferase (COMT) were not associated with a general increase in breast cancer risk. However, the CYP17 A2/A2 genotype was only observed in women with estrogen receptor (ER) positive breast cancer and not in ER negative breast cancer. The increased risk associated with elevated BMI was only observed in women homozygous for the CYP17 and COMT reference alleles. Similarly, the increased risk associated with extended use of oral contraceptives (≥ 15years), was only observed in women homozygous for the reference alleles of CYP17 and COMT. The GSTM1 homozygous gene deletion was associated with a significantly increased risk of breast cancer in postmenopausal women with a family history of breast cancer risk. These results suggest the polymorphic genes that control estrogen formation and disposition interact significantly with other risk factors to influence breast cancer risk. © 2010 Wiley Periodicals, Inc.

  10. Catechol-O-methyltransferase Val158Met polymorphism influences anxiety, depression, and disability, but not pressure pain sensitivity, in women with fibromyalgia syndrome.

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    Fernández-de-Las-Peñas, César; Ambite-Quesada, Silvia; Gil-Crujera, Antonio; Cigarán-Méndez, Margarita; Peñacoba-Puente, Cecilia

    2012-11-01

    Our aim was to assess the relationship of the Val158Met polymorphism to pain, anxiety, depression, functional ability, and pressure pain sensitivity in women with fibromyalgia (FMS). One hundred (n = 100) women with FMS diagnosed according to the American College of Rheumatology criteria participated. A numerical pain rate scale (0-10) was used to assess the intensity of pain; the Hospital Anxiety and Depression Scale was calculated to determine anxiety and depression; and functional ability was determined with the Fibromyalgia Impact Questionnaire. Further, pressure pain thresholds (PPTs) were bilaterally assessed over C5-C6 zygapophyseal joints, second metacarpal, and tibialis anterior muscles. Finally, after amplifying Val158Met polymorphisms by polymerase chain reaction, catechol-O-methyltransferase (COMT) genotype was divided into Val/Val, Val/Met, or Met/Met genotypes. Women with FMS with the Met/Met genotype exhibited higher disability (F = 11.836; P anxiety (F = 13.385; P anxiety but similar PPTs than those with Val/Met or Val/Val genotypes. This study is important because it strives to understand potential genetic factors that predispose some women with FMS to exhibit a more severe phenotypic expression of the disease. Future studies are needed to elucidate potential relevance of the differences. This study suggests that the Val158Met COMT polymorphism modulated some psychological variables but not pressure pain sensitivity in FMS because women with FMS carrying the Met/Met genotype exhibit higher disability, depression, and anxiety than but similar PPTs to those with Val/Met and Val/Val genotypes. This study provides further evidence of potential genetic factors that predispose women with FMS to exhibit the disease more severely. Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.

  11. Associations of Cigarette Smoking and Polymorphisms in Brain-Derived Neurotrophic Factor and Catechol-O-Methyltransferase with Neurocognition in Alcohol Dependent Individuals during Early Abstinence

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    Timothy eDurazzo

    2012-10-01

    Full Text Available Chronic cigarette smoking and polymorphisms in brain-derived neurotrophic factor (BDNF and catechol-o-methyltransferase (COMT are associated with neurocognition in normal controls and those with various neuropsychiatric conditions. The influence of these polymorphisms on neurocognition in alcohol dependence is unclear. The goal of this report was to investigate the associations of single nucleotide polymorphisms (SNP in BDNF Val66Met and COMT Val158Met with neurocognition in a treatment-seeking alcohol dependent cohort and determine if neurocognitive differences between non-smokers and smokers previously observed in this cohort persist when controlled for these functional SNPs. Genotyping was conducted on 70 primarily male treatment-seeking alcohol dependent participants (ALC who completed a comprehensive neuropsychological battery after 33 ± 9 days of monitored abstinence. Smoking ALC performed significantly worse than non-smoking ALC on the domains of auditory-verbal and visuospatial learning and memory, cognitive efficiency, general intelligence, processing speed and global neurocognition. In smoking ALC, greater number of years of smoking over lifetime was related to poorer performance on multiple domains. COMT Met homozygotes were superior to Val homozygotes on measures of executive skills and showed trends for higher general intelligence and visuospatial skills, while COMT Val/Met heterozygotes showed significantly better general intelligence than Val homozygotes. COMT Val homozygotes performed better than heterozygotes on auditory-verbal memory. BDNF genotype was not related to any neurocognitive domain. The findings are consistent with studies in normal controls and neuropsychiatric cohorts that observed COMT Met carriers showed better performance on measures of executive skills and general intelligence. Overall, the findings support to the expanding clinical movement to make smoking cessation programs available at the inception of

  12. Association between physical activity and BMD in young men is modulated by catechol-O-methyltransferase (COMT) genotype: the GOOD study.

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    Lorentzon, Mattias; Eriksson, Anna L; Nilsson, Staffan; Mellström, Dan; Ohlsson, Claes

    2007-08-01

    In this large population-based study in young men, we show that the COMT val158met polymorphism modulates the association between physical activity, aBMD (DXA), and trabecular vBMD (pQCT). Peak BMD is an important predictor of future risk of osteoporosis and is largely determined by genetic factors but also by environmental factors, among which physical activity (PA) is a strong contributor. Estrogens are believed to influence the mechanical strain signal generated by bones subjected to mechanical loading. Catechol-O-methyltransferase (COMT) is involved in the degradation of estrogens. A functional polymorphism in the COMT gene (val158met), results in a 60-75% difference in enzyme activity between the val (high activity = H) and met (low activity = L) variants. The aim of this study was to determine if the COMT val158met polymorphism modulates the association between PA and BMD in young men. The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study consists of 1068 men (age, 18.9 +/- 0.6 yr). Areal BMD (aBMD) was measured by DXA, whereas cortical and trabecular volumetric BMD (vBMD) were measured by pQCT. Study subjects were genotyped and classified as COMT(LL), COMT(HL), or COMT(HH). The amount (h/wk) of PA was determined through questionnaires. Using a linear regression model (including age, height, weight, smoking, and calcium intake as covariates), significant interactions between the COMT genotype and PA were seen for aBMD at all sites and for trabecular vBMD in both the radius and the tibia. The difference in adjusted aBMD and trabecular vBMD between high (>or=4 h/wk) and low PA (BMD in subjects with a low level of PA.

  13. How to consistently link extraversion and intelligence to the catechol-O-methyltransferase (COMT) gene: on defining and measuring psychological phenotypes in neurogenetic research.

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    Wacker, Jan; Mueller, Erik M; Hennig, Jürgen; Stemmler, Gerhard

    2012-02-01

    The evidence for associations between genetic polymorphisms and complex behavioral/psychological phenotypes (traits) has thus far been weak and inconsistent. Using the well-studied Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene as an example, we demonstrate that using theoretical models to guide phenotype definition and measuring the phenotypes of interest with a high degree of specificity reveals strong gene-behavior associations that are consistent with prior work and that would have otherwise gone unnoticed. Only after statistically controlling for irrelevant portions of phenotype variance did we observe strong (Cohen's d = 0.33-0.70) and significant associations between COMT Val158Met and both cognitive and affective traits in a healthy male sample (N = 201) in Study 1: Carriers of the Met allele scored higher in fluid intelligence (reasoning) but lower in both crystallized intelligence (general knowledge) and the agency facet of extraversion. In Study 2, we conceptually replicated the association of COMT Val158Met with the agency facet of extraversion after partialing irrelevant phenotype variance in a female sample (N = 565). Finally, through reanalysis of a large published data set we showed that Met allele carriers also scored higher in indicators of fluid intelligence after partialing verbal fluency. Because the Met allele codes for a less efficient variant of the enzyme COMT, resulting in higher levels of extrasynaptic prefrontal dopamine, these observations provide further support for a role for dopamine in both intelligence and extraversion. More importantly, the present findings have important implications for the definition of psychological phenotypes in neurogenetic research.

  14. Immediate reward bias in humans: fronto-parietal networks and a role for the catechol-O-methyltransferase 158(Val/Val) genotype.

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    Boettiger, Charlotte A; Mitchell, Jennifer M; Tavares, Venessa C; Robertson, Margaret; Joslyn, Geoff; D'Esposito, Mark; Fields, Howard L

    2007-12-26

    The tendency to choose lesser immediate benefits over greater long-term benefits characterizes alcoholism and other addictive disorders. However, despite its medical and socioeconomic importance, little is known about its neurobiological mechanisms. Brain regions that are activated when deciding between immediate or delayed rewards have been identified (McClure et al., 2004, 2007), as have areas in which responses to reward stimuli predict a paper-and-pencil measure of temporal discounting (Hariri et al., 2006). These studies assume "hot" and "cool" response selection systems, with the hot system proposed to generate impulsive choices in the presence of a proximate reward. However, to date, brain regions in which the magnitude of activity during decision making reliably predicts intertemporal choice behavior have not been identified. Here we address this question in sober alcoholics and non-substance-abusing control subjects and show that immediate reward bias directly scales with the magnitude of functional magnetic resonance imaging bold oxygen level-dependent (BOLD) signal during decision making at sites within the posterior parietal cortex (PPC), dorsal prefrontal cortex (dPFC), and rostral parahippocampal gyrus regions. Conversely, the tendency of an individual to wait for a larger, delayed reward correlates directly with BOLD signal in the lateral orbitofrontal cortex. In addition, genotype at the Val158Met polymorphism of the catechol-O-methyltransferase gene predicts both impulsive choice behavior and activity levels in the dPFC and PPC during decision making. These genotype effects remained significant after controlling for alcohol abuse history. These results shed new light on the neurobiological underpinnings of temporal discounting behavior and identify novel behavioral and neural consequences of genetic variation in dopamine metabolism.

  15. Catechol-O-methyltransferase gene variants may associate with negative symptom response and plasma concentrations of prolactin in schizophrenia after amisulpride treatment.

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    Chen, Chun-Yen; Yeh, Yi-Wei; Kuo, Shin-Chang; Ho, Pei-Shen; Liang, Chih-Sung; Yen, Che-Hung; Lu, Ru-Band; Huang, San-Yuan

    2016-03-01

    Catechol-O-methyltransferase (COMT) enzyme is involved in the pathogenesis of psychotic symptoms and may be associated with a therapeutic response to antipsychotic drugs. The aim of this study was to examine the relationship between COMT variants, plasma prolactin level, and the therapeutic effectiveness of amisulpride treatment in patients with schizophrenia. A 12-week naturalistic study of amisulpride treatment was carried out in 185 Han Chinese patients with schizophrenia. The patients were screened for 14 single-nucleotide polymorphisms of the COMT gene. The Positive and Negative Syndrome Scale (PANSS) was used to assess the improvement of psychopathological symptoms from the baseline to the end point in each subject. For better presentation of time-course changes in response status, a mixed model for repeated-measures (MMRM) analysis of symptom improvement during the 12-week treatment period was conducted. The change in plasma prolactin level after amisulpride treatment was also examined (n=51). No significant differences in the genotype frequencies of the COMT variants investigated were observed between responders and non-responders. Moreover, an MMRM analysis of psychopathological symptom improvement during the 12-week treatment course showed that it depended significantly on COMT variants (rs4680, rs4633, and rs6267), particularly regarding changes in negative symptoms. The increase in plasma prolactin levels observed was influenced by the COMT rs4680 variant and was positively correlated with a reduction in PANSS negative scores. Our results suggest that variation of the COMT gene is associated with treatment response regarding negative symptoms and prolactin changes after amisulpride treatment in patients with schizophrenia. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. The val158met polymorphism of human catechol-O-methyltransferase (COMT affects anterior cingulate cortex activation in response to painful laser stimulation

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    Musso Francesco

    2010-05-01

    Full Text Available Abstract Background Pain is a complex experience with sensory, emotional and cognitive aspects. Genetic and environmental factors contribute to pain-related phenotypes such as chronic pain states. Genetic variations in the gene coding for catechol-O-methyltransferase (COMT have been suggested to affect clinical and experimental pain-related phenotypes including regional μ-opioid system responses to painful stimulation as measured by ligand-PET (positron emission tomography. The functional val158met single nucleotide polymorphism has been most widely studied. However, apart from its impact on pain-induced opioid release the effect of this genetic variation on cerebral pain processing has not been studied with activation measures such as functional magnetic resonance imaging (fMRI, PET or electroencephalography. In the present fMRI study we therefore sought to investigate the impact of the COMT val158met polymorphism on the blood oxygen level-dependent (BOLD response to painful laser stimulation. Results 57 subjects were studied. We found that subjects homozygous for the met158 allele exhibit a higher BOLD response in the anterior cingulate cortex (ACC, foremost in the mid-cingulate cortex, than carriers of the val158 allele. Conclusion This result is in line with previous studies that reported higher pain sensitivity in homozygous met carriers. It adds to the current literature in suggesting that this behavioral phenotype may be mediated by, or is at least associated with, increased ACC activity. More generally, apart from one report that focused on pain-induced opioid release, this is the first functional neuroimaging study showing an effect of the COMT val158met polymorphism on cerebral pain processing.

  17. Depression and anxiety in relation to catechol-O-methyltransferase Val158Met genotype in the general population: The Nord-Trøndelag Health Study (HUNT

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    Zwart John-Anker

    2008-06-01

    Full Text Available Abstract Background The catechol-O-methyltransferase (COMT gene contains a functional polymorphism, Val158Met, which has been linked to anxiety and depression, but previous results are not conclusive. The aim of the present study was to examine the relationship between the Val158Met COMT gene polymorphism and anxiety and depression measured by the Hospital Anxiety and Depression Scale (HADS in the general adult population. Methods In the Nord-Trøndelag Health Study (HUNT the association between the Val158Met polymorphism and anxiety and depression was evaluated in a random sample of 5531 individuals. Two different cut off scores (≥ 8 and ≥ 11 were used to identify cases with anxiety (HADS-A and depression (HADS-D, whereas controls had HADS-A Results The COMT genotype distribution was similar between controls and individuals in the groups with anxiety and depression using cut-off scores of ≥ 8. When utilizing the alternative cut-off score HADS-D ≥ 11, Met/Met genotype and Met allele were less common among men with depression compared to the controls (genotype: p = 0.017, allele: p = 0.006. In the multivariate analysis, adjusting for age and heart disease, depression (HADS-D ≥ 11 was less likely among men with the Met/Met genotype than among men with the Val/Val genotype (OR = 0.37, 95% CI = 0.18–0.76. Conclusion In this population-based study, no clear association between the Val158Met polymorphism and depression and anxiety was revealed. The Met/Met genotype was less likely among men with depression defined as HADS-D ≥ 11, but this may be an incidental finding.

  18. Sensorimotor Gating Depends on Polymorphisms of the Serotonin-2A Receptor and Catechol-O-Methyltransferase, but Not on Neuregulin-1 Arg38Gln Genotype: A Replication Study

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    Quednow, Boris B.; Schmechtig, Anne; Ettinger, Ulrich; Petrovsky, Nadine; Collier, David A.; Vollenweider, Franz X.; Wagner, Michael; Kumari, Veena

    2009-01-01

    Background Prepulse inhibition (PPI) of the acoustic startle response (ASR) is an operational measure of sensorimotor gating and a promising endophenotype of schizophrenia. We have recently shown that the linked serotonin-2A receptor (5-HT2AR) A-1438 G and T102C polymorphisms modulate PPI in schizophrenia patients. Moreover, it was shown that genetic variation in the catechol-O-methyltransferase (COMT) and the neuregulin-1 (NRG-1) proteins influences PPI in schizophrenia patients and healthy volunteers. Therefore, we aimed to replicate these results and investigated the impact of the related polymorphisms on PPI in healthy human volunteers. Methods We analyzed the 5-HT2AR A-1438 G/T102C (rs6311/rs6313), the COMT Val158Met (rs4680), and the NRG-1 Arg38Gln (rs3924999) polymorphisms, assessing startle reactivity, habituation, and PPI of ASR in 107 healthy Caucasian volunteers. Results Subjects homozygous for the 5-HT2AR T102C-T/A-1438 G-A allele showed increased PPI levels. In particular, male subjects with the COMT Met158Met-genotype also showed elevated PPI. The NRG-1 Arg38Gln genotype did not have a significant impact on PPI. Startle reactivity was not affected by any of the investigated polymorphisms. Conclusions We confirmed in an independent sample of healthy volunteers that PPI is influenced by genetic variation in the 5-HT2AR gene. The influence of the COMT Val158Met genotype on PPI appears to be sex-specific. These results underscore the significance of the serotonin and dopamine systems in the modulation of sensorimotor gating. PMID:19545856

  19. Effect of catechol-O-methyltransferase-val158met-polymorphism on the automatization of motor skills - a post hoc view on an experimental data.

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    Krause, Daniel; Beck, Frieder; Agethen, Manfred; Blischke, Klaus

    2014-06-01

    The purpose of this study was to evaluate if the catechol-O-methyltransferase-val158met (COMT)-polymorphism, which is known to affect prefrontal dopaminergic metabolism, affects the automatization of motor skills. Twenty-two participants volunteered for gene analysis after they had participated in experiments in which they practiced a single-joint arm movement sequence 460-760 times under different feedback conditions. Motor automaticity was assessed in a pre-test and a post-test according to the dual-task paradigm, which incorporated a visuo-spatial secondary task. To account for the different practice conditions in the four original studies, dual-task cost reduction was assessed using single case effect sizes proportioned to the respective group mean. For the secondary task but not for the prioritized motor task, these relative single case effect sizes proved to be positively (and significantly) correlated with the number of met-alleles on the COMT-genotype, rs=.553; p=.004. Thus, the number of met-alleles indicated a tendency toward enhanced motor automatization. Thus, due to an increased prefrontal dopamine level, met-carriers may be able to develop a well formed and stable, spatially coded movement representation early in practice, thereby supporting the formation of a representation in motor coordinates in the course of extended practice, which later enables automatic movement execution. This process might also be enhanced by a prevalence of met-carriers to functionally evaluate positive feedback information (i.e., rewards) and to better maintain recent reward information in active working memory. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. The activity of catechol-O-methyltransferase (COMT) is not impaired by high doses of epigallocatechin-3-gallate (EGCG) in vivo.

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    Lorenz, Mario; Paul, Friedemann; Moobed, Minoo; Baumann, Gert; Zimmermann, Benno F; Stangl, Karl; Stangl, Verena

    2014-10-05

    Catechol-O-methyltransferase (COMT) inactivates many endogenous and exogenous compounds by O-methylation. Therefore, it represents a major enzyme of the metabolic pathway with important biological functions in hormonal and drug metabolism. The tea catechin epigallocatechin-3-gallate (EGCG) is known to inhibit COMT enzymatic activity in vitro. Based on beneficial in vitro results, EGCG is extensively used in human intervention studies in a variety of human diseases. Owing to its low bioavailability, rather high doses of EGCG are frequently applied that may impair COMT activity in vivo. Enzymatic activities of four functional COMT single-nucleotide polymorphisms (SNPs) were determined in red blood cells (RBCs) in 24 healthy human volunteers (14 women, 10 men). The subjects were supplemented with 750 mg of EGCG and EGCG plasma levels and COMT enzyme activities in erythrocytes were measured before and 2 h after intervention. The homozygous Val→Met substitution in the SNP rs4680 resulted in significantly decreased COMT activity. Enzymatic COMT activities in RBCs were also affected by the other three COMT polymorphisms. EGCG plasma levels significantly increased after intervention. They were not influenced by any of the COMT SNPs and different enzyme activities. Ingestion of 750 mg EGCG did not result in impairment of COMT activity. However, COMT activity was significantly increased by 24% after EGCG consumption. These results indicate that supplementation with a high dose of EGCG does not impair the activity of COMT. Consequently, it may not interfere with COMT-mediated metabolism and elimination of exogenous and endogenous COMT substrates. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Effect of Catechol-O-methyltransferase-gene (COMT) Variants on Experimental and Acute Postoperative Pain in 1,000 Women undergoing Surgery for Breast Cancer

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    Kambur, Oleg; Kaunisto, Mari A.; Tikkanen, Emmi; Leal, Suzanne M.; Ripatti, Samuli; Kalso, Eija A.

    2016-01-01

    Background Catechol-O-methyltransferase (COMT) metabolizes catecholamines in different tissues. Polymorphisms in COMT gene can attenuate COMT activity and increase sensitivity to pain. Human studies exploring the effect of COMT polymorphisms on pain sensitivity have mostly included small, heterogeneous samples and have ignored several important single nucleotide polymorphisms (SNPs). This study examines the effect of COMT polymorphisms on experimental and postoperative pain phenotypes in a large ethnically homogeneous female patient cohort. Methods Intensity of cold (+2–4°C) and heat (+48°C) pain and tolerance to cold pain were assessed in 1,000 patients scheduled for breast cancer surgery. Acute postoperative pain and oxycodone requirements were recorded. Twenty-two COMT SNPs were genotyped and their association with six pain phenotypes analyzed with linear regression. Results There was no association between any of the tested pain phenotypes and SNP rs4680. The strongest association signals were seen between rs165774 and heat pain intensity as well as rs887200 and cold pain intensity. In both cases, minor allele carriers reported less pain. Neither of these results remained significant after strict multiple testing corrections. When analyzed further, the effect of rs887200 was, however, shown to be significant and consistent throughout the cold pressure test. No evidence of association between the SNPs and postoperative oxycodone consumption was found. Conclusions SNPs rs887200 and rs165774 located in the untranslated regions of the gene had the strongest effects on pain sensitivity. Their effect on pain is described here for the first time. These results should be confirmed in further studies and the potential functional mechanisms of the variants studied. PMID:24343288

  2. [Effect of Electroacupuncture on Expression of Catechol-O-methyltransferase in the Inferior Colliculus and Auditory Cortex in Age-related Hearing Loss Guinea Pigs].

    Science.gov (United States)

    Liu, Shu-Yun; Deng, Li-Qiang; Yang, Ye; Yin, Ze-Deng

    2017-04-25

    To observe the expression of catechol-O-methyltransferase (COMT) in inferior colliculus and auditory cortex of guinea pigs with age-related hearing loss(AHL) induced by D-galactose, so as to explore the possible mechanism of electroacupuncture(EA) underlying preventing AHL. Thirty 3-month-old guinea pigs were randomly divided into control group, model group and EA group(n=10 in each group), and ten 18-month-old guinea pigs were allocated as elderly group. The AHL model was established by subcutaneous injection of D-galactose. EA was applied to bilateral "Yifeng"(SJ 17) and "Tinggong"(SI 19) for 15 min in the EA group while modeling, once daily for 6 weeks. After treatment, the latency of auditory brainstem response(ABR) Ⅲ wave was measured by a brain-stem evoked potentiometer. The expressions of COMT in the inferior colliculus and auditory cortex were detected by Western blot. Compared with the control group, the latencies of ABR Ⅲ wave were significantly prolonged and the expressions of COMT in the inferior colliculus and auditory cortex were significantly decreased in the model group and the elderly group(P<0.05). After the treatment, the latency of ABR Ⅲ wave was significantly shortened and the expressions of COMT in the inferior colliculus and auditory cortex were significantly increased in the EA group in comparison with the model group (P<0.05). EA at "Yifeng" (SJ 17) and "Tinggong" (SI 19) can improve the hearing of age-related deafness in guinea pigs, which may contribute to its effect in up-regulating the expression of COMT in the inferior colliculus and auditory cortex.

  3. Meta-analysis reveals a lack of association between a common catechol-O-methyltransferase (COMT) polymorphism val¹⁵⁸met and fibromyalgia.

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    Zhang, Lei; Zhu, Junwei; Chen, Yong; Zhao, Jianning

    2014-01-01

    This study is to evaluate the association between the catechol-O-methyltransferase (COMT) gene val(158)met polymorphism and FM risk. We performed a meta-analysis of 8 case-control studies that included 589 FM cases and 527 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, this meta-analysis showed that the COMT gene val(158)met polymorphism was not associated with FM risk in all genetic models, i.e., allele (met vs. val: OR=1.46, 95% CI=0.80-2.66, P heterpgeneity<0.001), homozygous (met/met vs. val/val: OR=1.72, 95% CI=0.61-4.87, P heterpgeneity<0.001), heterozygous (val/met vs. val/val: OR=1.25, 95% CI=0.82-1.92, P heterpgeneity=0.050), recessive (met/met vs. val/val+val/met: OR=1.52, 95% CI=0.60-3.86, P heterpgeneity<0.001) and dominant model (met/met+val/met vs. val/val: OR=1.52, 95% CI=0.80-2.90, P heterpgeneity<0.001). Similarly, there were no significant associations in the subgroup analyses by ethnicity and HWE. No publication bias was found in the present study. This meta-analysis suggests that the COMT gene val(158)met polymorphism is not associated with FM risk. Further large and well-designed studies are needed to confirm this association.

  4. Departure from multiplicative interaction for catechol-O-methyltransferase genotype and active/passive exposure to tobacco smoke among women with breast cancer

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    Wilk Jemma

    2006-01-01

    Full Text Available Abstract Background Women with homozygous polymorphic alleles of catechol-O-methyltransferase (COMT-LL metabolize 2-hydroxylated estradiol, a suspected anticarcinogenic metabolite of estrogen, at a four-fold lower rate than women with no polymorphic alleles (COMT-HH or heterozygous women (COMT-HL. We hypothesized that COMT-LL women exposed actively or passively to tobacco smoke would have higher exposure to 2-hydroxylated estradiol than never-active/never passive exposed women, and should therefore have a lower risk of breast cancer than women exposed to tobacco smoke or with higher COMT activity. Methods We used a case-only design to evaluate departure from multiplicative interaction between COMT genotype and smoking status. We identified 502 cases of invasive incident breast cancer and characterized COMT genotype. Information on tobacco use and other potential breast cancer risk factors were obtained by structured interviews. Results We observed moderate departure from multiplicative interaction for COMT-HL genotype and history of ever-active smoking (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI]: 0.7, 3.8 and more pronounced departure for women who smoked 40 or more years (aOR = 2.3, 95% CI: 0.8, 7.0. We observed considerable departure from multiplicative interaction for COMT-HL genotype and history of ever-passive smoking (aOR = 2.0, 95% CI: 0.8, 5.2 or for having lived with a smoker after age 20 (aOR = 2.8, 95% CI: 0.8, 10. Conclusion With greater control over potential misclassification errors and a large case-only population, we found evidence to support an interaction between COMT genotype and tobacco smoke exposure in breast cancer etiology.

  5. Epistatic and functional interactions of catechol-o-methyltransferase (COMT and AKT1 on neuregulin1-ErbB signaling in cell models.

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    Yoshitatsu Sei

    2010-05-01

    Full Text Available Neuregulin1 (NRG1-ErbB signaling has been implicated in the pathogenesis of cancer and schizophrenia. We have previously reported that NRG1-stimulated migration of B lymphoblasts is PI3K-AKT1dependent and impaired in patients with schizophrenia and significantly linked to the catechol-o-methyltransferase (COMT Val108/158Met functional polymorphism.We have now examined AKT1 activation in NRG1-stimulated B lymphoblasts and other cell models and explored a functional relationship between COMT and AKT1. NRG1-induced AKT1 phosphorylation was significantly diminished in Val carriers compared to Met carriers in both normal subjects and in patients. Further, there was a significant epistatic interaction between a putatively functional coding SNP in AKT1 (rs1130233 and COMT Val108/158Met genotype on AKT1 phosphorylation. NRG1 induced translocation of AKT1 to the plasma membrane also was impaired in Val carriers, while PIP(3 levels were not decreased. Interestingly, the level of COMT enzyme activity was inversely correlated with the cells' ability to synthesize phosphatidylserine (PS, a factor that attracts the pleckstrin homology domain (PHD of AKT1 to the cell membrane. Transfection of SH-SY5Y cells with a COMT Val construct increased COMT activity and significantly decreased PS levels as well as NRG1-induced AKT1 phosphorylation and migration. Administration of S-adenosylmethionine (SAM rescued all of these deficits. These data suggest that AKT1 function is influenced by COMT enzyme activity through competition with PS synthesis for SAM, which in turn dictates AKT1-dependent cellular responses to NRG1-mediated signaling.Our findings implicate genetic and functional interactions between COMT and AKT1 and may provide novel insights into pathogenesis of schizophrenia and other ErbB-associated human diseases such as cancer.

  6. Importance of membrane-bound catechol-O-methyltransferase in L-DOPA metabolism: a pharmacokinetic study in two types of Comt gene modified mice

    Science.gov (United States)

    Käenmäki, M; Tammimäki, A; Garcia-Horsman, JA; Myöhänen, T; Schendzielorz, N; Karayiorgou, M; Gogos, JA; Männistö, PT

    2009-01-01

    Background and purpose: Catechol-O-methyltransferase (COMT) metabolizes compounds containing catechol structures and has two forms: soluble (S-COMT) and membrane-bound (MB-COMT). Here we report the generation of a mouse line that expresses MB-COMT but not S-COMT. We compared the effects of deleting S-COMT only or both COMT forms on the pharmacokinetics of oral L-DOPA. Experimental approach: L-DOPA (10 mg·kg−1) and carbidopa (30 mg·kg−1) were given to mice by gastric tube, and samples were taken at various times. HPLC was used to measure L-DOPA in plasma and tissue samples, and dopamine and its metabolites in brain. Immunohistochemistry and Western blotting were used to characterize the distribution of COMT protein isoforms. Key results: Lack of S-COMT did not affect the levels of L-DOPA in plasma or peripheral tissues, whereas in the full COMT-knock-out mice, these levels were increased. The levels of 3-O-methyldopa were significantly decreased in the S-COMT-deficient mice. In the brain, L-DOPA levels were not significantly increased, and dopamine was increased only in females. The total COMT activity in the S-COMT-deficient mice was 22–47% of that in the wild-type mice. In peripheral tissues, female mice had lower COMT activity than the males. Conclusions and implications: In S-COMT-deficient mice, MB-COMT in the liver and the duodenum is able to O-methylate about one-half of exogenous L-DOPA. Sexual dimorphism and activity of the two COMT isoforms seems to be tissue specific and more prominent in peripheral tissues than in the brain. PMID:19930170

  7. Fetal Val108/158Met catechol-O-methyltransferase (COMT) polymorphism and placental COMT activity are associated with the development of preeclampsia.

    Science.gov (United States)

    Pertegal, Miriam; Fenoy, Francisco J; Hernández, Moisés; Mendiola, Jaime; Delgado, Juan L; Bonacasa, Bárbara; Corno, Andrés; López, Bernardo; Bosch, Vicente; Hernández, Isabel

    2016-01-01

    To evaluate the association between fetal and maternal catechol-O-methyltransferase (COMT) Val158Met and methyl tetrahydrofolate reductase (MTHFR) C677T functional polymorphisms and preeclampsia, examining its influence on placental COMT and in maternal 2-methoxyestradiol (2-ME) plasma levels. Prospective case-control study. University hospital. A total of 53 preeclamptic and 72 normal pregnant women. Maternal and cord blood samples and placental tissue samples were obtained. Maternal and fetal COMT and MTHFR polymorphisms were genotyped. Maternal plasma 2-ME and homocysteine levels, and expression and activity of placental COMT were measured. The odds ratio for the risk of preeclampsia for fetal COMT Met/Met was 3.22, and it increased to 8.65 when associated with fetal MTHFR TT. Placental COMT activity and expression were influenced by genotype, but COMT activity in preeclamptic placentas did not differ from control pregnancies. There was no association between any genotypes and maternal 2-ME. Homocysteine levels were higher in women with preeclampsia than in normal pregnancies, and were inversely correlated with 2-ME plasma levels, indicating that its altered metabolism may lower COMT activity in vivo. Fetal Met-Met COMT genotype reduces COMT placental expression and activity in vitro and increases preeclampsia, risk but it does not explain the difference in maternal 2-ME levels between preeclamptic and normal pregnancies. However, the preeclamptic patients had elevated homocysteine levels that correlated inversely with 2-ME, indicating that an altered methionine-homocysteine metabolism may contribute to reduce COMT activity in vivo and explain the decreased levels of 2-ME in preeclamptic women. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  8. Catechol-O-methyltransferase Val158-Met polymorphism and a response of hyperactive-impulsive symptoms to methylphenidate: A replication study from South Korea.

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    Park, Subin; Kim, Jae-Won; Kim, Bung-Nyun; Shin, Min-Sup; Yoo, Hee-Jeong; Cho, Soo-Churl

    2014-07-01

    We investigated the association between the catechol-O-methyltransferase (COMT) Val(158)-Met (rs4680) genotype and both subjective and objective treatment responses to methylphenidate in Korean children with attention-deficit/hyperactivity disorder (ADHD). We enrolled 120 medication-naïve children with ADHD in an open-label, 8-week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical Global Impression Scale and the ADHD Rating Scale-IV (ADHD-RS), and completed the Continuous Performance Test (CPT) before and after treatment. We found a significant association between the COMT Val/Val genotype and a good response, in terms of hyperactive-impulsive scores on the ADHD-RS (odds ratio (OR) = 2.61; p = 0.044) and response-time variability on the CPT (OR = 2.66; p = 0.028). The association of the COMT Val/Val genotype with a good response, in terms of response time variability, was significant in both the sub-sample of combined-type (OR = 3.45; p = 0.026) and sub-sample of inattentive-type (OR = 5.52; p = 0.029); but the association with a good response in terms of hyperactive-impulsive scores was not significant in sub-sample analyses. Although the reported nominally significant associations did not stay significant after correcting for multiple testing, our results support previous findings about the possible involvement of the COMT (Val(158)-Met) polymorphism in the treatment response to methylphenidate in children with ADHD. © The Author(s) 2014.

  9. Arterivirus nsp12 versus the coronavirus nsp16 2'-O-methyltransferase: comparison of the C-terminal cleavage products of two nidovirus pp1ab polyproteins.

    Science.gov (United States)

    Lehmann, Kathleen C; Hooghiemstra, Lisa; Gulyaeva, Anastasia; Samborskiy, Dmitry V; Zevenhoven-Dobbe, Jessika C; Snijder, Eric J; Gorbalenya, Alexander E; Posthuma, Clara C

    2015-09-01

    The 3'-terminal domain of the most conserved ORF1b in three of the four families of the order Nidovirales (except for the family Arteriviridae) encodes a (putative) 2'-O-methyltransferase (2'-O-MTase), known as non structural protein (nsp) 16 in the family Coronaviridae and implicated in methylation of the 5' cap structure of nidoviral mRNAs. As with coronavirus transcripts, arterivirus mRNAs are assumed to possess a 5' cap although no candidate MTases have been identified thus far. To address this knowledge gap, we analysed the uncharacterized nsp12 of arteriviruses, which occupies the ORF1b position equivalent to that of the nidovirus 2'-O-MTase (coronavirus nsp16). In our in-depth bioinformatics analysis of nsp12, the protein was confirmed to be family specific whilst having diverged much further than other nidovirus ORF1b-encoded proteins, including those of the family Coronaviridae. Only one invariant and several partially conserved, predominantly aromatic residues were identified in nsp12, which may adopt a structure with alternating α-helices and β-strands, an organization also found in known MTases. However, no statistically significant similarity was found between nsp12 and the twofold larger coronavirus nsp16, nor could we detect MTase activity in biochemical assays using recombinant equine arteritis virus (EAV) nsp12. Our further analysis established that this subunit is essential for replication of this prototypic arterivirus. Using reverse genetics, we assessed the impact of 25 substitutions at 14 positions, yielding virus phenotypes ranging from WT-like to non-viable. Notably, replacement of the invariant phenylalanine 109 with tyrosine was lethal. We concluded that nsp12 plays an essential role during EAV replication, possibly by acting as a co-factor for another enzyme.

  10. Electrochemical behavior of antioxidants: Part 3. Electrochemical studies of caffeic Acid–DNA interaction and DNA/carbon nanotube biosensor for DNA damage and protection

    Directory of Open Access Journals (Sweden)

    Refat Abdel-Hamid

    2016-05-01

    Full Text Available Multi-walled carbon nanotubes-modified glassy carbon electrode biosensor was used for electrochemical studies of caffeic acid–dsDNA interaction in phosphate buffer solution at pH 2.12. Caffeic acid, CAF, shows a well-defined cyclic voltammetric wave. Its anodic peak current decreases and the peak potential shifts positively on the addition of dsDNA. This behavior was ascribed to an interaction of CAF with dsDNA giving CAF–dsDNA complex by intercalative binding mode. The apparent binding constant of CAF–dsDNA complex was determined using amperometric titrations. The oxidative damage caused to DNA was detected using the biosensor. The damage caused by the reactive oxygen species, hydroxyl radical (·−OH generated by the Fenton system on the DNA-biosensor was detected. It was found that CAF has the capability of scavenging the hydroxide radical and protecting the DNA immobilized on the GCE surface.

  11. Gonadectomy and Hormone Replacement Exert Region- and Enzyme Isoform-Specific Effects on Monoamine Oxidase and Catechol-O-Methyltransferase Activity in Prefrontal Cortex and Neostriatum of Adult Male Rats

    Science.gov (United States)

    Meyers, B.; D'Agostino, A.; Walker, J.; Kritzer, M. F.

    2010-01-01

    Sex differences and gonadal hormone influences are well known for diverse aspects of forebrain amine and indolamine neurotransmitter systems, the cognitive and affective functions they govern and their malfunction in mental illness. This study explored whether hormone regulation/dysregulation of these systems could be related to gonadal steroid effects on catechol-O-methyltransferase and monoamine oxidase which are principal enzymatic controllers of forebrain dopamine, serotonin and norepinephrine levels. Driven by male over female differences in cortical enzyme activities, by male-specific associations between monoamine oxidase and catechol-O-methyltransferase gene polymorphisms and cognitive and dysfunction in disease and by male-specific consequences of gene knockouts in mice, the question of hormone sensitivity was addressed here using a male rat model where prefrontal dopamine levels and related behaviors are also known to be affected. Specifically, quantitative O-methylation and oxidative deamination assays were used to compare the activities of catechol-O-methyltransferase's soluble and membrane-bound isoforms and of monoamine oxidase's A and B isoforms in the pregenual medial prefrontal cortex and dorsal striatum of male rats that were sham operated, gonadectomized or gonadectomized and supplemented with testosterone propionate or with estradiol for 28 days. These studies revealed significant effects of hormone replacement but not gonadectomy on the soluble but not the membrane-bound isorfom of catechol-O-methyltransferase in both striatum and cortex. A significant, cortex-specific testosterone—but not estradiol—attenuated effect (increase) of gonadectomy on monoamine oxidase's A but not B isoform was also observed. Although none of these actions suggest potential roles in the reguation/dysregulation of prefrontal dopamine, the suppressive effects of testosterone on cortical monoamine oxidase-A that were observed could have bearing on the increased

  12. Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis.

    Science.gov (United States)

    Huang, Eric; Zai, Clement C; Lisoway, Amanda; Maciukiewicz, Malgorzata; Felsky, Daniel; Tiwari, Arun K; Bishop, Jeffrey R; Ikeda, Masashi; Molero, Patricio; Ortuno, Felipe; Porcelli, Stefano; Samochowiec, Jerzy; Mierzejewski, Pawel; Gao, Shugui; Crespo-Facorro, Benedicto; Pelayo-Terán, José M; Kaur, Harpreet; Kukreti, Ritushree; Meltzer, Herbert Y; Lieberman, Jeffrey A; Potkin, Steven G; Müller, Daniel J; Kennedy, James L

    2016-05-01

    The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response. Searches using PubMed, Web of Science, and PsycInfo databases (03/01/2015) yielded 23 studies investigating COMT Val158Met variation and antipsychotic response in schizophrenia and schizo-affective disorder. Responders/nonresponders were defined using each study's original criteria. If no binary response definition was used, authors were asked to define response according to at least 30% Positive and Negative Syndrome Scale score reduction (or equivalent in other scales). Analysis was conducted under a fixed-effects model. Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (ntotal=1416). Met/Met individuals were significantly more likely to respond than Val-carriers (P=.039, ORMet/Met=1.37, 95% CI: 1.02-1.85). Met/Met patients also experienced significantly greater improvement in positive symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024-0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly more likely to respond relative to Val-carriers (P=.0098, ORMet/Met=1.54, 95% CI: 1.11-2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65). Our findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients. This effect may be more pronounced for

  13. Catechol-O-methyltransferase Val158Met polymorphism is associated with increased risk of multiple uterine leiomyomas either positive or negative for MED12 exon 2 mutations.

    Science.gov (United States)

    Dzhemlikhanova, Lyailya Kh; Efimova, Olga A; Osinovskaya, Natalia S; Parfenyev, Sergey E; Niauri, Dariko A; Sultanov, Iskender Yu; Malysheva, Olga V; Pendina, Anna A; Shved, Natalia Yu; Ivashchenko, Tatyana E; Yarmolinskaya, Maria I; Kakhiani, Maka I; Gorovaya, Ekaterina A; Tkachenko, Antonina N; Baranov, Vladislav S

    2017-03-01

    To study the possible association of catechol-O-methyltransferase (COMT) Val158Met polymorphism with multiple and solitary uterine leiomyomas (ULs) and to check whether the COMT Val/Val genotype is associated with MED12 exon 2 mutations in fibroids. The COMT Val158Met allele and genotype frequencies were compared between age-matched women with ULs (n=104) and controls (n=59). Patients with UL were subcategorised by diagnosis of solitary (n=59) or multiple (n=45) fibroids and by the presence of somatic MED12 exon 2 mutations in at least one fibroid (n=32) or in neither fibroid (n=26). The association of COMT Val/Val genotype with the presence of any ULs, solitary/multiple ULs and ULs positive/negative for MED12 exon 2 mutations was evaluated by χ2 tests using a dominant genotype model (G/G vs G/A+A/A) and expressed as ORs and 95% CIs. The COMT Val/Val genotype frequency did not differ between the patients with UL and the controls (28.8% vs 18.6%, p=0.149, OR 1.77; CI 0.81 to 3.86). However, it was significantly higher in the patients who had multiple UL compared with the solitary UL (40% vs 20.3%, p=0.028, OR 2.61; CI 1.09 to 6.24) and to the controls (40% vs 18.6%, p=0.016, OR 2.91; CI 1.20 to 7.06). No association of the COMT Val/Val genotype with UL-specific MED12 exon 2 mutations was found (p=0.662, OR 0.77; CI 0.23 to 2.53). Women with COMT Val/Val genotype are at high risk of developing multiple uterine fibroids either positive or negative for MED12 exon 2 mutations. These data are important to design new strategies for UL prophylaxis and treatment. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  14. Green Tea Extract and Catechol-O-Methyltransferase Genotype Modify Fasting Serum Insulin and Plasma Adiponectin Concentrations in a Randomized Controlled Trial of Overweight and Obese Postmenopausal Women.

    Science.gov (United States)

    Dostal, Allison M; Samavat, Hamed; Espejo, Luis; Arikawa, Andrea Y; Stendell-Hollis, Nicole R; Kurzer, Mindy S

    2016-01-01

    Green tea consumption has been associated with favorable changes in body weight and obesity-related hormones, although it is not known whether these changes result from green tea polyphenols or caffeine. We examined the impact of decaffeinated green tea extract (GTE) containing 843 mg of (-)-epigallocatechin-3-gallate on anthropometric variables, obesity-associated hormones, and glucose homeostasis. The Minnesota Green Tea Trial was a 12-mo randomized, double-blind, placebo-controlled clinical trial of 937 healthy postmenopausal women assigned to either decaffeinated GTE (1315 mg total catechins/d) or a placebo, stratified by catechol-O-methyltransferase (COMT) genotype. This study was conducted in a subset of 237 overweight and obese participants [body mass index (BMI) ≥25 kg/m(2)]. No changes in energy intake, body weight, BMI, or waist circumference (WC) were observed over 12 mo in women taking GTE (n = 117) or placebo (n = 120). No differences were seen in circulating leptin, ghrelin, adiponectin, or glucose concentrations at month 12. Participants randomly assigned to GTE with baseline insulin ≥10 μIU/mL (n = 23) had a decrease in fasting serum insulin from baseline to month 12 (-1.43 ± 0.59 μIU/mL), whereas those randomly assigned to placebo with baseline insulin ≥10 μIU/mL (n = 19) had an increase in insulin over 12 mo (0.55 ± 0.64 μIU/mL, P < 0.01). Participants with the homozygous high-activity (G/G) form of COMT had significantly lower adiponectin (5.97 ± 0.50 compared with 7.58 ± 0.53 μg/mL, P = 0.03) and greater insulin concentrations (7.63 ± 0.53 compared with 6.18 ± 0.36 μIU/mL, P = 0.02) at month 12 compared with those with the low-activity (A/A) genotype, regardless of treatment group. Decaffeinated GTE was not associated with reductions in body weight, BMI, or WC and did not alter energy intake or mean hormone concentrations in healthy postmenopausal women over 12 mo. GTE decreased fasting insulin concentrations in those with

  15. Differential effects of the catechol-O-methyltransferase Val158Met genotype on the cognitive function of schizophrenia patients and healthy Japanese individuals.

    Directory of Open Access Journals (Sweden)

    Shoko Tsuchimine

    Full Text Available BACKGROUND: The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT gene has been associated with differences in prefrontal cognitive functions in patients with schizophrenia and healthy individuals. Several studies have indicated that the Met allele is associated with better performance on measures of cognitive function. We investigated whether the COMT Val158Met genotype was associated with cognitive function in 149 healthy controls and 118 patients with schizophrenia. METHODS: Cognitive function, including verbal memory, working memory, motor speed, attention, executive function and verbal fluency, was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS-J. We employed a one-way analysis of variance (ANOVA and a multiple regression analysis to determine the associations between the COMT Val158Met genotype and the BACS-J measurements. RESULTS: The one-way ANOVA revealed a significant difference in the scores on the Tower of London, a measure of executive function, between the different Val158Met genotypes in the healthy controls (p = 0.023, and a post-hoc analysis showed significant differences between the scores on the Tower of London in the val/val genotype group (18.6 ± 2.4 compared to the other two groups (17.6 ± 2.7 for val/met and 17.1 ± 3.2 for met/met; p = 0.027 and p = 0.024, respectively. Multiple regression analyses revealed that executive function was significantly correlated with the Val158Met genotype (p = 0.003. However, no evidence was found for an effect of the COMT on any cognitive domains of the BACS-J in the patients with schizophrenia. CONCLUSION: These data support the hypothesis that the COMT Val158Met genotype maintains an optimal level of dopamine activity. Further studies should be performed that include a larger sample size and include patients on and off medication, as these patients would help to confirm our findings.

  16. A Novel Sensitive Method to Measure Catechol-O-Methyltransferase Activity Unravels the Presence of This Activity in Extracellular Vesicles Released by Rat Hepatocytes.

    Science.gov (United States)

    Casal, Enriqueta; Palomo, Laura; Cabrera, Diana; Falcon-Perez, Juan M

    2016-01-01

    There is a clear need for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. One of the main enzymes to take into account in pharmacogenomics is catechol O-methyltransferase (COMT), which catalyzes the transfer of a methyl group from S -adenosylmethionine to catechols and catecholamines, like the neurotransmitters dopamine, epinephrine, and norepinephrine. Although, most of this enzyme is associated to intracellular vesicles, recently it has also been detected in extracellular vesicles secreted by hepatocytes and in serum circulating vesicles. COMT has implications in many neurological and psychiatric disorders like Parkinson's disease, chronic fatigue, pain response, schizophrenia, and bipolar disorders. Remarkably, genetic variations of COMT affect its activity and are associated to various human disorders from psychiatric diseases to estrogen-induced cancers. Consequently, the establishment of new methods to evaluate COMT activity is an important aspect to investigate the biology of this drug-metabolizing enzyme. Herein, we have developed a sensitive and selective method to determine COMT activity. We first optimized the activity in rat liver incubated with two different substrates; norepinephrine and dopamine. The enzymatically formed products (normetanephrine and 3-methoxytyramine, respectively) were extracted by solid-phase extraction using weak cation exchange cartridges, chromatographically separated, and detected and quantified using a mass spectrometer. The range of quantitation for both products was from 0.005 to 25 μg/mL. This methodology offers acceptable recovery for both enzymatic products (≥75%) and good accuracy and precision (≤15%). The lower limit of quantifications were 0.01 and 0.005 μM for 3-methoxytyramine and normetanephrine, respectively. Importantly, this sensitive assay was able to detect the presence of

  17. Binding of the Methyl DonorS-Adenosyl-l-Methionine to Middle East Respiratory Syndrome Coronavirus 2'-O-Methyltransferase nsp16 Promotes Recruitment of the Allosteric Activator nsp10.

    Science.gov (United States)

    Aouadi, Wahiba; Blanjoie, Alexandre; Vasseur, Jean-Jacques; Debart, Françoise; Canard, Bruno; Decroly, Etienne

    2017-03-01

    The Middle East respiratory syndrome coronavirus (MERS-CoV) nonstructural protein 16 (nsp16) is an S -adenosyl-l-methionine (SAM)-dependent 2'- O -methyltransferase (2'-O-MTase) that is thought to methylate the ribose 2'-OH of the first transcribed nucleotide (N 1 ) of viral RNA cap structures. This 2'-O-MTase activity is regulated by nsp10. The 2'- O methylation prevents virus detection by cell innate immunity mechanisms and viral translation inhibition by the interferon-stimulated IFIT-1 protein. To unravel the regulation of nsp10/nsp16 2'-O-MTase activity, we used purified MERS-CoV nsp16 and nsp10. First, we showed that nsp16 recruited N7-methylated capped RNA and SAM. The SAM binding promotes the assembly of the enzymatically active nsp10/nsp16 complex that converted 7m GpppG (cap-0) into 7m GpppG 2'Om (cap-1) RNA by 2'-OH methylation of N 1 in a SAM-dependent manner. The subsequent release of SAH speeds up nsp10/nsp16 dissociation that stimulates the reaction turnover. Alanine mutagenesis and RNA binding assays allowed the identification of the nsp16 residues involved in RNA recognition forming the RNA binding groove (K46, K170, E203, D133, R38, Y47, and Y181) and the cap-0 binding site (Y30, Y132, and H174). Finally, we found that nsp10/nsp16 2'-O-MTase activity is sensitive to known MTase inhibitors, such as sinefungin and cap analogues. This characterization of the MERS-CoV 2'-O-MTase is a preliminary step toward the development of molecules to inhibit cap 2'-O methylation and to restore the host antiviral response. IMPORTANCE MERS-CoV codes for a cap 2'- O -methyltransferase that converts cap-0 into cap-1 structure in order to prevent virus detection by cell innate immunity mechanisms. We report the biochemical properties of MERS-CoV 2'O-methyltransferase, which is stimulated by nsp10 acting as an allosteric activator of the nsp16 2'- O -methyltransferase possibly through enhanced RNA binding affinity. In addition, we show that SAM promotes the formation

  18. Cloning and expressing a highly functional and substrate specific farnesoic acid o-methyltransferase from the Asian citrus psyllid (Diaphorina citri Kuwayama)

    Science.gov (United States)

    The Asian citrus psyllid, Diaphorina citri, transmits a phloem-limited bacterium, Candidatus Liberibacter asiaticus that causes citrus greening disease. Because juvenile hormone (JH) plays an important role in adult and nymphal development, we studied the final steps in juvenile hormone biosynthesis...

  19. CCR1, an enzyme required for lignin biosynthesis in Arabidopsis, mediates cell proliferation exit for leaf development

    DEFF Research Database (Denmark)

    Xue, Jingshi; Luo, Dexian; Xu, Deyang

    2015-01-01

    A), an intermediate in lignin biosynthesis. FeA is known to have antioxidant activity, and the levels of reactive oxygen species (ROS) in ccr1 were markedly reduced. We also characterized another double mutant in CAFFEIC ACID O-METHYLTRANSFERASE (comt) and CAFFEOYL CoA 3-O-METHYLTRANSFERASE (ccoaomt), in which the Fe......A level was dramatically reduced. Cell proliferation in comt ccoaomt leaves was decreased, accompanied by elevated ROS levels, and the mutant phenotypes were partially rescued by treatment with FeA or another antioxidant (N-acetyl-L-cysteine). Taken together, our results suggest that CCR1, FeA and ROS...

  20. Chicoric Acid Found in Basil (Ocimum basilicum L.) Leaves

    Science.gov (United States)

    This is the first report to identify the presence of chicoric acid (cichoric acid; also known as dicaffeoyltartaric acid) in basil leaves. Rosmarinic acid, chicoric acid, and caftaric acid (in the order of most abundant to least; all derivatives of caffeic acid) were identified in fresh basil leaves...

  1. Synthesis of a Series of Caffeic Acid Phenethyl Amide (CAPA) Fluorinated Derivatives: Comparison of Cytoprotective Effects to Caffeic Acid Phenethyl Ester (CAPE)

    Science.gov (United States)

    2010-06-11

    analysis was performed using the JMP program (SAS). Acknowledgments This project was supported by the US Army Institute of Surgical Research, the Robert ... Robert , A.; Meunier, B.; Boissier, J.; Cosledan, F.; Gornitzka, H. Eur. J. Org. Chem. 2008. 26. Kunduzova, O. R.; Bianchi, P.; Parini, A.; Cambon, C...K. L.; Olubajo, O.; Buchhold, K.; Lewandowski , G. A.; Gusovsky, F.; McCulloh, D.; Daly, J. W.; Creveling, C. R. J. Med. Chem. 1986, 29, 1982. 30. Wang

  2. Voxelwise eigenvector centrality mapping of the human functional connectome reveals an influence of the catechol-O-methyltransferase val158met polymorphism on the default mode and somatomotor network.

    Science.gov (United States)

    Markett, Sebastian; Montag, Christian; Heeren, Behrend; Saryiska, Rayna; Lachmann, Bernd; Weber, Bernd; Reuter, Martin

    2016-06-01

    Functional connections between brain regions constitute the substrate of the human functional connectome, whose topography has been discussed as an endophenotype for psychiatric disorders. Genetic influences on the entire connectome, however, have been rarely investigated so far. We tested for connectome-wide influences of the val158met (rs4860) polymorphism on the catechol-O-methyltransferase (COMT) gene by applying formal network analysis and eigenvector centrality mapping on the voxel level to resting-state functional magnetic imaging data. This approach finds brain regions that are central in the network by aggregating local and global connectivity patterns, most importantly without the requirement to select regions or networks of interest. The COMT variant linked to high enzyme activity increased network centrality in distributed brain areas that are known to constitute the brain's default mode network. Further results also indicated a COMT influence on areas implicated in the somatomotor network. These findings are in line with the polymorphism's alleged role in cognitive processing and its role in psychotic disorders. The study is the first to demonstrate the influence of a functional and behaviorally relevant genetic variant on connectome-wide functional connectivity and is an important step toward establishing the functional connectome as an endophenotype for psychiatric and behavioral phenotypes.

  3. Monoamine Oxidase A (MAOA) and Catechol-O-Methyltransferase (COMT) Gene Polymorphisms Interact with Maternal Parenting in Association with Adolescent Reactive Aggression but not Proactive Aggression: Evidence of Differential Susceptibility.

    Science.gov (United States)

    Zhang, Wenxin; Cao, Cong; Wang, Meiping; Ji, Linqin; Cao, Yanmiao

    2016-04-01

    To date, whether and how gene-environment (G × E) interactions operate differently across distinct subtypes of aggression remains untested. More recently, in contrast with the diathesis-stress hypothesis, an alternative hypothesis of differential susceptibility proposes that individuals could be differentially susceptible to environments depending on their genotypes in a "for better and for worse" manner. The current study examined interactions between monoamine oxidase A (MAOA) T941G and catechol-O-methyltransferase (COMT) Val158Met polymorphisms with maternal parenting on two types of aggression: reactive and proactive. Moreover, whether these potential G × E interactions would be consistent with the diathesis-stress versus the differential susceptibility hypothesis was tested. Within the sample of 1399 Chinese Han adolescents (47.2 % girls, M age = 12.32 years, SD = 0.50), MAOA and COMT genes both interacted with positive parenting in their associations with reactive but not proactive aggression. Adolescents with T alleles/TT homozygotes of MAOA gene or Met alleles of COMT gene exhibited more reactive aggression when exposed to low positive parenting, but less reactive aggression when exposed to high positive parenting. These findings provide the first evidence for distinct G × E interaction effects on reactive versus proactive aggression and lend further support for the differential susceptibility hypothesis.

  4. [Expression of Catechol-O-Methyltransferase (Comt), Mineralocorticoid Receptor (Mlr), and Epithelial Sodium Channel (ENaC) Genes in Kidneys of Hypertensive ISIAH Rats at Rest and during Response to Stress].

    Science.gov (United States)

    Abramova, T O; Smolenskaya, S E; Antonov, E V; Redina, O E; Markel, A L

    2016-02-01

    Emotional stress plays a significant role in the processes of the development of arterial hypertension, especially in the presence of genetic predisposition. The origin and maintenance of hypertensive status during stress development can be activated by the sympathetic nervous system. An increase in sympathetic stimulation can, in turn, result in a change in the functions of kidneys, which provide fluid and electrolyte balance of the organism. A comparative study of the mRNA expression level of catechol-o-methyltransferase (Comt), mineralocorticoid receptor (Mlr), and β-subunit of epithelial sodium channel (β-ENaC) genes was conducted on the kidneys of hypertensive ISIAH rats and normotensive WAG rats at rest and after the effect of emotional stress. The discovered changes in the expression level of the selected genes confirm their involvement in increased sympathetic stimulation of the kidney, along with changes in the function of kidney regulation of fluid and electrolyte balance, which is an important factor of the development of sustained hypertension in the ISIAH rats strain.

  5. Executive function performance and change in aging is predicted by apolipoprotein E, intensified by catechol-O-methyltransferase and brain-derived neurotrophic factor, and moderated by age and lifestyle.

    Science.gov (United States)

    Sapkota, Shraddha; Bäckman, Lars; Dixon, Roger A

    2017-04-01

    Recent studies have reported several genetic, health, and aging interaction effects in predicting cognitive performance and change. We used an accelerated longitudinal design to examine interactions among genetic, lifestyle, and aging for executive function (EF) in non-demented older adults (n = 634; age range = 53-95 years). The polymorphisms were apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF). We tested (1) independent and additive effects of APOE, COMT, and BDNF and (2) APOE effect modification for COMT + BDNF, on EF performance and 9-year change as separated by age and lifestyle activities. First, APOE ε4+ carriers had poorer EF performance and steeper 9-year decline. Second, APOE ε4+ carriers with (1) BDNF Met/Met genotype and (2) increasing allelic risk in the COMT + BDNF risk panel had poorer EF performance; these effects were moderated by lifestyle activities (composite of everyday social, physical, and cognitive activities). Examining APOE effect modification for COMT + BDNF risk panel effects with other moderating factors may help identify complex neurobiological and genetic underpinnings of polygenic phenotypes such as EF in aging. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Dopamine receptor D2 and catechol-O-methyltransferase gene polymorphisms associated with anorexia nervosa in Chinese Han population: DRD2 and COMT gene polymorphisms were associated with AN.

    Science.gov (United States)

    Peng, Sufang; Yu, Shunying; Wang, Qian; Kang, Qing; Zhang, Yanxia; Zhang, Ran; Jiang, Wenhui; Qian, Yiping; Zhang, Haiyin; Zhang, Mingdao; Xiao, Zeping; Chen, Jue

    2016-03-11

    Dopamine receptor D2 (DRD2) and catechol-O-methyltransferase (COMT) are important in dopamine system which is proved to be associated with food-anticipatory behavior, food restriction, reward and motivation. This has made them good candidates for anorexia nervosa (AN). The aim of this work is to explore the roles of DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) gene polymorphisms in the susceptibility of AN within the Chinese Han population. We recruited 260AN patients with DSM-IV diagnosis criteria, and 247 unrelated, normal weight controls. DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) were genotyped in all subjects. We found rs1800497 and rs4633 were associated with the susceptibility of AN within the Chinese Han sample, and allele C of rs1800497 was a protective factor. There was a gene-gene interaction between rs1800497 of DRD2 gene and rs4633 of COMT gene. We concluded that rs1800497 and rs4633 play important roles in the AN susceptibility with respect to the Chinese Han population. The gene-gene interaction between DRD2 and COMT contributes to the risk of AN. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Genetic moderation of the effects of cannabis: catechol-O-methyltransferase (COMT) affects the impact of Δ9-tetrahydrocannabinol (THC) on working memory performance but not on the occurrence of psychotic experiences.

    Science.gov (United States)

    Tunbridge, Elizabeth M; Dunn, Graham; Murray, Robin M; Evans, Nicole; Lister, Rachel; Stumpenhorst, Katharina; Harrison, Paul J; Morrison, Paul D; Freeman, Daniel

    2015-11-01

    Cannabis use can induce cognitive impairments and psychotic experiences. A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val(158)Met) appears to influence the immediate cognitive and psychotic effects of cannabis, or ∆(9)-tetrahydrocannabinol (THC), its primary psychoactive ingredient. This study investigated the moderation of the impact of experimentally administered THC by COMT. Cognitive performance and psychotic experiences were studied in participants without a psychiatric diagnosis, using a between-subjects design (THC vs. placebo). The effect of COMT Val(158)Met genotype on the cognitive and psychotic effects of THC, administered intravenously in a double-blind, placebo-controlled manner to 78 participants who were vulnerable to paranoia, was examined. The results showed interactive effects of genotype and drug group (THC or placebo) on working memory, assayed using the Digit Span Backwards task. Specifically, THC impaired performance in COMT Val/Val, but not Met, carriers. In contrast, the effect of THC on psychotic experiences, measured using the Community Assessment of Psychic Experiences (CAPE) positive dimension, was unaffected by COMT genotype. This study is the largest to date examining the impact of COMT genotype on response to experimentally administered THC, and the first using a purely non-clinical cohort. The data suggest that COMT genotype moderates the cognitive, but not the psychotic, effects of acutely administered THC. © The Author(s) 2015.

  8. Permeability of rosmarinic acid in Prunella vulgaris and ursolic acid in Salvia officinalis extracts across Caco-2 cell monolayers

    Science.gov (United States)

    Rosmarinic acid (RA), a caffeic acid derivative found in high concentrations in Prunella vulgaris (self-heal), and ursolic acid (UA), a pentacyclic triterpene acid concentrated in Salvia officinalis (sage), have been traditionally used to treat inflammation in the mouth, and may also be of benefit t...

  9. Genetic Analysis of Strawberry Fruit Aroma and Identification of O-Methyltransferase FaOMT as the Locus Controlling Natural Variation in Mesifurane Content1[C][W][OA

    Science.gov (United States)

    Zorrilla-Fontanesi, Yasmín; Rambla, José-Luis; Cabeza, Amalia; Medina, Juan J.; Sánchez-Sevilla, José F.; Valpuesta, Victoriano; Botella, Miguel A.; Granell, Antonio; Amaya, Iraida

    2012-01-01

    Improvement of strawberry (Fragaria × ananassa) fruit flavor is an important goal in breeding programs. To investigate genetic factors controlling this complex trait, a strawberry mapping population derived from genotype ‘1392’, selected for its superior flavor, and ‘232’ was profiled for volatile compounds over 4 years by headspace solid phase microextraction coupled to gas chromatography and mass spectrometry. More than 300 volatile compounds were detected, of which 87 were identified by comparison of mass spectrum and retention time to those of pure standards. Parental line ‘1392’ displayed higher volatile levels than ‘232’, and these and many other compounds with similar levels in both parents segregated in the progeny. Cluster analysis grouped the volatiles into distinct chemically related families and revealed a complex metabolic network underlying volatile production in strawberry fruit. Quantitative trait loci (QTL) detection was carried out over 3 years based on a double pseudo-testcross strategy. Seventy QTLs covering 48 different volatiles were detected, with several of them being stable over time and mapped as major QTLs. Loci controlling γ-decalactone and mesifurane content were mapped as qualitative traits. Using a candidate gene approach we have assigned genes that are likely responsible for several of the QTLs. As a proof of concept we show that one homoeolog of the O-methyltransferase gene (FaOMT) is the locus responsible for the natural variation of mesifurane content. Sequence analysis identified 30 bp in the promoter of this FaOMT homoeolog containing putative binding sites for basic/helix-loop-helix, MYB, and BZIP transcription factors. This polymorphism fully cosegregates with both the presence of mesifurane and the high expression of FaOMT during ripening. PMID:22474217

  10. Lack of Cell Proliferative and Tumorigenic Effects of 4-Hydroxyestradiol in the Anterior Pituitary of Rats: Role of Ultrarapid O-Methylation Catalyzed by Pituitary Membrane-Bound Catechol-O-Methyltransferase.

    Science.gov (United States)

    Wang, Pan; Mills, Laura H; Song, Ji-Hoon; Yu, Jina; Zhu, Bao-Ting

    2017-07-17

    In animal models, estrogens are complete carcinogens in certain target sites. 4-Hydroxyestradiol (4-OH-E2), an endogenous metabolite of 17β-estradiol (E2), is known to have prominent estrogenic activity plus potential genotoxicity and mutagenicity. We report here our finding that 4-OH-E2 does not induce pituitary tumors in ACI female rats, whereas E2 produces 100% pituitary tumor incidence. To probe the mechanism, we conducted a short-term animal experiment to compare the proliferative effect of 4-OH-E2 in several organs. We found that, whereas 4-OH-E2 had little ability to stimulate pituitary cell proliferation in ovariectomized female rats, it strongly stimulates cell proliferation in certain brain regions of these animals. Further, when we used in vitro cultured rat pituitary tumor cells as models, we found that 4-OH-E2 has similar efficacy as E2 in stimulating cell proliferation, but its potency is approximately 3 orders of magnitude lower than that of E2. Moreover, we found that the pituitary tumor cells have the ability to selectively metabolize 4-OH-E2 (but not E2) with ultrahigh efficiency. Additional analysis revealed that the rat pituitary expresses a membrane-bound catechol-O-methyltransferase that has an ultralow Km value (in nM range) for catechol estrogens. On the basis of these observations, it is concluded that rapid metabolic disposition of 4-OH-E2 through enzymatic O-methylation in rat anterior pituitary cells largely contributes to its apparent lack of cell proliferative and tumorigenic effects in this target site.

  11. A Tetra-Primer Amplification Refractory System Technique for the Cost-Effective and Novel Genotyping of Eight Single-Nucleotide Polymorphisms of the Catechol-O-Methyltransferase Gene.

    Science.gov (United States)

    Wang, Cathy K; Aleksic, Ana; Xu, Michael S; Procyshyn, Ric M; Ross, Colin J; Vila-Rodriguez, Fidel; Ramos-Miguel, Alfredo; Yan, Ryan; Honer, William G; Barr, Alasdair M

    2016-08-01

    Catechol-O-methyltransferase (COMT) is an enzyme involved in the degradation of catecholamine neurotransmitters. Due to its role in neurotransmitter flux, multiple COMT variants have been associated with the development of psychiatric disorders. Notably, select single-nucleotide polymorphisms (SNPs) of the COMT gene have been implicated in schizophrenia risk, severity, and treatment response. In recognition of the value of a streamlined genotyping method for COMT SNP detection, this study was designed to develop a simple and economical tetra-primer amplification refractory mutation system (T-ARMS) assay for the concurrent detection of eight COMT SNPs: rs4680, rs737865, rs165599, rs2075507, rs4633, rs4818, rs6269, and rs165774. T-ARMS is a genotyping method that uses polymerase chain reaction (PCR) to amplify a multiplex reaction consisting of two primer pairs. T-ARMS primers are customized to each SNP and designed to generate different-sized allele-specific amplicons. This assay was applied to a total of 39 genomic DNA samples. Genotypic designations across the panel of SNPs were subsequently validated by Sanger sequencing. T-ARMS reliably and unambiguously detected all three genotypes (homozygous wild type, heterozygous, and homozygous mutant) for each of the eight COMT SNPs. Compared to traditional low-throughput methods that require post-PCR modification or high-throughput technologies that require sophisticated equipment, T-ARMS is a cost-effective and efficient assay that can be easily adapted by any standard molecular diagnostics laboratory. This T-ARMS assay provides a practical and robust method for COMT SNP detection.

  12. The Catechol-O-methyltransferase Val(108/158)Met Genetic Polymorphism cannot be Recommended as a Biomarker for the Prediction of Venlafaxine Efficacy in Patients Treated in Psychiatric Settings.

    Science.gov (United States)

    Taranu, Adela; Asmar, Khalil El; Colle, Romain; Ferreri, Florian; Polosan, Mircea; David, Denis; Becquemont, Laurent; Corruble, Emmanuelle; Verstuyft, Céline

    2017-11-01

    The antidepressant venlafaxine is known to increase the turnover of cerebral monoamines, which are catabolized by the catechol-O-methyltransferase (COMT). The COMT (Val(108/158)Met, rs4680) genetic polymorphism affects the cerebral COMT activity. But whether this genetic polymorphism is associated with response to venlafaxine remains unclear. We assessed the impact of the COMT Val(108/158)Met, rs4680 genetic polymorphism on the efficacy of venlafaxine in depressed patients. This study was nested in the METADAP cohort, a real-world naturalistic treatment study in psychiatric settings. A total of 206 Caucasian patients with a unipolar major depressive episode (DSM-IVTR) treated with venlafaxine and evaluated with the Hamilton Depression Rating Scale (HDRS) were studied. One hundred and eighty patients were genotyped for the COMT Val(108/158)Met, rs4680 genetic polymorphism and classified into three genotype subgroups: Val/Val, Val/Met and Met/Met. The COMT genotype was the explanatory variable, and the variables to be explained were HDRS score, HDRS score improvement over time, response rate and remission rate. Venlafaxine had a trend to higher efficacy in the Val/Val patients as compared to Met/Met carriers, as shown by the HDRS score improvement after 3 months of treatment, but this result was not significant in mixed models [Val/Val: 59.78% (±22.4); Val/Met: 51.64% (±26.3); Met/Met: 39.52% (±27.6)]. The percentage of responders and remitters after 3 months of treatment was not significantly different in the three genotype groups, although coherent trends were shown. The COMT Val(108/158)Met, rs4680 genetic polymorphism cannot be recommended as a biomarker for the prediction of venlafaxine efficacy in patients treated in psychiatric settings. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  13. The effect of caffeic acid phenethyl ester and thymoquinone on otitis media with effusion in rats.

    Science.gov (United States)

    Gülmez, Mehmet İhsan; Okuyucu, Şemsettin; Dokuyucu, Recep; Gökçe, Hasan

    2017-05-01

    In this study, we aimed to investigate the effect of CAPE and thymoquinone in experimental rat otitis media with effusion (OME) model. Intraoral approach of eustachian tube orifice cauterization were administered to 36 of 40 rats participating the study. After application of exclusion criterias, 22 rats with appropriate conditions were determined. Totally 26 rats (44 otitis model ears and 8 normal ears) were randomly divided into 5 groups. While group I was consisted of healthy rats, the other groups were consisted of rats with otitis model. Group I (saline + control group; n = 8 normal ears) and group II (saline + otitis model; n = 10 otitis model ears) received intraperitoneally saline solution. CAPE was given intraperitoneally to group III (CAPE + otitis model; n = 12 otitis model ears) at a concentration of 10 mg/kg for treatment of otitis media. Group IV (thymoquinone + otitis model; n = 12 otitis model ears) was treated orally with 10 mg/kg of thymoquinone. Group V (methylprednisolone + otitis model; n = 10 otitis model ears) was treated intraperitoneally with 1 mg/kg of methylprednisolone. Tympanic bulla samples were excised after 10th day of treatment and examined under light microscopy. Submucosal neutrophil leukocyte count of group I was significantly lower than other groups (II, IV, V) (respectively p < 0,0001, p < 0,001, p < 0,0001, Tukey test), while it was not significantly different from group III (p = 0,056, Tukey test). Submucosal neutrophil leukocyte count of group III was significantly lower than group II and group V (p = 0.029 ve p = 0.03, Tukey test). There was no significant difference between group IV and group V (p = 0,28, Tukey test). Based on these findings, it could be suggested that CAPE, anti inflammatory properties proven in the literature, plays an important role in OME treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Synthesis, Anti-HCV, Antioxidant and Reduction of Intracellular Reactive Oxygen Species Generation of a Chlorogenic Acid Analogue with an Amide Bond Replacing the Ester Bond.

    Science.gov (United States)

    Wang, Ling-Na; Wang, Wei; Hattori, Masao; Daneshtalab, Mohsen; Ma, Chao-Mei

    2016-06-08

    Chlorogenic acid is a well known natural product with important bioactivities. It contains an ester bond formed between the COOH of caffeic acid and the 3-OH of quinic acid. We synthesized a chlorogenic acid analogue, 3α-caffeoylquinic acid amide, using caffeic and quinic acids as starting materials. The caffeoylquinc acid amide was found to be much more stable than chlorogenic acid and showed anti-Hepatitis C virus (anti-HCV) activity with a potency similar to chlorogenic acid. The caffeoylquinc acid amide potently protected HepG2 cells against oxidative stress induced by tert-butyl hydroperoxide.

  15. Diversity of (dihydro) hydroxycinnamic acid conjugates in Colombian potato tubers

    NARCIS (Netherlands)

    Narvaez Cuenca, C.E.; Vincken, J.P.; Zheng, Chaoya; Gruppen, H.

    2013-01-01

    In potato tuber, caffeic acid (the predominant hydroxycinnamic acid (HCA)), its conjugates (HCAcs; i.e. chlorogenic acid (ChA), crypto-ChA, and neo-ChA), and anthocyanin-linked HCAs have been extensively described in the literature. In contrast, only little information is available on the occurrence

  16. Executive functions and selective attention are favored in middle-aged healthy women carriers of the Val/Val genotype of the catechol-o-methyltransferase gene: a behavioral genetic study

    Directory of Open Access Journals (Sweden)

    Gutiérrez-Muñoz Mayra

    2010-10-01

    Full Text Available Abstract Background Cognitive deficits such as poor memory, the inability to concentrate, deficits in abstract reasoning, attention and set-shifting flexibility have been reported in middle-aged women. It has been suggested that cognitive decline may be due to several factors which include hormonal changes, individual differences, normal processes of aging and age-related changes in dopaminergic neurotransmission. Catechol-O-methyltransferase (COMT, a common functional polymorphism, has been related to executive performance in young healthy volunteers, old subjects and schizophrenia patients. The effect of this polymorphism on cognitive function in middle-aged healthy women is not well known. The aim of the current study was to investigate whether measures of executive function, sustained attention, selective attention and verbal fluency would be different depending on the COMT genotype and task demand. Method We genotyped 74 middle-aged healthy women (48 to 65 years old for the COMT Val158Met polymorphism. We analyzed the effects of this polymorphism on executive functions (Wisconsin Card Sorting Test, selective attention (Stroop test, sustained attention (Continuous Performance Test and word generation (Verbal Fluency test, which are cognitive functions that involve the frontal lobe. Results There were 27 women with the Val/Val COMT genotype, 15 with the Met/Met genotype, and 32 with the Val/Met genotype. Women carriers of the Val/Val genotype performed better in executive functions, as indicated by a lower number of errors committed in comparison with the Met/Met or Val/Met groups. The correct responses on selective attention were higher in the Val/Val group, and the number of errors committed was higher in the Met/Met group during the incongruence trial in comparison with the Val/Val group. Performance on sustained attention and the number of words generated did not show significant differences between the three genotypes. Conclusion These

  17. Rožmarinska kislina: Rosmarinic acid:

    OpenAIRE

    Sova, Matej

    2012-01-01

    Rosmarinic acid, an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid, is an active component of several medicinal plants and spices. This article presents the biosynthesis of rosmarinic acid and provides a brief description of its main biological activities and potential therapeutic use. Rožmarinska kislina, ester kavne in 3,4-dihidroksifenilmlečne kisline, je aktivna sestavina številnih zdravilnih rastlin in začimb. V prispevku so predstavljeni njena biosinteza, kratek pregled gla...

  18. OH-radical induced degradation of hydroxybenzoic- and hydroxycinnamic acids and formation of aromatic products-A gamma radiolysis study

    Energy Technology Data Exchange (ETDEWEB)

    Krimmel, Birgit; Swoboda, Friederike [University of Vienna, Department of Nutritional Sciences, Section Radiation Biology (Austria); Solar, Sonja, E-mail: sonja.solar@univie.ac.a [University of Vienna, Department of Nutritional Sciences, Section Radiation Biology (Austria); Reznicek, Gottfried [Department of Pharmacognosy, Althanstrasse 14, A-1090 Vienna (Austria)

    2010-12-15

    The OH-radical induced degradation of hydroxybenzoic acids (HBA), hydroxycinnamic acids (HCiA) and methoxylated derivatives, as well as of chlorogenic acid and rosmarinic acid was studied by gamma radiolysis in aerated aqueous solutions. Primary aromatic products resulting from an OH-radical attachment to the ring (hydroxylation), to the position occupied by the methoxyl group (replacement -OCH{sub 3} by -OH) as well as to the propenoic acid side chain of the cinnamic acids (benzaldehyde formations) were analysed by HPLC-UV and LC-ESI-MS. A comparison of the extent of these processes is given for 3,4-dihydroxybenzoic acid, vanillic acid, isovanillic acid, syringic acid, cinnamic acid, 4-hydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid, chlorogenic acid, and rosmarinic acid. For all cinnamic acids and derivatives benzaldehydes were significant oxidation products. With the release of caffeic acid from chlorogenic acid the cleavage of a phenolic glycoside could be demonstrated. Reaction mechanisms are discussed.

  19. Incorporation of Chlorogenic Acids in Coffee Brew Melanoidins

    NARCIS (Netherlands)

    Bekedam, E.K.; Schols, H.A.; Boekel, van T.; Smit, G.

    2008-01-01

    The incorporation of chlorogenic acids (CGAs) and their subunits quinic and caffeic acids (QA and CA) in coffee brew melanoidins was studied. Fractions with different molecular weights, ionic charges, and ethanol solubilities were isolated from coffee brew. Fractions were saponified, and the

  20. Enzymatic Extraction of Hydroxycinnamic Acids from Coffee Pulp

    Directory of Open Access Journals (Sweden)

    Ernesto Favela-Torres

    2011-01-01

    Full Text Available Ferulic, caffeic, p-coumaric and chlorogenic acids are classified as hydroxycinnamic acids, presenting anticarcinogenic, anti-inflammatory and antioxidant properties. In this work, enzymatic extraction has been studied in order to extract high value-added products like hydroxycinnamic acids from coffee pulp. A commercial pectinase and enzyme extract produced by Rhizomucor pusillus strain 23aIV in solid-state fermentation using olive oil or coffee pulp (CP as an inducer of the feruloyl esterase activity were evaluated separately and mixed. The total content (covalently linked and free of ferulic, caffeic, p-coumaric and chlorogenic acids was 5276 mg per kg of coffee pulp. Distribution was as follows (in %: chlorogenic acid 58.7, caffeic acid 37.6, ferulic acid 2.1 and p-coumaric acid 1.5. Most of the hydroxycinnamic acids were covalently bound to the cell wall (in %: p-coumaric acid 97.2, caffeic acid 94.4, chlorogenic acid 76.9 and ferulic acid 73.4. The content of covalently linked hydroxycinnamic acid was used to calculate the enzyme extraction yield. The maximum carbon dioxide rate for the solid-state fermentation using olive oil as an inducer was higher and it was reached in a short cultivation time. Nevertheless, the feruloyl esterase (FAE activity (units per mg of protein obtained in the fermentation using CP as an inducer was 31.8 % higher in comparison with that obtained in the fermentation using olive oil as the inducer. To our knowledge, this is the first report indicating the composition of both esterified and free ferulic, caffeic, p-coumaric and chlorogenic acids in coffee pulp. The highest yield of extraction of hydroxycinnamic acids was obtained by mixing the produced enzyme extract using coffee pulp as an inducer and a commercial pectinase. Extraction yields were as follows (in %: chlorogenic acid 54.4, ferulic acid 19.8, p-coumaric acid 7.2 and caffeic acid 2.3. An important increase in the added value of coffee pulp was mainly

  1. Artificial biosynthesis of phenylpropanoic acids in a tyrosine overproducing Escherichia coli strain

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    Kang Sun-Young

    2012-12-01

    Full Text Available Abstract Background The phenylpropanoid metabolites are an extremely diverse group of natural products biosynthesized by plants, fungi, and bacteria. Although these compounds are widely used in human health care and nutrition services, their availability is limited by regional variations, and isolation of single compounds from plants is often difficult. Recent advances in synthetic biology and metabolic engineering have enabled artificial production of plant secondary metabolites in microorganisms. Results We develop an Escherichia coli system containing an artificial biosynthetic pathway that yields phenylpropanoic acids, such as 4-coumaric acid, caffeic acid, and ferulic acid, from simple carbon sources. These artificial biosynthetic pathways contained a codon-optimized tal gene that improved the productivity of 4-coumaric acid and ferulic acid, but not caffeic acid in a minimal salt medium. These heterologous pathways extended in E. coli that had biosynthesis machinery overproducing tyrosine. Finally, the titers of 4-coumaric acid, caffeic acid, and ferulic acid reached 974 mg/L, 150 mg/L, and 196 mg/L, respectively, in shake flasks after 36-hour cultivation. Conclusions We achieved one gram per liter scale production of 4-coumaric acid. In addition, maximum titers of 150 mg/L of caffeic acid and 196 mg/L of ferulic acid were achieved. Phenylpropanoic acids, such as 4-coumaric acid, caffeic acid, and ferulic acid, have a great potential for pharmaceutical applications and food ingredients. This work forms a basis for further improvement in production and opens the possibility of microbial synthesis of more complex plant secondary metabolites derived from phenylpropanoic acids.

  2. Effect of phenolic acids on glucose and organic acid metabolism by lactic acid bacteria from wine.

    Science.gov (United States)

    Campos, Francisco M; Figueiredo, Ana R; Hogg, Tim A; Couto, José A

    2009-06-01

    The influence of phenolic (p-coumaric, caffeic, ferulic, gallic and protocatechuic) acids on glucose and organic acid metabolism by two strains of wine lactic acid bacteria (Oenococcus oeni VF and Lactobacillus hilgardii 5) was investigated. Cultures were grown in modified MRS medium supplemented with different phenolic acids. Cellular growth was monitored and metabolite concentrations were determined by HPLC-RI. Despite the strong inhibitory effect of most tested phenolic acids on the growth of O. oeni VF, the malolactic activity of this strain was not considerably affected by these compounds. While less affected in its growth, the capacity of L. hilgardii 5 to degrade malic acid was clearly diminished. Except for gallic acid, the addition of phenolic acids delayed the metabolism of glucose and citric acid in both strains tested. It was also found that the presence of hydroxycinnamic acids (p-coumaric, caffeic and ferulic) increased the yield of lactic and acetic acid production from glucose by O. oeni VF and not by L. hilgardii 5. The results show that important oenological characteristics of wine lactic acid bacteria, such as the malolactic activity and the production of volatile organic acids, may be differently affected by the presence of phenolic acids, depending on the bacterial species or strain.

  3. Polimorfismos dos genes do receptor de serotonina (5-HT2A e da catecol-O-metiltransferase (COMT: fatores desencadeantes da fibromialgia? Serotonin receptor (5-HT 2A and catechol-O-methyltransferase (COMT gene polymorphisms: Triggers of fibromyalgia?

    Directory of Open Access Journals (Sweden)

    Josie Budag Matsuda

    2010-04-01

    fatigue, sleep disorders, anxiety, depression, memory loss, and dizziness. Although the physiological mechanisms that control fibromyalgia have not been precisely established, neuroendocrine, genetic or molecular factors may be involved in fibromyalgia. OBJECTIVE: The aim of the present study was to characterize serotonin receptor (5-HT2A and catecholO-methyltransferase (COMT gene polymorphisms in Brazilian patients with fibromyalgia and to evaluate the participation of these polymorphisms in the etiology of the disease. MATERIAL AND METHODS: Genomic DNA extracted from 102 blood samples (51 patients, 51 controls was used for molecular characterization of the 5-HT2A and COMT gene polymorphisms by PCR-RFLP. RESULTS: Analysis of the 5-HT2A polymorphism revealed a frequency of 25.49% C/C, 49.02% T/C and 25.49% T/T in patients, and of 17.65% C/C, 62.74% T/C and 19.61% T/T in the control group, with no differences between the two groups.Analysis of the COMT polymorphism in patients showed a frequency of 17.65% and 45.10% for genotypes H/H and L/H, respectively. In the control group the frequency was 29.42% for H/H and 60.78% for L/H, also with no differences between the two groups. However, there was a significant difference in the frequency of the L/L genotype between patients (37.25% and controls (9.8%, which permitted differentiation between the two groups. CONCLUSION: The L/L genotype was more frequent among fibromyalgia patients. Though considering a polygenic situation and environmental factors, the molecular study of the rs4680 SNP of the COMT gene may be helpful to the identification of susceptible individuals.

  4. Identification of Proteins of Altered Abundance in Oil Palm Infected with Ganoderma boninense

    Directory of Open Access Journals (Sweden)

    Jameel R. Al-Obaidi

    2014-03-01

    Full Text Available Basal stem rot is a common disease that affects oil palm, causing loss of yield and finally killing the trees. The disease, caused by fungus Ganoderma boninense, devastates thousands of hectares of oil palm plantings in Southeast Asia every year. In the present study, root proteins of healthy oil palm seedlings, and those infected with G. boninense, were analyzed by 2-dimensional gel electrophoresis (2-DE. When the 2-DE profiles were analyzed for proteins, which exhibit consistent significant change of abundance upon infection with G. boninense, 21 passed our screening criteria. Subsequent analyses by mass spectrometry and database search identified caffeoyl-CoA O-methyltransferase, caffeic acid O-methyltransferase, enolase, fructokinase, cysteine synthase, malate dehydrogenase, and ATP synthase as among proteins of which abundances were markedly altered.

  5. Identification of Proteins of Altered Abundance in Oil Palm Infected with Ganoderma boninense

    Science.gov (United States)

    Al-Obaidi, Jameel R.; Mohd-Yusuf, Yusmin; Razali, Nurhanani; Jayapalan, Jaime Jacqueline; Tey, Chin-Chong; Md-Noh, Normahnani; Junit, Sarni Mat; Othman, Rofina Yasmin; Hashim, Onn Haji

    2014-01-01

    Basal stem rot is a common disease that affects oil palm, causing loss of yield and finally killing the trees. The disease, caused by fungus Ganoderma boninense, devastates thousands of hectares of oil palm plantings in Southeast Asia every year. In the present study, root proteins of healthy oil palm seedlings, and those infected with G. boninense, were analyzed by 2-dimensional gel electrophoresis (2-DE). When the 2-DE profiles were analyzed for proteins, which exhibit consistent significant change of abundance upon infection with G. boninense, 21 passed our screening criteria. Subsequent analyses by mass spectrometry and database search identified caffeoyl-CoA O-methyltransferase, caffeic acid O-methyltransferase, enolase, fructokinase, cysteine synthase, malate dehydrogenase, and ATP synthase as among proteins of which abundances were markedly altered. PMID:24663087

  6. A simple method for enzymatic synthesis of unlabeled and radiolabeled Hydroxycinnamate-CoA

    Energy Technology Data Exchange (ETDEWEB)

    Rautergarten, Carsten; Baidoo, Edward; Keasling, Jay; Vibe Scheller, Henrik

    2011-07-20

    Hydroxycinnamate coenzyme A (CoA) thioesters are substrates for biosynthesis of lignin and hydroxycinna- mate esters of polysaccharides and other polymers. Hence, a supply of these substrates is essential for investigation of cell wall biosynthesis. In this study, three recombinant enzymes, caffeic acid 3-O-methyltransferase, 4-coumarate- CoA ligase 1, and 4-coumarate-CoA ligase 5, were cloned from wheat, tobacco, and Arabidopsis, respectively, and were used to synthesize {sup 14}C-feruloyl-CoA, caffeoyl-CoA, p-coumaroyl-CoA, feruloyl-CoA, and sinapoyl-CoA. The corresponding hydroxycinnamoyl-CoA thioesters were high-performance liquid chromatography purified, the only extraction/purification step necessary, with total yields between 88-95%. Radiolabeled {sup 14}C-feruloyl-CoA was generated from caffeic acid and S-adenosyl-{sup 14}C-methionine under the combined action of caffeic acid 3-O-methyltransferase and 4-coumarate-CoA ligase 1. About 70% of {sup 14}C-methyl groups from S-adenosyl methionine were incorporated into the final product. The methods presented are simple, fast, and efficient for the preparation of the hydroxycinnamate thioesters.

  7. Metabolic modeling of Rosmarinic acid biosynthetic pathway

    OpenAIRE

    Sundaram, Shanthy; Tripathi, Ashutosh; Gupta, Deepak K

    2010-01-01

    Rosmarinic acid (RA) is an ester of caffeic acid and 3, 4‐dihydroxyphenyllacticacid. It is commonly found in Coleus blumei, Salvia officinalis, Melissa officinalis and Rosmarinus officinalis. The biosynthesis of RA starts with precursor molecules L‐phenylalanine and L‐tyrosine. Simulation of RA biosynthetic pathway was done using Gepasi Software, includes the reaction kinetics of each step of the pathway and different integration methods such as Euler's method. Optimization of the significant...

  8. Biochemical Studies of Mycobacterial Fatty Acid Methyltransferase: A Catalyst for the Enzymatic Production of Biodiesel.

    Science.gov (United States)

    Petronikolou, Nektaria; Nair, Satish K

    2015-11-19

    Transesterification of fatty acids yields the essential component of biodiesel, but current processes are cost-prohibitive and generate waste. Recent efforts make use of biocatalysts that are effective in diverting products from primary metabolism to yield fatty acid methyl esters in bacteria. These biotransformations require the fatty acid O-methyltransferase (FAMT) from Mycobacterium marinum (MmFAMT). Although this activity was first reported in the literature in 1970, the FAMTs have yet to be biochemically characterized. Here, we describe several crystal structures of MmFAMT, which highlight an unexpected structural conservation with methyltransferases that are involved in plant natural product metabolism. The determinants for ligand recognition are analyzed by kinetic analysis of structure-based active-site variants. These studies reveal how an architectural fold employed in plant natural product biosynthesis is used in bacterial fatty acid O-methylation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Enhanced lignin monomer production caused by cinnamic Acid and its hydroxylated derivatives inhibits soybean root growth.

    Directory of Open Access Journals (Sweden)

    Rogério Barbosa Lima

    Full Text Available Cinnamic acid and its hydroxylated derivatives (p-coumaric, caffeic, ferulic and sinapic acids are known allelochemicals that affect the seed germination and root growth of many plant species. Recent studies have indicated that the reduction of root growth by these allelochemicals is associated with premature cell wall lignification. We hypothesized that an influx of these compounds into the phenylpropanoid pathway increases the lignin monomer content and reduces the root growth. To confirm this hypothesis, we evaluated the effects of cinnamic, p-coumaric, caffeic, ferulic and sinapic acids on soybean root growth, lignin and the composition of p-hydroxyphenyl (H, guaiacyl (G and syringyl (S monomers. To this end, three-day-old seedlings were cultivated in nutrient solution with or without allelochemical (or selective enzymatic inhibitors of the phenylpropanoid pathway in a growth chamber for 24 h. In general, the results showed that 1 cinnamic, p-coumaric, caffeic and ferulic acids reduced root growth and increased lignin content; 2 cinnamic and p-coumaric acids increased p-hydroxyphenyl (H monomer content, whereas p-coumaric, caffeic and ferulic acids increased guaiacyl (G content, and sinapic acid increased sinapyl (S content; 3 when applied in conjunction with piperonylic acid (PIP, an inhibitor of the cinnamate 4-hydroxylase, C4H, cinnamic acid reduced H, G and S contents; and 4 when applied in conjunction with 3,4-(methylenedioxycinnamic acid (MDCA, an inhibitor of the 4-coumarate:CoA ligase, 4CL, p-coumaric acid reduced H, G and S contents, whereas caffeic, ferulic and sinapic acids reduced G and S contents. These results confirm our hypothesis that exogenously applied allelochemicals are channeled into the phenylpropanoid pathway causing excessive production of lignin and its main monomers. By consequence, an enhanced stiffening of the cell wall restricts soybean root growth.

  10. Caffeic Acid Phenethyl Ester Loaded PLGA Nanoparticles: Effect of Various Process Parameters on Reaction Yield, Encapsulation Efficiency, and Particle Size

    Directory of Open Access Journals (Sweden)

    Serap Derman

    2015-01-01

    Full Text Available CAPE loaded PLGA nanoparticles were prepared using the oil in water (o/w single emulsion solvent evaporation methods. Five different processing parameters including initial CAPE amount, initial PLGA amount, PVA concentration in aqueous phase, PVA volume, and solvent type were screened systematically to improve encapsulation of hydrophobic CAPE molecule, simultaneously minimize particle size, and raise the reaction yield. Obtained results showed that the encapsulation efficiency of the nanoparticles significantly increased with the increase of the initial CAPE amount (p<0.05 and particle size (p<0.05. Furthermore, the particle size is significantly influenced by initial polymer amount (p<0.05 and surfactant concentration (p<0.05. By the optimization of process parameters, the nanoparticles produced 70±6% reaction yield, 89±3% encapsulation efficiency, -34.4±2.5 mV zeta potential, and 163±2 nm particle size with low polydispersity index 0.119±0.002. The particle size and surface morphology of optimized nanoparticles were studied and analyses showed that the nanoparticles have uniform size distribution, smooth surface, and spherical shape. Lyophilized nanoparticles with different CAPE and PLGA concentration in formulation were examined for in vitro release at physiological pH. Interestingly, the optimized nanoparticles showed a high (83.08% and sustained CAPE release (lasting for 16 days compared to nonoptimized nanoparticle.

  11. Efficacy of various naturally occurring caffeic acid derivatives in preventing post-harvest protein losses in forages

    Science.gov (United States)

    In red clover, oxidation of endogenous o-diphenols by polyphenol oxidase (PPO) inhibits post-harvest proteolyis. This system is transferable to alfalfa by providing PPO (via a transgene) and o-diphenol PPO substrates (via exogenous application). To exploit the PPO system for protein protection, it w...

  12. Cytoprotection of Human Endothelial Cells From Menadione Cytotoxicity by Caffeic Acid Phenethyl Ester: The Role of Heme Oxygenase-1

    Science.gov (United States)

    2008-06-08

    cells (HUVEC) to evaluate potential gene expression involvement. CAPE exhibited dose- dependent cytoprotection of HUVEC. A gene screen with...highly induced (8.25-fold) by CAPE compared to DMSO control. To validate this particular microarray screening result, quantitative real-time RT-PCR was...the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. The Journal of Biological Chemistry 279, 8919–8929. Minami, T

  13. Structural Basis for the Inhibition of a Phospholipase A2-Like Toxin by Caffeic and Aristolochic Acids.

    Directory of Open Access Journals (Sweden)

    Carlos A H Fernandes

    Full Text Available One of the main challenges in toxicology today is to develop therapeutic alternatives for the treatment of snake venom injuries that are not efficiently neutralized by conventional serum therapy. Venom phospholipases A2 (PLA2s and PLA2-like proteins play a fundamental role in skeletal muscle necrosis, which can result in permanent sequelae and disability. This leads to economic and social problems, especially in developing countries. In this work, we performed structural and functional studies with Piratoxin-I, a Lys49-PLA2 from Bothropspirajai venom, complexed with two compounds present in several plants used in folk medicine against snakebites. These ligands partially neutralized the myotoxic activity of PrTX-I towards binding on the two independent sites of interaction between Lys49-PLA2 and muscle membrane. Our results corroborate the previously proposed mechanism of action of PLA2s-like and provide insights for the design of structure-based inhibitors that could prevent the permanent injuries caused by these proteins in snakebite victims.

  14. Enrichment of maize and triticale bran with recombinant Aspergillus tubingensis ferulic acid esterase

    CSIR Research Space (South Africa)

    Zwane, EN

    2017-03-01

    Full Text Available from maize bran and triticale bran, respectively, and also significantly increased the levels of p-coumaric and caffeic acid from triticale bran. The cost-effective production of AtFAEA could therefore allow for the enrichment of brans generally used...

  15. Ferulic acid enhances IgE binding to peanut allergens in western blots.

    Science.gov (United States)

    Phenolic compounds at high concentrations are known to form insoluble complexes with proteins. We hypothesized that this complex formation could interfere with Western blot and ELISA assays for peanut allergens. To verify this, three simple phenolic compounds (ferulic, caffeic, and chlorogenic acids...

  16. A novel glutathione-hydroxycinnamic acid product generated in oxidative wine conditions.

    Science.gov (United States)

    Bouzanquet, Quentin; Barril, Celia; Clark, Andrew C; Dias, Daniel A; Scollary, Geoffrey R

    2012-12-12

    This study characterizes a novel glutathione-substituted dihydroxyphenyl compound formed during the oxidation of white wine and model wine solutions, which may contribute to the synergistic role of glutathione and hydroxycinnamic acids in delaying oxidative coloration. The critical components for the formation of the compound were found to be hydroxycinnamic acids and glutathione, while ascorbic acid enabled the product to accumulate to higher concentrations. The presence of the wine components important in other wine oxidation mechanisms, (+)-catechin, ethanol and/or tartaric acid, was not essential for the formation of this new compound. Via LC-MS/MS, HR-MS and (1)H NMR (1D and 2D NMR) analyses, the major isomer of the compound formed from glutathione and caffeic acid was found to be 4-[(E)-2'-(S)-glutathionyl ethenyl]-catechol (GEC). Equivalent products were also confirmed via LC-MS/MS for other hydroxycinnamic acids (i.e., ferulic and coumaric acids). Only trace amounts of GEC were formed with the quinic ester of caffeic acid (i.e., chlorogenic acid), and no equivalent product was found for cinnamic acid. GEC was detected in a variety of white wines supplemented with glutathione and caffeic acid. A radical mechanism for the formation of the styrene-glutathione derivatives is proposed.

  17. The effect of thyme oil low-density polyethylene impregnated pellets in polylactic acid sachets on storage quality of ready-to-eat avocado

    CSIR Research Space (South Africa)

    Bill, M

    2018-01-01

    Full Text Available the incidence severity of anthracnose and enabled the retention of dietary phytochemicals (p-coumaric, ferulic and caffeic acid, catechin and epicatechin), fatty acids, mannoheptulose, fruit firmness and taste compared to the currently used prochloraz® fungicide...

  18. Dietary phenolic acids and ascorbic acid: Influence on acid-catalyzed nitrosative chemistry in the presence and absence of lipids.

    Science.gov (United States)

    Combet, Emilie; El Mesmari, Aziza; Preston, Tom; Crozier, Alan; McColl, Kenneth E L

    2010-03-15

    Acid-catalyzed nitrosation and production of potentially carcinogenic nitrosative species is focused at the gastroesophageal junction, where salivary nitrite, derived from dietary nitrate, encounters the gastric juice. Ascorbic acid provides protection by converting nitrosative species to nitric oxide (NO). However, NO may diffuse into adjacent lipid, where it reacts with O(2) to re-form nitrosative species and N-nitrosocompounds (NOC). In this way, ascorbic acid promotes acid nitrosation. Using a novel benchtop model representing the gastroesophageal junction, this study aimed to clarify the action of a range of water-soluble antioxidants on the nitrosative mechanisms in the presence or absence of lipids. Caffeic, ferulic, gallic, or chlorogenic and ascorbic acids were added individually to simulated gastric juice containing secondary amines, with or without lipid. NO and O(2) levels were monitored by electrochemical detection. NOC were measured in both aqueous and lipid phases by gas chromatography-tandem mass spectrometry. In the absence of lipids, all antioxidants tested inhibited nitrosation, ranging from 35.9 + or - 7.4% with gallic acid to 93 + or - 0.6% with ferulic acid. In the presence of lipids, the impact of each antioxidant on nitrosation was inversely correlated with the levels of NO they generated (R(2) = 0.95, pascorbic acid promoted nitrosation, whereas ferulic and caffeic acids markedly inhibited nitrosation. Copyright 2010 Elsevier Inc. All rights reserved.

  19. The phenolic acids of some species of the Oenothera L. genus

    OpenAIRE

    Tadeusz Krzaczek; Anna Bogucka-Kocka; Renata Śnieżko

    2014-01-01

    The occurence and approximative quantitative proportions of the phenolic acids in four species of the Oenothera L. genus was determined by the method of TLC and HPLC. In all species of Oenothera L. genus the permanent occurrence of acids: 2-hydroxy-4-metoxybenzoic, salicylic, ferulic, syringic, vanillic, p-coumaric, p-hydroxybenzoic, p-hydroxyphenylacetic, γ-rezorcil, gentysic, protocatechuic, caffeic and gallic has been confirmed. Whereas the other phenolic acids: o-coumaric, o-hydroxyphenyl...

  20. Biogenesis of rosmarinic acid in Mentha

    Science.gov (United States)

    Ellis, B. E.; Towers, G. H. N.

    1970-01-01

    The biogenesis of rosmarinic acid (α-O-caffeoyl-3,4-dihydroxyphenyl-lactic acid), the second most common ester of caffeic acid in the plant kingdom, was studied in Mentha arvense and Mentha piperita. Administration of 14C-labelled compounds showed that, whereas the caffeoyl moiety was formed from phenylalanine via cinnamic acid and p-coumaric acid, the 3,4-dihydroxyphenyl-lactic acid moiety was formed from tyrosine and 3,4-dihydroxyphenylalanine. Time-course studies and the use of labelled rosmarinic acid showed that endogenous rosmarinic acid had a low turnover rate. The caffeoyl moiety did not appear to contribute to the formation of insoluble polymers, as has been suggested for chlorogenic acid in other plants. PMID:5484678

  1. RP-HPLC analysis of phenolic acids of selected Central European Carex L. (Cyperaceae) species and its implication for taxonomy.

    Science.gov (United States)

    Bogucka-Kocka, Anna; Szewczyk, Katarzyna; Janyszek, Magdalena; Janyszek, Sławomir; Cieśla, Łukasz

    2011-01-01

    Eighteen species belonging to the Carex genus were checked for the presence and the amount of eight phenolic acids (p-hydroxybenzoic, vanillic, caffeic, syringic, protocatechuic, p-coumaric, sinapic, and ferulic) by means of HPLC. Both the free and bonded phenolic acids were analyzed. The majority of the analyzed acids occurred in the studied species in relatively high amounts. The highest concentrations found were caffeic acid and p-coumaric acid, for which the detected levels were negatively correlated. A very interesting feature was the occurrence of sinapic acid, a compound very rarely detected in plant tissues. Its distribution across the analyzed set of species can be hypothetically connected with the humidity of plants' habitats. Several attempted tests of aggregative cluster analysis showed no similarity to the real taxonomical structure of the genus Carex. Thus, the phenolic acids' composition cannot be considered as the major taxonomical feature for the genus Carex.

  2. Sugarcane expressed sequences tags (ESTs encoding enzymes involved in lignin biosynthesis pathways

    Directory of Open Access Journals (Sweden)

    Ramos Rose Lucia Braz

    2001-01-01

    Full Text Available Lignins are phenolic polymers found in the secondary wall of plant conductive systems where they play an important role by reducing the permeability of the cell wall to water. Lignins are also responsible for the rigidity of the cell wall and are involved in mechanisms of resistance to pathogens. The metabolic routes and enzymes involved in synthesis of lignins have been largely characterized and representative genes that encode enzymes involved in these processes have been cloned from several plant species. The synthesis of lignins is liked to the general metabolism of the phenylpropanoids in plants, having enzymes (e.g. phenylalanine ammonia-lyase (PAL, cinnamate 4-hydroxylase (C4H and caffeic acid O-methyltransferase (COMT common to other processes as well as specific enzymes such as cinnamoyl-CoA reductase (CCR and cinnamyl alcohol dehydrogenase (CAD. Some maize and sorghum mutants, shown to have defective in CAD and/or COMT activity, are easier to digest because they have a reduced lignin content, something which has motivated different research groups to alter the lignin content and composition of model plants by genetic engineering try to improve, for example, the efficiency of paper pulping and digestibility. In the work reported in this paper, we have made an inventory of the sugarcane expressed sequence tag (EST coding for enzymes involved in lignin metabolism which are present in the sugarcane EST genome project (SUCEST database. Our analysis focused on the key enzymes ferulate-5-hydroxylase (F5H, caffeic acid O-methyltransferase (COMT, caffeoyl CoA O-methyltransferase (CCoAOMT, hydroxycinnamate CoA ligase (4CL, cinnamoyl-CoA reductase (CCR and cinnamyl alcohol dehydrogenase (CAD. The comparative analysis of these genes with those described in other species could be used as molecular markers for breeding as well as for the manipulation of lignin metabolism in sugarcane.

  3. Rosmarinic acid: a potent carbonic anhydrase isoenzymes inhibitor

    OpenAIRE

    Topal, Meryem; GÜLÇİN, İlhami

    2014-01-01

    Rosmarinic acid is a water-soluble ester of caffeic acid and 3,4-dihydroxyphenyllactic acids, and is mainly found in plant species including Boraginaceae and Lamiaceae. In this research, we determined the inhibition property of rosmarinic acid on carbonic anhydrase isoenzymes I and II (hCA I and II) purified from human erythrocytes by using Sepharose-4B affinity column chromatography. hCA I and II isoenzymes were obtained with a yield of 57.9% and 67.2% and 76.5- and 509.3-fold purifica...

  4. Functional analysis of a tomato salicylic acid methyl transferase and its role in synthesis of the flavor volatile methyl salicylate.

    Science.gov (United States)

    Tieman, Denise; Zeigler, Michelle; Schmelz, Eric; Taylor, Mark G; Rushing, Sarah; Jones, Jeffrey B; Klee, Harry J

    2010-04-01

    Methyl salicylate (MeSA) is a volatile plant secondary metabolite that is an important contributor to taste and scent of many fruits and flowers. It is synthesized from salicylic acid (SA), a phytohormone that contributes to plant pathogen defense. MeSA is synthesized by members of a family of O-methyltransferases. In order to elaborate the mechanism of MeSA synthesis in tomato, we screened a set of O-methyltransferases for activity against multiple substrates. An enzyme that specifically catalyzes methylation of SA, SlSAMT, as well as enzymes that act upon jasmonic acid and indole-3-acetic acid were identified. Analyses of transgenic over- and under-producing lines validated the function of SlSAMT in vivo. The SlSAMT gene was mapped to a position near the bottom of chromosome 9. Analysis of MeSA emissions from an introgression population derived from a cross with Solanum pennellii revealed a quantitative trait locus (QTL) linked to higher fruit methyl salicylate emissions. The higher MeSA emissions associate with significantly higher SpSAMT expression, consistent with SAMT gene expression being rate limiting for ripening-associated MeSA emissions. Transgenic plants that constitutively over-produce MeSA exhibited only slightly delayed symptom development following infection with the disease-causing bacterial pathogen, Xanthomonas campestris pv. vesicatoria (Xcv). Unexpectedly, pathogen-challenged leaves accumulated significantly higher levels of SA as well as glycosylated forms of SA and MeSA, indicating a disruption in control of the SA-related metabolite pool. Taken together, the results indicate that SlSAMT is critical for methyl salicylate synthesis and methyl salicylate, in turn, likely has an important role in controlling SA synthesis.

  5. HCT2, a Novel Hydroxycinnamoyl-Malate Transferase, is Responsible for Phaselic Acid (2-O-Caffeoyl-L-Malate) Biosynthesis in Red Clover

    Science.gov (United States)

    In red clover, post-harvest oxidation of o-diphenol caffeic acid derivatives to o-quinones by an endogenous polyphenol oxidase (PPO) prevents breakdown of forage protein during storage (1). Agronomically important forages like alfalfa lack both PPO and o-diphenols. Consequently, breakdown of their p...

  6. Effects of the Aqueous Extract from Tabebuia roseoalba and Phenolic Acids on Hyperuricemia and Inflammation

    Directory of Open Access Journals (Sweden)

    Zilma Schimith Ferraz-Filha

    2017-01-01

    Full Text Available Tabebuia species (Bignoniaceae have long been used in folk medicine as anti-inflammatory, antirheumatic, antimicrobial, and antitumor. The aim of this study was to investigate if aqueous extract from the leaves (AEL of Tabebuia roseoalba (Ridl. Sandwith, Bignoniaceae, and its constituents could be useful to decrease serum uric acid levels and restrain the gout inflammatory process. HPLC analysis identified caffeic acid and chlorogenic acid in AEL. Antihyperuricemic effects and inhibition of liver XOD (xanthine oxidoreductase by AEL and identified compounds were evaluated in hyperuricemic mice. Anti-inflammatory activity was evaluated on MSU (monosodium urate crystal-induced paw edema. In addition, AEL antioxidant activity in vitro was evaluated. AEL, caffeic, and chlorogenic acids were able to reduce serum uric acid levels in hyperuricemic mice probably through inhibition of liver xanthine oxidase activity and significantly decreased the paw edema induced by MSU crystals. AEL showed significant antioxidant activity in all evaluated assays. The results show that the AEL of Tabebuia roseoalba can be a promising agent for treatment for gout and inflammatory diseases. We suggest that caffeic and chlorogenic acids may be responsible for the activities demonstrated by the species.

  7. Reaction mechanism of isoflavone O-methyltransferase: A theoretical investigation

    Science.gov (United States)

    Cui, Feng-Chao; Pan, Xiao-Liang; Liu, Jing-Yao

    2011-01-01

    The methyl-transfer reaction mechanism catalyzed by Isoflavone O-methyl-transferase (IOMT) and the roles of several residues around the active site are investigated by employing density functional method. The calculations confirm that the proton transfer from daidzein to His257 occurs barrierlessly, and the methyl group is transferred from S-adenosyl-L-methionine (SAM) to phenolate ion in a single SN 2 step with a barrier of 17.0 kcal/mol, consistent with experimental value. Glu318 and Asp288 play important roles in lowering the reaction barrier.

  8. Catechol-O-methyltransferase and pain in rodents and humans

    OpenAIRE

    Kambur, Oleg

    2013-01-01

    Acute pain is an important warning signal, however, neuropathic pain and often chronic pain,lack a physiological function. Pain is a major clinical challenge and especially chronic and neuropathic pain are difficult to treat. On individual level, pain causes occupational and functional disability, suffering, and impairs quality of life. On a macro level pain and its direct and indirect consequences cause multi-billion expenses. Genetic factors and mechanisms underlying susceptibility to chron...

  9. Identification of Phenolic Acids and Changes in their Content during Fermentation and Ageing of White Wines Pošip and Rukatac

    Directory of Open Access Journals (Sweden)

    Tomislav Lovrić

    2002-01-01

    Full Text Available Identification of phenolic acids was performed and changes in their content during the production of autochthonous Croatian white wines Pošip and Rukatac (Vitis vinifera, L. were registered. In both varieties (Pošip, Rukatac the following phenolic acids were identified: gallic, protocatechuic and vanillic acids as hydroxybenzoic acids; and caffeic, p-coumaric and ferulic acids as hydroxycinnamic acids. It was found that there is a difference between hydroxybenzoic acid group and hydroxycinnamic acid group content and between their influences on the wine colour (colour intensity and hue.

  10. Hydroxycinnamic acids in cooked potato tubers fromSolanum tuberosumgroup Phureja.

    Science.gov (United States)

    Piñeros-Niño, Clara; Narváez-Cuenca, Carlos-Eduardo; Kushalappa, Ajjamada C; Mosquera, Teresa

    2017-05-01

    Hydroxycinnamic acids are phenolic compounds and are considered to have health promotion properties due to their antioxidant activity. Potato tubers of 113 genotypes of Solanum tuberosum group Phureja belonging to the Colombian Central Collection, landraces of potatoes, and commercial cultivars were evaluated for their hydroxycinnamic acids content. The composition of these compounds was analyzed using cooked tubers in two different agro-climatic conditions. The genotypes were analyzed for chlorogenic acid, neo -chlorogenic acid, crypto -chlorogenic acid, and caffeic acid by ultrahigh-performance liquid chromatography (UHPLC). Chlorogenic acid was the major representative and varied between 0.77 to 7.98 g kg -1  DW (dry weight) followed by crypto -chlorogenic acid (from 0.09 to 1.50 g kg -1  DW). Under moorland agro-climatic conditions even though the chlorogenic acid levels increased with respect to flatland agro-climatic conditions, the related isomer neo -chlorogenic acid decreased as compared to flatland conditions. The correlation between chlorogenic acid with the isomers, and with caffeic acid was positive. This study demonstrated that there is a wide variation in hydroxycinnamic acids contents in the germplasm studied, which can be exploited in breeding programs to contribute to human health.

  11. Multifunctional Cinnamic Acid Derivatives

    Dire