Determinants of aggressive behavior: Interactive effects of emotional regulation and inhibitory control.

PubMed

Hsieh, I-Ju; Chen, Yung Y

2017-01-01

Aggressive behavior can be defined as any behavior intended to hurt another person, and it is associated with many individual and social factors. This study examined the relationship between emotional regulation and inhibitory control in predicting aggressive behavior. Seventy-eight participants (40 males) completed self-report measures (Negative Mood Regulation Scale and Buss-Perry Aggression Questionnaire), a stop signal task, and engaged in a modified version of Taylor Aggression Paradigm (TAP) exercise, in which the outcome was used as a measure of direct physical aggression. We used a hierarchical, mixed-model multiple regression analysis test to examine the effects of emotion regulation and inhibitory control on physical reactive aggression. Results indicated an interaction between emotion regulation and inhibitory control on aggression. For participants with low inhibitory control only, there was a significant difference between high and low emotion regulation on aggression, such that low emotion regulation participants registered higher aggression than high emotion regulation participants. This difference was not found among participants with high inhibitory control. These results have implications for refining and targeting training and rehabilitation programs aimed at reducing aggressive behavior.

The influence of selected potential oncostatics of plant origin on the protein biosynthesis in vitro.

PubMed

Paszkiewicz-Gadek, A; Chlabicz, J; Gałasiński, W

1988-01-01

Five potential oncostatics of plant origin (reserpine, amphotericin B, rutoside, digoxin, dry aloe extract), and cyclic AMP were investigated for their effect on protein synthesis. The solutions of digoxin and dry aloe extract inhibited protein biosynthesis in vitro. The direct inhibiting effect of digoxin on the ribosomes suggests that this drug forms an inactive complex with this organelle. Therefore it can be concluded that ribosome is the target site of digoxin action. Aloin and aloeemodin are responsible for the inhibitory effect of the solution of dry aloe extract. They inhibit markedly [14C]-leucine incorporation into proteins. Aloin and aloeemodin do not influence directly the ribosomes, but they inhibit elongation factors and peptidyltransferase activities in the complete elongation system. Some preliminary experiments have shown that direct interaction between these substances and elongation factor EF-2 should be taken in account. This observation is the subject of further experiments, in which the characteristics of the inhibitory effect of the components isolated from dry aloe extract will be performed.

[The characteristics of the cholinoreceptors on the identified TAN neuron of the giant African snail Achatina fulica].

PubMed

Stepanov, I I; Losev, N A

1999-04-01

Acetylcholine, nicotine, a selective agonist of N-cholinoreceptors suberildicholine dibromide, as well as a selective agonist of M-cholinoreceptors 5-methylfurmethide inhibited spike discharges in a dose-dependent manner up to a complete ceasing of the firing in cholinoreceptors situated on the identified neurone TAN of African giant snail Achatina fulica. M-cholinoblocker metamizylum completely prevented the inhibitory effect of methylfurmethide. Central cholinoblocker aetherophen completely prevented the inhibitory effect of suberildicholine dibromide. Metamizylum or aetherophen used alone were only able to decrease the inhibitory effect of acetylcholine, whereas a mixture of these agents suppressed completely the acetylcholine-induced inhibition. The findings suggest that, on the TAN membrane, nicotinic and muscarinic cholinoreceptors co-exist and function in one and the same direction.

Inhibitory Effects of Thai Essential Oils on Potentially Aflatoxigenic Aspergillus parasiticus and Aspergillus flavus.

PubMed

Jantapan, Kittika; Poapolathep, Amnart; Imsilp, Kanjana; Poapolathep, Saranya; Tanhan, Phanwimol; Kumagai, Susumu; Jermnak, Usuma

2017-01-01

　The antiaflatoxigenic and antifungal activities of essential oils (EOs) of finger root (Boesenbergia rotunda (L.) Mansf.), pine (Pinus pinaster), rosewood (Aniba rosaedora), Siam benzoin (Styrax tonkinensis), Thai moringa (Moringa oleifera), and ylang ylang (Cananga odorata) were tested for Aspergillus parasiticus and Aspergillus flavus in potato dextrose broth. Aflatoxin B 1 (AFB 1 ) was extracted from culture using a QuEChERS-based extraction procedure and analyzed with high performance liquid chromatography (HPLC) coupled to a fluorescence detector. EO of pine showed the greatest inhibition of growth and AFB 1 production of A. parasiticus, followed by EOs of rosewood, finger root, Siam benzoin, and ylang ylang. EO of finger root gave the best inhibitory effects on A. flavus, followed by EOs of rosewood, pine, ylang ylang, and Siam benzoin. EO of Thai moringa did not show any significant inhibition of aflatoxigenic fungi. The antiaflatoxigenic activities of EOs correlated with their antifungal activities in the dosedependent manner. Comparison of the application of the five selected EOs in peanut pods by direct and vapor exposure indicated that the AFB 1 production inhibitory effects of the five EOs by direct exposure were faster and more effective than by vapor exposure. EO of finger root showed the best inhibition of AFB 1 production of A. flavus in peanut pods by direct exposure, followed by EOs of pine, rosewood, ylang ylang, and Siam benzoin.

Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies

PubMed Central

Duong, Minh Ngoc; Matera, Eva-Laure; Mathé, Doriane; Evesque, Anne; Valsesia-Wittmann, Sandrine; Clémenceau, Béatrice; Dumontet, Charles

2015-01-01

Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated. PMID:25523586

Training Attentional Control Improves Cognitive and Motor Task Performance.

PubMed

Ducrocq, Emmanuel; Wilson, Mark; Vine, Sam; Derakshan, Nazanin

2016-10-01

Attentional control is a necessary function for the regulation of goal-directed behavior. In three experiments we investigated whether training inhibitory control using a visual search task could improve task-specific measures of attentional control and performance. In Experiment 1 results revealed that training elicited a near-transfer effect, improving performance on a cognitive (antisaccade) task assessing inhibitory control. In Experiment 2 an initial far-transfer effect of training was observed on an index of attentional control validated for tennis. The principal aim of Experiment 3 was to expand on these findings by assessing objective gaze measures of inhibitory control during the performance of a tennis task. Training improved inhibitory control and performance when pressure was elevated, confirming the mechanisms by which cognitive anxiety impacts performance. These results suggest that attentional control training can improve inhibition and reduce taskspecific distractibility with promise of transfer to more efficient sporting performance in competitive contexts.

Transcranial Direct Current Stimulation in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD): A Pilot Study.

PubMed

Bandeira, Igor Dórea; Guimarães, Rachel Silvany Quadros; Jagersbacher, João Gabriel; Barretto, Thiago Lima; de Jesus-Silva, Jéssica Regina; Santos, Samantha Nunes; Argollo, Nayara; Lucena, Rita

2016-06-01

Studies investigating the possible benefits of transcranial direct current stimulation on left dorsolateral prefrontal cortex in children and adolescents with attention-deficit hyperactivity disorder (ADHD) have not been performed. This study assesses the effect of transcranial direct current stimulation in children and adolescents with ADHD on neuropsychological tests of visual attention, visual and verbal working memory, and inhibitory control. An auto-matched clinical trial was performed involving transcranial direct current stimulation in children and adolescents with ADHD, using SNAP-IV and subtests Vocabulary and Cubes of the Wechsler Intelligence Scale for Children III (WISC-III). Subjects were assessed before and after transcranial direct current stimulation sessions with the Digit Span subtest of the WISC-III, inhibitory control subtest of the NEPSY-II, Corsi cubes, and the Visual Attention Test (TAVIS-3). There were 9 individuals with ADHD according to Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria. There was statistically significant difference in some aspects of TAVIS-3 tests and the inhibitory control subtest of NEPSY-II. Transcranial direct current stimulation can be related to a more efficient processing speed, improved detection of stimuli, and improved ability to switch between an ongoing activity and a new one. © The Author(s) 2016.

Associative plasticity in intracortical inhibitory circuits in human motor cortex.

PubMed

Russmann, Heike; Lamy, Jean-Charles; Shamim, Ejaz A; Meunier, Sabine; Hallett, Mark

2009-06-01

Paired associative stimulation (PAS) is a transcranial magnetic stimulation technique inducing Hebbian-like synaptic plasticity in the human motor cortex (M1). PAS is produced by repetitive pairing of a peripheral nerve shock and a transcranial magnetic stimulus (TMS). Its effect is assessed by a change in size of a motor evoked response (MEP). MEP size results from excitatory and inhibitory influences exerted on cortical pyramidal cells, but no robust effects on inhibitory networks have been demonstrated so far. In 38 healthy volunteers, we assessed whether a PAS intervention influences three intracortical inhibitory circuits: short (SICI) and long (LICI) intracortical inhibitions reflecting activity of GABA(A) and GABA(B) interneurons, respectively, and long afferent inhibition (LAI) reflecting activity of somatosensory inputs. After PAS, MEP sizes, LICI and LAI levels were significantly changed while changes of SICI were inconsistent. The changes in LICI and LAI lasted 45 min after PAS. Their direction depended on the delay between the arrival time of the afferent volley at the cortex and the TMS-induced cortical activation during the PAS. PAS influences inhibitory circuits in M1. PAS paradigms can demonstrate Hebbian-like plasticity at selected inhibitory networks as well as excitatory networks.

Neural networks with excitatory and inhibitory components: Direct and inverse problems by a mean-field approach

NASA Astrophysics Data System (ADS)

di Volo, Matteo; Burioni, Raffaella; Casartelli, Mario; Livi, Roberto; Vezzani, Alessandro

2016-01-01

We study the dynamics of networks with inhibitory and excitatory leak-integrate-and-fire neurons with short-term synaptic plasticity in the presence of depressive and facilitating mechanisms. The dynamics is analyzed by a heterogeneous mean-field approximation, which allows us to keep track of the effects of structural disorder in the network. We describe the complex behavior of different classes of excitatory and inhibitory components, which give rise to a rich dynamical phase diagram as a function of the fraction of inhibitory neurons. Using the same mean-field approach, we study and solve a global inverse problem: reconstructing the degree probability distributions of the inhibitory and excitatory components and the fraction of inhibitory neurons from the knowledge of the average synaptic activity field. This approach unveils new perspectives on the numerical study of neural network dynamics and the possibility of using these models as a test bed for the analysis of experimental data.

High-disinhibition restrained eaters are disinhibited by self-regulatory depletion in the food-related inhibitory control.

PubMed

Zhou, Yizhou; Gao, Xiao; Chen, Hong; Kong, Fanchang

2017-08-01

Restrained eating for weight control and loss is becoming highly prevalent in many affluent societies, while most of the restrained eaters are rather unsuccessful in the long term. According to the strength model of self-control, the disinhibition effect of restrained eaters may occur after the depletion of self-control resources. However, no work has examined the direct impact of self-control resources on inhibitory control ability of restrained eaters. This study investigated the influences of self-control resources on the food-related inhibitory control among high-restraint/low-disinhibition restrained eaters, high-restraint/high-disinhibition restrained eaters and unrestrained eaters using stop signal task. Results reveal that there's no difference of food-related inhibitory control between three groups when the self-control resources are non-depleted, while high-restraint/high-disinhibition restrained eaters showing a decrease of food-related inhibitory control after ego-depletion. This disinhibition effect only seems to occur in samples of restrained eaters with a high tendency toward overeating. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of environmental statistics on inhibition of saccadic return

PubMed Central

Farrell, Simon; Ludwig, Casimir J. H.; Ellis, Lucy A.; Gilchrist, Iain D.

2009-01-01

Initiating an eye movement is slowed if the saccade is directed to a location that has been fixated in the recent past. We show that this inhibitory effect is modulated by the temporal statistics of the environment: If a return location is likely to become behaviorally relevant, inhibition of return is absent. By fitting an accumulator model of saccadic decision-making, we show that the inhibitory effect and the sensitivity to local statistics can be dissociated in their effects on the rate of accumulation of evidence, and the threshold controlling the amount of evidence needed to generate a saccade. PMID:20080778

Modulating inhibitory control with direct current stimulation of the superior medial frontal cortex.

PubMed

Hsu, Tzu-Yu; Tseng, Lin-Yuan; Yu, Jia-Xin; Kuo, Wen-Jui; Hung, Daisy L; Tzeng, Ovid J L; Walsh, Vincent; Muggleton, Neil G; Juan, Chi-Hung

2011-06-15

The executive control of voluntary action involves not only choosing from a range of possible actions but also the inhibition of responses as circumstances demand. Recent studies have demonstrated that many clinical populations, such as people with attention-deficit hyperactivity disorder, exhibit difficulties in inhibitory control. One prefrontal area that has been particularly associated with inhibitory control is the pre-supplementary motor area (Pre-SMA). Here we applied non-invasive transcranial direct current stimulation (tDCS) over Pre-SMA to test its role in this behavior. tDCS allows for current to be applied in two directions to selectively excite or suppress the neural activity of Pre-SMA. Our results showed that anodal tDCS improved efficiency of inhibitory control. Conversely, cathodal tDCS showed a tendency towards impaired inhibitory control. To our knowledge, this is the first demonstration of non-invasive intervention tDCS altering subjects' inhibitory control. These results further our understanding of the neural bases of inhibitory control and suggest a possible therapeutic intervention method for clinical populations. Copyright © 2011 Elsevier Inc. All rights reserved.

Neuroanatomical and Cognitive Mediators of Age-Related Differences in Episodic Memory

PubMed Central

Head, Denise; Rodrigue, Karen M.; Kennedy, Kristen M.; Raz, Naftali

2009-01-01

Aging is associated with declines in episodic memory. In this study, the authors used a path analysis framework to explore the mediating role of differences in brain structure, executive functions, and processing speed in age-related differences in episodic memory. Measures of regional brain volume (prefrontal gray and white matter, caudate, hippocampus, visual cortex), executive functions (working memory, inhibitory control, task switching, temporal processing), processing speed, and episodic memory were obtained in a sample of young and older adults. As expected, age was linked to reduction in regional brain volumes and cognitive performance. Moreover, neural and cognitive factors completely mediated age differences in episodic memory. Whereas hippocampal shrinkage directly affected episodic memory, prefrontal volumetric reductions influenced episodic memory via limitations in working memory and inhibitory control. Age-related slowing predicted reduced efficiency in temporal processing, working memory, and inhibitory control. Lastly, poorer temporal processing directly affected episodic memory. No direct effects of age on episodic memory remained once these factors were taken into account. These analyses highlight the value of a multivariate approach with the understanding of complex relationships in cognitive and brain aging. PMID:18590361

Desynchronizing electrical and sensory coordinated reset neuromodulation

PubMed Central

Popovych, Oleksandr V.; Tass, Peter A.

2012-01-01

Coordinated reset (CR) stimulation is a desynchronizing stimulation technique based on timely coordinated phase resets of sub-populations of a synchronized neuronal ensemble. It has initially been computationally developed for electrical deep brain stimulation (DBS), to enable an effective desynchronization and unlearning of pathological synchrony and connectivity (anti-kindling). Here we computationally show for ensembles of spiking and bursting model neurons interacting via excitatory and inhibitory adaptive synapses that a phase reset of neuronal populations as well as a desynchronization and an anti-kindling can robustly be achieved by direct electrical stimulation or indirect (synaptically-mediated) excitatory and inhibitory stimulation. Our findings are relevant for DBS as well as for sensory stimulation in neurological disorders characterized by pathological neuronal synchrony. Based on the obtained results, we may expect that the local effects in the vicinity of a depth electrode (realized by direct stimulation of the neurons' somata or stimulation of axon terminals) and the non-local CR effects (realized by stimulation of excitatory or inhibitory efferent fibers) of deep brain CR neuromodulation may be similar or even identical. Furthermore, our results indicate that an effective desynchronization and anti-kindling can even be achieved by non-invasive, sensory CR neuromodulation. We discuss the concept of sensory CR neuromodulation in the context of neurological disorders. PMID:22454622

Desynchronizing electrical and sensory coordinated reset neuromodulation.

PubMed

Popovych, Oleksandr V; Tass, Peter A

2012-01-01

Coordinated reset (CR) stimulation is a desynchronizing stimulation technique based on timely coordinated phase resets of sub-populations of a synchronized neuronal ensemble. It has initially been computationally developed for electrical deep brain stimulation (DBS), to enable an effective desynchronization and unlearning of pathological synchrony and connectivity (anti-kindling). Here we computationally show for ensembles of spiking and bursting model neurons interacting via excitatory and inhibitory adaptive synapses that a phase reset of neuronal populations as well as a desynchronization and an anti-kindling can robustly be achieved by direct electrical stimulation or indirect (synaptically-mediated) excitatory and inhibitory stimulation. Our findings are relevant for DBS as well as for sensory stimulation in neurological disorders characterized by pathological neuronal synchrony. Based on the obtained results, we may expect that the local effects in the vicinity of a depth electrode (realized by direct stimulation of the neurons' somata or stimulation of axon terminals) and the non-local CR effects (realized by stimulation of excitatory or inhibitory efferent fibers) of deep brain CR neuromodulation may be similar or even identical. Furthermore, our results indicate that an effective desynchronization and anti-kindling can even be achieved by non-invasive, sensory CR neuromodulation. We discuss the concept of sensory CR neuromodulation in the context of neurological disorders.

Parathyroid hormone is not an inhibitor of lipoprotein lipase activity.

PubMed

Arnadottir, M; Nilsson-Ehle, P

1994-01-01

The reduced lipoprotein lipase (LPL) activities in uraemia are reflected by increased serum triglyceride concentrations and reduced HDL cholesterol concentrations. Both hyperparathyroidism and circulating inhibitor(s) of LPL have been associated with the disturbances of lipid metabolism in uraemia. The aim of the present study was to investigate if parathyroid hormone (PTH) had an inhibitory effect on LPL activity. Plasma post-heparin LPL activities, plasma LPL inhibitory activities, serum PTHintact and serum PTHC-terminal concentrations were analysed in 20 patients on haemodialysis and 20 healthy controls. The effects of purified, human PTHintact and a carboxyterminal fragment of PTH (PTH39-84) on LPL activities in post-heparin plasma from healthy individuals and on the enzyme activity of purified, bovine milk LPL, activated with apolipoprotein CII, were studied. Patients had significantly higher plasma LPL inhibitory activities than controls, but there was no correlation between plasma LPL inhibitory activities and serum PTH concentrations. Neither PTHintact nor PTH39-84 had a significant effect on LPL activities in vitro. Thus there was no evidence of a direct inhibition of LPL activity by PTH under the present in-vivo or in-vitro conditions.

The effects of elevated pain inhibition on endurance exercise performance.

PubMed

Flood, Andrew; Waddington, Gordon; Keegan, Richard J; Thompson, Kevin G; Cathcart, Stuart

2017-01-01

The ergogenic effects of analgesic substances suggest that pain perception is an important regulator of work-rate during fatiguing exercise. Recent research has shown that endogenous inhibitory responses, which act to attenuate nociceptive input and reduce perceived pain, can be increased following transcranial direct current stimulation of the hand motor cortex. Using high-definition transcranial direct current stimulation (HD-tDCS; 2 mA, 20 min), the current study aimed to examine the effects of elevated pain inhibitory capacity on endurance exercise performance. It was hypothesised that HD-tDCS would enhance the efficiency of the endogenous pain inhibitory response and improve endurance exercise performance. Twelve healthy males between 18 and 40 years of age ( M  = 24.42 ± 3.85) were recruited for participation. Endogenous pain inhibitory capacity and exercise performance were assessed before and after both active and sham (placebo) stimulation. The conditioned pain modulation protocol was used for the measurement of pain inhibition. Exercise performance assessment consisted of both maximal voluntary contraction (MVC) and submaximal muscular endurance performance trials using isometric contractions of the non-dominant leg extensors. Active HD-tDCS (pre-tDCS, -.32 ± 1.33 kg; post-tDCS, -1.23 ± 1.21 kg) significantly increased pain inhibitory responses relative to the effects of sham HD-tDCS (pre-tDCS, -.91 ± .92 kg; post-tDCS, -.26 ± .92 kg; p  = .046). Irrespective of condition, peak MVC force and muscular endurance was reduced from pre- to post-stimulation. HD-tDCS did not significantly influence this reduction in maximal force (active: pre-tDCS, 264.89 ± 66.87 Nm; post-tDCS, 236.33 ± 66.51 Nm; sham: pre-tDCS, 249.25 ± 88.56 Nm; post-tDCS, 239.63 ± 67.53 Nm) or muscular endurance (active: pre-tDCS, 104.65 ± 42.36 s; post-tDCS, 93.07 ± 33.73 s; sham: pre-tDCS, 123.42 ± 72.48 s; post-tDCS, 100.27 ± 44.25 s). Despite increasing pain inhibitory capacity relative to sham stimulation, active HD-tDCS did not significantly elevate maximal force production or muscular endurance. These findings question the role of endogenous pain inhibitory networks in the regulation of exercise performance.

Virucidal activity of Colombian Lippia essential oils on dengue virus replication in vitro.

PubMed

Ocazionez, Raquel Elvira; Meneses, Rocio; Torres, Flor Angela; Stashenko, Elena

2010-05-01

The inhibitory effect of Lippia alba and Lippia citriodora essential oils on dengue virus serotypes replication in vitro was investigated. The cytotoxicity (CC50) was evaluated by the MTT assay and the mode of viral inhibitory effect was investigated with a plaque reduction assay. The virus was treated with the essential oil for 2 h at 37 masculineC before cell adsorption and experiments were conducted to evaluate inhibition of untreated-virus replication in the presence of oil. Antiviral activity was defined as the concentration of essential oil that caused 50% reduction of the virus plaque number (IC50). L. alba oil resulted in less cytotoxicity than L. citriodora oil (CC50: 139.5 vs. 57.6 microg/mL). Virus plaque reduction for all four dengue serotypes was observed by treatment of the virus before adsorption on cell. The IC50 values for L. alba oil were between 0.4-32.6 microg/mL and between 1.9-33.7 microg/mL for L. citriodora oil. No viral inhibitory effect was observed by addition of the essential oil after virus adsorption. The inhibitory effect of the essential oil seems to cause direct virus inactivation before adsorption on host cell.

Inhibitory effect of sodium hypochlorite and chlorhexidine digluconate in clinical isolates of Sporothrix schenckii.

PubMed

Madrid, Isabel Martins; Mattei, Antonella Souza; Santin, Rosema; dos Reis Gomes, Angelita; Cleff, Marlete Brum; Meireles, Mário Carlos Araújo

2012-05-01

The susceptibility of Sporothrix schenckii isolates from clinical cases of canine, feline and human sporotrichosis, and from the environment, was evaluated with 4% sodium hypochlorite and 6.6% chlorhexidine digluconate using the broth microdilution, agar diffusion and direct exposure techniques. The minimal inhibitory concentration was smaller than 0.8% for chlorhexidine digluconate and between 8% and 4% for sodium hypochlorite. Inhibition zones were not found in agar diffusion for sodium hypochlorite, and zones averaging 1.9 mm were found for chlorhexidine digluconate. In the direct exposure test, sodium hypochlorite demonstrated best performance at 20 min of contact, as chlorhexidine digluconate presented little antimicrobial activity. © 2011 Blackwell Verlag GmbH.

Time Course of Brain Network Reconfiguration Supporting Inhibitory Control.

PubMed

Popov, Tzvetan; Westner, Britta U; Silton, Rebecca L; Sass, Sarah M; Spielberg, Jeffrey M; Rockstroh, Brigitte; Heller, Wendy; Miller, Gregory A

2018-05-02

Hemodynamic research has recently clarified key nodes and links in brain networks implementing inhibitory control. Although fMRI methods are optimized for identifying the structure of brain networks, the relatively slow temporal course of fMRI limits the ability to characterize network operation. The latter is crucial for developing a mechanistic understanding of how brain networks shift dynamically to support inhibitory control. To address this critical gap, we applied spectrally resolved Granger causality (GC) and random forest machine learning tools to human EEG data in two large samples of adults (test sample n = 96, replication sample n = 237, total N = 333, both sexes) who performed a color-word Stroop task. Time-frequency analysis confirmed that recruitment of inhibitory control accompanied by slower behavioral responses was related to changes in theta and alpha/beta power. GC analyses revealed directionally asymmetric exchanges within frontal and between frontal and parietal brain areas: top-down influence of superior frontal gyrus (SFG) over both dorsal ACC (dACC) and inferior frontal gyrus (IFG), dACC control over middle frontal gyrus (MFG), and frontal-parietal exchanges (IFG, precuneus, MFG). Predictive analytics confirmed a combination of behavioral and brain-derived variables as the best set of predictors of inhibitory control demands, with SFG theta bearing higher classification importance than dACC theta and posterior beta tracking the onset of behavioral response. The present results provide mechanistic insight into the biological implementation of a psychological phenomenon: inhibitory control is implemented by dynamic routing processes during which the target response is upregulated via theta-mediated effective connectivity within key PFC nodes and via beta-mediated motor preparation. SIGNIFICANCE STATEMENT Hemodynamic neuroimaging research has recently clarified regional structures in brain networks supporting inhibitory control. However, due to inherent methodological constraints, much of this research has been unable to characterize the temporal dynamics of such networks (e.g., direction of information flow between nodes). Guided by fMRI research identifying the structure of brain networks supporting inhibitory control, results of EEG source analysis in a test sample ( n = 96) and replication sample ( n = 237) using effective connectivity and predictive analytics strategies advance a model of inhibitory control by characterizing the precise temporal dynamics by which this network operates and exemplify an approach by which mechanistic models can be developed for other key psychological processes. Copyright © 2018 the authors 0270-6474/18/384348-09$15.00/0.

Stability and instability of a neuron network with excitatory and inhibitory small-world connections.

PubMed

Yu, Dongyuan; Xu, Xu; Zhou, Jing; Li, Eric

2017-05-01

This study considers a delayed neural network with excitatory and inhibitory shortcuts. The global stability of the trivial equilibrium is investigated based on Lyapunov's direct method and the delay-dependent criteria are obtained. It is shown that both the excitatory and inhibitory shortcuts decrease the stability interval, but a time delay can be employed as a global stabilizer. In addition, we analyze the bounds of the eigenvalues of the adjacent matrix using matrix perturbation theory and then obtain the generalized sufficient conditions for local stability. The possibility of small inhibitory shortcuts is helpful for maintaining stability. The mechanisms of instability, bifurcation modes, and chaos are also investigated. Compared with methods based on mean-field theory, the proposed method can guarantee the stability of the system in most cases with random events. The proposed method is effective for cases where excitatory and inhibitory shortcuts exist simultaneously in the network. Copyright © 2017 Elsevier Ltd. All rights reserved.

A cross-cultural investigation of inhibitory control, generative fluency, and anxiety symptoms in Romanian and Russian preschoolers.

PubMed

Cheie, Lavinia; Veraksa, Aleksander; Zinchenko, Yuri; Gorovaya, Alexandra; Visu-Petra, Laura

2015-01-01

The current study focused on the early development of inhibitory control in 5- to 7-year-old children attending kindergarten in two Eastern-European countries, Romania and Russia. These two countries share many aspects of child-rearing and educational practices, previously documented to influence the development of inhibitory control. Using the Lurian-based developmental approach offered by the Developmental Neuropsychological Assessment battery, the study aimed to contribute to cross-cultural developmental neuropsychology by exploring (a) early interrelationships between subcomponents of inhibitory control (response suppression and attention control) and generative fluency (verbal and figural) in these two cultures, as well as (b) the predictive value of external factors (culture and maternal education) and individual differences (age, gender, nonverbal intelligence, trait anxiety) on inhibitory control and fluency outcomes in children from both countries. First, findings in both culture samples suggest that even at this young age, the construct of inhibitory control cannot be considered a unitary entity. Second, differences in maternal education were not predictive of either inhibitory control or fluency scores. However, children's attention control performance varied as a function of culture, and the direction of these cultural effects differed by whether the target outcome involved performance accuracy versus efficiency as an output. Findings also confirmed the previously documented intensive developmental improvement in preschoolers' inhibitory control during this period, influencing measures of response suppression and particularly attention control. Finally, the results further stress the importance of individual differences effects in trait anxiety on attention control efficiency across cultures.

[Photodegradation of naproxen in aqueous systems by UV irradiation: mechanism and toxicity of photolysis products].

PubMed

Ma, Du-juan; Liu, Guo-guang; Lü, Wen-ying; Yao, Kun; Zhou, Li-hua; Xie, Cheng-ping

2013-05-01

This paper studies the degradation mechanism, the reaction kinetics and the toxicity of photolysis products of naproxen in waters under UV irradiation (120 W mercury lamp) by quenching experiments of reactive oxygen species (ROS), oxygen concentration experiment and toxicity evaluation using Vibrio fischeri bacteria. The results demonstrated that NPX could be degraded effectively by UV irradiation and the photolysis pathways was the sum of the degradation by direct photolysis and self-sensitization via ROS, and the contribution rates of self-sensitized photodegradation were 0.1%, 80.2%, 35.7% via *OH, (1)O2, O2*-, respectively. The effect of oxygen concentration illustrated that dissolved oxygen had an inhibitory effect on the direct photodegradation of NPX, and the higher the oxygen content, the more obvious the inhibitory effect. The toxicity evaluation illustrated the formation of some intermediate products that were more toxic than NPX during the photodegradation of NPX. The process of NPX degradation in all cases could be fitted by the pseudo first-order kinetics model.

Brain State Effects on Layer 4 of the Awake Visual Cortex

PubMed Central

Zhuang, Jun; Bereshpolova, Yulia; Stoelzel, Carl R.; Huff, Joseph M.; Hei, Xiaojuan; Alonso, Jose-Manuel

2014-01-01

Awake mammals can switch between alert and nonalert brain states hundreds of times per day. Here, we study the effects of alertness on two cell classes in layer 4 of primary visual cortex of awake rabbits: presumptive excitatory “simple” cells and presumptive fast-spike inhibitory neurons (suspected inhibitory interneurons). We show that in both cell classes, alertness increases the strength and greatly enhances the reliability of visual responses. In simple cells, alertness also increases the temporal frequency bandwidth, but preserves contrast sensitivity, orientation tuning, and selectivity for direction and spatial frequency. Finally, alertness selectively suppresses the simple cell responses to high-contrast stimuli and stimuli moving orthogonal to the preferred direction, effectively enhancing mid-contrast borders. Using a population coding model, we show that these effects of alertness in simple cells—enhanced reliability, higher gain, and increased suppression in orthogonal orientation—could play a major role at increasing the speed of cortical feature detection. PMID:24623767

The Homeostatic Interaction Between Anodal Transcranial Direct Current Stimulation and Motor Learning in Humans is Related to GABAA Activity.

PubMed

Amadi, Ugwechi; Allman, Claire; Johansen-Berg, Heidi; Stagg, Charlotte J

2015-01-01

The relative timing of plasticity-induction protocols is known to be crucial. For example, anodal transcranial direct current stimulation (tDCS), which increases cortical excitability and typically enhances plasticity, can impair performance if it is applied before a motor learning task. Such timing-dependent effects have been ascribed to homeostatic plasticity, but the specific synaptic site of this interaction remains unknown. We wished to investigate the synaptic substrate, and in particular the role of inhibitory signaling, underpinning the behavioral effects of anodal tDCS in homeostatic interactions between anodal tDCS and motor learning. We used transcranial magnetic stimulation (TMS) to investigate cortical excitability and inhibitory signaling following tDCS and motor learning. Each subject participated in four experimental sessions and data were analyzed using repeated measures ANOVAs and post-hoc t-tests as appropriate. As predicted, we found that anodal tDCS prior to the motor task decreased learning rates. This worsening of learning after tDCS was accompanied by a correlated increase in GABAA activity, as measured by TMS-assessed short interval intra-cortical inhibition (SICI). This provides the first direct demonstration in humans that inhibitory synapses are the likely site for the interaction between anodal tDCS and motor learning, and further, that homeostatic plasticity at GABAA synapses has behavioral relevance in humans. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

THE ANTIBACTERIAL PROPERTIES OF SULFUR

PubMed Central

Weld, Julia T.; Gunther, Anne

1947-01-01

1. Saturated solutions of sulfur in alcohol (alcohol-sulfur) when diluted with broth are inhibitory to the growth of various Gram-positive bacteria and to C. hominis. By an arbitrary method of unitage with S. aureus as the test organism, our alcohol-sulfur contains 1,600 to 2,000 units per cc. and one unit contains between 0.24 and 0.34 gamma sulfur. The activity of a preparation is in general directly proportional to its sulfur content. 2. Solutions of sulfur in carbowax (carbowax-sulfur) when diluted with broth are likewise inhibitory to the growth of various Gram-positive bacteria and to C. hominis. When S. aureus is used as test organism, 1 unit contains between 0.1 and 0.2 gamma sulfur. The activity of these preparations is also in general directly proportional to their sulfur content. 3. Carbowax-sulfur when incorporated in agar in 1–500 to 1–2,000 dilution inhibits the growth of various Gram-positive aerobic and anaerobic bacteria, C. hominis, and certain dermatophytes. 4. Our experiments appear to show that both alcohol-sulfur and carbowax-sulfur owe their inhibitory properties to the sulfur particles that are dispersed throughout the medium when these sulfur preparations are diluted with broth. The inhibitory effect of these particles may or may not be due to a combination of the sulfur particles with substances in the medium in which they are suspended. 5. Evidence suggests that the activity of both alcohol-sulfur and carbowax-sulfur is due to sulfur in the same form. The inhibitory effect is characterized by prolonged bacteriostasis with similar activity over a wide range of dilutions. There is no evidence of true bactericidal action even with the highest concentrations used. PMID:19871634

Eye Gaze and Aging: Selective and Combined Effects of Working Memory and Inhibitory Control.

PubMed

Crawford, Trevor J; Smith, Eleanor S; Berry, Donna M

2017-01-01

Eye-tracking is increasingly studied as a cognitive and biological marker for the early signs of neuropsychological and psychiatric disorders. However, in order to make further progress, a more comprehensive understanding of the age-related effects on eye-tracking is essential. The antisaccade task requires participants to make saccadic eye movements away from a prepotent stimulus. Speculation on the cause of the observed age-related differences in the antisaccade task largely centers around two sources of cognitive dysfunction: inhibitory control (IC) and working memory (WM). The IC account views cognitive slowing and task errors as a direct result of the decline of inhibitory cognitive mechanisms. An alternative theory considers that a deterioration of WM is the cause of these age-related effects on behavior. The current study assessed IC and WM processes underpinning saccadic eye movements in young and older participants. This was achieved with three experimental conditions that systematically varied the extent to which WM and IC were taxed in the antisaccade task: a memory-guided task was used to explore the effect of increasing the WM load; a Go/No-Go task was used to explore the effect of increasing the inhibitory load; a 'standard' antisaccade task retained the standard WM and inhibitory loads. Saccadic eye movements were also examined in a control condition: the standard prosaccade task where the load of WM and IC were minimal or absent. Saccade latencies, error rates and the spatial accuracy of saccades of older participants were compared to the same measures in healthy young controls across the conditions. The results revealed that aging is associated with changes in both IC and WM. Increasing the inhibitory load was associated with increased reaction times in the older group, while the increased WM load and the inhibitory load contributed to an increase in the antisaccade errors. These results reveal that aging is associated with changes in both IC and WM.

Pleiotropic effects of bisphosphonates on osteosarcoma.

PubMed

Ohba, Tetsuro; Cates, Justin M M; Cole, Heather A; Slosky, David A; Haro, Hirotaka; Ichikawa, Jiro; Ando, Takashi; Schwartz, Herbert S; Schoenecker, Jonathan G

2014-06-01

Osteosarcoma is the most common primary malignant tumor of bone and accounts for half of all primary skeletal malignancies in children and teenagers. The prognosis for patients who fail or progress on first-line chemotherapy protocols is poor, therefore, additional adjuvant therapeutic strategies are needed. A recent feasibility study has demonstrated that the nitrogen-containing bisphosphonate zoledronic acid (ZOL) can be combined safely with conventional chemotherapy. However, the pharmacodynamics of bisphosphonate therapy is not well characterized. Osteosarcoma is a highly angiogenic tumor. Recent reports of the anti-angiogenic effects of bisphosphonates prompted us to determine whether nitrogen-containing bisphosphonate (ZOL and alendronate) treatment attenuates osteosarcoma growth by inhibition of osteoclast activity, tumor-mediated angiogenesis, or direct inhibitory effects on osteosarcoma. Here, we demonstrate that bisphosphonates directly inhibit VEGFR2 expression in endothelial cells, as well as endothelial cell proliferation and migration. Additionally, bisphosphonates also decrease VEGF-A expression in osteosarcoma (K7M3) cells, resulting in reduced stimulation of endothelial cell migration in co-culture assays. ZOL also decreases VEGFR1 expression in aggressive osteosarcoma cell lines (K7M3, 143B) and induces apoptosis of these cells, but has negligible effects on less aggressive osteosarcoma cell lines (K12 and TE85). In vivo ZOL treatment results in significant reduction in osteosarcoma-initiated angiogenesis and tumor growth in a murine model of osteosarcoma. In conclusion, bisphosphonates have diverse growth inhibitory effects on osteosarcoma through: (1) activation of apoptosis and inhibition of cell proliferation, (2) inhibition of VEGF-A and VEGFR1 expression by tumor cells, (3) inhibition of tumor-induced angiogenesis, and (4) direct inhibitory actions on endothelial cells. Published by Elsevier Inc.

The inhibitory effect of the various seed coating substances against rice seed borne fungi and their shelf-life during storage.

PubMed

Thobunluepop, Pitipong

2009-08-15

Presently, chemical seed treatments are in discussion due to their directly or indirectly impacts on human health or other living organisms. They may also negatively affect the ecosystem and the food chain. In rice seeds, chemicals may cause phytotoxic effects including seed degradation. Eugenol is the main component of clove (Eugenia caryophillis) oil, which was proved to act simultaneously as bactericide, virocide and especially fungicide. The in vitro study was aimed to compare the inhibitory effect of the following seed treatment substances against seed borne fungi and their shelf-life during 12 months of storage; conventional captan (CA), chitosan-lignosulphonate polymer (CL), eugenol incorporated into chitosan-lignosulphonate polymer (E+CL) and control (CO). The obtained results of fungi inhibition were classified in three groups, which showed at first that CA treatment led to a better, i.e., longer, inhibitory effect on Alternaria padwickii, Rhizoctonia solani, Curvularia sp., Aspergillus flavus and Aspergillus niger than E+CL. Secondly, E+CL coating polymer showed the longest inhibitory effect against Bipolaris oryzae and Nigrospora oryzae compared to CA and CL coating polymer. Finally, both CA and E+CL coating polymer had non-significant difference inhibitory effect on Fusarium moniliforme. The variant of CL coating polymer for seed coating was only during the first 6 months of storage able to inhibit all species of the observed seed borne fungi, whereas CA and E+CL coating polymer were capable to inhibit most of the fungi until 9 months of storage.

1,8-cineole inhibits both proliferation and elongation of BY-2 cultured tobacco cells.

PubMed

Yoshimura, Hiroko; Sawai, Yu; Tamotsu, Satoshi; Sakai, Atsushi

2011-03-01

Volatile monoterpenes such as 1,8-cineole inhibit the growth of Brassica campestris seedlings in a dose-dependent manner, and the growth-inhibitory effects are more severe for roots than hypocotyls. The preferential inhibition of root growth may be explained if the compounds inhibit cell proliferation more severely than cell elongation because root growth requires both elongation and proliferation of the constituent cells, whereas hypocotyl growth depends exclusively on elongation of existing cells. In order to examine this possibility, BY-2 suspension-cultured tobacco (Nicotiana tabacum) cells were treated with 1,8-cineole, and the inhibitory effects on cell proliferation and on cell elongation were assessed quantitatively. Treatment with 1,8-cineole lowered both the mitotic index and elongation of the cells in a dose-dependent manner, and the half-maximal inhibitory concentration (IC₅₀) for cell elongation was lower than that for cell proliferation. Moreover, 1,8-cineole also inhibited starch synthesis, with IC₅₀ lower than that for cell proliferation. Thus, the inhibitory effects of 1,8-cineole were not specific to cell proliferation; rather, 1,8-cineole seemed inhibitory to a variety of physiological activities when it was in direct contact with target cells. Based on these results, possible mechanisms for the mode of action of 1,8-cineole and for its preferential inhibition on root growth are discussed.

Frontal transcranial direct current stimulation (tDCS) abolishes list-method directed forgetting.

PubMed

Silas, Jonathan; Brandt, Karen R

2016-03-11

It is a point of controversy as to whether directed forgetting effects are a result of active inhibition or a change of context initiated by the instruction to forget. In this study we test the causal role of active inhibition in directed forgetting. By applying cathodal transcranial direct current stimulation (tDCS) over the right prefrontal cortex we suppressed cortical activity commonly associated with inhibitory control. Participants who underwent real brain stimulation before completing the directed forgetting paradigm showed no directed forgetting effects. Conversely, those who underwent sham brain stimulation demonstrated classical directed forgetting effects. We argue that these findings suggest that inhibition is the primary mechanism that results in directed forgetting costs and benefits. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inhibitory Effect of TNF-alpha Produced by Macrophages Stimulated with Grifola frondosa Extract (ME) on the Growth of Influenza A/Aichi/2/68 Virus in MDCK Cells.

PubMed

Obi, Nobuko; Hayashi, Katsumi; Miyahara, Tatsurou; Shimada, Yutaka; Terasawa, Katsutoshi; Watanabe, Masataka; Takeyama, Masahide; Obi, Ryosuke; Ochiai, Hiroshi

2008-01-01

We investigated the inhibitory effect of the conditioned medium (CM) from P338D1 (D1) cells, a murine macrophage cell line, stimulated for 10 hours with a fixed dose (100 mug/ml) of the extracts from the fruit bodies of Grifola frondosa (ME) or its ultra filtration-based fractions (MFs), on the growth of influenza A/Aichi/2/68 virus in Madin-Darby canine kidney cells. Direct addition of ME and 3 kinds of MFs (MF1, MF2 and MF3) to the infected cells had no obvious inhibitory effect. However, virus yields were reduced in the presence of CMs. Notably, the inhibitory effect of the CM prepared by using MF2 (molecular weight of 30 Kd to 100 Kd) was the strongest (28% reduction compared to the control). RT-PCR and ELISA assays showed that the CMs could induce the expression of TNF-alpha mRNA in D1 cells leading to production of TNF-alpha, known as an antiviral cytokine. These findings suggest that ME and MFs (especially MF-2) might induce the production of certain factors, including TNF-alpha, which are responsible for the inhibition of viral growth in vitro.

Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons

PubMed Central

Vong, Linh; Ye, Chianping; Yang, Zongfang; Choi, Brian; Chua, Streamson; Lowell, Bradford B.

2011-01-01

SUMMARY Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part due to incomplete knowledge regarding first order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first order neurons. While functionally relevant neurons have been identified, the observed effects have been small suggesting that most first order neurons remain unidentified. Here we take an alternative approach and test whether first order neurons are inhibitory (GABAergic, VGAT+) or excitatory (glutamatergic, VGLUT2+). Remarkably, the vast majority of leptin’s anti-obesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons likely mediates, at least in part, leptin’s anti-obesity effects. PMID:21745644

Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB.

PubMed

Riehemann, K; Behnke, B; Schulze-Osthoff, K

1999-01-08

Activation of transcription factor NF-kappaB is elevated in several chronic inflammatory diseases and is responsible for the enhanced expression of many proinflammatory gene products. Extracts from leaves of stinging nettle (Urtica dioica) are used as antiinflammatory remedies in rheumatoid arthritis. Standardized preparations of these extracts (IDS23) suppress cytokine production, but their mode of action remains unclear. Here we demonstrate that treatment of different cells with IDS23 potently inhibits NF-kappaB activation. An inhibitory effect was observed in response to several stimuli, suggesting that IDS23 suppressed a common NF-kappaB pathway. Inhibition of NF-kappaB activation by IDS23 was not mediated by a direct modification of DNA binding, but rather by preventing degradation of its inhibitory subunit IkappaB-alpha. Our results suggests that part of the antiinflammatory effect of Urtica extract may be ascribed to its inhibitory effect on NF-kappaB activation.

Inhibitory effect of rose hip (Rosa canina L.) on melanogenesis in mouse melanoma cells and on pigmentation in brown guinea pigs.

PubMed

Fujii, Takashi; Ikeda, Katsumi; Saito, Morio

2011-01-01

The compounds present in rose hips exerting an inhibitory action against melanogenesis in B16 mouse melanoma cells were investigated by dividing an aqueous extract of rose hips (RE) into four fractions. The 50% ethanol eluate from a DIAION HP-20 column significantly reduced the production of melanin and was mainly composed of procyanidin glycosides. We also found that this 50% ethanol eluate reduced the intracellular tyrosinase activity and also had a direct inhibitory effect on tyrosinase obtained as a protein mixture from the melanoma cell lysate. We also investigated the effect of orally administering RE on skin pigmentation in brown guinea pigs, and found that the pigmentation was inhibited together with the tyrosinase activity in the skin. These data collectively suggest that proanthocyanidins from RE inhibited melanogenesis in mouse melanoma cells and guinea pig skin, and could be useful as a skin-whitening agent when taken orally.

Effects of deep brain stimulation of the subthalamic nucleus on inhibitory and executive control over prepotent responses in Parkinson's disease

PubMed Central

Jahanshahi, Marjan

2013-01-01

Inhibition of inappropriate, habitual or prepotent responses is an essential component of executive control and a cornerstone of self-control. Via the hyperdirect pathway, the subthalamic nucleus (STN) receives inputs from frontal areas involved in inhibition and executive control. Evidence is reviewed from our own work and the literature suggesting that in Parkinson's disease (PD), deep brain stimulation (DBS) of the STN has an impact on executive control during attention-demanding tasks or in situations of conflict when habitual or prepotent responses have to be inhibited. These results support a role for the STN in an inter-related set of processes: switching from automatic to controlled processing, inhibitory and executive control, adjusting response thresholds and influencing speed-accuracy trade-offs. Such STN DBS-induced deficits in inhibitory and executive control may contribute to some of the psychiatric problems experienced by a proportion of operated cases after STN DBS surgery in PD. However, as no direct evidence for such a link is currently available, there is a need to provide direct evidence for such a link between STN DBS-induced deficits in inhibitory and executive control and post-surgical psychiatric complications experienced by operated patients. PMID:24399941

Effect of Fertilizers and Neem Cake Amendment in Soil on Spore Germination of Arthrobotrys dactyloides

PubMed Central

Kumar, D.; Jaiswal, R. K.

2005-01-01

Application of fertilizers such as urea, diammonium phosphate (DAP) and muriate of potash in soil adversely affected the spore germination of Arthrobotrys dactyloides. Amendment of soil with urea at the concentrations of 1.0%, 0.5% and 0.1% completely inhibited spore germination and direct trap formation on the conidium, whereas muriate of potash delayed and reduced the spore germination even at the lowest concentration. DAP also inhibited spore germination at 1.0% concentration, while at lower concentration the percentage of spore germination was reduced. Application of neem cake at the concentration of 0.5% also inhibited spore germination after 24 h of amendment. The inhibitory effect of neem cake was reduced after 15 days of amendment, while after 30 days after amendment the inhibitory effect was completely lost and the spore germinated by direct trap as in unamended soil. Nematodes were not attracted to ungerminated spores after 24 h of amendment. After 15 days of amendment nematodes were attracted to agar blocks containing fewer germinated spores after 24 h of incubation but after 48 h of incubation large number of nematodes were attracted and trapped by the germinated spores with direct traps. After 30 days of amendment, larger number of nematodes were attracted and trapped by direct traps. PMID:24049500

Weed growth inhibitors from Aspergillus fischeri TISTR 3272.

PubMed

Phattanawasin, P; Pojchanakom, K; Sotanaphun, U; Piyapolrungroj, N; Zungsontiporn, S

2007-12-01

Chloroform and ethyl acetate extracts of Aspergillus fischeri TISTR 3272 showed good growth inhibitory activity on Mimosa pigra and Echinochloa crus-galli. Bioassay-directed fractionation of the active extracts led to the isolation of five known compounds, (+)-terrein (1), (-)-6-hydroxymellein (2), two diketopiperazines (cyclo-(S-Pro-S-Leu) (3) and cyclo-(S-Pro-S-Val) (4)) and butyrolactone I (5). Compounds 2-5 were reported for the first time in this fungus. Their structural determinations were based on analyses of spectroscopic data and their weed growth inhibitory effects were assessed.

Engagement of CD22 on B cells with the monoclonal antibody epratuzumab stimulates the phosphorylation of upstream inhibitory signals of the B cell receptor.

PubMed

Lumb, Simon; Fleischer, Sarah J; Wiedemann, Annika; Daridon, Capucine; Maloney, Alison; Shock, Anthony; Dörner, Thomas

2016-06-01

The binding of antigen to the B cell receptor (BCR) results in a cascade of signalling events that ultimately drive B cell activation. Uncontrolled B cell activation is regulated by negative feedback loops that involve inhibitory co-receptors such as CD22 and CD32B that exert their functions following phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs). The CD22-targeted antibody epratuzumab has previously been shown to inhibit BCR-driven signalling events, but its effects on ITIM phosphorylation of CD22 and CD32B have not been properly evaluated. The present study therefore employed both immunoprecipitation and flow cytometry approaches to elucidate the effects of epratuzumab on direct phosphorylation of key tyrosine (Tyr) residues on both these proteins, using both transformed B cell lines and primary human B cells. Epratuzumab induced the phosphorylation of Tyr(822) on CD22 and enhanced its co-localisation with SHP-1. Additionally, in spite of high basal phosphorylation of other key ITIMs on CD22, in primary human B cells epratuzumab also enhanced phosphorylation of Tyr(807), a residue involved in the recruitment of Grb2. Such initiation events could explain the effects of epratuzumab on downstream signalling in B cells. Finally, we were able to demonstrate that epratuzumab stimulated the phosphorylation of Tyr(292) on the low affinity inhibitory Fc receptor CD32B which would further attenuate BCR-induced signalling. Together, these data demonstrate that engagement of CD22 with epratuzumab leads to the direct phosphorylation of key upstream inhibitory receptors of BCR signalling and may help to explain how this antibody modulates B cell function.

The neurite growth inhibitory effects of soluble TNFα on developing sympathetic neurons are dependent on developmental age.

PubMed

Nolan, Aoife M; Collins, Louise M; Wyatt, Sean L; Gutierrez, Humberto; O'Keeffe, Gerard W

2014-01-01

During development, the growth of neural processes is regulated by an array of cellular and molecular mechanisms which influence growth rate, direction and branching. Recently, many members of the TNF superfamily have been shown to be key regulators of neurite growth during development. The founder member of this family, TNFα can both promote and inhibit neurite growth depending on the cellular context. Specifically, transmembrane TNFα promotes neurite growth, while soluble TNFα inhibits it. While the growth promoting effects of TNFα are restricted to a defined developmental window of early postnatal development, whether the growth inhibitory effects of soluble TNFα occur throughout development is unknown. In this study we used the extensively studied, well characterised neurons of the superior cervical ganglion to show that the growth inhibitory effects of soluble TNFα are restricted to a specific period of late embryonic and early postnatal development. Furthermore, we show that this growth inhibitory effect of soluble TNFα requires NF-κB signalling at all developmental stages at which soluble TNFα inhibits neurite growth. These findings raise the possibility that increases in the amount of soluble TNFα in vivo, for example as a result of maternal inflammation, could negatively affect neurite growth in developing neurons at specific stages of development. Copyright © 2015 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Alcohols are inhibitors of Saccharomyces cerevisiae multidrug-resistance pumps Pdr5p and Snq2p.

PubMed

Gášková, Dana; Plášek, Jaromír; Zahumenský, Jakub; Benešová, Ivana; Buriánková, Luboslava; Sigler, Karel

2013-12-01

The effect of alcohols on cell membrane proteins has originally been assumed to be mediated by their primary action on membrane lipid matrix. Many studies carried out later on both animal and yeast cells have revealed that ethanol and other alcohols inhibit the functions of various membrane channels, receptors and solute transport proteins, and a direct interaction of alcohols with these membrane proteins has been proposed. Using our fluorescence diS-C3 (3) diagnostic assay for multidrug-resistance pump inhibitors in a set of isogenic yeast Pdr5p and Snq2p mutants, we found that n-alcohols (from ethanol to hexanol) variously affect the activity of both pumps. Beginning with propanol, these alcohols have an inhibitory effect that increases with increasing length of the alcohol acyl chain. While ethanol does not exert any inhibitory effect at any of the concentration used (up to 3%), hexanol exerts a strong inhibition at 0.1%. The alcohol-induced inhibition of MDR pumps was detected even in cells whose membrane functional and structural integrity were not compromised. This supports a notion that the inhibitory action does not necessarily involve only changes in the lipid matrix of the membrane but may entail a direct interaction of the alcohols with the pump proteins. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Subthalamic nucleus stimulation influences expression and suppression of impulsive behaviour in Parkinson’s disease

PubMed Central

Ridderinkhof, K. Richard; Elias, William J.; Frysinger, Robert C.; Bashore, Theodore R.; Downs, Kara E.; van Wouwe, Nelleke C.; van den Wildenberg, Wery P. M.

2010-01-01

Past studies show beneficial as well as detrimental effects of subthalamic nucleus deep-brain stimulation on impulsive behaviour. We address this paradox by investigating individuals with Parkinson’s disease treated with subthalamic nucleus stimulation (n = 17) and healthy controls without Parkinson’s disease (n = 17) on performance in a Simon task. In this reaction time task, conflict between premature response impulses and goal-directed action selection is manipulated. We applied distributional analytic methods to separate the strength of the initial response impulse from the proficiency of inhibitory control engaged subsequently to suppress the impulse. Patients with Parkinson’s disease were tested when stimulation was either turned on or off. Mean conflict interference effects did not differ between controls and patients, or within patients when stimulation was on versus off. In contrast, distributional analyses revealed two dissociable effects of subthalamic nucleus stimulation. Fast response errors indicated that stimulation increased impulsive, premature responding in high conflict situations. Later in the reaction process, however, stimulation improved the proficiency with which inhibitory control was engaged to suppress these impulses selectively, thereby facilitating selection of the correct action. This temporal dissociation supports a conceptual framework for resolving past paradoxical findings and further highlights that dynamic aspects of impulse and inhibitory control underlying goal-directed behaviour rely in part on neural circuitry inclusive of the subthalamic nucleus. PMID:20861152

The alpha-7 nicotinic acetylcholine receptor is involved in a direct inhibitory effect of nicotine on GnRH release: In vitro studies.

PubMed

Messi, Elio; Pimpinelli, Federica; Andrè, Valentina; Rigobello, Chiara; Gotti, Cecilia; Maggi, Roberto

2018-01-15

The activation of nicotinic cholinergic receptors (nAChR) inhibits the reproductive axis; however, it is not clear whether nicotine may directly modulate the release of hypothalamic gonadotropin-releasing hormone (GnRH). Experiments carried out in GT1-1 immortalized GnRH neurons reveal the presence of a single class of high affinity α4β2 and α7 nAchR subtypes. The exposure of GT1-1 cells to nicotine does not modify the basal accumulation of GnRH. However, nicotine was found to modify GnRH pulsatility in perifusion experiments and inhibits, the release of GnRH induced by prostaglandin E 1 or by K + -induced cell depolarization; these effects were reversed by D-tubocurarine and α-bungarotoxin. In conclusion, the results reported here indicate that: functional nAChRs are present on GT1-1 cells, the activation of the α-bungarotoxin-sensitive subclass (α7) produces an inhibitory effect on the release of GnRH and that the direct action of nicotine on GnRH neurons may be involved in reducing fertility of smokers. Copyright © 2017 Elsevier B.V. All rights reserved.

Inference of topology and the nature of synapses, and the flow of information in neuronal networks

NASA Astrophysics Data System (ADS)

Borges, F. S.; Lameu, E. L.; Iarosz, K. C.; Protachevicz, P. R.; Caldas, I. L.; Viana, R. L.; Macau, E. E. N.; Batista, A. M.; Baptista, M. S.

2018-02-01

The characterization of neuronal connectivity is one of the most important matters in neuroscience. In this work, we show that a recently proposed informational quantity, the causal mutual information, employed with an appropriate methodology, can be used not only to correctly infer the direction of the underlying physical synapses, but also to identify their excitatory or inhibitory nature, considering easy to handle and measure bivariate time series. The success of our approach relies on a surprising property found in neuronal networks by which nonadjacent neurons do "understand" each other (positive mutual information), however, this exchange of information is not capable of causing effect (zero transfer entropy). Remarkably, inhibitory connections, responsible for enhancing synchronization, transfer more information than excitatory connections, known to enhance entropy in the network. We also demonstrate that our methodology can be used to correctly infer directionality of synapses even in the presence of dynamic and observational Gaussian noise, and is also successful in providing the effective directionality of intermodular connectivity, when only mean fields can be measured.

Utilization of the water soluable fraction of wheat straw as a plant nutrient source

NASA Technical Reports Server (NTRS)

Mackowiak, C. L.; Garland, J. L.

1990-01-01

Recovery of water soluble, inorganic nutrients from the inedible portion of wheat was found to be an effective means of recycling nutrients within hydroponic systems. Through aqueous extraction (leaching), 60 percent of the total inorganic nutrient weight was removed from wheat straw and roots, although the recovery of individual nutrients varied. Leaching also removed about 20 percent of the total organic carbon from the biomass. In terms of dry weight, the leachate was comprised of approximately 60 percent organic and 40 percent inorganic compounds. Direct use of wheat straw leachate in static hydroponic systems had an inhibitory effect on wheat growth, both in the presence and absence of microorganisms. Biological treatment of leachate either with a mixed microbial community or the oyster mushroom Pleurotus ostreatus L., prior to use in hydroponic solutions, significantly reduced both the organic content and the inhibitory effects of the leachate. The inhibitory effects of unprocessed leachate appear to be a result of rapidly acting phytotoxic compounds that are detoxified by microbial activity. Leaching holds considerable promise as a method for nutrient recycling in a Controlled Ecological Life Support System (CELSS).

Transcranial direct current stimulation for hyperactivity and noncompliance in autistic disorder.

PubMed

D'Urso, Giordano; Bruzzese, Dario; Ferrucci, Roberta; Priori, Alberto; Pascotto, Antonio; Galderisi, Silvana; Altamura, Alfredo Carlo; Bravaccio, Carmela

2015-01-01

To evaluate the safety, efficacy, and feasibility of inhibitory transcranial direct current stimulation (tDCS) for the treatment of behavioural abnormalities of autistic patients. Twelve young adult patients with autistic disorder were enrolled. All subjects presented intellectual disability and most of them had speech impairment. The Aberrant Behavior Checklist (ABC) was administered as the primary outcome measure before and after a 2-week tDCS course. All subjects received 10 daily applications of 20 min/1.5 mA/cathodal (inhibitory) tDCS over the left dorso-lateral pre-frontal cortex. Eight out of 10 study completers improved in their abnormal behaviours, reaching an average reduction of 26.7% of the total ABC score. The remaining two patients showed no changes. In the whole group of completers, among the five subscales contributing to the significant reduction of the total score, the most remarkable and statistically significant change was seen in the subscale assessing hyperactivity and non-compliance (-35.9%, P = 0.002). No adverse effects were reported. Inhibitory tDCS improved the ABC rating scores for autistic behaviours. Owing to its ease of use, cost-effectiveness and the limited availability of specific treatment strategies, tDCS might be a valid therapeutic option to be tested in autistic patients.

Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice.

PubMed

Lesterhuis, W Joost; Punt, Cornelis J A; Hato, Stanleyson V; Eleveld-Trancikova, Dagmar; Jansen, Bastiaan J H; Nierkens, Stefan; Schreibelt, Gerty; de Boer, Annemiek; Van Herpen, Carla M L; Kaanders, Johannes H; van Krieken, Johan H J M; Adema, Gosse J; Figdor, Carl G; de Vries, I Jolanda M

2011-08-01

Tumor microenvironments feature immune inhibitory mechanisms that prevent T cells from generating effective antitumor immune responses. Therapeutic interventions aimed at disrupting these inhibitory mechanisms have been shown to enhance antitumor immunity, but they lack direct cytotoxic effects. Here, we investigated the effect of cytotoxic cancer chemotherapeutics on immune inhibitory pathways. We observed that exposure to platinum-based chemotherapeutics markedly reduced expression of the T cell inhibitory molecule programmed death receptor-ligand 2 (PD-L2) on both human DCs and human tumor cells. Downregulation of PD-L2 resulted in enhanced antigen-specific proliferation and Th1 cytokine secretion as well as enhanced recognition of tumor cells by T cells. Further analysis revealed that STAT6 controlled downregulation of PD-L2. Consistent with these data, patients with STAT6-expressing head and neck cancer displayed enhanced recurrence-free survival upon treatment with cisplatin-based chemoradiation compared with patients with STAT6-negative tumors, demonstrating the clinical relevance of platinum-induced STAT6 modulation. We therefore conclude that platinum-based anticancer drugs can enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capability of tumor cells. This dual action of platinum compounds may extend their therapeutic application in cancer patients and provides a rationale for their use in combination with immunostimulatory compounds.

Prenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders

PubMed Central

Fine, Rebecca; Zhang, Jie; Stevens, Hanna E.

2014-01-01

Prenatal stress is a risk factor for several psychiatric disorders in which inhibitory neuron pathology is implicated. A growing body of research demonstrates that inhibitory circuitry in the brain is directly and persistently affected by prenatal stress. This review synthesizes research that elucidates how this early, developmental risk factor impacts inhibitory neurons and how these findings intersect with research on risk factors and inhibitory neuron pathophysiology in schizophrenia, anxiety, autism and Tourette syndrome. The specific impact of prenatal stress on inhibitory neurons, particularly developmental mechanisms, may elucidate further the pathophysiology of these disorders. PMID:24751963

Identification of a pheromone regulating caste differentiation in termites.

PubMed

Matsuura, Kenji; Himuro, Chihiro; Yokoi, Tomoyuki; Yamamoto, Yuuka; Vargo, Edward L; Keller, Laurent

2010-07-20

The hallmark of social insects is their caste system: reproduction is primarily monopolized by queens, whereas workers specialize in the other tasks required for colony growth and survival. Pheromones produced by reigning queens have long been believed to be the prime factor inhibiting the differentiation of new reproductive individuals. However, there has been very little progress in the chemical identification of such inhibitory pheromones. Here we report the identification of a volatile inhibitory pheromone produced by female neotenics (secondary queens) that acts directly on target individuals to suppress the differentiation of new female neotenics and identify n-butyl-n-butyrate and 2-methyl-1-butanol as the active components of the inhibitory pheromone. An artificial pheromone blend consisting of these two compounds had a strong inhibitory effect similar to live neotenics. Surprisingly, the same two volatiles are also emitted by eggs, playing a role both as an attractant to workers and an inhibitor of reproductive differentiation. This dual production of an inhibitory pheromone by female reproductives and eggs probably reflects the recruitment of an attractant pheromone as an inhibitory pheromone and may provide a mechanism ensuring honest signaling of reproductive status with a tight coupling between fertility and inhibitory power. Identification of a volatile pheromone regulating caste differentiation in a termite provides insights into the functioning of social insect colonies and opens important avenues for elucidating the developmental pathways leading to reproductive and nonreproductive castes.

Identification of a pheromone regulating caste differentiation in termites

PubMed Central

Matsuura, Kenji; Himuro, Chihiro; Yokoi, Tomoyuki; Yamamoto, Yuuka; Vargo, Edward L.; Keller, Laurent

2010-01-01

The hallmark of social insects is their caste system: reproduction is primarily monopolized by queens, whereas workers specialize in the other tasks required for colony growth and survival. Pheromones produced by reining queens have long been believed to be the prime factor inhibiting the differentiation of new reproductive individuals. However, there has been very little progress in the chemical identification of such inhibitory pheromones. Here we report the identification of a volatile inhibitory pheromone produced by female neotenics (secondary queens) that acts directly on target individuals to suppress the differentiation of new female neotenics and identify n-butyl-n-butyrate and 2-methyl-1-butanol as the active components of the inhibitory pheromone. An artificial pheromone blend consisting of these two compounds had a strong inhibitory effect similar to live neotenics. Surprisingly, the same two volatiles are also emitted by eggs, playing a role both as an attractant to workers and an inhibitor of reproductive differentiation. This dual production of an inhibitory pheromone by female reproductives and eggs probably reflects the recruitment of an attractant pheromone as an inhibitory pheromone and may provide a mechanism ensuring honest signaling of reproductive status with a tight coupling between fertility and inhibitory power. Identification of a volatile pheromone regulating caste differentiation in a termite provides insights into the functioning of social insect colonies and opens important avenues for elucidating the developmental pathways leading to reproductive and nonreproductive castes. PMID:20615972

In vitro studies of the antirhinovirus activity of soluble intercellular adhesion molecule-1.

PubMed Central

Arruda, E; Crump, C E; Marlin, S D; Merluzzi, V J; Hayden, F G

1992-01-01

We studied the in vitro antirhinovirus activity of a soluble form of intercellular adhesion molecule-1 (sICAM-1). sICAM-1 inhibited the cytopathic effect of 10 representative human rhinovirus (HRV) serotypes of the major receptor group with, 50% effective concentrations (EC50s) of 0.1 to 7.9 micrograms/ml. Cell type-dependent variation in the inhibitory activity of sICAM-1 was observed for two major receptor group serotypes in HeLa cells (EC50, greater than 32 micrograms/ml), and no inhibitory effect was observed for two serotypes which use different cell receptors. Yield reduction assays showed that sICAM-1 inhibited the replication of HRV serotype 39 (HRV-39) in human adenoid explants in a concentration-dependent manner. No direct inactivation of infectivity of HRV-39 (EC50, 0.5 microgram/ml) was observed after incubation with sICAM-1 (32 micrograms/ml) for up to 24 h. Single-cycle-of-replication experiments with the addition of sICAM-1 at 10 micrograms/ml at different times showed that the inhibitory effect occurs only when sICAM-1 is added within 30 min after infection. In experiments in which absorption was carried out at 4 degrees C and then a single cycle of replication incubation was carried out at 33 degrees C, it was found that sICAM-1 at 10 micrograms/ml was inhibitory only when it was present during the absorption period. Our data show that sICAM-1 is inhibitory for representative major receptor group serotypes of HRV in two cell lines and human respiratory epithelium, that the interaction of sICAM-1 with HRV is readily reversible by dilution, and that the inhibitory effect of sICAM-1 on virus replication is present early in the infection cycle. PMID:1358025

Inhibitory mechanisms of glabridin on tyrosinase

NASA Astrophysics Data System (ADS)

Chen, Jianmin; Yu, Xiaojing; Huang, Yufeng

2016-11-01

Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin could lead to a variety of skin disorders. Glabridin, an isoflavan, isolated from the root of Glycyrrhiza glabra Linn, has exhibited several pharmacological activities, including excellent inhibitory effects on tyrosinase. In this paper, the inhibitory kinetics of glabridin on tyrosinase and their binding mechanisms were determined using spectroscopic, zebrafish model and molecular docking techniques. The results indicate that glabridin reversibly inhibits tyrosinase in a noncompetitive manner through a multiphase kinetic process with the IC50 of 0.43 μmol/L. It has been shown that glabridin had a strong ability to quench the intrinsic fluorescence of tyrosinase mainly through a static quenching procedure, suggesting a stable glabridin-tyrosinase complex may be generated. The results of molecular docking suggest that glabridin did not directly bind to the active site of tyrosinase. Moreover, according to the results of zebrafish model system, glabridin shows no effects on melanin synthesis in zebrafish but presents toxicity to zebrafish embryo. The possible inhibitory mechanisms, which will help to design and search for tyrosinase inhibitors especially for glabridin analogues, were proposed.

A Rapid Screen for Host-Encoded miRNAs with Inhibitory Effects against Ebola Virus Using a Transcription- and Replication-Competent Virus-Like Particle System.

PubMed

Wang, Zhongyi; Li, Jiaming; Fu, Yingying; Zhao, Zongzheng; Zhang, Chunmao; Li, Nan; Li, Jingjing; Cheng, Hongliang; Jin, Xiaojun; Lu, Bing; Guo, Zhendong; Qian, Jun; Liu, Linna

2018-05-16

MicroRNAs (miRNAs) may become efficient antiviral agents against the Ebola virus (EBOV) targeting viral genomic RNAs or transcripts. We previously conducted a genome-wide search for differentially expressed miRNAs during viral replication and transcription. In this study, we established a rapid screen for miRNAs with inhibitory effects against EBOV using a tetracistronic transcription- and replication-competent virus-like particle (trVLP) system. This system uses a minigenome comprising an EBOV leader region, luciferase reporter, VP40, GP, VP24, EBOV trailer region, and three noncoding regions from the EBOV genome and can be used to model the life cycle of EBOV under biosafety level (BSL) 2 conditions. Informatic analysis was performed to select up-regulated miRNAs targeting the coding regions of the minigenome with the highest binding energy to perform inhibitory effect screening. Among these miRNAs, miR-150-3p had the most significant inhibitory effect. Reverse transcription polymerase chain reaction (RT-PCR), Western blot, and double fluorescence reporter experiments demonstrated that miR-150-3p inhibited the reproduction of trVLPs via the regulation of GP and VP40 expression by directly targeting the coding regions of GP and VP40. This novel, rapid, and convenient screening method will efficiently facilitate the exploration of miRNAs against EBOV under BSL-2 conditions.

A Microsaccadic Account of Attentional Capture and Inhibition of Return in Posner Cueing

PubMed Central

Tian, Xiaoguang; Yoshida, Masatoshi; Hafed, Ziad M.

2016-01-01

Microsaccades exhibit systematic oscillations in direction after spatial cueing, and these oscillations correlate with facilitatory and inhibitory changes in behavioral performance in the same tasks. However, independent of cueing, facilitatory and inhibitory changes in visual sensitivity also arise pre-microsaccadically. Given such pre-microsaccadic modulation, an imperative question to ask becomes: how much of task performance in spatial cueing may be attributable to these peri-movement changes in visual sensitivity? To investigate this question, we adopted a theoretical approach. We developed a minimalist model in which: (1) microsaccades are repetitively generated using a rise-to-threshold mechanism, and (2) pre-microsaccadic target onset is associated with direction-dependent modulation of visual sensitivity, as found experimentally. We asked whether such a model alone is sufficient to account for performance dynamics in spatial cueing. Our model not only explained fine-scale microsaccade frequency and direction modulations after spatial cueing, but it also generated classic facilitatory (i.e., attentional capture) and inhibitory [i.e., inhibition of return (IOR)] effects of the cue on behavioral performance. According to the model, cues reflexively reset the oculomotor system, which unmasks oscillatory processes underlying microsaccade generation; once these oscillatory processes are unmasked, “attentional capture” and “IOR” become direct outcomes of pre-microsaccadic enhancement or suppression, respectively. Interestingly, our model predicted that facilitatory and inhibitory effects on behavior should appear as a function of target onset relative to microsaccades even without prior cues. We experimentally validated this prediction for both saccadic and manual responses. We also established a potential causal mechanism for the microsaccadic oscillatory processes hypothesized by our model. We used retinal-image stabilization to experimentally control instantaneous foveal motor error during the presentation of peripheral cues, and we found that post-cue microsaccadic oscillations were severely disrupted. This suggests that microsaccades in spatial cueing tasks reflect active oculomotor correction of foveal motor error, rather than presumed oscillatory covert attentional processes. Taken together, our results demonstrate that peri-microsaccadic changes in vision can go a long way in accounting for some classic behavioral phenomena. PMID:27013991

Effects of psychological stress on male fertility.

PubMed

Nargund, Vinod H

2015-07-01

Psychological stress can be defined as any uncomfortable 'emotional experience' accompanied by predictable biochemical, physiological and behavioural changes or responses. Many clinical studies looking at the effects of psychological stress on male fertility have shown that stress is associated with reduced paternity and abnormal semen parameters. Enough scientific evidence exists to suggest that psychological stress could severely affect spermatogenesis, mainly as a result of varying testosterone secretion. The hypothalamic-pituitary-adrenal axis has a direct inhibitory action on the hypothalamic-pituitary-gonadal (HPG) axis and Leydig cells in the testes. The newly discovered hormone, gonadotropin-inhibitory hormone (GnIH), also has an inhibitory effect on the HPG axis. Inhibition of the HPG axis results in a fall in testosterone levels, which causes changes in Sertoli cells and the blood-testis barrier, leading to the arrest of spermatogenesis. Germ cells also become vulnerable to gonadotoxins and oxidation. However, the extent and severity of the effects of psychological stress on human testes is difficult to study and data mostly come from animal models. Despite this limitation, stress as a causative factor in male infertility cannot be ignored and patients should be made aware of its effects on testicular function and fertility and helped to manage them.

Effects of some plant lectins on hydrogen peroxide release from macrophages induced with streptococcal preparation OK-432.

PubMed Central

Tomioka, H; Saito, H

1980-01-01

Concanavalin A and phytohemagglutinin were found to cause marked inhibition of H2O2 release from macrophages induced with killed streptococci (preparation OK-432). The inhibitory effect of these two lectins on the H2O2 release from macrophages was observed with spontaneous and wheat germ lectin-triggered H2O2 release. This suggests that the lectins act directly on the macrophage H2O2-releasing function, per se, but not on the wheat germ lectin-H2O2 release-enhancing process. Concanavalin A exhibited its inhibitory action on macrophage H2O2 release by specific binding to D-mannopyranoside receptor sites on the macrophage cell surface. Galactose-binding lectins, peanut agglutinin, and soybean agglutinin failed to inhibit, but, on the other hand, slightly enhanced macrophage H2O2 release. The effect of these five lectins on the phagocytosis of latex particles by macrophages was tested. Wheat germ lectin, concanavalin A, and phytohemagglutinin significantly depressed the macrophage phagocytosis, whereas peanut agglutinin and soybean agglutinin failed to show any inhibitory action. PMID:7399666

EF-1 alpha is a target site for an inhibitory effect of quercetin in the peptide elongation process.

PubMed

Marcinkiewicz, C; Gałasiński, W; Gindzieński, A

1995-01-01

The effect of quercetin (3,3',4',5,7-pentahydroxyflavone) on the polypeptide elongation system isolated from rat liver cells, was investigated. Quercetin inhibited [14C]leucine incorporation into proteins in vitro and the inhibitory effect is being directed towards the elongation factor eEF-1, but not to eEF-2 and ribosomes. Quercetin was found to form a complex with EF-1 alpha, which was inactive in GTP-dependent binding to ribosomes. It can be suggested that quercetin can block the total or the part of the domain of EF-1 alpha structure that is responsible for formation of the ternary complex EF-1 alpha-GTP-[14C]Phe-tRNA and therefore preventing formation of the quaternary complex with ribosomes.

[Relation between frequency modulation direction selectivity and forward masking of inferior collicular neurons: a study on in vivo intracellular recording in mice].

PubMed

Fu, Zi-Ying; Zeng, Hong; Tang, Jia; Li, Jie; Li, Juan; Chen, Qi-Cai

2013-06-25

It has been reported that the frequency modulation (FM) or FM direction sensitivity and forward masking of central auditory neurons are related with the neural inhibition, but there are some arguments, because no direct evidence of inhibitory synaptic input was obtained in previous studies using extracellular recording. In the present study, we studied the relation between FM direction sensitivity and forward masking of the inferior collicular (IC) neurons using in vivo intracellular recordings in 20 Mus musculus Km mice. Thirty seven with complete data among 93 neurons were analyzed and discussed. There was an inhibitory area which consisted of inhibitory postsynaptic potentials (IPSP) at high frequency side of frequency tuning of up-sweep FM (FMU) sensitive neurons (n = 12) and at low frequency side of frequency tuning of down-sweep FM (FMD) selective neurons (n = 8), while there was no any inhibitory area at both sides of frequency tuning of non-FM sweep direction (FMN) sensitive neurons (n = 17). Therefore, these results show that the inhibitory area at low or high frequency side of frequency tuning is one of the mechanisms for forming FM sweep direction sensitivity of IC neurons. By comparison of forward masking produced by FMU and FMD sound stimuli in FMU, FMD and FMN neurons, the selective FM sounds could produce stronger forward masking than the non-selective in FMU and FMD neurons, while there was no forward masking difference between FMU and FMD stimuli in the FMN neurons. We suggest that the post-action potential IPSP is a potential mechanism for producing stronger forward masking in FMU and FMD neurons.

Alcohol's acute effect on food intake is mediated by inhibitory control impairments.

PubMed

Christiansen, Paul; Rose, Abigail; Randall-Smith, Laura; Hardman, Charlotte A

2016-05-01

There is a strong association between alcohol misuse and excess weight. Although alcohol is highly calorific and may directly contribute to weight gain, it is also likely to have indirect effects on weight. Indeed, alcohol primes have been found to stimulate appetite and increase energy intake in experimental taste tests. The current study investigated whether the effects of alcohol on energy intake are the result of inhibitory control impairments and whether this effect is moderated by individual differences in dietary restraint. Sixty undergraduate females completed measures of dietary restraint and the Food Craving Questionnaire-State (FCQS). Following this, they were given an alcohol prime (0.6 g of alcohol per kg of body weight) or a placebo drink manipulated to smell and taste alcoholic. Participants then completed another FCQS and a color conflict Stroop to measure inhibitory control. Finally, participants were asked to taste cookies for 15 minutes. Participants in the alcohol condition performed worse on the Stroop (d = .61) and consumed more cookie calories (d = .61) than participants in the placebo condition. Notably, the effect of the experimental condition on the amount of cookies consumed was mediated by Stroop performance (Κ2 = .08), although this effect was not evident under high levels of restraint. There was no effect of experimental condition on any subscale of craving. The current study suggests that increased energy intake after alcohol administration may be the product of inhibitory control impairments. However, the most restrained eaters are able to maintain control over their eating behavior. (c) 2016 APA, all rights reserved).

Direct antigonadal activity of cannabinoids: suppression of rat granulosa cell functions.

PubMed

Adashi, E Y; Jones, P B; Hsueh, A J

1983-02-01

The direct effects of delta 9-tetrahydrocannabinol (THC) and related cannabinoids on ovarian granulosa cells were studied in vitro. Granulosa cells from immature, hypophysectomized, estrogen-treated rats were cultured for 2 days in an androstenedione-supplemented medium in the presence or absence of follicle-stimulating hormone (FSH) (10 ng/ml) with or without cannabinoids. FSH treatment increased progesterone and estrogen biosynthesis, whereas concomitant treatment with THC led to a dose-dependent inhibition of the FSH-stimulated accumulation of progesterone and estrogen with ED50 values of 3.5 +/- 0.3 X 10(-7) and 1.8 +/- 0.2 X 10(-6) M, respectively. Treatment with related but nonpsychoactive cannabinoids (cannabidiol, cannabinol, cannabigerol, or cannabichromene) was equally effective. The THC-induced inhibition of progesterone production was reversible and was associated with an inhibition of pregnenolone biosynthesis and a decrease of 3 beta-hydroxysteroid dehydrogenase activity. In addition, treatment with THC brought about a dose-dependent inhibition of the FSH-induced increase in luteinizing hormone (LH) receptors. The inhibitory effects of THC were not associated with changes in cell number, protein content, or cell viability. Thus, THC exerts direct inhibitory effects on FSH-dependent functions related to steroidogenesis and the acquisition of LH receptors, all of which are essential to follicular maturation. Because plasma concentrations of THC similar to those used in this study have been reported in human beings, repeated exposure of female users to THC may lead to ovarian dysfunction, due in part, to the direct antigonadal activity to THC.

Nootropic dipeptide noopept enhances inhibitory synaptic transmission in the hippocampus.

PubMed

Povarov, I S; Kondratenko, R V; Derevyagin, V I; Ostrovskaya, R U; Skrebitskii, V G

2015-01-01

Application of nootropic agent Noopept on hippocampal slices from Wistar rats enhanced the inhibitory component of total current induced by stimulation of Shaffer collaterals in CA1 pyramidal neurons, but did not affect the excitatory component. A direct correlation between the increase in the amplitude of inhibitory current and agent concentration was found. The substance did not affect the release of inhibitory transmitters from terminals in the pyramidal neurons, which indicated changes in GABAergic interneurons.

Direct current stimulation over the anterior temporal areas boosts semantic processing in primary progressive aphasia.

PubMed

Teichmann, Marc; Lesoil, Constance; Godard, Juliette; Vernet, Marine; Bertrand, Anne; Levy, Richard; Dubois, Bruno; Lemoine, Laurie; Truong, Dennis Q; Bikson, Marom; Kas, Aurélie; Valero-Cabré, Antoni

2016-11-01

Noninvasive brain stimulation in primary progressive aphasia (PPA) is a promising approach. Yet, applied to single cases or insufficiently controlled small-cohort studies, it has not clarified its therapeutic value. We here address the effectiveness of transcranial direct current stimulation (tDCS) on the semantic PPA variant (sv-PPA), applying a rigorous study design to a large, homogeneous sv-PPA cohort. Using a double-blind, sham-controlled counterbalanced cross-over design, we applied three tDCS conditions targeting the temporal poles of 12 sv-PPA patients. Efficiency was assessed by a semantic matching task orthogonally manipulating "living"/"nonliving" categories and verbal/visual modalities. Conforming to predominantly left-lateralized damage in sv-PPA and accounts of interhemispheric inhibition, we applied left hemisphere anodal-excitatory and right hemisphere cathodal-inhibitory tDCS, compared to sham stimulation. Prestimulation data, compared to 15 healthy controls, showed that patients had semantic disorders predominating with living categories in the verbal modality. Stimulation selectively impacted these most impaired domains: Left-excitatory and right-inhibitory tDCS improved semantic accuracy in verbal modality, and right-inhibitory tDCS improved processing speed with living categories and accuracy and processing speed in the combined verbal × living condition. Our findings demonstrate the efficiency of tDCS in sv-PPA by generating highly specific intrasemantic effects. They provide "proof of concept" for future applications of tDCS in therapeutic multiday regimes, potentially driving sustained improvement of semantic processing. Our data also support the hotly debated existence of a left temporal-pole network for verbal semantics selectively modulated through both left-excitatory and right-inhibitory brain stimulation. Ann Neurol 2016;80:693-707. © 2016 American Neurological Association.

Two opposite dose-dependent effects of diazinon on the motor activity of the rat ileum.

PubMed

Trailović, Saša M; Marjanović, Djordje S; Uzelac, Teodora Vidonja; Milovanović, Mirjana; Trailović, Jelena Nedeljković

2017-06-01

Acute poisoning with OPs may lead to a range of neurological effects, which cannot be explained by AChE inhibition alone. Several OPs interact directly with cholinergic receptors in mammals, but such data does not exist for invertebrates. The aim of current study was to investigate the direct and indirect effects of diazinon on the contractions of rat ileum and to compare those effects on the nervemuscle preparation of the Ascaris suum. In the presence of increasing concentrations of diazinon (3, 10 and 30nM), EFS-induced ileal contractions were increased significantly. In the same preparation, diazinon 3nM, significantly increased contractions induced by EFS, but did not affect the contractions caused by 5MFI. Contrarily, 1μM of diazinon significantly and reversibly inhibited the EFS-induced ileal contractions. Diazinon exhibited competitive and non-competitive inhibitions of 5MFI induced contractions. The control EC 50 of 5MFI was 2.48μM with R max =1.88g. In the presence of diazinon, EC 50 was 12.45μM, while R max was reduced to 0.43g. After washing, the EC 50 and R max values were again closer to the control level (3.80μM and 1.04g). Diazinon 1μM did not inhibit Ascaris suum contractions caused by ACh, but it increased the R max . Diazinon in our study exhibits two opposite effects on the motor activity of the ileum. In low nanomolar concentrations the dominat is its effect on AChE and the stimulation of contractions. Furthermore, in concentrations that approach micromolar values diazinon has a direct inhibitory effect on muscarinic receptors. The direct inhibitory effect of diazinon on A. suum contractions was not found. Copyright © 2017 Elsevier Ltd. All rights reserved.

Vitamin D binding protein-macrophage activating factor directly inhibits proliferation, migration, and uPAR expression of prostate cancer cells.

PubMed

Gregory, Kalvin J; Zhao, Bing; Bielenberg, Diane R; Dridi, Sami; Wu, Jason; Jiang, Weihua; Huang, Bin; Pirie-Shepherd, Steven; Fannon, Michael

2010-10-18

Vitamin D binding protein-macrophage activating factor (DBP-maf) is a potent inhibitor of tumor growth. Its activity, however, has been attributed to indirect mechanisms such as boosting the immune response by activating macrophages and inhibiting the blood vessel growth necessary for the growth of tumors. In this study we show for the first time that DBP-maf exhibits a direct and potent effect on prostate tumor cells in the absence of macrophages. DBP-maf demonstrated inhibitory activity in proliferation studies of both LNCaP and PC3 prostate cancer cell lines as well as metastatic clones of these cells. Flow cytometry studies with annexin V and propidium iodide showed that this inhibitory activity is not due to apoptosis or cell death. DBP-maf also had the ability to inhibit migration of prostate cancer cells in vitro. Finally, DBP-maf was shown to cause a reduction in urokinase plasminogen activator receptor (uPAR) expression in prostate tumor cells. There is evidence that activation of this receptor correlates with tumor metastasis. These studies show strong inhibitory activity of DBP-maf on prostate tumor cells independent of its macrophage activation.

Vitamin D Binding Protein-Macrophage Activating Factor Directly Inhibits Proliferation, Migration, and uPAR Expression of Prostate Cancer Cells

PubMed Central

Bielenberg, Diane R.; Dridi, Sami; Wu, Jason; Jiang, Weihua; Huang, Bin; Pirie-Shepherd, Steven; Fannon, Michael

2010-01-01

Background Vitamin D binding protein-macrophage activating factor (DBP-maf) is a potent inhibitor of tumor growth. Its activity, however, has been attributed to indirect mechanisms such as boosting the immune response by activating macrophages and inhibiting the blood vessel growth necessary for the growth of tumors. Methods and Findings In this study we show for the first time that DBP-maf exhibits a direct and potent effect on prostate tumor cells in the absence of macrophages. DBP-maf demonstrated inhibitory activity in proliferation studies of both LNCaP and PC3 prostate cancer cell lines as well as metastatic clones of these cells. Flow cytometry studies with annexin V and propidium iodide showed that this inhibitory activity is not due to apoptosis or cell death. DBP-maf also had the ability to inhibit migration of prostate cancer cells in vitro. Finally, DBP-maf was shown to cause a reduction in urokinase plasminogen activator receptor (uPAR) expression in prostate tumor cells. There is evidence that activation of this receptor correlates with tumor metastasis. Conclusions These studies show strong inhibitory activity of DBP-maf on prostate tumor cells independent of its macrophage activation. PMID:20976141

Identification of a xanthine oxidase-inhibitory component from Sophora flavescens using NMR-based metabolomics.

PubMed

Suzuki, Ryuichiro; Hasuike, Yuka; Hirabayashi, Moeka; Fukuda, Tatsuo; Okada, Yoshihito; Shirataki, Yoshiaki

2013-10-01

We demonstrate that NMR-based metabolomics studies can be used to identify xanthine oxidase-inhibitory compounds in the diethyl ether soluble fraction prepared from a methanolic extract of Sophora flavescens. Loading plot analysis, accompanied by direct comparison of 1H NMR spectraexhibiting characteristic signals, identified compounds exhibiting inhibitory activity. NMR analysis indicated that these characteristic signals were attributed to flavanones such as sophoraflavanone G and kurarinone. Sophoraflavanone G showed inhibitory activity towards xanthine oxidase in an in vitro assay.

Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles.

PubMed

Janciauskiene, S

2001-03-26

Serine proteinase inhibitors (Serpins) are irreversible suicide inhibitors of proteases that regulate diverse physiological processes such as coagulation, fibrinolysis, complement activation, angiogenesis, apoptosis, inflammation, neoplasia and viral pathogenesis. The molecular structure and physical properties of serpins permit these proteins to adopt a number of variant conformations under physiological conditions including the native inhibitory form and several inactive, non-inhibitory forms, such as complexes with protease or other ligands, cleaved, polymerised and oxidised. Alterations of a serpin which affect its structure and/or secretion and thus reduce its functional levels may result in pathology. Serpin dysfunction has been implicated in thrombosis, emphysema, liver cirrhosis, immune hypersensitivity and mental disorders. The loss of inhibitory activity of serpins necessarily results in an imbalance between proteases and their inhibitors, but it may also have other physiological effects through the generation of abnormal concentrations of modified, non-inhibitory forms of serpins. Although these forms of inhibitory serpins are detected in tissues and fluids recovered from inflammatory sites, the important questions of which conditions result in generation of different molecular forms of serpins, what biological function these forms have, and which of them are directly linked to pathologies and/or may be useful markers for characterisation of disease states, remain to be answered. Elucidation of the biological activities of non-inhibitory forms of serpins may provide useful insights into the pathogenesis of diseases and suggest new therapeutic strategies.

COMPARISON OF ACUTE NEUROBEHAVIORAL AND CHOLINESTERASE INHIBITORY EFFECTS OF N-METHYL CARBAMATES IN RAT

EPA Science Inventory

There are few studies evaluating direct functional and biochemical consequences of exposure. In the present study of the acute toxicity of seven N-methyl carbamate pesticides, we evaluated the dose-response profiles of cholinesterase (ChE) inhibition in brain and erythrocytes (R...

Optimization of Neuronal-Computer Interface

DTIC Science & Technology

2009-06-23

for the inhibitory neurotransmitter gamma-aminobutyric acid ( GABA ) receptor subunit as a general marker of inhibitory neurons (Beck et al., 1993...These analyses confirmed the presence of GABA -positive neurons (Fig. 4). Fig 4: Cultures contain inhibitory neurons. Cultures were subjected to double...immunofluorescent analyses for neurofilaments (anti-NF) using monoclonal antibody SMI-32 and a polyclonal antibody directed against the GABA receptor

Flexible brain network reconfiguration supporting inhibitory control.

PubMed

Spielberg, Jeffrey M; Miller, Gregory A; Heller, Wendy; Banich, Marie T

2015-08-11

The ability to inhibit distracting stimuli from interfering with goal-directed behavior is crucial for success in most spheres of life. Despite an abundance of studies examining regional brain activation, knowledge of the brain networks involved in inhibitory control remains quite limited. To address this critical gap, we applied graph theory tools to functional magnetic resonance imaging data collected while a large sample of adults (n = 101) performed a color-word Stroop task. Higher demand for inhibitory control was associated with restructuring of the global network into a configuration that was more optimized for specialized processing (functional segregation), more efficient at communicating the output of such processing across the network (functional integration), and more resilient to potential interruption (resilience). In addition, there were regional changes with right inferior frontal sulcus and right anterior insula occupying more central positions as network hubs, and dorsal anterior cingulate cortex becoming more tightly coupled with its regional subnetwork. Given the crucial role of inhibitory control in goal-directed behavior, present findings identifying functional network organization supporting inhibitory control have the potential to provide additional insights into how inhibitory control may break down in a wide variety of individuals with neurological or psychiatric difficulties.

Autoinhibition of ETV6 DNA Binding Is Established by the Stability of Its Inhibitory Helix

PubMed Central

De, Soumya; Okon, Mark; Graves, Barbara J.; McIntosh, Lawrence P.

2017-01-01

The ETS transcriptional repressor ETV6 (or TEL) is autoinhibited by an α-helix that sterically blocks its DNA-binding ETS domain. The inhibitory helix is marginally stable and unfolds when ETV6 binds to either specific or non-specific DNA. Using NMR spectroscopy, we show that folding of the inhibitory helix requires a buried charge–dipole interaction with helix H1 of the ETS domain. This interaction also contributes directly to autoinhibition by precluding a highly conserved dipole-enhanced hydrogen bond between the phosphodiester backbone of bound DNA and the N terminus of helix H1. To probe further the thermodynamic basis of autoinhibition, ETV6 variants were generated with amino acid substitutions introduced along the solvent exposed surface of the inhibitory helix. These changes were designed to increase the intrinsic helical propensity of the inhibitory helix without perturbing its packing interactions with the ETS domain. NMR-monitored amide hydrogen exchange measurements confirmed that the stability of the folded inhibitory helix increases progressively with added helix-promoting substitutions. This also results in progressively reinforced autoinhibition and decreased DNA-binding affinity. Surprisingly, locking the inhibitory helix onto the ETS domain by a disulfide bridge severely impairs, but does not abolish DNA binding. Weak interactions still occur via an interface displaced from the canonical ETS domain DNA-binding surface. Collectively, these studies establish a direct thermodynamic linkage between inhibitory helix stability and ETV6 autoinhibition, and demonstrate that helix unfolding does not strictly precede DNA binding. Modulating inhibitory helix stability provides a potential route for the in vivo regulation of ETV6 activity. PMID:26920109

The Antiviral Effect of Baicalin on Enterovirus 71 In Vitro

PubMed Central

Li, Xiang; Liu, Yuanyuan; Wu, Tingting; Jin, Yue; Cheng, Jianpin; Wan, Changbiao; Qian, Weihe; Xing, Fei; Shi, Weifeng

2015-01-01

Baicalin is a flavonoid compound extracted from Scutellaria roots that has been reported to possess antibacterial, anti-inflammatory, and antiviral activities. However, the antiviral effect of baicalin on enterovirus 71 (EV71) is still unknown. In this study, we found that baicalin showed inhibitory activity on EV71 infection and was independent of direct virucidal or prophylactic effect and inhibitory viral absorption. The expressions of EV71/3D mRNA and polymerase were significantly blocked by baicalin treatment at early stages of EV71 infection. In addition, baicalin could decrease the expressions of FasL and caspase-3, as well as inhibit the apoptosis of EV71-infected human embryonal rhabdomyosarcoma (RD) cells. Altogether, these results indicate that baicalin exhibits potent antiviral effect on EV71 infection, probably through inhibiting EV71/3D polymerase expression and Fas/FasL signaling pathways. PMID:26295407

Incentive effect on inhibitory control in adolescents with early-life stress: an antisaccade study.

PubMed

Mueller, Sven C; Hardin, Michael G; Korelitz, Katherine; Daniele, Teresa; Bemis, Jessica; Dozier, Mary; Peloso, Elizabeth; Maheu, Francoise S; Pine, Daniel S; Ernst, Monique

2012-03-01

Early-life stress (ES) such as adoption, change of caregiver, or experience of emotional neglect may influence the way in which affected individuals respond to emotional stimuli of positive or negative valence. These modified responses may stem from a direct alteration of how emotional stimuli are coded, and/or the cognitive function implicated in emotion modulation, such as self-regulation or inhibition. These ES effects have been probed on tasks either targeting reward and inhibitory function. Findings revealed deficits in both reward processing and inhibitory control in ES youths. However, no work has yet examined whether incentives can improve automatic response or inhibitory control in ES youths. To determine whether incentives would only improve self-regulated voluntary actions or generalize to automated motoric responses, participants were tested on a mixed eye movement task that included reflex-like prosaccades and voluntary controlled antisaccade eye movements. Seventeen adopted children (10 females, mean age 11.3 years) with a documented history of neglect and 29 typical healthy youths (16 females, mean age 11.9 years) performed the mixed prosaccade/antisaccade task during monetary incentive conditions or during no-incentive conditions. Across both saccade types, ES adolescents responded more slowly than controls. As expected, control participants committed fewer errors on antisaccades during the monetary incentive condition relative to the no-incentive condition. By contrast, ES youths failed to show this incentive-related improvement on inhibitory control. No significant incentive effects were found with prepotent prosaccades trials in either group. Finally, co-morbid psychopathology did not modulate the findings. These data suggest that youths with experience of early stress exhibit deficient modulation of inhibitory control by reward processes, in tandem with a reward-independent deficit in preparation for both automatic and controlled responses. These data may be relevant to interventions in ES youths. Published by Elsevier Ltd.

Bioassay-guided fractionation and identification of α-amylase inhibitors from Syzygium cumini leaves.

PubMed

Poongunran, Jeyakumaran; Perera, Handunge Kumudu Irani; Jayasinghe, Lalith; Fernando, Irushika Thushari; Sivakanesan, Ramaiah; Araya, Hiroshi; Fujimoto, Yoshinori

2017-12-01

Pancreatic α-amylase and α-glucosidase inhibitors serve as important strategies in the management of blood glucose. Even though Syzygium cumini (L.) Skeels (Myrtaceae) (SC) is used extensively to treat diabetes; scientific evidence on antidiabetic effects of SC leaves is scarce. SC leaf extract was investigated for α-amylase inhibitory effect and continued with isolation and identification of α-amylase inhibitors. Bioassay-guided fractionation was conducted using in vitro α-amylase inhibitory assay (with 20-1000 μg/mL test material) to isolate the inhibitory compounds from ethyl acetate extract of SC leaves. Structures of the isolated inhibitory compounds were elucidated using 1 H NMR and 13 C NMR spectroscopic analysis and direct TLC and HPLC comparison with authentic samples. Study period was from October 2013 to October 2015. An active fraction obtained with chromatographic separation of the extract inhibited porcine pancreatic α-amylase with an IC 50 of 39.9 μg/mL. Furthermore, it showed a strong inhibition on α-glucosidase with an IC 50 of 28.2 μg/mL. The active fraction was determined to be a 3:1 mixture of ursolic acid and oleanolic acid. Pure ursolic acid and oleanolic acid showed IC 50 values of 6.7 and 57.4 μg/mL, respectively, against α-amylase and 3.1 and 44.1 μg/mL respectively, against α-glucosidase. The present study revealed strong α-amylase and α-glucosidase inhibitory effects of ursolic acid and oleanolic acid isolated from SC leaves for the first time validating the use of SC leaves in antidiabetic therapy.

Characteristics of cholinoreceptors on identified TAN neurons of the ground snail Achatina fulica.

PubMed

Stepanov, I I; Losev, N A

2000-01-01

The characteristics of cholinoreceptors located on neurons TAN1, TAN2, and TAN3 of the ground snail Achatina fulica were studied by incubation of the central ganglia in a bath with cholinotropic preparations during intracellular recording of background neuron spike activity. Acetylcholine, nicotine, the selective n-cholinoreceptor agonist suberyldicholine, and the selective n-cholinoreceptor agonist 5-methylfurmethide concentration-dependently inhibited background spike activity to the level of complete blockade at concentrations of 500 microM. The m-cholinoblocker metamizil (500 microM) completely prevented the inhibitory activity of concentrations of 5-methylfurmethide of up to 500 microM. The central n-cholinoblocker etherophen (500 microM) completely blocked the inhibitory activity of 500 microM suberyldicholine. However, metamizil and etherophen added separately only partially decreased the inhibitory effects of acetylcholine but could not completely block the effect of acetylcholine. At the same time, mixtures of metamizil and etherophen (500 microM each) completely blocked the inhibition of background spike activity induced by acetylcholine. These results show that both classes of cholinoreceptors act on TAN neurons in the same direction.

Differential regulation of primary afferent input to spinal cord by muscarinic receptor subtypes delineated using knockout mice.

PubMed

Chen, Shao-Rui; Chen, Hong; Yuan, Wei-Xiu; Wess, Jürgen; Pan, Hui-Lin

2014-05-16

Stimulation of muscarinic acetylcholine receptors (mAChRs) inhibits nociceptive transmission at the spinal level. However, it is unclear how each mAChR subtype regulates excitatory synaptic input from primary afferents. Here we examined excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation in spinal cord slices from wild-type and mAChR subtype knock-out (KO) mice. In wild-type mice, mAChR activation with oxotremorine-M decreased the amplitude of monosynaptic EPSCs in ∼67% of neurons but increased it in ∼10% of neurons. The inhibitory effect of oxotremorine-M was attenuated by the M2/M4 antagonist himbacine in the majority of neurons, and the remaining inhibition was abolished by group II/III metabotropic glutamate receptor (mGluR) antagonists in wild-type mice. In M2/M4 double-KO mice, oxotremorine-M inhibited monosynaptic EPSCs in significantly fewer neurons (∼26%) and increased EPSCs in significantly more neurons (33%) compared with wild-type mice. Blocking group II/III mGluRs eliminated the inhibitory effect of oxotremorine-M in M2/M4 double-KO mice. In M2 single-KO and M4 single-KO mice, himbacine still significantly reduced the inhibitory effect of oxotremorine-M. However, the inhibitory and potentiating effects of oxotremorine-M on EPSCs in M3 single-KO and M1/M3 double-KO mice were similar to those in wild-type mice. In M5 single-KO mice, oxotremorine-M failed to potentiate evoked EPSCs, and its inhibitory effect was abolished by himbacine. These findings indicate that activation of presynaptic M2 and M4 subtypes reduces glutamate release from primary afferents. Activation of the M5 subtype either directly increases primary afferent input or inhibits it through indirectly stimulating group II/III mGluRs. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Differential Regulation of Primary Afferent Input to Spinal Cord by Muscarinic Receptor Subtypes Delineated Using Knockout Mice*

PubMed Central

Chen, Shao-Rui; Chen, Hong; Yuan, Wei-Xiu; Wess, Jürgen; Pan, Hui-Lin

2014-01-01

Stimulation of muscarinic acetylcholine receptors (mAChRs) inhibits nociceptive transmission at the spinal level. However, it is unclear how each mAChR subtype regulates excitatory synaptic input from primary afferents. Here we examined excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation in spinal cord slices from wild-type and mAChR subtype knock-out (KO) mice. In wild-type mice, mAChR activation with oxotremorine-M decreased the amplitude of monosynaptic EPSCs in ∼67% of neurons but increased it in ∼10% of neurons. The inhibitory effect of oxotremorine-M was attenuated by the M2/M4 antagonist himbacine in the majority of neurons, and the remaining inhibition was abolished by group II/III metabotropic glutamate receptor (mGluR) antagonists in wild-type mice. In M2/M4 double-KO mice, oxotremorine-M inhibited monosynaptic EPSCs in significantly fewer neurons (∼26%) and increased EPSCs in significantly more neurons (33%) compared with wild-type mice. Blocking group II/III mGluRs eliminated the inhibitory effect of oxotremorine-M in M2/M4 double-KO mice. In M2 single-KO and M4 single-KO mice, himbacine still significantly reduced the inhibitory effect of oxotremorine-M. However, the inhibitory and potentiating effects of oxotremorine-M on EPSCs in M3 single-KO and M1/M3 double-KO mice were similar to those in wild-type mice. In M5 single-KO mice, oxotremorine-M failed to potentiate evoked EPSCs, and its inhibitory effect was abolished by himbacine. These findings indicate that activation of presynaptic M2 and M4 subtypes reduces glutamate release from primary afferents. Activation of the M5 subtype either directly increases primary afferent input or inhibits it through indirectly stimulating group II/III mGluRs. PMID:24695732

Restoration of miR-1305 relieves the inhibitory effect of nicotine on periodontal ligament-derived stem cell proliferation, migration, and osteogenic differentiation.

PubMed

Chen, Zhuo; Liu, Hui-Li

2017-04-01

Nicotine hinders the regenerative potentials of human periodontal ligament-derived stem cells (PDLSCs) and delays the healing process of periodontal diseases, but the underlying mechanism remains unclear. miR-1305 upregulation and its potential target RUNX2 downregulation exist in the PDLSCs exposed to nicotine. In this study, we aimed to investigate whether nicotine inhibits PDLSC proliferation, migration, and osteogenic differentiation by increasing miR-1305 level and decreasing RUNX2 level. Quantitative real-time PCR (qRT-PCR) and Western blot assays were performed to detect the expression levels of miR-1305 and RUNX2 in the PDLSCs exposed to nicotine, respectively. PDLSCs with miR-1305 overexpression, low expression, or RUNX2 overexpression were constructed by lipofectin transfection. MTT, migration, and Western blot assays were applied to assess the effect of miR-1305 on PDLSC proliferation, migration, and osteogenic differentiation, respectively. Target prediction and luciferase reporter assays were performed to investigate the targets of miR-1305. Nicotine promoted miR-1305 expression and inhibited RUNX2 expression in PDLSCs. Cell proliferation, migration, and differentiation detection showed that nicotine suppressed proliferation, migration, and osteogenic differentiation of PDLSCs, and restoration of miR-1305 relieved the inhibitory effect of nicotine on PDLSCs. Moreover, we identified and validated that RUNX2 was a direct target of miR-1305, and upregulation of RUNX2 had similar effects with the downregulation of miR-1305 on relieving the inhibitory effect of nicotine on PDLSCs. Nicotine suppresses proliferation, migration, and osteogenic differentiation of PDLSCs, and restoration of miR-1305 relieves the inhibitory effect of nicotine on PDLSCs depending on its target RUNX2. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Dosage-dependent non-linear effect of L-dopa on human motor cortex plasticity.

PubMed

Monte-Silva, Katia; Liebetanz, David; Grundey, Jessica; Paulus, Walter; Nitsche, Michael A

2010-09-15

The neuromodulator dopamine affects learning and memory formation and their likely physiological correlates, long-term depression and potentiation, in animals and humans. It is known from animal experiments that dopamine exerts a dosage-dependent, inverted U-shaped effect on these functions. However, this has not been explored in humans so far. In order to reveal a non-linear dose-dependent effect of dopamine on cortical plasticity in humans, we explored the impact of 25, 100 and 200 mg of L-dopa on transcranial direct current (tDCS)-induced plasticity in twelve healthy human subjects. The primary motor cortex served as a model system, and plasticity was monitored by motor evoked potential amplitudes elicited by transcranial magnetic stimulation. As compared to placebo medication, low and high dosages of L-dopa abolished facilitatory as well as inhibitory plasticity, whereas the medium dosage prolonged inhibitory plasticity, and turned facilitatory plasticity into inhibition. Thus the results show clear non-linear, dosage-dependent effects of dopamine on both facilitatory and inhibitory plasticity, and support the assumption of the importance of a specific dosage of dopamine optimally suited to improve plasticity. This might be important for the therapeutic application of dopaminergic agents, especially for rehabilitative purposes, and explain some opposing results in former studies.

A novel role for WAVE1 in controlling actin network growth rate and architecture

PubMed Central

Sweeney, Meredith O.; Collins, Agnieszka; Padrick, Shae B.; Goode, Bruce L.

2015-01-01

Branched actin filament networks in cells are assembled through the combined activities of Arp2/3 complex and different WASP/WAVE proteins. Here we used TIRF and electron microscopy to directly compare for the first time the assembly kinetics and architectures of actin filament networks produced by Arp2/3 complex and dimerized VCA regions of WAVE1, WAVE2, or N-WASP. WAVE1 produced strikingly different networks from WAVE2 or N-WASP, which comprised unexpectedly short filaments. Further analysis showed that the WAVE1-specific activity stemmed from an inhibitory effect on filament elongation both in the presence and absence of Arp2/3 complex, which was observed even at low stoichiometries of WAVE1 to actin monomers, precluding an effect from monomer sequestration. Using a series of VCA chimeras, we mapped the elongation inhibitory effects of WAVE1 to its WH2 (“V”) domain. Further, mutating a single conserved lysine residue potently disrupted WAVE1's inhibitory effects. Taken together, our results show that WAVE1 has unique activities independent of Arp2/3 complex that can govern both the growth rates and architectures of actin filament networks. Such activities may underlie previously observed differences between the cellular functions of WAVE1 and WAVE2. PMID:25473116

Tolerance response of multidrug-resistant Salmonella enterica strains to habituation to Origanum vulgare L. essential oil

PubMed Central

Monte, Daniel F. M.; Tavares, Adassa G.; Albuquerque, Allan R.; Sampaio, Fábio C.; Oliveira, Tereza C. R. M.; Franco, Octavio L.; Souza, Evandro L.; Magnani, Marciane

2014-01-01

Multidrug-resistant Salmonella enterica isolates from human outbreaks or from poultry origin were investigated for their ability to develop direct-tolerance or cross-tolerance to sodium chloride, potassium chloride, lactic acid, acetic acid, and ciprofloxacin after habituation in subinhibitory amounts ( of the minimum inhibitory concentration – (MIC) and of the minimum inhibitory concentration – MIC) of Origanum vulgare L. essential oil (OVEO) at different time intervals. The habituation of S. enterica to OVEO did not induce direct-tolerance or cross-tolerance in the tested strains, as assessed by the modulation of MIC values. However, cells habituated to OVEO maintained or increased susceptibility to the tested antimicrobials agents, with up to fourfold double dilution decrease from previously determined MIC values. This study reports for the first time the non-inductive effect of OVEO on the acquisition of direct-tolerance or cross-tolerance in multidrug-resistant S. enterica strains to antimicrobial agents that are largely used in food preservation, as well as to CIP, the therapeutic drug of salmonellosis. PMID:25566231

Working Memory and Cognitive Flexibility Mediates Visuoconstructional Abilities in Older Adults with Heterogeneous Cognitive Ability.

PubMed

Ávila, Rafaela T; de Paula, Jonas J; Bicalho, Maria A; Moraes, Edgar N; Nicolato, Rodrigo; Malloy-Diniz, Leandro F; Diniz, Breno S

2015-05-01

Previous studies suggest that executive functions influence the performance on visuoconstructional tasks. This study aims to investigate whether the relationship between planning ability and the copy of complex figures is mediated by distinct components of executive functions (i.e., working memory, inhibitory control and cognitive flexibility). We included a 129 older adults with Alzheimer's disease (n=36, AD), mild cognitive impairment (MCI, n=67), and with no evidence of cognitive impairment (controls, n=26). We evaluated the mediation effect of planning abilities, working memory, cognitive flexibility and inhibitory control on visuoconstructional tasks using a multiple mediation models. We found a significant direct effect of planning on visuoconstructional abilities and a partial mediation effect of working memory and cognitive flexibility on visuoconstructional abilities. The present results indicate that the performance on visuoconstructional task is mediated by multiple interrelated executive functions components, in particular working memory and cognitive flexibility.

Immunotherapy and gene therapy as novel treatments for cancer

PubMed Central

Rangel-Sosa, Martha Montserrat; Aguilar-Córdova, Estuardo

2017-01-01

Abstract The immune system interacts closely with tumors during the disease development and progression to metastasis. The complex communication between the immune system and the tumor cells can prevent or promote tumor growth. New therapeutic approaches harnessing protective immunological mechanisms have recently shown very promising results. This is performed by blocking inhibitory signals or by activating immunological effector cells directly. Immune checkpoint blockade with monoclonal antibodies directed against the inhibitory immune receptors CTLA-4 and PD-1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is an anti-CTLA-4 antibody which demonstrated good results when administered to patients with melanoma. Gene therapy has also shown promising results in clinical trials. Particularly, Herpes simplex virus (HSV)-mediated delivery of the HSV thymidine kinase (TK) gene to tumor cells in combination with ganciclovir (GCV) may provide an effective suicide gene therapy for destruction of glioblastomas, prostate tumors and other neoplasias by recruiting tumor-infiltrating lymphocytes into the tumor. The development of new treatment strategies or combination of available innovative therapies to improve cell cytotoxic T lymphocytes trafficking into the tumor mass and the production of inhibitory molecules blocking tumor tissue immune-tolerance are crucial to improve the efficacy of cancer therapy. PMID:29213157

Direct Inhibitory Effect of Hypercalcemia on Renal Actions of Parathyroid Hormone

PubMed Central

Beck, Nama; Singh, Harbans; Reed, Sarah W.; Davis, Bernard B.

1974-01-01

The effects of calcium on the renal actions of parathyroid hormone (PTH) were studied in vivo and in vitro. In parathyroidectomized rats, variable levels of blood calcium concentration were induced by intravenous infusion of calcium. The renal responses to the injected PTH, i.e. phosphate and cyclic AMP excretion, were compared in these animals. After PTH injection, the increases of both phosphate and cyclic AMP excretion were less in the calcium-infused animals than in the control group without calcium infusion. There was an inverse correlation between the renal responses to PTH and plasma calcium concentration of 4.2-13.5 mg/100 ml. But calcium had no effect on phosphate excretion induced by infusion of dibutyryl cyclic AMP. In the in vitro experiments, the increase of cyclic AMP concentration in response to PTH was less in renal cortical slices taken from the calcium-infused animals than in ones from the control group without calcium infusion. Calcium also inhibited the activation of renal cortical adenylate cyclase in response to PTH, but calcium had no effect on phosphodiesterase. The data indicate that calcium directly inhibits renal actions of PTH both in vivo and in vitro. Such inhibitory mechanism is probably at or before the step of PTH-dependent cyclic AMP generation in the kidney. PMID:4359938

The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer.

PubMed

Khan, Mohammad W; Saadalla, Abdulrahman; Ewida, Ahmed H; Al-Katranji, Khalid; Al-Saoudi, Ghadier; Giaccone, Zachary T; Gounari, Fotini; Zhang, Ming; Frank, David A; Khazaie, Khashayarsha

2018-01-01

The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8 + T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.

The inhibitory effect of somatostatin peptides on the rat anococcygeus muscle in vitro.

PubMed Central

Priestley, T.; Woodruff, G. N.

1988-01-01

1. Electrically evoked contractions of the rat anococcygeus muscle were inhibited in a concentration-dependent manner by somatostatin-14 (SS14), -28 (SS28) and two synthetic hexapeptide analogues: L-363,301 (Pro-Phe-D-Trp-Lys-Thr-Phe) and L-363,586 (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), with pIC50 values of 7.41, 7.38, 7.07 and 8.34, respectively. 2. The inhibitory effects of SS14 were dependent on stimulation frequency and external calcium ion concentration. Calcium behaved as a non-competitive antagonist of SS14, it reduced the maximal inhibitory effect of the peptide and at a concentration of 5.08 mM it significantly affected the pIC50 value. 3. SS14 (3 x 10(-7) M) did not affect the tonic actions of bath-applied noradrenaline in the absence of field stimulation. 4. The effects of SS14 persisted in naloxone (10(-5) M) and were, therefore, not due to an action at opiate receptors. Furthermore, experiments involving the lyophilization of bath contents, showed no evidence to support an indirect mechanism involving the release of an endogenous inhibitory substance. 5. High concentrations (10(-5) M) of SS14 or L-363,301 inhibited the relaxation response evoked by electrical stimulation of guanethidine (3 x 10(-4) M)-treated preparations. 6. These results are consistent with similar actions of SS14 on other smooth muscle preparations and are presumed to reflect a presynaptic inhibition of transmitter release by a direct action on somatostatin receptors. The antagonistic effect of calcium on this response is discussed with reference to a possible role in receptor desensitization. PMID:2900039

Rapid Long-Range Disynaptic Inhibition Explains the Formation of Cortical Orientation Maps

PubMed Central

Antolík, Ján

2017-01-01

Competitive interactions are believed to underlie many types of cortical processing, ranging from memory formation, attention and development of cortical functional organization (e.g., development of orientation maps in primary visual cortex). In the latter case, the competitive interactions happen along the cortical surface, with local populations of neurons reinforcing each other, while competing with those displaced more distally. This specific configuration of lateral interactions is however in stark contrast with the known properties of the anatomical substrate, i.e., excitatory connections (mediating reinforcement) having longer reach than inhibitory ones (mediating competition). No satisfactory biologically plausible resolution of this conflict between anatomical measures, and assumed cortical function has been proposed. Recently a specific pattern of delays between different types of neurons in cat cortex has been discovered, where direct mono-synaptic excitation has approximately the same delay, as the combined delays of the disynaptic inhibitory interactions between excitatory neurons (i.e., the sum of delays from excitatory to inhibitory and from inhibitory to excitatory neurons). Here we show that this specific pattern of delays represents a biologically plausible explanation for how short-range inhibition can support competitive interactions that underlie the development of orientation maps in primary visual cortex. We demonstrate this statement analytically under simplifying conditions, and subsequently show using network simulations that development of orientation maps is preserved when long-range excitation, direct inhibitory to inhibitory interactions, and moderate inequality in the delays between excitatory and inhibitory pathways is added. PMID:28408869

CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds.

PubMed

Hargrove, Tatiana Y; Kim, Kwangho; de Nazaré Correia Soeiro, Maria; da Silva, Cristiane França; Batista, Denise da Gama Jaen; Batista, Marcos Meuser; Yazlovitskaya, Eugenia M; Waterman, Michael R; Sulikowski, Gary A; Lepesheva, Galina I

2012-12-01

CYP51 (sterol 14α-demethylase) is a cytochrome P450 enzyme essential for sterol biosynthesis and the primary target for clinical and agricultural antifungal azoles. The azoles that are currently in clinical use for systemic fungal infections represent modifications of two basic scaffolds, ketoconazole and fluconazole, all of them being selected based on their antiparasitic activity in cellular experiments. By studying direct inhibition of CYP51 activity across phylogeny including human pathogens Trypanosoma brucei , Trypanosoma cruzi and Leishmania infantum , we identified three novel protozoa-specific inhibitory scaffolds, their inhibitory potency correlating well with antiprotozoan activity. VNI scaffold (carboxamide containing β-phenyl-imidazoles) is the most promising among them: killing T. cruzi amastigotes at low nanomolar concentration, it is also easy to synthesize and nontoxic. Oral administration of VNI (up to 400 mg/kg) neither leads to mortality nor reveals significant side effects up to 48 h post treatment using an experimental mouse model of acute toxicity. Trypanosomatidae CYP51 crystal structures determined in the ligand-free state and complexed with several azole inhibitors as well as a substrate analog revealed high rigidity of the CYP51 substrate binding cavity, which must be essential for the enzyme strict substrate specificity and functional conservation. Explaining profound potency of the VNI inhibitory scaffold, the structures also outline guidelines for its further development. First steps of the VNI scaffold optimization have been undertaken; the results presented here support the notion that CYP51 structure-based rational design of more efficient, pathogen-specific inhibitors represents a highly promising direction.

Mapuche herbal medicine inhibits blood platelet aggregation.

PubMed

Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

2012-01-01

12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM) and collagen- (2.0 μg/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H(2)O), Amomyrtus luma (DCM : MeOH 1 : 1) and Cestrum parqui (DCM : MeOH 1 : 1). The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1), and L. apiculata (H(2)O) were substantial and confirmed by inhibition of platelet surface activation markers.

Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

PubMed Central

Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

2012-01-01

12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM) and collagen- (2.0 μg/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H2O), Amomyrtus luma (DCM : MeOH 1 : 1) and Cestrum parqui (DCM : MeOH 1 : 1). The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1), and L. apiculata (H2O) were substantial and confirmed by inhibition of platelet surface activation markers. PMID:22028732

Competitive inhibition of the nondepolarizing muscle relaxant rocuronium on nicotinic acetylcholine receptor channels in the rat superior cervical ganglia.

PubMed

Zhang, Chengmi; Wang, Zhenmeng; Zhang, Jinmin; Qiu, Haibo; Sun, Yuming; Yang, Liqun; Wu, Feixiang; Zheng, Jijian; Yu, Weifeng

2014-05-01

A number of case reports now indicate that rocuronium can induce a number of serious side effects. We hypothesized that these side effects might be mediated by the inhibition of nicotinic acetylcholine receptors (nAChRs) at superior cervical ganglion (SCG) neurons. Conventional patch clamp recordings were used to study the effects of rocuronium on nAChR currents from enzymatically dissociated rat SCG neurons. We found that ACh induced a peak transient inward current in rat SCG neurons. Additionally, rocuronium suppressed the peak ACh-evoked currents in rat SCG neurons in a concentration-dependent and competitive manner, and it increased the extent of desensitization of nAChRs. The inhibitory rate of rocuronium on nAChR currents did not change significantly at membrane potentials between -70 and -20 mV, suggesting that this inhibition was voltage independent. Lastly, rocuronium preapplication enhanced its inhibitory effect, indicating that this drug might prefer to act on the closed state of nAChR channels. In conclusion, rocuronium, at clinically relevant concentrations, directly inhibits nAChRs at the SCG by interacting with both opened and closed states. This inhibition is competitive, dose dependent, and voltage independent. Blockade of synaptic transmission in the sympathetic ganglia by rocuronium might have potentially inhibitory effects on the cardiovascular system.

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice.

PubMed

McCall, Nora M; Kotecki, Lydia; Dominguez-Lopez, Sergio; Marron Fernandez de Velasco, Ezequiel; Carlblom, Nicholas; Sharpe, Amanda L; Beckstead, Michael J; Wickman, Kevin

2017-02-01

The increase in dopamine (DA) neurotransmission stimulated by in vivo cocaine exposure is tempered by G protein-dependent inhibitory feedback mechanisms in DA neurons of the ventral tegmental area (VTA). G protein-gated inwardly rectifying K + (GIRK/Kir3) channels mediate the direct inhibitory effect of GABA B receptor (GABA B R) and D 2 DA receptor (D 2 R) activation in VTA DA neurons. Here we examined the effect of the DA neuron-specific loss of GIRK channels on D 2 R-dependent regulation of VTA DA neuron excitability and on cocaine-induced, reward-related behaviors. Selective ablation of Girk2 in DA neurons did not alter the baseline excitability of VTA DA neurons but significantly reduced the magnitude of D 2 R-dependent inhibitory somatodendritic currents and blunted the impact of D 2 R activation on spontaneous activity and neuronal excitability. Mice lacking GIRK channels in DA neurons exhibited increased locomotor activation in response to acute cocaine administration and an altered locomotor sensitization profile, as well as increased responding for and intake of cocaine in an intravenous self-administration test. These mice, however, showed unaltered cocaine-induced conditioned place preference. Collectively, our data suggest that feedback inhibition to VTA DA neurons, mediated by GIRK channel activation, tempers the locomotor stimulatory effect of cocaine while also modulating the reinforcing effect of cocaine in an operant-based self-administration task.

Inhibitory activities of some vitamins on the formation of cholesterol oxidation products in beef patties.

PubMed

Wong, Daniel; Wang, Mingfu

2013-09-04

The capacities of 15 vitamins to inhibit the formation of 7α-hydroxycholesterol, 7β-hydroxycholesterol, and 7-ketocholesterol were examined in beef patties. Their inhibitory activities were tested at a concentration of 0.4 mmol in 30 g of beef. Among them, L-ascorbic acid, retinoic acid, and α-(±)-tocopherol were found to exert a potent inhibitory effect (30-50%) on 7-ketocholesterol formation and (~20%) on 7α-hydroxycholesterol and 7β-hydroxycholesterol formations. Pyridoxamine inhibited 7-ketocholesterol formation by 60% with a statistically significant difference (p < 0.05) from that achieved in the control setup. To further elucidate the possible inhibitory mechanism of pyridoxamine against cholesterol oxidation, a chemical model with pyridoxamine added in the cholesterol oxidation system (heated at 140 °C for 240 min in dimethyl sulfoxide) was employed. It was demonstrated that pyridoxamine could directly react with 7-ketocholesterol via the addition reaction. The reaction involved a nucleophilic attack of the free amine group of pyridoxamine on 7-ketocholesterol (an α,β-unsaturated carbonyl compound). This type of reaction was also found to occur in beef patties by chromatographic and spectral analyses.

Behavioral Self-Regulation and Executive Function Both Predict Visuomotor Skills and Early Academic Achievement

ERIC Educational Resources Information Center

Becker, Derek R.; Miao, Alicia; Duncan, Robert; McClelland, Megan M.

2014-01-01

The present study explored direct and interactive effects between behavioral self-regulation (SR) and two measures of executive function (EF, inhibitory control and working memory), with a fine motor measure tapping visuomotor skills (VMS) in a sample of 127 prekindergarten and kindergarten children. It also examined the relative contribution of…

Differential behavioral and physiological effects of anodal transcranial direct current stimulation in healthy adults of younger and older age

PubMed Central

Heise, Kirstin-Friederike; Niehoff, Martina; Feldheim, J.-F.; Liuzzi, Gianpiero; Gerloff, Christian; Hummel, Friedhelm C.

2014-01-01

Changes in γ-aminobutyric acid (GABA) mediated synaptic transmission have been associated with age-related motor and cognitive functional decline. Since anodal transcranial direct current stimulation (atDCS) has been suggested to target cortical GABAergic inhibitory interneurons, its potential for the treatment of deficient inhibitory activity and functional decline is being increasingly discussed. Therefore, after-effects of a single session of atDCS on resting-state and event-related short-interval intracortical inhibition (SICI) as evaluated with double-pulse TMS and dexterous manual performance were examined using a sham-controlled cross-over design in a sample of older and younger participants. The atDCS effect on resting-state inhibition differed in direction, magnitude, and timing, i.e., late relative release of inhibition in the younger and early relative increase in inhibition in the older. More pronounced release of event-related inhibition after atDCS was exclusively seen in the older. Event-related modulation of inhibition prior to stimulation predicted the magnitude of atDCS-induced effects on resting-state inhibition. Specifically, older participants with high modulatory capacity showed a disinhibitory effect comparable to the younger. Beneficial effects on behavior were mainly seen in the older and in tasks requiring higher dexterity, no clear association with physiological changes was found. Differential effects of atDCS on SICI, discussed to reflect GABAergic inhibition at the level of the primary motor cortex, might be distinct in older and younger participants depending on the functional integrity of the underlying neural network. Older participants with preserved modulatory capacity, i.e., a physiologically “young” motor network, were more likely to show a disinhibitory effect of atDCS. These results favor individually tailored application of tDCS with respect to specific target groups. PMID:25071555

Spike-timing dependent inhibitory plasticity to learn a selective gating of backpropagating action potentials.

PubMed

Wilmes, Katharina Anna; Schleimer, Jan-Hendrik; Schreiber, Susanne

2017-04-01

Inhibition is known to influence the forward-directed flow of information within neurons. However, also regulation of backward-directed signals, such as backpropagating action potentials (bAPs), can enrich the functional repertoire of local circuits. Inhibitory control of bAP spread, for example, can provide a switch for the plasticity of excitatory synapses. Although such a mechanism is possible, it requires a precise timing of inhibition to annihilate bAPs without impairment of forward-directed excitatory information flow. Here, we propose a specific learning rule for inhibitory synapses to automatically generate the correct timing to gate bAPs in pyramidal cells when embedded in a local circuit of feedforward inhibition. Based on computational modeling of multi-compartmental neurons with physiological properties, we demonstrate that a learning rule with anti-Hebbian shape can establish the required temporal precision. In contrast to classical spike-timing dependent plasticity of excitatory synapses, the proposed inhibitory learning mechanism does not necessarily require the definition of an upper bound of synaptic weights because of its tendency to self-terminate once annihilation of bAPs has been reached. Our study provides a functional context in which one of the many time-dependent learning rules that have been observed experimentally - specifically, a learning rule with anti-Hebbian shape - is assigned a relevant role for inhibitory synapses. Moreover, the described mechanism is compatible with an upregulation of excitatory plasticity by disinhibition. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Discovered acetylcholinesterase inhibition and antibacterial activity of polyacetylenes in tansy root extract via effect-directed chromatographic fingerprints.

PubMed

Móricz, Ágnes M; Ott, Péter G; Morlock, Gertrud E

2018-03-30

The knowledge about the activity of polyacetylenes was extended by their new acetylcholinesterase inhibition and antibacterial activity against plant pathogenic bacteria. For this discovery, an utmost streamlined workflow, which we consider to be of high potential in the field of natural product or superfood search was developed. It demonstrates the combined power of biological, biochemical and chemical fingerprints. Bioactive components of tansy (Tanacetum vulgare L.) root extract were profiled and identified by high-performance thin-layer chromatography hyphenated with in situ effect-directed analysis, chemical derivatizations and high-resolution mass spectrometry (HPTLC-UV/Vis/FLD-EDA-HRMS). The effect-directed profiling was performed using four bacterial bioassays including two plant pathogens, an antioxidant assay and acetyl- and butyrylcholinesterase inhibitory assays. The chromatographic, spectral and powerful mass spectrometric study of zones that exerted substantial antibacterial and/or antioxidant and/or acetylcholinesterase inhibitory effects allowed these multi-potent zones to be identified as polyacetylenes. Five polyacetylene compounds were assigned to be 2-non-1-ene-3,5,7-triynyl-3-vinyl-oxirane, 2-(2,4-hexadiynylidene)-3,4-epoxy-1,6-dioxaspiro[4.5]decane, trans- and cis-2-(2,4-hexadiynylidene)-1,6-dioxaspiro[4.5]dec-3-ene and tetradeca-2,4,6-triine-8-en-12-one. This study clearly showed the advantage of the combined use of different ionization sources, i.e. electrospray ionization via an elution-head based interface and also the Direct Analysis in Real Time interface, for HRMS analysis of compounds from the same class with very similar chromatographic behavior and polarity. Copyright © 2018 Elsevier B.V. All rights reserved.

Is transcranial direct current stimulation a potential method for improving response inhibition?☆

PubMed Central

Kwon, Yong Hyun; Kwon, Jung Won

2013-01-01

Inhibitory control of movement in motor learning requires the ability to suppress an inappropriate action, a skill needed to stop a planned or ongoing motor response in response to changes in a variety of environments. This study used a stop-signal task to determine whether transcranial direct-current stimulation over the pre-supplementary motor area alters the reaction time in motor inhibition. Forty healthy subjects were recruited for this study and were randomly assigned to either the transcranial direct-current stimulation condition or a sham-transcranial direct-current stimulation condition. All subjects consecutively performed the stop-signal task before, during, and after the delivery of anodal transcranial direct-current stimulation over the pre-supplementary motor area (pre-transcranial direct-current stimulation phase, transcranial direct-current stimulation phase, and post-transcranial direct-current stimulation phase). Compared to the sham condition, there were significant reductions in the stop-signal processing times during and after transcranial direct-current stimulation, and change times were significantly greater in the transcranial direct-current stimulation condition. There was no significant change in go processing-times during or after transcranial direct-current stimulation in either condition. Anodal transcranial direct-current stimulation was feasibly coupled to an interactive improvement in inhibitory control. This coupling led to a decrease in the stop-signal process time required for the appropriate responses between motor execution and inhibition. However, there was no transcranial direct-current stimulation effect on the no-signal reaction time during the stop-signal task. Transcranial direct-current stimulation can adjust certain behaviors, and it could be a useful clinical intervention for patients who have difficulties with response inhibition. PMID:25206399

Is transcranial direct current stimulation a potential method for improving response inhibition?

PubMed

Kwon, Yong Hyun; Kwon, Jung Won

2013-04-15

Inhibitory control of movement in motor learning requires the ability to suppress an inappropriate action, a skill needed to stop a planned or ongoing motor response in response to changes in a variety of environments. This study used a stop-signal task to determine whether transcranial direct-current stimulation over the pre-supplementary motor area alters the reaction time in motor inhibition. Forty healthy subjects were recruited for this study and were randomly assigned to either the transcranial direct-current stimulation condition or a sham-transcranial direct-current stimulation condition. All subjects consecutively performed the stop-signal task before, during, and after the delivery of anodal transcranial direct-current stimulation over the pre-supplementary motor area (pre-transcranial direct-current stimulation phase, transcranial direct-current stimulation phase, and post-transcranial direct-current stimulation phase). Compared to the sham condition, there were significant reductions in the stop-signal processing times during and after transcranial direct-current stimulation, and change times were significantly greater in the transcranial direct-current stimulation condition. There was no significant change in go processing-times during or after transcranial direct-current stimulation in either condition. Anodal transcranial direct-current stimulation was feasibly coupled to an interactive improvement in inhibitory control. This coupling led to a decrease in the stop-signal process time required for the appropriate responses between motor execution and inhibition. However, there was no transcranial direct-current stimulation effect on the no-signal reaction time during the stop-signal task. Transcranial direct-current stimulation can adjust certain behaviors, and it could be a useful clinical intervention for patients who have difficulties with response inhibition.

Direction selectivity in the larval zebrafish tectum is mediated by asymmetric inhibition.

PubMed

Grama, Abhinav; Engert, Florian

2012-01-01

The extraction of the direction of motion is an important computation performed by many sensory systems and in particular, the mechanism by which direction-selective retinal ganglion cells (DS-RGCs) in the retina acquire their selective properties, has been studied extensively. However, whether DS-RGCs simply relay this information to downstream areas or whether additional and potentially de novo processing occurs in these recipient structures is a matter of great interest. Neurons in the larval zebrafish tectum, the largest retino-recipent area in this animal, show direction-selective (DS) responses to moving visual stimuli but how these properties are acquired is still unknown. In order to study this, we first used two-photon calcium imaging to classify the population responses of tectal cells to bars moving at different speeds and in different directions. Subsequently, we performed in vivo whole cell electrophysiology on these DS tectal neurons and we found that their inhibitory inputs were strongly biased toward the null direction of motion, whereas the excitatory inputs showed little selectivity. In addition, we found that excitatory currents evoked by a stimulus moving in the preferred direction occurred before the inhibitory currents whereas a stimulus moving in the null direction evoked currents in the reverse temporal order. The membrane potential modulations resulting from these currents were enhanced by the spike generation mechanism to generate amplified direction selectivity in the spike output. Thus, our results implicate a local inhibitory circuit in generating direction selectivity in tectal neurons.

Direction selectivity in the larval zebrafish tectum is mediated by asymmetric inhibition

PubMed Central

Grama, Abhinav; Engert, Florian

2012-01-01

The extraction of the direction of motion is an important computation performed by many sensory systems and in particular, the mechanism by which direction-selective retinal ganglion cells (DS-RGCs) in the retina acquire their selective properties, has been studied extensively. However, whether DS-RGCs simply relay this information to downstream areas or whether additional and potentially de novo processing occurs in these recipient structures is a matter of great interest. Neurons in the larval zebrafish tectum, the largest retino-recipent area in this animal, show direction-selective (DS) responses to moving visual stimuli but how these properties are acquired is still unknown. In order to study this, we first used two-photon calcium imaging to classify the population responses of tectal cells to bars moving at different speeds and in different directions. Subsequently, we performed in vivo whole cell electrophysiology on these DS tectal neurons and we found that their inhibitory inputs were strongly biased toward the null direction of motion, whereas the excitatory inputs showed little selectivity. In addition, we found that excitatory currents evoked by a stimulus moving in the preferred direction occurred before the inhibitory currents whereas a stimulus moving in the null direction evoked currents in the reverse temporal order. The membrane potential modulations resulting from these currents were enhanced by the spike generation mechanism to generate amplified direction selectivity in the spike output. Thus, our results implicate a local inhibitory circuit in generating direction selectivity in tectal neurons. PMID:22969706

Nicotinamide Inhibits the Lysosomal Cathepsin b-like Protease and Kills African Trypanosomes*

PubMed Central

Unciti-Broceta, Juan D.; Maceira, José; Morales, Sonia; García-Pérez, Angélica; Muñóz-Torres, Manuel E.; Garcia-Salcedo, Jose A.

2013-01-01

Nicotinamide, a soluble compound of the vitamin B3 group, has antimicrobial activity against several microorganisms ranging from viruses to parasite protozoans. However, the mode of action of this antimicrobial activity is unknown. Here, we investigate the trypanocidal activity of nicotinamide on Trypanosoma brucei, the causative agent of African trypanosomiasis. Incubation of trypanosomes with nicotinamide causes deleterious defects in endocytic traffic, disruption of the lysosome, failure of cytokinesis, and, ultimately, cell death. At the same concentrations there was no effect on a cultured mammalian cell line. The effects on endocytosis and vesicle traffic were visible within 3 h and can be attributed to inhibition of lysosomal cathepsin b-like protease activity. The inhibitory effect of nicotinamide was confirmed by a direct activity assay of recombinant cathepsin b-like protein. Taken together, these data demonstrate that inhibition of the lysosomal protease cathepsin b-like blocks endocytosis, causing cell death. In addition, these results demonstrate for the first time the inhibitory effect of nicotinamide on a protease. PMID:23443665

Production of rhamnolipids by Pseudomonas aeruginosa is inhibited by H2S but resumes in a co-culture with P. stutzeri: applications for microbial enhanced oil recovery.

PubMed

Zhao, Feng; Ma, Fang; Shi, Rongjiu; Zhang, Jie; Han, Siqin; Zhang, Ying

2015-09-01

Sulfate-reducing bacteria and H2S exist widely in oil production systems, and in situ production of rhamnolipids is promising for microbial enhanced oil recovery (MEOR). However, information of the effect of S(2-) on rhamnolipids production is scarce. Two facultative anaerobic rhamnolipids-producing bacterial strains, Pseudomonas aeruginosa SG and WJ-1, were used. Above 10 mg S(2-)/l, both cell growth and rhamnolipids production were inhibited. A large inoculum (9%, v/v) failed to completely relieve the inhibitory effect of 10 mg S(2-)/l. Below 30 mg S(2-)/l, both strains resumed rhamnolipid production through co-culturing with the denitrifying and sulphide-removing strain Pseudomonas stutzeri DQ1. H2S has a direct but reversible inhibitory effect on rhamnolipids production. Control of H2S in oilfields is indispensable to MEOR, and the co-culture method is effective in restoring rhamnolipid production in presence of S(2-).

Inhibitory effects of crude extracts from several plants on postharvest pathogens of citrus

NASA Astrophysics Data System (ADS)

Gong, Mingfu; Guan, Qinlan; Xu, Shanshan

2018-04-01

China is one of the most important origin of citrus. Enormous economic losses was caused by fungal diseases in citrus harvest storage every year. The effective antimicrobial substances of garlic, ginger, celery and pepper were extracted by ethanol extraction and water extraction respectively. The inhibitory effects of the crude extract on Penicillium sp. caused fungal diseases in citrus harvest storage were also determined. The results showed that the extracts of garlic, ginger and celery had inhibitory effect on P. sp., but the extracts of pepper had no inhibitory effect on P. sp.. The garlic ethanol extracts had the best inhibitory effect on P. citrinum.

Discovery of potent 1H-imidazo[4,5-b]pyridine-based c-Met kinase inhibitors via mechanism-directed structural optimization.

PubMed

An, Xiao-De; Liu, Hongyan; Xu, Zhong-Liang; Jin, Yi; Peng, Xia; Yao, Ying-Ming; Geng, Meiyu; Long, Ya-Qiu

2015-02-01

Starting from our previously identified novel c-Met kinase inhibitors bearing 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one scaffold, a global structural exploration was conducted to furnish an optimal binding motif for further development, directed by the enzyme inhibitory mechanism. First round SAR study picked two imidazonaphthyridinone frameworks with 1,8- and 3,5-disubstitution pattern as class I and class II c-Met kinase inhibitors, respectively. Further structural optimization on type II inhibitors by truncation of the imidazonaphthyridinone core and incorporation of an N-phenyl cyclopropane-1,1-dicarboxamide pharmacophore led to the discovery of novel imidazopyridine-based c-Met kinase inhibitors, displaying nanomolar enzyme inhibitory activity and improved Met kinase selectivity. More significantly, the new chemotype c-Met kinase inhibitors effectively inhibited Met phosphorylation and its downstream signaling as well as the proliferation of Met-dependent EBC-1 human lung cancer cells at submicromolar concentrations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Differential effects of leptin on ovarian metalloproteinases and their tissue inhibitors between in vivo and in vitro studies.

PubMed

Bilbao, M G; Di Yorio, M P; Faletti, A G

2011-04-01

In this study, we investigated the effect of leptin on the ovarian metalloproteinase system in the rat during the ovulatory process. Ovulation was induced in immature rats primed with gonadotropins. In both in vitro and in vivo experiments, we measured i) the protein expression of the ovarian metalloproteinases (matrix metalloproteinases, MMPs) and their tissue inhibitors (TIMPs) by western blot; ii) the gelatinase activity of the ovarian MMPs by zymography; and iii) the inhibitory action of TIMPs by reverse zymography. Using cultures of ovarian explants, leptin increased the activity but not the protein expression of MMP-2 and MMP-9 in both culture medium and ovarian tissue, and the protein expression of TIMPs, without a higher inhibitory action of the gelatinase activity. These results suggest either that the increase in TIMP proteins was not sufficient or that the inhibitory actions of TIMPs were impaired to suppress the MMP activity when the ovaries were directly exposed to leptin. To study the in vivo effect, rats received an acute treatment with high doses of leptin to inhibit ovulation. This treatment increased the expression of both the latent and the active forms of MMP-2 but did not result in a greater activity of MMP-2. In addition, the inhibitory action of TIMP-2 was also increased by this treatment. These results suggest that the administration of high doses of leptin could be regulating the follicle wall degradation, at least in part, by increasing the action of the ovarian TIMP-2 as a result of an extraovarian mechanism or signaling pathway.

Branch regeneration induced by sever damage in the brown alga Dictyota dichotoma (dictyotales, phaeophyceae).

PubMed

Tanaka, Atsuko; Hoshino, Yoichiro; Nagasato, Chikako; Motomura, Taizo

2017-05-01

Tissue wounds are mainly caused by herbivory, which is a serious threat for macro-algae, and brown algae are known to regenerate branches or buds in response to wounding. In the present paper, we describe a branch regeneration system, induced by sever damage, in the brown alga Dictyota dichotoma. Segmentations of juvenile thalli induced branch regenerations unless explants possessed apical cells. Apical excisions in distinct positions elucidated that disruption of an apical cell or disconnection of tissue with an apical cell triggered the branch regeneration. Furthermore, spatial positions of regenerated branches seemed to be regulated by the apical region, which was assumed to generate inhibitory effects for lateral branch regeneration. Mechanical incision, which disrupted tissue continuity with the apical region, induced branch regeneration preferentially below the incision. Although we were unable to identify the candidate inhibitory substance, our results suggested that the apical region may have an inhibitory effect on lateral branch regeneration. Additionally, observations of branch regeneration showed that all epidermal cells in D. dichotoma possess the ability to differentiate into apical cells, directly. This may be the first report of algal transdifferentiation during the wound-stress response.

Bilirubin Modulates Acetylcholine Receptors In Rat Superior Cervical Ganglionic Neurons In a Bidirectional Manner

PubMed Central

Zhang, Chengmi; Wang, Zhenmeng; Dong, Jing; Pan, Ruirui; Qiu, Haibo; Zhang, Jinmin; Zhang, Peng; Zheng, Jijian; Yu, Weifeng

2014-01-01

Autonomic dysfunction as a partial contributing factor to cardiovascular instability in jaundiced patients is often associated with increased serum bilirubin levels. Whether increased serum bilirubin levels could directly inhibit sympathetic ganglion transmission by blocking neuronal nicotinic acetylcholine receptors (nAChRs) remains to be elucidated. Conventional patch-clamp recordings were used to study the effect of bilirubin on nAChRs currents from enzymatically dissociated rat superior cervical ganglia (SCG) neurons. The results showed that low concnetrations (0.5 and 2 μM) of bilirubin enhanced the peak ACh-evoked currents, while high concentrations (3 to 5.5 µM) of bilirubin suppressed the currents with an IC50 of 4 ± 0.5 μM. In addition, bilirubin decreased the extent of desensitization of nAChRs in a concentration-dependent manner. This inhibitory effect of bilirubin on nAChRs channel currents was non-competitive and voltage independent. Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89. These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade. Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients. PMID:25503810

Network models of frequency modulated sweep detection.

PubMed

Skorheim, Steven; Razak, Khaleel; Bazhenov, Maxim

2014-01-01

Frequency modulated (FM) sweeps are common in species-specific vocalizations, including human speech. Auditory neurons selective for the direction and rate of frequency change in FM sweeps are present across species, but the synaptic mechanisms underlying such selectivity are only beginning to be understood. Even less is known about mechanisms of experience-dependent changes in FM sweep selectivity. We present three network models of synaptic mechanisms of FM sweep direction and rate selectivity that explains experimental data: (1) The 'facilitation' model contains frequency selective cells operating as coincidence detectors, summing up multiple excitatory inputs with different time delays. (2) The 'duration tuned' model depends on interactions between delayed excitation and early inhibition. The strength of delayed excitation determines the preferred duration. Inhibitory rebound can reinforce the delayed excitation. (3) The 'inhibitory sideband' model uses frequency selective inputs to a network of excitatory and inhibitory cells. The strength and asymmetry of these connections results in neurons responsive to sweeps in a single direction of sufficient sweep rate. Variations of these properties, can explain the diversity of rate-dependent direction selectivity seen across species. We show that the inhibitory sideband model can be trained using spike timing dependent plasticity (STDP) to develop direction selectivity from a non-selective network. These models provide a means to compare the proposed synaptic and spectrotemporal mechanisms of FM sweep processing and can be utilized to explore cellular mechanisms underlying experience- or training-dependent changes in spectrotemporal processing across animal models. Given the analogy between FM sweeps and visual motion, these models can serve a broader function in studying stimulus movement across sensory epithelia.

Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat

PubMed Central

Shepard, Paul D.

2016-01-01

The lateral habenula, a phylogenetically conserved epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the lateral habenula also directly targets dopamine neurons within the ventral tegmental area, suggesting that opposing actions may result from increased lateral habenula activity. In the present study, we tested the effect of habenular efferent stimulation on dopamine and nondopamine neurons in the ventral tegmental area of Sprague-Dawley rats using a parasagittal brain slice preparation. Single pulse stimulation of the fasciculus retroflexus excited 48% of dopamine neurons and 51% of nondopamine neurons in the ventral tegmental area of rat pups. These proportions were not altered by excision of the rostromedial tegmental nucleus and were evident in both cortical- and striatal-projecting dopamine neurons. Glutamate receptor antagonists blocked this excitation, and fasciculus retroflexus stimulation elicited evoked excitatory postsynaptic potentials with a nearly constant onset latency, indicative of a monosynaptic, glutamatergic connection. Comparison of responses in rat pups and young adults showed no significant difference in the proportion of neurons excited by fasciculus retroflexus stimulation. Our data indicate that the well-known, indirect inhibitory effect of lateral habenula activation on midbrain dopamine neurons is complemented by a significant, direct excitatory effect. This pathway may contribute to the role of midbrain dopamine neurons in processing aversive stimuli and salience. PMID:27358317

Direct and indirect antimicrobial effects and antioxidant activity of Cordia gilletii De Wild (Boraginaceae).

PubMed

Okusa, P N; Penge, O; Devleeschouwer, M; Duez, P

2007-07-25

Cordia gilletii De Wild (Boraginaceae) root bark is traditionally used in Democratic Republic of Congo (DRC) for the treatment of various disorders, including malaria, diarrhea, wounds and skin diseases; part of these activities may rely on antimicrobial and antioxidant properties. Successive extracts of root barks powder with n-hexane, dichloromethane, ethyl acetate, methanol and water were tested for antimicrobial activity, both direct and indirect (antibiotic resistance reversal), against 10 strains of bacteria and 1 strain of fungi by broth microdilution and agar diffusion methods. The eventual synergy between plant extracts and antibiotics was investigated by the determination of the fractional inhibitory concentration index (FIC index). The methanol extract showed direct antimicrobial activity against all tested microorganisms with minimum inhibitory concentrations (MIC) ranging between 125 and 1000 microg/ml, whereas the ethyl acetate and the dichloromethane extracts showed activity on four and three strains, respectively. 200 microg/ml of n-hexane and dichloromethane extracts decreased the MICs of penicillin and streptomycin 4-64-fold for methicillin-resistant Staphylococcus aureus. A synergistic effect was found between the methanol extract and tetracycline, whereas additive effects were observed for the other combinations tested. The methanol and dichloromethane extracts showed the greater antioxidant activity by scavenging the free radical DPPH with IC(50) values of 3.2 and 8.1 microg/ml, respectively. These results support the use of the plant in the treatment of infectious diseases and wounds; they warrant further studies as to the nature of active compounds.

Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat.

PubMed

Brown, P Leon; Shepard, Paul D

2016-09-01

The lateral habenula, a phylogenetically conserved epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the lateral habenula also directly targets dopamine neurons within the ventral tegmental area, suggesting that opposing actions may result from increased lateral habenula activity. In the present study, we tested the effect of habenular efferent stimulation on dopamine and nondopamine neurons in the ventral tegmental area of Sprague-Dawley rats using a parasagittal brain slice preparation. Single pulse stimulation of the fasciculus retroflexus excited 48% of dopamine neurons and 51% of nondopamine neurons in the ventral tegmental area of rat pups. These proportions were not altered by excision of the rostromedial tegmental nucleus and were evident in both cortical- and striatal-projecting dopamine neurons. Glutamate receptor antagonists blocked this excitation, and fasciculus retroflexus stimulation elicited evoked excitatory postsynaptic potentials with a nearly constant onset latency, indicative of a monosynaptic, glutamatergic connection. Comparison of responses in rat pups and young adults showed no significant difference in the proportion of neurons excited by fasciculus retroflexus stimulation. Our data indicate that the well-known, indirect inhibitory effect of lateral habenula activation on midbrain dopamine neurons is complemented by a significant, direct excitatory effect. This pathway may contribute to the role of midbrain dopamine neurons in processing aversive stimuli and salience. Copyright © 2016 the American Physiological Society.

Habituation of enterotoxigenic Staphylococcus aureus to Origanum vulgare L. essential oil does not induce direct-tolerance and cross-tolerance to salts and organic acids

PubMed Central

Tavares, Adassa Gama; do Monte, Daniel Farias Marinho; Albuquerque, Allan dos Reis; Sampaio, Fábio Correia; Magnani, Marciane; de Siqueira, José Pinto; de Souza, Evandro Leite

2015-01-01

Enterotoxigenic Staphylococcus aureus strains that were isolated from foods were investigated for their ability to develop direct-tolerance and cross-tolerance to sodium chloride (NaCl), potassium chloride (KCl), lactic acid (LA) and acetic acid (AA) after habituation in sublethal amounts (1/2 of the minimum inhibitory concentration - 1/2 MIC and 1/4 of the minimum inhibitory concentration - 1/4 MIC) of Origanum vulgare L. essential oil (OVEO). The habituation of S. aureus to 1/2 MIC and 1/4 MIC of OVEO did not induce direct-tolerance or cross-tolerance in the tested strains, as assessed by modulation of MIC values. Otherwise, exposing the strains to OVEO at sublethal concentrations maintained or increased the sensitivity of the cells to the tested stressing agents because the MIC values of OVEO, NaCl, KCl, LA and AA against the cells that were previously habituated to OVEO remained the same or decreased when compared with non-habituated cells. These data indicate that OVEO does not have an inductive effect on the acquisition of direct-tolerance or cross-tolerance in the tested enterotoxigenic strains of S. aureus to antimicrobial agents that are typically used in food preservation. PMID:26413067

Method of increasing radiation sensitivity by inhibition of beta one integrin

DOEpatents

Park, Catherine [San Francisco, CA; Bissell, Mina J [Berkeley, CA

2009-11-17

A method for increasing or monitoring apoptosis in tumor cells by the co-administration of ionizing radiation and an anti-integrin antibody. Increasing apoptosis reduces tumor growth in vivo and in a cell culture model. The antibody is directed against the beta-1 integrin subunit and is inhibitory of beta-1 integrin signaling. Other molecules having an inhibitory effect on beta-1 integrin, either in signaling or in binding to its cognate extracellular receptors may also be used. The present method is particularly of interest in treatment of tumor cells associated with breast cancer, wherein radiation is currently used alone. The present method further contemplates a monoclonal antibody suitable for human administration that may further comprise a radioisotope attached thereto.

Monetary rewards modulate inhibitory control

PubMed Central

Herrera, Paula M.; Speranza, Mario; Hampshire, Adam; Bekinschtein, Tristán A.

2014-01-01

The ability to override a dominant response, often referred to as behavioral inhibition, is considered a key element of executive cognition. Poor behavioral inhibition is a defining characteristic of several neurological and psychiatric populations. Recently, there has been increasing interest in the motivational dimension of behavioral inhibition, with some experiments incorporating emotional contingencies in classical inhibitory paradigms such as the Go/NoGo and Stop Signal Tasks (SSTs). Several studies have reported a positive modulatory effect of reward on performance in pathological conditions such as substance abuse, pathological gambling, and Attention Deficit Hyperactive Disorder (ADHD). However, experiments that directly investigate the modulatory effects of reward magnitudes on the performance of inhibitory tasks are scarce and little is known about the finer grained relationship between motivation and inhibitory control. Here we probed the effect of reward magnitude and context on behavioral inhibition with three modified versions of the widely used SST. The pilot study compared inhibition performance during six blocks alternating neutral feedback, low, medium, and high monetary rewards. Study One compared increasing vs. decreasing rewards, with low, high rewards, and neutral feedback; whilst Study Two compared low and high reward magnitudes alone also in an increasing and decreasing reward design. The reward magnitude effect was not demonstrated in the pilot study, probably due to a learning effect induced by practice in this lengthy task. The reward effect per se was weak but the context (order of reward) was clearly suggested in Study One, and was particularly strongly confirmed in study two. In addition, these findings revealed a “kick start effect” over global performance measures. Specifically, there was a long lasting improvement in performance throughout the task when participants received the highest reward magnitudes at the beginning of the protocol. These results demonstrate a dynamical behavioral inhibition capacity in humans, as illustrated by the reward magnitude modulation and initial reward history effects. PMID:24860469

Effect-directed analysis of cold-pressed hemp, flax and canola seed oils by planar chromatography linked with (bio)assays and mass spectrometry.

PubMed

Teh, Sue-Siang; Morlock, Gertrud E

2015-11-15

Cold-pressed hemp, flax and canola seed oils are healthy oils for human consumption as these are rich in polyunsaturated fatty acids and bioactive phytochemicals. However, bioactive information on the food intake side is mainly focused on target analysis. For more comprehensive information with regard to effects, single bioactive compounds present in the seed oil extracts were detected by effect-directed assays, like bioassays or an enzymatic assay, directly linked with chromatography and further characterized by mass spectrometry. This effect-directed analysis is a streamlined method for the analysis of bioactive compounds in the seed oil extracts. All effective compounds with regard to the five assays or bioassays applied were detected in the samples, meaning also bioactive breakdown products caused during oil processing, residues or contaminants, aside the naturally present bioactive phytochemicals. The investigated cold-pressed oils contained compounds that exert antioxidative, antimicrobial, acetylcholinesterase inhibitory and estrogenic activities. This effect-directed analysis can be recommended for bioactivity profiling of food to obtain profound effect-directed information on the food intake side. Copyright © 2015 Elsevier Ltd. All rights reserved.

Study on the mechanism of the bronchodilatory effects of Cynodon dactylon (Linn.) and identification of the active ingredient.

PubMed

Patel, Maulik R; Bhalodia, Yagnik S; Pathak, Nimish L; Patel, Maulik S; Suthar, Kunal; Patel, Nilesh; Golwala, Dharmesh K; Jivani, Nurudin P

2013-10-24

In the traditional medicine, Cynodon dactylon (Linn.) is used in asthma, but scientific studies to provide evidence for medicinal uses are sparse. Thus this study was undertaken to provide evidence for medicinal use in asthma as a bronchodilator, and to identify active ingredient(s). In vivo, acetylcholine (Ach)-induced bronchospasm was conducted in guinea pig while isolated rat tracheal strip was suspended in organ bath to measure the concentration response curve using multichannel data acquisition system. The chloroform extract of Cynodon dactylon (CECD) protected against Ach-induced bronchospasm in guinea pigs, similar to atropine. In the in vitro studies, CECD relaxed carbachol (CCh) and high K + -induced contraction of rat tracheal strip, similar to atropine and verapamil respectively, suggesting antimuscarinic and calcium channel blocking (CCB) activities, which were confirmed by right ward shifting of CCh and Ca +2 concentration response curve (CRC). The phosphodiestrase (PDE) inhibitory activity was confirmed by potentiation of isoprenaline-induced inhibitory response, similar to papaverine. Densitometry analyses led to the identification of scopoletin as an active ingredient. Effectively, it significantly inhibited high K + , and Ca +2 induced contractile response, similar to verapamil. The phosphodiestrase (PDE) inhibitory activity was confirmed by direct evidence of potentiation of isoprenaline-induced inhibitory response, similar to papaverine. These results suggest that the bronchodilator activity of CECD is partly due to presence of scopoletin, and mediated possibly through CCB and PDE inhibition. © 2013 Elsevier Ireland Ltd. All rights reserved.

Study on the mechanism of the bronchodilatory effects of Cynodon dactylon (Linn.) and identification of the active ingredient.

PubMed

Patel, Maulik R; Bhalodia, Yagnik S; Pathak, Nimish L; Patel, Maulik S; Suthar, Kunal; Patel, Nilesh; Golwala, Dharmesh K; Jivani, Nurudin P

2013-12-12

In the traditional medicine, Cynodon dactylon (Linn.) is used in asthma, but scientific studies to provide evidence for medicinal uses are sparse. Thus this study was undertaken to provide evidence for medicinal use in asthma as a bronchodilator, and to identify active ingredient(s). In vivo, acetylcholine (Ach)-induced bronchospasm was conducted in guinea pig while isolated rat tracheal strip was suspended in organ bath to measure the concentration response curve using multichannel data acquisition system. The chloroform extract of Cynodon dactylon (CECD) protected against Ach-induced bronchospasm in guinea pigs, similar to atropine. In the in vitro studies, CECD relaxed carbachol (CCh) and high K+-induced contraction of rat tracheal strip, similar to atropine and verapamil respectively, suggesting antimuscarinic and calcium channel blocking (CCB) activities, which were confirmed by right ward shifting of CCh and Ca(+2) concentration response curve (CRC). The phosphodiestrase (PDE) inhibitory activity was confirmed by potentiation of isoprenaline-induced inhibitory response, similar to papaverine. Densitometry analyses led to the identification of scopoletin as an active ingredient. Effectively, it significantly inhibited high K+, and Ca(+2) induced contractile response, similar to verapamil. The phosphodiestrase (PDE) inhibitory activity was confirmed by direct evidence of potentiation of isoprenaline-induced inhibitory response, similar to papaverine. These results suggest that the bronchodilator activity of CECD is partly due to presence of scopoletin, and mediated possibly through CCB and PDE inhibition.

Evidence for two concurrent inhibitory mechanisms during response preparation

PubMed Central

Duque, Julie; Lew, David; Mazzocchio, Riccardo; Olivier, Etienne; Ivry, Richard B.

2010-01-01

Inhibitory mechanisms are critically involved in goal-directed behaviors. To gain further insight into how such mechanisms shape motor representations during response preparation, motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) and H-reflexes were recorded from left hand muscles during choice reaction time tasks. The imperative signal, which indicated the required response, was always preceded by a preparatory cue. During the post-cue delay period, left MEPs were suppressed when the left hand had been cued for the forthcoming response, suggestive of a form of inhibition specifically directed at selected response representations. H-reflexes were also suppressed on these trials, indicating that the effects of this inhibition extend to spinal circuits. In addition, left MEPs were suppressed when the right hand was cued, but only when left hand movements were a possible response option before the onset of the cue. Notably, left hand H-reflexes were not modulated on these trials, consistent with a cortical locus of inhibition that lowers the activation of task-relevant, but non-selected responses. These results suggest the concurrent operation of two inhibitory mechanisms during response preparation: one decreases the activation of selected responses at the spinal level, helping to control when selected movements should be initiated by preventing their premature release; a second, upstream mechanism helps to determine what response to make during a competitive selection process. PMID:20220014

Single-molecule Analysis of Inhibitory Pausing States of V1-ATPase*

PubMed Central

Uner, Naciye Esma; Nishikawa, Yoshihiro; Okuno, Daichi; Nakano, Masahiro; Yokoyama, Ken; Noji, Hiroyuki

2012-01-01

V1-ATPase, the hydrophilic V-ATPase domain, is a rotary motor fueled by ATP hydrolysis. Here, we found that Thermus thermophilus V1-ATPase shows two types of inhibitory pauses interrupting continuous rotation: a short pause (SP, 4.2 s) that occurred frequently during rotation, and a long inhibitory pause (LP, >30 min) that terminated all active rotations. Both pauses occurred at the same angle for ATP binding and hydrolysis. Kinetic analysis revealed that the time constants of inactivation into and activation from the SP were too short to represent biochemically predicted ADP inhibition, suggesting that SP is a newly identified inhibitory state of V1-ATPase. The time constant of inactivation into LP was 17 min, consistent with one of the two time constants governing the inactivation process observed in bulk ATPase assay. When forcibly rotated in the forward direction, V1 in LP resumed active rotation. Solution ADP suppressed the probability of mechanical activation, suggesting that mechanical rotation enhanced inhibitory ADP release. These features were highly consistent with mechanical activation of ADP-inhibited F1, suggesting that LP represents the ADP-inhibited state of V1-ATPase. Mechanical activation largely depended on the direction and angular displacement of forced rotation, implying that V1-ATPase rotation modulates the off rate of ADP. PMID:22736762

Respiratory pattern changes during costovertebral joint movement.

PubMed

Shannon, R

1980-05-01

Experiments were conducted to determine if costovertebral joint manipulation (CVJM) could influence the respiratory pattern. Phrenic efferent activity (PA) was monitored in dogs that were anesthetized with Dial-urethane, vagotomized, paralyzed, and artificially ventilated. Ribs 6-10 (bilaterally) were cut and separated from ribs 5-11. Branches of thoracic nerves 5-11 were cut, leaving only the joint nerve supply intact. Manual joint movement in an inspiratory or expiratory direction had an inhibitory effect on PA. Sustained displacement of the ribs could inhibit PA for a duration equal to numerous respiratory cycles. CVJM in synchrony with PA resulted in an increased respiratory rate. The inspiratory inhibitory effect of joint receptor stimulation was elicited with manual chest compression in vagotomized spontaneously breathing dogs, but not with artificial lung inflation or deflation. It is concluded that the effect of CVJM on the respiratory pattern is due to stimulation of joint mechanoreceptors, and that they exert their influence in part via the medullary-pontine rhythm generator.

The RecF protein antagonizes RecX function via direct interaction

PubMed Central

Lusetti, Shelley L.; Hobbs, Michael D.; Stohl, Elizabeth A.; Chitteni-Pattu, Sindhu; Inman, Ross B.; Seifert, H. Steven; Cox, Michael M.

2014-01-01

Summary The RecX protein inhibits RecA filament extension leading to net filament disassembly. The RecF protein physically interacts with the RecX protein and protects RecA from the inhibitory effects of RecX. In vitro, efficient RecA filament formation onto SSB-coated circular single-stranded DNA in the presence of RecX occurs only when all of the RecFOR proteins are present. The RecOR proteins contribute only to RecA filament nucleation onto SSB-coated single-stranded DNA and are unable to counter the inhibitory effects of RecX on RecA filaments. RecF protein uniquely supports substantial RecA filament extension in the presence of RecX. In vivo, RecF protein counters a RecX-mediated inhibition of plasmid recombination. Thus, a significant positive contribution of RecF to RecA filament assembly is to antagonize the effects of the negative modulator, RecX, specifically during the extension phase. PMID:16387652

Inhibitory Control in Childhood Stuttering

ERIC Educational Resources Information Center

Eggers, Kurt; De Nil, Luc F.; Van den Bergh, Bea R. H.

2013-01-01

Purpose: The purpose of this study was to investigate whether previously reported parental questionnaire-based differences in inhibitory control (IC; Eggers, De Nil, & Van den Bergh, 2010) would be supported by direct measurement of IC using a computer task. Method: Participants were 30 children who stutter (CWS; mean age = 7;05 years) and 30…

Context specificity of inhibitory control in dogs

PubMed Central

MacLean, Evan L.; Hare, Brian A.

2014-01-01

Across three experiments, we explored whether a dog's capacity for inhibitory control is stable or variable across decision-making contexts. In the social task, dogs were first exposed to the reputations of a stingy experimenter that never shared food and a generous experimenter who always shared food. In subsequent test trials, dogs were required to avoid approaching the stingy experimenter when this individual offered (but withheld) a higher-value reward than the generous experimenter did. In the A-not-B task, dogs were required to inhibit searching for food in a previously rewarded location after witnessing the food being moved from this location to a novel hiding place. In the cylinder task, dogs were required to resist approaching visible food directly (because it was behind a transparent barrier), in favor of a detour reaching response. Overall, dogs exhibited inhibitory control in all three tasks. However, individual scores were not correlated between tasks, suggesting that context has a large effect on dogs' behavior. This result mirrors studies of humans, which have highlighted intra-individual variation in inhibitory control as a function of the decision-making context. Lastly, we observed a correlation between a subject's age and performance on the cylinder task, corroborating previous observations of age-related decline in dogs' executive function. PMID:23584618

Identification and isolation of the cyclooxygenase-2 inhibitory principle in Isatis tinctoria.

PubMed

Danz, H; Stoyanova, S; Wippich, P; Brattström, A; Hamburger, M

2001-07-01

Various extracts prepared from the traditional dye and medicinal plant Isatis tinctoria L. were submitted to a broad in vitro screening against 16 anti-inflammatory targets. Dichloromethane (DCM) extracts from dried leaves showed a marked cyclooxygenase (COX) inhibitory activity with a preferential effect on COX-2 catalysed prostaglandin synthesis. A supercritical fluid extraction (SFE) procedure employing CO2-modifier mixtures was developed by which the bioactivity profile and chromatographic fingerprint of the DCM extract could be reproduced. High-resolution activity directed on-line identification of the COX-2 inhibitory principle, using a combination of LC-DAD-MS with a microtitre-based bioassay, led to the identification of tryptanthrin (1) as the constituent responsible for essentially all COX-2 inhibitory activity in the crude extract. Following on-line identification, 1 was isolated at preparative scale and its structure confirmed by comparison with synthetic tryptanthrin. In an assay with lipopolysaccharide stimulated Mono Mac 6 cells, tryptanthrin (1) was of comparable potency (IC50 = 64 nM) than the preferential COX-2 inhibitors nimesulide (IC50 = 39 nM) and NS 398 (IC50 = 2 nM). The SFE extract and 1 showed no cytotoxicity in Mono Mac 6 and RAW 264.7 cells when tested at 100 microg/ml and 10 microM, respectively.

Intervention effects of five cations and their correction on hemolytic activity of tentacle extract from the jellyfish Cyanea capillata

PubMed Central

2017-01-01

Cations have generally been reported to prevent jellyfish venom-induced hemolysis through multiple mechanisms by spectrophotometry. Little attention has been paid to the potential interaction between cations and hemoglobin, potentially influencing the antagonistic effect of cations. Here, we explored the effects of five reported cations, La3+, Mn2+, Zn2+, Cu2+ and Fe2+, on a hemolytic test system and the absorbance of hemoglobin, which was further used to measure their effects on the hemolysis of tentacle extract (TE) from the jellyfish Cyanea capillata. All the cations displayed significant dose-dependent inhibitory effects on TE-induced hemolysis with various dissociation equilibrium constant (Kd) values as follows: La3+ 1.5 mM, Mn2+ 93.2 mM, Zn2+ 38.6 mM, Cu2+ 71.9 μM and Fe2+ 32.8 mM. The transparent non-selective pore blocker La3+ did not affect the absorbance of hemoglobin, while Mn2+ reduced it slightly. Other cations, including Zn2+, Cu2+ and Fe2+, greatly decreased the absorbance with Kd values of 35.9, 77.5 and 17.6 mM, respectively. After correction, the inhibitory Kd values were 1.4 mM, 45.8 mM, 128.5 μM and 53.1 mM for La3+, Zn2+, Cu2+ and Fe2+, respectively. Mn2+ did not inhibit TE-induced hemolysis. Moreover, the inhibitory extent at the maximal given dose of all cations except La3+ was also diminished. These corrected results from spectrophotometry were further confirmed by direct erythrocyte counting under microscopy. Our results indicate that the cations, except for La3+, can interfere with the absorbance of hemoglobin, which should be corrected when their inhibitory effects on hemolysis by jellyfish venoms are examined. The variation in the inhibitory effects of cations suggests that the hemolysis by jellyfish venom is mainly attributed to the formation of non-selective cation pore complexes over other potential mechanisms, such as phospholipases A2 (PLA2), polypeptides, protease and oxidation. Blocking the pore-forming complexes may be a primary strategy to improve the in vivo damage and mortality from jellyfish stings due to hemolytic toxicity. PMID:28503385

Cannabinoid CB1 Receptor Activation Mediates the Opposing Effects of Amphetamine on Impulsive Action and Impulsive Choice

PubMed Central

Wiskerke, Joost; Stoop, Nicky; Schetters, Dustin; Schoffelmeer, Anton N. M.; Pattij, Tommy

2011-01-01

It is well known that acute challenges with psychostimulants such as amphetamine affect impulsive behavior. We here studied the pharmacology underlying the effects of amphetamine in two rat models of impulsivity, the 5-choice serial reaction time task (5-CSRTT) and the delayed reward task (DRT), providing measures of inhibitory control, an aspect of impulsive action, and impulsive choice, respectively. We focused on the role of cannabinoid CB1 receptor activation in amphetamine-induced impulsivity as there is evidence that acute challenges with psychostimulants activate the endogenous cannabinoid system, and CB1 receptor activity modulates impulsivity in both rodents and humans. Results showed that pretreatment with either the CB1 receptor antagonist/inverse agonist SR141716A or the neutral CB1 receptor antagonist O-2050 dose-dependently improved baseline inhibitory control in the 5-CSRTT. Moreover, both compounds similarly attenuated amphetamine-induced inhibitory control deficits, suggesting that CB1 receptor activation by endogenously released cannabinoids mediates this aspect of impulsive action. Direct CB1 receptor activation by Δ9-Tetrahydrocannabinol (Δ9-THC) did, however, not affect inhibitory control. Although neither SR141716A nor O-2050 affected baseline impulsive choice in the DRT, both ligands completely prevented amphetamine-induced reductions in impulsive decision making, indicating that CB1 receptor activity may decrease this form of impulsivity. Indeed, acute Δ9-THC was found to reduce impulsive choice in a CB1 receptor-dependent way. Together, these results indicate an important, though complex role for cannabinoid CB1 receptor activity in the regulation of impulsive action and impulsive choice as well as the opposite effects amphetamine has on both forms of impulsive behavior. PMID:22016780

Firing-rate based network modeling of the dLGN circuit: Effects of cortical feedback on spatiotemporal response properties of relay cells.

PubMed

Mobarhan, Milad Hobbi; Halnes, Geir; Martínez-Cañada, Pablo; Hafting, Torkel; Fyhn, Marianne; Einevoll, Gaute T

2018-05-01

Visually evoked signals in the retina pass through the dorsal geniculate nucleus (dLGN) on the way to the visual cortex. This is however not a simple feedforward flow of information: there is a significant feedback from cortical cells back to both relay cells and interneurons in the dLGN. Despite four decades of experimental and theoretical studies, the functional role of this feedback is still debated. Here we use a firing-rate model, the extended difference-of-Gaussians (eDOG) model, to explore cortical feedback effects on visual responses of dLGN relay cells. For this model the responses are found by direct evaluation of two- or three-dimensional integrals allowing for fast and comprehensive studies of putative effects of different candidate organizations of the cortical feedback. Our analysis identifies a special mixed configuration of excitatory and inhibitory cortical feedback which seems to best account for available experimental data. This configuration consists of (i) a slow (long-delay) and spatially widespread inhibitory feedback, combined with (ii) a fast (short-delayed) and spatially narrow excitatory feedback, where (iii) the excitatory/inhibitory ON-ON connections are accompanied respectively by inhibitory/excitatory OFF-ON connections, i.e. following a phase-reversed arrangement. The recent development of optogenetic and pharmacogenetic methods has provided new tools for more precise manipulation and investigation of the thalamocortical circuit, in particular for mice. Such data will expectedly allow the eDOG model to be better constrained by data from specific animal model systems than has been possible until now for cat. We have therefore made the Python tool pyLGN which allows for easy adaptation of the eDOG model to new situations.

Effect of polygodial and its direct derivatives on the mammalian Na+/K+-ATPase activity.

PubMed

Garcia, Diogo Gomes; Gonçalves-de-Albuquerque, Cassiano Felippe; da Silva, Camila Ignácio; Kiss, Robert; Dasari, Ramesh; Chandra, Sunena; Kornienko, Alexander; Burth, Patricia

2018-07-15

The sesquiterpene polygodial is an agonist of the transient receptor potential vanilloid 1 (TRPV1). Our group recently reported the synthesis and anticancer effects of polygodial and its derivatives, and showed that these compounds retain activity against apoptosis- and multidrug-resistant cancer cells. Herein, we tested the inhibitory effect of these compounds on the activity of the enzyme Na + /K + -ATPase (NKA) from kidney (α 1 isoform) and brain (α 2 and α 3 isoforms) guinea pig extracts. Polygodial (1) displayed a dose-dependent inhibition of both kidney and brain purified NKA preparations, with higher sensitivity for the cerebral isoforms. Polygo-11,12-diol (2) and C11,C12-pyridazine derivative (3) proved to be poor inhibitors. Unsaturated ester (4) and 9-epipolygodial (5) inhibited NKA preparations from brain and kidney, with the same inhibitory potency. Nevertheless, they did not achieve maximum inhibition even at higher concentration. Comparing the inhibitory potency in crude homogenates and purified preparations of NKA, compounds 4 and 5 revealed a degree of selectivity toward the renal enzyme. Kinetic studies showed a non-competitive inhibition for Na + and K + by compounds 1, 4 and 5 and for ATP by 1 and 4. However, compound 5 presented a competitive inhibition type. Furthermore, K + -activated p-nitrophenylphosphatase activity of these purified preparations was not inhibited by 1, 4 and 5, suggesting that these compounds acted in the initial phase of the enzyme's catalytic cycle. These findings suggest that the antitumor action of polygodial and its analogues may be linked to their NKA inhibitory properties and reinforce that NKA may be an important target for cancer therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Multiple binding sites involved in the effect of choline esters on decarbamoylation of monomethylcarbamoyl- or dimethylcarbamoly-acetylcholinesterase.

PubMed Central

Sok, D E; Kim, Y B; Choi, S J; Jung, C H; Cha, S H

1994-01-01

Multiple binding sites for inhibitory choline esters in spontaneous decarbamoylation of dimethylcarbamoyl-acetylcholinesterase (AChE) were suggested from a wide range of IC50 values, in contrast with a limited range of AC50 values (concentration giving 50% of maximal activation) at a peripheral activatory site. Association of choline esters containing a long acyl chain (C7-C12) with the hydrophobic zone in the active site could be deduced from a linear relationship between the size of the acyl group and the inhibitory potency in either spontaneous decarbamoylation or acetylthiocholine hydrolysis. Direct support for laurylcholine binding to the active site might come from the competitive inhibition (Ki 33 microM) of choline-catalysed decarbamoylation by laurylcholine. Moreover, its inhibitory action was greater for monomethylcarbamoyl-AChE than for dimethylcarbamoyl-AChE, where there is a greater steric hindrance at the active centre. In further support, the inhibition of pentanoylthiocholine-induced decarbamoylation by laurylcholine was suggested to be due to laurylcholine binding to a central site rather than a peripheral site, similar to the inhibition of spontaneous decarbamoylation by laurylcholine. Supportive data for acetylcholine binding to the active site are provided by the results that acetylcholine is a competitive inhibitor (Ki 7.6 mM) of choline-catalysed decarbamoylation, and its inhibitory action was greater for monomethylcarbamoyl-AChE than for dimethylcarbamoyl-AChE. Meanwhile, choline esters with an acyl group of an intermediate size (C4-C6), more subject to steric exclusion at the active centre, and less associable with the hydrophobic zone, appear to bind preferentially to a peripheral activity site. Thus the multiple effects of choline esters may be governed by hydrophobicity and/or a steric effect exerted by the acyl moiety at the binding sites. PMID:8053896

Inhibitory control in bulimic-type eating disorders: a systematic review and meta-analysis.

PubMed

Wu, Mudan; Hartmann, Mechthild; Skunde, Mandy; Herzog, Wolfgang; Friederich, Hans-Christoph

2013-01-01

The aim of this meta-analysis was to summarise data from neuropsychological studies on inhibitory control to general and disease-salient (i.e., food/eating, body/shape) stimuli in bulimic-type eating disorders (EDs). A systematic literature search was conducted to identify eligible experimental studies. The outcome measures studied included the performance on established inhibitory control tasks in bulimic-type EDs. Effect sizes (Hedges' g) were pooled using random-effects models. For inhibitory control to general stimuli, 24 studies were included with a total of 563 bulimic-type ED patients: 439 had bulimia nervosa (BN), 42 had anorexia nervosa of the binge/purge subtype (AN-b), and 82 had binge eating disorder (BED). With respect to inhibitory control to disease-salient stimuli, 12 studies were included, representing a total of 218 BN patients. A meta-analysis of these studies showed decreased inhibitory control to general stimuli in bulimic-type EDs (g = -0.32). Subgroup analysis revealed impairments with a large effect in the AN-b group (g = -0.91), impairments with a small effect in the BN group (g = -0.26), and a non-significant effect in the BED group (g = -0.16). Greater impairments in inhibitory control were observed in BN patients when confronted with disease-salient stimuli (food/eating: g = -0.67; body/shape: g = -0.61). In conclusion, bulimic-type EDs showed impairments in inhibitory control to general stimuli with a small effect size. There was a significantly larger impairment in inhibitory control to disease salient stimuli observed in BN patients, constituting a medium effect size.

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction.

PubMed

Wu, Min; Dumalska, Iryna; Morozova, Elena; van den Pol, Anthony; Alreja, Meenakshi

2009-10-06

A link between energy balance and reproduction is critical for the survival of all species. Energy-consuming reproductive processes need to be aborted in the face of a negative energy balance, yet knowledge of the pathways mediating this link remains limited. Fasting and food restriction that inhibit fertility also upregulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure; MCH knockout mice are lean and have a higher metabolism but remain fertile. MCH also modulates sleep, drug abuse behavior, and mood, and MCH receptor antagonists are currently being developed as antiobesity and antidepressant drugs. Despite the clinical implications of MCH, the direct postsynaptic effects of MCH have never been reported in CNS neurons. Using patch-clamp recordings in brain slices from multiple lines of transgenic GFP mice, we demonstrate a strong inhibitory effect of MCH on an exclusive population of septal vGluT2-GnRH neurons that is activated by the puberty-triggering and preovulatory luteinizing hormone surge-mediating peptide, kisspeptin. MCH has no effect on kisspeptin-insensitive GnRH, vGluT2, cholinergic, or GABAergic neurons located within the same nucleus. The inhibitory effects of MCH are reproducible and nondesensitizing and are mediated via a direct postsynaptic Ba(2+)-sensitive K(+) channel mechanism involving the MCHR1 receptor. MCH immunoreactive fibers are in close proximity to vGluT2-GFP and GnRH-GFP neurons. Importantly, MCH blocks the excitatory effect of kisspeptin on vGluT2-GnRH neurons. Considering the role of MCH in regulating energy balance and of GnRH and kisspeptin in triggering puberty and maintaining fertility, MCH may provide a critical link between energy balance and reproduction directly at the level of the kisspeptin-activated vGluT2-GnRH neuron.

Inhibitory Effect of Crizotinib on Creatinine Uptake by Renal Secretory Transporter OCT2.

PubMed

Arakawa, Hiroshi; Omote, Saki; Tamai, Ikumi

2017-09-01

Crizotinib, a tyrosine kinase inhibitor, exhibits some cases of an increase in serum creatinine levels. Creatinine is excreted by not only glomerular filtration but also active secretion by organic cation transporters such as organic cation transporter 2 (OCT2). In the present study, we evaluated in vitro inhibitory effect of crizotinib on OCT2 by directly measuring creatinine uptake by OCT2. Coincubation of crizotinib reduced uptake of [ 14 C]creatinine by cultured HEK293 cells expressing OCT2 (HEK293/OCT2) in a concentration-dependent manner with IC 50 values of 1.58 ± 0.24 μM. Preincubation or both preincubation and coincubation (preincubation/coincubation) with crizotinib showed stronger inhibitory effect on [ 14 C]creatinine uptake compared with that in coincubation alone with IC 50 values of 0.499 ± 0.076 and 0.347 ± 0.040 μM, respectively. These IC 50 values of crizotinib on [ 3 H]N-methyl-4-phenylpyridinium acetate uptake by OCT2 were 10-20 times higher than those of [ 14 C]creatinine uptake. Furthermore, preincubation of crizotinib inhibited creatinine uptake by OCT2 in an apparently competitive manner. In conclusion, crizotinib at a clinically relevant concentration has the potential to inhibit creatinine transport by OCT2, suggesting an increase of serum creatinine levels in clinical use. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

UV-B Radiation Induces Macrophage Migration Inhibitory Factor–Mediated Melanogenesis through Activation of Protease-Activated Receptor-2 and Stem Cell Factor in Keratinocytes

PubMed Central

Enomoto, Akiko; Yoshihisa, Yoko; Yamakoshi, Takako; Ur Rehman, Mati; Norisugi, Osamu; Hara, Hiroshi; Matsunaga, Kenji; Makino, Teruhiko; Nishihira, Jun; Shimizu, Tadamichi

2011-01-01

UV radiation indirectly regulates melanogenesis in melanocytes through a paracrine regulatory mechanism involving keratinocytes. Protease-activated receptor (PAR)-2 activation induces melanosome transfer by increasing phagocytosis of melanosomes by keratinocytes. This study demonstrated that macrophage migration inhibitory factor (MIF) stimulated PAR-2 expression in human keratinocytes. In addition, we showed that MIF stimulated stem cell factor (SCF) release in keratinocytes; however, MIF had no effect on the release of endothelin-1 or prostaglandin E2 in keratinocytes. In addition, MIF had no direct effect on melanin and tyrosinase synthesis in cultured human melanocytes. The effect of MIF on melanogenesis was also examined using a three-dimensional reconstituted human epidermal culture model, which is a novel, commercially available, cultured human epidermis containing functional melanocytes. Migration inhibitory factor induced an increase in melanin content in the epidermis after a 9-day culture period. Moreover, melanin synthesis induced by UV-B stimulation was significantly down-regulated by anti-MIF antibody treatment. An in vivo study showed that the back skin of MIF transgenic mice had a higher melanin content than that of wild-type mice after 12 weeks of UV-B exposure. Therefore, MIF-mediated melanogenesis occurs mainly through the activation of PAR-2 and SCF expression in keratinocytes after exposure to UV-B radiation. PMID:21281800

Plants traditionally used in age-related brain disorders (dementia): an ethanopharmacological survey.

PubMed

Natarajan, Suganthy; Shunmugiah, Karutha Pandian; Kasi, Pandima Devi

2013-04-01

Epidemiological studies have shown that despite mortality due to communicable diseases, poverty and human conflicts, the incidence of dementia increases in the developing world in tandem with the ageing population. Although some FDA approved drugs are available for the treatment of dementia, the outcomes are often unsatisfactory. In traditional practices of medicine, numerous plants have been used to treat cognitive disorders, including neurodegenerative diseases such as Alzheimer's disease (AD) and other memory-related disorders. In western medicine most of the drugs used for the treatment of neurodegenerative disorders are derived from plant sources. This article reviews plants and their active constituents that have been used for their reputed cognitive-enhancing and antidementia effects. A literature survey in Science Direct, Pubmed, and Google Scholar was performed to gather information regarding drug discovery from plants sources for the treatment of congnitive disorders and dementia. More than forty herbal remedies were identified with cholinesterase inhibitory, anti-inflammatory, or antioxidant activities. Bioactive compounds include alkaloids, flavonoids, steroids, saponins, terpenoids, and essential oils. About eleven herbal plants with multipotent activity against AD are discussed. Literature surveys show that most of the research has been conducted on herbal remedies effect on cholinesterase inhibitory and antioxidant activities. Studies regarding the effect of herbal drugs on β-secretase inhibitory activity and antiaggregation property are lacking. This review provides leads for identifying potential new drugs from plant sources for the treatment of neurodegenerative disorders.

Hydrogen Peroxide Inhibits Cytochrome P450 Epoxygenases

PubMed Central

Larsen, Brandon T.; Gutterman, David D.; Sato, Atsushi; Toyama, Kazuyoshi; Campbell, William B.; Zeldin, Darryl C.; Manthati, Vijay L.; Falck, John R.; Miura, Hiroto

2008-01-01

The cytochrome P450 epoxygenase (CYP)-derived metabolites of arachidonic acid the epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (H2O2) both function as endothelium-derived hyperpolarizing factors (EDHFs) in the human coronary microcirculation. However, the relative importance of and potential interactions between these 2 vasodilators remain unexplored. We identified a novel inhibitory interaction between CYPs and H2O2 in human coronary arterioles, where EDHF-mediated vasodilatory mechanisms are prominent. Bradykinin induced vascular superoxide and H2O2 production in an endothelium-dependent manner and elicited a concentration-dependent dilation that was reduced by catalase but not by 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE), 6-(2-propargyloxyphenyl)hexanoic acid, sulfaphenazole, or iberiotoxin. However, in the presence of catalase, an inhibitory effect of these compounds was unmasked. In a tandem-bioassay preparation, application of bradykinin to endothelium-intact donor vessels elicited dilation of downstream endothelium-denuded detectors that was partially inhibited by donor-applied catalase but not by detector-applied EEZE; however, EEZE significantly inhibited dilation in the presence of catalase. EET production by human recombinant CYP 2C9 and 2J2, 2 major epoxygenase isozymes expressed in human coronary arterioles, was directly inhibited in a concentration-dependent fashion by H2O2 in vitro, as observed by high-performance liquid chromatography (HPLC); however, EETs were not directly sensitive to oxidative modification. H2O2 inhibited dilation to arachidonic acid but not to 11,12-EET. These findings suggest that an inhibitory interaction exists between 2 EDHFs in the human coronary microcirculation. CYP epoxygenases are directly inhibited by H2O2, and this interaction may modulate vascular EET bioavailability. PMID:17975109

Modification of CO2 avoidance behaviour in Drosophila by inhibitory odorants.

PubMed

Turner, Stephanie Lynn; Ray, Anandasankar

2009-09-10

The fruitfly Drosophila melanogaster exhibits a robust and innate olfactory-based avoidance behaviour to CO(2), a component of odour emitted from stressed flies. Specialized neurons in the antenna and a dedicated neuronal circuit in the higher olfactory system mediate CO(2) detection and avoidance. However, fruitflies need to overcome this avoidance response in some environments that contain CO(2) such as ripening fruits and fermenting yeast, which are essential food sources. Very little is known about the molecular and neuronal basis of this unique, context-dependent modification of innate olfactory avoidance behaviour. Here we identify a new class of odorants present in food that directly inhibit CO(2)-sensitive neurons in the antenna. Using an in vivo expression system we establish that the odorants act on the Gr21a/Gr63a CO(2) receptor. The presence of these odorants significantly and specifically reduces CO(2)-mediated avoidance behaviour, as well as avoidance mediated by 'Drosophila stress odour'. We propose a model in which behavioural avoidance to CO(2) is directly influenced by inhibitory interactions of the novel odours with CO(2) receptors. Furthermore, we observe differences in the temporal dynamics of inhibition: the effect of one of these odorants lasts several minutes beyond the initial exposure. Notably, animals that have been briefly pre-exposed to this odorant do not respond to the CO(2) avoidance cue even after the odorant is no longer present. We also show that related odorants are effective inhibitors of the CO(2) response in Culex mosquitoes that transmit West Nile fever and filariasis. Our findings have broader implications in highlighting the important role of inhibitory odorants in olfactory coding, and in their potential to disrupt CO(2)-mediated host-seeking behaviour in disease-carrying insects like mosquitoes.

The Development of Automatic and Controlled Inhibitory Retrieval Processes in True and False Recall

ERIC Educational Resources Information Center

Knott, Lauren M.; Howe, Mark L.; Wimmer, Marina C.; Dewhurst, Stephen A.

2011-01-01

In three experiments, we investigated the role of automatic and controlled inhibitory retrieval processes in true and false memory development in children and adults. Experiment 1 incorporated a directed forgetting task to examine controlled retrieval inhibition. Experiments 2 and 3 used a part-set cue and retrieval practice task to examine…

Tyrosinase inhibitory flavonoid from Juniperus communis fruits.

PubMed

Jegal, Jonghwan; Park, Sang-A; Chung, KiWung; Chung, Hae Young; Lee, Jaewon; Jeong, Eun Ju; Kim, Ki Hyun; Yang, Min Hye

2016-12-01

The fruits of Juniperus communis have been traditionally used in the treatment of skin diseases. In our preliminary experiment, the MeOH extract of J. communis effectively suppressed mushroom tyrosinase activity. Three monoflavonoids and five biflavonoids were isolated from J. communis by bioassay-guided isolation and their inhibitory effect against tyrosinase was evaluated. According to the results of all isolates, hypolaetin 7-O-β-xylopyranoside isolated from J. communis exhibited most potent effect of decreasing mushroom tyrosinase activity with an IC 50 value of 45.15 μM. Further study provided direct experimental evidence for hypolaetin 7-O-β-D-xylopyranoside-attenuated tyrosinase activity in α-MSH-stimulated B16F10 murine melanoma cell. Hypolaetin 7-O-β-D-xylopyranoside from the EtOAc fraction of J. communis was also effective at suppressing α-MSH-induced melanin synthesis. This is the first report of the enzyme tyrosinase inhibition by J. communis and its constituent. Therapeutic attempts with J. communis and its active component, hypolaetin 7-O-β-D-xylopyranoside, might be useful in treating melanin pigmentary disorders.

In vitro expression of Escherichia coli ribosomal protein genes: autogenous inhibition of translation.

PubMed Central

Yates, J L; Arfsten, A E; Nomura, M

1980-01-01

Escherichia coli ribosomal protein L1 (0.5 micro M) was found to inhibit the synthesis of both proteins of the L11 operon, L11 and L1, but not the synthesis of other proteins directed by lambda rifd 18 DNA. Similarly, S4 (1 micro M) selectively inhibited the synthesis of three proteins of the alpha operon, S13, S11, and S4, directed by lambda spcI DNA or a restriction enzyme fragment obtained from this DNA. S8 (3.6 micro M) also showed preferential inhibitory effects on the synthesis of some proteins encoded in the spc operon, L24 and L5 (and probably S14 and S8), directed by lambda spcl DNA or a restriction enzyme fragment carrying the genes for these proteins. The inhibitory effect of L1 was observed only with L1 and not with other proteins examined, including S4 and S8. Similarly, the effect of S4 was not observed with L1 or S8, and that of S8 was not seen with L1 or S4. Inhibition was shown to take place at the level of translation rather than transcription. Thus, at least some ribosomal proteins (L1 S4, and S8) have the ability to cause selective translational inhibition of the synthesis of certain ribosomal proteins whose genes are in the same operon as their own. These results support the hypothesis that certain free ribosomal proteins not assembled into ribosomes act as "autogenous" feedback inhibitors to regulate the synthesis of ribosomal proteins. Images PMID:6445562

Inhibitory effects of Agaricus blazei extracts on human myeloid leukemia cells.

PubMed

Kim, Chi-Fai; Jiang, Jing-Jing; Leung, Kwok-Nam; Fung, Kwok-Pui; Lau, Clara Bik-San

2009-03-18

Agaricus blazei has been used as an adjuvant in cancer chemotherapy and is found to inhibit the growth of various types of tumor cells. Our study has adopted a systematic and bioassay-guided approach to optimize the extraction of Agaricus blazei for anti-leukemic bioactive components. The tumor-selective growth inhibitory activity of the extracts on leukemic cell lines was evaluated in vitro and in vivo using tumor-bearing nude mice. Agaricus blazei extracts were prepared using different methods. MTT and tritiated thymidine incorporation assays were used to evaluate the in vitro anti-leukemic effects. The most potent extract was further investigated using NB-4 cells-bearing nude mice and mechanistic studies using DNA fragmentation assay and cell death detection ELISA. The JAB80E70 extract showed the most potent tumor-selective growth inhibitory activity against human leukemia NB-4 and K-562 cells. This is the first report of anti-leukemic activity of JAB80E70 in athymic nude mice bearing NB-4 cells. Using DNA fragmentation assays and cell death detection ELISA, JAB80E70 was found to induce apoptosis in NB-4 cells. However, the polysaccharide enriched fractions failed to show significant cytotoxicity on NB-4 cells in vitro. The JAB80E70 extract exhibited potent anti-leukemic effect in vitro and in vivo. The effect can be attributed, at least in part, to the induction of apoptosis. Besides, polysaccharides in Agaricus blazei may not possess direct anti-leukemic activity in vitro.

Effects of Furfural on the Respiratory Metabolism of Saccharomyces cerevisiae in Glucose-Limited Chemostats

PubMed Central

Sárvári Horváth, Ilona; Franzén, Carl Johan; Taherzadeh, Mohammad J.; Niklasson, Claes; Lidén, Gunnar

2003-01-01

Effects of furfural on the aerobic metabolism of the yeast Saccharomyces cerevisiae were studied by performing chemostat experiments, and the kinetics of furfural conversion was analyzed by performing dynamic experiments. Furfural, an important inhibitor present in lignocellulosic hydrolysates, was shown to have an inhibitory effect on yeast cells growing respiratively which was much greater than the inhibitory effect previously observed for anaerobically growing yeast cells. The residual furfural concentration in the bioreactor was close to zero at all steady states obtained, and it was found that furfural was exclusively converted to furoic acid during respiratory growth. A metabolic flux analysis showed that furfural affected fluxes involved in energy metabolism. There was a 50% increase in the specific respiratory activity at the highest steady-state furfural conversion rate. Higher furfural conversion rates, obtained during pulse additions of furfural, resulted in respirofermentative metabolism, a decrease in the biomass yield, and formation of furfuryl alcohol in addition to furoic acid. Under anaerobic conditions, reduction of furfural partially replaced glycerol formation as a way to regenerate NAD+. At concentrations above the inlet concentration of furfural, which resulted in complete replacement of glycerol formation by furfuryl alcohol production, washout occurred. Similarly, when the maximum rate of oxidative conversion of furfural to furoic acid was exceeded aerobically, washout occurred. Thus, during both aerobic growth and anaerobic growth, the ability to tolerate furfural appears to be directly coupled to the ability to convert furfural to less inhibitory compounds. PMID:12839784

Inhibitory effect on the proliferation of human heptoma induced by cell-permeable manganese superoxide dismutase.

PubMed

Guo, Hua; Zhang, Na; Liu, Di; Wang, Ping; Ma, Xingyuan

2016-10-01

Mitochondrial antioxidant manganese superoxide dismutase (MnSOD) belongs to a group of genes whose expression is generally decreased significantly in patients with hepatoma. The proliferation of cancer cells with low expression of MnSOD exhibit high sensitivity to the elevated expression of MnSOD. However, due to the lack of ability to penetrate the cell membrane, the direct use and study of SOD for cancer treatment are largely hampered. In this work, cell penetrating peptide TAT was fused to the N-terminus of MnSOD to facilitate the penetration of MnSOD through cell membranes. Results showed that TAT-MnSOD wt treatment induced evident inhibitory effect on the proliferation of heptoma, with minimal effect on normal cells. It was further demonstrated that both the penetration of cells and enzymatic activity of MnSOD are essential to its inhibitory function, because only TAT-MnSOD wt, not inactive TAT-MnSOD mutant or MnSOD could successfully inhibit cell proliferation and reduce the intra-celluar reactive oxygen species (ROS). In addition, the lower oxidative stress delayed the cell cycle at G2/M and significantly slowed HepG2 cell growth in association with the dephosphorylation of survivin. Our results help in understanding the regulatory effects of MnSOD on cell viability and redox homestasis of heptoma and promise potential applications of TAT-MnSOD wt for clinical cancer therapy. Copyright © 2016. Published by Elsevier Masson SAS.

Modifying Yeast Tolerance to Inhibitory Conditions of Ethanol Production Processes

PubMed Central

Caspeta, Luis; Castillo, Tania; Nielsen, Jens

2015-01-01

Saccharomyces cerevisiae strains having a broad range of substrate utilization, rapid substrate consumption, and conversion to ethanol, as well as good tolerance to inhibitory conditions are ideal for cost-competitive ethanol production from lignocellulose. A major drawback to directly design S. cerevisiae tolerance to inhibitory conditions of lignocellulosic ethanol production processes is the lack of knowledge about basic aspects of its cellular signaling network in response to stress. Here, we highlight the inhibitory conditions found in ethanol production processes, the targeted cellular functions, the key contributions of integrated -omics analysis to reveal cellular stress responses according to these inhibitors, and current status on design-based engineering of tolerant and efficient S. cerevisiae strains for ethanol production from lignocellulose. PMID:26618154

Isolation of proanthocyanidins from red wine, and their inhibitory effects on melanin synthesis in vitro.

PubMed

Fujimaki, Takahiro; Mori, Shoko; Horikawa, Manabu; Fukui, Yuko

2018-05-15

The red wines made from Vitis vinifera were identified as skin-whitening effectors by using in vitro assays. OPCs in the wine were evaluated for tyrosinase activity and melanogenesis. Strong tyrosinase inhibitory activity was observed in fractions with high oligomeric proanthocyanidin (OPC) content. Among OPC dimers, a strong inhibitory effect on tyrosinase was observed with OPCs which contain (+)-catechin as an upper unit. Melanogenesis inhibitory effect was observed with OPCs which have (-)-epicatechin as upper units. Also, OPC trimers, upper and middle units joined with 4 → 8 bonds, showed stronger effects compared to trimers with 4 → 6 linkages. Interestingly, (-)-epicatechin-(4β → 8)-(-)-epicatechin 3-O-gallate, which is a unique component of grapes has potent inhibitory effects on both tyrosinase and melanogenesis. Our data provide structural information about such active compounds. These results suggest that red wines containing OPC, have high melanogenesis inhibitory effect and are supposed to have skin-whitening effect. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhibitory effects of Bacillus subtilis on plant pathogens of conservatory in high latitudes

NASA Astrophysics Data System (ADS)

Xue, Chun-Mei; Wang, Xue; Yang, Jia-Li; Zhang, Yue-Hua

2018-03-01

Researching the effect of three kinds of Bacillus and their mixed strains inhibitory on common fungal diseases of conservatory vegetables. The results showed that B. megaterium culture medium had a significant inhibition effect on Cucumber Fusarium wilt, and the inhibition rate was up to 84.36%; B. mucilaginosus and B. megaterium sterile superna-tant had an obvious inhibitory effect on brown disease of eggplant, and the inhibition rate as high as 85.49%; B. subtilis sterile supernatant had a good inhibitory effect on the spore germination of C. Fusarium wilt, and the inhibition rate was 76.83%. The results revealed that Bacillus had a significant inhibitory effect on five common fungal pathogens. Three kinds of Bacillus can be used for the prevention and control of common fungal diseases in conservatory vegetables.

Region-specificity of GABAA receptor mediated effects on orientation and direction selectivity in cat visual cortical area 18.

PubMed

Jirmann, Kay-Uwe; Pernberg, Joachim; Eysel, Ulf T

2009-01-01

The role of GABAergic inhibition in orientation and direction selectivity has been investigated with the GABA(A)-Blocker bicuculline in the cat visual cortex, and results indicated a region specific difference of functional contributions of GABAergic inhibition in areas 17 and 18. In area 17 inhibition appeared mainly involved in sculpturing orientation and direction tuning, while in area 18 inhibition seemed more closely associated with temporal receptive field properties. However, different types of stimuli were used to test areas 17 and 18 and further studies performed in area 17 suggested an important influence of the stimulus type (single light bars vs. moving gratings) on the evoked responses (transient vs. sustained) and inhibitory mechanisms (GABA(A) vs. GABA(B)) which in turn might be more decisive for the specific results than the cortical region. To insert the missing link in this chain of arguments it was necessary to study GABAergic inhibition in area 18 with moving light bars, which has not been done so far. Therefore, in the present study we investigated area 18 cells responding to oriented moving light bars with extracellular recordings and reversible microiontophoretic blockade of GABAergig inhibition with bicuculline methiodide. The majority of neurons was characterized by a pronounced orientation specificity and variable degrees of direction selectivity. GABA(A)ergic inhibition significantly influenced preferred orientation and preferred direction in area 18. During the action of bicuculline orientation tuning width increased and orientation and direction selectivity indices decreased. Our results obtained in area 18 with moving bar stimuli, although in the proportion of affected cells similar to those described in area 17, quantitatively matched the findings for direction and orientation specificity obtained with moving gratings in area 18. Accordingly, stimulus type is not decisive in area 18 and the GABA(A) dependent, inhibitory intracortical computations involved in orientation specificity are indeed region-specific and in comparison to area 17 less effective in area 18.

Adaptive threshold hunting for the effects of transcranial direct current stimulation on primary motor cortex inhibition.

PubMed

Mooney, Ronan A; Cirillo, John; Byblow, Winston D

2018-06-01

Primary motor cortex excitability can be modulated by anodal and cathodal transcranial direct current stimulation (tDCS). These neuromodulatory effects may, in part, be dependent on modulation within gamma-aminobutyric acid (GABA)-mediated inhibitory networks. GABAergic function can be quantified non-invasively using adaptive threshold hunting paired-pulse transcranial magnetic stimulation (TMS). The previous studies have used TMS with posterior-anterior (PA) induced current to assess tDCS effects on inhibition. However, TMS with anterior-posterior (AP) induced current in the brain provides a more robust measure of GABA-mediated inhibition. The aim of the present study was to assess the modulation of corticomotor excitability and inhibition after anodal and cathodal tDCS using TMS with PA- and AP-induced current. In 16 young adults (26 ± 1 years), we investigated the response to anodal, cathodal, and sham tDCS in a repeated-measures double-blinded crossover design. Adaptive threshold hunting paired-pulse TMS with PA- and AP-induced current was used to examine separate interneuronal populations within M1 and their influence on corticomotor excitability and short- and long-interval inhibition (SICI and LICI) for up to 60 min after tDCS. Unexpectedly, cathodal tDCS increased corticomotor excitability assessed with AP (P = 0.047) but not PA stimulation (P = 0.74). SICI AP was reduced after anodal tDCS compared with sham (P = 0.040). Pearson's correlations indicated that SICI AP and LICI AP modulation was associated with corticomotor excitability after anodal (P = 0.027) and cathodal tDCS (P = 0.042). The after-effects of tDCS on corticomotor excitability may depend on the direction of the TMS-induced current used to make assessments, and on modulation within GABA-mediated inhibitory circuits.

Lactoferricin B-derived peptides with inhibitory effects on ECE-dependent vasoconstriction.

PubMed

Fernández-Musoles, Ricardo; López-Díez, José Javier; Torregrosa, Germán; Vallés, Salvador; Alborch, Enrique; Manzanares, Paloma; Salom, Juan B

2010-10-01

Endothelin-converting enzyme (ECE), a key peptidase in the endothelin (ET) system, cleaves inactive big ET-1 to produce active ET-1, which binds to ET(A) receptors to exert its vasoconstrictor and pressor effects. ECE inhibition could be beneficial in the treatment of hypertension. In this study, a set of eight lactoferricin B (LfcinB)-derived peptides, previously characterized in our laboratory as angiotensin-converting enzyme (ACE) inhibitory peptides, was examined for their inhibitory effects on ECE. In vitro inhibitory effects on ECE activity were assessed using both the synthetic fluorogenic peptide substrate V (FPS V) and the natural substrate big ET-1. To study vasoactive effects, an ex vivo functional assay was developed using isolated rabbit carotid artery segments. With FPS V, only four LfcinB-derived peptides induced inhibition of ECE activity, whereas the eight peptides showed ECE inhibitory effects with big ET-1 as substrate. Regarding the ex vivo assays, six LfcinB-derived peptides showed inhibition of big ET-1-induced, ECE-dependent vasoconstriction. A positive correlation between the inhibitory effects of LfcinB-derived peptides on ECE activity when using big ET-1 and the inhibitory effects on ECE-dependent vasoconstriction was shown. ECE-independent vasoconstriction induced by ET-1 was not affected, thus discarding effects of LfcinB-derived peptides on ET(A) receptors or intracellular signal transduction mechanisms. In conclusion, a combined in vitro and ex vivo method to assess the effects of potentially antihypertensive peptides on the ET system has been developed and applied to show the inhibitory effects on ECE-dependent vasoconstriction of six LfcinB-derived peptides, five of which were dual vasopeptidase (ACE/ECE) inhibitors. Copyright © 2010 Elsevier Inc. All rights reserved.

Neuromodulation of reciprocal glutamatergic inhibition between antagonistic motoneurons by 5-hydroxytryptamine (5-HT) in crayfish walking system.

PubMed

Pearlstein, E; Clarac, F; Cattaert, D

1998-01-23

In an in vitro preparation of the crayfish thoracic locomotor system, paired intracellular recordings were performed from antagonistic depressor (Dep) and levator (Lev) motoneurons (MNs) that control the second joint of walking legs. Connections between these two groups of MNs consist mainly of inhibitory connections and weak electrotonic synapses. Injection of depolarizing current into a Lev MN results in a hyperpolarization in a Dep MN, and vice versa. This reciprocal glutamatergic inhibition, is not changed in the presence of the sodium channel blocker tetrodotoxin (TTX) and therefore is likely supported by a direct connection between MNs. By contrast, reciprocal inhibition is largely reduced in the presence of 5-hydroxytryptamine (5-HT; 10 microM). Direct micro-application of glutamate pressure-ejected close to an intracellularly recorded MN, evoked an inhibitory response in that MN, accompanied by a decrease of input resistance. These two effects were dramatically reduced in the presence of 5-HT. Thus 5-HT could be involved in mechanisms of dynamic reconfigurations of the neural network controlling leg movements in crayfish.

Transcranial Direct Current Stimulation Improves Executive Dysfunctions in ADHD: Implications for Inhibitory Control, Interference Control, Working Memory, and Cognitive Flexibility.

PubMed

Nejati, Vahid; Salehinejad, Mohammad Ali; Nitsche, Michael A; Najian, Asal; Javadi, Amir-Homayoun

2017-09-01

This study examined effects of transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) on major executive functions (EFs), including response inhibition, executive control, working memory (WM), and cognitive flexibility/task switching in ADHD. ADHD children received (a) left anodal/right cathodal DLPFC tDCS and (b) sham stimulation in Experiment 1 and (a) left anodal DLPFC/right cathodal OFC tDCS, (b) left cathodal DLPFC/right anodal OFC tDCS, and (c) sham stimulation in Experiment 2. The current intensity was 1 mA for 15 min with a 72-hr interval between sessions. Participants underwent Go/No-Go task, N-back test, Wisconsin Card Sorting Test (WCST), and Stroop task after each tDCS condition. Anodal left DLPFC tDCS most clearly affected executive control functions (e.g., WM, interference inhibition), while cathodal left DLPFC tDCS improved inhibitory control. Cognitive flexibility/task switching benefited from combined DLPFC-OFC, but not DLPFC stimulation alone. Task-specific stimulation protocols can improve EFs in ADHD.

Antimicrobial activity of the essential oils of Thymus vulgaris L. measured using a bioimpedometric method.

PubMed

Marino, M; Bersani, C; Comi, G

1999-09-01

The essential oils obtained from Thymus vulgaris L. harvested at four ontogenetic stages were evaluated for their biological activity and chemical composition. The thyme essential oils were tested for their inhibitory effects against nine strains of gram-negative bacteria and six strains of gram-positive bacteria. The bioimpedance method was chosen for studying the antibacterial activity of the essential oils and the parameter chosen for defining and quantifying the antibacterial activity of the essential oils was the detection time. The plate counting technique was used to study the inhibitory effect by direct contact. All the thyme essential oils examined had a significant bacteriostatic activity against the microorganisms tested. This activity was more marked against the gram-positive bacteria. The oil from thyme in full flower was the most effective at stopping the growth of the microbial species examined. The oils tested were also shown to have good antibacterial activity by direct contact, which appeared to be more marked against the gram-negative bacteria. Only a few of the species were capable of recovering at least 50% of their metabolic function after contact with the inhibitor, while most of the strains were shown to have been inactivated almost completely. Escherichia coli O157:H7 was the most sensitive species, given that after contact with even the lowest concentration of oil cells could not be recovered.

Effects of inorganic ions on morphology of octacalcium phosphate grown on cation selective membrane at physiological temperature and pH in relation to enamel formation

NASA Astrophysics Data System (ADS)

Iijima, Mayumi; Moriwaki, Yutaka

1989-05-01

The crystal growth of octacalcium phosphate (OCP) is of particular interest, since there is a possibility that OCP is formed in the early stage of tooth enamel formation. In this study, the effects of CO2-3, Mg2+ and F-ions on the morphology of OCP were investigated in a membrane system, where a cation selective membrane was used to simulate amelogenesis. Reactions were carried out at pH 6.3, 6.5 and 6.8 for 3 days at 37°C. In most cases, these ions suppressed the crystal growth in the c-axis direction of OCP, particularly when they coexisted. The morphology of OCP crystal changed from ribbon-like to flake-like, depending on the inhibitory activity. The inhibitory activity, particularly that of F - ion, was suppressed at pH lower than pH 6.8. Antagonistic effect of Mg2+ and F-ion was observed at pH 6.5. In the case of F - ion, OCP crystals showed a unique pattern, which suggests hydrolysis of OCP and subsequent growth of apatite. These findings indicate that inorganic ions, particularly F - ion, influence the growth of OCP. Although CO2-3, Mg2+andF-ions coexisted, extended growth in the c-axis direction of OCP took place at pH 6.0.

Alzheimer Aβ disrupts the mitotic spindle and directly inhibits mitotic microtubule motors

PubMed Central

Borysov, Sergiy I; Granic, Antoneta; Padmanabhan, Jaya; Walczak, Claire E

2011-01-01

Chromosome mis-segregation and aneuploidy are greatly induced in Alzheimer disease and models thereof by mutant forms of the APP and PS proteins and by their product, the Aβ peptide. Here we employ human somatic cells and Xenopus egg extracts to show that Aβ impairs the assembly and maintenance of the mitotic spindle. Mechanistically, these defects result from Aβ's inhibition of mitotic motor kinesins, including Eg5, KIF4A and MCAK. In vitro studies show that oligomeric Aβ directly inhibits recombinant MCAK by a noncompetitive mechanism. In contrast, inhibition of Eg5 and KIF4A is competitive with respect to both ATP and microtubules, indicating that Aβ interferes with their interactions with the microtubules of the mitotic spindle. Consistently, increased levels of polymerized microtubules or of the microtubule stabilizing protein Tau significantly decrease the inhibitory effect of Aβ on Eg5 and KIF4A. Together, these results indicate that by disrupting the interaction between specific kinesins and microtubules and by exerting a direct inhibitory effect on the motor activity, excess Aβ deregulates the mechanical forces that govern the spindle and thereby leads to the generation of defective mitotic structures. The resulting defect in neurogenesis can account for the over 30% aneuploid/hyperploid, degeneration-prone neurons observed in Alzheimer disease brain. The finding of mitotic motors including Eg5 in mature post-mitotic neurons implies that their inhibition by Aβ may also disrupt neuronal function and plasticity. PMID:21566458

Evidence for a role of macrophage migration inhibitory factor in vascular disease.

PubMed

Chen, Zhiping; Sakuma, Masashi; Zago, Alexandre C; Zhang, Xiaobin; Shi, Can; Leng, Lin; Mizue, Yuka; Bucala, Richard; Simon, Daniel

2004-04-01

Inflammation plays an essential role in atherosclerosis and restenosis. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is widely expressed in vascular cells. However, there is no in vivo evidence that MIF participates directly in vascular injury and repair. Therefore, we investigated the effect of MIF blockade on the response to experimental angioplasty in atherosclerosis-susceptible mice. Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDL receptor-deficient mice treated with a neutralizing anti-MIF or isotype control monoclonal antibody. After 7 days and 28 days, intimal and medial sizes were measured and intima/media area ratio (I/M) was calculated. Intimal thickening and I/M were reduced significantly by anti-MIF compared with control antibody. Vascular injury was accompanied by progressive vessel enlargement or "positive remodeling" that was comparable in both treatment groups. MIF blockade was associated with reduced inflammation and cellular proliferation and increased apoptosis after injury. Neutralizing MIF bioactivity after experimental angioplasty in atherosclerosis-susceptible mice reduces vascular inflammation, cellular proliferation, and neointimal thickening. Although the molecular mechanisms responsible for these effects are not yet established, these data prompt further research directed at understanding the role of MIF in vascular disease and suggest novel therapeutic interventions for preventing atherosclerosis and restenosis.

Distractor inhibition: principles of operation during selective attention.

PubMed

Wyatt, Natalie; Machado, Liana

2013-02-01

Research suggests that although target amplification acts as the main determinant of the efficacy of selective attention, distractor inhibition contributes under some circumstances. Here we aimed to gain insight into the operating principles that regulate the use of distractor inhibition during selective attention. The results suggest that, in contrast to target amplification, distractor inhibition does not onset earlier or strengthen in response to advance location information. Instead, when the location of the impending distractor was predictable, evidence of inhibitory processing weakened. Furthermore, the results suggest that distractor inhibition does not operate as a compensatory mechanism for target amplification, as evidenced by the lack of an increase in inhibitory effects when reliance on target amplification was disrupted. Unexpected emergence of inhibitory effects for improbable targets provided evidence that distractor inhibition was at work even when no inhibitory effects manifested. Overall, the pattern of inhibitory effects is interpreted as indicating that, although distractor inhibition mounts primarily reactively rather than preemptively, advance information can help prevent overreaction to the distractor. Of course, less overreaction reduces the chances of behavioral inhibitory effects manifesting even when distractor inhibition has contributed to selective attention; thus, interpreting an absence of inhibitory effects should be done cautiously. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Licochalcones extracted from Glycyrrhiza inflata inhibit platelet aggregation accompanied by inhibition of COX-1 activity

PubMed Central

Okuda-Tanino, Asa; Sugawara, Daiki; Tashiro, Takumi; Iwashita, Masaya; Obara, Yutaro; Moriya, Takahiro; Tsushima, Chisato; Saigusa, Daisuke; Tomioka, Yoshihisa; Ishii, Kuniaki; Nakahata, Norimichi

2017-01-01

Licochalcones extracted from Glycyrrhiza inflata are known to have a variety of biological properties such as anti-inflammatory, anti-bacterial, and anti-tumor activities, but their action on platelet aggregation has not yet been reported. Therefore, in this study we investigated the effects of licochalcones on platelet aggregation. Collagen and U46619, a thromboxane A2 receptor agonist, caused rabbit platelet aggregation, which was reversed by pretreatment with licochalcones A, C and D in concentration-dependent manners. Among these compounds, licochalcone A caused the most potent inhibitory effect on collagen-induced platelet aggregation. However, the licochalcones showed marginal inhibitory effects on thrombin or ADP-induced platelet aggregation. In addition to rabbit platelets, licochalcone A attenuated collagen-induced aggregation in human platelets. Because licochalcone A also inhibited arachidonic acid-induced platelet aggregation and production of thromboxane A2 induced by collagen in intact platelets, we further examined the direct interaction of licochalcone A with cyclooxygenase (COX)-1. As expected, licochalcone A caused an inhibitory effect on both COX-1 and COX-2 in vitro. Regarding the effect of licochalcone A on COX-1 enzyme reaction kinetics, although licochalcone A showed a stronger inhibition of prostaglandin E2 synthesis induced by lower concentrations of arachidonic acid, Vmax values in the presence or absence of licochalcone A were comparable, suggesting that it competes with arachidonic acid at the same binding site on COX-1. These results suggest that licochalcones inhibit collagen-induced platelet aggregation accompanied by inhibition of COX-1 activity. PMID:28282426

ZnO nanoparticles modulate the ionic transport and voltage regulation of lysenin nanochannels.

PubMed

Bryant, Sheenah L; Eixenberger, Josh E; Rossland, Steven; Apsley, Holly; Hoffmann, Connor; Shrestha, Nisha; McHugh, Michael; Punnoose, Alex; Fologea, Daniel

2017-12-16

The insufficient understanding of unintended biological impacts from nanomaterials (NMs) represents a serious impediment to their use for scientific, technological, and medical applications. While previous studies have focused on understanding nanotoxicity effects mostly resulting from cellular internalization, recent work indicates that NMs may interfere with transmembrane transport mechanisms, hence enabling contributions to nanotoxicity by affecting key biological activities dependent on transmembrane transport. In this line of inquiry, we investigated the effects of charged nanoparticles (NPs) on the transport properties of lysenin, a pore-forming toxin that shares fundamental features with ion channels such as regulation and high transport rate. The macroscopic conductance of lysenin channels greatly diminished in the presence of cationic ZnO NPs. The inhibitory effects were asymmetrical relative to the direction of the electric field and addition site, suggesting electrostatic interactions between ZnO NPs and a binding site. Similar changes in the macroscopic conductance were observed when lysenin channels were reconstituted in neutral lipid membranes, implicating protein-NP interactions as the major contributor to the reduced transport capabilities. In contrast, no inhibitory effects were observed in the presence of anionic SnO 2 NPs. Additionally, we demonstrate that inhibition of ion transport is not due to the dissolution of ZnO NPs and subsequent interactions of zinc ions with lysenin channels. We conclude that electrostatic interactions between positively charged ZnO NPs and negative charges within the lysenin channels are responsible for the inhibitory effects on the transport of ions. These interactions point to a potential mechanism of cytotoxicity, which may not require NP internalization.

Activity and characterization of secondary metabolites produced by a new microorganism for control of plant diseases.

PubMed

Ko, Wen-Hsiung; Tsou, Yi-Jung; Lin, Mei-Ju; Chern, Lih-Ling

2010-09-30

Microorganisms capable of utilizing vegetable tissues for growth in soils were isolated and their vegetable broth cultures were individually sprayed directly on leaves to test their ability to control Phytophthora blight of bell pepper caused by Phytophthora capsici. Liquid culture of Streptomyces strain TKA-5, a previously undescribed species obtained in this study, displayed several desirable disease control characteristics in nature, including high potency, long lasting and ability to control also black leaf spot of spoon cabbage caused by Alternaria brassicicolca. The extract was fungicidal to P. capsici but fungistatic to A. brassicicola. It was stable at high temperature and high pH. However, after exposure to pH 2 for 24h, the extract was no longer inhibitory to P. capsici although it was still strongly inhibitory to A. brassicicola. After treatment with cation or anion exchange resins, the extract lost its inhibitory effect against P. capsici but not A. brassicicola. The results suggest that the extract contained two different kinds of inhibitory metabolites, one against P. capsici with both positive and negative charges on its molecule and another against A. brassicicola with no charges on its molecule. The inhibitory metabolites were soluble in ethanol or methanol but not in water, ether or chloroform. They were dialyzable in the membrane tubing with molecular weight cut-off of 10,000, 1000 or 500 but not 100, indicating that the inhibitors have a molecular weight between 500 and 100. Results also showed that both inhibitors are not proteins. Copyright 2010 Elsevier B.V. All rights reserved.

Therapeutic Antiviral Effect of the Nucleic Acid Polymer REP 2055 against Persistent Duck Hepatitis B Virus Infection

PubMed Central

Noordeen, Faseeha; Scougall, Catherine A.; Grosse, Arend; Qiao, Qiao; Ajilian, Behzad B.; Reaiche-Miller, Georget; Finnie, John; Werner, Melanie; Broering, Ruth; Schlaak, Joerg F.; Vaillant, Andrew; Jilbert, Allison R.

2015-01-01

Previous studies have demonstrated that nucleic acid polymers (NAPs) have both entry and post-entry inhibitory activity against duck hepatitis B virus (DHBV) infection. The inhibitory activity exhibited by NAPs prevented DHBV infection of primary duck hepatocytes in vitro and protected ducks from DHBV infection in vivo and did not result from direct activation of the immune response. In the current study treatment of primary human hepatocytes with NAP REP 2055 did not induce expression of the TNF, IL6, IL10, IFNA4 or IFNB1 genes, confirming the lack of direct immunostimulation by REP 2055. Ducks with persistent DHBV infection were treated with NAP 2055 to determine if the post-entry inhibitory activity exhibited by NAPs could provide a therapeutic effect against established DHBV infection in vivo. In all REP 2055-treated ducks, 28 days of treatment lead to initial rapid reductions in serum DHBsAg and DHBV DNA and increases in anti-DHBs antibodies. After treatment, 6/11 ducks experienced a sustained virologic response: DHBsAg and DHBV DNA remained at low or undetectable levels in the serum and no DHBsAg or DHBV core antigen positive hepatocytes and only trace amounts of DHBV total and covalently closed circular DNA (cccDNA) were detected in the liver at 9 or 16 weeks of follow-up. In the remaining 5/11 REP 2055-treated ducks, all markers of DHBV infection rapidly rebounded after treatment withdrawal: At 9 and 16 weeks of follow-up, levels of DHBsAg and DHBcAg and DHBV total and cccDNA in the liver had rebounded and matched levels observed in the control ducks treated with normal saline which remained persistently infected with DHBV. These data demonstrate that treatment with the NAP REP 2055 can lead to sustained control of persistent DHBV infection. These effects may be related to the unique ability of REP 2055 to block release of DHBsAg from infected hepatocytes. PMID:26560490

Structural Dynamics Investigation of Human Family 1 & 2 Cystatin-Cathepsin L1 Interaction: A Comparison of Binding Modes.

PubMed

Nandy, Suman Kumar; Seal, Alpana

2016-01-01

Cystatin superfamily is a large group of evolutionarily related proteins involved in numerous physiological activities through their inhibitory activity towards cysteine proteases. Despite sharing the same cystatin fold, and inhibiting cysteine proteases through the same tripartite edge involving highly conserved N-terminal region, L1 and L2 loop; cystatins differ widely in their inhibitory affinity towards C1 family of cysteine proteases and molecular details of these interactions are still elusive. In this study, inhibitory interactions of human family 1 & 2 cystatins with cathepsin L1 are predicted and their stability and viability are verified through protein docking & comparative molecular dynamics. An overall stabilization effect is observed in all cystatins on complex formation. Complexes are mostly dominated by van der Waals interaction but the relative participation of the conserved regions varied extensively. While van der Waals contacts prevail in L1 and L2 loop, N-terminal segment chiefly acts as electrostatic interaction site. In fact the comparative dynamics study points towards the instrumental role of L1 loop in directing the total interaction profile of the complex either towards electrostatic or van der Waals contacts. The key amino acid residues surfaced via interaction energy, hydrogen bonding and solvent accessible surface area analysis for each cystatin-cathepsin L1 complex influence the mode of binding and thus control the diverse inhibitory affinity of cystatins towards cysteine proteases.

Characterization of polysaccharides with marked inhibitory effect on lipid accumulation in Pleurotus eryngii.

PubMed

Chen, Jingjing; Yong, Yangyang; Xing, Meichun; Gu, Yifan; Zhang, Zhao; Zhang, Shizhu; Lu, Ling

2013-09-12

Mushrooms have a great potential for the production of useful bioactive metabolites. To explore the bioactive compounds from edible mushrooms for interfering with the development of macrophage-derived foam cells, which is recognized as the hallmark of early atherosclerosis, eight types of mushrooms polysaccharides had been selected to be tested. Consequently, different mushrooms polysaccharides displayed diverse component profiles. Of polysaccharides that we tested, the Pleurotus eryngii polysaccharide had the strongest inhibitory effect on lipid accumulation. Furthermore, through fractionation of DEAE-52 and Sephadex G-100, the polysaccharide from P. eryngii had been successfully purified and identified. By the analysis of IR, GC, and HPLC, the purified polysaccharide was estimated to be 30-38 kDa for the average molecular weight with the monosaccharide composition mainly composed of D-types of mannose, glucose and galactose. Findings presented in this report firstly provide direct evidence, which links the purified polysaccharide moiety with the biological function in foam-cell model. Copyright © 2013 Elsevier Ltd. All rights reserved.

Axonal GABAA receptors.

PubMed

Trigo, Federico F; Marty, Alain; Stell, Brandon M

2008-09-01

Type A GABA receptors (GABA(A)Rs) are well established as the main inhibitory receptors in the mature mammalian forebrain. In recent years, evidence has accumulated showing that GABA(A)Rs are prevalent not only in the somatodendritic compartment of CNS neurons, but also in their axonal compartment. Evidence for axonal GABA(A)Rs includes new immunohistochemical and immunogold data: direct recording from single axonal terminals; and effects of local applications of GABA(A)R modulators on action potential generation, on axonal calcium signalling, and on neurotransmitter release. Strikingly, whereas presynaptic GABA(A)Rs have long been considered inhibitory, the new studies in the mammalian brain mostly indicate an excitatory action. Depending on the neuron that is under study, axonal GABA(A)Rs can be activated by ambient GABA, by GABA spillover, or by an autocrine action, to increase either action potential firing and/or transmitter release. In certain neurons, the excitatory effects of axonal GABA(A)Rs persist into adulthood. Altogether, axonal GABA(A)Rs appear as potent neuronal modulators of the mammalian CNS.

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

Inhibitory effects of 2'-hydroxychalcones on rat lens aldose reductase and rat platelet aggregation.

PubMed

Lim, S S; Jung, S H; Ji, J; Shin, K H; Keum, S R

2000-11-01

Inhibitory effects of synthetic 2'-hydroxychalcone derivatives on rat lens aldose reductase (RLAR) and on platelet aggregation were investigated for the prevention or the treatment of chronic diabetic complications. 5'-chloro-4,2'-dihydroxychalcone (8) and 5'-chloro-3,2'-dihydroxychalcone (27) exhibited a potent inhibitory effect on rat platelet aggregation induced by ADP (IC50=0.10 and 0.06 mg/ml, respectively) and collagen (IC50=44 and 16 microg/ml, respectively) but showed relatively weak inhibitory activities on RLAR.

Evaluation of environmental bacterial communities as a factor affecting the growth of duckweed Lemna minor.

PubMed

Ishizawa, Hidehiro; Kuroda, Masashi; Morikawa, Masaaki; Ike, Michihiko

2017-01-01

Duckweed (family Lemnaceae ) has recently been recognized as an ideal biomass feedstock for biofuel production due to its rapid growth and high starch content, which inspired interest in improving their productivity. Since microbes that co-exist with plants are known to have significant effects on their growth according to the previous studies for terrestrial plants, this study has attempted to understand the plant-microbial interactions of a duckweed, Lemna minor , focusing on the growth promotion/inhibition effects so as to assess the possibility of accelerated duckweed production by modifying co-existing bacterial community. Co-cultivation of aseptic L. minor and bacterial communities collected from various aquatic environments resulted in changes in duckweed growth ranging from -24 to +14% compared to aseptic control. A number of bacterial strains were isolated from both growth-promoting and growth-inhibitory communities, and examined for their co-existing effects on duckweed growth. Irrespective of the source, each strain showed promotive, inhibitory, or neutral effects when individually co-cultured with L. minor . To further analyze the interactions among these bacterial strains in a community, binary combinations of promotive and inhibitory strains were co-cultured with aseptic L. minor , resulting in that combinations of promotive-promotive or inhibitory-inhibitory strains generally showed effects similar to those of individual strains. However, combinations of promotive-inhibitory strains tended to show inhibitory effects while only Aquitalea magnusonii H3 exerted its plant growth-promoting effect in all combinations tested. Significant change in biomass production was observed when duckweed was co-cultivated with environmental bacterial communities. Promotive, neutral, and inhibitory bacteria in the community would synergistically determine the effects. The results indicate the possibility of improving duckweed biomass production via regulation of co-existing bacterial communities.

Potent inhibitory effects of D-tagatose on the acid production and water-insoluble glucan synthesis of Streptococcus mutans GS5 in the presence of sucrose.

PubMed

Sawada, Daijo; Ogawa, Takaaki; Miyake, Minoru; Hasui, Yoshinori; Yamaguchi, Fuminori; Izumori, Ken; Tokuda, Masaaki

2015-01-01

We examined and compared the inhibitory effects of D-tagatose on the growth, acid production, and water-insoluble glucan synthesis of GS5, a bacterial strain of Streptococcus mutans, with those of xylitol, D-psicose, L-psicose and L-tagatose. GS5 was cultured for 12h in a medium containing 10% (w/v) of xylitol, D-psicose, L-psicose, D-tagatose or L-tagatose, and the inhibitory effect of GS5 growth was assessed. Each sugar showed different inhibitory effects on GS5. Both D-tagatose and xylitol significantly inhibited the acid production and water-insoluble glucan synthesis of GS5 in the presence of 1% (w/v) sucrose. However, the inhibitory effect of acid production by D-tagatose was significantly stronger than that of xylitol in presence of sucrose.

Biochemical Characterization of Ferulic Acid and Caffeic Acid Which Effectively Inhibit Melanin Synthesis via Different Mechanisms in B16 Melanoma Cells.

PubMed

Maruyama, Hiroko; Kawakami, Fumitaka; Lwin, Thet-Thet; Imai, Motoki; Shamsa, Fazel

2018-01-01

In this study, we examined the inhibitory effects of ferulic acid and caffeic acid on melanin production using a murine B16 melanoma cell line. The mechanisms by which the two acids inhibit melanin production were investigated by evaluating their effects on the activity of tyrosinase, which is involved is the first step of melanin biosynthesis. Ferulic acid showed no toxicity against the melanoma cells at any dose, whereas caffeic acid exerted cellular toxicity at concentrations higher than 0.35 mM. Both ferulic and caffeic acids effectively inhibited melanin production in the B16 melanoma cells. Ferulic acid reduced tyrosinase activity by directly binding to the enzyme, whereas no binding was observed between caffeic acid and tyrosinase. Both ferulic acid and caffeic acid inhibited casein kinase 2 (CK2)-induced phosphorylation of tyrosinase in a dose-dependent manner in vitro. Ferulic acid was found to be a more effective inhibitor of melanin production than caffeic acid; this difference in the inhibitory efficacy between the two substances could be attributable to the difference in their tyrosine-binding activity. Our analysis revealed that both substances also inhibited the CK2-mediated phosphorylation of tyrosinase.

Effect of steeping temperature on antioxidant and inhibitory activities of green tea extracts against α-amylase, α-glucosidase and intestinal glucose uptake.

PubMed

Liu, Shuyuan; Ai, Zeyi; Qu, Fengfeng; Chen, Yuqiong; Ni, Dejiang

2017-11-01

The objective of the present study was to evaluate the effect of steeping temperature on the biological activities of green tea, including the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging capacity, α-glucosidase and α-amylase inhibitory activities, and glucose uptake inhibitory activity in Caco-2 cells. Results showed that, with increasing extraction temperature, the polyphenol content increased, which contributed to enhance antioxidant activity and inhibitory effects on α-glucosidase and α-amylase. Green tea steeped at 100°C showed the highest DPPH radical-scavenging activity and inhibitory effects on α-glucosidase and α-amylase activities with EC 50 or IC 50 values of 6.15μg/mL, 0.09mg/mL, and 6.31mg/mL, respectively. However, the inhibitory potential on glucose uptake did not show an upward trend with increasing extraction temperature. Green tea steeped at 60°C had significantly stronger glucose uptake inhibitory activity (p<0.05). The integrated data suggested that steeping temperature should be considered when evaluating the biological activities of green tea. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of oxotremorine and physostigmine on the inhibitory avoidance impairment produced by amitriptyline in male and female mice.

PubMed

Monleón, Santiago; Urquiza, Adoración; Vinader-Caerols, Concepción; Parra, Andrés

2009-12-28

We have previously observed that amitriptyline and other antidepressants produce impairing effects on inhibitory avoidance (also called passive avoidance) in mice of both sexes. In the present study we investigated the involvement of the cholinergic system in the inhibitory avoidance impairment produced by acute amitriptyline in male and female CD1 mice. For this purpose, the effects on said task of acute i.p. administration of several doses of amitriptyline, either alone or in combination with the cholinergic agonists oxotremorine and physostigmine, were evaluated. Pre-training administration of 5, 7.5, 10 or 15 mg/kg of amitriptyline produced a significant impairment of inhibitory avoidance in both males and females. When oxotremorine (0.05 or 0.1 mg/kg) was co-administered with amitriptyline, the antidepressant's impairing effect was partially counteracted, although inhibitory avoidance learning was not significant. Physostigmine (0.15, 0.3 or 0.6 mg/kg) counteracted the impairment produced by amitriptyline, as mice treated with both drugs exhibited inhibitory avoidance learning. These results show that the inhibitory avoidance impairment produced by amitriptyline in male and female mice is mediated, at least partially, by the cholinergic system.

Inhibition of oxytocin and vasopressin neuron activity in rat hypothalamic paraventricular nucleus by relaxin-3-RXFP3 signalling.

PubMed

Kania, Alan; Gugula, Anna; Grabowiecka, Agnieszka; de Ávila, Camila; Blasiak, Tomasz; Rajfur, Zenon; Lewandowski, Marian H; Hess, Grzegorz; Timofeeva, Elena; Gundlach, Andrew L; Blasiak, Anna

2017-06-01

Relaxin-3 is a stress-responsive neuropeptide that acts at its cognate receptor, RXFP3, to alter behaviours including feeding. In this study, we have demonstrated a direct, RXFP3-dependent, inhibitory action of relaxin-3 on oxytocin and vasopressin paraventricular nucleus (PVN) neuron electrical activity, a putative cellular mechanism of orexigenic actions of relaxin-3. We observed a Gα i/o -protein-dependent inhibitory influence of selective RXFP3 activation on PVN neuronal activity in vitro and demonstrated a direct action of RXFP3 activation on oxytocin and vasopressin PVN neurons, confirmed by their abundant expression of RXFP3 mRNA. Moreover, we demonstrated that RXFP3 activation induces a cadmium-sensitive outward current, which indicates the involvement of a characteristic magnocellular neuron outward potassium current. Furthermore, we identified an abundance of relaxin-3-immunoreactive axons/fibres originating from the nucleus incertus in close proximity to the PVN, but associated with sparse relaxin-3-containing fibres/terminals within the PVN. The paraventricular nucleus of the hypothalamus (PVN) plays an essential role in the control of food intake and energy expenditure by integrating multiple neural and humoral inputs. Recent studies have demonstrated that intracerebroventricular and intra-PVN injections of the neuropeptide relaxin-3 or selective relaxin-3 receptor (RXFP3) agonists produce robust feeding in satiated rats, but the cellular and molecular mechanisms of action associated with these orexigenic effects have not been identified. In the present studies, using rat brain slices, we demonstrated that relaxin-3, acting through its cognate G-protein-coupled receptor, RXFP3, hyperpolarized a majority of putative magnocellular PVN neurons (88%, 22/25), including cells producing the anorexigenic neuropeptides, oxytocin and vasopressin. Importantly, the action of relaxin-3 persisted in the presence of tetrodotoxin and glutamate/GABA receptor antagonists, indicating its direct action on PVN neurons. Similar inhibitory effects on PVN oxytocin and vasopressin neurons were produced by the RXFP3 agonist, RXFP3-A2 (82%, 80/98 cells). In situ hybridization histochemistry revealed a strong colocalization of RXFP3 mRNA with oxytocin and vasopressin immunoreactivity in rat PVN neurons. A smaller percentage of putative parvocellular PVN neurons was sensitive to RXFP3-A2 (40%, 16/40 cells). These data, along with a demonstration of abundant peri-PVN and sparse intra-PVN relaxin-3-immunoreactive nerve fibres, originating from the nucleus incertus, the major source of relaxin-3 neurons, identify a strong inhibitory influence of relaxin-3-RXFP3 signalling on the electrical activity of PVN oxytocin and vasopressin neurons, consistent with the orexigenic effect of RXFP3 activation observed in vivo. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Direct negative chronotropic action of desflurane on sinoatrial node pacemaker activity in the guinea pig heart.

PubMed

Kojima, Akiko; Ito, Yuki; Kitagawa, Hirotoshi; Matsuura, Hiroshi; Nosaka, Shuichi

2014-06-01

Desflurane inhalation is associated with sympathetic activation and concomitant increase in heart rate in humans and experimental animals. There is, however, little information concerning the direct effects of desflurane on electrical activity of sinoatrial node pacemaker cells that determines the intrinsic heart rate. Whole-cell patch-clamp experiments were conducted on guinea pig sinoatrial node pacemaker cells to record spontaneous action potentials and ionic currents contributing to sinoatrial node automaticity, namely, hyperpolarization-activated cation current (If), T-type and L-type Ca currents (ICa,T and ICa,L, respectively), Na/Ca exchange current (INCX), and rapidly and slowly activating delayed rectifier K currents (IKr and IKs, respectively). Electrocardiograms were recorded from ex vivo Langendorff-perfused hearts and in vivo hearts. Desflurane at 6 and 12% decreased spontaneous firing rate of sinoatrial node action potentials by 15.9% (n = 11) and 27.6% (n = 10), respectively, which was associated with 20.4% and 42.5% reductions in diastolic depolarization rate, respectively. Desflurane inhibited If, ICa,T, ICa,L, INCX, and IKs but had little effect on IKr. The negative chronotropic action of desflurane was reasonably well reproduced in sinoatrial node computer model. Desflurane reduced the heart rate in Langendorff-perfused hearts. High concentration (12%) of desflurane inhalation was associated with transient tachycardia, which was totally abolished by pretreatment with the β-adrenergic blocker propranolol. Desflurane has a direct negative chronotropic action on sinoatrial node pacemaking activity, which is mediated by its inhibitory action on multiple ionic currents. This direct inhibitory action of desflurane on sinoatrial node automaticity seems to be counteracted by sympathetic activation associated with desflurane inhalation in vivo.

UV-B radiation induces macrophage migration inhibitory factor-mediated melanogenesis through activation of protease-activated receptor-2 and stem cell factor in keratinocytes.

PubMed

Enomoto, Akiko; Yoshihisa, Yoko; Yamakoshi, Takako; Ur Rehman, Mati; Norisugi, Osamu; Hara, Hiroshi; Matsunaga, Kenji; Makino, Teruhiko; Nishihira, Jun; Shimizu, Tadamichi

2011-02-01

UV radiation indirectly regulates melanogenesis in melanocytes through a paracrine regulatory mechanism involving keratinocytes. Protease-activated receptor (PAR)-2 activation induces melanosome transfer by increasing phagocytosis of melanosomes by keratinocytes. This study demonstrated that macrophage migration inhibitory factor (MIF) stimulated PAR-2 expression in human keratinocytes. In addition, we showed that MIF stimulated stem cell factor (SCF) release in keratinocytes; however, MIF had no effect on the release of endothelin-1 or prostaglandin E2 in keratinocytes. In addition, MIF had no direct effect on melanin and tyrosinase synthesis in cultured human melanocytes. The effect of MIF on melanogenesis was also examined using a three-dimensional reconstituted human epidermal culture model, which is a novel, commercially available, cultured human epidermis containing functional melanocytes. Migration inhibitory factor induced an increase in melanin content in the epidermis after a 9-day culture period. Moreover, melanin synthesis induced by UV-B stimulation was significantly down-regulated by anti-MIF antibody treatment. An in vivo study showed that the back skin of MIF transgenic mice had a higher melanin content than that of wild-type mice after 12 weeks of UV-B exposure. Therefore, MIF-mediated melanogenesis occurs mainly through the activation of PAR-2 and SCF expression in keratinocytes after exposure to UV-B radiation. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Phenolics from Ageratina adenophora roots and their phytotoxic effects on Arabidopsis thaliana seed germination and seedling growth.

PubMed

Zhou, Zhong-Yu; Liu, Wan-Xue; Pei, Gang; Ren, Hui; Wang, Jing; Xu, Qiao-Lin; Xie, Hai-Hui; Wan, Fang-Hao; Tan, Jian-Wen

2013-12-04

A bioassay-directed phytochemical study was conducted to investigate potential allelochemicals in the roots of the invasive plant Ageratina adenophora. Eleven phenolic compounds, including seven new ones, 7-hydroxy-8,9-dehydrothymol 9-O-trans-ferulate (1), 7-hydroxythymol 9-O-trans-ferulate (2), 7,8-dihydroxythymol 9-O-trans-ferulate (3), 7,8-dihydroxythymol 9-O-cis-ferulate (4), methyl (7R)-3-deoxy-4,5-epoxy-D-manno-2-octulosonate 8-O-trans-p-coumarate (5), methyl (7R)-3-deoxy-4,5-epoxy-D-manno-2-octulosonate 8-O-cis-p-coumarate (6), and 3-(2-hydroxyphenyl)propyl methyl malonate (7), were isolated from a bioactive subfraction of the ethanol extract of the roots of A. adenophora. The new structures were established on the basis of detailed spectroscopic analysis. The potential phytotoxic effects of these compounds on the germination of Arabidopsis thaliana seeds were tested by a filter paper assay. Compound 7 and known compounds 3-(2-hydroxyphenyl)-1-propanol (8) and o-coumaric acid (9) remarkably showed inhibition activity against Arabidopsis seed germination at a concentration of 1.0 mM. Compounds 1, 2, 5, 6, and 10 showed slight inhibitory activity at the test concentration after treatment for 3 days, while the other compounds showed no obvious inhibitory effects. Moreover, 7-9 were further found to show obvious inhibitory activity on retarding the seedling growth of Ar. thaliana cultured in soil medium.

Dose-dependent inhibition of gastric injury by hydrogen in alkaline electrolyzed drinking water

PubMed Central

2014-01-01

Background Hydrogen has been reported to relieve damage in many disease models, and is a potential additive in drinking water to provide protective effects for patients as several clinical studies revealed. However, the absence of a dose–response relationship in the application of hydrogen is puzzling. We attempted to identify the dose–response relationship of hydrogen in alkaline electrolyzed drinking water through the aspirin induced gastric injury model. Methods In this study, hydrogen-rich alkaline water was obtained by adding H2 to electrolyzed water at one atmosphere pressure. After 2 weeks of drinking, we detected the gastric mucosal damage together with MPO, MDA and 8-OHdG in rat aspirin induced gastric injury model. Results Hydrogen-dose dependent inhibition was observed in stomach mucosal. Under pH 8.5, 0.07, 0.22 and 0.84 ppm hydrogen exhibited a high correlation with inhibitory effects showed by erosion area, MPO activity and MDA content in the stomach. Gastric histology also demonstrated the inhibition of damage by hydrogen-rich alkaline water. However, 8-OHdG level in serum did not have significant hydrogen-dose dependent effect. pH 9.5 showed higher but not significant inhibitory response compared with pH 8.5. Conclusions Hydrogen is effective in relieving the gastric injury induced by aspirin-HCl, and the inhibitory effect is dose-dependent. The reason behind this may be that hydrogen-rich water directly interacted with the target tissue, while the hydrogen concentration in blood was buffered by liver glycogen, evoking a suppressed dose–response effect. Drinking hydrogen-rich water may protect healthy individuals from gastric damage caused by oxidative stress. PMID:24589018

Effects of serotonin (5-HT)1B receptor ligands on amphetamine-seeking behavior in rats.

PubMed

Miszkiel, Joanna; Przegaliński, Edmund

2013-01-01

Numerous studies have indicated that serotonin (5-HT)1B receptor ligands affect the behavioral effects of psychostimulants (cocaine, amphetamine), including the reinforcing activities of these drugs. To substantiate a role for those receptors in incentive motivation for amphetamine, we used the extinction/reinstatement model to examine the effects of the 5-HT1B receptor ligands on the reinstatement of extinguished amphetamine-seeking behavior. Rats trained to self-administer amphetamine (0.06 mg/kg/infusion) subsequently underwent the extinction procedure. These rats were then tested for the amphetamine-primed or amphetamine-associated cue-induced reinstatement of extinguished amphetamine-seeking behavior. The 5-HT1B receptor antagonist SB 216641 (5-7.5 mg/kg) attenuated the amphetamine (1.5 mg/kg)- and the amphetamine-associated cue combined with the threshold dose of amphetamine (0.5 mg/kg)-induced reinstatement of amphetamine-seeking behavior. The 5-HT1B receptor agonist CP 94253 (1.25-5 mg/kg) also inhibited the amphetamine-seeking behavior induced by amphetamine (1.5 mg/kg) but not by the cue combined with the threshold dose of amphetamine. The inhibitory effect of CP94253 on amphetamine-seeking behavior remained unaffected by the 5-HT1B receptor antagonist. Our results indicate that tonic activation of 5-HT1B receptors is involved in amphetamine- and cue-induced reinstatement of amphetamine-seeking behavior and that the inhibitory effects of 5-HT1B receptor antagonists on these phenomena are directly related to the motivational aspects of amphetamine abuse. The inhibitory effect of CP 94253 on amphetamine-seeking behavior seems to be unrelated to 5-HT1B receptor activation and may result from a general reduction of motivation.

Dose-dependent inhibition of gastric injury by hydrogen in alkaline electrolyzed drinking water.

PubMed

Xue, Jinling; Shang, Guodong; Tanaka, Yoshinori; Saihara, Yasuhiro; Hou, Lingyan; Velasquez, Natalia; Liu, Wenjun; Lu, Yun

2014-03-03

Hydrogen has been reported to relieve damage in many disease models, and is a potential additive in drinking water to provide protective effects for patients as several clinical studies revealed. However, the absence of a dose-response relationship in the application of hydrogen is puzzling. We attempted to identify the dose-response relationship of hydrogen in alkaline electrolyzed drinking water through the aspirin induced gastric injury model. In this study, hydrogen-rich alkaline water was obtained by adding H2 to electrolyzed water at one atmosphere pressure. After 2 weeks of drinking, we detected the gastric mucosal damage together with MPO, MDA and 8-OHdG in rat aspirin induced gastric injury model. Hydrogen-dose dependent inhibition was observed in stomach mucosal. Under pH 8.5, 0.07, 0.22 and 0.84 ppm hydrogen exhibited a high correlation with inhibitory effects showed by erosion area, MPO activity and MDA content in the stomach. Gastric histology also demonstrated the inhibition of damage by hydrogen-rich alkaline water. However, 8-OHdG level in serum did not have significant hydrogen-dose dependent effect. pH 9.5 showed higher but not significant inhibitory response compared with pH 8.5. Hydrogen is effective in relieving the gastric injury induced by aspirin-HCl, and the inhibitory effect is dose-dependent. The reason behind this may be that hydrogen-rich water directly interacted with the target tissue, while the hydrogen concentration in blood was buffered by liver glycogen, evoking a suppressed dose-response effect. Drinking hydrogen-rich water may protect healthy individuals from gastric damage caused by oxidative stress.

Inhibitory effect of flavonoids from citrus plants on Epstein-Barr virus activation and two-stage carcinogenesis of skin tumors.

PubMed

Iwase, Y; Takemura, Y; Ju-ichi, M; Ito, C; Furukawa, H; Kawaii, S; Yano, M; Mou, X Y; Takayasu, J; Tokuda, H; Nishino, H

2000-06-01

To search for possible anti-tumor promoters, thirteen flavones (1-13) obtained from the peel of Citrus plants 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 flavones, 3,5,6,7,8,3',4'-heptamethoxyflavone (HPT) (13) exhibited significant inhibitory effects on the EBV-EA activation induced by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA). Further, compound 13 exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.

Studying the Inhibitory Effect of Quercetin and Thymoquinone on Human Cytochrome P450 Enzyme Activities.

PubMed

Elbarbry, Fawzy; Ung, Aimy; Abdelkawy, Khaled

2018-01-01

Quercetin (QR) and thymoquinone (TQ) are herbal remedies that are currently extensively used by the general population to prevent and treat various chronic conditions. Therefore, investigating the potential of pharmacokinetic interactions caused by the concomitant use of these herbal remedies and conventional medicine is warranted to ensure patient safety. This study was conducted to determine the inhibitory effect of QR and TQ, two commonly used remedies, on the activities of selected cytochrome P450 (CYP) enzymes that play an important role in drug metabolism and/or toxicology. The in vitro studies were conducted using fluorescence-based high throughput assays using human c-DNA baculovirus expressed CYP enzymes. For measuring CYP2E1 activity, a validated High-performance liquid chromatography (HPLC) assay was utilized to measure the formation of 6-hydroxychlorzoxazone. The obtained half-maximum inhibitory concentration values with known positive control inhibitors of this study were comparable to the published values indicating accurate experimental techniques. Although QR did not show any significant effect on CYP1A2 and CYP2E1, it exhibited a strong inhibitory effect against CYP2D6 and a moderate effect against CYP2C19 and CYP3A4. On the other hand, TQ demonstrated a strong and a moderate inhibitory effect against CYP3A4 and CYP2C19, respectively. The findings of this study may indicate that consumption of QR or TQ, in the form of food or dietary supplements, with drugs that are metabolized by CYP2C19, CYP2D6, or CYP3A4 may cause significant herb-drug interactions. Neither QR nor TQ has any significant inhibitory effect on the activity of CYP1A2 or CYP2E1 enzymesBoth QR and TQ have a moderate to strong inhibitory effect on CYP3A4 activityQR has a moderate inhibitory effect on CYP2C19 and a strong inhibitory effect on CYP2D6Both QR and TQ are moderate inhibitors of the CYP2C9 activity. Abbreviations used: ABT: Aminobenztriazole, BZF: 7,8 Benzoflavone, CYP: Cytochrome P450, GB: Gingko Biloba, IC 50 : Half-maximum inhibitory concentration, KTZ: Ketoconazole, QND: Quinidine, QR: Quercetin, TCP: Tranylcypromine, TQ: Thymoquinone.

Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity

PubMed Central

Yonehara, Keisuke; Fiscella, Michele; Drinnenberg, Antonia; Esposti, Federico; Trenholm, Stuart; Krol, Jacek; Franke, Felix; Scherf, Brigitte Gross; Kusnyerik, Akos; Müller, Jan; Szabo, Arnold; Jüttner, Josephine; Cordoba, Francisco; Reddy, Ashrithpal Police; Németh, János; Nagy, Zoltán Zsolt; Munier, Francis; Hierlemann, Andreas; Roska, Botond

2016-01-01

Summary Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. Here we found that the mutation of FRMD7, a gene that is defective in human congenital nystagmus, leads to the selective loss of the horizontal optokinetic reflex in mice, as it does in humans. This is accompanied by the selective loss of horizontal direction selectivity in retinal ganglion cells and the transition from asymmetric to symmetric inhibitory input to horizontal direction-selective ganglion cells. In wild-type retinas, we found FRMD7 specifically expressed in starburst amacrine cells, the interneuron type that provides asymmetric inhibition to direction-selective retinal ganglion cells. This work identifies FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and it suggests the involvement of a specific inhibitory neuron type in the pathophysiology of a neurological disease. Video Abstract PMID:26711119

The direct relationship between inhibitory currents and local field potentials.

PubMed

Trevelyan, Andrew J

2009-12-02

The frequency profiles of various extracellular field oscillations are known to reflect functional brain states, yet we lack detailed explanations of how these brain oscillations arise. Of particular clinical relevance are the high-frequency oscillations (HFOs) associated with interictal events and the onset of seizures. These time periods are also when pyramidal firing appears to be vetoed by high-frequency volleys of inhibitory synaptic currents, thereby providing an inhibitory restraint that opposes epileptiform spread (Trevelyan et al., 2006, 2007). The pattern and timing of this inhibitory volley is suggestive of a causal relationship between the restraint and HFOs. I show that at these times, isolated inhibitory currents from single pyramidal cells have a similarity to the extracellular signal that significantly exceeds chance. The ability to extrapolate from discrete currents in single cells to the extracellular signal arises because these inhibitory currents are synchronized in local populations of pyramidal cells. The visibility of these inhibitory currents in the field recordings is greatest when local pyramidal activity is suppressed: the correlation between the inhibitory currents and the field signal becomes worse when local activity increases, suggestive of a switch from one source of HFO to another as the restraint starts to fail. This association suggests that a significant component of HFOs reflects the last act of defiance in the face of an advancing ictal event.

Immune Regulatory Activity of Vitamin D3 in Head and Neck Cancer

PubMed Central

Young, M. Rita I.; Day, Terry A.

2013-01-01

While vitamin D exhibits a multitude of cellular effects that can impact on cancer development and progression, this review focuses on its immune modulatory effects. These immune modulatory effects can be both direct and indirect. Compared to other cancer types, head and neck squamous cell carcinomas (HNSCC) have received less attention, but are a fascination immunologically because of the profound extent to which they inhibit immune defenses. This review describes the mechanisms of some of these immune inhibitory processes and how vitamin D can help overcome aspects of this immune suppression. PMID:24202334

Effect of fatty acids on Staphylococcus aureus delta-toxin hemolytic activity.

PubMed

Kapral, F A

1976-01-01

The lysis of human erythrocytes by Staphylococcus aureus delta-toxin proceeded without a lag and was directly proportional to toxin concentration and temperature of incubation. Lysis was complete within 8 min. Addition of saturated, straight-chain fatty acids of 13 to 19 carbons increased the activity of delta-toxin, whereas those with 21 to 23 carbons were inhibitory. Palmitic acid was the fatty acid most active in augmenting delta-toxin, but its effect could be abolished by the simultaneous addition of either tricosanoic acid or egg lecithin.

A novel role for WAVE1 in controlling actin network growth rate and architecture.

PubMed

Sweeney, Meredith O; Collins, Agnieszka; Padrick, Shae B; Goode, Bruce L

2015-02-01

Branched actin filament networks in cells are assembled through the combined activities of Arp2/3 complex and different WASP/WAVE proteins. Here we used TIRF and electron microscopy to directly compare for the first time the assembly kinetics and architectures of actin filament networks produced by Arp2/3 complex and dimerized VCA regions of WAVE1, WAVE2, or N-WASP. WAVE1 produced strikingly different networks from WAVE2 or N-WASP, which comprised unexpectedly short filaments. Further analysis showed that the WAVE1-specific activity stemmed from an inhibitory effect on filament elongation both in the presence and absence of Arp2/3 complex, which was observed even at low stoichiometries of WAVE1 to actin monomers, precluding an effect from monomer sequestration. Using a series of VCA chimeras, we mapped the elongation inhibitory effects of WAVE1 to its WH2 ("V") domain. Further, mutating a single conserved lysine residue potently disrupted WAVE1's inhibitory effects. Taken together, our results show that WAVE1 has unique activities independent of Arp2/3 complex that can govern both the growth rates and architectures of actin filament networks. Such activities may underlie previously observed differences between the cellular functions of WAVE1 and WAVE2. © 2015 Sweeney et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Mycobacterium leprae alters classical activation of human monocytes in vitro.

PubMed

Fallows, Dorothy; Peixoto, Blas; Kaplan, Gilla; Manca, Claudia

2016-01-01

Macrophages play a central role in the pathogenesis of leprosy, caused by Mycobacterium leprae. The polarized clinical presentations in leprosy are associated with differential immune activation. In tuberculoid leprosy, macrophages show a classical activation phenotype (M1), while macrophages in lepromatous disease display characteristics of alternative activation (M2). Bacille Calmette-Guérin (BCG) vaccination, which protects against leprosy, can promote sustained changes in monocyte response to unrelated pathogens and may preferentially direct monocytes towards an M1 protective phenotype. We previously reported that M. leprae can dampen the response of naïve human monocytes to a strong inducer of pro-inflammatory cytokines, such as BCG. Here, we investigated the ability of the pathogen to alter the direction of macrophage polarization and the impact of BCG vaccination on the monocyte response to M. leprae. We show that in vitro exposure of monocytes from healthy donors to M. leprae interferes with subsequent M1 polarization, indicated by lower levels of M1-associated cytokine/chemokines released and reduced expression of M1 cell surface markers. Exposure to M. leprae phenolic glycolipid (PGL) 1, instead of whole bacteria, demonstrated a similar effect on M1 cytokine/chemokine release. In addition, we found that monocytes from 10-week old BCG-vaccinated infants released higher levels of the pro-inflammatory cytokines TNF-α and IL-1β in response to M. leprae compared to those from unvaccinated infants. Exposure to M. leprae has an inhibitory effect on M1 macrophage polarization, likely mediated through PGL-1. By directing monocyte/macrophages preferentially towards M1 activation, BCG vaccination may render the cells more refractory to the inhibitory effects of subsequent M. leprae infection.

The median preoptic nucleus reciprocally modulates activity of arousal-related and sleep-related neurons in the perifornical lateral hypothalamus.

PubMed

Suntsova, Natalia; Guzman-Marin, Ruben; Kumar, Sunil; Alam, Md Noor; Szymusiak, Ronald; McGinty, Dennis

2007-02-14

The perifornical-lateral hypothalamic area (PF/LH) contains neuronal groups playing an important role in control of waking and sleep. Among the brain regions that regulate behavioral states, one of the strongest sources of projections to the PF/LH is the median preoptic nucleus (MnPN) containing a sleep-active neuronal population. To evaluate the role of MnPN afferents in the control of PF/LH neuronal activity, we studied the responses of PF/LH cells to electrical stimulation or local chemical manipulation of the MnPN in freely moving rats. Single-pulse electrical stimulation evoked responses in 79% of recorded PF/LH neurons. No cells were activated antidromically. Direct and indirect transsynaptic effects depended on sleep-wake discharge pattern of PF/LH cells. The majority of arousal-related neurons, that is, cells discharging at maximal rates during active waking (AW) or during AW and rapid eye movement (REM) sleep, exhibited exclusively or initially inhibitory responses to stimulation. Sleep-related neurons, the cells with elevated discharge during non-REM and REM sleep or selectively active in REM sleep, exhibited exclusively or initially excitatory responses. Activation of the MnPN via microdialytic application of L-glutamate or bicuculline resulted in reduced discharge of arousal-related and in excitation of sleep-related PF/LH neurons. Deactivation of the MnPN with muscimol caused opposite effects. The results indicate that the MnPN contains subset(s) of neurons, which exert inhibitory control over arousal-related and excitatory control over sleep-related PF/LH neurons. We hypothesize that MnPN sleep-active neuronal group has both inhibitory and excitatory outputs that participate in the inhibitory control of arousal-promoting PF/LH mechanisms.

Electrophysiological evidence showing muscarinic agonist-antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons.

PubMed

Sugawara, Yuto; Kikuchi, Yui; Yoneda, Mitsugu; Ohno-Shosaku, Takako

2016-07-01

The atypical antipsychotic clozapine is widely used for treatment-resistant schizophrenic patients. Clozapine and its major active metabolite, N-desmethylclozapine (NDMC), have complex pharmacological properties, and interact with various neurotransmitter receptors. There are several biochemical studies reporting that NDMC exhibits a partial agonist profile at the human recombinant M1 muscarinic receptors. However, direct electrophysiological evidence showing the ability of NDMC to activate native M1 receptors in intact neurons is poor. Using rat hippocampal neurons, we previously demonstrated that activation of muscarinic receptors by a muscarinic agonist, oxotremorine M (oxo-M), induces a decrease in outward K(+)current at -40mV. In the present study, using this muscarinic current response we assessed agonist and antagonist activities of clozapine and NDMC at native muscarinic receptors in intact hippocampal excitatory and inhibitory neurons. Suppression of the oxo-M-induced current response by the M1 antagonist pirenzepine was evident only in excitatory neurons, while the M3 antagonist darifenacin was effective in both types of neurons. Muscarinic agonist activity of NDMC was higher than that of clozapine, higher in excitatory neurons than in inhibitory neurons, sensitive to pirenzepine, and partially masked when co-applied with clozapine. Muscarinic antagonist activity of clozapine as well as NDMC was not different between excitatory and inhibitory neurons, but clozapine was more effective than NDMC. These results demonstrate that NDMC has the ability to activate native M1 receptors expressed in hippocampal excitatory neurons, but its agonist activity might be limited in clozapine-treated patients because of the presence of excessive clozapine with muscarinic antagonist activity. Copyright © 2016 Elsevier B.V. All rights reserved.

The neural networks of inhibitory control in posttraumatic stress disorder

PubMed Central

Falconer, Erin; Bryant, Richard; Felmingham, Kim L.; Kemp, Andrew H.; Gordon, Evian; Peduto, Anthony; Olivieri, Gloria; Williams, Leanne M.

2008-01-01

Objective Posttraumatic stress disorder (PTSD) involves deficits in information processing that may reflect hypervigilence and deficient inhibitory control. To date, however, no PTSD neuroimaging study has directly examined PTSD-related changes in executive inhibition. Our objective was to investigate the hypothesis that executive inhibitory control networks are compromised in PTSD. Methods Functional magnetic resonance imaging (fMRI) was used during a Go/No-Go inhibition task completed by a sample of patients with PTSD (n = 23), a matched sample of healthy (i.e. without trauma exposure) control participants (n = 23) and a sample of control participants with trauma exposure who did not meet criteria for PTSD (n = 17). Results Participants with PTSD showed more inhibition-related errors than did individuals without trauma exposure. During inhibition, control participants activated a right-lateralized cortical inhibitory network, whereas patients with PTSD activated only the left lateral frontal cortex. PTSD was associated with a reduction in right cortical activation and increased activation of striatal and somatosensory regions. Conclusion The increased inhibitory error and reduced right frontal cortical activation are consistent with compromised inhibitory control in PTSD, while the increased activation of brain regions associated with sensory processing and a greater demand on inhibitory control may reflect enhanced stimulus processing in PTSD, which may undermine cortical control mechanisms. PMID:18787658

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

Positive interaction of thyme (red) essential oil with human polymorphonuclear granulocytes in eradicating intracellular Candida albicans.

PubMed

Tullio, Vivian; Mandras, Narcisa; Allizond, Valeria; Nostro, Antonia; Roana, Janira; Merlino, Chiara; Banche, Giuliana; Scalas, Daniela; Cuffini, Anna Maria

2012-10-01

The essential oils have started to be recognized for their potential antimicrobial role only in recent years. Clinical experience showed that the efficacy of antimicrobial agents depends not only on their direct effect on a given microorganism but also on the functional activity of the host immune system. Since data on the effects of essential oils on the innate immune system are scanty and fragmentary, the aim of this study was to evaluate the influence of thyme (red) essential oil (EO), at subinhibitory/inhibitory concentrations, on intracellular killing activity by human polymorphonuclear granulocytes (PMNs) against Candida albicans. In order to provide a frame of reference for the activity of this EO, its in vitro killing activity in the absence of PMNs was also evaluated.Results showed that EO at subminimal inhibitory (subMIC)/minimal inhibitory (MIC) concentrations significantly enhanced intracellular killing of C. albicans in comparison with EO-free controls and was comparable to the positive control (fluconazole). In in vitro killing assays without PMNs, we observed progressive growth of the yeast cells in the presence of EO subMIC/MIC concentrations. A positive antifungal interaction with phagocytes could explain why this EO, which appeared to be only fungistatic in time-kill assays, had efficacy in killing yeast cells once incubated with PMNs. Georg Thieme Verlag KG Stuttgart · New York.

A direct translaminar inhibitory circuit tunes cortical output

PubMed Central

Pluta, Scott; Naka, Alexander; Veit, Julia; Telian, Gregory; Yao, Lucille; Hakim, Richard; Taylor, David; Adesnik, Hillel

2015-01-01

Summary Anatomical and physiological experiments have outlined a blueprint for the feed-forward flow of activity in cortical circuits: signals are thought to propagate primarily from the middle cortical layer, L4, up to L2/3, and down to the major cortical output layer, L5. Pharmacological manipulations, however, have contested this model and suggested that L4 may not be critical for sensory responses of neurons in either superficial or deep layers. To address these conflicting models we reversibly manipulated L4 activity in awake, behaving mice using cell-type specific optogenetics. In contrast to both prevailing models, we show that activity in L4 directly suppresses L5, in part by activating deep, fast spiking inhibitory neurons. Our data suggest that the net impact of L4 activity is to sharpen the spatial representations of L5 neurons. Thus we establish a novel translaminar inhibitory circuit in the sensory cortex that acts to enhance the feature selectivity of cortical output. PMID:26414615

Learning place cells, grid cells and invariances with excitatory and inhibitory plasticity

PubMed Central

2018-01-01

Neurons in the hippocampus and adjacent brain areas show a large diversity in their tuning to location and head direction, and the underlying circuit mechanisms are not yet resolved. In particular, it is unclear why certain cell types are selective to one spatial variable, but invariant to another. For example, place cells are typically invariant to head direction. We propose that all observed spatial tuning patterns – in both their selectivity and their invariance – arise from the same mechanism: Excitatory and inhibitory synaptic plasticity driven by the spatial tuning statistics of synaptic inputs. Using simulations and a mathematical analysis, we show that combined excitatory and inhibitory plasticity can lead to localized, grid-like or invariant activity. Combinations of different input statistics along different spatial dimensions reproduce all major spatial tuning patterns observed in rodents. Our proposed model is robust to changes in parameters, develops patterns on behavioral timescales and makes distinctive experimental predictions. PMID:29465399

The sub-inhibitory theory for antibiotic growth promoters.

PubMed

Broom, Leon J

2017-09-01

Antibiotics have played a critical role in the prevention, control, and treatment of bacterial diseases in humans and animals, and as growth promoters (AGPs) when used at sub-therapeutic concentrations in animal production. Numerous hypotheses have been proposed for the effectiveness of AGPs, which have largely centered on the beneficial modulation of the intestinal microbiota. However, these hypotheses have been doubted by some researchers, as AGPs are fed at concentrations that would typically be below minimum inhibitory concentrations (sub-MIC) for the antibiotic used. More recently, pro-inflammatory immune responses have been associated with poor growth performance, and this, along with reported direct, anti-inflammatory effects of some antibiotics, have led to suggestions that reducing the nutrient cost of (intestinal) inflammation may explain the growth promoting or permitting effect of AGPs. However, doubts about antibacterial effects of AGPs, and the search for alternative explanations, overlook the sub-MIC effects of antibiotics. This paper summarizes some of the reported sub-MIC effects of antibiotics and considers these in the context of helping to explain the mode of action of AGPs and effects seen in studies in vivo. This leads to suggestions for the features that alternatives to AGPs could exhibit to achieve similar performance efficacy as AGPs. © 2017 Poultry Science Association Inc.

Prostaglandin E2 inhibits Tr1 cell differentiation through suppression of c-Maf

PubMed Central

Hooper, Kirsten Mary; Kong, Weimin

2017-01-01

Prostaglandin E2 (PGE2), a major lipid mediator abundant at inflammatory sites, acts as a proinflammatory agent in models of inflammatory/autoimmune diseases by promoting CD4 Th1/Th17 differentiation. Regulatory T cells, including the IL-10 producing Tr1 cells counterbalance the proinflammatory activity of effector Th1/Th17 cells. Tr1 cell differentiation and function are induced by IL-27, and depend primarily on sustained expression of c-Maf in addition to AhR and Blimp-1. In agreement with the in vivo proinflammatory role of PGE2, here we report for the first time that PGE2 inhibits IL-27-induced differentiation and IL-10 production of murine CD4+CD49b+LAG-3+Foxp3- Tr1 cells. The inhibitory effect of PGE2 was mediated through EP4 receptors and induction of cAMP, leading to a significant reduction in c-Maf expression. Although PGE2 reduced IL-21 production in differentiating Tr1 cells, its inhibitory effect on Tr1 differentiation and c-Maf expression also occurred independent of IL-21 signaling. PGE2 did not affect STAT1/3 activation, AhR expression and only marginally reduced Egr-2/Blimp-1 expression. The effect of PGE2 on CD4+CD49b+LAG-3+ Tr1 differentiation was not associated with either induction of Foxp3 or IL-17 production, suggesting a lack of transdifferentiation into Foxp3+ Treg or effector Th17 cells. We recently reported that PGE2 inhibits the expression and production of IL-27 from activated conventional dendritic cells (cDC) in vivo and in vitro. The present study indicates that PGE2 also reduces murine Tr1 differentiation and function directly by acting on IL-27-differentiating Tr1 cells. Together, the ability of PGE2 to inhibit IL-27 production by cDC, and the direct inhibitory effect on Tr1 differentiation mediated through reduction in c-Maf expression, represent a new mechanistic perspective for the proinflammatory activity of PGE2. PMID:28604806

Oxyresveratrol, a Stilbene Compound from Morus alba L. Twig Extract Active Against Trichophyton rubrum.

PubMed

Lu, Hai-Peng; Jia, Ya-Nan; Peng, Ya-Lin; Yu, Yan; Sun, Si-Long; Yue, Meng-Ting; Pan, Min-Hui; Zeng, Ling-Shu; Xu, Li

2017-12-01

Morus alba L. (mulberry) twig is known to have an inhibitory effect on pathogens in traditional Chinese medicine. In the present study, the dermophytic fungus, Trichophyton rubrum, was used to evaluate the inhibitory effect of total M. alba twig extract and extracts obtained using solvents with different polarities by the method of 96-well MTT colorimetry. The main active substance was isolated and identified by tracking its activity. In addition, the inhibitory effects of active extracts and a single active substance were investigated in combination with miconazole nitrate. Our data indicated that ethyl acetate extracts of mulberry twig (TEE) exhibited a desired inhibitory activity on T. rubrum with the minimum inhibitory concentration (MIC) of 1.000 mg/mL. With activity tracking, the main substance showing antimicrobial activity was oxyresveratrol (OXY), which was isolated from TEE. Its MIC for inhibiting the growth of T. rubrum was 0.500 mg/mL. The combined use of miconazole nitrate and OXY showed a synergistic inhibitory effect, as shown by a significant decrease in the MIC of both components. Based on the OXY content in TEE, the contribution rate of OXY to the inhibitory effect of TEE on T. rubrum was 80.52%, so it was determined to be the main antimicrobial substance in M. alba twig. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Metabotropic glutamate receptor-mediated signaling dampens the HPA axis response to restraint stress

PubMed Central

Evanson, Nathan K.; Herman, James P.

2015-01-01

Glutamate is an important neurotransmitter in regulation of the neural portion of hypothalamus-pituitary-adrenal (HPA) axis activity, and signals through ionotropic and metabotropic receptors. In the current studies we investigated the role of hypothalamic paraventricular group I metabotropic glutamate receptors in regulation of the HPA axis response to restraint stress in rats. Direct injection of the group I metabotropic glutamate receptor agonist 3,5-dihydroxyphenylglycine (DHPG) into the PVN prior to restraint leads to blunting of the HPA axis response in awake animals. Consistent with this result, infusion of the group I receptor antagonist hexyl-homoibotenic acid (HIBO) potentiates the HPA axis response to restraint. The excitatory effect of blocking paraventricular group I metabotropic glutamate signaling is blocked by co-administration of dexamethasone into the PVN. However, the inhibitory effect of DHPG is not affected by co-administration of the cannabinoid CB1 receptor antagonist AM-251 into the PVN. Together, these results suggest that paraventricular group I metabotropic glutamate receptor signaling acts to dampen HPA axis reactivity. This effect appears to be similar to the rapid inhibitory effect of glucocorticoids at the PVN, but is not mediated by endocannabinoid signaling. PMID:25701594

Metabotropic glutamate receptor-mediated signaling dampens the HPA axis response to restraint stress.

PubMed

Evanson, Nathan K; Herman, James P

2015-10-15

Glutamate is an important neurotransmitter in the regulation of the neural portion of hypothalamus-pituitary-adrenal (HPA) axis activity, and signals through ionotropic and metabotropic receptors. In the current studies we investigated the role of hypothalamic paraventricular group I metabotropic glutamate receptors in the regulation of the HPA axis response to restraint stress in rats. Direct injection of the group I metabotropic glutamate receptor agonist 3,5-dihydroxyphenylglycine (DHPG) into the PVN prior to restraint leads to blunting of the HPA axis response in awake animals. Consistent with this result, infusion of the group I receptor antagonist hexyl-homoibotenic acid (HIBO) potentiates the HPA axis response to restraint. The excitatory effect of blocking paraventricular group I metabotropic glutamate signaling is blocked by co-administration of dexamethasone into the PVN. However, the inhibitory effect of DHPG is not affected by co-administration of the cannabinoid CB1 receptor antagonist AM-251 into the PVN. Together, these results suggest that paraventricular group I metabotropic glutamate receptor signaling acts to dampen HPA axis reactivity. This effect appears to be similar to the rapid inhibitory effect of glucocorticoids at the PVN, but is not mediated by endocannabinoid signaling. Copyright © 2015 Elsevier Inc. All rights reserved.

Re-188 Enhances the Inhibitory Effect of Bevacizumab in Non-Small-Cell Lung Cancer.

PubMed

Xiao, Jie; Xu, Xiaobo; Li, Xiao; Li, Yanli; Liu, Guobing; Tan, Hui; Shen, Hua; Shi, Hongcheng; Cheng, Dengfeng

2016-09-30

The malignant behaviors of solid tumors such as growth, infiltration and metastasis are mainly nourished by tumor neovascularization. Thus, anti-angiogenic therapy is key to controlling tumor progression. Bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) antibody, plus chemotherapy or biological therapy can prolong survival for cancer patients, but treatment-related mortality is a concern. To improve inhibitory effect and decrease side-effects on non-small-cell lung cancer (NSCLC), we used Re-188, which is a β emitting radionuclide, directly labeled with bevacizumab for radioimmunotherapy in a human A549 tumor model. Cytotoxic assay data showed that, after 188 ReO₄ - or 188 Re-bevacizumab at different concentration for 4 and 24 h, a time- and radioactivity does-dependent reduction in cell viability occurred. Also, an apoptosis assay conformed great apoptosis in the 188 Re-bevacizumab group compared with controls and other treatment groups. In vivo, tumor volumes in the 188 Re-bevacizumab (11.1 MBq/mice) group were not reduced but growth was delayed compared with other groups. Thus, 188 Re-bevacizumab enhanced the therapeutic effect of bevacizumab, suggesting a potential therapeutic strategy for NSCLC treatment.

The inhibitory effect of Thymus vulgaris extracts on the planktonic form and biofilm structures of six human pathogenic bacteria

PubMed Central

Mohsenipour, Zeinab; Hassanshahian, Mehdi

2015-01-01

Objective: Microorganisms are responsible for many problems in industry and medicine because of biofilm formation. Therefore, this study was aimed to examine the effect of Thymus vulgaris (T. vulgaris) extracts on the planktonic form and biofilm structures of six pathogenic bacteria. Materials and methods: Antimicrobial activities of the plant extracts against the planktonic form of the bacteria were determined using the disc diffusion method. MIC and MBC values were evaluated using macrobroth dilution technique. Anti-biofilm effects were assessed by microtiter plate method. Results: According to disc diffusion test (MIC and MBC), the ability of Thymus vulgaris (T. vulgaris ) extracts for inhibition of bacteria in planktonic form was confirmed. In dealing with biofilm structures, the inhibitory effect of the extracts was directly correlated to their concentration. Except for the inhibition of biofilm formation, efficacy of each extract was independent from type of solvent. Conclusion: According to the potential of Thymus vulgaris (T. vulgaris) extracts to inhibit the test bacteria in planktonic and biofilm form, it can be suggested that Thymus vulgaris (T. vulgaris) extracts can be applied as antimicrobial agents against the pathogenic bacteria particularly in biofilm forms. PMID:26442753

ηηDiazepam-induced loss of inhibitory synapses mediated by PLCδ/ Ca 2+ /calcineurin signalling downstream of GABAA receptors.

PubMed

Nicholson, Martin W; Sweeney, Aaron; Pekle, Eva; Alam, Sabina; Ali, Afia B; Duchen, Michael; Jovanovic, Jasmina N

2018-06-14

Benzodiazepines facilitate the inhibitory actions of GABA by binding to γ-aminobutyric acid type A receptors (GABA A Rs), GABA-gated chloride/bicarbonate channels, which are the key mediators of transmission at inhibitory synapses in the brain. This activity underpins potent anxiolytic, anticonvulsant and hypnotic effects of benzodiazepines in patients. However, extended benzodiazepine treatments lead to development of tolerance, a process which, despite its important therapeutic implications, remains poorly characterised. Here we report that prolonged exposure to diazepam, the most widely used benzodiazepine in clinic, leads to a gradual disruption of neuronal inhibitory GABAergic synapses. The loss of synapses and the preceding, time- and dose-dependent decrease in surface levels of GABA A Rs, mediated by dynamin-dependent internalisation, were blocked by Ro 15-1788, a competitive benzodiazepine antagonist, and bicuculline, a competitive GABA antagonist, indicating that prolonged enhancement of GABA A R activity by diazepam is integral to the underlying molecular mechanism. Characterisation of this mechanism has revealed a metabotropic-type signalling downstream of GABA A Rs, involving mobilisation of Ca 2+ from the intracellular stores and activation of the Ca 2+ /calmodulin-dependent phosphatase calcineurin, which, in turn, dephosphorylates GABA A Rs and promotes their endocytosis, leading to disassembly of inhibitory synapses. Furthermore, functional coupling between GABA A Rs and Ca 2+ stores was sensitive to phospholipase C (PLC) inhibition by U73122, and regulated by PLCδ, a PLC isoform found in direct association with GABA A Rs. Thus, a PLCδ/Ca 2+ /calcineurin signalling cascade converts the initial enhancement of GABA A Rs by benzodiazepines to a long-term downregulation of GABAergic synapses, this potentially underpinning the development of pharmacological and behavioural tolerance to these widely prescribed drugs.

Measurement of xanthine oxidase inhibition activity of phenolics and flavonoids with a modified cupric reducing antioxidant capacity (CUPRAC) method.

PubMed

Ozyürek, Mustafa; Bektaşoğlu, Burcu; Güçlü, Kubilay; Apak, Reşat

2009-03-16

Various dietary polyphenolics have been found to show an inhibitory effect on xanthine oxidase (XO) which mediates oxidative stress-originated diseases because of its ability to generate reactive oxygen species (ROS), including superoxide anion radical (O(2)(-)) and hydrogen peroxide. XO activity has usually been determined by following the rate of uric acid formation from xanthine-xanthine oxidase (X-XO) system using the classical XO activity assay (UV-method) at 295nm. Since some polyphenolics have strong absorption from the UV to visible region, XO-inhibitory activity of polyphenolics was alternatively determined without interference by directly measuring the formation of uric acid and hydrogen peroxide using the modified CUPRAC (cupric reducing antioxidant capacity) spectrophotometric method at 450nm. The CUPRAC absorbance of the incubation solution due to the reduction of Cu(II)-neocuproine reagent by the products of the X-XO system decreased in the presence of polyphenolics, the difference being proportional to the XO inhibition ability of the tested compound. The structure-activity relationship revealed that the flavones and flavonols with a 7-hydroxyl group such as apigenin, luteolin, kaempferol, quercetin, and myricetin inhibited XO-inhibitory activity at low concentrations (IC(50) values from 1.46 to 1.90microM), while the flavan-3-ols and naringin were less inhibitory. The findings of the developed method for quercetin and catechin in the presence of catalase were statistically alike with those of HPLC. In addition to polyphenolics, five kinds of herbs were evaluated for their XO-inhibitory activity using the developed method. The proposed spectrophotometric method was practical, low-cost, rapid, and could reliably assay uric acid and hydrogen peroxide in the presence of polyphenols (flavonoids, simple phenolic acids and hydroxycinnamic acids), and less open to interferences by UV-absorbing substances.

Language learning without control: the role of the PFC.

PubMed

Friederici, Angela D; Mueller, Jutta L; Sehm, Bernhard; Ragert, Patrick

2013-05-01

Learning takes place throughout lifetime but differs in infants and adults because of the development of the PFC, a brain region responsible for cognitive control. To test this hypothesis, adults were investigated in a language learning paradigm under inhibitory, cathodal transcranial direct current stimulation over PFC. The experiment included a learning session interspersed with test phases and a test-only session. The stimulus material required the learning of grammatical dependencies between two elements in a novel language. In a parallel design, cathodal transcranial direct current stimulation over the left PFC, right PFC, or sham stimulation was applied during the learning session but not during the test-only session. Event-related brain potentials (ERPs) were recorded during both sessions. Whereas no ERP learning effects were observed during the learning session, different ERP learning effects as a function of prior stimulation type were found during the test-only session, although behavioral learning success was equal across conditions. With sham stimulation, the ERP learning effect was reflected in a centro-parietal N400-like negativity indicating lexical processes. Inhibitory stimulation over the left PFC, but not over the right PFC, led to a late positivity similar to that previously observed in prelinguistic infants indicating associative learning. The present data demonstrate that adults can learn with and without cognitive control using different learning mechanisms. In the presence of cognitive control, adult language learning is lexically guided, whereas it appears to be associative in nature when PFC control is downregulated.

[Effect of tea extracts, catechin and caffeine against type-I allergic reaction].

PubMed

Shiozaki, T; Sugiyama, K; Nakazato, K; Takeo, T

1997-07-01

The antiallergic effects of green tea, oolong tea, and black tea extracts by hot water were examined. These extracts inhibited the passive cutaneous anaphylaxis (PCA) reaction of rat after oral administration. Three tea catechins, (--)-epigallocatechin (EGC), (--)-epicatechin gallate (ECg), and (--)-epigallocatechin gallate (EGCg) isolated from green tea showed stronger inhibitory effects than that of a green tea extract on the PCA reaction. The inhibitory effects of EGC and EGCg on the PCA reaction were greater than that of ECg. Caffeine also showed a inhibitory effect on the PCA reaction. These results indicate that tea could provide a significant protection against the type-I allergic reaction. These findings also suggest that tea catechins and caffeine play an important role in having an inhibitory effect on the type-I allergic reaction.

Competition and cooperation among similar representations: toward a unified account of facilitative and inhibitory effects of lexical neighbors.

PubMed

Chen, Qi; Mirman, Daniel

2012-04-01

One of the core principles of how the mind works is the graded, parallel activation of multiple related or similar representations. Parallel activation of multiple representations has been particularly important in the development of theories and models of language processing, where coactivated representations (neighbors) have been shown to exhibit both facilitative and inhibitory effects on word recognition and production. Researchers generally ascribe these effects to interactive activation and competition, but there is no unified explanation for why the effects are facilitative in some cases and inhibitory in others. We present a series of simulations of a simple domain-general interactive activation and competition model that is broadly consistent with more specialized domain-specific models of lexical processing. The results showed that interactive activation and competition can indeed account for the complex pattern of reversals. Critically, the simulations revealed a core computational principle that determines whether neighbor effects are facilitative or inhibitory: strongly active neighbors exert a net inhibitory effect, and weakly active neighbors exert a net facilitative effect.

Relationship between physiological excitatory and inhibitory measures of excitability in the left vs. right human motor cortex and peripheral electrodermal activity.

PubMed

Bracco, Martina; Turriziani, Patrizia; Smirni, Daniela; Mangano, Renata Giuseppa; Oliveri, Massimiliano

2017-02-22

The current study was aimed at investigating the relationships of excitatory and inhibitory circuits of the left vs. right primary motor cortex with peripheral electrodermal activity (EDA). Ten healthy subjects participated in two experimental sessions. In each session, EDA was recorded for 10min from the palmar surface of the left hand. Immediately after EDA recording, Transcranial Magnetic Stimulation (TMS) was used to probe excitatory and inhibitory circuits of the left or right primary motor cortex using two protocols of stimulation: the input-output curve for recording of motor evoked potentials, for testing excitatory circuits; the long-interval cortical inhibition (LICI) protocol, for testing inhibitory circuits. In both cases, motor evoked potentials were recorded with surface electrodes from a contralateral hand muscle. The main results showed that in the right motor cortex, excitatory circuits directly correlate and inhibitory circuits inversely correlate with sympathetic activation. In the left motor cortex, both excitatory and inhibitory circuits are inversely correlated with sympathetic activation. These findings may suggest a bi-hemispheric mode of control of vegetative system by motor cortices, with the right hemisphere mainly involved in sympathetic control. Copyright © 2017. Published by Elsevier B.V.

Synthesis and anti-inflammatory effect of chalcones and related compounds.

PubMed

Hsieh, H K; Lee, T H; Wang, J P; Wang, J J; Lin, C N

1998-01-01

Mast cell and neutrophil degranulations are the important players in inflammatory disorders. Combined with potent inhibition of chemical mediators released from mast cells and neutrophil degranulations, it could be a promising anti-inflammatory agent. 2',5'-Dihydroxychalcone has been reported as a potent chemical mediator and cyclooxygenase inhibitor. In an effort to continually develop potent anti-inflammatory agents, a novel series of chalcone, 2'- and 3'-hydroxychalcones, 2',5'-dihydroxychalcones and flavanones were continually synthesized to evaluate their inhibitory effects on the activation of mast cells and neutrophils and the inhibitory effect on phlogist-induced hind-paw edema in mice. A series of chalcones and related compounds were prepared by Claisen-Schmidt condensation of appropriate acetophenones with appropriate aromatic aldehyde and the anti-inflammatory activities of these synthetic compounds were studied on inhibitory effects on the activation of mast cells and neutrophils. Some chalcones showed strong inhibitory effects on the release of beta-glucuronidase and histamine from rat peritoneal mast cells stimulated with compound 48/80. Almost all chalcones and 4'-hydroxyflavanone exhibited potent inhibitory effects on the release of beta-glucuronidase and lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP). Some chalcones showed potent inhibitory effects on superoxide formation of rat neutrophils stimulated with fMLP/cytochalasin B (CB) or phorbol myristate acetate (PMA). 2',3-Dihydroxy-, 2',5'-dihydroxy-4-chloro-, and 2',5'-dihydroxychalcone showed remarkable inhibitory effects on hind-paw edema induced by polymyxin B in normal as well as in adrenalectomized mice. These results indicated that the anti-inflammatory effects of these compounds were mediated, at least partly, through the suppression of chemical mediators released from mast cells and neutrophils.

Inhibition by sodium nitroprusside of the expression of inducible nitric oxide synthase in rat neutrophils.

PubMed Central

Mariotto, S; Cuzzolin, L; Adami, A; Del Soldato, P; Suzuki, H; Benoni, G

1995-01-01

A well-known nitric oxide (NO)-releasing compound, sodium nitroprusside (SNP), decreases in a dose-dependent manner NO synthase (NOS) activity induced in rat neutrophils by treatment with lipopolysaccharide (LPS). This inhibitory action of SNP seems not to be due to its direct effect on the enzyme activity. The strong nitrosonium ion (NO+) character of SNP could be responsible for its inhibition of NOS induction in neutrophils. PMID:7542530

Two mechanisms of oral malodor inhibition by zinc ions.

PubMed

Suzuki, Nao; Nakano, Yoshio; Watanabe, Takeshi; Yoneda, Masahiro; Hirofuji, Takao; Hanioka, Takashi

2018-01-18

The aim of this study was to reveal the mechanisms by which zinc ions inhibit oral malodor. The direct binding of zinc ions to gaseous hydrogen sulfide (H2S) was assessed in comparison with other metal ions. Nine metal chlorides and six metal acetates were examined. To understand the strength of H2S volatilization inhibition, the minimum concentration needed to inhibit H2S volatilization was determined using serial dilution methods. Subsequently, the inhibitory activities of zinc ions on the growth of six oral bacterial strains related to volatile sulfur compound (VSC) production and three strains not related to VSC production were evaluated. Aqueous solutions of ZnCl2, CdCl2, CuCl2, (CH3COO)2Zn, (CH3COO)2Cd, (CH3COO)2Cu, and CH3COOAg inhibited H2S volatilization almost entirely. The strengths of H2S volatilization inhibition were in the order Ag+ > Cd2+ > Cu2+ > Zn2+. The effect of zinc ions on the growth of oral bacteria was strain-dependent. Fusobacterium nucleatum ATCC 25586 was the most sensitive, as it was suppressed by medium containing 0.001% zinc ions. Zinc ions have an inhibitory effect on oral malodor involving the two mechanisms of direct binding with gaseous H2S and suppressing the growth of VSC-producing oral bacteria.

Two mechanisms of oral malodor inhibition by zinc ions

PubMed Central

Suzuki, Nao; Nakano, Yoshio; Watanabe, Takeshi; Yoneda, Masahiro; Hirofuji, Takao; Hanioka, Takashi

2018-01-01

Abstract Objectives The aim of this study was to reveal the mechanisms by which zinc ions inhibit oral malodor. Material and Methods The direct binding of zinc ions to gaseous hydrogen sulfide (H2S) was assessed in comparison with other metal ions. Nine metal chlorides and six metal acetates were examined. To understand the strength of H2S volatilization inhibition, the minimum concentration needed to inhibit H2S volatilization was determined using serial dilution methods. Subsequently, the inhibitory activities of zinc ions on the growth of six oral bacterial strains related to volatile sulfur compound (VSC) production and three strains not related to VSC production were evaluated. Results Aqueous solutions of ZnCl2, CdCl2, CuCl2, (CH3COO)2Zn, (CH3COO)2Cd, (CH3COO)2Cu, and CH3COOAg inhibited H2S volatilization almost entirely. The strengths of H2S volatilization inhibition were in the order Ag+ > Cd2+ > Cu2+ > Zn2+. The effect of zinc ions on the growth of oral bacteria was strain-dependent. Fusobacterium nucleatum ATCC 25586 was the most sensitive, as it was suppressed by medium containing 0.001% zinc ions. Conclusions Zinc ions have an inhibitory effect on oral malodor involving the two mechanisms of direct binding with gaseous H2S and suppressing the growth of VSC-producing oral bacteria. PMID:29364345

CDK2 and mTOR are direct molecular targets of isoangustone A in the suppression of human prostate cancer cell growth.

PubMed

Lee, Eunjung; Son, Joe Eun; Byun, Sanguine; Lee, Seung Joon; Kim, Yeong A; Liu, Kangdong; Kim, Jiyoung; Lim, Soon Sung; Park, Jung Han Yoon; Dong, Zigang; Lee, Ki Won; Lee, Hyong Joo

2013-10-01

Licorice extract which is used as a natural sweetener has been shown to possess inhibitory effects against prostate cancer, but the mechanisms responsible are poorly understood. Here, we report a compound, isoangustone A (IAA) in licorice that potently suppresses the growth of aggressive prostate cancer and sought to clarify its mechanism of action. We analyzed its inhibitory effects on the growth of PTEN-deleted human prostate cancer cells, in vitro and in vivo. Administration of IAA significantly attenuated the growth of prostate cancer cell cultures and xenograft tumors. These effects were found to be attributable to inhibition of the G1/S phase cell cycle transition and the accumulation of p27(kip1). The elevated p27(kip1) expression levels were concurrent with the decrease of its phosphorylation at threonine 187 through suppression of CDK2 kinase activity and the reduced phosphorylation of Akt at Serine 473 by diminishing the kinase activity of the mammalian target of rapamycin (mTOR). Further analysis using recombinant proteins and immunoprecipitated cell lysates determined that IAA exerts suppressive effects against CDK2 and mTOR kinase activity by direct binding with both proteins. These findings suggested that the licorice compound IAA is a potent molecular inhibitor of CDK2 and mTOR, with strong implications for the treatment of prostate cancer. Thus, licorice-derived extracts with high IAA content warrant further clinical investigation for nutritional sources for prostate cancer patients. Copyright © 2013 Elsevier Inc. All rights reserved.

Mechanisms underlying electrical and mechanical responses of the bovine retractor penis to inhibitory nerve stimulation and to an inhibitory extract.

PubMed Central

Byrne, N. G.; Muir, T. C.

1985-01-01

The response of the bovine retractor penis (BRP) to stimulation of non-adrenergic, non-cholinergic (NANC) inhibitory nerves and to an inhibitory extract prepared from this muscle have been studied using intracellular microelectrode, sucrose gap and conventional mechanical recording techniques. Both inhibitory nerve stimulation and inhibitory extract hyperpolarized the membrane potential and relaxed spontaneous or guanethidine (3 X 10(-5) M)-induced tone. These effects were accompanied by an increase in membrane resistance. Following membrane potential displacement from an average value of -53 +/- 7 mV (n = 184; Byrne & Muir, 1984) inhibitory potentials to nerve stimulation were abolished at approximately -30 mV; there was no evidence of reversal. Displacement by inward hyperpolarizing current over the range -45 to -60 mV increased the inhibitory response to nerve stimulation and to inhibitory extract; at more negative potential values (above approximately -60 mV) the inhibitory potential decreased and was abolished (approximately -103 mV). There was no evidence of reversal. Removal of [K+]o reversibly reduced hyperpolarization to nerve stimulation and inhibitory extract. No enhancement was observed. Increasing the [K+]o to 20 mM reduced the inhibitory potential to nerve stimulation but this was restored by passive membrane hyperpolarization. Inhibitory potentials were obtained at membrane potential values exceeding that of the estimated EK (-49 mV). [Cl-]o-free or [Cl-]o-deficient solutions reduced and abolished (after some 20-25 min) the hyperpolarization produced by inhibitory nerve stimulation or inhibitory extract. The inhibitory potential amplitude following nerve stimulation was not restored by passive displacement of the membrane potential from -26 to -104 mV approximately. Ouabain (1-5 X 10(-5) M) reduced then (45-60 min later) abolished the inhibitory potential to nerve stimulation. The effects of this drug on the extract were not investigated. It is concluded that the inhibitory response to nerve stimulation and extract in the BRP may involve several ionic species. However, unlike that in gastrointestinal muscles the NANC response in the BRP is accompanied by an increased membrane resistance and does not primarily involve K+. The underlying mechanisms for the inhibitory response to both NANC nerve stimulation and inhibitory extract appear to be similar, compatible with the view that the latter may contain the inhibitory transmitter released from these nerves in this tissue. PMID:4027462

The effects of aromatic amino acid derivatives on the excitability of an identifiable giant neurone of the African giant snail (Achatina fulica Férussac).

PubMed Central

Takeuchi, H.; Tamura, H.

1980-01-01

1 The effects of derivatives of aromatic amino acids on the excitability of an identifiable giant neurone (TAN, tonically autoactive neurone) of the African giant snail (Achatina fulica Férussac) were examined. 2 The following substances had marked inhibitory effects on TAN using bath application: N-beta-phenylpropionyl-L-Tyr and N-beta-phenylpropionyl-L-Trp (critical concentration, 3 x 10(-7) M), N-beta-phenylpropionyl-L-Phe, N-cinnamoyl-DL-Trp and N-phenoxyacetyl-L-Trp (critical concentration, 10(-5) to 3 x 10(-5) M). However, N-beta-phenylpropionyl-D-Tyr and N-beta-phenylpropionyl tyramine had no effect. 3 Microdrop (150 micrometers in diameter) application of N-beta-phenylpropionyl-L-Tyr or N-beta-phenylpropionyl-l-trp containing about 100 pg resulted in marked inhibitory effects on TAN. The effect was observed in Ca2+-free, Mg2+-rich (24 mM) solution. Substitution of Cl- by acetate did not alter the response. This indicates that the two substances act directly on the TAN membrane and not via synaptic influences, and that the inhibition produced by the two substances is not due to the permeability increase of the TAN membrane to Cl-. PMID:7378654

UV-A radiation effects on higher plants: Exploring the known unknown.

PubMed

Verdaguer, Dolors; Jansen, Marcel A K; Llorens, Laura; Morales, Luis O; Neugart, Susanne

2017-02-01

Ultraviolet-A radiation (UV-A: 315-400nm) is a component of solar radiation that exerts a wide range of physiological responses in plants. Currently, field attenuation experiments are the most reliable source of information on the effects of UV-A. Common plant responses to UV-A include both inhibitory and stimulatory effects on biomass accumulation and morphology. UV-A effects on biomass accumulation can differ from those on root: shoot ratio, and distinct responses are described for different leaf tissues. Inhibitory and enhancing effects of UV-A on photosynthesis are also analysed, as well as activation of photoprotective responses, including UV-absorbing pigments. UV-A-induced leaf flavonoids are highly compound-specific and species-dependent. Many of the effects on growth and development exerted by UV-A are distinct to those triggered by UV-B and vary considerably in terms of the direction the response takes. Such differences may reflect diverse UV-perception mechanisms with multiple photoreceptors operating in the UV-A range and/or variations in the experimental approaches used. This review highlights a role that various photoreceptors (UVR8, phototropins, phytochromes and cryptochromes) may play in plant responses to UV-A when dose, wavelength and other conditions are taken into account. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Physical activity behavior predicts endogenous pain modulation in older adults.

PubMed

Naugle, Kelly M; Ohlman, Thomas; Naugle, Keith E; Riley, Zachary A; Keith, NiCole R

2017-03-01

Older adults compared with younger adults are characterized by greater endogenous pain facilitation and a reduced capacity to endogenously inhibit pain, potentially placing them at a greater risk for chronic pain. Previous research suggests that higher levels of self-reported physical activity are associated with more effective pain inhibition and less pain facilitation on quantitative sensory tests in healthy adults. However, no studies have directly tested the relationship between physical activity behavior and pain modulatory function in older adults. This study examined whether objective measures of physical activity behavior cross-sectionally predicted pain inhibitory function on the conditioned pain modulation (CPM) test and pain facilitation on the temporal summation (TS) test in healthy older adults. Fifty-one older adults wore an accelerometer on the hip for 7 days and completed the CPM and TS tests. Measures of sedentary time, light physical activity (LPA), and moderate to vigorous physical activity (MVPA) were obtained from the accelerometer. Hierarchical linear regressions were conducted to determine the relationship of TS and CPM with levels of physical activity, while controlling for demographic, psychological, and test variables. The results indicated that sedentary time and LPA significantly predicted pain inhibitory function on the CPM test, with less sedentary time and greater LPA per day associated with greater pain inhibitory capacity. Additionally, MVPA predicted pain facilitation on the TS test, with greater MVPA associated with less TS of pain. These results suggest that different types of physical activity behavior may differentially impact pain inhibitory and facilitatory processes in older adults.

Unique contributions of emotion regulation and executive functions in predicting the quality of parent-child interaction behaviors.

PubMed

Shaffer, Anne; Obradović, Jelena

2017-03-01

Parenting is a cognitive, emotional, and behavioral endeavor, yet limited research investigates parents' executive functions and emotion regulation as predictors of how parents interact with their children. The current study is a multimethod investigation of parental self-regulation in relation to the quality of parenting behavior and parent-child interactions in a diverse sample of parents and kindergarten-age children. Using path analyses, we tested how parent executive functions (inhibitory control) and lack of emotion regulation strategies uniquely relate to both sensitive/responsive behaviors and positive/collaborative behaviors during observed interaction tasks. In our analyses, we accounted for parent education, financial stress, and social support as socioeconomic factors that likely relate to parent executive function and emotion regulation skills. In a diverse sample of primary caregivers (N = 102), we found that direct assessment of parent inhibitory control was positively associated with sensitive/responsive behaviors, whereas parent self-reported difficulties in using emotion regulation strategies were associated with lower levels of positive and collaborative dyadic behaviors. Parent education and financial stress predicted inhibitory control, and social support predicted emotion regulation difficulties; parent education was also a significant predictor of sensitive/responsive behaviors. Greater inhibitory control skills and fewer difficulties identifying effective emotion regulation strategies were not significantly related in our final path model. We discuss our findings in the context of current and emerging parenting interventions. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Structural Dynamics Investigation of Human Family 1 & 2 Cystatin-Cathepsin L1 Interaction: A Comparison of Binding Modes

PubMed Central

Nandy, Suman Kumar; Seal, Alpana

2016-01-01

Cystatin superfamily is a large group of evolutionarily related proteins involved in numerous physiological activities through their inhibitory activity towards cysteine proteases. Despite sharing the same cystatin fold, and inhibiting cysteine proteases through the same tripartite edge involving highly conserved N-terminal region, L1 and L2 loop; cystatins differ widely in their inhibitory affinity towards C1 family of cysteine proteases and molecular details of these interactions are still elusive. In this study, inhibitory interactions of human family 1 & 2 cystatins with cathepsin L1 are predicted and their stability and viability are verified through protein docking & comparative molecular dynamics. An overall stabilization effect is observed in all cystatins on complex formation. Complexes are mostly dominated by van der Waals interaction but the relative participation of the conserved regions varied extensively. While van der Waals contacts prevail in L1 and L2 loop, N-terminal segment chiefly acts as electrostatic interaction site. In fact the comparative dynamics study points towards the instrumental role of L1 loop in directing the total interaction profile of the complex either towards electrostatic or van der Waals contacts. The key amino acid residues surfaced via interaction energy, hydrogen bonding and solvent accessible surface area analysis for each cystatin-cathepsin L1 complex influence the mode of binding and thus control the diverse inhibitory affinity of cystatins towards cysteine proteases. PMID:27764212

Antihypertensive properties of lactoferricin B-derived peptides.

PubMed

Ruiz-Giménez, Pedro; Ibáñez, Aida; Salom, Juan B; Marcos, Jose F; López-Díez, Jose Javier; Vallés, Salvador; Torregrosa, Germán; Alborch, Enrique; Manzanares, Paloma

2010-06-09

A set of eight lactoferricin B (LfcinB)-derived peptides was examined for inhibitory effects on angiotensin I-converting enzyme (ACE) activity and ACE-dependent vasoconstriction, and their hypotensive effect in spontaneously hypertensive rats (SHR). Peptides were derived from different elongations both at the C-terminal and N-terminal ends of the representative peptide LfcinB(20-25), which is known as the LfcinB antimicrobial core. All of the eight LfcinB-derived peptides showed in vitro inhibitory effects on ACE activity with different IC(50) values. Moreover, seven of them showed ex vivo inhibitory effects on ACE-dependent vasoconstriction. No clear correlation between in vitro and ex vivo inhibitory effects was found. Only LfcinB(20-25) and one of its fragments, F1, generated after a simulated gastrointestinal digestion, showed significant antihypertensive effects in SHR after oral administration. Remarkably, F1 did not show any effect on ACE-dependent vasoconstriction in contrast to the inhibitory effect showed by LfcinB(20-25). In conclusion, two LfcinB-derived peptides lower blood pressure and exhibit potential as orally effective antihypertensive compounds, yet a complete elucidation of the mechanism(s) involved deserves further ongoing research.

No Evidence for Inhibitory Deficits or Altered Reward Processing in ADHD: Data From a New Integrated Monetary Incentive Delay Go/No-Go Task.

PubMed

Demurie, Ellen; Roeyers, Herbert; Wiersema, Jan R; Sonuga-Barke, Edmund

2016-04-01

Cognitive and motivational factors differentially affect individuals with mental health problems such as ADHD. Here we introduce a new task to disentangle the relative contribution of inhibitory control and reward anticipation on task performance in children with ADHD and/or autism spectrum disorders (ASD). Typically developing children, children with ADHD,  ASD, or both disorders worked during separate sessions for monetary or social rewards in go/no-go tasks with varying inhibitory load levels. Participants also completed a monetary temporal discounting (TD) task. As predicted, task performance was sensitive to both the effects of anticipated reward amount and inhibitory load. Reward amount had different effects depending on inhibitory load level. TD correlated with inhibitory control in the ADHD group. The integration of the monetary incentive delay and go/no-go paradigms was successful. Surprisingly, there was no evidence of inhibitory control deficits or altered reward anticipation in the clinical groups. © The Author(s) 2013.

Inhibitory phonetic priming: Where does the effect come from?

PubMed

Dufour, Sophie; Frauenfelder, Ulrich Hans

2016-01-01

Both phonological and phonetic priming studies reveal inhibitory effects that have been interpreted as resulting from lexical competition between the prime and the target. We present a series of phonetic priming experiments that contrasted this lexical locus explanation with that of a prelexical locus by manipulating the lexical status of the prime and the target and the task used. In the related condition of all experiments, spoken targets were preceded by spoken primes that were phonetically similar but shared no phonemes with the target (/bak/-/dεt/). In Experiments 1 and 2, word and nonword primes produced an inhibitory effect of equal size in shadowing and same-different tasks respectively. Experiments 3 and 4 showed robust inhibitory phonetic priming on both word and nonword targets in the shadowing task, but no effect at all in a lexical decision task. Together, these findings show that the inhibitory phonetic priming effect occurs independently of the lexical status of both the prime and the target, and only in tasks that do not necessarily require the activation of lexical representations. Our study thus argues in favour of a prelexical locus for this effect.

Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

DTIC Science & Technology

2016-10-01

Siah1/2 inhibitory peptide that effectively inhibits Siah1/2 activity, which was found to effectively attenuate the growth of prostate cancer tumors in...effectiveness on cell growth with potent toxicity. Second, we set to advance a Siah inhibitory peptide that we recently developed in parallel, as...vivo when transplanted subcutaneously or orthotopically into the prostate site. The assessment of the Siah1/2 inhibitory peptide in genetic models of

Vitisin B, a resveratrol tetramer, inhibits migration through inhibition of PDGF signaling and enhancement of cell adhesiveness in cultured vascular smooth muscle cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ong, Eng-Thaim; Hwang, Tsong-Long; Huang, Yu-Ling

2011-10-15

Vascular smooth muscle cells (VSMCs) play an important role in normal vessel formation and in the development and progression of cardiovascular diseases. Grape plants contain resveratrol monomer and oligomers and drinking of wine made from grape has been linked to 'French Paradox'. In this study we evaluated the effect of vitisin B, a resveratrol tetramer, on VSMC behaviors. Vitisin B inhibited basal and PDGF-induced VSMC migration. Strikingly, it did not inhibit VSMC proliferation but inversely enhanced cell cycle progression and proliferation. Among the tested resveratrol oligomers, vitisin B showed an excellent inhibitory activity and selectivity on PDGF signaling. The anti-migratorymore » effect by vitisin B was due to direct inhibition on PDGF signaling but was independent of interference with PDGF binding to VSMCs. Moreover, the enhanced VSMC adhesiveness to matrix contributed to the anti-migratory effect by vitisin B. Fluorescence microscopy revealed an enhanced reorganization of actin cytoskeleton and redistribution of activated focal adhesion proteins from cytosol to the peripheral edge of the cell membrane. This was confirmed by the observation that enhanced adhesiveness was repressed by the Src inhibitor. Finally, among the effects elicited by vitisin B, only the inhibitory effect toward basal migration was partially through estrogen receptor activation. We have demonstrated here that a resveratrol tetramer exhibited dual but opposite actions on VSMCs, one is to inhibit VSMC migration and the other is to promote VSMC proliferation. The anti-migratory effect was through a potent inhibition on PDGF signaling and novel enhancement on cell adhesion. - Highlights: > Several resveratrol oligomers from grape plants are examined on VSMC behaviors. > Tetraoligomer vitisin B shows excellent inhibitory activity and selectivity. > It exerts dual but opposing actions: anti-migratory and pro-proliferative effects. > The anti-migratory effect results from anti-PDGF signaling and pro-adhesiveness. > The more resveratrols oligomerize, the more potent effects they exert.« less

Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts.

PubMed

Wu, Chi-Hao; Yen, Gow-Chin

2005-04-20

The objective of this study was to investigate the inhibitory effect of naturally occurring flavonoids on individual stage of protein glycation in vitro using the model systems of delta-Gluconolactone assay (early stage), BSA-methylglyoxal assay (middle stage), BSA-glucose assay, and G.K. peptide-ribose assay (last stage). In the early stage of protein glycation, luteolin, qucertin, and rutin exhibited significant inhibitory activity on HbA1C formation (p < 0.01), which were more effective than that of aminoguanidine (AG, 10 mM), a well-known inhibitor for advanced glycation endproducts (AGEs). For the middle stage, luteolin and rutin developed more significant inhibitory effect on methylglyoxal-medicated protein modification, and the IC50's were 66.1 and 71.8 microM, respectively. In the last stage of glycation, luteolin was found to be potent inhibitors of both the AGEs formation and the subsequent cross-linking of proteins. In addition, phenyl-tert-butyl-nitron served as a spin-trapping agent, and electron spin resonance (ESR) was used to explore the possible mechanism of the inhibitory effect of flavonoids on glycation. The results indicated that protein glycation was accompanied by oxidative reactions, as the ESR spectra showed a clear-cut radical signal. Statistical analysis showed that inhibitory capability of flavonoids against protein glycation was remarkably related to the scavenging free radicals derived from glycoxidation process (r = 0.79, p < 0.01). Consequently, the inhibitory mechanism of flavonoids against glycation was, at least partly, due to their antioxidant properties.

Working memory capacity predicts listwise directed forgetting in adults and children.

PubMed

Aslan, Alp; Zellner, Martina; Bäuml, Karl-Heinz T

2010-05-01

In listwise directed forgetting, participants are cued to forget previously studied material and to learn new material instead. Such cueing typically leads to forgetting of the first set of material and to memory enhancement of the second. The present study examined the role of working memory capacity in adults' and children's listwise directed forgetting. Working memory capacity was assessed with complex span tasks. In Experiment 1 working memory capacity predicted young adults' directed-forgetting performance, demonstrating a positive relationship between working memory capacity and each of the two directed-forgetting effects. In Experiment 2 we replicated the finding with a sample of first and a sample of fourth-grade children, and additionally showed that working memory capacity can account for age-related increases in directed-forgetting efficiency between the two age groups. Following the view that directed forgetting is mediated by inhibition of the first encoded list, the results support the proposal of a close link between working memory capacity and inhibitory function.

Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors

PubMed Central

Kardava, Lela; Moir, Susan; Wang, Wei; Ho, Jason; Buckner, Clarisa M.; Posada, Jacqueline G.; O’Shea, Marie A.; Roby, Gregg; Chen, Jenny; Sohn, Hae Won; Chun, Tae-Wook; Pierce, Susan K.; Fauci, Anthony S.

2011-01-01

Chronic immune activation in HIV-infected individuals leads to accumulation of exhausted tissue-like memory B cells. Exhausted lymphocytes display increased expression of multiple inhibitory receptors, which may contribute to the inefficiency of HIV-specific antibody responses. Here, we show that downregulation of B cell inhibitory receptors in primary human B cells led to increased tissue-like memory B cell proliferation and responsiveness against HIV. In human B cells, siRNA knockdown of 9 known and putative B cell inhibitory receptors led to enhanced B cell receptor–mediated (BCR-mediated) proliferation of tissue-like memory but not other B cell subpopulations. The strongest effects were observed with the putative inhibitory receptors Fc receptor–like–4 (FCRL4) and sialic acid–binding Ig-like lectin 6 (Siglec-6). Inhibitory receptor downregulation also led to increased levels of HIV-specific antibody-secreting cells and B cell–associated chemokines and cytokines. The absence of known ligands for FCRL4 and Siglec-6 suggests these receptors may regulate BCR signaling through their own constitutive or tonic signaling. Furthermore, the extent of FCLR4 knockdown effects on BCR-mediated proliferation varied depending on the costimulatory ligand, suggesting that inhibitory receptors may engage specific pathways in inhibiting B cell proliferation. These findings on HIV-associated B cell exhaustion define potential targets for reversing the deleterious effect of inhibitory receptors on immune responses against persistent viral infections. PMID:21633172

The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo.

PubMed

Uchii, Masako; Sakai, Mariko; Hotta, Yuhei; Saeki, Satoshi; Kimoto, Naoya; Hamaguchi, Akinori; Kitayama, Tetsuya; Kunori, Shunji

2017-11-01

Saxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2) cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibitory potency of saxagliptin on DPP-4 activity persisted after washout, while that of sitagliptin was clearly reduced. In normal rats, a single treatment of saxagliptin or sitagliptin inhibited the plasma DPP-4 activity to similar levels. The inhibitory action of saxagliptin on the renal DPP-4 activity was retained, even when its inhibitory effect on the plasma DPP-4 activity disappeared. However, the inhibitory action of sitagliptin on the renal DPP-4 activity was abolished in correlation with the inhibition of the plasma DPP-4 activity. In situ staining showed that saxagliptin suppressed the DPP-4 activity in both glomerular and tubular cells and its inhibitory effects were significantly higher than those of sitagliptin. Saxagliptin exerted a sustained inhibitory effect on the renal DPP-4 activity in vitro and in vivo. The long binding action of saxagliptin in renal tubular cells might involve the sustained inhibition of renal DPP-4. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Enhancing action of LSD on neuronal responsiveness to serotonin in a brain structure involved in obsessive-compulsive disorder.

PubMed

Zghoul, Tarek; Blier, Pierre

2003-03-01

Potent serotonin (5-HT) reuptake inhibitors are the only drugs that consistently exert a therapeutic action in obsessive-compulsive disorder (OCD). Given that some hallucinogens were reported to exert an anti-OCD effect outlasting their psychotomimetic action, possible modifications of neuronal responsiveness to 5-HT by LSD were examined in two rat brain structures: one associated with OCD, the orbitofrontal cortex (OFC), and another linked to depression, the hippocampus. The effects of concurrent microiontophoretic application of LSD and 5-HT were examined on neuronal firing rate in the rat OFC and hippocampus under chloral hydrate anaesthesia. In order to determine whether LSD could also exert a modification of 5-HT neuronal responsiveness upon systemic administration, after a delay when hallucinosis is presumably no longer present, it was given once daily (100 microg/kg i.p.) for 4 d and the experiments were carried out 24 h after the last dose. LSD attenuated the firing activity of OFC neurons, and enhanced the inhibitory effect of 5-HT when concomitantly ejected on the same neurons. In the hippocampus, LSD also decreased firing rate by itself but decreased the inhibitory action of 5-HT. The inhibitory action of 5-HT was significantly greater in the OFC, but smaller in the hippocampus, when examined after subacute systemic administration of LSD. It is postulated that some hallucinogens could have a beneficial action in OCD by enhancing the responsiveness to 5-HT in the OFC, and not necessarily in direct relation to hallucinosis. The latter observation may have theoretical implications for the pharmacotherapy of OCD.

Cadherin-10 Maintains Excitatory/Inhibitory Ratio through Interactions with Synaptic Proteins

PubMed Central

Jones, Kelly A.; Kopeikina, Katherine J.; Burette, Alain C.; Copits, Bryan A.; Forrest, Marc P.; Fawcett-Patel, Jessica M.

2017-01-01

Appropriate excitatory/inhibitory (E/I) balance is essential for normal cortical function and is altered in some psychiatric disorders, including autism spectrum disorders (ASDs). Cell-autonomous molecular mechanisms that control the balance of excitatory and inhibitory synapse function remain poorly understood; no proteins that regulate excitatory and inhibitory synapse strength in a coordinated reciprocal manner have been identified. Using super-resolution imaging, electrophysiology, and molecular manipulations, we show that cadherin-10, encoded by CDH10 within the ASD risk locus 5p14.1, maintains both excitatory and inhibitory synaptic scaffold structure in cultured cortical neurons from rats of both sexes. Cadherin-10 localizes to both excitatory and inhibitory synapses in neocortex, where it is organized into nanoscale puncta that influence the size of their associated PSDs. Knockdown of cadherin-10 reduces excitatory but increases inhibitory synapse size and strength, altering the E/I ratio in cortical neurons. Furthermore, cadherin-10 exhibits differential participation in complexes with PSD-95 and gephyrin, which may underlie its role in maintaining the E/I ratio. Our data provide a new mechanism whereby a protein encoded by a common ASD risk factor controls E/I ratios by regulating excitatory and inhibitory synapses in opposing directions. SIGNIFICANCE STATEMENT The correct balance between excitatory/inhibitory (E/I) is crucial for normal brain function and is altered in psychiatric disorders such as autism. However, the molecular mechanisms that underlie this balance remain elusive. To address this, we studied cadherin-10, an adhesion protein that is genetically linked to autism and understudied at the cellular level. Using a combination of advanced microscopy techniques and electrophysiology, we show that cadherin-10 forms nanoscale puncta at excitatory and inhibitory synapses, maintains excitatory and inhibitory synaptic structure, and is essential for maintaining the correct balance between excitation and inhibition in neuronal dendrites. These findings reveal a new mechanism by which E/I balance is controlled in neurons and may bear relevance to synaptic dysfunction in autism. PMID:29030434

Too (mentally) busy to chill: Cognitive load and inhibitory cues interact to moderate triggered displaced aggression.

PubMed

Vasquez, Eduardo A; Howard-Field, Joanna

2016-11-01

Inhibitory information can be expected to reduce triggered displaced aggression by signaling the potential for negative consequences as a result of acting aggressively. We examined how cognitive load might interfere with these aggression-reducing effects of inhibitory cues. Participants (N = 80) were randomly assigned to a condition in a 2 (cognitive load: high/low) × 2 (inhibiting cues: yes/no) between-subjects design. Following procedures in the TDA paradigm, participants received an initial provocation from the experimenter and a subsequent triggering annoyance from another individual. In the inhibitory cue condition, participants were told, before they had the opportunity to aggress, that others would learn of their aggressive responses. In the high cognitive load condition, participants rehearsed a 10-digit number while aggressing. Those in the low cognitive load condition rehearsed a three digit number. We found significant main effects of cognitive load and inhibitory cue, which were qualified by the expected load × inhibitory cue interaction. Thus, inhibitory cues reduced displaced aggression under low-cognitive load. However, when participants in the inhibitory cue condition were under cognitive load, aggression increased, suggesting that mental busyness interfered with the full use of inhibitory information. Aggr. Behav. 42:598-604, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Human EAG channels are directly modulated by PIP2 as revealed by electrophysiological and optical interference investigations

PubMed Central

Han, Bo; He, Kunyan; Cai, Chunlin; Tang, Yin; Yang, Linli; Heinemann, Stefan H.; Hoshi, Toshinori; Hou, Shangwei

2016-01-01

Voltage-gated ether à go-go (EAG) K+ channels are expressed in various types of cancer cells and also in the central nervous system. Aberrant overactivation of human EAG1 (hEAG1) channels is associated with cancer and neuronal disorders such as Zimmermann-Laband and Temple-Baraitser syndromes. Although hEAG1 channels are recognized as potential therapeutic targets, regulation of their functional properties is only poorly understood. Here, we show that the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) is a potent inhibitory gating modifier of hEAG1 channels. PIP2 inhibits the channel activity by directly binding to a short N-terminal segment of the channel important for Ca2+/calmodulin (CaM) binding as evidenced by bio-layer interferometry measurements. Conversely, depletion of endogenous PIP2 either by serotonin-induced phospholipase C (PLC) activation or by a rapamycin-induced translocation system enhances the channel activity at physiological membrane potentials, suggesting that PIP2 exerts a tonic inhibitory influence. Our study, combining electrophysiological and direct binding assays, demonstrates that hEAG1 channels are subject to potent inhibitory modulation by multiple phospholipids and suggests that manipulations of the PIP2 signaling pathway may represent a strategy to treat hEAG1 channel-associated diseases. PMID:27005320

Microwave-assisted synthesis and tyrosinase inhibitory activity of chalcone derivatives.

PubMed

Liu, Jinbing; Chen, Changhong; Wu, Fengyan; Zhao, Liangzhong

2013-07-01

A series of chalcones and their derivatives were synthesized, and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that some of the synthesized compounds exhibited significant inhibitory activity, and four compounds exhibited more potent tyrosinase inhibitory activity than the reference standard inhibitor kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one). Specifically, 1-(-1-(4-methoxyphen- yl)-3-phenylallylidene)thiosemicarbazide (18) exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value of 0.274 μM. The inhibition mechanism analysis of 1-(-1-(2,4-dihydroxyphenyl)-3-phenylallylidene) thiosemicarbazide (16) and 1-(-1-(4-methoxyphenyl)-3-phenylallylidene) thiosemicarbazide (18) demonstrated that the inhibitory effects of the two compounds on the tyrosinase were irreversible. Preliminary structure activity relationships' analysis suggested that further development of such compounds might be of interest. © 2013 John Wiley & Sons A/S.

Lactoferricin-related peptides with inhibitory effects on ACE-dependent vasoconstriction.

PubMed

Centeno, José M; Burguete, María C; Castelló-Ruiz, María; Enrique, María; Vallés, Salvador; Salom, Juan B; Torregrosa, Germán; Marcos, José F; Alborch, Enrique; Manzanares, Paloma

2006-07-26

A selection of lactoferricin B (LfcinB)-related peptides with an angiotensin I-converting enzyme (ACE) inhibitory effect have been examined using in vitro and ex vivo functional assays. Peptides that were analyzed included a set of sequence-related antimicrobial hexapeptides previously reported and two representative LfcinB-derived peptides. In vitro assays using hippuryl-L-histidyl-L-leucine (HHL) and angiotensin I as substrates allowed us to select two hexapeptides, PACEI32 (Ac-RKWHFW-NH2) and PACEI34 (Ac-RKWLFW-NH2), and also a LfcinB-derived peptide, LfcinB17-31 (Ac-FKCRRWQWRMKKLGA-NH2). Ex vivo functional assays using rabbit carotid arterial segments showed PACEI32 (both D- and L-enantiomers) and LfcinB17-31 have inhibitory effects on ACE-dependent angiotensin I-induced contraction. None of the peptides exhibited in vitro ACE inhibitory activity using bradykinin as the substrate. In conclusion, three bioactive lactoferricin-related peptides exhibit inhibitory effects on both ACE activity and ACE-dependent vasoconstriction with potential to modulate hypertension that deserves further investigation.

The reducing agent dithiothreitol (DTT) does not abolish the inhibitory nicotinic response recorded from rat dorsolateral septal neurons

NASA Technical Reports Server (NTRS)

Sorenson, E. M.; Gallagher, J. P.

1993-01-01

Previous intracellular recordings have demonstrated that dorsolateral septal nucleus (DLSN) neurons express a novel nicotinic receptor which produces a direct membrane hyperpolarization when activated by nicotinic agonists. Activation of the classical excitatory nicotinic receptors has been shown to require a disulfide bond involving the cysteines at positions 192 and 193 of the alpha subunits of the receptor. Reduction of this cystine bond with dithiothreitol (DTT) abolishes agonist activation of excitatory nicotinic receptors. We have now examined whether DTT treatment of the inhibitory nicotinic receptor on DLSN neurons also abolishes the inhibitory nicotinic response. We find that the inhibitory response persists after treatment of the neurons with 1 mM DTT, even if the reduction is followed by alkylation of the receptor with bromoacetylcholine to prevent possible reformation of disulfide bonds. This result suggests that the agonist binding site on the inhibitory nicotinic receptor does not require an intact disulfide bond, similar to the bond on the alpha subunit of the excitatory nicotinic receptor, for agonist activation of the receptor. Some of these results have been previously reported in abstract form.

Auditory cortical plasticity induced by intracortical microstimulation under pharmacological blockage of inhibitory synapses.

PubMed

Yokota, R; Takahashi, H; Funamizu, A; Uchihara, M; Suzurikawa, J; Kanzaki, R

2006-01-01

Electrical stimulation that can reorganize our neural system has a potential for promising neurorehabilitation. We previously demonstrated that temporally controlled intracortical microstimulation (ICMS) could induce the spike time-dependant plasticity and modify tuning properties of cortical neurons as desired. A 'pairing' ICMS following tone-induced excitatory post-synaptic potentials (EPSPs) produced potentiation in response to the paired tones, while an 'anti-pairing' ICMS preceding the tone-induced EPSPs resulted in depression. However, the conventional ICMS affected both excitatory and inhibitory synapses, and thereby could not quantify net excitatory synaptic effects. In the present work, we evaluated the ICMS effects under a pharmacological blockage of inhibitory inputs. The pharmacological blockage enhanced the ICMS effects, suggesting that inhibitory inputs determine a plastic degree of the neural system. Alternatively, the conventional ICMS had an inadequate timing to control excitatory synaptic inputs, because inhibitory synapse determined the latency of total neural inputs.

Inhibitory effect and mechanism of acarbose combined with gymnemic acid on maltose absorption in rat intestine

PubMed Central

Luo, Hong; Wang, Le Feng; Imoto, Toshiaki; Hiji, Yasutake

2001-01-01

AIM: To compare the combinative and individual effect of acarbose and gymnemic acid (GA) on maltose absorption and hydrolysis in small intestine to determine whether nutrient control in diabetic care can be improved by combination of them. METHODS: The absorption and hydrolysis of maltose were studied by cyclic perfusion of intestinal loops in situ and motility of the intestine was recorded with the intestinal ring in vitro using Wistar rats. RESULTS: The total inhibitory rate of maltose absorption was improved by the combination of GA (0.1 g/L-1.0 g/L) and acarbose (0.1 mmol/L-2.0 mmol/L) throughout their effective duration (P < 0.05, U test of Mann-Whitney), although the improvement only could be seen at a low dosage during the first hour. With the combination, inhibitory duration of acarbose on maltose absorption was prolonged to 3 h and the inhibitory effect onset of GA was fastened to 15 min. GA suppressed the intestinal mobility with a good correlation (r = 0.98) to the inhibitory effect of GA on maltose absorption and the inhibitory effect of 2 mmol/L (high dose) acarbose on maltose hydrolysis was dual modulated by 1 g/L GA in vivo indicating that the combined effects involved the functional alteration of intestinal barriers. CONCLUSION: There are augmented effects of acarbose and GA, which involve pre-cellular and paracellular barriers. Diabetic care can be improved by employing the combination. PMID:11819725

Effects of Display Complexity on Location and Feature Inhibition

PubMed Central

K.Hu, Frank; Fan, Zhiwei; Samuel, Arthur G.; He, ShuChang

2013-01-01

Inhibition of return (IOR) refers to the slowing of reaction times to a target when a preceding stimulus has occupied the same location in space. Recently, we observed a robust inhibitory effect for color and shape in moderately complex displays: It is more difficult to detect a target with a particular nonspatial attribute if a stimulus with the same attribute was recently the focus of attention. Such nonspatial inhibitory effects have not generally been found in simpler displays. In the present study, we test how location-based and nonspatial inhibitory effects vary as a function of display complexity (8, 6, 4 and 2 locations). The results demonstrated that: (1) location based inhibition effects were much stronger in more complex displays, whereas the nonspatial inhibition was only slightly stronger in more complex displays; (2) Nonspatial inhibitory effects emerged at longer SOAs than location-based effects; and (3) Nonspatial inhibition only appeared when cues and targets occurred in the same locations, confirming that pure feature repetition does not produce a cost. Taken together, the results are consistent with perceptual processes based on object files that are organized by spatial location. Using somewhat more complex displays than are most commonly employed provides a more sensitive method to observe the role of inhibitory processes in facilitating visual search. In addition, using a relatively wide set of cue-target timing relationships is necessary in order to clearly see how inhibitory effects operate. PMID:23907617

The Direct Inhibitory Effect of Dutasteride or Finasteride on Androgen Receptor Activity is Cell Line Specific

PubMed Central

Chhipa, Rishi Raj; Halim, Danny; Cheng, Jinrong; Zhang, Huan Yi; Mohler, James L.; Ip, Clement; Wu, Yue

2014-01-01

BACKGROUND Finasteride and dutasteride were developed originally as 5α-reductase inhibitors to block the conversion of testosterone to dihydrotestosterone (DHT). These drugs may possess off-target effects on the androgen receptor (AR) due to their structural similarity to DHT. METHODS A total of 4 human prostate cancer cell models were examined: LNCaP (T877A mutant AR), 22Rv1 (H874Y mutant AR), LAPC4 (wild type AR) and VCaP (wild type AR). Cells were cultured in 10% charcoal-stripped fetal bovine serum, either with or without DHT added to the medium. AR activity was evaluated using the ARE-luciferase assay or the expression of AR regulated genes. RESULTS Dutasteride was more potent than finasteride in interfering with DHT-stimulated AR signaling. Disruption of AR function was accompanied by decreased cell growth. Cells that rely on DHT for protection against death were particularly vulnerable to dutasteride. Different prostate cancer cell models exhibited different sensitivities to dutasteride and finasteride. LNCaP was most sensitive, LAPC4 and VCaP were intermediate, while 22Rv1 was least sensitive. Regardless of the AR genotype, if AR was transfected into drug-sensitive cells, AR was inhibited by drug treatment; and if AR was transfected into drug-resistant cells, AR was not inhibited. CONCLUSIONS The direct inhibitory effect of dutasteride or finasteride on AR signaling is cell line specific. Mutations in the ligand binding domain of AR do not appear to play a significant role in influencing the AR antagonistic effect of these drugs. Subcellular constituent is an important factor in determining the drug effect on AR function. PMID:23813737

miR-543 promotes gastric cancer cell proliferation by targeting SIRT1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Juan; Dong, Guoying; Wang, Bo

SIRT1, a class III histone deacetylase, exerts inhibitory effects on tumorigenesis and is downregulated in gastric cancer. However, the role of microRNAs in the regulation of SIRT1 in gastric cancer is still largely unknown. Here, we identified miR-543 as a predicted upstream regulator of SIRT1 using 3 different bioinformatics databases. Mimics of miR-543 significantly inhibited the expression of SIRT1, whereas an inhibitor of miR-543 increased SIRT1 expression. MiR-543 directly targeted the 3′-UTR of SIRT1, and both of the two binding sites contributed to the inhibitory effects. In gastric epithelium-derived cell lines, miR-543 promoted cell proliferation and cell cycle progression, andmore » overexpression of SIRT1 rescued the above effects of miR-543. The inhibitory effects of miR-543 on SIRT1 were also validated using clinical gastric cancer samples. Moreover, we found that miR-543 expression was positively associated with tumor size, clinical grade, TNM stage and lymph node metastasis in gastric cancer patients. Our results identify a new regulatory mechanism of miR-543 on SIRT1 expression in gastric cancer, and raise the possibility that the miR-543/SIRT1 pathway may serve as a potential target for the treatment of gastric cancer. - Highlights: • SIRT1 is a novel target of miR-543. • miR-543 promotes gastric cancer cell proliferation and cell cycle progression by targeting SIRT1. • miR-543 is upregulated in GC and positively associated with tumor size, clinical grade, TNM stage and lymph node metastasis. • miR-543 is negatively correlated with SIRT1 expression in gastric cancer tissues.« less

Effect of crude glycerol-derived inhibitors on ethanol production by Enterobacter aerogenes.

PubMed

Lee, Sang Jun; Kim, Sung Bong; Kang, Seong Woo; Han, Sung Ok; Park, Chulhwan; Kim, Seung Wook

2012-01-01

In this study, ethanol production from pure and crude glycerol using Enterobacter aerogenes ATCC 29007 was evaluated under anaerobic culture conditions. Inhibitory effects of substrate concentrations, pH, and salt concentrations were investigated based on crude glycerol components. Ethanol production was performed with pure glycerol concentrations ranging from 5 to 30 g/L to evaluate the effects of substrate concentration and osmotic pressure. The consumed glycerol was 5-14.33 g/L, and the yield of ethanol was higher than 0.75 mol ethanol/mol glycerol after 24 h of cultivation. To evaluate the inhibitory effects of salts (NaCl and KCl), experiments were performed with 0-20 g/L of each salt. Inhibitory effects of salts were strongest at high salt concentrations. The inhibitory effect of pH was performed in the pH range 4-10, and cell growth and ethanol production were highest at pH 5-6. Also, ethanol production was slightly inhibited at low concentration of crude glycerol comparison with pure glycerol. However, significant inhibitory effects were not observed at 1.5 and 2% crude glycerol which showed higher ethanol production compared to pure glycerol.

Inhibitory effect of leonurine on the formation of advanced glycation end products.

PubMed

Huang, Lianqi; Yang, Xin; Peng, Anlin; Wang, Hui; Lei, Xiang; Zheng, Ling; Huang, Kun

2015-02-01

Long-term hyperglycemia is a typical symptom of diabetes mellitus (DM) which can cause a high level of protein glycation and lead to the formation of advanced glycation end products (AGEs). The accumulation of AGEs in turn deteriorates DM and its complications. Insulin, the only hormone that directly decreases blood sugar in vivo, is vulnerable to glycation which causes the loss of its biological activity. In this study, we used a porcine insulin (PI)-methylglyoxal (MGO) model to investigate the inhibitory effect of leonurine (LN), a natural alkaloid extracted from Herba leonuri, on AGE formation. Assays including AGE-specific fluorescence, and fructosamine level and carbonyl group content determination showed that LN can dose-dependently suppress PI glycation. A significantly decreased cross-linking level on the glycated PI was also proven by SDS-PAGE electrophoresis. A further liquid chromatography-mass spectrometry study suggested that LN may inhibit PI glycation through trapping MGO and keeping it from reacting with PI. Our results thus indicate that LN is a promising anti-glycation agent for the prevention of diabetes and its complications via inhibiting AGE formation.

Development of a novel method for determination of mercury based on its inhibitory effect on horseradish peroxidase activity followed by monitoring the surface plasmon resonance peak of gold nanoparticles

NASA Astrophysics Data System (ADS)

Khodaveisi, Javad; Shabani, Ali Mohammad Haji; Dadfarnia, Shayessteh; Moghadam, Masoud Rohani; Hormozi-Nezhad, Mohammad Reza

2016-01-01

A highly sensitive and simple indirect spectrophotometric method has been developed for the determination of trace amounts of inorganic mercury (Hg2 +) in aqueous media. The method is based on the inhibitory effect of Hg2 + on the activity of horseradish peroxidase (HRP) in the oxidation of ascorbic acid by hydrogen peroxide followed by the reduction of Au3 + to Au-NPs by unreacted ascorbic acid and the measurement of the absorbance of localized surface plasmon resonance (LSPR) peak of gold nanoparticles (at 530 nm) which is directly proportional to the concentration of Hg2 +. Under the optimum conditions, the calibration curve was linear in the concentration range of 1-220 ng mL- 1. Limits of detection (LOD) and quantification (LOQ) were 0.2 and 0.7 ng mL- 1, respectively and the relative standard deviation at 100 ng mL- 1 level of Hg2 + was 2.6%. The method was successfully applied to the determination of mercury in different water samples.

Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity

PubMed Central

Ching, Tsui-Ting; Chiang, Wei-Chung; Chen, Ching-Shih; Hsu, Ao-Lin

2011-01-01

Summary One goal of aging research is to develop interventions that combat age-related illnesses and slow aging. Although numerous mutations have been shown to achieve this in various model organisms, only a handful of chemicals have been identified to slow aging. Here we report that celecoxib, a non-steroidal anti-inflammatory drug (NSAID) widely used to treat pain and inflammation, extends C. elegans lifespan and delays the age-associated physiological changes, such as motor activity declines. Celecoxib also delays the progression of age-related proteotoxicity as well as tumor growth in C. elegans. Celecoxib was originally developed as a potent COX-2 inhibitor. However, the result from a structural-activity analysis demonstrated that the anti-aging effect of celecoxib might be independent of its COX-2 inhibitory activity, as analogs of celecoxib that lack cyclooxygenase-2 (COX-2) inhibitory activity produces a similar effect on lifespan. Furthermore, we found that celecoxib acts directly on 3’-phosphoinositide-dependent kinase-1 (PDK-1), a component of the insulin/IGF-1 signaling (IIS) cascade to increase lifespan. PMID:21348927

Plant-Derived Polyphenols Interact with Staphylococcal Enterotoxin A and Inhibit Toxin Activity

PubMed Central

Shimamura, Yuko; Aoki, Natsumi; Sugiyama, Yuka; Tanaka, Takashi; Murata, Masatsune; Masuda, Shuichi

2016-01-01

This study was performed to investigate the inhibitory effects of 16 different plant-derived polyphenols on the toxicity of staphylococcal enterotoxin A (SEA). Plant-derived polyphenols were incubated with the cultured Staphylococcus aureus C-29 to investigate the effects of these samples on SEA produced from C-29 using Western blot analysis. Twelve polyphenols (0.1–0.5 mg/mL) inhibited the interaction between the anti-SEA antibody and SEA. We examined whether the polyphenols could directly interact with SEA after incubation of these test samples with SEA. As a result, 8 polyphenols (0.25 mg/mL) significantly decreased SEA protein levels. In addition, the polyphenols that interacted with SEA inactivated the toxin activity of splenocyte proliferation induced by SEA. Polyphenols that exerted inhibitory effects on SEA toxic activity had a tendency to interact with SEA. In particular, polyphenol compounds with 1 or 2 hexahydroxydiphenoyl groups and/or a galloyl group, such as eugeniin, castalagin, punicalagin, pedunculagin, corilagin and geraniin, strongly interacted with SEA and inhibited toxin activity at a low concentration. These polyphenols may be used to prevent S. aureus infection and staphylococcal food poisoning. PMID:27272505

Plant-Derived Polyphenols Interact with Staphylococcal Enterotoxin A and Inhibit Toxin Activity.

PubMed

Shimamura, Yuko; Aoki, Natsumi; Sugiyama, Yuka; Tanaka, Takashi; Murata, Masatsune; Masuda, Shuichi

2016-01-01

This study was performed to investigate the inhibitory effects of 16 different plant-derived polyphenols on the toxicity of staphylococcal enterotoxin A (SEA). Plant-derived polyphenols were incubated with the cultured Staphylococcus aureus C-29 to investigate the effects of these samples on SEA produced from C-29 using Western blot analysis. Twelve polyphenols (0.1-0.5 mg/mL) inhibited the interaction between the anti-SEA antibody and SEA. We examined whether the polyphenols could directly interact with SEA after incubation of these test samples with SEA. As a result, 8 polyphenols (0.25 mg/mL) significantly decreased SEA protein levels. In addition, the polyphenols that interacted with SEA inactivated the toxin activity of splenocyte proliferation induced by SEA. Polyphenols that exerted inhibitory effects on SEA toxic activity had a tendency to interact with SEA. In particular, polyphenol compounds with 1 or 2 hexahydroxydiphenoyl groups and/or a galloyl group, such as eugeniin, castalagin, punicalagin, pedunculagin, corilagin and geraniin, strongly interacted with SEA and inhibited toxin activity at a low concentration. These polyphenols may be used to prevent S. aureus infection and staphylococcal food poisoning.

Effect-directed analysis via hyphenated high-performance thin-layer chromatography for bioanalytical profiling of sunflower leaves.

PubMed

Móricz, Ágnes M; Ott, Péter G; Yüce, Imanuel; Darcsi, András; Béni, Szabolcs; Morlock, Gertrud E

2018-01-19

High-performance thin-layer chromatography (HPTLC) coupled with effect-directed analysis was used for non-targeted screening of sunflower leaf extract for components exhibiting antioxidant, antibacterial and/or cholinesterase enzyme inhibitory effects. The active compounds were characterized by HPTLC-electrospray ionization-high resolution mass spectrometry (ESI-HRMS) and HPTLC-Direct Analysis in Real Time (DART)-MS/MS. The latter ambient ionization technique (less soft than ESI) resulted in oxidation and fragmentation products and characteristic fragment ions. NMR spectroscopy after targeted isolation via preparative normal phase flash chromatography and semi-preparative reversed phase high-performance liquid chromatography supported the identification of two diterpenes to be (-)-kaur-16-en-19-oic acid and 15-α-angeloyloxy-ent-kaur-16-en-19-oic acid. Both compounds found to be multi-potent as they inhibited acetylcholinesterase and butyrylcholinesterase and showed antibacterial effects against Gram-positive Bacillus subtilis and Gram-negative Aliivibrio fischeri bacteria. Kaurenoic acid was also active against the Gram-negative pepper pathogenic Xanthomonas euvesicatoria bacteria. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibitory Effect of Long-Chain Fatty Acids on Biogas Production and the Protective Effect of Membrane Bioreactor

PubMed Central

Dasa, Kris Triwulan; Westman, Supansa Y.; Cahyanto, Muhammad Nur; Niklasson, Claes

2016-01-01

Anaerobic digestion of lipid-containing wastes for biogas production is often hampered by the inhibitory effect of long-chain fatty acids (LCFAs). In this study, the inhibitory effects of LCFAs (palmitic, stearic, and oleic acid) on biogas production as well as the protective effect of a membrane bioreactor (MBR) against LCFAs were examined in thermophilic batch digesters. The results showed that palmitic and oleic acid with concentrations of 3.0 and 4.5 g/L resulted in >50% inhibition on the biogas production, while stearic acid had an even stronger inhibitory effect. The encased cells in the MBR system were able to perform better in the presence of LCFAs. This system exhibited a significantly lower percentage of inhibition than the free cell system, not reaching over 50% at any LCFA concentration tested. PMID:27699172

Evaluation of Anti-Toxoplasma gondii Effect of Ursolic Acid as a Novel Toxoplasmosis Inhibitor.

PubMed

Choi, Won Hyung; Lee, In Ah

2018-05-09

This study was carried out to evaluate the anti-parasitic effect of ursolic acid against Toxoplasma gondii ( T. gondii ) that induces toxoplasmosis, particularly in humans. The anti-parasitic effects of ursolic acid against T. gondii -infected cells and T. gondii were evaluated through different specific assays, including immunofluorescence staining and animal testing. Ursolic acid effectively inhibited the proliferation of T. gondii when compared with sulfadiazine, and consistently induced anti- T. gondii activity/effect. In particular, the formation of parasitophorous vacuole membrane (PVM) in host cells was markedly decreased after treating ursolic acid, which was effectively suppressed. Moreover, the survival rate of T. gondii was strongly inhibited in T. gondii group treated with ursolic acid, and then 50% inhibitory concentration (IC 50 ) against T. gondii was measured as 94.62 μg/mL. The T. gondii -infected mice treated with ursolic acid indicated the same survival rates and activity as the normal group. These results demonstrate that ursolic acid causes anti- T. gondii action and effect by strongly blocking the proliferation of T. gondii through the direct and the selective T. gondii -inhibitory ability as well as increases the survival of T. gondii -infected mice. This study shows that ursolic acid has the potential to be used as a promising anti- T. gondii candidate substance for developing effective anti-parasitic drugs.

Control of Inhibition by the Direct Action of Cannabinoids on GABAA Receptors.

PubMed

Golovko, Tatiana; Min, Rogier; Lozovaya, Natalia; Falconer, Caroline; Yatsenko, Natalia; Tsintsadze, Timur; Tsintsadze, Vera; Ledent, Catherine; Harvey, Robert J; Belelli, Delia; Lambert, Jeremy J; Rozov, Andrei; Burnashev, Nail

2015-09-01

Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB1 receptors (CB1Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABAA receptors (GABAARs), potentiating currents activated by micromolar concentrations of γ-aminobutyric acid (GABA). However, the impact of this direct interaction on GABAergic inhibition in central nervous system is unknown. Here we report that currents mediated by recombinant GABAARs activated by high (synaptic) concentrations of GABA as well as GABAergic inhibitory postsynaptic currents (IPSCs) at neocortical fast spiking (FS) interneuron to pyramidal neuron synapses are suppressed by exogenous and endogenous cannabinoids in a CB1R-independent manner. This IPSC suppression may account for disruption of inhibitory control of pyramidal neurons by FS interneurons. At FS interneuron to pyramidal neuron synapses, endocannabinoids induce synaptic low-pass filtering of GABAAR-mediated currents evoked by high-frequency stimulation. The CB1R-independent suppression of inhibition is synapse specific. It does not occur in CB1R containing hippocampal cholecystokinin-positive interneuron to pyramidal neuron synapses. Furthermore, in contrast to synaptic receptors, the activity of extrasynaptic GABAARs in neocortical pyramidal neurons is enhanced by cannabinoids in a CB1R-independent manner. Thus, cannabinoids directly interact differentially with synaptic and extrasynaptic GABAARs, providing a potent novel context-dependent mechanism for regulation of inhibition. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Inhibition of electron transport on the oxygen-evolving side of photosystem II by an antiserum to a polypeptide isolated from the thylakoid membrane.

PubMed

Schmid, G H; Menke, W; Koenig, F; Radunz, A

1976-01-01

A polypeptide fraction with the apparent molecular weight 11 000 was isolated from stroma-freed chloroplasts from Anthirrhinum majus. An antiserum to this polypeptide fraction inhibits photosynthetic electron transport in chloroplasts from Nicotiana tabacum. The relative degree of inhibition is pH dependent and has its maximum at pH 7.4. The maximal inhibition observed was 93%. The dependence of the inhibition on the amount of antiserum yields a sigmoidal curve which hints at a cooperative effect. A calculation of the Hill interaction coefficient gave the value of 10. The inhibition occurs on the water splitting side of photosystem II between the sites of electron donation of tetramethyl benzidine and diphenylcarbazide. Tetramethyl benzidine donates its electrons before the site where diphenylcarbazide feeds in its electrons. Analysis of the steady state level of the variable fluorescence also indicates that the inhibition site is on the water splitting side of photosystem II. Tris-washed chloroplasts are equally inhibited by the antiserum and the inhibition is also observed in the presence of an inhibitor of photophosphorylation like dicyclohexyl carbodiimide and in the presence of the uncoupler carbonylcyanide m-chlorophenyl hydrazone (CCCP) which means that the inhibitory action is directed towards the electron transport chain. Valinomycin which is supposed to affect the cation permeability of the thylakoid membrane has no influence on the inhibitory action of the antiserum. The same is valid for gramicidin. Methylamine on the other hand can induce a state in the thylakoids in which the antiserum is not effective. If the antibodies are already adsorbed prior to the methylamine addition then the high inhibitory effect by the antiserum remains unchanged upon addition of methylamine. From the experiments it follows that a component from the vicinity of photosystem II is accessible to antibodies that is, the component is located in the outer surface of the thylakoid membrane. It appears that the inhibitory effect is produced in the course of the light reaction.

Novel nootropic dipeptide Noopept increases inhibitory synaptic transmission in CA1 pyramidal cells.

PubMed

Kondratenko, Rodion V; Derevyagin, Vladimir I; Skrebitsky, Vladimir G

2010-05-31

Effects of newly synthesized nootropic and anxiolytic dipeptide Noopept on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) significantly increased the frequency of spike-dependant spontaneous IPSCs whereas spike-independent mIPSCs remained unchanged. It was suggested that Noopept mediates its effect due to the activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Transcranial Direct Current Stimulation (tDCS): A Beginner's Guide for Design and Implementation

PubMed Central

Thair, Hayley; Holloway, Amy L.; Newport, Roger; Smith, Alastair D.

2017-01-01

Transcranial direct current stimulation (tDCS) is a popular brain stimulation method that is used to modulate cortical excitability, producing facilitatory or inhibitory effects upon a variety of behaviors. There is, however, a current lack of consensus between studies, with many results suggesting that polarity-specific effects are difficult to obtain. This article explores some of these differences and highlights the experimental parameters that may underlie their occurrence. We provide a general, practical snapshot of tDCS methodology, including what it is used for, how to use it, and considerations for designing an effective and safe experiment. Our aim is to equip researchers who are new to tDCS with the essential knowledge so that they can make informed and well-rounded decisions when designing and running successful experiments. By summarizing the varied approaches, stimulation parameters, and outcomes, this article should help inform future tDCS research in a variety of fields. PMID:29213226

Protective effects of Mucuna pruriens seed extract pretreatment against cardiovascular and respiratory depressant effects of Calloselasma rhodostoma (Malayan pit viper) venom in rats.

PubMed

Fung, S Y; Tan, N H; Sim, S M

2010-12-01

The protective effects of Mucuna pruriens seed extract (MPE) against the cardio-respiratory depressant and neuromuscular paralytic effects induced by injection of Calloselasma rhodostoma (Malayan pit viper) venom in anaesthetized rats were investigated. While MPE pretreatment did not reverse the inhibitory effect of the venom on the gastrocnemius muscle excitability, it significantly attenuated the venom-induced cardio-respiratory depressant effects (p < 0.05). The protection effects may have an immunological mechanism, as indicated by the presence of several proteins in the venom that are immunoreactive against anti-MPE. However, we cannot rule out the possibility that the pretreatment may exert a direct, non-immunological protective action against the venom.

The Influence of the Toxin/Antitoxin mazEF on Growth and Survival of Listeria monocytogenes under Stress.

PubMed

Curtis, Thomas D; Takeuchi, Ippei; Gram, Lone; Knudsen, Gitte M

2017-01-13

A major factor in the resilience of Listeria monocytogenes is the alternative sigma factor B (σ B ). Type II Toxin/Antitoxin (TA) systems are also known to have a role in the bacterial stress response upon activation via the ClpP or Lon proteases. Directly upstream of the σ B operon in L. monocytogenes is the TA system mazEF , which can cleave mRNA at UACMU sites. In this study, we showed that the mazEF TA locus does not affect the level of persister formation during treatment with antibiotics in lethal doses, but exerts different effects according to the sub-inhibitory stress added. Growth of a Δ mazEF mutant was enhanced relative to the wildtype in the presence of sub-inhibitory norfloxacin and at 42 °C, but was decreased when challenged with ampicillin and gentamicin. In contrast to studies in Staphylococcus aureus , we found that the mazEF locus did not affect transcription of genes within the σ B operon, but MazEF effected the expression of the σ B -dependent genes opuCA and lmo0880 , with a 0.22 and 0.05 fold change, respectively, compared to the wildtype under sub-inhibitory norfloxacin conditions. How exactly this system operates remains an open question, however, our data indicates it is not analogous to the system of S. aureus , suggesting a novel mode of action for MazEF in L. monocytogenes.

High-performance thin-layer chromatographic methods in the evaluation of the antioxidant and anti-hyperglycemic activity of Myrmecodia platytyrea as a promising opportunity in diabetes treatment.

PubMed

Agatonovic-Kustrin, S; Morton, D W; Adam, A; Mizaton, H H; Zakaria, H

2017-12-29

The steady increase of diabetes is becoming a major burden on health care systems. As diabetic complications arise from oxidative stress, an antioxidant therapy along with anti-diabetic drugs is recommended. Myrmecodia or ant plant is highly valued as a traditional medicine in West Papua. It is used as an alternative treatment for diabetes, as the substances produced by ants can reduce blood sugar levels. The aim of this study was to develop and establish high-performance thin-layer chromatographic (HPTLC)-bioautographic methods to measure the antioxidant and hypoglycemic effects in different extracts from Myrmecodia platytyrea and to compare them with sterol content. Antioxidant activity in methanol, ethanol, dichloromethane (DCM) and ethyl acetate (EA) extracts were measured with a direct HPTLC-2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) assay, while hypoglycemic effects were assessed using a newly developed α-amylase inhibitory activity assay. Stigmasterol is observed, after derivatization with anisaldehyde, as purple colored zones under visible light at hRF values of 0.66. The highest antioxidant activity was observed in the ethanol extract which is rich in polyphenols and flavonoids, while the DCM extract did not show antioxidant activity, but had significant α-amylase inhibitory activity. The highest α-amylase inhibitory activity was observed in the EA and DCM extracts and was related to their stigmasterol content. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Absolute Side-chain Structure at Position 13 Is Required for the Inhibitory Activity of Bromein*

PubMed Central

Sawano, Yoriko; Hatano, Ken-ichi; Miyakawa, Takuya; Tanokura, Masaru

2008-01-01

Bromelain isoinhibitor (bromein), a cysteine proteinase inhibitor from pineapple stem, has a unique double-chain structure. The bromein precursor protein includes three homologous inhibitor domains, each containing an interchain peptide between the light and heavy chains. The interchain peptide in the single-chain precursor is immediately processed by bromelain, a target proteinase. In the present study, to clarify the essential inhibitory site of bromein, we constructed 44 kinds of site-directed and deletion mutants and investigated the inhibitory activity of each toward bromelain. As a result, the complete chemical structure of Leu13 in the light chain was revealed to be essential for inhibition. Pro12 prior to the leucine residue was also involved in the inhibitory activity and would control the location of the leucine side chain by the fixed φ dihedral angle of proline. Furthermore, the five-residue length of the interchain peptide was strictly required for the inhibitory activity. On the other hand, no inhibitory activity against bromelain was observed by the substitution of proline for the N terminus residue Thr15 of the interchain peptide. In summary, these mutational analyses of bromein demonstrated that the appropriate position and conformation of Leu13 are absolutely crucial for bromelain inhibition. PMID:18948264

The Long-Lasting Enhancing Effect of Distigmine on Acetylcholine-Induced Contraction of Guinea Pig Detrusor Smooth Muscle Correlates with Its Anticholinesterase Activity.

PubMed

Obara, Keisuke; Ogawa, Tsukasa; Chino, Daisuke; Tanaka, Yoshio

2017-01-01

Distigmine bromide (distigmine), a reversible, long-lasting cholinesterase (ChE) inhibitor, is used for the treatment of underactive bladder in Japan and has been shown to potentiate urinary bladder (UB) contractility. We studied the duration of distigmine's potentiating effects on acetylcholine (ACh)-induced UB contraction and its inhibitory effects on ChE activity, and compared that with those of other ChE inhibitors (neostigmine, pyridostigmine, and ambenonium). The duration of potentiating/inhibitory effects of ChE inhibitors, including distigmine, on ACh-induced guinea pig UB contraction/ChE activity was evaluated for 12 h following washout. Dissociation rate constants (k) of the inhibitors were also tentatively calculated based on the time courses of their ChE inhibitory effects. The potentiating effect of distigmine (10 -6  M) on ACh-induced UB contraction and its inhibitory effect on ChE activity were significantly sustained 12 h after washout. The potentiating effect of other ChE inhibitors on ACh-induced UB contraction, however, was sustained only until 3 h after washout. The ChE inhibitory effects of these inhibitors dissipated in a time-dependent manner after washout, with more than 75% of ChE activity restored by 4 h after washout. The k values of ChE inhibitors approached 0.50 h -1 , except for distigmine, where k could not be determined. Compared with that of other ChE inhibitors, the potentiating effect of distigmine on UB contractile function was significantly more sustainable following washout, which was likely associated with its corresponding long-lasting ChE inhibitory effect. Distigmine may associate more strongly with UB ChE than other ChE inhibitors, which would partly explain its sustained effects.

The moderating role of state inhibitory control in the effect of evaluative conditioning on temptation and unhealthy snacking.

PubMed

Haynes, Ashleigh; Kemps, Eva; Moffitt, Robyn

2015-12-01

The current study sought to test the effect of a brief evaluative conditioning intervention on experienced temptation to indulge, and consumption of, unhealthy snack foods. We expected that a training task associating unhealthy food with negative affect would result in lower experienced temptation across the sample, but would lead to lower snack consumption only among individuals with low state inhibitory control. Undergraduate women (N=134) aged 17-25 years were randomised to complete an evaluative conditioning procedure pairing unhealthy food with either positive or negative affect. Snack consumption was subsequently assessed using a taste-test procedure which offered four snack foods for ad libitum consumption. Participants also reported the strength of their experienced temptation to indulge in the foods presented. Additionally, they completed a Stop Signal Task as a measure of state inhibitory control. As predicted, participants in the food negative condition ate less than those in the food positive condition, but this effect was only observed among individuals with low inhibitory control. The same moderation pattern was observed for the effect of evaluative conditioning on temptation: only participants with low inhibitory control reported feeling less tempted by the snack foods in the food negative condition compared to the food positive condition. In addition, temptation mediated the effect of evaluative conditioning on intake for individuals with low inhibitory control. Findings suggest that evaluative conditioning of unhealthy food stimuli could be especially useful for reducing temptation and consumption of unhealthy snacks in situations where individuals experience low inhibitory control capacity. Copyright © 2015 Elsevier Inc. All rights reserved.

Isolation method (direct plating or enrichment) does not affect antimicrobial susceptibility of Campylobacter from chicken carcasses

USDA-ARS?s Scientific Manuscript database

To determine if Campylobacter isolation method influenced antimicrobial susceptibility results, the minimum inhibitory concentrations (MIC) of nine antimicrobials were compared for 291 pairs of Campylobacter isolates recovered from chicken carcass rinse samples using direct plating and an enrichment...

Inhibitory effects of different ATP-sensitive potassium channel openers on electrically generated and carbachol-induced contractions of porcine and human detrusor muscle.

PubMed

Badawi, Jasmin Katrin; Ding, Andrea; Bross, Stephan

2008-02-01

The inhibitory effects of different potassium channel openers (PCOs) on electrically generated and carbachol-induced contractions of porcine and human detrusor muscle were examined. PCOs could be an interesting substance class for treatment of detrusor overactivity. Experiments were performed on muscle strips suspended in a tissue bath. Human tissue originated from patients who underwent total cystectomy. The concentration-relaxation curves of the first-generation PCOs cromakalim and pinacidil and the untypical PCO minoxidil were performed using carbachol-precontracted detrusor muscle strips of pigs and humans. Additionally, the inhibitory effects of cromakalim, pinacidil and minoxidil on electrically generated contractions of porcine detrusor muscle were examined. Furthermore, the inhibitory effect of the second-generation, bladder-selective PCO ZM 226600 on electrically generated contractions of the human detrusor muscle was determined. Frequency-response curves were performed before and after incubation with one PCO used in two different concentrations. In humans, cromakalim and pinacidil led to a maximum decrease of 73.5 and 68.4% and showed mean pD2 values of 6.65 and 5.5, respectively. In pigs, cromakalim and pinacidil led to a maximum decrease of 90.6 and 93.6% and showed mean pD2 values of 6.39 and 5.01, respectively. Minoxidil did not significantly decrease the precontraction at the highest used concentration in both species. Cromakalim exhibited the biggest inhibitory effect being significant at 10(-5) and 10(-6) M. Pinacidil showed only a significant inhibitory effect at 10(-5) M which was smaller than that of cromakalim. At 3 x 10(-6) M only a very small effect occurred at 1 Hz. Minoxidil did not inhibit the contractions at both examined concentrations except for a very small effect at 1 Hz. In humans, ZM 226600 exhibited at 10(-6) and 10(-5) M a significant inhibitory effect. At 10(-7) M it was only significant at one frequency.

Fertility control of rodent pests: a review of the inhibitory effects of plant extracts on ovarian function.

PubMed

Tran, Tung Thanh; Hinds, Lyn A

2013-03-01

Plant extracts can inhibit fertility by adversely affecting, directly or indirectly, reproductive processes ranging from gonadal function and development to gestation. This review focuses on plant extracts that disrupt ovarian function in rodents. Extracts from at least 40 plant species exert some of their disruptive reproductive effects at the ovarian level. Of those, 13 plants induce a reduction in the number and type of ovarian follicles and also cause disruption to the oestrous cycle. Their effects are short term and reversible once treatment ceases. Protection of plant extracts to prevent their degradation before uptake in the gastrointestinal tract could enhance short-term efficacy but would not enhance the longevity of their effects. Identification and further testing of the specific chemicals responsible for reproductive effects would be beneficial. The adoption of a standard protocol for treatment and assessment of the inhibitory effects of potential control agents on reproductive function in rodents is essential. Treatment with higher concentrations of extracts in conjunction with other extracts or with other chemosterilants could have potential complementary effects and lead to more rapid and permanent changes in ovarian function. An orally delivered agent(s) that causes major depletion of all follicle types, and particularly of non-regenerating primordial follicles, could be an ideal fertility control product and serve as an additional tool for population control of pest rodents. Copyright © 2012 Society of Chemical Industry.

Silibinin prevents prostate cancer cell-mediated differentiation of naïve fibroblasts into cancer-associated fibroblast phenotype by targeting TGF β2.

PubMed

Ting, Harold J; Deep, Gagan; Jain, Anil K; Cimic, Adela; Sirintrapun, Joseph; Romero, Lina M; Cramer, Scott D; Agarwal, Chapla; Agarwal, Rajesh

2015-09-01

Tumor microenvironment (TM) is an essential element in prostate cancer (PCA), offering unique opportunities for its prevention. TM includes naïve fibroblasts that are recruited by nascent neoplastic lesion and altered into 'cancer-associated fibroblasts' (CAFs) that promote PCA. A better understanding and targeting of interaction between PCA cells and fibroblasts and inhibiting CAF phenotype through non-toxic agents are novel approaches to prevent PCA progression. One well-studied cancer chemopreventive agent is silibinin, and thus, we examined its efficacy against PCA cells-mediated differentiation of naïve fibroblasts into a myofibroblastic-phenotype similar to that found in CAFs. Silibinin's direct inhibitory effect on the phenotype of CAFs derived directly from PCA patients was also assessed. Human prostate stromal cells (PrSCs) exposed to control conditioned media (CCM) from human PCA PC3 cells showed more invasiveness, with increased alpha-smooth muscle actin (α-SMA) and vimentin expression, and differentiation into a phenotype we identified in CAFs. Importantly, silibinin (at physiologically achievable concentrations) inhibited α-SMA expression and invasiveness in differentiated fibroblasts and prostate CAFs directly, as well as indirectly by targeting PCA cells. The observed increase in α-SMA and CAF-like phenotype was transforming growth factor (TGF) β2 dependent, which was strongly inhibited by silibinin. Furthermore, induction of α-SMA and CAF phenotype by CCM were also strongly inhibited by a TGFβ2-neutralizing antibody. The inhibitory effect of silibinin on TGFβ2 expression and CAF-like biomarkers was also observed in PC3 tumors. Together, these findings highlight the potential usefulness of silibinin in PCA prevention through targeting the CAF phenotype in the prostate TM. © 2014 Wiley Periodicals, Inc.

Emergent gamma synchrony in all-to-all interneuronal networks.

PubMed

Ratnadurai-Giridharan, Shivakeshavan; Khargonekar, Pramod P; Talathi, Sachin S

2015-01-01

We investigate the emergence of in-phase synchronization in a heterogeneous network of coupled inhibitory interneurons in the presence of spike timing dependent plasticity (STDP). Using a simple network of two mutually coupled interneurons (2-MCI), we first study the effects of STDP on in-phase synchronization. We demonstrate that, with STDP, the 2-MCI network can evolve to either a state of stable 1:1 in-phase synchronization or exhibit multiple regimes of higher order synchronization states. We show that the emergence of synchronization induces a structural asymmetry in the 2-MCI network such that the synapses onto the high frequency firing neurons are potentiated, while those onto the low frequency firing neurons are de-potentiated, resulting in the directed flow of information from low frequency firing neurons to high frequency firing neurons. Finally, we demonstrate that the principal findings from our analysis of the 2-MCI network contribute to the emergence of robust synchronization in the Wang-Buzsaki network (Wang and Buzsáki, 1996) of all-to-all coupled inhibitory interneurons (100-MCI) for a significantly larger range of heterogeneity in the intrinsic firing rate of the neurons in the network. We conclude that STDP of inhibitory synapses provide a viable mechanism for robust neural synchronization.

Emergent gamma synchrony in all-to-all interneuronal networks

PubMed Central

Ratnadurai-Giridharan, Shivakeshavan; Khargonekar, Pramod P.; Talathi, Sachin S.

2015-01-01

We investigate the emergence of in-phase synchronization in a heterogeneous network of coupled inhibitory interneurons in the presence of spike timing dependent plasticity (STDP). Using a simple network of two mutually coupled interneurons (2-MCI), we first study the effects of STDP on in-phase synchronization. We demonstrate that, with STDP, the 2-MCI network can evolve to either a state of stable 1:1 in-phase synchronization or exhibit multiple regimes of higher order synchronization states. We show that the emergence of synchronization induces a structural asymmetry in the 2-MCI network such that the synapses onto the high frequency firing neurons are potentiated, while those onto the low frequency firing neurons are de-potentiated, resulting in the directed flow of information from low frequency firing neurons to high frequency firing neurons. Finally, we demonstrate that the principal findings from our analysis of the 2-MCI network contribute to the emergence of robust synchronization in the Wang-Buzsaki network (Wang and Buzsáki, 1996) of all-to-all coupled inhibitory interneurons (100-MCI) for a significantly larger range of heterogeneity in the intrinsic firing rate of the neurons in the network. We conclude that STDP of inhibitory synapses provide a viable mechanism for robust neural synchronization. PMID:26528174

Pollen extracts and constituent sugars increase growth of a trypanosomatid parasite of bumble bees

PubMed Central

Thursfield, Lucy

2017-01-01

Phytochemicals produced by plants, including at flowers, function in protection against plant diseases, and have a long history of use against trypanosomatid infection. Floral nectar and pollen, the sole food sources for many species of insect pollinators, contain phytochemicals that have been shown to reduce trypanosomatid infection in bumble and honey bees when fed as isolated compounds. Nectar and pollen, however, consist of phytochemical mixtures, which can have greater antimicrobial activity than do single compounds. This study tested the hypothesis that pollen extracts would inhibit parasite growth. Extracts of six different pollens were tested for direct inhibitory activity against cell cultures of the bumble bee trypanosomatid gut parasite Crithidia bombi. Surprisingly, pollen extracts increased parasite growth rather than inhibiting it. Pollen extracts contained high concentrations of sugars, mainly the monosaccharides glucose and fructose. Experimental manipulations of growth media showed that supplemental monosaccharides (glucose and fructose) increased maximum cell density, while a common floral phytochemical (caffeic acid) with inhibitory activity against other trypanosomatids had only weak inhibitory effects on Crithidia bombi. These results indicate that, although pollen is essential for bees and other pollinators, pollen may promote growth of intestinal parasites that are uninhibited by pollen phytochemicals and, as a result, can benefit from the nutrients that pollen provides. PMID:28503378

Prolyl endopeptidase and thrombin inhibitory diterpenoids from the bark of Xylopia aethiopica.

PubMed

Diderot, Noungoue Tchamo; Silvere, Ngouela; Yasin, Amsha; Zareen, Seema; Fabien, Zelefack; Etienne, Tsamo; Choudhary, M Iqbal; Atta-Ur-Rahman

2005-09-01

The inhibitory effects of seven diterpenes, belonging to three different structural classes and isolated from the bark of Xylopia aethiopica, were investigated against the enzymes prolyl endopeptidase (PEP) and alpha-thrombin. Five compounds exhibited inhibitory activity against them.

Directed Forgetting in Direct and Indirect Tests of Memory: Seeking Evidence of Retrieval Inhibition Using Electrophysiological Measures

ERIC Educational Resources Information Center

Van Hooff, Johanna C.; Whitaker, T. Aisling; Ford, Ruth M.

2009-01-01

We investigated whether directed forgetting as elicited by the item-cueing method results solely from "differential rehearsal" of to-be-remembered vs. to-be-forgotten words or, additionally, from "inhibitory" processes that actively impair retrieval of to-be-forgotten words. During study, participants (N = 24) were instructed to remember half of a…

Inhibitory control and adaptive behaviour in children with mild intellectual disability.

PubMed

Gligorović, M; Buha Ðurović, N

2014-03-01

Inhibitory control, as one of the basic mechanisms of executive functions, is extremely important for adaptive behaviour. The relation between inhibitory control and adaptive behaviour is the most obvious in cases of behavioural disorders and psychopathology. Considering the lack of studies on this relation in children with disabilities, the aim of our research is to determine the relation between inhibitory control and adaptive behaviour in children with mild intellectual disability. The sample consists of 53 children with mild intellectual disability. Selection criteria were: IQ between 50 and 70, age between 10 and 14, absence of bilingualism, and with no medical history of neurological impairment, genetic and/or emotional problems. Modified Day-Night version of the Stroop task, and Go-no-Go Tapping task were used for the assessment of inhibitory control. Data on adaptive behaviour were obtained by applying the first part of AAMR (American Association on Mental Retardation) Adaptive Behaviour Scale-School, Second Edition (ABS-S:2). Significant relationships were determined between some aspects of inhibitory control and the most of assessed domains of adaptive behaviour. Inhibitory control measures, as a unitary inhibition model, significantly predict results on Independent Functioning, Economic Activity, Speech and Language Development, and Number and Times domains of the ABS-S:2. Inhibitory control, assessed by second part of the Stroop task, proved to be a significant factor in practical (Independent Functioning) and conceptual (Economic Activity, Speech and Language Development, and Numbers and Time) adaptive skills. The first part of the Stroop task, as a measure of selective attention, proved to be a significant factor in language and numerical demands, along with second one. Inhibitory control through motor responses proved to be a significant factor in independent functioning, economic activities, language and self-direction skills. We can conclude that inhibitory control represents a significant developmental factor of different adaptive behaviour domains in children with mild intellectual disability. © 2012 The Authors. Journal of Intellectual Disability Research © 2012 John Wiley & Sons Ltd, MENCAP & IASSIDD.

Effects of Vancomycin Versus Nafcillin in Enhancing Killing of Methicillin-Susceptible Staphylococcus aureus Causing Bacteremia by Human Cathelicidin LL37

PubMed Central

Le, Jennifer; Dam, Quang; Schweizer, Marin; Thienphrapa, Wdee; Nizet, Victor; Sakoulas, George

2016-01-01

Recent studies have demonstrated that anti-staphylococcal beta-lactam antibiotics, like nafcillin, render methicillin-resistant Staphylococcus aureus (MRSA) more susceptible to killing by innate host defense peptides (HDPs), such as cathelicidin LL-37. We compared the effects of growth in 1/4 minimum inhibitory concentration (MIC) of nafcillin or vancomycin on LL-37 killing of 92 methicillin-susceptible S. aureus (MSSA) isolates. For three randomly selected strains among these, we examined the effects of nafcillin, vancomycin, daptomycin, or linezolid on LL-37 killing and autolysis. Growth in the presence of sub-inhibitory nafcillin significantly enhanced LL-37 killing of MSSA compared to vancomycin and antibiotic-free controls. Nafcillin also reduced MSSA production of the golden staphylococcal pigment staphyloxanthin in 39% of pigmented strains vs. 14% for vancomycin. Among antibiotics tested, only nafcillin resulted in significantly increased MSSA autolysis. These studies point to additional mechanisms of anti-staphylococcal activity of nafcillin beyond direct bactericidal activity, properties that vancomycin and other antibiotic classes do not exhibit. The ability of nafcillin to enhance sensitivity to innate host defense peptides may contribute to its superior effectiveness against MSSA as suggested by studies comparing clinical outcomes to vancomycin treatment. PMID:27234592

"Happy goat says": The effect of a food selection inhibitory control training game of children's response inhibition on eating behavior.

PubMed

Jiang, Qianxia; He, Dexian; Guan, Wanyi; He, Xianyou

2016-12-01

Recent studies suggest that when inhibitory control is lacking, people are more inclined to indulge in high-calorie food, but inhibitory control can be trained. In this study, a daily-life training game was used to train children and investigate whether strengthening or weakening inhibitory control influences food intake in opposite directions. The baseline of response inhibition was measured by the go/no-go task, and the baseline of food intake was measured by a bogus food taste task. Then, participants performed a food selection training game named "Happy goat says" with three within-subject conditions: the first type of instruction was always paired without a go signal (inhibition manipulation); the second type of instruction was always presented with a go signal (impulsivity manipulation); and the third type of instruction was presented either with a go or no-go signal, both in 50% of the time (control manipulation). Following these manipulations, they went through the go/no-go task and bogus food taste task. In the pre-training food taste task, commission errors were positively correlated with body mass index. Relative to a control group playing Lego blocks (n = 20), the trained group showed a performance improvement on the go/no-go task. The intake of food in the inhibition manipulation was significantly less in the post-training food taste task. These findings demonstrate that children can gain control over the consumption of high-calorie food after a daily-life response inhibition training game. Copyright © 2016 Elsevier Ltd. All rights reserved.

Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion

PubMed Central

Ecker, Christine; Hallahan, Brian; Deeley, Quinton; Craig, Michael; Murphy, Clodagh; Johnston, Patrick; Spain, Debbie; Gillan, Nicola; Gudbrandsen, Maria; Brammer, Michael; Giampietro, Vincent; Lamar, Melissa; Page, Lisa; Toal, Fiona; Schmitz, Nicole; Cleare, Anthony; Robertson, Dene; Rubia, Katya; Murphy, Declan G. M.

2014-01-01

It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely ‘normalizing’ the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target. PMID:25070512

Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion.

PubMed

Daly, Eileen; Ecker, Christine; Hallahan, Brian; Deeley, Quinton; Craig, Michael; Murphy, Clodagh; Johnston, Patrick; Spain, Debbie; Gillan, Nicola; Gudbrandsen, Maria; Brammer, Michael; Giampietro, Vincent; Lamar, Melissa; Page, Lisa; Toal, Fiona; Schmitz, Nicole; Cleare, Anthony; Robertson, Dene; Rubia, Katya; Murphy, Declan G M

2014-09-01

It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

Rational Tuning of Visual Cycle Modulator Pharmacodynamics

PubMed Central

Kiser, Philip D.; Zhang, Jianye; Badiee, Mohsen; Kinoshita, Junzo; Peachey, Neal S.; Tochtrop, Gregory P.

2017-01-01

Modulators of the visual cycle have been developed for treatment of various retinal disorders. These agents were designed to inhibit retinoid isomerase [retinal pigment epithelium-specific 65 kDa protein (RPE65)], the rate-limiting enzyme of the visual cycle, based on the idea that attenuation of visual pigment regeneration could reduce formation of toxic retinal conjugates. Of these agents, certain ones that contain primary amine groups can also reversibly form retinaldehyde Schiff base adducts, which contributes to their retinal protective activity. Direct inhibition of RPE65 as a therapeutic strategy is complicated by adverse effects resulting from slowed chromophore regeneration, whereas effective retinal sequestration can require high drug doses with potential off-target effects. We hypothesized that the RPE65-emixustat crystal structure could help guide the design of retinaldehyde-sequestering agents with varying degrees of RPE65 inhibitory activity. We found that addition of an isopropyl group to the central phenyl ring of emixustat and related compounds resulted in agents effectively lacking in vitro retinoid isomerase inhibitory activity, whereas substitution of the terminal 6-membered ring with branched moieties capable of stronger RPE65 interaction potentiated inhibition. The isopropyl derivative series produced discernible visual cycle suppression in vivo, albeit much less potently than compounds with a high affinity for the RPE65 active site. These agents were distributed into the retina and formed Schiff base adducts with retinaldehyde. Except for one compound [3-amino-1-(3-isopropyl-5-((2,6,6-trimethylcyclohex-1-en-1-yl)methoxy)phenyl)propan-1-ol (MB-007)], these agents conferred protection against retinal phototoxicity, suggesting that both direct RPE65 inhibition and retinal sequestration are mechanisms of potential therapeutic relevance. PMID:28476927

Inhibitory effects of some plant essential oils against Arcobacter butzleri and potential for rosemary oil as a natural food preservative.

PubMed

Irkin, Reyhan; Abay, Secil; Aydin, Fuat

2011-03-01

We investigated the inhibitory activity of commercially marketed essential oils of mint, rosemary, orange, sage, cinnamon, bay, clove, and cumin against Arcobacter butzleri and Arcobacter skirrowii and the effects of the essential oil of rosemary against A. butzleri in a cooked minced beef system. Using the disc diffusion method to determine the inhibitory activities of these plant essential oils against strains of Arcobacter, we found that those of rosemary, bay, cinnamon, and clove had strong inhibitory activity against these organisms, whereas the essential oils of cumin, mint, and sage failed to show inhibitory activity against most of the Arcobacter strains tested. The 0.5% (vol/wt) essential oil of rosemary was completely inhibitory against A. butzleri in the cooked minced beef system at 4°C. These essential oils may be further investigated as a natural solution to the food industry by creating an additional barrier (hurdle technology) to inhibit the growth of Arcobacter strains.

Effects of sales promotions, weight status, and impulsivity on purchases in a supermarket.

PubMed

Nederkoorn, Chantal

2014-05-01

Several environmental factors contribute to increased food consumption and play a role in the prevalence of obesity, like portion size, accessibility and relative price of high caloric foods, food commercials, and sales promotions. However, not everyone seems equally sensitive to these environmental cues and both obesity and impulsivity appears to play a role. In this study, food purchases in an internet supermarket are tested in 118 participants, with or without sales promotions for snack foods. Both weight status and response inhibition, an index of impulsivity, are measured. Participants with less inhibitory control purchased in total more calories from the internet supermarket then participants with more inhibitory control. In addition, sales promotion, weight status, and inhibitory control appeared to interact in their effect on snack food purchases: participants with less inhibitory control and overweight bought more calories of snacks in the sales promotions condition, but not in the control condition. For the other participants, with normal weight and/or high inhibitory control, sales promotions had no effect on their purchases of calories of snacks. It seems that especially the combination of low inhibitory control and overweight makes participants vulnerable for environmental cues. Copyright © 2013 The Obesity Society.

Production of the angiotensin I converting enzyme inhibitory peptides and isolation of four novel peptides from jellyfish (Rhopilema esculentum) protein hydrolysate.

PubMed

Liu, Xin; Zhang, Miansong; Shi, Yaping; Qiao, Ruojin; Tang, Wei; Sun, Zhenliang

2016-07-01

Angiotensin I converting enzyme (ACE) plays an important role in regulating blood pressure in the human body. ACE inhibitory peptides derived from food proteins could exert antihypertensive effects without side effects. Jellyfish (Rhopilema esculentum) is an important fishery resource suitable for production of ACE inhibitory peptides. The objective of this study was to optimize the hydrolysis conditions for production of protein hydrolysate from R. esculentum (RPH) with ACE inhibitory activity, and to isolate and identify the ACE inhibitory peptides from RPH. Rhopilema esculentum protein was hydrolyzed with Compound proteinase AQ to produce protein hydrolysate with ACE inhibitory activity, and the hydrolysis conditions were optimized using response surface methodology. The optimum parameters for producing peptides with the highest ACE inhibitory activity were as follows: hydrolysis time 3.90 h, hydrolysis temperature 58 °C, enzyme:substrate ratio 2.8% and pH 7.60. Under these conditions, the ACE inhibitory rate reached 32.21%. In addition, four novel ACE inhibitory peptides were isolated, and their amino acids sequences were identified as Val-Gly-Pro-Tyr, Phe-Thr-Tyr-Val-Pro-Gly, Phe-Thr-Tyr-Val-Pro-Gly-Ala and Phe-Gln-Ala-Val-Trp-Ala-Gly, respectively. The IC50 value of the purified peptides for ACE inhibitory activity was 8.40, 23.42, 21.15 and 19.11 µmol L(-1) . These results indicate that the protein hydrolysate prepared from R. esculentum might be a commercial competitive source of ACE inhibitory ingredients to be used in functional foods. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

Early adversity, RSA, and inhibitory control: evidence of children's neurobiological sensitivity to social context.

PubMed

Skowron, Elizabeth A; Cipriano-Essel, Elizabeth; Gatzke-Kopp, Lisa M; Teti, Douglas M; Ammerman, Robert T

2014-07-01

This study examined parasympathetic physiology as a moderator of the effects of early adversity (i.e., child abuse and neglect) on children's inhibitory control. Children's respiratory sinus arrhythmia (RSA) was assessed during a resting baseline, two joint challenge tasks with mother, and an individual frustration task. RSA assessed during each of the joint parent-child challenge tasks moderated the effects of child maltreatment (CM) status on children's independently-assessed inhibitory control. No moderation effect was found for RSA assessed at baseline or in the child-alone challenge task. Among CM-exposed children, lower RSA levels during the joint task predicted the lowest inhibitory control, whereas higher joint task RSA was linked to higher inhibitory control scores that were indistinguishable from those of non-CM children. Results are discussed with regard to the importance of considering context specificity (i.e., individual and caregiver contexts) in how biomarkers inform our understanding of individual differences in vulnerability among at-risk children. © 2013 Wiley Periodicals, Inc.

Early Adversity, RSA, and Inhibitory Control: Evidence of Children’s Neurobiological Sensitivity to Social Context

PubMed Central

Skowron, Elizabeth A.; Cipriano-Essel, Elizabeth; Gatzke-Kopp, Lisa M.; Teti, Douglas M.; Ammerman, Robert T.

2014-01-01

This study examined parasympathetic physiology as a moderator of the effects of early adversity (i.e., child abuse and neglect) on children’s inhibitory control. Children’s respiratory sinus arrhythmia (RSA) was assessed during a resting baseline, two joint challenge tasks with mother, and an individual frustration task. RSA assessed during each of the joint parent–child challenge tasks moderated the effects of child maltreatment (CM) status on children’s independently-assessed inhibitory control. No moderation effect was found for RSA assessed at baseline or in the child-alone challenge task. Among CM-exposed children, lower RSA levels during the joint task predicted the lowest inhibitory control, whereas higher joint task RSA was linked to higher inhibitory control scores that were indistinguishable from those of non-CM children. Results are discussed with regard to the importance of considering context specificity (i.e., individual and caregiver contexts) in how biomarkers inform our understanding of individual differences in vulnerability among at-risk children. PMID:24142832

Fraction from human and rat liver which is inhibitory for proliferation of liver cells.

PubMed

Chen, T S; Ottenweller, J; Luke, A; Santos, S; Keeting, P; Cuy, R; Lea, M A

1989-01-01

A comparative study was undertaken with human and rat liver of a fraction reported to have growth inhibitory activity when prepared from rat liver. Fractions which were soluble in 70% ethanol and insoluble in 87% ethanol were prepared from liver cytosols. Electrophoretic analysis under denaturing conditions indicated that there were several quantitative or qualitative differences in the fractions from the two species. Fractions from both human and rat liver were found to be inhibitory for the incorporation of 3H-thymidine into DNA of foetal chick hepatocytes. Under conditions in which the rat fraction inhibited precursor incorporation into DNA of rat liver epithelial cells there was not a significant inhibitory effect with the fraction from human liver. DNA synthesis in a rat hepatoma cell line was not significantly inhibited by preparations from either species. The data suggested that corresponding fractions from both rat and human liver could have inhibitory effects on precursor incorporation into DNA but the magnitude of the effects and target cell specificity may differ.

Broad-Spectrum Inhibition of HIV-1 by a Monoclonal Antibody Directed against a gp120-Induced Epitope of CD4

PubMed Central

Burastero, Samuele E.; Frigerio, Barbara; Lopalco, Lucia; Sironi, Francesca; Breda, Daniela; Longhi, Renato; Scarlatti, Gabriella; Canevari, Silvana; Figini, Mariangela; Lusso, Paolo

2011-01-01

To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1. PMID:21818294

Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.

PubMed

Burastero, Samuele E; Frigerio, Barbara; Lopalco, Lucia; Sironi, Francesca; Breda, Daniela; Longhi, Renato; Scarlatti, Gabriella; Canevari, Silvana; Figini, Mariangela; Lusso, Paolo

2011-01-01

To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.

False responses of Renilla luciferase reporter control to nuclear receptor TR4.

PubMed

Zhang, Dongyun; Atlasi, Sam S; Patel, Krishna K; Zhuang, Zihao; Heaney, Anthony P

2017-06-01

Renilla luciferase reporter is a widely used internal control in dual luciferase reporter assay system, where its transcription is driven by a constitutively active promoter. However, the authenticity of the Renilla luciferase response in some experimental settings has recently been questioned. Testicular receptor 4 (TR4, also known as NR2C2) belongs to the subfamily 2 of nuclear receptors. TR4 binds to a direct repeat regulatory element in the promoter of a variety of target genes and plays a key role in tumorigenesis, lipoprotein regulation, and central nervous system development. In our experimental system using murine pituitary corticotroph tumor AtT20 cells to investigate TR4 actions on POMC transcription, we found that overexpression of TR4 resulted in reduced Renilla luciferase expression whereas knockdown TR4 increased Renilla luciferase expression. The TR4 inhibitory effect was mediated by the TR4 DNA-binding domain and behaved similarly to the GR and its agonist, Dexamethasone. We further demonstrated that the chimeric intron, commonly present in various Renilla plasmid backbones such as pRL-Null, pRL-SV40, and pRL-TK, was responsible for TR4's inhibitory effect. The results suggest that an intron-free Renilla luciferase reporter may provide a satisfactory internal control for TR4 at certain dose range. Our findings advocate caution on the use of Renilla luciferase as an internal control in TR4-directed studies to avoid misleading data interpretation.

Enzyme inhibitory and radical scavenging effects of some antidiabetic plants of Turkey.

PubMed

Orhan, Nilüfer; Hoçbaç, Sanem; Orhan, Didem Deliorman; Asian, Mustafa; Ergun, Fatma

2014-06-01

Ethnopharmacological field surveys demonstrated that many plants, such as Gentiana olivieri, Helichrysum graveolens, Helichrysum plicatum ssp. plicatum, Juniperus oxycedrus ssp. oxycedrus, Juniperus communis var. saxatilis, Viscum album (ssp. album, ssp. austriacum), are used as traditional medicine for diabetes in different regions of Anatolia. The present study was designed to evaluate the in vitro antidiabetic effects of some selected plants, tested in animal models recently. α-glucosidase and α-amylase enzyme inhibitory effects of the plant extracts were investigated and Acarbose was used as a reference drug. Additionally, radical scavenging capacities were determined using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) ABTS radical cation scavenging assay and total phenolic content of the extracts were evaluated using Folin Ciocalteu method. H. graveolens ethanol extract exhibited the highest inhibitory activity (55.7 % ± 2.2) on α-amylase enzyme. Additionally, J. oxycedrus hydro-alcoholic leaf extract had potent α-amylase inhibitory effect, while the hydro-alcoholic extract of J. communis fruit showed the highest α-glucosidase inhibitory activity (IC50: 4.4 μg/ml). Results indicated that, antidiabetic effect of hydro-alcoholic extracts of H. graveolens capitulums, J. communis fruit and J. oxycedrus leaf might arise from inhibition of digestive enzymes.

Inhibition of Aspergillus niger and Aspergillus flavus by some herbs and spices.

PubMed

Yin, M C; Cheng, W S

1998-01-01

The inhibitory effect of water-soluble extracts of garlic bulbs, green garlic, green onions, hot peppers, ginger, Chinese parsley, and basil on the growth of Aspergillus niger and Aspergillus flavus was examined. Garlic bulbs, green garlic, and green onions showed an inhibitory effect against these two fungi. The influence of heat, acid, and salt upon the inhibitory effect of these three herbs was further studied. Increasing the temperature from 60 to 100 degrees C resulted in a significant (P < 0.05) decrease in the inhibitory effect of garlic bulbs against the fungi tested. Green garlic and green onion lost their antifungal activity against A. niger after being treated at 80 and 60 degrees, respectively. For A. flavus, the inhibitory effect of green garlic declined significantly (P < 0.05) with an increase in temperature. However, the antifungal activity of green onions against A. flavus was heat stable. For both fungi tested in this study, the antifungal activity of these spice plants was not affected by acid treatments at pH values 2, 4, or 6, or salt by treatments at concentrations of 0.1, 0.2, 0.3, and 0.4 M (P > 0.05).

Control of Excitation/Inhibition Balance in a Hippocampal Circuit by Calcium Sensor Protein Regulation of Presynaptic Calcium Channels.

PubMed

Nanou, Evanthia; Lee, Amy; Catterall, William A

2018-05-02

Activity-dependent regulation controls the balance of synaptic excitation to inhibition in neural circuits, and disruption of this regulation impairs learning and memory and causes many neurological disorders. The molecular mechanisms underlying short-term synaptic plasticity are incompletely understood, and their role in inhibitory synapses remains uncertain. Here we show that regulation of voltage-gated calcium (Ca 2+ ) channel type 2.1 (Ca V 2.1) by neuronal Ca 2+ sensor (CaS) proteins controls synaptic plasticity and excitation/inhibition balance in a hippocampal circuit. Prevention of CaS protein regulation by introducing the IM-AA mutation in Ca V 2.1 channels in male and female mice impairs short-term synaptic facilitation at excitatory synapses of CA3 pyramidal neurons onto parvalbumin (PV)-expressing basket cells. In sharp contrast, the IM-AA mutation abolishes rapid synaptic depression in the inhibitory synapses of PV basket cells onto CA1 pyramidal neurons. These results show that CaS protein regulation of facilitation and inactivation of Ca V 2.1 channels controls the direction of short-term plasticity at these two synapses. Deletion of the CaS protein CaBP1/caldendrin also blocks rapid depression at PV-CA1 synapses, implicating its upregulation of inactivation of Ca V 2.1 channels in control of short-term synaptic plasticity at this inhibitory synapse. Studies of local-circuit function revealed reduced inhibition of CA1 pyramidal neurons by the disynaptic pathway from CA3 pyramidal cells via PV basket cells and greatly increased excitation/inhibition ratio of the direct excitatory input versus indirect inhibitory input from CA3 pyramidal neurons to CA1 pyramidal neurons. This striking defect in local-circuit function may contribute to the dramatic impairment of spatial learning and memory in IM-AA mice. SIGNIFICANCE STATEMENT Many forms of short-term synaptic plasticity in neuronal circuits rely on regulation of presynaptic voltage-gated Ca 2+ (Ca V ) channels. Regulation of Ca V 2.1 channels by neuronal calcium sensor (CaS) proteins controls short-term synaptic plasticity. Here we demonstrate a direct link between regulation of Ca V 2.1 channels and short-term synaptic plasticity in native hippocampal excitatory and inhibitory synapses. We also identify CaBP1/caldendrin as the calcium sensor interacting with Ca V 2.1 channels to mediate rapid synaptic depression in the inhibitory hippocampal synapses of parvalbumin-expressing basket cells to CA1 pyramidal cells. Disruption of this regulation causes altered short-term plasticity and impaired balance of hippocampal excitatory to inhibitory circuits. Copyright © 2018 the authors 0270-6474/18/384430-11$15.00/0.

Inhibitory effects of magnolol on voltage-gated Na+ and K+ channels of NG108-15 cells.

PubMed

Gong, Chi-Li; Wong, Kar-Lok; Cheng, Ka-Shun; Kuo, Chang-Shin; Chao, Chia-Chia; Tsai, Min-Fan; Leung, Yuk-Man

2012-05-05

Magnolol, a polyphenolic compound isolated from Houpu, a Chinese herb from the bark of Magnolia officinalis, has been reported to have in vitro and in vivo neuroprotective effects. In spite of these reported beneficial effects, studies on the direct impact of magnolol on neuronal ion channels have been scarce. Whether magnolol affects voltage-gated Na(+) channels (VGSC) and voltage-gated K(+) (Kv) channels is unknown. Using the whole-cell voltage-clamp method, we studied the effects of magnolol on voltage-gated ion channels in neuronal NG108-15 cells. Magnolol inhibited VGSC channels with mild state-dependence (IC(50) of 15 and 30 μM, at holding potentials of -70 and -100 mV, respectively). No frequency-dependence was observed in magnolol block. Magnolol caused a left-shift of 18 mV in the steady-state inactivation curve but did not affect the voltage-dependence of activation. Magnolol inhibited Kv channels with an IC(50) of 21 μM, and it caused a 20-mV left-shift in the steady-state inactivation curve without affecting the voltage-dependence of activation. In conclusion, magnolol is an inhibitor of both VGSC and Kv channels and these inhibitory effects may in part contribute to some of the reported neuroprotective effects of magnolol. Copyright © 2012 Elsevier B.V. All rights reserved.

Cannabinoid WIN 55,212-2 inhibits TRPV1 in trigeminal ganglion neurons via PKA and PKC pathways.

PubMed

Wang, Wei; Cao, Xuehong; Liu, Changjin; Liu, Lieju

2012-02-01

Although the inhibitory effect of cannabinoids on transient receptor potential vanilloid 1 (TRPV1) channel may explain the efficacy of peripheral cannabinoids in antihyperalgesia and antinociceptive actions, the mechanism for cannabinoid-induced inhibition of TRPV1 in primary sensory neurons is not understood. Therefore, we explored how WIN55,212-2 (WIN, a synthetic cannabinoid) inhibited TRPV1 in rat trigeminal ganglion neurons. A "bell"-shaped concentration-dependent curve was obtained from the effects of WIN on TRPV1 channel. The maximal inhibition on capsaicin-induced current (I (cap)) by WIN was at a concentration of 10(-9) M, and at this concentration I (cap) was reduced by 95 ± 1.6%. When the concentration of WIN was at 10(-6) M, it displayed a stimulatory effect on I (cap). In this study, several intracellular signaling transduction pathways were tested to study whether they were involved in the inhibitory effects of WIN on I (cap). We found that the inhibitory effect of WIN on I (cap) was completely reversed by PKA antagonists H-89 and KT5720 as well as by PKC antagonists BIM and staurosporine. It was also found that the inhibitory effect was partly reversed by PKG antagonist PKGi, while G-protein antagonist GDP-βs/pertussis toxin (PTX) and PLC antagonist U-73122 had no effect on the inhibitory effect of WIN on I(cap). These results suggest that several intracellular signaling transduction pathways including PKA and PKC systems underlie the inhibitory effects of WIN on I (cap); however, G protein-coupled receptors CB1 or CB2 were not involved.

Bovine κ-casein inhibits human rotavirus (HRV) infection via direct binding of glycans to HRV.

PubMed

Inagaki, M; Muranishi, H; Yamada, K; Kakehi, K; Uchida, K; Suzuki, T; Yabe, T; Nakagomi, T; Nakagomi, O; Kanamaru, Y

2014-05-01

Human rotavirus (HRV) is a major etiologic agent of severe infantile gastroenteritis. κ-Casein (κ-CN) from both human and bovine mature milk has been reported to have anti-HRV activity; however, the mechanism of this activity is poorly understood. The present study examined the molecular basis for the protective effect of bovine κ-CN derived from late colostrum (6-7 d after parturition) and from mature milk. Among the components of casein, κ-CN is the only glycosylated protein that has been identified. Therefore, we investigated whether the glycan residues in κ-CN were involved in the anti-HRV activity. Desialylated CN obtained by neuraminidase treatment exhibited anti-HRV activity, whereas deglycosylated CN obtained by o-glycosidase treatment lacked antiviral activity, indicating that glycans were responsible for the antiviral activity of CN. Furthermore, an evanescent-field fluorescence-assisted assay showed that HRV particles directly bound to heated casein (at 95°C for 30 min) in a viral titer-dependent manner. Although the heated κ-CN retained inhibitory activity in a neutralization assay, the activity was weaker than that observed before heat treatment. Our findings indicate that the inhibitory mechanism of bovine κ-CN against HRV involves direct binding to viral particles via glycan residues. In addition, heat-labile structures in κ-CN may play an important role in maintenance of κ-CN binding to HRV. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Harmane inhibits serotonergic dorsal raphe neurons in the rat.

PubMed

Touiki, Khalid; Rat, Pascal; Molimard, Robert; Chait, Abderrahman; de Beaurepaire, Renaud

2005-11-01

Harmane and norharmane (two beta-carbolines) are tobacco components or products. The effects of harmane and norharmane on serotonergic raphe neurons remain unknown. Harmane and norharmane are inhibitors of the monoamine oxidases A (MAO-A) and B (MAO-B), respectively. To study the effects of harmane, norharmane, befloxatone (MAOI-A), and selegiline (MAOI-B) on the firing of serotonergic neurons. To compare the effects of these compounds to those of nicotine (whose inhibitory action on serotonergic neurons has been previously described). The effects of cotinine, a metabolite of nicotine known to interact with serotonergic systems, are also tested. In vivo electrophysiological recordings of serotonergic dorsal raphe neurons in the anaesthetized rat. Nicotine, harmane, and befloxatone inhibited serotonergic dorsal raphe neurons. The other compounds had no effects. The inhibitory effect of harmane (rapid and long-lasting inhibition) differed from that of nicotine (short and rapidly reversed inhibition) and from that of befloxatone (slow, progressive, and long-lasting inhibition). The inhibitory effects of harmane and befloxatone were reversed by the 5-HT1A antagonist WAY 100 635. Pretreatment of animals with p-chlorophenylalanine abolished the inhibitory effect of befloxatone, but not that of harmane. Nicotine, harmane, and befloxatone inhibit the activity of raphe serotonergic neurons. Therefore, at least two tobacco compounds, nicotine and harmane, inhibit the activity of serotonergic neurons. The mechanism by which harmane inhibits serotonergic dorsal raphe neurons is likely unrelated to a MAO-A inhibitory effect.

In vitro antagonistic growth effects of Lactobacillus fermentum and lactobacillus salivarius and their fermentative broth on periodontal pathogens.

PubMed

Chen, Ling-Ju; Tsai, Hsiu-Ting; Chen, Wei-Jen; Hsieh, Chu-Yang; Wang, Pi-Chieh; Chen, Chung-Shih; Wang, Lina; Yang, Chi-Chiang

2012-10-01

As lactobacilli possess an antagonistic growth property, these bacteria may be beneficial as bioprotective agents for infection control. However, whether the antagonistic growth effects are attributed to the lactobacilli themselves or their fermentative broth remains unclear. The antagonistic growth effects of Lactobacillus salivarius and Lactobacillus fermentum as well as their fermentative broth were thus tested using both disc agar diffusion test and broth dilution method, and their effects on periodontal pathogens, including Streptococcus mutans, Streptococcus sanguis, and Porphyromonas gingivalis in vitro at different concentrations and for different time periods were also compared. Both Lactobacillus salivarius and Lactobacillus fermentum and their concentrated fermentative broth were shown to inhibit significantly the growth of Streptococcus mutans, Streptococcus sanguis, and Porphyromonas gingivalis, although different inhibitory effects were observed for different pathogens. The higher the counts of lactobacilli and the higher the folds of concentrated fermentative broth, the stronger the inhibitory effects are observed. The inhibitory effect is demonstrated to be dose-dependent. Moreover, for the lactobacilli themselves, Lactobacillus fermentum showed stronger inhibitory effects than Lactobacillus salivarius. However, the fermentative broth of Lactobacillus fermentum showed weaker inhibitory effects than that of Lactobacillus salivarius. These data suggested that lactobacilli and their fermentative broth exhibit antagonistic growth activity, and consumption of probiotics or their broth containing lactobacilli may benefit oral health.

Does inhibitory control training improve health behaviour? A meta-analysis.

PubMed

Allom, Vanessa; Mullan, Barbara; Hagger, Martin

2016-06-01

Inhibitory control training has been hypothesised as a technique that will improve an individual's ability to overrule impulsive reactions in order to regulate behaviour consistent with long-term goals. A meta-analysis of 19 studies of inhibitory control training and health behaviours was conducted to determine the effect of inhibitory control training on reducing harmful behaviours. Theoretically driven moderation analyses were also conducted to determine whether extraneous variables account for heterogeneity in the effect; in order to facilitate the development of effective intervention strategies. Moderators included type of training task, behaviour targeted, measurement of behaviour and training duration. A small but homogeneous effect of training on behaviour was found, d(+)  = 0.378, CI95 = [0.258, 0.498]. Moderation analyses revealed that the training paradigm adopted, and measurement type influenced the size of the effect such that larger effects were found for studies that employed go/no-go (GNG) training paradigms rather than stop-signal task paradigms, and objective outcome measures that were administered immediately yielded the largest and most consistent effects on behaviour. Results suggest that GNG inhibitory control training paradigms can influence health behaviour, but perhaps only in the short-term. Future research is required to systematically examine the influence of training duration, and the longevity of the training effect. Determining these factors could provide the basis for cost-effective and efficacious health-promoting interventions.

Which Approach Is More Effective in the Selection of Plants with Antimicrobial Activity?

PubMed Central

Silva, Ana Carolina Oliveira; Santana, Elidiane Fonseca; Saraiva, Antonio Marcos; Coutinho, Felipe Neves; Castro, Ricardo Henrique Acre; Pisciottano, Maria Nelly Caetano; Amorim, Elba Lúcia Cavalcanti; Albuquerque, Ulysses Paulino

2013-01-01

The development of the present study was based on selections using random, direct ethnopharmacological, and indirect ethnopharmacological approaches, aiming to evaluate which method is the best for bioprospecting new antimicrobial plant drugs. A crude extract of 53 species of herbaceous plants collected in the semiarid region of Northeast Brazil was tested against 11 microorganisms. Well-agar diffusion and minimum inhibitory concentration (MIC) techniques were used. Ten extracts from direct, six from random, and three from indirect ethnopharmacological selections exhibited activities that ranged from weak to very active against the organisms tested. The strain most susceptible to the evaluated extracts was Staphylococcus aureus. The MIC analysis revealed the best result for the direct ethnopharmacological approach, considering that some species yielded extracts classified as active or moderately active (MICs between 250 and 1000 µg/mL). Furthermore, one species from this approach inhibited the growth of the three Candida strains. Thus, it was concluded that the direct ethnopharmacological approach is the most effective when selecting species for bioprospecting new plant drugs with antimicrobial activities. PMID:23878595

Dynamical responses to external stimuli for both cases of excitatory and inhibitory synchronization in a complex neuronal network.

PubMed

Kim, Sang-Yoon; Lim, Woochang

2017-10-01

For studying how dynamical responses to external stimuli depend on the synaptic-coupling type, we consider two types of excitatory and inhibitory synchronization (i.e., synchronization via synaptic excitation and inhibition) in complex small-world networks of excitatory regular spiking (RS) pyramidal neurons and inhibitory fast spiking (FS) interneurons. For both cases of excitatory and inhibitory synchronization, effects of synaptic couplings on dynamical responses to external time-periodic stimuli S ( t ) (applied to a fraction of neurons) are investigated by varying the driving amplitude A of S ( t ). Stimulated neurons are phase-locked to external stimuli for both cases of excitatory and inhibitory couplings. On the other hand, the stimulation effect on non-stimulated neurons depends on the type of synaptic coupling. The external stimulus S ( t ) makes a constructive effect on excitatory non-stimulated RS neurons (i.e., it causes external phase lockings in the non-stimulated sub-population), while S ( t ) makes a destructive effect on inhibitory non-stimulated FS interneurons (i.e., it breaks up original inhibitory synchronization in the non-stimulated sub-population). As results of these different effects of S ( t ), the type and degree of dynamical response (e.g., synchronization enhancement or suppression), characterized by the dynamical response factor [Formula: see text] (given by the ratio of synchronization degree in the presence and absence of stimulus), are found to vary in a distinctly different way, depending on the synaptic-coupling type. Furthermore, we also measure the matching degree between the dynamics of the two sub-populations of stimulated and non-stimulated neurons in terms of a "cross-correlation" measure [Formula: see text]. With increasing A , based on [Formula: see text], we discuss the cross-correlations between the two sub-populations, affecting the dynamical responses to S ( t ).

ANS acuity and mathematics ability in preschoolers from low-income homes: contributions of inhibitory control.

PubMed

Fuhs, Mary Wagner; McNeil, Nicole M

2013-01-01

Recent findings by Libertus, Feigenson, and Halberda (2011) suggest that there is an association between the acuity of young children's approximate number system (ANS) and their mathematics ability before exposure to instruction in formal schooling. The present study examined the generalizability and validity of these findings in a sample of preschoolers from low-income homes. Children attending Head Start (N = 103) completed measures to assess ANS acuity, mathematics ability, receptive vocabulary, and inhibitory control. Results showed only a weak association between ANS acuity and mathematics ability that was reduced to non-significance when controlling for a direct measure of receptive vocabulary. Results also revealed that inhibitory control plays an important role in the relation between ANS acuity and mathematics ability. Specifically, ANS acuity accounted for significant variance in mathematics ability over and above receptive vocabulary, but only for ANS acuity trials in which surface area conflicted with numerosity. Moreover, this association became non-significant when controlling for inhibitory control. These results suggest that early mathematical experiences prior to formal schooling may influence the strength of the association between ANS acuity and mathematics ability and that inhibitory control may drive that association in young children. © 2012 Blackwell Publishing Ltd.

Inhibitory effects of Citrus hassaku extract and its flavanone glycosides on melanogenesis.

PubMed

Itoh, Kimihisa; Hirata, Noriko; Masuda, Megumi; Naruto, Shunsuke; Murata, Kazuya; Wakabayashi, Keitaro; Matsuda, Hideaki

2009-03-01

The 50% ethanolic extract (CH-ext) obtained from the unripe fruit of Citrus hassaku exhibited significant tyrosinase inhibitory activity. The CH-ext showed antioxidant activity, such as superoxide dismutase (SOD)-like activity and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity. Activity-guided fractionation of the CH-ext indicated that flavanone glycoside-rich fractions showed potent tyrosinase inhibitory activity. Further examination revealed that the tyrosinase inhibitory activity and antioxidant activity of the CH-ext were attributable to naringin and neohesperidin, respectively. The CH-ext showed inhibition of melanogenesis without any effects on cell proliferation in cultured murine B16 melanoma cells after glucosamine exposure. The topical application of the CH-ext to the dorsal skin of brownish guinea pigs showed in vivo preventive effects against UVB-induced pigmentation.

Cholinesterase inhibitors from the roots of Harpagophytum procumbens.

PubMed

Bae, Yoon Ho; Cuong, To Dao; Hung, Tran Manh; Kim, Jeong Ah; Woo, Mi Hee; Byeon, Jeong Su; Choi, Jae Sue; Min, Byung Sun

2014-01-01

Inhibition of cholinesterase has been proposed to be a therapeutic target for the treatment of Alzheimer's diseases. In our preliminary screening study on the acetylcholinesterase (AChE) inhibitory activity, an ethyl acetate soluble fraction of the roots of Harpagophytum procumbens (Pedaliaceae) was found to inhibit AChE activity at the concentration of 100 μg/mL. Ten compounds (1-10) were isolated from the active fraction and evaluated for their inhibitory effect on AChE and butyrylcholinesterase (BChE). Among the isolates, verbascosides (5, 6, and 8) containing a caffeoyl and a 3,4-dihydroxyphenethyl groups in their structures, showed effective AChE inhibitory activity and also possessed BChE inhibitory activity. The findings suggest that verbascoside derivatives may be partially related to the anti-Alzheimer effect of this medicinal plant.

Porritoxins, metabolites of Alternaria porri, as anti-tumor-promoting active compounds.

PubMed

Horiuchi, Masayuki; Tokuda, Harukuni; Ohnishi, Keiichiro; Yamashita, Masakazu; Nishino, Hoyoku; Maoka, Takashi

2006-02-01

To search for possible cancer chemopreventive agents from natural sources, we performed primary screening of metabolites of Alternaria porri by examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The ethyl acetate extract of A. porri showed the inhibitory effect on EBV-EA activation. Three porritoxins (1-3) were obtained as inhibitory active compounds for EBV-EA from ethyl acetate extract. 6-(3',3'-Dimethylallyloxy)-4-methoxy-5-methylphthalide (2) showed the strongest activity among them. Inhibitory effect of porritoxin (1) and (2) was superior to that of beta-carotene, a well-known anti-tumor promoter. Furthermore, the structure-activity correlation of porritoxins and their related compounds were discussed.

Commercial valerian interactions with [3H]Flunitrazepam and [3H]MK-801 binding to rat synaptic membranes.

PubMed

Ortiz, José G; Rassi, Nicole; Maldonado, Patricia M; González-Cabrera, Silvia; Ramos, Igmeris

2006-09-01

Valeriana officinalis extracts are used in folkloric medicine for their sedative, hypnotic and tranquilizer effects. Using [3H]flunitrazepam binding as an indicator, the interactions of commercial Valerian extracts with GABA(A) receptors were examined. There was considerable fluctuation among the different extracts, some mildly enhanced [3H]flunitrazepam binding, others had no effect and others had inhibitory effects, independent of standardization by valerenic acid. Central depression can also be accomplished by a reduction of excitatory transmission. Valerian extracts had modest inhibitory effects on [3H]MK-801 binding, an indicator of NMDA-Valerian interactions. Spectral analyses (UV region) did not show marked differences among the different extracts. The inhibitory effects of one of the extracts on [3H]flunitrazepam binding was somewhat stable, while on [3H]MK-801 binding the inhibitory effects were lost within months. These results suggest that particular care should be taken in analysing and interpreting results from commercial Valerian preparations. Copyright (c) 2006 John Wiley & Sons, Ltd.

Development and evaluation of a simple and effective RT-qPCR inhibitory assay for detection of the efficacy of compounds towards HIV reverse transcriptase.

PubMed

Marino-Merlo, Francesca; Frezza, Caterina; Papaianni, Emanuela; Valletta, Elena; Mastino, Antonio; Macchi, Beatrice

2017-11-01

Assessing the actual efficacy of compounds to directly inhibit HIV reverse transcriptase (RT) activity is a main goal in preclinical antiretroviral studies. Our previous studies demonstrated that the effects of inhibitor compounds towards HIV-RT could be efficiently assessed through a simple cell-free assay based on conventional reverse transcription PCR. In the present study, we describe a modified variant of our assay, termed RT real-time quantitative PCR inhibitory assay (RT-qPCR-IA), in which the ability of compounds to restrict the complementary DNA (cDNA) generation by HIV-RT using a specific RNA template is performed by the real-time technique, in order to improve both accuracy and sensitivity of the method. As specific RNA template, RNA extracted from stable transfectants ectopically expressing the herpes simplex virus 1 glycoprotein D gene was utilized. HIV-RT, of both commercial or house-made viral lysate origin, was employed for the assay. To assess the reliability of RT-qPCR-IA, we performed a comparative, quantitative analysis of the dose-dependent effect exerted by known nucleotide and non-nucleotide reverse-transcriptase inhibitors, using the SYBR Green dye chemistry as detection system. The results obtained with RT-qPCR-IA were compared to that obtained using a one-step PicoGreen technology-based commercial kit. The outcome of our study indicates that the development of the novel RT-qPCR-IA will provide rapid and accurate evaluation of the inhibitory efficacy of compounds towards HIV-RT activity. This evaluation could be very useful for large-scale screening of potential new anti-HIV drugs.

Design, synthesis, and antimelanogenic effects of (2-substituted phenyl-1,3-dithiolan-4-yl)methanol derivatives

PubMed Central

Kim, Do Hyun; Kim, Su Jeong; Ullah, Sultan; Yun, Hwi Young; Chun, Pusoon; Moon, Hyung Ryong

2017-01-01

The authors designed and synthesized 17 (2-substituted phenyl-1,3-dithiolan-4-yl) methanol (PDTM) derivatives to find a new chemical scaffold, showing excellent tyrosinase-inhibitory activity. Their tyrosinase-inhibitory activities were evaluated against mushroom tyrosinase at 50 μM, and five of the PDTM derivatives (PDTM3, PDTM7–PDTM9, and PDTM13) were found to inhibit mushroom tyrosinase more than kojic acid or arbutin, the positive controls. Of seventeen PDTMs, PDTM3 (half-maximal inhibitory concentration 13.94±1.76 μM), with a 2,4-dihydroxyphenyl moiety, exhibited greatest inhibitory effects (kojic acid half-maximal inhibitory concentration 18.86±2.14 μM). Interestingly, PDTM compounds with no hydroxyl group, PDTM7–PDTM9, also had stronger inhibitory activities than kojic acid. In silico studies of interactions between tyrosinase and the five PDTMs suggested their binding affinities were closely related to their tyrosinase-inhibitory activities. Cell-based experiments performed using B16F10 mouse-skin melanoma cells showed that PDTM3 effectively inhibited melanogenesis and cellular tyrosinase activity. A cell-viability study conducted using B16F10 cells indicated that the antimelanogenic effect of PDTM3 was not attributable to its cytotoxicity. Kinetic studies showed PDTM3 competitively inhibited tyrosinase, indicating binding to the tyrosinase-active site. We found that PDTM3 with a new chemical scaffold could be a promising candidate for skin-whitening agents, and that the 1,3-dithiolane ring could be used as a chemical scaffold for potent tyrosinase inhibition. PMID:28352157

The Antifungal Inhibitory Concentration Effectiveness Test From Ethanol Seed Arabica Coffee (Coffea arabica) Extract Against The Growth Of Candida albicans Patient Isolate With In Vitro Method

NASA Astrophysics Data System (ADS)

Satria Rakatama, Adam; Pramono, Andri; Yulianti, Retno

2018-03-01

Candida albicans are the most frequent cause of Vulvovaginalis Candidiasis infection. Its treatment using antifungal drugs, are oftenly caused side effects. The reduction of C.albicans growth and the reduction of antifungal drugs side effect, were our main purposed. Our study objective is determine the effectiveness of inhibitory power of arabica coffee seed ethanol extract on the growth of C.albicans patient isolates. The type of this research is experimental research. Kirby-bauer method with the Saboraud Dextrose Agar (SDA) media was used in this experiment. Inhibitory zone was observed around the disc, to determine the inhibitory power. The results showed that the inhibitory zone was formed on arabica coffee seed ethanol extract on 10%, 20%, 40%, and 80% concentration. Kruskal-Wallis test results (p<0,05) showed that there was a significant difference in mean between the concentration groups tested against the treatment group. The inhibitory zone was formed because of biochemical compound in arabica coffee seed such as caffeine, phenol, alkaloids, flavonoids, and saponins. Inhibitory zone in C.albicans patient isolates were smaller compared with C.albicans ATCC 90028 as gold standard. This showed that the virulence of C.albicans from patients isolates were higher. We concluded that arabica coffee seed ethanol extract could inhibiting the growth of C.albicans patient isolates. Optimization of coffee seed ethanol extract to obtain maximum active ingredients still needs to be done. This knowledge is expected to be used for the beginning manufacturer antifungal drug from natural product.

Multilingual Stroop Performance: Effects of Trilingualism and Proficiency on Inhibitory Control

ERIC Educational Resources Information Center

Marian, Viorica; Blumenfeld, Henrike K.; Mizrahi, Elena; Kania, Ursula; Cordes, Anne-Kristin

2013-01-01

Previous research suggests that multilinguals' languages are constantly co-activated and that experience managing this co-activation changes inhibitory control function. The present study examined language interaction and inhibitory control using a colour-word Stroop task. Multilingual participants were tested in their three most proficient…

Suppression of human macrophage function in vitro by delta 9-tetrahydrocannabinol.

PubMed

Specter, S; Lancz, G; Goodfellow, D

1991-11-01

The ability of macrophages to function in the presence of delta 9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, was evaluated. THC added to macrophage cultures prepared from human peripheral blood inhibited macrophage spreading and phagocytosis of yeast. The effects of THC were concentration dependent, with inhibitory effects observed from 10 to 1 micrograms/ml or lower. These results suggest that macrophages are more sensitive to THC than are lymphocytes because macrophage functions were inhibited by THC at concentrations that did not affect lymphocyte function. Thus, inhibition of lymphocyte function(s) by THC could be attributed to a direct effect of the drug on macrophages which indirectly results in lowered lymphoid cell activity.

Flavor Enhancer From Catfish (Clarias batrachus) Bekasam Powder and Angiotensin-I-Converting Enzyme (ACE) Inhibitory Activity in Various Dishes

NASA Astrophysics Data System (ADS)

Lestari, Yanesti N.; Murwani, Retno; Agustini, Tri W.

2018-02-01

Flavor enhancer is characterized by high glutamic acid content and it can be obtained from fermented food such as Bekasam. Fermented food had inhibitory effect on Angiotensin-I-Converting Enzyme (ACE) activity which is advantageous for hypertension. However, such activity was not known to sustain in food system. The aim of this research was to study addition of flavour enhancer from Catfish Bekasam Powder (CBP) in various food systems and to determine the ACE inhibitory (ACEI) activity in the food system. Four food system consisted of carrot, champignon, and chicken meat dishes were boiled in water and added with CBP or MSG. Each food system was added with graded level of CBP (0%; 0.5%; 0.8%; 1.1%; and 1,4%) and for control monosodium glutamate (MSG) was used. ACEI activity in each food system and organoleptic test using multiple comparison differentiation on 15 semi-trained panellists were determined. The results showed that there were fluctuation of ACEI activity in the carrot, champignon, and chicken meat dishes (p=0.017; 0.043; and 0.032). The MSG containing dishes showed the lowest ACEI activity. Addition of graded level of CBP on carrot, champignon, and chicken meat dishes were directly proportional to glutamic acid content but inversely proportional to ACEI activity (p<0.05). The addition of commercial MSG on all dishes increased glutamic acid content but reduced ACE-inhibitory activity significantly (p<0.05). Comparing CBP to MSG addition in champignon dish revealed that increasing level of CBP increased the flavour preference of the panellists. On the contrary the higher the addition CBP in noodle and chicken meat dishes the worse were the flavour score (p<0.05). It can be concluded that the addition of CBP as flavour enhancer on various dishes can deliver better flavour and ACE-inhibitory activity than the addition of commercial MSG.

Incorporation of liposomes containing squid tunic ACE-inhibitory peptides into fish gelatin.

PubMed

Mosquera, Mauricio; Giménez, Begoña; Montero, Pilar; Gómez-Guillén, Maria Carmen

2016-02-01

Hydrolysates from collagen of jumbo squid (Dosidicus gigas) tunics have shown excellent angiotensin I-converting enzyme (ACE)-inhibitory activity. However, peptides directly included in food systems may suffer a decrease in activity, which could be minimized by loading them into nanoliposomes. A fraction of peptides with molecular weights <1 kDa obtained from hydrolyzed squid tunics, with reasonably high ACE-inhibitory activity (half-maximal inhibitory concentration IC50 = 0.096 g L(-1)), was encapsulated in phosphatidylcholine nanoliposomes. The peptide concentration affected the encapsulation efficiency and the stability of the resulting liposomes, which remained with a high zeta potential value (-54.3 mV) for at least 1 week at the most suitable peptide concentration. The optimal peptide concentration was established as 1.75 g L(-1). Liposomes obtained with this peptide concentration showed an encapsulation efficiency of 53%, a zeta potential of -59 mV, an average diameter of 70.3 nm and proved to be stable in the pH range 3-7 at 4 °C. Liposomes containing ACE-inhibitory peptides were incorporated in fish gelatin without detriment to the rheological properties and thermal stability of the resulting cold-induced gel. The ACE-inhibitory activity of the peptide fraction, which was not affected by the encapsulation process, conferred the bioactive potential to the nanoliposome-containing gelatin gel. © 2015 Society of Chemical Industry.

Extinction Generates Outcome-Specific Conditioned Inhibition.

PubMed

Laurent, Vincent; Chieng, Billy; Balleine, Bernard W

2016-12-05

Extinction involves altering a previously established predictive relationship between a cue and its outcome by repeatedly presenting that cue alone. Although it is widely accepted that extinction generates some form of inhibitory learning [1-4], direct evidence for this claim has been lacking, and the nature of the associative changes induced by extinction have, therefore, remained a matter of debate [5-8]. In the current experiments, we used a novel behavioral approach that we recently developed and that provides a direct measure of conditioned inhibition [9] to compare the influence of extinguished and non-extinguished cues on choice between goal-directed actions. Using this approach, we provide direct evidence that extinction generates outcome-specific conditioned inhibition. Furthermore, we demonstrate that this inhibitory learning is controlled by the infralimbic cortex (IL); inactivation of the IL using M4 DREADDs abolished outcome-specific inhibition and rendered the cue excitatory. Importantly, we found that context modulated this inhibition. Outside its extinction context, the cue was excitatory and functioned as a specific predictor of its previously associated outcome, biasing choice toward actions earning the same outcome. In its extinction context, however, the cue acted as a specific inhibitor and biased choice toward actions earning different outcomes. Context modulation of these excitatory and inhibitory memories was mediated by the dorsal hippocampus (HPC), suggesting that the HPC and IL act in concert to control the influence of conditioned inhibitors on choice. These findings demonstrate for the first time that extinction turns a cue into a net inhibitor that can influence choice via counterfactual action-outcome associations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparison of effects of green tea catechins on apicomplexan hexose transporters and mammalian orthologues.

PubMed

Slavic, Ksenija; Derbyshire, Elvira T; Naftalin, Richard J; Krishna, Sanjeev; Staines, Henry M

2009-11-01

Here we have investigated the inhibitory properties of green tea catechins on the Plasmodium falciparum hexose transporter (PfHT), the Babesia bovis hexose transporter 1 (BboHT1) and the mammalian facilitative glucose transporters, GLUT1 and GLUT5, expressed in Xenopus laevis oocytes. (-)-Epicatechin-gallate (ECG) and (-)-epigallocatechin-gallate (EGCG) inhibited D-glucose transport by GLUT1 and PfHT, and D-fructose transport by GLUT5, with apparent K(i) values between 45 and 117 microM. BboHT1 was more potently inhibited by the ungallated catechins (-)-epicatechin (EC) and (-)-epigallocatechin (EGC), with apparent K(i) values of 108 and 168 microM, respectively. Site-directed mutagenesis experiments provided little further support for previously reported models of catechin binding to hexose transporters. Furthermore, P. falciparum growth inhibition by catechins was not affected by the external D-glucose concentration. Our results provide new data on the inhibitory action of catechins against sugar transporters but were unable to elucidate the antimalarial mechanism of action of these agents.

Stop feeling: inhibition of emotional interference following stop-signal trials.

PubMed

Kalanthroff, Eyal; Cohen, Noga; Henik, Avishai

2013-01-01

Although a great deal of literature has been dedicated to the mutual links between emotion and the selective attention component of executive control, there is very little data regarding the links between emotion and the inhibitory component of executive control. In the current study we employed an emotional stop-signal task in order to examine whether emotion modulates and is modulated by inhibitory control. Results replicated previous findings showing reduced inhibitory control [longer stop-signal reaction time (SSRT)] following negative, compared to neutral pictures. Most importantly, results show decreased emotional interference following stop-signal trials. These results show that the inhibitory control component of executive control can serve to decrease emotional effects. We suggest that inhibitory control and emotion have a two-way connection in which emotion disrupts inhibitory control and activation of inhibitory control disrupts emotion.

Novel synthetic kojic acid-methimazole derivatives inhibit mushroom tyrosinase and melanogenesis.

PubMed

Chen, Ming-Jen; Hung, Chih-Chuan; Chen, Yan-Ru; Lai, Shih-Ting; Chan, Chin-Feng

2016-12-01

In this study, two kojic acid-methimazole (2-mercapto-1-methylimidazole, MMI, 1) derivatives, 5-hydroxy-2-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-4H-pyran-4-one (compound 4) and 5-methoxy-2-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-4H-pyran-4-one (compound 5), were synthesized to examine their inhibitory kinetics on mushroom tyrosinase. Compound 4 exhibited a potent inhibitory effect on monophenolase activity in a dose-dependent manner, with an IC 50 value of 0.03 mM. On diphenolase activity, compound 4 exhibited a less inhibitory effect (IC 50  = 1.29 mM) but was stronger than kojic acid (IC 50  = 1.80 mM). Kinetic analysis indicated that compound 4 was both as a noncompetitive monophenolase and diphenolase inhibitor. By contrast, compound 5 exhibited no inhibitory effects on mushroom tyrosinase activity. The IC 50 value of compound 4 for the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity was 4.09 mM, being much higher than the IC 50 of compound 4 for inhibiting the tyrosinase activity. The results indicated that the antioxidant activity of compound 4 may be partly related to the potent inhibitory effect on mushroom tyrosinase. Compound 4 also exerted a potent inhibitory effect on intracellular melanin formation in B16/F10 murine melanoma cells, and caused no cytotoxicity. Furthermore, compound 4 induced no adverse effects on the Hen's egg test-chorioallantoic membrane (HET-CAM). Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Effect of vanadium compounds on acid phosphatase activity.

PubMed

Vescina, C M; Sálice, V C; Cortizo, A M; Etcheverry, S B

1996-01-01

The direct effect of different vanadium compounds on acid phosphatase (ACP) activity was investigated. Vanadate and vanadyl but not pervanadate inhibited the wheat germ ACP activity. These vanadium derivatives did not alter the fibroblast Swiss 3T3 soluble fraction ACP activity. Using inhibitors of tyrosine phosphatases (PTPases), the wheat germ ACP was partially characterized as a PTPase. This study suggests that the inhibitory ability of different vanadium derivatives to modulate ACP activity seems to depend on the geometry around the vanadium atom more than on the oxidation state. Our results indicate a correlation between the PTPase activity and the sensitivity to vanadate and vanadyl cation.

Different Effects of Human Umbilical Cord Mesenchymal Stem Cells on Glioblastoma Stem Cells by Direct Cell Interaction or Via Released Soluble Factors

PubMed Central

Bajetto, Adriana; Pattarozzi, Alessandra; Corsaro, Alessandro; Barbieri, Federica; Daga, Antonio; Bosio, Alessia; Gatti, Monica; Pisaturo, Valerio; Sirito, Rodolfo; Florio, Tullio

2017-01-01

Glioblastoma (GBM), the most common primary brain tumor in adults, is an aggressive, fast-growing and highly vascularized tumor, characterized by extensive invasiveness and local recurrence. In GBM and other malignancies, cancer stem cells (CSCs) are believed to drive invasive tumor growth and recurrence, being responsible for radio- and chemo-therapy resistance. Mesenchymal stem cells (MSCs) are multipotent progenitors that exhibit tropism for tumor microenvironment mediated by cytokines, chemokines and growth factors. Initial studies proposed that MSCs might exert inhibitory effects on tumor development, although, to date, contrasting evidence has been provided. Different studies reported either MSC anti-tumor activity or their support to tumor growth. Here, we examined the effects of umbilical cord (UC)-MSCs on in vitro GBM-derived CSC growth, by direct cell-to-cell interaction or indirect modulation, via the release of soluble factors. We demonstrate that UC-MSCs and CSCs exhibit reciprocal tropism when co-cultured as 3D spheroids and their direct cell interaction reduces the proliferation of both cell types. Contrasting effects were obtained by UC-MSC released factors: CSCs, cultured in the presence of conditioned medium (CM) collected from UC-MSCs, increased proliferation rate through transient ERK1/2 and Akt phosphorylation/activation. Analysis of the profile of the cytokines released by UC-MSCs in the CM revealed a strong production of molecules involved in inflammation, angiogenesis, cell migration and proliferation, such as IL-8, GRO, ENA-78 and IL-6. Since CXC chemokine receptor 2 (CXCR2), a receptor shared by several of these ligands, is expressed in GBM CSCs, we evaluated its involvement in CSC proliferation induced by UC-MSC-CM. Using the CXCR2 antagonist SB225002, we observed a partial but statistically significant inhibition of CSC proliferation and migration induced by the UC-MSC-released cytokines. Conversely, CXCR2 blockade did not reduce the reciprocal tropism between CSCs and UC-MSCs grown as spheroids. In conclusion, we show that direct (cell-to-cell contact) or indirect (via the release of soluble factors) interactions between GBM CSCs and UC-MSCs in co-culture produce divergent effects on cell growth, invasion and migration, with the former mainly causing an inhibitory response and the latter a stimulatory one, involving a paracrine activation of CXCR2. PMID:29081734

Different Effects of Human Umbilical Cord Mesenchymal Stem Cells on Glioblastoma Stem Cells by Direct Cell Interaction or Via Released Soluble Factors.

PubMed

Bajetto, Adriana; Pattarozzi, Alessandra; Corsaro, Alessandro; Barbieri, Federica; Daga, Antonio; Bosio, Alessia; Gatti, Monica; Pisaturo, Valerio; Sirito, Rodolfo; Florio, Tullio

2017-01-01

Glioblastoma (GBM), the most common primary brain tumor in adults, is an aggressive, fast-growing and highly vascularized tumor, characterized by extensive invasiveness and local recurrence. In GBM and other malignancies, cancer stem cells (CSCs) are believed to drive invasive tumor growth and recurrence, being responsible for radio- and chemo-therapy resistance. Mesenchymal stem cells (MSCs) are multipotent progenitors that exhibit tropism for tumor microenvironment mediated by cytokines, chemokines and growth factors. Initial studies proposed that MSCs might exert inhibitory effects on tumor development, although, to date, contrasting evidence has been provided. Different studies reported either MSC anti-tumor activity or their support to tumor growth. Here, we examined the effects of umbilical cord (UC)-MSCs on in vitro GBM-derived CSC growth, by direct cell-to-cell interaction or indirect modulation, via the release of soluble factors. We demonstrate that UC-MSCs and CSCs exhibit reciprocal tropism when co-cultured as 3D spheroids and their direct cell interaction reduces the proliferation of both cell types. Contrasting effects were obtained by UC-MSC released factors: CSCs, cultured in the presence of conditioned medium (CM) collected from UC-MSCs, increased proliferation rate through transient ERK1/2 and Akt phosphorylation/activation. Analysis of the profile of the cytokines released by UC-MSCs in the CM revealed a strong production of molecules involved in inflammation, angiogenesis, cell migration and proliferation, such as IL-8, GRO, ENA-78 and IL-6. Since CXC chemokine receptor 2 (CXCR2), a receptor shared by several of these ligands, is expressed in GBM CSCs, we evaluated its involvement in CSC proliferation induced by UC-MSC-CM. Using the CXCR2 antagonist SB225002, we observed a partial but statistically significant inhibition of CSC proliferation and migration induced by the UC-MSC-released cytokines. Conversely, CXCR2 blockade did not reduce the reciprocal tropism between CSCs and UC-MSCs grown as spheroids. In conclusion, we show that direct (cell-to-cell contact) or indirect (via the release of soluble factors) interactions between GBM CSCs and UC-MSCs in co-culture produce divergent effects on cell growth, invasion and migration, with the former mainly causing an inhibitory response and the latter a stimulatory one, involving a paracrine activation of CXCR2.

Inhibitory and blocking monoclonal antibody epitopes on merozoite surface protein 1 of the malaria parasite Plasmodium falciparum.

PubMed

Uthaipibull, C; Aufiero, B; Syed, S E; Hansen, B; Guevara Patiño, J A; Angov, E; Ling, I T; Fegeding, K; Morgan, W D; Ockenhouse, C; Birdsall, B; Feeney, J; Lyon, J A; Holder, A A

2001-04-13

Merozoite surface protein 1 (MSP-1) is a precursor to major antigens on the surface of Plasmodium spp. merozoites, which are involved in erythrocyte binding and invasion. MSP-1 is initially processed into smaller fragments; and at the time of erythrocyte invasion one of these of 42 kDa (MSP-1(42)) is subjected to a second processing, producing 33 kDa and 19 kDa fragments (MSP-1(33) and MSP-1(19)). Certain MSP-1-specific monoclonal antibodies (mAbs) react with conformational epitopes contained within the two epidermal growth factor domains that comprise MSP-1(19), and are classified as either inhibitory (inhibit processing of MSP-1(42) and erythrocyte invasion), blocking (block the binding and function of the inhibitory mAb), or neutral (neither inhibitory nor blocking). We have mapped the epitopes for inhibitory mAbs 12.8 and 12.10, and blocking mAbs such as 1E1 and 7.5 by using site-directed mutagenesis to change specific amino acid residues in MSP-1(19) and abolish antibody binding, and by using PEPSCAN to measure the reaction of the antibodies with every octapeptide within MSP-1(42). Twenty-six individual amino acid residue changes were made and the effect of each on the binding of mAbs was assessed by Western blotting and BIAcore analysis. Individual changes had either no effect, or reduced, or completely abolished the binding of individual mAbs. No two antibodies had an identical pattern of reactivity with the modified proteins. Using PEPSCAN each mAb reacted with a number of octapeptides, most of which were derived from within the first epidermal growth factor domain, although 1E1 also reacted with peptides spanning the processing site. When the single amino acid changes and the reactive peptides were mapped onto the three-dimensional structure of MSP-1(19), it was apparent that the epitopes for the mAbs could be defined more fully by using a combination of both mutagenesis and PEPSCAN than by either method alone, and differences in the fine specificity of binding for all the different antibodies could be distinguished. The incorporation of several specific amino acid changes enabled the design of proteins that bound inhibitory but not blocking antibodies. These may be suitable for the development of MSP-1-based vaccines against malaria. Copyright 2001 Academic Press.

Inhibition to excitation ratio regulates visual system responses and behavior in vivo.

PubMed

Shen, Wanhua; McKeown, Caroline R; Demas, James A; Cline, Hollis T

2011-11-01

The balance of inhibitory to excitatory (I/E) synaptic inputs is thought to control information processing and behavioral output of the central nervous system. We sought to test the effects of the decreased or increased I/E ratio on visual circuit function and visually guided behavior in Xenopus tadpoles. We selectively decreased inhibitory synaptic transmission in optic tectal neurons by knocking down the γ2 subunit of the GABA(A) receptors (GABA(A)R) using antisense morpholino oligonucleotides or by expressing a peptide corresponding to an intracellular loop of the γ2 subunit, called ICL, which interferes with anchoring GABA(A)R at synapses. Recordings of miniature inhibitory postsynaptic currents (mIPSCs) and miniature excitatory PSCs (mEPSCs) showed that these treatments decreased the frequency of mIPSCs compared with control tectal neurons without affecting mEPSC frequency, resulting in an ∼50% decrease in the ratio of I/E synaptic input. ICL expression and γ2-subunit knockdown also decreased the ratio of optic nerve-evoked synaptic I/E responses. We recorded visually evoked responses from optic tectal neurons, in which the synaptic I/E ratio was decreased. Decreasing the synaptic I/E ratio in tectal neurons increased the variance of first spike latency in response to full-field visual stimulation, increased recurrent activity in the tectal circuit, enlarged spatial receptive fields, and lengthened the temporal integration window. We used the benzodiazepine, diazepam (DZ), to increase inhibitory synaptic activity. DZ increased optic nerve-evoked inhibitory transmission but did not affect evoked excitatory currents, resulting in an increase in the I/E ratio of ∼30%. Increasing the I/E ratio with DZ decreased the variance of first spike latency, decreased spatial receptive field size, and lengthened temporal receptive fields. Sequential recordings of spikes and excitatory and inhibitory synaptic inputs to the same visual stimuli demonstrated that decreasing or increasing the I/E ratio disrupted input/output relations. We assessed the effect of an altered I/E ratio on a visually guided behavior that requires the optic tectum. Increasing and decreasing I/E in tectal neurons blocked the tectally mediated visual avoidance behavior. Because ICL expression, γ2-subunit knockdown, and DZ did not directly affect excitatory synaptic transmission, we interpret the results of our study as evidence that partially decreasing or increasing the ratio of I/E disrupts several measures of visual system information processing and visually guided behavior in an intact vertebrate.

Activity of Norspermidine on Bacterial Biofilms of Multidrug-Resistant Clinical Isolates Associated with Persistent Extremity Wound Infections.

PubMed

Cardile, Anthony P; Woodbury, Ronald L; Sanchez, Carlos J; Becerra, Sandra C; Garcia, Rebecca A; Mende, Katrin; Wenke, Joseph C; Akers, Kevin S

2017-01-01

Biofilm formation is a major virulence factor for numerous pathogenic bacteria and is cited as a central event in the pathogenesis of chronic human infections, which is in large part due to excessive extracellular matrix secretion and metabolic changes that occur within the biofilm rendering them highly tolerant to antimicrobial treatments. Polyamines, including norspermidine, play central roles in bacterial biofilm development, but have also recently been shown to inhibit biofilm formation in select strains of various pathogenic bacteria. The aim of this study was to evaluate in vitro the biofilm dispersive and inhibitory activities of norspermidine against multidrug-resistant clinical isolates of Acinetobacter baumannii(n = 4), Klebsiella pneumoniae (n = 3), Pseudomonas aeruginosa (n = 5) and Staphylococcus aureus (n = 4) associated with chronic extremity wound infections using the semi-quantitative 96-well plate method and confocal laser microscopy. In addition to the antibiofilm activity, biocompatibility of norspermidine was also evaluated by measuring toxicity in vitro to human cell lines and whole porcine tissue explants using MTT viability assay and histological analysis. Norspermidine (5-20 mM) had variable dispersive and inhibitory activity on biofilms which was dependent on both the strain and species. Of the clinical bacterial species evaluated herein, A. baumannii isolates were the most sensitive to the effect of norspermidine, which was in part due to the inhibitory effects of norspermidine on bacterial motility and expression of genes involved in the production of homoserine lactones and quorum sensing molecules both essential for biofilm formation. Importantly, exposure of cell lines and whole tissues to norspermidine for prolonged periods of time (≥24 h) was observed to reduce viability and alter tissue histology in a time and concentration dependent manner, with 20 mM exposure having the greatest negative effects on both tissues and individual cell lines. Collectively our findings demonstrate that, similar to other polyamines, norspermidine displays both inhibitory and dispersive activities on biofilms of clinical multidrug-resistant bacterial isolates, in particular for strains of A. baumannii. Additionally our findings suggest that direct application may be considered on tissues, albeit for limited exposure times.

[Evaluate drug interaction of multi-components in Morus alba leaves based on α-glucosidase inhibitory activity].

PubMed

Ji, Tao; Su, Shu-Lan; Guo, Sheng; Qian, Da-Wei; Ouyang, Zhen; Duan, Jin-Ao

2016-06-01

Column chromatography was used for enrichment and separation of flavonoids, alkaloids and polysaccharides from the extracts of Morus alba leaves; glucose oxidase method was used with sucrose as the substrate to evaluate the multi-components of M. alba leaves in α-glucosidase inhibitory models; isobole method, Chou-Talalay combination index analysis and isobolographic analysis were used to evaluate the interaction effects and dose-effect characteristics of two components, providing scientific basis for revealing the hpyerglycemic mechanism of M. alba leaves. The components analysis showed that flavonoid content was 5.3%; organic phenolic acids content was 10.8%; DNJ content was 39.4%; and polysaccharide content was 18.9%. Activity evaluation results demonstrated that flavonoids, alkaloids and polysaccharides of M. alba leaves had significant inhibitory effects on α-glucosidase, and the inhibitory rate was increased with the increasing concentration. Alkaloids showed most significant inhibitory effects among these three components. Both compatibility of alkaloids and flavonoids, and the compatibility of alkaloids and polysaccharides demonstrated synergistic effects, but the compatibility of flavonoids and polysaccharides showed no obvious synergistic effects. The results have confirmed the interaction of multi-components from M. alba leaves to regulate blood sugar, and provided scientific basis for revealing hpyerglycemic effectiveness and mechanism of the multi-components from M. alba leaves. Copyright© by the Chinese Pharmaceutical Association.

Inhibitory effect of Xenorhabdus nematophila TB on plant pathogens Phytophthora capsici and Botrytis cinerea in vitro and in planta

PubMed Central

Fang, Xiangling; Zhang, Manrang; Tang, Qian; Wang, Yonghong; Zhang, Xing

2014-01-01

Entomopathogenic bacteria Xenorhabdus spp. produce secondary metabolites with potential antimicrobial activity for use in agricultural productions. This study evaluated the inhibitory effect of X. nematophila TB culture on plant pathogens Botrytis cinerea and Phytophthora capsici. The cell-free filtrate of TB culture showed strong inhibitory effects (>90%) on mycelial growth of both pathogens. The methanol-extracted bioactive compounds (methanol extract) of TB culture also had strong inhibitory effects on mycelial growth and spore germinations of both pathogens. The methanol extract (1000 μg/mL) and cell-free filtrate both showed strong therapeutic and protective effects (>70%) on grey mold both in detached tomato fruits and plants, and leaf scorch in pepper plants. This study demonstrates X. nematophila TB produces antimicrobial metabolites of strong activity on plant pathogens, with great potential for controlling tomato grey mold and pepper leaf scorch and being used in integrated disease control to reduce chemical application. PMID:24599183

Inhibitory effect of Xenorhabdus nematophila TB on plant pathogens Phytophthora capsici and Botrytis cinerea in vitro and in planta.

PubMed

Fang, Xiangling; Zhang, Manrang; Tang, Qian; Wang, Yonghong; Zhang, Xing

2014-03-06

Entomopathogenic bacteria Xenorhabdus spp. produce secondary metabolites with potential antimicrobial activity for use in agricultural productions. This study evaluated the inhibitory effect of X. nematophila TB culture on plant pathogens Botrytis cinerea and Phytophthora capsici. The cell-free filtrate of TB culture showed strong inhibitory effects (>90%) on mycelial growth of both pathogens. The methanol-extracted bioactive compounds (methanol extract) of TB culture also had strong inhibitory effects on mycelial growth and spore germinations of both pathogens. The methanol extract (1000 μg/mL) and cell-free filtrate both showed strong therapeutic and protective effects (>70%) on grey mold both in detached tomato fruits and plants, and leaf scorch in pepper plants. This study demonstrates X. nematophila TB produces antimicrobial metabolites of strong activity on plant pathogens, with great potential for controlling tomato grey mold and pepper leaf scorch and being used in integrated disease control to reduce chemical application.

Inhibitory effects of polyphenols in leaves of Artemisia princeps PAMP on protein fragmentation by Cu(II)-H2O2 in vitro.

PubMed

Toda, Shizuo

2004-01-01

The leaves of Artemisia princeps PAMP have traditionally been used as teas and foods in Japan. Polyphenols in Artemisia plants have been shown to have inhibitory effects against biological damages. The inhibitory effects of polyphenols in the leaves of A. princeps PAMP were investigated on protein fragmentation induced by Cu(II)-H(2)O(2) in vitro. The total polyphenol content in the leaves of A. princeps PAMP was 4.58%. The condensed tannin content was 0.62% by vanillin assay and 0.14% by proanthrocyanidin assay. The polyphenols in the leaves of A. princeps PAMP inhibited bovine albumin fragmentation by Cu(II)-H(2)O(2). The effects of polyphenols in the leaves of A. princeps PAMP were similar to those of tannic acid, studied as a related polyphenol. These results demonstrated that the leaves of A. princeps PAMP have inhibitory effects on protein fragmentation damage.

Inhibitory effects of furanocoumarin derivatives in Kampo extract medicines on P-glycoprotein at the blood-brain barrier.

PubMed

Iwanaga, Kazunori; Yoneda, Shinji; Hamahata, Yukimi; Miyazaki, Makoto; Shibano, Makio; Taniguchi, Masahiko; Baba, Kimiye; Kakemi, Masawo

2011-01-01

Furanocoumarin derivatives, known as components of grapefruit juice, showing inhibitory effects against P-glycoprotein (P-gp) in the intestine are also contained in the plants of rutaceae and umbelliferae families, which are used as components of Kampo extract medicines. In this study, we investigated the inhibitory effects of byakangelicol and rivulobirin A, known as furanocoumarins showing P-gp inhibitory effect using Caco-2 monolayer, against P-gp at the blood-brain barrier (BBB) under both in vitro and in vivo conditions. First we studied the membrane permeability of furanocoumarins to clarify whether they can be absorbed from the intestine. Both furanocoumarins showed high permeability through the Caco-2 monolayer, suggesting that they can easily reach the systemic circulation after oral administration. Then, we evaluated the effect of these furanocoumarins on the uptake of calcein acetoxymethyl ester (calcein-AM), a P-gp substrate, into bovine brain microvascular endothelial cells (BBMEC). Both furanocoumarins significantly increased the uptake amount of calcein-AM into BBMEC by the inhibition of P-gp at the BBB in vitro. Next we also investigated the P-gp inhibitory effect of these furanocoumarins at the rat BBB in vivo using verapamil as a P-gp substrate. Both furanocoumarins increased the B/P ratio of verapamil compared to the control, even under in vivo conditions; however, the extent of the inhibitory effect was much lower than in vitro condition. In conclusion, byakangelicol and rivulobirin A may inhibit P-gp expressed at the BBB even under in vivo conditions. Further studies using Kampo extract medicines under in vivo condition are necessary for safe drug therapy.

Inhibitory Behavioral Control: A Stochastic Dynamic Causal Modeling Study Using Network Discovery Analysis

PubMed Central

Steinberg, Joel L.; Cunningham, Kathryn A.; Lane, Scott D.; Kramer, Larry A.; Narayana, Ponnada A.; Kosten, Thomas R.; Bechara, Antoine; Moeller, F. Gerard

2015-01-01

Abstract This study employed functional magnetic resonance imaging (fMRI)-based dynamic causal modeling (DCM) to study the effective (directional) neuronal connectivity underlying inhibitory behavioral control. fMRI data were acquired from 15 healthy subjects while they performed a Go/NoGo task with two levels of NoGo difficulty (Easy and Hard NoGo conditions) in distinguishing spatial patterns of lines. Based on the previous inhibitory control literature and the present fMRI activation results, 10 brain regions were postulated as nodes in the effective connectivity model. Due to the large number of potential interconnections among these nodes, the number of models for final analysis was reduced to a manageable level for the whole group by conducting DCM Network Discovery, which is a recently developed option within the Statistical Parametric Mapping software package. Given the optimum network model, the DCM Network Discovery analysis found that the locations of the driving input into the model from all the experimental stimuli in the Go/NoGo task were the amygdala and the hippocampus. The strengths of several cortico-subcortical connections were modulated (influenced) by the two NoGo conditions. Specifically, connectivity from the middle frontal gyrus (MFG) to hippocampus was enhanced by the Easy condition and further enhanced by the Hard NoGo condition, possibly suggesting that compared with the Easy NoGo condition, stronger control from MFG was needed for the hippocampus to discriminate/learn the spatial pattern in order to respond correctly (inhibit), during the Hard NoGo condition. PMID:25336321

Quantitative evaluation of inhibitory effect of various substances on anaerobic ammonia oxidation (anammox).

PubMed

Nakamura, Tomotaka; Harigaya, Yuhki; Kimura, Yuya; Kuroiwa, Megumi; Kurata, Yuhri; Isaka, Kazuichi; Suwa, Yuichi

2017-09-01

The inhibitory effect of 20 substances of various chemical species on the anaerobic ammonia oxidation (anammox) activity of an enrichment culture, predominated by Candidatus Brocadia, was determined systematically by using a 15 N tracer technique. The initial anammox rate was determined during first 25 min with a small-scale anaerobic batch incubation supplemented with possible inhibitors. Although Cu 2+ and Mn 2+ did not inhibit anammox, the remaining 18 substances [Ni 2+ , Zn 2+ , Co 2+ , [Formula: see text] , Fe 2+ , 4 amines, ethylenediaminetetraacetic acid (EDTA), ethylenediamine-N,N'-bis (2-hydroxyphenylacetic acid) (EDDHA), citric acid, nitrilotriacetic acid (NTA), N,N-dimethylacetamide (DMA), 1,4-dioxane, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) and tetrahydrofuran (THF)] were inhibitory. Inhibitory effect of NTA, EDDHA, THF, DMF, DMA and amines on anammox was first determined in this study. Inhibitory effects of metals were re-evaluated because chelators, which may interfere inhibitory effect, have been used to dissolve metal salts into assay solution. The relative anammox activities as a function of concentration of each substance were described successfully (R 2  > 0.91) either with a linear inhibition model or with a Michaelis-Menten-based inhibition model. IC 50 values were estimated based on either model, and were compared. The IC 50 values of the 4 chelators (0.06-2.7 mM) and 5 metal ions (0.02-1.09 mM) were significantly lower than those of the 4 amines (10.6-29.1 mM) and 5 organic solvents (3.5-82 mM). Although it did not show any inhibition within 25 min, 0.1 mM Cu 2+ completely inhibited anammox activity in 240 min, suggesting that the inhibitory effect caused by Cu 2+ is time-dependent. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

[Comparison of anti-angiogenic effect in vitro between ranibizumab and bevacizumab].

PubMed

Souto, Alexandre Cupello; Maricato, Juliana Terzi; Denapoli, Priscila Martins Andrade; Sallum, Juliana Maria Ferraz; Han, Sang Won

2011-01-01

To evaluate the comparative in-vitro antiangiogenic effect of Bevacizumab and Ranibizumab. Endothelial venous umbilical cells culture (ECV304) cultivated in F12 media with addition of 10% Fetal Bovine Serum, were plaqued and treated with clinically relevant concentrations of Bevacizumab and Ranibizumab just after the scratch done in the middle of the culture (scratch methodology). Measurements of the linear size of the area free of cell proliferation were done 24, 48 and 72 hours after the scratch day point. All the experiments were done in triplicate and statistical analysis were done with T-student test. Inhibitory effect was observed just at the concentrations of 0.5 and 0.7 mg/ml in both drugs. At 0.7 mg/ml, Ranibizumab demonstrated a more potent proliferative inhibitory effect than Bevacizumab. At the same concentration, Ranibizumab was three times more potent than Ranibizumab. Inhibitory effect was observed just in the first 24 hours for both drugs. Ranibizumab demonstrates an increased effect when compared to Bevacizumab and this is related more to the different molar rate of each drug than related to a real better proliferative inhibitory effect.

Self-restraint spillover: Inhibitory control disrupts appetite regulation among ruminators.

PubMed

Schlinkert, Caroline; Koole, Sander L

2017-10-23

People can use inhibitory control to temporarily inhibit their personal preferences to achieve their long-term goals. According to the ego fixation model (Koole et al., 2014), ruminators have difficulties relaxing inhibitory control, leading them to continue inhibiting their personal needs, even when this is no longer required by the situation. Inhibitory control may thus disrupt healthy appetite regulation among ruminators. Among 324 Dutch undergraduate students (218 women; M age  = 21.5), different inhibitory control states were manipulated by varying whether or not participants exerted inhibitory control (Study 1) or priming high versus low inhibitory control (Study 2). All participants then performed a food-tasting task. Healthy appetite regulation was defined as a positive correlation between level of food deprivation and preference for high-calorie foods. For taste ratings, the interaction between inhibitory control and rumination was significant in each study: Inhibitory control disrupted healthy appetite regulation in taste preferences among ruminators, but not among non-ruminators. For eating behavior, the same interaction effect was significant when the two studies were combined. Inhibitory control disrupts healthy appetite regulation among ruminators. These findings suggest the need for caution in interventions that rely on inhibitory control, especially among samples with compulsive thought tendencies. © 2017 Wiley Periodicals, Inc.

Inhibitory effect of D3 dopamine receptors on neuropeptide Y‑induced migration in vascular smooth muscle cells.

PubMed

Xia, Xue-Wei; Zhou, Yong-Qiao; Luo, Hao; Zeng, Chunyu

2017-10-01

Abnormal migration of vascular smooth muscle cells (VSMCs) serves an important role in hypertension, atherosclerosis and restenosis following angioplasty, which is regulated numerous hormonal and humoral factors, including neuropeptide Y (NPY) and dopamine. Dopamine and NPY are both sympathetic neurotransmitters, and a previous study reported that NPY increased VSMC proliferation, while dopamine receptor inhibited it. Therefore, the authors wondered whether or not there is an inhibitory effect of dopamine receptor on NPY‑mediated VSMC migration. The present study demonstrated that stimulation with NPY dose‑dependence (10‑10‑10‑7M, 24 h) increased VSMC migration, the stimulatory effect of NPY was via the Y1 receptor. This is because, in the presence of the Y1 receptor antagonist, BIBP3226 (10‑7 M), the stimulatory effect of NPY on VSMC migration was blocked. Activation of the D3 receptor by PD128907 dose‑dependence (10‑11‑10‑8 M) reduced the stimulatory effect of NPY on VSMC migration. The effect of PD128907 was via the D3 receptor, because the inhibitory effect of PD128907 on NPY‑mediated migration was blocked by the D3 receptor antagonist, U99194. The authors' further study suggested that the inhibitory effect of the D3 receptor was via the PKA signaling pathway, in the presence of the PKA inhibitor, 14‑22 (10‑6 M), the inhibitory effect of PD128907 on VSMC migration was blocked. Moreover, the inhibitory effect of PD128907 was imitated by PKA activator, Sp‑cAMP [S], in the presence of Sp‑cAMP [S], the NPY‑mediated stimulatory effect on VSMC migration was abolished. The present study indicated that activation of the D3 receptor inhibits NPY Y1‑mediated migration on VSMCs, PKA is involved in the signaling pathway.

Management of landfill leachate: The legacy of European Union Directives.

PubMed

Brennan, R B; Healy, M G; Morrison, L; Hynes, S; Norton, D; Clifford, E

2016-09-01

Landfill leachate is the product of water that has percolated through waste deposits and contains various pollutants, which necessitate effective treatment before it can be released into the environment. In the last 30years, there have been significant changes in landfill management practices in response to European Union (EU) Directives, which have led to changes in leachate composition, volumes produced and treatability. In this study, historic landfill data, combined with leachate characterisation data, were used to determine the impacts of EU Directives on landfill leachate management, composition and treatability. Inhibitory compounds including ammonium (NH4-N), cyanide, chromium, nickel and zinc, were present in young leachate at levels that may inhibit ammonium oxidising bacteria, while arsenic, copper and silver were present in young and intermediate age leachate at concentrations above inhibitory thresholds. In addition, the results of this study show that while young landfills produce less than 50% of total leachate by volume in the Republic of Ireland, they account for 70% of total annual leachate chemical oxygen demand (COD) load and approximately 80% of total 5-day biochemical oxygen demand (BOD5) and NH4-N loads. These results show that there has been a decrease in the volume of leachate produced per tonne of waste landfilled since enactment of the Landfill Directive, with a trend towards increased leachate strength (particularly COD and BOD5) during the initial five years of landfill operation. These changes may be attributed to changes in landfill management practices following the implementation of the Landfill Directive. However, this study did not demonstrate the impact of decreasing inputs of biodegradable municipal waste on leachate composition. Increasingly stringent wastewater treatment plant (WWTP) emission limit values represent a significant threat to the sustainability of co-treatment of leachate with municipal wastewater. In addition, the seasonal variation in leachate production poses a risk to effective co-treatment in municipal WWTPs, as periods of high leachate production coincide with periods of maximum hydraulic loading in WWTPs. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of clavulanic acid on minimal inhibitory concentrations of 16 antimicrobial agents tested against Legionella pneumophila.

PubMed Central

Pohlod, D J; Saravolatz, L D; Quinn, E L; Somerville, M M

1980-01-01

A total of 15 Legionella pneumophilia isolated were tested against 16 antimicrobial agents used singly and in combination with clavulanic acid. When combined with clavulanic acid, 4 of the 16 antimicrobial agents produced no enhanced effect. However, the minimal inhibitory concentrations of 12 of the antimicrobial agents were reduced by one-half to one-third when in combination with clavulanic acid. These reductions reflected only a one-dilution decrease, however, in the original minimal inhibitory concentrations. Thus, clavulanic acid combinations appear to be only nominally effective beta-lactamase inhibitors against L. pneumophilia. PMID:6969575

Enzyme inhibitory and radical scavenging effects of some antidiabetic plants of Turkey

PubMed Central

Orhan, Nilüfer; Hoçbaç, Sanem; Orhan, Didem Deliorman; Asian, Mustafa; Ergun, Fatma

2014-01-01

Objective(s): Ethnopharmacological field surveys demonstrated that many plants, such as Gentiana olivieri, Helichrysum graveolens, Helichrysum plicatum ssp. plicatum, Juniperus oxycedrus ssp. oxycedrus, Juniperus communis var. saxatilis, Viscum album (ssp. album, ssp. austriacum), are used as traditional medicine for diabetes in different regions of Anatolia. The present study was designed to evaluate the in vitro antidiabetic effects of some selected plants, tested in animal models recently. Materials and Methods: α-glucosidase and α-amylase enzyme inhibitory effects of the plant extracts were investigated and Acarbose was used as a reference drug. Additionally, radical scavenging capacities were determined using 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) ABTS radical cation scavenging assay and total phenolic content of the extracts were evaluated using Folin Ciocalteu method. Results: H. graveolens ethanol extract exhibited the highest inhibitory activity (55.7 % ± 2.2) on α-amylase enzyme. Additionally, J. oxycedrus hydro-alcoholic leaf extract had potent α-amylase inhibitory effect, while the hydro-alcoholic extract of J. communis fruit showed the highest α-glucosidase inhibitory activity (IC50: 4.4 μg/ml). Conclusion: Results indicated that, antidiabetic effect of hydro-alcoholic extracts of H. graveolens capitulums, J. communis fruit and J. oxycedrus leaf might arise from inhibition of digestive enzymes. PMID:25140204

Selective serotonin reuptake inhibitors: measurement of effect on platelet function.

PubMed

McCloskey, Donna Jo; Postolache, Teodor T; Vittone, Bernard J; Nghiem, Khanh L; Monsale, Jude L; Wesley, Robert A; Rick, Margaret E

2008-03-01

Selective serotonin reuptake inhibitors (SSRIs) reduce platelet serotonin and are associated with increased gastrointestinal bleeding, an effect that is enhanced when taken with NSAIDs or aspirin. The best method to evaluate hemorrhagic events in patients taking SSRIs has not been determined. Platelet aggregation, which is not widely available, shows SSRI inhibition of platelet function; we tested whether a platelet function analyzer could detect SSRI inhibition of platelet function. Two groups of outpatients with mood disorders were recruited; each patient was taking a stable dose of either an SSRI or bupropion for at least 6 weeks. They were tested using the platelet function analyzer-100 (PFA-100; Dade International Inc, Miami, Fla) concomitantly with platelet aggregation. Fifty-eight patients were analyzed. We detected significant differences between the groups using aggregation methods with arachidonic acid (aggregation, P = 0.00001; release, P = 0.009) and collagen (aggregation, P = 0.016; release, P = 0.006). The PFA-100 did not detect differences between the groups or results outside the reference range. The PFA-100 does not detect the inhibitory effects of SSRIs on platelet function, but it can be used to direct evaluation of bleeding in a patient taking an SSRI. Abnormal PFA-100 results suggest additional evaluation for von Willebrand disease, other platelet inhibitory medications, or underlying intrinsic platelet dysfunction.

Effect of lignocellulose-derived inhibitors on the growth and D-lactic acid production of Sporolactobacillus inulinus YBS1-5.

PubMed

Bai, Zhongzhong; Gao, Zhen; He, Bingfang; Wu, Bin

2015-10-01

The impact of lignocellulose-derived inhibitors on the cell growth and D-lactic production of Sporolactobacillus inulinus YBS1-5 was investigated. At high concentrations, both furans and phenolics, such as furfural, HMF, syringaldehyde and vanillin, affected cell growth and D-lactic acid production and syringaldehyde exhibited the highest. Further experiments showed that only vanillin caused cellular membrane damage. Based on the Biolog approach, in vivo studies on intact S. inulinus cells indicated that phenolics had a stronger inhibitory effect than furan derivatives on the metabolic activity of the concerned substrates related with the key enzymes of D-lactic acid fermentation. The direct in vitro inhibitory effect of the model compounds on the four key enzymes displayed similar patterns. Syringaldehyde was the strongest inhibitor. In general, comparison with published results for other microorganisms indicated that strain YBS1-5 was a robust microorganism against inhibitors of lignocellulose hydrolysate. Notably, in concentrated corn stover hydrolysate, S. inulinus YBS1-5 produced 70.7 g/L D-lactic acid, which was 87.7 % of the yield from the control experiment. However, the fermentation time was prolonged 36 h. In order to improve fermentation rate, a detoxification technology or more robust mutant to phenolics especially syringaldehyde should be developed.

Monocyte Locomotion Inhibitory Factor Produced by E. histolytica Improves Motor Recovery and Develops Neuroprotection after Traumatic Injury to the Spinal Cord

PubMed Central

Bermeo, Gabriela; García, Elisa; Flores-Romero, Adrian; Rico-Rosillo, Guadalupe; Marroquín, Rubén; Flores, Carmina; Blanco-Favela, Francisco; Silva-García, Raúl

2013-01-01

Monocyte locomotion inhibitory factor (MLIF) is a pentapeptide produced by Entamoeba histolytica that has a potent anti-inflammatory effect. Either MLIF or phosphate buffered saline (PBS) was administered directly onto the spinal cord (SC) immediately after injury. Motor recovery was evaluated. We also analyzed neuroprotection by quantifying the number of surviving ventral horn motor neurons and the persistence of rubrospinal tract neurons. To evaluate the mechanism through which MLIF improved the outcome of SC injury, we quantified the expression of inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) genes at the site of injury. Finally, the levels of nitric oxide and of lipid peroxidation were also determined in peripheral blood. Results showed that MLIF improved the rate of motor recovery and this correlated with an increased survival of ventral horn and rubrospinal neurons. These beneficial effects were in turn associated with a reduction in iNOS gene products and a significant upregulation of IL-10 and TGF-β expression. In the same way, MLIF reduced the concentration of nitric oxide and the levels of lipid peroxidation in systemic circulation. The present results demonstrate for the first time the neuroprotective effects endowed by MLIF after SC injury. PMID:24294606

Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor▿

PubMed Central

Fletcher, P.; Harman, S.; Azijn, H.; Armanasco, N.; Manlow, P.; Perumal, D.; de Bethune, M.-P.; Nuttall, J.; Romano, J.; Shattock, R.

2009-01-01

Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate. PMID:19029331

Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.

PubMed

Fletcher, P; Harman, S; Azijn, H; Armanasco, N; Manlow, P; Perumal, D; de Bethune, M-P; Nuttall, J; Romano, J; Shattock, R

2009-02-01

Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.

Antigen induced inhibition of autoimmune response to rat male accessory glands: role of thymocytes on the efferent phase of the suppression.

PubMed

Ferro, M E; Romero-Piffiguer, M; Rivero, V; Yranzo-Volonte, N; Correa, S; Riera, C M

1991-01-01

In the present study, we report that Cy-sensitive, MRAG-adherent spleen mononuclear (SpM) inductor-phase T suppressor (Ts) cells obtained from rats pretreated with low doses of a purified fraction (FI) of rat male accessory gland antigens (RAG) are mainly OX19+ and W3/25+. Furthermore, thymocytes from rats pretreated with FI of RAG restore the suppression of the autoimmune response to RAG autoantigens in irradiated recipients of SpM inductor-phase Ts cells. In contrast, thymocytes from rats pretreated with rat heart saline extract (unrelated antigen) did not recuperate the suppression of the autoimmune response detected by macrophage migration inhibitory factor (MIF) and delayed-type hypersensitivity. The suppressor thymocytes did not directly exert their inhibitory effect because they were not effective to suppress the autoimmune response to RAG autoantigens when irradiated recipients did not receive SpM inductor-phase Ts cells. The effect of these thymocytes was found in PNA--but not in PNA+ thymic cell population. The perithymic injection of Toxoplasma gondii did block their suppressor activity. The present report clearly shows an active participation of thymus in the efferent phase of the suppressor circuit that controls the autoimmune response to MRAG. The implications of these findings are discussed.

Reward Improves Cancellation and Restraint Inhibition Across Childhood and Adolescence

PubMed Central

Sinopoli, Katia J.; Schachar, Russell; Dennis, Maureen

2011-01-01

Inhibitory control allows for the regulation of thought and action, and interacts with motivational variables, such as reward, to modify behavior adaptively as environments change. We examined the effects of reward on two distinct forms of inhibitory control, cancellation and restraint. Typically developing children and adolescents completed two versions of the stop signal task (cancellation and restraint) under three reward conditions (neutral, low reward, and high reward), where rewards were earned for successful inhibitory control. Rewards improved both cancellation and restraint inhibition, with similar effects of reward on each form of inhibitory control. Rewards did not alter the speed of response execution in either task, suggesting that rewards specifically altered inhibition processes without influencing processes related to response execution. Adolescents were faster and less variable than children when executing and inhibiting their responses. There were similar developmental effects of reward on the speed of inhibitory control, but group differences were found in terms of accuracy of inhibition in the restraint task. These results clarify how reward modulates two different forms of regulatory behavior in children and adolescents. PMID:21744952

Phytochemical composition and antibacterial activity of the essential oils from different parts of sea buckthorn (Hippophae rhamnoides L.).

PubMed

Yue, Xuan-Feng; Shang, Xiao; Zhang, Zhi-Juan; Zhang, Yan-Ni

2017-04-01

Essential oils from the seed, pulp, and leaf of sea buckthorn were obtained with hydrodistillation, and their phytochemical composition was analyzed through gas chromatography-mass spectrometry. Furthermore, the antibacterial activity of the oils was tested on five food-borne bacteria by spectrometry and evaluated in terms of minimum inhibitory concentration. The results indicate that the composition of all essential oils is dominated by free fatty acids, esters, and alkanes. Minimum inhibitory concentration values on each bacterium were obtained for oils from different parts. The oils from different parts exhibited nearly equal inhibitory effect on Staphylococcus aureus. The pulp oil was found to be the most effective for the rest of bacteria tested except Escherichia coli, on which seed oil shows twice the inhibitory effect to that of leaf or pulp oil. Three natural inhibitory examples were found comparable with or even better than the positive control: pulp oil on Bacillus subtilis, and pulp oil and leaf oil on Bacillus coagulans. Copyright © 2016. Published by Elsevier B.V.

Heat injury and recovery of Streptococcus faecium associated with the souring of chub-packed luncheon meat.

PubMed

Bell, R G; De Lacy, K M

1984-10-01

The presence of NaCl in the heating medium provided some protection from lethal heat damage for cells of a Streptococcus faecium strain isolated from luncheon meat whereas the presence of NaNO2 either alone or in addition to NaCl, had no significant effect on cell survival. Subsequent recovery and growth of heat-damaged cells was retarded by the presence of NaCl. When NaNO2 was present in addition to NaCl the inhibitory effect of the latter was reduced. These principal components of the luncheon-meat-cure are apparently opposed in their activities on post-heating recovery and growth of Strep. faecium. Product stability, i.e. duration of the lag before growth occurs, is directly related to the severity of the heat treatment and to the concentration of NaCl in the product. Therefore the resistance of pasteurized chub-packed luncheon meat to streptococcal spoilage during storage at temperatures conducive to microbial growth results from a prolonged heat-induced salt-maintained pre-growth adjustment phase rather than to any inherent inhibitory property of the luncheon meat to the growth of non-heat-damaged Strep. faecium cells.

Development of a novel method for determination of mercury based on its inhibitory effect on horseradish peroxidase activity followed by monitoring the surface plasmon resonance peak of gold nanoparticles.

PubMed

Khodaveisi, Javad; Shabani, Ali Mohammad Haji; Dadfarnia, Shayessteh; Moghadam, Masoud Rohani; Hormozi-Nezhad, Mohammad Reza

2016-01-15

A highly sensitive and simple indirect spectrophotometric method has been developed for the determination of trace amounts of inorganic mercury (Hg(2+)) in aqueous media. The method is based on the inhibitory effect of Hg(2+) on the activity of horseradish peroxidase (HRP) in the oxidation of ascorbic acid by hydrogen peroxide followed by the reduction of Au(3+) to Au-NPs by unreacted ascorbic acid and the measurement of the absorbance of localized surface plasmon resonance (LSPR) peak of gold nanoparticles (at 530 nm) which is directly proportional to the concentration of Hg(2+). Under the optimum conditions, the calibration curve was linear in the concentration range of 1-220 ng mL(-1). Limits of detection (LOD) and quantification (LOQ) were 0.2 and 0.7 ng mL(-1), respectively and the relative standard deviation at 100 ng mL(-1) level of Hg(2+) was 2.6%. The method was successfully applied to the determination of mercury in different water samples. Copyright © 2015 Elsevier B.V. All rights reserved.

Study on Medicinal Plant Active Substances Extraction and Antibacterial Activity of Houttuynia Cordata

NASA Astrophysics Data System (ADS)

Yubin, Ji; Junjun, Yang; Miao, Yu; Yue, Cao; Shizhen, Guo; Anna, Qiao

2017-12-01

This study was about the effective component extraction from Houttuynia cordata by steam distillation and antibacterial effect on Escherichia coli, Staphylococcus aureus and Bacillus subtilis. The extraction of Herba Houttuyniae extract of Escherichia coli, Staphylococcus aureus and Bacillus subtilis were certain inhibitory effect of, which inhibitory effect on Staphylococcus aureus the most obvious.

Stimulatory and inhibitory effects of PKC isozymes are mediated by serine/threonine PKC sites of the Cav2.3α1 subunits.

PubMed

Rajagopal, Senthilkumar; Burton, Brittney K; Fields, Blanche L; El, India O; Kamatchi, Ganesan L

2017-05-01

Protein kinase C (PKC) isozymes modulate voltage-gated calcium (Ca v ) currents through Ca v 2.2 and Ca v 2.3 channels by targeting serine/threonine (Ser/Thr) phosphorylation sites of Ca v α 1 subunits. Stimulatory (Thr-422, Ser-2108 and Ser-2132) and inhibitory (Ser-425) sites were identified in the Ca v 2.2α 1 subunits to PKCs βII and ε. In the current study, we investigated if the homologous sites of Ca v 2.3α 1 subunits (stimulatory: Thr-365, Ser-1995 and Ser-2011; inhibitory: Ser-369) behaved in similar manner. Several Ala and Asp mutants were constructed in Ca v 2.3α 1 subunits in such a way that the Ser/Thr sites can be examined in isolation. These mutants or WT Ca v 2.3α 1 along with auxiliary β 1b and α 2 /δ subunits were expressed in Xenopus oocytes and the effects of PKCs βII and ε studied on the barium current (I Ba ). Among these sites, stimulatory Thr-365 and Ser-1995 and inhibitory Ser-369 behaved similar to their homologs in Ca v 2.2α 1 subunits. Furthermore PKCs produced neither stimulation nor inhibition when stimulatory Thr-365 or Ser-1995 and inhibitory Ser-369 were present together. However, the PKCs potentiated the I Ba when two stimulatory sites, Thr-365 and Ser-1995 were present together, thus overcoming the inhibitory effect of Ser-369. Taken together net PKC effect may be the difference between the responses of the stimulatory and inhibitory sites. Copyright © 2017 Elsevier Inc. All rights reserved.

Bilingual Contexts Modulate the Inhibitory Control Network

PubMed Central

Yang, Jing; Ye, Jianqiao; Wang, Ruiming; Zhou, Ke; Wu, Yan Jing

2018-01-01

The present functional magnetic resonance imaging (fMRI) study investigated influences of language contexts on inhibitory control and the underlying neural processes. Thirty Cantonese–Mandarin–English trilingual speakers, who were highly proficient in Cantonese (L1) and Mandarin (L2), and moderately proficient in English (L3), performed a picture-naming task in three dual-language contexts (L1-L2, L2-L3, and L1-L3). After each of the three naming tasks, participants performed a flanker task, measuring contextual effects on the inhibitory control system. Behavioral results showed a typical flanker effect in the L2-L3 and L1-L3 condition, but not in the L1-L2 condition, which indicates contextual facilitation on inhibitory control performance by the L1-L2 context. Whole brain analysis of the fMRI data acquired during the flanker tasks showed more neural activations in the right prefrontal cortex and subcortical areas in the L2-L3 and L1-L3 condition on one hand as compared to the L1-L2 condition on the other hand, suggesting greater involvement of the cognitive control areas when participants were performing the flanker task in L2-L3 and L1-L3 contexts. Effective connectivity analyses displayed a cortical-subcortical-cerebellar circuitry for inhibitory control in the trilinguals. However, contrary to the right-lateralized network in the L1-L2 condition, functional networks for inhibitory control in the L2-L3 and L1-L3 condition are less integrated and more left-lateralized. These findings provide a novel perspective for investigating the interaction between bilingualism (multilingualism) and inhibitory control by demonstrating instant behavioral effects and neural plasticity as a function of changes in global language contexts. PMID:29636713

Bilingual Contexts Modulate the Inhibitory Control Network.

PubMed

Yang, Jing; Ye, Jianqiao; Wang, Ruiming; Zhou, Ke; Wu, Yan Jing

2018-01-01

The present functional magnetic resonance imaging (fMRI) study investigated influences of language contexts on inhibitory control and the underlying neural processes. Thirty Cantonese-Mandarin-English trilingual speakers, who were highly proficient in Cantonese (L1) and Mandarin (L2), and moderately proficient in English (L3), performed a picture-naming task in three dual-language contexts (L1-L2, L2-L3, and L1-L3). After each of the three naming tasks, participants performed a flanker task, measuring contextual effects on the inhibitory control system. Behavioral results showed a typical flanker effect in the L2-L3 and L1-L3 condition, but not in the L1-L2 condition, which indicates contextual facilitation on inhibitory control performance by the L1-L2 context. Whole brain analysis of the fMRI data acquired during the flanker tasks showed more neural activations in the right prefrontal cortex and subcortical areas in the L2-L3 and L1-L3 condition on one hand as compared to the L1-L2 condition on the other hand, suggesting greater involvement of the cognitive control areas when participants were performing the flanker task in L2-L3 and L1-L3 contexts. Effective connectivity analyses displayed a cortical-subcortical-cerebellar circuitry for inhibitory control in the trilinguals. However, contrary to the right-lateralized network in the L1-L2 condition, functional networks for inhibitory control in the L2-L3 and L1-L3 condition are less integrated and more left-lateralized. These findings provide a novel perspective for investigating the interaction between bilingualism (multilingualism) and inhibitory control by demonstrating instant behavioral effects and neural plasticity as a function of changes in global language contexts.

Inhibition of glucosyltransferase activity by antisera to known serotypes of Streptococcus mutans.

PubMed

Evans, R T; Genco, R J

1973-02-01

Using a recently developed assay for glucosyltransferase activity based on (14)C-glucose incorporation into an alcohol-insoluble polysaccharide, we were able to study inhibition by antibody of this enzyme activity. Rabbit antibody was relatively specific for the strain of Streptoccus mutans from which the enzyme was obtained. Absorption studies showed that neither removal of antibodies directed to dextran nor absorption with intact bacteria offset the enzyme-inhibitory capacity of these sera, whereas absorption with partially purified enzyme did result in removal of the inhibitory capacity.

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. Copyright (c) 2009 John Wiley & Sons, Ltd.

Effect of inhibitory feedback on correlated firing of spiking neural network.

PubMed

Xie, Jinli; Wang, Zhijie

2013-08-01

Understanding the properties and mechanisms that generate different forms of correlation is critical for determining their role in cortical processing. Researches on retina, visual cortex, sensory cortex, and computational model have suggested that fast correlation with high temporal precision appears consistent with common input, and correlation on a slow time scale likely involves feedback. Based on feedback spiking neural network model, we investigate the role of inhibitory feedback in shaping correlations on a time scale of 100 ms. Notably, the relationship between the correlation coefficient and inhibitory feedback strength is non-monotonic. Further, computational simulations show how firing rate and oscillatory activity form the basis of the mechanisms underlying this relationship. When the mean firing rate holds unvaried, the correlation coefficient increases monotonically with inhibitory feedback, but the correlation coefficient keeps decreasing when the network has no oscillatory activity. Our findings reveal that two opposing effects of the inhibitory feedback on the firing activity of the network contribute to the non-monotonic relationship between the correlation coefficient and the strength of the inhibitory feedback. The inhibitory feedback affects the correlated firing activity by modulating the intensity and regularity of the spike trains. Finally, the non-monotonic relationship is replicated with varying transmission delay and different spatial network structure, demonstrating the universality of the results.

Low-frequency rTMS inhibitory effects in the primary motor cortex: Insights from TMS-evoked potentials.

PubMed

Casula, Elias P; Tarantino, Vincenza; Basso, Demis; Arcara, Giorgio; Marino, Giuliana; Toffolo, Gianna Maria; Rothwell, John C; Bisiacchi, Patrizia S

2014-09-01

The neuromodulatory effects of repetitive transcranial magnetic stimulation (rTMS) have been mostly investigated by peripheral motor-evoked potentials (MEPs). New TMS-compatible EEG systems allow a direct investigation of the stimulation effects through the analysis of TMS-evoked potentials (TEPs). We investigated the effects of 1-Hz rTMS over the primary motor cortex (M1) of 15 healthy volunteers on TEP evoked by single pulse TMS over the same area. A second experiment in which rTMS was delivered over the primary visual cortex (V1) of 15 healthy volunteers was conducted to examine the spatial specificity of the effects. Single-pulse TMS evoked four main components: P30, N45, P60 and N100. M1-rTMS resulted in a significant decrease of MEP amplitude and in a significant increase of P60 and N100 amplitude. There was no effect after V1-rTMS. 1-Hz rTMS appears to increase the amount of inhibition following a TMS pulse, as demonstrated by the higher N100 and P60, which are thought to originate from GABAb-mediated inhibitory post-synaptic potentials. Our results confirm the reliability of the TMS-evoked N100 as a marker of cortical inhibition and provide insight into the neuromodulatory effects of 1-Hz rTMS. The present finding could be of relevance for therapeutic and diagnostic purposes. Copyright © 2014 Elsevier Inc. All rights reserved.

Dopamine transporter-dependent and -independent actions of trace amine beta-phenylethylamine.

PubMed

Sotnikova, Tatyana D; Budygin, Evgeny A; Jones, Sara R; Dykstra, Linda A; Caron, Marc G; Gainetdinov, Raul R

2004-10-01

Beta-phenylethylamine (beta-PEA) is an endogenous amine that is found in trace amounts in the brain. It is believed that the locomotor-stimulating action of beta-PEA, much like amphetamine, depends on its ability to increase extracellular dopamine (DA) concentrations owing to reversal of the direction of dopamine transporter (DAT)-mediated DA transport. beta-PEA can also bind directly to the recently identified G protein-coupled receptors, but the physiological significance of this interaction is unclear. To assess the mechanism by which beta-PEA mediates its effects, we compared the neurochemical and behavioral effects of this amine in wild type (WT), heterozygous and 'null' DAT mutant mice. In microdialysis studies, beta-PEA, administered either systemically or locally via intrastriatal infusion, produced a pronounced outflow of striatal DA in WT mice whereas no increase was detected in mice lacking the DAT (DAT-KO mice). Similarly, in fast-scan voltammetry studies beta-PEA did not alter DA release and clearance rate in striatal slices from DAT-KO mice. In behavioral studies beta-PEA produced a robust but transient increase in locomotor activity in WT and heterozygous mice. In DAT-KO mice, whose locomotor activity and stereotypy are increased in a novel environment, beta-PEA (10-100 mg/kg) exerted a potent inhibitory action. At high doses, beta-PEA induced stereotypies in WT and heterozygous mice; some manifestations of stereotypy were also observed in the DAT-KO mice. These data demonstrate that the DAT is required for the striatal DA-releasing and hyperlocomotor actions of beta-PEA. The inhibitory action on hyperactivity and certain stereotypies induced by beta-PEA in DAT-KO mice indicate that targets other than the DAT are responsible for these effects.

Expression of a DNA Replication Gene Cluster in Bacteriophage T4: Genetic Linkage and the Control of Gene Product Interactions

PubMed Central

Gerald, W. L.; Karam, J. D.

1984-01-01

The results of this study bear on the relationship between genetic linkage and control of interactions between the protein products of different cistrons. In T4 bacteriophage, genes 45 and 44 encode essential components of the phage DNA replication multiprotein complex. T4 gene 45 maps directly upstream of gene 44 relative to the overall direction of reading of this region of the phage chromosome, but it is not known whether these two genes are cotranscribed. It has been shown that a nonsense lesion of T4 gene 45 exerts a cis-dominant inhibitory effect on growth of a missense mutant of gene 44 but not on growth of phage carrying the wild-type gene 44 allele. In previous work, we confirmed these observations on polarity of the gene 45 mutation but detected no polar effects by this lesion on synthesis of either mutant or wild-type gene 44 protein. In the present study, we demonstrate that mRNA for gene 44 protein is separable by gel electrophoresis from gene 45-protein-encoding mRNA. That is, the two proteins are not synthesized from one polycistronic message, and the cis-dominant inhibitory effect of the gene 45 mutation on gene 44 function is probably expressed at a posttranslational stage. We propose that close genetic linkage, whether or not it provides shared transcriptional and translational regulatory signals for certain clusters of functionally related cistrons, may determine the intracellular compartmentalization for synthesis of proteins encoded by these clusters. In prokaryotes, such linkage-dependent compartmentation may minimize the diffusion distances between gene products that are synthesized at low levels and are destined to interact. PMID:6745641

Comparative assessment of three in vitro exposure methods for combustion toxicity.

PubMed

Lestari, Fatma; Markovic, Boban; Green, Anthony R; Chattopadhyay, Gautam; Hayes, Amanda J

2006-01-01

A comparative assessment of three approaches for the use of human cells in vitro to investigate combustion toxicity was conducted. These included one indirect and two direct (passive and dynamic) exposure methods. The indirect method used an impinger system in which culture medium was used to trap the toxicants, whilst the direct exposure involved the use of a Horizontal Harvard Navicyte Chamber at the air/liquid interface. The cytotoxic effects of thermal decomposition products were assessed using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay (Promega) on a selection of human cells including: HepG2, A549 and skin fibroblasts. A small scale laboratory fire test using a vertical tube furnace was designed for the generation of combustion products. Polymethyl methacrylate (PMMA) was selected as a model polymer to study the cytotoxic effects of combustion products. NOAEC (no observable adverse effect concentration), IC10 (10% inhibitory concentration), IC50 (50% inhibitory concentration) and TLC (total lethal concentration) values were determined from dose response curves. Assessment using the NRU (neutral red uptake) and ATP (adenosine triphosphate) assays on human lung derived cells (A549) was also undertaken. Comparison between in vitro cytotoxicity results against published toxicity data for PMMA combustion and predicted LC50 (50% lethal concentration) values calculated from identified compounds using GCMS (gas chromatography mass spectrometry) was determined. The results suggested that the indirect exposure method did not appear to simulate closely exposure via inhalation, whilst exposure at the air/liquid interface by using the dynamic method proved to be a more representative method of human inhalation. This exposure method may be a potential system for in vitro cytotoxicity testing in combustion toxicity. Copyright 2005 John Wiley & Sons, Ltd.

A Randomized, Double-Blind, Sham-Controlled Trial of Transcranial Direct Current Stimulation in Attention-Deficit/Hyperactivity Disorder

PubMed Central

Cosmo, Camila; Baptista, Abrahão Fontes; de Araújo, Arão Nogueira; do Rosário, Raphael Silva; Miranda, José Garcia Vivas; Montoya, Pedro; de Sena, Eduardo Pondé

2015-01-01

Background Current standardized treatments for cognitive impairment in attention-deficit/hyperactivity disorder remain limited and their efficacy restricted. Transcranial direct current stimulation (tDCS) is a promising tool for enhancing cognitive performance in several neuropsychiatric disorders. Nevertheless, the effects of tDCS in reducing cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD) have not yet been investigated. Methods A parallel, randomized, double-blind, sham-controlled trial was conducted to examine the efficacy of tDCS on the modulation of inhibitory control in adults with ADHD. Thirty patients were randomly allocated to each group and performed a go/no-go task before and after a single session of either anodal stimulation (1 mA) over the left dorsolateral prefrontal cortex or sham stimulation. Results A nonparametric two-sample Wilcoxon rank-sum (Mann-Whitney) test revealed no significant differences between the two groups of individuals with ADHD (tDCS vs. sham) in regard to behavioral performance in the go/no go tasks. Furthermore, the effect sizes of group differences after treatment for the primary outcome measures—correct responses, impulsivity and omission errors—were small. No adverse events resulting from stimulation were reported. Conclusion According to these findings, there is no evidence in support of the use of anodal stimulation over the left dorsolateral prefrontal cortex as an approach for improving inhibitory control in ADHD patients. To the best of our knowledge, this is the first clinical study to assess the cognitive effects of tDCS in individuals with ADHD. Further research is needed to assess the clinical efficacy of tDCS in this population. Trial Registration ClinicalTrials.gov NCT01968512 PMID:26267861

A Randomized, Double-Blind, Sham-Controlled Trial of Transcranial Direct Current Stimulation in Attention-Deficit/Hyperactivity Disorder.

PubMed

Cosmo, Camila; Baptista, Abrahão Fontes; de Araújo, Arão Nogueira; do Rosário, Raphael Silva; Miranda, José Garcia Vivas; Montoya, Pedro; de Sena, Eduardo Pondé

2015-01-01

Current standardized treatments for cognitive impairment in attention-deficit/hyperactivity disorder remain limited and their efficacy restricted. Transcranial direct current stimulation (tDCS) is a promising tool for enhancing cognitive performance in several neuropsychiatric disorders. Nevertheless, the effects of tDCS in reducing cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD) have not yet been investigated. A parallel, randomized, double-blind, sham-controlled trial was conducted to examine the efficacy of tDCS on the modulation of inhibitory control in adults with ADHD. Thirty patients were randomly allocated to each group and performed a go/no-go task before and after a single session of either anodal stimulation (1 mA) over the left dorsolateral prefrontal cortex or sham stimulation. A nonparametric two-sample Wilcoxon rank-sum (Mann-Whitney) test revealed no significant differences between the two groups of individuals with ADHD (tDCS vs. sham) in regard to behavioral performance in the go/no go tasks. Furthermore, the effect sizes of group differences after treatment for the primary outcome measures-correct responses, impulsivity and omission errors--were small. No adverse events resulting from stimulation were reported. According to these findings, there is no evidence in support of the use of anodal stimulation over the left dorsolateral prefrontal cortex as an approach for improving inhibitory control in ADHD patients. To the best of our knowledge, this is the first clinical study to assess the cognitive effects of tDCS in individuals with ADHD. Further research is needed to assess the clinical efficacy of tDCS in this population. ClinicalTrials.gov NCT01968512.

miR-598 acts as a tumor suppressor in human gastric cancer by targeting IGF-1R.

PubMed

Liu, Na; Yang, Hua; Wang, Hong

2018-01-01

In recent years, the aberrant expression of miR-598 in tumorigenesis has been demonstrated, as well as the fact that the IGF-1R pathway is also involved in the development of human gastric cancer (GC). The present study aimed to investigate the molecular mechanisms underlying miR-598-regulated IGF-1R expression in human GC. We analyzed the expression of miR-598 and IGF-1R in GC samples and cells, and evaluated the clinical significance of miR-598 and IGF-1R in GC patients. Furthermore, in vitro and in vivo assays were used to investigate the molecular mechanisms of miR-598 and IGF-1R. miR-598 expression was frequently downregulated in GC tissues and cells, and significantly correlated with poor prognosis, vascular invasion, TNM stage, and lymph node metastases as well as IGF-1R expression. The overexpression of miR-598 obviously inhibited cell proliferation, migration, invasion, and induced cell cycle arrest in the G1/S phase, and increased the apoptosis of GC cells. The overexpression of miR-598 also significantly inhibited ERK1/2 and Akt phosphorylation level. In vivo assay validated the inhibitory effect of miR-598 on tumor growth. Further studies showed that miR-598 inhibited IGF-1R protein expression by directly targeting its 3'-UTR. Besides, over-expression of IGF-1R reversed the inhibitory effects of miR-598, while suppression of IGF-1R expression showed inverse effects. miR-598 suppresses GC cell proliferation, migration and invasion by directly targeting IGF-1R expression. Thus, miR-598 may be a useful target for GC patients.

The spatial extent of excitatory and inhibitory zones in the receptive field of superficial layer hypercomplex cells

PubMed Central

Sillito, A. M.

1977-01-01

1. An investigation has been made of the extent of inhibitory and excitatory components in the receptive field of superficial layer hypercomplex cells in the cat's striate cortex and the relation of the components to the length preference exhibited by these cells. 2. Maximal responses were produced by an optimal length stimulus moving through a restricted region of the receptive field. The length of this receptive field region was less than the total length of the excitatory zone as mapped with a very short slit. Slits of similar length to the excitatory zone produced a smaller response than an optimal length slit. 3. An increase of slit length so that it passed over receptive field regions either side of the excitatory zone resulted in an elimination of the response. When background discharge levels were increased by the iontophoretic application of D, L-homocysteic acid slits of this length were observed to produce a suppression of the resting discharge as they passed over the receptive field. They did not modify the resting discharge level when it was induced by the iontophoretic application of the GABA antagonist bicuculline. This data is taken to indicate that long slits activate a powerful post-synaptic inhibitory input to the cell. 4. Maximal inhibitory effects were only observed if the testing slit passed over the receptive field centre. That is slits with a gap positioned midway along their length so as to exclude the optimal excitatory response region surprisingly tended to produce excitatory effects rather than the expected inhibitory effects. It appears that simultaneous stimulation of the receptive field centre is a precondition for the inhibitory effect of stimulation of regions either side of the excitatory zone to be activated. 5. It is suggested that the interneurones mediating the inhibitory input to the superficial layer hypercomplex cells are driven both by cells in adjacent hypercolumns with receptive fields spatially displaced to either side of the excitatory zone and by cells in the same column, optimal inhibitory effects only being achieved when both sets of input to the interneurone are activated. PMID:604459

[Inhibition effects of Houttuynia cordata Thunb. on Microcystis aeruginosa].

PubMed

Liu, Lu; Li, Cheng; Xia, Wentong; Yang, Xiaohui; Zhang, Tingting

2014-05-01

To research the inhibitory effect of Houttuynia cordata Thunb. on Microcystis aeruginosa. M. aeruginosat were treated respectively by H. cordata leaching solution or H. cordata extracts. H. cordata leaching solution extracted by water and the H. cordata extracts extracted by organic solvent (acetone, ethyl acetate, petroleum ether and ethanol, respectively). The inhibition ratios were calculated according to the M. aeruginosa densities, and the allelochemicals of the extract that had the best inhibitiory effect on M. aeruginosa were identified by GC-MS analysis. It was proved that leaching solution of H. cordata and four crude extracts had good inhibitory effect on M. aeruginosa. The inhibitory effects of the four crude extracts were the fraction extracted by ethyl acetate, the fraction extracted by ethanol, the fraction extracted by acetone and the fraction extracted by petroleum ether form strong to weak in turn. Then, the allelochemicals of the fraction extracted by ethyl acetate were indentified, mainly including acetonyldimethylcarbinol, 2,2-dimethyl-3-hexanone, 6-chlorohexanoic and 4-cyanophenyl ester. H. cordata has strong inhibitory effect on water-blooming cyanobacteria and the potential to develop into an ecological M. aeruginosa inhibiting agent.

Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

PubMed Central

Manzke, Till; Niebert, Marcus; Koch, Uwe R.; Caley, Alex; Vogelgesang, Steffen; Hülsmann, Swen; Ponimaskin, Evgeni; Müller, Ulrike; Smart, Trevor G.; Harvey, Robert J.; Richter, Diethelm W.

2010-01-01

Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine receptor α3 subtype (GlyRα3), which controls glutamatergic and glycinergic neuronal discharges, subject to serotonergic modulation. Serotonin receptor type 1A–specific (5-HTR1A–specific) modulation directly induced dephosphorylation of GlyRα3 receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR1A and GlyRα3. The 5-HTR1A–GlyRα3 signaling pathway was distinct from opioid receptor signaling and efficiently counteracted opioid-induced depression of breathing and consequential apnea in mice. Paradoxically, this rescue of breathing originated from enhanced glycinergic synaptic inhibition of glutamatergic and glycinergic neurons and caused disinhibition of their target neurons. Together, these effects changed respiratory phase alternations and ensured rhythmic breathing in vivo. GlyRα3-deficient mice had an irregular respiratory rhythm under baseline conditions, and systemic 5-HTR1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR1A–GlyRα3 signaling pathway offers a mechanistic basis for pharmacological treatment of opioid-induced apnea and other breathing disturbances caused by disorders of inhibitory synaptic transmission, such as hyperekplexia, hypoxia/ischemia, and brainstem infarction. PMID:20978350

Inhibition-Induced Forgetting Results from Resource Competition between Response Inhibition and Memory Encoding Processes.

PubMed

Chiu, Yu-Chin; Egner, Tobias

2015-08-26

Response inhibition is a key component of executive control, but its relation to other cognitive processes is not well understood. We recently documented the "inhibition-induced forgetting effect": no-go cues are remembered more poorly than go cues. We attributed this effect to central-resource competition, whereby response inhibition saps attention away from memory encoding. However, this proposal is difficult to test with behavioral means alone. We therefore used fMRI in humans to test two neural predictions of the "common resource hypothesis": (1) brain regions associated with response inhibition should exhibit greater resource demands during encoding of subsequently forgotten than remembered no-go cues; and (2) this higher inhibitory resource demand should lead to memory encoding regions having less resources available during encoding of subsequently forgotten no-go cues. Participants categorized face stimuli by gender in a go/no-go task and, following a delay, performed a surprise recognition memory test for those faces. Replicating previous findings, memory was worse for no-go than for go stimuli. Crucially, forgetting of no-go cues was predicted by high inhibitory resource demand, as quantified by the trial-by-trial ratio of activity in neural "no-go" versus "go" networks. Moreover, this index of inhibitory demand exhibited an inverse trial-by-trial relationship with activity in brain regions responsible for the encoding of no-go cues into memory, notably the ventrolateral prefrontal cortex. This seesaw pattern between the neural resource demand of response inhibition and activity related to memory encoding directly supports the hypothesis that response inhibition temporarily saps attentional resources away from stimulus processing. Recent behavioral experiments showed that inhibiting a motor response to a stimulus (a "no-go cue") impairs subsequent memory for that cue. Here, we used fMRI to test whether this "inhibition-induced forgetting effect" is caused by competition for neural resources between the processes of response inhibition and memory encoding. We found that trial-by-trial variations in neural inhibitory resource demand predicted subsequent forgetting of no-go cues and that higher inhibitory demand was furthermore associated with lower concurrent activation in brain regions responsible for successful memory encoding of no-go cues. Thus, motor inhibition and stimulus encoding appear to compete with each other: when more resources have to be devoted to inhibiting action, less are available for encoding sensory stimuli. Copyright © 2015 the authors 0270-6474/15/3511936-10$15.00/0.

Microbial transformation of nucleosides

NASA Technical Reports Server (NTRS)

Lamba, S. S.

1979-01-01

A study involving the use of coulter counter in studying the effects of neomycin on E. coli, S. aureus and A. aerogenes was completed. The purpose of this was to establish proper technique for enumeration of cells per ml. It was found that inhibitory effects on growth of E. coli and A. aerogenes, both gram negative organisms, were directly related to the concentration of neomycin used. However, in case S. aureus, a gram positive organism, a decreased inhibition was noted at higher concentrations. A paper entitled, Use of Coulter Counter in Studying Effect of Drugs on Cells in Culture 1 - Effects of Neomycin on E. coli, S. aureus and A. aerogenes, is attached in the appendix. Laboratory procedures were also established to study the effects of nucleoside antibiotic cordycepin on He La cell grown in suspension cultures.

No Retrieval-Induced Forgetting Using Item-Specific Independent Cues: Evidence against a General Inhibitory Account

ERIC Educational Resources Information Center

Camp, Gino; Pecher, Diane; Schmidt, Henk G.

2007-01-01

Retrieval practice with particular items from memory can impair the recall of related items on a later memory test. This retrieval-induced forgetting effect has been ascribed to inhibitory processes (M. C. Anderson & B. A. Spellman, 1995). A critical finding that distinguishes inhibitory from interference explanations is that forgetting is found…

The Effect of Inhibitory Control on General Mathematics Achievement and Fraction Comparison in Middle School Children

ERIC Educational Resources Information Center

Gómez, David Maximiliano; Jiménez, Abelino; Bobadilla, Roberto; Reyes, Cristián; Dartnell, Pablo

2015-01-01

Individual differences in inhibitory control have been shown to relate to general mathematics achievement, but whether this relation varies for specific areas within mathematics is a question that remains open. Here, we evaluate if inhibitory processes play a specific role in the particular case of fraction comparison, where learners must ignore…

Antitubercular activity and inhibitory effect on Epstein-Barr virus activation of sterols and polyisoprenepolyols from an edible mushroom, Hypsizigus marmoreus.

PubMed

Akihisa, Toshihiro; Franzblau, Scott Gary; Tokuda, Harukuni; Tagata, Masaaki; Ukiya, Motohiko; Matsuzawa, Tsunetomo; Metori, Koichi; Kimura, Yumiko; Suzuki, Takashi; Yasukawa, Ken

2005-06-01

Seven sterols (1-7) and eight polyisoprenepolyols (8-15), isolated from the non-saponifiable lipid fraction of the dichloromethane extract of an edible mushroom, Hypsizigus marmoreus (Buna-shimeji), were tested for their antitubercular activity against Mycobacterium tuberculosis strain H37Rv using the Microplate Alamar Blue Assay (MABA). Six sterols (2-7) and two polyisoprenepolyols (8, 12) showed a minimum inhibitory concentration (MIC) in the range of 1-51 microg/ml, while the others (1, 9-11, 13-15) were inactive (MIC>128 microg/ml). The seven sterols (1-7) and three polyisoprenepolyols (8, 10, 12) were further evaluated for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Sterols 6 and 7 showed potent inhibitory effects while preserving the high viability of Raji cells.

Influence of baking enzymes on antimicrobial activity of five bacteriocin-like inhibitory substances produced by lactic acid bacteria isolated from Lithuanian sourdoughs.

PubMed

Narbutaite, V; Fernandez, A; Horn, N; Juodeikiene, G; Narbad, A

2008-12-01

To evaluate the effect of four different baking enzymes on the inhibitory activity of five bacteriocin-like inhibitory substances (BLIS) produced by lactic acid bacteria (LAB) isolated from Lithuanian sourdoughs. The overlay assay and the Bioscreen methods revealed that the five BLIS exhibited an inhibitory effect against spore germination and vegetative outgrowth of Bacillus subtilis, the predominant species causing ropiness in bread. The possibility that the observed antibacterial activity of BLIS might be lost after treatment with enzymes used for baking purposes was also examined. The enzymes tested; hemicellulase, lipase, amyloglucosidase and amylase had little or no effect on the majority of the antimicrobial activities associated with the five BLIS studied. This study suggests a potential application in the sourdough baking industry for these antimicrobial producing LAB strains in the control of B. subtilis spore germination and vegetative outgrowth.

Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens

PubMed Central

Ishikawa, Masago; Otaka, Mami; Neumann, Peter A; Wang, Zhijian; Cook, James M; Schlüter, Oliver M; Dong, Yan; Huang, Yanhua H

2013-01-01

Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway, a neural circuit that mediates behavioural responses elicited by natural rewards as well as by cocaine and other drugs of abuse. In addition to the well-known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, directly regulating NAc medium spiny neurons (MSNs). However, the cellular nature of VTA-to-NAc fast synaptic transmission and its roles in drug-induced adaptations are not well understood. Using viral-mediated in vivo expression of channelrhodopsin 2, the present study dissected fast excitatory and inhibitory synaptic transmission from the VTA to NAc MSNs in rats. Our results suggest that, following repeated exposure to cocaine (15 mg kg−1 day−1× 5 days, i.p., 1 or 21 day withdrawal), a presynaptic enhancement of excitatory transmission and suppression of inhibitory transmission occurred at different withdrawal time points at VTA-to-NAc core synapses. In contrast, no postsynaptic alterations were detected at either type of synapse. These results suggest that changes in VTA-to-NAc fast excitatory and inhibitory synaptic transmissions may contribute to cocaine-induced alteration of the brain reward circuitry. PMID:23918773

Hedgehog Promotes Production of Inhibitory Interneurons in Vivo and in Vitro from Pluripotent Stem Cells

PubMed Central

Anderson, Nickesha C.; Chen, Christopher Y.; Grabel, Laura

2016-01-01

Loss or damage of cortical inhibitory interneurons characterizes a number of neurological disorders. There is therefore a great deal of interest in learning how to generate these neurons from a pluripotent stem cell source so they can be used for cell replacement therapies or for in vitro drug testing. To design a directed differentiation protocol, a number of groups have used the information gained in the last 15 years detailing the conditions that promote interneuron progenitor differentiation in the ventral telencephalon during embryogenesis. The use of Hedgehog peptides and agonists is featured prominently in these approaches. We review here the data documenting a role for Hedgehog in specifying interneurons in both the embryonic brain during development and in vitro during the directed differentiation of pluripotent stem cells. PMID:29615590

Contribution of Transcranial Direct Current Stimulation on Inhibitory Control to Assess the Neurobiological Aspects of Attention Deficit Hyperactivity Disorder: Randomized Controlled Trial

PubMed Central

Baptista, Abrahão Fontes; de Sena, Eduardo Pondé

2015-01-01

Background The applicability of transcranial direct current stimulation (tDCS) in individuals with attention deficit hyperactivity disorder (ADHD) has not yet been investigated. This low-cost, non-invasive, and safe technique optimized to modulate the inhibitory response might be a useful treatment option for those affected by this condition. Objective The aim of this single center, parallel, randomized, double-blinded, sham-controlled trial is to investigate the efficacy of transcranial direct current stimulation over the prefrontal cortex on the modulation of inhibitory control in adults with attention deficit hyperactivity disorder. Methods A total of 60 individuals will be divided into 2 groups by block randomization to receive active or sham stimulation. Anodal stimulation over the left dorsolateral prefrontal cortex will be applied at 1 mA during a single 20-minute session. Before and after interventions, subjects will perform 2 go/no go tasks and the brain electrical activity will be recorded by electroencephalogram (EEG) with 32 channels, according to the 10-20 international EEG system. Results The trial began in May 2013 and we are currently performing the statistical analysis for the secondary outcomes. Conclusions The findings from this study will provide preliminary results about the role of prefrontal cortex activation through tDCS on ADHD patients. Trial Registration Clinicaltrials.gov NCT01968512; http://clinicaltrials.gov/ct2/show/NCT01968512 (Archived by WebCite at www.webcitation.org/6YMSW2tkD). PMID:25986784

Contribution of transcranial direct current stimulation on inhibitory control to assess the neurobiological aspects of attention deficit hyperactivity disorder: randomized controlled trial.

PubMed

Cosmo, Camila; Baptista, Abrahão Fontes; de Sena, Eduardo Pondé

2015-05-18

The applicability of transcranial direct current stimulation (tDCS) in individuals with attention deficit hyperactivity disorder (ADHD) has not yet been investigated. This low-cost, non-invasive, and safe technique optimized to modulate the inhibitory response might be a useful treatment option for those affected by this condition. The aim of this single center, parallel, randomized, double-blinded, sham-controlled trial is to investigate the efficacy of transcranial direct current stimulation over the prefrontal cortex on the modulation of inhibitory control in adults with attention deficit hyperactivity disorder. A total of 60 individuals will be divided into 2 groups by block randomization to receive active or sham stimulation. Anodal stimulation over the left dorsolateral prefrontal cortex will be applied at 1 mA during a single 20-minute session. Before and after interventions, subjects will perform 2 go/no go tasks and the brain electrical activity will be recorded by electroencephalogram (EEG) with 32 channels, according to the 10-20 international EEG system. The trial began in May 2013 and we are currently performing the statistical analysis for the secondary outcomes. The findings from this study will provide preliminary results about the role of prefrontal cortex activation through tDCS on ADHD patients. Clinicaltrials.gov NCT01968512; http://clinicaltrials.gov/ct2/show/NCT01968512 (Archived by WebCite at www.webcitation.org/6YMSW2tkD).

Old plants newly discovered: Cassia sieberiana D.C. and Cassia abbreviata Oliv. Oliv. root extracts inhibit in vitro HIV-1c replication in peripheral blood mononuclear cells (PBMCs) by different modes of action.

PubMed

Leteane, Melvin M; Ngwenya, Barbara N; Muzila, Mbaki; Namushe, Amos; Mwinga, John; Musonda, Rosemary; Moyo, Sikhulile; Mengestu, Yehualashete B; Abegaz, Berhanu M; Andrae-Marobela, Kerstin

2012-05-07

Despite advances in anti-retroviral therapy which has transformed HIV/AIDS from a fatal to a manageable chronic disease, increasing viral drug resistance, side effects and uneven access to anti-retroviral drugs remain considerable therapeutic challenges. Partly as a consequence of these shortcomings and partly based on the fact that HIV/AIDS gives rise to opportunistic infections whose symptoms have been managed in Africa in an HIV/AIDS-independent context by traditional healers for centuries, many HIV/AIDS patients use herbal medicines. The aim of this study was to screen selected medicinal plants from Botswana, used by traditional healers to treat/manage HIV/AIDS, for inhibitory activities on HIV replication. Based on an ethnomedical survey, ethanolic tannin-containing and tannin-free extracts from 10 medicinal plants were tested for inhibitory properties against a clone of HIV-1c (MJ(4)) measuring cytopathic effect protection and levels of viral p24 antigen in infected PBMCs. Cassia sieberiana D.C., Cassia abbreviata Oliv. Oliv. and Plumbago zeylanica L. extracts showed significant inhibition of HIV-1c (MJ(4)) replication. The inhibitory activity of the Plumbago zeylanica extract could be attributed to its tannin content. Anti-HIV activity of Cassia sieberiana root and bark extracts, and Cassia abbreviata root extracts occurred in a concentration-dependent manner with an effective concentration (EC(50)) of 65.1μg/ml, 85.3μg/ml and 102.8μg/ml, respectively. Experiments to elucidate possible mechanism(s) of action revealed that Cassia sieberiana root and bark extracts blocked HIV replication at its binding- (EC(50)=70.2μg/ml and 90.8μg/ml, respectively) and entry stage (EC(50)=88.9μg/ml and 100.5μg/ml, respectively) while Cassia abbreviata extracts did not. We report here for the first time a direct inhibitory effect on HIV-1c replication of extracts from two extremely popular medicinal plants, Cassia sieberiana and Cassia abbreviata. Considering the traditional uses of both Cassia species, our findings strongly suggest pilot clinical observational studies involving traditional healers to further evaluate the therapeutic potential of the Cassia extracts. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

INHIBITORY EFFECTS OF VOLATILE ORGANIC COMPOUNDS ON NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS.

EPA Science Inventory

INHIBITORY EFFECTS OF VOLATILE ORGANIC COMPOUNDS ON NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS.
A.S. Bale*; P.J. Bushnell; C.A. Meacham; T.J. Shafer
Neurotoxicology Division, NHEERL, ORD, US Environmental Protection Agency, Research Triangle Park, NC, USA
Toluene (TOL...

Toxic effect of two kinds of mineral collectors on soil microbial richness and activity: analysis by microcalorimetry, microbial count, and enzyme activity assay.

PubMed

Bararunyeretse, Prudence; Yao, Jun; Dai, Yunrong; Bigawa, Samuel; Guo, Zunwei; Zhu, Mijia

2017-01-01

Flotation reagents are hugely and increasingly used in mining and other industrial and economic activities from which an important part is discharged into the environment. China could be the most affected country by the resulting pollution. However, their ecotoxicological dimension is still less addressed and understood. This study aimed to analyze the toxic effect of sodium isobutyl xanthate (SIBX) and sodium isopropyl xanthate (SIPX) to soil microbial richness and activity and to make a comparison between the two compounds in regard to their effects on soil microbial and enzymes activities. Different methods, including microcalorimetry, viable cell counts, cell density, and catalase and fluorescein diacetate (FDA) hydrololase activities measurement, were applied. The two chemicals exhibited a significant inhibitory effect (P < 0.05 or P < 0.01) to all parameters, SIPX being more adverse than SIBX. As the doses of SIBX and SIPX increased from 5 to 300 μg g -1 soil, their inhibitory ratio ranged from 4.84 to 45.16 % and from 16.13 to 69.68 %, respectively. All parameters fluctuated with the incubation time (10-day period). FDA hydrolysis was more directly affected but was relatively more resilient than catalase activity. Potential changes of those chemicals in the experimental media and complementarity between experimental techniques were justified.

STRUCTURAL CHARACTERISTICS AND ANTIHYPERTENSIVE EFFECTS OF ANGIOTENSIN-I-CONVERTING ENZYME INHIBITORY PEPTIDES IN THE RENIN-ANGIOTENSIN AND KALLIKREIN KININ SYSTEMS

PubMed Central

Manoharan, Sivananthan; Shuib, Adawiyah Suriza; Abdullah, Noorlidah

2017-01-01

Background: The commercially available synthetic angiotensin-I-converting enzyme (ACE) inhibitors are known to exert negative side effects which have driven many research groups globally to discover the novel ACE inhibitors. Method: Literature search was performed within the PubMed, ScienceDirect.com and Google Scholar. Results: The presence of proline at the C-terminal tripeptide of ACE inhibitor can competitively inhibit the ACE activity. The effects of other amino acids are less studied leading to difficulties in predicting potent peptide sequences. The broad specificity of the enzyme may be due to the dual active sites observed on the somatic ACE. The inhibitors may not necessarily competitively inhibit the enzyme which explains why some reported inhibitors do not have the common ACE inhibitor characteristics. Finally, the in vivo assay has to be carried out before the peptides as the antihypertensive agents can be claimed. The peptides must be absorbed into circulation without being degraded, which will affect their bioavailability and potency. Thus, peptides with strong in vitro IC50 values do not necessarily have the same effect in vivo and vice versa. Conclusion: The relationship between peptide amino acid sequence and inhibitory activity, in vivo studies of the active peptides and bioavailability must be studied before the peptides as antihypertensive agents can be claimed. PMID:28573254

Inhibitory effect of corn silk on skin pigmentation.

PubMed

Choi, Sang Yoon; Lee, Yeonmi; Kim, Sung Soo; Ju, Hyun Min; Baek, Ji Hwoon; Park, Chul-Soo; Lee, Dong-Hyuk

2014-03-03

In this study, the inhibitory effect of corn silk on melanin production was evaluated. This study was performed to investigate the inhibitory effect of corn silk on melanin production in Melan-A cells by measuring melanin production and protein expression. The corn silk extract applied on Melan-A cells at a concentration of 100 ppm decreased melanin production by 37.2% without cytotoxicity. This was a better result than arbutin, a positive whitening agent, which exhibited a 26.8% melanin production inhibitory effect at the same concentration. The corn silk extract did not suppress tyrosinase activity but greatly reduced the expression of tyrosinase in Melan-A cells. In addition, corn silk extract was applied to the human face with hyperpigmentation, and skin color was measured to examine the degree of skin pigment reduction. The application of corn silk extract on faces with hyperpigmentation significantly reduced skin pigmentation without abnormal reactions. Based on the results above, corn silk has good prospects for use as a material for suppressing skin pigmentation.

Inhibitory Effect of Waste Glass Powder on ASR Expansion Induced by Waste Glass Aggregate

PubMed Central

Liu, Shuhua; Wang, Shu; Tang, Wan; Hu, Ningning; Wei, Jianpeng

2015-01-01

Detailed research is carried out to ascertain the inhibitory effect of waste glass powder (WGP) on alkali-silica reaction (ASR) expansion induced by waste glass aggregate in this paper. The alkali reactivity of waste glass aggregate is examined by two methods in accordance with the China Test Code SL352-2006. The potential of WGP to control the ASR expansion is determined in terms of mean diameter, specific surface area, content of WGP and curing temperature. Two mathematical models are developed to estimate the inhibitory efficiency of WGP. These studies show that there is ASR risk with an ASR expansion rate over 0.2% when the sand contains more than 30% glass aggregate. However, WGP can effectively control the ASR expansion and inhibit the expansion rate induced by the glass aggregate to be under 0.1%. The two mathematical models have good simulation results, which can be used to evaluate the inhibitory effect of WGP on ASR risk. PMID:28793603

Designed Ankyrin Repeat Proteins: A New Approach to Mimic Complex Antigens for Diagnostic Purposes?

PubMed Central

Hausammann, Stefanie; Vogel, Monique; Kremer Hovinga, Johanna A.; Lacroix-Desmazes, Sebastien; Stadler, Beda M.; Horn, Michael P.

2013-01-01

Inhibitory antibodies directed against coagulation factor VIII (FVIII) can be found in patients with acquired and congenital hemophilia A. Such FVIII-inhibiting antibodies are routinely detected by the functional Bethesda Assay. However, this assay has a low sensitivity and shows a high inter-laboratory variability. Another method to detect antibodies recognizing FVIII is ELISA, but this test does not allow the distinction between inhibitory and non-inhibitory antibodies. Therefore, we aimed at replacing the intricate antigen FVIII by Designed Ankyrin Repeat Proteins (DARPins) mimicking the epitopes of FVIII inhibitors. As a model we used the well-described inhibitory human monoclonal anti-FVIII antibody, Bo2C11, for the selection on DARPin libraries. Two DARPins were selected binding to the antigen-binding site of Bo2C11, which mimic thus a functional epitope on FVIII. These DARPins inhibited the binding of the antibody to its antigen and restored FVIII activity as determined in the Bethesda assay. Furthermore, the specific DARPins were able to recognize the target antibody in human plasma and could therefore be used to test for the presence of Bo2C11-like antibodies in a large set of hemophilia A patients. These data suggest, that our approach might be used to isolate epitopes from different sets of anti-FVIII antibodies in order to develop an ELISA-based screening assay allowing the distinction of inhibitory and non-inhibitory anti-FVIII antibodies according to their antibody signatures. PMID:23626669

Effects of Neuromodulation on Excitatory-Inhibitory Neural Network Dynamics Depend on Network Connectivity Structure

NASA Astrophysics Data System (ADS)

Rich, Scott; Zochowski, Michal; Booth, Victoria

2018-01-01

Acetylcholine (ACh), one of the brain's most potent neuromodulators, can affect intrinsic neuron properties through blockade of an M-type potassium current. The effect of ACh on excitatory and inhibitory cells with this potassium channel modulates their membrane excitability, which in turn affects their tendency to synchronize in networks. Here, we study the resulting changes in dynamics in networks with inter-connected excitatory and inhibitory populations (E-I networks), which are ubiquitous in the brain. Utilizing biophysical models of E-I networks, we analyze how the network connectivity structure in terms of synaptic connectivity alters the influence of ACh on the generation of synchronous excitatory bursting. We investigate networks containing all combinations of excitatory and inhibitory cells with high (Type I properties) or low (Type II properties) modulatory tone. To vary network connectivity structure, we focus on the effects of the strengths of inter-connections between excitatory and inhibitory cells (E-I synapses and I-E synapses), and the strengths of intra-connections among excitatory cells (E-E synapses) and among inhibitory cells (I-I synapses). We show that the presence of ACh may or may not affect the generation of network synchrony depending on the network connectivity. Specifically, strong network inter-connectivity induces synchronous excitatory bursting regardless of the cellular propensity for synchronization, which aligns with predictions of the PING model. However, when a network's intra-connectivity dominates its inter-connectivity, the propensity for synchrony of either inhibitory or excitatory cells can determine the generation of network-wide bursting.

Inhibitory activities of the alkaloids from Coptidis Rhizoma against aldose reductase.

PubMed

Jung, Hyun Ah; Yoon, Na Young; Bae, Hyun Ju; Min, Byung-Sun; Choi, Jae Sue

2008-11-01

As part of our ongoing search of natural sources for therapeutic and preventive agents for diabetic complications, the rat lens aldose reductase (RLAR) inhibitory effect of Coptidis Rhizoma (the rhizome of Coptis chinensis Franch) was evaluated. Its extract and fractions exhibited broad and moderate RLAR inhibitory activities of 38.9 approximately 67.5 microg/mL. In an attempt to identify bioactive components, six quaternary protoberberine-type alkaloids (berberine, palmatine, jateorrhizine, epiberberine, coptisine, and groenlandicine) and one quaternary aporphine-type alkaloid (magnoflorine) were isolated from the most active n-BuOH fraction, and the chemical structures therein were elucidated on the basis of spectroscopic evidence and comparison with published data. The anti-diabetic complications capacities of seven C. chinensis-derived alkaloids were evaluated via RLAR and human recombinant AR (HRAR) inhibitory assays. Although berberine and palmatine were previously reported as prime contributors to AR inhibition, these two major components exhibited no AR inhibitory effects at a higher concentration of 50 microg/ml in the present study. Conversely, epiberberine, coptisine, and groenlandicine exhibited moderate inhibitory effects with IC(50) values of 100.1, 118.4, 140.1 microM for RLAR and 168.1, 187.3, 154.2 microM for HRAR. The results clearly indicated that the presence of the dioxymethylene group in the D ring and the oxidized form of the dioxymethylene group in the A ring were partly responsible for the AR inhibitory activities of protoberberine-type alkaloids. Therefore, Coptidis Rhizoma, and the alkaloids contained therein, would clearly have beneficial uses in the development of therapeutic and preventive agents for diabetic complications and diabetes mellitus.

TGF-β Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning.

PubMed

Luo, Sarah X; Timbang, Leah; Kim, Jae-Ick; Shang, Yulei; Sandoval, Kadellyn; Tang, Amy A; Whistler, Jennifer L; Ding, Jun B; Huang, Eric J

2016-12-20

Neural circuits involving midbrain dopaminergic (DA) neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor β (TGF-β) signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-β type II receptor in DA neurons also disrupts the balance in TGF-β1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-β signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus-reward associations. These results support a role for TGF-β in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Occipital Nerve Field Transcranial Direct Current Stimulation Normalizes Imbalance Between Pain Detecting and Pain Inhibitory Pathways in Fibromyalgia.

PubMed

De Ridder, Dirk; Vanneste, Sven

2017-04-01

Occipital nerve field (OCF) stimulation with subcutaneously implanted electrodes is used to treat headaches, more generalized pain, and even failed back surgery syndrome via unknown mechanisms. Transcranial direct current stimulation (tDCS) can predict the efficacy of implanted electrodes. The purpose of this study is to unravel the neural mechanisms involved in global pain suppression, mediated by occipital nerve field stimulation, within the realm of fibromyalgia. Nineteen patients with fibromyalgia underwent a placebo-controlled OCF tDCS. Electroencephalograms were recorded at baseline after active and sham stimulation. In comparison with healthy controls, patients with fibromyalgia demonstrate increased dorsal anterior cingulate cortex, increased premotor/dorsolateral prefrontal cortex activity, and an imbalance between pain-detecting dorsal anterior cingulate cortex and pain-suppressing pregenual anterior cingulate cortex activity, which is normalized after active tDCS but not sham stimulation associated with increased pregenual anterior cingulate cortex activation. The imbalance improvement between the pregenual anterior cingulate cortex and the dorsal anterior cingulate cortex is related to clinical changes. An imbalance assumes these areas communicate and, indeed, abnormal functional connectivity between the dorsal anterior cingulate cortex and pregenual anterior cingulate cortex is noted to be caused by a dysfunctional effective connectivity from the pregenual anterior cingulate cortex to the dorsal anterior cingulate cortex, which improves and normalizes after real tDCS but not sham tDCS. In conclusion, OCF tDCS exerts its effect via activation of the descending pain inhibitory pathway and de-activation of the salience network, both of which are abnormal in fibromyalgia.

Inhibition mechanisms of hemoglobin, immunoglobulin G, and whole blood in digital and real-time PCR.

PubMed

Sidstedt, Maja; Hedman, Johannes; Romsos, Erica L; Waitara, Leticia; Wadsö, Lars; Steffen, Carolyn R; Vallone, Peter M; Rådström, Peter

2018-04-01

Blood samples are widely used for PCR-based DNA analysis in fields such as diagnosis of infectious diseases, cancer diagnostics, and forensic genetics. In this study, the mechanisms behind blood-induced PCR inhibition were evaluated by use of whole blood as well as known PCR-inhibitory molecules in both digital PCR and real-time PCR. Also, electrophoretic mobility shift assay was applied to investigate interactions between inhibitory proteins and DNA, and isothermal titration calorimetry was used to directly measure effects on DNA polymerase activity. Whole blood caused a decrease in the number of positive digital PCR reactions, lowered amplification efficiency, and caused severe quenching of the fluorescence of the passive reference dye 6-carboxy-X-rhodamine as well as the double-stranded DNA binding dye EvaGreen. Immunoglobulin G was found to bind to single-stranded genomic DNA, leading to increased quantification cycle values. Hemoglobin affected the DNA polymerase activity and thus lowered the amplification efficiency. Hemoglobin and hematin were shown to be the molecules in blood responsible for the fluorescence quenching. In conclusion, hemoglobin and immunoglobulin G are the two major PCR inhibitors in blood, where the first affects amplification through a direct effect on the DNA polymerase activity and quenches the fluorescence of free dye molecules, and the latter binds to single-stranded genomic DNA, hindering DNA polymerization in the first few PCR cycles. Graphical abstract PCR inhibition mechanisms of hemoglobin and immunoglobulin G (IgG). Cq quantification cycle, dsDNA double-stranded DNA, ssDNA single-stranded DNA.

In vivo evidence for the involvement of tachykinin NK3 receptors in the hexamethonium-resistant inhibitory transmission in the rat colon.

PubMed

Lecci, A; Giuliani, S; Tramontana, M; Meini, S; De Giorgio, R; Maggi, C A

1996-05-01

In urethane-anaesthetized rats, moderate colonic distention (0.5 ml) induced reflex rhythmic contractions (5 mm Hg amplitude and 1.1 cycles/min frequency). Senktide (1-10 nmol/kg, i.v.), a tachykinin NK3 receptor selective agonist, transiently suppressed distension-induced contractions. SR 142,801 (1-10 mumol/kg i.v.), a non-peptide tachykinin NK3 receptor antagonist, had no effect on distension-induced contractions but prevented the inhibitory effect of senktide. Infusion of N-omega-nitro-1-arginine methyl esther hydrochloride (L-NAME, 20 mumol/ml/h, i.v) increased the amplitude of colonic contractions and decreased the inhibitory effect of senktide. Hexamethonium (15 mumol/ml/h, i.v.) or atropine (1 mumol/ml/h, i.v.) inhibited the distension-induced contractions. In hexamethonium- or atropine-treated rats, senktide (10 nmol/kg) transiently and selectively enhanced the amplitude of contractions. Also SR 142,801 (10 mumol/kg), but not its inactive enantiomer SR 142,806, increased both amplitude and frequency of contractions. During continuous infusion of L-NAME and hexamethonium or atropine both frequency and amplitude of distension-induced colonic contractions were higher than when in hexamethonium or atropine only. Senktide (10 nmol/kg) had no effect and SR 142,801 (10 mumol/kg) produced a slight enhancement of colonic contractions. Infusion of sodium nitroprusside (3 mumol/ml/h, i.v.) decreased amplitude and frequency of distension-induced contractions. SR 142,801 had no effect in the presence of the nitric oxide (NO) donor. We conclude that tachykinins acting through NK3 receptors exert at least four different actions on colonic motility activated by distension: 1) a hexamethonium-resistant, NO-dependent, suppressant effect on contractions; 2) a hexamethonium-sensitive, NO-independent inhibitory effect on the amplitude of contractions; 3) a hexamethonium-resistant, NO-independent inhibitory effect on the amplitude of contractions and 4) a hexamethonium resistant and L-NAME-sensitive excitatory effect on amplitude of contractions. The prevalent inhibitory effect evoked in normal conditions along with the excitatory activity induced by SR 142,801 on hexamethonium-resistant colonic motility indicates that tachykinins, acting through neuronal NK3 receptors, activate NO-dependent and NO-independent inhibitory neurotransmission in the rat colon.

Concentration-Dependent Inhibitory Effect of Baicalin on the Plasma Protein Binding and Metabolism of Chlorzoxazone, a CYP2E1 Probe Substrate, in Rats In Vitro and In Vivo

PubMed Central

Gao, Na; Zou, Dan; Qiao, Hai-Ling

2013-01-01

Some of the components found in herbs may be inhibitors or inducers of cytochrome P450 enzymes, which may therefore result in undesired herb-drug interactions. As a component extracted from Radix Scutellariae, the direct effect of baicalin on cytochrome P450 has not been investigated sufficiently. In this study, we investigated concentration-dependent inhibitory effect of baicalin on the plasma protein binding and metabolism of chlorzoxazone (CZN), a model CYP2E1 probe substrate, in rats in vitro and in vivo. Animal experiment was a randomized, three-period crossover design. Significant changes in pharmacokinetic parameters of CZN such as Cmax, t1/2 and Vd were observed after treatment with baicalin in vivo (P<0.05). Cmax decreased by 25% and 33%, whereas t1/2 increased by 34% and 53%, Vd increased by 37% and 50% in 225 mg/kg and 450 mg/kg baicalin-treated rats, respectively. The AUC and CL of CZN were not affected (P>0.05). Correlation analysis showed that the changes in CZN concentrations and baicalin concentrations were in good correlation (r>0.99). In vitro experiments, baicalin decreased the formation of 6-OH-chlorzoxazone in a concentration-dependent manner and exhibited a competitive inhibition in rat liver microsomes, with a Ki value of 145.8 µM. The values of Cmax/Ki were 20 and 39 after treatment with baicalin (225 and 450 mg/kg), respectively. Protein binding experiments in vivo showed that the plasma free-fraction (fu) of CZN increased 2.6-fold immediately after baicalin treatment (450 mg/kg) and in vitro showed that baicalin (125–2500 mg/L) increased the unbound CZN from 1.63% to 3.58%. The results indicate that pharmacokinetic changes in CZN are induced by inhibitory effect of baicalin on the plasma protein binding of CZN and CYP2E1 activity. PMID:23301016

Modulating phonemic fluency performance in healthy subjects with transcranial magnetic stimulation over the left or right lateral frontal cortex.

PubMed

Smirni, Daniela; Turriziani, Patrizia; Mangano, Giuseppa Renata; Bracco, Martina; Oliveri, Massimiliano; Cipolotti, Lisa

2017-07-28

A growing body of evidence have suggested that non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), can improve the performance of aphasic patients in language tasks. For example, application of inhibitory rTMS or tDCs over the right frontal lobe of dysphasic patients resulted in improved naming abilities. Several studies have also reported that in healthy controls (HC) tDCS application over the left prefrontal cortex (PFC) improve performance in naming and semantic fluency tasks. The aim of this study was to investigate in HC, for the first time, the effects of inhibitory repetitive TMS (rTMS) over left and right lateral frontal cortex (BA 47) on two phonemic fluency tasks (FAS or FPL). 44 right-handed HCs were administered rTMS or sham over the left or right lateral frontal cortex in two separate testing sessions, with a 24h interval, followed by the two phonemic fluency tasks. To account for possible practice effects, an additional 22 HCs were tested on only the phonemic fluency task across two sessions with no stimulation. We found that rTMS-inhibition over the left lateral frontal cortex significantly worsened phonemic fluency performance when compared to sham. In contrast, rTMS-inhibition over the right lateral frontal cortex significantly improved phonemic fluency performance when compared to sham. These results were not accounted for practice effects. We speculated that rTMS over the right lateral frontal cortex may induce plastic neural changes to the left lateral frontal cortex by suppressing interhemispheric inhibitory interactions. This resulted in an increased excitability (disinhibition) of the contralateral unstimulated left lateral frontal cortex, consequently enhancing phonemic fluency performance. Conversely, application of rTMS over the left lateral frontal cortex may induce a temporary, virtual lesion, with effects similar to those reported in left frontal patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhibition of secretary PLA₂--VRV-PL-VIIIa of Russell's viper venom by standard aqueous stem bark extract of Mangifera indica L.

PubMed

Dhananjaya, B L; Sudarshan, S

2015-03-01

The aqueous extract of Mangifera indica is known to possess anti-snake venom activities. However, its inhibitory potency and mechanism of action on multi-toxic phospholipases A2s, which are the most toxic and lethal component of snake venom is still unknown. Therefore, this study was carried out to evaluate the modulatory effect of standard aqueous bark extract of M. indica on VRV-PL-VIIIa of Indian Russells viper venom. Mangifera indica extract dose dependently inhibited the GIIB sPLA2 (VRV-PL-VIIIa) activity with an IC50 value of 6.8±0.3 μg/ml. M. indica extract effectively inhibited the indirect hemolytic activity up to 96% at ~40 μg/ml concentration. Further, M. indica extract at different concentrations (0-50 μg/ml) inhibited the edema formed in a dose dependent manner. It was found that there was no relieve of inhibitory effect of the extract when examined as a function of increased substrate and calcium concentration. The inhibition was irreversible as evident from binding studies. The in vitro inhibition is well correlated with in situ and in vivo edema inducing activities. As the inhibition is independent of substrate, calcium concentration and was irreversible, it can be concluded that M. indica extracts mode of inhibition could be due to direct interaction of components present in the extract with PLA2 enzyme. In conclusion, the aqueous extract of M. indica effectively inhibits svPLA2 (Snake venom phospholipase A2) enzymatic and its associated toxic activities, which substantiate its anti-snake venom properties. Further in-depth studies are interesting to known on the role and mechanism of the principal inhibitory constituents present in the extract, so as to develop them into potent anti-snake venom and as an anti-inflammatory agent.

Inhibitory Effects of Gymnema (Gymnema sylvestre) Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis

PubMed Central

Yasukawa, Ken; Okuda, Sakiko; Nobushi, Yasuhito

2014-01-01

Ethanol extracts of gymnema (Gymnema sylvestre) leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear) in mice. The tested compounds showed marked anti-inflammatory effects, with a 50% inhibitory dose of 50–555 nmol/ear. PMID:24734106

Inhibitory Effects of Gymnema (Gymnema sylvestre) Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis.

PubMed

Yasukawa, Ken; Okuda, Sakiko; Nobushi, Yasuhito

2014-01-01

Ethanol extracts of gymnema (Gymnema sylvestre) leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear) in mice. The tested compounds showed marked anti-inflammatory effects, with a 50% inhibitory dose of 50-555 nmol/ear.

Structure of the inhibitory region of troponin by site directed spin labeling electron paramagnetic resonance

PubMed Central

Brown, Louise J.; Sale, Ken L.; Hills, Ron; Rouviere, Clement; Song, Likai; Zhang, Xiaojun; Fajer, Piotr G.

2002-01-01

Site-directed spin labeling EPR (SDSL-EPR) was used to determine the structure of the inhibitory region of TnI in the intact cardiac troponin ternary complex. Maeda and collaborators have modeled the inhibitory region of TnI (skeletal 96–112: the structural motif that communicates the Ca2+ signal to actin) as a kinked α-helix [Vassylyev, D., Takeda, S., Wakatsuki, S., Maeda, K. & Maeda, Y. (1998) Proc. Natl. Acad. Sci. USA 95, 4847–4852), whereas Trewhella and collaborators have proposed the same region to be a flexible β-hairpin [Tung, C. S., Wall, M. E., Gallagher, S. C. & Trewhella, J. (2000) Protein Sci. 9, 1312–1326]. To distinguish between the two models, residues 129–145 of cardiac TnI were mutated sequentially to cysteines and labeled with the extrinsic spin probe, MTSSL. Sequence-dependent solvent accessibility was measured as a change in power saturation of the spin probe in the presence of the relaxation agent. In the ternary complex, the 129–137 region followed a pattern characteristic of a regular 3.6 residues/turn α-helix. The following region, residues 138–145, showed no regular pattern in solvent accessibility. Measurements of 4 intradomain distances within the inhibitory sequence, using dipolar EPR, were consistent with an α-helical structure. The difference in side-chain mobility between the ternary (C⋅I⋅T) and binary (C⋅I) complexes revealed a region of interaction of TnT located at the N-terminal end of the inhibitory sequence, residues 130–135. The above findings for the troponin complex in solution do not support either of the computational models of the binary complex; however, they are in very good agreement with a preliminary report of the x-ray structure of the cardiac ternary complex [Takeda, S. Yamashita, A., Maeda, K. & Maeda, Y. (2002) Biophys. J. 82, 832]. PMID:12239350

GMP reverses the facilitatory effect of glutamate on inhibitory avoidance task in rats.

PubMed

Rubin, M A; Jurach, A; da Costa Júnior, E M; Lima, T T; Jiménez-Bernal, R E; Begnini, J; Souza, D O; de Mello, C F

1996-09-02

Previous studies have demonstrated that post-training intrahippocampal glutamate administration improves inhibitory avoidance task performance in rats. Antagonism of the agonist actions of glutamate by guanine nucleotides has been shown at the molecular and behavioural level. In the present investigation we demonstrate that intrahippocampal co-administration of GMP (guanosine 5'-monophosphate) reverses the facilitatory effect of glutamate on the inhibitory avoidance learning paradigm and inhibits [3H]glutamate binding in hippocampal synaptic plasma membranes. These results suggest that guanine nucleotides may modulate glutamate actions.

Short communication: Effect of casein haplotype on angiotensin-converting enzyme inhibitory and antioxidant capacities of milk casein from Italian Holstein cows before and following in vitro digestion with gastrointestinal enzymes.

PubMed

Perna, Annamaria; Simonetti, Amalia; Gambacorta, Emilio

2016-09-01

The aim of this work was to investigate the effect of casein haplotype (αS1, β, and κ) on antioxidative and angiotensin-converting enzyme (ACE) inhibitory capacities of milk casein from Italian Holstein cows before and following in vitro digestion with gastrointestinal enzymes. The antioxidant capacity was measured using 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid and ferric-reducing antioxidant power assays, whereas ACE inhibition was determined by ACE-inhibitory assay. The ACE-inhibitory and antioxidant capacities of milk casein increased during in vitro gastrointestinal digestion. Casein haplotype significantly influenced the antioxidative and ACE-inhibitory capacities of digested casein. In particular, BB-A(2)A(1)-AA casein and BB-A(1)A(1)-AA casein showed the highest ACE-inhibitory capacity, BB-A(2)A(2)-AA casein showed the highest antioxidant capacity, whereas BB-A(2)A(2)-BB casein showed the lowest biological capacity. To date, few studies have been done on the effect of casein haplotype on biological capacity of milk casein, thus the present study sets the basis for a new knowledge that could lead to the production of milk with better nutraceutical properties. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Comparison of the acute effects of high-intensity interval training and continuous aerobic walking on inhibitory control.

PubMed

Kao, Shih-Chun; Westfall, Daniel R; Soneson, Jack; Gurd, Brendon; Hillman, Charles H

2017-09-01

The purpose of this study was to investigate the effects of a single bout of high-intensity interval training (HIIT) and continuous aerobic exercise (CAE) on inhibitory control. The P3 component of the stimulus-locked ERP was collected in 64 young adults during a modified flanker task following 20 min of seated rest, 20 min of CAE, and 9 min of HIIT on separate days in counterbalanced order. Participants exhibited shorter overall reaction time following CAE and HIIT compared to seated rest. Response accuracy improved following HIIT in the task condition requiring greater inhibitory control compared to seated rest and CAE. P3 amplitude was larger following CAE compared to seated rest and HIIT. Decreased P3 amplitude and latency were observed following HIIT compared to seated rest. The current results replicated previous findings indicating the beneficial effect of acute CAE on behavioral and neuroelectric indices of inhibitory control. With a smaller duration and volume of exercise, a single bout of HIIT resulted in additional improvements in inhibitory control, paralleled by a smaller and more efficient P3 component. In sum, the current study demonstrated that CAE and HIIT differentially facilitate inhibitory control and its underlying neuroelectric activation, and that HIIT may be a time-efficient approach for enhancing cognitive health. © 2017 Society for Psychophysiological Research.

The involvement of ethylene in regulation of Arabidopsis gravitropism

NASA Astrophysics Data System (ADS)

Li, Ning; Zhu, Lin

Plant gravitropism is a directional response to gravity stimulus. This response involves a com-plex signaling network. Ethylene, a major plant hormone, has been found to modulate grav-itropism. The biosynthesis of ethylene is induced by the gravi-stimulus and the requirement for ethylene during gravitropism is tissue-dependent. While ethylene plays a modulating role in inflorescence stems, the light-grown hypocotyls of Arabidopsis requires ethylene to achieve a maximum gravicurvature. Because both inhibitory and stimulatory effects of ethylene on gravitropism have been overwhelmingly documented, there is a need to postulate a new theory to consolidate the apparently contradictory results. A dual-and-opposing effects (DOE) theory is therefore hypothesized to address how ethylene is involved in regulation of Arabidopsis grav-itropism, in which it is suggested that both stimulatory and inhibitory effects act on the same organ of a plant and co-exist at the same time in a mutually opposing manner. The final out-come of gravitropic response is determined by the dynamic display between the two opposing effects. A prolonged pretreatment of ethylene promotes the gravitropism in both inflorescence and light-grown hypocotyls, while a short ethylene pretreatment inhibits gravitropism. Gener-ally speaking, the inhibitory effect of ethylene is dominant over the expression of the stimula-tory effect in light-grown hypocotyls, whereas the stimulatory effect is dominant in inflorescence stem. Each effect is also positively correlated with concentrations of ethylene and in a time-dependent manner. The stimulatory effect occurs slowly but continues to react after the removal of ethylene, whereas the inhibitory effect takes place abruptly and diminishes shortly after its removal. Forward genetic screening based on the DOE phenotype of ethylene-treated Arabidop-sis has revealed a novel component in gravity signaling pathway: EGY1 (ethylene-dependent gravitropism-deficient and yellow green 1, Chen et al 2005; Guo et al 2008). To address the molecular mechanism by which ethylene regulates gravitropism, a cutting-edge phosphopro-teomics approach has been adopted to discover new components involved in ethylene signaling pathways (Li et al 2009). Two putative ethylene response transcription factors: EIL1 and ERF110, have been identified to contain ethylene-regulated phosphorylation sites, the phos-phorylation status of which are ethylene treatment-dependent but EIN2-independent, strongly suggestive of the existence of novel signaling components mediating an alternative ethylene signal pathway. Combination of the time-dependent ethylene treatments with the systematic profiling of protein phosphorylation using functional phosphoproteomics among Arabidopsis ethylene response mutants is able to provide more valuable information about the molecular mechanisms underlying ethylene and gravity signaling pathways. (This work is supported by grants: RPC07/08.SC16, 661408, 661207, N HKUST627/06, DAG04/05.SC08, HKUST6105/01M, and HKUST6413/06M)

Dynamics of excitatory and inhibitory networks are differentially altered by selective attention.

PubMed

Snyder, Adam C; Morais, Michael J; Smith, Matthew A

2016-10-01

Inhibition and excitation form two fundamental modes of neuronal interaction, yet we understand relatively little about their distinct roles in service of perceptual and cognitive processes. We developed a multidimensional waveform analysis to identify fast-spiking (putative inhibitory) and regular-spiking (putative excitatory) neurons in vivo and used this method to analyze how attention affects these two cell classes in visual area V4 of the extrastriate cortex of rhesus macaques. We found that putative inhibitory neurons had both greater increases in firing rate and decreases in correlated variability with attention compared with putative excitatory neurons. Moreover, the time course of attention effects for putative inhibitory neurons more closely tracked the temporal statistics of target probability in our task. Finally, the session-to-session variability in a behavioral measure of attention covaried with the magnitude of this effect. Together, these results suggest that selective targeting of inhibitory neurons and networks is a critical mechanism for attentional modulation. Copyright © 2016 the American Physiological Society.

Dynamics of excitatory and inhibitory networks are differentially altered by selective attention

PubMed Central

Snyder, Adam C.; Morais, Michael J.

2016-01-01

Inhibition and excitation form two fundamental modes of neuronal interaction, yet we understand relatively little about their distinct roles in service of perceptual and cognitive processes. We developed a multidimensional waveform analysis to identify fast-spiking (putative inhibitory) and regular-spiking (putative excitatory) neurons in vivo and used this method to analyze how attention affects these two cell classes in visual area V4 of the extrastriate cortex of rhesus macaques. We found that putative inhibitory neurons had both greater increases in firing rate and decreases in correlated variability with attention compared with putative excitatory neurons. Moreover, the time course of attention effects for putative inhibitory neurons more closely tracked the temporal statistics of target probability in our task. Finally, the session-to-session variability in a behavioral measure of attention covaried with the magnitude of this effect. Together, these results suggest that selective targeting of inhibitory neurons and networks is a critical mechanism for attentional modulation. PMID:27466133

Effect of inhibitory firing pattern on coherence resonance in random neural networks

NASA Astrophysics Data System (ADS)

Yu, Haitao; Zhang, Lianghao; Guo, Xinmeng; Wang, Jiang; Cao, Yibin; Liu, Jing

2018-01-01

The effect of inhibitory firing patterns on coherence resonance (CR) in random neuronal network is systematically studied. Spiking and bursting are two main types of firing pattern considered in this work. Numerical results show that, irrespective of the inhibitory firing patterns, the regularity of network is maximized by an optimal intensity of external noise, indicating the occurrence of coherence resonance. Moreover, the firing pattern of inhibitory neuron indeed has a significant influence on coherence resonance, but the efficacy is determined by network property. In the network with strong coupling strength but weak inhibition, bursting neurons largely increase the amplitude of resonance, while they can decrease the noise intensity that induced coherence resonance within the neural system of strong inhibition. Different temporal windows of inhibition induced by different inhibitory neurons may account for the above observations. The network structure also plays a constructive role in the coherence resonance. There exists an optimal network topology to maximize the regularity of the neural systems.

Improvement of ACE inhibitory activity of casein hydrolysate by Maillard reaction with xylose.

PubMed

Hong, Xu; Meng, Jun; Lu, Rong-Rong

2015-01-01

The Maillard reaction is widely used to improve the functional properties or biological activities of food. The purpose of this study was to investigate the effect of the Maillard reaction on angiotensin I converting enzyme (ACE) inhibitory activity in a casein hydrolysate-xylose system. Two-step hydrolysis was used to prepare casein ACE inhibitory peptides. Maillard reaction products (MRPs) were prepared by heating hydrolyzed casein with xylose at pH 8.0, 110 °C for up to 16 h. The results showed that the content of free amino group decreased (P < 0.05); however, browning intensity and absorbance at 294 nm increased because of the Maillard reaction (P < 0.05). The ACE inhibitory activity improved greatly within 2 h (from 63.48% to 90.23%), which was mainly due to carbonyl ammonia condensation reaction in the MRPs. The study shows that the Maillard reaction under appropriate conditions can improve the ACE inhibitory activity of casein hydrolysate effectively. © 2014 Society of Chemical Industry.

Structural Basis for the Effective Myostatin Inhibition of the Mouse Myostatin Prodomain-Derived Minimum Peptide.

PubMed

Asari, Tomo; Takayama, Kentaro; Nakamura, Akari; Shimada, Takahiro; Taguchi, Akihiro; Hayashi, Yoshio

2017-01-12

Myostatin inhibition is one of the promising strategies for treating muscle atrophic disorders, including muscular dystrophy. It is well-known that the myostatin prodomain derived from the myostatin precursor acts as an inhibitor of mature myostatin. In our previous study, myostatin inhibitory minimum peptide 1 (WRQNTRYSRIEAIKIQILSKLRL-amide) was discovered from the mouse myostatin prodomain. In the present study, alanine scanning of 1 demonstrated that the key amino acid residues for the effective inhibitory activity are rodent-specific Tyr and C-terminal aliphatic residues, in addition to N-terminal Trp residue. Subsequently, we designed five Pro-substituted peptides and examined the relationship between secondary structure and inhibitory activity. As a result, we found that Pro-substitutions of Ala or Gln residues around the center of 1 significantly decreased both α-helicity and inhibitory activity. These results suggested that an α-helical structure possessing hydrophobic faces formed around the C-terminus is important for inhibitory activity.

Potent Inhibitory Effect of Chinese Dietary Spices on Fatty Acid Synthase.

PubMed

Jiang, Bing; Liang, Yan; Sun, Xuebing; Liu, Xiaoxin; Tian, Weixi; Ma, Xiaofeng

2015-09-01

Dietary spices have been adopted in cooking since ancient times to enhance flavor and also as food preservatives and disease remedies. In China, the use of spices and other aromatic plants as food flavoring is an integral part of dietary behavior, but relatively little is known about their functions. Fatty acid synthase (FAS) has been recognized as a remedy target, and its inhibitors might be applied in disease treatment. The present work was designed to assess the inhibitory activities on FAS of spices extracts in Chinese menu. The in vitro inhibitory activities on FAS of 22 extracts of spices were assessed by spectrophotometrically monitoring oxidation of NADPH at 340 nm. Results showed that 20 spices extracts (90.9 %) exhibited inhibitory activities on FAS, with half inhibition concentration (IC(50)) values ranging from 1.72 to 810.7 μg/ml. Among them, seven spices showed strong inhibitory effect with IC(50) values lower than 10 μg/ml. These findings suggest that a large proportion of the dietary spices studied possess promising inhibitory activities on FAS, and subsequently might be applied in the treatment of obesity and obesity-related human diseases.

Inhibitory effect of emodin on human hepatoma cell line SMMC-7721 and its mechanism.

PubMed

Zhang, Xia; Chen, Yingping; Zhang, Ting; Zhang, Yaming

2015-03-01

Da Huang (Radix et Rhizoma Rhei) is the dried root or rhizome of Rheum palmatum L., Rheum tanguticum Maxim ex Balf. or Rheum officinale Braill of family Polygonaceae. It has heat clearing, damp drying, fire purging and toxin removing effects. Because of its definite curative efficacy, it has been widely applied in clinical settings. To study the inhibitory effect of emodin on human hepatoma cell line SMMC-7721 and its mechanism. MTT assay, flow cytometry and electron microscopy were used to investigate the inhibitory effect of different concentrations of emodin on human hepatoma cell line SMMC-7721. 12 h, 24 h and 48 h after the action of 20, 40 and 80 umol/L emodin on SMMC-7721 cells, the proliferation of human hepatoma SMMC-7721 cells was inhibited; the inhibitory effects showed time-and concentration-dependence. 48 h after the action of different concentrations of emodin on SMMC-7721 cells, cells in G2/M phase increased significantly, while the proportion of S phase cells gradually declined. Emodin can inhibit human hepatoma cell line SMMC-7721.

Inhibitory effect of strychnine on acetylcholine receptor activation in bovine adrenal medullary chromaffin cells.

PubMed Central

Kuijpers, G A; Vergara, L A; Calvo, S; Yadid, G

1994-01-01

1. Strychnine, which is known as a potent and selective antagonist of the inhibitory glycine receptor in the central nervous system, inhibits the nicotinic stimulation of catecholamine release from bovine cultured adrenal chromaffin cells in a concentration-dependent (1-100 microM) manner. At 10 microM nicotine, the IC50 value for strychnine is approximately 30 microM. Strychnine also inhibits the nicotine-induced membrane depolarization and increase in intracellular Ca2+ concentration. 2. The inhibitory action of strychnine is reversible and is selective for nicotinic stimulation, with no effect observed on secretion elicited by a high external K+ concentration, histamine or angiotensin II. 3. Strychnine competes with nicotine in its effect, but not modify the apparent positive cooperatively of the nicotine binding sites. In the absence of nicotine, strychnine has no effect on catecholamine release. Glycine does not affect catecholamine release nor the inhibitory action of strychnine on this release. 4. These results suggest that strychnine interacts with the agonist binding site of the nicotinic acetylcholine receptor in chromaffin cells, thus exerting a pharmacological effect independently of the glycine receptor. PMID:7834198

In vitro inhibitory effects of pulvinic acid derivatives isolated from Chinese edible mushrooms, Boletus calopus and Suillus bovinus, on cytochrome P450 activity.

PubMed

Huang, Yu-Ting; Onose, Jun-ichi; Abe, Naoki; Yoshikawa, Kunie

2009-04-23

Increasing attention has been focused on food-drug interactions. We have investigated the inhibitory effect of Chinese edible mushrooms, Boletus calopus and Suillus bovinus, on cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4, the main drug-metabolizing enzymes. Three pulvinic acid derivatives, atromentic acid (1), variegatic acid (2), and xerocomic acid (3), isolated from Boletus calopus and Suillus bovinus, revealed nonspecific inhibitory effects on all four CYPs. Using these compounds, the maximum IC50 values obtained with CYP3A4 in vitro were atromentic acid (1), 65.1+/-3.9 microM; variegatic acid (2), 2.2+/-0.1 microM; and xerocomic acid (3), 2.4+/-0.1 microM. Variegatic acid (2) and xerocomic acid (3) were effective inhibitors, comparable to cimetidine, dicoumarol, erythromycin, safrole, and uniconazole. Variegatic acid (2) and xerocomic acid (3) efficiently reduced ferryl myoglobin in CYPs. Reduction of ferryl heme to ferric heme is likely the mechanism of the nonspecific inhibitory effects of these compounds on CYPs.

Xenon inhibits excitatory but not inhibitory transmission in rat spinal cord dorsal horn neurons

PubMed Central

2010-01-01

Background The molecular targets for the promising gaseous anaesthetic xenon are still under investigation. Most studies identify N-methyl-D-aspartate (NMDA) receptors as the primary molecular target for xenon, but the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid (AMPA) receptors is less clear. In this study we evaluated the effect of xenon on excitatory and inhibitory synaptic transmission in the superficial dorsal horn of the spinal cord using in vitro patch-clamp recordings from rat spinal cord slices. We further evaluated the effects of xenon on innocuous and noxious stimuli using in vivo patch-clamp method. Results In vitro, xenon decreased the amplitude and area under the curve of currents induced by exogenous NMDA and AMPA and inhibited dorsal root stimulation-evoked excitatory postsynaptic currents. Xenon decreased the amplitude, but not the frequency, of miniature excitatory postsynaptic currents. There was no discernible effect on miniature or evoked inhibitory postsynaptic currents or on the current induced by inhibitory neurotransmitters. In vivo, xenon inhibited responses to tactile and painful stimuli even in the presence of NMDA receptor antagonist. Conclusions Xenon inhibits glutamatergic excitatory transmission in the superficial dorsal horn via a postsynaptic mechanism. There is no substantial effect on inhibitory synaptic transmission at the concentration we used. The blunting of excitation in the dorsal horn lamina II neurons could underlie the analgesic effect of xenon. PMID:20444263

Effects of acute buspirone administration on inhibitory control and sexual discounting in cocaine users.

PubMed

Strickland, Justin C; Bolin, B Levi; Romanelli, Michael R; Rush, Craig R; Stoops, William W

2017-01-01

Cocaine users display deficits in inhibitory control and make impulsive choices that may increase risky behavior. Buspirone is an anxiolytic that activates dopaminergic and serotonergic systems and improves impulsive choice (i.e., reduces sexual risk-taking intent) in cocaine users when administered chronically. We evaluated the effects of acutely administered buspirone on inhibitory control and impulsive choice. Eleven subjects with a recent history of cocaine use completed this within-subject, placebo-controlled study. Subjects performed two cued go/no-go and a sexual risk delay-discounting task following oral administration of buspirone (10 and 30 mg), triazolam (0.375 mg; positive control), and placebo (negative control). Physiological and psychomotor performance and subject-rated data were also collected. Buspirone failed to change inhibitory control or impulsive choice; however, slower reaction times were observed at the highest dose tested. Buspirone did not produce subject-rated drug effects but dose-dependently decreased diastolic blood pressure. Triazolam impaired psychomotor performance and increased ratings of positive subject-rated effects (e.g., Like Drug). These findings indicate that acutely administered buspirone has little impact on behavioral measures of inhibitory control and impulsive sexual decision-making. Considering previous findings with chronic dosing, these findings highlight that the behavioral effects of buspirone differ as a function of dosing conditions. Copyright © 2017 John Wiley & Sons, Ltd.

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

PubMed Central

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

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

Chromenylchalcones with inhibitory effects on monoamine oxidase B.

PubMed

Jo, Geunhyeong; Ahn, Seunghyun; Kim, Bong-Gyu; Park, Hye Ri; Kim, Young Hwa; Choo, Hyun Ah; Koh, Dongsoo; Chong, Youhoon; Ahn, Joong-Hoon; Lim, Yoongho

2013-12-15

Structure-activity relationship (SAR) calculations were used to find monoamine oxidase-B (MAO-B) inhibitors by identifying pharmacophores exhibiting high inhibitory activities. Several such chromenylchalcones were designed and synthesized accordingly. Their inhibitory effects on MAO-B were determined using an HPLC-based method and an MAO-B enzyme assay kit. (E)-3-(6-Methoxy-2H-chromen-3-yl)-1-(2-methoxyphenyl)prop-2-en-1-one exhibited a half-maximal inhibitory concentration of 320 nM. Its molecular-level binding mode with the three-dimensional structure of MAO-B was elucidated using an in silico docking study. The chromenylchalcone scaffold, which is derived from natural products including isoflavonoids and chalcones, had not been previously reported as an MAO-B inhibitor. Copyright © 2013 Elsevier Ltd. All rights reserved.

Ultraviolet-Visible (UV-Vis) and Fluorescence Spectroscopic Investigation of the Interactions of Ionic Liquids and Catalase.

PubMed

Dong, Xing; Fan, Yunchang; Yang, Peng; Kong, Jichuan; Li, Dandan; Miao, Juan; Hua, Shaofeng; Hu, Chaobing

2016-11-01

The inhibitory effects of nine ionic liquids (ILs) on the catalase activity were investigated using fluorescence, absorption ultraviolet-visible spectroscopy. The interactions of ILs and catalase on the molecular level were studied. The experimental results indicated that ILs could inhibit the catalase activity and their inhibitory abilities depended on their chemical structures. Fluorescence experiments showed that hydrogen bonding played an important role in the interaction process. The inhibitory abilities of ILs on catalase activity could be simply described by their hydrophobicity and hydrogen bonding abilities. Unexpected less inhibitory effects of trifluoromethanesulfonate (TfO - ) might be ascribed to its larger size, which makes it difficult to go through the substrate channel of catalase to the active site. © The Author(s) 2016.

[The influence of mitomycin C and paclitaxel on the proliferation and apoptosis of human pulmonary fibroblast].

PubMed

Chen, Nan; Zhang, Jie; Xu, Min; Wang, Ting; Wang, Yu-ling; Pei, Ying-hua

2013-09-01

To observe the inhibitory effect and potential mechanism of mitomycin C and paclitaxel on the proliferation of Human Pulmonary Fibroblast in vitro. So as to providing an experimental reference for the design of drug eluting airway stents. Cell viability was measured by MTT assay after different concentrations of mitomycin C or paclitaxel varying from 10(-1)1 mol/L to 10(-4) mol/L had been applied to the fibroblasts for 24, 48 or 72 h, respectively. Cell apoptosis was assessed by flow cytometry using dual staining with annexin V-FITC and propidium iodide 48 h after administering mitomycin C or paclitaxel at a concentration of 5×10(-6), 10(-5), 5×10(-5), 10(-4), 2×10(-4) mol/L, respectively. And the morphological character of cell apoptosis was observed by Hoechst 33342 fluorescent staining. The results of MTT revealed that cell proliferation were inhibited by mitomycin C and paclitaxel at all concentrations and exposure times. Among them, the inhibitory effect of mitomycin C were weak when the concentrations were between 10(-1)1 mol/L to 10(-8) mol/L. And within this context, the inhibitory ratio didn't correspond to the elevation of the concentration or the prolongation of the exposure times.However, when the concentration were between 10(-7) mol/L to 10(-4) mol/L, the inhibitory ratio rise progressively as the elevation of the concentration at all exposure times. The inhibitory ratio were 53.52%, 60.23%, 89.81% and 96.47% respectively when cells were treated by 10(-7), 10(-6), 10(-5) mol/L and 10(-4) mol/L mitomycin C for 72 h. An apparent "threshold dose effect" was observed in the paclitaxel treated groups.It's worth noting that the inhibitory ratio was only 48.22% when the cells had already been treated by 10(-5) mol/L paclitaxel for 72 h.However, when the concentration had reached 10(-4) mol/L, the inhibitory ratio sharply climbed to 93.38% even the cells had only been treated for 24 h. And the inhibitory ratio continued to rise as time prolonged. The results of cell apoptosis were consistent with MTT.When a significant inhibitory effect were detected by MTT, remarkable cell apoptosis could be observed by flow cytometry, and typical apoptotic cell could be identified by Hoechst 33342 fluorescent staining. A certain concentration of mitomycin C or paclitaxel can inhibit Human Pulmonary Fibroblast proliferation in vitro. Both of these two drugs have potential value for the preparation of drug eluting airway stents. In order to ensure the inhibitory effect, the eluting concentration of mitomycin C and paclitaxel should not be less than 10(-7) mol/L and 10(-5) mol/L. But the eluting concentration of these two drugs should not exceed 10(-4) mol/L when both of the inhibitory ratio of these two drugs were higher than 95%.On this basis, elevating the drug concentration has little significance for improving the inhibitory effect, but increase the risk of systemic toxicity. Inducing cell apoptosis is one of the potential mechanisms of mitomycin C and paclitaxel in inhibiting cell proliferation.

Role of F1C fimbriae, flagella, and secreted bacterial components in the inhibitory effect of probiotic Escherichia coli Nissle 1917 on atypical enteropathogenic E. coli infection.

PubMed

Kleta, Sylvia; Nordhoff, Marcel; Tedin, Karsten; Wieler, Lothar H; Kolenda, Rafal; Oswald, Sibylle; Oelschlaeger, Tobias A; Bleiss, Wilfried; Schierack, Peter

2014-05-01

Enteropathogenic Escherichia coli (EPEC) is recognized as an important intestinal pathogen that frequently causes acute and persistent diarrhea in humans and animals. The use of probiotic bacteria to prevent diarrhea is gaining increasing interest. The probiotic E. coli strain Nissle 1917 (EcN) is known to be effective in the treatment of several gastrointestinal disorders. While both in vitro and in vivo studies have described strong inhibitory effects of EcN on enteropathogenic bacteria, including pathogenic E. coli, the underlying molecular mechanisms remain largely unknown. In this study, we examined the inhibitory effect of EcN on infections of porcine intestinal epithelial cells with atypical enteropathogenic E. coli (aEPEC) with respect to single infection steps, including adhesion, microcolony formation, and the attaching and effacing phenotype. We show that EcN drastically reduced the infection efficiencies of aEPEC by inhibiting bacterial adhesion and growth of microcolonies, but not the attaching and effacing of adherent bacteria. The inhibitory effect correlated with EcN adhesion capacities and was predominantly mediated by F1C fimbriae, but also by H1 flagella, which served as bridges between EcN cells. Furthermore, EcN seemed to interfere with the initial adhesion of aEPEC to host cells by secretion of inhibitory components. These components do not appear to be specific to EcN, but we propose that the strong adhesion capacities enable EcN to secrete sufficient local concentrations of the inhibitory factors. The results of this study are consistent with a mode of action whereby EcN inhibits secretion of virulence-associated proteins of EPEC, but not their expression.

Evaluation of the tannic acid inhibitory effect against the NorA efflux pump of Staphylococcus aureus.

PubMed

Tintino, Saulo R; Oliveira-Tintino, Cícera D M; Campina, Fábia F; Silva, Raimundo L P; Costa, Maria do S; Menezes, Irwin R A; Calixto-Júnior, João T; Siqueira-Junior, José P; Coutinho, Henrique D M; Leal-Balbino, Tereza C; Balbino, Valdir Q

2016-08-01

During the early periods of antibiotic usage, bacterial infections were considered tamed. However, widespread antibiotic use has promoted the emergence of antibiotic-resistant pathogens, including multidrug resistant strains. Active efflux is a mechanism for bacterial resistance to inhibitory substances, known simply as drug efflux pumps. The bacterium Staphylococcus aureus is an important pathogenic bacterium responsible for an array of infections. The NorA efflux pump has been shown to be responsible for moderate fluoroquinolone resistance of S. aureus. The inhibition of the efflux pump was assayed using a sub-inhibitory concentration of standard efflux pump inhibitors and tannic acid (MIC/8), where its capacity to decrease the MIC of Ethidium bromide (EtBr) and antibiotics due to the possible inhibitory effect of these substances was observed. The MICs of EtBr and antibiotics were significantly reduced in the presence of tannic acid, indicating the inhibitory effect of this agent against the efflux pumps of both strains causing a three-fold reduction of the MIC when compared with the control. These results indicate the possible usage of tannic acid as an adjuvant in antibiotic therapy against multidrug resistant bacteria (MDR). Copyright © 2016 Elsevier Ltd. All rights reserved.

Inhibitory Effects of Polyacetylene Compounds from Panax ginseng on Neurotrophin Receptor-Mediated Hair Growth.

PubMed

Suzuki, Aoi; Matsuura, Daisuke; Kanatani, Hirotoshi; Yano, Shingo; Tsunakawa, Mitsuo; Matsuyama, Shigeru; Shigemori, Hideyuki

2017-01-01

Neurotrophins play an important role in the control of the hair growth cycle. Therefore, neurotrophin receptor antagonists have therapeutic potential for the treatment of hair growth disorders. In this study, we investigated the inhibitory effect of Panax ginseng, a medicinal plant commonly used to treat alopecia, on the binding of neurotrophins to their receptors. In addition, we isolated and characterized the bioactive compounds of P. ginseng extracts. P. ginseng hexane extracts strongly inhibited brain-derived neurotrophic factor (BDNF)-TrkB and β-nerve growth factor (β-NGF)-p75 neurotrophin receptor (p75NTR) binding. Furthermore, we identified the following 6 polyacetylene compounds as the bioactive components in P. ginseng hexane extract: panaxynol (1), panaxydol (2), panaxydol chlorohydrin (3), 1,8-heptadecadiene-4,6-diyne-3,10-diol (4), panaxytriol (5), and dihydropanaxacol (6). In particular, compounds 4, 5, and 6 significantly inhibited BDNF-TrkB binding in a dose-dependent manner. To identify the structural component mediating the inhibitory effect, we investigated the effects of the hydroxyl moiety in these compounds. We found that the inhibitory effect of panaxytriol (5) was strong, whereas the inhibitory effect of Ac-panaxytriol (7) was relatively weak. Our findings suggest that P. ginseng-derived polyacetylenes with a hydroxyl moiety might provide therapeutic benefits to patients with hair growth disorders such as alopecia by inhibiting the binding of neurotrophins to their receptors. Although saponins have been proposed to be the primary mediators of the effects of P. ginseng on hair growth, this study revealed that polyacetylene compounds exert similar effects.

Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases.

PubMed

Bautista-Aguilera, Óscar M; Hagenow, Stefanie; Palomino-Antolin, Alejandra; Farré-Alins, Víctor; Ismaili, Lhassane; Joffrin, Pierre-Louis; Jimeno, María L; Soukup, Ondřej; Janočková, Jana; Kalinowsky, Lena; Proschak, Ewgenij; Iriepa, Isabel; Moraleda, Ignacio; Schwed, Johannes S; Romero Martínez, Alejandro; López-Muñoz, Francisco; Chioua, Mourad; Egea, Javier; Ramsay, Rona R; Marco-Contelles, José; Stark, Holger

2017-10-02

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H 3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg -1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Investigations of the inhibitory effects of tocopherol (vitamin E) on free radical deterioration of cellular membranes

NASA Technical Reports Server (NTRS)

Richardson, D.

1975-01-01

The inhibitory effects are investigated of d,1-alpha-tocopherol and d,1-alpha-tocopheryl acetate on the free radical deterioration of cellular membranes. The level of toxicity of d,1-alpha-tocopherol and d,1-alpha-tocopheryl acetate in mice is determined.

Developmental Effects of Incentives on Response Inhibition

ERIC Educational Resources Information Center

Geier, Charles F.; Luna, Beatriz

2012-01-01

Inhibitory control and incentive processes underlie decision making, yet few studies have explicitly examined their interaction across development. Here, the effects of potential rewards and losses on inhibitory control in 64 adolescents (13- to 17-year-olds) and 42 young adults (18- to 29-year-olds) were examined using an incentivized antisaccade…

Growth regulation of the mammalian ocular lens by vitreous humor.

PubMed

Banerjee, A; Parafina, J; Bagchi, M

1992-05-01

Experiments were performed in our laboratory to study the effects of a mammalian 8 kD vitreous humor (VH) factor on the DNA synthesis and mitosis of the epithelial cells of organ cultured rabbit lens. The 8 kD polypeptide factor was purified from mature rabbit vitreous humor by liquid chromatography. Proliferative activities of the epithelial cells of organ cultured lenses were stimulated by 3% rabbit serum. The data from our experiments depicted that the 8 kD VH factor effectively inhibits DNA synthesis and mitosis by the epithelial cells of the organ cultured lens. Our experiments also showed that this 8 kD VH factor can maintain its growth inhibitory activity even when heated for 3 min at 95 degrees C. The growth inhibitory effect of the 8 kD VH factor was dose dependent. Using iodinated vitreal proteins it was demonstrated that the VH proteins are able to enter or bind to lens epithelial cells. The growth inhibitory effect of the 8 kD VH factor was also tested on tissue cultured lens epithelial cells. These experiments showed that the 8 kD VH factor has no growth inhibitory effect on the tissue cultured lens epithelial cells. This experiment has been repeated many times using different concentrations of the factor. These observations suggest that the 8 kD VH factor may have receptors in the lens capsular material (extracellular matrix) and the factor-receptor binding is essential for the growth inhibitory effect.

Novel whey-derived peptides with inhibitory effect against angiotensin-converting enzyme: in vitro effect and stability to gastrointestinal enzymes.

PubMed

Tavares, Tânia; Contreras, Maria Del Mar; Amorim, Manuela; Pintado, Manuela; Recio, Isidra; Malcata, F Xavier

2011-05-01

Whey protein concentrate (WPC) was subjected to enzymatic hydrolysis by proteases from the flowers of Cynara cardunculus, and the resulting angiotensin-converting enzyme (ACE)-inhibitory effect was monitored. The whole WPC hydrolysate exhibited an IC(50) value of 52.9 ± 2.9 μg/mL, whereas the associated peptide fraction with molecular weight below 3 kDa scored 23.6 ± 1.1 μg/mL. The latter fraction was submitted to RP-HPLC, and 6 fractions were resolved that exhibited ACE-inhibitory effects. Among the various peptides found, a total of 14 were identified via sequencing with an ion-trap mass spectrometer. Eleven of these peptides were synthesized de novo--to validate their ACE-inhibitory effect, and also to ascertain their stability when exposed to simulated gastrointestinal digestion. Among them, three novel, highly potent peptides were found, corresponding to α-lactalbumin f(16-26)--with the sequence KGYGGVSLPEW, α-lactalbumin f(97-104) with DKVGINYW, and β-lactoglobulin f(33-42) with DAQSAPLRVY; their IC(50) values were as low as 0.80 ± 0.1, 25.2 ± 1.0 and 13.0 ± 1.0 μg/mL, respectively. None of them remained stable in the presence of gastrointestinal enzymes: they were partially, or even totally hydrolyzed to smaller peptides--yet the observed ACE-inhibitory effects were not severely affected for two of those peptides. Copyright © 2011 Elsevier Inc. All rights reserved.

Age-Related Changes in Antisaccade Task Performance: Inhibitory Control or Working-Memory Engagement?

ERIC Educational Resources Information Center

Eenshuistra, R.M.; Ridderinkhof, K.R.; Molen, M.W.v.d.

2004-01-01

In antisaccade tasks, subjects are required to generate a saccade in the direction opposite to the location of a sudden-onset target stimulus. Compared to young adults, older adults tend to make more reflex-like eye movements towards the target, and/or show longer saccadic onset latencies on correct direct antisaccades. To better understand the…

Dual inhibition of nitric oxide and prostaglandin E2 production by polysubstituted 2-aminopyrimidines.

PubMed

Zídek, Zdeněk; Kverka, Miloslav; Dusilová, Adéla; Kmoníčková, Eva; Jansa, Petr

2016-07-01

The present in vitro experiments demonstrate inhibitory effects of polysubstituted 2-aminopyrimidines on high output production of nitric oxide (NO) and prostaglandin E2 (PGE2) stimulated by interferon-γ and lipopolysaccharide (LPS) in peritoneal macrophages of mouse and rat origin. PGE2 production was inhibited also in LPS-activated human peripheral blood mononuclear cells. A tight dependence of the suppressive activities on chemical structure of pyrimidines was observed. Derivatives containing hydroxyl groups at the C-4 and C-6 positions of pyrimidine ring were devoid of any influence on NO and PGE2. Remarkable inhibitory potential was acquired by the replacement of hydroxyl groups with chlorine, the 4,6-dichloro derivatives being more effective than the monochloro analogues. The effects were further intensified by modification of the amino group at the C-2 position, changing it to the (N,N-dimethylamino)methyleneamino or the formamido ones. There was no substantial difference in the expression of NO-inhibitory effects among derivatives containing distinct types of substituents at the C-5 position (hydrogen, methyl, ethyl, propyl, butyl, phenyl, and benzyl). In contrast to NO, larger substituents then methyl were required to inhibit PGE2 production. Overall, no significant correlation between the extent of NO and PGE2 suppression was observed. The IC50s of derivatives with the strongest effects on both NO and PGE2 were within the range of 2-10 μM. Their NO-inhibitory potential of pyrimidines was stronger than that of non-steroidal anti-inflammatory drugs (NSAIDs) aspirin and indomethacin. The PGE2-inhibitory effectiveness of pyrimidines was about the same as that of aspirin, but weaker as compared to indomethacin. The NO- and PGE2-inhibitory activity of tested pyrimidines has been found associated with decreased expression of iNOS mRNA and COX-2 mRNA, respectively, and with post-translation interactions. Selected NO-/PGE2-inhibitory derivatives decreased severity of intestinal inflammation in murine model of ulcerative colitis. Copyright © 2016 Elsevier Inc. All rights reserved.

[Killing effect of icotinib combined with CIK on human lung adenocarcinoma cells in vitro].

PubMed

Yao, B Q; Jia, Y; Guo, J Q; Zhao, Q; Sun, H; Zhang, J P

2017-08-23

Objective: To explore the inhibitory effect of icotinib combined with cytokine induced killer (CIK) on various human lung adenocarcinoma cell lines in vitro. Methods: The inhibitory effect of icotinib alone or icotinib combined with CIK on HCC827 and A549 cells was detected by cell counting kit-8(CCK-8). The apoptosis was detected by flow cytometry via Annexin V/PI staining. The effect of icotinib on CIK phenotype was detected by flow cytometry. Results: The inhibitory rates of HCC827 cells treated with 1.5, 3, 6, 12 μmol/L icotinib were (5.64±0.05)%, (8.62±0.45)%, (14.57±0.65)% and (18.52±0.91)%, respectively. The inhibitory rates of A549 cells were (1.64±0.48)%, (2.09±0.28)%, (3.69±0.45)%, (4.41±0.58)%, respectively. At the same concentration, the inhibitory rate of HCC827 cells with icotinib treatment was significantly higher than that of A549 cells ( P <0.05). When the effector/target ratio was 10∶1, 20∶1 or 40∶1, the inhibitory rates of HCC827 cells co-cultured with CIK were (15.17±2.33)%, (42.59±7.18)%, (62.59±8.95)%, respectively, and the inhibitory rates of A549 were(16.99±2.81)%, (46.31±1.89)%, (58.24±4.23)%, respectively. The inhibitory rate of HCC827 cells co-cultured with CIK was not significantly different from that of A549 cells at the same effector/target ratio ( P (10∶1)=0.299, P (20∶1)=0.318, P (40∶1)=0.366). When the effector/target ratio of CIK combined with 6 μmol/L icotinib was 10∶1, 20∶1 or 40∶1, the inhibitory rates of HCC827 cells were (37.07±3.50)%, (76.03±6.55)%, (80.34±10.69)%, respectively, and the inhibitory rates of A549 cells were(25.72±1.41)%, (52.76±3.82)%, (62.26±1.94)%, respectively. The inhibitory rates of 6 μmol/L icotinib combined with CIK were significantly higher than those of icotinib group and CIK group alone at the same effector/target ratio ( P <0.05), except for the effector/target ratio at 40︰1 on A549 cells ( P =0.089). Moreover, all of the combination index (CI) of combined group were <1 ( P <0.05). The apoptotic rates of HCC827 and A549 cells induced by icotinib combined with CIK were significantly higher than those of icotinib group and blank control group ( P <0.05), especially the proportion of late apoptotic or necrotic cells.Increasing effector/target ratio of CIK contributed to stronger inhibition( P <0.05). The expressional rate of CIK phenotype with or without icotinib treatment was not significantly different from each other( P >0.05). Conclusions: EGFR mutant lung adenocarcinoma cells are more sensitive to icotinib, while the EGFR mutation status has no effect on the killing effect of CIK cells. icotinib combined with CIK has a synergistic effect on the inhibition of tumor growth, and icotinib has no any impact on the phenotype of CIK cells.

Efficient method for the detection of microbially-produced antibacterial substances from food systems.

PubMed

Morgan, S M; Hickey, R; Ross, R P; Hill, C

2000-07-01

A novel method for the isolation of microbially-derived inhibitory substances from food sources was developed. The method involves an enrichment step coupled to a killing assay which is initially carried out in multiwell plates. The technique has advantages in that large numbers of samples can be tested in parallel. The assay can be completed in less than 60 h and is more sensitive than direct plating due to the enrichment step. This novel screening approach was compared with the standard direct plating approach in an effort to identify the antimicrobial potential of a number of Kefir grains. Kefir grains were incubated in 10% reconstituted skim milk for 20 h at 32 degrees C to enable production of any potential biopreservatives. Following overnight incubation, fermentates were aliquoted into multi-well plates and a known number of indicator cells was added to each well. The fermentates were incubated for a further 20 h and counts were carried out to determine whether a reduction in indicator cell numbers had occurred. A reduction in cell-forming units indicated the presence of an inhibitory substance and these inhibitory fermentates were selected for further investigation. Using the protocol outlined, Kefir fermentates capable of inhibiting Listeria innocua DPC1770 and Escherichia coli O157:H45 were identified.

The effect of celery (Apium graveolens L.) on fertility: A systematic review.

PubMed

Kooti, Wesam; Moradi, Maryam; Peyro, Khadijeh; Sharghi, Maedeh; Alamiri, Fatima; Azami, Milad; Firoozbakht, Mohammad; Ghafourian, Mehri

2017-10-06

Background Fertility and infertility problems are among the complex issues in medicine. The use of herbal products in the treatment of fertility has been considered as an alternative to synthetic drugs. Celery containing known compounds can have an impact on the fertility rate. The aim of this study was to do a systematic review on conducted studies in conjunction with the celery and reproduction. Methods Required papers were searched from databases like Science direct, PubMed, Scopus, and Springer. Keywords used in this study were "Apium graveolens L.", "fertility", "reproductive system", "sperm", "testis", "delivery", "sexual hormone", "LH", "FSH", "testosterone", "semen", "male", and "female". Out of 238 collected articles (published in the period 1995 to 2015), 222 were excluded due to non-relevance and lack of access to the original article. Results The notable points were the different results seen by different researchers during different treatment periods or at different doses. Of the 16 studies reviewed in this study, 13 studies have mentioned the positive effect of celery on fertility, while three studies reported the inhibitory effects of this plant. Conclusions Celery can have protective effects against substances such as sodium valproate, propylene glycol, and diethyl phthalate causing damages to the testicular structure and spermatogenesis. In this regard, the doses used and the treatment time while using the plant must be accurately investigated. Since there are compounds such as apigenin, the celery can induce inhibitory effects on fertility in case of chronic use or high concentration.

Cryptococcus neoformans inhibits nitric oxide synthesis caused by CpG-oligodeoxynucleotide-stimulated macrophages in a fashion independent of capsular polysaccharides.

PubMed

Xiao, Gang; Miyazato, Akiko; Inden, Ken; Nakamura, Kiwamu; Shiratori, Kohei; Nakagawa, Kiyotaka; Miyazawa, Teruo; Suzuki, Kazuo; Kaku, Mitsuo; Kawakami, Kazuyoshi

2008-03-01

Cryptococcus neoformans is eradicated by macrophages via production of NO. Unmethylated CpG-ODN protect mice from infection with this fungal pathogen by inducing IFN-gamma. The present study was designed to elucidate the effect of C. neoformans on the synthesis of NO by alveolar macrophages. For this purpose, MH-S, an alveolar macrophage cell line, was stimulated with CpG-ODN in the presence of IFN-gamma. A highly virulent strain of C. neoformans with thick capsule suppressed the production of NO. Capsular polysaccharides were not essential for this suppression, because there was no difference between acapsular mutant (Cap67) and its parent strain. Physical or close interaction of Cap67 with MH-S was necessary, as shown by the loss of such effect when direct contact was interfered by nitrocellulose membrane. Similar effects were observed by disrupted as well as intact Cap67. Whereas the inhibitory effect of intact Cap67 was completely abrogated by heat treatment, disrupted Cap67 did not receive such influence. Finally, disrupted Cap67 did not show any inhibitory effect on the TLR9-mediated activation of NF-kappaB in a luciferase reporter assay with HEK293T cells, although the TLR4-mediated activation was suppressed. These results revealed that C. neoformans suppressed the synthesis of NO by CpG-ODN and IFN-gamma-stimulated macrophages in a fashion independent of capsular polysaccharides, although the precise mechanism remains to be elucidated.

[Investigation on Inhibitory Capacities of Seventeen Herbal Extracts on Oxidative Stress using Ultraviolet and Fluorescence Spectroscopy].

PubMed

Hou, Guang-yue; Zheng, Zhong; Song, Feng-rui; Liu, Zhi-qiang; Zhao, Bing

2015-03-01

Diabetic patients usually suffer from complications and the long-term secondary complications are the main cause of morbidity and mortality. The hyperglycemia-induced oxidative stress is one of the important pathogenesis of diabetic complications, while the oxidative stress is associated with the lipid peroxidation reaction and the formation of advanced glycation end products (AGEs). Our study was focus on the pathogenesis of diabetic complications and based on the oxidative stress reaction. In this research, the oxidative stress inhibiting effects of seventeen herbal extracts were studied based on spectroscopic methodology. The capacities of herbal extracts against the lipid peroxidation reaction of rat liver in vitro were investigated using spectrophotometric method. It showed that the inhibitory activity of Radix Scutellariae and Flos Sophorae Immaturus were better than other herbal extracts. Additionally, the herbal extracts rich in flavonoids, alkaloids and lignanoids showed good inhibitory activities on the lipid peroxidation reaction. On the contrary, the saponin-rich herbal extracts possessed weak inhibitory effects. We applied the BSA/glucose (fructose) system combined with fluorescent spectroscopy to determine the inhibitory activities of herbal extracts in glycation model reactions. The results showed that the AGEs formation inhibitory activity of Flos Sophorae Immaturus, Radix Scutellariae and Rhizoma Anemarrhenae were better than others in the BSA/glucose (fructose) system by fluorescene analysis. The results demonstrated that the herbal extracts rich in flavonoids were found to be more effective than that of those herbal extracts as alkaloids and terpenoids class in inhibiting oxidative stress, while the saponin-rich herbal extracts showed weak inhibitory activities against oxidative stress. The Flos Sophorae Immaturus and Radix Scutellariae extracts had better inhibitory activity to the oxidative stress, so their pharmacological activity could be explored in further investigations. These results demonstrated in this assay could provide a reference for the study of pharmacological activity, and thus lays the foundation for the further study of the application of natural products in the prevention and treatment of diabetic complications.

Different mechanisms are involved in the antibody mediated inhibition of ligand binding to the urokinase receptor: a study based on biosensor technology.

PubMed

List, K; Høyer-Hansen, G; Rønne, E; Danø, K; Behrendt, N

1999-01-01

Certain monoclonal antibodies are capable of inhibiting the biological binding reactions of their target proteins. At the molecular level, this type of effect may be brought about by completely different mechanisms, such as competition for common binding determinants, steric hindrance or interference with conformational properties of the receptor critical for ligand binding. This distinction is central when employing the antibodies as tools in the elucidation of the structure-function relationship of the protein in question. We have studied the effect of monoclonal antibodies against the urokinase plasminogen activator receptor (uPAR), a protein located on the surface of various types of malignant and normal cells which is involved in the direction of proteolytic degradation reactions in the extracellular matrix. We show that surface plasmon resonance/biomolecular interaction analysis (BIA) can be employed as a highly useful tool to characterize the inhibitory mechanism of specific antagonist antibodies. Two inhibitory antibodies against uPAR, mAb R3 and mAb R5, were shown to exhibit competitive and non-competitive inhibition, respectively, of ligand binding to the receptor. The former antibody efficiently blocked the receptor against subsequent ligand binding but was unable to promote the dissociation of a preformed receptor-ligand complex. The latter antibody was capable of binding the preformed complex, forming a transient trimolecular assembly, and promoting the dissociation of the uPA/uPAR complex. The continuous recording of binding and dissociation, obtained in BIA, is central in characterizing these phenomena. The identification of a non-competitive inhibitory mechanism against this receptor reveals the presence of a determinant which influences the binding properties of a remote site in the molecular structure and which could be an important target for a putative synthetic antagonist.

Neuromuscular paralysis by the basic phospholipase A2 subunit of crotoxin from Crotalus durissus terrificus snake venom needs its acid chaperone to concurrently inhibit acetylcholine release and produce muscle blockage.

PubMed

Cavalcante, Walter L G; Noronha-Matos, José B; Timóteo, Maria A; Fontes, Marcos R M; Gallacci, Márcia; Correia-de-Sá, Paulo

2017-11-01

Crotoxin (CTX), a heterodimeric phospholipase A 2 (PLA 2 ) neurotoxin from Crotalus durissus terrificus snake venom, promotes irreversible blockade of neuromuscular transmission. Indirect electrophysiological evidence suggests that CTX exerts a primary inhibitory action on transmitter exocytosis, yet contribution of a postsynaptic action of the toxin resulting from nicotinic receptor desensitization cannot be excluded. Here, we examined the blocking effect of CTX on nerve-evoked transmitter release measured directly using radioisotope neurochemistry and video microscopy with the FM4-64 fluorescent dye. Experiments were conducted using mice phrenic-diaphragm preparations. Real-time fluorescence video microscopy and liquid scintillation spectrometry techniques were used to detect transmitter exocytosis and nerve-evoked [ 3 H]-acetylcholine ([ 3 H]ACh) release, respectively. Nerve-evoked myographic recordings were also carried out for comparison purposes. Both CTX (5μg/mL) and its basic PLA 2 subunit (CB, 20μg/mL) had biphasic effects on nerve-evoked transmitter exocytosis characterized by a transient initial facilitation followed by a sustained decay. CTX and CB reduced nerve-evoked [ 3 H]ACh release by 60% and 69%, respectively, but only the heterodimer, CTX, decreased the amplitude of nerve-evoked muscle twitches. Data show that CTX exerts a presynaptic inhibitory action on ACh release that is highly dependent on its intrinsic PLA 2 activity. Given the high safety margin of the neuromuscular transmission, one may argue that the presynaptic block caused by the toxin is not enough to produce muscle paralysis unless a concurrent postsynaptic inhibitory action is also exerted by the CTX heterodimer. Copyright © 2017. Published by Elsevier Inc.

Dopamine inhibits reproduction in female zebrafish (Danio rerio) via three pituitary D2 receptor subtypes.

PubMed

Fontaine, Romain; Affaticati, Pierre; Yamamoto, Kei; Jolly, Cécile; Bureau, Charlotte; Baloche, Sylvie; Gonnet, Françoise; Vernier, Philippe; Dufour, Sylvie; Pasqualini, Catherine

2013-02-01

In many teleosts, the stimulatory control of gonadotrope axis by GnRH is opposed by an inhibitory control by dopamine (DA). The functional importance of this inhibitory pathway differs widely from one teleostean species to another. The zebrafish (Danio rerio) is a teleost fish that has become increasingly popular as an experimental vertebrate model. However, the role of DA in the neuroendocrine control of its reproduction has never been studied. Here the authors evaluated in sexually regressed female zebrafish the effects of in vivo treatments with a DA D2 receptor (D2-R) antagonist domperidone, or a GnRH agonist, alone and in combination, on the pituitary level of FSHβ and LHβ transcripts, the gonadosomatic index, and the ovarian histology. Only the double treatment with GnRH agonist and domperidone could induce an increase in the expression of LHβ, in the gonadosomatic index, and a stimulation of ovarian vitellogenesis, indicating that removal of dopaminergic inhibition is required for the stimulatory action of GnRH and reactivation of ovarian function to occur. Using double immunofluorescent staining on pituitary, the authors showed in this species the innervation of LH cells by tyrosine-hydroxylase immunoreactive fibers. Finally, using in situ hybridization and immunofluorescence, the authors showed that the three subtypes of zebrafish DA D2-R (D2a, D2b, and D2c) were expressed in LH-producing cells, suggesting that they all may be involved in mediating this inhibition. These results show for the first time that, in zebrafish, DA has a direct and potent inhibitory action capable of opposing the stimulatory effect of GnRH in the neuroendocrine control of reproduction.

GABAA- and glycine-mediated inhibitory modulation of the cough reflex in the caudal nucleus tractus solitarii of the rabbit.

PubMed

Cinelli, Elenia; Iovino, Ludovica; Bongianni, Fulvia; Pantaleo, Tito; Mutolo, Donatella

2016-09-01

Cough-related sensory inputs from rapidly adapting receptors (RARs) and C fibers are processed by second-order neurons mainly located in the caudal nucleus tractus solitarii (NTS). Both GABAA and glycine receptors have been proven to be involved in the inhibitory control of second-order cells receiving RAR projections. We investigated the role of these receptors within the caudal NTS in the modulation of the cough reflex induced by either mechanical or chemical stimulation of the tracheobronchial tree in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections (30-50 nl) of the receptor antagonists bicuculline and strychnine as well as of the receptor agonists muscimol and glycine were performed. Bicuculline (0.1 mM) and strychnine (1 mM) caused decreases in peak abdominal activity and marked increases in respiratory frequency due to decreases in both inspiratory time (Ti) and expiratory time (Te), without concomitant changes in arterial blood pressure. Noticeably, these microinjections induced potentiation of the cough reflex consisting of increases in the cough number associated with decreases either in cough-related Ti after bicuculline or in both cough-related Ti and Te after strychnine. The effects caused by muscimol (0.1 mM) and glycine (10 mM) were in the opposite direction to those produced by the corresponding antagonists. The results show that both GABAA and glycine receptors within the caudal NTS mediate a potent inhibitory modulation of the pattern of breathing and cough reflex responses. They strongly suggest that disinhibition is one important mechanism underlying cough regulation and possibly provide new hints for novel effective antitussive strategies. Copyright © 2016 the American Physiological Society.

A pilot investigation of acute inhibitory control training in cocaine users.

PubMed

Alcorn, Joseph L; Pike, Erika; Stoops, William S; Lile, Joshua A; Rush, Craig R

2017-05-01

Disrupted response inhibition and presence of drug-cue attentional bias in cocaine-using individuals have predicted poor treatment outcomes. Inhibitory control training could help improve treatment outcomes by strengthening cognitive control. This pilot study assessed the effects of acute inhibitory control training to drug- and non-drug-related cues on response inhibition performance and cocaine-cue attentional bias in cocaine-using individuals. Participants who met criteria for a cocaine-use disorder underwent five sessions of inhibitory control training to either non-drug-related cues (i.e., rectangles) or cocaine cues (n=10/condition) in a single day. Response inhibition and attentional bias were assessed prior to and following training using the stop-signal task and visual-probe task with eye tracking, respectively. Training condition groups did not differ on demographics, inhibitory control training performance, response inhibition, or cocaine-cue attentional bias. Response inhibition performance improved as a function of inhibitory control training in both conditions. Cocaine-cue attentional bias was observed, but did not change as a function of inhibitory control training in either condition. Response inhibition in cocaine-using individuals was augmented by acute inhibitory control training, which may improve treatment outcomes through better behavioral inhibition. Future studies should investigate longer-term implementation of inhibitory control training, as well as combining inhibitory control training with other treatment modalities. Copyright © 2017 Elsevier B.V. All rights reserved.

Transcranial direct current stimulation enhances recovery of stereopsis in adults with amblyopia.

PubMed

Spiegel, Daniel P; Li, Jinrong; Hess, Robert F; Byblow, Winston D; Deng, Daming; Yu, Minbin; Thompson, Benjamin

2013-10-01

Amblyopia is a neurodevelopmental disorder of vision caused by abnormal visual experience during early childhood that is often considered to be untreatable in adulthood. Recently, it has been shown that a novel dichoptic videogame-based treatment for amblyopia can improve visual function in adult patients, at least in part, by reducing inhibition of inputs from the amblyopic eye to the visual cortex. Non-invasive anodal transcranial direct current stimulation has been shown to reduce the activity of inhibitory cortical interneurons when applied to the primary motor or visual cortex. In this double-blind, sham-controlled cross-over study we tested the hypothesis that anodal transcranial direct current stimulation of the visual cortex would enhance the therapeutic effects of dichoptic videogame-based treatment. A homogeneous group of 16 young adults (mean age 22.1 ± 1.1 years) with amblyopia were studied to compare the effect of dichoptic treatment alone and dichoptic treatment combined with visual cortex direct current stimulation on measures of binocular (stereopsis) and monocular (visual acuity) visual function. The combined treatment led to greater improvements in stereoacuity than dichoptic treatment alone, indicating that direct current stimulation of the visual cortex boosts the efficacy of dichoptic videogame-based treatment. This intervention warrants further evaluation as a novel therapeutic approach for adults with amblyopia.

Assessment of antibacterial properties of newer dentin bonding agents: An in vitro study.

PubMed

Sampath, Pavitra B; Hegde, Mithra N; Hegde, Priyadarshini

2011-07-01

To evaluate and compare the antibacterial activity of newer dentin bonding agents on Streptococcus mutans using the direct contact test. Streptococcus mutans was used as test organism and a direct contact test was performed. The dentin bonding agents to be tested were grouped as Group I, Clearfil Protect Bond, Group II, Adper Easy One, and Group III, Prime and Bond NT. For the direct contact test, three microtiter plates consisting of 96 wells each were taken (288 wells). These wells were divided into three groups of 96 wells; 16 wells of a microtiter plate were utilized, of which four were designated as 'A' wells (with the dentin bonding agent and bacterial suspension), another four as 'B' wells (without the dentin bonding agent, but with the bacterial suspension), another four as the 'C' wells (with the tested material, but without bacteria, which served as the negative control), and the remaining four as the 'D' wells (without the dentin bonding agent, which served as the positive control). Each group was treated with their respective bonding agents as per the manufactures instructions. Broth of 15 μL was then transferred from the A wells into an adjacent set of B wells containing fresh medium (215 μL). This resulted in two sets of four wells for each tested material containing an equal volume of liquid medium, so that bacterial growth was monitored both in the presence and in the absence of the tested material. The plate was placed for incubation at 37°C in the microplate reader and the optical density in each well was measured at 600 nm. The readings were taken at regular intervals. (Every 30 minutes for 16 hours). The Dentin bonding agents evaluated in this study showed different inhibitory effects. Clearfil Protect Bond and Prime and Bond NT were most effective, and Adper Easy One was least effective against Streptococcus mutans. The Dentin bonding agents evaluated in this study showed different inhibitory effects. Clearfil Protect Bond and Prime and Bond NT were most effective, and Adper Easy One was the least effective against Streptococcus mutans. Hence, the incorporation of antibacterial agents into the dentin bonding agents may become an essential factor in inhibiting residual bacteria in the cavity and secondary caries.

Different inhibitory potency of febuxostat towards mammalian and bacterial xanthine oxidoreductases: insight from molecular dynamics

PubMed Central

Kikuchi, Hiroto; Fujisaki, Hiroshi; Furuta, Tadaomi; Okamoto, Ken; Leimkühler, Silke; Nishino, Takeshi

2012-01-01

Febuxostat, a drug recently approved in the US, European Union and Japan for treatment of gout, inhibits xanthine oxidoreductase (XOR)-mediated generation of uric acid during purine catabolism. It inhibits bovine milk XOR with a Ki in the picomolar-order, but we found that it is a much weaker inhibitor of Rhodobacter capsulatus XOR, even though the substrate-binding pockets of mammalian and bacterial XOR are well-conserved as regards to catalytically important residues and three-dimensional structure, and both permit the inhibitor to be accommodated in the active site, as indicated by computational docking studies. To clarify the reason for the difference of inhibitory potency towards the two XORs, we performed molecular dynamics simulations. The results indicate that differences in mobility of hydrophobic residues that do not directly interact with the substrate account for the difference in inhibitory potency. PMID:22448318

Lateral Orbitofrontal Cortical Modulation on the Medial Prefrontal Cortex-Amygdala Pathway: Differential Regulation of Intra-Amygdala GABAA and GABAB Receptors.

PubMed

Chang, Chun-Hui

2017-07-01

The basolateral complex of the amygdala receives inputs from neocortical areas, including the medial prefrontal cortex and lateral orbitofrontal cortex. Earlier studies have shown that lateral orbitofrontal cortex activation exerts an inhibitory gating on medial prefrontal cortex-amygdala information flow. Here we examined the individual role of GABAA and GABAB receptors in this process. In vivo extracellular single-unit recordings were done in anesthetized rats. We searched amygdala neurons that fire in response to medial prefrontal cortex activation, tested lateral orbitofrontal cortex gating at different delays (lateral orbitofrontal cortex-medial prefrontal cortex delays: 25, 50, 100, 250, 500, and 1000 milliseconds), and examined differential contribution of GABAA and GABAB receptors with iontophoresis. Relative to baseline, lateral orbitofrontal cortex stimulation exerted an inhibitory modulatory gating on the medial prefrontal cortex-amygdala pathway and was effective up to a long delay of 500 ms (long-delay latencies at 100, 250, and 500 milliseconds). Moreover, blockade of intra-amygdala GABAA receptors with bicuculline abolished the lateral orbitofrontal cortex inhibitory gating at both short- (25 milliseconds) and long-delay (100 milliseconds) intervals, while blockade of GABAB receptors with saclofen reversed the inhibitory gating at long delay (100 milliseconds) only. Among the majority of the neurons examined (8 of 9), inactivation of either GABAA or GABAB receptors during baseline did not change evoked probability per se, suggesting that local feed-forward inhibitory mechanism is pathway specific. Our results suggest that the effect of lateral orbitofrontal cortex inhibitory modulatory gating was effective up to 500 milliseconds and that intra-amygdala GABAA and GABAB receptors differentially modulate the short- and long-delay lateral orbitofrontal cortex inhibitory gating on the medial prefrontal cortex-amygdala pathway. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Fear Conditioning Selectively Disrupts Noradrenergic Facilitation of GABAergic Inhibition in the Basolateral Amygdala

PubMed Central

Skelly, M. J.; Ariwodola, O. J.; Weiner, J. L.

2016-01-01

Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1- and β3-AR agonists (1μM A61603 and 10μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. PMID:27720769

Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala.

PubMed

Skelly, M J; Ariwodola, O J; Weiner, J L

2017-02-01

Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. Copyright © 2016 Elsevier Ltd. All rights reserved.

THE MECHANISM OF THE INHIBITION OF HEMOLYSIS

PubMed Central

Ponder, Eric

1945-01-01

This paper contains a description of some of the inhibitory, and occasionally acceleratory, effects of sols of lecithins, cholesterol, and proteins in hemolytic systems containing simple lysins, together with investigations on the nature of the reactions by means of which the effects are brought about. The principal conclusions are: A. As regards sols of lecithins. 1. In lysin-inhibitor-cell systems, distearyl lecithin is an inhibitor of saponin and digitonin hemolysis, part of the effect being the result of a reaction with the components of the red cell surface and part being the result of a reaction with lysin in the bulk phase of the system. Lecithin ab ovo (Merck) is an accelerator of saponin hemolysis and either an accelerator or an inhibitor of digitonin hemolysis according to the initial concentration of lysin present in the system. Soybean lecithin is an inhibitor of both saponin and digitonin hemolysis, but both soybean lecithin and lecithin ab ovo contain also a hemolytic, or acceleratory, component. 2. The inhibitory effects depend on the order in which the components of the hemolytic system are mixed together. Distearyl lecithin is about 5 times more inhibitory in cell-inhibitor-lysin systems than in lysin-inhibitor-cell systems containing saponin, digitonin, or taurocholate. Lecithin ab ovo is more inhibitory in cell-inhibitor-lysin systems when the time of contact between cells and inhibitor is short, but when it is long, the hemolytic properties of the lecithin offset its inhibitory properties. A similar state of affairs is observed with soybean lecithin. 3. An increase in temperature decreases the inhibitory effect of distearyl lecithin in systems containing saponin or digitonin. B. As regards sols of cholesterol. 4. The quantity of lysin Δ apparently inhibited by a quantity Q of cholesterol sol is dependent on both the type of red cell and the number of red cells added to the system. 5. Δ is a non-linear function of Q and of c 1, the initial quantity of lysin present in the hemolytic system, Δ generally increasing as c 1 increases. 6. The inhibitory effect of cholesterol sols is essentially due to a reaction between the cholesterol and the lysin in the bulk phase of the system, modified by what appear to be redistribution effects which depend on the kind and number of red cells added to complete the hemolytic system. 7. The value of Δ depends on the temperature and on the length of time during which the cholesterol and the lysin remain in contact before the addition of the cells. 8. Distearyl lecithin considerably enhances the inhibitory effects of cholesterol sols. C. As regards the proteins. 9. Freshly prepared serum globulin is inhibitory in systems containing saponin, digitonin, taurocholate, and oleate, and the effect is due to reactions in the bulk phase of the system, modified by redistribution effects. 10. Serum albumin either accelerates or inhibits lysis by saponin, depending on the initial concentration of lysin, and the inhibition depends on such factors as the type of red cell used and the time of contact. In the case of sodium taurocholate, the inhibition has a very marked pH dependence. D. As regards plasma. 11. The way in which the inhibitory effect depends on the length of time during which inhibitor and lysin are in contact before the addition of the cells is not the same when plasma is used as an inhibitor as when a cholesterol sol is used as the inhibitor. The amount of cholesterol sol which is equal in inhibitory power to a given amount of plasma accordingly varies according to the length of the time of contact which is selected. 12. The inhibitory effect in systems containing saponin, plasma, and red cells can be shown to depend on the order in which the components are mixed, when the concentration of the plasma is small. 13. The question as to how much of the inhibitory power of plasma can be accounted for by the contained cholesterol (total or free) is one which can be answered only if the experimental conditions are defined with respect to initial concentration of lysin, time of contact, and several other variables. Very roughly, about 50 per cent of the total inhibition of plasma, or a little more, can be attributed to the cholesterol fraction. 14. Since the inhibitory effects of plasma are the result of reactions in the bulk phase of the system, complicated by redistributions among the phases, of reactions between some of its components and components of the red cell surface, and of enhancing effects of its components upon each other, it is not surprising that nothing better than an empirical expression should have been found to describe the inhibition quantitatively. PMID:19873439

Molecular action of sulphonylureas on KATP channels: a real partnership between drugs and nucleotides.

PubMed

de Wet, Heidi; Proks, Peter

2015-10-01

Sulphonylureas stimulate insulin secretion from pancreatic β-cells primarily by closing ATP-sensitive K(+) channels in the β-cell plasma membrane. The mechanism of channel inhibition by these drugs is unusually complex. As direct inhibitors of channel activity, sulphonylureas act only as partial antagonists at therapeutic concentrations. However, they also exert an additional indirect inhibitory effect via modulation of nucleotide-dependent channel gating. In this review, we summarize current knowledge and recent advances in our understanding of the molecular mechanism of action of these drugs. © 2015 Authors; published by Portland Press Limited.

Atmospheric pressure cold plasma as an antifungal therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun Peng; Wu Haiyan; Sun Yi

2011-01-10

A microhollow cathode based, direct-current, atmospheric pressure, He/O{sub 2} (2%) cold plasma microjet was used to inactive antifungal resistants Candida albicans, Candida krusei, and Candida glabrata in air and in water. Effective inactivation (>90%) was achieved in 10 min in air and 1 min in water. Antifungal susceptibility tests showed drastic reduction of the minimum inhibitory concentration after plasma treatment. The inactivation was attributed to the reactive oxygen species generated in plasma or in water. Hydroxyl and singlet molecular oxygen radicals were detected in plasma-water system by electron spin resonance spectroscopy. This approach proposed a promising clinical dermatology therapy.

Influence of oculomotor nerve afferents on central endings of primary trigeminal fibers.

PubMed

Manni, E; Bortolami, R; Pettorossi, V E; Lucchi, M L; Callegari, E; Draicchio, F

1987-12-01

Painful fibers running in the third nerve and originating from the ophthalmic trigeminal area send their central projections at level of substantia gelatinosa of nucleus caudalis trigemini. The central endings of these fibers form axoaxonic synapses with trigeminal fibers entering the brain stem through the trigeminal root. The effect of electrical stimulation of the third nerve central stump on the central endings of trigeminal afferent fibers consists in an increased excitability, possibly resulting in a presynaptic inhibition. This inhibitory influence is due to both direct and indirect connections of the third nerve afferent fibers with the trigeminal ones.

Activation of Phosphoinositide Metabolism by Cholinergic Agents.

DTIC Science & Technology

1990-12-16

acid significantly inhibited NE-induced [3H]IP1 production in slices that had been prelabelled with [3H]inositol and baclofen , a specific GABAB...agonist, was as effective as GABA in enhancing the response to NE (Figure 15). Neither GABA nor baclofen significantly blocked the inhibitory effect of...quisqualate, but baclofen reduced the inhibitory effect of arachidonic acid. Effects of NMDA receptor antagonists on phosphoinositide hydrolysis MK-801 is

Clostridium perfringens epsilon toxin targets granule cells in the mouse cerebellum and stimulates glutamate release.

PubMed

Lonchamp, Etienne; Dupont, Jean-Luc; Wioland, Laetitia; Courjaret, Raphaël; Mbebi-Liegeois, Corinne; Jover, Emmanuel; Doussau, Frédéric; Popoff, Michel R; Bossu, Jean-Louis; de Barry, Jean; Poulain, Bernard

2010-09-30

Epsilon toxin (ET) produced by C. perfringens types B and D is a highly potent pore-forming toxin. ET-intoxicated animals express severe neurological disorders that are thought to result from the formation of vasogenic brain edemas and indirect neuronal excitotoxicity. The cerebellum is a predilection site for ET damage. ET has been proposed to bind to glial cells such as astrocytes and oligodendrocytes. However, the possibility that ET binds and attacks the neurons remains an open question. Using specific anti-ET mouse polyclonal antibodies and mouse brain slices preincubated with ET, we found that several brain structures were labeled, the cerebellum being a prominent one. In cerebellar slices, we analyzed the co-staining of ET with specific cell markers, and found that ET binds to the cell body of granule cells, oligodendrocytes, but not astrocytes or nerve endings. Identification of granule cells as neuronal ET targets was confirmed by the observation that ET induced intracellular Ca(2+) rises and glutamate release in primary cultures of granule cells. In cultured cerebellar slices, whole cell patch-clamp recordings of synaptic currents in Purkinje cells revealed that ET greatly stimulates both spontaneous excitatory and inhibitory activities. However, pharmacological dissection of these effects indicated that they were only a result of an increased granule cell firing activity and did not involve a direct action of the toxin on glutamatergic nerve terminals or inhibitory interneurons. Patch-clamp recordings of granule cell somata showed that ET causes a decrease in neuronal membrane resistance associated with pore-opening and depolarization of the neuronal membrane, which subsequently lead to the firing of the neuronal network and stimulation of glutamate release. This work demonstrates that a subset of neurons can be directly targeted by ET, suggesting that part of ET-induced neuronal damage observed in neuronal tissue is due to a direct effect of ET on neurons.

Clostridium perfringens Epsilon Toxin Targets Granule Cells in the Mouse Cerebellum and Stimulates Glutamate Release

PubMed Central

Lonchamp, Etienne; Dupont, Jean-Luc; Wioland, Laetitia; Courjaret, Raphaël; Mbebi-Liegeois, Corinne; Jover, Emmanuel; Doussau, Frédéric; Popoff, Michel R.; Bossu, Jean-Louis; de Barry, Jean; Poulain, Bernard

2010-01-01

Epsilon toxin (ET) produced by C. perfringens types B and D is a highly potent pore-forming toxin. ET-intoxicated animals express severe neurological disorders that are thought to result from the formation of vasogenic brain edemas and indirect neuronal excitotoxicity. The cerebellum is a predilection site for ET damage. ET has been proposed to bind to glial cells such as astrocytes and oligodendrocytes. However, the possibility that ET binds and attacks the neurons remains an open question. Using specific anti-ET mouse polyclonal antibodies and mouse brain slices preincubated with ET, we found that several brain structures were labeled, the cerebellum being a prominent one. In cerebellar slices, we analyzed the co-staining of ET with specific cell markers, and found that ET binds to the cell body of granule cells, oligodendrocytes, but not astrocytes or nerve endings. Identification of granule cells as neuronal ET targets was confirmed by the observation that ET induced intracellular Ca2+ rises and glutamate release in primary cultures of granule cells. In cultured cerebellar slices, whole cell patch-clamp recordings of synaptic currents in Purkinje cells revealed that ET greatly stimulates both spontaneous excitatory and inhibitory activities. However, pharmacological dissection of these effects indicated that they were only a result of an increased granule cell firing activity and did not involve a direct action of the toxin on glutamatergic nerve terminals or inhibitory interneurons. Patch-clamp recordings of granule cell somata showed that ET causes a decrease in neuronal membrane resistance associated with pore-opening and depolarization of the neuronal membrane, which subsequently lead to the firing of the neuronal network and stimulation of glutamate release. This work demonstrates that a subset of neurons can be directly targeted by ET, suggesting that part of ET-induced neuronal damage observed in neuronal tissue is due to a direct effect of ET on neurons. PMID:20941361

[Peptidergic modulation of the hippocampus synaptic activity].

PubMed

Skrebitskiĭ, V G; Kondratenko, R V; Povarov, I S; Dereviagin, V I

2011-11-01

Effects of two newly synthesized nootropic and anxiolytic dipeptides: Noopept and Selank on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) or Selank (2 microM) significantly increased the frequency of spike-dependent spontaneous m1PSCs, whereas spike-independent mlPSCs remained unchanged. It was suggested that both peptides mediated their effect sue to activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion, at least for Noonent.

Joint toxicity of methamidophos and cadmium acting on Abelmoschus manihot.

PubMed

Wang, Xiao-Fei; Zhou, Qi-Xing

2005-01-01

Joint toxicity of methamidophos and cadmium (Cd) on the ornamental Abelmoschus manihot was firstly examined and compared with single-factor effects of the two pollutants using ecotoxicological indexes including the inhibitory rate of seed germination, root elongation and inhibitory concentration 50% (IC50). The results indicated that methamidophos and Cd had unobvious( p > 0.05) effects on seed germination of the ornamental. There were significant( p < 0.05) inhibitory effects of Cd on root elongation of the tested plant. When the concentration of added Cd was low( < 20 mg/L), significant antagonistic effects on root elongation were observed. And synergic effects were observed when Cd was added in high dose( > 20 mg/L). However, the analysis of joint effects indicated that there were antagonistic effects between Cd and methamidophos under all the treatments. At the high concentration of Cd, joint toxicity of methamidophos and Cd was more dependent on concentration of Cd.

Spiking and Excitatory/Inhibitory Input Dynamics of Barrel Cells in Response to Whisker Deflections of Varying Velocity and Angular Direction.

PubMed

Patel, Mainak

2018-01-15

The spiking of barrel regular-spiking (RS) cells is tuned for both whisker deflection direction and velocity. Velocity tuning arises due to thalamocortical (TC) synchrony (but not spike quantity) varying with deflection velocity, coupled with feedforward inhibition, while direction selectivity is not fully understood, though may be due partly to direction tuning of TC spiking. Data show that as deflection direction deviates from the preferred direction of an RS cell, excitatory input to the RS cell diminishes minimally, but temporally shifts to coincide with the time-lagged inhibitory input. This work constructs a realistic large-scale model of a barrel; model RS cells exhibit velocity and direction selectivity due to TC input dynamics, with the experimentally observed sharpening of direction tuning with decreasing velocity. The model puts forth the novel proposal that RS→RS synapses can naturally and simply account for the unexplained direction dependence of RS cell inputs - as deflection direction deviates from the preferred direction of an RS cell, and TC input declines, RS→RS synaptic transmission buffers the decline in total excitatory input and causes a shift in timing of the excitatory input peak from the peak in TC input to the delayed peak in RS input. The model also provides several experimentally testable predictions on the velocity dependence of RS cell inputs. This model is the first, to my knowledge, to study the interaction of direction and velocity and propose physiological mechanisms for the stimulus dependence in the timing and amplitude of RS cell inputs. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Reduction of Fusarium rot and maintenance of fruit quality in melon using eco-friendly hot water treatment.

PubMed

Sui, Yuan; Droby, Samir; Zhang, Danfeng; Wang, Wenjie; Liu, Yongsheng

2014-12-01

Significant losses in harvested fruit can be directly attributable to decay fungi and quality deterioration. Hot water treatment (HWT) has been demonstrated to be an effective and economic environment-friendly approach for managing postharvest decay and maintaining fruit quality. In this study, the effects of HWT (45 °C for 10, 15, 20, and 25 min) on in vitro growth of Fusarium oxysporum, in vivo Fusarium rot, and natural decay of melon were investigated. HWT inhibited spore germination and germ tube elongation of F. oxysporum. Protein impairment and ATP consumption triggered by HWT contributed to the inhibitory effect. Results of in vivo studies showed that HWT effectively controlled Fusarium rot and natural decay of melon. Correspondingly, HWT induced a significant increase in content of total phenolic compounds and lignin of melon. These findings indicate that the effects of HWT on Fusarium rot may be associated with the direct fungal inhibition and the elicitation of defense responses in fruit. Importantly, HWT used in this study had beneficial effects on fruit quality as well. HWT may represent an effective non-chemical approach for management of postharvest Fusarium rot.

Selective Attention and Inhibitory Deficits in ADHD: Does Subtype or Comorbidity Modulate Negative Priming Effects?

ERIC Educational Resources Information Center

Pritchard, Verena E.; Neumann, Ewald; Rucklidge, Julia J.

2008-01-01

Selective attention has durable consequences for behavior and neural activation. Negative priming (NP) effects are assumed to reflect a critical inhibitory component of selective attention. The performance of adolescents with Attention Deficit/Hyperactivity Disorder (ADHD) was assessed across two conceptually based NP tasks within a selective…

Inhibitory Effect of Autoclaving Whey-Based Medium on Propionic Acid Production by Propionibacterium shermanii.

PubMed

Anderson, T M; Bodie, E A; Goodman, N; Schwartz, R D

1986-02-01

Propionic acid production by Propionibacterium shermanii was compared in pasteurized and autoclaved whey-based media. Propionic acid production decreased with increasing whey concentration in autoclaved media but not in pasteurized media. Increasing the yeast extract concentration from 5 to 10 g/liter greatly reduced the inhibitory effect of autoclaving.

Comparison of effects of green tea catechins on apicomplexan hexose transporters and mammalian orthologues

PubMed Central

Slavic, Ksenija; Derbyshire, Elvira T.; Naftalin, Richard J.; Krishna, Sanjeev; Staines, Henry M.

2009-01-01

Here we have investigated the inhibitory properties of green tea catechins on the Plasmodium falciparum hexose transporter (PfHT), the Babesia bovis hexose transporter 1 (BboHT1) and the mammalian facilitative glucose transporters, GLUT1 and GLUT5, expressed in Xenopus laevis oocytes. (−)-Epicatechin-gallate (ECG) and (−)-epigallocatechin-gallate (EGCG) inhibited d-glucose transport by GLUT1 and PfHT, and d-fructose transport by GLUT5, with apparent Ki values between 45 and 117 μM. BboHT1 was more potently inhibited by the ungallated catechins (−)-epicatechin (EC) and (−)-epigallocatechin (EGC), with apparent Ki values of 108 and 168 μM, respectively. Site-directed mutagenesis experiments provided little further support for previously reported models of catechin binding to hexose transporters. Furthermore, P. falciparum growth inhibition by catechins was not affected by the external d-glucose concentration. Our results provide new data on the inhibitory action of catechins against sugar transporters but were unable to elucidate the antimalarial mechanism of action of these agents. PMID:19577593

Evaluation of human D-amino acid oxidase inhibition by anti-psychotic drugs in vitro.

PubMed

Shishikura, Miho; Hakariya, Hitomi; Iwasa, Sumiko; Yoshio, Takashi; Ichiba, Hideaki; Yorita, Kazuko; Fukui, Kiyoshi; Fukushima, Takeshi

2014-06-01

It is of importance to determine whether antipsychotic drugs currently prescribed for schizophrenia exert D-amino acid oxidase (DAO)-inhibitory effects. We first investigated whether human (h)DAO can metabolize D-kynurenine (D-KYN) to produce the fluorescent compound kynurenic acid (KYNA) by using high-performance liquid chromatography with mass spectrometry, and fluorescence spectrometry. After confirmation of KYNA production from D-KYN by hDAO, 8 first- and second-generation antipsychotic drugs, and 6 drugs often prescribed concomitantly, were assayed for hDAO-inhibitory effects by using in vitro fluorometric methods with D-KYN as the substrate. DAO inhibitors 3-methylpyrazole-5-carboxylic acid and 4H-thieno[3,2-b]pyrrole-5-carboxylic acid inhibited KYNA production in a dose-dependent manner. Similarly, the second-generation antipsychotics blonanserin and risperidone were found to possess relatively strong hDAO-inhibitory effects in vitro (5.29 ± 0.47 μM and 4.70 ± 0.17 μM, respectively). With regard to blonanserin and risperidone, DAO-inhibitory effects should be taken into consideration in the context of their in vivo pharmacotherapeutic efficacy.

Inhibitory effects of toxic compounds on nitrification process for cokes wastewater treatment.

PubMed

Kim, Young Mo; Park, Donghee; Lee, Dae Sung; Park, Jong Moon

2008-04-15

Cokes wastewater is one of the most toxic industrial effluents since it contains high concentrations of toxic compounds such as phenols, cyanides and thiocyanate. Although activated sludge process has been adapted to treat this wastewater, nitrification process has been occasionally upset by serious inhibitory effects of toxic compounds. In this study, therefore, we examined inhibitory effects of ammonia, thiocyanate, free cyanide, ferric cyanide, phenol and p-cresol on nitrification in an activated sludge system, and then correlated their threshold concentrations with the full-scale pre-denitrification process for treating cokes wastewater. Ammonia below 350 mg/L did not cause substrate inhibition for nitrifying bacteria. Thiocyanate above 200mg/L seemed to inhibit nitrification, but it was due to the increased loading of ammonia produced from its biodegradation. Free cyanide above 0.2mg/L seriously inhibited nitrification, but ferric cyanide below 100mg/L did not. Phenol and p-cresol significantly inhibited nitrification above 200 mg/L and 100mg/L, respectively. Meantime, activated carbon was added to reduce inhibitory effects of phenol and free cyanide.

Effects of leukemia inhibitory factor and basic fibroblast growth factor on free radicals and endogenous stem cell proliferation in a mouse model of cerebral infarction.

PubMed

Huang, Weihui; Li, Yadan; Lin, Yufeng; Ye, Xue; Zang, Dawei

2012-07-05

The present study established a mouse model of cerebral infarction by middle cerebral artery occlusion, and monitored the effect of 25 μg/kg leukemia inhibitory factor and (or) basic fibroblast growth factor administration 2 hours after model establishment. Results showed that following administration, the number of endogenous neural stem cells in the infarct area significantly increased, malondialdehyde content in brain tissue homogenates significantly decreased, nitric oxide content, glutathione peroxidase and superoxide dismutase activity significantly elevated, and mouse motor function significantly improved as confirmed by the rotarod and bar grab tests. In particular, the effect of leukemia inhibitory factor in combination with basic fibroblast growth factor was the most significant. Results indicate that leukemia inhibitory factor and basic fibroblast growth factor can improve the microenvironment after cerebral infarction by altering free radical levels, improving the quantity of endogenous neural stem cells, and promoting neurological function of mice with cerebral infarction.

Chemo-enzymatic synthesis of vinyl and l-ascorbyl phenolates and their inhibitory effects on advanced glycation end products.

PubMed

Hwang, Seung Hwan; Wang, Zhiqiang; Lim, Soon Sung

2017-01-01

This study successfully established the feasibility of a two-step chemo-enzymatic synthesis of l-ascorbyl phenolates. Intermediate vinyl phenolates were first chemically produced and then underwent trans-esterification with l-ascorbic acid in the presence of Novozyme 435® (Candida Antarctica lipase B) as a catalyst. Twenty vinyl phenolates and 11 ascorbyl phenolates were subjected to in vitro bioassays to investigate their inhibitory activity against advanced glycation end products (AGEs). Among them, vinyl 4-hydroxycinnamate (17VP), vinyl 4-hydroxy-3-methoxycinnamate (18VP), vinyl 4-hydroxy-3,5-dimethoxycinnamate (20VP), ascorbyl 4-hydroxy-3-methoxycinnamate (18AP) and ascorbyl 3,4-dimethoxycinnamate (19AP) showed 2-10 times stronger inhibitory activities than positive control (aminoguanidine and its precursors). These results indicated that chemo-enzymatically synthesized compounds have AGE inhibitory effect and thus are effective in either preventing or retarding glycation protein formation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inhibitory effect of selective cyclooxygenase-2 inhibitor etoricoxib on human organic anion transporter 3 (hOAT3).

PubMed

Honjo, Hiroaki; Uwai, Yuichi; Iwamoto, Kikuo

2011-04-01

It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) delay the elimination of methotrexate. One of the mechanisms is thought to be inhibition of methotrexate uptake via human organic anion transporter 3 (hOAT3, SLC22A8) in the renal proximal tubule by NSAIDs. In this study, we evaluated the inhibitory effects of selective cyclooxygenase-2 inhibitor etoricoxib on hOAT3 by uptake experiments using Xenopus laevis oocytes. The injection of hOAT3 cRNA stimulated the uptake of methotrexate into the oocytes, and its transport was inhibited by etoricoxib. Etoricoxib inhibited estrone sulfate uptake by hOAT3 dose dependently, and the 50% inhibitory concentration was estimated to be 9.8 µM. Eadie-Hofstee plot analysis showed that etoricoxib inhibited hOAT3 in a competitive manner. These findings show that etoricoxib has inhibitory effect on hOAT3, and that the potential is comparable to that of traditional NSAIDs. ©2011 Bentham Science Publishers Ltd.

Successful inhibitory control over an immediate reward is associated with attentional disengagement in visual processing areas.

PubMed

O'Connor, David A; Rossiter, Sarah; Yücel, Murat; Lubman, Dan I; Hester, Robert

2012-09-01

We examined the neural basis of the capacity to resist an immediately rewarding stimulus in order to obtain a larger delayed reward. This was investigated with a Go/No-go task employing No-go targets that provided two types of reward outcomes. These were contingent on inhibitory control performance: failure to inhibit Reward No-go targets provided a small monetary reward with immediate feedback; while successful inhibitory control resulted in larger rewards with delayed feedback based on the highest number of consecutive inhibitions. We observed faster Go trial responses with maintained levels of inhibition accuracy during the Reward No-go condition compared to a neutral No-go condition. Comparisons between conditions of BOLD activity showed successful inhibitory control over rewarding No-Go targets was associated with hypoactivity in regions previously associated with regulating emotion and inhibitory control, including insula and right inferior frontal gyrus. In addition, regions previously associated with visual processing centers that are modulated as a function of visual attention, namely the left fusiform and right superior temporal gyri, were hypoactive. These findings suggest a role for attentional disengagement as an aid to withholding response over a rewarding stimulus and are consistent with the notion that gratification can be delayed by directing attention away from immediate rewards. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Comparable effects of low-intensity electromagnetic irradiation at the frequency of 51.8 and 53 GHz and antibiotic ceftazidime on Lactobacillus acidophilus growth and survival.

PubMed

Soghomonyan, Diana; Trchounian, Armen

2013-01-01

The effects of low-intensity electromagnetic irradiation (EMI) with the frequencies of 51.8 and 53 GHz on Lactobacillus acidophilus growth and survival were revealed. These effects were compared with antibacterial effects of antibiotic ceftazidime. Decrease in bacterial growth rate by EMI was comparable with the inhibitory effect of ceftazidime (minimal inhibitory concentration-16 μM) and no enhanced action was observed with combined effects of EMI and the antibiotic. However, EMI-enhanced antibiotic inhibitory effect on bacterial survival. The kinetics of the bacterial suspension oxidation-reduction potential up to 24 h of the growth was changed by EMI and ceftazidime. The changes were more strongly expressed by combined effects of EMI and antibiotic especially up to 12 h. Moreover, EMI did not change overall energy (glucose)-dependent H(+) efflux across the membrane but it increased N,N'-dicyclohexylcarbodiimide (DCCD)-inhibited H(+) efflux. In contrast, this EMI in combination with ceftazidime decreased DCCD-sensitive H(+) efflux. Low-intensity EMI had inhibitory effect on L. acidophilus bacterial growth and survival. The effect on bacterial survival was more significant in the combination with ceftazidime. The H(+)-translocating F 0 F 1-ATPase, for which DCCD is specific inhibitor, might be a target for EMI and ceftazidime. The revealed bactericide effects on L. acidophilus can be applied in biotechnology, food producing and safety technology.

Effects of OK-432 (picibanil) on the estrogen receptors of MCF-7 cells and potentiation of antiproliferative effects of tamoxifen in combination with OK-432.

PubMed

Aoyagi, H; Iino, Y; Takeo, T; Horii, Y; Morishita, Y; Horiuchi, R

1997-01-01

OK-432 (picibanil), a streptococcal preparation, has a strong biological response modifier (BRM) function and is expected to produce clinical improvement and prolongation of survival in treated cancer patients in Japan. We were interested in whether OK-432 augments estrogen receptor (ER) levels in breast cancer. To investigate the effect of the BRMs on cellular growth and the characteristics of ER and progesterone receptors (PgR) in the human breast cancer cell line MCF-7, we used OK-432, Krestin (PSK), a protein-bound polysaccharide extracted from Coriolus versicolor, and lentinan, a fungal branched (1...3)-beta-D-glycan. OK432 and PSK dose dependently inhibited DNA synthesis of MCF-7 cells, and the 50% inhibitory concentrations of OK-432 and PSK were 1.2 KE (klinische Einheit, clinical unit)/ml and 200 micrograms/ml, respectively. Lentinan showed no direct anticancer effect in vitro. We found that OK-432 induced a 2-fold increase in ER levels in MCF-7 cells at 0.005 KE/ml, but not in PgR. Lentinan and low-dose PSK did not change ER or PgR levels, but high-dose PSK decreased ER and PgR. We also studied the combined effect of OK-432 and antiestrogens, tamoxifen (TAM) and DP-TAT-59. The combined treatment with OK-432 and TAM showed an additive inhibitory effect on MCF-7 cells. These results suggest that OK-432 may augment the therapeutic effect of TAM in breast cancer.

An event-related potential investigation of the acute effects of aerobic and coordinative exercise on inhibitory control in children with ADHD.

PubMed

Ludyga, Sebastian; Brand, Serge; Gerber, Markus; Weber, Peter; Brotzmann, Mark; Habibifar, Fahimeh; Pühse, Uwe

2017-12-01

The current body of evidence suggests that an aerobic exercise session has a beneficial effect on inhibitory control, whereas the impact of coordinative exercise on this executive function has not yet been examined in children with ADHD. Therefore, the present study aims to investigate the acute effects of aerobic and coordinative exercise on behavioral performance and the allocation of attentional resources in an inhibitory control task. Using a cross-over design, children with ADHD-combined type and healthy comparisons completed a Flanker task before and after 20min moderately-intense cycling exercise, coordinative exercise and an inactive control condition. During the task, stimulus-locked event-related potentials were recorded with electroencephalography. Both groups showed an increase of P300 amplitude and decrease of reaction time after exercise compared to the control condition. Investigating the effect of exercise modality, aerobic exercise led to greater increases of P300 amplitude and reductions in reaction time than coordinative exercise in children with ADHD. The findings suggest that a single exercise bout improves inhibitory control and the allocation of attentional resources. There were some indications that an aerobic exercise session seems to be more efficient than coordinative exercise in reducing the inhibitory control deficits that persist in children with ADHD. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Hunger, inhibitory control and distress-induced emotional eating.

PubMed

van Strien, Tatjana; Ouwens, Machteld A; Engel, Carmen; de Weerth, Carolina

2014-08-01

Self-reported emotional eating has been found to significantly moderate distress-induced food intake, with low emotional eaters eating less after a stress task than after a control task and high emotional eaters eating more. The aim of the present study was to explore possible underlying mechanisms by assessing possible associations with (1) ability to experience the typical post-stress reduction of hunger and (2) inhibitory control. We studied these effects in 54 female students who were preselected on the basis of extremely high or low scores on an emotional eating questionnaire. Using a within subject design we measured the difference of actual food or snack intake after a control or a stress task (Trier Social Stress Test). As expected, the moderator effect of emotional eating on distress-induced food intake was found to be only present in females with a failure to report the typical reduction of hunger immediately after a stress task (an a-typical hunger stress response). Contrary to our expectations, this moderator effect of emotional eating was also found to be only present in females with high ability to stop motor impulses (high inhibitory control). These findings suggest that an a-typical hunger stress response but not poor inhibitory control may underlie the moderator effect of emotional eating on distress-induced food intake. However, inhibitory control may play a role whether or not there is a moderator effect of self-reported emotional eating on distress-induced food intake. Copyright © 2014 Elsevier Ltd. All rights reserved.

The effect of hydromorphone therapy on psychophysical measurements of the descending inhibitory pain systems in patients with chronic radicular pain.

PubMed

Suzan, Erica; Treister, Roi; Pud, Dorit; Haddad, May; Eisenberg, Elon

2015-01-01

Conditioned pain modulation (CPM) and offset analgesia (OA) are considered to represent paradigms of descending inhibitory pain modulation in humans. This study tested the effects of hydromorphone therapy on descending inhibitory pain modulation, as measured by changes from baseline in the magnitudes of CPM and OA. Prospective evaluation. Institute of Pain Medicine, Rambam Health Care Campus. Patients with chronic radicular pain. Thirty patients received 4 weeks of oral hydromorphone treatment at an individually titrated dose (mean ± standard deviation dose of 11.6 ± 4.8 mg/day). CPM and OA were assessed before and after hydromorphone treatment. CPM was assessed by subtracting the response to a painful phasic heat stimulus administered simultaneously with a conditioning cold pain stimulus, from the response to the same heat stimulus administered alone. The OA paradigm consisted of a three-temperature stimuli train (T1 = 49°C [5 seconds], T2 = 50°C [5 seconds], and T3 = 49°C [20 seconds]). The magnitude of OA was quantified by subtracting minimal pain scores obtained during T3 from the maximal pain scores obtained during T2. CPM scores changed from a baseline of 17.7 ± 20.6 to 21 ± 20.4 following treatment, and OA scores changed from 7.8 ± 20.5 to 9.7 ± 14.6. Wilcoxon signed rank test indicated that these changes were not significant (CPM: P = 0.22; OA: P = 0.44). McNemar test revealed that the percentage of patients who exhibited a change in the direction of CPM or OA in response to hydromorphone treatment was not significant (CPM: P = 0.37; OA: P = 0.48). These results suggest that the descending inhibitory pain modulation, as manifested in humans by CPM and OA, is unlikely to be mediated by hydromorphone therapy. Wiley Periodicals, Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Eunjung; Son, Joe Eun; Byun, Sanguine

Licorice extract which is used as a natural sweetener has been shown to possess inhibitory effects against prostate cancer, but the mechanisms responsible are poorly understood. Here, we report a compound, isoangustone A (IAA) in licorice that potently suppresses the growth of aggressive prostate cancer and sought to clarify its mechanism of action. We analyzed its inhibitory effects on the growth of PTEN-deleted human prostate cancer cells, in vitro and in vivo. Administration of IAA significantly attenuated the growth of prostate cancer cell cultures and xenograft tumors. These effects were found to be attributable to inhibition of the G1/S phasemore » cell cycle transition and the accumulation of p27{sup kip1}. The elevated p27{sup kip1} expression levels were concurrent with the decrease of its phosphorylation at threonine 187 through suppression of CDK2 kinase activity and the reduced phosphorylation of Akt at Serine 473 by diminishing the kinase activity of the mammalian target of rapamycin (mTOR). Further analysis using recombinant proteins and immunoprecipitated cell lysates determined that IAA exerts suppressive effects against CDK2 and mTOR kinase activity by direct binding with both proteins. These findings suggested that the licorice compound IAA is a potent molecular inhibitor of CDK2 and mTOR, with strong implications for the treatment of prostate cancer. Thus, licorice-derived extracts with high IAA content warrant further clinical investigation for nutritional sources for prostate cancer patients. - Highlights: • Isoangustone A suppresses growth of PC3 and LNCaP prostate cancer cells. • Administration of isoangustone A inhibits tumor growth in mice. • Treatment of isoangustone A induces cell cycle arrest and accumulation of p27{sup kip1}. • Isoangustone A inhibits CDK2 and mTOR activity. • Isoangustone A directly binds with CDK2 and mTOR complex in prostate cancer cells.« less

Ses proteins as possible targets for vaccine development against Staphylococcus epidermidis infections.

PubMed

Hofmans, Dorien; Khodaparast, Laleh; Khodaparast, Ladan; Vanstreels, Els; Shahrooei, Mohammad; Van Eldere, Johan; Van Mellaert, Lieve

2018-05-09

The opportunistic pathogen Staphylococcus epidermidis is progressively involved in device-related infections. Since these infections involve biofilm formation, antibiotics are not effective. Conversely, a vaccine can be advantageous to prevent these infections. In view of vaccine development, predicted surface proteins were evaluated on their potential as a vaccine target. Immunoglobulins directed against S. epidermidis surface proteins SesB, M, O, Q and R, were used to firstly affirm their surface location. Further, inhibitory effects of these IgGs on biofilm formation were determined in vitro on polystyrene and polyurethane surfaces and in vivo using a subcutaneous catheter mouse model. We also examined the opsonophagocytic capacity of these IgGs. Surface localization of the five Ses proteins was demonstrated both for planktonic and sessile cells, though to a variable extent. Ses-specific IgGs added to planktonic cells had a variable inhibitory effect on cell adhesion to polystyrene, while only anti-SesO IgGs decreased cell attachment to polyurethane catheters. Although phagocytic killing was only obtained after opsonisation with SesB-specific IgGs, a significant reduction of in vivo formed biofilms was observed after administration of SesB-, SesM- and SesO-specific IgGs. Regardless of their characterization or function, S. epidermidis surface proteins can be adequate targets for vaccine development aiming the prevention of device-related infections caused by invasive S. epidermidis strains. Copyright © 2018 Elsevier Ltd. All rights reserved.

Protein Kinase Inhibitor γ reciprocally regulates osteoblast and adipocyte differentiation by downregulating Leukemia Inhibitory Factor

PubMed Central

Chen, Xin; Hausman, Bryan S.; Luo, Guangbin; Zhou, Guang; Murakami, Shunichi; Rubin, Janet; Greenfield, Edward M.

2013-01-01

The Protein Kinase Inhibitor (Pki) gene family inactivates nuclear PKA and terminates PKA-induced gene expression. We previously showed that Pkig is the primary family member expressed in osteoblasts and that Pkig knockdown increases the effects of parathyroid hormone and isoproterenol on PKA activation, gene expression, and inhibition of apoptosis. Here, we determined whether endogenous levels of Pkig regulate osteoblast differentiation. Pkig is the primary family member in MEFs, murine marrow-derived mesenchymal stem cells, and human mesenchymal stem cells. Pkig deletion increased forskolin-dependent nuclear PKA activation and gene expression and Pkig deletion or knockdown increased osteoblast differentiation. PKA signaling is known to stimulate adipogenesis; however, adipogenesis and osteogenesis are often reciprocally regulated. We found that the reciprocal regulation predominates over the direct effects of PKA since adipogenesis was decreased by Pkig deletion or knockdown. Pkig deletion or knockdown simultaneously increased osteogenesis and decreased adipogenesis in mixed osteogenic/adipogenic medium. Pkig deletion increased PKA-induced expression of Leukemia Inhibitory Factor (Lif) mRNA and LIF protein. LIF neutralizing antibodies inhibited the effects on osteogenesis and adipogenesis of either Pkig deletion in MEFs or PKIγ knockdown in both murine and human mesenchymal stem cells. Collectively, our results show that endogenous levels of Pkig reciprocally regulate osteoblast and adipocyte differentiation and that this reciprocal regulation is mediated in part by LIF. PMID:23963683

The role of orthography in the semantic activation of neighbors.

PubMed

Hino, Yasushi; Lupker, Stephen J; Taylor, Tamsen E

2012-09-01

There is now considerable evidence that a letter string can activate semantic information appropriate to its orthographic neighbors (e.g., Forster & Hector's, 2002, TURPLE effect). This phenomenon is the focus of the present research. Using Japanese words, we examined whether semantic activation of neighbors is driven directly by orthographic similarity alone or whether there is also a role for phonological similarity. In Experiment 1, using a relatedness judgment task in which a Kanji word-Katakana word pair was presented on each trial, an inhibitory effect was observed when the initial Kanji word was related to an orthographic and phonological neighbor of the Katakana word target but not when the initial Kanji word was related to a phonological but not orthographic neighbor of the Katakana word target. This result suggests that phonology plays little, if any, role in the activation of neighbors' semantics when reading familiar words. In Experiment 2, the targets were transcribed into Hiragana, a script they are typically not written in, requiring readers to engage in phonological coding. In that experiment, inhibitory effects were observed in both conditions. This result indicates that phonologically mediated semantic activation of neighbors will emerge when phonological processing is necessary in order to understand a written word (e.g., when that word is transcribed into an unfamiliar script). PsycINFO Database Record (c) 2012 APA, all rights reserved.

Possible involvement of membrane lipids peroxidation and oxidation of catalytically essential thiols of the cerebral transmembrane sodium pump as component mechanisms of iron-mediated oxidative stress-linked dysfunction of the pump's activity

PubMed Central

Omotayo, T.I.; Akinyemi, G.S.; Omololu, P.A.; Ajayi, B.O.; Akindahunsi, A.A.; Rocha, J.B.T.; Kade, I.J.

2014-01-01

The precise molecular events defining the complex role of oxidative stress in the inactivation of the cerebral sodium pump in radical-induced neurodegenerative diseases is yet to be fully clarified and thus still open. Herein we investigated the modulation of the activity of the cerebral transmembrane electrogenic enzyme in Fe2+-mediated in vitro oxidative stress model. The results show that Fe2+ inhibited the transmembrane enzyme in a concentration dependent manner and this effect was accompanied by a biphasic generation of aldehydic product of lipid peroxidation. While dithiothreitol prevented both Fe2+ inhibitory effect on the pump and lipid peroxidation, vitamin E prevented only lipid peroxidation but not inhibition of the pump. Besides, malondialdehyde (MDA) inhibited the pump by a mechanism not related to oxidation of its critical thiols. Apparently, the low activity of the pump in degenerative diseases mediated by Fe2+ may involve complex multi-component mechanisms which may partly involve an initial oxidation of the critical thiols of the enzyme directly mediated by Fe2+ and during severe progression of such diseases; aldehydic products of lipid peroxidation such as MDA may further exacerbate this inhibitory effect by a mechanism that is likely not related to the oxidation of the catalytically essential thiols of the ouabain-sensitive cerebral electrogenic pump. PMID:25618580

Novel direct factor Xa inhibitory compounds from Tenebrio molitor with anti-platelet aggregation activity.

PubMed

Lee, Wonhwa; Kim, Mi-Ae; Park, InWha; Hwang, Jae Sam; Na, MinKyun; Bae, Jong-Sup

2017-11-01

Tenebrio molitor is an edible insect that has antimicrobial, anticancer, and antihypertensive effects. The aim of this study was to identify the unreported bioactive compounds from T. molitor larvae with inhibitory activities against factor Xa (FXa) and platelet aggregation. Isolated compounds were evaluated for their anti-FXa and anti-platelet aggregation properties by monitoring clotting time, platelet aggregation, FXa activity, and thrombus formation. A diketopiperazine (1, cyclo( L -Pro- L -Tyr)) and a phenylethanoid (2, N-acetyltyramine) were isolated and inhibited the catalytic activity of FXa in a mixed inhibition model and inhibited platelet aggregation induced by adenosine diphosphate (ADP) and U46619. They inhibited ADP- and U46619-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) and the expression of P-selectin and PAC-1 in platelets. They also improved the production of nitric oxide and inhibited the oversecretion of endothelin-1 compared to that of the ADP- or U46619-treated group. In an animal model of arterial and pulmonary thrombosis, the isolated compounds showed enhanced antithrombotic effects. They also elicited anticoagulant effects in mice. Compounds 1-2 inhibited ADP-, collagen-, or U46619-induced platelet aggregation and showed similar anti-thrombotic efficacy to rivaroxaban, a positive control. Therefore, 1-2 could serve as candidates and provide scaffolds for the development of new anti-FXa and anti-platelet drugs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of Heterogeneity on Decorrelation Mechanisms in Spiking Neural Networks: A Neuromorphic-Hardware Study

NASA Astrophysics Data System (ADS)

Pfeil, Thomas; Jordan, Jakob; Tetzlaff, Tom; Grübl, Andreas; Schemmel, Johannes; Diesmann, Markus; Meier, Karlheinz

2016-04-01

High-level brain function, such as memory, classification, or reasoning, can be realized by means of recurrent networks of simplified model neurons. Analog neuromorphic hardware constitutes a fast and energy-efficient substrate for the implementation of such neural computing architectures in technical applications and neuroscientific research. The functional performance of neural networks is often critically dependent on the level of correlations in the neural activity. In finite networks, correlations are typically inevitable due to shared presynaptic input. Recent theoretical studies have shown that inhibitory feedback, abundant in biological neural networks, can actively suppress these shared-input correlations and thereby enable neurons to fire nearly independently. For networks of spiking neurons, the decorrelating effect of inhibitory feedback has so far been explicitly demonstrated only for homogeneous networks of neurons with linear subthreshold dynamics. Theory, however, suggests that the effect is a general phenomenon, present in any system with sufficient inhibitory feedback, irrespective of the details of the network structure or the neuronal and synaptic properties. Here, we investigate the effect of network heterogeneity on correlations in sparse, random networks of inhibitory neurons with nonlinear, conductance-based synapses. Emulations of these networks on the analog neuromorphic-hardware system Spikey allow us to test the efficiency of decorrelation by inhibitory feedback in the presence of hardware-specific heterogeneities. The configurability of the hardware substrate enables us to modulate the extent of heterogeneity in a systematic manner. We selectively study the effects of shared input and recurrent connections on correlations in membrane potentials and spike trains. Our results confirm that shared-input correlations are actively suppressed by inhibitory feedback also in highly heterogeneous networks exhibiting broad, heavy-tailed firing-rate distributions. In line with former studies, cell heterogeneities reduce shared-input correlations. Overall, however, correlations in the recurrent system can increase with the level of heterogeneity as a consequence of diminished effective negative feedback.

Membrane vesicles shed by oligodendroglioma cells induce neuronal apoptosis.

PubMed

D'Agostino, Stefania; Salamone, Monica; Di Liegro, Italia; Vittorelli, M Letizia

2006-11-01

In order to investigate the mechanism by which oligodendrogliomas cause neuronal damage, media conditioned by G26/24 oligodendroglioma cells, were fractionated into shed vesicles and vesicle-free supernatants, and added to primary cultures of rat fetal cortical neurons. After one night treatment with vesicles, a reproducible, dose-dependent, inhibitory effect on neurite outgrowth was already induced and, after 48-72 h of incubation, neuronal apoptosis was evident. Vesicle-free supernatants and vesicles shed by NIH-3T3 cells had no inhibitory effects on neurons. Western blot analyses showed that treated neurons expressed a decreased amount of neurofilament (NF), growth-associated protein (GAP-43) and microtubule-associated protein (MAP-2). Moreover procaspase-3 and -8 were activated while Bcl-2 expression was reduced. Vesicles were found positive for the proapoptotic molecule, Fas-ligand (Fas-L), and for the B isoform of Nogo protein, a myelin component with inhibitory effects on neurons. Nogo B involvement in the vesicle effects was analyzed both by testing the neutralizing capability of anti-Nogo antibodies and by removing the Nogo receptor from neurons by phospholipase C digestion. These treatments did not revert the vesicle effects. To test the role of Fas-L, vesicles were treated with functional anti-Fas-L monoclonals. Vesicle inhibitory and proapoptotic effects were reduced. Vesicles shed by ovarian carcinoma cells (OvCa), which are known to vehicle biologically active Fas-L, had similar effects on neurons to those of oligodendroglioma vesicles, and their inhibitory effects were also reduced by anti Fas-L antibodies. We therefore conclude that vesicles shed by G26/24 cells induce neuronal apoptosis at least partially by a Fas-L mediated mechanism.

Effects of Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) on contractile activity of circular smooth muscle of the rat distal colon.

PubMed

Kito, Yoshihiko; Teramoto, Noriyoshi

2012-11-01

The Japanese Kampo medicines Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) have been used to treat symptoms of human diarrhea on an empirical basis as Japanese traditional medicines. However, it remains unclear how these drugs affect smooth muscle tissues in the distal colon. The aim of the present study was to investigate the effects of TJ-14 and TJ-60 on the contractile activity of circular smooth muscle from the rat distal colon. TJ-14 and TJ-60 (both 1 mg/ml) inhibited spontaneous contractions of circumferentially cut preparations with the mucosa intact. Blockade of nitric oxide (NO) synthase or soluble guanylate cyclase activity abolished the inhibitory effects of TJ-60 but only attenuated the inhibitory effects of TJ-14. Apamin (1 μM), a blocker of small-conductance Ca(2+)-activated K(+) channels (SK channels), attenuated the inhibitory effects of 5 mg/ml TJ-60 but not those of 5 mg/ml TJ-14. TJ-14 suppressed contractile responses (phasic contractions and off-contractions) evoked by transmural nerve stimulation and increased basal tone, whereas TJ-60 had little effect on these parameters. These results suggest that 1 mg/ml TJ-14 or TJ-60 likely inhibits spontaneous contractions of the rat distal colon through the production of NO. Activation of SK channels seems to be involved in the inhibitory effects of 5 mg/ml TJ-60. Since TJ-14 has potent inhibitory effects on myogenic and neurogenic contractile activity, TJ-14 may be useful in suppressing gastrointestinal motility.

Beta-interferon inhibits cell infection by Trypanosoma cruzi

NASA Technical Reports Server (NTRS)

Kierszenbaum, F.; Sonnenfeld, G.

1984-01-01

Beta interferon has been shown to inhibit the capacity of bloodstream forms of the flagellate Trypanosoma cruzi, the causative agent of Chagas' disease, to associate with and infect mouse peritoneal macrophages and rat heart myoblasts. The inhibitory effect was abrogated in the presence of specific antibodies to the interferon. Pretreatment of the parasites with interferon reduced their infectivity for untreated host cells, whereas pretreament of either type of host cell did not affect the interaction. The effect of interferon on the trypanosomes was reversible; the extent of the inhibitory effect was significantly reduced afer 20 min, and was undetectable after 60 min when macrophages were used as host cells. For the myoblasts, 60 min elapsed before the inhibitory effect began to subside and 120 min elapsed before it became insignificant or undetectable.

Essential Oils from Ugandan Aromatic Medicinal Plants: Chemical Composition and Growth Inhibitory Effects on Oral Pathogens

PubMed Central

Ocheng, Francis; Bwanga, Freddie; Joloba, Moses; Softrata, Abier; Azeem, Muhammad; Pütsep, Katrin; Borg-Karlson, Anna-Karin; Obua, Celestino; Gustafsson, Anders

2015-01-01

The study assessed the growth inhibitory effects of essential oils extracted from ten Ugandan medicinal plants (Bidens pilosa, Helichrysum odoratissimum, Vernonia amygdalina, Hoslundia opposita, Ocimum gratissimum, Cymbopogon citratus, Cymbopogon nardus, Teclea nobilis, Zanthoxylum chalybeum, and Lantana trifolia) used traditionally in the management of oral diseases against oral pathogens. Chemical compositions of the oils were explored by GC-MS. Inhibitory effects of the oils were assessed on periodontopathic Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans and cariogenic Streptococcus mutans and Lactobacillus acidophilus using broth dilution methods at concentrations of 1%, 0.1%, and 0.01%. The most sensitive organism was A. actinomycetemcomitans. Its growth was markedly inhibited by six of the oils at all the concentrations tested. Essential oil from C. nardus exhibited the highest activity with complete growth inhibition of A. actinomycetemcomitans and P. gingivalis at all the three concentrations tested, the major constituents in the oil being mainly oxygenated sesquiterpenes. Most of the oils exhibited limited effects on L. acidophilus. We conclude that essential oils from the studied plants show marked growth inhibitory effects on periodontopathic A. actinomycetemcomitans and P. gingivalis, moderate effects on cariogenic S. mutans, and the least effect on L. acidophilus. The present study constitutes a basis for further investigations and development of certain oils into alternative antiplaque agents. PMID:26170872

What Do We Really Know about Cognitive Inhibition? Task Demands and Inhibitory Effects across a Range of Memory and Behavioural Tasks

PubMed Central

Noreen, Saima; MacLeod, Malcolm D.

2015-01-01

Our study explores inhibitory control across a range of widely recognised memory and behavioural tasks. Eighty-seven never-depressed participants completed a series of tasks designed to measure inhibitory control in memory and behaviour. Specifically, a variant of the selective retrieval-practice and the Think/No-Think tasks were employed as measures of memory inhibition. The Stroop-Colour Naming and the Go/No-Go tasks were used as measures of behavioural inhibition. Participants completed all 4 tasks. Task presentation order was counterbalanced across 3 separate testing sessions for each participant. Standard inhibitory forgetting effects emerged on both memory tasks but the extent of forgetting across these tasks was not correlated. Furthermore, there was no relationship between memory inhibition tasks and either of the main behavioural inhibition measures. At a time when cognitive inhibition continues to gain acceptance as an explanatory mechanism, our study raises fundamental questions about what we actually know about inhibition and how it is affected by the processing demands of particular inhibitory tasks. PMID:26270470

What Do We Really Know about Cognitive Inhibition? Task Demands and Inhibitory Effects across a Range of Memory and Behavioural Tasks.

PubMed

Noreen, Saima; MacLeod, Malcolm D

2015-01-01

Our study explores inhibitory control across a range of widely recognised memory and behavioural tasks. Eighty-seven never-depressed participants completed a series of tasks designed to measure inhibitory control in memory and behaviour. Specifically, a variant of the selective retrieval-practice and the Think/No-Think tasks were employed as measures of memory inhibition. The Stroop-Colour Naming and the Go/No-Go tasks were used as measures of behavioural inhibition. Participants completed all 4 tasks. Task presentation order was counterbalanced across 3 separate testing sessions for each participant. Standard inhibitory forgetting effects emerged on both memory tasks but the extent of forgetting across these tasks was not correlated. Furthermore, there was no relationship between memory inhibition tasks and either of the main behavioural inhibition measures. At a time when cognitive inhibition continues to gain acceptance as an explanatory mechanism, our study raises fundamental questions about what we actually know about inhibition and how it is affected by the processing demands of particular inhibitory tasks.

Dieckol, a phlorotannin isolated from a brown seaweed, Ecklonia cava, inhibits adipogenesis through AMP-activated protein kinase (AMPK) activation in 3T3-L1 preadipocytes.

PubMed

Ko, Seok-Chun; Lee, Myoungsook; Lee, Ji-Hyeok; Lee, Seung-Hong; Lim, Yunsook; Jeon, You-Jin

2013-11-01

In this study, we assessed the potential inhibitory effect of 5 species of brown seaweeds on adipogenesis the differentiation of 3T3-L1 preadipocytes into mature adipocytes by measuring Oil-Red O staining. The Ecklonia cava extract tested herein evidenced profound adipogenesis inhibitory effect, compared to that exhibited by the other four brown seaweed extracts. Thus, E. cava was selected for isolation of active compounds and finally the three polyphenol compounds of phlorotannins were obtained and their inhibitory effect on adipogenesis was observed. Among the phlorotannins, dieckol exhibited greatest potential adipogenesis inhibition and down-regulated the expression of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding proteins (C/EBPα), sterol regulatory element-binding protein 1 (SREBP1) and fatty acid binding protein 4 (FABP4) in a dose-dependent manner. The specific mechanism mediating the effects of dieckol was confirmed by AMP-activated protein kinase (AMPK) activation. These results demonstrate inhibitory effect of dieckol compound on adipogenesis through the activation of the AMPK signal pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

Antioxidant effects of 14 Chinese traditional medicinal herbs against human low-density lipoprotein oxidation.

PubMed

Lin, Hsin-Hung; Charles, Albert Linton; Hsieh, Chang-Wei; Lee, Ya-Chi; Ciou, Jhih-Ying

2015-01-01

The relationship between the antioxidant activities and inhibitory effect of 14 Chinese medicinal herbs against oxidized low-density lipoprotein (LDL) formation was evaluated. Prolongation of the lag phase of LDL oxidation depended on the concentration of the herbs. The concentration of each herb that was able to prolong the lag time by about two-fold was calculated and expressed as doubling-time concentration. The lower the doubling-time concentration, the stronger the inhibitory effect exhibited toward LDL oxidation. Among them, Chrysanthemi Flos (Chrysanthemum morifolium ramat; gān jú huā), Crataegi Fructus (Crataegus pinnatifida Bge. var. major N.E.Br.; shān zhā), and Roselle (Hibiscus sabdariffa Linn.; luò shén) showed significant inhibitory effects. Correlation coefficients between doubling-time concentration and radical-scavenging activities were high; the total phenolic content was also high. In conclusion, phenolic compounds contributed not only to antioxidant activities, but also to the inhibitory effect against LDL oxidation. Chrysanthemi Flos, Crataegi Fructus, and H. sabdariffa, with lower doubling-time concentrations, could be potent phytochemical agents to reduce LDL oxidation and prevent the progression of atherosclerosis.

Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

PubMed Central

Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

2016-01-01

Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV. PMID:26909355

Variola virus E3L Zα domain, but not its Z-DNA binding activity, is required for PKR inhibition.

PubMed

Thakur, Meghna; Seo, Eun Joo; Dever, Thomas E

2014-02-01

Responding to viral infection, the interferon-induced, double-stranded RNA (dsRNA)-activated protein kinase PKR phosphorylates translation initiation factor eIF2α to inhibit cellular and viral protein synthesis. To overcome this host defense mechanism, many poxviruses express the protein E3L, containing an N-terminal Z-DNA binding (Zα) domain and a C-terminal dsRNA-binding domain (dsRBD). While E3L is thought to inhibit PKR activation by sequestering dsRNA activators and by directly binding the kinase, the role of the Zα domain in PKR inhibition remains unclear. Here, we show that the E3L Zα domain is required to suppress the growth-inhibitory properties associated with expression of human PKR in yeast, to inhibit PKR kinase activity in vitro, and to reverse the inhibitory effects of PKR on reporter gene expression in mammalian cells treated with dsRNA. Whereas previous studies revealed that the Z-DNA binding activity of E3L is critical for viral pathogenesis, we identified point mutations in E3L that functionally uncouple Z-DNA binding and PKR inhibition. Thus, our studies reveal a molecular distinction between the nucleic acid binding and PKR inhibitory functions of the E3L Zα domain, and they support the notion that E3L contributes to viral pathogenesis by targeting PKR and other components of the cellular anti-viral defense pathway.

The Emotional Gatekeeper: A Computational Model of Attentional Selection and Suppression through the Pathway from the Amygdala to the Inhibitory Thalamic Reticular Nucleus

PubMed Central

Bullock, Daniel; Barbas, Helen

2016-01-01

In a complex environment that contains both opportunities and threats, it is important for an organism to flexibly direct attention based on current events and prior plans. The amygdala, the hub of the brain's emotional system, is involved in forming and signaling affective associations between stimuli and their consequences. The inhibitory thalamic reticular nucleus (TRN) is a hub of the attentional system that gates thalamo-cortical signaling. In the primate brain, a recently discovered pathway from the amygdala sends robust projections to TRN. Here we used computational modeling to demonstrate how the amygdala-TRN pathway, embedded in a wider neural circuit, can mediate selective attention guided by emotions. Our Emotional Gatekeeper model demonstrates how this circuit enables focused top-down, and flexible bottom-up, allocation of attention. The model suggests that the amygdala-TRN projection can serve as a unique mechanism for emotion-guided selection of signals sent to cortex for further processing. This inhibitory selection mechanism can mediate a powerful affective ‘framing’ effect that may lead to biased decision-making in highly charged emotional situations. The model also supports the idea that the amygdala can serve as a relevance detection system. Further, the model demonstrates how abnormal top-down drive and dysregulated local inhibition in the amygdala and in the cortex can contribute to the attentional symptoms that accompany several neuropsychiatric disorders. PMID:26828203

A noninhibitory mutant of the caveolin-1 scaffolding domain enhances eNOS-derived NO synthesis and vasodilation in mice

PubMed Central

Bernatchez, Pascal; Sharma, Arpeeta; Bauer, Philip M.; Marin, Ethan; Sessa, William C.

2011-01-01

Aberrant regulation of eNOS and associated NO release are directly linked with various vascular diseases. Caveolin-1 (Cav-1), the main coat protein of caveolae, is highly expressed in endothelial cells. Its scaffolding domain serves as an endogenous negative regulator of eNOS function. Structure-function analysis of Cav-1 has shown that phenylalanine 92 (F92) is critical for the inhibitory actions of Cav-1 toward eNOS. Herein, we show that F92A–Cav-1 and a mutant cell–permeable scaffolding domain peptide called Cavnoxin can increase basal NO release in eNOS-expressing cells. Cavnoxin reduced vascular tone ex vivo and lowered blood pressure in normal mice. In contrast, similar experiments performed with eNOS- or Cav-1–deficient mice showed that the vasodilatory effect of Cavnoxin is abolished in the absence of these gene products, which indicates a high level of eNOS/Cav-1 specificity. Mechanistically, biochemical assays indicated that noninhibitory F92A–Cav-1 and Cavnoxin specifically disrupted the inhibitory actions of endogenous Cav-1 toward eNOS and thereby enhanced basal NO release. Collectively, these data raise the possibility of studying the inhibitory influence of Cav-1 on eNOS without interfering with the other actions of endogenous Cav-1. They also suggest a therapeutic application for regulating the eNOS/Cav-1 interaction in diseases characterized by decreased NO release. PMID:21804187

Differential effects of social isolation in adolescent and adult mice on behavior and cortical gene expression.

PubMed

Lander, Sharon S; Linder-Shacham, Donna; Gaisler-Salomon, Inna

2017-01-01

Intact function of the medial prefrontal cortex (mPFC) function relies on proper development of excitatory and inhibitory neuronal populations and on integral myelination processes. Social isolation (SI) affects behavior and brain circuitry in adulthood, but previous rodent studies typically induced prolonged (post-weaning) exposure and failed to directly compare between the effects of SI in adolescent and adulthood. Here, we assessed the impact of a 3-week SI period, starting in mid-adolescence (around the onset of puberty) or adulthood, on a wide range of behaviors in adult male mice. Additionally, we asked whether adolescent SI would differentially affect the expression of excitatory and inhibitory neuronal markers and myelin-related genes in mPFC. Our findings indicate that mid-adolescent or adult SI increase anxiogenic behavior and locomotor activity. However, SI in adolescence uniquely affects the response to the psychotomimetic drug amphetamine, social and novelty exploration and performance in reversal and attentional set shifting tasks. Furthermore, adolescent but not adult SI increased the expression of glutamate markers in the adult mPFC. Our results imply that adolescent social deprivation is detrimental for normal development and may be particularly relevant to the investigation of developmental psychopathology. Copyright © 2016 Elsevier B.V. All rights reserved.

Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma.

PubMed

Ding, Ning; Li, Xitao; Shi, Yunfei; Ping, Lingyan; Wu, Lina; Fu, Kai; Feng, Lixia; Zheng, Xiaohui; Song, Yuqin; Pan, Zhengying; Zhu, Jun

2015-06-20

The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment.

Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma

PubMed Central

Ding, Ning; Li, Xitao; Shi, Yunfei; Ping, Lingyan; Wu, Lina; Fu, Kai; Feng, Lixia; Zheng, Xiaohui; Song, Yuqin; Pan, Zhengying; Zhu, Jun

2015-01-01

The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment. PMID:25944695

miR-137, a new target for post-stroke depression?

PubMed Central

Zhao, Lixia; Li, Huazi; Guo, Ruiyou; Ma, Teng; Hou, Rongyao; Ma, Xiaowei; Du, Yifeng

2013-01-01

Expression of miR-137 is downregulated in brain tissue from patients with depression and suicidal behavior, and is also downregulated in peripheral blood from stroke patients. However, it is not yet known if miR-137 acts as a bridge between stroke and depression. To test this, we used middle cerebral artery occlusion and chronic mild stress to establish a post-stroke depression model in rats. Compared with controls, we found significantly lower miR-137 levels in the brain and peripheral blood from post-stroke depression rats. Injection of a miR-137 antagonist into the brain ventricles upregulated miR-137 levels, and improved behavioral changes in post-stroke depression rats. Luciferase assays showed miR-137 bound to the 3’UTR of Grin2A, regulating Grin2A expression in a neuronal cell line. Grin2A gene overexpression in the brain of post-stroke depression rats, noticeably suppressed the inhibitory effect of miR-137 on post-stroke depression. Overall, our results show that miR-137 suppresses Grin2A protein expression through binding to Grin2A mRNA, thereby exerting an inhibitory effect on post-stroke depression. Our results offer a new therapeutic direction for post-stroke depression. PMID:25206554

Spice phenolics inhibit human PMNL 5-lipoxygenase.

PubMed

Prasad, N Satya; Raghavendra, R; Lokesh, B R; Naidu, K Akhilender

2004-06-01

A wide variety of phenolic compounds and flavonoids present in spices possess potent antioxidant, antimutagenic and anticarcinogenic activities. We examined whether 5-lipoxygenase (5-LO), the key enzyme involved in biosynthesis of leukotrienes is a possible target for the spices. Effect of aqueous extracts of turmeric, cloves, pepper, chili, cinnamon, onion and also their respective active principles viz., curcumin, eugenol, piperine, capsaicin, cinnamaldehyde, quercetin, and allyl sulfide were tested on human PMNL 5-LO activity by spectrophotomeric and HPLC methods. The formation of 5-LO product 5-HETE was significantly inhibited in a concentration-dependent manner with IC(50) values of 0.122-1.44 mg for aqueous extracts of spices and 25-83 microM for active principles, respectively. The order of inhibitory activity was of quercetin>eugenol>curcumin>cinnamaldehyde>piperine>capsaicin>allyl sulfide. Quercetin, eugenol and curcumin with one or more phenolic ring and methoxy groups in their structure showed high inhibitory effect, while the non-phenolic spice principle allyl sulfide showed least inhibitory effect on 5-LO. The inhibitory effect of quercetin, curcumin and eugenol was similar to that of synthetic 5-LO inhibitors-phenidone and NDGA. Moreover, the inhibitory potency of aqueous extracts of spice correlated with the active principles of their respective spices. The synergistic or antagonistic effect of mixtures of spice active principles and spice extracts were investigated and all the combinations of spice active principles/extracts exerted synergistic effect in inhibiting 5-LO activity. These findings clearly suggest that phenolic compounds present in spices might have physiological role in modulating 5-LO pathway.

Effects of chalcone derivatives on lipoxygenase and cyclooxygenase activities of mouse epidermis.

PubMed

Nakadate, T; Aizu, E; Yamamoto, S; Kato, R

1985-09-01

The effects of chalcone derivatives on 12-lipoxygenase and cyclooxygenase of mouse epidermis were investigated. The chalcone derivatives which have 3,4-dihydroxycinnamoyl structure in the molecule, such as 3,4-dihydroxychalcone, 3,4,2'-trihydroxychalcone, 3,4,4'-trihydroxychalcone and 3,4,2'4'-tetrahydroxychalcone, potently inhibited epidermal 12-lipoxygenase activity. Although some of them also inhibited cyclooxygenase activity at relatively high concentrations, the inhibitory effects of these chalcone derivatives on 12-lipoxygenase were 10 times or more potent than their effects on cyclooxygenase. The chalcone derivatives which have cinnamoyl or 4-hydroxycinnamoyl structure, instead of 3,4-dihydroxycinnamoyl structure, in the molecule, showed little or no inhibitory effects on either 12-lipoxygenase or cyclooxygenase activities. The inhibitory effects of chalcone derivatives on 12-lipoxygenase and cyclooxygenase of mouse epidermis are dependent on the particular structure, i.e. 3,4-dihydroxycinnamoyl structure, of the chalcone derivatives.

Constituents of PG201 (Layla(®)), a multi-component phytopharmaceutical, with inhibitory activity on LPS-induced nitric oxide and prostaglandin E2 productions in macrophages.

PubMed

Kim, Hyun Ji; Kim, Hye Mi; Ryu, Byeol; Lee, Woo-Seok; Shin, Ji-Sun; Lee, Kyung-Tae; Jang, Dae Sik

2016-02-01

Fourteen compounds, coumarin (1), demethylsuberosin (2), xanthotoxin (3), psoralen (4), decursinol (5), decursin (6), decursinol angelate (7), chikusetsusaponin IVa (8), chikusetsusaponin IVa methyl ester (9), ethyl caffeate (10), syringaresinol (11), cnidilide (12), farnesol (13), and linoleic acid (14), were isolated from phytopharmaceutical PG201 (Layla(®)) by activity-guided fractionation utilizing inhibitory activity on nitric oxide (NO) production in vitro. The isolates 1-14 were evaluated for their inhibitory activity on LPS-induced NO and prostaglandin E2 (PGE2) productions in RAW 264.7 cells. All the compounds except 14 displayed suppressive effects on LPS-induced NO and PGE2 production with IC50 values ranging from 8 to 60 μM. Among these, compound 10 showed the most potent inhibitory effect on NO production from RAW 264.7 cells with an IC50 value of 8.25 μM. Compounds 2, 9, and 10 exhibited high inhibitory effects on PGE2 production with the IC50 values of 9.42, 7.51, and 6.49 μM, respectively. These findings suggest that compounds 2, 9, and 10 are the potential anti-inflammatory active constituents of PG201 and further study may be needed to explain their mechanism of action.

A cyclohexanecarboxamide derivative with inhibitory effects on Schistosoma mansoni cercarial serine protease and penetration of mice skin by the parasite.

PubMed

Bahgat, Mahmoud; Aboul-Enein, Mohamed N; El Azzouny, Aida A; Maghraby, Amany; Ruppel, Andreas; Soliman, Wael M

2009-01-01

A cyclohexanecarboxamide derivative, N-phenyl-N-[1-(piperidine-1-carbonyl)cyclohexyl] benzamide (MNRC-5), was evaluated for its inhibitory effects on Schistosoma mansoni cercarial serine protease activity and cercarial penetration. MNRC-5 exerted an inhibitory effect on S. mansoni cercarial serine protease at serial concentrations of the specific chromogenic substrate Boc-Val-Leu-Gly-Arg-PNA for such enzyme family and the inhibitory coefficient (Ki) value was deduced. Moreover, topical treatment of mice tails with the most potent inhibitory concentration of MNRC-5 formulated in jojoba oil successfully blocked cercarial penetration as demonstrated by a significant reduction (75%; p < 0.05) in the recovered S. mansoni worms from treated mice in comparison to control ones whose tails were painted with jojoba oil base containing no MNRC-5. In addition, the IgM and IgG reactivities to crude S. mansoni cercarial, worm and egg antigens were generally lower in sera from treated infected mice than untreated infected mice. In conclusion, we report on a new serine protease inhibitor capable for blocking penetration of host skin by S. mansoni cercariae as measured by lowering worm burden and decrease in the levels of both IgM and IgG towards different bilharzial antigens upon topical treatment.

Cholinesterase inhibitory effects of Rhizophora lamarckii, Avicennia officinalis, Sesuvium portulacastrum and Suaeda monica: Mangroves inhabiting an Indian coastal area (Vellar Estuary).

PubMed

Suganthy, Natarajan; Pandian, Shanmugiahthevar Karutha; Devi, Kasi Pandima

2009-06-01

Alzheimer's disease is a progressive neurodegenerative illness accounting for approximately 50% of all types of dementia in elderly people. The only symptomatic treatment proven effective to date is the use of cholinesterase inhibitors to augment surviving cholinergic activity. The purpose of this study is to investigate cholinesterase inhibitory activity of mangroves as an alternative medicine for the treatment of Alzheimer's disease. About nine mangrove plants, which were used as folk medicine in tropical countries, were collected from Parangipettai, Vellar estuary, Tamilnadu, India. Nile Tilapia muscle homogenate was used as source of enzyme. Inhibitory effect of methanolic leaf extract was assessed under in vitro condition by incubating various concentration of the extract with total cholinesterase and butyryl cholinesterase and assessing their residual activities by Ellman's colorimetric method. The results showed that of the nine plants screened Rhizophora lamarckii, Suaeda monica, Avicennia officinalis and Sesuvium portulacastrum showed 50% inhibitory activity to both TChE and BChE at concentrations less than 2 mg/mL when compared to other plant extracts, which was comparable to the standard drug Donepezil. Phytochemical analysis showed the presence of alkaloids in high concentration which might be correlated to its cholinesterase inhibitory activity.