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Sample records for ache inhibitory activity

  1. Sesquiterpenes and a monoterpenoid with acetylcholinesterase (AchE) inhibitory activity from Valeriana officinalis var. latiofolia in vitro and in vivo.

    PubMed

    Chen, Heng-Wen; He, Xuan-Hui; Yuan, Rong; Wei, Ben-Jun; Chen, Zhong; Dong, Jun-Xing; Wang, Jie

    2016-04-01

    Acetylcholinesterase Inhibitor (AchEI) is the most extensive in all anti-dementia drugs. The extracts and isolated compounds from the Valeriana genus have shown anti-dementia bioactivity. Four new sesquiterpenoids (1-4) and a new monoterpenoid (5) were isolated from the root of Valeriana officinalis var. latiofolia. The acetylcholinesterase (AchE) inhibitory activity of isolates was evaluated by modified Ellman method in vitro. Learning and memory ability of compound 4 on mice was evaluated by the Morris water maze. The contents of acetylcholine (Ach), acetylcholine transferase (ChAT) and AchE in mice brains were determined by colorimetry. The results showed IC50 of compound 4 was 0.161 μM in vitro. Compared with the normal group, the learning and memory ability of mice and the contents of Ach and ChAT decreased in model group mice (P<0.01), while the AchE increased (P<0.01). Compared with the model group, Ach and ChAT in the positive control group, the high-dose group and the medium-dose group increased (P<0.01), while the AchE decreased (P<0.01). Compound 4 can improve the learning and memory abilities of APPswe/PSΔE9 double-transgenic mice, and the mechanism may be related to the regulation of the relative enzyme in the cholinergic system. PMID:26976216

  2. Searching for the Multi-Target-Directed Ligands against Alzheimer's disease: discovery of quinoxaline-based hybrid compounds with AChE, H₃R and BACE 1 inhibitory activities.

    PubMed

    Huang, Wenhai; Tang, Li; Shi, Ying; Huang, Shufang; Xu, Lei; Sheng, Rong; Wu, Peng; Li, Jia; Zhou, Naiming; Hu, Yongzhou

    2011-12-01

    A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H(3)R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT-25. A virtual database consisting of quinoxaline derivatives was first screened on a pharmacophore model of BACE 1 inhibitors, and then filtered by a molecular docking model of AChE. Seventeen quinoxaline derivatives with high score values were picked out, synthesized and evaluated for their biological activities. Compound 11a, the most effective MTDL, showed the potent activity to H(3)R/AChE/BACE 1 (H(3)R antagonism, IC(50)=280.0 ± 98.0 nM; H(3)R inverse agonism, IC(50)=189.3 ± 95.7 nM; AChE, IC(50)=483 ± 5 nM; BACE 1, 46.64±2.55% inhibitory rate at 20 μM) and high selectivity over H(1)R/H(2)R/H(4)R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes.

  3. Circannual rhythms of acetylcholinesterase (AChE) activity in the freshwater fish Cnesterodon decemmaculatus.

    PubMed

    Menéndez-Helman, Renata J; Ferreyroa, Gisele V; dos Santos Afonso, Maria; Salibián, Alfredo

    2015-01-01

    The use of biomarkers as a tool to assess responses of organisms exposed to pollutants in toxicity bioassays, as well as in aquatic environmental risk assessment protocols, requires the understanding of the natural fluctuation of the particular biomarker. The aim of this study was to characterize the intrinsic variations of acetylcholinesterase (AChE) activity in tissues of a native freshwater teleost fish to be used as biomarker in toxicity tests, taking into account both seasonal influence and fish size. Specific AChE activity was measured by the method of Ellman et al. (1961) in homogenates of fish anterior section finding a seasonal variability. The highest activity was observed in summer, decreasing significantly below 40% in winter. The annual AChE activity cycle in the anterior section was fitted to a sinusoidal function with a period of 11.2 months. Moreover, an inverse relationship between enzymatic activity and the animal size was established. The results showed that both the fish length and seasonal variability affect AChE activity. AChE activity in fish posterior section showed a similar trend to that in the anterior section, while seasonal variations of the activity in midsection were observed but differences were not statistically significant. In addition, no relationship between AChE and total tissue protein was established in the anterior and posterior sections suggesting that the circannual rhythms observed are AChE-specific responses. Results highlight the importance of considering both the fish size and season variations to reach valid conclusions when AChE activity is employed as neurotoxicity biomarker.

  4. Effect of pharmaceuticals exposure on acetylcholinesterase (AchE) activity and on the expression of AchE gene in the monogonont rotifer, Brachionus koreanus.

    PubMed

    Rhee, Jae-Sung; Kim, Bo-Mi; Jeong, Chang-Bum; Park, Heum Gi; Leung, Kenneth Mei Yee; Lee, Young-Mi; Lee, Jae-Seong

    2013-11-01

    Pharmaceuticals are widely used in human and veterinary medicine. However, they are emerging as a significant contaminant in aquatic environments through wastewater. Due to the persistent and accumulated properties of pharmaceuticals via the food web, their potential harmful effects on aquatic animals are a great concern. In this study, we investigated the effects of six pharmaceuticals: acetaminophen, ATP; atenolol, ATN; carbamazepine, CBZ; oxytetracycline, OTC; sulfamethoxazole, SMX; and trimethoprim, TMP on acetylcholinesterase (AChE; EC 3.1.1.7) activity and its transcript expression with chlorpyrifos (as a positive control) in the monogonont rotifer, Brachionus koreanus. ATP, CBZ, and TMP exposure also remarkably inhibited Bk-AChE activity at 100 μg/L (24 h) and 1000 μg/L (12 h and 24 h). ATP, CBZ, and TMP exposure showed a significant decrease in the Bk-AChE mRNA level in a concentration-dependent manner. However, in the case of OTC and SMX, a slight decrease in Bk-AChE mRNA expression was found but only at the highest concentration. The time-course experiments showed that ATP positively induced Bk-AChE mRNA 12 h after exposure at both 100 and 1000 μg/L, while the Bk-AChE mRNA expression was significantly downregulated over 6 to 24 h after exposure to 1000 μg/L of CBZ, OTC, SMX, and TMP. Our findings suggest that Bk-AChE would be a useful biomarker for risk assessment of pharmaceutical compounds as an early signal of their toxicity in aquatic environments. Particularly, ATP, CBZ, and TMP may have a toxic cholinergic effect on rotifer B. koreanus by inhibiting AChE activity. PMID:24028855

  5. A selective molecularly imprinted polymer for immobilization of acetylcholinesterase (AChE): an active enzyme targeted and efficient method.

    PubMed

    Demirci, Gökhan; Doğaç, Yasemin İspirli; Teke, Mustafa

    2015-11-01

    In the present study, we immobilized acetylcholinesterase (AChE) enzyme onto acetylcholine removed imprinted polymer and acetylcholine containing polymer. First, the polymers were produced with acetylcholine, substrate of AChE, by dispersion polymerization. Then, the enzyme was immobilized onto the polymers by using two different methods: In the first method (method A), acetylcholine was removed from the polymer, and then AChE was immobilized onto this polymer (acetylcholine removed imprinted polymer). In the second method (method B), AChE was immobilized onto acetylcholine containing polymer by affinity. In method A, enzyme-specific species (binding sites) occurred by removing acetylcholine from the polymer. The immobilized AChE reached 240% relative specific activity comparison with free AChE because the active enzyme molecules bounded onto the polymer. Transmission electron microscopy results were taken before and after immobilization of AChE for the assessment of morphological structure of polymer. Also, the experiments, which include optimum temperature (25-65 °C), optimum pH (3-10), thermal stability (4-70 °C), kinetic parameters, operational stability and reusability, were performed to determine the characteristic of the immobilized AChE.

  6. Bactericidal activity of ACH-702 against nondividing and biofilm Staphylococci.

    PubMed

    Podos, Steven D; Thanassi, Jane A; Leggio, Melissa; Pucci, Michael J

    2012-07-01

    Many bacterial infections involve slow or nondividing bacterial growth states and localized high cell densities. Antibiotics with demonstrated bactericidal activity rarely remain bactericidal at therapeutic concentrations under these conditions. The isothiazoloquinolone (ITQ) ACH-702 is a potent, bactericidal compound with activity against many antibiotic-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We evaluated its bactericidal activity under conditions where bacterial cells were not dividing and/or had slowed their growth. Against S. aureus cultures in stationary phase, ACH-702 showed concentration-dependent bactericidal activity and achieved a 3-log-unit reduction in viable cell counts within 6 h of treatment at ≥ 16× MIC values; in comparison, the bactericidal quinolone moxifloxacin and the additional comparator compounds vancomycin, linezolid, and rifampin at 16× to 32× MICs showed little or no bactericidal activity against stationary-phase cells. ACH-702 at 32× MIC retained bactericidal activity against stationary-phase S. aureus across a range of inoculum densities. ACH-702 did not kill cold-arrested cells yet remained bactericidal against cells arrested by protein synthesis inhibitors, suggesting that its bactericidal activity against nondividing cells requires active metabolism but not de novo protein synthesis. ACH-702 also showed a degree of bactericidal activity at 16× MIC against S. epidermidis biofilm cells that was superior to that of moxifloxacin, rifampin, and vancomycin. The bactericidal activity of ACH-702 against stationary-phase staphylococci and biofilms suggests potential clinical utility in infections containing cells in these physiological states. PMID:22547614

  7. Selenofuranoside Ameliorates Memory Loss in Alzheimer-Like Sporadic Dementia: AChE Activity, Oxidative Stress, and Inflammation Involvement.

    PubMed

    Chiapinotto Spiazzi, Cristiano; Bucco Soares, Melina; Pinto Izaguirry, Aryele; Musacchio Vargas, Laura; Zanchi, Mariane Magalhães; Frasson Pavin, Natasha; Ferreira Affeldt, Ricardo; Seibert Lüdtke, Diogo; Prigol, Marina; Santos, Francielli Weber

    2015-01-01

    Alzheimer's disease (AD) is becoming more common due to the increase in life expectancy. This study evaluated the effect of selenofuranoside (Se) in an Alzheimer-like sporadic dementia animal model. Male mice were divided into 4 groups: control, Aβ, Se, and Aβ + Se. Single administration of Aβ peptide (fragments 25-35; 3 nmol/3 μL) or distilled water was administered via intracerebroventricular (i.c.v.) injection. Selenofuranoside (5 mg/kg) or vehicle (canola oil) was administered orally 30 min before Aβ and for 7 subsequent days. Memory was tested through the Morris water maze (MWM) and step-down passive-avoidance (SDPA) tests. Antioxidant defenses along with reactive species (RS) were assessed. Inflammatory cytokines levels and AChE activity were measured. SOD activity was inhibited in the Aβ group whereas RS were increased. AChE activity, GSH, and IL-6 levels were increased in the Aβ group. These changes were reflected in impaired cognition and memory loss, observed in both behavioral tests. Se compound was able to protect against memory loss in mice in both behavioral tests. SOD and AChE activities as well as RS and IL-6 levels were also protected by Se administration. Therefore, Se is promising for further studies.

  8. Screening of POP pollution by AChE and EROD activities in Zebra mussels from the Italian Great Lakes.

    PubMed

    Binelli, A; Ricciardi, Francesco; Riva, Consuelo; Provini, Alfredo

    2005-12-01

    The increase of ethoxyresorufin dealkylation (EROD) and the inhibition of acetylcholinesterase (AChE) as biomarkers have been commonly used in vertebrates for the persistent organic pollutants (POPs) biomonitoring of aquatic environments, but very few studies have been performed for invertebrates. Previous researches demonstrated the interference due to some chemicals on EROD and AChE activities of the freshwater bivalve Zebra mussel (Dreissena polymorpha) in laboratory and field studies, showing its possible use for the screening of POP effects. We investigated the contamination of the Italian sub-alpine great lakes (Maggiore, Lugano, Como, Iseo, Garda) by the biomarker approach on Zebra mussel specimens collected at 17 sampling sites with different morphometric characteristics and anthropization levels. Results showed a homogeneous contamination of AChE inhibitors in Lake Garda, Maggiore, Como and Iseo with values ranging from 0.5 to 3 nmol/min/mg proteins and with an average inhibition of about 66% to controls. The planar compounds pollution, able to activate the EROD activity, seems higher in some sampling stations of Lake Garda, Como and Iseo (2-4 pmol/min/mg proteins) than that measured in Lake Lugano (1.5-3 pmol/min/mg proteins). On the contrary, the enzyme activity in Lake Maggiore showed an interesting opposite effect of AhR-binding compounds and trace metals. Finally, the possible use of Zebra mussel specimens maintained at laboratory conditions as controls against the selection of the less polluted sampling site is discussed.

  9. Evaluation of the Toxicity, AChE Activity and DNA Damage Caused by Imidacloprid on Earthworms, Eisenia fetida.

    PubMed

    Wang, Kai; Qi, Suzhen; Mu, Xiyan; Chai, Tingting; Yang, Yang; Wang, Dandan; Li, Dongzhi; Che, Wunan; Wang, Chengju

    2015-10-01

    Imidacloprid is a well-known pesticide and it is timely to evaluate its toxicity to earthworms (Eisenia fetida). In the present study, the effect of imidacloprid on reproduction, growth, acetylcholinesterase (AChE) and DNA damage in earthworms was assessed using an artificial soil medium. The median lethal concentration (LC50) and the median number of hatched cocoons (EC50) of imidacloprid to earthworms was 3.05 and 0.92 mg/kg respectively, the lowest observed effect concentration of imidacloprid about hatchability, growth, AChE activity and DNA damage was 0.02, 0.5, 0.1 and 0.5 mg/kg, respectively.

  10. Screening for antimalarial and acetylcholinesterase inhibitory activities of some Iranian seaweeds.

    PubMed

    Ghannadi, A; Plubrukarn, A; Zandi, K; Sartavi, K; Yegdaneh, A

    2013-04-01

    Alcoholic extracts of 8 different types of seaweeds from Iran's Persian Gulf were tested for their antimalarial and acetylcholinesterase enzyme (AChE) inhibitory activities for the first time. A modified Ellman and Ingkaninan method was used for measuring AChE inhibitory activity in which galanthamine was used as the reference. The antimalarial assay was performed using microculture radioisotope technique. Mefloquine and dihydroartemisinin were uased as the standards. The extract of Sargassum boveanum (Sargasseae family) showed the highest AChE inhibitory activity (IC50 equals to 1 mg ml(-1)) while Cystoseira indica (Cystoseiraceae family) exhibited the least activity (IC50 of 11 mg ml(-1)). The species from Rhodophyta (Gracilaria corticata and Gracilaria salicornia) also showed moderate activities (IC509.5, 8.7 mg ml(-1), respectively). All extracts were inactive in antimalarial assay. PMID:24019820

  11. Anticholinesterase inhibitory activity of quaternary alkaloids from Tinospora crispa.

    PubMed

    Yusoff, Mashitah; Hamid, Hazrulrizawati; Houghton, Peter

    2014-01-01

    Quaternary alkaloids are the major alkaloids isolated from Tinospora species. A previous study pointed to the necessary presence of quaternary nitrogens for strong acetylcholinesterase (AChE) inhibitory activity in such alkaloids. Repeated column chromatography of the vine of Tinospora crispa extract led to the isolation of one new protoberberine alkaloid, 4,13-dihydroxy-2,8,9-trimethoxydibenzo[a,g]quinolizinium (1), along with six known alkaloids-dihydrodiscretamine (2), columbamine (3), magnoflorine (4), N-formylannonaine (5), N-formylnornuciferine (6), and N-trans-feruloyltyramine (7). The seven compounds were isolated and structurally elucidated by spectroscopic analysis. Two known alkaloids, namely, dihydrodiscretamine and columbamine are reported for the first time for this plant. The compounds were tested for AChE inhibitory activity using Ellman's method. In the AChE inhibition assay, only columbamine (3) showed strong activity with IC50 48.1 µM. The structure-activity relationships derived from these results suggest that the quaternary nitrogen in the skeleton has some effect, but that a high degree of methoxylation is more important for acetylcholinesterase inhibition. PMID:24448061

  12. Screening of selected Indian medicinal plants for acetylcholinesterase inhibitory activity.

    PubMed

    Vinutha, B; Prashanth, D; Salma, K; Sreeja, S L; Pratiti, D; Padmaja, R; Radhika, S; Amit, A; Venkateshwarlu, K; Deepak, M

    2007-01-19

    Seventy-six plant extracts including methanolic and successive water extracts from 37 Indian medicinal plants were investigated for acetylcholinesterase (AChE) inhibitory activity (in vitro). Results indicated that methanolic extracts to be more active than water extracts. The potent AChE inhibiting methanolic plant extracts included Withania somnifera (root), Semecarpus anacardium (stem bark), Embelia ribes (Root), Tinospora cordifolia (stem), Ficus religiosa (stem bark) and Nardostachys jatamansi (rhizome). The IC(50) values obtained for these extracts were 33.38, 16.74, 23.04, 38.36, 73.69 and 47.21mug/ml, respectively. These results partly substantiate the traditional use of these herbs for improvement of cognition. PMID:16950584

  13. Kinetic evidence that desensitized nAChR may promote transitions of active nAChR to desensitized states during sustained exposure to agonists in skeletal muscle.

    PubMed

    Manthey, Arthur A

    2006-06-01

    During prolonged exposure of postjunctional nicotinic acetylcholine receptors (nAChR) of skeletal muscle to acetylcholine (ACh), agonist-activated nAChR (nAChRa) gradually fall into a refractory "desensitized" state (nAChRd), which no longer supports the high-conductance channel openings characteristic of the initially active nAChRa. In the present study, the possibility was examined that nAChRd, rather than simply constituting a passive "trap" for nAChRa, may actively promote further conversions of nAChRa to nAChRd in a formally autocatalytic manner. Single-ion whole-cell voltage-clamp currents (Na+ and Li+ in separate trials) were measured using two KCl-filled capillary electrodes (5-10 MOmega) implanted at the postjunctional locus of single frog skeletal muscle fibers (Rana pipiens) equilibrated in 30 mM K+ bath media to eliminate mechanical responses. Various nAChR agonists (carbamylcholine, acetylcholine, suberyldicholine) at different concentrations were delivered focally by positive pressure microjet. It was found that the decline of postmaximal agonist-induced currents under these different conditions (driven by the growth of the subpool of nAChRd) consistently followed an autocatalytic logistic rule modified for population growth of fixed units in a planar array: [Formula: see text] (where y represents the remaining agonist-induced current at time t, A=initial maximum current, and n is a constant). Some further experimental features that might result from a self-promoting growth of nAChRd were also tested, namely, (1) the effect of increased nAChRa and (2) the effect of increased nAChRd. Increase in agonist concentration of the superfusate, by increasing the planar density of active nAChRa at the outset, should enhance the probability of autocatalytic interactions with emerging nAChRd, hence, the rate of decline of agonist-induced current, and this was a consistent finding under all conditions tested. Raising the initial level of desensitized nAChRd by

  14. Alkaloid metabolite profiles by GC/MS and acetylcholinesterase inhibitory activities with binding-mode predictions of five Amaryllidaceae plants.

    PubMed

    Cortes, Natalie; Alvarez, Rafael; Osorio, Edison H; Alzate, Fernando; Berkov, Strahil; Osorio, Edison

    2015-01-01

    Acetylcholinesterase (AChE) enzymatic inhibition is an important target for the management of Alzheimer disease (AD) and AChE inhibitors are the mainstay drugs for its treatment. In order to discover new sources of potent AChE inhibitors, a combined strategy is presented based on AChE-inhibitory activity and chemical profiles by GC/MS, together with in silico studies. The combined strategy was applied on alkaloid extracts of five Amaryllidaceae species that grow in Colombia. Fifty-seven alkaloids were detected using GC/MS, and 21 of them were identified by comparing their mass-spectral fragmentation patterns with standard reference spectra in commercial and private library databases. The alkaloid extracts of Zephyranthes carinata exhibited a high level of inhibitory activity (IC50 = 5.97 ± 0.24 μg/mL). Molecular modeling, which was performed using the structures of some of the alkaloids present in this extract and the three-dimensional crystal structures of AChE derived from Torpedo californica, disclosed their binding configuration in the active site of this AChE. The results suggested that the alkaloids 3-epimacronine and lycoramine might be of interest for AChE inhibition. Although the galanthamine group is known for its potential utility in treating AD, the tazettine-type alkaloids should be evaluated to find more selective compounds of potential benefit for AD. PMID:25305596

  15. Chlorpyrifos and Malathion have opposite effects on behaviors and brain size that are not correlated to changes in AChE activity

    PubMed Central

    Richendrfer, Holly; Creton, Robbert

    2015-01-01

    Organophosphates, a type of neurotoxicant pesticide, are used globally for the treatment of pests on croplands and are therefore found in a large number of conventional foods. These pesticides are harmful and potentially deadly if ingested or inhaled in large quantities by causing a significant reduction in acetylcholinesterase (AChE) activity in the central and peripheral nervous system. However, much less is known about the effects of exposure to small quantities of the pesticides on neural systems and behavior during development. In the current study we used zebrafish larvae in order to determine the effects of two of the most widely used organophosphates, chlorpyrifos and malathion, on zebrafish behavior and AChE activity. Embryos and larvae were exposed to the organophosphates during different time points in development and then tested at 5 days post-fertilization for behavioral, neurodevelopmental and AChE abnormalities. The results of the study indicate that chlorpyrifos and malathion cause opposing behaviors in the larvae such as swim speed (hypoactivity vs. hyperactivity) and rest. Additionally, the pesticides affect only certain behaviors, such as thigmotaxis, during specific time points in development that are unrelated to changes in AChE activity. Larvae treated with malathion but not chlorpyrifos also had significantly smaller forebrain and hindbrain regions compared to controls by 5 days post-fertilization. We conclude that exposure to very low concentrations of organophosphate pesticides during development cause abnormalities in behavior and brain size. PMID:25983063

  16. Labdane-type diterpenoids from Leonurus heterophyllus and their cholinesterase inhibitory activity.

    PubMed

    Hung, Tran Manh; Luan, Tran Cong; Vinh, Bui The; Cuong, To Dao; Min, Byung Sun

    2011-04-01

    In the course of screening plants used in natural medicines as memory enhancers, a 70% ethanol extract of the aerial parts of Leonurus heterophyllus showed significant AChE inhibitory activity. Bioassay-guided fractionation and repeated column chromatography led to the isolation of a new labdane-type diterpenoids (1), named leoheteronin F, and six known compounds (2-7). The chemical structures of isolated compounds were elucidated based on extensive 1D and 2D NMR spectroscopic data. The isolates 1-7 were investigated in vitro for their anticholinesterase activity using mouse cortex AChE enzyme. Leoheteronin A (5) and leopersin G (7), which possess a 15,16-epoxy group at the side chain, were found to be potent in the inhibition of AChE.

  17. ACR-12 ionotropic acetylcholine receptor complexes regulate inhibitory motor neuron activity in Caenorhabditis elegans.

    PubMed

    Petrash, Hilary A; Philbrook, Alison; Haburcak, Marian; Barbagallo, Belinda; Francis, Michael M

    2013-03-27

    Heterogeneity in the composition of neurotransmitter receptors is thought to provide functional diversity that may be important in patterning neural activity and shaping behavior (Dani and Bertrand, 2007; Sassoè-Pognetto, 2011). However, this idea has remained difficult to evaluate directly because of the complexity of neuronal connectivity patterns and uncertainty about the molecular composition of specific receptor types in vivo. Here we dissect how molecular diversity across receptor types contributes to the coordinated activity of excitatory and inhibitory motor neurons in the nematode Caenorhabditis elegans. We show that excitatory and inhibitory motor neurons express distinct populations of ionotropic acetylcholine receptors (iAChRs) requiring the ACR-12 subunit. The activity level of excitatory motor neurons is influenced through activation of nonsynaptic iAChRs (Jospin et al., 2009; Barbagallo et al., 2010). In contrast, synaptic coupling of excitatory and inhibitory motor neurons is achieved through a second population of iAChRs specifically localized at postsynaptic sites on inhibitory motor neurons. Loss of ACR-12 iAChRs from inhibitory motor neurons leads to reduced synaptic drive, decreased inhibitory neuromuscular signaling, and variability in the sinusoidal motor pattern. Our results provide new insights into mechanisms that establish appropriately balanced excitation and inhibition in the generation of a rhythmic motor behavior and reveal functionally diverse roles for iAChR-mediated signaling in this process. PMID:23536067

  18. Lanostanoids with acetylcholinesterase inhibitory activity from the mushroom Haddowia longipes.

    PubMed

    Zhang, Shuang-Shuang; Ma, Qing-Yun; Huang, Sheng-Zhuo; Dai, Hao-Fu; Guo, Zhi-Kai; Yu, Zhi-Fang; Zhao, You-Xing

    2015-02-01

    Nine lanostanoids, together with nine known ones, were isolated from the ethyl acetate extract of the fruiting bodies of the mushroom Haddowia longipes. Their structures were elucidated as 11-oxo-ganoderiol D, lanosta-8-en-7,11-dioxo-3β-acetyloxy-24,25,26-trihydroxy, lanosta-8-en-7-oxo-3β-acetyloxy-11β,24,25,26-tetrahydroxy, lanosta-7,9(11)-dien-3β-acetyloxy-24,25,26-trihydroxy, lanosta-7,9(11)-dien-3β-acetyloxy-24,26-dihydroxy-25-methoxy, 11-oxo-lucidadiol, 11β-hydroxy-lucidadiol, lucidone H and lanosta-7,9(11),24E-trien-3β-acetyloxy-26,27-dihydroxy by analysing their 1D/2D NMR and MS spectra. In addition, bioassays of inhibitory activity against acetylcholinesterase (AChE) of all compounds showed that thirteen compounds possessed inhibitory activity against AChE with the percentage inhibition ranging from 10.3% to 42.1% when tested at 100 μM.

  19. Microwave assisted synthesis, cholinesterase enzymes inhibitory activities and molecular docking studies of new pyridopyrimidine derivatives.

    PubMed

    Basiri, Alireza; Murugaiyah, Vikneswaran; Osman, Hasnah; Kumar, Raju Suresh; Kia, Yalda; Ali, Mohamed Ashraf

    2013-06-01

    A series of hitherto unreported pyrido-pyrimidine-2-ones/pyrimidine-2-thiones were synthesized under microwave assisted solvent free reaction conditions in excellent yields and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activity. Among the pyridopyrimidine derivatives, 7e and 7l displayed 2.5- and 1.5-fold higher enzyme inhibitory activities against AChE as compared to standard drug, galanthamine, with IC50 of 0.80 and 1.37 μM, respectively. Interestingly, all the compounds except 6k, 7j and 7k displayed higher inhibitory potential against BChE enzyme in comparison to standard with IC50 ranging from 1.18 to 18.90 μM. Molecular modeling simulations of 7e and 7l was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) and human butyrylcholinesterase (hBChE) enzymes to disclose binding interaction and orientation of these molecule into the active site gorge of respective receptors.

  20. Acetylcholinesterase inhibitory activity of Thai traditional nootropic remedy and its herbal ingredients.

    PubMed

    Tappayuthpijarn, Pimolvan; Itharat, Arunporn; Makchuchit, Sunita

    2011-12-01

    The incidence of Alzheimer disease (AD) is increasing every year in accordance with the increasing of elderly population and could pose significant health problems in the future. The use of medicinal plants as an alternative prevention or even for a possible treatment of the AD is, therefore, becoming an interesting research issue. Acetylcholinesterase (AChE) inhibitors are well-known drugs commonly used in the treatment of AD. The aim of the present study was to screen for AChE inhibitory activity of the Thai traditional nootropic recipe and its herbal ingredients. The results showed that ethanolic extracts of four out of twenty-five herbs i.e. Stephania pierrei Diels. Kaempfera parviflora Wall. ex Baker, Stephania venosa (Blume) Spreng, Piper nigrum L at 0.1 mg/mL showed % AChE inhibition of 89, 64, 59, 50; the IC50 were 6, 21, 29, 30 microg/mL respectively. The other herbs as well as combination of the whole recipe had no synergistic inhibitory effect on AChE activity. However some plants revealed antioxidant activity. More research should have be performed on this local wisdom remedy to verify the uses in scientific term. PMID:22619927

  1. mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells

    PubMed Central

    2014-01-01

    Background Epithelial-mesenchymal transition (EMT) has been proposed as a mechanism in the progression of airway diseases and cancer. Here, we explored the role of acetylcholine (ACh) and the pathway involved in the process of EMT, as well as the effects of mAChRs antagonist. Methods Human lung epithelial cells were stimulated with carbachol, an analogue of ACh, and epithelial and mesenchymal marker proteins were evaluated using western blot and immunofluorescence analyses. Results Decreased E-cadherin expression and increased vimentin and α-SMA expression induced by TGF-β1 in alveolar epithelial cell (A549) were significantly abrogated by the non-selective mAChR antagonist atropine and enhanced by the acetylcholinesterase inhibitor physostigmine. An EMT event also occurred in response to physostigmine alone. Furthermore, ChAT express and ACh release by A549 cells were enhanced by TGF-β1. Interestingly, ACh analogue carbachol also induced EMT in A549 cells as well as in bronchial epithelial cells (16HBE) in a time- and concentration-dependent manner, the induction of carbachol was abrogated by selective antagonist of M1 (pirenzepine) and M3 (4-DAMP) mAChRs, but not by M2 (methoctramine) antagonist. Moreover, carbachol induced TGF-β1 production from A549 cells concomitantly with the EMT process. Carbachol-induced EMT occurred through phosphorylation of Smad2/3 and ERK, which was inhibited by pirenzepine and 4-DAMP. Conclusions Our findings for the first time indicated that mAChR activation, perhaps via M1 and M3 mAChR, induced lung epithelial cells to undergo EMT and provided insights into novel therapeutic strategies for airway diseases in which lung remodeling occurs. PMID:24678619

  2. Bromotyrosine Alkaloids with Acetylcholinesterase Inhibitory Activity from the Thai Sponge Acanthodendrilla sp.

    PubMed

    Sirimangkalakitti, Natchanun; Olatunji, Opeyemi J; Changwichit, Kanokwan; Saesong, Tongchai; Chamni, Supakarn; Chanvorachote, Pithi; Ingkaninan, Kornkanok; Plubrukarn, Anuchit; Suwanborirux, Khanit

    2015-11-01

    Twenty bromotyrosine alkaloids, including a new compound, 13-oxosubereamolline D (5), were isolated from the Thai sponge Acanthodendrilla sp. Their structures were determined by analyses of 1D- and 2D-NMR, high-resolution mass, and circular dichroism data. The complete 1H and 13C NMR assignments of 5,7β-dichlorocavernicolin (19) and 5,7α-dichlorocavernicolin (20) are described herein for the first time. The acetylcholinesterase (AChE) inhibitory activity of all isolated compounds was evaluated. Only homoaerothionin (7) and fistularin 1 (10) exhibited inhibitory activity against human recombinant AChE (hrAChE) with IC50s of 4.5 and 47.5 µM, respectively. The hrAChE inhibition kinetics of 7, the most potent alkaloid, showed increased Km and unchanged Vmaxvalues, suggesting its competitive mode of inhibition. The spirocyclohexadienylisoxazole and the length of the alkyl diamine linkage were proposed as the crucial parts for its strong inhibitory activity. This finding indicates a therapeutic potential for 7 in acetylcholine-related diseases, most importantly Alzheimer's disease. PMID:26749833

  3. Nicotine activates YAP1 through nAChRs mediated signaling in esophageal squamous cell cancer (ESCC).

    PubMed

    Zhao, Yue; Zhou, Wei; Xue, Liyan; Zhang, Weimin; Zhan, Qimin

    2014-01-01

    Cigarette smoking is an established risk factor for esophageal cancers. Yes-associated protein 1 (YAP1), the key transcription factor of the mammalian Hippo pathway, has been reported to be an oncogenic factor for many cancers. In this study, we find nicotine administration can induce nuclear translocation and activation of YAP1 in ESCC. Consistently, we observed nuclear translocation and activation of YAP1 by knockdown of CHRNA3, which is a negative regulator of nicotine signaling in bronchial and esophageal cancer cells. Nicotine administration or CHRNA3 depletion substantially increased proliferation and migration in esophageal cancer cells. Interestingly, we find that YAP1 physically interacts with nAChRs, and nAChRs-signaling dissociates YAP1 from its negative regulatory complex composed with α-catenin, β-catenin and 14-3-3 in the cytoplasm, leading to upregulation and nuclear translocation of YAP1. This process likely requires PKC activation, as PKC specific inhibitor Enzastaurin can block nicotine induced YAP1 activation. In addition, we find nicotine signaling also inhibits the interaction of YAP1 with P63, which contributes to the inhibitory effect of nicotine on apoptosis. Using immunohistochemistry analysis we observed upregulation of YAP1 in a significant portion of esophageal cancer samples. Consistently, we have found a significant association between YAP1 upregulation and cigarette smoking in the clinical esophageal cancer samples. Together, these findings suggest that the nicotine activated nAChRs signaling pathway which further activates YAP1 plays an important role in the development of esophageal cancer, and this mechanism may be of a general significance for the carcinogenesis of smoking related cancers.

  4. An expedient synthesis, acetylcholinesterase inhibitory activity, and molecular modeling study of highly functionalized hexahydro-1,6-naphthyridines.

    PubMed

    Almansour, Abdulrahman I; Kumar, Raju Suresh; Arumugam, Natarajan; Basiri, Alireza; Kia, Yalda; Ali, Mohamed Ashraf

    2015-01-01

    A series of hexahydro-1,6-naphthyridines were synthesized in good yields by the reaction of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones with cyanoacetamide in the presence of sodium ethoxide under simple mixing at ambient temperature for 6-10 minutes and were assayed for their acetylcholinesterase (AChE) inhibitory activity using colorimetric Ellman's method. Compound 4e with methoxy substituent at ortho-position of the phenyl rings displayed the maximum inhibitory activity with IC50 value of 2.12 μM. Molecular modeling simulation of 4e was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) enzyme to disclose binding interaction and orientation of this molecule into the active site gorge of the receptor. PMID:25710037

  5. An Expedient Synthesis, Acetylcholinesterase Inhibitory Activity, and Molecular Modeling Study of Highly Functionalized Hexahydro-1,6-naphthyridines

    PubMed Central

    Almansour, Abdulrahman I.; Suresh Kumar, Raju; Arumugam, Natarajan; Basiri, Alireza; Kia, Yalda; Ashraf Ali, Mohamed

    2015-01-01

    A series of hexahydro-1,6-naphthyridines were synthesized in good yields by the reaction of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones with cyanoacetamide in the presence of sodium ethoxide under simple mixing at ambient temperature for 6–10 minutes and were assayed for their acetylcholinesterase (AChE) inhibitory activity using colorimetric Ellman's method. Compound 4e with methoxy substituent at ortho-position of the phenyl rings displayed the maximum inhibitory activity with IC50 value of 2.12 μM. Molecular modeling simulation of 4e was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) enzyme to disclose binding interaction and orientation of this molecule into the active site gorge of the receptor. PMID:25710037

  6. GC-MS investigation and acetylcholinesterase inhibitory activity of Galanthus rizehensis.

    PubMed

    Sarikaya, Buket Bozkurt; Somer, Nehir Unver; Kaya, Gulen Irem; Onur, Mustafa Ali; Bastida, Jaume; Berkov, Strahil

    2013-01-01

    GC-MS (gas chromatography-mass spectrometry) analyses of alkaloids in the aerial parts and bulbs of Galanthus rizehensis Stern (Amaryllidaceae), collected during two different vegetation periods, was performed. Twenty three alkaloids were identified in four different alkaloid extracts. Acetylcholinesterase (AChE) inhibitory activities of the alkaloid extracts were tested. Both the highest alkaloid diversity and the most potent inhibitory activity (IC50 12.94 microg/ml) were obtained in extracts from the bulbs of G. rizehensis collected during the fruiting period.

  7. Intracellular activity of tedizolid phosphate and ACH-702 versus Mycobacterium tuberculosis infected macrophages

    PubMed Central

    2014-01-01

    Background Due to the emergency of multidrug-resistant strains of Mycobacterium tuberculosis, is necessary the evaluation of new compounds. Findings Tedizolid, a novel oxazolidinone, and ACH-702, a new isothiazoloquinolone, were tested against M. tuberculosis infected THP-1 macrophages. These two compounds significantly decreased the number of intracellular mycobacteria at 0.25X, 1X, 4X and 16X the MIC value. The drugs were tested either in nanoparticules or in free solution. Conclusion Tedizolid and ACH-702 have a good intracellular killing activity comparable to that of rifampin or moxifloxacin. PMID:24708819

  8. An in vitro AChE inhibition assay combined with UF-HPLC-ESI-Q-TOF/MS approach for screening and characterizing of AChE inhibitors from roots of Coptis chinensis Franch.

    PubMed

    Zhao, Hengqiang; Zhou, Siduo; Zhang, Minmin; Feng, Jinhong; Wang, Shanshan; Wang, Daijie; Geng, Yanling; Wang, Xiao

    2016-02-20

    In this study, an in vitro acetylcholinesterase (AChE) inhibition assay based on microplate reader combined with ultrafiltration high performance liquid chromatography-electrospray quadrupole time of flight mass (UF-HPLC-ESI-Q-TOF/MS) was developed for the rapid screening and identification of acetylcholinesterase inhibitors (AChEI) from roots of Coptis chinensis Franch. Incubation conditions such as enzyme concentration, incubation time, incubation temperature and co-solvent was optimized so as to get better screening results. Five alkaloids including columbamine, jatrorrhizine, coptisine, palmatine and berberine were found with AChE inhibition activity in the 80% ethanol extract of C. chinensis Franch. The screened compounds were identified by HPLC-DAD-ESI-Q-TOF/MS compared with the reference stands and literatures. The screened results were verified by in vitro AChE inhibition assays, palmatine showed the best AChE inhibitory activities with IC50 values of 36.6μM among the five compounds. Results of the present study indicated that the combinative method using in vitro AChE inhibition assay and UF-HPLC-ESI-Q-TOF/MS could be widely applied for rapid screening and identification of AChEI from complex TCM extract.

  9. Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer's disease.

    PubMed

    Tommonaro, Giuseppina; García-Font, Nuria; Vitale, Rosa Maria; Pejin, Boris; Iodice, Carmine; Cañadas, Sixta; Marco-Contelles, José; Oset-Gasque, María Jesús

    2016-10-21

    Avarol is a marine sesquiterpenoid hydroquinone, previously isolated from the marine sponge Dysidea avara Schmidt (Dictyoceratida), with antiinflammatory, antitumor, antioxidant, antiplatelet, anti-HIV, and antipsoriatic effects. Recent findings indicate that some thio-avarol derivatives exhibit acetylcholinesterase (AChE) inhibitory activity. The multiple pharmacological properties of avarol, thio-avarol and/or their derivatives prompted us to continue the in vitro screening, focusing on their AChE inhibitory and neuroprotective effects. Due to the complex nature of Alzheimer's disease (AD), there is a renewed search for new, non hepatotoxic anticholinesterasic compounds. This paper describes the synthesis and in vitro biological evaluation of avarol-3'-thiosalicylate (TAVA) and thiosalycil-prenyl-hydroquinones (TPHs), as non hepatotoxic anticholinesterasic agents, showing a good neuroprotective effect on the decreased viability of SHSY5Y human neuroblastoma cells induced by oligomycin A/rotenone and okadaic acid. A molecular modeling study was also undertaken on the most promising molecules within the series to elucidate their AChE binding modes and in particular the role played by the carboxylate group in enzyme inhibition. Among them, TPH4, bearing a geranylgeraniol substituent, is the most significant Electrophorus electricus AChE (EeAChE) inhibitor (IC50 = 6.77 ± 0.24 μM), also endowed with a moderate serum horse butyrylcholinesterase (eqBuChE) inhibitory activity, being also the least hepatotoxic and the best neuroprotective compound of the series. Thus, TPHs represents a new family of synthetic compounds, chemically related to the natural compound avarol, which has been discovered for the potential treatment of AD. Findings prove the relevance of TPHs as a new possible generation of competitive AChE inhibitors pointing out the importance of the salycilic substituents on the hydroquinone ring. Since these compounds do not belong to the class of

  10. Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer's disease.

    PubMed

    Tommonaro, Giuseppina; García-Font, Nuria; Vitale, Rosa Maria; Pejin, Boris; Iodice, Carmine; Cañadas, Sixta; Marco-Contelles, José; Oset-Gasque, María Jesús

    2016-10-21

    Avarol is a marine sesquiterpenoid hydroquinone, previously isolated from the marine sponge Dysidea avara Schmidt (Dictyoceratida), with antiinflammatory, antitumor, antioxidant, antiplatelet, anti-HIV, and antipsoriatic effects. Recent findings indicate that some thio-avarol derivatives exhibit acetylcholinesterase (AChE) inhibitory activity. The multiple pharmacological properties of avarol, thio-avarol and/or their derivatives prompted us to continue the in vitro screening, focusing on their AChE inhibitory and neuroprotective effects. Due to the complex nature of Alzheimer's disease (AD), there is a renewed search for new, non hepatotoxic anticholinesterasic compounds. This paper describes the synthesis and in vitro biological evaluation of avarol-3'-thiosalicylate (TAVA) and thiosalycil-prenyl-hydroquinones (TPHs), as non hepatotoxic anticholinesterasic agents, showing a good neuroprotective effect on the decreased viability of SHSY5Y human neuroblastoma cells induced by oligomycin A/rotenone and okadaic acid. A molecular modeling study was also undertaken on the most promising molecules within the series to elucidate their AChE binding modes and in particular the role played by the carboxylate group in enzyme inhibition. Among them, TPH4, bearing a geranylgeraniol substituent, is the most significant Electrophorus electricus AChE (EeAChE) inhibitor (IC50 = 6.77 ± 0.24 μM), also endowed with a moderate serum horse butyrylcholinesterase (eqBuChE) inhibitory activity, being also the least hepatotoxic and the best neuroprotective compound of the series. Thus, TPHs represents a new family of synthetic compounds, chemically related to the natural compound avarol, which has been discovered for the potential treatment of AD. Findings prove the relevance of TPHs as a new possible generation of competitive AChE inhibitors pointing out the importance of the salycilic substituents on the hydroquinone ring. Since these compounds do not belong to the class of

  11. AChE for DNA degradation.

    PubMed

    Sánchez-Osuna, María; Yuste, Victor J

    2015-06-01

    DNA hydrolysis is a biochemical process often associated with different forms of cell death, including apoptosis. In a recent paper published in Cell Discovery, Du et al. report that synaptic acetylcholinesterase (AChE-S) shows an unexpected enzymatic activity as DNase switched on after cytotoxic insults. PMID:25930710

  12. Isolation, diversity and acetylcholinesterase inhibitory activity of the culturable endophytic fungi harboured in Huperzia serrata from Jinggang Mountain, China.

    PubMed

    Wang, Ya; Lai, Zheng; Li, Xi-Xi; Yan, Ri-Ming; Zhang, Zhi-Bin; Yang, Hui-Lin; Zhu, Du

    2016-02-01

    Huperzia serrata has many important medicinal properties with proven pharmacological potential. Some of these properties may be mediated by its endophytic fungi. To test this hypothesis, in the present study, we provided a first insights into evaluating the species composition and acetylcholinesterase (AChE) inhibitory activity of the culturable endophytic fungi of H. serrata from the regional at Jinggang Mountain in southeastern China. A total number of 885 fungal isolates distributed across 44 genera and 118 putative species were obtained from 1422 fragments of fine H. serrata roots, stems and leaves base on ITS-rDNA sequences BLAST analysis. The endophytic fungi were phylogenetically diverse and species-rich, with high rate of colonization and isolation. The assemble of endophytic fungi consisted mainly of Ascomycota (97.15%), followed by Basidiomycota (1.92%) and unknown fungal species (0.90%). Colletotrichum (64.29%), Phyllosticta (3.39%), Hypoxylon (2.81%), Xylaria (2.25%) and Nigrospora (2.04%) were the most abundant genera, whereas the remaining genera were infrequent groups. Although, roots yielded low abundance strains, the diverse and species-rich were both higher than that of stems and leaves. In addition, out of the 247 endophytic fungi strains determinated, 221 fungal extracts showed AChE inhibition activities in vitro. Among them, 22 endophytic fungi strains achieved high inhibitory activity (≥50%) on AChE which belongs to 13 genera and five incertae sedis strains. Four endophytic fungi designated as JS4 (Colletotrichum spp.), FL14 (Ascomycota spp.), FL9 (Sarcosomataceae spp.) and FL7 (Dothideomycetes spp.) were displayed highly active (≥80%) against AChE, which the inhibition effects were even more intense than the positive control. Our findings highlight that H. serrata grown in Jinggang Mountain harbors a rich and fascinating endophytic fungus community with potential AChE inhibitory activity, which could further broaden the natural

  13. Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease.

    PubMed

    Zhou, An; Hu, Jianping; Wang, Lirong; Zhong, Guochen; Pan, Jian; Wu, Zeyu; Hui, Ailing

    2015-10-01

    Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2) = 0.552 and r(2) = 0.983 and an optimal CoMSIA model with q(2) = 0.581 and r(2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green).

  14. Screening the methanol extracts of some Iranian plants for acetylcholinesterase inhibitory activity

    PubMed Central

    Gholamhoseinian, A.; Moradi, M.N.; Sharifi-far, F.

    2009-01-01

    Acetylcholinesterase (AChE) is the main enzyme for the breakdown of acetylcholine. Nowadays, usage of the inhibitors of this enzyme is one of the most important types of treatment of mild to moderate neurodegenerative diseases such as Alzheimer’s disease. Herbal medicines can be a new source of inhibitors of this enzyme. In this study we examined around 100 different plants to evaluate their inhibitory properties for AChE enzyme. Plants were scientifically identified and their extracts were prepared by methanol percolation. Acetylcholinesterase activity was measured using a colorimetric method in the presence or absence of the extracts. Eserine was used as a positive control. Methanol extracts of the Levisticum officinale, Bergeris integrima and Rheum ribes showed more than 50% AChE inhibitory activity. The inhibition kinetics were studied in the presence of the most effective extracts. L. officinale and B. integrima inhibited AChE activity in a non-competitive manner, while R. ribes competitively inhibitied the enzyme as revealed by double-reciprocal Linweaver-Burk plot analysis. Under controlled condition, Km and Vmax values of the enzyme were found to be 9.4 mM and 0.238 mM/min, respectively. However, in the presence of L. officinale, B. integrima, and R. ribes extracts, Vmax values were 0.192, 0.074 and 0.238 mM/min, respectively. Due to the competitive inhibition of the enzyme by R. ribes extract, the Km value of 21.2 mM was obtained. The concentration required for 50% enzyme inhibition (IC50 value) was 0.5, 0.9, and 0.95 mg/ml for the L. officinale, B. integrima and R. ribes extracts, respectively. The IC50 of the eserine was determined to be 0.8 mg/ml. PMID:21589805

  15. Selective activation of α7 nicotinic acetylcholine receptor (nAChRα7) inhibits muscular degeneration in mdx dystrophic mice.

    PubMed

    Leite, Paulo Emílio Correa; Gandía, Luís; de Pascual, Ricardo; Nanclares, Carmen; Colmena, Inés; Santos, Wilson C; Lagrota-Candido, Jussara; Quirico-Santos, Thereza

    2014-07-21

    Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChRα7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChRα7(+/+) wild-type and nAChRα7(-/-) knockout mice with muscular injury induced with 60µL 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChRα7 agonist PNU282987 (0.3mg/kg and 1.0mg/kg) and the antagonist methyllycaconitine (MLA at 1.0mg/kg) injected intraperitoneally for 7 days. Selective nAChRα7 activation of mdx mice with PNU282987 reduced circulating levels of lactate dehydrogenase (LDH, a marker of cell death by necrosis) and the area of perivascular inflammatory infiltrate, and production of inflammatory mediators TNFα and metalloprotease MMP-9 activity. Conversely, PNU282987 treatment increased MMP-2 activity, an indication of muscular tissue remodeling associated with regeneration, in both mdx mice and WTα7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on α7KO, and MLA abolished the nAChRα7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChRα7 activation inhibits muscular inflammation and activates tissue remodeling by increasing muscular regeneration. These effects were not accompanied with fibrosis and/or deposition of non-functional collagen. The nAChRα7 activation may be considered as a potential target for pharmacological strategies to reduce inflammation and activate mechanisms of muscular regeneration. PMID:24833065

  16. Activation of nicotinic ACh receptors with α4 subunits induces adenosine release at the rat carotid body

    PubMed Central

    Conde, Sílvia V; Monteiro, Emília C

    2006-01-01

    The effect of ACh on the release of adenosine was studied in rat whole carotid bodies, and the nicotinic ACh receptors involved in the stimulation of this release were characterized. ACh and nicotinic ACh receptor agonists, cytisine, DMPP and nicotine, caused a concentration-dependent increase in adenosine production during normoxia, with nicotine being more potent and efficient in stimulating adenosine release from rat CB than cytisine and DMPP. D-Tubocurarine, mecamylamine, DHβE and α-bungarotoxin, nicotinic ACh receptor antagonists, caused a concentration-dependent reduction in the release of adenosine evoked by hypoxia. The rank order of potency for nicotinic ACh receptor antagonists that inhibit adenosine release was DHβE>mecamylamine>D-tubocurarine>α-bungarotoxin. The effect of the endogenous agonist, ACh, which was mimicked by nicotine, was antagonized by DHβE, a selective nicotinic receptor antagonist. The ecto-5′-nucleotidase inhibitor AOPCP produces a 72% inhibition in the release of adenosine from CB evoked by nicotine. Taken together, these data indicate that ACh induced the production of adenosine, mainly from extracellular ATP catabolism at the CB through a mechanism that involves the activation of nicotinic receptors with α4 and β2 receptor subunits. PMID:16444287

  17. Mechanism of interaction of novel uncharged, centrally active reactivators with OP-hAChE conjugates.

    PubMed

    Radić, Zoran; Sit, Rakesh K; Garcia, Edzna; Zhang, Limin; Berend, Suzana; Kovarik, Zrinka; Amitai, Gabriel; Fokin, Valery V; Barry Sharpless, K; Taylor, Palmer

    2013-03-25

    A library of more than 200 novel uncharged oxime reactivators was used to select and refine lead reactivators of human acetylcholinesterase (hAChE) covalently conjugated with sarin, cyclosarin, VX, paraoxon and tabun. N-substituted 2-hydroxyiminoacetamido alkylamines were identified as best reactivators and reactivation kinetics of the lead oximes, RS41A and RS194B, were analyzed in detail. Compared to reference pyridinium reactivators, 2PAM and MMB4, molecular recognition of RS41A reflected in its Kox constant was compromised by an order of magnitude on average for different OP-hAChE conjugates, without significant differences in the first order maximal phosphorylation rate constant k(2). Systematic structural modifications of the RS41A lead resulted in several-fold improvement with reactivator, RS194B. Kinetic analysis indicated K(ox) reduction for RS194B as the main kinetic constant leading to efficient reactivation. Subtle structural modifications of RS194B were used to identify essential determinants for efficient reactivation. Computational molecular modeling of RS41A and RS194B interactions with VX inhibited hAChE, bound reversibly in Michaelis type complex and covalently in the pentacoordinate reaction intermediate suggests that the faster reactivation reaction is a consequence of a tighter RS194B interactions with hAChE peripheral site (PAS) residues, in particular with D74, resulting in lower interaction energies for formation of both the binding and reactivation states. Desirable in vitro reactivation properties of RS194B, when coupled with its in vivo pharmacokinetics and disposition in the body, reveal the potential of this oxime design as promising centrally and peripherally active antidotes for OP toxicity.

  18. Isolation and characterization of pediocin AcH chimeric protein mutants with altered bactericidal activity.

    PubMed

    Miller, K W; Schamber, R; Osmanagaoglu, O; Ray, B

    1998-06-01

    A collection of pediocin AcH amino acid substitution mutants was generated by PCR random mutagenesis of DNA encoding the bacteriocin. Mutants were isolated by cloning mutagenized DNA into an Escherichia coli malE plasmid that directs the secretion of maltose binding protein-pediocin AcH chimeric proteins and by screening transformant colonies for bactericidal activity against Lactobacillus plantarum NCDO955 (K. W. Miller, R. Schamber, Y. Chen, and B. Ray, 1998. Appl. Environ. Microbiol. 64:14-20, 1998). In all, 17 substitution mutants were isolated at 14 of the 44 amino acids of pediocin AcH. Seven mutants (N5K, C9R, C14S, C14Y, G37E, G37R, and C44W) were completely inactive against the pediocin AcH-sensitive strains L. plantarum NCDO955, Listeria innocua Lin11, Enterococcus faecalis M1, Pediococcus acidilactici LB42, and Leuconostoc mesenteroides Ly. A C24S substitution mutant constructed by other means also was inactive against these bacteria. Nine other mutants (K1N, W18R, I26T, M31T, A34D, N41K, H42L, K43N, and K43E) retained from <1% to approximately 60% of wild-type activity when assayed against L. innocua Lin11. One mutant, K11E, displayed approximately 2. 8-fold-higher activity against this indicator. About one half of the mutations mapped to amino acids that are conserved in the pediocin-like family of bacteriocins. All four cysteines were found to be required for activity, although only C9 and C14 are conserved among pediocin-like bacteriocins. Several basic amino acids as well as nonpolar amino acids located within the hydrophobic C-terminal region also were found to be important. The mutations are discussed in the context of structural models that have been proposed for the bacteriocin.

  19. Toxicological and Biochemical Characterizations of AChE in Phosalone-Susceptible and Resistant Populations of the Common Pistachio Psyllid, Agonoscena pistaciae

    PubMed Central

    Alizadeh, Ali; Talebi-Jahromi, Khalil; Hosseininaveh, Vahid; Ghadamyari, Mohammad

    2014-01-01

    The toxicological and biochemical characteristics of acetylcholinesterases (AChE) in nine populations of the common pistachio psyllid, Agonoscena pistaciae Burckhardt and Lauterer (Hemiptera: Psyllidae), were investigated in Kerman Province, Iran. Nine A. pistaciae populations were collected from pistachio orchards, Pistacia vera L. (Sapindales: Anacardiaceae), located in Rafsanjan, Anar, Bam, Kerman, Shahrbabak, Herat, Sirjan, Pariz, and Paghaleh regions of Kerman province. The previous bioassay results showed these populations were susceptible or resistant to phosalone, and the Rafsanjan population was most resistant, with a resistance ratio of 11.3. The specific activity of AChE in the Rafsanjan population was significantly higher than in the susceptible population (Bam). The affinity (KM) and hydrolyzing efficiency (Vmax) of AChE on acetylthiocholine iodide, butyrylthiocholine iodide, and propionylthiocholine odide as artificial substrates were clearly lower in the Bam population than that in the Rafsanjan population. These results indicated that the AChE of the Rafsanjan population had lower affinity to these substrates than that of the susceptible population. The higher Vmax value in the Rafsanjan population compared to the susceptible population suggests a possible over expression of AChE in the Rafsanjan population. The in vitro inhibitory effect of several organophosphates and carbamates on AChE of the Rafsanjan and Bam populations was determined. Based on I50, the results showed that the ratios of AChE insensitivity of the resistant to susceptible populations were 23 and 21.7-fold to monocrotophos and phosphamidon, respectively. Whereas, the insensitivity ratios for Rafsanjan population were 0.86, 0.8, 0.78, 0.46, and 0.43 for carbaryl, eserine, propoxur, m-tolyl methyl carbamate, and carbofuran, respectively, suggesting negatively correlated sensitivity to organophosphate-insensitive AChE. Therefore, AChE from the Rafsanjan population showed negatively

  20. Toxicological and biochemical characterizations of AChE in phosalone-susceptible and resistant populations of the common pistachio psyllid, Agonoscena pistaciae.

    PubMed

    Alizadeh, Ali; Talebi-Jahromi, Khalil; Hosseininaveh, Vahid; Ghadamyari, Mohammad

    2014-01-01

    The toxicological and biochemical characteristics of acetylcholinesterases (AChE) in nine populations of the common pistachio psyllid, Agonoscena pistaciae Burckhardt and Lauterer (Hemiptera: Psyllidae), were investigated in Kerman Province, Iran. Nine A. pistaciae populations were collected from pistachio orchards, Pistacia vera L. (Sapindales: Anacardiaceae), located in Rafsanjan, Anar, Bam, Kerman, Shahrbabak, Herat, Sirjan, Pariz, and Paghaleh regions of Kerman province. The previous bioassay results showed these populations were susceptible or resistant to phosalone, and the Rafsanjan population was most resistant, with a resistance ratio of 11.3. The specific activity of AChE in the Rafsanjan population was significantly higher than in the susceptible population (Bam). The affinity (K(M)) and hydrolyzing efficiency (Vmax) of AChE on acetylthiocholine iodide, butyrylthiocholine iodide, and propionylthiocholine odide as artificial substrates were clearly lower in the Bam population than that in the Rafsanjan population. These results indicated that the AChE of the Rafsanjan population had lower affinity to these substrates than that of the susceptible population. The higher Vmax value in the Rafsanjan population compared to the susceptible population suggests a possible over expression of AChE in the Rafsanjan population. The in vitro inhibitory effect of several organophosphates and carbamates on AChE of the Rafsanjan and Bam populations was determined. Based on I50, the results showed that the ratios of AChE insensitivity of the resistant to susceptible populations were 23 and 21.7-fold to monocrotophos and phosphamidon, respectively. Whereas, the insensitivity ratios for Rafsanjan population were 0.86, 0.8, 0.78, 0.46, and 0.43 for carbaryl, eserine, propoxur, m-tolyl methyl carbamate, and carbofuran, respectively, suggesting negatively correlated sensitivity to organophosphate-insensitive AChE. Therefore, AChE from the Rafsanjan population showed negatively

  1. In Vitro Anti-AChE, Anti-BuChE, and Antioxidant Activity of 12 Extracts of Eleutherococcus Species

    PubMed Central

    2016-01-01

    Neurodegenerative diseases are one of the most occurring diseases in developed and developing countries. The aim of this work focused on the screening of the natural inhibitors of AChE and BuChE and antioxidants in Eleutherococcus species. We found that the ethanol extracts of E. setchuenensis and E. sessiliflorus showed the strongest inhibition towards AChE (IC50: 0.3 and 0.3 mg/mL, resp.). Among chloroform extracts, the most active appeared to be E. gracilistylus (IC50: 0.37 mg/mL). In turn, the ethanol extract of E. henryi inhibited the strongest BuChE with IC50 value of 0.13 mg/mL. Among chloroform extracts, E. gracilistylus, E. setchuenensis, and E. sessiliflorus appeared to be the strongest with IC50 values of 0.12, 0.18, and 0.19 mg/mL. HPTLC screening confirmed the presence of inhibitors in extracts. All extracts exhibited anti-DPPH⁎ activity and single antioxidants have been identified. To the best of our knowledge, no information was available on this activity of compounds in Eleutherococcus. These studies provide a biochemical basis for the regulation of AChE and BuChE and encourage us to continue isolation of active compounds. PMID:27803761

  2. Activity of nAChRs Containing α9 Subunits Modulates Synapse Stabilization via Bidirectional Signaling Programs

    PubMed Central

    Murthy, Vidya; Taranda, Julián; Elgoyhen, A. Belén; Vetter, Douglas E.

    2010-01-01

    Although the synaptogenic program for cholinergic synapses of the neuromuscular junction is well known, little is known of the identity or dynamic expression patterns of proteins involved in non-neuromuscular nicotinic synapse development. We have previously demonstrated abnormal presynaptic terminal morphology following loss of nicotinic acetylcholine receptor (nAChR) α9 subunit expression in adult cochleae. However, the molecular mechanisms underlying these changes have remained obscure. To better understand synapse formation and the role of cholinergic activity in the synaptogenesis of the inner ear, we exploit the nAChR α9 subunit null mouse. In this mouse, functional acetylcholine (ACh) neurotransmission to the hair cells is completely silenced. Results demonstrate a premature, effusive innervation to the synaptic pole of the outer hair cells in α9 null mice coinciding with delayed expression of cell adhesion proteins during the period of effusive contact. Collapse of the ectopic innervation coincides with an age-related hyperexpression pattern in the null mice. In addition, we document changes in expression of presynaptic vesicle recycling/trafficking machinery in the α9 null mice that suggests a bidirectional information flow between the target of the neural innervation (the hair cells) and the presynaptic terminal that is modified by hair cell nAChR activity. Loss of nAChR activity may alter transcriptional activity, as CREB binding protein expression is decreased coincident with the increased expression of N-Cadherin in the adult α9 null mice. Finally, by using mice expressing the nondesensitizing α9 L9′T point mutant nAChR subunit, we show that increased nAChR activity drives synaptic hyperinnervation. PMID:19790106

  3. acetylcholinesterase inhibitory potential and insecticidal activity of an endophytic Alternaria sp. from Ricinus communis.

    PubMed

    Singh, Bahaderjeet; Thakur, Abhinay; Kaur, Sanehdeep; Chadha, B S; Kaur, Amarjeet

    2012-11-01

    Keeping in view the vast potential of endophytic fungi to produce bioactive molecules, this study aimed at isolating and screening endophytes for the production of acetylcholinesterase inhibitors. Fifty-four endophytic fungi were isolated from Ricinus communis and screened for their AChE inhibitory activity using Ellman's colorimetric assay method. Six isolates were found to possess AChE inhibitory activity with maximum inhibition of 78 % being evinced by culture Cas1 which was identified to be Alternaria sp. on the basis of molecular as well as microscopic methods. Optimization of inhibitor production was carried out using one factor at a time approach. Maximum production of inhibitor was obtained on potato dextrose broth after 10 days incubation. The IC(50) of the chloroform extract was observed to be 40 μg/ml. The extract was purified on silica gel and eluted stepwise with a gradient of chloroform/methanol. The insecticidal potential of the extract was evaluated by feeding the larvae of Spodoptera litura on diet containing varying concentrations of the extract. It was observed that with increase in the concentration of the extract, mortality of the larvae increased. The culture has the potential of being exploited in medicine as well as a biocontrol agent.

  4. Biochemical effects of glyphosate based herbicide, Excel Mera 71 on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content on teleostean fishes.

    PubMed

    Samanta, Palas; Pal, Sandipan; Mukherjee, Aloke Kumar; Ghosh, Apurba Ratan

    2014-09-01

    Effects of glyphosate based herbicide, Excel Mera 71 at a dose of 17.20mg/l on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content were measured in different tissues of two Indian air-breathing teleosts, Anabas testudineus (Bloch) and Heteropneustes fossilis (Bloch) during an exposure period of 30 days under laboratory condition. AChE activity was significantly increased in all the investigated tissues of both fish species and maximum elevation was observed in brain of H. fossilis, while spinal cord of A. testudineus showed minimum increment. Fishes showed significant increase LPO levels in all the tissues; highest was observed in gill of A. testudineus but lowest LPO level was observed in muscle of H. fossilis. CAT was also enhanced in both the fishes, while GST activity in liver diminished substantially and minimum was observed in liver of A. testudineus. Total protein content showed decreased value in all the tissues, maximum reduction was observed in liver and minimum in brain of A. testudineus and H. fossilis respectively. The results indicated that Excel Mera 71 caused serious alterations in the enzyme activities resulting into severe deterioration of fish health; so, AChE, LPO, CAT and GST can be used as suitable indicators of herbicidal toxicity. PMID:24927388

  5. Biochemical effects of glyphosate based herbicide, Excel Mera 71 on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content on teleostean fishes.

    PubMed

    Samanta, Palas; Pal, Sandipan; Mukherjee, Aloke Kumar; Ghosh, Apurba Ratan

    2014-09-01

    Effects of glyphosate based herbicide, Excel Mera 71 at a dose of 17.20mg/l on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content were measured in different tissues of two Indian air-breathing teleosts, Anabas testudineus (Bloch) and Heteropneustes fossilis (Bloch) during an exposure period of 30 days under laboratory condition. AChE activity was significantly increased in all the investigated tissues of both fish species and maximum elevation was observed in brain of H. fossilis, while spinal cord of A. testudineus showed minimum increment. Fishes showed significant increase LPO levels in all the tissues; highest was observed in gill of A. testudineus but lowest LPO level was observed in muscle of H. fossilis. CAT was also enhanced in both the fishes, while GST activity in liver diminished substantially and minimum was observed in liver of A. testudineus. Total protein content showed decreased value in all the tissues, maximum reduction was observed in liver and minimum in brain of A. testudineus and H. fossilis respectively. The results indicated that Excel Mera 71 caused serious alterations in the enzyme activities resulting into severe deterioration of fish health; so, AChE, LPO, CAT and GST can be used as suitable indicators of herbicidal toxicity.

  6. Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice.

    PubMed

    Somm, Emmanuel; Guérardel, Audrey; Maouche, Kamel; Toulotte, Audrey; Veyrat-Durebex, Christelle; Rohner-Jeanrenaud, Françoise; Maskos, Uwe; Hüppi, Petra S; Schwitzgebel, Valérie M

    2014-05-01

    Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels well characterized in neuronal signal transmission. Moreover, recent studies have revealed nAChR expression in nonneuronal cell types throughout the body, including tissues involved in metabolism. In the present study, we screen gene expression of nAChR subunits in pancreatic islets and adipose tissues. Mice pancreatic islets present predominant expression of α7 and β2 nAChR subunits but at a lower level than in central structures. Characterization of glucose and energy homeostasis in α7β2nAChR(-/-) mice revealed no major defect in insulin secretion and sensitivity but decreased glycemia apparently unrelated to gluconeogenesis or glycogenolysis. α7β2nAChR(-/-) mice presented an increase in lean and bone body mass and a decrease in fat storage with normal body weight. These observations were associated with elevated spontaneous physical activity in α7β2nAChR(-/-) mice, mainly due to elevation in fine vertical (rearing) activity while their horizontal (ambulatory) activity remained unchanged. In contrast to α7nAChR(-/-) mice presenting glucose intolerance and insulin resistance associated to excessive inflammation of adipose tissue, the present metabolic phenotyping of α7β2nAChR(-/-) mice revealed a metabolic improvement possibly linked to the increase in spontaneous physical activity related to central β2nAChR deficiency.

  7. Insights into cholinesterase inhibitory and antioxidant activities of five Juniperus species.

    PubMed

    Orhan, Nilufer; Orhan, Ilkay Erdogan; Ergun, Fatma

    2011-09-01

    In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory and antioxidant activities of the aqueous and ethanol extracts of the leaves, ripe fruits, and unripe fruits of Juniperus communis ssp. nana, Juniperus oxycedrus ssp. oxycedrus, Juniperus sabina, Juniperus foetidissima, and Juniperus excelsa were investigated in the present study. Cholinesterase inhibition of the extracts was screened using ELISA microplate reader. Antioxidant activity of the extracts was tested by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical scavenging, ferrous ion-chelating, and ferric-reducing antioxidant power (FRAP) assays. Total phenol and flavonoid contents of the extracts were determined spectrophotometrically. The extracts had low or no inhibition towards AChE, whereas the leaf aqueous extract of J. foetidissima showed the highest BChE inhibition (93.94 ± 0.01%). The leaf extracts usually exerted higher antioxidant activity. We herein describe the first study on anticholinesterase and antioxidant activity by the methods of ferrous ion-chelating, superoxide radical scavenging, and ferric-reducing antioxidant power (FRAP) assays of the mentioned Juniperus species.

  8. Toxicity and mAChRs binding activity of Cassiopea xamachana venom from Puerto Rican coasts.

    PubMed

    Radwan, Faisal F Y; Román, Laura G; Baksi, Krishna; Burnett, Joseph W

    2005-01-01

    A separation of toxic components from the upside down jellyfish Cassiopea xamachana (Cx) was carried out to study their cytotoxic effects and examine whether these effects are combined with a binding activity to cell membrane receptors. Nematocysts containing toxins were isolated from the autolysed tentacles, ruptured by sonication, and the crude venom (CxTX) was separated from the pellets by ultracentrifugation. For identifying its bioactive components, CxTX was fractionated by gel filtration chromatography into six fractions (named fraction I-VI). The toxicity of CxTX and fractions was tested on mice; however, the hemolytic activity was tested on saline washed human erythrocytes. The LD50 of CxTX was 0.75 microg/g of mouse body and for fraction III, IV and VI were 0.28, 0.25 and 0.12 microg/g, respectively. Fractions I, II and V were not lethal at doses equivalent to LD50 1 microg/g. The hemolytic and phospholipase A2 (PLA2) activities of most fractions were well correlated with their mice toxicity. However, fraction VI, which contains the low molecular mass protein components (< or =10 kDa), has shown no PLA2 activity but highest toxicity to mice, highest hemolytic activity, and bound significantly to the acetylcholine muscarinic receptors (mAChRs) isolated from rat brain. The results suggested that fraction VI contains proteinaceous components contributing to most of cytolysis as well as membrane binding events. Meanwhile, fraction IV has shown high PLA2 that may contribute to the venom lethality and paralytic effects. PMID:15581689

  9. Inhibitory effect of ebselen on cerebral acetylcholinesterase activity in vitro: kinetics and reversibility of inhibition.

    PubMed

    Martini, Franciele; Bruning, César Augusto; Soares, Suelen Mendonca; Nogueira, Cristina Wayne; Zeni, Gilson

    2015-01-01

    Ebselen is a synthetic organoselenium compound that has been considered a potential pharmacological agent with low toxicity, showing antioxidant, anti-inflammatory and neuroprotective effects. It is bioavailable, blood-brain barrier permeant and safe based on cellular toxicity and Phase I-III clinical trials. There is evidence that ebselen inhibits acetylcholinesterase (AChE) activity, an enzyme that plays a key role in the cholinergic system by hydrolyzing acetylcholine (ACh), in vitro and ex vivo. This system has a well-known relationship with cognitive process, and AChE inhibitors, such as donepezil and galantamine, have been used to treat cognitive deficits, mainly in the Alzheimer's Disease (AD). However, these drugs have poor bioavailability and a number of side effects, including gastrointestinal upsets and hepatotoxicity. In this way, this study aimed to evaluate the effect of ebselen on cerebral AChE activity in vitro and to determine the kinetic profile and the reversibility of inhibition by dialysis. Ebselen inhibited the cerebral AChE activity with an IC50 of 29 µM, similar to IC50 found with pure AChE from electric eel, demonstrating a mixed and reversible inhibition of AChE, since it increased Km and decreased Vmax. The AChE activity was recovered within 60 min of dialysis. Therefore, the use of ebselen as a therapeutic agent for treatment of AD should be considered, although memory behavior tasks are needed to support such hypothesis. PMID:25312723

  10. Abietane-type diterpenoids from the roots of Caryopteris mongolica and their cholinesterase inhibitory activities.

    PubMed

    Murata, Toshihiro; Ishikawa, Yoshinobu; Saruul, Erdenebileg; Selenge, Erdenechimeg; Sasaki, Kenroh; Umehara, Kaoru; Yoshizaki, Fumihiko; Batkhuu, Javzan

    2016-10-01

    Eleven abietane-type diterpenoids and two known abietanes were isolated from the roots of Caryopteris mongolica, and their structures were characterized. The absolute configurations at C-5 and C-10 were determined from the NMR data, including from the nuclear Overhauser effect and CD spectra, and the absolute configuration of C-16 in the hydroxypropyl group was determined via a modified Mosher's method. Furthermore, the previously unknown absolute configuration of the C-15 of cyrtophyllone B was determined to be in an R-configuration using X-ray crystallography. To estimate the preventive effects of the isolates for neurodegenerative disease development, their inhibitory activities against acetylcholinesterase (AChE) from human erythrocytes and butyrylcholinesterase (BChE) from horse serum were evaluated.

  11. Abietane-type diterpenoids from the roots of Caryopteris mongolica and their cholinesterase inhibitory activities.

    PubMed

    Murata, Toshihiro; Ishikawa, Yoshinobu; Saruul, Erdenebileg; Selenge, Erdenechimeg; Sasaki, Kenroh; Umehara, Kaoru; Yoshizaki, Fumihiko; Batkhuu, Javzan

    2016-10-01

    Eleven abietane-type diterpenoids and two known abietanes were isolated from the roots of Caryopteris mongolica, and their structures were characterized. The absolute configurations at C-5 and C-10 were determined from the NMR data, including from the nuclear Overhauser effect and CD spectra, and the absolute configuration of C-16 in the hydroxypropyl group was determined via a modified Mosher's method. Furthermore, the previously unknown absolute configuration of the C-15 of cyrtophyllone B was determined to be in an R-configuration using X-ray crystallography. To estimate the preventive effects of the isolates for neurodegenerative disease development, their inhibitory activities against acetylcholinesterase (AChE) from human erythrocytes and butyrylcholinesterase (BChE) from horse serum were evaluated. PMID:27298275

  12. AChE inhibition: one dominant factor for swimming behavior changes of Daphnia magna under DDVP exposure.

    PubMed

    Ren, Zongming; Zhang, Xu; Wang, Xiaoguang; Qi, Pingping; Zhang, Biao; Zeng, Yang; Fu, Rongshu; Miao, Mingsheng

    2015-02-01

    As a key enzyme that hydrolyzes the neurotransmitter acetylcholine in cholinergic synapses of both vertebrates and invertebrates, acetylcholinesterase (AChE) is strongly inhibited by organophosphates. AChE inhibition may induce the decrease of swimming ability. According to previous research, swimming behavior of different aquatic organisms could be affected by different chemicals, and there is a shortage of research on direct correlation analysis between swimming behavior and biochemical indicators. Therefore, swimming behavior and whole-body AChE activity of Daphnia magna under dichlorvos (DDVP) exposure were identified in order to clarify the relationship between behavioral responses and AChE inhibition in this study. In the beginning, AChE activity was similar in all treatments with the control. During all exposures, the tendency of AChE activity inhibition was the same as the behavioral responses of D. magna. The AChE activity of individuals without movement would decrease to about zero in several minutes. The correlation analysis between swimming behavior of D. magna and AChE activity showed that the stepwise behavioral response was mainly decided by AChE activity. All of these results suggested that the toxicity characteristics of DDVP as an inhibitor of AChE on the swimming behavior of organisms were the same, and the AChE activity inhibition could induce loss of the nerve conduction ability, causing hyperactivity, loss of coordination, convulsions, paralysis and other kinds of behavioral changes, which was illustrated by the stepwise behavioral responses under different environmental stresses.

  13. Lipoxygenase inhibitory activity of alkyl protocatechuates.

    PubMed

    Ha, Tae Joung; Shimizu, Kuniyoshi; Kubo, Isao

    2014-09-15

    Alkyl 3,4-dihydroxybenzoates (protocatechuates) inhibited linoleic acid peroxidation catalyzed by soybean lipoxygenase-1 (EC 1.13.11.12, Type 1). Their inhibitory activities displayed a parabolic function of their lipophilicity and maximized with alkyl chain lengths of between C11 and C14. Tetradecanyl protocatechuate exhibited the most potent inhibition with an IC50 of 0.05 μM, followed by dodecyl (lauryl) protocatechuate with an IC50 of 0.06 μM. However, their parent compound, protocatechuic acid, did not show this inhibitory activity up to 200 μM, indicating that the alkyl chain length is significantly related to the inhibition activity. The allosteric (or cooperative) inhibition of soybean lipoxygenase-1 of longer alkyl protocatechuates is reversible but in combination with their iron binding ability to disrupt the active site competitively and to interact with the hydrophobic portion surrounding near the active site (sequential action). In the case of dodecyl protocatechuate, the enzyme quickly binds this protocatechuate and then its dodecyl group undergoes a slow interaction with the hydrophobic domain in close proximity to the active site in the enzyme. The inhibition kinetics analyzed by Lineweaver-Burk plots indicates that octyl protocatechuate is a competitive inhibitor and the inhibition constant (Ki) was obtained as 0.23 μM but dodecyl protocatechuate is a slow binding inhibitor.

  14. Neuroprotective effect of cellular prion protein (PrPC) is related with activation of alpha7 nicotinic acetylcholine receptor (α7nAchR)-mediated autophagy flux.

    PubMed

    Jeong, Jae-Kyo; Park, Sang-Youel

    2015-09-22

    Activation of the alpha7 nicotinic acetylcholine receptor (α7nAchR) is regulated by prion protein (PrPC) expression and has a neuroprotective effect by modulating autophagic flux. In this study, we hypothesized that PrPC may regulate α7nAchR activation and that may prevent prion-related neurodegenerative diseases by regulating autophagic flux. PrP(106-126) treatment decreased α7nAchR expression and activation of autophagic flux. In addition, the α7nAchR activator PNU-282987 enhanced autophagic flux and protected neuron cells against PrP(106-126)-induced apoptosis. However, activation of autophagy and the protective effects of PNU-282987 were inhibited in PrPC knockout hippocampal neuron cells. In addition, PrPC knockout hippocampal neuron cells showed decreased α7nAchR expression levels. Adenoviral overexpression of PrPC in PrPC knockout hippocampal neuron cells resulted in activation of autophagic flux and inhibition of prion peptide-mediated cell death via α7nAchR activation. This is the first report demonstrating that activation of α7nAchR-mediated autophagic flux is regulated by PrPC, and that activation of α7nAchR regulated by PrPC expression may play a pivotal role in protection of neuron cells against prion peptide-induced neuron cell death by autophagy. These results suggest that α7nAchR-mediated autophagic flux may be involved in the pathogenesis of prion-related diseases and may be a therapeutic target for prion-related neurodegenerative diseases.

  15. Neuroprotective effect of cellular prion protein (PrPC) is related with activation of alpha7 nicotinic acetylcholine receptor (α7nAchR)-mediated autophagy flux.

    PubMed

    Jeong, Jae-Kyo; Park, Sang-Youel

    2015-09-22

    Activation of the alpha7 nicotinic acetylcholine receptor (α7nAchR) is regulated by prion protein (PrPC) expression and has a neuroprotective effect by modulating autophagic flux. In this study, we hypothesized that PrPC may regulate α7nAchR activation and that may prevent prion-related neurodegenerative diseases by regulating autophagic flux. PrP(106-126) treatment decreased α7nAchR expression and activation of autophagic flux. In addition, the α7nAchR activator PNU-282987 enhanced autophagic flux and protected neuron cells against PrP(106-126)-induced apoptosis. However, activation of autophagy and the protective effects of PNU-282987 were inhibited in PrPC knockout hippocampal neuron cells. In addition, PrPC knockout hippocampal neuron cells showed decreased α7nAchR expression levels. Adenoviral overexpression of PrPC in PrPC knockout hippocampal neuron cells resulted in activation of autophagic flux and inhibition of prion peptide-mediated cell death via α7nAchR activation. This is the first report demonstrating that activation of α7nAchR-mediated autophagic flux is regulated by PrPC, and that activation of α7nAchR regulated by PrPC expression may play a pivotal role in protection of neuron cells against prion peptide-induced neuron cell death by autophagy. These results suggest that α7nAchR-mediated autophagic flux may be involved in the pathogenesis of prion-related diseases and may be a therapeutic target for prion-related neurodegenerative diseases. PMID:26295309

  16. Neuroprotective effects of donepezil against Aβ42-induced neuronal toxicity are mediated through not only enhancing PP2A activity but also regulating GSK-3β and nAChRs activity.

    PubMed

    Noh, Min-Young; Koh, Seong H; Kim, Sung-Min; Maurice, Tangui; Ku, Sae-Kwang; Kim, Seung H

    2013-11-01

    The main purpose of this study was to evaluate whether donepezil, acetylcholinesterase inhibitor, shown to play a protective role through inhibiting glycogen synthesis kinase-3β (GSK-3β) activity, could also exert neuroprotective effects by stimulating protein phosphatase 2A (PP2A) activity in the amyloid-beta (Aβ)42-induced neuronal toxicity model of Alzheimer's disease. In Aβ42-induced toxic conditions, each PP2A and GSK-3β activity measured at different times showed time-dependent reverse pattern toward the direction of accelerating neuronal deaths with the passage of time. In addition, donepezil pre-treatment showed dose-dependent stepwise increase of neuronal viability and stimulation of PP2A activity. However, such effects on them were significantly reduced through the depletion of PP2A activity with either okadaic acid or PP2Ac siRNA. In spite of blocked PP2A activity in this Aβ42 insult, however, donepezil pretreatment showed additional significant recovering effect on neuronal viability when compared to the value without donepezil. Moreover, donepezil partially recovered its dephosphorylating effect on hyperphosphorylated tau induced by Aβ42. This observation led us to assume that additional mechanisms of donepezil, including its inhibitory effect on GSK-3β activity and/or the activation role of nicotinic acetylcholine receptors (nAChRs), might be involved. Taken together, our results suggest that the neuroprotective effects of donepezil against Aβ42-induced neurotoxicity are mediated through activation of PP2A, but its additional mechanisms including regulation of GSK-3β and nAChRs activity would partially contribute to its effects. We investigated neuroprotective mechanisms of donepezil against Aβ42 toxicity: Donepezil increased neuronal viability with reduced p-tau by enhancing PP2A activity. Despite of blocked PP2A activity, donepezil showed additional recovering effect on neuronal viability, which findings led us to assume that additional

  17. Nicotine enhances both excitatory and inhibitory synaptic inputs to inspiratory-activated airway vagal preganglionic neurons.

    PubMed

    Zhou, Xujiao; Chen, Yonghua; Ge, Dengyun; Yuan, Wenjun; Wang, Jijiang

    2013-01-01

    The airway vagal preganglionic neurons (AVPNs) supply the essential excitatory drive to the postganglionic neurons and dominate the neural control of the airway both physiologically and pathophysiologically. The AVPNs express multiple subunits of nicotinic acetylcholine receptors (nAChRs), but the influences of exogenous nicotine and endogenous acetylcholine are unknown. This study examined the effects of nicotine and endogenous acetylcholine on retrogradely labelled, functionally identified inspiratory-activated AVPNs (IA-AVPNs) using the patch-clamp technique. Nicotine (10 μmol l(-1)) significantly increased the frequency and amplitude of the spontaneous EPSCs of IA-AVPNs, and these effects were insensitive to methyllycaconitine (MLA, 100 nmol l(-1)), an antagonist of the α7 type of nAChR, but was prevented by dihydro-β-erythroidine (DHβE, 3 μmol l(-1)), an antagonist of the α4β2 type of nAChR. Nicotine caused a tonic inward current in IA-AVPNs, which was reduced by MLA or DHβE alone, but was not abolished by co-application of MLA and DHβE. Nicotine caused a significant increase in the frequency of GABAergic and glycinergic spontaneous IPSCs and significantly increased the amplitude of glycinergic spontaneous IPSCs, all of which were prevented by DHβE. Nicotine had no effects on the miniature EPSCs or miniature IPSCs following pretreatment with TTX. Under current clamp, nicotine caused depolarization and increased the firing rate of IA-AVPNs during inspiratory intervals. Neostigmine (10 μmol l(-1)), an acetylcholinesterase inhibitor, mimicked the effects of nicotine. These results demonstrate that nicotine and endogenous ACh enhance the excitatory and inhibitory synaptic inputs of IA-AVPNs and cause a postsynaptic excitatory current and that the nicotinic effects are mediated presynaptically by activation of the α4β2 type of nAChR and postsynaptically by activation of multiple nAChRs, including α7 and α4β2 types.

  18. Cholinesterase inhibitory activity of isoquinoline alkaloids from three Cryptocarya species (Lauraceae).

    PubMed

    Wan Othman, Wan Nurul Nazneem; Liew, Sook Yee; Khaw, Kooi Yeong; Murugaiyah, Vikneswaran; Litaudon, Marc; Awang, Khalijah

    2016-09-15

    Alzheimer's disease is the most common form of dementia among older adults. Acetylcholinesterase and butyrylcholinesterase are two enzymes involved in the breaking down of the neurotransmitter acetylcholine. Inhibitors for these enzymes have potential to prolong the availability of acetylcholine. Hence, the search for such inhibitors especially from natural products is needed in developing potential drugs for Alzheimer's disease. The present study investigates the cholinesterase inhibitory activity of compounds isolated from three Cryptocarya species towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Nine alkaloids were isolated; (+)-nornantenine 1, (-)-desmethylsecoantofine 2, (+)-oridine 3, (+)-laurotetanine 4 from the leaves of Cryptocarya densiflora BI., atherosperminine 5, (+)-N-methylisococlaurine 6, (+)-N-methyllaurotetanine 7 from the bark of Cryptocarya infectoria Miq., 2-methoxyatherosperminine 8 and (+)-reticuline 9 from the bark of Cryptocarya griffithiana Wight. In general, most of the alkaloids showed higher inhibition towards BChE as compared to AChE. The phenanthrene type alkaloid; 2-methoxyatherosperminine 8, exhibited the most potent inhibition against BChE with IC50 value of 3.95μM. Analysis of the Lineweaver-Burk (LB) plot of BChE activity over a range of substrate concentration suggested that 2-methoxyatherosperminine 8 exhibited mixed-mode inhibition with an inhibition constant (Ki) of 6.72μM. Molecular docking studies revealed that 2-methoxyatherosperminine 8 docked well at the choline binding site and catalytic triad of hBChE (butyrylcholinesterase from Homo sapiens); hydrogen bonding with Tyr 128 and His 438 residues respectively. PMID:27492195

  19. Extracts and constituents of Leontopodium alpinum enhance cholinergic transmission: Brain ACh increasing and memory improving properties

    PubMed Central

    Hornick, Ariane; Schwaiger, Stefan; Rollinger, Judith M.; Vo, Nguyen Phung; Prast, Helmut; Stuppner, Hermann

    2012-01-01

    Leontopodium alpinum (‘Edelweiss’) was phytochemically investigated for constituents that might enhance cholinergic neurotransmission. The potency to increase synaptic availability of acetylcholine (ACh) in rat brain served as key property for the bioguided isolation of cholinergically active compounds using different chromatographic techniques. The dichlormethane (DCM) extract of the root, fractions and isolated constituents were injected i.c.v. and the effect on brain ACh was detected via the push–pull technique. The DCM extract enhanced extracellular ACh concentration in rat brain and inhibited acetylcholinesterase (AChE) in vitro. The extracellular level of brain ACh was significantly increased by the isolated sesquiterpenes, isocomene and 14-acetoxyisocomene, while silphiperfolene acetate and silphinene caused a small increasing tendency. Only silphiperfolene acetate showed in vitro AChE inhibitory activity, thus suggesting the other sesquiterpenes to stimulate cholinergic transmission by an alternative mechanism of action. Isocomene was further investigated with behavioural tasks in mice. It restored object recognition in scopolamine-impaired mice and showed nootropic effects in the T-maze alternation task in normal and scopolamine-treated mice. Additionally, this sesquiterpene reduced locomotor activity of untreated mice in the open field task, while the activity induced by scopolamine was abolished. The enhancement of synaptic availability of ACh, the promotion of alternation, and the amelioration of scopolamine-induced deficit are in accordance with a substance that amplifies cholinergic transmission. Whether the mechanism of action is inhibition of AChE or another pro-cholinergic property remains to be elucidated. Taken together, isocomene and related constituents of L. alpinum deserve further interest as potential antidementia agents in brain diseases associated with cholinergic deficits. PMID:18541221

  20. Cardanol-derived AChE inhibitors: Towards the development of dual binding derivatives for Alzheimer's disease.

    PubMed

    Lemes, Laís Flávia Nunes; de Andrade Ramos, Giselle; de Oliveira, Andressa Souza; da Silva, Fernanda Motta R; de Castro Couto, Gina; da Silva Boni, Marina; Guimarães, Marcos Jorge R; Souza, Isis Nem O; Bartolini, Manuela; Andrisano, Vincenza; do Nascimento Nogueira, Patrícia Coelho; Silveira, Edilberto Rocha; Brand, Guilherme D; Soukup, Ondřej; Korábečný, Jan; Romeiro, Nelilma C; Castro, Newton G; Bolognesi, Maria Laura; Romeiro, Luiz Antonio Soares

    2016-01-27

    Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 μM, and a similar inhibition profile of the human isoform (IC50 = 5.7 μM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 μM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development. PMID:26735910

  1. Flavoring extracts of Hemidesmus indicus roots and Vanilla planifolia pods exhibit in vitro acetylcholinesterase inhibitory activities.

    PubMed

    Kundu, Anish; Mitra, Adinpunya

    2013-09-01

    Acetylcholinesterase inhibitors (AChEIs) are important for treatment of Alzheimer's disease and other neurological disorders. Search for potent and safe AChEIs from plant sources still continues. In the present work, we explored fragrant plant extracts that are traditionally used in flavoring foods, namely, Hemidesmus indicus and Vanilla planifolia, as possible sources for AChEI. Root and pod extracts of H. indicus and V. planifolia, respectively, produce fragrant phenolic compounds, 2-hydroxy-4-methoxybenzaldehyde (MBALD) and 4-hydroxy-3-methoxybenzaldehyde (vanillin). These methoxybenzaldehydes were shown to have inhibitory potential against acetylcholinesterase (AChE). Vanillin (IC50 = 0.037 mM) was detected as more efficient inhibitor than MBALD (IC50 = 0.047 mM). This finding was supported by kinetic analysis. Thus, plant-based food flavoring agents showed capacity in curing Alzheimer's disease and other neurological dysfunctions.

  2. Monoamine oxidase inhibitory activities of heterocyclic chalcones.

    PubMed

    Minders, Corné; Petzer, Jacobus P; Petzer, Anél; Lourens, Anna C U

    2015-11-15

    Studies have shown that natural and synthetic chalcones (1,3-diphenyl-2-propen-1-ones) possess monoamine oxidase (MAO) inhibition activities. Of particular importance to the present study is a report that a series of furanochalcones acts as MAO-B selective inhibitors. Since the effect of heterocyclic substitution, other than furan (and more recently thiophene, piperidine and quinoline) on the MAO inhibitory properties of the chalcone scaffold remains unexplored, the aim of this study was to synthesise and evaluate further heterocyclic chalcone analogues as inhibitors of the human MAOs. For this purpose, heterocyclic chalcone analogues that incorporate pyrrole, 5-methylthiophene, 5-chlorothiophene and 6-methoxypyridine substitution were examined. Seven of the nine synthesised compounds exhibited IC50 values <1 μM for the inhibition of MAO-B, with all compounds exhibiting higher affinities for MAO-B compared to the MAO-A isoform. The most potent MAO-B inhibitor (4h) displays an IC50 value of 0.067 μM while the most potent MAO-A inhibitor (4e) exhibits an IC50 value of 3.81 μM. It was further established that selected heterocyclic chalcones are reversible and competitive MAO inhibitors. 4h, however, may exhibit tight-binding to MAO-B, a property linked to its thiophene moiety. We conclude that high potency chalcones such as 4h represent suitable leads for the development of MAO-B inhibitors for the treatment of Parkinson's disease and possibly other neurodegenerative disorders.

  3. Acetylcholinesterase inhibitory, antioxidant and phytochemical properties of selected medicinal plants of the Lamiaceae family.

    PubMed

    Vladimir-Knežević, Sanda; Blažeković, Biljana; Kindl, Marija; Vladić, Jelena; Lower-Nedza, Agnieszka D; Brantner, Adelheid H

    2014-01-09

    The present study aimed to evaluate acetylcholinesterase (AChE) inhibitory and antioxidant activities of Lamiaceae medicinal plants growing wild in Croatia. Using Ellman's colorimetric assay all tested ethanolic extracts and their hydroxycinnamic acid constituents demonstrated in vitro AChE inhibitory properties in a dose dependent manner. The extracts of Mentha x piperita, M. longifolia, Salvia officinalis, Satureja montana, Teucrium arduini, T. chamaedrys, T. montanum, T. polium and Thymus vulgaris at 1 mg/mL showed strong inhibitory activity against AChE. The antioxidant potential of the investigated Lamiaceae species was assessed by DPPH• scavenging activity and total antioxidant capacity assays, in comparison with hydroxycinnamic acids and trolox. The extracts differed greatly in their total hydroxycinnamic derivatives content, determined spectrophotometrically. Rosmarinic acid was found to be the predominant constituent in most of the investigated medicinal plants (by RP-HPLC) and had a substantial influence on their AChE inhibitory and antioxidant properties, with the exception of Teucrium species. These findings indicate that Lamiaceae species are a rich source of various natural AChE inhibitors and antioxidants that could be useful in the prevention and treatment of Alzheimer's and other related diseases.

  4. PACAP induces plasticity at autonomic synapses by nAChR-dependent NOS1 activation and AKAP-mediated PKA targeting.

    PubMed

    Jayakar, Selwyn S; Pugh, Phyllis C; Dale, Zack; Starr, Eric R; Cole, Samantha; Margiotta, Joseph F

    2014-11-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide found at synapses throughout the central and autonomic nervous system. We previously found that PACAP engages a selective G-protein coupled receptor (PAC1R) on ciliary ganglion neurons to rapidly enhance quantal acetylcholine (ACh) release from presynaptic terminals via neuronal nitric oxide synthase (NOS1) and cyclic AMP/protein kinase A (PKA) dependent processes. Here, we examined how PACAP stimulates NO production and targets resultant outcomes to synapses. Scavenging extracellular NO blocked PACAP-induced plasticity supporting a retrograde (post- to presynaptic) NO action on ACh release. Live-cell imaging revealed that PACAP stimulates NO production by mechanisms requiring NOS1, PKA and Ca(2+) influx. Ca(2+)-permeable nicotinic ACh receptors composed of α7 subunits (α7-nAChRs) are potentiated by PKA-dependent PACAP/PAC1R signaling and were required for PACAP-induced NO production and synaptic plasticity since both outcomes were drastically reduced following their selective inhibition. Co-precipitation experiments showed that NOS1 associates with α7-nAChRs, many of which are perisynaptic, as well as with heteromeric α3*-nAChRs that generate the bulk of synaptic activity. NOS1-nAChR physical association could facilitate NO production at perisynaptic and adjacent postsynaptic sites to enhance focal ACh release from juxtaposed presynaptic terminals. The synaptic outcomes of PACAP/PAC1R signaling are localized by PKA anchoring proteins (AKAPs). PKA regulatory-subunit overlay assays identified five AKAPs in ganglion lysates, including a prominent neuronal subtype. Moreover, PACAP-induced synaptic plasticity was selectively blocked when PKA regulatory-subunit binding to AKAPs was inhibited. Taken together, our findings indicate that PACAP/PAC1R signaling coordinates nAChR, NOS1 and AKAP activities to induce targeted, retrograde plasticity at autonomic synapses. Such

  5. Xanthine oxidase inhibitory activity of Hungarian wild-growing mushrooms.

    PubMed

    Ványolós, Attila; Orbán-Gyapai, Orsolya; Hohmann, Judit

    2014-08-01

    Mushrooms represent a remarkable and yet largely unexplored source of new, biologically active natural products. In this work, we report on the xanthine oxidase (XO) inhibitory activity of 47 wild-growing mushrooms native to Hungary. Aqueous and organic (n-hexane, chloroform, and 50% methanol) extracts of selected mushrooms from different families were screened for their XO inhibitory activities. Among the 188 extracts investigated, the chloroform and 50% methanol fractions proved to be the most effective. Some species exhibited high inhibitory activity, e.g., Hypholoma fasciculare (IC50  =67.76 ± 11.05 µg/mL), Suillus grevillei (IC50  =13.28 ± 1.58 µg/mL), and Tricholoma populinum (IC50  =85.08 ± 15.02 µg/mL); others demonstrated moderate or weak activity. Additional studies are warranted to characterize the compounds responsible for the XO inhibitory activity of mushroom extracts.

  6. Chemical composition, aroma evaluation, and inhibitory activity towards acetylcholinesterase of essential oils from Gynura bicolor DC.

    PubMed

    Miyazawa, Mitsuo; Nakahashi, Hiroshi; Usami, Atsushi; Matsuda, Naoki

    2016-04-01

    The compositions of the essential oils obtained from leaves and stems of Gynura bicolor DC. were analyzed by GC-MS. One hundred eight components of these oils were identified. (E)-β-caryophyllene (31.42 %), α-pinene (17.11 %), and bicyclogermacrene (8.09 %) were found to be the main components of the leaf oil, while α-pinene (61.42 %), β-pinene (14.39 %), and myrcene (5.10 %) were the major constituents of the stem oil. We found 73 previously unidentified components in these oils from G. bicolor. The oils were also subjected to odor evaluation. Eleven and 12 aroma-active compounds were detected in the leaf and stem oils, respectively. The abilities of these oils to inhibit acetylcholinesterase (AChE) activity were determined. The sesquiterpenoids in the oils were found to inhibit AChE activity more strongly than the monoterpenoids in the oils did. It was suggested that the three main components in each essential oil act synergistically against AChE activity. These results show that the essential oils obtained from G. bicolor are a good dietary source of AChE activity inhibition.

  7. Activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) reverses referred mechanical hyperalgesia induced by colonic inflammation in mice.

    PubMed

    Costa, Robson; Motta, Emerson M; Manjavachi, Marianne N; Cola, Maíra; Calixto, João B

    2012-10-01

    In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) on dextran sulphate sodium (DSS)-induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. Referred mechanical hyperalgesia was evaluated for 7 days after the beginning of 4% DSS intake. Referred mechanical hyperalgesia started within 1 day after beginning DSS drinking, peaked at 3 days and persisted for 7 days. This time course profile perfectly matched with the appearance of signs of colitis. Both acute and chronic oral treatments with nicotine (0.1-1.0 mg/kg, p.o.) were effective in inhibiting the established referred mechanical hyperalgesia. The antinociceptive effect of nicotine was completely abrogated by cotreatment with the selective α7 nAchR antagonist methyllycaconitine (MLA) (1.0 mg/kg). Consistent with these results, i.p. treatment with the selective α7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using α7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases.

  8. Linarin Inhibits the Acetylcholinesterase Activity In-vitro and Ex-vivo.

    PubMed

    Feng, Xinchi; Wang, Xin; Liu, Youping; Di, Xin

    2015-01-01

    Linarin is a flavone glycoside in the plants Flos chrysanthemi indici, Buddleja officinalis, Cirsium setosum, Mentha arvensis and Buddleja davidii, and has been reported to possess analgesic, antipyretic, anti-inflammatory and neuroprotective activities. In this paper, linarin was investigated for its AChE inhibitory potential both in-vitro and ex-vivo. Ellman's colorimetric method was used for the determination of AChE inhibitory activity in mouse brain. In-vitro assays revealed that linarin inhibited AChE activity with an IC50 of 3.801 ± 1.149 μM. Ex-vivo study showed that the AChE activity was significantly reduced in both the cortex and hippocampus of mice treated intraperitoneally with various doses of linarin (35, 70 and 140 mg/Kg). The inhibition effects produced by high dose of linarin were the same as that obtained after huperzine A treatment (0.5 mg/Kg). Molecular docking study revealed that both 4'-methoxyl group and 7-O-sugar moiety of linarin played important roles in ligand-receptor binding and thus they are mainly responsible for AChE inhibitory activity. In view of its potent AChE inhibitory activity, linarin may be a promising therapeutic agent for the treatment of some diseases associated with AChE, such as glaucoma, myasthenia gravis, gastric motility and Alzheimer's disease.

  9. Linarin Inhibits the Acetylcholinesterase Activity In-vitro and Ex-vivo

    PubMed Central

    Feng, Xinchi; Wang, Xin; Liu, Youping; Di, Xin

    2015-01-01

    Linarin is a flavone glycoside in the plants Flos chrysanthemi indici, Buddleja officinalis, Cirsium setosum, Mentha arvensis and Buddleja davidii, and has been reported to possess analgesic, antipyretic, anti-inflammatory and neuroprotective activities. In this paper, linarin was investigated for its AChE inhibitory potential both in-vitro and ex-vivo. Ellman’s colorimetric method was used for the determination of AChE inhibitory activity in mouse brain. In-vitro assays revealed that linarin inhibited AChE activity with an IC50 of 3.801 ± 1.149 μM. Ex-vivo study showed that the AChE activity was significantly reduced in both the cortex and hippocampus of mice treated intraperitoneally with various doses of linarin (35, 70 and 140 mg/Kg). The inhibition effects produced by high dose of linarin were the same as that obtained after huperzine A treatment (0.5 mg/Kg). Molecular docking study revealed that both 4’-methoxyl group and 7-O-sugar moiety of linarin played important roles in ligand-receptor binding and thus they are mainly responsible for AChE inhibitory activity. In view of its potent AChE inhibitory activity, linarin may be a promising therapeutic agent for the treatment of some diseases associated with AChE, such as glaucoma, myasthenia gravis, gastric motility and Alzheimer’s disease. PMID:26330885

  10. Natural AChE Inhibitors from Plants and their Contribution to Alzheimer’s Disease Therapy

    PubMed Central

    Murray, Ana Paula; Faraoni, María Belén; Castro, María Julia; Alza, Natalia Paola; Cavallaro, Valeria

    2013-01-01

    As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer’s disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer’s disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition. PMID:24381530

  11. Antioxidative/acetylcholinesterase inhibitory activity of some Asteraceae plants.

    PubMed

    Mekinić, Ivana Generalić; Burcul, Franko; Blazević, Ivica; Skroza, Danijela; Kerum, Daniela; Katalinić, Visnja

    2013-04-01

    The extracts obtained by 80% EtOH from some Asteraceae plants (Calendula officinalis, Inula helenium, Arctium lappa, Artemisia absinthium and Achillea millefolium) were studied. Rosmarinic acid, one of the main compounds identified in all extracts, was determined quantitatively by using HPLC. In addition, spectrophotometric methods were evaluated as an alternative for rosmarinic acid content determination. Total phenolic content was also established for all extracts. A. millefolium extract was found to have the highest content of rosmarinic acid as well as total phenols. All extracts were tested for antioxidant and acetylcholinesterase inhibitory activity. A. millefolium was shown to possess the best antioxidant activity (for all tested methods) as well as acetylcholinesterase inhibitory activity. Highly positive linear relationships were obtained between antioxidant/acetylcholinesterase inhibitory activity and the determined rosmarinic acid content indicating its significance for the observed activities. PMID:23738456

  12. Laboratory and Simulated Field Bioassays to Evaluate Larvicidal Activity of Pinus densiflora Hydrodistillate, Its Constituents and Structurally Related Compounds against Aedes albopictus, Aedes aegypti and Culex pipiens pallens in Relation to Their Inhibitory Effects on Acetylcholinesterase Activity.

    PubMed

    Lee, Dong Chan; Ahn, Young-Joon

    2013-01-01

    The toxicity of Pinus densiflora (red pine) hydrodistillate, its 19 constituents and 28 structurally related compounds against early third-instar larvae of Aedes albopictus (Ae. albopictus), Aedes aegypti (Ae. aegypti) and Culex pipiens palles (Cx. p. pallens) was examined using direct-contact bioassays. The efficacy of active compounds was further evaluated in semi-field bioassays using field-collected larval Cx. p. pallens. Results were compared with those of two synthetic larvicides, temephos and fenthion. In laboratory bioassays, Pinus densiflora hydrodistillate was found to have 24 h LC50 values of 20.33, 21.01 and 22.36 mg/L against larval Ae. albopictus, Ae. aegypti and Cx. p. pallens respectively. Among the identified compounds, thymol, δ-3-carene and (+)-limonene exhibited the highest toxicity against all three mosquito species. These active compounds were found to be nearly equally effective in field trials as well. In vitro bioassays were conducted to examine the acetylcholinesterase (AChE) inhibitory activity of 10 selected compounds. Results showed that there is a noticeable correlation between larvicidal activity and AChE inhibitory activity. In light of global efforts to find alternatives for currently used insecticides against disease vector mosquitoes, Pinus densiflora hydrodistillate and its constituents merit further research as potential mosquito larvicides.

  13. Laboratory and Simulated Field Bioassays to Evaluate Larvicidal Activity of Pinus densiflora Hydrodistillate, Its Constituents and Structurally Related Compounds against Aedes albopictus, Aedes aegypti and Culex pipiens pallens in Relation to Their Inhibitory Effects on Acetylcholinesterase Activity

    PubMed Central

    Lee, Dong Chan; Ahn, Young-Joon

    2013-01-01

    The toxicity of Pinus densiflora (red pine) hydrodistillate, its 19 constituents and 28 structurally related compounds against early third-instar larvae of Aedes albopictus (Ae. albopictus), Aedes aegypti (Ae. aegypti) and Culex pipiens palles (Cx. p. pallens) was examined using direct-contact bioassays. The efficacy of active compounds was further evaluated in semi-field bioassays using field-collected larval Cx. p. pallens. Results were compared with those of two synthetic larvicides, temephos and fenthion. In laboratory bioassays, Pinus densiflora hydrodistillate was found to have 24 h LC50 values of 20.33, 21.01 and 22.36 mg/L against larval Ae. albopictus, Ae. aegypti and Cx. p. pallens respectively. Among the identified compounds, thymol, δ-3-carene and (+)-limonene exhibited the highest toxicity against all three mosquito species. These active compounds were found to be nearly equally effective in field trials as well. In vitro bioassays were conducted to examine the acetylcholinesterase (AChE) inhibitory activity of 10 selected compounds. Results showed that there is a noticeable correlation between larvicidal activity and AChE inhibitory activity. In light of global efforts to find alternatives for currently used insecticides against disease vector mosquitoes, Pinus densiflora hydrodistillate and its constituents merit further research as potential mosquito larvicides. PMID:26464387

  14. Serum chemotactic inhibitory activity: heat activation of chemotactic inhibition.

    PubMed Central

    Epps, D E; Williams, R C

    1976-01-01

    Serum chemotactic inhibitory activity (CIA) was studied in 46 patients with various systemic diseases, using a system consisting of normal human leukocytes as indicator cells and 10% fresh normal serum as a control chemotactic attractant. It was shown, as previously reported, that an association exists between CIA and skin test anergy. Heat treatment of sera at 56 C for 30 min increased both the incidence and the degree of chemotactic inhibition observed in these patients. The effects of heat treatment of sera containing CIA on other chemotactic attractants (C3a, bacteria-derived chemotactic factor (BF), and casein) are shown. Before heat treatment, some sera suppressed chemotaxis mediated by BF in the absence of suppression of normal serum-mediated chemotaxis, indicating the possible involvement of more than one system of inhibition. Multiple systems were further supported by data indicating that room temperature incubation resulted in a loss of CIA as measured by normal serum-mediated chemotoxis with no apparent decrease in the inhibition of BF -mediated chemotaxis. Separation of sera containing CIA by Sephadex G-200 showed chemotactic inhibitory activity to be increased in both the void volume region. Experiments showed that heat treating before separation resulted in similar increases in both peaks, implying the presence of an antagonist to CIA. Experiments demonstrating that sera containing CIA do not suppress casein-mediated chemotaxis by means of an irreversible inactivation of chemotactic factor are included along with experiments demonstrating a cellular mode of action. The possible presence of two systems of chemotactic inhibition, one acting directly upon chemotactic factors and one interacting with the responding cell, are discussed. PMID:773824

  15. Xanthine oxidase inhibitory activity of Vietnamese medicinal plants.

    PubMed

    Nguyen, Mai Thanh Thi; Awale, Suresh; Tezuka, Yasuhiro; Tran, Quan Le; Watanabe, Hiroshi; Kadota, Shigetoshi

    2004-09-01

    Among 288 extracts, prepared from 96 medicinal plants used in Vietnamese traditional medicine to treat gout and related symptoms, 188 demonstrated xanthine oxidase (XO) inhibitory activity at 100 microg/ml, with 46 having greater than 50% inhibition. At 50 microg/ml, 168 of the extracts were active, with 21 possessing more than 50% inhibition. At 25 microg/ml, 146 extracts exhibited inhibitory activity, with 8 showing over 50% inhibition, while 126 extracts presented activity at 10 microg/ml, with 2 having greater than 50% inhibition. The MeOH extracts of Artemisia vulgaris, Caesalpinia sappan (collected at the Seven-Mountain area), Blumea balsamifera (collected in Lam Dong province), Chrysanthemum sinense and MeOH-H(2)O extract of Tetracera scandens (Khanh Hoa province) exhibited strong XO inhibitory activity with IC(50) values less than 20 microg/ml. The most active extract was the MeOH extract of the flower of C. sinense with an IC(50) value of 5.1 microg/ml. Activity-guided fractionation of the MeOH extract led to the isolation of caffeic acid (1), luteolin (2), eriodictyol (3), and 1,5-di-O-caffeoylquinic acid (4). All these compounds showed significant XO inhibitory activity in a concentration-dependent manner, and the activity of 2 was more potent (IC(50) 1.3 microM) than the clinically used drug, allopurinol (IC(50) 2.5 microM). PMID:15340229

  16. Acetylcholinesterase Inhibitory Activity of Pigment Echinochrome A from Sea Urchin Scaphechinus mirabilis

    PubMed Central

    Lee, Sung Ryul; Pronto, Julius Ryan D.; Sarankhuu, Bolor-Erdene; Ko, Kyung Soo; Rhee, Byoung Doo; Kim, Nari; Mishchenko, Natalia P.; Fedoreyev, Sergey A.; Stonik, Valentin A.; Han, Jin

    2014-01-01

    Echinochrome A (EchA) is a dark-red pigment of the polyhydroxynaphthoquinone class isolated from sea urchin Scaphechinus mirabilis. Acetylcholinesterase (AChE) inhibitors are used in the treatment of various neuromuscular disorders, and are considered as strong therapeutic agents for the treatment of Alzheimer’s disease (AD). Although EchA is clinically used to treat ophthalmic diseases and limit infarct formation during ischemia/reperfusion injury, anti-AChE effect of EchA is still unknown. In this study, we investigated the anti-AChE effect of EchA in vitro. EchA and its exhausted form which lost anti-oxidant capacity did not show any significant cytotoxicy on the H9c2 and A7r5 cells. EchA inhibited AChE with an irreversible and uncompetitive mode. In addition, EchA showed reactive oxygen species scavenging activity, particularly with nitric oxide. These findings indicate new therapeutic potential for EchA in treating reduced acetylcholine-related diseases including AD and provide an insight into developing new AChE inhibitors. PMID:24918454

  17. Decorrelation of Neural-Network Activity by Inhibitory Feedback

    PubMed Central

    Einevoll, Gaute T.; Diesmann, Markus

    2012-01-01

    Correlations in spike-train ensembles can seriously impair the encoding of information by their spatio-temporal structure. An inevitable source of correlation in finite neural networks is common presynaptic input to pairs of neurons. Recent studies demonstrate that spike correlations in recurrent neural networks are considerably smaller than expected based on the amount of shared presynaptic input. Here, we explain this observation by means of a linear network model and simulations of networks of leaky integrate-and-fire neurons. We show that inhibitory feedback efficiently suppresses pairwise correlations and, hence, population-rate fluctuations, thereby assigning inhibitory neurons the new role of active decorrelation. We quantify this decorrelation by comparing the responses of the intact recurrent network (feedback system) and systems where the statistics of the feedback channel is perturbed (feedforward system). Manipulations of the feedback statistics can lead to a significant increase in the power and coherence of the population response. In particular, neglecting correlations within the ensemble of feedback channels or between the external stimulus and the feedback amplifies population-rate fluctuations by orders of magnitude. The fluctuation suppression in homogeneous inhibitory networks is explained by a negative feedback loop in the one-dimensional dynamics of the compound activity. Similarly, a change of coordinates exposes an effective negative feedback loop in the compound dynamics of stable excitatory-inhibitory networks. The suppression of input correlations in finite networks is explained by the population averaged correlations in the linear network model: In purely inhibitory networks, shared-input correlations are canceled by negative spike-train correlations. In excitatory-inhibitory networks, spike-train correlations are typically positive. Here, the suppression of input correlations is not a result of the mere existence of correlations between

  18. Xanthine oxidase inhibitory activity of alkyl gallates.

    PubMed

    Masuoka, Noriyoshi; Nihei, Ken-ichi; Kubo, Isao

    2006-08-01

    A series (C1-C12) of alkyl gallates was examined for their effects on the activity of xanthine oxidase. Octyl (C8), decyl (C10), and dodecyl (C12) gallates competitively inhibited uric acid formation generated by xanthine oxidase, and the inhibition increased upon increasing the alkyl chain length. Interestingly, neither menthyl nor bornyl gallates inhibited uric acid formation. These data indicate that the hydrophobic alkyl portion is associated with the xanthine-binding site in the Mo-binding domain. It is likely that the linear alkyl portion interacts with the hydrophobic domain close to the binding site, and the hydrophobic interaction is crucial to inhibit the xanthine oxidase reaction. On the other hand, all of gallic acid and its esters equally suppress superoxide anion generation catalyzed by xanthine oxidase at low concentration. The suppression is not due to scavenging activity of these gallates but due to reduction of xanthine oxidase by these gallates. The reduced enzyme catalyzes the reaction to generate hydrogen peroxide and uric acid.

  19. IN VITRO ACETYLCHOLINESTERASE AND BUTYRYLCHOLINESTERASE INHIBITORY POTENTIALS OF JATROPHA GOSSYPIFOLIA PLANT EXTRACTS.

    PubMed

    Saleem, Hammad; Ahmad, Irshad; Shahid, Muhammad Nabeel; Gill, Muhammad Shoaib Ali; Nadeem, Muhammad Faisal; Mahmood, Waqas; Rashid, Imran

    2016-01-01

    Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), which breakdown acetylcholine and butyrylcholine, are considered as a promising strategy in the management of Alzheimer's disease (AD). Traditional accounts of indigenous plant Jatopha gossypyfolia suggest presence of important medicinal activities including improvement of memory functioning. To establish correlation of its use as anti-Alzheimer, AChE and BuChE inhibitory activity of extracts obtained from different parts of plant Jatropha gossypyfolia belonging to the family Euphorbiaceae were tested. Extracts from leaves, stem bark and roots were prepared by maceration. Enzyme inhibitory activity was carried out by using standard in vitro AChE and BuChE inhibition assays (Ellman's assay method) and the percentage inhibition was calculated. The results showed that roots dichloromethane fraction (65.43 ± 0.11), roots methanol fraction (62.79 ± 0.34) and leaves dichloromethane fraction (57.71 ± 0.15) showed significant acetylcholinesterase inhibitory activity compared to other fractions when compared with standard serine (91.29 ± 1.17). Similarly, butyrylcholinesterase enzyme inhibitory results showed that roots dichloromethane fraction (80.46 ± 0.44), JGLE (77.34 ± 0.34) showed significant BuChE enzyme inhibitory activity as compared to other fractions when compared with standard eserine (82.82 ± 1.09). Dichloromethane extracts showed higher enzyme inhibition comparatively. Highest AChE and BuChE inhibition was observed with leaf extracts of ethyl acetate fraction. In conclusion, the plant extracts exhibited presence of bioactive compounds with significant AChE and BuChE inhibition supporting traditional use of this herb in the management of AD. However, further investigation of the plant is required. PMID:27180434

  20. Analysis of AchE and LDH in mollusc, Lamellidens marginalis after exposure to chlorpyrifos.

    PubMed

    Amanullah, B; Stalin, A; Prabu, P; Dhanapal, S

    2010-07-01

    The enzymes Acetylcholinesterase (AchE) and Lactatedehydrogenase (LDH) are used as biological markers in the present study. Enzymes are highly sensitive and used to evaluate the biological effects of organophosphate pesticide chlorpyrifos in freshwater mussel Lamellidens marginalis. The test organisms were exposed to sub-lethal concentration (5 ppm) of chlorpyrifos for 30 days and allowed to recover for seven days. A distinct reduction of the enzyme AchE (34 +/- 3.3 U l(-1)) was found in the treated hepatopancreas. A significant increase in LDH activity in gill, hepatopancreas and muscle was observed. There was a significant recovery in AchE and LDH in the different tissues, after seven days recovery period.. Hence, the changes in the enzymes are found as the best biomarkering tool to evaluate the effect of organophosphate pesticide chlorpyrifos on the aquatic biota.

  1. Dihydroasparagusic acid: antioxidant and tyrosinase inhibitory activities and improved synthesis.

    PubMed

    Venditti, Alessandro; Mandrone, Manuela; Serrilli, Anna Maria; Bianco, Armandodoriano; Iannello, Carmelina; Poli, Ferruccio; Antognoni, Fabiana

    2013-07-17

    Dihydroasparagusic acid (DHAA) is the reduced form of asparagusic acid, a sulfur-containing flavor component produced by Asparagus plants. In this work, DHAA was synthetically produced by modifying some published protocols, and the synthesized molecule was tested in several in vitro assays (DPPH, ABTS, FRAP-ferrozine, BCB, deoxyribose assays) to evaluate its radical scavenging activity. Results show that DHAA is endowed with a significant in vitro antioxidant activity, comparable to that of Trolox. DHAA was also evaluated for its inhibitory activity toward tyrosinase, an enzyme involved, among others, in melanogenesis and in browning processes of plant-derived foods. DHAA was shown to exert an inhibitory effect on tyrosinase activity, and the inhibitor kinetics, analyzed by a Lineweaver-Burk plot, exhibited a competitive mechanism. Taken together, these results suggest that DHAA may be considered as a potentially active molecule for use in various fields of application, such as pharmaceutical, cosmetics, agronomic and food. PMID:23790134

  2. AChE biosensor based on zinc oxide sol-gel for the detection of pesticides.

    PubMed

    Sinha, Ravi; Ganesana, Mallikarjunarao; Andreescu, Silvana; Stanciu, Lia

    2010-02-28

    Zinc oxide has been used as a matrix for immobilization of acetylcholinesterase (AChE) and detection of the pesticide paraoxon. The immobilized enzyme retained its enzymatic activity up to three months when stored in phosphate buffered saline (pH 7.4) at 4 degrees C. An amperometric biosensor for the detection of paraoxon was designed. The biosensor detected paraoxon in the range 0.035-1.38 ppm and can be used to detect other AChE inhibiting organophosphate pesticides. PMID:20113735

  3. Insecticidal and Enzyme Inhibitory Activities of Sparassol and Its Analogues against Drosophila suzukii.

    PubMed

    Kim, Junheon; Jang, Miyeon; Lee, Kyoung-Tae; Yoon, Kyungjae Andrew; Park, Chung Gyoo

    2016-07-13

    Drosophila suzukii is an economically important pest in America and Europe as well as in Asia. Sparassol and methyl orsellinate are naturally produced by the cultivating mushrooms Sparassis cripta and Sparassis latifolia. Fumigant and contact toxicities of synthetic sparassol and its analogues, methyl orsellinate and methyl 2,4-dimethoxy-6-methylbenzoate (DMB), were investigated. Negligible fumigant activity was observed from the tested compounds. However, DMB showed the strongest contact toxicity, followed by sparassol and methyl orsellinate. The possible modes of action of the compounds were assessed for their acetylcholinesterase (AChE)- and glutathione S-transferase (GST)-inhibiting activities. AChE activity was weakly inhibited by methyl orsellinate and DMB, but GST was inhibited by sparassol, methyl orsellinate, and DMB. Thus, DMB could be a promising alternative to common insecticides as it can be easily synthesized from sparassol, which is the natural product of Sparassis species. Sparassis species could be an industrial resource of DMB. PMID:27327201

  4. Synthesis and inhibitory activity of ureidophosphonates, against acetylcholinesterase: pharmacological assay and molecular modeling.

    PubMed

    Kaboudin, Babak; Arefi, Marzban; Emadi, Saeed; Sheikh-Hasani, Vahid

    2012-01-01

    A novel method has been developed for the synthesis of 1-ureidophosphonates through a three components condensation of aldehyde with amine and diethylphosphite in the presence of sulfanilic acid as catalyst followed by subsequent reaction of the product with isocyanate. This method is easy, rapid, and good yielding. The anticholinesterase (AChE) activities (inhibition potency through IC(50)) of newly synthesized 1-ureidophosphonates were also investigated. The activities of the synthesized compounds toward the enzyme AChE were determined and compared in terms of their molecular structures and it was found, through molecular docking simulations, that the most potent derivative (compound 3i) inhibited the enzyme through binding to the peripheral anionic site (PAS) and not to its acylation site (A site).

  5. Phenolic compounds with IL-6 inhibitory activity from Aster yomena.

    PubMed

    Kim, A Ryun; Jin, Qinglong; Jin, Hong-Guang; Ko, Hae Ju; Woo, Eun-Rhan

    2014-07-01

    A new biflavonoid, named asteryomenin (1), as well as six known phenolic compounds, esculetin (2), 4-O-β-D-glucopyranoside-3-hydroxy methyl benzoate (3), caffeic acid (4), isoquercitrin (5), isorhamnetin-3-O-glucoside (6), and apigenin (7) were isolated from the aerial parts of Aster yomena. The structures of compounds (1-7) were identified based on 1D and 2D NMR, including (1)H-(1)H COSY, HSQC, HMBC and NOESY spectroscopic analyses. Compounds 2-7 were isolated from this plant for the first time. For these isolates, the inhibitory activity of IL-6 production in the TNF-α stimulated MG-63 cell was examined. Among these isolates, compounds 4 and 7 appeared to have potent inhibitory activity of IL-6 production in the TNF-α stimulated MG-63 cell, while compounds 1-3 and 5-6 showed moderate activity.

  6. Urease inhibitory activities of β-boswellic acid derivatives

    PubMed Central

    2013-01-01

    Background and the purpose of the study Boswellia carterii have been used in traditional medicine for many years for management different gastrointestinal disorders. In this study, we wish to report urease inhibitory activity of four isolated compound of boswellic acid derivative. Methods 4 pentacyclic triterpenoid acids were isolated from Boswellia carterii and identified by NMR and Mass spectroscopic analysis (compounds 1, 3-O-acetyl-9,11-dehydro-β-boswellic acid; 2, 3-O-acetyl-11-hydroxy-β-boswellic acid; 3. 3-O- acetyl-11-keto-β-boswellic acid and 4, 11-keto-β-boswellic acid. Their inhibitory activity on Jack bean urease were evaluated. Docking and pharmacophore analysis using AutoDock 4.2 and Ligandscout 3.03 programs were also performed to explain possible mechanism of interaction between isolated compounds and urease enzyme. Results It was found that compound 1 has the strongest inhibitory activity against Jack bean urease (IC50 = 6.27 ± 0.03 μM), compared with thiourea as a standard inhibitor (IC50 = 21.1 ± 0.3 μM). Conclusion The inhibition potency is probably due to the formation of appropriate hydrogen bonds and hydrophobic interactions between the investigated compounds and urease enzyme active site and confirms its traditional usage. PMID:23351363

  7. A novel isopimarane diterpenoid with acetylcholinesterase inhibitory activity from Nepeta sorgerae, an endemic species to the Nemrut Mountain.

    PubMed

    Yilmaz, Anil; Cağlar, Pinar; Dirmenci, Tuncay; Gören, Nezhun; Topçu, Gülaçti

    2012-06-01

    From the dichloromethane extract of Nepeta sorgerae, the isolation and structure elucidation are now reported of a new isopimarane diterpenoid, named sorgerolone, and two known triterpenoids, oleanolic acid and ursolic acid. Antioxidant activity of the extracts and the isolated terpenoids was determined by the DPPH free radical scavenging and lipid peroxidation inhibition (beta-carotene bleaching) methods. Anticholinesterase activity of the extracts and isolates was investigated by Ellman's method against AChE and BChE enzymes. Although the antioxidant activity results were low, the AChE enzyme inhibition of the extracts and terpenoids was very promising.

  8. A novel isopimarane diterpenoid with acetylcholinesterase inhibitory activity from Nepeta sorgerae, an endemic species to the Nemrut Mountain.

    PubMed

    Yilmaz, Anil; Cağlar, Pinar; Dirmenci, Tuncay; Gören, Nezhun; Topçu, Gülaçti

    2012-06-01

    From the dichloromethane extract of Nepeta sorgerae, the isolation and structure elucidation are now reported of a new isopimarane diterpenoid, named sorgerolone, and two known triterpenoids, oleanolic acid and ursolic acid. Antioxidant activity of the extracts and the isolated terpenoids was determined by the DPPH free radical scavenging and lipid peroxidation inhibition (beta-carotene bleaching) methods. Anticholinesterase activity of the extracts and isolates was investigated by Ellman's method against AChE and BChE enzymes. Although the antioxidant activity results were low, the AChE enzyme inhibition of the extracts and terpenoids was very promising. PMID:22816286

  9. Screening of siddha medicinal plants for its in-vitro acetylcholinesterase and butyrylcholinesterase inhibitory activity

    PubMed Central

    Kadiyala, Madhuri; Ponnusankar, Sivasankaran; Elango, Kannan

    2014-01-01

    Background: The plants selected for the study were traditionally used in siddha system of medicine in neurological disorders. Aim: The aim of the following study isto screen the plant species for both acetylcholinesterase (AchE) and butyrylcholinesterase (BuchE) inhibition by in-vitro Ellman's method and a thin layer chromatography bioautographic assay for newer drug candidates for the treatment of Alzheimer's disease. Materials and Methods: Ellman's colorimetric method was performed in a 96 well micro plate for cholinesterases inhibition using galantamine as standard drug. Results: Present studies confirmed that out of all the tested extracts Hemidesmus indicus R.Br (HI) showed considerable IC50 values for AchE (28.40 ± 0.92 μg/mL) and BuchE (43.47 ± 0.64 μg/mL) inhibition which indicates that HI extract has considerable specificity toward AchE and BuchE compared with all the tested extracts and the activity was followed by Vernonia anthelmintica (VA) Willd and Saussurea lappa Clarke (SL). The bioautograms also confirmed the activity potent extracts. Conclusion: Besides various bioactivities HI, VA and SL exhibited considerable cholinesterases inhibition making it to consider these species for further investigation of new compounds. PMID:24991106

  10. Potential xanthine oxidase inhibitory activity of endophytic Lasiodiplodia pseudotheobromae.

    PubMed

    Kapoor, Neha; Saxena, Sanjai

    2014-07-01

    Xanthine oxidase is considered as a potential target for treatment of hyperuricemia. Hyperuricemia is predisposing factor for gout, chronic heart failure, atherosclerosis, tissue injury, and ischemia. To date, only two inhibitors of xanthine oxidase viz. allopurinol and febuxostat have been clinically approved for used as drugs. In the process of searching for new xanthine oxidase inhibitors, we screened culture filtrates of 42 endophytic fungi using in vitro qualitative and quantitative XO inhibitory assays. The qualitative assay exhibited potential XO inhibition by culture filtrates of four isolates viz. #1048 AMSTITYEL, #2CCSTITD, #6AMLWLS, and #96 CMSTITNEY. The XO inhibitory activity was present only in the chloroform extract of the culture filtrates. Chloroform extract of culture filtrate #1048 AMSTITYEL exhibited the highest inhibition of XO with an IC50 value of 0.61 μg ml(-1) which was better than allopurinol exhibiting an IC50 of 0.937 μg ml(-1) while febuxostat exhibited a much lower IC50 of 0.076 μg ml(-1). Further, molecular phylogenetic tools and morphological studies were used to identify #1048 AMSTITYEL as Lasiodiplodia pseudotheobromae. This is the first report of an endophytic Lasiodiplodia pseudotheobromae from Aegle marmelos exhibiting potential XO Inhibitory activity.

  11. Histamine release inhibitory activity of Piper nigrum leaf.

    PubMed

    Hirata, Noriko; Naruto, Shunsuke; Inaba, Kazunori; Itoh, Kimihisa; Tokunaga, Masashi; Iinuma, Munekazu; Matsuda, Hideaki

    2008-10-01

    Oral administration of a methanolic extract of Piper nigrum leaf (PN-ext, 50, 200 and 500 mg/kg) showed a potent dose-dependent inhibition of dinitrofluorobenzene (DNFB)-induced cutaneous reaction at 1 h [immediate phase response (IPR)] after and 24 h [late phase response (LPR)] after DNFB challenge in mice which were passively sensitized with anti-dinitrophenyl (DNP) IgE antibody. Ear swelling inhibitory effect of PN-ext (50, 200 and 500 mg/kg, per os (p.o.)) on very late phase response (vLPR) in the model mice was significant but weaker than that on IPR. Oral administration of PN-ext (50, 200 and 500 mg/kg for 7 d) inhibited picryl chloride (PC)-induced ear swelling in PC sensitized mice. PN-ext exhibited in vitro inhibitory effect on compound 48/80-induced histamine release from rat peritoneal mast cells. Two lignans of PN-ext, (-)-cubebin (1) and (-)-3,4-dimethoxy-3,4-desmethylenedioxycubebin (2), were identified as major active principles having histamine release inhibitory activity.

  12. Potential xanthine oxidase inhibitory activity of endophytic Lasiodiplodia pseudotheobromae.

    PubMed

    Kapoor, Neha; Saxena, Sanjai

    2014-07-01

    Xanthine oxidase is considered as a potential target for treatment of hyperuricemia. Hyperuricemia is predisposing factor for gout, chronic heart failure, atherosclerosis, tissue injury, and ischemia. To date, only two inhibitors of xanthine oxidase viz. allopurinol and febuxostat have been clinically approved for used as drugs. In the process of searching for new xanthine oxidase inhibitors, we screened culture filtrates of 42 endophytic fungi using in vitro qualitative and quantitative XO inhibitory assays. The qualitative assay exhibited potential XO inhibition by culture filtrates of four isolates viz. #1048 AMSTITYEL, #2CCSTITD, #6AMLWLS, and #96 CMSTITNEY. The XO inhibitory activity was present only in the chloroform extract of the culture filtrates. Chloroform extract of culture filtrate #1048 AMSTITYEL exhibited the highest inhibition of XO with an IC50 value of 0.61 μg ml(-1) which was better than allopurinol exhibiting an IC50 of 0.937 μg ml(-1) while febuxostat exhibited a much lower IC50 of 0.076 μg ml(-1). Further, molecular phylogenetic tools and morphological studies were used to identify #1048 AMSTITYEL as Lasiodiplodia pseudotheobromae. This is the first report of an endophytic Lasiodiplodia pseudotheobromae from Aegle marmelos exhibiting potential XO Inhibitory activity. PMID:24801403

  13. The dual-acting H3 receptor antagonist and AChE inhibitor UW-MD-71 dose-dependently enhances memory retrieval and reverses dizocilpine-induced memory impairment in rats.

    PubMed

    Khan, Nadia; Saad, Ali; Nurulain, Syed M; Darras, Fouad H; Decker, Michael; Sadek, Bassem

    2016-01-15

    Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual

  14. Altered GPI modification of insect AChE improves tolerance to organophosphate insecticides.

    PubMed

    Kakani, Evdoxia G; Bon, Suzanne; Massoulié, Jean; Mathiopoulos, Kostas D

    2011-03-01

    The olive fruit fly Bactrocera oleae is the most destructive and intractable pest of olives. The management of B. oleae has been based on the use of organophosphate (OP) insecticides, a practice that induced resistance. OP-resistance in the olive fly was previously shown to be associated with two mutations in the acetylcholinesterase (AChE) enzyme that, apparently, hinder the entrance of the OP into the active site. The search for additional mutations in the ace gene that encodes AChE revealed a short deletion of three glutamines (Δ3Q) from a stretch of five glutamines, in the C-terminal peptide that is normally cleaved and substituted by a GPI anchor. We verified that AChEs from B. oleae and other Dipterans are actually GPI-anchored, although this is not predicted by the "big-PI" algorithm. The Δ3Q mutation shortens the unusually long hydrophilic spacer that follows the predicted GPI attachment site and may thus improve the efficiency of GPI anchor addition. We expressed the wild type B. oleae AChE, the natural mutant Δ3Q and a constructed mutant lacking all 5 consecutive glutamines (Δ5Q) in COS cells and compared their kinetic properties. All constructs presented identical K(m) and k(cat) values, in agreement with the fact that the mutations did not affect the catalytic domain of the enzyme. In contrast, the mutants produced higher AChE activity, suggesting that a higher proportion of the precursor protein becomes GPI-anchored. An increase in the number of GPI-anchored molecules in the synaptic cleft may reduce the sensitivity to insecticides.

  15. Angiotensin-converting enzyme inhibitory activity in Mexican Fresco cheese.

    PubMed

    Torres-Llanez, M J; González-Córdova, A F; Hernandez-Mendoza, A; Garcia, H S; Vallejo-Cordoba, B

    2011-08-01

    The objective of this study was to evaluate if Mexican Fresco cheese manufactured with specific lactic acid bacteria (LAB) presented angiotensin I-converting enzyme inhibitory (ACEI) activity. Water-soluble extracts (3 kDa) obtained from Mexican Fresco cheese prepared with specific LAB (Lactococcus, Lactobacillus, Enterococcus, and mixtures: Lactococcus-Lactobacillus and Lactococcus-Enterococcus) were evaluated for ACEI activity. Specific peptide fractions with high ACEI were analyzed using reverse phase-HPLC coupled to mass spectrometry for determination of amino acid sequence. Cheese containing Enterococcus faecium or a Lactococcus lactis ssp. lactis-Enterococcus faecium mixture showed the largest number of fractions with ACEI activity and the lowest half-maximal inhibitory concentration (IC(50); <10 μg/mL). Various ACEI peptides derived from β-casein [(f(193-205), f(193-207), and f(193-209)] and α(S1)-casein [f(1-15), f(1-22), f(14-23), and f(24-34)] were found. The Mexican Fresco cheese manufactured with specific LAB strains produced peptides with potential antihypertensive activity.

  16. Xanthine oxidase inhibitory activity of extracts prepared from Polygonaceae species.

    PubMed

    Orbán-Gyapai, Orsolya; Lajter, Ildikó; Hohmann, Judit; Jakab, Gusztáv; Vasas, Andrea

    2015-03-01

    The xanthine oxidase (XO) inhibitory activity of aqueous and organic extracts of 27 selected species belonging in five genera (Fallopia, Oxyria, Persicaria, Polygonum and Rumex) of the family Polygonaceae occurring in the Carpathian Basin were tested in vitro. From different plant parts (aerial parts, leaves, flowers, fruits and roots), a total of 196 extracts were prepared by subsequent extraction with methanol and hot H2O and solvent-solvent partition of the MeOH extract yielding n-hexane, chloroform and 50% MeOH subextracts. It was found that the chloroform subextracts and/or the remaining 50% MeOH extracts of Fallopia species (F. bohemica, F. japonica and F. sachalinensis), Rumex species (R. acetosa, R. acetosella, R. alpinus, R. conglomeratus, R. crispus, R. hydrolapathus, R. pulcher, R. stenophyllus, R. thyrsiflorus, R. obtusifolius subsp. subalpinus, R. patientia) and Polygonum bistorta, Polygonum hydropiper, Polygonum lapathifolium and Polygonum viviparum demonstrated the highest XO inhibitory activity (>85% inhibition) at 400 µg/mL. The IC50 values of the active extracts were also determined. On the basis of the results, these plants, and especially P. hydropiper and R. acetosella, are considered worthy of activity-guided phytochemical investigations.

  17. Chlorpyrifos and Chlorpyrifos-Oxon Inhibit Axonal Growth by Interfering with the Morphogenic Activity of Acetylcholinesterase

    PubMed Central

    Yang, Dongren; Howard, Angela; Bruun, Donald; Ajua-Alemanj, Mispa; Pickart, Cecile; Lein, Pamela J.

    2008-01-01

    A primary role of acetylcholinesterase (AChE) is regulation of cholinergic neurotransmission by hydrolysis of synaptic acetylcholine. In the developing nervous system, however, AChE also functions as a morphogenic factor to promote axonal growth. This raises the question of whether organophosphorus pesticides (OPs) that are known to selectively bind to and inactivate the enzymatic function of AChE also interfere with its morphogenic function to perturb axonogenesis. To test this hypothesis, we exposed primary cultures of sensory neurons derived from embryonic rat dorsal root ganglia (DRG) to chlorpyrifos (CPF) or its oxon metabolite (CPFO). Both OPs significantly decreased axonal length at concentrations that had no effect on cell viability, protein synthesis or the enzymatic activity of AChE. Comparative analyses of the effects of CPF and CPFO on axonal growth in DRG neurons cultured from AChE nullizygous (AChE−/−) versus wildtype (AChE+/+) mice indicated that while these OPs inhibited axonal growth in AChE+/+ DRG neurons, they had no effect on axonal growth in AChE−/− DRG neurons. However, transfection of AChE−/− DRG neurons with cDNA encoding full-length AChE restored the wildtype response to the axon inhibitory effects of OPs. These data indicate that inhibition of axonal growth by OPs requires AChE, but the mechanism involves inhibition of the morphogenic rather than enzymatic activity of AChE. These findings suggest a novel mechanism for explaining not only the functional deficits observed in children and animals following developmental exposure to OPs, but also the increased vulnerability of the developing nervous system to OPs. PMID:18076960

  18. A Mechanism-based 3D-QSAR Approach for Classification and Prediction of Acetylcholinesterase Inhibitory Potency of Organophosphate and Carbamate Analogs

    EPA Science Inventory

    Organophosphate (OP) and carbamate esters can inhibit acetylcholinesterase (AChE) by binding covalently to a serine residue in the enzyme active site, and their inhibitory potency depends largely on affinity for the enzyme and the reactivity of the ester. Despite this understandi...

  19. Design, Synthesis and Inhibitory Activity of Photoswitchable RET Kinase Inhibitors

    NASA Astrophysics Data System (ADS)

    Ferreira, Rubén; Nilsson, Jesper R.; Solano, Carlos; Andréasson, Joakim; Grøtli, Morten

    2015-05-01

    REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase required for normal development and maintenance of neurons of the central and peripheral nervous systems. Deregulation of RET and hyperactivity of the RET kinase is intimately connected to several types of human cancers, most notably thyroid cancers, making it an attractive therapeutic target for small-molecule kinase inhibitors. Novel approaches, allowing external control of the activity of RET, would be key additions to the signal transduction toolbox. In this work, photoswitchable RET kinase inhibitors based on azo-functionalized pyrazolopyrimidines were developed, enabling photonic control of RET activity. The most promising compound displays excellent switching properties and stability with good inhibitory effect towards RET in cell-free as well as live-cell assays and a significant difference in inhibitory activity between its two photoisomeric forms. As the first reported photoswitchable small-molecule kinase inhibitor, we consider the herein presented effector to be a significant step forward in the development of tools for kinase signal transduction studies with spatiotemporal control over inhibitor concentration in situ.

  20. Xanthine oxidase inhibitory activity of some Indian medical plants.

    PubMed

    Umamaheswari, Muthuswamy; AsokKumar, Kuppusamy; Somasundaram, Arumugam; Sivashanmugam, Thirumalaisamy; Subhadradevi, Varadharajan; Ravi, Thenvungal Kochupapy

    2007-02-12

    Xanthine oxidase inhibitory activity was assayed from six species belonging to different families traditionally used for the treatment of gout and related symptoms by indigenous people of India. The aqueous, methanol-water mixture and methanolic extract of these plants were used for the experiment. Of the 18 extracts assayed, 14 extracts demonstrated xanthine oxidase inhibitory activity at 100 microg/ml, among which 10 extracts showed an inhibition greater than 50% and IC(50) values below 100 microg/ml. The methanolic extracts of Coccinia grandis, Datura metel, Strychnos nux-vomica and Vitex negundo showed more than 50% inhibition, hence, they were screened for their in vivo hypouricaemic activity against potassium oxonate-induced hyperuricaemia in mice. Methanolic extracts of Coccinia grandis and Vitex negundo showed a significant decrease in the serum urate level (3.90+/-0.07 mg/dl, P<0.001) and (6.26+/-0.06 mg/dl, P<0.01), respectively, when compared to hyperuricaemic control (11.42+/-0.14 mg/dl). This effect is almost similar to the serum urate level of allopurinol (3.89+/-0.07 mg/dl).

  1. Design, Synthesis and Inhibitory Activity of Photoswitchable RET Kinase Inhibitors

    PubMed Central

    Ferreira, Rubén; Nilsson, Jesper R.; Solano, Carlos; Andréasson, Joakim; Grøtli, Morten

    2015-01-01

    REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase required for normal development and maintenance of neurons of the central and peripheral nervous systems. Deregulation of RET and hyperactivity of the RET kinase is intimately connected to several types of human cancers, most notably thyroid cancers, making it an attractive therapeutic target for small-molecule kinase inhibitors. Novel approaches, allowing external control of the activity of RET, would be key additions to the signal transduction toolbox. In this work, photoswitchable RET kinase inhibitors based on azo-functionalized pyrazolopyrimidines were developed, enabling photonic control of RET activity. The most promising compound displays excellent switching properties and stability with good inhibitory effect towards RET in cell-free as well as live-cell assays and a significant difference in inhibitory activity between its two photoisomeric forms. As the first reported photoswitchable small-molecule kinase inhibitor, we consider the herein presented effector to be a significant step forward in the development of tools for kinase signal transduction studies with spatiotemporal control over inhibitor concentration in situ. PMID:25944708

  2. Origin of aromatase inhibitory activity via proteochemometric modeling.

    PubMed

    Simeon, Saw; Spjuth, Ola; Lapins, Maris; Nabu, Sunanta; Anuwongcharoen, Nuttapat; Prachayasittikul, Virapong; Wikberg, Jarl E S; Nantasenamat, Chanin

    2016-01-01

    Aromatase, the rate-limiting enzyme that catalyzes the conversion of androgen to estrogen, plays an essential role in the development of estrogen-dependent breast cancer. Side effects due to aromatase inhibitors (AIs) necessitate the pursuit of novel inhibitor candidates with high selectivity, lower toxicity and increased potency. Designing a novel therapeutic agent against aromatase could be achieved computationally by means of ligand-based and structure-based methods. For over a decade, we have utilized both approaches to design potential AIs for which quantitative structure-activity relationships and molecular docking were used to explore inhibitory mechanisms of AIs towards aromatase. However, such approaches do not consider the effects that aromatase variants have on different AIs. In this study, proteochemometrics modeling was applied to analyze the interaction space between AIs and aromatase variants as a function of their substructural and amino acid features. Good predictive performance was achieved, as rigorously verified by 10-fold cross-validation, external validation, leave-one-compound-out cross-validation, leave-one-protein-out cross-validation and Y-scrambling tests. The investigations presented herein provide important insights into the mechanisms of aromatase inhibitory activity that could aid in the design of novel potent AIs as breast cancer therapeutic agents. PMID:27190705

  3. Origin of aromatase inhibitory activity via proteochemometric modeling

    PubMed Central

    Simeon, Saw; Spjuth, Ola; Lapins, Maris; Nabu, Sunanta; Anuwongcharoen, Nuttapat; Prachayasittikul, Virapong; Wikberg, Jarl E.S.

    2016-01-01

    Aromatase, the rate-limiting enzyme that catalyzes the conversion of androgen to estrogen, plays an essential role in the development of estrogen-dependent breast cancer. Side effects due to aromatase inhibitors (AIs) necessitate the pursuit of novel inhibitor candidates with high selectivity, lower toxicity and increased potency. Designing a novel therapeutic agent against aromatase could be achieved computationally by means of ligand-based and structure-based methods. For over a decade, we have utilized both approaches to design potential AIs for which quantitative structure–activity relationships and molecular docking were used to explore inhibitory mechanisms of AIs towards aromatase. However, such approaches do not consider the effects that aromatase variants have on different AIs. In this study, proteochemometrics modeling was applied to analyze the interaction space between AIs and aromatase variants as a function of their substructural and amino acid features. Good predictive performance was achieved, as rigorously verified by 10-fold cross-validation, external validation, leave-one-compound-out cross-validation, leave-one-protein-out cross-validation and Y-scrambling tests. The investigations presented herein provide important insights into the mechanisms of aromatase inhibitory activity that could aid in the design of novel potent AIs as breast cancer therapeutic agents. PMID:27190705

  4. Origin of aromatase inhibitory activity via proteochemometric modeling.

    PubMed

    Simeon, Saw; Spjuth, Ola; Lapins, Maris; Nabu, Sunanta; Anuwongcharoen, Nuttapat; Prachayasittikul, Virapong; Wikberg, Jarl E S; Nantasenamat, Chanin

    2016-01-01

    Aromatase, the rate-limiting enzyme that catalyzes the conversion of androgen to estrogen, plays an essential role in the development of estrogen-dependent breast cancer. Side effects due to aromatase inhibitors (AIs) necessitate the pursuit of novel inhibitor candidates with high selectivity, lower toxicity and increased potency. Designing a novel therapeutic agent against aromatase could be achieved computationally by means of ligand-based and structure-based methods. For over a decade, we have utilized both approaches to design potential AIs for which quantitative structure-activity relationships and molecular docking were used to explore inhibitory mechanisms of AIs towards aromatase. However, such approaches do not consider the effects that aromatase variants have on different AIs. In this study, proteochemometrics modeling was applied to analyze the interaction space between AIs and aromatase variants as a function of their substructural and amino acid features. Good predictive performance was achieved, as rigorously verified by 10-fold cross-validation, external validation, leave-one-compound-out cross-validation, leave-one-protein-out cross-validation and Y-scrambling tests. The investigations presented herein provide important insights into the mechanisms of aromatase inhibitory activity that could aid in the design of novel potent AIs as breast cancer therapeutic agents.

  5. Xanthine oxidase inhibitory activity of Lychnophora species from Brazil ("Arnica").

    PubMed

    Filha, Z S Ferraz; Vitolo, I F; Fietto, L G; Lombardi, J A; Saúde-Guimarães, D A

    2006-08-11

    Twenty-two extracts from five Lychnophora species and one Lychnophoriopsis species, traditionally used in Brazil as analgesic, anti-inflammatory, and to treat bruise and rheumatism were examined for the inhibition of xanthine oxidase (XO), the enzyme that catalyses the metabolism of hypoxanthine and xanthine into uric acid. Sixteen extracts were tested. All of them were found to have excellent XO inhibitory activity, with inhibitions greater than 38% at 100 microg/mL in the assay mixture. The most active plants examined were Lychnophora trichocarpha, Lychnophora ericoides, Lychnophora staavioides and Lychnophoriopsis candelabrum, with inhibitions of 77%, 78%, 66% and 63% at 100 microg/mL, respectively, and IC(50) values of 6.16, 8.28, 33.97 and 37.70 microg/mL, respectively.

  6. Average activity of excitatory and inhibitory neural populations

    NASA Astrophysics Data System (ADS)

    Roulet, Javier; Mindlin, Gabriel B.

    2016-09-01

    We develop an extension of the Ott-Antonsen method [E. Ott and T. M. Antonsen, Chaos 18(3), 037113 (2008)] that allows obtaining the mean activity (spiking rate) of a population of excitable units. By means of the Ott-Antonsen method, equations for the dynamics of the order parameters of coupled excitatory and inhibitory populations of excitable units are obtained, and their mean activities are computed. Two different excitable systems are studied: Adler units and theta neurons. The resulting bifurcation diagrams are compared with those obtained from studying the phenomenological Wilson-Cowan model in some regions of the parameter space. Compatible behaviors, as well as higher dimensional chaotic solutions, are observed. We study numerical simulations to further validate the equations.

  7. Aldose reductase inhibitory activity of compounds from Zea mays L.

    PubMed

    Kim, Tae Hyeon; Kim, Jin Kyu; Kang, Young-Hee; Lee, Jae-Yong; Kang, Il Jun; Lim, Soon Sung

    2013-01-01

    Aldose reductase (AR) inhibitors have a considerable therapeutic potential against diabetes complications and do not increase the risk of hypoglycemia. Through bioassay-guided fractionation of an EtOH extract of the kernel from purple corn (Zea mays L.), 7 nonanthocyanin phenolic compounds (compound 1-7) and 5 anthocyanins (compound 8-12) were isolated. These compounds were investigated by rat lens aldose reductase (RLAR) inhibitory assays. Kinetic analyses of recombinant human aldose reductase (rhAR) were performed, and intracellular galactitol levels were measured. Hirsutrin, one of 12 isolated compounds, showed the most potent RLAR inhibitory activity (IC(50), 4.78 μ M). In the kinetic analyses using Lineweaver-Burk plots of 1/velocity and 1/substrate concentration, hirsutrin showed competitive inhibition against rhAR. Furthermore, hirsutrin inhibited galactitol formation in rat lens and erythrocytes sample incubated with a high concentration of galactose; this finding indicates that hirsutrin may effectively prevent osmotic stress in hyperglycemia. Therefore, hirsutrin derived from Zea mays L. may be a potential therapeutic agent against diabetes complications. PMID:23586057

  8. Acetylcholinesterase (AChE) gene modification in transgenic animals: functional consequences of selected exon and regulatory region deletion.

    PubMed

    Camp, Shelley; Zhang, Limin; Marquez, Michael; de la Torre, Brian; Long, Jeffery M; Bucht, Goran; Taylor, Palmer

    2005-12-15

    . delaTorre, P. Taylor, Knockout mice with deletions of alternatively spliced exons of Acetylcholinesterase, in: N.C. Inestrosa, E.O. Campus (Eds.), VII International Meeting on Cholinesterases, Pucon-Chile Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects. P. Universidad Catholica de Chile-FONDAP Biomedicina, 2004, pp. 43-48; R.Y.Y. Chan, C. Boudreau-Larivière, L.A. Angus, F. Mankal, B.J. Jasmin, An intronic enhancer containing an N-box motif is required for synapse- and tissue-specific expression of the acetylcholinesterase gene in skeletal muscle fibers. Proc. Natl. Acad. Sci. USA 96 (1999) 4627-4632], is also presented. The intronic region was floxed and then deleted by mating with Ella-cre transgenic mice. The deletion of this region produced a dramatic phenotype; a mouse with near normal AChE expression in brain and other CNS tissues, but no AChE expression in muscle. Phenotype and AChE tissue activities are compared with the total AChE knockout mouse [W. Xie, J.A. Chatonnet, P.J. Wilder, A. Rizzino, R.D. McComb, P. Taylor, S.H. Hinrichs, O. Lockridge, Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase. J. Pharmacol. Exp. Ther. 293 (3) (2000) 896-902].

  9. Predicting Monoamine Oxidase Inhibitory Activity through Ligand-Based Models

    PubMed Central

    Vilar, Santiago; Ferino, Giulio; Quezada, Elias; Santana, Lourdes; Friedman, Carol

    2013-01-01

    The evolution of bio- and cheminformatics associated with the development of specialized software and increasing computer power has produced a great interest in theoretical in silico methods applied in drug rational design. These techniques apply the concept that “similar molecules have similar biological properties” that has been exploited in Medicinal Chemistry for years to design new molecules with desirable pharmacological profiles. Ligand-based methods are not dependent on receptor structural data and take into account two and three-dimensional molecular properties to assess similarity of new compounds in regards to the set of molecules with the biological property under study. Depending on the complexity of the calculation, there are different types of ligand-based methods, such as QSAR (Quantitative Structure-Activity Relationship) with 2D and 3D descriptors, CoMFA (Comparative Molecular Field Analysis) or pharmacophoric approaches. This work provides a description of a series of ligand-based models applied in the prediction of the inhibitory activity of monoamine oxidase (MAO) enzymes. The controlled regulation of the enzymes’ function through the use of MAO inhibitors is used as a treatment in many psychiatric and neurological disorders, such as depression, anxiety, Alzheimer’s and Parkinson’s disease. For this reason, multiple scaffolds, such as substituted coumarins, indolylmethylamine or pyridazine derivatives were synthesized and assayed toward MAO-A and MAO-B inhibition. Our intention is to focus on the description of ligand-based models to provide new insights in the relationship between the MAO inhibitory activity and the molecular structure of the different inhibitors, and further study enzyme selectivity and possible mechanisms of action. PMID:23231398

  10. Native New Zealand plants with inhibitory activity towards Mycobacterium tuberculosis

    PubMed Central

    2010-01-01

    Background Plants have long been investigated as a source of antibiotics and other bioactives for the treatment of human disease. New Zealand contains a diverse and unique flora, however, few of its endemic plants have been used to treat tuberculosis. One plant, Laurelia novae-zelandiae, was reportedly used by indigenous Maori for the treatment of tubercular lesions. Methods Laurelia novae-zelandiae and 44 other native plants were tested for direct anti-bacterial activity. Plants were extracted with different solvents and extracts screened for inhibition of the surrogate species, Mycobacterium smegmatis. Active plant samples were then tested for bacteriostatic activity towards M. tuberculosis and other clinically-important species. Results Extracts of six native plants were active against M. smegmatis. Many of these were also inhibitory towards M. tuberculosis including Laurelia novae-zelandiae (Pukatea). M. excelsa (Pohutukawa) was the only plant extract tested that was active against Staphylococcus aureus. Conclusions Our data provide support for the traditional use of Pukatea in treating tuberculosis. In addition, our analyses indicate that other native plant species possess antibiotic activity. PMID:20537175

  11. Inhibitory neurotransmission regulates vagal efferent activity and gastric motility.

    PubMed

    McMenamin, Caitlin A; Travagli, R Alberto; Browning, Kirsteen N

    2016-06-01

    The gastrointestinal tract receives extrinsic innervation from both the sympathetic and parasympathetic nervous systems, which regulate and modulate the function of the intrinsic (enteric) nervous system. The stomach and upper gastrointestinal tract in particular are heavily influenced by the parasympathetic nervous system, supplied by the vagus nerve, and disruption of vagal sensory or motor functions results in disorganized motility patterns, disrupted receptive relaxation and accommodation, and delayed gastric emptying, amongst others. Studies from several laboratories have shown that the activity of vagal efferent motoneurons innervating the upper GI tract is inhibited tonically by GABAergic synaptic inputs from the adjacent nucleus tractus solitarius. Disruption of this influential central GABA input impacts vagal efferent output, hence gastric functions, significantly. The purpose of this review is to describe the development, physiology, and pathophysiology of this functionally dominant inhibitory synapse and its role in regulating vagally determined gastric functions. PMID:27302177

  12. Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver.

    PubMed

    Yokota, Shin-Ichi; Nakamura, Kaai; Ando, Midori; Kamei, Hiroyasu; Hakuno, Fumihiko; Takahashi, Shin-Ichiro; Shibata, Shigenobu

    2014-01-01

    Although fasting induces hepatic triglyceride (TG) accumulation in both rodents and humans, little is known about the underlying mechanism. Because parasympathetic nervous system activity tends to attenuate the secretion of very-low-density-lipoprotein-triglyceride (VLDL-TG) and increase TG stores in the liver, and serum cholinesterase activity is elevated in fatty liver disease, the inhibition of the parasympathetic neurotransmitter acetylcholinesterase (AChE) may have some influence on hepatic lipid metabolism. To assess the influence of AChE inhibition on lipid metabolism, the effect of physostigmine, an AChE inhibitor, on fasting-induced increase in liver TG was investigated in mice. In comparison with ad libitum-fed mice, 30 h fasting increased liver TG accumulation accompanied by a downregulation of sterol regulatory element-binding protein 1 (SREBP-1) and liver-fatty acid binding-protein (L-FABP). Physostigmine promoted the 30 h fasting-induced increase in liver TG levels in a dose-dependent manner, accompanied by a significant fall in plasma insulin levels, without a fall in plasma TG. Furthermore, physostigmine significantly attenuated the fasting-induced decrease of both mRNA and protein levels of SREBP-1 and L-FABP, and increased IRS-2 protein levels in the liver. The muscarinic receptor antagonist atropine blocked these effects of physostigmine on liver TG, serum insulin, and hepatic protein levels of SREBP-1 and L-FABP. These results demonstrate that AChE inhibition facilitated fasting-induced TG accumulation with up regulation of the hepatic L-FABP and SREBP-1 in mice, at least in part via the activation of muscarinic acetylcholine receptors. Our studies highlight the crucial role of parasympathetic regulation in fasting-induced TG accumulation, and may be an important source of information on the mechanism of hepatic disorders of lipid metabolism. PMID:25383314

  13. Acetylcholinesterase (AChE) is an important link in the apoptotic pathway induced by hyperglycemia in Y79 retinoblastoma cell line

    PubMed Central

    Masha'our, R. Shehadeh; Heinrich, R.; Garzozi, H. J.; Perlman, I.

    2012-01-01

    Acetylcholinesterase (AChE) expression was found to be induced in the mammalian CNS, including the retina, by different types of stress leading to cellular apoptosis. Here, we tested possible involvement of AChE in hyperglycemia-induced apoptosis in a retinal cell line. Y79 retinoblastoma cells were incubated in starvation media (1% FBS and 1 mg/ml glucose) for 16–24 h, and then exposed to hyperglycemic environment by raising extracellular glucose concentrations to a final level of 3.5 mg/ml or 6 mg/ml. Similar levels of mannitol were used as control for hyperosmolarity. Cells were harvested at different time intervals for analysis of apoptosis and AChE protein expression. Apoptosis was detected by the cleavage of Poly ADP-ribose polymerase (PARP) using western blot, and by Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end-labeling (TUNEL) assay. AChE protein expression and activity was detected by western blot and by the Karnovsky and Roots method, respectively. MissionTM shRNA for AChE was used to inhibit AChE protein expression. Treating Y79 cells with 3.5 mg/ml of glucose, but not with 3.5 mg/ml mannitol, induced apoptosis which was confirmed by TUNEL assay and by cleavage of PARP. A part of the signaling pathway accompanying the apoptotic process involved up-regulation of the AChE-R variant and an N-extended AChE variant as verified at the mRNA and protein level. Inhibition of AChE protein expression by shRNA protected Y79 cell from entering the apoptotic pathway. Our data suggest that expression of an N-extended AChE variant, most probably an R isoform, is involved in the apoptotic pathway caused by hyperglycemia in Y79 cells. PMID:22685426

  14. Acetylcholinesterase (AChE) is an important link in the apoptotic pathway induced by hyperglycemia in Y79 retinoblastoma cell line.

    PubMed

    Masha'our, R Shehadeh; Heinrich, R; Garzozi, H J; Perlman, I

    2012-01-01

    Acetylcholinesterase (AChE) expression was found to be induced in the mammalian CNS, including the retina, by different types of stress leading to cellular apoptosis. Here, we tested possible involvement of AChE in hyperglycemia-induced apoptosis in a retinal cell line. Y79 retinoblastoma cells were incubated in starvation media (1% FBS and 1 mg/ml glucose) for 16-24 h, and then exposed to hyperglycemic environment by raising extracellular glucose concentrations to a final level of 3.5 mg/ml or 6 mg/ml. Similar levels of mannitol were used as control for hyperosmolarity. Cells were harvested at different time intervals for analysis of apoptosis and AChE protein expression. Apoptosis was detected by the cleavage of Poly ADP-ribose polymerase (PARP) using western blot, and by Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end-labeling (TUNEL) assay. AChE protein expression and activity was detected by western blot and by the Karnovsky and Roots method, respectively. Mission(TM) shRNA for AChE was used to inhibit AChE protein expression. Treating Y79 cells with 3.5 mg/ml of glucose, but not with 3.5 mg/ml mannitol, induced apoptosis which was confirmed by TUNEL assay and by cleavage of PARP. A part of the signaling pathway accompanying the apoptotic process involved up-regulation of the AChE-R variant and an N-extended AChE variant as verified at the mRNA and protein level. Inhibition of AChE protein expression by shRNA protected Y79 cell from entering the apoptotic pathway. Our data suggest that expression of an N-extended AChE variant, most probably an R isoform, is involved in the apoptotic pathway caused by hyperglycemia in Y79 cells. PMID:22685426

  15. Comparative study on short- and long-term behavioral consequences of organophosphate exposure: relationship to AChE mRNA expression.

    PubMed

    López-Granero, Caridad; Cardona, Diana; Giménez, Estela; Lozano, Rafael; Barril, José; Aschner, Michael; Sánchez-Santed, Fernando; Cañadas, Fernando

    2014-01-01

    Organophosphates (OPs) affect behavior by inhibiting acetylcholinesterase (AChE). While the cognitive short-term effects may be directly attributed to this inhibition, the mechanisms that underlie OP's long-term cognitive effects remain controversial and poorly understood. Accordingly, two experiments were designed to assess the effects of OPs on cognition, and to ascertain whether both the short- and long-term effects of are AChE-dependent. A single subcutaneous dose of 250 mg/kg chlorpyrifos (CPF), 1.5mg/kg diisopropylphosphorofluoridate (DFP) or 15 mg/kg parathion (PTN) was administered to male Wistar rats. Spatial learning was evaluated 72 h or 23 weeks after exposure, and impulsive choice was tested at 10 and 30 weeks following OPs administration (experiment 1 and 2, respectively). Brain soluble and membrane-bound AChE activity, synaptic AChE-S mRNA, read-through AChE-R mRNA and brain acylpeptide hydrolase (APH) activity (as alternative non-cholinergic target) were analyzed upon completion of the behavioral testing (17 and 37 weeks after OPs exposure). Both short- and long-term CPF treatment caused statistically significant effects on spatial learning, while PTN treatment led only to statistically significant short-term effects. Neither CPF, DFP nor PTN affected the long-term impulsivity response. Long-term exposure to CPF and DFP significantly decreased AChE-S and AChE-R mRNA, while in the PTN treated group only AChE-S mRNA levels were decreased. However, after long-term OP exposure, soluble and membrane-bound AChE activity was indistinguishable from controls. Finally, no changes were noted in brain APH activity in response to OP treatment. Taken together, this study demonstrates long-term effects of OPs on AChE-S and AChE-R mRNA in the absence of changes in AChE soluble and membrane-bound activity. Thus, changes in AChE mRNA expression imply non-catalytic properties of the AChE enzyme.

  16. Bacterial maximum non-inhibitory and minimum inhibitory concentrations of different water activity depressing solutes.

    PubMed

    Cebrián, G; Arroyo, C; Mañas, P; Condón, S

    2014-10-01

    The NaCl MNICs (maximum non-inhibitory concentrations) and MICs (minimum inhibitory concentrations) for growth of various strains of six bacterial species were determined and then compared with those obtained for seven other solutes. The influence of prior growth conditions on the MNICs and MICs was also evaluated. No significant changes on the MNICs and MICs were found among the strains studied within each species. Among all factors investigated, only growth phase -for Gram-negatives- and growth at high NaCl concentrations led to a change in the NaCl MNICs. Species could be classified depending on its NaCl MNICs and MICs (in decreasing order) as follows: Staphylococcus aureus, Listeria monocytogenes, Cronobacter sakazakii, Enterococcus faecium, Escherichia coli and Salmonella Typhimurium. Similar results were obtained for KCl, LiCl, and sodium acetate, but not for the remaining solutes investigated (sucrose, glycerol, MgCl2 and CaCl2). Results obtained indicate that, in general, Gram-negatives showed lower MNICs and MICs than Gram-positives for all the solutes, S. aureus being the most solute tolerant microorganism. When compared on a molar basis, glycerol showed the highest MNICs and MICs for all the microorganisms -except for S. aureus- and LiCl the lowest ones. NaCl MNICs and MICs were not significantly different from those of KCl when compared on a molar basis. Therefore, the inhibitory action of NaCl could not be linked to the specific action of Na(+). Results also showed that the Na(+) tolerance of some species was Cl(-) dependent whereas for others it was not, and that factors others than aw-decrease contribute to the inhibitory action of LiCl, CaCl2 and MgCl2.

  17. Chlorpyrifos and chlorpyrifos-oxon inhibit axonal growth by interfering with the morphogenic activity of acetylcholinesterase

    SciTech Connect

    Yang Dongren; Howard, Angela; Bruun, Donald; Ajua-Alemanj, Mispa; Pickart, Cecile; Lein, Pamela J.

    2008-04-01

    A primary role of acetylcholinesterase (AChE) is regulation of cholinergic neurotransmission by hydrolysis of synaptic acetylcholine. In the developing nervous system, however, AChE also functions as a morphogenic factor to promote axonal growth. This raises the question of whether organophosphorus pesticides (OPs) that are known to selectively bind to and inactivate the enzymatic function of AChE also interfere with its morphogenic function to perturb axonogenesis. To test this hypothesis, we exposed primary cultures of sensory neurons derived from embryonic rat dorsal root ganglia (DRG) to chlorpyrifos (CPF) or its oxon metabolite (CPFO). Both OPs significantly decreased axonal length at concentrations that had no effect on cell viability, protein synthesis or the enzymatic activity of AChE. Comparative analyses of the effects of CPF and CPFO on axonal growth in DRG neurons cultured from AChE nullizygous (AChE{sup -/-}) versus wild type (AChE{sup +/+}) mice indicated that while these OPs inhibited axonal growth in AChE{sup +/+} DRG neurons, they had no effect on axonal growth in AChE{sup -/-} DRG neurons. However, transfection of AChE{sup -/-} DRG neurons with cDNA encoding full-length AChE restored the wild type response to the axon inhibitory effects of OPs. These data indicate that inhibition of axonal growth by OPs requires AChE, but the mechanism involves inhibition of the morphogenic rather than enzymatic activity of AChE. These findings suggest a novel mechanism for explaining not only the functional deficits observed in children and animals following developmental exposure to OPs, but also the increased vulnerability of the developing nervous system to OPs.

  18. Inhibitory effects of ionic liquids on the lactic dehydrogenase activity.

    PubMed

    Dong, Xing; Fan, Yunchang; Zhang, Heng; Zhong, Yingying; Yang, Yang; Miao, Juan; Hua, Shaofeng

    2016-05-01

    Ionic liquids (ILs) were widely used in scientific and industrial application and have been reported to possess potential toxicity to the environment and human health. The effects of six typical N-methylimidazolium-based ILs ([Cnmim]X, n=4, 6, 8; X=Br(-), Cl(-), BF4(-), CF3SO3(-)) on the lactic dehydrogenase (LDH) activity and the molecular interaction mechanism of ILs and the LDH were investigated with the aid of spectroscopic techniques. Experimental results showed that the LDH activity was inhibited in the presence of ILs. For the ILs with the same anion but different cations, their inhibitory ability on the LDH activity increased with increasing the alkyl chain length on the IL cation. Thermodynamic parameters, enthalpy change (ΔH) and entropy change (ΔS) were obtained by analyzing the fluorescence behavior of LDH with the addition of ILs. Both positive ΔH and ΔS suggested that hydrophobicity was the major driven force in the interaction process as expected. PMID:26802246

  19. In Vitro Activity of ACH-702, a New Isothiazoloquinolone, against Nocardia brasiliensis Compared with Econazole and the Carbapenems Imipenem and Meropenem Alone or in Combination with Clavulanic Acid ▿

    PubMed Central

    Vera-Cabrera, Lucio; Campos-Rivera, Mayra Paola; Escalante-Fuentes, Wendy G.; Pucci, Michael J.; Ocampo-Candiani, Jorge; Welsh, Oliverio

    2010-01-01

    The in vitro activities of ACH-702 and other antimicrobials against 30 Nocardia brasiliensis isolates were tested. The MIC50 (MIC for 50% of the strains tested) and MIC90 values of ACH-702 were 0.125 and 0.5 μg/ml. The same values for econazole were 2 and 4 μg/ml. The MIC50 and MIC90 values of imipenem and meropenem were 64 and >64 μg/ml and 2 and 8 μg/ml, respectively; the addition of clavulanic acid to the carbapenems had no effect. PMID:20308390

  20. Cholinestrase inhibitory effects of geranylated flavonoids from Paulownia tomentosa fruits.

    PubMed

    Cho, Jung Keun; Ryu, Young Bae; Curtis-Long, Marcus J; Ryu, Hyung Won; Yuk, Heung Joo; Kim, Dae Wook; Kim, Hye Jin; Lee, Woo Song; Park, Ki Hun

    2012-04-15

    Alzheimer's disease is rapidly becoming one of the most prevalent human diseases. Inhibition of human acetylcholinestrase (hAChE) and butyrylcholinestrase (BChE) has been linked to amelioration of Alzheimer's symptoms and research into inhibitors is of critical importance. Purification of the methanol extract of Paulownia tomentosa fruits yielded potent hAChE and BChE inhibitory flavonoids (1-9). A comparative activity screen indicated that a geranyl group at C6 is crucial for both hAChE and BChE. For example, diplacone (8) showed 250-fold higher efficacy than its parent eriodictyol (12). IC(50)s of diplacone (8) were 7.2 μM for hAChE and 1.4 μM for BChE. Similar trends were also observed for 4'-O-methyldiplacone (4) (vs its parent, hesperetin 10) and mimulone (7) (vs its parent, naringenin 11). Representative inhibitors (1-8) showed mixed inhibition kinetics as well as time-dependent, reversible inhibition toward hAChE. The binding affinities of these compounds to hAChE were investigated by monitoring quenching of inherent enzyme fluorescence. The affinity constants (K(SA)) increased in proportion to inhibitory potencies. PMID:22445674

  1. Acetylcholinesterase Regulates Skeletal In Ovo Development of Chicken Limbs by ACh-Dependent and -Independent Mechanisms

    PubMed Central

    Spieker, Janine; Ackermann, Anica; Salfelder, Anika; Vogel-Höpker, Astrid; Layer, Paul G.

    2016-01-01

    Formation of the vertebrate limb presents an excellent model to analyze a non-neuronal cholinergic system (NNCS). Here, we first analyzed the expression of acetylcholinesterase (AChE) by IHC and of choline acetyltransferase (ChAT) by ISH in developing embryonic chicken limbs (stages HH17-37). AChE outlined formation of bones, being strongest at their distal tips, and later also marked areas of cell death. At onset, AChE and ChAT were elevated in two organizing centers of the limb anlage, the apical ectodermal ridge (AER) and zone of polarizing activity (ZPA), respectively. Thereby ChAT was expressed shortly after AChE, thus strongly supporting a leading role of AChE in limb formation. Then, we conducted loss-of-function studies via unilateral implantation of beads into chicken limb anlagen, which were soaked in cholinergic components. After varying periods, the formation of cartilage matrix and of mineralizing bones was followed by Alcian blue (AB) and Alizarin red (AR) stainings, respectively. Both acetylcholine (ACh)- and ChAT-soaked beads accelerated bone formation in ovo. Notably, inhibition of AChE by BW284c51, or by the monoclonal antibody MAB304 delayed cartilage formation. Since bead inhibition of BChE was mostly ineffective, an ACh-independent action during BW284c51 and MAB304 inhibition was indicated, which possibly could be due to an enzymatic side activity of AChE. In conclusion, skeletogenesis in chick is regulated by an ACh-dependent cholinergic system, but to some extent also by an ACh-independent aspect of the AChE protein. PMID:27574787

  2. Acetylcholinesterase Regulates Skeletal In Ovo Development of Chicken Limbs by ACh-Dependent and -Independent Mechanisms.

    PubMed

    Spieker, Janine; Ackermann, Anica; Salfelder, Anika; Vogel-Höpker, Astrid; Layer, Paul G

    2016-01-01

    Formation of the vertebrate limb presents an excellent model to analyze a non-neuronal cholinergic system (NNCS). Here, we first analyzed the expression of acetylcholinesterase (AChE) by IHC and of choline acetyltransferase (ChAT) by ISH in developing embryonic chicken limbs (stages HH17-37). AChE outlined formation of bones, being strongest at their distal tips, and later also marked areas of cell death. At onset, AChE and ChAT were elevated in two organizing centers of the limb anlage, the apical ectodermal ridge (AER) and zone of polarizing activity (ZPA), respectively. Thereby ChAT was expressed shortly after AChE, thus strongly supporting a leading role of AChE in limb formation. Then, we conducted loss-of-function studies via unilateral implantation of beads into chicken limb anlagen, which were soaked in cholinergic components. After varying periods, the formation of cartilage matrix and of mineralizing bones was followed by Alcian blue (AB) and Alizarin red (AR) stainings, respectively. Both acetylcholine (ACh)- and ChAT-soaked beads accelerated bone formation in ovo. Notably, inhibition of AChE by BW284c51, or by the monoclonal antibody MAB304 delayed cartilage formation. Since bead inhibition of BChE was mostly ineffective, an ACh-independent action during BW284c51 and MAB304 inhibition was indicated, which possibly could be due to an enzymatic side activity of AChE. In conclusion, skeletogenesis in chick is regulated by an ACh-dependent cholinergic system, but to some extent also by an ACh-independent aspect of the AChE protein. PMID:27574787

  3. Inhibitory Effects of Angelica Polysaccharide on Activation of Mast Cells

    PubMed Central

    Mao, Wei-An; Sun, Yuan-Yuan; Mao, Jing-Yi; Wang, Li; Zhang, Jian; Zhou, Jie; Rahman, Khalid; Ye, Ying

    2016-01-01

    This study was designed to investigate the inhibitory effects of Angelica polysaccharide (AP) on activation of mast cells and its possible molecular mechanism. In our study, we determined the proinflammatory cytokines and allergic mediators in anti-DNP IgE stimulated RBL-2H3 cells and found that AP (50, 100, and 200 μg/mL) significantly decreased the release of histamine, β-hexosaminidase, leukotrienes C4 (LTC4), IL-1, IL-4, TNF-α, IL-6, and human monocyte chemotactic protein-1 (MCP-1/CCL2) (p < 0.05). In addition, Ca2+ entry was inhibited by treatment with AP. AP also downregulated the protein expressions of p-Fyn, p-Akt, p-P38, IL-4, TNF-α, and NF-κB p65 in both Fyn gene upregulated and normal RBL-2H3 cells (p < 0.05). Collectively, our results showed that AP could inhibit the activation of mast cells via suppressing the releases of proinflammatory cytokines allergic mediators, Gab2/PI3-K/Akt and Fyn/Syk pathways. PMID:27200102

  4. Inhibitory activity of spices and essential oils on psychrotrophic bacteria.

    PubMed

    Fabio, A; Corona, A; Forte, E; Quaglio, P

    2003-01-01

    This study was designed to evaluate "in vitro" the inhibitory effects of spices and essential oils on the growth of psycrotrophic food-borne bacteria: Aeromonas hydrophila, Listeria monocytogenes and Yersinia enterocolitica. The sensitivity to nine spices and their oils (chilli, cinnamon, cloves, ginger, nutmeg, oregano, rosemary, sage, thyme) was studied. Antibacterial activity was evaluated on liquid and solid medium. Spices: 1% concentration of each spice was added separately to Triptic Soy Broth and then inoculated to contain 10(8)/ml organism and held to 4 degrees C for 7 days. Populations of test organism were determined on Triptic Soy Agar. Oils: Inhibition of growth was tested by using the paper disc agar diffusion method (at 35, 20 and 4 degrees C) and measuring their inhibition zone. MIC was determined by the broth microdilution method. Some culinary spices produce antibacterial activity: inhibition of growth ranged from complete (cinnamon and cloves against A. hydrophila) to no inhibition. Antibacterial inhibition zone ranged from 8 mm to 45 mm: thyme essential oil showed the greatest inhibition against A. hydrophila. PMID:12578319

  5. Toward the Prediction of FBPase Inhibitory Activity Using Chemoinformatic Methods

    PubMed Central

    Hao, Ming; Zhang, Shuwei; Qiu, Jieshan

    2012-01-01

    Currently, Chemoinformatic methods are used to perform the prediction for FBPase inhibitory activity. A genetic algorithm-random forest coupled method (GA-RF) was proposed to predict fructose 1,6-bisphosphatase (FBPase) inhibitors to treat type 2 diabetes mellitus using the Mold2 molecular descriptors. A data set of 126 oxazole and thiazole analogs was used to derive the GA-RF model, yielding the significant non-cross-validated correlation coefficient r2ncv and cross-validated r2cv values of 0.96 and 0.67 for the training set, respectively. The statistically significant model was validated by a test set of 64 compounds, producing the prediction correlation coefficient r2pred of 0.90. More importantly, the building GA-RF model also passed through various criteria suggested by Tropsha and Roy with r2o and r2m values of 0.90 and 0.83, respectively. In order to compare with the GA-RF model, a pure RF model developed based on the full descriptors was performed as well for the same data set. The resulting GA-RF model with significantly internal and external prediction capacities is beneficial to the prediction of potential oxazole and thiazole series of FBPase inhibitors prior to chemical synthesis in drug discovery programs. PMID:22837677

  6. The 5 alpha-reductase inhibitory components from heartwood of Artocarpus incisus: structure-activity investigations.

    PubMed

    Shimizu, K; Fukuda, M; Kondo, R; Sakai, K

    2000-02-01

    The methanol extract of heartwood of Artocarpus incisus showed potent 5 alpha-reductase inhibitory activity. We investigated the 5 alpha-reductase inhibitory effects of nine compounds isolated from A. incisus. Chlorophorin (IC50 = 37 microM) and artocarpin (IC50 = 85 microM) showed more potent inhibitory effects than did alpha-linolenic acid, which is known as a naturally occurring potent inhibitor. Structure-activity investigations suggested that the presence of an isoprene substituent (prenyl and geranyl) would enhance 5 alpha-reductase inhibitory effects.

  7. New Cholinesterase Inhibitory Constituents from Lonicera quinquelocularis

    PubMed Central

    Khan, Dilfaraz; Khan, Hidayat Ullah; Khan, Farmanullah; Khan, Shafiullah; Badshah, Syed; Khan, Abdul Samad; Samad, Abdul; Ali, Farman; Khan, Ihsanullah; Muhammad, Nawshad

    2014-01-01

    A phytochemical investigation on the ethyl acetate soluble fraction of Lonicera quinquelocularis (whole plant) led to the first time isolation of one new phthalate; bis(7-acetoxy-2-ethyl-5-methylheptyl) phthalate (3) and two new benzoates; neopentyl-4-ethoxy-3, 5-bis (3-methyl-2-butenyl benzoate (4) and neopentyl-4-hydroxy-3, 5-bis (3-methyl-2-butenyl benzoate (5) along with two known compounds bis (2-ethylhexyl phthalate (1) and dioctyl phthalate (2). Their structures were established on the basis of spectroscopic analysis and by comparison with available data in the literature. All the compounds (1–5) were tested for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities in dose dependent manner. The IC50 (50% inhibitory effect) values of compounds 3 and 5 against AChE were 1.65 and 3.43 µM while the values obtained against BChE were 5.98 and 9.84 µM respectively. Compounds 2 and 4 showed weak inhibition profile. PMID:24733024

  8. New cholinesterase inhibitory constituents from Lonicera quinquelocularis.

    PubMed

    Khan, Dilfaraz; Khan, Hidayat Ullah; Khan, Farmanullah; Khan, Shafiullah; Badshah, Syed; Khan, Abdul Samad; Samad, Abdul; Ali, Farman; Khan, Ihsanullah; Muhammad, Nawshad

    2014-01-01

    A phytochemical investigation on the ethyl acetate soluble fraction of Lonicera quinquelocularis (whole plant) led to the first time isolation of one new phthalate; bis(7-acetoxy-2-ethyl-5-methylheptyl) phthalate (3) and two new benzoates; neopentyl-4-ethoxy-3, 5-bis (3-methyl-2-butenyl benzoate (4) and neopentyl-4-hydroxy-3, 5-bis (3-methyl-2-butenyl benzoate (5) along with two known compounds bis (2-ethylhexyl phthalate (1) and dioctyl phthalate (2). Their structures were established on the basis of spectroscopic analysis and by comparison with available data in the literature. All the compounds (1-5) were tested for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities in dose dependent manner. The IC50 (50% inhibitory effect) values of compounds 3 and 5 against AChE were 1.65 and 3.43 µM while the values obtained against BChE were 5.98 and 9.84 µM respectively. Compounds 2 and 4 showed weak inhibition profile.

  9. A mechanism-based 3D-QSAR approach for classification and prediction of acetylcholinesterase inhibitory potency of organophosphate and carbamate analogs.

    PubMed

    Lee, Sehan; Barron, Mace G

    2016-04-01

    Organophosphate (OP) and carbamate esters can inhibit acetylcholinesterase (AChE) by binding covalently to a serine residue in the enzyme active site, and their inhibitory potency depends largely on affinity for the enzyme and the reactivity of the ester. Despite this understanding, there has been no mechanism-based in silico approach for classification and prediction of the inhibitory potency of ether OPs or carbamates. This prompted us to develop a three dimensional prediction framework for OPs, carbamates, and their analogs. Inhibitory structures of a compound that can form the covalent bond were identified through analysis of docked conformations of the compound and its metabolites. Inhibitory potencies of the selected structures were then predicted using a previously developed three dimensional quantitative structure-active relationship. This approach was validated with a large number of structurally diverse OP and carbamate compounds encompassing widely used insecticides and structural analogs including OP flame retardants and thio- and dithiocarbamate pesticides. The modeling revealed that: (1) in addition to classical OP metabolic activation, the toxicity of carbamate compounds can be dependent on biotransformation, (2) OP and carbamate analogs such as OP flame retardants and thiocarbamate herbicides can act as AChEI, (3) hydrogen bonds at the oxyanion hole is critical for AChE inhibition through the covalent bond, and (4) π-π interaction with Trp86 is necessary for strong inhibition of AChE. Our combined computation approach provided detailed understanding of the mechanism of action of OP and carbamate compounds and may be useful for screening a diversity of chemical structures for AChE inhibitory potency. PMID:27055524

  10. Antioxidant Activity and α-Glucosidase Inhibitory Activities of the Polycondensate of Catechin with Glyoxylic Acid

    PubMed Central

    Ma, Hanjun; Liu, Benguo

    2016-01-01

    In order to investigate polymeric flavonoids, the polycondensate of catechin with glyoxylic acid (PCG) was prepared and its chemically antioxidant, cellular antioxidant (CAA) and α-glucosidase inhibitory activities were evaluated. The DPPH and ABTS radical scavenging activities and antiproliferative effect of PCG were lower than those of catechin, while PCG had higher CAA activity than catechin. In addition, PCG had very high α-glucosidase inhibitory activities (IC50 value, 2.59 μg/mL) in comparison to catechin (IC50 value, 239.27 μg/mL). Inhibition kinetics suggested that both PCG and catechin demonstrated a mixture of noncompetitive and anticompetitive inhibition. The enhanced CAA and α-glucosidase inhibitor activities of PCG could be due to catechin polymerization enhancing the binding capacity to the cellular membrane and enzymes. PMID:26960205

  11. Phosphatidylinositol turnover (PI) during synaptic activation results from the release of a stimulatory and in inhibitory agonist

    SciTech Connect

    Bencherif, M.; Rubio, R.; Berne, R.M.

    1986-03-05

    PI has been implicated in the process of synaptic transmission and is increased by agonists. It has been suggested that PI is involved in cellular Ca/sup + +/ mobilization and the process represents a series of hydrolytic reactions with inositol as the final product. Hence, the rate of release of /sup 3/H-inositol (/sup 3/H-Ins) from prelabelled inositol phospholipids can be used as an index of PI. In the /sup 3/H-inositol prelabelled frog sympathetic ganglia, they studied the effect of synaptic activity on PI. PI did not change during orthodromic stimulation (20 Hz, 5 min). However, upon cessation of the stimulation, PI increased rapidly and remained elevated for at least 30 min. This increase in PI was reduced by suffusing the ganglia with either acetylcholine or adenosine. In the presence of atropine (5 ..mu..M), orthodromic stimulation increased PI. They hypothesized that synaptic activation releases a long-lasting stimulatory agonist and a short-lived inhibitory (Ach/adenosine) agonist(s) affecting PI. To test this idea, 2 sympathetic ganglia were used. One was prelabelled with /sup 3/H-inositol and the other was not. The two ganglia were placed together in a 5 ..mu..l drop of Ringers solution containing atropine. Orthodromic stimuli were applied to the non-labelled ganglion and elicited release of /sup 3/H-Ins from the non-stimulated ganglion.

  12. Novel series of tacrine-tianeptine hybrids: Synthesis, cholinesterase inhibitory activity, S100B secretion and a molecular modeling approach.

    PubMed

    Ceschi, Marco Antonio; da Costa, Jessie Sobieski; Lopes, João Paulo Bizarro; Câmara, Viktor Saraiva; Campo, Leandra Franciscato; Borges, Antonio César de Amorim; Gonçalves, Carlos Alberto Saraiva; de Souza, Daniela Fraga; Konrath, Eduardo Luis; Karl, Ana Luiza Martins; Guedes, Isabella Alvim; Dardenne, Laurent Emmanuel

    2016-10-01

    Tianeptine was linked to various 9-aminoalkylamino-1,2,3,4-tetrahydroacridines using EDC·HCl/HOBt to afford a series of tacrine-tianeptine hybrids. The hybrids were tested for their ability to inhibit AChE and BuChE and IC50 values in the nanomolar concentration scale were obtained. AChE molecular modeling studies of these hybrids indicated that tacrine moiety interacts in the bottom of the gorge with the catalytic active site (CAS) while tianeptine binds to peripheral anionic site (PAS). Furthermore, the compounds 2g and 2e were able to reduce the in vitro basal secretion of S100B, suggesting its therapeutic action in some cases or stages of Alzheimer's disease.

  13. Novel series of tacrine-tianeptine hybrids: Synthesis, cholinesterase inhibitory activity, S100B secretion and a molecular modeling approach.

    PubMed

    Ceschi, Marco Antonio; da Costa, Jessie Sobieski; Lopes, João Paulo Bizarro; Câmara, Viktor Saraiva; Campo, Leandra Franciscato; Borges, Antonio César de Amorim; Gonçalves, Carlos Alberto Saraiva; de Souza, Daniela Fraga; Konrath, Eduardo Luis; Karl, Ana Luiza Martins; Guedes, Isabella Alvim; Dardenne, Laurent Emmanuel

    2016-10-01

    Tianeptine was linked to various 9-aminoalkylamino-1,2,3,4-tetrahydroacridines using EDC·HCl/HOBt to afford a series of tacrine-tianeptine hybrids. The hybrids were tested for their ability to inhibit AChE and BuChE and IC50 values in the nanomolar concentration scale were obtained. AChE molecular modeling studies of these hybrids indicated that tacrine moiety interacts in the bottom of the gorge with the catalytic active site (CAS) while tianeptine binds to peripheral anionic site (PAS). Furthermore, the compounds 2g and 2e were able to reduce the in vitro basal secretion of S100B, suggesting its therapeutic action in some cases or stages of Alzheimer's disease. PMID:27392529

  14. Differential activity-dependent, homeostatic plasticity of two neocortical inhibitory circuits.

    PubMed

    Bartley, Aundrea F; Huang, Z Josh; Huber, Kimberly M; Gibson, Jay R

    2008-10-01

    Chronic changes in neuronal activity homeostatically regulate excitatory circuitry. However, little is known about how activity regulates inhibitory circuits or specific inhibitory neuron types. Here, we examined the activity-dependent regulation of two neocortical inhibitory circuits--parvalbumin-positive (Parv+) and somatostatin-positive (Som+)--using paired recordings of synaptically coupled neurons. Action potentials were blocked for 5 days in slice culture, and unitary synaptic connections among inhibitory/excitatory neuron pairs were examined. Chronic activity blockade caused similar and distinct changes between the two inhibitory circuits. First, increases in intrinsic membrane excitability and excitatory synaptic drive in both inhibitory subtypes were consistent with the homeostatic regulation of firing rate of these neurons. On the other hand, inhibitory synapses originating from these two subtypes were differentially regulated by activity blockade. Parv+ unitary inhibitory postsynaptic current (uIPSC) strength was decreased while Som+ uIPSC strength was unchanged. Using short-duration stimulus trains, short-term plasticity for both unitary excitatory postsynaptic current (uEPSCs) and uIPSCs was unchanged in Parv+ circuitry while distinctively altered in Som+ circuitry--uEPSCs became less facilitating and uIPSCs became more depressing. In the context of recurrent inhibition, these changes would result in a frequency-dependent shift in the relative influence of each circuit. The functional changes at both types of inhibitory connections appear to be mediated by increases in presynaptic release probability and decreases in synapse number. Interestingly, these opposing changes result in decreased Parv+-mediated uIPSCs but balance out to maintain normal Som+-mediated uIPSCs. In summary, these results reveal that inhibitory circuitry is not uniformly regulated by activity levels and may provide insight into the mechanisms of both normal and pathological

  15. Two Ganoderma species: profiling of phenolic compounds by HPLC-DAD, antioxidant, antimicrobial and inhibitory activities on key enzymes linked to diabetes mellitus, Alzheimer's disease and skin disorders.

    PubMed

    Zengin, Gokhan; Sarikurkcu, Cengiz; Gunes, Erdogan; Uysal, Ahmet; Ceylan, Ramazan; Uysal, Sengul; Gungor, Halil; Aktumsek, Abdurrahman

    2015-08-01

    This work reports the antioxidant, antimicrobial, and inhibitory effects of methanol and water extracts from Ganoderma applanatum (GAM: methanol extract and GAW: water extract) and G. resinaceum (GRM: methanol extract and GRW: water extract) against cholinesterase, tyrosinase, α-amylase and α-glucosidase. The total phenolics, flavonoids contents, and HPLC profile of phenolic components present in the extracts, were also determined. Antioxidant activities were investigated by using different assays, including DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum and metal chelating assays. Antimicrobial activity of the tested Ganoderma extracts was also studied by the broth microdilution method. Generally, the highest antioxidant (59.24 mg TEs per g extract for DPPH, 41.32 mg TEs per g extract for ABTS, 41.35 mg TEs per g extract for CUPRAC, 49.68 mg TEs per g extract for FRAP, 130.57 mg AAEs per g extract for phosphomolybdenum and 26.92 mg EDTAEs per g extract) and enzyme inhibitory effects (1.47 mg GALAEs per g extract for AChE, 1.51 mg GALAEs per g extract for BChE, 13.40 mg KAEs per g extract for tyrosinase, 1.13 mmol ACEs per g extract for α-amylase and 2.20 mmol ACEs per g extract for α-glucosidase) were observed in GRM, which had the highest concentrations of phenolics (37.32 mg GAEs g(-1) extract). Again, Ganoderma extracts possess weak antibacterial and antifungal activities. Apigenin and protocatechuic acid were determined as the main components in GRM (1761 μg per g extract) and GAM (165 μg per g extract), respectively. The results suggest that the Ganoderma species may be considered as a candidate for preparing new food supplements and can represent a good model for the development of new drug formulations.

  16. Testosterone 5alpha-reductase inhibitory active constituents of Piper nigrum leaf.

    PubMed

    Hirata, Noriko; Tokunaga, Masashi; Naruto, Shunsuke; Iinuma, Munekazu; Matsuda, Hideaki

    2007-12-01

    Previously we reported that Piper nigrum leaf extract showed a potent stimulation effect on melanogenesis and that (-)-cubebin (1) and (-)-3,4-dimethoxy-3,4-desmethylenedioxycubebin (2) were isolated as active constituents. As a part of our continuous studies on Piper species for the development of cosmetic hair-care agents, testosterone 5alpha-reductase inhibitory activity of aqueous ethanolic extracts obtained from several different parts of six Piper species, namely Piper nigrum, P. methysticum, P. betle, P. kadsura, P. longum, and P. cubeba, were examined. Among them, the extracts of P. nigrum leaf, P. nigrum fruit and P. cubeba fruit showed potent inhibitory activity. Activity-guided fractionation of P. nigrum leaf extract led to the isolation of 1 and 2. Fruits of P. cubeba contain 1 as a major lignan, thus inhibitory activity of the fruit may be attributable to 1. As a result of further assay on other known constituents of the cited Piper species, it was found that piperine, a major alkaloid amide of P. nigrum fruit, showed potent inhibitory activity, thus a part of the inhibitory activity of P. nigrum fruit may depend on piperine. The 5alpha-reductase inhibitory activities of 1 and piperine were found for the first time. In addition, the P. nigrum leaf extract showed in vivo anti-androgenic activity using the hair regrowth assay in testosterone sensitive male C57Black/6CrSlc strain mice.

  17. Ligand Binding at the α4-α4 Agonist-Binding Site of the α4β2 nAChR Triggers Receptor Activation through a Pre-Activated Conformational State

    PubMed Central

    Indurthi, Dinesh C.; Lewis, Trevor M.; Ahring, Philip K.; Balle, Thomas; Chebib, Mary; Absalom, Nathan L.

    2016-01-01

    The α4β2 nicotinic acetylcholine receptor (nAChR) is the most abundant subtype in the brain and exists in two functional stoichiometries: (α4)3(β2)2 and (α4)2(β2)3. A distinct feature of the (α4)3(β2)2 receptor is the biphasic activation response to the endogenous agonist acetylcholine, where it is activated with high potency and low efficacy when two α4-β2 binding sites are occupied and with low potency/high efficacy when a third α4-α4 binding site is occupied. Further, exogenous ligands can bind to the third α4-α4 binding site and potentiate the activation of the receptor by ACh that is bound at the two α4-β2 sites. We propose that perturbations of the recently described pre-activation step when a third binding site is occupied are a key driver of these distinct activation properties. To investigate this, we used a combination of simple linear kinetic models and voltage clamp electrophysiology to determine whether transitions into the pre-activated state were increased when three binding sites were occupied. We separated the binding at the two different sites with ligands selective for the α4-β2 site (Sazetidine-A and TC-2559) and the α4-α4 site (NS9283) and identified that when a third binding site was occupied, changes in the concentration-response curves were best explained by an increase in transitions into a pre-activated state. We propose that perturbations of transitions into a pre-activated state are essential to explain the activation properties of the (α4)3(β2)2 receptor by acetylcholine and other ligands. Considering the widespread clinical use of benzodiazepines, this discovery of a conserved mechanism that benzodiazepines and ACh potentiate receptor activation via a third binding site can be exploited to develop therapeutics with similar properties at other cys-loop receptors. PMID:27552221

  18. Chemical constituents from Sonneratia ovata Backer and their in vitro cytotoxicity and acetylcholinesterase inhibitory activities.

    PubMed

    Nguyen, Thi-Hoai-Thu; Pham, Huu-Viet-Thong; Pham, Nguyen-Kim-Tuyen; Quach, Ngo-Diem-Phuong; Pudhom, Khanitha; Hansen, Poul Erik; Nguyen, Kim-Phi-Phung

    2015-06-01

    Sonneratia ovata Backer, Sonneratiaceae, is a widespread plant in mangrove forests in Vietnam, Cambodia, Thailand, Indonesia. Sonneratia ovata's chemical composition remains mostly unknown. Therefore, we now report on the structural elucidation of three new phenolics, sonnerphenolic A (1), sonnerphenolic B (2), and sonnerphenolic C (23), a new cerebroside, sonnercerebroside (3) together with nineteen known compounds, including nine lignans (5-13), two steroids (14, 15), two triterpenoids (16, 17), three gallic acid derivatives (18-20), two phenolic derivatives (4, 22) and a 1-O-benzyl-β-d-glucopyranose (21) isolated from the leaves of Sonneratia ovata. Their chemical structures were established by spectroscopic data, as well as high resolution mass spectra and comparison with literature data. The in vitro acetylcholinesterase (AChE) inhibition and cytotoxic activities against HeLa (human epithelial carcinoma), NCI-H460 (human lung cancer), MCF-7 (human breast cancer) cancer cell lines and PHF (primary human fibroblast) cell were evaluated on some extracts and purified compounds at a concentration of 100 μg/mL. Compounds (5, 6, 23) exhibited cytotoxicity against the MCF-7 cell line with the IC50 values of 146.9±9.0, 114.5±7.2, and 112.8±9.4 μM, respectively, while they showed nontoxic with the normal cell (PHF) with IC50s >277 μM. Among 15 tested compounds, (S)-rhodolatouchol (22) showed inhibition against AChE with an IC50 value of 96.1±14.5 μM.

  19. Inhibitory effect of curcuminoids and tetrahydrocurcuminoids on equine activated neutrophils and myeloperoxidase activity.

    PubMed

    Franck, T; Kohnen, S; Grulke, S; Neven, P; Goutman, Y; Peters, F; Pirotte, B; Deby-Dupont, G; Serteyn, D

    2008-01-01

    In the horse, the inflammation response to various pathologies (intestinal strangulations, laminitis, etc.) involves an excessive stimulation of the polymorphonuclear neutrophils releasing reactive oxygen species (ROS) and myeloperoxidase (MPO). The aim of the present work was to study the effect of natural polyphenols, curcuminoids and tetrahydrocurcuminoids (THC) on isolated stimulated equine neutrophils and on the activity of purified MPO. The ROS production and the release of MPO by activated neutrophils were measured by chemiluminescence and ELISA techniques, respectively. The activity of purified MPO was measured by studying its nitration, chlorination or oxidation capacity and by using an original method called SIEFED allowing the study of drug interaction with the enzyme without interferences of the medium. Curcuminoids and THC had dose-dependent inhibitory effects on ROS production and MPO release by activated neutrophils and on purified MPO activity. We suggest that the higher efficacy of curcuminoids versus THC could be explained, at least partially, by its chemical structure: the conjugated double bounds and the plane structure of curcuminoids made easier the neutralization of the radical species generated by activated neutrophils and the interaction of the drug with the active site of MPO. These inhibitory effects of curcuminoids on the oxidant activity of equine neutrophils and on MPO activity open therapeutic perspectives in equine pathologies with excessive inflammatory reactions.

  20. Synthesis of sulfanilamide derivatives and investigation of in vitro inhibitory activities and antimicrobial and physical properties.

    PubMed

    Turkmen, Hasan; Zengin, Gulay; Buyukkircali, Belkis

    2011-06-01

    Novel sulfanilamide derivatives were synthesized and evaluated for carbonic anhydrase inhibitory activity as a target for the treatment of glaucoma, and antibacterial properties for use in chemotherapy. Synthesized compounds were characterized by FT-IR, (1)H NMR, (13)C NMR and photoluminescence. In vitro inhibitory activities were measured by UV-Vis and some of the compounds were found have greater inhibitory effects than the lead compound sulfanilamide. The correlation between inhibitory activity, biological properties and the physicochemical properties of water solubility and partition coefficients was also investigated. Sulfanilamide derivatives gave intense emissions upon irradiation by UV light and a dimethyl substituted compound and a cyclic analog have photoluminescence quantum yields 42% and 31% and long excited-state lifetimes of 3.92 and 2.91 ns, respectively. PMID:21429552

  1. A Novel Direct Factor Xa Inhibitory Peptide with Anti-Platelet Aggregation Activity from Agkistrodon acutus Venom Hydrolysates.

    PubMed

    Chen, Meimei; Ye, Xiaohui; Ming, Xin; Chen, Yahui; Wang, Ying; Su, Xingli; Su, Wen; Kong, Yi

    2015-01-01

    Snake venom is a natural substance that contains numerous bioactive proteins and peptides, nearly all of which have been identified over the last several decades. In this study, we subjected snake venom to enzymatic hydrolysis to identify previously unreported bioactive peptides. The novel peptide ACH-11 with the sequence LTFPRIVFVLG was identified with both FXa inhibition and anti-platelet aggregation activities. ACH-11 inhibited the catalytic function of FXa towards its substrate S-2222 via a mixed model with a Ki value of 9.02 μM and inhibited platelet aggregation induced by ADP and U46619 in a dose-dependent manner. Furthermore, ACH-11 exhibited potent antithrombotic activity in vivo. It reduced paralysis and death in an acute pulmonary thrombosis model by 90% and attenuated thrombosis weight in an arterio-venous shunt thrombosis model by 57.91%, both at a dose of 3 mg/kg. Additionally, a tail cutting bleeding time assay revealed that ACH-11 did not prolong bleeding time in mice at a dose of 3 mg/kg. Together, our results reveal that ACH-11 is a novel antithrombotic peptide exhibiting both FXa inhibition and anti-platelet aggregation activities, with a low bleeding risk. We believe that it could be a candidate or lead compound for new antithrombotic drug development. PMID:26035670

  2. Anticholinesterase activity of 7-methoxyflavones isolated from Kaempferia parviflora.

    PubMed

    Sawasdee, Pattara; Sabphon, Chalisa; Sitthiwongwanit, Duangporn; Kokpol, Udom

    2009-12-01

    The rhizome of Kaempferia parviflora or kra-chai-dum (in Thai) is used traditionally as a folk medicine. The preliminary cholinesterase inhibitory screening of this plant extract exhibited significant acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Thirteen known methoxyflavones (1-13) were isolated and their structures were completely elucidated based on NMR analysis and compared with literature reports. Minor compounds 12-13 were reported for the first time from this species. The cholinesterase inhibitory test results showed that the highest potential inhibitors toward AChE and BChE were 5,7,4'-trimethoxyflavone (6) and 5,7-dimethoxyflavone (7), respectively, with the percentage inhibitory activity varying over 43-85%. The structure-activity relationship study led to the conclusion that compounds bearing 5,7-dimethoxy groups and a free substituent at C-3 had a significant inhibitory effect at a concentration of 0.1 mg/mL, but those bearing a 5-hydroxyl group reduced the inhibitory potency. On the other hand, flavones bearing a 3'- or 5'-methoxy group did not influence the inhibitory effect. Interestingly, 5,7-dimethoxyflavone (7) exhibited strong selectivity for BChE over AChE which may be of great interest to modify as a treatment agent for Alzheimer's disease. PMID:19548291

  3. Inhibitory effect of hemin on the mutagenic activities of carcinogens.

    PubMed

    Arimoto, S; Negishi, T; Hayatsu, H

    1980-11-01

    An inhibitory effect of hemin on mutagenicities of a range of carcinogens was found by adding hemin to the preincubation mixture of the Ames' test. Strong inhibitions were observed for benzo[alpha]pyrene, 3-methylcholanthrene, 7,10-dimethylbenz[alpha]anthracene, chrysene, 2-acetylaminofluorene, 2-nitrofluorene and aflatoxin B1. Generally, 50% inhibition was caused by an amount of hemin 1--2 equivalents to the mutagen. Excess of hemin caused complete inhibitions. Hemin did not affect the mutagenicities of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, 4-nitroquinoline-1-oxide, nitromin, N-methyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine, N-nitrosodi-n-butyl-amine, quinoxaline-1,4-dioxide and carbadox. Biliverdin, bilirubin and chlorophyllin were also effective as inhibitors for the mutagenicity of benzo[alpha]pyrene. PMID:7226136

  4. Synaptic basis for intense thalamocortical activation of feedforward inhibitory cells in neocortex.

    PubMed

    Cruikshank, Scott J; Lewis, Timothy J; Connors, Barry W

    2007-04-01

    The thalamus provides fundamental input to the neocortex. This input activates inhibitory interneurons more strongly than excitatory neurons, triggering powerful feedforward inhibition. We studied the mechanisms of this selective neuronal activation using a mouse somatosensory thalamocortical preparation. Notably, the greater responsiveness of inhibitory interneurons was not caused by their distinctive intrinsic properties but was instead produced by synaptic mechanisms. Axons from the thalamus made stronger and more frequent excitatory connections onto inhibitory interneurons than onto excitatory cells. Furthermore, circuit dynamics allowed feedforward inhibition to suppress responses in excitatory cells more effectively than in interneurons. Thalamocortical excitatory currents rose quickly in interneurons, allowing them to fire action potentials before significant feedforward inhibition emerged. In contrast, thalamocortical excitatory currents rose slowly in excitatory cells, overlapping with feedforward inhibitory currents that suppress action potentials. These results demonstrate the importance of selective synaptic targeting and precise timing in the initial stages of neocortical processing.

  5. Synthesis and acetylcholinesterase inhibitory activity of polyhydroxylated sulfated steroids: structure/activity studies.

    PubMed

    Richmond, Victoria; Murray, Ana P; Maier, Marta S

    2013-11-01

    Disulfated and trisulfated steroids have been synthesized from cholesterol and their acetylcholinesterase inhibitory activity has been evaluated. In our studies we have found that the activity was not only dependent on the location of the sulfate groups but on their configurations. 2β,3α,6α-trihydroxy-5α-cholestan-6-one trisulfate (18) was the most active steroid with an IC50 value of 15.48 μM comparable to that of 2β,3α-dihydroxy-5α-cholestan-6-one disulfate (1). Both compounds were found to be less active than the reference compound eserine. The butyrylcholinesterase activity of 1 and 18 was one magnitude lower than that against acetylcholinesterase revealing a selective inhibitor profile.

  6. Structural requirement of isoflavonones for the inhibitory activity of interleukin-5.

    PubMed

    Jung, Sang-Hun; Cho, Soo-Hyun; Dang, The Hung; Lee, Jee-Hyun; Ju, Jung-Hun; Kim, Mi-Kyung; Lee, Seung-Ho; Ryu, Jae-Chun; Kim, Youngsoo

    2003-05-01

    Sophoricoside isolated from Sophora japonica is a glycoside of isoflavonone as an inhibitor of interleukin (IL)-5. To identify structural requirements of this isoflavonone for its inhibitory activity against IL-5, isoflavonones, isoflavanones, and their glycosides were prepared and their inhibitory activity was tested against IL-5. Among them, 5-benzyloxy-3-(4-hydroxyphenyl)chromen-4-one (4b, 87.9% inhibition at 50 microM, IC(50)=15.3 microM) shows the most potent activity, comparable with that of sophoricoside. The important structural requirements of these isoflavonone analogs exhibiting the inhibitory activity against IL-5 were recognized as (1) planarity of chromen-4-one ring, (2) existence of phenolic hydroxyl at 4-position of B ring, and (3) introduction of benzyloxy at 5-position, which may act as a bulky group for occupying hydrophobic pocket in putative binding site. However the glucopyranosyl moiety of sophoricoside is not an essential motif for the activity. PMID:12767605

  7. Inhibitory activity of isoniazid and ethionamide against Cryptococcus biofilms.

    PubMed

    Cordeiro, Rossana de Aguiar; Serpa, Rosana; Marques, Francisca Jakelyne de Farias; de Melo, Charlline Vládia Silva; Evangelista, Antonio José de Jesus; Mota, Valquíria Ferreira; Brilhante, Raimunda Sâmia Nogueira; Bandeira, Tereza de Jesus Pinheiro Gomes; Rocha, Marcos Fábio Gadelha; Sidrim, José Júlio Costa

    2015-11-01

    In recent years, the search for drugs to treat systemic and opportunistic mycoses has attracted great interest from the scientific community. This study evaluated the in vitro inhibitory effect of the antituberculosis drugs isoniazid and ethionamide alone and combined with itraconazole and fluconazole against biofilms of Cryptococcus neoformans and Cryptococcus gattii. Antimicrobials were tested at defined concentrations after susceptibility assays with Cryptococcus planktonic cells. In addition, we investigated the synergistic interaction of antituberculosis drugs and azole derivatives against Cryptococcus planktonic cells, as well as the influence of isoniazid and ethionamide on ergosterol content and cell membrane permeability. Isoniazid and ethionamide inhibited both biofilm formation and viability of mature biofilms. Combinations formed by antituberculosis drugs and azoles proved synergic against both planktonic and sessile cells, showing an ability to reduce Cryptococcus biofilms by approximately 50%. Furthermore, isoniazid and ethionamide reduced the content of ergosterol in Cryptococcus spp. planktonic cells and destabilized or permeabilized the fungal cell membrane, leading to leakage of macromolecules. Owing to the paucity of drugs able to inhibit Cryptococcus biofilms, we believe that the results presented here might be of interest in the designing of new antifungal compounds.

  8. Honey, pollen, and propolis extracts show potent inhibitory activity against the zinc metalloenzyme carbonic anhydrase.

    PubMed

    Sahin, H; Aliyazicioglu, R; Yildiz, O; Kolayli, S; Innocenti, A; Supuran, C T

    2011-06-01

    Three different honey extracts from the endemic plant in the Black Sea region Rhododendron ponticum, were investigated for their inhibitory effects against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), more precisely the human (h) isoforms hCA I and hCA II. Hexane, methanol, ethanol, and water solid-phase extractions (SPEs) showed inhibitory activity towards the two CA isozymes which were related to the total phenolic content. The highest inhibitory effects (0.036-0.039 mg/mL) were those of propolis methanolic extract. Among the three different samples investigated here, the aqueous extracts showed lower inhibitory effects compared to the organic solvent SPE extracts (in the range of 1.150- 5.144 mg/mL). The studied honey extracts constitute an interesting source of phenolic derivatives that might serve to identify lead compounds, targeting the physiologically relevant enzymes CA I and CA II.

  9. An acetylcholinesterase (AChE) biosensor with enhanced solvent resistance based on chitosan for the detection of pesticides.

    PubMed

    Warner, John; Andreescu, Silvana

    2016-01-01

    Solvent tolerance of immobilized enzymes is important for many biosensing and biotechnological applications. In this paper we report an acetylcholinesterase (AChE) biosensor based on chitosan that exhibits high solvent resistance and enables sensitive detection of pesticides in presence of a high content of organic solvents. The solvent effect was established comparatively for the enzyme immobilized in chitosan and covalently cross-linked with glutaraldehyde. The activity of the immobilized AChE was dependent on the immobilization method and solvent type. The enzyme entrapped in chitosan fully conserved its activity in up to 25% methanol, 15% acetonitrile and 100% cyclohexane while the enzyme cross-linked with glutaraldehyde gradually lost its activity starting at 5% acetonitrile and methanol, and showed variable levels in cyclohexane. The detection limits of the biosensor for paraoxon were: 7.5 nM in 25% methanol, 100 nM in 15% acetonitrile and 2.5 μM in 100% cyclohexane. This study demonstrates that chitosan provides an excellent immobilization environment for AChE biosensors designed to operate in environments containing high amounts of organic solvents. It also highlights the effect of the immobilization material and solvent type on enzyme stability. These findings can enable future selection of the immobilization matrix and solvent type for the development of organic phase enzyme based systems.

  10. An acetylcholinesterase (AChE) biosensor with enhanced solvent resistance based on chitosan for the detection of pesticides.

    PubMed

    Warner, John; Andreescu, Silvana

    2016-01-01

    Solvent tolerance of immobilized enzymes is important for many biosensing and biotechnological applications. In this paper we report an acetylcholinesterase (AChE) biosensor based on chitosan that exhibits high solvent resistance and enables sensitive detection of pesticides in presence of a high content of organic solvents. The solvent effect was established comparatively for the enzyme immobilized in chitosan and covalently cross-linked with glutaraldehyde. The activity of the immobilized AChE was dependent on the immobilization method and solvent type. The enzyme entrapped in chitosan fully conserved its activity in up to 25% methanol, 15% acetonitrile and 100% cyclohexane while the enzyme cross-linked with glutaraldehyde gradually lost its activity starting at 5% acetonitrile and methanol, and showed variable levels in cyclohexane. The detection limits of the biosensor for paraoxon were: 7.5 nM in 25% methanol, 100 nM in 15% acetonitrile and 2.5 μM in 100% cyclohexane. This study demonstrates that chitosan provides an excellent immobilization environment for AChE biosensors designed to operate in environments containing high amounts of organic solvents. It also highlights the effect of the immobilization material and solvent type on enzyme stability. These findings can enable future selection of the immobilization matrix and solvent type for the development of organic phase enzyme based systems. PMID:26695264

  11. Inhibitory activities of 2-pyridinecarboxylic acid analogs on phytogrowth and enzymes.

    PubMed

    Sakagami, Y; Tsujibo, H; Hirai, Y; Yamada, T; Numata, A; Inamori, Y

    1999-11-01

    Five 2-pyridinecarboxylic acid-related compounds (1, 2 and 5-7) showed germination inhibition against the seed of Brassica campestris L. subsp. rapa HOOK fil et ANDERS at a concentration of 5.0 x 10(-4) M. These compounds also demonstrated inhibitory activity on the growth of the root of this plant at a concentration of 3.0 x 10(-4) M; among these compounds, 2-pyridylacetic acid (5) showed the strongest inhibitory activity, and the effect was slightly stronger than that of sodium 2,4-dichlorophenoxyacetate (2,4-D) used as a positive control. The amounts of chlorophyll in the cotyledons of this plant treated with these active compounds was lower than that of the control group. Four compounds (1 and 5-7) with germination inhibition also showed inhibitory activities against alpha-amylase and carboxypeptidase A, and 5 was the strongest inhibitor toward both enzymes.

  12. [Activation and inhibitory types of brain neuronal sinchronisation: genesis and functional significance].

    PubMed

    Shul'gina, G I

    2007-01-01

    The generalization of studies of the systemic work of cortical neurons during the information processing initiated in Livanov's laboratory allows us to make the following conclusions in terms of the modem state of the problem. In different brain structures, there is a considerable degree of correlation between neuronal activities and slow potential oscillations. In the state of rest or deep extinction, the synchronization of brain neurons increases by the inhibitory type. In the active state of the brain, the degree of neuronal synchronization increases by the activation type. Both processes are determined by the involvement of the whole brain inhibitory or activation systems, respectively. A relative augmentation of inhibitory processes results in a restriction of information transmission in the cortex and prevents its fixation in memory of the system. A decrease in inhibition facilitates the excitation thransmission in the interconnected brain structures. Synchronous convergence of ordered polse flows ensures the information fixation during learning.

  13. Glucosidase inhibitory activity and antioxidant activity of flavonoid compound and triterpenoid compound from Agrimonia Pilosa Ledeb

    PubMed Central

    2014-01-01

    Background In Chinese traditional medicine, Agrimonia pilosa Ledeb (APL) exhibits great effect on treatment of type 2 diabetes mellitus (T2DM), however its mechanism is still unknown. Considering that T2DM are correlated with postprandial hyperglycemia and oxidative stress, we investigated the α-glucosidase inhibitory activity and the antioxidant activity of flavonoid compound (FC) and triterpenoid compound (TC) from APL. Methods Entire plants of APL were extracted using 95% ethanol and 50% ethanol successively. The resulting extracts were partitioned and isolated by applying liquid chromatography using silica gel column and Sephadex LH 20 column to give FC and TC. The content of total flavonoids in FC and the content of total triterpenoids in TC were determined by using UV spectrophotometry. HPLC analysis was used to identify and quantify the monomeric compound in FC and TC. The α-glucosidase inhibitory activities were determined using the chromogenic method with p-nitrophenyl-α-D-glucopyranoside as substrate. Antioxidant activities were assessed through three kinds of radical scavenging assays (DPPH radical, ABTS radical and hydroxyl radical) & β-carotene-linoleic acid assay. Results The results indicate FC is abundant of quercitrin, and hyperoside, and TC is abundant of 1β, 2β, 3β, 19α-tetrahydroxy-12-en-28-oic acid (265.2 mg/g) and corosolic acid (100.9 mg/g). The FC & the TC have strong α-glucosidase inhibitory activities with IC50 of 8.72 μg/mL and 3.67 μg/mL, respectively. We find that FC show competitive inhibition against α-glucosidase, while the TC exhibits noncompetitive inhibition. Furthermore, The FC exhibits significant radical scavenging activity with the EC50 values of 7.73 μg/mL, 3.64 μg/mL and 5.90 μg/mL on DPPH radical, hydroxyl radical and ABTS radical, respectively. The FC also shows moderate anti-lipid peroxidation activity with the IC50 values of 41.77 μg/mL on inhibiting β-carotene bleaching. Conclusion These results

  14. Acetylcholinesterase (AChE) and heat shock proteins (Hsp70) of gypsy moth (Lymantria dispar L.) larvae in response to long-term fluoranthene exposure.

    PubMed

    Mrdaković, Marija; Ilijin, Larisa; Vlahović, Milena; Matić, Dragana; Gavrilović, Anja; Mrkonja, Aleksandra; Perić-Mataruga, Vesna

    2016-09-01

    Polycyclic aromatic hydrocarbons (PAHs) may affect biochemical and physiological processes in living organisms, thus impairing fitness related traits and influencing their populations. This imposes the need for providing early-warning signals of pollution. Our study aimed to examine changes in the activity of acetylcholinesterase (AChE) and the concentration of heat shock proteins (Hsp70) in homogenates of brain tissues of fifth instar gypsy moth (Lymantria dispar L.) larvae, exposed to the ubiquitous PAH, fluoranthene, supplemented to the rearing diet. Significantly increased activity of AChE in larvae fed on the diets with high fluoranthene concentrations suggests the necessity for elucidation of the role of AChE in these insects when exposed to PAH pollution. Significant induction of Hsp70 in gypsy moth larvae reared on the diets containing low fluoranthene concentrations, indicate that changes in the level of Hsp70 might be useful as an indicator of pollution in this widespread forest species. PMID:27343862

  15. Acetylcholinesterase (AChE) and heat shock proteins (Hsp70) of gypsy moth (Lymantria dispar L.) larvae in response to long-term fluoranthene exposure.

    PubMed

    Mrdaković, Marija; Ilijin, Larisa; Vlahović, Milena; Matić, Dragana; Gavrilović, Anja; Mrkonja, Aleksandra; Perić-Mataruga, Vesna

    2016-09-01

    Polycyclic aromatic hydrocarbons (PAHs) may affect biochemical and physiological processes in living organisms, thus impairing fitness related traits and influencing their populations. This imposes the need for providing early-warning signals of pollution. Our study aimed to examine changes in the activity of acetylcholinesterase (AChE) and the concentration of heat shock proteins (Hsp70) in homogenates of brain tissues of fifth instar gypsy moth (Lymantria dispar L.) larvae, exposed to the ubiquitous PAH, fluoranthene, supplemented to the rearing diet. Significantly increased activity of AChE in larvae fed on the diets with high fluoranthene concentrations suggests the necessity for elucidation of the role of AChE in these insects when exposed to PAH pollution. Significant induction of Hsp70 in gypsy moth larvae reared on the diets containing low fluoranthene concentrations, indicate that changes in the level of Hsp70 might be useful as an indicator of pollution in this widespread forest species.

  16. Functional Analysis and Molecular Docking studies of Medicinal Compounds for AChE and BChE in Alzheimer’s Disease and Type 2 Diabetes Mellitus

    PubMed Central

    Kaladhar, Dowluru SVGK; Yarla, Nagendra Sastry; Anusha, N.

    2013-01-01

    Acetylcholinesterase and Butyrylcholinesterase share unravelling link with components of metabolic syndromes that’s characterised by low levels of HDL cholesterol, obesity, high fast aldohexose levels, hyper-trigliceridaemia and high blood pressure, by regulation of cholinergic transmission and therefore the enzyme activity within a living system. The phosphomotifs associated with amino acid and tyrosine binding motifs in AChE and BChE were known to be common. Phylogenetic tree was constructed to these proteins usinf UPGMA and Maximum Likelihood methods in MEGA software has shown interaction of AChE and BChE with ageing diseases like Alzheimer’s disease and Diabetes. AChE has shown closely related to BChE, retinol dehydrogenase and β-polypeptide. The present studies is also accomplished that AChE, BChE, COLQ, HAND1, APP, NLGN2 and NGF proteins has interactions with diseases such as Alzheimer’s and D2M using Pathwaylinker and STRING. Medicinal compounds like Ortho-7, Dibucaine and HI-6 are predicted as good targets for modeled AChE and BChE proteins based on docking studies. Hence perceptive studies of cholinesterase structure and the biological mechanisms of inhibition are necessary for effective drug development. PMID:23936743

  17. Inhibitory Activity of (+)-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility

    PubMed Central

    Yang, Yi; Nguyen, Thanh Thi; Jeong, Min-Hye; Crişan, Florin; Yu, Young Hyun; Ha, Hyung-Ho; Choi, Kyung Hee; Jeong, Hye Gwang; Jeong, Tae Cheon; Lee, Kwang Youl; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2016-01-01

    Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+)-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+)-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+)-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+)-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+)-usnic acid and cetuximab. These results implied that (+)-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+)-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action. PMID:26751081

  18. Photolabeling a Nicotinic Acetylcholine Receptor (nAChR) with an (α4)3(β2)2 nAChR-Selective Positive Allosteric Modulator.

    PubMed

    Hamouda, Ayman K; Deba, Farah; Wang, Ze-Jun; Cohen, Jonathan B

    2016-05-01

    Positive allosteric modulators (PAMs) of nicotinic acetylcholine (ACh) receptors (nAChRs) have potential clinical applications in the treatment of nicotine dependence and many neuropsychiatric conditions associated with decreased brain cholinergic activity, and 3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrrazol-4-yl)isoxazole (CMPI) has been identified as a PAM selective for neuronal nAChRs containing theα4 subunit. In this report, we compare CMPI interactions with low-sensitivity (α4)3(β2)2 and high-sensitivity (α4)2(β2)3 nAChRs, and with muscle-type nAChRs. In addition, we use the intrinsic reactivity of [(3)H]CMPI upon photolysis at 312 nm to identify its binding sites inTorpedonAChRs. Recording fromXenopusoocytes, we found that CMPI potentiated maximally the responses of (α4)3(β2)2nAChR to 10μM ACh (EC10) by 400% and with anEC50of ∼1µM. CMPI produced a left shift of the ACh concentration-response curve without altering ACh efficacy. In contrast, CMPI inhibited (∼35% at 10µM) ACh responses of (α4)2(β2)3nAChRs and fully inhibited human muscle andTorpedonAChRs with IC50values of ∼0.5µM. Upon irradiation at 312 nm, [(3)H]CMPI photoincorporated into eachTorpedo[(α1)2β1γδ] nAChR subunit. Sequencing of peptide fragments isolated from [(3)H]CMPI-photolabeled nAChR subunits established photolabeling of amino acids contributing to the ACh binding sites (αTyr(190),αTyr(198),γTrp(55),γTyr(111),γTyr(117),δTrp(57)) that was fully inhibitable by agonist and lower-efficiency, state-dependent [(3)H]CMPI photolabeling within the ion channel. Our results establish that CMPI is a potent potentiator of nAChRs containing anα4:α4 subunit interface, and that its intrinsic photoreactivy makes it of potential use to identify its binding sites in the (α4)3(β2)2nAChR. PMID:26976945

  19. Cyclolinopeptides, cyclic peptides from flaxseed with osteoclast differentiation inhibitory activity.

    PubMed

    Kaneda, Toshio; Yoshida, Haruka; Nakajima, Yuki; Toishi, Minako; Nugroho, Alfarius Eko; Morita, Hiroshi

    2016-04-01

    Flaxseed (Linum usitatissimum seed) is widely used in food and natural health products. In our search for osteoclast differentiation inhibitors, some cyclic peptides isolated from flaxseed, known as the cyclolinopeptides, were discovered to have osteoclast differentiation inhibition activity. The osteoclast differentiation inhibition activity of cyclolinopeptides A-I (1-9) and their related derivatives (10-14) are described herein. Cyclolinopeptides F, H and I (6, 8 and 9), in particular, showed potent osteoclast differentiation inhibition activity. PMID:26923696

  20. Effect of reactive site loop elongation on the inhibitory activity of C1-inhibitor.

    PubMed

    Bos, Ineke G A; Lubbers, Yvonne T P; Eldering, Eric; Abrahams, Jan Pieter; Hack, C Erik

    2004-06-01

    The serine protease inhibitor C1-Inhibitor (C1-Inh) inhibits several complement- and contact-system proteases, which play an important role in inflammation. C1-Inh has a short reactive site loop (RSL) compared to other serpins. RSL length determines the inhibitory activity of serpins. We investigated the effect of RSL elongation on inhibitory activity of C1-Inh by insertion of one or two alanine residues in the RSL. One of five mutants had an increased association rate with kallikrein, but was nevertheless a poor inhibitor because of a simultaneous high stoichiometry of inhibition (>10). The association rate of the other variants was lower than that of wild-type C1-Inh. These data suggest that the relatively weak inhibitory activity of C1-Inh is not the result of its short RSL. The short RSL of C1-Inh has, surprisingly, the optimal length for inhibition.

  1. Radical scavenging and angiotensin converting enzyme inhibitory activities of standardized extracts of Ficus racemosa stem bark.

    PubMed

    Ahmed, Faiyaz; Siddesha, Jalahalli M; Urooj, Asna; Vishwanath, Bannikuppe S

    2010-12-01

    The present study evaluated the radical scavenging and angiotensin converting enzyme (ACE) inhibitory activity of cold and hot aqueous extracts of Ficus racemosa (Moraceae) stem bark. The extracts were standardized using HPLC. Radical scavenging activity was determined using 1,1-diphenyl-2-picrylhydrazyl radical and angiotensin converting enzyme inhibitory activity using rabbit lung and partially purified porcine kidney ACE. HPLC profiles of cold aqueous extract (FRC) showed the presence of bergenin, an isocoumarin, while hot aqueous extract (FRH) was found to contain ferulic acid, kaempferol and coumarin in addition to bergenin. FRH showed significantly higher (p ≤ 0.01) radical scavenging activity than FRC and butylated hydroxytoluene (BHT), consequently resulting in a significantly lower (p ≤ 0.01) IC₅₀ value than FRC and BHT. Both the extracts exhibited a dose dependent inhibition of porcine kidney and rabbit lung ACE. FRH showed significantly higher (p ≤ 0.01) activity than FRC with lower IC(50) values of 1.36 and 1.91 μg/mL respectively, for porcine kidney and rabbit lung ACE, compared with those of FRC (128 and 291 μg/mL). Further, a significant correlation (r = 0.893; p ≤ 0.05) was observed between radical scavenging activity and ACE-inhibitory activity. This is the first report on the ACE-inhibitory activity of F. racemosa stem bark suggesting its potential to be utilized as a therapeutic alternative for hypertension. PMID:20564493

  2. Behavioral state-specific inhibitory postsynaptic potentials impinge on cat lumbar motoneurons during active sleep.

    PubMed

    Morales, F R; Boxer, P; Chase, M H

    1987-11-01

    High-gain intracellular records were obtained from lumbar motoneurons in intact, undrugged cats during naturally occurring states of wakefulness, quiet sleep, and active sleep. Spontaneous, discrete, inhibitory postsynaptic potentials (IPSPs) were found to impinge on lumbar motoneurons during all states of sleep and wakefulness. IPSPs which occurred during wakefulness and quiet sleep were of relatively low amplitude and had a low frequency of occurrence. During the state of active sleep there occurred a great increase in inhibitory input. This was the result of the appearance of large-amplitude IPSPs and of an increase in the frequency of low-amplitude IPSPs which were indistinguishable from those recorded during wakefulness and quiet sleep. In addition to a difference in amplitude, the time course of the large IPSPs recorded during active sleep further differentiated them from the smaller IPSPs recorded during wakefulness, quiet sleep, and active sleep; i.e., their rise-time and half-width were of longer duration and their rate-of-rise was significantly faster. We suggest that the large, active sleep-specific IPSPs reflect the activity of a group of inhibitory interneurons which are inactive during wakefulness and quiet sleep and which discharge during active sleep. These as yet unidentified interneurons would then serve as the last link in the brain stem-spinal cord inhibitory system which is responsible for producing muscle atonia during the state of active sleep. PMID:3666087

  3. Inhibitory Activities of Alkyl Syringates and Related Compounds on Aflatoxin Production.

    PubMed

    Furukawa, Tomohiro; Iimura, Kurin; Kimura, Taichi; Yamamoto, Toshiyoshi; Sakuda, Shohei

    2016-06-07

    Inhibitors of aflatoxin production of aflatoxigenic fungi are useful for preventing aflatoxin contamination in crops. As methyl syringate weakly inhibits aflatoxin production, aflatoxin production inhibitory activities of additional alkyl syringates with alkyl chains from ethyl to octyl were examined. Inhibitory activity toward aflatoxin production of Aspergillus flavus became stronger as the length of the alkyl chains on the esters became longer. Pentyl, hexyl, heptyl, and octyl syringates showed strong activity at 0.05 mM. Heptyl and octyl parabens, and octyl gallate also inhibited aflatoxin production as strongly as octyl syringate. Alkyl parabens and alkyl gallates inhibit the complex II activity of the mitochondrial respiration chain; thus, whether alkyl syringates inhibit complex II activity was examined. Inhibitory activities of alkyl syringates toward complex II also became stronger as the length of the alkyl chains increased. The complex II inhibitory activity of octyl syringate was comparable to that of octyl paraben and octyl gallate. These results suggest that alkyl syringates, alkyl parabens, and alkyl gallates, including commonly used food additives, are useful for aflatoxin control.

  4. Costus afer Possesses Carbohydrate Hydrolyzing Enzymes Inhibitory Activity and Antioxidant Capacity In Vitro

    PubMed Central

    Tchamgoue, Armelle D.; Tchokouaha, Lauve R. Y.; Tarkang, Protus A.; Kuiate, Jules-Roger; Agbor, Gabriel A.

    2015-01-01

    Diabetes mellitus is a metabolic disorder of glucose metabolism which correlates with postprandial hyperglycemia and oxidative stress. Control of blood glucose level is imperative in the management of diabetes. The present study tested the hypothesis that Costus afer, an antihyperglycemic medicinal plant, possesses inhibitory activity against carbohydrate hydrolyzing enzymes. Hexane, ethyl acetate, methanol, and water extracts were prepared from the leaf, stem, and rhizome of C. afer and subjected to phytochemical screening, assayed for α-amylase and α-glucosidase inhibitory activities and antioxidant capacity (determined by total phenolic and total flavonoids contents, ferric reducing antioxidant power (FRAP), and DPPH radical scavenging activity). All extracts inhibited α-amylase and α-glucosidase activities. Ethyl acetate rhizome and methanol leaf extracts exhibited the best inhibitory activity against α-amylase and α-glucosidase (IC50: 0.10 and 5.99 mg/mL), respectively. Kinetic analysis revealed two modes of enzyme inhibition (competitive and mixed). All extracts showed antioxidant capacity, with hexane extracts exhibiting the best activity. DPPH assay revealed that methanol leaf, rhizome, and ethyl acetate stem extracts (IC50 < 5 mg/mL) were the best antioxidants. The presence of bioactive compounds such as flavonoids, alkaloids, phenols, and tannins may account for the antioxidant capacity and carbohydrate hydrolyzing enzyme inhibitory activity of C. afer. PMID:26246844

  5. Inhibitory Activities of Alkyl Syringates and Related Compounds on Aflatoxin Production.

    PubMed

    Furukawa, Tomohiro; Iimura, Kurin; Kimura, Taichi; Yamamoto, Toshiyoshi; Sakuda, Shohei

    2016-01-01

    Inhibitors of aflatoxin production of aflatoxigenic fungi are useful for preventing aflatoxin contamination in crops. As methyl syringate weakly inhibits aflatoxin production, aflatoxin production inhibitory activities of additional alkyl syringates with alkyl chains from ethyl to octyl were examined. Inhibitory activity toward aflatoxin production of Aspergillus flavus became stronger as the length of the alkyl chains on the esters became longer. Pentyl, hexyl, heptyl, and octyl syringates showed strong activity at 0.05 mM. Heptyl and octyl parabens, and octyl gallate also inhibited aflatoxin production as strongly as octyl syringate. Alkyl parabens and alkyl gallates inhibit the complex II activity of the mitochondrial respiration chain; thus, whether alkyl syringates inhibit complex II activity was examined. Inhibitory activities of alkyl syringates toward complex II also became stronger as the length of the alkyl chains increased. The complex II inhibitory activity of octyl syringate was comparable to that of octyl paraben and octyl gallate. These results suggest that alkyl syringates, alkyl parabens, and alkyl gallates, including commonly used food additives, are useful for aflatoxin control. PMID:27338472

  6. Inhibitory Activities of Alkyl Syringates and Related Compounds on Aflatoxin Production

    PubMed Central

    Furukawa, Tomohiro; Iimura, Kurin; Kimura, Taichi; Yamamoto, Toshiyoshi; Sakuda, Shohei

    2016-01-01

    Inhibitors of aflatoxin production of aflatoxigenic fungi are useful for preventing aflatoxin contamination in crops. As methyl syringate weakly inhibits aflatoxin production, aflatoxin production inhibitory activities of additional alkyl syringates with alkyl chains from ethyl to octyl were examined. Inhibitory activity toward aflatoxin production of Aspergillus flavus became stronger as the length of the alkyl chains on the esters became longer. Pentyl, hexyl, heptyl, and octyl syringates showed strong activity at 0.05 mM. Heptyl and octyl parabens, and octyl gallate also inhibited aflatoxin production as strongly as octyl syringate. Alkyl parabens and alkyl gallates inhibit the complex II activity of the mitochondrial respiration chain; thus, whether alkyl syringates inhibit complex II activity was examined. Inhibitory activities of alkyl syringates toward complex II also became stronger as the length of the alkyl chains increased. The complex II inhibitory activity of octyl syringate was comparable to that of octyl paraben and octyl gallate. These results suggest that alkyl syringates, alkyl parabens, and alkyl gallates, including commonly used food additives, are useful for aflatoxin control. PMID:27338472

  7. Inhibitory Activity of Podophyllotoxin and Matairesinol-derivative Lignans on the Root Growth of Brassica campestris.

    PubMed

    Arimoto, M; Matsuura, S; Muro, C; Tsujibo, H; Matsumura, E; Yamaguchi, H; Inamori, Y

    1994-01-01

    All the lignans tested in a bioassay with Brassica campestris L. subsp. rapa Hook. fil. et Anders inhibited the root growth of this plant, except for deoxypicropodophyllin. The effects of functional groups in the molecule on the inhibitory activity of these compounds were studied. It is suggested that the methylenedioxyl group and the stereochemical configuration of the lactone junction of podophyllotoxin derivatives were closely related to the inhibitory activity. The O-methyl derivative of two hydroxyl groups of matairesinol greatly enhanced the inhibition of root growth in this plant.

  8. Lipase inhibitory activity of chlorophyll a, isofucosterol and saringosterol isolated from chloroform fraction of Sargassum thunbergii.

    PubMed

    Kim, Koth-Bong-Woo-Ri; Kim, Min-Ji; Ahn, Dong-Hyun

    2014-01-01

    Three compounds (chlorophyll a, isofucosterol and saringosterol) were isolated from chloroform fraction of Sargassum thunbergii extract. The three compounds had two- to fourfold lower lipase inhibitory activity than that of the CHCl3:MeOH (C:M) (100:1) fraction (fraction I, 83.78% at 1 mg/mL). These results suggested that the high lipase inhibitory activity of fraction I was attributable to the actions of the three compounds. Therefore, S. thunbergii has potential for application as an anti-obesity agent.

  9. Inhibitory potential of some Romanian medicinal plants against enzymes linked to neurodegenerative diseases and their antioxidant activity

    PubMed Central

    Paun, Gabriela; Neagu, Elena; Albu, Camelia; Radu, Gabriel Lucian

    2015-01-01

    Context: Eryngium planum, Geum urbanum and Cnicus benedictus plants are an endemic botanical from the Romanian used in folk medicine. Objective: The extracts from three Romanian medicinal plants were investigated for their possible neuroprotective potential. Materials and Methods: Within this study, in vitro neuroprotective activity of the extracts of E. planum, G. urbanum, and C. benedictus plants were investigated via inhibition of acetylcholinesterase (AChE) and tyrosinase (TYR). Total content of phenolics, flavonoids, and proanthocyanidins, high-performance liquid chromatography profile of the main phenolic compounds and antioxidant activity were also determined. Results: Among the tested extracts, the best inhibition of AChE (88.76 ± 5.2%) and TYR (88.5 ± 5.2%) was caused by C. benedictus ethanol (EtOH) extract. The G. urbanum extracts exerted remarkable scavenging effect against 2, 2-diphenyl-1-picrylhydrazyl (IC50, 7.8 ± 0.5 μg/mL aqueous extract, and IC50, 1.3 ± 0.1 μg/mL EtOH extract, respectively) and reducing power, whereas the EtOH extract of C. benedictus showed high scavenging activity (IC50, 0.609 ± 0.04 mg/mL), also. Conclusion: According to our knowledge, this is the first study that demonstrates in vitro neuroprotective effects of E. planum, G. urbanum and C. benedictus. PMID:26109755

  10. Intensified vmPFC surveillance over PTSS under perturbed microRNA-608/AChE interaction

    PubMed Central

    Lin, T; Simchovitz, A; Shenhar-Tsarfaty, S; Vaisvaser, S; Admon, R; Hanin, G; Hanan, M; Kliper, E; Bar-Haim, Y; Shomron, N; Fernandez, G; Lubin, G; Fruchter, E; Hendler, T; Soreq, H

    2016-01-01

    Trauma causes variable risk of posttraumatic stress symptoms (PTSS) owing to yet-unknown genome–neuronal interactions. Here, we report co-intensified amygdala and ventromedial prefrontal cortex (vmPFC) emotional responses that may overcome PTSS in individuals with the single-nucleotide polymorphism (SNP) rs17228616 in the acetylcholinesterase (AChE) gene. We have recently shown that in individuals with the minor rs17228616 allele, this SNP interrupts AChE suppression by microRNA (miRNA)-608, leading to cortical elevation of brain AChE and reduced cortisol and the miRNA-608 target GABAergic modulator CDC42, all stress-associated. To examine whether this SNP has effects on PTSS and threat-related brain circuits, we exposed 76 healthy Israel Defense Forces soldiers who experienced chronic military stress to a functional magnetic resonance imaging task of emotional and neutral visual stimuli. Minor allele individuals predictably reacted to emotional stimuli by hyperactivated amygdala, a hallmark of PTSS and a predisposing factor of posttraumatic stress disorder (PTSD). Despite this, minor allele individuals showed no difference in PTSS levels. Mediation analyses indicated that the potentiated amygdala reactivity in minor allele soldiers promoted enhanced vmPFC recruitment that was associated with their limited PTSS. Furthermore, we found interrelated expression levels of several miRNA-608 targets including CD44, CDC42 and interleukin 6 in human amygdala samples (N=7). Our findings suggest that miRNA-608/AChE interaction is involved in the threat circuitry and PTSS and support a model where greater vmPFC regulatory activity compensates for amygdala hyperactivation in minor allele individuals to neutralize their PTSS susceptibility. PMID:27138800

  11. Inhibitory effects of cefotaxime on the activity of mushroom tyrosinase.

    PubMed

    Hu, Yong-Hua; Zhuang, Jiang-Xing; Yu, Feng; Cui, Yi; Yu, Wen-Wen; Yan, Chong-Ling; Chen, Qing-Xi

    2016-04-01

    Tyrosinase (EC 1.14.18.1) catalyzes both the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones that form brown or black pigments. In the present paper, cefotaxime, a cephalosporin antibacterial drug, was tested as an inhibitor of tyrosinase. The results show that cefotaxime inhibits both the monophenolase and diphenolase activities of tyrosinase. For the monophenolase activity, cefotaxime increased the lag time and decreased the steady-state activity with an IC50 of 3.2 mM. For the diphenolase activity, the inhibition by cefotaxime is reversible and mix-I type with an IC50 of 0.14 mM. The inhibition constants (K(I) and K(IS)) were determined to be 0.14 and 0.36 mM, respectively. The molecular mechanism of inhibition of tyrosinase by cefotaxime was determined by fluorescence quenching and molecular docking. The results demonstrated that cefotaxime was a static quencher of tyrosinase and that cefotaxime could dock favorably in the active site of tyrosinase. This research may offer a lead for designing and synthesizing novel and effective tyrosinase inhibitors in the future.

  12. Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities

    PubMed Central

    Lv, Wei; Liu, Jinzhong; Skaar, Todd C.; Flockhart, David A.; Cushman, Mark

    2015-01-01

    Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer. PMID:25751283

  13. Ultrasonic extraction of polysaccharides from Laminaria japonica and their antioxidative and glycosidase inhibitory activities

    NASA Astrophysics Data System (ADS)

    Wan, Peng; Yang, Xiaoman; Cai, Bingna; Chen, Hua; Sun, Huili; Chen, Deke; Pan, Jianyu

    2015-08-01

    In the present study, ultrasonic extraction technique (UET) is used to improve the yield of polysaccharides from Laminaria japonica (LJPs). And their antioxidative as well as glycosidase inhibitory activities are investigated. Box-Behnken design (BBD) combined with response surface methodology (RSM) is applied to optimize ultrasonic extraction for polysaccharides. The optimized conditions are obtained as extraction time at 54 min, ultrasonic power at 1050 W, extraction temperature at 80°C and ratio of material to solvent at 1:50 (g mL-1). Under these optimal ultrasonic extraction conditions, an actual experimental yield (5.75% ± 0.3%) is close to the predicted result (5.67%) with no significant difference ( P > 0.05). Vitro antioxidative and glycosidase inhibitory activities tests indicate that the crude polysaccharides (LJP) and two major ethanol precipitated fractions (LJP1 and LJP2) are in a concentration-dependent manner. LJP2 (30%-60% ethanol precipitated polysaccharides) possesses the strongest α-glucosidase inhibitory activity and moderate scavenging activity against hydroxyl radicals (66.09% ± 2.19%, 3.0 mg mL-1). Also, the inhibitory activity against α-glucosidase (59.08% ± 3.79%, 5.0 mg mL-1) is close to that of acarbose (63.99% ± 3.27%, 5.0 mg mL-1). LJP1 (30% ethanol precipitated polysaccharides) exhibits the strongest scavenging activity against hydroxyl radicals (99.80% ± 0.00%, 3.0 mg mL-1) and moderate α-glucosidase inhibitory activity (47.76% ± 1.92%, 5.0 mg mL-1). LJP shows the most remarkable DPPH scavenging activity (66.20% ± 0.11%, 5.0 mg mL-1) but weakest α-glucosidase inhibitory activity (37.77% ± 1.30%, 5.0 mg mL-1). However, all these LJPs exert weak inhibitory effects against α-amylase. These results show that UET is an effective method for extracting bioactive polysaccharides from seaweed materials. LJP1 and LJP2 can be developed as a potential ingredient in hypoglycemic agents or functional food for the management of

  14. Activation of phosphorothionate pesticides based on a cytochrome P450 BM-3 (CYP102 A1) mutant for expanded neurotoxin detection in food using acetylcholinesterase biosensors.

    PubMed

    Schulze, Holger; Schmid, Rolf D; Bachmann, Till T

    2004-03-15

    A novel enzymatic in vitro activation method for phosphorothionates has been developed to allow their detection with acetylcholinesterase (AChE) biosensors. Activation is necessary because this group of insecticides shows nearly no inhibitory effect toward AChE in their pure nonmetabolized form. In contrast, they exert a strong inhibitory effect on AChE after oxidation as it takes place by metabolic activation in higher organisms. Standard chemical methods to oxidize phosphorothionates showed inherent disadvantages that impede their direct use in food analysis. In contrast, a genetically engineered triple mutant of P450 BM-3 (CYP102 A1) could convert the two frequently used insecticides parathion and chlorpyrifos into their oxo variants as was confirmed by GC/MS measurements. The wild-type protein was unable to do so. In the case of chlorpyrifos, the enzymatic activation was as good as the chemical oxidation. In the case of parathion, the P450 activation was more efficient than the oxidation by NBS but neither activation method yielded an AChE inhibition that was as high as with paraoxon. The application of the method to infant food in combination with a disposable AChE biosensor enabled detection of chlorpyrifos and parathion at concentrations down to 20 microg/kg within an overall assay time of 95 min. PMID:15018574

  15. Competition between activating and inhibitory processes in photobiology

    NASA Astrophysics Data System (ADS)

    Friedmann, Harry; Lubart, Rachel

    1996-01-01

    We discuss light-induced stimulation and inhibition of biological activity by means of three types of competing processes. In the visible region, these competing processes are the formation by photosensitization of reactive oxygen species (ROS) which stimulate the redox activity of the respiratory chain (RC) on the one hand, and intramolecular electronic- vibrational energy transfer from an endogenous photosensitizer to an enzyme of the RC, thereby bringing this enzyme into an inactive configuration and paralyzing the RC, on the other hand. Moreover, there is competition between stimulation of the redox activity of the RC by the ROS and a slower process where the enzymes of the RC react with the ROS, again paralyzing the RC. This paralysis of the RC plays a dominant role in photodynamic therapy, where exogenous photosensitizers together with a sufficiently large visible light-energy dose lead to overproduction of ROS. Finally, in the far-red region, there is competition between reactivation of the ATPase ion pumps in the cell membrane and inhibition of the enzymes in the RC as a result of vibrational overtone excitation. Photobioactivation is shown to lead to enhanced transient Ca2+ concentration increase (calcium oscillations) in the cytosol, thereby triggering further biological activity such as afflux of intercellular messengers which open gated ion channels in neighboring cells, producing calcium waves. Addition of ROS scavengers or quenchers such as SOD in the presence of catalase neutralizes photobiomodulation induced by visible light.

  16. Involvement of β3-adrenoceptors in the inhibitory control of cholinergic activity in human bladder: Direct evidence by [(3)H]-acetylcholine release experiments in the isolated detrusor.

    PubMed

    D' Agostino, Gianluigi; Maria Condino, Anna; Calvi, Paolo

    2015-07-01

    Bladder overactivity (OAB) is a multifactorial bladder disorder that requires therapeutics superior to the current pharmacological treatment with muscarinic antagonists. β3-adrenoceptor (β3-ADR) agonists represent a novel promising approach that differently addresses the parasympathetic pathway, but the clinical efficacy of these drugs has not been fully elucidated to date. Therefore, we aimed to study the pharmacological mechanisms activated by β3-ADR agonists at muscular and neural sites in the isolated human bladder. Detrusor smooth muscle strips obtained from male patients undergoing total cystectomy were labelled with tritiated choline and stimulated with electrical field stimulation (EFS). EFS produced smooth muscle contraction and simultaneous acetylcholine ([(3)H]-ACh) release, which mostly reflects the neural origin of acetylcholine. Isoprenaline (INA), BRL37344 and mirabegron inhibited the EFS-evoked contraction and [(3)H]-ACh release in a concentration-dependent manner, yielding concentration-response curves (CRCs) that were shifted to the right by the selective β3-ADR antagonists L-748,337 and SR59230A. Based on the agonist potency estimates (pEC50) and apparent affinities (pKb) of antagonists evaluated from the CRCs of agonists, our data confirm the occurrence of β3-ADRs at muscle sites. Moreover, our data are consistent with the presence of inhibitory β3-ADRs that are functionally expressed at the neural site. Taken together, these findings elucidate the mechanisms activated by β3-ADR agonists because neural β3-ADRs participate in the inhibition of detrusor motor drive by reducing the amount of acetylcholine involved in the cholinergic pathway. PMID:25861936

  17. Acetylcholinesterase inhibitory dimeric indole derivatives from the marine actinomycetes Rubrobacter radiotolerans.

    PubMed

    Li, Jian Lin; Huang, Lei; Liu, Juan; Song, Yan; Gao, Jie; Jung, Jee H; Liu, Yonghong; Chen, Guangtong

    2015-04-01

    Investigation of the bioactive secondary metabolites of the marine actinomycetes Rubrobacter radiotolerans led to the isolation and characterization of two naturally rare dimeric indole derivatives (1 and 2). The structures of these new compounds were elucidated by spectroscopic data interpretation, and the absolute configurations were assigned by CD calculations. The acetylcholinesterase (AchE) inhibitory activity of compounds 1 and 2 was evaluated, both of which showed moderate activity with IC50 values of 11.8 and 13.5μM, respectively.

  18. Angiotensin converting enzyme inhibitory activity of soy protein subjected to selective hydrolysis and thermal processing.

    PubMed

    Margatan, Wynnie; Ruud, Kirsten; Wang, Qian; Markowski, Todd; Ismail, Baraem

    2013-04-10

    Soy protein isolate (SPI) and β-conglycinin- and glycinin-rich fractions were hydrolyzed using papain and pepsin. Protein denaturation, profiling, and peptide identification were carried out following DSC, SDS-PAGE, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The in vitro antihypertensive activity of the hydrolysates was compared by determining the angiotensin converting enzyme (ACE) inhibitory activity. SDS-PAGE and LC-MS/MS analysis confirmed pepsin selectivity to glycinin and papain partial selectivity to β-conglycinin when the protein is least denatured. Both the papain-hydrolyzed SPI and the papain-hydrolyzed β-conglycinin-rich fraction had more than double the ACE inhibitory activity of that of pepsin-hydrolyzed SPI and pepsin-hydrolyzed glycinin-rich fraction. This observation indicated that β-conglycinin is a better precursor for antihypertensive peptides than glycinin. Additionally, the inhibitory activity of the papain-hydrolyzed SPI was thermally stable. This work demonstrated, for the first time, that selective hydrolysis to release peptides with ACE inhibitory activity can be accomplished without inducing extensive hydrolysis and performing unnecessary fractionation. PMID:23514371

  19. Pyochelin potentiates the inhibitory activity of gallium on Pseudomonas aeruginosa.

    PubMed

    Frangipani, Emanuela; Bonchi, Carlo; Minandri, Fabrizia; Imperi, Francesco; Visca, Paolo

    2014-09-01

    Gallium (Ga) is an iron mimetic that has successfully been repurposed for antibacterial chemotherapy. To improve the antibacterial potency of Ga on Pseudomonas aeruginosa, the effect of complexation with a variety of siderophores and synthetic chelators was tested. Ga complexed with the pyochelin siderophore (at a 1:2 ratio) was more efficient than Ga(NO3)3 in inhibiting P. aeruginosa growth, and its activity was dependent on increased Ga entrance into the cell through the pyochelin translocon.

  20. Pyochelin potentiates the inhibitory activity of gallium on Pseudomonas aeruginosa.

    PubMed

    Frangipani, Emanuela; Bonchi, Carlo; Minandri, Fabrizia; Imperi, Francesco; Visca, Paolo

    2014-09-01

    Gallium (Ga) is an iron mimetic that has successfully been repurposed for antibacterial chemotherapy. To improve the antibacterial potency of Ga on Pseudomonas aeruginosa, the effect of complexation with a variety of siderophores and synthetic chelators was tested. Ga complexed with the pyochelin siderophore (at a 1:2 ratio) was more efficient than Ga(NO3)3 in inhibiting P. aeruginosa growth, and its activity was dependent on increased Ga entrance into the cell through the pyochelin translocon. PMID:24957826

  1. COX-2 and sPLA2 inhibitory activity of aqueous extract and polyphenols of Rhizophora mangle (red mangrove).

    PubMed

    Marrero, Evangelina; Sánchez, Janet; de Armas, Elizabeth; Escobar, Arturo; Melchor, Gleiby; Abad, M J; Bermejo, Paulina; Villar, Angel M; Megías, J; Alcaraz, Maria J

    2006-06-01

    The aqueous extract of Rhizophora mangle bark and its polyphenolic fractions showed remarkable in vitro antiinflammatory activity in a preliminary study. The low molecular weight fraction exhibited cyclooxygenase-2 inhibitory activity while the total aqueous extract and the low molecular weight fraction showed secretory phospholipase A(2) inhibitory activity. PMID:16698195

  2. An Update on Natural Products with Carbonic Anhydrase Inhibitory Activity.

    PubMed

    Karioti, Anastasia; Carta, Fabrizio; Supuran, Claudiu T

    2016-01-01

    Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological processes. They represent a typical example of enzyme convergent evolution, as six genetically unrelated families of such enzymes were described so far. It is more than 70 years that synthetic compounds, mainly sulfonamides, have been used in clinical practice as diuretics and systemic acting antiglaucoma drugs. Recent studies using natural product libraries and isolated constituents from natural sources (such as fungi and plants) have disclosed novel chemotypes possessing carbonic anhydrase inhibition activities. These natural sources offer new opportunities in the search for new and more effective carbonic anhydrase inhibitors, and may serve as new leads for the design and development of future drugs. This review will discuss the most recent advances in the search of naturally occurring products and their synthetic derivatives that inhibit the CAs and their mechanisms of action at molecular level. Plant extracts are not considered in the present review. PMID:26654592

  3. Matrix metalloproteinase-1 inhibitory activity of Kaempferia pandurata Roxb.

    PubMed

    Shim, Jae-Seok; Choi, Eun-Jung; Lee, Chan-Woo; Kim, Han-Sung; Hwang, Jae-Kwan

    2009-06-01

    Matrix metalloproteinase (MMP)-1 is a superfamily of zinc-dependent endopeptidases that are capable of degrading all components of the extracellular matrix. Kaempferia pandurata extract (0.01-0.5 microg/mL) significantly reduced the expression of MMP-1 and induced the expression of type 1 procollagen at the protein and mRNA levels in a dose-dependent manner. Ultraviolet (UV)-induced MMP-1 initiates cleavage of fibrillar collagen. Once cleaved by MMP-1, collagen can be further degraded by elevated levels of MMP-3 and MMP-9. It was found that increased MMP-1 expression due to UV irradiation was mediated by activation of mitogen-activated protein kinases such as extracellular-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38 kinase. Treatment of K. pandurata extract in the range of 0.01-0.5 microg/mL inhibited the UV-induced phosphorylations of ERK, JNK, and p38, respectively. Moreover, inhibition of phosphorylated ERK, JNK, and p38 by K. pandurata extract resulted in decreased c-Fos expression and c-Jun phosphorylation induced by UV light. The results strongly suggest that K. pandurata is potentially useful for the prevention and treatment of skin aging.

  4. Evaluation of the Antioxidant Activities and Tyrosinase Inhibitory Property from Mycelium Culture Extracts

    PubMed Central

    Park, Ki Moon; Kwon, Kyung Min; Lee, Seung Ho

    2015-01-01

    Since mushrooms have many bioactive components, they have been used as components in folk medicine. Because mycelium has an advantage when it comes to large-scale production, this study aimed to evaluate the antioxidant properties and anti-tyrosinase activity from 55 mycelia in culture media. Relatively high 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging capacity was detected from the ethanol extract of culture media including mycelium (EECiM) of Morchella esculenta var. esculenta (MEVE), Auricularia polytricha (APO), Tremella aurantia (TAU), Volvariella bombycina (VBO), and Oudemansiella sp. (Osp), which also showed strong reducing power and inhibitory activity in relation to the thiobarbituric acid (TBA) value. On the other hand, relatively high tyrosinase inhibitory activity was detected in Inonotus mikadoi (IMI), Coriolus versicolor (CVE), Volvariella volvacea (VVO), Panellus serotinus (PSE), Auricularia auricula (AAU), and Fomitopsis sp. (Fsp). Interestingly, the APO EECiM exhibited the highest DPPH radical scavenging rate (77.5 ± 4.3%) and reducing power (1.18 ± 0.041), while the highest inhibitory power of the TBA value and antityrosinase activity were detected in that of TAU (64.5 ± 4.1%) and IMI (46.0 ± 7.5%), respectively. Overall, our study suggested potential candidates for EECiMs that exhibited powerful antioxidant and tyrosinase inhibitory properties and might be used as natural antioxidant tyrosinase inhibitor. PMID:26345142

  5. Nobiletin metabolites: synthesis and inhibitory activity against matrix metalloproteinase-9 production.

    PubMed

    Oshitari, Tetsuta; Okuyama, Yuji; Miyata, Yoshiki; Kosano, Hiroshi; Takahashi, Hideyo; Natsugari, Hideaki

    2011-08-01

    A divergent synthesis of nobiletin metabolites was developed through highly oxygenated acetophenone derivative. We used commercially available methyl 3,4,5-trimethoxybenzoate as a starting material for concise preparation of the key intermediate, 2'-hydroxy-3',4',5',6'-tetramethoxyacetophenone (I). These metabolites showed strong inhibitory activity against matrix metalloproteinase-9 production in human lens epithelial cells.

  6. Phenolic constituents of Carex vulpinoidea seeds and their tyrosinase inhibitory activities.

    PubMed

    Niesen, Daniel B; Ma, Hang; Yuan, Tao; Bach, Alvin C; Henry, Geneive E; Seeram, Navindra P

    2015-03-01

    Two new phenolics, a stilbenoid, vulpinoideol A (1), and a chalcone, vulpinoideol B (2), along with ten known compounds (3-12) were isolated from Carex vulpinoidea Michx. seeds. The structures of compounds 1-12 were elucidated based on spectrometric and spectroscopic analyses including HRESIMS, 1D and 2D NMR data. All compounds were evaluated for their tyrosinase enzyme inhibitory activities.

  7. Bioactive diterpenoids from Trigonostemon chinensis: Structures, NO inhibitory activities, and interactions with iNOS.

    PubMed

    Xu, Jing; Peng, Maoqin; Sun, Xiaocong; Liu, Xingyu; Tong, Ling; Su, Guochen; Ohizumi, Yasushi; Lee, Dongho; Guo, Yuanqiang

    2016-10-01

    A phytochemical investigation to obtain new NO inhibitors led to the isolation of two new (1 and 2) and four known (3-6) diterpenoids from Trigonostemon chinensis. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analyses, and the absolute configurations of new compounds were established by experimental and calculated ECD spectra. The inhibitory activities on lipopolysaccharide-induced NO production in murine microglial BV-2 cells of these diterpenoids were evaluated, and all of the compounds showed inhibitory effects. The interactions of bioactive compounds with iNOS protein were also studied by molecular docking. PMID:27570243

  8. Activity Prediction and Molecular Mechanism of Bovine Blood Derived Angiotensin I-Converting Enzyme Inhibitory Peptides

    PubMed Central

    Zhang, Ting; Nie, Shaoping; Liu, Boqun; Yu, Yiding; Zhang, Yan; Liu, Jingbo

    2015-01-01

    Development of angiotensin I-converting enzyme (ACE, EC 3.4.15.1) inhibitory peptides from food protein is under extensive research as alternative for the prevention of hypertension. However, it is difficult to identify peptides released from food sources. To accelerate the progress of peptide identification, a three layer back propagation neural network model was established to predict the ACE-inhibitory activity of pentapeptides derived from bovine hemoglobin by simulated enzyme digestion. The pentapeptide WTQRF has the best predicted value with experimental IC50 23.93 μM. The potential molecular mechanism of the WTQRF / ACE interaction was investigated by flexible docking. PMID:25768442

  9. Activity prediction and molecular mechanism of bovine blood derived angiotensin I-converting enzyme inhibitory peptides.

    PubMed

    Zhang, Ting; Nie, Shaoping; Liu, Boqun; Yu, Yiding; Zhang, Yan; Liu, Jingbo

    2015-01-01

    Development of angiotensin I-converting enzyme (ACE, EC 3.4.15.1) inhibitory peptides from food protein is under extensive research as alternative for the prevention of hypertension. However, it is difficult to identify peptides released from food sources. To accelerate the progress of peptide identification, a three layer back propagation neural network model was established to predict the ACE-inhibitory activity of pentapeptides derived from bovine hemoglobin by simulated enzyme digestion. The pentapeptide WTQRF has the best predicted value with experimental IC50 23.93 μM. The potential molecular mechanism of the WTQRF / ACE interaction was investigated by flexible docking. PMID:25768442

  10. Blumeaenes A-J, sesquiterpenoid esters from Blumea balsamifera with NO inhibitory activity.

    PubMed

    Chen, Ming; Qin, Jiang-Jiang; Fu, Jian-Jun; Hu, Xiao-Jia; Liu, Xiao-Hua; Zhang, Wei-Dong; Jin, Hui-Zi

    2010-06-01

    Chemical examination of the ethanol extract of the aerial parts of Blumea balsamifera led to the isolation of ten new sesquiterpenoid esters, blumeaenes A-J (1- 10), with 13 known flavonoids. Their structures were determined mainly by use of 1D and 2D NMR spectroscopic techniques. All sesquiterpenoid esters were tested for their inhibitory activity against LPS-induced NO production in RAW264.7 macrophages. Compounds 1, 4 and 5 showed slight inhibitory effect on the production of NO with IC(50) values of 40.06, 46.35 and 57.80 microg/mL, respectively. PMID:20101563

  11. Protein glycation inhibitory activity and antioxidant capacity of clove extract.

    PubMed

    Suantawee, Tanyawan; Wesarachanon, Krittaporn; Anantsuphasak, Kanokphat; Daenphetploy, Tanuch; Thien-Ngern, Sroshin; Thilavech, Thavaree; Pasukamonset, Porntip; Ngamukote, Sathaporn; Adisakwattana, Sirichai

    2015-06-01

    Syzygium aromaticum (L.) (clove) is one of the most widely cultivated spices in many tropical countries. The aim of this study was to determine the phytochemical content, the antioxidant properties and the antiglycation properties of aqueous extract of clove against fructose-mediated protein glycation and oxidation. The result showed that the content of total phenolics and flavonoids in clove extract was 239.58 ± 0.70 mg gallic acid equivalents/g dried extract and 65.67 ± 0.01 mg catechin equivalents/g dried extract, respectively. In addition, clove exhibited antioxidant properties including DPPH radical scavenging activity (IC50 = 0.29 ± 0.01 mg/ml), Trolox equivalent antioxidant capacity (4.69 ± 0.03 μmol Trolox equivalents/mg dried extract), ferric reducing antioxidant power (20.55 ± 0.11 μmol ascorbic acid equivalents/mg dried extract), Oxygen radical absorbance capacity (31.12 ± 0.21 μmol Trolox equivalents/mg dried extract), hydroxyl radical scavenging activity (0.15 ± 0.04 mg Trolox equivalents/mg dried extract), and superoxide radical scavenging activity (18.82 ± 0.50 mg Trolox equivalents/mg dried extract). The aqueous extract of clove (0.25-1.00 mg/ml) significantly inhibited the formation of fluorescent advanced glycation end products (AGEs) and non-fluorescent AGEs (N(ɛ)-(carboxymethyl) lysine (CML)) in glycated BSA during 4 weeks of incubation. The extract also markedly prevented oxidation-induced protein damage by decreasing protein carbonyl formation and protecting against the loss of protein thiol group. These results clearly demonstrated that a polyphenol enriched clove extract, owing to its antioxidant, was capable to inhibit the formation of AGEs and protein glycation. The findings might lead to the possibility of using the clove extract for targeting diabetic complications.

  12. Urease Inhibitory Activities of some Commonly Consumed Herbal Medicines.

    PubMed

    Mahernia, Shabnam; Bagherzadeh, Kowsar; Mojab, Faraz; Amanlou, Massoud

    2015-01-01

    Urease enzyme has a crucial role in the persistent habitation of Helicobacter pylori (H. pylori) that induces gastrointestinal diseases, in particular gastritis, duodenal, peptic ulcer, and gastric cancer. Plants have long been utilized as the biggest source of substances with medicinal properties from natural origin and therefore result in less toxicity and adverse side effects upon usage. 15 medicinal plant extracts were examined against Jack bean urease activity by Berthelot reaction. Each herb was extracted using 80% aqueous methanol. The more effective extracts were further tested and their IC50 values were determined. Three plant extracts including Ginkgo biloba, Rhus coriaria, and Matricaria inodora were found to be the most effective ones with IC50 values of 36.17, 80.29, and 100.6 μg/mL, respectively. PMID:26330884

  13. Urease Inhibitory Activities of some Commonly Consumed Herbal Medicines

    PubMed Central

    Mahernia, Shabnam; Bagherzadeh, Kowsar; Mojab, Faraz; Amanlou, Massoud

    2015-01-01

    Urease enzyme has a crucial role in the persistent habitation of Helicobacter pylori (H. pylori) that induces gastrointestinal diseases, in particular gastritis, duodenal, peptic ulcer, and gastric cancer. Plants have long been utilized as the biggest source of substances with medicinal properties from natural origin and therefore result in less toxicity and adverse side effects upon usage. 15 medicinal plant extracts were examined against Jack bean urease activity by Berthelot reaction. Each herb was extracted using 80% aqueous methanol. The more effective extracts were further tested and their IC50 values were determined. Three plant extracts including Ginkgo biloba, Rhus coriaria, and Matricaria inodora were found to be the most effective ones with IC50 values of 36.17, 80.29, and 100.6 μg/mL, respectively. PMID:26330884

  14. Natural Product Compounds with Aromatase Inhibitory Activity: An Update

    PubMed Central

    Balunas, Marcy J.; Kinghorn, A. Douglas

    2010-01-01

    Several synthetic aromatase inhibitors are currently in clinical use for the treatment of postmenopausal women with hormone-receptor positive breast cancer. However, these treatments may lead to untoward side effects and so a search for new aromatase inhibitors continues, especially those for which the activity is promoter-specific, targeting the breast-specific promoters I.3 and II. Recently, numerous natural product compounds have been found to inhibit aromatase in non-cellular, cellular, and in vivo studies. These investigations, covering the last two years, as well as additional studies that have focused on the evaluation of natural product compounds as promoter-specific aromatase inhibitors or as aromatase inducers, are described in this review. PMID:20635310

  15. A novel inhibitory nucleo-cortical circuit controls cerebellar Golgi cell activity

    PubMed Central

    Ankri, Lea; Husson, Zoé; Pietrajtis, Katarzyna; Proville, Rémi; Léna, Clément; Yarom, Yosef; Dieudonné, Stéphane; Uusisaari, Marylka Yoe

    2015-01-01

    The cerebellum, a crucial center for motor coordination, is composed of a cortex and several nuclei. The main mode of interaction between these two parts is considered to be formed by the inhibitory control of the nuclei by cortical Purkinje neurons. We now amend this view by showing that inhibitory GABA-glycinergic neurons of the cerebellar nuclei (CN) project profusely into the cerebellar cortex, where they make synaptic contacts on a GABAergic subpopulation of cerebellar Golgi cells. These spontaneously firing Golgi cells are inhibited by optogenetic activation of the inhibitory nucleo-cortical fibers both in vitro and in vivo. Our data suggest that the CN may contribute to the functional recruitment of the cerebellar cortex by decreasing Golgi cell inhibition onto granule cells. DOI: http://dx.doi.org/10.7554/eLife.06262.001 PMID:25965178

  16. Angiotensin I-Converting Enzyme (ACE) Inhibitory Activity and ACE Inhibitory Peptides of Salmon (Salmo salar) Protein Hydrolysates Obtained by Human and Porcine Gastrointestinal Enzymes

    PubMed Central

    Darewicz, Małgorzata; Borawska, Justyna; Vegarud, Gerd E.; Minkiewicz, Piotr; Iwaniak, Anna

    2014-01-01

    The objectives of the present study were two-fold: first, to detect whether salmon protein fractions possess angiotensin I-converting enzyme (ACE) inhibitory properties and whether salmon proteins can release ACE inhibitory peptides during a sequential in vitro hydrolysis (with commercial porcine enzymes) and ex vivo digestion (with human gastrointestinal enzymes). Secondly, to evaluate the ACE inhibitory activity of generated hydrolysates. A two-step ex vivo and in vitro model digestion was performed to simulate the human digestion process. Salmon proteins were degraded more efficiently by porcine enzymes than by human gastrointestinal juices and sarcoplasmic proteins were digested/hydrolyzed more easily than myofibrillar proteins. The ex vivo digested myofibrillar and sarcoplasmic duodenal samples showed IC50 values (concentration required to decrease the ACE activity by 50%) of 1.06 and 2.16 mg/mL, respectively. The in vitro hydrolyzed myofibrillar and sarcoplasmic samples showed IC50 values of 0.91 and 1.04 mg/mL, respectively. Based on the results of in silico studies, it was possible to identify 9 peptides of the ex vivo hydrolysates and 7 peptides of the in vitro hydrolysates of salmon proteins of 11 selected peptides. In both types of salmon hydrolysates, ACE-inhibitory peptides IW, IY, TVY and VW were identified. In the in vitro salmon protein hydrolysates an ACE-inhibitory peptides VPW and VY were also detected, while ACE-inhibitory peptides ALPHA, IVY and IWHHT were identified in the hydrolysates generated with ex vivo digestion. In our studies, we documented ACE inhibitory in vitro effects of salmon protein hydrolysates obtained by human and as well as porcine gastrointestinal enzymes. PMID:25123137

  17. Angiotensin I-converting enzyme (ACE) inhibitory activity and ACE inhibitory peptides of salmon (Salmo salar) protein hydrolysates obtained by human and porcine gastrointestinal enzymes.

    PubMed

    Darewicz, Małgorzata; Borawska, Justyna; Vegarud, Gerd E; Minkiewicz, Piotr; Iwaniak, Anna

    2014-08-13

    The objectives of the present study were two-fold: first, to detect whether salmon protein fractions possess angiotensin I-converting enzyme (ACE) inhibitory properties and whether salmon proteins can release ACE inhibitory peptides during a sequential in vitro hydrolysis (with commercial porcine enzymes) and ex vivo digestion (with human gastrointestinal enzymes). Secondly, to evaluate the ACE inhibitory activity of generated hydrolysates. A two-step ex vivo and in vitro model digestion was performed to simulate the human digestion process. Salmon proteins were degraded more efficiently by porcine enzymes than by human gastrointestinal juices and sarcoplasmic proteins were digested/hydrolyzed more easily than myofibrillar proteins. The ex vivo digested myofibrillar and sarcoplasmic duodenal samples showed IC50 values (concentration required to decrease the ACE activity by 50%) of 1.06 and 2.16 mg/mL, respectively. The in vitro hydrolyzed myofibrillar and sarcoplasmic samples showed IC50 values of 0.91 and 1.04 mg/mL, respectively. Based on the results of in silico studies, it was possible to identify 9 peptides of the ex vivo hydrolysates and 7 peptides of the in vitro hydrolysates of salmon proteins of 11 selected peptides. In both types of salmon hydrolysates, ACE-inhibitory peptides IW, IY, TVY and VW were identified. In the in vitro salmon protein hydrolysates an ACE-inhibitory peptides VPW and VY were also detected, while ACE-inhibitory peptides ALPHA, IVY and IWHHT were identified in the hydrolysates generated with ex vivo digestion. In our studies, we documented ACE inhibitory in vitro effects of salmon protein hydrolysates obtained by human and as well as porcine gastrointestinal enzymes.

  18. Synthesis and quorum sensing inhibitory activity of key phenolic compounds of ginger and their derivatives.

    PubMed

    Kumar, N Vijendra; Murthy, Pushpa S; Manjunatha, J R; Bettadaiah, B K

    2014-09-15

    Phenolic components of ginger (Zingiber officinale Roscoe) viz. [6]-gingerol, [6]-shogaol and zingerone exhibited quorum sensing inhibitory activity (QSI) against Chromobacterium violaceum and Pseudomonas aeruginosa. The inhibitory activity of all the compounds was studied by zone inhibition, pyocyanin, and violacein assay. All the compounds displayed good inhibition at 500ppm. [6]-Azashogaol, a new derivative of [6]-shogaol has been synthesized by Beckmann rearrangement of its oxime in the presence of ZnCl2. The structure elucidation of this new derivative was carried out by 1D ((1)H NMR and (13)C NMR) and 2D-NMR (COSY, HSQC and NOESY) spectral studies. This compound showed good QSI activity against P. aeruginosa. An isoxazoline derivative of [6]-gingerol was prepared and it exhibited good QSI activity. Present study illustrated that, the phenolic compounds of ginger and their derivatives form a class of compounds with promising QSI activity. PMID:24767081

  19. Inhibitory effect of morinda citrifolia L. On lipoprotein lipase activity.

    PubMed

    Pak-Dek, M S; Abdul-Hamid, A; Osman, A; Soh, C S

    2008-10-01

    Efficacy of Morinda citrifolia L. leaf (MLE) and fruit extracts (MFE) in inhibiting lipoprotein lipase (LPL) was determined in vitro. The result of the study showed that the highest inhibition on the LPL activity was exhibited by MLE (66%+/- 2.1%), which is significantly higher than that demonstrated by MFE (54.5%+/- 2.5%), green tea extract (GTE) (54.5%+/- 2.6%), and catechin (43.6%+/- 6.1%). Percent of LPL inhibition increase with concentration of the extracts. Quantitative analysis of the extracts revealed the presence of high levels of (+)-catechin at 63.5 +/- 17 and 53.7 +/- 5.7 mg/g in MLE and MFE, respectively, although not as high as that found in GTE (530.6 +/- 42 mg/g). Appreciable amount of epicatechin was found in all extracts tested, while rutin was only found in MLE and MFE. The study suggested that both leaf and fruit of M. citrifolia may be used as antiobesity agents in body weight management.

  20. Estimation of excitatory and inhibitory synaptic conductance variations in motoneurons during locomotor-like rhythmic activity.

    PubMed

    Kobayashi, Ryota; Nishimaru, Hiroshi; Nishijo, Hisao

    2016-10-29

    The rhythmic activity of motoneurons (MNs) that underlies locomotion in mammals is generated by synaptic inputs from the locomotor network in the spinal cord. Thus, the quantitative estimation of excitatory and inhibitory synaptic conductances is essential to understand the mechanism by which the network generates the functional motor output. Conductance estimation is obtained from the voltage-current relationship measured by voltage-clamp- or current-clamp-recording with knowledge of the leak parameters of the recorded neuron. However, it is often difficult to obtain sufficient data to estimate synaptic conductances due to technical difficulties in electrophysiological experiments using in vivo or in vitro preparations. To address this problem, we estimated the average variations in excitatory and inhibitory synaptic conductance during a locomotion cycle from a single voltage trace without measuring the leak parameters. We found that the conductance variations can be accurately reconstructed from a voltage trace of 10 cycles by analyzing synthetic data generated from a computational model. Next, the conductance variations were estimated from mouse spinal MNs in vitro during drug-induced-locomotor-like activity. We found that the peak of excitatory conductance occurred during the depolarizing phase of the locomotor cycle, whereas the peak of inhibitory conductance occurred during the hyperpolarizing phase. These results suggest that the locomotor-like activity is generated by push-pull modulation via excitatory and inhibitory synaptic inputs. PMID:27561702

  1. Inhibitory effect of several fluoroquinolones on hepatic microsomal cytochrome P-450 1A activities in dogs.

    PubMed

    Regmi, N L; Abd El-Aty, A M; Kuroha, M; Nakamura, M; Shimoda, M

    2005-12-01

    We examined inhibitory effects of ofloxacin (OFX), orbifloxacin (OBFX), ciprofloxacin (CFX), enrofloxacin (EFX) and norfloxacin (NFX) on cytochrome P-450 1A (CYP1A) activities using hepatic microsomes from four beagle dogs. Ethoxyresorufin O-de-ethylation was referred as CYP1A activities. All the fluoroquinolones inhibited the reaction in a noncompetitive manner. The determined inhibitory constants were the followings; 10.1 +/- 3.8 mM for OFX, 6.43 +/- 2.01 mM for OBFX, 0.726 +/- 0.134 mM for CFX, 4.06 +/- 1.19 mM for EFX and 4.75 +/- 1.63 mM for NFX respectively. As these values are >100-fold of plasma concentrations after a clinical single dose of the fluoroquinolones, it is suggested that the inhibitory effect on CYP1A activities is not so high to elicit drug-drug interaction with CYP1A substrates, when these fluoroquinolones are co-administered. Mechanism based inhibition was also examined in this study. Of the five fluoroquinolones examined, OFX, OBFX and CFX had this inhibition manner. As this inhibition is irreversible, inhibitory effects of the three fluoroquinolones may accumulate, when they are repeatedly administered. Therefore, OFX, OBFX and CFX may result in substantial drug-drug interaction with a CYP1A substrate even in clinical states. As EFX is metabolized to CFX in the body, it may also have the same possibility.

  2. Sugar compositions, α-glucosidase inhibitory and amylase inhibitory activities of polysaccharides from leaves and flowers of Camellia sinensis obtained by different extraction methods.

    PubMed

    Wang, Yuanfeng; Yang, Zhiwei; Wei, Xinlin

    2010-11-01

    The sugar compositions, α-glucosidase inhibitory and α-amylase inhibitory activities of polysaccharides from leaves and flowers of green tea (Camellia sinensis) obtained by hot water extraction (HWE), boiled water extraction (BWE) and enzymatic extraction (EE) were investigated. The yields, sugar contents and monosaccharide compositions of tea leaves polysaccharides (TLPS) and tea flower polysaccharides (TFPS) were all significantly affected by extraction methods. The contents of acidic polysaccharides (APS) extracted by BWE and EE were both much more than those by HWE. The yields of TLPS and TFPS were determined as EE>BWE>HWE. Enzyme and higher temperature could improve the contents of APS and yields of TLPS and TFPS. TLPS and TFPS were all mainly composed of Rha, Ara, Gal, Glu and GalA, very little molar contents of GluA, Xyl and Man. It seemed that enzyme extraction could be more conducive to increase the content of Ara, Gal and GaLA. The molecular weights of TFPS were larger than those of TLPS. The molecular weights of polysaccharides obtained by EE decreased. Proteins in tea leaves and tea flowers might be decomposed by EE by observing UV peaks and IR absorption. peaks. The α-glucosidase inhibitory and amylase inhibitory activities of TLPS and TFPS obtained by EE were lower than those by water extracted method. The inhibitory percentages of TLPS and TFPS against α-amylase were all lower than α-glucosidase for different extractions.

  3. Effect of Jatropha curcas Peptide Fractions on the Angiotensin I-Converting Enzyme Inhibitory Activity

    PubMed Central

    Segura-Campos, Maira R.; Peralta-González, Fanny; Castellanos-Ruelas, Arturo; Chel-Guerrero, Luis A.; Betancur-Ancona, David A.

    2013-01-01

    Hypertension is one of the most common worldwide diseases in humans. Angiotensin I-converting enzyme (ACE) plays an important role in regulating blood pressure and hypertension. An evaluation was done on the effect of Alcalase hydrolysis of defatted Jatropha curcas kernel meal on ACE inhibitory activity in the resulting hydrolysate and its purified fractions. Alcalase exhibited broad specificity and produced a protein hydrolysate with a 21.35% degree of hydrolysis and 34.87% ACE inhibition. Ultrafiltration of the hydrolysate produced peptide fractions with increased biological activity (24.46–61.41%). Hydrophobic residues contributed substantially to the peptides' inhibitory potency. The 5–10 and <1 kDa fractions were selected for further fractionation by gel filtration chromatography. ACE inhibitory activity (%) ranged from 22.66 to 45.96% with the 5–10 kDa ultrafiltered fraction and from 36.91 to 55.83% with the <1 kDa ultrafiltered fraction. The highest ACE inhibitory activity was observed in F2 (IC50 = 6.7 μg/mL) from the 5–10 kDa fraction and F1 (IC50 = 4.78 μg/mL) from the <1 kDa fraction. ACE inhibitory fractions from Jatropha kernel have potential applications in alternative hypertension therapies, adding a new application for the Jatropha plant protein fraction and improving the financial viability and sustainability of a Jatropha-based biodiesel industry. PMID:24224169

  4. Chemical Evidence for Potent Xanthine Oxidase Inhibitory Activity of Ethyl Acetate Extract of Citrus aurantium L. Dried Immature Fruits.

    PubMed

    Liu, Kun; Wang, Wei; Guo, Bing-Hua; Gao, Hua; Liu, Yang; Liu, Xiao-Hong; Yao, Hui-Li; Cheng, Kun

    2016-03-02

    Xanthine oxidase is a key enzyme which can catalyze hypoxanthine and xanthine to uric acid causing hyperuricemia in humans. Xanthine oxidase inhibitory activities of 24 organic extracts of four species belonging to Citrus genus of the family Rutaceae were assayed in vitro. Since the ethyl acetate extract of C. aurantium dried immature fruits showed the highest xanthine oxidase inhibitory activity, chemical evidence for the potent inhibitory activity was clarified on the basis of structure identification of the active constituents. Five flavanones and two polymethoxyflavones were isolated and evaluated for inhibitory activity against xanthine oxidase in vitro. Of the compounds, hesperetin showed more potent inhibitory activity with an IC50 value of 16.48 μM. For the first time, this study provides a rational basis for the use of C. aurantium dried immature fruits against hyperuricemia.

  5. Antioxidant, antimicrobial and tyrosinase inhibitory activities of xanthones isolated from Artocarpus obtusus F.M. Jarrett.

    PubMed

    Hashim, Najihah Mohd; Rahmani, Mawardi; Ee, Gwendoline Cheng Lian; Sukari, Mohd Aspollah; Yahayu, Maizatulakmal; Amin, Muhamad Aizat Mohd; Ali, Abd Manaf; Go, Rusea

    2012-05-21

    One of the most promising plants in biological screening test results of thirteen Artocarpus species was Artocarpus obtusus FM Jarrett and detailed phytochemical investigation of powdered dried bark of the plant has led to the isolation and identification of three xanthones; pyranocycloartobiloxanthone A (1), dihydroartoindonesianin C (2) and pyranocycloartobiloxanthone B (3). These compounds were screened for antioxidant, antimicrobial and tyrosinase inhibitory activities. Pyranocycloartobiloxanthone A (1) exhibited a strong free radical scavenger towards DPPH free radicals with IC50 value of 2 µg/mL with prominent discoloration observed in comparison with standard ascorbic acid, α-tocopherol and quercetin, The compound also exhibited antibacterial activity against methicillin resistant Staphylococcus aureus (ATCC3359) and Bacillus subtilis (clinically isolated) with inhibition zone of 20 and 12 mm, respectively. However the other two xanthones were found to be inactive. For the tyrosinase inhibitory activity, again compound (1) displayed strong activity comparable with the standard kojic acid.

  6. Secondary Metabolites Produced by an Endophytic Fungus Pestalotiopsis sydowiana and Their 20S Proteasome Inhibitory Activities.

    PubMed

    Xia, Xuekui; Kim, Soonok; Liu, Changheng; Shim, Sang Hee

    2016-01-01

    Fungal endophytes have attracted attention due to their functional diversity. Secondary metabolites produced by Pestalotiopsis sydowiana from a halophyte, Phragmites communis Trinus, were investigated. Eleven compounds, including four penicillide derivatives (1-4) and seven α-pyrone analogues (5-10) were isolated from cultures of P. sydowiana. The compounds were identified based on spectroscopic data. The inhibitory activities against the 20S proteasome were evaluated. Compounds 1-3, 5, and 9-10 showed modest proteasome inhibition activities, while compound 8 showed strong activity with an IC50 of 1.2 ± 0.3 μM. This is the first study on the secondary metabolites produced by P. sydowiana and their proteasome inhibitory activities. The endophytic fungus P. sydowiana might be a good resource for proteasome inhibitors. PMID:27447600

  7. 2'-Epi-uscharin from the latex of Calotropis gigantea with HIF-1 inhibitory activity.

    PubMed

    Parhira, Supawadee; Zhu, Guo-Yuan; Jiang, Ren-Wang; Liu, Liang; Bai, Li-Ping; Jiang, Zhi-Hong

    2014-04-23

    Two stereoisomeric cardenolides, uscharin (1) and a new compound, 2'-epi-uscharin (2), were isolated from the latex of Calotropis gigantea (Asclepiadaceae). Their structures were fully elucidated based on their spectroscopic data, X-ray crystallographic data and chemical evidences. Both epimers (1 and 2) exhibited strong inhibitory effects on HIF-1 activity with different magnitudes. Compound 1 showed much more potent activity than 2 and digoxin, a well-known HIF-1 inhibitor. Discrepancy in potencies between 1 and 2 revealed the contribution of a β-configuration of 2' hydroxyl moiety for HIF-1 inhibitory activity. This is a first report of the activity of HIF-1 inhibition of thiazoline ring-containing cardenolides.

  8. 2‧-Epi-uscharin from the Latex of Calotropis gigantea with HIF-1 Inhibitory Activity

    NASA Astrophysics Data System (ADS)

    Parhira, Supawadee; Zhu, Guo-Yuan; Jiang, Ren-Wang; Liu, Liang; Bai, Li-Ping; Jiang, Zhi-Hong

    2014-04-01

    Two stereoisomeric cardenolides, uscharin (1) and a new compound, 2'-epi-uscharin (2), were isolated from the latex of Calotropis gigantea (Asclepiadaceae). Their structures were fully elucidated based on their spectroscopic data, X-ray crystallographic data and chemical evidences. Both epimers (1 and 2) exhibited strong inhibitory effects on HIF-1 activity with different magnitudes. Compound 1 showed much more potent activity than 2 and digoxin, a well-known HIF-1 inhibitor. Discrepancy in potencies between 1 and 2 revealed the contribution of a β-configuration of 2' hydroxyl moiety for HIF-1 inhibitory activity. This is a first report of the activity of HIF-1 inhibition of thiazoline ring-containing cardenolides.

  9. Inhibitory role of monovalent ions on rat brain cortex adenylyl cyclase activity.

    PubMed

    Nikolic, Ivana; Mitrovic, Marina; Zelen, Ivanka; Zaric, Milan; Kastratovic, Tatjana; Stanojevic, Marijana; Nenadovic, Milutin; Stojanovic, Tomislav

    2013-10-01

    Adenylyl cyclases, comprise of a large family of enzymes that catalyze synthesis of the cyclic AMP from ATP. The aim of our study was to determine the effect of monovalent ions on both basal, stimulated adenylate cyclase EC 4.6.1.1 (AC) activity and C unit of AC and on GTPase active G-protein in the synaptic membranes of rat brain cortex. The effect of ion concentration from 30 to 200 mM (1 mM MgCl2) showed dose-dependent and significant inhibition of the basal AC activity, stimulated and unstimulated C unit activity. Stimulation of AC with 5 μM GTPγS in the presence of 50-200 mM of tested salts showed inhibitory effect on the AC activity. From our results it could be postulated that the investigated monovalent ions exert inhibitory effect on the AC complex activity by affecting the intermolecular interaction of the activated α subunit of G/F protein and the C unit of AC complex an inhibitory influence of tested monovalent ions on these molecular interaction.

  10. Use of a novel radiometric method to assess the inhibitory effect of donepezil on acetylcholinesterase activity in minimally diluted tissue samples

    PubMed Central

    Kikuchi, Tatsuya; Okamura, Toshimitsu; Arai, Takuya; Obata, Takayuki; Fukushi, Kiyoshi; Irie, Toshiaki; Shiraishi, Tetsuya

    2010-01-01

    Background and purpose: Cholinesterase inhibitors have been widely used for the treatment of patients with dementia. Monitoring of the cholinesterase activity in the blood is used as an indicator of the effect of the cholinesterase inhibitors in the brain. The selective measurement of cholinesterase with low tissue dilution is preferred for accurate monitoring; however, the methods have not been established. Here, we investigated the effect of tissue dilution on the action of cholinesterase inhibitors using a novel radiometric method with selective substrates, N-[14C]methylpiperidin-4-yl acetate ([14C]MP4A) and (R)-N-[14C]methylpiperidin-3-yl butyrate ([14C]MP3B_R), for AChE and butyrylcholinesterase (BChE) respectively. Experimental approach: We investigated the kinetics of hydrolysis of [14C]-MP4A and [14C]-MP3B_R by cholinesterases, and evaluated the selectivity of [14C]MP4A and [14C]MP3B_R for human AChE and BChE, respectively, compared with traditional substrates. Then, IC50 values of cholinesterase inhibitors in minimally diluted and highly diluted tissues were measured with [14C]MP4A and [14C]MP3B_R. Key results: AChE and BChE activities were selectively measured as the first-order hydrolysis rates of [14C]-MP4A and [14C]MP3B_R respectively. The AChE selectivity of [14C]MP4A was an order of magnitude higher than traditional substrates used for the AChE assay. The IC50 values of specific AChE and BChE inhibitors, donepezil and ethopropazine, in 1.2-fold diluted human whole blood were much higher than those in 120-fold diluted blood. In addition, the IC50 values of donepezil in monkey brain were dramatically decreased as the tissue was diluted. Conclusions and implications: This method would effectively monitor the activity of cholinesterase inhibitors used for therapeutics, pesticides and chemical warfare agents. PMID:20401964

  11. Effect of hyperoxaluria on the inhibitory activity of a 45-kD urinary protein.

    PubMed

    Selvam, Ramasamy; Balakrishnan, Selvakumar; Kalaiselvi, Periandavan

    2002-02-01

    Proteins are thought to play a major role in stone formation and structurally abnormal proteins have been reported to be present in the urine of stone formers. This study was aimed to determine whether hyperoxaluria modifies the kinetic properties of urinary inhibitory proteins. Hyperoxaluria was induced by feeding 1% ethylene glycol to rats. Oxalate, uric acid and calcium excretion were increased progressively during hyperoxaluria, while magnesium level was decreased. Urinary proteins were separated on a DEAE-cellulose column by eluting with stepwise increasing salt concentration in 0.05 M Tris-HCl buffer (pH 7.0). Each protein fraction was studied for its crystallization inhibitory potential by the spectrophotometric method. The protein eluted in 0.3 M NaCl containing buffer had the maximal nucleation as well as inhibitory activity. The protein had a molecular weight of 45 kD. In hyperoxaluria, the urinary excretion of this protein significantly increased. In the crystal growth assay, the control rat 45-kD protein inhibited nucleation by 75% and aggregation by 100%. In contrast, it is very interesting to note that the protein derived from 28th day hyperoxaluric urine, behaved as a promoter of nucleation (-113%, percentage inhibition) and weak inhibitor of aggregation (28%). A significantly high negative correlation (r = -0.97) between oxalate excretion and the inhibitory activity of the 45-kD protein was observed suggesting a modification of the protein by oxalate. PMID:11818706

  12. Telomerase inhibitory effects of medicinal mushrooms and lichens, and their anticancer activity.

    PubMed

    Xu, Baojun; Li, Chantian; Sung, Changkeun

    2014-01-01

    Telomerase has been widely accepted as a cancer marker and a promising therapeutic target for novel anticancer drugs. The aim of this study was to investigate the in vitro telomerase inhibitory effects of mushrooms and their anticancer properties. The inhibitory effects of mushrooms and lichens against telomerase activity of HL-60 cells were systematically assessed using polymerase chain reaction based on assay of telomeric repeat amplification protocol. Telomerase inhibitory samples were further tested for antiproliferation effects against the gastric cell line SNU-1 using the MTT method. Ethyl acetate extract of Pleurotus ostreatus, ethyl acetate and water extracts of Lasiosphaera fenzlii, hexane extract of Strobilomyces floccopus, water extract of Sarcodon aspratus, and hexane, ethyl acetate, and water extracts from Umbilicaria esculenta showed strong positive telomerase inhibitory activity. Hexane extract of S. floccopus and water extracts from the edible lichen U. esculenta exhibited strong anticancer effects against SNU-1 cells through antiproliferation assay. The water extract of U. esculenta has a great potential to be developed into an anticancer agent that targets telomerase.

  13. Cytochrome P450-inhibitory activity of parabens and phthalates used in consumer products.

    PubMed

    Ozaki, Hitomi; Sugihara, Kazumi; Watanabe, Yoko; Ohta, Shigeru; Kitamura, Shigeyuki

    2016-01-01

    The in vitro cytochrome P450 (CYP)-inhibitory effects of 11 parabens and 7 phthalates used in consumer products, as well as their hydrolytic metabolites, were investigated, using rat liver microsomes as an enzyme source. The effects on individual CYP isozymes were evaluated by assaying inhibition of activities towards specific substrates, i.e., ethoxyresorufin O-dealkylase (EROD), methoxyresorufin O-dealkylase (MROD), pentoxyresorufin O-dealkylase (PROD), 7-benzyloxy-4-trifluoromethylcoumarin dealkylase (BFCD), 7-methoxy-4-trifluoromethylcoumarin dealkylase (MFCD) and 7-ethoxy-4-trifluoromethylcoumarin dealkylase (EFCD) activities. These activities were dose-dependently inhibited, most potently by medium-side-chain parabens (C6-9) and phthalates (C4-6), and less potently by shorter- and longer-side-chain esters. The hydrolytic product of parabens, 4-hydroxybenzoic acid, was not inhibitory, while those of phthalates, phthalic acid monoesters, showed lower inhibitory activity than the parent phthalates. Parabens showed relatively potent inhibition of MFCD activity, considered to be mainly due to CYP2C, and phthalates showed relatively potent inhibition of PROD activity, considered to be mainly due to CYP2B. PMID:27432241

  14. Cytochrome P450-inhibitory activity of parabens and phthalates used in consumer products.

    PubMed

    Ozaki, Hitomi; Sugihara, Kazumi; Watanabe, Yoko; Ohta, Shigeru; Kitamura, Shigeyuki

    2016-01-01

    The in vitro cytochrome P450 (CYP)-inhibitory effects of 11 parabens and 7 phthalates used in consumer products, as well as their hydrolytic metabolites, were investigated, using rat liver microsomes as an enzyme source. The effects on individual CYP isozymes were evaluated by assaying inhibition of activities towards specific substrates, i.e., ethoxyresorufin O-dealkylase (EROD), methoxyresorufin O-dealkylase (MROD), pentoxyresorufin O-dealkylase (PROD), 7-benzyloxy-4-trifluoromethylcoumarin dealkylase (BFCD), 7-methoxy-4-trifluoromethylcoumarin dealkylase (MFCD) and 7-ethoxy-4-trifluoromethylcoumarin dealkylase (EFCD) activities. These activities were dose-dependently inhibited, most potently by medium-side-chain parabens (C6-9) and phthalates (C4-6), and less potently by shorter- and longer-side-chain esters. The hydrolytic product of parabens, 4-hydroxybenzoic acid, was not inhibitory, while those of phthalates, phthalic acid monoesters, showed lower inhibitory activity than the parent phthalates. Parabens showed relatively potent inhibition of MFCD activity, considered to be mainly due to CYP2C, and phthalates showed relatively potent inhibition of PROD activity, considered to be mainly due to CYP2B.

  15. Muscarinic ACh Receptors Contribute to Aversive Olfactory Learning in Drosophila

    PubMed Central

    Silva, Bryon; Molina-Fernández, Claudia; Ugalde, María Beatriz; Tognarelli, Eduardo I.; Angel, Cristian; Campusano, Jorge M.

    2015-01-01

    The most studied form of associative learning in Drosophila consists in pairing an odorant, the conditioned stimulus (CS), with an unconditioned stimulus (US). The timely arrival of the CS and US information to a specific Drosophila brain association region, the mushroom bodies (MB), can induce new olfactory memories. Thus, the MB is considered a coincidence detector. It has been shown that olfactory information is conveyed to the MB through cholinergic inputs that activate acetylcholine (ACh) receptors, while the US is encoded by biogenic amine (BA) systems. In recent years, we have advanced our understanding on the specific neural BA pathways and receptors involved in olfactory learning and memory. However, little information exists on the contribution of cholinergic receptors to this process. Here we evaluate for the first time the proposition that, as in mammals, muscarinic ACh receptors (mAChRs) contribute to memory formation in Drosophila. Our results show that pharmacological and genetic blockade of mAChRs in MB disrupts olfactory aversive memory in larvae. This effect is not explained by an alteration in the ability of animals to respond to odorants or to execute motor programs. These results show that mAChRs in MB contribute to generating olfactory memories in Drosophila. PMID:26380118

  16. Contributions of β2 subunit-containing nAChRs to chronic nicotine-induced alterations in cognitive flexibility in mice

    PubMed Central

    Cole, Robert D.; Poole, Rachel L.; Guzman, Dawn M.; Gould, Thomas J.; Parikh, Vinay

    2014-01-01

    Rationale Deficits in executive functions underlie compulsive drug use and understanding how nicotine influences these cognitive processes may provide important information on neurobiological substrates of nicotine addiction. Accumulating evidence suggests that β2 subunit-containing nicotinic receptors (nAChRs) are involved in the reinforcing process of nicotine addiction. Whether these nAChRs also contributes to the detrimental effects of chronic nicotine on flexible decision-making is not known. Objectives In the present study, the effects of chronic nicotine were assessed in mice with partial or complete deletion of the β2-subunit containing nAChR gene (β2+/- or β2-/-) performing an operant cognitive flexibility task. Results Visual discrimination learning was not affected in saline-treated β2 nAChR mutants as compared to the wild-type (β2+/+) mice; yet, chronic nicotine facilitated acquisition of visual discrimination in all genotypes. The acquisition of new egocentric response strategy set-shifting remained similar in all genotypes and there was no effect of treatment. Chronic nicotine treatment impaired reversal learning in β2+/+ mice by increasing response perseveration to the previously rewarded stimulus. Moreover, the acquisition of inverted stimulus-reward contingencies did not differ between β2+/+ and β2-/- mice exposed to chronic nicotine. Interestingly, nicotine-induced reversal learning deficits were not observed in β2+/- mice. Conclusions Collectively, these findings suggest that β2 subunit-containing nAChRs are not critical for visual discrimination learning and extradimensional rule shift. However, sustained activation of these nAChRs with nicotine may interfere with inhibitory control processes influencing affective shifts in stimulus-reward contingencies. PMID:25281224

  17. Acute larvicidal activity against mosquitoes and oxygen consumption inhibitory activity of dihydroguaiaretic acid derivatives.

    PubMed

    Nishiwaki, Hisashi; Tabara, Yoshimi; Kishida, Taro; Nishi, Kosuke; Shuto, Yoshihiro; Sugahara, Takuya; Yamauchi, Satoshi

    2015-03-11

    (-)-Dihydroguaiaretic acid (DGA) and its derivatives having 3-hydroxyphenyl (3-OH-DGA) and variously substituted phenyl groups instead of 3-hydroxy-4-methoxyphenyl groups were synthesized to measure their larvicidal activity against the mosquito Culex pipiens Linnaeus, 1758 (Diptera: Culicidae). Compared with DGA and 3-OH-DGA (LC50 (M), 3.52 × 10(-5) and 4.57 × 10(-5), respectively), (8R,8'R)-lignan-3-ol (3) and its 3-Me (10), 2-OH (12), 3-OH (13), and 2-OMe (15) derivatives showed low potency (ca. 6-8 × 10(-5) M). The 4-Me derivative (11) showed the lowest potency (12.1 × 10(-5) M), and the 2-F derivative (4) showed the highest (2.01 × 10(-5) M). All of the synthesized compounds induced an acute toxic symptom against mosquito larvae, with potency varying with the type and position of the substituents. The 4-F derivative (6), which killed larvae almost completely within 45 min, suppressed the O2 consumption of the mitochondrial fraction, demonstrating that this compound inhibited mitochondrial O2 consumption contributing to a respiratory inhibitory activity.

  18. Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons.

    PubMed

    Drew, Liam J; Kheirbek, Mazen A; Luna, Victor M; Denny, Christine A; Cloidt, Megan A; Wu, Melody V; Jain, Swati; Scharfman, Helen E; Hen, René

    2016-06-01

    Robust incorporation of new principal cells into pre-existing circuitry in the adult mammalian brain is unique to the hippocampal dentate gyrus (DG). We asked if adult-born granule cells (GCs) might act to regulate processing within the DG by modulating the substantially more abundant mature GCs. Optogenetic stimulation of a cohort of young adult-born GCs (0 to 7 weeks post-mitosis) revealed that these cells activate local GABAergic interneurons to evoke strong inhibitory input to mature GCs. Natural manipulation of neurogenesis by aging-to decrease it-and housing in an enriched environment-to increase it-strongly affected the levels of inhibition. We also demonstrated that elevating activity in adult-born GCs in awake behaving animals reduced the overall number of mature GCs activated by exploration. These data suggest that inhibitory modulation of mature GCs may be an important function of adult-born hippocampal neurons. © 2015 Wiley Periodicals, Inc.

  19. A cortico-hippocampal learning rule shapes inhibitory microcircuit activity to enhance hippocampal information flow

    PubMed Central

    Basu, Jayeeta; Srinivas, Kalyan V.; Cheung, Stephanie K.; Taniguchi, Hiroki; Huang, Z. Josh

    2013-01-01

    Summary How does coordinated activity between distinct brain regions implement a set of learning rules to sculpt information processing in a given neural circuit? Using interneuron cell-type specific optical activation and pharmacogenetic silencing in vitro, we show that temporally precise pairing of direct entorhinal perforant path (PP) and trisynaptic Schaffer collateral (SC) inputs to CA1 pyramidal cells selectively suppresses SC-associated perisomatic inhibition from cholecystokinin (CCK) expressing interneurons. The CCK interneurons provide a surprisingly strong feed-forward inhibitory drive to effectively control the coincident excitation of CA1 pyramidal neurons by convergent inputs. Thus, in-phase cortico-hippocampal activity provides a powerful heterosynaptic learning rule for long-term gating of information flow through the hippocampal excitatory macrocircuit by the silencing of the CCK inhibitory microcircuit. PMID:24050406

  20. Antimicrobial and quorum sensing inhibitory activities of the pericarp of Garcinia mangostana.

    PubMed

    Asfour, Hani Z

    2016-07-01

    A prenylated xanthone, α-mangostin was separated from the alcoholic extract of Garcinia mangostana pericarp. Its structure was established by different spectroscopic analysis. The total methanolic extract (TME) and different fractions of G. mangostana pericarp as well as α-mangostin were assessed for their antimicrobial and quorum sensing inhibitory effects (QSI). The TME, CHCl3 fraction, and α-mangostin exhibited strong activity against all tested strains. While, EtOAc, n-BuOH, and aqueous fractions showed moderate activity against some of the tested organisms. In addition TME, CHCl3, EtOAc, and α-mangostin showed promising QSI, while n-BuOH and aqueous fractions showed moderate activity. Minimal inhibitory concentration (MIC) for TME, CHCl3 fractions, and α-mangostin was also assessed. PMID:27592485

  1. Inhibitory effect of vanillin on cellulase activity in hydrolysis of cellulosic biomass.

    PubMed

    Li, Yun; Qi, Benkun; Wan, Yinhua

    2014-09-01

    Pretreatment of lignocellulosic material produces a wide variety of inhibitory compounds, which strongly inhibit the following enzymatic hydrolysis of cellulosic biomass. Vanillin is a kind of phenolics derived from degradation of lignin. The effect of vanillin on cellulase activity for the hydrolysis of cellulose was investigated in detail. The results clearly showed that vanillin can reversibly and non-competitively inhibit the cellulase activity at appropriate concentrations and the value of IC50 was estimated to be 30 g/L. The inhibition kinetics of cellulase by vanillin was studied using HCH-1 model and inhibition constants were determined. Moreover, investigation of three compounds with similar structure of vanillin on cellulase activity demonstrated that aldehyde group and phenolic hydroxyl groups of vanillin had inhibitory effect on cellulase. These results provide valuable and detailed information for understanding the inhibition of lignin derived phenolics on cellulase.

  2. Synthesis of some novel hydrazone and 2-pyrazoline derivatives: monoamine oxidase inhibitory activities and docking studies.

    PubMed

    Evranos-Aksöz, Begüm; Yabanoğlu-Çiftçi, Samiye; Uçar, Gülberk; Yelekçi, Kemal; Ertan, Rahmiye

    2014-08-01

    A novel series of 2-pyrazoline and hydrazone derivatives were synthesized and investigated for their human monoamine oxidase (hMAO) inhibitory activity. All compounds inhibited the hMAO isoforms (MAO-A or MAO-B) competitively and reversibly. With the exception of 5i, which was a selective MAO-B inhibitor, all derivatives inhibited hMAO-A potently and selectively. According to the experimental Ki values, compounds 6e and 6h exhibited the highest inhibitory activity towards the hMAO-A, whereas compound 5j, which carries a bromine atom at R(4) of the A ring of the pyrazoline, appeared to be the most selective MAO-A inhibitor. Tested compounds were docked computationally into the active site of the hMAO-A and hMAO-B isozymes. The computationally obtained results were in good agreement with the corresponding experimental values.

  3. Isolation and analysis of polysaccharide showing high hyaluronidase inhibitory activity in Nostochopsis lobatus MAC0804NAN.

    PubMed

    Yamaguchi, Yuji; Koketsu, Mamoru

    2016-03-01

    An active substance with high hyaluronidase inhibitory effect was isolated from the edible cyanobacterium Nostochopsis lobatus MAC0804NAN strain and characterized. The active component in the hot water extract was purified by anion exchange and gel filtration chromatography and was found to be a polysaccharide. The IC(50) against hyaluronidase of the purified polysaccharide was 7.18 μg/ml whose inhibitory activity is 14.5 times stronger than that of disodium cromoglycate (DSCG), an anti-allergy medication. The carbohydrate composition which was analyzed by GC-MS and NMR was found to be composed mainly of glucose, glucuronic acid, fucose, 2-O-methylfucose, mannose, galactose and xylose.

  4. Inhibitory compound of tyrosinase activity from the sprout of Polygonum hydropiper L. (Benitade).

    PubMed

    Miyazawa, Mitsuo; Tamura, Naotaka

    2007-03-01

    A tyrosinase inhibitor was isolated from the sprout of Polygonum hydropiper L. (Benitade) by activity-guided fractionation and identified as (2R,3R)-+-taxifolin (1) by spectroscopic means. Compound 1 inhibited 70% of tyrosinase activity at a concentration of 0.50 mM. ID50 (50% inhibition dose) value of compound 1 was 0.24 mM. As compared with tyrosinase inhibitor known cosmetic agent such as arbutin and kojic acid, compound 1 was more inhibited than the former and showed inhibitory effect equal to that of the latter. To study the inhibitory effect of (2R,3R)-+-taxifolin derivatives against tyrosinase activity, 3,7,3',4'-taxifolin tetraacetate (2) and 5,7,3',4'-taxifolin teramethyl ether (3) were also assayed together with compound 1.

  5. Oncostatin M and leukaemia inhibitory factor trigger signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 pathways but result in heterogeneous cellular responses in trophoblast cells.

    PubMed

    Chaiwangyen, Wittaya; Ospina-Prieto, Stephanie; Morales-Prieto, Diana M; Pereira de Sousa, Francisco Lazaro; Pastuschek, Jana; Fitzgerald, Justine S; Schleussner, Ekkehard; Markert, Udo R

    2016-04-01

    Leukaemia inhibitory factor (LIF) and oncostatin M (OSM) are pleiotropic cytokines present at the implantation site that are important for the normal development of human pregnancy. These cytokines share the cell membrane receptor subunit gp130, resulting in similar functions. The aim of this study was to compare the response to LIF and OSM in several trophoblast models with particular regard to intracellular mechanisms and invasion. Four trophoblast cell lines with different characteristics were used: HTR-8/SVneo, JEG-3, ACH-3P and AC1-M59 cells. Cells were incubated with LIF, OSM (both at 10ngmL(-1)) and the signal transducer and activator of transcription (STAT) 3 inhibitor S3I-201 (200µM). Expression and phosphorylation of STAT3 (tyr(705)) and extracellular regulated kinase (ERK) 1/2 (thr(202/204)) and the STAT3 DNA-binding capacity were analysed by Western blotting and DNA-binding assays, respectively. Cell viability and invasiveness were assessed by the methylthiazole tetrazolium salt (MTS) and Matrigel assays. Enzymatic activity of matrix metalloproteinase (MMP)-2 and MMP-9 was investigated by zymography. OSM and LIF triggered phosphorylation of STAT3 and ERK1/2, followed by a significant increase in STAT3 DNA-binding activity in all tested cell lines. Stimulation with LIF but not OSM significantly enhanced invasion of ACH-3P and JEG-3 cells, but not HTR-8/SVneo or AC1-M59 cells. Similarly, STAT3 inhibition significantly decreased the invasiveness of only ACH-3P and JEG-3 cells concomitant with decreases in secreted MMP-2 and MMP-9. OSM shares with LIF the capacity to activate ERK1/2 and STAT3 pathways in all cell lines tested, but their resulting effects are dependent on cell type. This suggests that LIF and OSM may partially substitute for each other in case of deficiencies or therapeutic interventions. PMID:25247600

  6. Evaluation of the effect of Thai breadfruit's heartwood extract on melanogenesis-inhibitory and antioxidation activities.

    PubMed

    Donsing, Piyaporn; Limpeanchob, Nanteetip; Viyoch, Jarupa

    2008-01-01

    The aim of this study was to clarify the melanogenesis-inhibitory and antioxidant activity of Thai breadfruit's heartwood extract for application as a skin-lightening agent. The heartwood of breadfruit (Artocarpus incisus ) grown in Phitsanulok Province, Thailand, was extracted by using diethyl ether or methanol. The amount of artocarpin, a major component of A. incisus extract, was determined by using the HPLC method. The artocarpin content found in ether extract was 45.19 +/- 0.45% w/w, whereas that in methanol extract was 19.61 +/- 0.05% w/w. The ether extract was then evaluated for tyrosinase-inhibitory, melanogenesis-inhibitory, and antioxidant activities. The tyrosinase-inhibitory activity was tested in vitro by monitoring the inhibition of the extract against the formation of DOPAchrome by tyrosinase enzyme. The results showed that the tyrosinase-inhibitory activity of the extract was in a dose-dependent manner. The obtained IC50 value was 10.26 +/- 3.04 microg/ml, while kojic acid, a well-known tyrosinase inhibitor, provided an IC50 of 7.89 +/- 0.18 microg/ml. Melanocyte B16F1 melanoma cells (ATCC No. CRL-6323) were then used for determination of the melanogenesis-inhibitory activity of the extract, comparing it to hydroquinone, kojic acid, and purified artocarpin. The amount of melanin produced by the cells was monitored by measuring an absorbence at 490 nm. The obtained results indicated that A. incisus extract at a concentration of 2 to 25 microg/ml was able to decrease the melanin production of the melanocyte B16F1 cells. The obtained micrograph also confirmed that the extract did not change the cell morphology but reduced the melanin content by inhibiting melanin synthesis, whereas the purified artocarpin at a concentration of 4.5 microg/ml caused changes in cell morphology. Additionally, the extract exhibited antioxidant activity in a dose-dependent manner at an EC50 of 169.53 +/- 9.73 microg/ml, according to DPPH assay. The obtained results indicated

  7. Antioxidant and lipase inhibitory activities and essential oil composition of pomegranate peel extracts.

    PubMed

    Hadrich, Fatma; Cher, Slim; Gargouri, Youssef Talel; Adel, Sayari

    2014-01-01

    The chemical composition of essential oil, antioxidant and pancreatic lipase inhibitory activities of various solvent extracts obtained from pomegranate peelTunisian cultivar was evaluated. Gas chromatography/mass spectrometry was used to determine the composition of the PP essential oil. Nine-teen components were identified and the main compounds were the camphor (60.32%) and the benzaldehyde (20.98%). The phenolic and flavonoids content varied from 0 to 290.10 mg Gallic acid equivalent and from 5.2 to 20.43 mg catechin equivalent/g dried extract. The antioxidant activity of various solvent extracts from pomegranate peel was also investigated using various in vitro assays as the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical method, β-carotene bleaching and reducing power assays.Methanol and ethanol extracts showed the most potent antioxidant activity in all assays tested followed by water and acetone extracts. The inhibitory effect of the pomegranate peelextracts on porcine pancreatic lipase was evaluated and the results showed that ethanol and methanol extracts markedly reduced lipase activity. Generally, the highestlipase activity inhibitory (100%) was observed at a concentration of 1 mg/ml after 30 min of incubation. LC-MS analysis of ethanol extract showed the presence of four components which are cholorogenic acid, mannogalloylhexoside, gallic acid and ellagic acid. Our findings demonstrate that the ethanol extract from pomegranate peel might be a good candidate for furtherinvestigations of new bioactive substances. PMID:24770478

  8. Novel bis-(−)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property

    SciTech Connect

    Zheng, Wei; Li, Juan; Qiu, Zhuibai; Xia, Zheng; Li, Wei; Yu, Lining; Chen, Hailin; Chen, Jianxing; Chen, Yan; Hu, Zhuqin; Zhou, Wei; Shao, Biyun; Cui, Yongyao; Xie, Qiong; Chen, Hongzhuan

    2012-10-01

    The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(−)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC{sub 50} values of 9.63 μM (for ZLA) and 8.64 μM (for ZLB), and prevent AChE-induced amyloid-β (Aβ) aggregation with IC{sub 50} values of 49.1 μM (for ZLA) and 55.3 μM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Aβ aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD. -- Highlights: ► Two novel bis-(−)-nor-meptazinol derivatives are designed and synthesized. ► ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency. ► They are potential leads for disease-modifying treatment of Alzheimer's disease.

  9. Inhibitory activity in vitro of probiotic lactobacilli against oral Candida under different fermentation conditions.

    PubMed

    Jiang, Q; Stamatova, I; Kari, K; Meurman, J H

    2015-01-01

    Clinical studies have shown that probiotics positively affect oral health by decreasing gum bleeding and/or reducing salivary counts of certain oral pathogens. Our aim was to investigate the inhibitory effect of six probiotic lactobacilli against opportunistic oral Candida species. Sugar utilisation by both lactobacilli and Candida was also assessed. Agar overlay assay was utilised to study growth inhibition of Candida albicans, Candida glabrata and Candida krusei by Lactobacillus rhamnosus GG, Lactobacillus casei Shirota, Lactobacillus reuteri SD2112, Lactobacillus brevis CD2, Lactobacillus bulgaricus LB86 and L. bulgaricus LB Lact. The inhibitory effect was measured at pH 5.5, 6.4, and 7.2, respectively, and in the presence of five different carbohydrates in growth medium (glucose, fructose, lactose, sucrose, and sorbitol). Growth and final pH values were measured at two-hour time points to 24 h. L. rhamnosus GG showed the strongest inhibitory activity in fructose and glucose medium against C. albicans, followed by L. casei Shirota, L. reuteri SD2112 and L. brevis CD2. None of the lactobacilli tested affected the growth of C. krusei. Only L. rhamnosus GG produced slight inhibitory effect on C. glabrata. The lower pH values led to larger inhibition zones. Sugar fermentation profiles varied between the strains. L. casei Shirota grew in the presence of all sugars tested, whereas L. brevis CD2 could utilise only glucose and fructose. All Candida species metabolised the available sugars but the most rapid growth was observed with C. glabrata. The results suggest that commercially available probiotics differ in their inhibitory activity and carbohydrate utilisation; the above properties are modified by different pH values and sugars with more pronounced inhibition at lower pH.

  10. Susceptibility of enterococci. I. Inhibitory and bactericidal activity of several chemoantibiotics against Streptococcus faecalis and Streptococcus faecium.

    PubMed

    Fabbri, A; Manno, G; Tacchella, A; Belli, M L; Palmero, C

    1986-10-01

    The authors present a microbiological study of 100 strains of Enterococcus (70 strains of Streptococcus faecalis and 30 strains of Streptococcus faecium) tested for susceptibility to the following antibiotics, amoxicillin, ampicillin + flucloxacillin, piperacillin, rifampicin, vancomycin, netilmicin, ofloxacin, and norfloxacin. The assessment of minimum inhibitory and minimum bactericidal concentrations of these substances indicates that all have good inhibitory activity except netilmicin, which is active at higher concentrations; with rifampicin and vancomycin showing very poor bactericidal activity. The bactericidal activity of penicillins was hard to assess because of tolerance and paradoxical effect phenomena. The quinolones showed good inhibitory and bactericidal activity.

  11. Effects of incentives, age, and behavior on brain activation during inhibitory control: a longitudinal fMRI study.

    PubMed

    Paulsen, David J; Hallquist, Michael N; Geier, Charles F; Luna, Beatriz

    2015-02-01

    We investigated changes in brain function supporting inhibitory control under age-controlled incentivized conditions, separating age- and performance-related activation in an accelerated longitudinal design including 10- to 22-year-olds. Better inhibitory control correlated with striatal activation during neutral trials, while Age X Behavior interactions in the striatum indicated that in the absence of extrinsic incentives, younger subjects with greater reward circuitry activation successfully engage in greater inhibitory control. Age was negatively correlated with ventral amygdala activation during Loss trials, suggesting that amygdala function more strongly mediates bottom-up processing earlier in development when controlling the negative aspects of incentives to support inhibitory control. Together, these results indicate that with development, reward-modulated cognitive control may be supported by incentive processing transitions in the amygdala, and from facilitative to obstructive striatal function during inhibitory control. PMID:25284272

  12. Effects of incentives, age, and behavior on brain activation during inhibitory control: A longitudinal fMRI study

    PubMed Central

    Paulsen, David J.; Hallquist, Michael N.; Geier, Charles F.; Luna, Beatriz

    2014-01-01

    We investigated changes in brain function supporting inhibitory control under age-controlled incentivized conditions, separating age- and performance-related activation in an accelerated longitudinal design including 10- to 22-year-olds. Better inhibitory control correlated with striatal activation during neutral trials, while Age × Behavior interactions in the striatum indicated that in the absence of extrinsic incentives, younger subjects with greater reward circuitry activation successfully engage in greater inhibitory control. Age was negatively correlated with ventral amygdala activation during Loss trials, suggesting that amygdala function more strongly mediates bottom-up processing earlier in development when controlling the negative aspects of incentives to support inhibitory control. Together, these results indicate that with development, reward-modulated cognitive control may be supported by incentive processing transitions in the amygdala, and from facilitative to obstructive striatal function during inhibitory control. PMID:25284272

  13. Rubus coreanus Miquel Inhibits Acetylcholinesterase Activity and Prevents Cognitive Impairment in a Mouse Model of Dementia

    PubMed Central

    Kim, Cho Rong; Choi, Soo Jung; Oh, Seung Sang; Kwon, Yoon Kyung; Lee, Na Young; Park, Gwi Gun; Kim, Youn-Jung; Heo, Ho Jin; Jun, Woo Jin; Park, Cheung-Seog; Shin, Dong-Hoon

    2013-01-01

    Abstract To find acetylcholinesterase (AChE) inhibitors for the prevention of neurological disorders, such as Alzheimer's disease, ethanol extracts of promising traditional edible Korean plants were tested. Among them, Rubus coreanus Miquel extract exhibited the most significant AChE inhibitory activity. The effect of R. coreanus extract on trimethyltin-induced memory impairment in mice was investigated using Y-maze and passive avoidance tests. Our results showed that administration of R. coreanus extract significantly improved alternation behavior and step-through latency. In addition, R. coreanus extract was sequentially fractionated, and the purified constituent was determined to be 3,4,5-trihydroxybenzoic acid. PMID:24044488

  14. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells: Involvement of nicotinic acetylcholine receptor (nAChR) and {beta}-adrenergic receptor signaling pathways

    SciTech Connect

    Shin, Vivian Yvonne; Jin, H.C.; Ng, Enders K.O.; Yu Jun; Leung, W.K.; Cho, C.H.; Sung, J.J.Y.

    2008-12-01

    Induction of cyclooxygenase-2 (COX-2) associates with cigarette smoke exposure in many malignancies. Nicotine and its derivative, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are the two important components in cigarette smoke that contributes to cancer development. However, the molecular mechanism(s) by which nicotine or NNK promotes gastric carcinogenesis remains largely unknown. We found that nicotine and NNK significantly enhanced cell proliferation in AGS cells that expressed both alpha7 nicotinic acetylcholine receptor ({alpha}7 nAChR) and {beta}-adrenergic receptors. Treatment of cells with {alpha}-bungarotoxin ({alpha}-BTX, {alpha}7nAChR antagonist) or propranolol ({beta}-adrenergic receptor antagonist) blocked NNK-induced COX-2/PGE{sub 2} and cell proliferation, while nicotine-mediated cell growth and COX-2/PGE{sub 2} induction can only be suppressed by propranolol, but not {alpha}-BTX. Moreover, in contrast to the dependence of growth promoting effect of nicotine on Erk activation, inhibitor of p38 mitogen-activated protein kinase (MAPK) repressed NNK-induced COX-2 upregulation and resulted in suppression of cell growth. In addition, nicotine and NNK mediated COX-2 induction via different receptors to modulate several G1/S transition regulatory proteins and promote gastric cancer cell growth. Selective COX-2 inhibitor (SC-236) caused G1 arrest and abrogated nicotine/NNK-induced cell proliferation. Aberrant expression of cyclin D1 and other G1 regulatory proteins are reversed by blockade of COX-2. These results pointed to the importance of adrenergic and nicotinic receptors in gastric tumor growth through MAPK/COX-2 activation, which may perhaps provide a chemoprevention strategy for cigarette smoke-related gastric carcinogenesis.

  15. Discovery, structure-activity relationship study, and oral analgesic efficacy of cyproheptadine derivatives possessing N-type calcium channel inhibitory activity.

    PubMed

    Yamamoto, Takashi; Niwa, Seiji; Iwayama, Satoshi; Koganei, Hajime; Fujita, Shin-ichi; Takeda, Tomoko; Kito, Morikazu; Ono, Yukitsugu; Saitou, Yuki; Takahara, Akira; Iwata, Seinosuke; Yamamoto, Hiroshi; Shoji, Masataka

    2006-08-01

    Antiallergic drug cyproheptadine (Cyp) is known to have inhibitory activities for L-type calcium channels in addition to histamine and serotonin receptors. Since we found that Cyp had an inhibitory activity against N-type calcium channel, Cyp was optimized to obtain more selective N-type calcium channel blocker with analgesic action. As a consequence of the optimization, we found 13 with potent N-type calcium channel inhibitory activity which had lower inhibitory activities against L-type calcium channel, histamine (H1), and serotonin (5-HT2A) receptors than those of Cyp. 13 showed an oral analgesic activity in rat formalin-induced pain model.

  16. Antioxidant and enzyme inhibitory activities of Plebeian herba (Salvia plebeia R. Br.) under different cultivation conditions.

    PubMed

    Chen, Lei; Kang, Young-Hwa

    2014-03-12

    An adaptation of cultural management to the specific cultural system, as well as crop demand, can further result in the improvement of the quality of horticultural products. Therefore, this study focused on the antioxidant and enzyme inhibitory activities of Plebeian herba (Salvia plebeia R. Br.) grown in hydroponics in comparison with those of the plant grown in soil. The antioxidant activities of Plebeian herba extract were measured as 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging abilities as well as the reducing power by decreasing nitric oxide (NO) and superoxide dismutase activity (SOD) in vitro. Interestingly, by comparison with hydroponics and traditional cultivation, Plebeian herba cultivated in nutrition-based soil improved inhibitory effect on free radicals of DPPH, ABTS, and NO and increased the contents of phenolics such as caffeic acid (1), luteolin-7-glucoside (2), homoplantaginin (3), hispidulin (4), and eupatorin. Free radical scavenging and SOD activity, as well as α-glucosidase inhibitory effect, were higher in Plebeian herba grown in nutrition-based soil than in plants grown in hydroponics and traditional condition. PMID:24422962

  17. Sequential injection spectrophotometric system for evaluation of mushroom tyrosinase-inhibitory activity.

    PubMed

    Moonrungsee, Nuntaporn; Shimamura, Tomoko; Kashiwagi, Takehiro; Jakmunee, Jaroon; Higuchi, Keiro; Ukeda, Hiroyuki

    2012-11-15

    A sequential injection (SI) spectrophotometric method with absorbance detection at 475 nm has been developed for evaluating activity of some compounds on an inhibition of the mushroom tyrosinase. The method involved a reaction of 3,4-dihydroxyphenylalanine (L-DOPA) and mushroom tyrosinase to form the o-dopaquinone. The decrease of the o-dopaquinone was related to an increase of tyrosinase-inhibitory activity. Under the optimum conditions (concentration and volume of L-DOPA and mushroom tyrosinase of 2.0 mM, 60 μL and 142 U mL(-1), 15 μL, respectively), some antioxidant compounds were examined for the tyrosinase-inhibitory activity. A batch enzymatic assay of tyrosinase-inhibitory activity was applied as the reference method for comparison. The results of IC(50) values obtained from the proposed method and the batch method were correlated well, with r(2) of 0.969. The SIA provides higher precision and degrees of automation, consumes smaller amounts of chemicals and it is simpler and faster than the batch method.

  18. Antioxidant and enzyme inhibitory activities of Plebeian herba (Salvia plebeia R. Br.) under different cultivation conditions.

    PubMed

    Chen, Lei; Kang, Young-Hwa

    2014-03-12

    An adaptation of cultural management to the specific cultural system, as well as crop demand, can further result in the improvement of the quality of horticultural products. Therefore, this study focused on the antioxidant and enzyme inhibitory activities of Plebeian herba (Salvia plebeia R. Br.) grown in hydroponics in comparison with those of the plant grown in soil. The antioxidant activities of Plebeian herba extract were measured as 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging abilities as well as the reducing power by decreasing nitric oxide (NO) and superoxide dismutase activity (SOD) in vitro. Interestingly, by comparison with hydroponics and traditional cultivation, Plebeian herba cultivated in nutrition-based soil improved inhibitory effect on free radicals of DPPH, ABTS, and NO and increased the contents of phenolics such as caffeic acid (1), luteolin-7-glucoside (2), homoplantaginin (3), hispidulin (4), and eupatorin. Free radical scavenging and SOD activity, as well as α-glucosidase inhibitory effect, were higher in Plebeian herba grown in nutrition-based soil than in plants grown in hydroponics and traditional condition.

  19. Antioxidant, Iron Chelating and Tyrosinase Inhibitory Activities of Extracts from Talinum triangulare Leach Stem

    PubMed Central

    Oliveira Amorim, Ana Paula; Campos de Oliveira, Márcia Cristina; de Azevedo Amorim, Thiago; Echevarria, Aurea

    2013-01-01

    The aim of this work is to evaluate the antioxidant activity against the radical species DPPH, the reducing capacity against Fe II ions, and the inhibitory activity on the tyrosinase enzyme of the T. triangulare. Hydromethanolic crude extract provided two fractions after the liquid/liquid partition with chloroform. The Folin-Ciocalteu method determined the total phenolic content of the crude extract (CE) and the hydromethanolic fraction (Fraction 1), resulting in a concentration of 0.5853 g/100 g for Fraction 1, and 0.1400 g/100 g for the CE. Taking into account the results of the DPPH, the free radical scavenging capacity was confirmed. The formation of complexes with Fe II ions was evaluated by UV/visible spectrometry; results showed that CE has complexing power similar to the positive control (Gingko biloba extract).The inhibitory capacity of samples against the tyrosinase enzyme was determined by the oxidation of L-DOPA, providing IC50 values of 13.3 μg·mL−1 (CE) and 6.6 μg·mL−1 (Fraction 1). The values indicate that Fraction 1 was more active and showed a higher inhibitory power on the tyrosinase enzyme than the ascorbic acid, used as positive control. The hydromethanolic extract of T. triangulare proved to have powerful antioxidant activity and to inhibit the tyrosinase enzyme; its potential is increased after the partition with chloroform. PMID:26784338

  20. Galantamine derivatives with indole moiety: Docking, design, synthesis and acetylcholinesterase inhibitory activity.

    PubMed

    Atanasova, Mariyana; Stavrakov, Georgi; Philipova, Irena; Zheleva, Dimitrina; Yordanov, Nikola; Doytchinova, Irini

    2015-09-01

    The inhibitors of acetylcholinesterase are the main therapy against Alzheimer's disease. Among them, galantamine is the best tolerated and the most prescribed drug. In the present study, 41 galantamine derivatives with known acetylcholinesterase inhibitory activities expressed as IC50 were selected from the literature and docked into a recombinant human acetylcholinesterase by GOLD. A linear relationship between GoldScores and pIC50 values was found and used to design and predict novel galantamine derivatives with indole moiety in the side chain. The four best predicted compounds were synthesized and tested for inhibitory activity. All of them were between 11 and 95 times more active than galantamine. The novel galantamine derivatives with indole moiety have dual site binding to the enzyme--the galantamine moiety binds to the catalytic anionic site and the indole moiety binds to peripheral anionic site. Additionally, the indole moiety of one of the novel inhibitors binds in a region, close to the peripheral anionic site of the enzyme, where the Ω-loop of amyloid beta peptide adheres to acetylcholinesterase. This compound emerges as a promising lead compound for multi-target anti-Alzheimer therapy not only because of the strong inhibitory activity, but also because it is able to block the amyloid beta deposition on acetylcholinesterase. PMID:26260334

  1. FKBP-12 exhibits an inhibitory activity on calcium oxalate crystal growth in vitro.

    PubMed Central

    Han, In Sook; Nakagawa, Yasushi; Park, Jong Wook; Suh, Min Ho; Suh, Sung Il; Shin, Song Woo; Ahn, Su Yul; Choe, Byung Kil

    2002-01-01

    Urolithiasis and calcium oxalate crystal deposition diseases are still significant medical problems. In the course of nephrocalcin cDNA cloning, we have identified FKBP-12 as an inhibitory molecule of calcium oxalate crystal growth. lambdagt 11 cDNA libraries were constructed from renal carcinoma tissues and screened for nephrocalcin cDNA clones using anti-nephrocalcin antibody as a probe. Clones expressing recombinant proteins, which appeared to be antigenically cross-reactive to nephrocalcin, were isolated and their DNA sequences and inhibitory activities on the calcium oxalate crystal growth were determined. One of the clone lambda gt 11 #31-1 had a partial fragment (80 bp) of FKBP-12 cDNA as an insert. Therefore, a full-length FKBP-12 cDNA was PCR-cloned from the lambda gt 11 renal carcinoma cDNA library and was subcloned into an expression vector. The resultant recombinant FKBP-12 exhibited an inhibitory activity on the calcium oxalate crystal growth (Kd=10(-7) M). Physiological effect of the extracellular FKBP-12 was investigated in terms of macrophage activation and proinflammatory cytokine gene induction. Extracellular FKBP-12 failed to activate macrophages even at high concentrations. FKBP-12 seems an anti-stone molecule for the oxalate crystal deposition disease and recurrent stone diseases. PMID:11850587

  2. Melanogenesis inhibitory activity of two generic drugs: cinnarizine and trazodone in mouse B16 melanoma cells.

    PubMed

    Chang, Te-Sheng; Lin, Victor Chia-Hsiang

    2011-01-01

    More than 200 generic drugs were screened to identify the inhibitory activity on melanogenesis in mouse B16 melanoma cells. Cinnarizine and trazodone were identified as melanogenesis inhibitors. The inhibitory effects of the two drugs on cell survival, melanogenesis, and tyrosinase activity were investigated. The results showed that both cinnarizine and trazodone inhibited melanogenesis in B16 cells by a dose-dependent manner at the non-cytotoxic concentrations. Based on the results of the present study, seeking new melanogenesis inhibitors from generic drugs is an alternative approach to developing new depigmenting agents in cosmeceuticals. Moreover, cinnarizine and trazodone were proven to be good candidates as skin-whitening agents for treatment of skin hyperpigmentation. PMID:22272104

  3. Melanogenesis Inhibitory Activity of Two Generic Drugs: Cinnarizine and Trazodone in Mouse B16 Melanoma Cells

    PubMed Central

    Chang, Te-Sheng; Lin, Victor Chia-Hsiang

    2011-01-01

    More than 200 generic drugs were screened to identify the inhibitory activity on melanogenesis in mouse B16 melanoma cells. Cinnarizine and trazodone were identified as melanogenesis inhibitors. The inhibitory effects of the two drugs on cell survival, melanogenesis, and tyrosinase activity were investigated. The results showed that both cinnarizine and trazodone inhibited melanogenesis in B16 cells by a dose-dependent manner at the non-cytotoxic concentrations. Based on the results of the present study, seeking new melanogenesis inhibitors from generic drugs is an alternative approach to developing new depigmenting agents in cosmeceuticals. Moreover, cinnarizine and trazodone were proven to be good candidates as skin-whitening agents for treatment of skin hyperpigmentation. PMID:22272104

  4. Jojoba seed meal proteins associated with proteolytic and protease inhibitory activities.

    PubMed

    Shrestha, Madan K; Peri, Irena; Smirnoff, Patricia; Birk, Yehudith; Golan-Goldhirsh, Avi

    2002-09-25

    The jojoba, Simmondsia chinensis, is a characteristic desert plant native to the Sonoran desert. The jojoba meal after oil extraction is rich in protein. The major jojoba proteins were albumins (79%) and globulins (21%), which have similar amino acid compositions and also showed a labile thrombin-inhibitory activity. SDS-PAGE showed two major proteins at 50 kDa and 25 kDa both in the albumins and in the globulins. The 25 kDa protein has trypsin- and chymotrypsin-inhibitory activities. In vitro digestibility of the globulins and albumins resembled that of casein and soybean protein concentrates and was increased after heat treatment. The increased digestibility achieved by boiling may be attributed to inactivation of the protease inhibitors and denaturation of proteins.

  5. Predicting the DPP-IV inhibitory activity pIC₅₀ based on their physicochemical properties.

    PubMed

    Gu, Tianhong; Yang, Xiaoyan; Li, Minjie; Wu, Milin; Su, Qiang; Lu, Wencong; Zhang, Yuhui

    2013-01-01

    The second development program developed in this work was introduced to obtain physicochemical properties of DPP-IV inhibitors. Based on the computation of molecular descriptors, a two-stage feature selection method called mRMR-BFS (minimum redundancy maximum relevance-backward feature selection) was adopted. Then, the support vector regression (SVR) was used in the establishment of the model to map DPP-IV inhibitors to their corresponding inhibitory activity possible. The squared correlation coefficient for the training set of LOOCV and the test set are 0.815 and 0.884, respectively. An online server for predicting inhibitory activity pIC50 of the DPP-IV inhibitors as described in this paper has been given in the introduction.

  6. Structure activity relationship modelling of milk protein-derived peptides with dipeptidyl peptidase IV (DPP-IV) inhibitory activity.

    PubMed

    Nongonierma, Alice B; FitzGerald, Richard J

    2016-05-01

    Quantitative structure activity type models were developed in an attempt to predict the key features of peptide sequences having dipeptidyl peptidase IV (DPP-IV) inhibitory activity. The models were then employed to help predict the potential of peptides, which are currently reported in the literature to be present in the intestinal tract of humans following milk/dairy product ingestion, to act as inhibitors of DPP-IV. Two models (z- and v-scale) for short (2-5 amino acid residues) bovine milk peptides, behaving as competitive inhibitors of DPP-IV, were developed. The z- and the v-scale models (p<0.05, R(2) of 0.829 and 0.815, respectively) were then applied to 56 milk protein-derived peptides previously reported in the literature to be found in the intestinal tract of humans which possessed a structural feature of DPP-IV inhibitory peptides (P at the N2 position). Ten of these peptides were synthetized and tested for their in vitro DPP-IV inhibitory properties. There was no agreement between the predicted and experimentally determined DPP-IV half maximal inhibitory concentrations (IC50) for the competitive peptide inhibitors. However, the ranking for DPP-IV inhibitory potency of the competitive peptide inhibitors was conserved. Furthermore, potent in vitro DPP-IV inhibitory activity was observed with two peptides, LPVPQ (IC50=43.8±8.8μM) and IPM (IC50=69.5±8.7μM). Peptides present within the gastrointestinal tract of human may have promise for the development of natural DPP-IV inhibitors for the management of serum glucose.

  7. Antioxidative and melanogenesis-inhibitory activities of caffeoylquinic acids and other compounds from moxa.

    PubMed

    Akihisa, Toshihiro; Kawashima, Kohta; Orido, Masashi; Akazawa, Hiroyuki; Matsumoto, Masahiro; Yamamoto, Ayako; Ogihara, Eri; Fukatsu, Makoto; Tokuda, Harukuni; Fuji, Jizaemon

    2013-03-01

    The MeOH extract of moxa, the processed leaves of Artemisia princeps PAMP. (Asteraceae), exhibited potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity and melanogenesis-inhibitory activity in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16 melanoma cells. Eight caffeoylquinic acids, 1 and 6-12, five flavonoids, 13-17, two benzoic acid derivatives, 18 and 19, three coumarin derivatives, 20-22, four steroids, 23-26, and six triterpenoids, 27-32, were isolated from the MeOH extract. Upon evaluation of compounds 1, 6-23, and four semisynthetic caffeoylquinic acid esters, 2-5, for their DPPH radical-scavenging activity, 15 compounds, 1-13, 17, and 19, showed potent activities (IC(50) 3.1-16.8 μM). The 15 compounds exhibited, moreover, potent inhibitory activities (51.1-92.5% inhibition) against peroxidation of linoleic acid emulsion at 10 μg/ml concentration. In addition, when 27 compounds, 1-8, 10, 12, 13, 15-18, 20-25, and 27-32, were evaluated for their inhibitory activity against melanogenesis in α-MSH-stimulated B16 melanoma cells, five caffeoylquinic acids, i.e., chlorogenic acid (1), ethyl chlorogenate (3), propyl chlorogenate (4), isopropyl chlorogenate (5), and butyl chlorogenate (6), along with homoorientin (17) and vanillic acid (18), exhibited inhibitory activities with 33-62% reduction of melanin content at 100 μM concentration with no or almost no toxicity to the cells (89-114% of cell viability at 100 μM). Western blot analysis showed that compound 6 reduced the protein levels of microphtalmia-associated transcription factor (MITF), tyrosinase, tyrosine-related protein 1 (TRP-1), and TRP-2 mostly in a concentration-dependent manner, suggesting that this compound inhibits melanogenesis on α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of tyrosinase, TRP-1, and TRP-2. Furthermore, four compounds, 13, 15, 16, and 30, exhibited

  8. Characterization of a T-superfamily conotoxin TxVC from Conus textile that selectively targets neuronal nAChR subtypes.

    PubMed

    Wang, Shuo; Du, Tianpeng; Liu, Zhuguo; Wang, Sheng; Wu, Ying; Ding, Jiuping; Jiang, Ling; Dai, Qiuyun

    2014-11-01

    T-superfamily conotoxins have a typical cysteine pattern of "CC-CC", and are known to mainly target calcium or sodium ion channels. Recently, we screened the targets of a series of T-superfamily conotoxins and found that a new T-superfamily conotoxin TxVC (KPCCSIHDNSCCGL-NH2) from the venom of Conus textile. It selectively targeted the neuronal nicotinic acetylcholine receptor (nAChR) subtypes α4β2 and α3β2, with IC50 values of 343.4 and 1047.2nM, respectively, but did not exhibit obvious pharmacological effects on voltage-gated potassium, sodium or calcium channel in DRG cells, the BK channels expressed in HEK293 cells, or the Kv channels in LβT2 cells. The changes in the inhibitory activities of its Ala mutants, the NMR structure, and molecular simulation results based on other conotoxins targeting nAChR α4β2, all demonstrated that the residues Ile(6) and Leu(14) were the main hydrophobic pharmacophores. To our best knowledge, this is the first T-superfamily conotoxin that inhibits neuronal nAChRs and possesses high binding affinity to α4β2. This finding will expand the knowledge of the targets of T-superfamily conotoxins and the motif information could help the design of new nAChR inhibitors.

  9. Cholinesterases in development: AChE as a firewall to inhibit cell proliferation and support differentiation.

    PubMed

    Layer, Paul G; Klaczinski, Janine; Salfelder, Anika; Sperling, Laura E; Thangaraj, Gopenath; Tuschl, Corina; Vogel-Höpker, Astrid

    2013-03-25

    Acetylcholinesterase (AChE) is a most remarkable protein, not only because it is one of the fastest enzymes in nature, but also since it appears in many molecular forms and is regulated by elaborate genetic networks. AChE is expressed in many tissues during development and in mature organisms, as well as in healthy and diseased states. In search for alternative, "non-classical" functions of cholinesterases (ChEs), AChE could either work within the frame of classic cholinergic systems, but in non-neural tissues ("non-synaptic function"), or act non-enzymatically. Here, we review briefly some of the major ideas and advances of this field, and report on some recent progress from our own experimental work, e.g. that (i) non-neural ChEs have pronounced, predominantly enzymatic effects on early embryonic (limb) development in chick and mouse, that (ii) retinal R28 cells of the rat overexpressing synaptic AChE present a significantly decreased cell proliferation, and that (iii) in developing chick retina ACh-synthesizing and ACh-degrading cells originate from the same postmitotic precursor cells, which later form two locally opposing cell populations. We suggest that such distinct distributions of ChAT(+) vs. AChE(+) cells in the inner half retina provide graded distributions of ACh, which can direct cell differentiation and network formation. Thus, as corroborated by works from many labs, AChE can be considered a highly co-opting protein, which can combine enzymatic and non-enzymatic functions within one molecule. PMID:23047026

  10. Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking.

    PubMed

    Imramovsky, Ales; Stepankova, Sarka; Vanco, Jan; Pauk, Karel; Monreal-Ferriz, Juana; Vinsova, Jarmila; Jampilek, Josef

    2012-08-24

    A series of twenty-five novel salicylanilide N-alkylcarbamates were investigated as potential acetylcholinesterase inhibitors. The compounds were tested for their ability to inhibit acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.). Experimental lipophilicity was determined, and the structure-activity relationships are discussed. The mode of binding in the active site of AChE was investigated by molecular docking. All the discussed compounds expressed significantly higher AChE inhibitory activity than rivastigmine and slightly lower than galanthamine. Disubstitution by chlorine in C'(₃,₄) of the aniline ring and the optimal length of hexyl-undecyl alkyl chains in the carbamate moiety provided the most active AChE inhibitors. Monochlorination in C'(₄) exhibited slightly more effective AChE inhibitors than in C'(₃). Generally it can be stated that compounds with higher lipophilicity showed higher inhibition, and the activity of the compounds is strongly dependent on the length of the N-alkyl chain.

  11. Bioactive Compounds, Antioxidant, Xanthine Oxidase Inhibitory, Tyrosinase Inhibitory and Anti-Inflammatory Activities of Selected Agro-Industrial By-products

    PubMed Central

    Oskoueian, Ehsan; Abdullah, Norhani; Hendra, Rudi; Karimi, Ehsan

    2011-01-01

    Evaluation of abundantly available agro-industrial by-products for their bioactive compounds and biological activities is beneficial in particular for the food and pharmaceutical industries. In this study, rapeseed meal, cottonseed meal and soybean meal were investigated for the presence of bioactive compounds and antioxidant, anti-inflammatory, xanthine oxidase and tyrosinase inhibitory activities. Methanolic extracts of rapeseed meal showed significantly (P < 0.01) higher phenolics and flavonoids contents; and significantly (P < 0.01) higher DPPH and nitric oxide free radical scavenging activities when compared to that of cottonseed meal and soybean meal extracts. Ferric thiocyanate and thiobarbituric acid tests results showed rapeseed meal with the highest antioxidant activity (P < 0.01) followed by BHT, cotton seed meal and soybean meal. Rapeseed meal extract in xanthine oxidase and tyrosinase inhibitory assays showed the lowest IC50 values followed by cottonseed and soybean meals. Anti-inflammatory assay using IFN-γ/LPS stimulated RAW 264.7 cells indicated rapeseed meal is a potent source of anti-inflammatory agent. Correlation analysis showed that phenolics and flavonoids were highly correlated to both antioxidant and anti-inflammatory activities. Rapeseed meal was found to be promising as a natural source of bioactive compounds with high antioxidant, anti-inflammatory, xanthine oxidase and tyrosinase inhibitory activities in contrast to cotton and soybean meals. PMID:22272095

  12. Evaluation of Xanthine Oxidase Inhibitory Potential and In vivo Hypouricemic Activity of Dimocarpus longan Lour. Extracts

    PubMed Central

    Sheu, Shi-Yuan; Fu, Yuan-Tsung; Huang, Wen-Dar; Chen, Yung-Ann; Lei, Yi-Chih; Yao, Chun-Hsu; Hsu, Feng-Lin; Kuo, Tzong-Fu

    2016-01-01

    Background: Longan is a fruit tree known to contain many phenolic components, which are capable of protecting people from oxidative damage through an anti-inflammatory mechanism. It may be also worthwhile to study the effect on lowering uric acid activity. Materials and Methods: This study investigates the lowering of uric acid using longan extracts, including flowers, pericarps, seeds, leaves, and twigs, on potassium-oxonate-induced hyperuricemia mice and its inhibitory actions against xanthine oxidase (XO) activities. Results: The findings revealed that ethyl acetate fraction of longan extracts exhibited strong XO-inhibitory activity, and the flower extracts (IC50 = 115.8 μg/mL) revealed more potent XO-inhibitory activity to those of pericarps (118.9 μg/mL), twigs (125.3 μg/mL), seeds (262.5 μg/mL), and leaves (331.1 μg/mL) in vitro. In addition, different dosages of longan extract (50–100 mg/kg) were administered to hyperuricemic mice. The lowering effect of longan extracts on uric acid at 75 mg/kg markedly reduced plasma uric acid levels in decreasing order: Flowers (80%) > seeds (72%) > pericarps (64%) > twigs (59%) > leaves (41%), compared with allopurinol (89%). Finally, 10 isolated phytochemicals from longan flowers were then examined in vitro. The results indicated that proanthocyanidin A2 and acetonylgeraniin A significantly inhibited XO activity in vitro. This is the first report providing new insights into the urate-reducing effect of phenolic dimer and hydrolyzable tannin, which can be developed to potential hypouricemic agents. SUMMARY Longan flower extracts possess more potent XO-inhibitory activity than pericarps, twigs, seeds, and leaves in vitroThe lowering effect of longan flowers and seeds extracts markedly reduced plasma uric acid levels as compared to allopurinol in vivoThe extract proanthocyanidin A2 and acetonylgeraniin A were demonstrated potent XO inhibitory activity in vitro Abbreviations used: PO: Potassium-oxonate, XO: xanthine

  13. Hypotensive and Angiotensin-Converting Enzyme Inhibitory Activities of Eisenia fetida Extract in Spontaneously Hypertensive Rats

    PubMed Central

    Mao, Shumei; Li, Chengde

    2015-01-01

    Objectives. This study aimed to investigate the antihypertensive effects of an Eisenia fetida extract (EFE) and its possible mechanisms in spontaneously hypertensive rats (SHR rats). Methods. Sixteen-week-old SHR rats and Wistar-Kyoto rats (WKY rats) were used in this study. Rats were, respectively, given EFE (EFE group), captopril (captopril group), or phosphate-buffered saline (PBS) (normal control group and SHR group) for 4 weeks. ACE inhibitory activity of EFE in vitro was determined. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using a Rat Tail-Cuff Blood Pressure System. Levels of angiotensin II (Ang II), aldosterone (Ald), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1α) in plasma were determined by radioimmunoassay, and serum nitric oxide (NO) concentration was measured by Griess reagent systems. Results. EFE had marked ACE inhibitory activity in vitro (IC50 = 2.5 mg/mL). After the 4-week drug management, SHR rats in EFE group and in captopril group had lower SBP and DBP, lower levels of Ang II and Ald, and higher levels of 6-keto-PGF1α and NO than the SHR rats in SHR group. Conclusion. These results indicate that EFE has hypotensive effects in SHR rats and its effects might be associated with its ACE inhibitory activity. PMID:26798397

  14. Medicinal Plants and Their Inhibitory Activities against Pancreatic Lipase: A Review.

    PubMed

    Seyedan, Atefehalsadat; Alshawsh, Mohammed Abdullah; Alshagga, Mustafa Ahmed; Koosha, Sanaz; Mohamed, Zahurin

    2015-01-01

    Obesity is recognized as a major life style disorder especially in developing countries and it is prevailing at an alarming speed in new world countries due to fast food intake, industrialization, and reduction of physical activity. Furthermore, it is associated with a vast number of chronic diseases and disabilities. To date, relatively effective drugs, from either natural or synthetic sources, are generally associated with serious side effects, often leading to cessation of clinical trials or even withdrawal from the market. In order to find new compounds which are more effective or with less adverse effects compared to orlistat, the drug that has been approved for obesity, new compounds isolated from natural products are being identified and screened for antiobesity effects, in particular, for their pancreatic lipase inhibitory effect. Pancreatic lipase inhibitory activity has been extensively used for the determination of potential efficacy of natural products as antiobesity agents. In attempts to identify natural products for overcoming obesity, more researches have been focused on the identification of newer pancreatic lipase inhibitors with less unpleasant adverse effects. In this review, we consider the potential role of plants that have been investigated for their pancreatic lipase inhibitory activity.

  15. Synthesis and in vitro α-chymotrypsin inhibitory activity of 6-chlorobenzimidazole derivatives.

    PubMed

    Siddiqui, Hina; Farooq, Rabia; Marasini, Bishnu P; Malik, Rizwana; Syed, Naima; Moin, Syed Tarique; Atta-Ur-Rahman; Choudhary, M Iqbal

    2016-08-15

    A library of benzimidazole derivatives 1-20 were synthesized, and studied for their α-chymotrypsin (α-CT) inhibitory activity in vitro. Kinetics and molecular docking studies were performed to identify the type of inhibition. Compound 1 was found to be a good inhibitor of α-chymotrypsin enzyme (IC50=14.8±0.1μM, Ki=16.4μM), when compared with standard chymostatin (IC50=5.7±0.13μM). Compounds 2-8, 15, 17, and 18 showed significant inhibitory activities. All the inhibitors were found to be competitive inhibitors, except compound 17, which was a mixed type inhibitor. The substituents (R) in para and ortho positions of phenyl ring B, apparently played a key role in the inhibitory potential of the series. Compounds 1-20 were also studied for their cytotoxicity profile by using 3T3 mouse fibroblast cells and compounds 3, 5, 6, 8, 12-14, 16, 17, 19, and 20 were found to be cytotoxic. Molecular docking was performed on the most active members of the series in comparison to the standard compound, chymostatin, to identify the most likely binding modes. The compounds reported here can serve as templates for further studies for new inhibitors of α-chymotrypsin and other chymotrypsin-like serine proteases enzymes. PMID:27374882

  16. Medicinal Plants and Their Inhibitory Activities against Pancreatic Lipase: A Review

    PubMed Central

    Seyedan, Atefehalsadat; Alshawsh, Mohammed Abdullah; Alshagga, Mustafa Ahmed; Koosha, Sanaz; Mohamed, Zahurin

    2015-01-01

    Obesity is recognized as a major life style disorder especially in developing countries and it is prevailing at an alarming speed in new world countries due to fast food intake, industrialization, and reduction of physical activity. Furthermore, it is associated with a vast number of chronic diseases and disabilities. To date, relatively effective drugs, from either natural or synthetic sources, are generally associated with serious side effects, often leading to cessation of clinical trials or even withdrawal from the market. In order to find new compounds which are more effective or with less adverse effects compared to orlistat, the drug that has been approved for obesity, new compounds isolated from natural products are being identified and screened for antiobesity effects, in particular, for their pancreatic lipase inhibitory effect. Pancreatic lipase inhibitory activity has been extensively used for the determination of potential efficacy of natural products as antiobesity agents. In attempts to identify natural products for overcoming obesity, more researches have been focused on the identification of newer pancreatic lipase inhibitors with less unpleasant adverse effects. In this review, we consider the potential role of plants that have been investigated for their pancreatic lipase inhibitory activity. PMID:26640503

  17. Medicinal Plants and Their Inhibitory Activities against Pancreatic Lipase: A Review.

    PubMed

    Seyedan, Atefehalsadat; Alshawsh, Mohammed Abdullah; Alshagga, Mustafa Ahmed; Koosha, Sanaz; Mohamed, Zahurin

    2015-01-01

    Obesity is recognized as a major life style disorder especially in developing countries and it is prevailing at an alarming speed in new world countries due to fast food intake, industrialization, and reduction of physical activity. Furthermore, it is associated with a vast number of chronic diseases and disabilities. To date, relatively effective drugs, from either natural or synthetic sources, are generally associated with serious side effects, often leading to cessation of clinical trials or even withdrawal from the market. In order to find new compounds which are more effective or with less adverse effects compared to orlistat, the drug that has been approved for obesity, new compounds isolated from natural products are being identified and screened for antiobesity effects, in particular, for their pancreatic lipase inhibitory effect. Pancreatic lipase inhibitory activity has been extensively used for the determination of potential efficacy of natural products as antiobesity agents. In attempts to identify natural products for overcoming obesity, more researches have been focused on the identification of newer pancreatic lipase inhibitors with less unpleasant adverse effects. In this review, we consider the potential role of plants that have been investigated for their pancreatic lipase inhibitory activity. PMID:26640503

  18. Angiotensin I-converting enzyme inhibitory activity of gelatin hydrolysates and identification of bioactive peptides.

    PubMed

    Herregods, Griet; Van Camp, John; Morel, Nicole; Ghesquière, Bart; Gevaert, Kris; Vercruysse, Lieselot; Dierckx, Stephan; Quanten, Erwin; Smagghe, Guy

    2011-01-26

    In this project we report on the angiotensin I-converting enzyme (ACE)-inhibitory activity of a bovine gelatin hydrolysate (Bh2) that was submitted to further hydrolysis by different enzymes. The thermolysin hydrolysate (Bh2t) showed the highest in vitro ACE inhibitory activity, and interestingly a marked in vivo blood pressure-lowering effect was demonstrated in spontaneously hypertensive rats (SHR). In contrast, Bh2 showed no effect in SHR, confirming the need for the extra thermolysin hydrolysis. Hence, an angiotensin I-evoked contractile response in isolated rat aortic rings was inhibited by Bh2t, but not by Bh2, suggesting ACE inhibition as the underlying antihypertensive mechanism for Bh2t. Using mass spectrometry, seven small peptides, AG, AGP, VGP, PY, QY, DY and IY or LY or HO-PY were identified in Bh2t. As these peptides showed ACE inhibitory activity and were more prominent in Bh2t than in Bh2, the current data provide evidence that these contribute to the antihypertensive effect of Bh2t.

  19. Dipeptidyl peptidase-IV inhibitory activity of dimeric dihydrochalcone glycosides from flowers of Helichrysum arenarium.

    PubMed

    Morikawa, Toshio; Ninomiya, Kiyofumi; Akaki, Junji; Kakihara, Namiko; Kuramoto, Hiroyuki; Matsumoto, Yurie; Hayakawa, Takao; Muraoka, Osamu; Wang, Li-Bo; Wu, Li-Jun; Nakamura, Seikou; Yoshikawa, Masayuki; Matsuda, Hisashi

    2015-10-01

    A methanol extract of everlasting flowers of Helichrysum arenarium L. Moench (Asteraceae) was found to inhibit the increase in blood glucose elevation in sucrose-loaded mice at 500 mg/kg p.o. The methanol extract also inhibited the enzymatic activity against dipeptidyl peptidase-IV (DPP-IV, IC50 = 41.2 μg/ml), but did not show intestinal α-glucosidase inhibitory activities. From the extract, three new dimeric dihydrochalcone glycosides, arenariumosides V-VII (2-4), were isolated, and the stereostructures were elucidated based on their spectroscopic properties and chemical evidence. Of the constituents, several flavonoid constituents, including 2-4, were isolated, and these isolated constituents were investigated for their DPP-IV inhibitory effects. Among them, chalconaringenin 2'-O-β-D-glucopyranoside (16, IC50 = 23.1 μM) and aureusidin 6-O-β-D-glucopyranoside (35, 24.3 μM) showed relatively strong inhibitory activities.

  20. New diterpenoids with estrogen sulfotransferase inhibitory activity from Leonurus sibiricus L.

    PubMed

    Narukawa, Yuji; Niimura, Akiko; Noguchi, Hitomi; Tamura, Hiroomi; Kiuchi, Fumiyuki

    2014-01-01

    Four new diterpenoids (1-4), along with eight known diterpenoids (5-12) were isolated from the acetone extract of Leonurus herb (aerial parts of Leonurus sibiricus L.). The structures of the compounds were determined by spectroscopic methods. Among the isolated compounds, compounds 2, 3, 8, 9 and 10 showed inhibitory activity against human liver cytosol estrogen sulfotransferase (E-ST), which plays a key role in the maintenance of cellular estrogen levels. Compound 2 showed the strongest activity with an IC50 value of 7.9 μM, which is comparable to the activity of the positive control, meclofenamic acid (IC50 5.4 μM).

  1. The availability of attentional resources modulates the inhibitory strength related to weakly activated priming.

    PubMed

    Wang, Yongchun; Wang, Yonghui; Liu, Peng; Dai, Dongyang; Di, Meilin; Chen, Qiang

    2016-08-01

    The current study investigated the role of attention in inhibitory processes (the inhibitory processes described in the current study refer only to those associated with masked or flanked priming) using a mixed paradigm involving the negative compatibility effect (NCE) and object-based attention. Accumulating evidence suggests that attention can be spread more easily within the same object, which increases the availability of attentional resources, than across different objects. Accordingly, we manipulated distractor location (with primes presented in the same object versus presented in different objects) together with prime/target compatibility (compatible versus incompatible) and prime-distractor stimulus onset asynchrony (SOA, 23 ms vs 70 ms). The aim was to investigate whether inhibitory processes related to weakly activated priming, which have been previously assumed to be automatic, depend on the availability of attentional resources. The results of Experiment 1 showed a significant NCE for the 70-ms SOA when the prime and distractor were presented in the same object (greater attentional resource availability); however, reversed NCEs were obtained for all other conditions. Experiment 2 was designed to disentangle whether the results of Experiment 1 were affected by the prime position, and the results indicated that the prime position did not modulate the NCE in Experiment 1. Together, these results are consistent with the claim that the availability of attentional resources modulates the inhibitory strength related to weakly activated priming. Specifically, if attentional resources are assigned to the distractor when it is presented in the same object as the prime, the strength of the inhibition elicited by the distractor may increase and reverse the activation elicited by the prime, which could lead to a significant NCE. PMID:27198916

  2. α7nAchR/NMDAR coupling affects NMDAR function and object recognition.

    PubMed

    Li, Shupeng; Nai, Qiang; Lipina, Tatiana V; Roder, John C; Liu, Fang

    2013-12-20

    The α7 nicotinic acetylcholine receptor (nAchR) and NMDA glutamate receptor (NMDAR) are both ligand-gated ion channels permeable to Ca2+ and Na+. Previous studies have demonstrated functional modulation of NMDARs by nAchRs, although the molecular mechanism remains largely unknown. We have previously reported that α7nAchR forms a protein complex with the NMDAR through a protein-protein interaction. We also developed an interfering peptide that is able to disrupt the α7nAchR-NMDAR complex and blocks cue-induced reinstatement of nicotine-seeking in rat models of relapse. In the present study, we investigated whether the α7nAchR-NMDAR interaction is responsible for the functional modulation of NMDAR by α7nAchR using both electrophysiological and behavioral tests. We have found that activation of α7nAchR upregulates NMDAR-mediated whole cell currents and LTP of mEPSC in cultured hippocampal neurons, which can be abolished by the interfering peptide that disrupts the α7nAchR-NMDAR interaction. Moreover, administration of the interfering peptide in mice impairs novel object recognition but not Morris water maze performance. Our results suggest that α7nAchR/NMDAR coupling may selectively affect some aspects of learning and memory.

  3. Clinical application of clustered-AChR for the detection of SNMG

    PubMed Central

    Zhao, Guang; Wang, Xiaoqing; Yu, Xiaowen; Zhang, Xiutian; Guan, Yangtai; Jiang, Jianming

    2015-01-01

    Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction (NMJ). However, accumulating evidence has indicated that MG patients whose serum anti-acetylcholine receptor (AChR) antibodies are not detectable (serumnegative MG; SNMG) in routine assays share similar clinical features with anti-AChR antibody-positive MG patients. We hypothesized that SNMG patients would have low-affinity antibodies to AChRs that would not be detectable using traditional methods but that might be detected by binding to AChR on the cell membrane, particularly if they were clustered at the high density observed at the NMJ. We expressed AChR subunits with the clustering protein rapsyn (an AChR-associated protein at the synapse) in human embryonic kidney (HEK) cells, and we tested the binding of the antibodies using immunofluorescence. With this approach, AChR antibodies to rapsyn-clustered AChR could be detected in the sera from 45.83% (11/24) of SNMG patients, as confirmed with fluorescence-activated cell sorting (FACS). This was the first application in China of cell-based AChR antibody detection. More importantly, this sensitive (and specific) approach could significantly increase the diagnosis rate of SNMG. PMID:26068604

  4. Growth inhibitory activity of extracts and compounds from Cimicifuga species on human breast cancer cells

    PubMed Central

    Einbond, Linda Saxe; Wen-Cai, Ye; He, Kan; Wu, Hsan-au; Cruz, Erica; Roller, Marc; Kronenberg, Fredi

    2008-01-01

    The purpose of this report is to explore the growth inhibitory effect of extracts and compounds from black cohosh and related Cimicifuga species on human breast cancer cells and to determine the nature of the active components. Black cohosh fractions enriched for triterpene glycosides and purified components from black cohosh and related Asian species were tested for growth inhibition of the ER− Her2 overexpressing human breast cancer cell line MDA-MB-453. Growth inhibitory activity was assayed using the Coulter Counter, MTT and colony formation assays. Results suggested that the growth inhibitory activity of black cohosh extracts appears to be related to their triterpene glycoside composition. The most potent Cimicifuga component tested was 25-acetyl-7,8-didehydrocimigenol 3-O-β-D-xylopyranoside, which has an acetyl group at position C-25. It had an IC50 of 3.2 µg/ml (5 µM) compared to7.2 µg/ml (12.1 µM) for the parent compound 7,8-didehydrocimigenol 3-O-β-D-xylopyranoside. Thus, the acetyl group at position C-25 enhances growth inhibitory activity. The purified triterpene glycoside actein (β-D-xylopyranoside), with an IC50 equal to 5.7 µg/ml (8.4 µM), exhibited activity comparable to cimigenol 3-O-β-D-xyloside. MCF7 (ER+Her2 low) cells transfected for Her2 are more sensitive than the parental MCF7 cells to the growth inhibitory effects of actein from black cohosh, indicating that Her2 plays a role in the action of actein. The effect of actein on Her2 overexpressing MDA-MB-453 and MCF7 (ER+Her2 low) human breast cancer cells was examined by fluorescent microscopy. Treatment with actein altered the distribution of actin filaments and induced apoptosis in these cells. These findings, coupled with our previous evidence that treatment with the triterpene glycoside actein induced a stress response and apoptosis in human breast cancer cells, suggest that compounds from Cimicifuga species may be useful in the prevention and treatment of human breast cancer

  5. Phagocytic receptors activate and immune inhibitory receptor SIRPα inhibits phagocytosis through paxillin and cofilin.

    PubMed

    Gitik, Miri; Kleinhaus, Rachel; Hadas, Smadar; Reichert, Fanny; Rotshenker, Shlomo

    2014-01-01

    The innate immune function of phagocytosis of apoptotic cells, tissue debris, pathogens, and cancer cells is essential for homeostasis, tissue repair, fighting infection, and combating malignancy. Phagocytosis is carried out in the central nervous system (CNS) by resident microglia and in both CNS and peripheral nervous system by recruited macrophages. While phagocytosis proceeds, bystander healthy cells protect themselves by sending a "do not eat me" message to phagocytes as CD47 on their surface ligates immune inhibitory receptor SIRPα on the surface of phagocytes and SIRPα then produces the signaling which inhibits phagocytosis. This helpful mechanism becomes harmful when tissue debris and unhealthy cells inhibit their own phagocytosis by employing the same mechanism. However, the inhibitory signaling that SIRPα produces has not been fully revealed. We focus here on how SIRPα inhibits the phagocytosis of the tissue debris "degenerated myelin" which hinders repair in axonal injury and neurodegenerative diseases. We tested whether SIRPα inhibits phagocytosis by regulating cytoskeleton function through paxillin and cofilin since (a) the cytoskeleton generates the mechanical forces that drive phagocytosis and (b) both paxillin and cofilin control cytoskeleton function. Paxillin and cofilin were transiently activated in microglia as phagocytosis was activated. In contrast, paxillin and cofilin were continuously activated and phagocytosis augmented in microglia in which SIRPα expression was knocked-down by SIRPα-shRNA. Further, levels of phagocytosis, paxillin activation, and cofilin activation positively correlated with one another. Taken together, these observations suggest a novel mechanism whereby paxillin and cofilin are targeted to control phagocytosis by both the activating signaling that phagocytic receptors produce by promoting the activation of paxillin and cofilin and the inhibiting signaling that immune inhibitory SIRPα produces by promoting the

  6. Discovery of Diverse Small Molecule Chemotypes with Cell-Based PKD1 Inhibitory Activity

    PubMed Central

    Sharlow, Elizabeth R.; Mustata Wilson, Gabriela; Close, David; Leimgruber, Stephanie; Tandon, Manuj; Reed, Robyn B.; Shun, Tong Ying; Wang, Q. Jane; Wipf, Peter; Lazo, John S.

    2011-01-01

    Protein kinase D (PKD) is a novel family of serine/threonine kinases regulated by diacylglycerol, which is involved in multiple cellular processes and various pathological conditions. The limited number of cell-active, selective inhibitors has historically restricted biochemical and pharmacological studies of PKD. We now markedly expand the PKD1 inhibitory chemotype inventory with eleven additional novel small molecule PKD1 inhibitors derived from our high throughput screening campaigns. The in vitro IC50s for these eleven compounds ranged in potency from 0.4 to 6.1 µM with all of the evaluated compounds being competitive with ATP. Three of the inhibitors (CID 1893668, (1Z)-1-(3-ethyl-5-methoxy-1,3-benzothiazol-2-ylidene)propan-2-one; CID 2011756, 5-(3-chlorophenyl)-N-[4-(morpholin-4-ylmethyl)phenyl]furan-2-carboxamide; CID 5389142, (6Z)-6-[4-(3-aminopropylamino)-6-methyl-1H-pyrimidin-2-ylidene]cyclohexa-2,4-dien-1-one) inhibited phorbol ester-induced endogenous PKD1 activation in LNCaP prostate cancer cells in a concentration-dependent manner. The specificity of these compounds for PKD1 inhibitory activity was supported by kinase assay counter screens as well as by bioinformatics searches. Moreover, computational analyses of these novel cell-active PKD1 inhibitors indicated that they were structurally distinct from the previously described cell-active PKD1 inhibitors while computational docking of the new cell-active compounds in a highly conserved ATP-binding cleft suggests opportunities for structural modification. In summary, we have discovered novel PKD1 inhibitors with in vitro and cell-based inhibitory activity, thus successfully expanding the structural diversity of small molecule inhibitors available for this important pharmacological target. PMID:21998636

  7. Melanogenesis-inhibitory activity and cancer chemopreventive effect of glucosylcucurbic acid from shea (Vitellaria paradoxa) kernels.

    PubMed

    Zhang, Jie; Kurita, Masahiro; Ebina, Kodai; Ukiya, Motohiko; Tokuda, Harukuni; Yasukawa, Ken; Masters, Eliot T; Shimizu, Naoto; Akihisa, Momoko; Feng, Feng; Akihisa, Toshihiro

    2015-04-01

    Two jasmonate derivatives, glucosylcucurbic acid (1) and methyl glucosylcucurbate (2), were isolated from the MeOH extract of defatted shea (Vitellaria paradoxa; Sapotaceae) kernels. These and their deglucosylated derivatives, cucurbic acid (3) and methyl cucurbate (4), were evaluated for their melanogenesis-inhibitory and cancer chemopreventive potencies. Compounds 1, 3, and 4 exhibited potent melanogenesis-inhibitory activities in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16 melanoma cells. Western-blot analysis revealed that compounds 1 and 3 reduced the protein levels of MITF (=microphthalmia-associated transcription factor), tyrosinase, TRP-1 (=tyrosine-related protein 1), and TRP-2 mostly in a concentration-dependent manner. In addition, compound 1 exhibited inhibitory effects against Epstein-Barr virus early antigen (EBV-EA) activation induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, against TPA-induced inflammation in mice, and against skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter. PMID:25879500

  8. Absolute Configurations and NO Inhibitory Activities of Terpenoids from Curcuma longa.

    PubMed

    Xu, Jing; Ji, Feifei; Kang, Jing; Wang, Hao; Li, Shen; Jin, Da-Qing; Zhang, Qiang; Sun, Hongwei; Guo, Yuanqiang

    2015-06-24

    Curcuma longa L., belonging to the Zingiberaceae family, is a perennial herb and has been used as a spice and a pigment in the food industry. In the ongoing search for inhibitory reagents of NO production and survey of the chemical composition of natural vegetable foods, the chemical constituents of C. longa used as spice were investigated. This investigation resulted in the isolation of 2 new terpenoids and 14 known analogues. Their structures were established on the basis of the extensive analyses of 1D and 2D NMR spectroscopic data, and the absolute configurations of 1-4 were elucidated by comparison of the calculated and experimental ECD spectra. Among them, compound 1 is a rare norditerpene with an ent-labdane skeleton, and 2 is a skeletally novel sesquiterpene having an eight-membered ring. All of the compounds were found to possess NO inhibitory activities in murine microglial BV-2 cells. The discovery of two new compounds in this chemical investigation further disclosed the chemical composition of C. longa used a food spice, and the bioassay implied that the natural food spice C. longa, containing terpenoids with NO inhibitory activities, may be potentially promotive to human health.

  9. Inhibitory activity of cigarette-smoke condensate on the mutagenicity of heterocyclic amines.

    PubMed

    Lee, C K; Munoz, J A; Fulp, C; Chang, K M; Rogers, J C; Borgerding, M F; Doolittle, D J

    1994-07-01

    Cigarette-smoke condensate (CSC) is a complex mixture containing over 3800 identified chemicals including nicotine, water, mutagens, antimutagens, cytotoxins and inert chemicals. Although CSC is mutagenic in the Ames test, its effect on the activity of other mutagens has not been characterized. Using the Ames Salmonella bacterial mutagenesis assay, we found CSC exerts a significant inhibitory effect on mutagens requiring bioactivation. Those studied included heterocyclic amines (Glu-P-1, Glu-P-2, IQ, MeIQ, Trp-P-1 and Trp-P-2), benzo[a]pyrene (B[a]P) and aflatoxin B1. However, CSC had no effect on the activity of direct-acting mutagens (2-nitrofluorene, sodium azide, 4-nitro-1,2-phenylenediamine, 4-nitroquinoline N-oxide and methyl methanesulfonate). With indirect-acting mutagens, the reduced number of revertants observed in the presence of CSC was not attributable to cytotoxicity. CSC exhibited a potent inhibitory effect on the cytochrome P-450 dependent monooxygenases, ethoxyresorufin O-deethylase and B[a]P hydroxylase. This suggests inhibition of the cytochrome P-450 isozymes as one possible mechanism for the antimutagenicity of CSC. Fractionation studies of CSC revealed that the neutral, weakly acidic (phenolic) and basic fractions are all effective as antimutagens against Glu-P-1, a representative heterocyclic amine. This indicates that several classes of chemicals contribute to the inhibitory effect of CSC on the mutagenicity of the heterocyclic amines. PMID:7517501

  10. Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward.

    PubMed

    Henderson, Brandon J; Wall, Teagan R; Henley, Beverley M; Kim, Charlene H; Nichols, Weston A; Moaddel, Ruin; Xiao, Cheng; Lester, Henry A

    2016-03-01

    Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway.

  11. Isolation, characterization, and NO inhibitory activities of sesquiterpenes from Blumea balsamifera.

    PubMed

    Xu, Jing; Jin, Da-qing; Liu, Cuizhou; Xie, Chunfeng; Guo, Yuanqiang; Fang, Lingzhi

    2012-08-15

    Blumea balsamifera belongs to the family Compositae, and its leaves have been used as a flavoring ingredient and a tea. A phytochemical investigation of the aerial parts of B. balsamifera led to the isolation of 10 new (1-10) and 1 known (11) sesquiterpenes. Their structures were elucidated on the basis of extensive one- and two-dimensional nuclear magnetic resonance (heteronuclear multiple-quantum coherence, heteronuclear multiple-bond correlation, (1)H-(1)H correlation spectroscopy, and nuclear Overhauser effect spectrometry) spectroscopic data analyses, and the structure of compound 1 was confirmed by X-ray crystallography. The inhibitory activities on lipopolysaccharide-induced NO production in murine microglial BV-2 cells of these sesquiterpenes were evaluated, and all of the compounds showed inhibitory effects. PMID:22823402

  12. New compound with DNA Topo I inhibitory activity purified from Penicillium oxalicum HSY05.

    PubMed

    Liu, Bing; Wang, Hai-Feng; Zhang, Li-Hua; Liu, Fang; He, Feng-Jun; Bai, Jiao; Hua, Hui-Ming; Chen, Gang; Pei, Yue-Hu

    2015-01-01

    Strain HSY05 was isolated from sea sediment collected from the South China Sea and was later identified as Penicillium oxalicum by 16S rDNA sequence analysis. Various chromatographic processes led to the isolation and purification of two metabolites from the fermentation culture of HSY05, including one new compound, 2,2',4,4'-tetrahyoxy-8'-methyl-6-methoxy-acyl-ethyl-diphenylmethanone (1), and a known compound secalonic acid D (SAD, 2), as characterised by UV, IR, 1D, 2D-NMR and MS data. The inhibitory activities against topoisomerase I of these two compounds were evaluated. The result showed that in addition to the known topo I inhibitor SAD (2), compound 1 also exhibited a moderate inhibitory effect.

  13. Chemical constituents of Swertia longifolia Boiss. with α-amylase inhibitory activity

    PubMed Central

    Saeidnia, Soodabeh; Ara, Leila; Hajimehdipoor, Homa; Read, Roger W.; Arshadi, Sattar; Nikan, Marjan

    2016-01-01

    α-Amylase inhibitors play a critical role in the control of diabetes and many of medicinal plants have been found to act as α-amylase inhibitors. Swertia genus, belonging to the family Gentianaceae, comprises different species most of which have been used in traditional medicine of several cultures as antidiabetic, anti-pyretic, analgesic, liver and gastrointestinal tonic. Swertia longifolia Boiss. is the only species of Swertia growing in Iran. In the present investigation, phytochemical study of S. longifolia was performed and α-amylase inhibitory effects of the plant fractions and purified compounds were determined. Aerial parts of the plant were extracted with hexane, chloroform, methanol and water, respectively. The components of the hexane and chloroform fractions were isolated by different chromatographic methods and their structures were determined by 1H NMR and 13C NMR data. α-Amylase inhibitory activity was determined by a colorimetric assay using 3,5-dinitro salysilic acid. During phytochemical examination, α-amyrin, β-amyrin and β-sitosterol were purified from the hexane fraction, while ursolic acid, daucosterol and swertiamarin were isolated from chloroform fraction. The results of the biochemical assay revealed α-amylase inhibitory activity of hexane, chloroform, methanol and water fractions, of which the chloroform and methanol fractions were more potent (IC50 16.8 and 18.1 mg/ml, respectively). Among examined compounds, daucosterol was found to be the most potent α-amylase inhibitor (57.5% in concentration 10 mg/ml). With regard to α-amylase inhibitory effects of the plant extracts, purified constituents, and antidiabetic application of the species of Swertia genus in traditional medicine of different countries, S. longifolia seems more appropriate species for further mechanistic antidiabetic evaluations. PMID:27051429

  14. Increased alpha band activity indexes inhibitory competition across a border during figure assignment.

    PubMed

    Sanguinetti, Joseph L; Trujillo, Logan T; Schnyer, David M; Allen, John J B; Peterson, Mary A

    2016-09-01

    Figure-ground assignment is thought to entail inhibitory competition between potential objects on opposite sides of a shared border; the winner is perceived as the figure, and the loser as the shapeless ground. Computational models and response time measures support this understanding but to date no online measure of inhibitory competition during figure-ground assignment has been reported. The current study assays electroencephalogram (EEG) alpha power as a measure of inhibitory competition during figure-ground assignment. Activity in the EEG alpha band has been linked to functional inhibition in the brain, and it has been proposed that increased alpha power reflects increased inhibition. In 2 experiments participants viewed silhouettes designed so that the insides would be perceived as figures. Real-world silhouettes depicted namable objects. Novel silhouettes depicted novel objects on the insides of their borders, but varied in the amount of hypothesized cross-border competition for figural status: In "Low-Competition" silhouettes, the borders suggested novel objects on the outside as well as on the inside. In "High-Competition" silhouettes the borders suggested portions of real-world objects on the outside; these compete with the figural properties favoring the inside as figure. Participants accurately categorized both types of novel silhouettes as "novel" objects and were unaware of the real world objects suggested on the outside of the High-Competition silhouettes. In both experiments, we observed more alpha power while participants viewed High- rather than Low-Competition novel silhouettes. These are the first results to show via an online index of neural activity that figure assignment entails inhibitory competition.

  15. Chemical constituents of Swertia longifolia Boiss. with α-amylase inhibitory activity.

    PubMed

    Saeidnia, Soodabeh; Ara, Leila; Hajimehdipoor, Homa; Read, Roger W; Arshadi, Sattar; Nikan, Marjan

    2016-01-01

    α-Amylase inhibitors play a critical role in the control of diabetes and many of medicinal plants have been found to act as α-amylase inhibitors. Swertia genus, belonging to the family Gentianaceae, comprises different species most of which have been used in traditional medicine of several cultures as antidiabetic, anti-pyretic, analgesic, liver and gastrointestinal tonic. Swertia longifolia Boiss. is the only species of Swertia growing in Iran. In the present investigation, phytochemical study of S. longifolia was performed and α-amylase inhibitory effects of the plant fractions and purified compounds were determined. Aerial parts of the plant were extracted with hexane, chloroform, methanol and water, respectively. The components of the hexane and chloroform fractions were isolated by different chromatographic methods and their structures were determined by (1)H NMR and (13)C NMR data. α-Amylase inhibitory activity was determined by a colorimetric assay using 3,5-dinitro salysilic acid. During phytochemical examination, α-amyrin, β-amyrin and β-sitosterol were purified from the hexane fraction, while ursolic acid, daucosterol and swertiamarin were isolated from chloroform fraction. The results of the biochemical assay revealed α-amylase inhibitory activity of hexane, chloroform, methanol and water fractions, of which the chloroform and methanol fractions were more potent (IC50 16.8 and 18.1 mg/ml, respectively). Among examined compounds, daucosterol was found to be the most potent α-amylase inhibitor (57.5% in concentration 10 mg/ml). With regard to α-amylase inhibitory effects of the plant extracts, purified constituents, and antidiabetic application of the species of Swertia genus in traditional medicine of different countries, S. longifolia seems more appropriate species for further mechanistic antidiabetic evaluations. PMID:27051429

  16. Biflavonoids of Dacrydium balansae with potent inhibitory activity on dengue 2 NS5 polymerase.

    PubMed

    Coulerie, Paul; Eydoux, Cécilia; Hnawia, Edouard; Stuhl, Laetitia; Maciuk, Alexandre; Lebouvier, Nicolas; Canard, Bruno; Figadère, Bruno; Guillemot, Jean-Claude; Nour, Mohammed

    2012-05-01

    In order to find new molecules for antiviral drug design, we screened 102 ethyl acetate extracts from New-Caledonian flora for antiviral activity against the dengue 2 virus RNA-dependant RNA polymerase (DV-NS5 RdRp). The leaf extract of Dacrydium balansae, which strongly inhibited the DV-NS5, was submitted to bioguided fractionation. Four biflavonoids ( 1- 4), three sterols ( 5- 7), and two stilbene derivatives ( 8- 9) were identified and evaluated for their antiviral potential on the DV-NS5 RdRp. Biflavonoids appeared to be potent inhibitors of DV-NS5 RdRp with IC (50)s between 0.26 and 3.12 µM. Inhibitory activity evaluations against the RNA polymerase from other Flaviviridae viruses allowed us to conclude that these compounds are specific inhibitors of the DV RNA polymerase. The strongest inhibitions were observed with hinokiflavone ( 4), but podocarpusflavone A ( 2) is the strongest noncytotoxic inhibitor of the DV-NS5 and it also displayed polymerase inhibitory activity in a DV replicon. A preliminary structure-activity relationship study (SARs) revealed the necessity of the biflavonoid skeleton, the influence of number and position of methoxylations, and the importance of a free rotation of the linkage between the two apigenin monomers of the biflavonoids. To the best of our knowledge, podocarpusflavone A ( 2) is the strongest noncytotoxic non-nucleotide molecule exhibiting a specific inhibitory activity against the RNA polymerase domain of DV-NS5 and thus is promising for chemotherapy development against dengue fever. PMID:22411725

  17. Trivalent metal ions based on inorganic compounds with in vitro inhibitory activity of matrix metalloproteinase 13.

    PubMed

    Wen, Hanyu; Qin, Yuan; Zhong, Weilong; Li, Cong; Liu, Xiang; Shen, Yehua

    2016-10-01

    Collagenase-3 (MMP-13) inhibitors have attracted considerable attention in recent years and have been developed as a therapeutic target for a variety of diseases, including cancer. Matrix metalloproteinases (MMPs) can be inhibited by a multitude of compounds, including hydroxamic acids. Studies have shown that materials and compounds containing trivalent metal ions, particularly potassium hexacyanoferrate (III) (K3[Fe(CN)6]), exhibit cdMMP-13 inhibitory potential with a half maximal inhibitory concentration (IC50) of 1.3μM. The target protein was obtained by refolding the recombinant histidine-tagged cdMMP-13 using size exclusion chromatography (SEC). The secondary structures of the refolded cdMMP-13 with or without metal ions were further analyzed via circular dichroism and the results indicate that upon binding with metal ions, an altered structure with increased domain stability was obtained. Furthermore, isothermal titration calorimetry (ITC) experiments demonstrated that K3[Fe(CN)6]is able to bind to MMP-13 and endothelial cell tube formation tests provide further evidence for this interaction to exhibit anti-angiogenesis potential. To the best of our knowledge, no previous report of an inorganic compound featuring a MMP-13 inhibitory activity has ever been reported in the literature. Our results demonstrate that K3[Fe(CN)6] is useful as a new effective and specific inhibitor for cdMMP-13 which may be of great potential for future drug screening applications. PMID:27542739

  18. Screening of plants containing Naja naja siamensis cobra venom inhibitory activity using modified ELISA technique.

    PubMed

    Daduang, Sakda; Sattayasai, Nison; Sattayasai, Jintana; Tophrom, Pattara; Thammathaworn, Achra; Chaveerach, Arunrat; Konkchaiyaphum, Monruedee

    2005-06-15

    Enzyme-linked immunosorbent assay (ELISA) has been modified for screening plants with antagonistic activity to Naja naja siamensis cobra venom. Aqueous extracts from plants were investigated for their inhibitory effects on the binding of anti-cobra venom antibody to antigen, cobra venom, fixed onto 96-well microtiter plates. Ingredients in extracts were allowed to react with immobilized venom before the subsequent addition of antivenom antibody. Venom components affected by exposure to the extracts, unable to interact with their specific antibody, were predicted to be unable to bind to their native destinations or natural receptors. Curcuma cf. zedoaria, an old Thai medicinal plant, showed clear inhibitory activity in the ELISA test. Neurotoxin and protein degradative enzymes, major components in venom, were identified as targets of this extract in Western immunoblotting analysis. Ingredients in the extract showed high affinity to the toxin in competition assay by immunoprecipitation. The extract attenuated toxin activity by extending contraction time of diaphragm muscle after envenomation and had a potency to protect cellular proteins from venom degradative enzymes. Curcuma parviflora, with less activity in ELISA, exhibited acceptable results in two experiments but negative results in two experiments, whereas Curcuma longa, having low activity in the ELISA test, never showed any favorable results. Screening of 36 samples could classify plants into an inhibition range of 0 to 86%. This modified ELISA is recommended as a preliminary screening method for inhibitors with a large number of samples.

  19. Ongoing Network State Controls the Length of Sleep Spindles via Inhibitory Activity

    PubMed Central

    Barthó, Péter; Slézia, Andrea; Mátyás, Ferenc; Faradzs-Zade, Lejla; Ulbert, István; Harris, Kenneth D.; Acsády, László

    2014-01-01

    Summary Sleep spindles are major transient oscillations of the mammalian brain. Spindles are generated in the thalamus; however, what determines their duration is presently unclear. Here, we measured somatic activity of excitatory thalamocortical (TC) cells together with axonal activity of reciprocally coupled inhibitory reticular thalamic cells (nRTs) and quantified cycle-by-cycle alterations in their firing in vivo. We found that spindles with different durations were paralleled by distinct nRT activity, and nRT firing sharply dropped before the termination of all spindles. Both initial nRT and TC activity was correlated with spindle length, but nRT correlation was more robust. Analysis of spindles evoked by optogenetic activation of nRT showed that spindle probability, but not spindle length, was determined by the strength of the light stimulus. Our data indicate that during natural sleep a dynamically fluctuating thalamocortical network controls the duration of sleep spindles via the major inhibitory element of the circuits, the nRT. PMID:24945776

  20. Inhibitory short-term plasticity modulates neuronal activity in the rat entopeduncular nucleus in vitro.

    PubMed

    Lavian, Hagar; Korngreen, Alon

    2016-04-01

    The entopeduncular nucleus (EP) is one of the basal ganglia output nuclei integrating synaptic information from several pathways within the basal ganglia. The firing of EP neurons is modulated by two streams of inhibitory synaptic transmission, the direct pathway from the striatum and the indirect pathway from the globus pallidus. These two inhibitory pathways continuously modulate the firing of EP neurons. However, the link between these synaptic inputs to neuronal firing in the EP is unclear. To investigate this input-output transformation we performed whole-cell and perforated-patch recordings from single neurons in the entopeduncular nucleus in rat brain slices during repetitive stimulation of the striatum and the globus pallidus at frequencies within the in vivo activity range of these neurons. These recordings, supplemented by compartmental modelling, showed that GABAergic synapses from the striatum, converging on EP dendrites, display short-term facilitation and that somatic or proximal GABAergic synapses from the globus pallidus show short-term depression. Activation of striatal synapses during low presynaptic activity decreased postsynaptic firing rate by continuously increasing the inter-spike interval. Conversely, activation of pallidal synapses significantly affected postsynaptic firing during high presynaptic activity. Our data thus suggest that low-frequency striatal output may be encoded as progressive phase shifts in downstream nuclei of the basal ganglia while high-frequency pallidal output may continuously modulate EP firing.

  1. Anti-listeria activity of poly(lactic acid)/sawdust particle biocomposite film impregnated with pediocin PA-1/AcH and its use in raw sliced pork.

    PubMed

    Woraprayote, Weerapong; Kingcha, Yutthana; Amonphanpokin, Pannawit; Kruenate, Jittiporn; Zendo, Takeshi; Sonomoto, Kenji; Benjakul, Soottawat; Visessanguan, Wonnop

    2013-10-15

    A novel poly(lactic acid) (PLA)/sawdust particle (SP) biocomposite film with anti-listeria activity was developed by incorporation of pediocin PA-1/AcH (Ped) using diffusion coating method. Sawdust particle played an important role in embedding pediocin into the hydrophobic PLA film. The anti-listeria activity of the PLA/SP biocomposite film incorporated with Ped (PLA/SP+Ped) was detected, while no activity against the tested pathogen was observed for the control PLA films (without SP and/or Ped). Dry-heat treatment of film before coating with Ped resulted in the highest Ped adsorption (11.63 ± 3.07 μg protein/cm(2)) and the highest anti-listeria activity. A model study of PLA/SP+Ped as a food-contact antimicrobial packaging on raw sliced pork suggests a potential inhibition of Listeria monocytogenes (99% of total listerial population) on raw sliced pork during the chilled storage. This study supports the feasibility of using PLA/SP+Ped film to reduce the initial load of L. monocytogenes on the surface of raw pork.

  2. Inhibitory effect of flavonoid derivatives on Epstein-Barr virus activation and two-stage carcinogenesis of skin tumors.

    PubMed

    Iwase, Y; Takemura, Y; Ju-ichi, M; Mukainaka, T; Ichiishi, E; Ito, C; Furukawa, H; Yano, M; Tokuda, H; Nishino, H

    2001-11-28

    To search for possible anti-tumor promoters, ten flavonoid derivatives (1-10) synthesized from morin and quercetin were examined for their inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation by a short-term in vitro assay. Of these compounds, pentaallyl ethers (9, 10) showed significant inhibitory effects on EBV-EA activation induced by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate. Further, quercetin pentaallyl ether (10) exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.

  3. Nanoparticles Ease Aching Joints in Mice

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_161188.html Nanoparticles Ease Aching Joints in Mice Treatment might one ... News) -- New research in mice suggests that tiny nanoparticles might one day be a better way to ...

  4. Synthesis of Triazole Schiff’s Base Derivatives and Their Inhibitory Kinetics on Tyrosinase Activity

    PubMed Central

    Wang, Hui-Fang; Zheng, Jing; Cui, Yi; Fang, Xin-Yu; Zhang, Lin-Min; Chen, Qing-Xi

    2015-01-01

    In the present study, new Schiff’s base derivatives: (Z)-4-amino-5-(2-(3- fluorobenzylidene)hydrazinyl)-4H-1,2,4-triazole-3-thiol (Y1), (Z)-3-((2-(4-amino-5- mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y2), (Z)-2-((2-(4-amino-5- mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y3) and 3-((Z)-(2-(4- (((E)-3-hydroxybenzylidene)amino)-5-mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y4) were synthesized and their structures were characterized by LC-MS, IR and 1H NMR. The inhibitory effects of these compounds on tyrosinase activites were evaluated. Compounds Y1, Y2 and Y3 showed potent inhibitory effects with respective IC50 value of 12.5, 7.0 and 1.5 μM on the diphenolase activities. Moreover, the inhibition mechanisms were determined to be reversible and mixed types. Interactions of the compounds with tyrosinase were further analyzed by fluorescence quenching, copper interaction, and molecular simulation assays. The results together with the anti-tyrosinase activities data indicated that substitution on the second position of benzene ring showed superior ant-ityrosinase activities than that on third position, and that hydroxyl substitutes were better than fluorine substitutes. In addition, two benzene rings connecting to the triazole ring would produce larger steric hindrance, and affect the bonding between tyrosinase and inhibitors to decrease the inhibitory effects. The anti-tyrosinase effects of these compounds were in contrast to their antioxidant activities. In summary, this research will contribute to the development and design of antityrosinase agents. PMID:26422245

  5. Synthesis of Triazole Schiff's Base Derivatives and Their Inhibitory Kinetics on Tyrosinase Activity.

    PubMed

    Yu, Feng; Jia, Yu-Long; Wang, Hui-Fang; Zheng, Jing; Cui, Yi; Fang, Xin-Yu; Zhang, Lin-Min; Chen, Qing-Xi

    2015-01-01

    In the present study, new Schiff's base derivatives: (Z)-4-amino-5-(2-(3- fluorobenzylidene)hydrazinyl)-4H-1,2,4-triazole-3-thiol (Y1), (Z)-3-((2-(4-amino-5- mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y2), (Z)-2-((2-(4-amino-5- mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y3) and 3-((Z)-(2-(4- (((E)-3-hydroxybenzylidene)amino)-5-mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y4) were synthesized and their structures were characterized by LC-MS, IR and 1H NMR. The inhibitory effects of these compounds on tyrosinase activites were evaluated. Compounds Y1, Y2 and Y3 showed potent inhibitory effects with respective IC50 value of 12.5, 7.0 and 1.5 μM on the diphenolase activities. Moreover, the inhibition mechanisms were determined to be reversible and mixed types. Interactions of the compounds with tyrosinase were further analyzed by fluorescence quenching, copper interaction, and molecular simulation assays. The results together with the anti-tyrosinase activities data indicated that substitution on the second position of benzene ring showed superior ant-ityrosinase activities than that on third position, and that hydroxyl substitutes were better than fluorine substitutes. In addition, two benzene rings connecting to the triazole ring would produce larger steric hindrance, and affect the bonding between tyrosinase and inhibitors to decrease the inhibitory effects. The anti-tyrosinase effects of these compounds were in contrast to their antioxidant activities. In summary, this research will contribute to the development and design of antityrosinase agents. PMID:26422245

  6. Alpha-amylase inhibitory activity and phytochemical study of Zhumeria majdae Rech. f. and Wendelbo

    PubMed Central

    Mirshafie, Behnaz; Mokhber-Dezfouli, Najmeh; Manayi, Azadeh; Saeidnia, Soodabeh; Ajani, Yousef; Gohari, Ahmad Reza

    2015-01-01

    Background: Zhumeria majdae (Lamiaceae) is an endemic species growing in the South parts of Iran especially Hormozgan province. The plant is so-called Mohrekhosh locally and widely used for medicinal purposes including stomachache and dysmenorrhea. Objective: In order to separation and identification of the main flavonoid glycosides of the plant (aerial parts including leaves, stems, flowers, and fruits were used) and evaluation of its alpha-amylase inhibitory (AAI) activity, methanolic extract was prepared and fractionated to botanolic portion. Materials and Methods: Isolation of the main compounds of the butanol extract of the plant have been performed using different column chromatography methods such as high-performance liquid chromatography (C18 column) and Sephadex LH-20 as well. The isolated compounds were identified by Hydrogen-1 nuclear magnetic resonance and Carbon-13 nuclear magnetic resonance spectra and comparison with those reported in previous literature. Moreover, inhibitory activity of the butanolic extract of the plant against alpha-amylase enzyme was examined in different concentrations (15–30 mg/mL), where acarbose used as a positive control. Results: Three flavonoid glycosides: Linarin (1), hispidulin-7-O-(4-O-acetyl-rutinoside) (2), hispidulin-7-O-rutinoside (3) were successfully identified in the extract. The activity of alpha amylase enzyme was dose-dependently suppressed by the butanol extract. The extract exhibited the highest inhibition at 30 mg/mL toward enzyme (77.9 ± 2.1%), while acarbose inhibited the enzyme at 20 mg/mL by 73.9 ± 1.9%. The inhibitory concentrations of 50% for the extract and acarbose were calculated at 24.5 ± 2.1 and 6.6 ± 3.1 mg/mL, respectively. Conclusion: Z. majdae contains glycosylated flavones and could be a good candidate for anti-diabetic evaluations in animal and clinical trials due to possessing AAI activity. PMID:26692743

  7. Definition of an electronic profile of compounds with inhibitory activity against hematin aggregation in malaria parasite.

    PubMed

    Portela, César; Afonso, Carlos M M; Pinto, Madalena M M; Ramos, Maria João

    2004-06-15

    Malaria is one of the most important parasitic diseases, affecting almost half of the world and posing a threat to the other half. Xanthone derivatives can behave as antimalarial drugs in the same mechanistic way as chloroquine and other related quinolines. This action is due to the inhibition of the detoxification pathway of the parasite, responsible for the production of hemozoin. We report a study of the electronic properties of the xanthonic and quinolinic compounds based on DFT calculations, in order to determine a pattern that could be applied to the development of new potentially active antimalarial molecules. As a result, a new interpretation of structure-activity relationship of the quinoline antimalarial drugs, and of the active hydroxylated xanthones is proposed here. We conclude that electronic features rather than steric factors control primarily the inhibitory activity of the studied compounds against hematin aggregation, concurring to a potential antimalarial activity.

  8. Growth-inhibitory activity of natural and synthetic isothiocyanates against representative human microbial pathogens

    PubMed Central

    Kurepina, Natalia; Kreiswirth, Barry N.; Mustaev, Arkady

    2013-01-01

    Aims The aim of this study was to test the growth inhibition activity of isothiocyanates (ITC), defense compounds of plants, against common human microbial pathogens. Methods and Results In this study we have tested the growth inhibitory activity of a diverse collection of new and previously known representative ITC of various structural classes against pathogenic bacteria, fungi and molds by a serial dilution method. Generally, the compounds were more active against Gram-positive bacteria and fungi exhibiting species-specific bacteriostatic or bactericidal effect. The most active compounds inhibited the growth of both drug-susceptible and multi drug resistant (MDR) pathogens at micromolar concentrations. In the case of Mycobacterium tuberculosis some compounds were more active against MDR, rather than against susceptible strains. The average anti-microbial activity for some of new derivatives was significantly higher than previously reported for the most active ITC compounds. The structure-activity relationship (SAR) established for various classes of ITC with Bacillus cereus (model organism for B. anthracis) followed a distinct pattern, thereby enabling prediction of new more efficient inhibitors. Remarkably, tested bacteria failed to develop resistance to ITC. While effectively inhibiting microbial growth, ITCs displayed moderate toxicity towards eukaryotic cells. Conclusions High antimicrobial activity coupled with moderate toxicity grants further thorough studies of the ITC compounds aimed at elucidation of their cellular targets and inhibitory mechanism. Significance and impact of the study This systematic study identified new ITC compounds highly active against common human microbial pathogens at the concentrations comparable with those for currently used antimicrobial drugs (e.g. rifampicin, fluconazole). Tested representative pathogens do not develop resistance to the inhibitors. These properties justify further evaluation of ITC compounds as potential

  9. Biotransformation of isoimperatorin and imperatorin by Glomerella cingulata and beta-secretase inhibitory activity.

    PubMed

    Marumoto, Shinsuke; Miyazawa, Mitsuo

    2010-01-01

    Biotransformation studies conducted on the furanocoumarins isoimperatorin (1) and imperatorin (3) have revealed that 1 was metabolized by Glomerella cingulata to give the corresponding reduced acid, 6,7-furano-5-prenyloxy hydrocoumaric acid (2), and 3 was transformed by G. cingulata to give the dealkylated metabolite, xanthotoxol (4) in high yields (83% and 81%), respectively. The structures of the new compound 2 have been established on the basis of spectral data. The metabolites 2 and 4 were tested for the beta-secretase (BACE1) inhibitory activity in vitro, and metabolite 2 slightly inhibited the beta-secretase activity with an IC(50) value of 185.6+/-6.8 microM. The metabolite 4 was less potent activity than compounds 1-3. In addition, methyl ester (2Me), methyl ether (2a) and methyl ester and ether (2aMe) of 2 were synthesized, and investigated for the ability to inhibit beta-secretase. Compound 2aMe exhibited the best beta-secretase inhibitory activity at the IC(50) value 16.2+/-1.2 microM and found to be the 2aMe showed competitive mode of inhibition against beta-secretase with K(i) value 11.3+/-2.8 microM. PMID:19939683

  10. Phenolics from strawberry cv. Falandi and their antioxidant and α-glucosidase inhibitory activities.

    PubMed

    Yang, Dan; Xie, Haihui; Jiang, Yueming; Wei, Xiaoyi

    2016-03-01

    Three new phenolic glucosides, falandiosides A (1), B (2), and C (6) were isolated from strawberry (Fragaria×ananassa Duch.) cv. Falandi fruit, together with three flavone glucuronides (3-5), eleven lignan glycosides (12-22), and five others. Their structures were determined by spectroscopic methods. All the known phenolics were reported from strawberry for the first time. They were evaluated for antioxidant and α-glucosidase inhibitory activities. Three new and fifteen known phenolics showed potent 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical cation scavenging activity with IC50 values of 22.50-4.28μM in comparison to l-ascorbic acid (14.21μM). Quercetin 3-(6-methylglucuronide) (4), (+)-isolariciresinol 9'-glucoside (12), and (-)-isolariciresinol 9'-glucoside (13) were active in scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. Moreover, compounds 12 and 13 had moderate ferric reducing antioxidant power (FRAP) values. Further, two new and seven known phenolics exhibited more potent α-glucosidase inhibitory activity with IC50 values of 537.43-25.39μM than acarbose (619.94μM).

  11. Nanocapsular dispersion of cinnamaldehyde for enhanced inhibitory activity against aflatoxin production by Aspergillus flavus.

    PubMed

    Li, Hongbo; Shen, Qingshan; Zhou, Wei; Mo, Haizhen; Pan, Daodong; Hu, Liangbin

    2015-01-01

    Cinnamaldehyde (CA) is marginally soluble in water, making it challenging to evenly disperse it in foods, and resulting in lowered anti-A. flavus efficacy. In the present study, nano-dispersed CA (nano-CA) was prepared to increase its aqueous solubility. Free and nano-dispersed CA were compared in terms of their inhibitory activity against fungal growth and aflatoxin production of A. flavus both in Sabouraud Dextrose (SD) culture and in peanut butter. Our results indicated that free CA inhibited the mycelia growth and aflatoxin production of A. flavus with a minimal inhibitory concentration (MIC) value of 1.0 mM, but promoted the aflatoxin production at some concentrations lower than the MIC. Nano-CA had a lower MIC value of 0.8 mM against A. flavus, and also showed improved activity against aflatoxin production without the promotion at lower dose. The solidity of peanut butter had an adverse impact on the antifungal activity of free CA, whereas nano-dispersed CA showed more than 2-fold improved activity against the growth of A. flavus. Free CA still promoted AFB1 production at the concentration of 0.25 mM, whereas nano-CA showed more efficient inhibition of AFB1 production in the butter. PMID:25853318

  12. T Cells Expressing Constitutively Active Akt Resist Multiple Tumor-associated Inhibitory Mechanisms

    PubMed Central

    Sun, Jiali; Dotti, Gianpietro; Huye, Leslie E; Foster, Aaron E; Savoldo, Barbara; Gramatges, Maria M; Spencer, David M; Rooney, Cliona M

    2010-01-01

    Adoptive transfer of antigen-specific cytotoxic T lymphocytes has shown promise for the therapy of cancer. However, tumor-specific T cells are susceptible to diverse inhibitory signals from the tumor microenvironment. The Akt/protein kinase B plays a central role in T-cell proliferation, function, and survival and we hypothesized that expression of constitutively active Akt (caAkt) in T cells could provide resistance to many of these tumor-associated inhibitory mechanisms. caAkt expression in activated human T cells increased proliferation and cytokine production, a likely result of their sustained expression of nuclear factor-κB (NF-κB) and provided resistance to apoptosis by upregulating antiapoptotic molecules. caAkt expressing T cells (caAkt-T-cells) were also relatively resistant to suppression by and conversion into regulatory T cells (Tregs). These characteristics provided a survival advantage to T cells cocultured with tumor cells in vitro; CD3/28-stimulated T cells expressing a chimeric antigen receptor (CAR) specific for disialoganglioside (GD2) that redirected their activity to the immunosuppressive, GD2-expressing neuroblastoma cell line, LAN-1, resisted tumor-induced apoptosis when co-expressing transgenic caAkt. In conclusion, caAkt-transduced T cells showed resistance to several evasion strategies employed by tumors and may therefore enhance the antitumor activity of adoptively transferred T lymphocytes. PMID:20842106

  13. Inhibitory activity against plasmin, trypsin, and elastase in rennet whey and in cheese fortified with whey protein.

    PubMed

    Benfeldt, C; Sørensen, J; Petersen, T E

    1998-03-01

    The inhibitory activity against trypsin, elastase, and plasmin was determined in samples of Danbo 45+ that were manufactured from milk pasteurized at 72, 80, and 90 degrees C for 15, 30 and 60 s; the corresponding rennet wheys; and Havarti 45+ manufactured from milk concentrated 1.8-fold, 2.7-fold, and 4.6-fold by ultrafiltration. A sensitive colorimetric assay demonstrated that the incorporation of thermally denatured whey proteins into the cheese curd by pasteurization resulted in a decreased proteinase inhibitory activity against trypsin and elastase in Danbo 45+ and against trypsin, elastase, and plasmin in the corresponding rennet wheys. However, incorporation of native whey proteins into Havarti 45+ by ultrafiltration of the cheese milk resulted in an increased inhibitory activity against trypsin and elastase in the cheeses. Cheese manufactured from milk concentrated 1.8-fold, 2.7-fold, or 4.6-fold displayed trypsin inhibitory activity that was 1.8, 2.9, and 5.1 times, respectively, that of the reference cheese. Similarly, the elastase inhibitory activity in the cheeses increased 2.2, 3.2 and 7.8 times. The increased inhibitory activity in cheese fortified with native whey protein likely contributes to the decreased proteolysis and altered ripening characteristics of the resulting cheeses, and further, the method can be adapted to detection of other inhibitors if sufficiently sensitive substrates are available.

  14. Flavonoids and its derivatives from Callistephus chinensis flowers and their inhibitory activities against alpha-glucosidase

    PubMed Central

    Zhang, Xiaoshu; Liu, Zhenting; Bi, Xiuli; Liu, Jingxin; Li, Wei; Zhao, Yuqing

    2013-01-01

    Inhibitors of carbohydrate-hydrolysing enzymes play an important role for the treatment of diabetes. One of the therapeutic methods for decreasing of postprandial hyperglycemia is to retard absorption of glucose by the inhibition of carbohydrate- hydrolysing enzymes, such as α-glucosidase, in the digestive organs. To investigate the therapeutic potential of compounds from natural sources, Callistephus chinensis flowers (CCF) were tested for inhibition of α-glucosidase, and acarboes was used as the positive control. The 70 % ethanol extract of CCF exhibited significant α-glucosidase inhibitory activities with IC50 value of 8.14 μg/ml. The stepwise polarity fractions of CCF were tested further for in vitro inhibition of α-glucosidase. The ethyl acetate (EtOAc) fraction exhibited the most significant inhibitory activity. Eight pure compounds, apigenin, apigenin-7-O-β-D- glucoside, kaempferol, hyperin, naringenin, quercetin, luteolin, and kaempferol-7-O-β-D- glucoside, were isolated (using enzyme assay-guide fractionation method) from the EtOAc fraction. Among these, quercetin was the most active one (IC50 values 2.04 μg/ml), and it appears that the inhibiting percentages are close to acarbose (IC50 values 2.24 μg/ml), the positive control, on α-glucosidase inhibition. HPLC/UV analysis indicated that the major components of CCF are kaempferol, hyperin and quercetin. The presented results revealed that CCF containing these eight flavonoids could be a useful natural source in the development of a novel α-glucosidase inhibitory agent against diabetic complications. PMID:27298611

  15. DC-159a Shows Inhibitory Activity against DNA Gyrases of Mycobacterium leprae

    PubMed Central

    Yamaguchi, Tomoyuki; Yokoyama, Kazumasa; Nakajima, Chie

    2016-01-01

    Background Fluoroquinolones are a class of antibacterial agents used for leprosy treatment. Some new fluoroquinolones have been attracting interest due to their remarkable potency that is reportedly better than that of ofloxacin, the fluoroquinolone currently recommended for treatment of leprosy. For example, DC-159a, a recently developed 8-methoxy fluoroquinolone, has been found to be highly potent against various bacterial species. Nonetheless, the efficacy of DC-159a against Mycobacterium leprae is yet to be examined. Methodology/Principal Findings To gather data that can support highly effective fluoroquinolones as candidates for new remedies for leprosy treatment, we conducted in vitro assays to assess and compare the inhibitory activities of DC-159a and two fluoroquinolones that are already known to be more effective against M. leprae than ofloxacin. The fluoroquinolone-inhibited DNA supercoiling assay using recombinant DNA gyrases of wild type and ofloxacin-resistant M. leprae revealed that inhibitory activities of DC-159a and sitafloxacin were at most 9.8- and 11.9-fold higher than moxifloxacin. Also the fluoroquinolone–mediated cleavage assay showed that potencies of those drugs were at most 13.5- and 9.8-fold higher than moxifloxacin. In addition, these two drugs retained their inhibitory activities even against DNA gyrases of ofloxacin-resistant M. leprae. Conclusions/Significance The results indicated that DC-159a and sitafloxacin are more effective against wild type and mutant M. leprae DNA gyrases than moxifloxacin, suggesting that these antibacterial drugs can be good candidates that may supersede current fluoroquinolone remedies. DC-159a in particular is very promising because it is classified in a subgroup of fluoroquinolones that is known to be less likely to cause adverse effects. Our results implied that DC-159a is well worth further investigation to ascertain its in vivo effectiveness and clinical safety for humans. PMID:27681932

  16. Effects of Total Ginsenosides on the Feeding Behavior and Two Enzymes Activities of Mythimna separata (Walker) Larvae

    PubMed Central

    Zhang, Ai-Hua; Tan, Shi-Qiang; Zhao, Yan; Lei, Feng-Jie; Zhang, Lian-Xue

    2015-01-01

    Ginsenosides, the main effective components of Panax ginseng C.A. Meyer and Panax quinquefolius L., are important allelochemicals of ginseng. Although many studies have targeted the pharmacological, chemical, and clinical properties of ginsenosides, little is known about their ecological role in ginseng population adaptation and evolution. Pests rarely feed on ginseng, and it is not known why. This study investigated the effects of total ginsenosides on feeding behavior and activities of acetylcholinesterase (AChE) and glutathione s-transferase (GST) in Mythimna separata (Walker) larvae. The results showed that the total ginsenosides had significant antifeeding activity against M. separata larvae, determined by nonselective and selective antifeeding bioassays. In addition, the total ginsenosides had inhibitory effects on the activities of GST and AChE. The antifeeding ratio was the highest at 8 h, then decreased, and was the lowest at 16 h. Both GST and AChE activities decreased from 0 h to 48 h in all total ginsenosides treatments but increased at 72 h. Total ginsenosides had antifeeding activity against M. separata larvae and inhibitory effects on the activities of GST and AChE. PMID:26074991

  17. Nitric oxide inhibitory activity of monogalactosylmonoacylglycerols from a freshwater microalgae Chlorella sorokiniana.

    PubMed

    Banskota, Arjun H; Stefanova, Roumiana; Gallant, Pamela; Osborne, Jane A; Melanson, Ronald; O'Leary, Stephen J B

    2013-01-01

    Chemical investigation of the freshwater microalgae Chlorella sorokiniana led to the isolation of a new monogalactosylmonoacylglycerol, namely, (2S)-1-O-(7Z,10Z-hexadecadienoyl)-3-O-β-D-galactopyranosylglycerol (1) together with a known glycolipid (2S)-1-O-(7Z,10Z,13Z-hexadecatrienoyl)-3-O-β-D-galactopyranosylglycerol (2). Both monogalactosylmonoacylglycerols showed dose-dependent nitric oxide (NO) inhibitory activity against lipopolysaccharide-induced NO production in RAW264.7 macrophage cells suggesting their possible use as anti-inflammatory agents. PMID:22703524

  18. Four New Flavonoids with α-Glucosidase Inhibitory Activities from Morus alba var. tatarica.

    PubMed

    Zhang, Ya-Long; Luo, Jian-Guang; Wan, Chuan-Xing; Zhou, Zhong-Bo; Kong, Ling-Yi

    2015-11-01

    Four new flavonoids, mortatarins A-D (1-4, resp.), along with eight known flavonoids (5-12) were isolated from the root bark of Morus alba var. tatarica. Their structures were established on the basis of spectroscopic data analysis, and the absolute configuration of 4 was determined by analysis of its CD spectrum. All isolates were tested for inhibitory activities against α-glucosidase. Compounds 4, 7, and 8 exhibited a significant degree of inhibition with IC50 values of 5.0 ± 0.3, 7.5 ± 0.5, and 5.9 ± 0.2 μM, respectively. PMID:26567954

  19. Synthesis and p38 Inhibitory Activity of Some Novel Substituted N,N'-Diarylurea Derivatives.

    PubMed

    Zhu, Dianxi; Xing, Qifeng; Cao, Ruiyuan; Zhao, Dongmei; Zhong, Wu

    2016-01-01

    We have identified a novel series of substituted N,N'-diarylurea p38α inhibitors. The inhibitory activity of the target compounds against the enzyme p38α, MAPKAPK2 in BHK cells, TNF-α release in LPS-stimulated THP-1 cells and p38α binding experiments were tested. Among these compounds, 25a inhibited the p38α enzyme with an IC50 value of 0.47 nM and a KD value of 1.54 × 10(-8) and appears to be the most promising one in the series. PMID:27223276

  20. Flavonol dimers from callus cultures of Dysosma versipellis and their in vitro neuraminidase inhibitory activities.

    PubMed

    Chen, Ridao; Duan, Ruigang; Wei, Yannan; Zou, Jianhua; Li, Junwei; Liu, Xiaoyue; Wang, Haiyan; Guo, Ying; Li, Qiuhong; Dai, Jungui

    2015-12-01

    A chemical investigation of callus cultures of Dysosma versipellis led to the isolation of five new flavonol dimers, dysoverines A-E (1-5), together with 12 known compounds (6-17). The structures of new compounds were determined by the extensive spectroscopic data analyses. The biosynthetic pathway of the new compounds was proposed to involve O-methylation, prenylation, and Diels-Alder cycloaddition, which successively occurred in cultured plant cells. Compounds 1-17 exhibited in vitro neuraminidase inhibitory activities with the IC50 values of 31.0-93.9μM. PMID:26481138

  1. Four New Flavonoids with α-Glucosidase Inhibitory Activities from Morus alba var. tatarica.

    PubMed

    Zhang, Ya-Long; Luo, Jian-Guang; Wan, Chuan-Xing; Zhou, Zhong-Bo; Kong, Ling-Yi

    2015-11-01

    Four new flavonoids, mortatarins A-D (1-4, resp.), along with eight known flavonoids (5-12) were isolated from the root bark of Morus alba var. tatarica. Their structures were established on the basis of spectroscopic data analysis, and the absolute configuration of 4 was determined by analysis of its CD spectrum. All isolates were tested for inhibitory activities against α-glucosidase. Compounds 4, 7, and 8 exhibited a significant degree of inhibition with IC50 values of 5.0 ± 0.3, 7.5 ± 0.5, and 5.9 ± 0.2 μM, respectively.

  2. The inhibitory effect of metals and other ions on acid phosphatase activity from Vigna aconitifolia seeds.

    PubMed

    Srivastava, Pramod Kumar; Anand, Asha

    2015-01-01

    Sensitivity of acid phosphatase from Vigna aconitifolia seeds to metal ions, fluoride, and phosphate was examined. All the effectors had different degree of inhibitory effect on the enzyme. Among metal ions, molybdate and ferric ion were observed to be most potent inhibitors and both exhibited mixed type of inhibition. Acid phosphatase activity was inhibited by Cu2+ in a noncompetitive manner. Zn and Mn showed mild inhibition on the enzyme activity. Inhibition kinetics analysis explored molybdate as a potent inhibitor for acid phosphatase in comparison with other effectors used in this study. Fluoride was the next most strong inhibitor for the enzyme activity, and caused a mixed type of inhibition. Phosphate inhibited the enzyme competitively, which demonstrates that inhibition due to phosphate is one of the regulatory factors for enzyme activity.

  3. Evaluation of antioxidant activity and inhibitory effect on nitric oxide production of some common vegetables.

    PubMed

    Bor, Jung-Yi; Chen, Hui-Yin; Yen, Gow-Chin

    2006-03-01

    The objectives of this study were to study the antioxidant activities and nitric oxide (NO) scavenging effects of vegetables in vitro systems and to study the inhibitory effects of vegetables on the NO production and NO-induced DNA damage in RAW 264.7 macrophage. The results indicated that water extracts from Indian lotus, Jew's ear, shiitake, eggplant, and winter mushroom showed stronger antioxidant activity and free-radical-scavenging ability than that of other vegetable extracts. The scavenging effects of vegetable extracts on NO derived from sodium nitroprusside (SNP) were in decreasing order of water spinach > Indian lotus > eggplant and garland chrysanthemum. In the macrophage model system, the water extracts from fresh daylily flower, sponge gourd, pea sprout, and eggplant exhibited over 80% inhibition on NO generation stimulated by lipopolysaccharide. The extract from fresh daylily flower that expressed the strongest inhibition on NO production was attributed to the ability to reduce the inducible nitric oxide synthase (iNOS) induction. However, the extracts from pea sprout and eggplant suppressed the NO production by scavenging on NO and inactivating toward iNOS enzyme. In addition, the water extracts from fresh daylily flower, sponge gourd, pea sprout, and eggplant also showed over 40% inhibitory effect on DNA damage induced by SNP in RAW 264.7 macrophage. The data also indicated that eggplant and pea sprout extracts contained higher total phenolic compounds, anthocyanins, and ascorbic acids and appeared to be responsible for their antioxidant activities and scavenging effects on NO derived from SNP. PMID:16506819

  4. Hypocholesterolemic Effect and In Vitro Pancreatic Lipase Inhibitory Activity of an Opuntia ficus-indica Extract

    PubMed Central

    Flores-Fernandez, Jose Miguel; Fernandez-Flores, Ofelia; Gutierrez-Mercado, Yanet; Carmona-de la Luz, Joel; Sandoval-Salas, Fabiola; Mendez-Carreto, Carlos

    2015-01-01

    Cholesterol control is fundamental for prevention of cardiovascular disorders. In this work, the hypocholesterolemic activity of an aqueous Opuntia ficus-indica extract (AOE) was tested in triton-induced mice. The inhibitory activity on pancreatic lipase enzyme was evaluated in vitro by the same extract. Furthermore, polyphenol content of the extract was evaluated. Hypercholesterolemia was induced in three groups of mice by intraperitoneal administration of Triton WR-1339. After induction of hypercholesterolemia, the groups were treated with an AOE (500 mg/kg) and saline solution and the positive control group with orlistat, respectively. Cholesterol levels were measured 24 h later in peripheral blood. The levels of blood cholesterol after administration of AOE significantly decreased compared to negative control. The inhibitory activity of AOE on pancreatic lipase enzyme was evaluated at concentrations from 60 to 1000 μg/mL. The AOE inhibited the pancreatic lipase with an IC50 = 588.5 μg/mL. The AOE had a high content of polyphenolic compounds. These results show that AOE is able to prevent hypercholesterolemia by pancreatic lipase inhibition, in part due to its polyphenolic compounds. PMID:26078966

  5. Inhibitory effects of fruit juices on cytochrome P450 2C9 activity in vitro.

    PubMed

    Hidaka, Muneaki; Nagata, Masashi; Kawano, Yohei; Sekiya, Hiroshi; Kai, Hirofumi; Yamasaki, Keishi; Okumura, Manabu; Arimori, Kazuhiko

    2008-02-01

    There is limited information on the effect of fruits on human cytochrome P450 (CYP) 2C9 activity. The objective of this study was to determine the effect of fruit juice on CYP2C9-mediated drug metabolism. Nine citrus fruits and eight tropical fruits were chosen. We investigated effects of the fruits on diclofenac 4'-hydroxylation and tolbutamide hydroxylation by human liver microsomes. Among the fruits, pineapple juice showed potent inhibition of CYP2C9 activity. The addition of 25 microl (5.0% v/v) of pineapple juice resulted in almost complete inhibition. Next we examined the inhibitory effect of bromelain, a cysteine protease in pineapple. Bromelain also strongly inhibited CYP2C9 activity. In addition, E-64, a cysteine protease inhibitor, almost entirely blocked inhibition by pineapple juice and bromelain. Thus we found that pineapple juice was a potent inhibitor of CYP2C9, and that the inhibitory effect might be due to the bromelain contained in pineapple.

  6. Superoxide radicals scavenging and xanthine oxidase inhibitory activity of magnesium lithospermate B from Salvia miltiorrhiza.

    PubMed

    Liu, Xiaoyu; Chen, Ruohua; Shang, Yanjun; Jiao, Binghua; Huang, Caiguo

    2009-06-01

    In this study we investigated the superoxide radicals scavenging effect and xanthine oxidase inhibitory activity by magnesium lithospermate B, which was originally isolated from the roots of Salvia miltiorrhiza (also named Danshen or Dansham), an important herb in Oriental medicine. Superoxide radicals were generated both in beta-NADH/PMS system and xanthine/ xanthine oxidase system. Magnesium lithospermate B significantly inhibited the reduction of NBT induced by superoxide radicals with an IC(50) of 29.8 microg/mL and 4.06 microg/mL respectively in the two systems. Further study suggested that magnesium lithospermate B can directly inhibit xanthine oxidase and exhibits competitive inhibition. Magnesium lithospermate B was also found to have the hypouricemic activity in vivo against potassium oxonate-induced hyperuricaemia in mice. After oral administration of magnesium lithospermate B at doses of 10, 20 and 30 mg/kg, there was a significant decrease in the serum urate level when compared to the hyperuricemia control. In addition, magnesium lithospermate B significantly protected HL-60 cells from superoxide radicals-induced apoptosis in the xanthine/ xanthine oxidase reactions. This study provided evidence that magnesium lithospermate B exhibits direct superoxide radicals scavenging and xanthine oxidase inhibitory activity.

  7. Neuraminidase inhibitory activities of quaternary isoquinoline alkaloids from Corydalis turtschaninovii rhizome.

    PubMed

    Kim, Jang Hoon; Ryu, Young Bae; Lee, Woo Song; Kim, Young Ho

    2014-11-01

    Clostridium perfringens is a Gram-positive spore-forming bacterium that causes food poisoning. The neuraminidase (NA) protein of C. perfringens plays a pivotal role in bacterial proliferation and is considered a novel antibacterial drug target. Based on screens for novel NA inhibitors, a 95% EtOH extract of Corydalis turtschaninovii rhizome showed NA inhibitory activity (68% at 30 μg/ml), which resulted in the isolation of 10 isoquinoline alkaloids; namely, palmatine (1), berberine (2), coptisine (3), pseudodehydrocorydaline (4), jatrorrhizine (5), dehydrocorybulbine (6), pseudocoptisine (7), glaucine (8), corydaline (9) and tetrahydrocoptisine (10). Interestingly, seven quaternary isoquinoline alkaloids 1-7 (IC50 = 12.8 ± 1.5 to 65.2 ± 4.5 μM) showed stronger NA inhibitory activity than the tertiary alkaloids 8-10. In addition, highly active compounds 1 and 2 showed reversible non-competitive behavior based on a kinetic study. Molecular docking simulations using the Autodock 4.2 software increased our understanding of receptor-ligand binding of these compounds. In addition, we demonstrated that compounds 1 and 2 suppressed bacterial growth.

  8. Spectroscopic studies on the inhibitory effects of ionic liquids on lipase activity

    NASA Astrophysics Data System (ADS)

    Fan, Yunchang; Dong, Xing; Li, Xiaojing; Zhong, Yingying; Kong, Jichuan; Hua, Shaofeng; Miao, Juan; Li, Yan

    2016-04-01

    The effects of ionic liquids (ILs) on the lipase activity were studied by UV-Vis spectroscopy and the IL-lipase interaction mechanism at the molecular level was investigated by fluorescence technique. Experimental results indicated that the lipase activity was inhibited by ILs and the degree of inhibition highly depended on the chemical structures of ILs. The inhibitory ability of the Cl-- and Br--based ILs increased with increasing the alkyl chain length in the IL cation. Thermodynamic parameters, enthalpy change (ΔH) and entropy change (ΔS) were obtained by analyzing the fluorescence behavior of lipase with the addition of ILs. Both ΔH and ΔS were positive suggesting hydrophobicity was the major driven force for the Cl-- and Br--based ILs. For the BF4--, CF3SO3--, ClO4-- and N(CN)2--based ILs, hydrogen bonding was the main driven force. For a more comprehensive understanding of the effects of ILs on lipase activity, the roles of hydrophobicity and hydrogen bonding must be considered simultaneously. A regression-based equation was developed to describe the relationship of the inhibitory ability of ILs and their hydrophobicity and hydrogen bonding ability.

  9. Spectroscopic studies on the inhibitory effects of ionic liquids on lipase activity.

    PubMed

    Fan, Yunchang; Dong, Xing; Li, Xiaojing; Zhong, Yingying; Kong, Jichuan; Hua, Shaofeng; Miao, Juan; Li, Yan

    2016-04-15

    The effects of ionic liquids (ILs) on the lipase activity were studied by UV-Vis spectroscopy and the IL-lipase interaction mechanism at the molecular level was investigated by fluorescence technique. Experimental results indicated that the lipase activity was inhibited by ILs and the degree of inhibition highly depended on the chemical structures of ILs. The inhibitory ability of the Cl(-)- and Br(-)-based ILs increased with increasing the alkyl chain length in the IL cation. Thermodynamic parameters, enthalpy change (ΔH) and entropy change (ΔS) were obtained by analyzing the fluorescence behavior of lipase with the addition of ILs. Both ΔH and ΔS were positive suggesting hydrophobicity was the major driven force for the Cl(-)- and Br(-)-based ILs. For the BF4(-)-, CF3SO3(-)-, ClO4(-)- and N(CN)2(-)-based ILs, hydrogen bonding was the main driven force. For a more comprehensive understanding of the effects of ILs on lipase activity, the roles of hydrophobicity and hydrogen bonding must be considered simultaneously. A regression-based equation was developed to describe the relationship of the inhibitory ability of ILs and their hydrophobicity and hydrogen bonding ability. PMID:26836454

  10. Hypocholesterolemic Effect and In Vitro Pancreatic Lipase Inhibitory Activity of an Opuntia ficus-indica Extract.

    PubMed

    Padilla-Camberos, Eduardo; Flores-Fernandez, Jose Miguel; Fernandez-Flores, Ofelia; Gutierrez-Mercado, Yanet; Carmona-de la Luz, Joel; Sandoval-Salas, Fabiola; Mendez-Carreto, Carlos; Allen, Kirk

    2015-01-01

    Cholesterol control is fundamental for prevention of cardiovascular disorders. In this work, the hypocholesterolemic activity of an aqueous Opuntia ficus-indica extract (AOE) was tested in triton-induced mice. The inhibitory activity on pancreatic lipase enzyme was evaluated in vitro by the same extract. Furthermore, polyphenol content of the extract was evaluated. Hypercholesterolemia was induced in three groups of mice by intraperitoneal administration of Triton WR-1339. After induction of hypercholesterolemia, the groups were treated with an AOE (500 mg/kg) and saline solution and the positive control group with orlistat, respectively. Cholesterol levels were measured 24 h later in peripheral blood. The levels of blood cholesterol after administration of AOE significantly decreased compared to negative control. The inhibitory activity of AOE on pancreatic lipase enzyme was evaluated at concentrations from 60 to 1000 μg/mL. The AOE inhibited the pancreatic lipase with an IC50 = 588.5 μg/mL. The AOE had a high content of polyphenolic compounds. These results show that AOE is able to prevent hypercholesterolemia by pancreatic lipase inhibition, in part due to its polyphenolic compounds.

  11. The inhibitory activity of pomelo essential oil on the bacterial biofilms development on soft contact lenses.

    PubMed

    Saviuc, Crina; Dascălu, Luminita; Chifiriuc, Mariana Carmen; Rădulescu, Valeria; Oprea, Eliza; Popa, Marcela; Hristu, Radu; Stanciu, George; Lazăr, Veronica

    2010-01-01

    The aim of present study was to investigate the microbial colonization of worn contact lenses (CLs) and to evaluate the inhibitory effect of pomelo (Citrus maxima) peels essential oil on the biofilm development on unworn CLs. The essential oil was isolated by steam distillation and analyzed by gas chromatography coupled with mass spectrometry, twenty compounds being isolated. The antimicrobial activity of pomelo oil was tested against S. epidermidis and P. aeruginosa strains, known for their ability to develop biofilms on prosthetic devices, by qualitative screening methods and quantitative assay of the minimal inhibitory concentrations (MIC) in order to evaluate the antibiofilm activity. Our study revealed that all worn CLs where 100% colonized by staphylococci and Enterobacteriaceae strains. The pomelo essential oil inhibited the development of bacterial biofilms formed by Gram-positive and Gram-negative microorganisms on soft CLs, its antibiofilm activity being specific and dependent on different physical parameters (contact time and temperature). The architecture of bacterial biofilms developed on soft contact lenses was analyzed using confocal scanning laser microscopy (CSLM). PMID:21434591

  12. Oleanane-type triterpenoids of Aceriphyllum rossii and their diacylglycerol acyltransferase-inhibitory activity.

    PubMed

    Seo, Jee-Hee; Kim, Mun-Ock; Han, Ah-Reum; Kwon, Eun-Bin; Kang, Myung Ji; Cho, Sungchan; Moon, Dong-Oh; Noh, Jung-Ran; Lee, Chul-Ho; Kim, Young-Soo; Lee, Hyun-Sun

    2015-02-01

    Six known triterpenoid compounds, 3-oxoolean-12-en-27-oic acid (1), gypsogenic acid (2), 3α-hydroxyolean-12-en-27-oic acid (3), 3β-hydroxyolean-12-en-27-oic acid (4), aceriphyllic acid A (5), and oleanolic acid (6), were isolated from the roots of Aceriphyllum rossii. Their chemical structures were determined by comparison with available (1)H-NMR and (13)C-NMR data on known compounds. All the isolated compounds were evaluated for inhibitory activity against human diacylglycerol acyltransferases 1 and 2. Most of the isolates exhibited a better inhibitory activity against diacylglycerol acyltransferase 2 (IC50: 11.6-44.2 µM) than against diacylglycerol acyltransferase 1 (IC50: 22.7-119.5 µM). In particular, compounds 1 and 5 showed strong inhibition efficacy towards diacylglycerol acyltransferases 1 and 2, and appeared to act competitively against oleoyl-CoA in vitro. The results also indicated that both compounds reduced newly synthesized triacylglycerol in HuTu80 and HepG2 cells. Oral administration of compound 1 significantly reduced postprandial triacylglycerol in mice following an oral lipid challenge. In conclusion, the current study indicates that compound 1 suppresses both de novo triacylglycerol biosynthesis and resynthesis through the inhibition of diacylglycerol acyltransferase activity, and therefore may be a useful agent for treating diseases associated with a high triacylglycerol level.

  13. Mutation at Glu23 eliminates the neuron growth inhibitory activity of human metallothionein-3

    SciTech Connect

    Ding Zhichun; Teng Xinchen; Cai Bin; Wang Hui; Zheng Qi; Wang Yang; Zhou Guoming; Zhang Mingjie; Wu Houming; Sun Hongzhe . E-mail: hsun@hku.hk; Huang Zhongxian . E-mail: zxhuang@fudan.edu.cn

    2006-10-20

    Human metallothionein-3 (hMT3), first isolated and identified as a neuronal growth inhibitory factor (GIF), is a metalloprotein expressed predominantly in brain. However, untill now, the exact mechanism of the bioactivity of hMT3 is still unknown. In order to study the influence of acid-base catalysis on S-nitrosylation of hMT3, we constructed the E23K mutant of hMT3. During the course of bioassay, we found out unexpectedly that mutation at E23 of hMT3 eliminates the neuronal growth inhibitory activity completely. To the best of our knowledge, it is First report that other residues, besides the TCPCP motif, in the {beta}-domain can alter the bioactivity of hMT3. In order to figure out the causes for the loss of bioactivity of the E23K mutant, the biochemical properties were characterized by UV-vis spectroscopy, CD spectroscopy, pH titration, DTNB reaction, EDTA reaction, and SNOC reaction. All data demonstrated that stability of the metal-thiolate cluster and overall structure of the E23K mutant were not altered too much. However, the reaction of the E23K mutant with SNOC exhibited biphasic kinetics and the mutant protein released zinc ions much faster than hMT3 in the initial step, while hMT3 exhibited single kinetic process. The 2D [{sup 1}H-{sup 15}N] HSQC was also employed to characterize structural changes during the reaction of hMT3 with varying mounts of nitric oxide. It was shown that the resonance of Glu23 disappeared at a molar ratio of NO to protein of 4. Based on these results, we suggest that mutation at Glu23 may alter the NO metabolism and/or affect zinc homeostasis in brain, thus altering the neuronal growth inhibitory activity.

  14. Enzyme Inhibitory Properties, Antioxidant Activities, and Phytochemical Profile of Three Medicinal Plants from Turkey

    PubMed Central

    Zengin, Gokhan; Guler, Gokalp Ozmen; Aktumsek, Abdurrahman; Ceylan, Ramazan; Picot, Carene Marie Nancy; Mahomoodally, M. Fawzi

    2015-01-01

    We aimed to investigate the inhibitory potential of three medicinal plants (Hedysarum varium, Onobrychis hypargyrea, and Vicia truncatula) from Turkey against key enzymes involved in human pathologies, namely, diabetes (α-amylase and α-glucosidase), neurodegenerative disorders (tyrosinase, acetylcholinesterase, and butyrylcholinesterase), and hyperpigmentation (tyrosinase). The antioxidant potential, phenolic and flavonoid content of ethyl acetate, and methanolic and aqueous extracts were investigated using in vitro assays. The total antioxidant capacity (TAC), β-carotene/linoleic acid bleaching activity, 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH•), 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+), cupric ion reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and metal chelating activity on ferrous ions were used to evaluate the antioxidant capabilities of the extracts. The half-maximal inhibitory concentrations (IC50) of the extracts on cholinesterase, tyrosinase, and α-amylase were significantly higher than the references, galantamine, kojic acid, and acarbose, respectively. The half-maximal effective concentrations (EC50) of the extracts on TAC, CUPRAC, and FRAP were significantly higher than trolox. The phenol and flavonoid contents of the plant extracts were in the range 20.90 ± 0.190–83.25 ± 0.914 mg gallic acid equivalent/g extract and 1.45 ± 0.200–39.71 ± 0.092 mg rutin equivalent/g extract, respectively. The plants were found to possess moderate antioxidant capacities and interesting inhibitory action against key enzymes. PMID:26798334

  15. Enzyme Inhibitory Properties, Antioxidant Activities, and Phytochemical Profile of Three Medicinal Plants from Turkey.

    PubMed

    Zengin, Gokhan; Guler, Gokalp Ozmen; Aktumsek, Abdurrahman; Ceylan, Ramazan; Picot, Carene Marie Nancy; Mahomoodally, M Fawzi

    2015-01-01

    We aimed to investigate the inhibitory potential of three medicinal plants (Hedysarum varium, Onobrychis hypargyrea, and Vicia truncatula) from Turkey against key enzymes involved in human pathologies, namely, diabetes (α-amylase and α-glucosidase), neurodegenerative disorders (tyrosinase, acetylcholinesterase, and butyrylcholinesterase), and hyperpigmentation (tyrosinase). The antioxidant potential, phenolic and flavonoid content of ethyl acetate, and methanolic and aqueous extracts were investigated using in vitro assays. The total antioxidant capacity (TAC), β-carotene/linoleic acid bleaching activity, 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH(•)), 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(•+)), cupric ion reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and metal chelating activity on ferrous ions were used to evaluate the antioxidant capabilities of the extracts. The half-maximal inhibitory concentrations (IC50) of the extracts on cholinesterase, tyrosinase, and α-amylase were significantly higher than the references, galantamine, kojic acid, and acarbose, respectively. The half-maximal effective concentrations (EC50) of the extracts on TAC, CUPRAC, and FRAP were significantly higher than trolox. The phenol and flavonoid contents of the plant extracts were in the range 20.90 ± 0.190-83.25 ± 0.914 mg gallic acid equivalent/g extract and 1.45 ± 0.200-39.71 ± 0.092 mg rutin equivalent/g extract, respectively. The plants were found to possess moderate antioxidant capacities and interesting inhibitory action against key enzymes. PMID:26798334

  16. Quassinoids from the stems of Picrasma quassioides and their cytotoxic and NO production-inhibitory activities.

    PubMed

    Xu, Jian; Xiao, Di; Song, Wei-Wu; Chen, Lei; Liu, Wen-Yuan; Xie, Ning; Feng, Feng; Qu, Wei

    2016-04-01

    Three new C20 quassinoids nigakilactone P (1), picraqualide F (2), nigakilactone Q (3), along with eight known quassinoids (4-11), were isolated from the 95% EtOH extract of the stems of Picrasma quassioides. The structures of the new compounds were elucidated by means of HRESIMS and different NMR techniques. Assignments of relative and absolute configurations for these compounds were achieved on the basis of ROESY spectra and quantum chemical ECD calculation. In vitro activity assays, none of the compounds showed cytotoxic (IC50>50 μM) and NO production-inhibitory activities (IC50>30 μM), and the structure-activity relationships of quassinoids were summarized. In addition, the chemotaxonomic significance of the isolated compounds was also discussed.

  17. Inhibitory effect of pinaverium bromide on gastrointestinal contractile activity in conscious dogs.

    PubMed

    Itoh, Z; Takahashi, I

    1981-01-01

    The inhibitory effect of 4-(6-bromoveratryl)-4-(2-[2-(6,6-dimethyl-2-norpinyl)-ethoxy]-ethyl)-morpholinium hydroxide (pinaverium bromide), a quaternary ammonium derivative, on the contractile activity of the gastrointestinal tract from the stomach to the colon was investigated in six conscious dogs. Gastrointestinal motor activity was monitored by means of chronically implanted force transducers. Pinaverium bromide was continuously administered i.v. for 30 min in doses of 10 and 20 mg/kg/h during both the digestive and interdigestive states. It was found that pinaverium bromide strongly inhibited gastrointestinal contractile activity during both the digestive and interdigestive states; contractions in the stomach were most strongly inhibited; however, those in the small and large bowels were also significantly inhibited. No significant side effects in the circulatory and respiratory systems and the gastrointestinal tract such as nausea, vomiting or diarrhea were observed during and after the infusion of this agent. PMID:7197953

  18. Development of cyclobutene- and cyclobutane-functionalized fatty acids with inhibitory activity against Mycobacterium tuberculosis

    PubMed Central

    Sittiwong, Wantanee; Zinniel, Denise K.; Fenton, Robert J.; Marshall, Darrel; Story, Courtney B.; Kim, Bohkyung; Lee, Ji-Young; Powers, Robert; Barletta, Raúl G.

    2014-01-01

    Eleven fatty acid analogs incorporating four-membered carbocycles (cyclobutenes, cyclobutanes, cyclobutanones, and cyclobutanols) were investigated for the ability to inhibit growth of Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb). A number of the analogs displayed inhibitory activity against both mycobacterial species in minimal media. Several of the molecules displayed potent levels of inhibition against Mtb with MIC values equal to or below those obtained with the anti-tuberculosis drugs D-cycloserine and isoniazid. In contrast, two of the analogs displaying the greatest activity against Mtb failed to inhibit E. coli growth under either set of conditions. Thus, the active molecules identified here (1, 2, 6, and 8) may provide the basis for development of anti-mycobacterial agents against Mtb. PMID:24902951

  19. In vitro inhibitory activity of essential oil vapors against Ascosphaera apis.

    PubMed

    Kloucek, Pavel; Smid, Jakub; Flesar, Jaroslav; Havlik, Jaroslav; Titera, Dalibor; Rada, Vojtech; Drabek, Ondrej; Kokoska, Ladislav

    2012-02-01

    This work evaluates the in vitro inhibitory activity of 70 essential oils (EOs) in the vapor phase for the control of Chalkbrood disease caused by Ascosphaera apis Maassen ex Claussen (Olive et Spiltoir). Two wild strains isolated from infected honey bee colonies together with one standard collection strain were tested by the microatmosphere method. From 70 EOs, 39 exhibited an antifungal effect against A. apis standard and wild strains. The greatest antifungal action was observed for EO vapors from Armoracia rusticana, followed by Thymus vulgaris, Cymbopogon flexosus, Origanum vulgare and Allium sativum. An investigation of chemical composition by GC-MS revealed, that the most active EOs contained allyl isothiocyanate, citral, carvacrol and diallyl sulfides as the main constituents. The chemical composition plays a key role, as activities of different EOs from the same botanical species were different according to their composition. PMID:22474973

  20. Inhibitory effect of plant Manilkara subsericea against biological activities of Lachesis muta snake venom.

    PubMed

    De Oliveira, Eduardo Coriolano; Fernandes, Caio Pinho; Sanchez, Eladio Flores; Rocha, Leandro; Fuly, André Lopes

    2014-01-01

    Snake venom is composed of a mixture of substances that caused in victims a variety of pathophysiological effects. Besides antivenom, literature has described plants able to inhibit injuries and lethal activities induced by snake venoms. This work describes the inhibitory potential of ethanol, hexane, ethyl acetate, or dichloromethane extracts and fractions from stem and leaves of Manilkara subsericea against in vivo (hemorrhagic and edema) and in vitro (clotting, hemolysis, and proteolysis) activities caused by Lachesis muta venom. All the tested activities were totally or at least partially reduced by M. subsericea. However, when L. muta venom was injected into mice 15 min first or after the materials, hemorrhage and edema were not inhibited. Thus, M. subsericea could be used as antivenom in snakebites of L. muta. And, this work also highlights Brazilian flora as a rich source of molecules with antivenom properties.

  1. Inhibitory Effect of Plant Manilkara subsericea against Biological Activities of Lachesis muta Snake Venom

    PubMed Central

    De Oliveira, Eduardo Coriolano; Fernandes, Caio Pinho; Sanchez, Eladio Flores; Fuly, André Lopes

    2014-01-01

    Snake venom is composed of a mixture of substances that caused in victims a variety of pathophysiological effects. Besides antivenom, literature has described plants able to inhibit injuries and lethal activities induced by snake venoms. This work describes the inhibitory potential of ethanol, hexane, ethyl acetate, or dichloromethane extracts and fractions from stem and leaves of Manilkara subsericea against in vivo (hemorrhagic and edema) and in vitro (clotting, hemolysis, and proteolysis) activities caused by Lachesis muta venom. All the tested activities were totally or at least partially reduced by M. subsericea. However, when L. muta venom was injected into mice 15 min first or after the materials, hemorrhage and edema were not inhibited. Thus, M. subsericea could be used as antivenom in snakebites of L. muta. And, this work also highlights Brazilian flora as a rich source of molecules with antivenom properties. PMID:24511532

  2. Data on synthesis of methylene bisphosphonates and screening of their inhibitory activity towards HIV reverse transcriptase.

    PubMed

    Yanvarev, D V; Korovina, A N; Usanov, N N; Khomich, O A; Vepsäläinen, J; Puljula, E; Kukhanova, M K; Kochetkov, S N

    2016-09-01

    Inorganic pyrophosphate (PPi) mimetics designed on a basis of methylenediphosphonic acid backbone are promising inhibitors of two key HIV replication enzymes, IN [1] and RT [2]. Herein, we present chemical synthesis of eleven methylenebisphosphonates (BPs) with their NMR and HRMS analysis synthesized via five different ways. Also, we present data on inhibition of HIV RT catalyzed phosphorolysis and polymerization by synthesized BPs using two methods based on denaturing urea PAGE. Tests were also performed for thymidine analogue mutations reverse transcriptase (TAM RT), which was expressed and purified for that. Structure-activity relationships and inhibitory activity data of synthesized BPs are presented in "Methylene bisphosphonates as the inhibitors of HIV RT phosphorolytic activity" [2]. PMID:27547792

  3. Quassinoids from the stems of Picrasma quassioides and their cytotoxic and NO production-inhibitory activities.

    PubMed

    Xu, Jian; Xiao, Di; Song, Wei-Wu; Chen, Lei; Liu, Wen-Yuan; Xie, Ning; Feng, Feng; Qu, Wei

    2016-04-01

    Three new C20 quassinoids nigakilactone P (1), picraqualide F (2), nigakilactone Q (3), along with eight known quassinoids (4-11), were isolated from the 95% EtOH extract of the stems of Picrasma quassioides. The structures of the new compounds were elucidated by means of HRESIMS and different NMR techniques. Assignments of relative and absolute configurations for these compounds were achieved on the basis of ROESY spectra and quantum chemical ECD calculation. In vitro activity assays, none of the compounds showed cytotoxic (IC50>50 μM) and NO production-inhibitory activities (IC50>30 μM), and the structure-activity relationships of quassinoids were summarized. In addition, the chemotaxonomic significance of the isolated compounds was also discussed. PMID:26851344

  4. Inhibitory evaluation of oligonol on α-glucosidase, protein tyrosine phosphatase 1B, cholinesterase, and β-secretase 1 related to diabetes and Alzheimer's disease.

    PubMed

    Choi, Jae Sue; Bhakta, Himanshu Kumar; Fujii, Hajime; Min, Byung-Sun; Park, Chan Hum; Yokozawa, Takako; Jung, Hyun Ah

    2016-03-01

    Oligonol is a low-molecular-weight form of polyphenol that is derived from lychee fruit extract and contains catechin-type monomers and oligomers of proanthocyanidins. This study investigates the anti-diabetic activities of oligonol via α-glucosidase and human recombinant protein tyrosine phosphatase 1B (PTP1B) assays, as well as its anti-Alzheimer activities by evaluating the ability of this compound to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Oligonol exhibited potent concentration-dependent anti-diabetic activities by inhibiting α-glucosidase and PTP1B with IC50 values of 23.14 µg/mL and 1.02 µg/mL, respectively. Moreover, a kinetics study revealed that oligonol inhibited α-glucosidase (K i = 22.36) and PTP1B (K i = 8.51) with characteristics typical of a mixed inhibitor. Oligonol also displayed potent concentration-dependent inhibitory activity against AChE and BChE with IC50 values of 4.34 µg/mL and 2.07 µg/mL, respectively. However, oligonol exhibited only marginal concentration-dependent BACE1 inhibitory activity with an IC50 value of 130.45 µg/mL. A kinetics study revealed mixed-type inhibition against AChE (K i = 4.65) and BACE1 (K i = 58.80), and noncompetitive-type inhibition against BChE (K i = 9.80). Furthermore, oligonol exhibited dose-dependent inhibitory activity against peroxynitrite (ONOO(-))-mediated protein tyrosine nitration. These results indicate that oligonol has strong preventative potential in diabetes mellitus and in Alzheimer's disease. PMID:26724817

  5. Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy.

    PubMed

    Ievglevskyi, O; Isaev, D; Netsyk, O; Romanov, A; Fedoriuk, M; Maximyuk, O; Isaeva, E; Akaike, N; Krishtal, O

    2016-08-01

    Acid-sensing ion channels (ASICs) play an important role in numerous functions in the central and peripheral nervous systems ranging from memory and emotions to pain. The data correspond to a recent notion that each neuron and many glial cells of the mammalian brain express at least one member of the ASIC family. However, the mechanisms underlying the involvement of ASICs in neuronal activity are poorly understood. However, there are two exceptions, namely, the straightforward role of ASICs in proton-based synaptic transmission in certain brain areas and the role of the Ca(2+)-permeable ASIC1a subtype in ischaemic cell death. Using a novel orthosteric ASIC antagonist, we have found that ASICs specifically control the frequency of spontaneous inhibitory synaptic activity in the hippocampus. Inhibition of ASICs leads to a strong increase in the frequency of spontaneous inhibitory postsynaptic currents. This effect is presynaptic because it is fully reproducible in single synaptic boutons attached to isolated hippocampal neurons. In concert with this observation, inhibition of the ASIC current diminishes epileptic discharges in a low Mg(2+) model of epilepsy in hippocampal slices and significantly reduces kainate-induced discharges in the hippocampus in vivo Our results reveal a significant novel role for ASICs.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'. PMID:27377725

  6. ACE-I Inhibitory Activity from Phaseolus lunatus and Phaseolus vulgaris Peptide Fractions Obtained by Ultrafiltration.

    PubMed

    Betancur-Ancona, David; Dávila-Ortiz, Gloria; Chel-Guerrero, Luis Antonio; Torruco-Uco, Juan Gabriel

    2015-11-01

    The involvement of angiotensin-I-converting enzyme (ACE-I) as one of the mechanisms controlling blood pressure is being studied to find alternative means of control of hypertension on human beings. On the market there are synthetic drugs that can control it, but these can cause undesirable health side effects. In this work was assessed the fractionation by ultrafiltration of the Lima bean (Phaseolus lunatus) and Jamapa bean (Phaseolus vulgaris), protein hydrolysates obtained with Alcalase(®) and Flavourzyme(®) on ACE-I inhibitory activity. Four membranes of different molecular cutoffs (10, 5, 3, and 1 kDa) were used. Fractions that had a higher inhibitory activity in both legumes were denominated as E (<1 kDa) with IC50 of 30.3 and 51.8 μg/mL values for the P. lunatus with Alcalase and Flavourzyme, respectively, and for the Phaseolus vulgaris with Alcalase and Flavourzyme with about 63.8 and 65.8 μg/mL values, respectively. The amino acid composition of these fractions showed residues in essential amino acids, which make a good source of energy and amino acids. On the other hand, the presence of hydrophobic amino acids such as V and P is a determining factor in the ACE-I inhibitor effect. The results suggest the possibility of obtaining and utilizing these peptide fractions in the development and innovation of a functional product that helps with treatment and/or prevention of hypertension.

  7. The effects of inhibitory control training for preschoolers on reasoning ability and neural activity.

    PubMed

    Liu, Qian; Zhu, Xinyi; Ziegler, Albert; Shi, Jiannong

    2015-09-23

    Inhibitory control (including response inhibition and interference control) develops rapidly during the preschool period and is important for early cognitive development. This study aimed to determine the training and transfer effects on response inhibition in young children. Children in the training group (N = 20; 12 boys, mean age 4.87 ± 0.26 years) played "Fruit Ninja" on a tablet computer for 15 min/day, 4 days/week, for 3 weeks. Children in the active control group (N = 20; 10 boys, mean age 4.88 ± 0.20 years) played a coloring game on a tablet computer for 10 min/day, 1-2 days/week, for 3 weeks. Several cognitive tasks (involving inhibitory control, working memory, and fluid intelligence) were used to evaluate the transfer effects, and electroencephalography (EEG) was performed during a go/no-go task. Progress on the trained game was significant, while performance on a reasoning task (Raven's Progressive Matrices) revealed a trend-level improvement from pre- to post-test. EEG indicated that the N2 effect of the go/no-go task was enhanced after training for girls. This study is the first to show that pure response inhibition training can potentially improve reasoning ability. Furthermore, gender differences in the training-induced changes in neural activity were found in preschoolers.

  8. Antioxidant activity and ACE-inhibitory of Class II hydrophobin from wild strain Trichoderma reesei.

    PubMed

    Khalesi, Mohammadreza; Jahanbani, Raheleh; Riveros-Galan, David; Sheikh-Hassani, Vahid; Sheikh-Zeinoddin, Mahmoud; Sahihi, Mehdi; Winterburn, James; Derdelinckx, Guy; Moosavi-Movahedi, Ali Akbar

    2016-10-01

    There are several possible uses of the Class II hydrophobin HFBII in clinical applications. To fully understand and exploit this potential however, the antioxidant activity and ACE-inhibitory potential of this protein need to be better understood and have not been previously reported. In this study, the Class II hydrophobin HFBII was produced by the cultivation of wild type Trichoderma reesei. The crude hydrophobin extract obtained from the fermentation process was purified using reversed-phase liquid chromatography and the identity of the purified HFBII verified by MALDI-TOF (molecular weight: 7.2kDa). Subsequently the antioxidant activities of different concentrations of HFBII (0.01-0.40mg/mL) were determined. The results show that for HFBII concentrations of 0.04mg/mL and upwards the protein significantly reduced the presence of ABTS(+) radicals in the medium, the IC50 value found to be 0.13mg/mL. Computational modeling highlighted the role of the amino acid residues located in the conserved and exposed hydrophobic patch on the surface of the HFBII molecule and the interactions with the aromatic rings of ABTS. The ACE-inhibitory effect of HFBII was found to occur from 0.5mg/mL and upwards, making the combination of HFBII with strong ACE-inhibitors attractive for use in the healthcare industry. PMID:27211298

  9. Screening of α-Glucosidase Inhibitory Activity from Some Plants of Apocynaceae, Clusiaceae, Euphorbiaceae, and Rubiaceae

    PubMed Central

    Elya, Berna; Basah, Katrin; Mun'im, Abdul; Yuliastuti, Wulan; Bangun, Anastasia; Septiana, Eva Kurnia

    2012-01-01

    Diabetes mellitus (DM) is recognized as a serious global health problem that is characterized by high blood sugar levels. Type 2 DM is more common in diabetic populations. In this type of DM, inhibition of α-glucosidase is a useful treatment to delay the absorption of glucose after meals. As a megabiodiversity country, Indonesia still has a lot of potential unexploited forests to be developed as a medicine source, including as the α-glucosidase inhibitor. In this study, we determine the α-glucosidase inhibitory activity of 80% ethanol extracts of leaves and twigs of some plants from the Apocynaceae, Clusiaceae, Euphorbiaceae, and Rubiaceae. Inhibitory activity test of the α-glucosidase was performed in vitro using spectrophotometric methods. Compared with the control acarbose (IC50 117.20 μg/mL), thirty-seven samples of forty-five were shown to be more potent α-glucosidase inhibitors with IC50 values in the range 2.33–112.02 μg/mL. PMID:22187534

  10. Isolation of natural compounds from Phlomis stewartii showing α-glucosidase inhibitory activity.

    PubMed

    Jabeen, Bushra; Riaz, Naheed; Saleem, Muhammad; Naveed, Muhammad Akram; Ashraf, Muhammad; Alam, Umber; Rafiq, Hafiza Mehwish; Tareen, Rasool Bakhsh; Jabbar, Abdul

    2013-12-01

    Stewartiiside (1), a phenylethanoid glycoside and three 28-nortriterpenoids: stewertiisins A-C [(17R)-19(18→17)-abeo-3α,18β,23,24-tetrahydroxy-28-norolean-12-ene, 2; (17R)-19(18→17)-abeo-2α,16β,18β,23,24-pentahydroxy-28-norolean-12-en-3-one, 3; (17R)-19(18→17)-abeo-2α,3α,23,24-tetrahydroxy-28-noroleane-11,13-diene, 4] together with eight known compounds: lunariifolioside (5), notohamosin A (6), phlomispentanol (7), isorhamnetin 3-(6-p-coumaroyl)-β-D-glucopyranoside (8), tiliroside (9), caffeic acid (10), p-hydrxybenzoic acid (11) and oleanolic acid (12) were isolated from the ethyl acetate soluble fraction of the methanolic extract of whole plant of Phlomis stewartii. The structures of these isolates (1-12) were elucidated by the combination of 1D ((1)H and (13)C NMR), 2D (HMQC, HMBC COSY, NOESY) NMR spectroscopy and mass spectrometry (EIMS, HREIMS, FABMS, HRFABMS) and in comparison with literature data of related compounds. All the isolates (1-12) showed α-glucosidase inhibitory activity with IC50 values ranging between 14.5 and 355.4 μM, whereas, compounds 1, 5, 9 and 10 showed promising α-glucosidase inhibitory activity with IC50 values below 30 μM.

  11. Investigation of aromatase inhibitory activity of metal complexes of 8-hydroxyquinoline and uracil derivatives

    PubMed Central

    Prachayasittikul, Veda; Pingaew, Ratchanok; Nantasenamat, Chanin; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

    2014-01-01

    Purpose Estrogens play important roles in the pathogenesis and progression of breast cancer as well as estrogen-related diseases. Aromatase is a key enzyme in the rate-limiting step of estrogen production, in which its inhibition is one strategy for controlling estrogen levels to improve prognosis of estrogen-related cancers and diseases. Herein, a series of metal (Mn, Cu, and Ni) complexes of 8-hydroxyquinoline (8HQ) and uracil derivatives (4–9) were investigated for their aromatase inhibitory and cytotoxic activities. Methods The aromatase inhibition assay was performed according to a Gentest™ kit using CYP19 enzyme, wherein ketoconazole and letrozole were used as reference drugs. The cytotoxicity was tested on normal embryonic lung cells (MRC-5) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results Only Cu complexes (6 and 9) exhibited aromatase inhibitory effect with IC50 0.30 and 1.7 μM, respectively. Cytotoxicity test against MRC-5 cells showed that Mn and Cu complexes (5 and 6), as well as free ligand 8HQ, exhibited activity with IC50 range 0.74–6.27 μM. Conclusion Cu complexes (6 and 9) were found to act as a novel class of aromatase inhibitor. Our findings suggest that these 8HQ–Cu–uracil complexes are promising agents that could be potentially developed as a selective anticancer agent for breast cancer and other estrogen-related diseases. PMID:25152615

  12. Production of feline leukemia inhibitory factor with biological activity in Escherichia coli.

    PubMed

    Kanegi, R; Hatoya, S; Tsujimoto, Y; Takenaka, S; Nishimura, T; Wijewardana, V; Sugiura, K; Takahashi, M; Kawate, N; Tamada, H; Inaba, T

    2016-07-15

    Leukemia inhibitory factor (LIF) is a cytokine which is essential for oocyte and embryo development, embryonic stem cell, and induced pluripotent stem cell maintenance. Leukemia inhibitory factor improves the maturation of oocytes in the human and the mouse. However, feline LIF (fLIF) cloning and effects on oocytes during IVM have not been reported. Thus, we cloned complete cDNA of fLIF and examined its biological activity and effects on oocytes during IVM in the domestic cat. The aminoacid sequence of fLIF revealed a homology of 81% or 92% with that of mouse or human. The fLIF produced by pCold TF DNA in Escherichia coli was readily soluble and after purification showed bioactivity in maintaining the undifferentiated state of mouse embryonic stem cells and enhancing the proliferation of human erythrocyte leukemia cells. Furthermore, 10- and 100-ng/mL fLIF induced cumulus expansion with or without FSH and EGF (P < 0.05). The rate of metaphase II oocytes was also improved with 100-ng/mL fLIF (P < 0.05). We therefore confirmed the successful production for the first time of biologically active fLIF and revealed its effects on oocytes during IVM in the domestic cat. Feline LIF will further improve reproduction and stem cell research in the feline family. PMID:27020881

  13. The effects of inhibitory control training for preschoolers on reasoning ability and neural activity

    PubMed Central

    Liu, Qian; Zhu, Xinyi; Ziegler, Albert; Shi, Jiannong

    2015-01-01

    Inhibitory control (including response inhibition and interference control) develops rapidly during the preschool period and is important for early cognitive development. This study aimed to determine the training and transfer effects on response inhibition in young children. Children in the training group (N = 20; 12 boys, mean age 4.87 ± 0.26 years) played “Fruit Ninja” on a tablet computer for 15 min/day, 4 days/week, for 3 weeks. Children in the active control group (N = 20; 10 boys, mean age 4.88 ± 0.20 years) played a coloring game on a tablet computer for 10 min/day, 1–2 days/week, for 3 weeks. Several cognitive tasks (involving inhibitory control, working memory, and fluid intelligence) were used to evaluate the transfer effects, and electroencephalography (EEG) was performed during a go/no-go task. Progress on the trained game was significant, while performance on a reasoning task (Raven’s Progressive Matrices) revealed a trend-level improvement from pre- to post-test. EEG indicated that the N2 effect of the go/no-go task was enhanced after training for girls. This study is the first to show that pure response inhibition training can potentially improve reasoning ability. Furthermore, gender differences in the training-induced changes in neural activity were found in preschoolers. PMID:26395158

  14. The effects of inhibitory control training for preschoolers on reasoning ability and neural activity.

    PubMed

    Liu, Qian; Zhu, Xinyi; Ziegler, Albert; Shi, Jiannong

    2015-01-01

    Inhibitory control (including response inhibition and interference control) develops rapidly during the preschool period and is important for early cognitive development. This study aimed to determine the training and transfer effects on response inhibition in young children. Children in the training group (N = 20; 12 boys, mean age 4.87 ± 0.26 years) played "Fruit Ninja" on a tablet computer for 15 min/day, 4 days/week, for 3 weeks. Children in the active control group (N = 20; 10 boys, mean age 4.88 ± 0.20 years) played a coloring game on a tablet computer for 10 min/day, 1-2 days/week, for 3 weeks. Several cognitive tasks (involving inhibitory control, working memory, and fluid intelligence) were used to evaluate the transfer effects, and electroencephalography (EEG) was performed during a go/no-go task. Progress on the trained game was significant, while performance on a reasoning task (Raven's Progressive Matrices) revealed a trend-level improvement from pre- to post-test. EEG indicated that the N2 effect of the go/no-go task was enhanced after training for girls. This study is the first to show that pure response inhibition training can potentially improve reasoning ability. Furthermore, gender differences in the training-induced changes in neural activity were found in preschoolers. PMID:26395158

  15. QSAR prediction of HIV-1 protease inhibitory activities using docking derived molecular descriptors.

    PubMed

    Fatemi, Mohammad H; Heidari, Afsane; Gharaghani, Sajjad

    2015-03-21

    In this study, application of a new hybrid docking-quantitative structure activity relationship (QSAR) methodology to model and predict the HIV-1 protease inhibitory activities of a series of newly synthesized chemicals is reported. This hybrid docking-QSAR approach can provide valuable information about the most important chemical and structural features of the ligands that affect their inhibitory activities. Docking studies were used to find the actual conformations of chemicals in active site of HIV-1 protease. Then the molecular descriptors were calculated from these conformations. Multiple linear regression (MLR) and least square support vector machine (LS-SVM) were used as QSAR models, respectively. The obtained results reveal that statistical parameters of the LS-SVM model are better than the MLR model, which indicate that there are some non-linear relations between selected molecular descriptors and anti-HIV activities of interested chemicals. The correlation coefficient (R), root mean square error (RMSE) and average absolute error (AAE) for LS-SVM are: R=0.988, RMSE=0.207 and AAE=0.145 for the training set, and R=0.965, RMSE=0.403 and AAE=0.338 for the test set. Leave one out cross validation test was used for assessment of the predictive power and validity of models which led to cross-validation correlation coefficient QUOTE of 0.864 and 0.850 and standardized predicted relative error sum of squares (SPRESS) of 0.553 and 0.581 for LS-SVM and MLR models, respectively.

  16. Inhibitory activity of Thai condiments on pandemic strain of Vibrio parahaemolyticus.

    PubMed

    Vuddhakul, Varaporn; Bhoopong, Phuangthip; Hayeebilan, Fadeeya; Subhadhirasakul, Sanan

    2007-06-01

    Antibacterial activity of 13 condiments used in Thai cooking was investigated with a pandemic strain of Vibrio parahaemolyticus. Using a disk diffusion technique, freshly squeezed extracts from galangal, garlic and lemon, at a concentration of 10 microl/disk produced a clear zone of 13.6+/-0.5, 11.6+/-0.5 and 8.6+/-1.2mm, respectively. The inhibitory activity of these 3 condiments on pandemic strains was not significantly different from that on non-pandemic strains of V. parahaemolyticus. Because of its popularity in seafood cooking, galangal was subjected to further investigation. Only a chloroform extract of galangal inhibited growth of V. parahaemolyticus producing a clear zone of 9.5+/-0.5, 12.0+/-0 and 13.5+/-0.5mm diameter at concentrations of 25, 50 and 100 microg/disk, respectively. One active component is identified as 1'-acetoxychavicol acetate. The activity of galangal was not reduced at pH 3 or in the presence of 0.15% bile salt but was reduced by freeze and spray drying. Heating a fresh preparation of galangal to 100 degrees C but not 50 degrees C for 30 min also reduced growth inhibition. Therefore, using fresh galangal in cooking was recommended. The MIC and MBC of a freshly squeezed preparation of galangal were 1:16 and 1:16, respectively. This is the first report of an inhibitory activity of a Thai medicinal plant, galangal that is used in Thai cooking, on the pandemic strain of V. parahaemolyticus.

  17. Analysis of free ACh and 5-HT in milk from four different species and their bioactivity on 5-HT(3) and nACh receptors.

    PubMed

    Gallegos-Perez, Jose-Luis; Limon, Agenor; Reyes-Ruiz, Jorge M; Alshanqeeti, Ali S; Aljohi, Mohammad A; Miledi, Ricardo

    2014-07-25

    Milk is one of the most beneficial aliments and is highly recommended in normal conditions; however, in certain disorders, like irritable bowel syndrome, cow milk and dairy products worsen the gastric symptoms and their use is not recommended. Among the most recognized milk-induced gatrointestinal symptoms are abdominal pain, nausea and vomiting, which are processes controlled by cholinergic and serotonergic transmission. Whether the presence of bioavailable ACh and 5-HT in milk may contribute to normal peristalsis, or to the developing of these symptoms, is not known. In this work we attempt to determine whether the content of free ACh and 5-HT is of physiological significance in milk from four different species: cow (bovine), goat, camel and human. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to identify and quantify free ACh and 5-HT in milk, and activation of the serotonergic and cholinergic ionotropic receptors was investigated using electrophysiological experiments. Our principal hypothesis was that milk from these four species had sufficient free ACh and 5-HT to activate their correspondent receptors expressed in a heterologous system. Our results showed a more complex picture, in which free ACh and 5-HT and their ability to activate cholinergic and serotonergic receptors are not correlated. This work is a first step to elucidate whether 5-HT and ACh, at the concentrations present in the milk, can be associated to a direct function in the GI.

  18. Discovery of Highly Potent and Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists Containing an Isoxazolylpyridine Ether Scaffold that Demonstrate Antidepressant-like Activity. Part II

    PubMed Central

    Yu, Li-Fang; Eaton, J. Brek; Fedolak, Allison; Zhang, Han-Kun; Hanania, Taleen; Brunner, Dani; Lukas, Ronald J.; Kozikowski, Alan P.

    2012-01-01

    In our continued efforts to develop α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure activity relationship (SAR) exploration of certain isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [3H]epibatidine binding studies together with functional assays based on 86Rb+ ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity, but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent promising lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics. PMID:23092294

  19. Dibenzocyclooctadiene lignans from Schisandra chinensis and their inhibitory activity on NO production in lipopolysaccharide-activated microglia cells.

    PubMed

    Hu, Di; Yang, Zhiyou; Yao, Xuechun; Wang, Hua; Han, Na; Liu, Zhihui; Wang, Yu; Yang, Jingyu; Yin, Jun

    2014-08-01

    Four dibenzocyclooctadiene lignans, schisanchinins A-D, and 10 known compounds were isolated from the EtOAc extract of fruits of Schisandra chinensis (Turcz.) Baill. Structures of compounds 1-4 were elucidated using a combination of spectroscopic techniques, including MS, UV and IR, NMR ((1)H NMR, (13)C NMR, HMQC, HMBC). The stereochemistry of the chiral centers and the biphenyl configuration were determined using NOESY, as well as analysis of CD spectra. In vitro activity assays showed that 11 of the 14 compounds exhibited inhibitory activity on lipopolysaccharide (LPS)-induced NO release in primary murine BV2 microglia cells.

  20. Signaling pathways engaged by NK cell receptors: double concerto for activating receptors, inhibitory receptors and NK cells.

    PubMed

    Tomasello, E; Bléry, M; Vély, F; Vivier, E

    2000-04-01

    Despite the absence of antigen-specific receptors at their surface, NK cells can selectively eliminate virus-infected cells, tumor cells and allogenic cells. A dynamic and precisely coordinated balance between activating and inhibitory receptors governs NK cell activation programs. Multiple activating and inhibitory NK cell surface molecules have been described, a group of them acting as receptors for MHC class I molecules. In spite of their heterogeneity, activating NK cell receptors present remarkable structural and functional homologies with T cell- and B cell-antigen receptors. Inhibitory NK cell receptors operate at early stages of activating cascades by recruiting protein tyrosine phosphatases via intra- cytoplasmic motifs (ITIM), a strategy which is widely conserved in hematopoietic and non-hematopoietic cells.

  1. Inhibitory responses in Aplysia pleural sensory neurons act to block excitability, transmitter release, and PKC Apl II activation.

    PubMed

    Dunn, Tyler W; Farah, Carole A; Sossin, Wayne S

    2012-01-01

    Expression of the 5-HT(1Apl(a)) receptor in Aplysia pleural sensory neurons inhibited 5-HT-mediated translocation of the novel PKC Apl II in sensory neurons and prevented PKC-dependent synaptic facilitation at sensory to motoneuron synapses (Nagakura et al. 2010). We now demonstrate that the ability of inhibitory receptors to block PKC activation is a general feature of inhibitory receptors and is found after expression of the 5-HT(1Apl(b)) receptor and with activation of endogenous dopamine and FMRFamide receptors in sensory neurons. Pleural sensory neurons are heterogeneous for their inhibitory response to endogenous transmitters, with dopamine being the most prevalent, followed by FMRFamide, and only a small number of neurons with inhibitory responses to 5-HT. The inhibitory response is dominant, reduces membrane excitability and synaptic efficacy, and can reverse 5-HT facilitation at both naive and depressed synapses. Indeed, dopamine can reverse PKC translocation during the continued application of 5-HT. Reversal of translocation can also be seen after translocation mediated by an analog of diacylglycerol, suggesting inhibition is not through blockade of diacylglycerol production. The effects of inhibition on PKC translocation can be rescued by phosphatidic acid, consistent with the inhibitory response involving a reduction or block of production of this lipid. However, phosphatidic acid could not recover PKC-dependent synaptic facilitation due to an additional inhibitory effect on the non-L-type calcium flux linked to synaptic transmission. In summary, we find a novel mechanism downstream of inhibitory receptors linked to inhibition of PKC activation in Aplysia sensory neurons. PMID:21994260

  2. Cholinesterases inhibitory and antioxidant activities of Harpagophytum procumbens from in vitro systems.

    PubMed

    Georgiev, Milen I; Alipieva, Kalina; Orhan, Ilkay Erdogan

    2012-02-01

    A previous report showed that extracts of cell suspension and transformed root cultures of Harpagophytum procumbens (commonly known as Devil's claw), an African plant with high medicinal value, exhibit strong antiinflammatory characteristics. The present work tests the ability of extracts, phenylethanoid-containing fractions and the major phenylethanoid glycoside isolated from the Devil's claw cultures, to inhibit acetylcholinesterase and butyrylcholinesterase, and the antioxidant activity in iron-related systems (e.g. ferric-reducing antioxidant power and ferrous ion-chelating capacity). The results indicated that the phenylethanoid fractions may be attractive for various commercial purposes since they displayed significant cholinesterase inhibitory activity (even higher than that of pure galanthamine in the case of butyrylcholinesterase inhibition assay). Crude methanolic extracts from cell and hairy root cultures of Devil's claw exhibited strong ferrous ion-chelating capacity (1.5-2 times higher than pure butylated hydroxyanisole, used as positive standard). PMID:21721061

  3. Synthesis and characterization of tritylthioethanamine derivatives with potent KSP inhibitory activity.

    PubMed

    Rodriguez, Delany; Ramesh, Chinnasamy; Henson, Lauren H; Wilmeth, Lori; Bryant, Bj K; Kadavakollu, Samuel; Hirsch, Rebecca; Montoya, Johnelle; Howell, Porsha R; George, Jon M; Alexander, David; Johnson, Dennis L; Arterburn, Jeffrey B; Shuster, Charles B

    2011-09-15

    Assembly of a bipolar mitotic spindle requires the action of class 5 kinesins, and inhibition or depletion of this motor results in mitotic arrest and apoptosis. S-Trityl-l-cysteine is an allosteric inhibitor of vertebrate Kinesin Spindle Protein (KSP) that has generated considerable interest due to its anti-cancer properties, however, poor pharmacological properties have limited the use of this compound. We have modified the triphenylmethyl and cysteine groups, guided by biochemical and cell-based assays, to yield new cysteinol and cysteamine derivatives with increased inhibitory activity, greater efficacy in model systems, and significantly enhanced potency against the NCI60 tumor panel. These results reveal a promising new class of conformationally-flexible small molecules as allosteric KSP inhibitors for use as research tools, with activities that provide impetus for further development as anti-tumor agents.

  4. α-Glucosidase inhibitory activity of marine sponges collected in Mauritius waters.

    PubMed

    Ramanjooloo, Avin; Cresteil, Thierry; Lebrasse, Cindy; Beedessee, Girish; Oogarah, Preeti; van Soest, Rob W M; Marie, Daniel E P

    2015-01-01

    This report describes the use of α-glucosidase to evaluate the anti-diabetic potential of extracts from marine sponges collected in the Mauritius waters. Initial screening at 1.0 mg/mL of 141 extracts obtained from 47 sponge species revealed 10 extracts with inhibitory activity greater than 85%. Seven of the 10 extracts were further tested at 0.1 and 0.01 mg/mL and only the methanol extract of two sponges namely Acanthostylotella sp. (ASSM) and Echinodictyum pykei (EPM) showed inhibition activity greater than 60% at 0.1 mg/mL with an IC50 value of 0.16 ± 0.02 and 0.04 ± 0.01 mg/mL, respectively, while being inactive at 0.01 mg/mL.

  5. Feedback Activation of Leukemia Inhibitory Factor Receptor Limits Response to Histone Deacetylase Inhibitors in Breast Cancer.

    PubMed

    Zeng, Hanlin; Qu, Jia; Jin, Nan; Xu, Jun; Lin, Chenchu; Chen, Yi; Yang, Xinying; He, Xiang; Tang, Shuai; Lan, Xiaojing; Yang, Xiaotong; Chen, Ziqi; Huang, Min; Ding, Jian; Geng, Meiyu

    2016-09-12

    Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies. However, the efficacy of HDAC inhibitors in solid tumors remains uncertain. This study takes breast cancer as a model to understand mechanisms accounting for limited response of HDAC inhibitors in solid tumors and to seek combination solutions. We discover that feedback activation of leukemia inhibitory factor receptor (LIFR) signaling in breast cancer limits the response to HDAC inhibition. Mechanistically, HDAC inhibition increases histone acetylation at the LIFR gene promoter, which recruits bromodomain protein BRD4, upregulates LIFR expression, and activates JAK1-STAT3 signaling. Importantly, JAK1 or BRD4 inhibition sensitizes breast cancer to HDAC inhibitors, implicating combination inhibition of HDAC with JAK1 or BRD4 as potential therapies for breast cancer. PMID:27622335

  6. Some aspects of the inhibitory activity of hypolaetin-8-glucoside in acute inflammation.

    PubMed

    Villar, A; Gascó, M A; Alcaraz, M J

    1987-07-01

    Hypolaetin-8-glucoside (H-8-G) has been examined for its mode of action in several models of acute inflammation. Its anti-inflammatory activity in carrageenan-induced inflammation of the rat hind-paw is not affected either by adrenalectomy or by phentolamine given with propranolol. H-8-G and its aglycone, hypolaetin, did not antagonize the actions of histamine, 5-hydroxytryptamine (5-HT), bradykinin or prostaglandin E2 (PGE2) on various smooth muscle preparations in-vitro, but protected erythrocytes from heat-induced lysis. The glycoside was more potent than troxerutin on capillary permeability increased by histamine and exerted inhibitory effects on protein exudation, leucocyte migration and beta-glucuronidase activity in the carrageenan air pouch, thereby showing some difference from indomethacin. These results are discussed in relation to the features of non-steroidal anti-inflammatory drugs (NSAID) and flavonoid anti-inflammatory actions.

  7. Feeding deterrent and growth inhibitory activities of PONNEEM, a newly developed phytopesticidal formulation against Helicoverpa armigera (Hubner)

    PubMed Central

    Packiam, Soosaimanickam Maria; Baskar, Kathirvelu; Ignacimuthu, Savarimuthu

    2014-01-01

    Objective To assess the feeding deterrent, growth inhibitory and egg hatchability effects of PONNEEM on Helicoverpa armigera (H. armigera). Methods Five oil formulations were prepared at different ratios to assess the feeding deterrent, growth inhibitory and egg hatchability effects on H. armigera. Results Invariably all the newly formulated phytopesticidal oil formulations showed the feeding deterrent and growth inhibitory activities against H. armigera. The maximum feeding deterrent activity of 88.44% was observed at 15 µL/L concentration of PONNEEM followed by formulation A (74.54%). PONNEEM was found to be effective in growth inhibitory activities and egg hatchability at 10 µL/L concentration. It exhibited statistically significant feeding deterrent activity and growth inhibitory activity compared with all the other treatments. Conclusions PONNEEM was found to be effective phytopesticidal formulation to control the larval stage of H. armigera. This is the first report for the feeding deterrent activity of PONNEEM against H. armigera. This newly formulated phytopesticide was patented in India. PMID:25183105

  8. The NRTIs Lamivudine, Stavudine and Zidovudine Have Reduced HIV-1 Inhibitory Activity in Astrocytes

    PubMed Central

    Gray, Lachlan R.; Tachedjian, Gilda; Ellett, Anne M.; Roche, Michael J.; Cheng, Wan-Jung; Guillemin, Gilles J.; Brew, Bruce J.; Turville, Stuart G.; Wesselingh, Steve L.; Gorry, Paul R.; Churchill, Melissa J.

    2013-01-01

    HIV-1 establishes infection in astrocytes and macroage-lineage cells of the central nervous system (CNS). Certain antiretroviral drugs (ARVs) can penetrate the CNS, and are therefore often used in neurologically active combined antiretroviral therapy (Neuro-cART) regimens, but their relative activity in the different susceptible CNS cell populations is unknown. Here, we determined the HIV-1 inhibitory activity of CNS-penetrating ARVs in astrocytes and macrophage-lineage cells. Primary human fetal astrocytes (PFA) and the SVG human astrocyte cell line were used as in vitro models for astrocyte infection, and monocyte-derived macrophages (MDM) were used as an in vitro model for infection of macrophage-lineage cells. The CNS-penetrating ARVs tested were the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir (ABC), lamivudine (3TC), stavudine (d4T) and zidovudine (ZDV), the non-NRTIs efavirenz (EFV), etravirine (ETR) and nevirapine (NVP), and the integrase inhibitor raltegravir (RAL). Drug inhibition assays were performed using single-round HIV-1 entry assays with luciferase viruses pseudotyped with HIV-1 YU-2 envelope or vesicular stomatitis virus G protein (VSV-G). All the ARVs tested could effectively inhibit HIV-1 infection in macrophages, with EC90s below concentrations known to be achievable in the cerebral spinal fluid (CSF). Most of the ARVs had similar potency in astrocytes, however the NRTIs 3TC, d4T and ZDV had insufficient HIV-1 inhibitory activity in astrocytes, with EC90s 12-, 187- and 110-fold greater than achievable CSF concentrations, respectively. Our data suggest that 3TC, d4T and ZDV may not adequately target astrocyte infection in vivo, which has potential implications for their inclusion in Neuro-cART regimens. PMID:23614033

  9. Associations of Physical Activity, Sports Participation and Active Commuting on Mathematic Performance and Inhibitory Control in Adolescents

    PubMed Central

    Huang, Tao; Gejl, Anne Kær; Froberg, Karsten

    2016-01-01

    Objectives To examine objectively measured physical activity level, organized sports participation and active commuting to school in relation to mathematic performance and inhibitory control in adolescents. Methods The design was cross-sectional. A convenient sample of 869 sixth and seventh grade students (12–14 years) was invited to participate in the study. A total of 568 students fulfilled the inclusion criteria and comprised the final sample for this study. Mathematic performance was assessed by a customized test and inhibitory control was assessed by a modified Eriksen flanker task. Physical activity was assessed with GT3X and GT3X+ accelerometers presented in sex-specific quartiles of mean counts per minute and mean minutes per day in moderate-to-vigorous physical activity. Active commuting and sports participation was self-reported. Mixed model regression was applied. Total physical activity level was stratified by bicycling status in order to bypass measurement error subject to the accelerometer. Results Non-cyclists in the 2nd quartile of counts per minute displayed a higher mathematic score, so did cyclists in the 2nd and 3rd quartile of moderate-to-vigorous physical activity relative to the least active quartile. Non-cyclists in the 3rd quartile of counts per minute had an improved reaction time and cyclists in the 2nd quartile of counts per minute and moderate-to-vigorous physical activity displayed an improved accuracy, whereas non-cyclists in the 2nd quartile of counts per minute showed an inferior accuracy relative to the least active quartile. Bicycling to school and organized sports participation were positively associated with mathematic performance. Conclusions Sports participation and bicycling were positively associated with mathematic performance. Results regarding objectively measured physical activity were mixed. Although, no linear nor dose-response relationship was observed there was no indication of a higher activity level impairing the

  10. Aldose Reductase Inhibitory Activity of Compounds from  Zea mays L.

    PubMed Central

    Kim, Tae Hyeon; Kim, Jin Kyu; Kang, Young-Hee; Lee, Jae-Yong; Kang, Il Jun; Lim, Soon Sung

    2013-01-01

    Aldose reductase (AR) inhibitors have a considerable therapeutic potential against diabetes complications and do not increase the risk of hypoglycemia. Through bioassay-guided fractionation of an EtOH extract of the kernel from purple corn (Zea mays L.), 7 nonanthocyanin phenolic compounds (compound 1–7) and 5 anthocyanins (compound 8–12) were isolated. These compounds were investigated by rat lens aldose reductase (RLAR) inhibitory assays. Kinetic analyses of recombinant human aldose reductase (rhAR) were performed, and intracellular galactitol levels were measured. Hirsutrin, one of 12 isolated compounds, showed the most potent RLAR inhibitory activity (IC50, 4.78 μM). In the kinetic analyses using Lineweaver-Burk plots of 1/velocity and 1/substrate concentration, hirsutrin showed competitive inhibition against rhAR. Furthermore, hirsutrin inhibited galactitol formation in rat lens and erythrocytes sample incubated with a high concentration of galactose; this finding indicates that hirsutrin may effectively prevent osmotic stress in hyperglycemia. Therefore, hirsutrin derived from Zea mays L. may be a potential therapeutic agent against diabetes complications. PMID:23586057

  11. Melanogenesis inhibitory activity of sesquiterpenes from Canarium ovatum resin in mouse B16 melanoma cells.

    PubMed

    Kikuchi, Takashi; Watanabe, Kensuke; Tochigi, Yuichi; Yamamoto, Ayako; Fukatsu, Makoto; Ezaki, Yoichiro; Tanaka, Reiko; Akihisa, Toshihiro

    2012-08-01

    Four known sesquiterpene alcohols, i.e., 1-4, ten triterpene alcohols, i.e., 5-14, and four triterpene acids, i.e., 15-18, were isolated from the MeOH extract of Canarium ovatum resin (elemi resin). Upon evaluation of the previously described compounds 1-18 on the melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), three sesquiterpene alcohols, i.e., cryptomeridiol (1), 4-epicryptomeridiol (2), and cadin-1(14)-ene-7α,11-diol (4), exhibited inhibitory effects with 27.4-34.1 and 39.0-56.9% reduction of melanin content at 50 and 100 μM, respectively, with no or very low toxicity to the cells (80.9-103.9% of cell viability at 100 μM). Western-blot analysis revealed that compounds 1 and 2 reduced the protein levels of MITF (=microphtalmia-associated transcription factor), tyrosinase, and TRP-2 (=tyrosine-related protein 2), mostly in a concentration-dependent manner, suggesting that these compounds exhibit melanogenesis inhibitory activity on α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of tyrosinase and TRP-2. Three sesquiterpene alcohols, i.e., 1, 2, and 4, are, therefore, considered to be valuable as potential skin-whitening agents.

  12. Evaluation of antioxidant and xanthine oxidase inhibitory activity of different solvent extracts of leaves of Citrullus colocynthis

    PubMed Central

    Nessa, Fazilatun; Khan, Saeed A.

    2014-01-01

    Background: Citrullus colocynthis is a folk medicinal plan of United Arab Emirates. Several studies on this plant reported and focused on the biological and toxicological profile of fruits pulp. The present study focused on the antioxidant potency of leaf extract of this plant. Aim: To evaluate the antioxidant and xanthine oxidase (XO) inhibitory activities of C. colocynthis by chemical method. Materials and Methods: Four different solvent extracts (methanol-CCM, methanol: water (1:1)-CCMW, chloroform-CCC and hexane-CCH) of leaves of C. colocynthis were investigated for their free radical scavenging activity using DPPH radical as a substrate, lipid peroxidation (LPO) inhibitory activity using a model system consisting of β-carotene-linoleic acid, superoxide radical scavenging activity (enzymatically/nonenzymatically) and XO inhibitory activity. A dose response curve was plotted for determining SC50 and IC50 values for expressing the results of free radical scavenging activity and XO inhibitory activities respectively. Results: The high polyphenolic content of CCM and CCMW extract showed highest antioxidant activity irrespective the method used for this investigation. The overall results decreased in the order of: CCM > CCMW > CCC > CCH. CCH extract was inactive towards chemically generated superoxide radical and poor DPPH radical scavengers. The results of LPO inhibitory activities of leaves extract (0.1, 0.5 and 1.0 mg/mL) also decreased in the order of: CCM > CCMW > CCC > CCH. Overall 1.0 mg/mL leaves extract showed highest antioxidant potency amongst the studied concentration. Conclusion: CCMW and CCM extract of C. colocynthis exhibited promising antioxidants and XO inhibitory activities. PMID:25002802

  13. In vitro antioxidant properties, HIV-1 reverse transcriptase and acetylcholinesterase inhibitory effects of traditional herbal preparations sold in South Africa.

    PubMed

    Ndhlala, Ashwell R; Finnie, Jeffrey F; Van Staden, Johannes

    2010-01-01

    The antioxidant potentials for fourteen multipurpose traditional herbal preparations sold in South Africa were determined using the DPPH radical scavenging, ferric reducing power and β-carotene-linoleic acid model system, the anti-HIV-1 reverse transcriptase (RT) enzyme inhibitory effects using an ELISA kit and acetylcholinesterase (AChE) enzyme inhibition using the microtitre plate assay. Nine of the herbal mixtures (Umzimba omubi, Umuthi wekukhwehlela ne zilonda, Mvusa ukunzi, Umpatisa inkosi, Imbiza ephuzwato, Vusa umzimba, Supreme one hundred, Sejeso herbal mixture Ingwe® and Ingwe® special muti) exhibited higher antioxidant potentials, while only four (Imbiza ephuzwato, Ingwe® muthi mixture, Sejeso herbal mixture Ingwe® and African potato extract™ showed potent activity against the RT enzyme. Nine mixtures (Imbiza ephuzwato, Umpatisa inkosi, African potato extract™, Sejeso herbal mixture Ingwe®, Vusa umzimba; Ingwe® muthi mixture, Ibhubezi™, Lion izifozonke Ingwe® and Ingwe® special muti) showed AChE enzyme inhibitory activity greater than 50%. The observed activity exhibited by some of the herbal mixtures gives some credence to the manufacturers' claims and goes part of the way towards validating their use against certain conditions such as oxidative stress, HIV/AIDS proliferation and some mental conditions. It is however, desirable to carry out further studies to determine the effects of mixing plant species/parts in one mixture on the antioxidant potency as well as isolating active constituents from the herbal mixtures. PMID:20938401

  14. Electronic structure calculations toward new potentially AChE inhibitors

    NASA Astrophysics Data System (ADS)

    de Paula, A. A. N.; Martins, J. B. L.; Gargano, R.; dos Santos, M. L.; Romeiro, L. A. S.

    2007-10-01

    The main purpose of this study was the use of natural non-isoprenoid phenolic lipid of cashew nut shell liquid from Anacardium occidentale as lead material for generating new potentially candidates of acetylcholinesterase inhibitors. Therefore, we studied the electronic structure of 15 molecules derivatives from the cardanol using the following groups: methyl, acetyl, N, N-dimethylcarbamoyl, N, N-dimethylamine, N, N-diethylamine, piperidine, pyrrolidine, and N-benzylamine. The calculations were performed at RHF level using 6-31G, 6-31G(d), 6-31+G(d) and 6-311G(d,p) basis functions. Among the proposed compounds we found that the structures with substitution by acetyl, N, N-dimethylcarbamoyl, N, N-dimethylamine, and pyrrolidine groups were better correlated to rivastigmine indicating possible activity.

  15. Syntheses of new 3-thiazolyl coumarin derivatives, in vitro α-glucosidase inhibitory activity, and molecular modeling studies.

    PubMed

    Salar, Uzma; Taha, Muhammad; Khan, Khalid Mohammed; Ismail, Nor Hadiani; Imran, Syahrul; Perveen, Shahnaz; Gul, Sahib; Wadood, Abdul

    2016-10-21

    3-Thiazolylcoumarin derivatives 1-14 were synthesized via one-pot two step reactions, and screened for in vitro α-glucosidase inhibitory activity. All compounds showed inhibitory activity in the range of IC50 = 0.12 ± 0.01-16.20 ± 0.23 μM as compared to standard acarbose (IC50 = 38.25 ± 0.12 μM), and also found to be nontoxic. Molecular docking study was carried out in order to establish the structure-activity relationship (SAR) which demonstrated that electron rich centers at one and electron withdrawing centers at the other end of the molecules showed strong inhibitory activity. All the synthesized compounds were characterized by spectroscopic techniques such as EI-MS, HREI-MS, (1)H NMR and (13)C NMR. CHN analysis was also performed.

  16. [Effects of Bt corn straw insecticidal proteins on enzyme activities of Eisenia fetida].

    PubMed

    Shu, Ying-hua; Ma, Hong-hui; Du, Yan; Wang, Jian-wu

    2011-08-01

    Bacillus thuringiensis (Bt) proteins released from Bt corn can enter soil ecosystem via returning straw into field, root exudation, and pollen fluttering-down. In this study, the straws of Bt corn and its near-isogenic non-Bt line were added into soil with an application rate of 5% and 7.5% to breed Eisenia fetida, and the total protein content and the activities of acetylcholine esterase (AchE), glutathione peroxidase (GSH-PX), catalase (CAT), and superoxide dismutase (SOD) in E. fetida were determined after 7 and 14 days. Under the same application rate of the straws, the total protein content and GSH-PX activity of E. fetida decreased while the AchE, CAT, and SOD activities increased on the 14th day, compared with those on the 7th day. The Bt corn straw increased the SOD activity and decreased the AchE and GSH-PX activities, but had less effects on the total protein content and CAT activity, compared with non-Bt corn straw. All the results suggested that Bt corn straw had no inhibitory effect on E. fetida total protein but could inhibit the AchE and GSH-PX activities, and could not induce CAT activity but induce SOD activity within a short time.

  17. Probing the origins of aromatase inhibitory activity of disubstituted coumarins via QSAR and molecular docking

    PubMed Central

    Worachartcheewan, Apilak; Suvannang, Naravut; Prachayasittikul, Supaluk; Prachayasittikul, Virapong; Nantasenamat, Chanin

    2014-01-01

    This study investigated the quantitative structure-activity relationship (QSAR) of imidazole derivatives of 4,7-disubstituted coumarins as inhibitors of aromatase, a potential therapeutic protein target for the treatment of breast cancer. Herein, a series of 3,7- and 4,7-disubstituted coumarin derivatives (1-34) with R1 and R2 substituents bearing aromatase inhibitory activity were modeled as a function of molecular and quantum chemical descriptors derived from low-energy conformer geometrically optimized at B3LYP/6-31G(d) level of theory. Insights on origins of aromatase inhibitory activity was afforded by the computed set of 7 descriptors comprising of F10[N-O], Inflammat-50, Psychotic-80, H-047, BELe1, B10[C-O] and MAXDP. Such significant descriptors were used for QSAR model construction and results indicated that model 4 afforded the best statistical performance. Good predictive performance were achieved as verified from the internal (comprising the training and the leave-one-out cross-validation (LOO-CV) sets) and external sets affording the following statistical parameters: R2Tr = 0.9576 and RMSETr = 0.0958 for the training set; Q2CV = 0.9239 and RMSECV = 0.1304 for the LOO-CV set as well as Q2Ext = 0.7268 and RMSEExt = 0.2927 for the external set. Significant descriptors showed correlation with functional substituents, particularly, R1 in governing high potency as aromatase inhibitor. Molecular docking calculations suggest that key residues interacting with the coumarins were predominantly lipophilic or non-polar while a few were polar and positively-charged. Findings illuminated herein serve as the impetus that can be used to rationally guide the design of new aromatase inhibitors. PMID:26417339

  18. Inhibitory effect of synthetic cannabinoids on CYP1A activity in mouse liver microsomes.

    PubMed

    Ashino, Takashi; Hakukawa, Kanae; Itoh, Yuka; Numazawa, Satoshi

    2014-01-01

    Synthetic cannabinoids developed by chemical modification are believed to bind to cannabinoid receptors and cause neurological effects similar to cannabis; however, their effects on drug metabolizing enzymes are unknown. This study aimed to elucidate the effect of synthetic cannabinoids on cytochrome P450 1A activity. Naphthoylindole, a basic structure of the major synthetic cannabinoids, strongly inhibited CYP1A activity in a competitive manner; the apparent Ki value was 0.40 μM. The N-Alkylated derivatives of naphthoylindole, MAM-2201 and JWH-019, also inhibited CYP1A activity in a concentration-dependent manner; however, their inhibitory effects were weaker than naphthoylindole. An adamantylamidoindole derivative, STS-135, showed inhibition of CYP1A activity in a concentrationdependent manner, but the adamantoylindole derivatives, AB-001 and AM-1248, did not. A tetramethylcyclopropanoylindole derivative, UR-144, showed a weak inhibition of CYP1A activity at high concentrations. These results suggest that synthetic cannabinoids and their basic molecules are capable of inhibiting CYP1A enzymatic activity.

  19. Inhibitory effect of synthetic cannabinoids on CYP1A activity in mouse liver microsomes.

    PubMed

    Ashino, Takashi; Hakukawa, Kanae; Itoh, Yuka; Numazawa, Satoshi

    2014-01-01

    Synthetic cannabinoids developed by chemical modification are believed to bind to cannabinoid receptors and cause neurological effects similar to cannabis; however, their effects on drug metabolizing enzymes are unknown. This study aimed to elucidate the effect of synthetic cannabinoids on cytochrome P450 1A activity. Naphthoylindole, a basic structure of the major synthetic cannabinoids, strongly inhibited CYP1A activity in a competitive manner; the apparent Ki value was 0.40 μM. The N-Alkylated derivatives of naphthoylindole, MAM-2201 and JWH-019, also inhibited CYP1A activity in a concentration-dependent manner; however, their inhibitory effects were weaker than naphthoylindole. An adamantylamidoindole derivative, STS-135, showed inhibition of CYP1A activity in a concentrationdependent manner, but the adamantoylindole derivatives, AB-001 and AM-1248, did not. A tetramethylcyclopropanoylindole derivative, UR-144, showed a weak inhibition of CYP1A activity at high concentrations. These results suggest that synthetic cannabinoids and their basic molecules are capable of inhibiting CYP1A enzymatic activity. PMID:25374372

  20. Phosphodiesterase-1 Inhibitory Activity of Two Flavonoids Isolated from Pistacia integerrima J. L. Stewart Galls

    PubMed Central

    Saleem, Muhammad; Uddin, Ghias; Siddiqui, Bina S.; Khan, Haroon; Raza, Muslim; Hamid, Syeda Zehra; Khan, Ajmal; Maione, Francesco; Mascolo, Nicola

    2015-01-01

    Pistacia integerrima is one of twenty species among the genus Pistacia. Long horn-shaped galls that develop on this plant are harvested and used in Ayurveda and Indian traditional medicine to make “karkatshringi”, a herbal medicine used for the treatment of asthma and different disorders of respiratory tract. However, until now, the molecular mechanisms of action of “karkatshringi” and its chemical characterization are partially known. This study deals with the isolation and characterization of the active constituents from the methanolic extract of P. integerrima galls and it was also oriented to evaluate in vitro and in silico their potential enzymatic inhibitory activity against phosphodiesterase-1 (PDE1), a well-known enzyme involved in airway smooth muscle activity and airway inflammation. Our results showed that the methanolic extract of P. integerrima galls and some of its active constituents [naringenin (1) and 3,5,7,4′-tetrahydroxy-flavanone (2)] are able in vitro to inhibit PDE1 activity (59.20 ± 4.95%, 75.90 ± 5.90%, and 65.25 ± 5.25%, resp.) and demonstrate in silico an interesting interaction with this enzymatic site. Taken together, our results add new knowledge of chemical constituents responsible for the biological activity of P. integerrima and contextually legitimate the use of this plant in folk medicine. PMID:25945110

  1. Sesquiterpenoids from the Rhizomes of Curcuma phaeocaulis and Their Inhibitory Effects on LPS-Induced TLR4 Activation.

    PubMed

    Jang, Hyun-Jae; Kim, Jin-Han; Oh, Hyun-Mee; Kim, Min-Suk; Jo, Jin Ha; Jung, Kyungsook; Lee, Soyoung; Kim, Young-Ho; Lee, Woo Song; Lee, Seung Woong; Rho, Mun-Chual

    2016-01-01

    Two new guaiane-type (2, 6) and one new furanogermacrane-type (11) sesquiterpenoids have been isolated along with twelve known compounds from an EtOAc-soluble extract of Curcuma phaeocaulis rhizomes. The structures of the isolated compounds were elucidated using a combination of NMR, MS, and circular dichroism (CD) spectra. The inhibitory effects of each compound on lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4) activation in THP-1-Blue cells were assessed, and compound 4 showed more potent inhibitory activity against LPS-stimulated TLR4 activation. PMID:27373668

  2. Protease and protease inhibitory activity in pregnant and postpartum involuting uterus

    SciTech Connect

    Milwidsky, A.; Beller, U.; Palti, Z.; Mayer, M.

    1982-08-15

    The presence of two distinct proteolytic activities in the rat uterus was confirmed with /sup 14/C-labeled globin used as a sensitive protein substrate and following release of label into the trichloroacetic acid-soluble supernatant fraction. Protease I is a cytoplasmic acid protease while protease II is associated with the pellet fraction, can be extracted by 0.6 M sodium chloride, and is active at pH 7.0. Protease I activity is low during pregnancy and markedly increases at term achieving maximal activity at day 3 post partum with a subsequent decline to preterm activity values. Lactation did not affect the uterine protease I activity. Protease II activity is not significantly different during pregnancy, at term, and post partum. The presence of an inhibitor of protease I was suggested by a decrease in enzyme activity with an increased cytosolic protein concentration. The inhibitor also lessened bovine trypsin activity but had no effect on protease II. Although its inhibitory potency on trypsin fluctuated during the various uterine physiologic stages, these changes appeared to be statistically insignificant. Human uterine samples were also found to contain the two protease activities with similar changes in protease I post partum. It is suggested that, both in the rat and in man, uterine involution post partum is associated with a marked increase in activity of acid cytosolic protease, while a particulate neutral protease and a soluble inhibitor of trypsin, which are also present in uterine cells, do not appear to play a significant role in the dissolution of uterine tissues after parturition.

  3. Lactobacillus isolates from weaned piglets' mucosa with inhibitory activity against common porcine pathogens.

    PubMed

    Hacin, B; Rogelj, I; Matijasić, B B

    2008-01-01

    Twelve lactobacilli isolates from mucosa of 3-5-week-old weaned pigs were found to exert good antimicrobial activity against common porcine pathogens (S. aureus, B. cereus, E. coli, C. perfringens). Two of them produced in addition to lactic acid also considerable amounts of acetic acid, and 6 of them produced hydrogen peroxide and metabolites other than organic acids. Isolates 4/26 and 2/25 (identified as L. crispatus or L. amylovorus) were inhibitory against most strains of S. aureus, B. cereus and E. coli, and especially the strain 4/26 survived well in simulated gastric and intestinal juice. Diarrhea-causing E. coli O8K88H9 Ent(+) was successfully inhibited by the growing culture as well as by the catalase-treated and neutralized supernatant of L. reuteri 12/26. Mucin degradation and multiple resistance to antibiotics were not observed.

  4. Monoamine Oxidase Inhibitory Activity of Novel Pyrazoline Analogues: Curcumin Based Design and Synthesis.

    PubMed

    Badavath, Vishnu Nayak; Baysal, İpek; Ucar, Gulberk; Sinha, Barij Nayan; Jayaprakash, Venkatesan

    2016-01-14

    A series of new 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenolderivatives, 4-13, were synthesized and tested for their human MAO inhibitory activity. All the compounds were found to be selective and reversible toward hMAO-A except 4, a selective inhibitor of hMAO-B and 12, a nonselective inhibitor. Compound 7 was found to be a potent inhibitor of hMAO-A with Ki = 0.06 ± 0.003 μM and was having selectivity index of (SI = 1.02 × 10(-5)). It was found to be better than standard drug, Moclobemide (hMAO-A with Ki = 0.11 ± 0.01 μM) with selectivity index of SI = 0.049. Molecular docking simulation was carried out to understand the crucial interactions responsible for selectivity and potency. PMID:26819666

  5. Sense of impending doom: inhibitory activity in waiting blood donors who subsequently experience vasovagal symptoms.

    PubMed

    Gilchrist, Philippe T; Ditto, Blaine

    2015-01-01

    This study examined autonomic and hemodynamic processes associated with the development of naturally occurring vasovagal responses. Data from a study assessing the physiological correlates of an intervention to reduce vasovagal responses in blood donors were examined (Ditto et al., 2009). Ninety-eight participants were assigned randomly to groups that either practiced applied tension or not. Dependent variables included ratings of vasovagal symptoms, heart rate, blood pressure, and other parameters derived from ambulatory impedance cardiography. Participants who subsequently experienced vasovagal symptoms had a lower ratio between low and high frequency components (LF/HF HRV) of heart rate variability (HRV) before blood donation, suggesting lower sympathetic nervous system activity. They also showed sharper decreases in total peripheral resistance and lower respiration rates. The results suggest that vasovagal reactions that begin during anticipation of a medical procedure may be characterized by an inhibitory process from the outset and do not support the belief that reactions follow a diphasic pattern.

  6. Four new sesquiterpenes from the rhizomes of Curcuma phaeocaulis and their iNOS inhibitory activities.

    PubMed

    Ma, Jiang-Hao; Wang, Ying; Liu, Yue; Gao, Su-Yu; Ding, Li-Qin; Zhao, Feng; Chen, Li-Xia; Qiu, Feng

    2015-05-01

    Three new guaiane-type sesquiterpenes named phaeocaulisins K-M (1-3), and one germacrane-type sesquiterpenoid with new ring system of 1,5- and 1,8-ether groups named phagermadiol (4), were isolated from rhizomes of Curcuma phaeocaulis. Their structures were established based on extensive spectroscopic analysis. Compound 1, the first example of norsesquiterpene with tropone backbone, and compound 3 with a novel 1,2-dioxolane sesquiterpene alcohol were isolated from the genus Curcuma. All of the isolated compounds were tested for inhibitory activity against lipopolysaccharide-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compound 3 inhibited NO production with IC50 value of 6.05 ± 0.43 μM. The plausible biosynthetic pathway for compounds 3 and 4 in C. phaeocaulis was also discussed.

  7. Xanthones from the botanical dietary supplement mangosteen (Garcinia mangostana) with aromatase inhibitory activity.

    PubMed

    Balunas, Marcy J; Su, Bin; Brueggemeier, Robert W; Kinghorn, A Douglas

    2008-07-01

    Twelve xanthone constituents of the botanical dietary supplement mangosteen (the pericarp of Garcinia mangostana) were screened using a noncellular, enzyme-based microsomal aromatase inhibition assay. Of these compounds, garcinone D (3), garcinone E (5), alpha-mangostin (8), and gamma-mangostin (9) exhibited dose-dependent inhibitory activity. In a follow-up cell-based assay using SK-BR-3 breast cancer cells that express high levels of aromatase, the most potent of these four xanthones was gamma-mangostin (9). Because xanthones may be consumed in substantial amounts from commercially available mangosteen products, the consequences of frequent intake of mangosteen botanical dietary supplements require further investigation to determine their possible role in breast cancer chemoprevention.

  8. Chemical constituents of Blumea balsamifera of Indonesia and their protein tyrosine phosphatase 1B inhibitory activity.

    PubMed

    Saifudin, Azis; Tanaka, Ken; Kadota, Shigetoshi; Tezuka, Yasuhiro

    2012-07-01

    A methanol extract of the leaves of Blumea balsamifera (L.) DC. (Asteraceae) afforded a new guaian-type sesquiterpene, epiblumeaene K (1), together with four known guaian-type sesquiterpenes (2-5), three known sesquiterpenes (6-8), and nine known flavonoids (9-17) by a combination of chromatography and preparative TLC techniques. Their structures were elucidated by extensive spectroscopic methods and comparison with the literature data. Among the isolated compounds, a known sesquiterpene, beta-caryophyllene 8R,9R-oxide (6), exhibited a significant PTP1B inhibitory activity in a dose-dependent manner, with an IC50 value of 25.8 microM (5.62 microg/mL). PMID:22908553

  9. Glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding.

    PubMed

    Suyama, Shigetomo; Maekawa, Fumihiko; Maejima, Yuko; Kubota, Naoto; Kadowaki, Takashi; Yada, Toshihiko

    2016-01-01

    Adiponectin regulates glucose and lipid metabolism, acting against metabolic syndrome and atherosclerosis. Accumulating evidence suggest that adiponectin acts on the brain including hypothalamic arcuate nucleus (ARC), where proopiomelanocortin (POMC) neurons play key roles in feeding regulation. Several studies have examined intracerebroventricular (ICV) injection of adiponectin and reported opposite effects, increase or decrease of food intake. These reports used different nutritional states. The present study aimed to clarify whether adiponectin exerts distinct effects on food intake and ARC POMC neurons depending on the glucose concentration. Adiponectin was ICV injected with or without glucose for feeding experiments and administered to ARC slices with high or low glucose for patch clamp experiments. We found that adiponectin at high glucose inhibited POMC neurons and increased food intake while at low glucose it exerted opposite effects. The results demonstrate that glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding. PMID:27503800

  10. Inhibitory activity of Aloe vera gel on some clinically isolated cariogenic and periodontopathic bacteria.

    PubMed

    Fani, Mohammadmehdi; Kohanteb, Jamshid

    2012-03-01

    Aloe vera is a medicinal plant with anti-inflammatory, antimicrobial, antidiabetic and immune-boosting properties. In the present study we investigated the inhibitory activities of Aloe vera gel on some cariogenic (Streptococcus mutans), periodontopathic (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis) and an opportunistic periodontopathogen (Bacteroides fragilis) isolated from patients with dental caries and periodontal diseases. Twenty isolates of each of these bacteria were investigated for their sensitivity to Aloe vera gel using the disk diffusion and microdilution methods. S. mutans was the species most sensitive to Aloe vera gel with a MIC of 12.5 µg/ml, while A. actinomycetemcomitans, P. gingivalis, and B. fragilis were less sensitive, with a MIC of 25-50 µg/ml (P < 0.01). Based on our present findings it is concluded that Aloe vera gel at optimum concentration could be used as an antiseptic for prevention of dental caries and periodontal diseases.

  11. Glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding

    PubMed Central

    Suyama, Shigetomo; Maekawa, Fumihiko; Maejima, Yuko; Kubota, Naoto; Kadowaki, Takashi; Yada, Toshihiko

    2016-01-01

    Adiponectin regulates glucose and lipid metabolism, acting against metabolic syndrome and atherosclerosis. Accumulating evidence suggest that adiponectin acts on the brain including hypothalamic arcuate nucleus (ARC), where proopiomelanocortin (POMC) neurons play key roles in feeding regulation. Several studies have examined intracerebroventricular (ICV) injection of adiponectin and reported opposite effects, increase or decrease of food intake. These reports used different nutritional states. The present study aimed to clarify whether adiponectin exerts distinct effects on food intake and ARC POMC neurons depending on the glucose concentration. Adiponectin was ICV injected with or without glucose for feeding experiments and administered to ARC slices with high or low glucose for patch clamp experiments. We found that adiponectin at high glucose inhibited POMC neurons and increased food intake while at low glucose it exerted opposite effects. The results demonstrate that glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding. PMID:27503800

  12. Screening of some medicinal plants from cameroon for beta-lactamase inhibitory activity.

    PubMed

    Gangoué-Piéboji, Joseph; Baurin, Stéphane; Frère, Jean-Marie; Ngassam, Pierre; Ngameni, Bathelemy; Azebaze, Anatole; Pegnyemb, Dieudonné Emmanuel; Watchueng, Jean; Goffin, Colette; Galleni, Moreno

    2007-03-01

    In efforts to find new bioactive beta-lactamase inhibitors, this study investigated 16 Cameroonian plants belonging to 10 families which were evaluated for anti-beta-lactamase activity. The investigation showed that extracts 2, 6, 3 and 5 of the 16 plants investigated presented interesting in vitro beta-lactamase inhibition (over 90%), respectively, of the beta-lactamases TEM-1, OXA-10, IMP-1 and P99. These extracts were from Mammea africana (all beta-lactamases), Garcinia lucida, G. kola (OXA-10, IMP-1 and P99), Bridelia micrantha (OXA-10, P99), Ochna afzelii (OXA-10, P99), Prunus africana (IMP-1) and Adenia lobata (TEM-1). After elimination of tannins (according to the European Pharmacopoeia) the extracts from B. micrantha, G. lucida and M. africana were tested further for their anti-beta-lactamase activity. The extracts from B. micrantha and G. lucida exhibited potent inhibitory activity, respectively, of beta-lactamase OXA-10 (IC(50) = 0.02 mg/mL) and P99 (IC(50) = 0.01 mg/mL). The anti-beta-lactamase activity of M. africana extract was weak. The isolation and the structural elucidation of the active constituents of G. lucida and B. micrantha will provide useful leads in the development of beta-lactamase inhibitors.

  13. Structural and Kinetic Analyses of Macrophage Migration Inhibitory Factor Active Site Interactions

    SciTech Connect

    Crichlow, G.; Lubetsky, J; Leng, L; Bucala, R; Lolis, E

    2009-01-01

    Macrophage migration inhibitory factor (MIF) is a secreted protein expressed in numerous cell types that counters the antiinflammatory effects of glucocorticoids and has been implicated in sepsis, cancer, and certain autoimmune diseases. Interestingly, the structure of MIF contains a catalytic site resembling the tautomerase/isomerase sites of microbial enzymes. While bona fide physiological substrates remain unknown, model substrates have been identified. Selected compounds that bind in the tautomerase active site also inhibit biological functions of MIF. It had previously been shown that the acetaminophen metabolite, N-acetyl-p-benzoquinone imine (NAPQI), covalently binds to the active site of MIF. In this study, kinetic data indicate that NAPQI inhibits MIF both covalently and noncovalently. The structure of MIF cocrystallized with NAPQI reveals that the NAPQI has undergone a chemical alteration forming an acetaminophen dimer (bi-APAP) and binds noncovalently to MIF at the mouth of the active site. We also find that the commonly used protease inhibitor, phenylmethylsulfonyl fluoride (PMSF), forms a covalent complex with MIF and inhibits the tautomerase activity. Crystallographic analysis reveals the formation of a stable, novel covalent bond for PMSF between the catalytic nitrogen of the N-terminal proline and the sulfur of PMSF with complete, well-defined electron density in all three active sites of the MIF homotrimer. Conclusions are drawn from the structures of these two MIF-inhibitor complexes regarding the design of novel compounds that may provide more potent reversible and irreversible inhibition of MIF.

  14. Determination of a-glucosidase inhibitory activity from selected Fabaceae plants.

    PubMed

    Dej-Adisai, Sukanya; Pitakbut, Thanet

    2015-09-01

    Nineteen plants from Fabaceae family, which were used in Thai traditional medicine for treatment of diabetes, were determined of α-glucosidase inhibitory activity via enzymatic reaction. In this reaction, α-glucosidase was used as enzyme, which, reacted with the substrate, p-nitrophenol-D-glucopyranoside (pNPG). After that the product, p-nitro phenol (pNP) will be occurred and observed the yellow colour at 405 nm. In this study, acarbose was used as positive standard which, inhibited this enzyme with IC₅₀ as 331 ± 4.73 μg/ml. Caesalpinia pulcherrima leaves showed the highest activity with IC₅₀ as 436.97 ± 9.44 μg/ml. Furthermore, Bauhinia malabarica leaves presented moderately activity with IC₅₀ as 745.08 ± 11.15 μg/ml. However, the other plants showed mild to none activity of α-glucosidase inhibition. Accordingly, this study can support anti-diabetes of these plants in traditional medicine and it will be the database of the biological activity of Fabaceae plant.

  15. Cytotoxic and HIV-1 enzyme inhibitory activities of Red Sea marine organisms

    PubMed Central

    2014-01-01

    Background Cancer and HIV/AIDS are two of the greatest public health and humanitarian challenges facing the world today. Infection with HIV not only weakens the immune system leading to AIDS and increasing the risk of opportunistic infections, but also increases the risk of several types of cancer. The enormous biodiversity of marine habitats is mirrored by the molecular diversity of secondary metabolites found in marine animals, plants and microbes which is why this work was designed to assess the anti-HIV and cytotoxic activities of some marine organisms of the Red Sea. Methods The lipophilic fractions of methanolic extracts of thirteen marine organisms collected from the Red Sea (Egypt) were screened for cytotoxicity against two human cancer cell lines; leukaemia (U937) and cervical cancer (HeLa) cells. African green monkey kidney cells (Vero) were used as normal non-malignant control cells. The extracts were also tested for their inhibitory activity against HIV-1 enzymes, reverse transcriptase (RT) and protease (PR). Results Cytotoxicity results showed strong activity of the Cnidarian Litophyton arboreum against U-937 (IC50; 6.5 μg/ml ±2.3) with a selectivity index (SI) of 6.45, while the Cnidarian Sarcophyton trochliophorum showed strong activity against HeLa cells (IC50; 5.2 μg/ml ±1.2) with an SI of 2.09. Other species showed moderate to weak cytotoxicity against both cell lines. Two extracts showed potent inhibitory activity against HIV-1 protease; these were the Cnidarian jelly fish Cassiopia andromeda (IC50; 0.84 μg/ml ±0.05) and the red algae Galaxura filamentosa (2.6 μg/ml ±1.29). It is interesting to note that the most active extracts against HIV-1 PR, C. andromeda and G. filamentosa showed no cytotoxicity in the three cell lines at the highest concentration tested (100 μg/ml). Conclusion The strong cytotoxicity of the soft corals L. arboreum and S. trochliophorum as well as the anti-PR activity of the jelly fish C. andromeda and the red

  16. Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis

    PubMed Central

    Ben Mkaddem, Sanae; Hayem, Gilles; Jönsson, Friederike; Rossato, Elisabetta; Boedec, Erwan; Boussetta, Tarek; El Benna, Jamel; Launay, Pierre; Goujon, Jean-Michel; Benhamou, Marc; Bruhns, Pierre; Monteiro, Renato C.

    2014-01-01

    Rheumatoid arthritis–associated (RA-associated) inflammation is mediated through the interaction between RA IgG immune complexes and IgG Fc receptors on immune cells. Polymorphisms within the gene encoding the human IgG Fc receptor IIA (hFcγRIIA) are associated with an increased risk of developing RA. Within the hFcγRIIA intracytoplasmic domain, there are 2 conserved tyrosine residues arranged in a noncanonical immunoreceptor tyrosine–based activation motif (ITAM). Here, we reveal that inhibitory engagement of the hFcγRIIA ITAM either with anti-hFcγRII F(ab′)2 fragments or intravenous hIgG (IVIg) ameliorates RA-associated inflammation, and this effect was characteristic of previously described inhibitory ITAM (ITAMi) signaling for hFcαRI and hFcγRIIIA, but only involves a single tyrosine. In hFcγRIIA-expressing mice, arthritis induction was inhibited following hFcγRIIA engagement. Moreover, hFcγRIIA ITAMi-signaling reduced ROS and inflammatory cytokine production through inhibition of guanine nucleotide exchange factor VAV-1 and IL-1 receptor–associated kinase 1 (IRAK-1), respectively. ITAMi signaling was mediated by tyrosine 304 (Y304) within the hFcγRIIA ITAM, which was required for recruitment of tyrosine kinase SYK and tyrosine phosphatase SHP-1. Anti-hFcγRII F(ab′)2 treatment of inflammatory synovial cells from RA patients inhibited ROS production through induction of ITAMi signaling. These data suggest that shifting constitutive hFcγRIIA-mediated activation to ITAMi signaling could ameliorate RA-associated inflammation. PMID:25061875

  17. N-containing sugars from Morus alba and their glycosidase inhibitory activities.

    PubMed

    Asano, N; Oseki, K; Tomioka, E; Kizu, H; Matsui, K

    1994-06-17

    The reexamination of N-containing sugars from the roots of Morus alba by improved purification procedures led to the isolation of eighteen N-containing sugars, including seven that were isolated from the leaves of Morus bombycis. These N-containing sugars are 1-deoxynojirimycin (1), N-methyl-1-deoxynojirimycin (2), fagomine (3), 3-epi-fagomine (4), 1,4-dideoxy-1,4-imino-D-arabinitol (5), 1,4-dideoxy-1,4-imino-D-ribitol (6), calystegin B2 (1 alpha,2 beta,3 alpha,4 beta-tetrahydroxy-nor-tropane, 7), calystegin C1 (1 alpha,2 beta,3 alpha,4 beta,6 alpha-pentahydroxy-nor-tropane, 8), 1,4-dideoxy-1,4-imino-(2-O-beta-D-glucopyranosyl)-D-arabinitol (9), and nine glycosides of 1. These glycosides consist of 2-O- and 6-O-alpha-D-galactopyranosyl-1-deoxynojirimycins (10 and 11, respectively), 2-O-, 3-O- and 4-O-alpha-D-glucopyranosyl-1-deoxynojirimycins (12, 13, and 14, respectively), and 2-O-, 3-O-, 4-O- and 6-O-beta-D-glucopyranosyl-1-deoxynojirimycins (15, 16, 17, and 18, respectively). Compound 4 is a new member of polyhydroxylated piperidine alkaloids, and the isolation of 6 is the first report of its natural occurrence. It has recently been found that the polyhydroxy-nor-tropane alkaloids possess potent glycosidase inhibitory activities. Calystegin A3 is the trihydroxy-nor-tropane, and calystegins B1 and B2 are the tetrahydroxy-nor-tropane. Calystegin C1, a new member of calystegins, is the first naturally occurring pentahydroxy-nor-tropane alkaloid. The inhibitory activities of these compounds were investigated against rat digestive glycosidases and various commercially available glycosidases.

  18. Inhibitory activity of coumarins from Artemisia capillaris against advanced glycation endproduct formation.

    PubMed

    Jung, Hyun Ah; Park, Jin Ju; Islam, Md Nurul; Jin, Seung Eun; Min, Byung-Sun; Lee, Je-Hyun; Sohn, Hee Sook; Choi, Jae Sue

    2012-06-01

    Since glycation can lead to the onset of diabetic complications due to chronic hyperglycemia, several indigenous Artemisia species were evaluated as potential inhibitors of advanced glycation endproducts (AGE). Among them, the Artemisia capillaris plant demonstrated the highest AGE inhibitory activity. Repeated column chromatography was performed to isolate a new acylated flavonoid glycoside, acacetin-7-O-(6″-O-acetyl)-β-D-glucopyranosyl-(1→2)[α-L-rhamnopyranosyl]-(1→6)-β-D-glucopyranoside, along with 11 known flavonoids (acacetin-7-O-β-D-glucopyranosyl-(1→2)[α-L-rhamnopyranosyl]-(1→6)-β-D-glucopyranoside, linarin, quercetin, hyperoside, isorhamnetin, isorhamnetin 3-galactoside, isorhamnetin 3-glucoside, isorhamnetin 3-arabinoside, isorhamnetin 3-robinobioside, arcapillin, and cirsilineol), six coumarins (umbelliferone, esculetin, scopoletin, scopolin, isoscopolin, and scoparone), and two phenolic derivatives (4,5-di-O-caffeoylquinic acid and chlorogenic acid). In determining the structure-activity relationship (SAR), it was found that the presence and position of hydroxyl group of test coumarins (coumarin, esculin, isoscopoletin, daphnetin, 4-methylcoumarin, and six isolated coumarins) may play a crucial role in AGE inhibition. A free hydroxyl group at C-7 and a glucosyl group instead of a methoxyl group at C-6 are two important parameters for the inhibitory potential of coumarins on AGE formation. A. capillaris and five key AGE inhibitors, including 4,5-di-Ocaffeoylquinic acid, umbelliferone, esculetin, esculin, and scopoletin, were identified as potential candidates for use as therapeutic or preventive agents for diabetic complications and oxidative stress-related diseases. We understand this to be the first detailed study on the SAR of coumarins in AGE inhibition.

  19. Characterization of Inhibitory GABA-A Receptor Activation during Spreading Depolarization in Brain Slice

    PubMed Central

    Aiba, Isamu; Shuttleworth, C. William

    2014-01-01

    Spreading depolarization (SD) is a slowly propagating wave of near complete depolarizations of neurons and glia. Previous studies have reported large GABA releases during SD, but there is limited understanding of how GABA release and receptor activation are regulated and influence the propagating SD wavefront, as well as an excitatory phase immediately following the passage of SD. The present study characterized GABA-A type receptor (GABAAR) currents during SD generated by KCl microinjection in acute hippocampal slices from adult mice. Spontaneous GABAAR-mediated currents (sIPSCs) were initially enhanced, and were followed by a large outward current at the wavefront. sIPSC were then transiently supressed during the late SD phase, resulting in a significant reduction of the sIPSC/sEPSC ratio. The large outward current generated during SD was eliminated by the GABAAR antagonist gabazine, but the channel potentiator/agonist propofol failed to potentiate the current, likely because of a ceiling effect. Extracellular Cl− decreases recorded during SD were reduced by the antagonist but were not increased by the potentiator. Together with effects of GABAAR modulators on SD propagation rate, these results demonstrate a significant inhibitory role of the initial GABAAR activation and suggest that intracellular Cl− loading is insufficient to generate excitatory GABAAR responses during SD propagation. These results provide a mechanistic explanation for facilitating effects of GABAAR antagonists, and the lack of inhibitory effect of GABAAR potentiators on SD propagation. In addition, selective suppression of GABA transmission in the late SD period and the lack of effect of GABAA modulators on the duration of SD suggests that GABA modulation may not be effective approach to protect neurons during the vulnerable phase of SD. PMID:25338191

  20. Design of multi-target compounds as AChE, BACE1, and amyloid-β(1-42) oligomerization inhibitors: in silico and in vitro studies.

    PubMed

    Hernández-Rodríguez, Maricarmen; Correa-Basurto, José; Martínez-Ramos, Federico; Padilla-Martínez, Itzia Irene; Benítez-Cardoza, Claudia G; Mera-Jiménez, Elvia; Rosales-Hernández, Martha Cecilia

    2014-01-01

    Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models.

  1. Design of multi-target compounds as AChE, BACE1, and amyloid-β(1-42) oligomerization inhibitors: in silico and in vitro studies.

    PubMed

    Hernández-Rodríguez, Maricarmen; Correa-Basurto, José; Martínez-Ramos, Federico; Padilla-Martínez, Itzia Irene; Benítez-Cardoza, Claudia G; Mera-Jiménez, Elvia; Rosales-Hernández, Martha Cecilia

    2014-01-01

    Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models. PMID:24762947

  2. Cell Assembly Dynamics of Sparsely-Connected Inhibitory Networks: A Simple Model for the Collective Activity of Striatal Projection Neurons

    PubMed Central

    Angulo-Garcia, David; Berke, Joshua D.; Torcini, Alessandro

    2016-01-01

    Striatal projection neurons form a sparsely-connected inhibitory network, and this arrangement may be essential for the appropriate temporal organization of behavior. Here we show that a simplified, sparse inhibitory network of Leaky-Integrate-and-Fire neurons can reproduce some key features of striatal population activity, as observed in brain slices. In particular we develop a new metric to determine the conditions under which sparse inhibitory networks form anti-correlated cell assemblies with time-varying activity of individual cells. We find that under these conditions the network displays an input-specific sequence of cell assembly switching, that effectively discriminates similar inputs. Our results support the proposal that GABAergic connections between striatal projection neurons allow stimulus-selective, temporally-extended sequential activation of cell assemblies. Furthermore, we help to show how altered intrastriatal GABAergic signaling may produce aberrant network-level information processing in disorders such as Parkinson’s and Huntington’s diseases. PMID:26915024

  3. Synthesis, crystal structures, fluorescence and xanthine oxidase inhibitory activity of pyrazole-based 1,3,4-oxadiazole derivatives

    NASA Astrophysics Data System (ADS)

    Qi, De-Qiang; Yu, Chuan-Ming; You, Jin-Zong; Yang, Guang-Hui; Wang, Xue-Jie; Zhang, Yi-Ping

    2015-11-01

    A series of pyrazole-based 1,3,4-oxadiazole derivatives were rationally designed and synthesized in good yields by following a convenient route. All the newly synthesized molecules were fully characterized by IR, 1H NMR and elemental analysis. Eight compounds were structurally determined by single crystal X-ray diffraction analysis. The fluorescence properties of all the compounds were investigated in dimethyl sulfoxide media. In addition, these newly synthesized compounds were evaluated for in vitro inhibitory activity against commercial enzyme xanthine oxidase (XO) by measuring the formation of uric acid from xanthine. Among the compounds synthesized and tested, 3d and 3e were found to be moderate inhibitory activity against commercial XO with IC50 = 72.4 μM and 75.6 μM. The studies gave a new insight in further optimization of pyrazole-based 1,3,4-oxadiazole derivatives with excellent fluorescence properties and XO inhibitory activity.

  4. Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward

    PubMed Central

    Henderson, Brandon J.; Wall, Teagan R.; Henley, Beverley M.; Kim, Charlene H.; Nichols, Weston A.; Moaddel, Ruin; Xiao, Cheng

    2016-01-01

    Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway. SIGNIFICANCE STATEMENT Menthol, the most popular flavorant for tobacco products, has been considered simply a benign flavor additive. However, as we show here

  5. Characterization of inhibitory mechanism and antifungal activity between group-1 and group-2 phytocystatins from taro (Colocasia esculenta).

    PubMed

    Wang, Ke-Ming; Kumar, Senthil; Cheng, Yi-Sheng; Venkatagiri, Shripathi; Yang, Ai-Hwa; Yeh, Kai-Wun

    2008-10-01

    Tarocystatin from Colocasia esculenta, a group-2 phytocystatin, is a defense protein against phytopathogenic nematodes and fungi. It is composed of a highly conserved N-terminal region, which is homological to group-1 cystatin, and a repetitive peptide at the C-terminus. The purified recombinant proteins of tarocystatin, such as full-length (FL), N-terminus (Nt) and C-terminus (Ct) peptides, were produced and their inhibitory activities against papain as well as their antifungal effects were investigated. Kinetic analysis revealed that FL peptide exhibited mixed type inhibition (K(ia) = 0.098 microM and K(ib) = 0.252 microM) and Nt peptide showed competitive inhibition (K(i) = 0.057 microM), whereas Ct peptide possessed weak papain activation properties. A shift in the inhibitory pattern from competitive inhibition of Nt peptide alone to mixed type inhibition of FL peptide implied that the Ct peptide has an regulatory effect on the function of FL peptide. Based on the inhibitory kinetics of FL (group-2) and Nt (group-1) peptides on papain activity, an inhibitory mechanism of group-2 phytocystatins and a regulatory mechanism of extended Ct peptide have each been proposed. By contrast, the antifungal activity of Nt peptide appeared to be greater than that of FL peptide, and the Ct peptide showed no effect on antifungal activity, indicating that the antifungal effect is not related to proteinase inhibitory activity. The results are valid for most phytocystatins with respect to the inhibitory mechanism against cysteine proteinase.

  6. Characterization of inhibitory mechanism and antifungal activity between group-1 and group-2 phytocystatins from taro (Colocasia esculenta).

    PubMed

    Wang, Ke-Ming; Kumar, Senthil; Cheng, Yi-Sheng; Venkatagiri, Shripathi; Yang, Ai-Hwa; Yeh, Kai-Wun

    2008-10-01

    Tarocystatin from Colocasia esculenta, a group-2 phytocystatin, is a defense protein against phytopathogenic nematodes and fungi. It is composed of a highly conserved N-terminal region, which is homological to group-1 cystatin, and a repetitive peptide at the C-terminus. The purified recombinant proteins of tarocystatin, such as full-length (FL), N-terminus (Nt) and C-terminus (Ct) peptides, were produced and their inhibitory activities against papain as well as their antifungal effects were investigated. Kinetic analysis revealed that FL peptide exhibited mixed type inhibition (K(ia) = 0.098 microM and K(ib) = 0.252 microM) and Nt peptide showed competitive inhibition (K(i) = 0.057 microM), whereas Ct peptide possessed weak papain activation properties. A shift in the inhibitory pattern from competitive inhibition of Nt peptide alone to mixed type inhibition of FL peptide implied that the Ct peptide has an regulatory effect on the function of FL peptide. Based on the inhibitory kinetics of FL (group-2) and Nt (group-1) peptides on papain activity, an inhibitory mechanism of group-2 phytocystatins and a regulatory mechanism of extended Ct peptide have each been proposed. By contrast, the antifungal activity of Nt peptide appeared to be greater than that of FL peptide, and the Ct peptide showed no effect on antifungal activity, indicating that the antifungal effect is not related to proteinase inhibitory activity. The results are valid for most phytocystatins with respect to the inhibitory mechanism against cysteine proteinase. PMID:18785929

  7. Ni nanoparticle catalyzed growth of MWCNTs on Cu NPs @ a-C:H substrate

    NASA Astrophysics Data System (ADS)

    Ghodselahi, T.; Solaymani, S.; Akbarzadeh Pasha, M.; Vesaghi, M. A.

    2012-11-01

    NiCu NPs @ a-C:H thin films with different Cu content were prepared by co-deposition by RF-sputtering and RF-plasma enhanced chemical vapor deposition (RF-PECVD) from acetylene gas and Cu and Ni targets. The prepared samples were used as catalysts for growing multi-wall carbon nanotubes (MWCNTs) from liquid petroleum gas (LPG) at 825 °C by thermal chemical vapor deposition (TCVD). By addition of Cu NPs @ a-C:H thin layer as substrate for Ni NPs catalyst, the density of the grown CNTs is greatly enhanced in comparison to bare Si substrate. Furthermore the average diameter of the grown CNTs decreases by decreasing of Cu content of Cu NPs @ a-C:H thin layer. However Cu NPs @ a-C:H by itself has no catalytic property in MWCNTs growth. Morphology and electrical and optical properties of Cu NPs @ a-C:H thin layer is affected by Cu content and each of them is effective parameter on growth of MWCNTs based on Ni NPs catalyst. Moreover, adding of a low amount of Ni NPs doesn't vary optical, electrical and morphology properties of Cu NPs @ a-C:H thin layer but it has a profound effect on its catalytic activity. Finally the density and diameter of MWCNTs can be optimized by selection of the Cu NPs @ a-C:H thin layer as substrate of Ni NPs.

  8. Inhibitory effects of stress on postprandial gastric myoelectrical activity and vagal tone in healthy subjects.

    PubMed

    Yin, J; Levanon, D; Chen, J D Z

    2004-12-01

    The aim was to investigate gastric myoelectrical activity (GMA) and vagal activity in response to stress. The study was performed in 10 healthy subjects in three sessions (control, relaxation and stress). The control session was composed of 30-min recordings before and 30-min recordings after a test meal. The protocol of two other sessions was similar except that the fasting recording was extended to 60 min and the subjects were continuously watching a horror movie (stress) or guided meditation tape (relaxation) after the 30-min baseline. GMA was recorded using electrogastrography and heart rate variability (HRV) was derived from the electrocardiogram. Meal resulted in a postprandial increase in the dominant frequency (2.91 cpm vs 3.17 cpm, P < 0.007), dominant power (30.0 dB vs 32.5 dB, P < 0.05), and percentage of normal slow waves (79.8%vs 87.4%, P = 0.09). Similar responses were found in the relaxation session. Stress inhibited all these normal postprandial response and reduced the regularity of gastric slow waves (82.0%vs 66.0%, P < 0.01). In addition, spectral analysis of the HRV demonstrated an inhibition of postprandial vagal activity and an increase of postprandial sympathetic activity with stress. Stress has an inhibitory effect on postprandial GMA and this may involve both vagal and sympathetic pathway.

  9. Green Synthesis and Urease Inhibitory Activity of Spiro-Pyrimidinethiones/Spiro-Pyrimidinones-Barbituric Acid Derivatives

    PubMed Central

    Mohammadi Ziarani, Ghodsi; Asadi, Shima; Faramarzi, Sakineh; Amanlou, Massoud

    2015-01-01

    Sulfonic acid functionalized SBA-15 (SBA-Pr-SO3H) with pore size 6 nm as an efficient heterogeneous nanoporous solid acid catalyst exhibited good catalytic activity in the Biginelli-like reaction in the synthesis of spiroheterobicyclic rings with good yield and good recyclability. Spiro-pyrimidinethiones/spiro-pyrimidinones-barbituric acid derivatives were synthesized in a simple and efficient method using the one-pot three-component reaction of a cyclic 1,3- dicarbonyl compounds (barbituric acid), an aromatic aldehyde and urea or thiourea in the presence of nanoporous silica SBA-Pr-SO3H under solvent free conditions. Urease inhibitory activity of spiro compounds were tested against Jack bean urease using Berthelot alkaline phenol–hypochlorite method. Five of 13 compounds were inhibitor and two of them were enzyme activators. Analysis of the docking results showed that, in most of the spiro molecules, one of the carbonyl groups is coordinated with both nickel atoms, while the other one is involved in the formation of hydrogen bonds with important active-site residues. The effect of inserting two methyl groups on N atoms of barbiturate ring, S substituted, ortho, meta and para substituted compounds were investigated too. PMID:26664377

  10. Angiotensin-I Converting Enzyme (ACE) Inhibitory and Anti-Oxidant Activities of Sea Cucumber (Actinopyga lecanora) Hydrolysates.

    PubMed

    Ghanbari, Raheleh; Zarei, Mohammad; Ebrahimpour, Afshin; Abdul-Hamid, Azizah; Ismail, Amin; Saari, Nazamid

    2015-01-01

    In recent years, food protein-derived hydrolysates have received considerable attention because of their numerous health benefits. Amongst the hydrolysates, those with anti-hypertensive and anti-oxidative activities are receiving special attention as both activities can play significant roles in preventing cardiovascular diseases. The present study investigated the angiotensin-I converting enzyme (ACE) inhibitory and anti-oxidative activities of Actinopyga lecanora (A. lecanora) hydrolysates, which had been prepared by alcalase, papain, bromelain, flavourzyme, pepsin, and trypsin under their optimum conditions. The alcalase hydrolysate showed the highest ACE inhibitory activity (69.8%) after 8 h of hydrolysis while the highest anti-oxidative activities measured by 2,2-diphenyl 1-1-picrylhydrazyl radical scavenging (DPPH) (56.00%) and ferrous ion-chelating (FIC) (59.00%) methods were exhibited after 24 h and 8 h of hydrolysis, respectively. The ACE-inhibitory and anti-oxidative activities displayed dose-dependent trends, and increased with increasing protein hydrolysate concentrations. Moreover, strong positive correlations between angiotensin-I converting enzyme (ACE) inhibitory and anti-oxidative activities were also observed. This study indicates that A. lecanora hydrolysate can be exploited as a source of functional food owing to its anti-oxidant as well as anti-hypertension functions. PMID:26690117

  11. Angiotensin-I Converting Enzyme (ACE) Inhibitory and Anti-Oxidant Activities of Sea Cucumber (Actinopyga lecanora) Hydrolysates

    PubMed Central

    Ghanbari, Raheleh; Zarei, Mohammad; Ebrahimpour, Afshin; Abdul-Hamid, Azizah; Ismail, Amin; Saari, Nazamid

    2015-01-01

    In recent years, food protein-derived hydrolysates have received considerable attention because of their numerous health benefits. Amongst the hydrolysates, those with anti-hypertensive and anti-oxidative activities are receiving special attention as both activities can play significant roles in preventing cardiovascular diseases. The present study investigated the angiotensin-I converting enzyme (ACE) inhibitory and anti-oxidative activities of Actinopyga lecanora (A. lecanora) hydrolysates, which had been prepared by alcalase, papain, bromelain, flavourzyme, pepsin, and trypsin under their optimum conditions. The alcalase hydrolysate showed the highest ACE inhibitory activity (69.8%) after 8 h of hydrolysis while the highest anti-oxidative activities measured by 2,2-diphenyl 1-1-picrylhydrazyl radical scavenging (DPPH) (56.00%) and ferrous ion-chelating (FIC) (59.00%) methods were exhibited after 24 h and 8 h of hydrolysis, respectively. The ACE-inhibitory and anti-oxidative activities displayed dose-dependent trends, and increased with increasing protein hydrolysate concentrations. Moreover, strong positive correlations between angiotensin-I converting enzyme (ACE) inhibitory and anti-oxidative activities were also observed. This study indicates that A. lecanora hydrolysate can be exploited as a source of functional food owing to its anti-oxidant as well as anti-hypertension functions. PMID:26690117

  12. Simultaneous quantitative analysis of 12 methoxyflavones with melanogenesis inhibitory activity from the rhizomes of Kaempferia parviflora.

    PubMed

    Ninomiya, Kiyofumi; Matsumoto, Taku; Chaipech, Saowanee; Miyake, Sohachiro; Katsuyama, Yushi; Tsuboyama, Akihiro; Pongpiriyadacha, Yutana; Hayakawa, Takao; Muraoka, Osamu; Morikawa, Toshio

    2016-04-01

    A methanol extract from the rhizomes of Kaempferia parviflora Wall. ex Baker (Zingiberaceae) has shown inhibitory effects against melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC50 = 9.6 μg/mL). Among 25 flavonoids and three acetophenones isolated previously (1-28), several constituents including 5-hydroxy-7,3',4'-trimethoxyflavone (6, IC50 = 8.8 μM), 5,7,3',4'-tetramethoxyflavone (7, 8.6 μM), 5,3'-dihydroxy-3,7,4'-trimethoxyflavone (12, 2.9 μM), and 5-hydroxy-3,7,3',4'-tetramethoxyflavone (13, 3.5 μM) showed inhibitory effects without notable cytotoxicity at the effective concentrations. Compounds 6, 7, 12, and 13 inhibited the expression of tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA, which could be the mechanism of their melanogenesis inhibitory activity. In addition, a quantitative analytical method for 12 methoxyflavones (1, 2, 4-11, 13, and 14) in the extract was developed using HPLC. The optimal condition for separation and detection of these constituents were achieved on an ODS column (3 μm particle size, 2.1 mm i.d. × 100 mm) with MeOH-0.1 % aqueous acetic acid solvent systems as the mobile phase, and the detection and quantitation limits of the method were estimated to be 0.08-0.66 ng and 0.22-2.00ng, respectively. The relative standard deviation values of intra- and interday precision were lower than 0.95 and 1.08 %, respectively, overall mean recoveries of all flavonoids were 97.9-102.9 %, and the correlation coefficients of all the calibration curves showed good linearity within the test ranges. For validation of the protocol, extracts of three kinds of the plant's rhizomes collected from different regions in Thailand (Leoi, Phetchabun, and Chiang Mai provinces) were evaluated. The results indicated that the assay was reproducible, precise, and could be readily utilized for the quality evaluation of the plant materials. PMID:26711832

  13. A new iridoid glycoside and potential MRB inhibitory activity of isolated compounds from the rhizomes of Cyperus rotundus L.

    PubMed

    Zhou, Zhongliu; Yin, Wenqing; Zhang, Hualin; Feng, Zongcai; Xia, Jingmin

    2013-01-01

    A new iridoid glycoside, rotunduside (1), along with four known iridoid glycosides, 10-O-p-hydroxybenzoyltheviridoside (2), 10-O-vanilloyltheviridoside (3), 6″-O-(trans-p-coumaroyl)-procumbide (4) and loganic acid (5), was isolated from the rhizomes of Cyperus rotundus L. Their chemical structures were elucidated on the basis of UV, IR, MS and NMR spectroscopic analyses. In addition, the macrophages respiratory burst (MRB) inhibitory activity of the isolated compounds was reported. Compound 2 exhibited considerable MRB inhibitory activity in the test with IC50 value of ~37 μM. PMID:23356789

  14. Antioxidant, antibacterial and ACE-inhibitory activity of four monofloral honeys in relation to their chemical composition.

    PubMed

    León-Ruiz, Virginia; González-Porto, Amelia V; Al-Habsi, Nasser; Vera, Soledad; San Andrés, María Paz; Jauregi, Paula

    2013-11-01

    Different monofloral honeys from Castilla-La Mancha (Spain) have been studied in order to determine their main functional and biological properties. Thyme honey and chestnut honey possess the highest antioxidant capacity, which is due to their high vitamin C (in thyme honey) and total polyphenolic content (in chestnut honey). On the other hand, chestnut honey showed high antimicrobial activity against Staphylococcus aureus and Escherichia coli, whilst others had no activity against S. aureus and showed very small activity against E. coli. Moreover it was found that the antimicrobial activity measured in chestnut honey was partly due to its lysozyme content. In addition the angiotensin I-converting enzyme (ACE) inhibitory activity was measured, and the ACE inhibition is one mechanism by which antihypertensive activity is exerted in vivo. All the types of honey showed some activity but chestnut honey had the highest ACE inhibitory activity. PMID:24056722

  15. Inhibitory Potency of 4-Carbon Alkanes and Alkenes toward CYP2E1 Activity

    PubMed Central

    Hartman, Jessica H.; Miller, Grover P.; Boysen, Gunnar

    2016-01-01

    CYP2E1 has been implicated in the bioactivation of many small molecules into reactive metabolites which form adducts with proteins and DNA, and thus a better understanding of the molecular determinants of its selectivity are critical for accurate toxicological predictions. In this study, we determined the potency of inhibition of human CYP2E1 for various 4-carbon alkanes, alkenes and alcohols. In addition, known CYP2E1 substrates and inhibitors including 4-methylpyrazole, aniline, and dimethylnitrosamine were included to determine their relative potencies. Of the 1,3-butadiene-derived metabolites studied, 3,4-epoxy-1-butene was the strongest inhibitor with an IC50 of 110 μM compared to 1700 μM and 6600 μM for 1,2-butenediol and 1,2:3,4-diepoxybutane, respectively. Compared to known inhibitors, inhibitory potency of 3,4-epoxy-1-butene is between 4-methylpyrazole (IC50 = 1.8 μM) and dimethylnitrosamine (IC50 = 230 μM). All three butadiene metabolites inhibit CYP2E1 activity through a simple competitive mechanism. Among the 4-carbon compounds studied, the presence and location of polar groups seems to influence inhibitory potency. To further examine this notion, the investigation was extended to include structurally and chemically similar analogs, including propylene oxide and various butane alcohols. Those results demonstrated preferential recognition of CYP2E1 toward the type and location of polar and hydrophobic structural elements. Taken together, CYP2E1 metabolism may be modified in vivo by exposure to 4-carbon compounds, such as drugs, and nutritional constituents, a finding that highlights the complexity of exposure to mixtures. PMID:24561005

  16. Stimulation of Phenolics, Antioxidant and α-Glucosidase Inhibitory Activities During Barley (Hordeum vulgare L.) Seed Germination.

    PubMed

    Ha, K-S; Jo, S-H; Mannam, V; Kwon, Y-I; Apostolidis, E

    2016-06-01

    The rationale of this study was to enhance the nutritional quality of dry barley seeds. In this study we are evaluating the effect of germination on barley seeds relevant to total phenolic contents, antioxidant activity (in terms of DPPH free-radical scavenging) and the in vitro α-glucosidase inhibitory activities. Barley seeds were germinated for 18.5, 24, 30, 48, and 67 h and then extracted in water. The total phenolic contents, antioxidant activities and α-glucosidase inhibitory activities changed with germination time. More specifically, within the first 48 h of germination the total phenolic content increased from 1.1 mg/g fresh weight (0 h) to 3.4 mg/g fresh weight (48 h) and then slightly reduced by 67 h. Similarly, α-glucosidase inhibitory activity was significantly increased from an IC50 128.82 mg/mL (0 h) to an IC50 18.88 mg/mL (48 h) and then slightly reduced by 67 h. Significant maltase inhibitory activity was observed only with 48 h-germinated extract. Antioxidant activities increased continuously from an IC50 15.72 mg/mL at 0 h to and IC50 5.72 mg/mL after 48 h of germination. Based on our observations, barley seed germination was over after 48 h. During the progress of germination phenolic compounds are becoming available and are more easily extracted. After 48 h, lignification is initiated resulting to the decreased total phenolic content and observed antioxidant and carbohydrate hydrolyzing enzyme inhibition activities. The above results indicate the positive effect of germination in barley seeds for enhanced antioxidant and α-glucosidase inhibitory activities.

  17. Alkaloids from Hippeastrum argentinum and Their Cholinesterase-Inhibitory Activities: An in Vitro and in Silico Study.

    PubMed

    Ortiz, Javier E; Pigni, Natalia B; Andujar, Sebastián A; Roitman, German; Suvire, Fernando D; Enriz, Ricardo D; Tapia, Alejandro; Bastida, Jaume; Feresin, Gabriela E

    2016-05-27

    Two new alkaloids, 4-O-methylnangustine (1) and 7-hydroxyclivonine (2) (montanine and homolycorine types, respectively), and four known alkaloids were isolated from the bulbs of Hippeastrum argentinum, and their cholinesterase-inhibitory activities were evaluated. These compounds were identified using GC-MS, and their structures were defined by physical data analysis. Compound 2 showed weak butyrylcholinesterase (BuChE)-inhibitory activity, with a half-maximal inhibitory concentration (IC50) value of 67.3 ± 0.09 μM. To better understand the experimental results, a molecular modeling study was also performed. The combination of a docking study, molecular dynamics simulations, and quantum theory of atoms in molecules calculations provides new insight into the molecular interactions of compound 2 with BuChE, which were compared to those of galantamine.

  18. Alkaloids from Hippeastrum argentinum and Their Cholinesterase-Inhibitory Activities: An in Vitro and in Silico Study.

    PubMed

    Ortiz, Javier E; Pigni, Natalia B; Andujar, Sebastián A; Roitman, German; Suvire, Fernando D; Enriz, Ricardo D; Tapia, Alejandro; Bastida, Jaume; Feresin, Gabriela E

    2016-05-27

    Two new alkaloids, 4-O-methylnangustine (1) and 7-hydroxyclivonine (2) (montanine and homolycorine types, respectively), and four known alkaloids were isolated from the bulbs of Hippeastrum argentinum, and their cholinesterase-inhibitory activities were evaluated. These compounds were identified using GC-MS, and their structures were defined by physical data analysis. Compound 2 showed weak butyrylcholinesterase (BuChE)-inhibitory activity, with a half-maximal inhibitory concentration (IC50) value of 67.3 ± 0.09 μM. To better understand the experimental results, a molecular modeling study was also performed. The combination of a docking study, molecular dynamics simulations, and quantum theory of atoms in molecules calculations provides new insight into the molecular interactions of compound 2 with BuChE, which were compared to those of galantamine. PMID:27096334

  19. Potent inhibitory effects of N-aryl S-alkylthiocarbamate derivatives on the dopa oxidase activity of mushroom tyrosinase.

    PubMed

    Lee, Kun Ho; Koketsu, Mamoru; Choi, Sang Yoon; Lee, Kang Jin; Lee, Pyeongjae; Ishihara, Hideharu; Kim, Sun Yeou

    2005-07-01

    This study reports the potent inhibitory effect of N-aryl S-alkylthiocarbamate derivatives on mushroom tyrosinase (MT) activity. N-Aryl S-alkylthiocarbamate derivatives were found to exhibit a potent inhibitory effect on the dopa (3,4-dihydroxyphenylalanine) oxidase activity of mushroom tyrosinase. Most of the N-aryl S-alkylthiocarbamate derivatives (compounds from A to J) exhibited higher inhibitory effects than kojic acid (IC50=318 microM), a well known tyrosinase inhibitor. Tyrosinase was the most inhibited by S-phenetyl N-phenylthiocarbamate (compound E, IC50=7.25 microM), and this inhibition was 44 times stronger than that of kojic acid. Compound E exhibited 95.0% of inhibition at 100 microM. A kinetic study of MT inhibition by compound E using the Lineweaver-Burk plots analysis was performed. And the kinetics profiles observed suggest that compound E competitively inhibits MT.

  20. Antifungal and Zearalenone Inhibitory Activity of Pediococcus pentosaceus Isolated from Dairy Products on Fusarium graminearum.

    PubMed

    Sellamani, Muthulakshmi; Kalagatur, Naveen K; Siddaiah, Chandranayaka; Mudili, Venkataramana; Krishna, Kadirvelu; Natarajan, Gopalan; Rao Putcha, Venkata L

    2016-01-01

    The present study was aimed to evaluate the bio-control efficacy of Pediococcus pentosaceus isolated from traditional fermented dairy products originated from India, against the growth and zearalenone (ZEA) production of Fusarium graminearum. The cell-free supernatants of P. pentosaceus (PPCS) were prepared and chemical profiling was carried out by GC-MS and MALDI-TOF analysis. Chemical profiling of PPCS evidenced that, the presence of phenolic antioxidants, which are responsible for the antifungal activity. Another hand, MALDI-TOF analysis also indicated the presence of antimicrobial peptides. To know the antioxidant potential of PPCS, DPPH free radical scavenging assay was carried out and IC50 value was determined as 32 ± 1.89 μL/mL. The antifungal activity of P. pentosaceus was determined by dual culture overlay technique and zone of inhibition was recorded as 47 ± 2.81%, and antifungal activity of PPCS on F. graminearum was determined by micro-well dilution and scanning electron microscopic techniques. The minimum inhibitory concentration (MIC) of PPCS was determined as 66 ± 2.18 μL/mL in the present study. Also a clear variation in the micromorphology of mycelia treated with MIC value of PPCS compared to untreated control was documented. Further, the mechanism of growth inhibition was revealed by ergosterol analysis and determination of reactive oxygen species (ROS) in PPCS treated samples. The effects of PPCS on mycelial biomass and ZEA production were observed in a dose-dependent manner. The mechanism behind the suppression of ZEA production was studied by reverse transcriptase qPCR analysis of ZEA metabolic pathway genes (PKS4 and PKS13), and results showed that there is a dose dependent down-regulation of target gene expression in PPCS treated samples. The results of the present study were collectively proved that, the antifungal and ZEA inhibitory activity of PPCS against F. graminearum and it may find a potential application in agriculture and food

  1. Antifungal and Zearalenone Inhibitory Activity of Pediococcus pentosaceus Isolated from Dairy Products on Fusarium graminearum

    PubMed Central

    Sellamani, Muthulakshmi; Kalagatur, Naveen K.; Siddaiah, Chandranayaka; Mudili, Venkataramana; Krishna, Kadirvelu; Natarajan, Gopalan; Rao Putcha, Venkata L.

    2016-01-01

    The present study was aimed to evaluate the bio-control efficacy of Pediococcus pentosaceus isolated from traditional fermented dairy products originated from India, against the growth and zearalenone (ZEA) production of Fusarium graminearum. The cell-free supernatants of P. pentosaceus (PPCS) were prepared and chemical profiling was carried out by GC-MS and MALDI-TOF analysis. Chemical profiling of PPCS evidenced that, the presence of phenolic antioxidants, which are responsible for the antifungal activity. Another hand, MALDI-TOF analysis also indicated the presence of antimicrobial peptides. To know the antioxidant potential of PPCS, DPPH free radical scavenging assay was carried out and IC50 value was determined as 32 ± 1.89 μL/mL. The antifungal activity of P. pentosaceus was determined by dual culture overlay technique and zone of inhibition was recorded as 47 ± 2.81%, and antifungal activity of PPCS on F. graminearum was determined by micro-well dilution and scanning electron microscopic techniques. The minimum inhibitory concentration (MIC) of PPCS was determined as 66 ± 2.18 μL/mL in the present study. Also a clear variation in the micromorphology of mycelia treated with MIC value of PPCS compared to untreated control was documented. Further, the mechanism of growth inhibition was revealed by ergosterol analysis and determination of reactive oxygen species (ROS) in PPCS treated samples. The effects of PPCS on mycelial biomass and ZEA production were observed in a dose-dependent manner. The mechanism behind the suppression of ZEA production was studied by reverse transcriptase qPCR analysis of ZEA metabolic pathway genes (PKS4 and PKS13), and results showed that there is a dose dependent down-regulation of target gene expression in PPCS treated samples. The results of the present study were collectively proved that, the antifungal and ZEA inhibitory activity of PPCS against F. graminearum and it may find a potential application in agriculture and food

  2. PvD1 defensin, a plant antimicrobial peptide with inhibitory activity against Leishmania amazonensis.

    PubMed

    do Nascimento, Viviane V; Mello, Érica de O; Carvalho, Laís P; de Melo, Edésio J T; Carvalho, André de O; Fernandes, Katia V S; Gomes, Valdirene M

    2015-01-01

    Plant defensins are small cysteine-rich peptides and exhibit antimicrobial activity against a variety of both plant and human pathogens. Despite the broad inhibitory activity that plant defensins exhibit against different micro-organisms, little is known about their activity against protozoa. In a previous study, we isolated a plant defensin named PvD1 from Phaseolus vulgaris (cv. Pérola) seeds, which was seen to be deleterious against different yeast cells and filamentous fungi. It exerted its effects by causing an increase in the endogenous production of ROS (reactive oxygen species) and NO (nitric oxide), plasma membrane permeabilization and the inhibition of medium acidification. In the present study, we investigated whether PvD1 could act against the protozoan Leishmania amazonensis. Our results show that, besides inhibiting the proliferation of L. amazonensis promastigotes, the PvD1 defensin was able to cause cytoplasmic fragmentation, formation of multiple cytoplasmic vacuoles and membrane permeabilization in the cells of this organism. Furthermore, we show, for the first time, that PvD1 defensin was located within the L. amazonensis cells, suggesting the existence of a possible intracellular target. PMID:26285803

  3. Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin.

    PubMed

    Nieto, Carla I; Cabildo, María Pilar; Cornago, María Pilar; Sanz, Dionisia; Claramunt, Rosa M; Torralba, María Carmen; Torres, María Rosario; Elguero, José; García, José A; López, Ana; Acuña-Castroviejo, Darío

    2015-01-01

    A series of new (E)-3(5)-[β-(aryl)-ethenyl]-5(3)-phenyl-1H-pyrazoles bearing fluorine atoms at different positions of the aryl group have been synthesized starting from the corresponding β-diketones. All compounds have been characterized by elemental analysis, DSC as well as NMR (¹H, (13)C, (19)F and (15)N) spectroscopy in solution and in solid state. Three structures have been solved by X-ray diffraction analysis, confirming the tautomeric forms detected by solid state NMR. The in vitro study of their inhibitory potency and selectivity on the activity of nNOS and eNOS (calcium-calmodulin dependent) as well as iNOS (calcium-calmodulin independent) isoenzymes is presented. A qualitative structure-activity analysis allowed the establishment of a correlation between the presence/ absence of different substituents with the inhibition data proving that fluorine groups enhance the biological activity. (E)-3(5)-[β-(3-Fluoro-4-hydroxyphenyl)-ethenyl]-5(3)-phenyl-1H-pyrazole (13), is the best inhibitor of iNOS, being also more selective towards the other two isoforms. PMID:26343623

  4. Synthesis, structures and urease inhibitory activity of cobalt(III) complexes with Schiff bases.

    PubMed

    Jing, Changling; Wang, Cunfang; Yan, Kai; Zhao, Kedong; Sheng, Guihua; Qu, Dan; Niu, Fang; Zhu, Hailiang; You, Zhonglu

    2016-01-15

    A series of new cobalt(III) complexes were prepared. They are [CoL(1)(py)3]·NO3 (1), [CoL(2)(bipy)(N3)]·CH3OH (2), [CoL(3)(HL(3))(N3)]·NO3 (3), and [CoL(4)(MeOH)(N3)] (4), where L(1), L(2), L(3) and L(4) are the deprotonated form of N'-(2-hydroxy-5-methoxybenzylidene)-3-methylbenzohydrazide, N'-(2-hydroxybenzylidene)-3-hydroxylbenzohydrazide, 2-[(2-dimethylaminoethylimino)methyl]-4-methylphenol, and N,N'-bis(5-methylsalicylidene)-o-phenylenediamine, respectively, py is pyridine, and bipy is 2,2'-bipyridine. The complexes were characterized by infrared and UV-Vis spectra, and single crystal X-ray diffraction. The Co atoms in the complexes are in octahedral coordination. Complexes 1 and 4 show effective urease inhibitory activities, with IC50 values of 4.27 and 0.35 μmol L(-1), respectively. Complex 2 has medium activity against urease, with IC50 value of 68.7 μmol L(-1). While complex 3 has no activity against urease. Molecular docking study of the complexes with Helicobacter pylori urease was performed.

  5. Inhibitory effects on phospholipase A2 and antivenin activity of melanin extracted from Thea sinensis Linn.

    PubMed

    Hung, Yao-Ching; Sava, Vasyl; Hong, Meng-Yen; Huang, G Steven

    2004-03-01

    Antivenin activity of melanin extracted from black tea (MEBT) was reported for the first time. The antagonistic effect of MEBT was evaluated for Agkistrodon contortrix laticinctus (broadbanded copperhead), Agkistrodon halys blomhoffii (Japanese mamushi), and Crotalus atrox (western diamondback rattlesnake) snake venoms administered i.p. to ICR mice. MEBT was injected i.p. immediately after the venom administration in dose of 3 mg per mouse in the same place of venom injection. MEBT demonstrated neutralization effect against all venoms tested. The greatest antivenin effect of MEBT was found against Japanese mamushi snake venom. In this case, half the mice died within 2.5 +/- 0.7 h after injection of 0.9 mg/kg of venom. An immediate injection of MEBT substantially reduced the toxic effect of venom and extended time at the 50% level of survival up to 52.3 +/- 2.3 h. The antivenin activity of MEBT is due to chelating of Ca++ and non-specific binding of phospholipase A2. The inhibitory effect of MEBT on phospholipase A2 assessed for different venoms was similar to that obtained with pure enzyme. Low toxicity of MEBT in combination with its antagonistic activity against different venoms may allow effective life-saving treatment against snakebites. Such application of MEBT is important when identification of the snake is impossible or if specific treatment is unavailable.

  6. PvD1 defensin, a plant antimicrobial peptide with inhibitory activity against Leishmania amazonensis

    PubMed Central

    do Nascimento, Viviane V.; Mello, Érica de O.; Carvalho, Laís P.; de Melo, Edésio J.T.; Carvalho, André de O.; Fernandes, Katia V.S.; Gomes, Valdirene M.

    2015-01-01

    Plant defensins are small cysteine-rich peptides and exhibit antimicrobial activity against a variety of both plant and human pathogens. Despite the broad inhibitory activity that plant defensins exhibit against different micro-organisms, little is known about their activity against protozoa. In a previous study, we isolated a plant defensin named PvD1 from Phaseolus vulgaris (cv. Pérola) seeds, which was seen to be deleterious against different yeast cells and filamentous fungi. It exerted its effects by causing an increase in the endogenous production of ROS (reactive oxygen species) and NO (nitric oxide), plasma membrane permeabilization and the inhibition of medium acidification. In the present study, we investigated whether PvD1 could act against the protozoan Leishmania amazonensis. Our results show that, besides inhibiting the proliferation of L. amazonensis promastigotes, the PvD1 defensin was able to cause cytoplasmic fragmentation, formation of multiple cytoplasmic vacuoles and membrane permeabilization in the cells of this organism. Furthermore, we show, for the first time, that PvD1 defensin was located within the L. amazonensis cells, suggesting the existence of a possible intracellular target. PMID:26285803

  7. New urushiols with platelet aggregation inhibitory activities from resin of Toxicodendron vernicifluum.

    PubMed

    Xie, Ya; Zhang, Jie; Liu, Wenyuan; Xie, Ning; Feng, Feng; Qu, Wei

    2016-07-01

    Eight new urushiol-type compounds (1-7b), along with seven known compounds were isolated from the resin of Toxicodendron vernicifluum Stokes. Their structures were determined by extensive spectroscopic methods, included (1)H NMR, (13)C NMR, HMQC, HMBC, HRESIMS, EI-MS in combination with CD methods. All the compounds except 7a and 7b were evaluated for their anti-platelet aggregation activities in vitro. Among them, compound 5 (IC50=5.12±0.85μmol/L), with a vic-diol moiety in the long alkyl chain showed the most potent inhibitory of platelet aggregation activity induced by ADP. In addition, compound 6 showed the effect of anti-platelet aggregation induced by AA with the IC50 value of 3.09±0.70μmol/L. Thus, these compounds might be the active components to the traditional use of Resina Toxicodendri for breaking up blood stasis, which could be related to the anti-platelet aggregation. PMID:27156871

  8. Troglitazone enhances tamoxifen-induced growth inhibitory activity of MCF-7 cells

    SciTech Connect

    Yu, Hong-Nu; Noh, Eun-Mi; Lee, Young-Rae; Roh, Si-Gyun; Song, Eun-Kyung; Han, Myung-Kwan; Lee, Yong-Chul; Shim, In Kyong; Lee, Seung Jin; Jung, Sung Hoo; Kim, Jong-Suk Youn, Hyun Jo

    2008-12-05

    Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligands have been identified as a potential source of therapy for human cancers. However, PPAR{gamma} ligands have a limitation for breast cancer therapy, since estrogen receptor {alpha} (ER{sub {alpha}}) negatively interferes with PPAR{gamma} signaling in breast cancer cells. Here we show that ER{sub {alpha}} inhihits PPAR{gamma} transactivity and ER{sub {alpha}}-mediated inhibition of PPAR{gamma} transactivity is blocked by tamoxifen, an estrogen receptor blocker. The activation of ER{sub {alpha}} with 17-{beta}-estradiol blocked PPRE transactivity induced by troglitazone, a PPAR{gamma} ligand, indicating the resistance of ER{sub {alpha}}-positive breast cancer cells to troglitazone. Indeed, troglitazone inhibited the growth of ER{sub {alpha}}-negative MDA-MB-231 cells more than that of ER{sub {alpha}}-positive MCF-7 cells. Combination of troglitazone with tamoxifen led to a marked increase in growth inhibition of ER{sub {alpha}}-positive MCF-7 cells compared to either agent alone. Our data indicates that troglitazone enhances the growth inhibitory activity of tamoxifen in ER{sub {alpha}}-positive MCF-7 cells.

  9. Triterpenoids of sour jujube show pronounced inhibitory effect on human tumor cells and antioxidant activity.

    PubMed

    Qiao, Aimin; Wang, Yihai; Xiang, Limin; Zhang, Zhenxue; He, Xiangjiu

    2014-10-01

    Sour jujube is a common fruit and traditional medicine in China. Bioactivity-guided fractionation of sour jujube was used to determine the chemical identity of potent antiproliferative and antioxidant constituents. Four novel ursane-type triterpenoids, together with 8 known were isolated and identified. The new triterpenoids were elucidated to be 2α,3β,13β,23-tetrahydroxy-urs-11-en-28-oic acid (3), 2α,3β-dihydroxy-urs-20(30)-en-28-oic acid (9), 2α,3β,28-trihydroxy-urs-20(30)-ene (10), and 3β,12β,13β-trihydroxy-ursan-28-oic acid (11). Among the triterpenoids isolated, 2α,3β,19α-trihydroxy-urs-12-en-28-oic acid (7), 9 and 10 showed high potent inhibitory activity toward the proliferation of HepG2 cells, which the IC50 values were lower than 5 μM. Compounds 9 and 10 also exhibited pronounced activity against MCF-7 cells, with IC50 value of 0.8 ± 0.03 and 1.5 ± 0.1 μM, respectively. Compound 10 showed high antioxidant activity with an EC50 of 0.8 ± 0.02 μM, which was 18.9 times higher than ascorbic acid in antioxidant capacity.

  10. Inhibitory action of NoxA1 on dual oxidase activity in airway cells.

    PubMed

    Pacquelet, Sandrine; Lehmann, Mandy; Luxen, Sylvia; Regazzoni, Karine; Frausto, Monika; Noack, Deborah; Knaus, Ulla G

    2008-09-01

    Imbalance between pro- and antioxidant mechanisms in the lungs can compromise pulmonary functions, including blood oxygenation, host defense, and maintenance of an anti-inflammatory environment. Thus, tight regulatory control of reactive oxygen species is critical for proper lung function. Increasing evidence supports a role for the NADPH oxidase dual oxidase (Duox) as an important source for regulated H2O2 production in the respiratory tract epithelium. In this study Duox expression, function, and regulation were investigated in a fully differentiated, mucociliary airway epithelium model. Duox-mediated H2O2 generation was dependent on calcium flux, which was required for dissociation of the NADPH oxidase regulatory protein Noxa1 from plasma membrane-bound Duox. A functional Duox1-based oxidase was reconstituted in model cell lines to permit mutational analysis of Noxa1 and Duox1. Although the activation domain of Noxa1 was not required for Duox function, mutation of a proline-rich domain in the Duox C terminus, a potential interaction motif for the Noxa1 Src homology domain 3, caused up-regulation of basal and stimulated H2O2 production. Similarly, knockdown of Noxa1 in airway cells increased basal H2O2 generation. Our data indicate a novel, inhibitory function for Noxa1 in Duox regulation. This represents a new paradigm for control of NADPH oxidase activity, where second messenger-promoted conformational change of the Nox structure promotes oxidase activation by relieving constraint induced by regulatory components.

  11. Bioactive fraction of Saraca indica prevents diabetes induced cataractogenesis: An aldose reductase inhibitory activity

    PubMed Central

    Somani, Gauresh; Sathaye, Sadhana

    2015-01-01

    Background: The present study was designed to investigate the effect of Saraca indica (SI) flowers extract and different bioactive fraction on in vitro aldose reductase (AR) inhibitory activity, high glucose-induced cataract in goat lens and in vivo streptozotocin (STZ; 45 mg/kg, i.p) induced cataract in rats. Methods: Extract of flowers of SI tested for inhibition against rat lens AR. Furthermore, bioactive fraction was investigated against high glucose-induced opacification of the lens in vitro lens culture and STZ induced diabetic cataract in rats. Identification of the bioactive component was attempted through high-performance thin-layer chromatography, high-performance liquid chromatography and liquid chromatography-mass spectrometry analysis. Results: Ethyl acetate fraction of S. indica (EASI) produced maximum inhibition that may be due to high phenolic content. Goat lenses in media containing glucose developed a distinctly opaque ring in 72 h and treatment with EASI fraction lowered lens opacity in 72 h. Prolonged treatment with EASI to STZ-induced diabetic rats inhibited the AR activity and delayed cataract progression in a dose dependent manner. Conclusion: Ethyl acetate fraction of S. indica fraction has potential to inhibit rat lens AR enzyme and prevent cataractogenesis not only in goat lens model (in vitro), but also in STZ induced diabetic rats (in vivo). This study is suggestive of the anticataract activity of EASI fraction that could be attributed to the phytoconstituents present in the same. PMID:25709218

  12. Flavonoids from Millettia nitida var. hirsutissima with their anticoagulative activities and inhibitory effects on NO production.

    PubMed

    Liao, Xiao-Lin; Luo, Jian-Guang; Kong, Ling-Yi

    2013-10-01

    Two new compounds, (2R)-7,3'-dihydroxy-6,4'-methoxyflavan (1) and (3R)-7,4'-dihydroxy-2'-methoxyisoflavan (2), along with 12 known flavonoids (3-14), were isolated from the vine stems of Millettia nitida var. hirsutissima. The structures of the isolated compounds were elucidated based on spectroscopic analyses and comparison of literature data. All of the isolates were evaluated for their effects on in-vitro anticoagulative assay and on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated RAW264.7 macrophages. As a result, all compounds showed weak antiplatelet aggregation activities and compounds 4, 5, 7, 8 and 9 demonstrated antithrombin activity with a good dose-effect relationship from 5 to 100 μg mL⁻¹ in rabbit plasma. Compounds 8, 9, 10 and 14 exhibited inhibitory effects on LPS-induced NO production in RAW264.7 macrophages with IC₅₀ values of 4.79 ± 0.20, 8.23 ± 0.35, 5.23 ± 0.11 and 6.30 ± 0.30 μg mL⁻¹, respectively. PMID:23359229

  13. Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin.

    PubMed

    Nieto, Carla I; Cabildo, María Pilar; Cornago, María Pilar; Sanz, Dionisia; Claramunt, Rosa M; Torralba, María Carmen; Torres, María Rosario; Elguero, José; García, José A; López, Ana; Acuña-Castroviejo, Darío

    2015-08-28

    A series of new (E)-3(5)-[β-(aryl)-ethenyl]-5(3)-phenyl-1H-pyrazoles bearing fluorine atoms at different positions of the aryl group have been synthesized starting from the corresponding β-diketones. All compounds have been characterized by elemental analysis, DSC as well as NMR (¹H, (13)C, (19)F and (15)N) spectroscopy in solution and in solid state. Three structures have been solved by X-ray diffraction analysis, confirming the tautomeric forms detected by solid state NMR. The in vitro study of their inhibitory potency and selectivity on the activity of nNOS and eNOS (calcium-calmodulin dependent) as well as iNOS (calcium-calmodulin independent) isoenzymes is presented. A qualitative structure-activity analysis allowed the establishment of a correlation between the presence/ absence of different substituents with the inhibition data proving that fluorine groups enhance the biological activity. (E)-3(5)-[β-(3-Fluoro-4-hydroxyphenyl)-ethenyl]-5(3)-phenyl-1H-pyrazole (13), is the best inhibitor of iNOS, being also more selective towards the other two isoforms.

  14. Inhibitory activity of monoacylglycerols on biofilm formation in Aeromonas hydrophila, Streptococcus mutans, Xanthomonas oryzae, and Yersinia enterocolitica.

    PubMed

    Ham, Youngseok; Kim, Tae-Jong

    2016-01-01

    Biofilm provides a bacterial hiding place by forming a physical barrier and causing physiological changes in cells. The elimination of biofilm is the main goal of hygiene. Chemicals that are inhibitory to biofilm formation have been developed for use in food, personal hygiene products, and medical instruments. Monoacylglycerols are recognized as safe and are used in food as emulsifiers. In this study, the inhibitory activity of monoacylglycerols on bacterial biofilm formation was evaluated systematically with four bacterial strains, Aeromonas hydrophila, Streptococcus mutans, Xanthomonas oryzae, and Yersinia enterocolitica. Monoacylglycerols with two specific lengths of fatty acid moiety, monolaurin and monobehenin, were found to have strong inhibitory activity toward bacterial biofilm formation of S. mutans, X. oryzae, and Y. enterocolitica in a strain specific manner. First, this result suggested that biofilm formation was not inhibited by the detergent characteristics of monoacylglycerols. This suggestion was supported by the inhibitory action of monolaurin on biofilm development but not on the initial cell attachment of Y. enterocolitica in flow cytometric observation. Second, it was also suggested that two distinct response mechanisms to monoacylglycerols existed in bacteria. The existence of these two inhibitory response mechanisms was bacterial strain specific. PMID:27652099

  15. Phytogrowth-inhibitory activities of sulfur-containing compounds. II. The inhibitory activities of thiosalicylic acid and dihydro-2(3H)-thiophenone-related compounds on plant growth.

    PubMed

    Inamori, Y; Muro, C; Yoshioka, M; Yamada, M; Tsujibo, H; Kusano, G; Watanabe, M; Fujimoto, M

    1993-08-01

    Thiosalicylic acid (I) showed rather strong inhibitory activity on the growth of roots of all plants treated except Abelmoschus esculentus Moench at the concentration of 5.0 x 10(-4) M. This compound strongly inhibited the growth of the root of Echinochloa utilis Ohwi et Yabuno even at the low concentration of 5.0 x 10(-5) M. Dihydro-2(3H)-thiophenone (VII) also exhibited inhibitory activity on the growth of roots of all plants treated except Glycine max Merrill. Both compounds inhibited the germination of seeds of some plants at the concentration of 1.0 x 10(-3) M. In I-related compounds (I-V), methyl acetylthiosalicylate (IV) had the strongest inhibitory activity, while in VII-related compounds (VII-XI), 4-hydroxy-2(5H)-thiophenone (VIII) showed the most potent inhibitory activity. The amount of chlorophyll in the cotyledon of Brassica campestris L. subsp. rapa Hook. f. et Anders treated with all compounds except tetrahydrothiophene (XI) was lower than that of the control group.

  16. Inhibitory activity of flavonoids from Prunus davidiana and other flavonoids on total ROS and hydroxyl radical generation.

    PubMed

    Jung, Hyun Ah; Jung, Mee Jung; Kim, Ji Young; Chung, Hae Young; Choi, Jae Sue

    2003-10-01

    Since reactive oxygen species (ROS) and hydroxyl radicals (*OH) play an important role in the pathogenesis of many human degenerative diseases, much attention has focused on the development of safe and effective antioxidants. Preliminary experiments have revealed that the methanol (MeOH) extract of the stem of Prunus davidiana exerts inhibitory/scavenging activities on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, total ROS and peroxynitrites (ONOO-). In the present study, the antioxidant activities of this MeOH extract and the organic solvent-soluble fractions, dichloromethane (CH2Cl2), ethyl acetate (EtOAc), and n-butanol (n-BuOH), and the water layer of P. davidiana stem were evaluated for the potential to inhibit *OH and total ROS generation in kidney homogenates using 2',7'-dichlorodihydrofluorescein diacetate (DCHF-DA), and for the potential to scavenge authentic ONOO-. We also evaluated the inhibitory activity of seven flavonoids isolated from P. davidiana stem, kaempferol, kaempferol 7-O-beta-D-glucoside, (+)-catechin, dihydrokaempferol, hesperetin 5-O-beta-D-glucoside, naringenin and its 7-O-beta-D-glucoside, on the total ROS, *OH and ONOO- systems. For the further elucidation of the structure-inhibitory activity relationship of flavonoids on total ROS and *OH generation, we measured the antioxidant activity of sixteen flavonoids available, including three active flavonoids isolated from P. davidiana, on the total ROS and *OH systems. We found that the inhibitory activity on total ROS generation increases in strength with more numerous hydroxyl groups on their structures. Also, the presence of an ortho-hydroxyl group, whether on the A-ring or B-ring, and a 3-hydroxyl group on the C-ring increased the inhibitory activity on both total ROS and *OH generation.

  17. GABAA receptor activity shapes the formation of inhibitory synapses between developing medium spiny neurons

    PubMed Central

    Arama, Jessica; Abitbol, Karine; Goffin, Darren; Fuchs, Celine; Sihra, Talvinder S.; Thomson, Alex M.; Jovanovic, Jasmina N.

    2015-01-01

    Basal ganglia play an essential role in motor coordination and cognitive functions. The GABAergic medium spiny neurons (MSNs) account for ~95% of all the neurons in this brain region. Central to the normal functioning of MSNs is integration of synaptic activity arriving from the glutamatergic corticostriatal and thalamostriatal afferents, with synaptic inhibition mediated by local interneurons and MSN axon collaterals. In this study we have investigated how the specific types of GABAergic synapses between the MSNs develop over time, and how the activity of GABAA receptors (GABAARs) influences this development. Isolated embryonic (E17) MSNs form a homogenous population in vitro and display spontaneous synaptic activity and functional properties similar to their in vivo counterparts. In dual whole-cell recordings of synaptically connected pairs of MSNs, action potential (AP)-activated synaptic events were detected between 7 and 14 days in vitro (DIV), which coincided with the shift in GABAAR operation from depolarization to hyperpolarization, as detected indirectly by intracellular calcium imaging. In parallel, the predominant subtypes of inhibitory synapses, which innervate dendrites of MSNs and contain GABAAR α1 or α2 subunits, underwent distinct changes in the size of postsynaptic clusters, with α1 becoming smaller and α2 larger over time, while both the percentage and the size of mixed α1/α2-postsynaptic clusters were increased. When activity of GABAARs was under chronic blockade between 4–7 DIV, the structural properties of these synapses remained unchanged. In contrast, chronic inhibition of GABAARs between 7–14 DIV led to reduction in size of α1- and α1/α2-postsynaptic clusters and a concomitant increase in number and size of α2-postsynaptic clusters. Thus, the main subtypes of GABAergic synapses formed by MSNs are regulated by GABAAR activity, but in opposite directions, and thus appear to be driven by different molecular mechanisms. PMID

  18. Fumigant toxicity of Oriental sweetgum (Liquidambar orientalis) and valerian (Valeriana wallichii) essential oils and their components, including their acetylcholinesterase inhibitory activity, against Japanese termites (Reticulitermes speratus).

    PubMed

    Park, Il-Kwon

    2014-01-01

    This study investigated the fumigant toxicity of oriental sweetgum (Liquidambar orientalis) and valerian (Valeriana wallichii) essential oils and their components against the Japanese termite (Reticulitermes speratus). The fumigant toxicity of oriental sweetgum and valerian oil differed significantly according to exposure time. Oriental sweetgum showed toxicity at short exposure times (2 days), and the toxicity of valerian oil was high 7 days after treatment. The main constituents of oriental sweetgum and valerian oils were tested individually for their fumigant toxicity against Japanese termites. Among the test compounds, benzyl alcohol, acetophenone, 1-phenyl-1-ethanol, hydrocinnamyl alcohol, trans-cinnamyl aldehyde, trans-cinnamyl alcohol, cis-asarone, styrene, and cis-ocimene showed toxicity against Japanese termites 7 days after treatment. Hydrocinnamyl alcohol and trans-cinnamyl alcohol were found to be the major contributors to the fumigant antitermitic toxicity of oriental sweetgum oil. The acetylcholinesterase (AChE) inhibition activity of two oils and their constituents was tested to determine their mode of action. Only cis-ocimene showed strong AChE inhibition activity with an IC50 value of 0.131 mg/mL. Further studies are warranted to determine the potential of these essential oils and their constituents as fumigants for termite control. PMID:25153870

  19. Fumigant toxicity of Oriental sweetgum (Liquidambar orientalis) and valerian (Valeriana wallichii) essential oils and their components, including their acetylcholinesterase inhibitory activity, against Japanese termites (Reticulitermes speratus).

    PubMed

    Park, Il-Kwon

    2014-08-19

    This study investigated the fumigant toxicity of oriental sweetgum (Liquidambar orientalis) and valerian (Valeriana wallichii) essential oils and their components against the Japanese termite (Reticulitermes speratus). The fumigant toxicity of oriental sweetgum and valerian oil differed significantly according to exposure time. Oriental sweetgum showed toxicity at short exposure times (2 days), and the toxicity of valerian oil was high 7 days after treatment. The main constituents of oriental sweetgum and valerian oils were tested individually for their fumigant toxicity against Japanese termites. Among the test compounds, benzyl alcohol, acetophenone, 1-phenyl-1-ethanol, hydrocinnamyl alcohol, trans-cinnamyl aldehyde, trans-cinnamyl alcohol, cis-asarone, styrene, and cis-ocimene showed toxicity against Japanese termites 7 days after treatment. Hydrocinnamyl alcohol and trans-cinnamyl alcohol were found to be the major contributors to the fumigant antitermitic toxicity of oriental sweetgum oil. The acetylcholinesterase (AChE) inhibition activity of two oils and their constituents was tested to determine their mode of action. Only cis-ocimene showed strong AChE inhibition activity with an IC50 value of 0.131 mg/mL. Further studies are warranted to determine the potential of these essential oils and their constituents as fumigants for termite control.

  20. Phytogrowth-inhibitory and antibacterial activities of 2,5-dihydroxy-1,4-dithiane and its derivatives.

    PubMed

    Inamori, Y; Ohno, Y; Nishihata, S; Tsujibo, H; Baba, K

    1990-01-01

    2,5-Dihydroxy-1,4-dithiane (I) and its derivatives (II-IV) showed rather marked inhibitory activities on the growth of the roots of two plant species. All compounds tested had phytogrowth-inhibitory activities. These compounds markedly inhibited the growth of the two plant species at the concentration of 1.0 x 10(-3) M. Seeds of Brassica rapa treated with 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane (III) and its diacetate (IV) at the same concentration failed to germinate. Among these compounds, IV showed the most potent inhibitory activity on the two plant species. The radicles of both plant species treated with these compounds at concentrations higher than 1.0 x 10(-4) M showed negative geotropism, even though germination occurred. The compounds except for 2,5-diacetoxy-1,4-dithiane (II) also had antibacterial activities. In particular, III had rather marked antibacterial activity and its minimal inhibitory concentration (MIC) for Staphylococcus aureus IFO-3060 and Escherichia coli IFO-12734 was 4.0 micrograms/ml.

  1. Yeasts from Colombian Kumis as source of peptides with Angiotensin I converting enzyme (ACE) inhibitory activity in milk.

    PubMed

    Chaves-López, Clemencia; Tofalo, Rosanna; Serio, Annalisa; Paparella, Antonello; Sacchetti, Giampiero; Suzzi, Giovanna

    2012-09-17

    This study investigated the possibility of using yeast strains in fermented milks to obtain products with high Angiotensin I-converting enzyme (ACE) inhibitory activity and low bitter taste. Ninety-three yeast strains isolated from Colombian Kumis in different geographic regions were molecularly identified, and their milk fermentation performances were determined. Molecular identification evidenced that Galactomyces geotrichum, Pichia kudriavzevii, Clavispora lusitaniae and Candida tropicalis, were the dominant species. Eighteen out of 93 strains produced fermented milk with ACE-inhibitory (ACEI) activity values ranging from 8.69 to 88.19%. Digestion of fermented milk samples by pepsin and pancreatin demonstrated an increase in ACEI activity, with C. lusitaniae KL4A as the best producer of ACEI peptides. Moreover, sensory analysis of the products containing the major ACE-inhibitory activity pointed out that P. kudriavzevii KL84A and Kluyveromyces marxianus KL26A could be selected as potential adjunct starter cultures in Kumis, since they made a considerable contribution to the ACE inhibitory activity and produced fermented milk without bitter taste. In this study we observed that Colombian Kumis can be an excellent vehicle for the isolation of yeasts with a potential to enhance bioactive peptides produced during milk fermentation. PMID:22938834

  2. Inhibitory effect of mitragynine on human cytochrome P450 enzyme activities

    PubMed Central

    Hanapi, N. A.; Ismail, S.; Mansor, S. M.

    2013-01-01

    Context: To date, many findings reveal that most of the modern drugs have the ability to interact with herbal drugs. Aims: This study was conducted to determine the inhibitory effects of mitragynine on cytochrome P450 2C9, 2D6 and 3A4 activities. Methods and Material: The in vitro study was conducted using a high-throughput luminescence assay. Statistical Analysis: Statistical analysis was conducted using one-way ANOVA and Dunnett's test with P < 0.05 vs. control. The IC50 values were calculated using the GraphPad Prism® 5 (Version 5.01, GraphPad Software, Inc., USA). Results: Assessment using recombinant enzymes showed that mitragynine gave the strongest inhibitory effect on CYP2D6 with an IC50 value of 0.45±0.33 mM, followed by CYP2C9 and CYP3A4 with IC50 values of 9.70±4.80 and 41.32±6.74 μM respectively. Positive inhibitors appropriate for CYP2C9, CYP2D6, and CYP3A4 which are sulfaphenazole, quinidine and ketoconazole were used respectively. Vmax values of CYP2C9, CYP2D6 and CYP3A4 were 0.0005, 0.01155 and 0.0137 μM luciferin formed/pmol/min respectively. Km values of CYP2C9, CYP2D6, and CYP3A4 were 32.65, 56.01, and 103.30 μM respectively. Mitragynine noncompetitively inhibits CYP2C9 and CYP2D6 activities with the Ki values of 61.48 and 12.86 μM respectively. On the other hand, mitragynine inhibits CYP3A4 competitively with a Ki value of 379.18 μM. Conclusions: The findings of this study reveal that mitragynine might inhibit cytochrome P450 enzyme activities, specifically CYP2D6. Therefore, administration of mitragynine together with herbal or modern drugs which follow the same metabolic pathway may contribute to herb-drug interactions. PMID:24174816

  3. Central and direct regulation of testicular activity by gonadotropin-inhibitory hormone and its receptor.

    PubMed

    Ubuka, Takayoshi; Son, You Lee; Tobari, Yasuko; Narihiro, Misato; Bentley, George E; Kriegsfeld, Lance J; Tsutsui, Kazuyoshi

    2014-01-01

    Gonadotropin-inhibitory hormone (GnIH) was first identified in Japanese quail to be an inhibitor of gonadotropin synthesis and release. GnIH peptides have since been identified in all vertebrates, and all share an LPXRFamide (X = L or Q) motif at their C-termini. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147), which inhibits cAMP signaling. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN) in birds and the dorsomedial hypothalamic area (DMH) in most mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function via GPR147 expressed in gonadotropes. Further, GnIH inhibits gonadotropin-releasing hormone (GnRH)-induced gonadotropin subunit gene transcription by inhibiting the adenylate cyclase/cAMP/PKA-dependent ERK pathway in an immortalized mouse gonadotrope cell line (LβT2 cells). GnIH neurons also project to GnRH neurons that express GPR147 in the preoptic area (POA) in birds and mammals. Accordingly, GnIH can inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as by directly inhibiting pituitary gonadotrope activity. GnIH and GPR147 can thus centrally suppress testosterone secretion and spermatogenesis by acting in the hypothalamic-pituitary-gonadal axis. GnIH and GPR147 are also expressed in the testis of birds and mammals, possibly acting in an autocrine/paracrine manner to suppress testosterone secretion and spermatogenesis. GnIH expression is also regulated by melatonin, stress, and social environment in birds and mammals. Accordingly, the GnIH-GPR147 system may play a role in transducing physical and social environmental information to regulate optimal testicular activity in birds and mammals. This review discusses central and direct inhibitory effects of GnIH and GPR147 on testosterone secretion and spermatogenesis in birds and mammals.

  4. Calystegins of Physalis alkekengi var. francheti (Solanaceae). Structure determination and their glycosidase inhibitory activities.

    PubMed

    Asano, N; Kato, A; Oseki, K; Kizu, H; Matsui, K

    1995-04-15

    calystegin B2, showed no activity against any glycosidases tested. Since calystegin B3, a 2-epimer of calystegin B2, also exhibited only a weak inhibitory activity, it was concluded that the equatorially oriented OH group at C2 is the essential feature for recognition and strong binding by the active site of glycosidases.(ABSTRACT TRUNCATED AT 400 WORDS)

  5. New Alkaloids from Green Vegetable Soybeans and Their Inhibitory Activities on the Proliferation of Concanavalin A-Activated Lymphocytes.

    PubMed

    Wang, Taoyun; Zhao, Jianping; Li, Xiaoran; Xu, Qiongming; Liu, Yanli; Khan, Ikhlas A; Yang, Shilin

    2016-03-01

    A comprehensive phytochemical study of the chemical constituents of green vegetable soybeans resulted in the isolation of two new alkaloids, soyalkaloid A, 1, and isoginsenine, 2, together with four known ones, ginsenine, 3, (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, 4, (1R,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, 5, and indole-3-carboxylic acid, 6. The structures of compounds 1-6 were elucidated on the basis of spectroscopic and chemical analyses. All of the alkaloids were isolated from soybeans for the first time, and compound 1 was a new indole-type alkaloid with a novel carbocyclic skeleton. Their inhibitory activities on the proliferation of concanalin A-activated lymphocytes were assessed by CCK8 assay.

  6. Mouse mammary tumors display Stat3 activation dependent on leukemia inhibitory factor signaling

    PubMed Central

    Quaglino, Ana; Schere-Levy, Carolina; Romorini, Leonardo; Meiss, Roberto P; Kordon, Edith C

    2007-01-01

    Introduction It has been demonstrated that leukemia inhibitory factor (LIF) induces epithelium apoptosis through Stat3 activation during mouse mammary gland involution. In contrast, it has been shown that this transcription factor is commonly activated in breast cancer cells, although what causes this effect remains unknown. Here we have tested the hypothesis that locally produced LIF can be responsible for Stat3 activation in mouse mammary tumors. Methods The studies were performed in different tumorigenic and non-tumorigenic mammary cells. The expression of LIF and LIF receptor was tested by RT-PCR analysis. In tumors, LIF and Stat3 proteins were analyzed by immunohistochemistry, whereas Stat3 and extracellular signal-regulated kinase (ERK)1/2 expression and phosphorylation were studied by Western blot analysis. A LIF-specific blocking antibody was used to determine whether this cytokine was responsible for Stat3 phosphorylation induced by conditioned medium. Specific pharmacological inhibitors (PD98059 and Stat3ip) that affect ERK1/2 and Stat3 activation were used to study their involvement in LIF-induced effects. To analyze cell survival, assays with crystal violet were performed. Results High levels of LIF expression and activated Stat3 were found in mammary tumors growing in vivo and in their primary cultures. We found a single mouse mammary tumor cell line, LM3, that showed low levels of activated Stat3. Incidentally, these cells also showed very little expression of LIF receptor. This suggested that autocrine/paracrine LIF would be responsible for Stat3 activation in mouse mammary tumors. This hypothesis was confirmed by the ability of conditioned medium of mammary tumor primary cultures to induce Stat3 phosphorylation, activity that was prevented by pretreatment with LIF-blocking antibody. Besides, we found that LIF increased tumor cell viability. Interestingly, blocking Stat3 activation enhanced this effect in mammary tumor cells. Conclusion LIF is

  7. Inhibitory activity of synthesized acetylated Procyanidin B1 analogs against HeLa S3 cells proliferation.

    PubMed

    Okamoto, Syuhei; Ishihara, Sayaka; Okamoto, Taisuke; Doi, Syoma; Harui, Kota; Higashino, Yusuke; Kawasaki, Takashi; Nakajima, Noriyuki; Saito, Akiko

    2014-01-01

    Proanthocyanidins, also known as condensed tannins and/or oligomeric flavonoids, occur in many edible plants and have various interesting biological activities. Previously, we reported a synthetic method for the preparation of various procyanidins in pure form and described their biological activities. Here, we describe the synthesis of procyanidin B1 acetylated analogs and discuss their inhibition activities against HeLa S3 cell proliferation. Surprisingly, the lower-unit acetylated procyanidin B1 strongly inhibited the proliferation of HeLa S3 cells. This molecule showed much stronger inhibitory activity than did epigallocatechin-3-O-gallate (EGCG), green tea polyphenol, and dimeric compounds that included EGCG as a unit. This result suggests that the phenolic hydroxyl groups of the upper-units in flavan-3-ols are important for their inhibitory activity against cancer cell proliferation and that a hydrophobic lower unit dimer enhances this activity. PMID:24500007

  8. Regulator of G-protein signaling 18 integrates activating and inhibitory signaling in platelets.

    PubMed

    Gegenbauer, Kristina; Elia, Giuliano; Blanco-Fernandez, Alfonso; Smolenski, Albert

    2012-04-19

    Regulator of G-protein signaling 18 (RGS18) is a GTPase-activating protein for the G-α-q and G-α-i subunits of heterotrimeric G-proteins that turns off signaling by G-protein coupled receptors. RGS18 is highly expressed in platelets. In the present study, we show that the 14-3-3γ protein binds to phosphorylated serines 49 and 218 of RGS18. Platelet activation by thrombin, thromboxane A2, or ADP stimulates the association of 14-3-3 and RGS18, probably by increasing the phosphorylation of serine 49. In contrast, treatment of platelets with prostacyclin and nitric oxide, which trigger inhibitory cyclic nucleotide signaling involving cyclic AMP-dependent protein kinase A (PKA) and cyclic GMP-dependent protein kinase I (PKGI), induces the phosphorylation of serine 216 of RGS18 and the detachment of 14-3-3. Serine 216 phosphorylation is able to block 14-3-3 binding to RGS18 even in the presence of thrombin, thromboxane A2, or ADP. 14-3-3-deficient RGS18 is more active compared with 14-3-3-bound RGS18, leading to a more pronounced inhibition of thrombin-induced release of calcium ions from intracellular stores. Therefore, PKA- and PKGI-mediated detachment of 14-3-3 activates RGS18 to block Gq-dependent calcium signaling. These findings indicate cross-talk between platelet activation and inhibition pathways at the level of RGS18 and Gq. PMID:22234696

  9. Calcineurin-NFAT activation and DSCR-1 auto-inhibitory loop: how is homoeostasis regulated?

    PubMed

    Minami, Takashi

    2014-04-01

    Calcineurin-nuclear factor of activated T cells (NFAT) signalling plays a critical role not only in the immune and nervous systems, but also in cardiovascular development and pathological endothelial cell activation during angiogenesis or inflammation. Studies in NFAT-null mice demonstrated that there is high redundancy between functions of the different NFAT family members. Deletion of only one NFAT causes mild phenotypes, but compound deletions of multiple NFAT family members leads to severe abnormalities in multiple organ systems. Genome-wide transcription analysis revealed that many NFAT target genes are related to cell growth and inflammation, whereas the gene most strongly induced by NFAT in endothelial cells is an auto-inhibitory molecule, Down syndrome critical region (DSCR)-1. The NFAT-DSCR-1 signalling axis may vary depending on the cell-type or signal dosage level under the microenvironment. In the endothelium, stable expression of the DSCR-1 short isoform attenuates septic inflammatory shock, tumour growth and tumour metastasis to lung. Moreover, dysfunction of DSCR-1 and the NFAT priming kinase, DYRK1A, prevents NFAT nuclear occupancy. This change in NFAT nuclear localization is responsible for many of the features of Down syndrome. Thus, fine-tuning of the NFAT-DSCR-1 negative feedback loop may enable therapeutic manipulation in vasculopathic diseases.

  10. Lanostane triterpenoids from Ganoderma curtisii and their NO production inhibitory activities of LPS-induced microglia.

    PubMed

    Jiao, Yang; Xie, Ting; Zou, Lu-Hui; Wei, Qian; Qiu, Li; Chen, Li-Xia

    2016-08-01

    Twenty-nine lanostane triterpenoids (1-29) were obtained from the EtOH extract of fruiting bodies of the Ganoderma curtisii. Among them, compound 1 was a new lanostane triterpenoid and compounds 2-5 were isolated from the genus Ganoderma for the first time and their structures were unambiguously identified in this work. The NMR data of the four known lanostane triterpenoids (2-5) were reported for the first time because their structures were all tentatively characterized by interpreting the MS data from the methanol extract of Ganoderma lucidum or from the metabolites in rat bile after oral administration of crude extract of the fruiting bodies of G. lucidum using fragmentation rules. Their anti-inflammatory activities were tested by measuring their inhibitory effects on nitric oxide (NO) production in BV-2 microglia cells activated by lipopolysaccharide. Their IC50 values were in a range from 3.65±0.41 to 28.04±2.81μM. PMID:27335254

  11. Characterization of DicB by partially masking its potent inhibitory activity of cell division.

    PubMed

    Yang, Shaoyuan; Pei, Hairun; Zhang, Xiaoying; Wei, Qiang; Zhu, Jia; Zheng, Jimin; Jia, Zongchao

    2016-07-01

    DicB, a protein encoded by the Kim (Qin) prophage in Escherichia coli, inhibits cell division through interaction with MinC. Thus far, characterization of DicB has been severely hampered owing to its potent activity which ceases cell division and leads to cell death. In this work, through fusing maltose-binding protein to the N-terminus of DicB (MBP-DicB), we successfully expressed and purified recombinant DicB that enabled in vitro analysis for the first time. More importantly, taking advantage of the reduced inhibitory activity of MBP-DicB, we were able to study its effects on cell growth and morphology. Inhibition of cell growth by MBP-DicB was systematically evaluated using various DicB constructs, and their corresponding effects on cell morphology were also investigated. Our results revealed that the N-terminal segment of DicB plays an essential functional role, in contrast to its C-terminal tail. The N-terminus of DicB is of critical importance as even the first amino acid (following the initial Met) could not be removed, although it could be mutated. This study provides the first glimpse of the molecular determinants underlying DicB's function. PMID:27466443

  12. Calcineurin-NFAT activation and DSCR-1 auto-inhibitory loop: how is homoeostasis regulated?

    PubMed

    Minami, Takashi

    2014-04-01

    Calcineurin-nuclear factor of activated T cells (NFAT) signalling plays a critical role not only in the immune and nervous systems, but also in cardiovascular development and pathological endothelial cell activation during angiogenesis or inflammation. Studies in NFAT-null mice demonstrated that there is high redundancy between functions of the different NFAT family members. Deletion of only one NFAT causes mild phenotypes, but compound deletions of multiple NFAT family members leads to severe abnormalities in multiple organ systems. Genome-wide transcription analysis revealed that many NFAT target genes are related to cell growth and inflammation, whereas the gene most strongly induced by NFAT in endothelial cells is an auto-inhibitory molecule, Down syndrome critical region (DSCR)-1. The NFAT-DSCR-1 signalling axis may vary depending on the cell-type or signal dosage level under the microenvironment. In the endothelium, stable expression of the DSCR-1 short isoform attenuates septic inflammatory shock, tumour growth and tumour metastasis to lung. Moreover, dysfunction of DSCR-1 and the NFAT priming kinase, DYRK1A, prevents NFAT nuclear occupancy. This change in NFAT nuclear localization is responsible for many of the features of Down syndrome. Thus, fine-tuning of the NFAT-DSCR-1 negative feedback loop may enable therapeutic manipulation in vasculopathic diseases. PMID:24505143

  13. In vitro metabolism of pyripyropene A and ACAT inhibitory activity of its metabolites.

    PubMed

    Matsuda, Daisuke; Ohshiro, Taichi; Ohtawa, Masaki; Yamazaki, Hiroyuki; Nagamitsu, Tohru; Tomoda, Hiroshi

    2015-01-01

    Pyripyropene A (PPPA, 1) of fungal origin, a selective inhibitor of acyl-CoA:cholesterol acyltransferase 2 (ACAT2), proved orally active in atherogenic mouse models. The in vitro metabolites of 1 in liver microsomes and plasma of human, rabbit, rat and mouse were analyzed by ultra fast liquid chromatography and liquid chromatography/tandem mass spectrometry. In the liver microsomes from all species, successive hydrolysis occurred at the 1-O-acetyl residue, then at the 11-O-acetyl residue of 1, while the 7-O-acetyl residue was resistant to hydrolysis. Furthermore, dehydrogenation of the newly generated 11-alcoholic hydroxyl residue occurred in human and mouse-liver microsomes, while oxidation of the pyridine ring occurred in human and rabbit liver microsomes. On the other hand, hydrolysis of the 7-O-acetyl residue proceeded only in the mouse plasma. These data indicated that the in vitro metabolic profiles of 1 have subtle differences among animal species. All of the PPPA metabolites observed in liver microsomes and plasma markedly decreased ACAT2 inhibitory activity. These findings will help us to synthesize new PPPA derivatives more effective in in vivo study than 1. PMID:25005817

  14. Inhibitory activity of S-adenosylhomocysteine hydrolase inhibitors against human cytomegalovirus replication.

    PubMed

    Snoeck, R; Andrei, G; Neyts, J; Schols, D; Cools, M; Balzarini, J; De Clercq, E

    1993-07-01

    Various acyclic and carbocyclic adenosine analogues, which are apparently targeted at the S-adenosylhomocysteine (AdoHcy) hydrolase have been reported to inhibit the replication of a number of pox-, rhabdo-, paramyxo-, arena-, and reoviruses. Here we show that this activity spectrum extends to human cytomegalovirus (HCMV). Of the compounds tested, neplanocin A, 3-deazaneplanocin A, 6'-C-methylneplanocin A and 5'-noraristeromycin were found to be the most potent inhibitors of HCMV replication in vitro. Their 50% inhibitory concentration ranged from 0.05 to 1.35 micrograms/ml. In general, the anti-HCMV activity of the adenosine analogues correlated well with their affinity (Ki) for AdoHcy hydrolase, suggesting that AdoHcy hydrolase may be considered as a target enzyme for anti-HCMV agents. For four compounds (3-deazaneplanocin A, 6'-C-methylneplanocin A (isomers I and II) and 3-deazaadenosine), anti-HCMV potency was greater than could be expected solely from their interaction with AdoHcy hydrolase, suggesting that these compounds may be functioning by an additional mechanism. PMID:8215298

  15. Alkylphloroglucinol derivatives and triterpenoids with soluble epoxide hydrolase inhibitory activity from Callistemon citrinus.

    PubMed

    Khanh, Pham Ngoc; Duc, Ho Viet; Huong, Tran Thu; Son, Ninh The; Ha, Vu Thi; Van, Doan Thi; Tai, Bui Huu; Kim, Ji Eun; Jo, Ah Reum; Kim, Young Ho; Cuong, Nguyen Manh

    2016-03-01

    Phytochemical analysis of the leaves and stems of Callistemon citrinus (Curtis) Skeels led to the isolation of two new alkylphloroglucinols, gallomyrtucommulone E and F (1 and 2), along with four other known alkylphloroglucinol derivatives, gallomyrtucommulone A (3), endoperoxide G3 (4), myrtucommulone B (5), callistenone B (6) and five known triterpenoids, including betulinic acid (7), 3β-acetylmorolic acid (8), 3β-hydroxy-urs-11-en-13(28)-olide (9), diospyrolide (10) and ursolic acid (11). The structures of the natural compounds were determined from the spectroscopic evidences including 1D-/2D-NMR and HR-MS spectrometry. All the isolated compounds were assessed for the effects on the sEH inhibitory activity. The acylphloroglucinols myrtucommulone B (5)/callistenone B (6) (in mixture), and two triterpenoids, ursolic acid (11) and 3β-hydroxy-urs-11-en-13(28)-olide (9) displayed strong inhibition of sEH activity, with IC50 values of 0.7, 11.2 and 24.8 μM, respectively. PMID:26548595

  16. Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode.

    PubMed

    Forneris, Federico; Wu, Jin; Xue, Xiaoguang; Ricklin, Daniel; Lin, Zhuoer; Sfyroera, Georgia; Tzekou, Apostolia; Volokhina, Elena; Granneman, Joke Cm; Hauhart, Richard; Bertram, Paula; Liszewski, M Kathryn; Atkinson, John P; Lambris, John D; Gros, Piet

    2016-05-17

    Regulators of complement activation (RCA) inhibit complement-induced immune responses on healthy host tissues. We present crystal structures of human RCA (MCP, DAF, and CR1) and a smallpox virus homolog (SPICE) bound to complement component C3b. Our structural data reveal that up to four consecutive homologous CCP domains (i-iv), responsible for inhibition, bind in the same orientation and extended arrangement at a shared binding platform on C3b. Large sequence variations in CCP domains explain the diverse C3b-binding patterns, with limited or no contribution of some individual domains, while all regulators show extensive contacts with C3b for the domains at the third site. A variation of ~100° rotation around the longitudinal axis is observed for domains binding at the fourth site on C3b, without affecting the overall binding mode. The data suggest a common evolutionary origin for both inhibitory mechanisms, called decay acceleration and cofactor activity, with variable C3b binding through domains at sites ii, iii, and iv, and provide a framework for understanding RCA disease-related mutations and immune evasion. PMID:27013439

  17. Characterization of DicB by partially masking its potent inhibitory activity of cell division

    PubMed Central

    Yang, Shaoyuan; Pei, Hairun; Zhang, Xiaoying; Wei, Qiang; Zhu, Jia; Zheng, Jimin; Jia, Zongchao

    2016-01-01

    DicB, a protein encoded by the Kim (Qin) prophage in Escherichia coli, inhibits cell division through interaction with MinC. Thus far, characterization of DicB has been severely hampered owing to its potent activity which ceases cell division and leads to cell death. In this work, through fusing maltose-binding protein to the N-terminus of DicB (MBP–DicB), we successfully expressed and purified recombinant DicB that enabled in vitro analysis for the first time. More importantly, taking advantage of the reduced inhibitory activity of MBP–DicB, we were able to study its effects on cell growth and morphology. Inhibition of cell growth by MBP–DicB was systematically evaluated using various DicB constructs, and their corresponding effects on cell morphology were also investigated. Our results revealed that the N-terminal segment of DicB plays an essential functional role, in contrast to its C-terminal tail. The N-terminus of DicB is of critical importance as even the first amino acid (following the initial Met) could not be removed, although it could be mutated. This study provides the first glimpse of the molecular determinants underlying DicB's function. PMID:27466443

  18. Structure-activity relationships of vanillic acid ester analogs in inhibitory effect of antigen-mediated degranulation in rat basophilic leukemia RBL-2H3 cells.

    PubMed

    Ishimata, Nao; Ito, Hideyuki; Tai, Akihiro

    2016-08-01

    Methyl vanillate (1) showed strong degranulation inhibitory activity among vanillin derivatives tested. In order to find structure-activity relationships for developing anti-allergic agents with simple structures and potent activity, we synthesized several vanillic acid (VA) ester derivatives with C1-C4 and C8 alkyl chains and evaluated their degranulation inhibitory activities. The most active compound of VA ester derivatives was derivative 5 with a C4 straight alkyl chain, and derivative 5 exhibited approximately three-fold greater inhibitory activity than that of 1. Moreover, we designed 8 types of analogs based on 5, and we found that the minimum structure for potent degranulation inhibitory activity requires direct connection of the butyl ester moiety on the benzene ring and at least one hydroxyl group on the benzene ring. Butyl meta or para hydroxyl benzoate (10 or 11) has a simpler structure than that of 5 and exhibited more potent degranulation inhibitory activity than that of 5. PMID:27324979

  19. Potentiation of Acetylcholine-Mediated Facilitation of Inhibitory Synaptic Transmission by an Azaindolizione Derivative, ZSET1446 (ST101), in the Rat Hippocampus.

    PubMed

    Takeda, Kentaro; Yamaguchi, Yoshimasa; Hino, Masataka; Kato, Fusao

    2016-02-01

    The integrity of the hippocampal network depends on the coordination of excitatory and inhibitory signaling, which are under dynamic control by various regulatory influences such as the cholinergic systems. ZSET1446 (ST101; spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) is a newly synthesized azaindolizinone derivative that significantly improves learning deficits in various types of Alzheimer disease (AD) models in rats. We examined the effect of ZSET1446 on the nicotinic acetylcholine (ACh) receptor (nAChR)-mediated regulation of synaptic transmission in hippocampal slices of rats. ZSET1446 significantly potentiated the facilitatory effect of nicotine and ACh on the frequency of spontaneous postsynaptic currents (sPSCs) recorded in CA1 pyramidal neurons with a maximum effect at 100 pM (tested range, 10 pM-1000 pM). The basal sPSC frequency without ACh was not affected. Such potentiation by ZSET1446 was observed in both the pharmacologic isolations of inhibitory and excitatory sPSCs and markedly reduced by blockade of either α7 or α4β2 nAChRs. ZSET1446 did not affect ACh-activated inward currents or depolarization of interneurons in the stratum radiatum and the lacunosum moleculare. These results indicate that ZSET1446 potentiates the nicotine-mediated enhancement of synaptic transmission in the hippocampal neurons without affecting nAChRs themselves, providing a novel possible mechanism of procognitive action that might improve learning deficits in clinical therapy.

  20. Phytochemical screening and evaluation of in vitro angiotensin-converting enzyme inhibitory activity of Artocarpus altilis leaf.

    PubMed

    Siddesha, Jalahalli M; Angaswamy, Nataraju; Vishwanath, Bannikuppe S

    2011-12-01

    This study investigates the effect of Artocarpus altilis leaf extracts on angiotensin-converting enzyme (ACE) activity. Among the extracts tested, hot ethanol extract exhibited a potent ACE-inhibitory activity with an IC₅₀ value of 54.08 ± 0.29 µg mL⁻¹ followed by cold ethyl acetate extract (IC₅₀ of 85.44 ± 0.85 µg mL⁻¹). In contrast, the hot aqueous extracts showed minimum inhibition with the IC₅₀ value of 765.52 ± 11.97 µg mL⁻¹ at the maximum concentration tested. Further, the phytochemical analysis indicated the varied distribution of tannins, phenolics, glycosides, saponins, steroids, terpenoids and anthraquinones in cold and hot leaf extracts. The correlation between the phytochemical analysis and ACE-inhibitory activity suggests that the high content of glycosidic and phenolic compounds could be involved in exerting ACE-inhibitory activity. In conclusion, this study supports the utilisation of A. altilis leaf in the folk medicine for the better treatment of hypertension. Further studies on isolation and characterisation of specific ACE-inhibitory molecule(s) from ethyl acetate, ethanol and methanol extracts of A. altilis leaf would be highly interesting.

  1. Douglas-fir root-associated microorganisms with inhibitory activity towards fungal plant pathogens and human bacterial pathogens.

    PubMed

    Axelrood, P E; Clarke, A M; Radley, R; Zemcov, S J

    1996-07-01

    A microbial culture collection composed of 1820 bacterial strains, including 298 actinomycete strains, was established from the roots of Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) seedlings harvested from conifer nurseries and forest sites. Two hundred and thirty-four strains inhibited the growth of Fusarium, Cylindrocarpon, and (or) Pythium spp. in in vitro assays. A significantly greater proportion of bacterial strains from actinomycete genera exhibited antifungal properties compared with bacterial strains from nonactinomycete genera. Eighty-nine percent of identified inhibitory strains were Streptomyces, Streptoverticillium, Bacillus, Pseudomonas, or Burkholderia species. The actinomycete species were isolated almost exclusively from forest seedlings. Recovery of inhibitory strains representing 29 microbial species was enhanced using a variety of methods to isolate microorganisms from the roots of seedlings from nursery and forest sites. Bacterial strains (including actinomycete strains) with antifungal activity were tested for in vitro growth inhibition of six clinical human bacterial pathogens (Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, and Pseudomonas aeruginosa). Forty-eight percent of the tested strains inhibited one or more human pathogens, Inhibitory activity towards fungal and bacterial pathogens was strain specific, not species specific, and many inhibitory strains exhibited broad-spectrum activity. Strains with antifungal activity against several conifer root pathogens were also more likely to inhibit multiple species of clinical bacterial pathogens.

  2. Determination of antioxidant capacity and a-amylase inhibitory activity of the essential oils from citronella grass and lemongrass

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of the present study was to determine the antioxidant capacity of and in vitro a-amylase inhibitory activity of the essential oils extracted from citronella grass and lemongrass. The chemical composition of the extracted essential oils was determined by GC-MS. The antioxidant capacity ...

  3. Inhibitory effect of putranjivain A on allergic inflammation through suppression of mast cell activation

    SciTech Connect

    Kim, Hui-Hun; Park, Seung-Bin; Lee, Soyoung; Kwon, Taeg Kyu; Shin, Tae-Yong; Park, Pil-Hoon; Lee, Seung-Ho; Kim, Sang-Hyun

    2014-02-01

    A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. Putranjivain A (PJA), member of ellagitannin, is known to possess beneficial effects including anti-cancer and anti-viral activities. The aim of the present study was to elucidate whether PJA modulates the allergic inflammatory reaction and to study its possible mechanisms of action using mast cell-based in vitro and in vivo models. The study was performed in anaphylaxis mouse model and cultured mast cells. PJA inhibited the expression of pro-inflammatory cytokines in immunoglobulin E-stimulated mast cells. PJA reduced this expression by inhibiting nuclear factor (NF)-κB and nuclear factor of activated T cell. The oral administration of PJA reduced systemic and cutaneous anaphylaxis, the release of serum histamine, and the expression of the histamine H{sub 1} receptor. In addition, PJA attenuated the activation of mast cells. PJA inhibited the release of histamine from various types of mast cells by the suppression of intracellular calcium. The inhibitory activity of PJA on the allergic reaction was similar to that of disodium cromoglycate, a known anti-allergic drug. These results suggest that PJA can facilitate the prevention or treatment of allergic inflammatory diseases mediated by mast cells. - Highlights: • PJA reduced the degranulation of mast cells. • PJA inhibited the production of inflammatory cytokines. • The effect of PJA on allergic reaction was comparable to the DSCG. • PJA might be a candidate for the treatment of allergic inflammatory diseases.

  4. Inhibitory mechanism of an extract of Althaea officinalis L. on endothelin-1-induced melanocyte activation.

    PubMed

    Kobayashi, Akemi; Hachiya, Akira; Ohuchi, Atsushi; Kitahara, Takashi; Takema, Yoshinori

    2002-02-01

    It is known that expression of endothelin-1 (ET-1) increases in the epidermis after UVB irradiation, and that this plays an important role during the induction of pigmentation both as a mitogen and as a melanogen for normal human melanocytes (NHMC). When ET-1 acts on NHMC via the endothelin B receptor (ET(B)R) on their cell surface, mobilization of intracellular calcium is induced, which is followed by activation of Raf-1 located upstream of mitogen activated protein kinase (MAPK). We have continued the search for new agent which inhibit this calcium mobilization and we have found that an extract of Althaea officinalis L. has such an action. In this study, we investigated the precise inhibitory mechanism of this botanical extract on the ET-1-induced activation of melanocytes. Treatment of NHMC with this extract abrogated the stimulatory effect of ET-1 on proliferation and also on activation of MAPK in the intracellular signal transduction pathway, but did not affect the binding of ET-1 to the ET(B)R or the production of Inositol 1,4,5-Trisphosphate (IP3). Further, when this extract was used to treat normal human keratinocytes (NHKC), secretion of ET-1 by those cells was reduced. Taken together, these findings indicate that an extract of A. officinalis inhibits both the secretion of ET-1 from NHKC and the action of ET-1 on NHMC mainly by suppressing the ET-1-induced calcium mobilization without the modification of IP3 production, which in turn suggests that this extract is a useful ingredient for a whitening agent.

  5. Inhibitory and Cytotoxic Activities of Chrysin on Human Breast Adenocarcinoma Cells by Induction of Apoptosis

    PubMed Central

    Samarghandian, Saeed; Azimi-Nezhad, Mohsen; Borji, Abasalt; Hasanzadeh, Malihe; Jabbari, Farahzad; Farkhondeh, Tahereh; Samini, Mohammad

    2016-01-01

    Objectives: Chrysin, an active natural bioflavonoid found in honey and many plant extracts, was first known for its antioxidant and anti-inflammatory effects. The fact that antioxidants have several inhibitory effects against different diseases, such as cancer, led to search for food rich in antioxidants. In this study, we investigated the antiproliferative and apoptotic effects of chrysin on the cultured human breast cancer cells (MCF-7). Materials and Methods: Cells were cultured in Roswell Park Memorial Institute medium and treated with different chrysin concentrations for three consecutive days. Cell viability was quantitated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The percentage of apoptotic cells was determined by flow cytometry using Annexin V-fluorescein isothiocyanate. Results: The MTT assay showed that chrysin had an antiproliferative effect on MCF-7 cells in a dose- and time-dependent manner. The 50% cell growth inhibition values for chrysin against MCF-7 cells were 19.5 and 9.2 μM after 48 and 72 h, respectively. Chrysin induced apoptosis in MCF-7 cells as determined by flow cytometry. Chrysin inhibits the growth of the breast cancer cells by inducing cancer cell apoptosis which may, in part, explain its anticancer activity. Conclusion: This study shows that chrysin could also be considered as a promising chemotherapeutic agent and anticancer activity in treatment of the breast cancer cells in future. SUMMARY Chrysin had an antiproliferative effect on human breast cancer cells (MCF-7) cells in a dose- and time-dependent mannerChrysin induced apoptosis in MCF-7 cells, as determined by flow cytometryChrysin inhibits the growth of the breast cancer cells by inducing cancer cell apoptosisChrysin may have anticancer activity. Abbreviations used: Human breast cancer cells (MCF-7), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), phosphate-buffered saline (PBS), normal fibroblast mouse (L929). PMID

  6. Fumigant toxicity and acetylcholinesterase inhibitory activity of 4 Asteraceae plant essential oils and their constituents against Japanese termite (Reticulitermes speratus Kolbe).

    PubMed

    Seo, Seon-Mi; Kim, Junheon; Kang, Jaesoon; Koh, Sang-Hyun; Ahn, Young-Joon; Kang, Kyu-Suk; Park, Il-Kwon

    2014-07-01

    This study investigated the fumigant toxicity of 4 Asteraceae plant essential oils and their constituents against the Japanese termite Reticulitermes speratus Kolbe. Fumigant toxicity varied with plant essential oils or constituents, exposure time, and concentration. Among the tested essential oils, those from Chamaemelum nobile exhibited the strongest fumigant toxicity, followed by those from Santolina chamaecyparissus, Ormenis multicaulis, and Eriocephalus punctulatus at 2 days after treatment. In all, 15, 24, 19, and 9 compounds were identified in the essential oils from C. nobile, E. punctulatus, O. multicaulis, and S. chamaecyparissus, respectively, by using gas chromatography, gas chromatography-mass spectrometry, or open-column chromatography. The identified compounds were tested individually for their fumigant toxicity against Japanese termites. Among the test compounds, trans-pinocarveol, caryophyllene oxide, sabinene hydrate, and santolina alcohol showed strong fumigant toxicity against Japanese termites. Acetylcholinesterase (AChE) inhibition activity of the identified compounds from C. nobile, E. punctulatus, O. multicaulis, and S. chamaecyparissus essential oils were tested to determine the mode of their action. The IC50 values of (+)-α-pinene, (-)-limonene, (-)-α-pinene, β-pinene, and β-phellandrene against Japanese termite AChE were 0.03, 0.13, 0.41, 0.42, and 0.67mg/mL, respectively. Further studies are warranted to determine the potential of these essential oils and their constituents as fumigants for termite control.

  7. In vitro α-amylase and α-glucosidase inhibitory effects and cytotoxic activity of Albizia antunesiana extracts

    PubMed Central

    Chipiti, Talent; Ibrahim, Mohammed Auwal; Singh, Moganavelli; Islam, Md. Shahidul

    2015-01-01

    Context: Diabetes mellitus is a chronic disease, and its incidence is tremendously increasing globally. Decreasing postprandial hyperglycemia by retarding glucose absorption through inhibiting carbohydrates digesting enzymes (α-amylase and α-glucosidase) is one of many approaches used for the management of this disease. Objectives: The leaf and root aqueous and ethanol extracts of Albizia antunesiana were investigated for α-amylase and α-glucosidase inhibitory and cytotoxic activity in vitro. Materials and Methods: The α-amylase and α-glucosidase activities were measured in the presence of aqueous and ethanol extracts of the plant parts using starch and p-nitrophenyl-D-glucopyranoside as substrates respectively. Furthermore, cytotoxic effects of the extracts were investigated on HEK (human embryonic kidney) 293 cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay. Results: The results showed that ethanolic root extract of A. antunesiana had mild α-amylase and strong α-glucosidase inhibitory activity with half-maximal inhibitory concentration values of 30.68 and 4.35 µg/mL, respectively. The aqueous root extract showed mild α-glucosidase but no α-amylase inhibitory activity. Cytotoxicity studies on the extracts using the MTT assay revealed that the ethanolic (leaf and root) extracts were relatively nontoxic at tested concentrations on the HEK 293 cell lines. However, the aqueous extracts (leaf and root) were cytotoxic at concentrations above 50 µg/mL. Conclusion: Data from this study suggest that the ethanolic root extract of A. antunesiana possess in vitro α-amylase and α-glucosidase inhibitory activities and are not cytotoxic at least in an in vitro condition. PMID:26664010

  8. Pretreatment of garlic powder using sweep frequency ultrasound and single frequency countercurrent ultrasound: optimization and comparison for ACE inhibitory activities.

    PubMed

    Ma, Haile; Huang, Liurong; Peng, Lei; Wang, Zhenbin; Yang, Qiaorong

    2015-03-01

    The sweep frequency ultrasound (SFU) and single frequency countercurrent ultrasound (SFCU) pretreatments were modeled and compared based on production of angiotensin I-converting enzyme (ACE) inhibitory peptides from garlic hydrolysates. Two mathematical models were developed to show the effect of each variable and their combinatorial interactions on ACE inhibitory activity. The optimum levels of the parameters in SFU were determined using uniform design, which revealed these as follows: total ultrasonic time 1.5 h, on-time of pulse 18 s and off-time of pulse 3 s. Under optimized conditions, the experimental values of SFU and SFCU were 65.88% and 67.78%, which agreed closely with the predicted values of 63.44% and 67.33%. The SFU and SFCU pretreatments both resulted in higher ACE inhibitory activity compared with untreated garlic (p<0.05). However, there were no significant differences in the ACE inhibitory activities and IC₅₀ values obtained from SFCU and SFU pretreatments under optimum conditions (p>0.05).

  9. Retroviral reverse transcriptase inhibitory activity in Thai herbs and spices: screening with Moloney murine leukemia viral enzyme.

    PubMed

    Suthienkul, O; Miyazaki, O; Chulasiri, M; Kositanont, U; Oishi, K

    1993-12-01

    Fifty-seven Thai herbs and spices were examined for their retroviral reverse transcriptase inhibitory activity. All herbs and spices were extracted with hot-water and methanol. Reverse transcriptase inhibitory activity of the extracts was determined by using Moloney Murine Leukemia Virus reverse transcriptase (M-MuLV-RT) reacted with 3H-dTTP and radioactivity measured with a scintillation counter. Eighty-one per cent (46/57) of hot-water extracts and 54% (31/57) of methanol extracts showed inhibitory activities. At a concentration of 125 micrograms/ml, 13% (6/46) of hot-water extracts, namely Eugenia caryophyllus Bullock et Harrison, Phyllanthus urinaria Linn., Terminalia belerica Roxb., Nelumbo nucifera Gaertn., Psidium guajava Linn. and Lawsonia inermis Linn., had a relative inhibitory ratio (IR) over 50%. They showed ratios of 100%, 91%, 75%, 74%, 61% and 60%, respectively. For methanol extracts, only 10% (3/31) had IR values over 50%. They were T. belerica, E. caryophyllus and N. nucifera which exhibited IR values of 83%, 54% and 54%, respectively. PMID:7524165

  10. Inhibitory effect of some tropical green leafy vegetables on key enzymes linked to Alzheimer's disease and some pro-oxidant induced lipid peroxidation in rats' brain.

    PubMed

    Oboh, Ganiyu; Akinyemi, Ayodele Jacobson; Ademiluyi, Adedayo Oluwaseun; Bello, Fatai Olumide

    2014-05-01

    This study sought to investigate the inhibitory effect of some commonly consumed Nigerian green leafy vegetables (raw and blanched) on acetylcholinesterase and butyrylcholinesterase (key enzyme linked to Alzheimer's disease) activities and some pro-oxidants (FeSO4, Sodium nitroprusside and Quinolinic acid) induced lipid peroxidation in rat brain in vitro. Three commonly consumed green leafy vegetables in Nigeria [Amarantus cruentus (Arowojeja), Struchium sparganophora (Ewuro-odo) and Telfairia occidentalis (Ugwu] were blanched in hot water for 10 min, and the extracts of the raw and blanched vegetables were prepared and used for subsequent analysis. The result revealed that all the vegetables inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity as well as the pro-oxidants induced lipid peroxidation in rat brain in a dose dependent manner; however, Amarantus cruentus extract (EC50 = 97.9 μg/ml) had the highest inhibitory effect on acetylcholinesterase activity while Telfairia occidentalis extract (EC50 = 52.7 μg/ml) had the highest inhibitory effect on butyrylcholinesterase activity. However, blanching of the vegetables caused a significant (P < 0.05) decrease in the inhibitory effect of the vegetables on AChE activities while it enhanced the inhibition of the pro-oxidants induced lipid peroxidation in rat brain in vitro. Therefore, some of the possible mechanism by which green leafy vegetables exert their neuroprotective activities could be through the inhibition of acetylcholinesterase and butyrylcholinesterase activities and prevention of lipid peroxidation in the brain. However, blanching of the vegetables could reduce their ability to inhibit acetylcholinesterase and butyrylcholinesterase activity. PMID:24803694

  11. Systematic synthesis of galloyl-substituted procyanidin B1 and B2, and their ability of DPPH radical scavenging activity and inhibitory activity of DNA polymerases.

    PubMed

    Saito, Akiko; Mizushina, Yoshiyuki; Ikawa, Hiroshi; Yoshida, Hiromi; Doi, Yuki; Tanaka, Akira; Nakajima, Noriyuki

    2005-04-15

    Six galloyl-substituted procyanidin B1 and B2, 3-O-gallate, 3''-O-gallate, and 3,3''-di-O-gallate, were systematically synthesized with the condensation method using TMSOTf as a catalyst. Their ability of DPPH radical scavenging activity and DNA polymerase inhibitory activity were also investigated. The results indicated that the galloyl group of these compounds is very important for both activities. 3,3''-Di-O-gallate dimers acted as strong inhibitor against DNA polymerase alpha and beta, whereas the desgalloyl and monogalloyl compounds did not exhibit any appreciable inhibitory activity against the DNA polymerase beta.

  12. P-glycoprotein inhibitory activity of two phenolic compounds, (-)-syringaresinol and tricin from Sasa borealis.

    PubMed

    Jeong, Yeon Hee; Chung, Soo Yeon; Han, Ah-Reum; Sung, Min Kyung; Jang, Dae Sik; Lee, Jun; Kwon, Youngjoo; Lee, Hwa Jeong; Seo, Eun-Kyoung

    2007-01-01

    (-)-Syringaresinol and tricin, isolated from the AcOEt-soluble extract of the whole plants of Sasa borealis (Gramineae), showed inhibitory effects on the P-glycoprotein in adriamycin-resistant human breast cancer cells, MCF-7/ADR. PMID:17256728

  13. Inhibitory effects of docosyl p-coumarate on DNA topoisomerase activity and human cancer cell growth.

    PubMed

    Mizushina, Yoshiyuki; Nishimura, Katsumi; Takenaka, Yukiko; Takeuchi, Toshifumi; Sugawara, Fumio; Yoshida, Hiromi; Tanahashi, Takao

    2010-10-01

    We previously found six compounds of alkyl p-coumarates from a composite plant Artemisia annua L., and chemically synthesized these compounds (cis-isomer of C20, C22 and C24, and trans-isomer of C20, C22 and C24 of p-coumarates are compounds 1-6, respectively). This report describes the inhibitory activities of these alkyl p-coumarates against DNA polymerase (pol), DNA topoisomerase (topo), and human cancer cell growth. Among the compounds tested, compounds 1 and 4 weakly inhibited repair-related pol beta activity, but no compound influenced the activity of replicative pol alpha. Compounds 4-6 and compounds 2 and 5 were potent inhibitors of human topos I and II, respectively. Compounds 2, 4, 5 and 6 also suppressed the growth of human colon carcinoma cell line, HCT116, with or without p53, suggesting that cell growth inhibition had the same tendency as the inhibition of topos rather than pols. Compound 5 (docosyl p-coumarate), which was the strongest inhibitor of topo II and cancer cell growth in the compounds tested, halted HCT116 p53(+/+) cells in G2/M phases, and induced apoptosis, although this compound did not affect the cell cycle of HCT116 p53(-/-) cells. These results suggest that the effect of p53-dependent cell cycle arrest may be effective for topo inhibition by com-pound 5. From these findings, the action mode of alkyl p-coumarates as an anti-cancer agent is discussed. PMID:20811721

  14. Leukemia inhibitory factor promotes tumor growth and metastasis in human osteosarcoma via activating STAT3.

    PubMed

    Liu, Bin; Lu, Yi; Li, Jinzhi; Liu, Yanping; Liu, Jian; Wang, Weiguo

    2015-10-01

    The leukemia inhibitory factor (LIF) has been demonstrated to be an oncogene and participated in multiple procedures during the initiation and progression of many human malignancies. However, the role of LIF in osteosarcoma is still largely unknown. Here, we performed a series of in vitro and in vivo experiments to investigate the expression and biological functions of LIF in osteosarcoma. Compared to that in the non-cancerous tissues, LIF was significantly overexpressed in a panel of 68 osteosarcoma samples (p < 0.0001). Moreover, the overexpression of LIF was significantly correlated with advanced tumor stage, larger tumor size, and shorter overall survival. In addition, knockdown of LIF notably suppressed the proliferation and invasion of osteosarcoma via blocking the STAT3 signal pathway; in contrast, treatment with the recombinant LIF protein significantly promoted the growth and invasion of osteosarcoma through enhancing the phosphorylation of STAT3, which can be partially neutralized by the STAT3 inhibitor, HO-3867. In conclusion, we demonstrated that LIF was frequently overexpressed in osteosarcoma, which could promote the growth and invasion through activating the STAT3 pathway. Our findings proposed that LIF might be a potent therapeutic target for osteosarcoma.

  15. Anoctamin Calcium-Activated Chloride Channels May Modulate Inhibitory Transmission in the Cerebellar Cortex.

    PubMed

    Zhang, Weiping; Schmelzeisen, Steffen; Parthier, Daniel; Frings, Stephan; Möhrlen, Frank

    2015-01-01

    Calcium-activated chloride channels of the anoctamin (alias TMEM16) protein family fulfill critical functions in epithelial fluid transport, smooth muscle contraction and sensory signal processing. Little is known, however, about their contribution to information processing in the central nervous system. Here we examined the recent finding that a calcium-dependent chloride conductance impacts on GABAergic synaptic inhibition in Purkinje cells of the cerebellum. We asked whether anoctamin channels may underlie this chloride conductance. We identified two anoctamin channel proteins, ANO1 and ANO2, in the cerebellar cortex. ANO1 was expressed in inhibitory interneurons of the molecular layer and the granule cell layer. Both channels were expressed in Purkinje cells but, while ANO1 appeared to be retained in the cell body, ANO2 was targeted to the dendritic tree. Functional studies confirmed that ANO2 was involved in a calcium-dependent mode of ionic plasticity that reduces the efficacy of GABAergic synapses. ANO2 channels attenuated GABAergic transmission by increasing the postsynaptic chloride concentration, hence reducing the driving force for chloride influx. Our data suggest that ANO2 channels are involved in a Ca2+-dependent regulation of synaptic weight in GABAergic inhibition. Thus, in balance with the chloride extrusion mechanism via the co-transporter KCC2, ANO2 appears to regulate ionic plasticity in the cerebellum.

  16. Sulforaphane Analogues with Heterocyclic Moieties: Syntheses and Inhibitory Activities against Cancer Cell Lines.

    PubMed

    Shi, Ye-Hui; Dai, Dong-Fang; Li, Jing; Dong, Yan-Wei; Jiang, Yin; Li, Huan-Gong; Gao, Yuan; Chong, Chuan-Ke; Li, Hui-Ying; Chu, Xiao-Qian; Yang, Cheng; Zhang, Quan; Tong, Zhong-Sheng; Bai, Cui-Gai; Chen, Yue

    2016-01-01

    Recent studies have shown that sulforaphane (SFN) selectively inhibits the growth of ALDH⁺ breast cancer stem-like cells.Herein, a series of SFN analogues were synthesized and evaluated against breast cancer cell lines MCF-7 and SUM-159, and the leukemia stem cell-like cell line KG-1a. These SFN analogues were characterized by the replacement of the methyl group with heterocyclic moieties, and the replacement of the sulfoxide group with sulfide or sulfone. A growth inhibitory assay indicated that the tetrazole analogs 3d, 8d and 9d were significantly more potent than SFN against the three cancer cell lines. Compound 14c, the water soluble derivative of tetrazole sulfide 3d, demonstrated higher potency against KG-1a cell line than 3d. SFN, 3d and 14c significantly induced the activation of caspase-3, and reduced the ALDH⁺ subpopulation in the SUM159 cell line, while the marketed drug doxrubicin(DOX) increased the ALDH⁺ subpopulation. PMID:27110751

  17. Leukemia inhibitory factor promotes tumor growth and metastasis in human osteosarcoma via activating STAT3.

    PubMed

    Liu, Bin; Lu, Yi; Li, Jinzhi; Liu, Yanping; Liu, Jian; Wang, Weiguo

    2015-10-01

    The leukemia inhibitory factor (LIF) has been demonstrated to be an oncogene and participated in multiple procedures during the initiation and progression of many human malignancies. However, the role of LIF in osteosarcoma is still largely unknown. Here, we performed a series of in vitro and in vivo experiments to investigate the expression and biological functions of LIF in osteosarcoma. Compared to that in the non-cancerous tissues, LIF was significantly overexpressed in a panel of 68 osteosarcoma samples (p < 0.0001). Moreover, the overexpression of LIF was significantly correlated with advanced tumor stage, larger tumor size, and shorter overall survival. In addition, knockdown of LIF notably suppressed the proliferation and invasion of osteosarcoma via blocking the STAT3 signal pathway; in contrast, treatment with the recombinant LIF protein significantly promoted the growth and invasion of osteosarcoma through enhancing the phosphorylation of STAT3, which can be partially neutralized by the STAT3 inhibitor, HO-3867. In conclusion, we demonstrated that LIF was frequently overexpressed in osteosarcoma, which could promote the growth and invasion through activating the STAT3 pathway. Our findings proposed that LIF might be a potent therapeutic target for osteosarcoma. PMID:26271643

  18. Storkhead box 2 and melanoma inhibitory activity promote oral squamous cell carcinoma progression

    PubMed Central

    Sasahira, Tomonori; Nishiguchi, Yukiko; Fujiwara, Rina; Kurihara, Miyako; Kirita, Tadaaki; Bosserhoff, Anja Katrin; Kuniyasu, Hiroki

    2016-01-01

    Background Storkhead box protein 2 (STOX2) is a transcriptional factor associated with pre-eclampsia with fetal growth restriction. We recently reported that melanoma inhibitory activity (MIA) promotes oral squamous cell carcinoma (OSCC) progression. However, the relationship between STOX2 and MIA remains unknown in malignancies. Methods We used immunohistochemistry and PCR to investigate MIA and STOX2 expression in OSCC. We also performed functional analysis in human OSCC cells. Results MIA and STOX2 mRNA levels were higher in OSCCs than in normal oral epithelial cells, and upregulation of STOX2 was significantly correlated with overexpression of MIA. Immunostaining for STOX2 was associated with nodal metastasis (P = 0.0002) and MIA expression (P < 0.0001). Furthermore, MIA expression (P = 0.0035) and STOX2 expression (P = 0.0061) were associated with poor outcome in OSCCs. In vitro analysis using OSCC cells revealed that MIA increased expression of STOX2 by paracrine manner. Moreover, STOX2 accelerated OSCC cell growth, invasion, suppressed apoptosis, and enhanced resistance to paclitaxel, cisplatin, and 5-FU. Conclusions Our results suggest that MIA-STOX2 signaling may be a useful diagnostic and therapeutic target in OSCCs. PMID:27050375

  19. Anoctamin Calcium-Activated Chloride Channels May Modulate Inhibitory Transmission in the Cerebellar Cortex.

    PubMed

    Zhang, Weiping; Schmelzeisen, Steffen; Parthier, Daniel; Frings, Stephan; Möhrlen, Frank

    2015-01-01

    Calcium-activated chloride channels of the anoctamin (alias TMEM16) protein family fulfill critical functions in epithelial fluid transport, smooth muscle contraction and sensory signal processing. Little is known, however, about their contribution to information processing in the central nervous system. Here we examined the recent finding that a calcium-dependent chloride conductance impacts on GABAergic synaptic inhibition in Purkinje cells of the cerebellum. We asked whether anoctamin channels may underlie this chloride conductance. We identified two anoctamin channel proteins, ANO1 and ANO2, in the cerebellar cortex. ANO1 was expressed in inhibitory interneurons of the molecular layer and the granule cell layer. Both channels were expressed in Purkinje cells but, while ANO1 appeared to be retained in the cell body, ANO2 was targeted to the dendritic tree. Functional studies confirmed that ANO2 was involved in a calcium-dependent mode of ionic plasticity that reduces the efficacy of GABAergic synapses. ANO2 channels attenuated GABAergic transmission by increasing the postsynaptic chloride concentration, hence reducing the driving force for chloride influx. Our data suggest that ANO2 channels are involved in a Ca2+-dependent regulation of synaptic weight in GABAergic inhibition. Thus, in balance with the chloride extrusion mechanism via the co-transporter KCC2, ANO2 appears to regulate ionic plasticity in the cerebellum. PMID:26558388

  20. Anoctamin Calcium-Activated Chloride Channels May Modulate Inhibitory Transmission in the Cerebellar Cortex

    PubMed Central

    Parthier, Daniel; Frings, Stephan; Möhrlen, Frank

    2015-01-01

    Calcium-activated chloride channels of the anoctamin (alias TMEM16) protein family fulfill critical functions in epithelial fluid transport, smooth muscle contraction and sensory signal processing. Little is known, however, about their contribution to information processing in the central nervous system. Here we examined the recent finding that a calcium-dependent chloride conductance impacts on GABAergic synaptic inhibition in Purkinje cells of the cerebellum. We asked whether anoctamin channels may underlie this chloride conductance. We identified two anoctamin channel proteins, ANO1 and ANO2, in the cerebellar cortex. ANO1 was expressed in inhibitory interneurons of the molecular layer and the granule cell layer. Both channels were expressed in Purkinje cells but, while ANO1 appeared to be retained in the cell body, ANO2 was targeted to the dendritic tree. Functional studies confirmed that ANO2 was involved in a calcium-dependent mode of ionic plasticity that reduces the efficacy of GABAergic synapses. ANO2 channels attenuated GABAergic transmission by increasing the postsynaptic chloride concentration, hence reducing the driving force for chloride influx. Our data suggest that ANO2 channels are involved in a Ca2+-dependent regulation of synaptic weight in GABAergic inhibition. Thus, in balance with the chloride extrusion mechanism via the co-transporter KCC2, ANO2 appears to regulate ionic plasticity in the cerebellum. PMID:26558388

  1. Alpha-amylase inhibitory activity and sterol composition of the marine algae, Sargassum glaucescens

    PubMed Central

    Payghami, Nasrin; Jamili, Shahla; Rustaiyan, Abdolhossein; Saeidnia, Soodabeh; Nikan, Marjan; Gohari, Ahmad Reza

    2015-01-01

    Background: Sargassum species (phaeophyceae) are economically important brown algae in southern parts of Iran. Sargassum is mainly harvested as a row material in alginate production industries and is a source of plant foods or plant bio-stimulants even a component of animal foods. Objective: In this study, Sargassum glaucescens, collected from the seashore of Chabahar, was employed for phytochemical and biological evaluations. Materials and Methods: For that purpose, the dried algae was extracted by methanol and subjected to different chromatographic separation methods. Results: Six sterols, fucosterol (1), 24(S)-hydroxy-24-vinylcholesterol (2), 24(R)-hydroxy-24-vinylcholesterol (3), stigmasterol (4), β-sitosterol (5) and cholesterol (6) were identified by spectroscopic methods including 1H-NMR, 13C-NMR and mass spectroscopy. In vitro alpha-amylase inhibitory test was performed on the methanolic extract and the results revealed a potent inhibition (IC50 = 8.9 ± 2.4 mg/mL) of the enzyme compared to acarbose as a positive control. Conclusion: Various biological activities and distribution of sterols in Sargassum genus have been critically reviewed here. The results concluded that these algae are a good candidate for further anti-diabetic investigations in animals and human. PMID:26692744

  2. The inhibitory activity of linalool against the filamentous growth and biofilm formation in Candida albicans.

    PubMed

    Hsu, Chih-Chieh; Lai, Wen-Lin; Chuang, Kuei-Chin; Lee, Meng-Hwan; Tsai, Ying-Chieh

    2013-07-01

    Candida spp. are part of the natural human microbiota, but they also represent important opportunistic human pathogens. Biofilm-associated Candida albicans infections are clinically relevant due to their high levels of resistance to traditional antifungal agents. In this study, we investigated the ability of linalool to inhibit the formation of C. albicans biofilms and reduce existing C. albicans biofilms. Linalool exhibited antifungal activity against C. albicans ATCC 14053, with a minimum inhibitory concentration (MIC) of 8 mM. Sub-MIC concentrations of linalool also inhibited the formation of germ tubes and biofilms in that strain. The defective architecture composition of C. albicans biofilms exposed to linalool was characterized by scanning electron microscopy. The expression levels of the adhesin genes HWP1 and ALS3 were downregulated by linalool, as assessed by real-time RT-PCR. The expression levels of CYR1 and CPH1, which encode components of the cAMP-PKA and MAPK hyphal formation regulatory pathways, respectively, were also suppressed by linalool, as was the gene encoding their upstream regulator, Ras1. The expression levels of long-term hyphae maintenance associated genes, including UME6, HGC1, and EED1, were all suppressed by linalool. These results indicate that linalool may have therapeutic potential in the treatment of candidiasis associated with medical devices because it interferes with the morphological switch and biofilm formation of C. albicans.

  3. Inhibitory Effects of Glycyrrhetinic Acid on DNA Polymerase and Inflammatory Activities

    PubMed Central

    Ishida, Tsukasa; Mizushina, Yoshiyuki; Yagi, Saori; Irino, Yasuhiro; Nishiumi, Shin; Miki, Ikuya; Kondo, Yasuyuki; Mizuno, Shigeto; Yoshida, Hiromi; Azuma, Takeshi; Yoshida, Masaru

    2012-01-01

    We investigated the inhibitory effect of three glycyrrhizin derivatives, such as Glycyrrhizin (compound 1), dipotassium glycyrrhizate (compound 2) and glycyrrhetinic acid (compound 3), on the activity of mammalian pols. Among these derivatives, compound 3 was the strongest inhibitor of mammalian pols α, β, κ, and λ, which belong to the B, A, Y, and X families of pols, respectively, whereas compounds 1 and 2 showed moderate inhibition. Among the these derivatives tested, compound 3 displayed strongest suppression of the production of tumor necrosis factor-α (TNF-α) induced by lipopolysaccharide (LPS) in a cell-culture system using mouse macrophages RAW264.7 and peritoneal macrophages derived from mice. Moreover, compound 3 was found to inhibit the action of nuclear factor-κB (NF-κB) in engineered human embryonic kidney (HEK) 293 cells. In addition, compound 3 caused greater reduction of 12-O-tetradecanoylphorbol-13-acetate-(TPA-) induced acute inflammation in mouse ear than compounds 1 and 2. In conclusion, this study has identified compound 3, which is the aglycone of compounds 1 and 2, as a promising anti-inflammatory candidate based on mammalian pol inhibition. PMID:21785649

  4. Inhibitory activities against rice pathogens of 8-hydroxy-2,4,6-octatriynamide from Agrocybe sp.

    PubMed

    Zheng, Yongbiao; Xu, Xiaoping; Wu, Yabin

    2016-03-01

    8-Hydroxy-2,4,6-octatriynamide, a natural polyacetylene with inhibitory activities against rice pathogens, was isolated from the liquid fermentation broth of strain Agrocybe sp. YB2005 during screening for new natural chemical agents to control rice pathogens. 8-hydroxy-2,4,6-octatriynamide was purified by consecutive chromatography over a Cl8 reversed phase silica gel, sephadex LH-20 and silica gel. The chemical structure of 8-hydroxy-2,4,6-octatriynamide was elucidated through spectroscopic analyses, including 1D- and 2D-NMR, ESI mass spectrometry and X-ray single crystal diffraction. Bioassays showed that 8-hydroxy-2,4,6-octatriynamide could significantly inhibit growth of Xanthomonas oryzae with an MIC of 53.1 μM in a 96-well plate and the growth of Rhizoctonia solani at 1.02 mM in a 24-well plate. When rice leaves were inoculated with Magnaporthe grisea and cultured in artificial nutrition liquid containing 0.34 mM 8-hydroxy-2,4,6-octatriynamide, no rice blast was observed. The present study implied that 8-hydroxy-2,4,6-octatriynamide could be a candidate agent against rice pathogens. PMID:26861586

  5. [Inhibitory effect of imperatorin and isoimperatorin on activity of cytochrome P450 enzyme in human and rat liver microsomes].

    PubMed

    Cao, Yan; Zhong, Yu-Huan; Yuan, Mei; Li, Hua; Zhao, Chun-Jie

    2013-04-01

    Imperatorin (IM) and isoimperatorin (ISOIM) are major active components of common herbal medicines from Umbelliferae plants, and widely used in clinic. This article studies the inhibitory effect of IM and ISOIM on the activity of cytochrome P450 (CYP) enzyme, and assesses their potential drug-drug interaction. IM and ISOIM were incubated separately with human or rat liver microsomes for 30 min, with phenacetin, bupropion, tolbutamide, S-mephenytoin, dextromethorphan and midazolam as probe substrates. Metabolites of the CYP probe substrates were determined by LC-MS/MS, and IC50 values were calculated to assess the inhibitory effect of the two drugs on human CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4 enzymes, as well as on rat CYP1A2, 2B6, 2D2 and 3A1/2, and grade their inhibitory intensity. In human liver microsomes, IM and ISOIM showed different inhibitory effects on all of the six CYP isoenzymes. They were strong inhibitors for 1A2 and 2B6. The IC50 values were 0.05 and 0.20 micromol x L(-1) for 1A2, and 0.18 and 1.07 micromol x L(-1) for 2B6, respectively. They also showed moderate inhibitory effect on 2C19, and weak effect on 2C9, 2D6 and 3A4. In rat liver microsomes, IM and ISOIM were identified as moderate inhibitors for 1A2, with IC50 values of 1.95 and 2.98 micromol x L(-1). They were moderate and weak inhibitors for 2B6, with IC50 values of 6.22 and 21.71 micromol x L(-1), respectively. They also had weaker inhibitory effect on 2D2 and 3A1/2. The results indicated that IM and ISOIM had extensive inhibitory effects on human CYP enzymes. They are strong inhibitors of CYP1 A2 and 2B6 enzymes. However, it is worth noting the interaction arising from the inhibitory effect of CYP enzymes in clinic.

  6. Prediction of Inhibitory Activity of Epidermal Growth Factor Receptor Inhibitors Using Grid Search-Projection Pursuit Regression Method

    PubMed Central

    Du, Hongying; Hu, Zhide; Bazzoli, Andrea; Zhang, Yang

    2011-01-01

    The epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK) is an important protein target for anti-tumor drug discovery. To identify potential EGFR inhibitors, we conducted a quantitative structure–activity relationship (QSAR) study on the inhibitory activity of a series of quinazoline derivatives against EGFR tyrosine kinase. Two 2D-QSAR models were developed based on the best multi-linear regression (BMLR) and grid-search assisted projection pursuit regression (GS-PPR) methods. The results demonstrate that the inhibitory activity of quinazoline derivatives is strongly correlated with their polarizability, activation energy, mass distribution, connectivity, and branching information. Although the present investigation focused on EGFR, the approach provides a general avenue in the structure-based drug development of different protein receptor inhibitors. PMID:21811593

  7. Iridoids from Fraxinus excelsior with adipocyte differentiation-inhibitory and PPARalpha activation activity.

    PubMed

    Bai, Naisheng; He, Kan; Ibarra, Alvin; Bily, Antoine; Roller, Marc; Chen, Xiaozhuo; Rühl, Ralph

    2010-01-01

    Two new secoiridoid glucosides, excelsides A (1) and B (2), were isolated from the seeds of Fraxinus excelsior. Their structures were elucidated as (2S,4S,3E)-methyl 3-ethylidene-4-(2-methoxy-2-oxoethyl)-2-[(6-O-beta-D-glucopyranosyl-beta-d-glucopyranosyl)oxy]-3,4-dihydro-2H-pyran-5-carboxylate and (2S,4S,3E)-methyl 3-ethylidene-4-{2-[2-(4-hydroxyphenyl)ethyl]oxy-2-oxoethyl}-2-[(6-O-beta-d-glucopyranosyl-beta-d-glucopyranosyl)oxy]-3,4-dihydro-2H-pyran-5-carboxylate, respectively, on the basis of NMR and MS data. Eight known compounds were identified as nuzhenide (3), GI3 (4), GI5 (5), ligstroside (6), oleoside 11-methyl ester (7), oleoside dimethyl ester (8), 1'''-O-beta-D-glucosylformoside (9), and salidroside (10). Compounds 1-9 inhibited adipocyte differentiation in 3T3-L1 cells. Dilutions of the aqueous extract of F. excelsior (1:10,000) as well as compounds 2, 3, 4, 5, and 8 activated the peroxisome proliferator-mediated receptor-alpha (PPARalpha) reporter cell system in the range of 10(-4) M, compared to 10(-7)-10(-8) M for the synthetic PPARalpha activator, WY14,643. Both biological activity profiles support the hypothesis that inhibition of adipocyte differentiation and PPARalpha-mediated mechanisms might be relevant pathways for the antidiabetic activity of F. excelsior extract.

  8. Breast Milk of HIV-Positive Mothers Has Potent and Species-Specific In Vivo HIV-Inhibitory Activity

    PubMed Central

    Wahl, Angela; Baker, Caroline; Spagnuolo, Rae Ann; Stamper, Lisa W.; Fouda, Genevieve G.; Permar, Sallie R.; Hinde, Katie; Kuhn, Louise; Bode, Lars; Aldrovandi, Grace M.

    2015-01-01

    ABSTRACT Despite the nutritional and health benefits of breast milk, breast milk can serve as a vector for mother-to-child HIV transmission. Most HIV-infected infants acquire HIV through breastfeeding. Paradoxically, most infants breastfed by HIV-positive women do not become infected. This is potentially attributed to anti-HIV factors in breast milk. Breast milk of HIV-negative women can inhibit HIV infection. However, the HIV-inhibitory activity of breast milk from HIV-positive mothers has not been evaluated. In addition, while significant differences in breast milk composition between transmitting and nontransmitting HIV-positive mothers have been correlated with transmission risk, the HIV-inhibitory activity of their breast milk has not been compared. This knowledge may significantly impact the design of prevention approaches in resource-limited settings that do not deny infants of HIV-positive women the health benefits of breast milk. Here, we utilized bone marrow/liver/thymus humanized mice to evaluate the in vivo HIV-inhibitory activity of breast milk obtained from HIV-positive transmitting and nontransmitting mothers. We also assessed the species specificity and biochemical characteristics of milk's in vivo HIV-inhibitory activity and its ability to inhibit other modes of HIV infection. Our results demonstrate that breast milk of HIV-positive mothers has potent HIV-inhibitory activity and indicate that breast milk can prevent multiple routes of infection. Most importantly, this activity is unique to human milk. Our results also suggest multiple factors in breast milk may contribute to its HIV-inhibitory activity. Collectively, our results support current recommendations that HIV-positive mothers in resource-limited settings exclusively breastfeed in combination with antiretroviral therapy. IMPORTANCE Approximately 240,000 children become infected with HIV annually, the majority via breastfeeding. Despite daily exposure to virus in breast milk, most infants

  9. Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades

    PubMed Central

    Jiang, Cheng-shi; Liang, Lin-fu; Guo, Yue-wei

    2012-01-01

    This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented. PMID:22941286

  10. Memory retrieval of inhibitory avoidance requires histamine H1 receptor activation in the hippocampus.

    PubMed

    Fabbri, Roberta; Furini, Cristiane Regina Guerino; Passani, Maria Beatrice; Provensi, Gustavo; Baldi, Elisabetta; Bucherelli, Corrado; Izquierdo, Ivan; de Carvalho Myskiw, Jociane; Blandina, Patrizio

    2016-05-10

    Retrieval represents a dynamic process that may require neuromodulatory signaling. Here, we report that the integrity of the brain histaminergic system is necessary for retrieval of inhibitory avoidance (IA) memory, because rats depleted of histamine through lateral ventricle injections of α-fluoromethylhistidine (a-FMHis), a suicide inhibitor of histidine decarboxylase, displayed impaired IA memory when tested 2 d after training. a-FMHis was administered 24 h after training, when IA memory trace was already formed. Infusion of histamine in hippocampal CA1 of brain histamine-depleted rats (hence, amnesic) 10 min before the retention test restored IA memory but was ineffective when given in the basolateral amygdala (BLA) or the ventral medial prefrontal cortex (vmPFC). Intra-CA1 injections of selective H1 and H2 receptor agonists showed that histamine exerted its effect by activating the H1 receptor. Noteworthy, the H1 receptor antagonist pyrilamine disrupted IA memory retrieval in rats, thus strongly supporting an active involvement of endogenous histamine; 90 min after the retention test, c-Fos-positive neurons were significantly fewer in the CA1s of a-FMHis-treated rats that displayed amnesia compared with in the control group. We also found reduced levels of phosphorylated cAMP-responsive element binding protein (pCREB) in the CA1s of a-FMHis-treated animals compared with in controls. Increases in pCREB levels are associated with retrieval of associated memories. Targeting the histaminergic system may modify the retrieval of emotional memory; hence, histaminergic ligands might reduce dysfunctional aversive memories and improve the efficacy of exposure psychotherapies.

  11. Inhibitory effects of kiwifruit extract on human platelet aggregation and plasma angiotensin-converting enzyme activity.

    PubMed

    Dizdarevic, Lili L; Biswas, Dipankar; Uddin, M D Main; Jørgenesen, Aud; Falch, Eva; Bastani, Nasser E; Duttaroy, Asim K

    2014-01-01

    Previous human studies suggest that supplementation with kiwifruits lowers several cardiovascular risk factors such as platelet hyperactivity, blood pressure and plasma lipids. The cardiovascular health benefit of fruit and vegetables is usually attributed to the complex mixture of phytochemicals therein; however, kiwifruit's cardioprotective factors are not well studied. In this study, we investigated the effects of kiwifruit extract on human blood platelet aggregation and plasma angiotensin-converting enzyme (ACE) activity. A sugar-free, heat-stable aqueous extract with molecular mass less than 1000 Da was prepared from kiwifruits. Typically, 100 g kiwifruits produced 66.3 ± 5.8 mg (1.2 ± 0.1 mg CE) of sugar-free kiwifruit extract (KFE). KFE inhibited both human platelet aggregation and plasma ACE activity in a dose-dependent manner. KFE inhibited platelet aggregation in response to ADP, collagen and arachidonic acid, and inhibitory action was mediated in part by reducing TxA2 synthesis. The IC50 for ADP-induced platelet aggregation was 1.6 ± 0.2 mg/ml (29.0 ± 3.0 μg CE/ml), whereas IC50 for serum ACE was 0.6 ± 0.1 mg/ml (11.0 ± 1.2 μg CE/ml). Consuming 500 mg of KFE (9.0 mg CE) in 10 g margarine inhibited ex vivo platelet aggregation by 12.7%, 2 h after consumption by healthy volunteers (n = 9). All these data indicate that kiwifruit contains very potent antiplatelet and anti-ACE components. Consuming kiwifruits might be beneficial as both preventive and therapeutic regime in cardiovascular disease. PMID:24219176

  12. Inhibitory effects of kiwifruit extract on human platelet aggregation and plasma angiotensin-converting enzyme activity.

    PubMed

    Dizdarevic, Lili L; Biswas, Dipankar; Uddin, M D Main; Jørgenesen, Aud; Falch, Eva; Bastani, Nasser E; Duttaroy, Asim K

    2014-01-01

    Previous human studies suggest that supplementation with kiwifruits lowers several cardiovascular risk factors such as platelet hyperactivity, blood pressure and plasma lipids. The cardiovascular health benefit of fruit and vegetables is usually attributed to the complex mixture of phytochemicals therein; however, kiwifruit's cardioprotective factors are not well studied. In this study, we investigated the effects of kiwifruit extract on human blood platelet aggregation and plasma angiotensin-converting enzyme (ACE) activity. A sugar-free, heat-stable aqueous extract with molecular mass less than 1000 Da was prepared from kiwifruits. Typically, 100 g kiwifruits produced 66.3 ± 5.8 mg (1.2 ± 0.1 mg CE) of sugar-free kiwifruit extract (KFE). KFE inhibited both human platelet aggregation and plasma ACE activity in a dose-dependent manner. KFE inhibited platelet aggregation in response to ADP, collagen and arachidonic acid, and inhibitory action was mediated in part by reducing TxA2 synthesis. The IC50 for ADP-induced platelet aggregation was 1.6 ± 0.2 mg/ml (29.0 ± 3.0 μg CE/ml), whereas IC50 for serum ACE was 0.6 ± 0.1 mg/ml (11.0 ± 1.2 μg CE/ml). Consuming 500 mg of KFE (9.0 mg CE) in 10 g margarine inhibited ex vivo platelet aggregation by 12.7%, 2 h after consumption by healthy volunteers (n = 9). All these data indicate that kiwifruit contains very potent antiplatelet and anti-ACE components. Consuming kiwifruits might be beneficial as both preventive and therapeutic regime in cardiovascular disease.

  13. Inhibitory effect of CuSO₄ on α-glucosidase activity in ddY mice.

    PubMed

    Yoshikawa, Yutaka; Hirata, Ryoko; Yasui, Hiroyuki; Hattori, Masakazu; Sakurai, Hiromu

    2010-01-01

    We investigated the effects of divalent alkaline earth and first-row transition metal and zinc ions on α-glucosidase activity in vitro and in vivo. CuSO₄ and ZnSO₄ exhibited a high α-glucosidase inhibitory effect in vitro. The IC(50) values of CuSO₄ were 0.77 ± 0.01 (substrate; maltose) and 0.78 ± 0.01 (substrate; sucrose), and those of ZnSO₄ were 5.49 ± 0.14 (substrate; maltose) and 4.70 ± 0.06 (substrate; sucrose) for yeast α-glucosidase. On the basis of Lineweaver-Burk plots, both CuSO₄ and ZnSO₄ exhibited different modes of inhibition against α-glucosidase. Subsequently, oral glucose and sucrose tolerance tests (OGTT and OSTT) were performed on non-diabetic ddY mice to examine the effect of the metal ions on their blood glucose levels. As a result of single oral administration of CuSO₄ in non-diabetic ddY mice, a significant and potent lowering of the blood glycemic response toward disaccharide, sucrose, ingestion was observed at 45 min after doses of 0.08 and 0.24 mmol kg(-1) body weight. In contrast, the CuSO₄ administration showed no suppression of the elevation of blood glucose levels in mice after a monosaccharide, glucose, administration. These results indicate that CuSO₄ suppresses disaccharide digestion by inhibiting α-glucosidase activity in the epithelium of the small intestine, suggesting that antidiabetic Cu complexes with some ligands have a similar action mechanism to that of α-glucosidase inhibitor, acarbose, currently used for clinical purposes. PMID:21072376

  14. Fermentation with Aspergillus awamori enhanced contents of amino nitrogen and total phenolics as well as the low-density lipoprotein oxidation inhibitory activity of black soybeans.

    PubMed

    Chen, Yu-Fei; Lee, Shiow-Ling; Chou, Cheng-Chun

    2011-04-27

    A solid fermentation was performed on black soybeans with Aspergillus awamori. The effects of fermentation on the contents of total phenolics and amino nitrogen and on the inhibitory effect on low-density lipoprotein (LDL) oxidation of black soybeans were examined. Results revealed that fermentation significantly enhanced the LDL oxidation inhibitory activity and total phenolics and amino nitrogen contents of black soybeans. The increased content of amino nitrogen was closely related to the enhanced LDL oxidation inhibitory activity of fermented black soybeans and its water extract. Fermentation temperature and length affected the LDL oxidation inhibitory effect exerted by the prepared fermented black soybeans. The A. awamori-fermented black soybean prepared at 30 °C for 3 days exhibited the highest inhibitory effect on LDL oxidation. The bioactive principles related to the inhibitory effect on LDL oxidation in black soybeans, regardless of fermentation, could be most efficiently extracted with water rather than 80% methanol or 80% ethanol.

  15. Lymphocyte-derived ACh regulates local innate but not adaptive immunity

    PubMed Central

    Reardon, Colin; Duncan, Gordon S.; Brüstle, Anne; Brenner, Dirk; Tusche, Michael W.; Olofsson, Peder S.; Rosas-Ballina, Mauricio; Tracey, Kevin J.; Mak, Tak W.

    2013-01-01

    Appropriate control of immune responses is a critical determinant of health. Here, we show that choline acetyltransferase (ChAT) is expressed and ACh is produced by B cells and other immune cells that have an impact on innate immunity. ChAT expression occurs in mucosal-associated lymph tissue, subsequent to microbial colonization, and is reduced by antibiotic treatment. MyD88-dependent Toll-like receptor up-regulates ChAT in a transient manner. Unlike the previously described CD4+ T-cell population that is stimulated by norepinephrine to release ACh, ChAT+ B cells release ACh after stimulation with sulfated cholecystokinin but not norepinephrine. ACh-producing B-cells reduce peritoneal neutrophil recruitment during sterile endotoxemia independent of the vagus nerve, without affecting innate immune cell activation. Endothelial cells treated with ACh in vitro reduced endothelial cell adhesion molecule expression in a muscarinic receptor-dependent manner. Despite this ability, ChAT+ B cells were unable to suppress effector T-cell function in vivo. Therefore, ACh produced by lymphocytes has specific functions, with ChAT+ B cells controlling the local recruitment of neutrophils. PMID:23297238

  16. Muscle-specific kinase (MuSK) autoantibodies suppress the MuSK pathway and ACh receptor retention at the mouse neuromuscular junction

    PubMed Central

    Ghazanfari, Nazanin; Morsch, Marco; Reddel, Stephen W; Liang, Simon X; Phillips, William D

    2014-01-01

    Muscle-specific kinase