Balanced feedforward inhibition and dominant recurrent inhibition in olfactory cortex

PubMed Central

Large, Adam M.; Vogler, Nathan W.; Mielo, Samantha; Oswald, Anne-Marie M.

2016-01-01

Throughout the brain, the recruitment of feedforward and recurrent inhibition shapes neural responses. However, disentangling the relative contributions of these often-overlapping cortical circuits is challenging. The piriform cortex provides an ideal system to address this issue because the interneurons responsible for feedforward and recurrent inhibition are anatomically segregated in layer (L) 1 and L2/3 respectively. Here we use a combination of optical and electrical activation of interneurons to profile the inhibitory input received by three classes of principal excitatory neuron in the anterior piriform cortex. In all classes, we find that L1 interneurons provide weaker inhibition than L2/3 interneurons. Nonetheless, feedforward inhibitory strength covaries with the amount of afferent excitation received by each class of principal neuron. In contrast, intracortical stimulation of L2/3 evokes strong inhibition that dominates recurrent excitation in all classes. Finally, we find that the relative contributions of feedforward and recurrent pathways differ between principal neuron classes. Specifically, L2 neurons receive more reliable afferent drive and less overall inhibition than L3 neurons. Alternatively, L3 neurons receive substantially more intracortical inhibition. These three features—balanced afferent drive, dominant recurrent inhibition, and differential recruitment by afferent vs. intracortical circuits, dependent on cell class—suggest mechanisms for olfactory processing that may extend to other sensory cortices. PMID:26858458

The role of (dis)inhibition in creativity: decreased inhibition improves idea generation.

PubMed

Radel, Rémi; Davranche, Karen; Fournier, Marion; Dietrich, Arne

2015-01-01

There is now a large body of evidence showing that many different conditions related to impaired fronto-executive functioning are associated with the enhancement of some types of creativity. In this paper, we pursue the possibility that the central mechanism associated with this effect might be a reduced capacity to exert inhibition. We tested this hypothesis by exhausting the inhibition efficiency through prolonged and intensive practice of either the Simon or the Eriksen Flanker task. Performance on another inhibition task indicated that only the cognitive resources for inhibition of participants facing high inhibition demands were impaired. Subsequent creativity tests revealed that exposure to high inhibition demands led to enhanced fluency in a divergent thinking task (Alternate Uses Task), but no such changes occurred in a convergent task (Remote Associate Task; studies 1a and 1b). The same manipulation also led to a hyper-priming effect for weakly related primes in a Lexical Decision Task (Study 2). Together, these findings suggest that inhibition selectively affects some types of creative processes and that, when resources for inhibition are lacking, the frequency and the originality of ideas was facilitated. Copyright © 2014 Elsevier B.V. All rights reserved.

Episodic Inhibition

ERIC Educational Resources Information Center

Racsmany, Mihaly; Conway, Martin A.

2006-01-01

Six experiments examined the proposal that an item of long-term knowledge can be simultaneously inhibited and activated. In 2 directed forgetting experiments items to-be-forgotten were found to be inhibited in list-cued recall but activated in lexical decision tasks. In 3 retrieval practice experiments, unpracticed items from practiced categories…

Inhibition of lactation.

PubMed

Llewellyn-Jones, D

1975-01-01

The mechanism and hormonal regulation of lactation is explained and illustrated with a schematic representation. Circulating estrogen above a critical amount seems to be the inhibitory factor controlling lactation during pregnancy. Once delivery occurs, the level of estrogen falls, that of prolactin rises, and lactation begins. Nonsuckling can be used to inhibit lactation. Estrogens can also be used to inhibit lactation more quickly and with less pain. The reported association between estrogens and puerperal thromboembolism cannot be considered conclusive due to defects in the reporting studies. There is no reason not to use estrogens in lactation inhibition except for women over 35 who experienced a surgical delivery. Alternative therapy is available for these women. The recently-developed drug, brom-ergocryptine, may replace other methods of lactation inhibition.

Hypothermia Inhibits Endothelium-Independent Vascular Contractility via Rho-kinase Inhibition

PubMed Central

Chung, Yoon Hee; Oh, Keon Woong; Kim, Sung Tae; Park, Eon Sub; Je, Hyun Dong; Yoon, Hyuk-Jun; Sohn, Uy Dong; Jeong, Ji Hoon; La, Hyen-Oh

2018-01-01

The present study was undertaken to investigate the influence of hypothermia on endothelium-independent vascular smooth muscle contractility and to determine the mechanism underlying the relaxation. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Hypothermia significantly inhibited fluoride-, thromboxane A2-, phenylephrine-, and phorbol ester-induced vascular contractions regardless of endothelial nitric oxide synthesis, suggesting that another pathway had a direct effect on vascular smooth muscle. Hypothermia significantly inhibited the fluoride-induced increase in pMYPT1 level and phorbol ester-induced increase in pERK1/2 level, suggesting inhibition of Rho-kinase and MEK activity and subsequent phosphorylation of MYPT1 and ERK1/2. These results suggest that the relaxing effect of moderate hypothermia on agonist-induced vascular contraction regardless of endothelial function involves inhibition of Rho-kinase and MEK activities. PMID:28208012

Semantic processing and response inhibition.

PubMed

Chiang, Hsueh-Sheng; Motes, Michael A; Mudar, Raksha A; Rao, Neena K; Mansinghani, Sethesh; Brier, Matthew R; Maguire, Mandy J; Kraut, Michael A; Hart, John

2013-11-13

The present study examined functional MRI (fMRI) BOLD signal changes in response to object categorization during response selection and inhibition. Young adults (N=16) completed a Go/NoGo task with varying object categorization requirements while fMRI data were recorded. Response inhibition elicited increased signal change in various brain regions, including medial frontal areas, compared with response selection. BOLD signal in an area within the right angular gyrus was increased when higher-order categorization was mandated. In addition, signal change during response inhibition varied with categorization requirements in the left inferior temporal gyrus (lIT). lIT-mediated response inhibition when inhibiting the response only required lower-order categorization, but lIT mediated both response selection and inhibition when selecting and inhibiting the response required higher-order categorization. The findings characterized mechanisms mediating response inhibition associated with semantic object categorization in the 'what' visual object memory system.

Relative contribution of homologous recombination and non-homologous end-joining to DNA double-strand break repair after oxidative stress in Saccharomyces cerevisiae.

PubMed

Letavayová, Lucia; Marková, Eva; Hermanská, Katarína; Vlcková, Viera; Vlasáková, Danusa; Chovanec, Miroslav; Brozmanová, Jela

2006-05-10

Oxidative damage to DNA seems to be an important factor in developing many human diseases including cancer. It involves base and sugar damage, base-free sites, DNA-protein cross-links and DNA single-strand (SSB) and double-strand (DSB) breaks. Oxidative DSB can be formed in various ways such as their direct induction by the drug or their generation either through attempted and aborted repair of primary DNA lesions or through DNA replication-dependent conversion of SSB. In general, two main pathways are responsible for repairing DSB, homologous recombination (HR) and non-homologous end-joining (NHEJ), with both of them being potential candidates for the repair of oxidative DSB. We have examined relative contribution of HR and NHEJ to cellular response after oxidative stress in Saccharomyces cerevisiae. Therefore, cell survival, mutagenesis and DSB induction and repair in the rad52, yku70 and rad52 yku70 mutants after hydrogen peroxide (H(2)O(2)), menadione (MD) or bleomycin (BLM) exposure were compared to those obtained for the corresponding wild type. We show that MD exposure does not lead to observable DSB induction in yeast, suggesting that the toxic effects of this agent are mediated by other types of DNA damage. Although H(2)O(2) treatment generates some DSB, their yield is relatively low and hence DSB may only partially be responsible for toxicity of H(2)O(2), particularly at high doses of the agent. On the other hand, the basis of the BLM toxicity resides primarily in DSB induction. Both HR and NHEJ act on BLM-induced DSB, although their relative participation in the process is not equal. Based on our results we suggest that the complexity and/or the quality of the BLM-induced DSB might represent an obstacle for the NHEJ pathway.

Sparse Coding and Lateral Inhibition Arising from Balanced and Unbalanced Dendrodendritic Excitation and Inhibition

PubMed Central

Migliore, Michele; Hines, Michael L.; Shepherd, Gordon M.

2014-01-01

The precise mechanism by which synaptic excitation and inhibition interact with each other in odor coding through the unique dendrodendritic synaptic microcircuits present in olfactory bulb is unknown. Here a scaled-up model of the mitral–granule cell network in the rodent olfactory bulb is used to analyze dendrodendritic processing of experimentally determined odor patterns. We found that the interaction between excitation and inhibition is responsible for two fundamental computational mechanisms: (1) a balanced excitation/inhibition in strongly activated mitral cells, leading to a sparse representation of odorant input, and (2) an unbalanced excitation/inhibition (inhibition dominated) in surrounding weakly activated mitral cells, leading to lateral inhibition. These results suggest how both mechanisms can carry information about the input patterns, with optimal level of synaptic excitation and inhibition producing the highest level of sparseness and decorrelation in the network response. The results suggest how the learning process, through the emergent development of these mechanisms, can enhance odor representation of olfactory bulb. PMID:25297097

Should we stop thinking about inhibition? Searching for individual and age differences in inhibition ability.

PubMed

Rey-Mermet, Alodie; Gade, Miriam; Oberauer, Klaus

2018-04-01

Inhibition is often conceptualized as a unitary construct reflecting the ability to ignore and suppress irrelevant information. At the same time, it has been subdivided into inhibition of prepotent responses (i.e., the ability to stop dominant responses) and resistance to distracter interference (i.e., the ability to ignore distracting information). The present study investigated the unity and diversity of inhibition as a psychometric construct, and tested the hypothesis of an inhibition deficit in older age. We measured inhibition in young and old adults with 11 established laboratory tasks: antisaccade, stop-signal, color Stroop, number Stroop, arrow flanker, letter flanker, Simon, global-local, positive and negative compatibility tasks, and n-2 repetition costs in task switching. In both age groups, the inhibition measures from individual tasks had good reliabilities, but correlated only weakly among each other. Structural equation modeling identified a 2-factor model with factors for inhibition of prepotent responses and resistance to distracter interference. Older adults scored worse in the inhibition of prepotent response, but better in the resistance to distracter interference. However, the model had low explanatory power. Together, these findings call into question inhibition as a psychometric construct and the hypothesis of an inhibition deficit in older age. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants.

PubMed

Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

2016-01-08

Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity.

Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases--Not Glycolipid Processing Enzymes.

PubMed

Sayce, Andrew C; Alonzi, Dominic S; Killingbeck, Sarah S; Tyrrell, Beatrice E; Hill, Michelle L; Caputo, Alessandro T; Iwaki, Ren; Kinami, Kyoko; Ide, Daisuke; Kiappes, J L; Beatty, P Robert; Kato, Atsushi; Harris, Eva; Dwek, Raymond A; Miller, Joanna L; Zitzmann, Nicole

2016-03-01

It has long been thought that iminosugar antiviral activity is a function of inhibition of endoplasmic reticulum-resident α-glucosidases, and on this basis, many iminosugars have been investigated as therapeutic agents for treatment of infection by a diverse spectrum of viruses, including dengue virus (DENV). However, iminosugars are glycomimetics possessing a nitrogen atom in place of the endocyclic oxygen atom, and the ubiquity of glycans in host metabolism suggests that multiple pathways can be targeted via iminosugar treatment. Successful treatment of patients with glycolipid processing defects using iminosugars highlights the clinical exploitation of iminosugar inhibition of enzymes other than ER α-glucosidases. Evidence correlating antiviral activity with successful inhibition of ER glucosidases together with the exclusion of alternative mechanisms of action of iminosugars in the context of DENV infection is limited. Celgosivir, a bicyclic iminosugar evaluated in phase Ib clinical trials as a therapeutic for the treatment of DENV infection, was confirmed to be antiviral in a lethal mouse model of antibody-enhanced DENV infection. In this study we provide the first evidence of the antiviral activity of celgosivir in primary human macrophages in vitro, in which it inhibits DENV secretion with an EC50 of 5 μM. We further demonstrate that monocyclic glucose-mimicking iminosugars inhibit isolated glycoprotein and glycolipid processing enzymes and that this inhibition also occurs in primary cells treated with these drugs. By comparison to bicyclic glucose-mimicking iminosugars which inhibit glycoprotein processing but do not inhibit glycolipid processing and galactose-mimicking iminosugars which do not inhibit glycoprotein processing but do inhibit glycolipid processing, we demonstrate that inhibition of endoplasmic reticulum-resident α-glucosidases, not glycolipid processing, is responsible for iminosugar antiviral activity against DENV. Our data suggest that

Behavioral inhibition and obsessive-compulsive disorder.

PubMed

Coles, Meredith E; Schofield, Casey A; Pietrefesa, Ashley S

2006-01-01

Behavioral inhibition is frequently cited as a vulnerability factor for development of anxiety. However, few studies have examined the unique relationship between behavioral inhibition and obsessive-compulsive disorder (OCD). Therefore, the current study addressed the relationship between behavioral inhibition and OCD in a number of ways. In a large unselected student sample, frequency of current OC symptoms was significantly correlated with retrospective self-reports of total levels of childhood behavioral inhibition. In addition, frequency of current OC symptoms was also significantly correlated with both social and nonsocial components of behavioral inhibition. Further, there was evidence for a unique relationship between behavioral inhibition and OC symptoms beyond the relationship of behavioral inhibition and social anxiety. In addition, results showed that reports of childhood levels of behavioral inhibition significantly predicted levels of OCD symptoms in adulthood. Finally, preliminary evidence suggested that behavioral inhibition may be more strongly associated with some types of OC symptoms than others, and that overprotective parenting may moderate the impact of behavioral inhibition on OC symptoms. The current findings suggest the utility of additional research examining the role of behavioral inhibition in the etiology of OCD.

Contingent involuntary motoric inhibition: the involuntary inhibition of a motor response contingent on top-down goals.

PubMed

Anderson, Brian A; Folk, Charles L

2012-12-01

Effective motor control involves both the execution of appropriate responses and the inhibition of inappropriate responses that are evoked by response-associated stimuli. The inhibition of a motor response has traditionally been characterized as either a voluntary act of cognitive control or a low-level perceptual bias arising from processes such as inhibition of return and priming. Involuntary effects of top-down goals on motoric inhibition have been reported, but involve the perseveration of an inhibitory strategy. It is unknown whether the inhibition of a motor response can be selectively triggered by a goal-relevant stimulus, reflecting the automatic activation of a top-down inhibitory strategy. Here we show that irrelevant flankers that share the color of a no-go target elicit the inhibition of their associated motor response while other-colored flankers do not, even when participants have sufficient time to prepare for the upcoming target while ignoring the flankers. Our results demonstrate contingent involuntary motoric inhibition: motoric inhibition can be automatically triggered by a stimulus based on top-down goals.

Amiloride inhibits the initiation of Coxsackievirus and poliovirus RNA replication by inhibiting VPg uridylylation.

PubMed

Ogram, Sushma A; Boone, Christopher D; McKenna, Robert; Flanegan, James B

2014-09-01

The mechanism of amiloride inhibition of Coxsackievirus B3 (CVB3) and poliovirus type 1 (PV1) RNA replication was investigated using membrane-associated RNA replication complexes. Amiloride was shown to inhibit viral RNA replication and VPgpUpU synthesis. However, the drug had no effect on polymerase elongation activity during either (-) strand or (+) strand synthesis. These findings indicated that amiloride inhibited the initiation of RNA synthesis by inhibiting VPg uridylylation. In addition, in silico binding studies showed that amiloride docks in the VPg binding site on the back of the viral RNA polymerase, 3D(pol). Since VPg binding at this site on PV1 3D(pol) was previously shown to be required for VPg uridylylation, our results suggest that amiloride inhibits VPg binding to 3D(pol). In summary, our findings are consistent with a model in which amiloride inhibits VPgpUpU synthesis and viral RNA replication by competing with VPg for binding to 3D(pol). Copyright © 2014 Elsevier Inc. All rights reserved.

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

Inhibition in Autism: Children with Autism Have Difficulty Inhibiting Irrelevant Distractors but Not Prepotent Responses

ERIC Educational Resources Information Center

Adams, Nena C.; Jarrold, Christopher

2012-01-01

Resistance to distractor inhibition tasks have previously revealed impairments in children with autism. However, on the classic Stroop task and other prepotent response tasks, children with autism show intact inhibition. These data may reflect a distinction between prepotent response and resistance to distractor inhibition. The current study…

Corrosion inhibiting organic coatings

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

Sasson, E.

1984-10-16

A corrosion inhibiting coating comprises a mixture of waxes, petroleum jelly, a hardener and a solvent. In particular, a corrosion inhibiting coating comprises candelilla wax, carnauba wax, microcrystalline waxes, white petrolatum, an oleoresin, lanolin and a solvent.

GPM Timeline Inhibits For IT Processing

NASA Technical Reports Server (NTRS)

Dion, Shirley K.

2014-01-01

The Safety Inhibit Timeline Tool was created as one approach to capturing and understanding inhibits and controls from IT through launch. Global Precipitation Measurement (GPM) Mission, which launched from Japan in March 2014, was a joint mission under a partnership between the National Aeronautics and Space Administration (NASA) and the Japan Aerospace Exploration Agency (JAXA). GPM was one of the first NASA Goddard in-house programs that extensively used software controls. Using this tool during the GPM buildup allowed a thorough review of inhibit and safety critical software design for hazardous subsystems such as the high gain antenna boom, solar array, and instrument deployments, transmitter turn-on, propulsion system release, and instrument radar turn-on. The GPM safety team developed a methodology to document software safety as part of the standard hazard report. As a result of this process, a new tool safety inhibit timeline was created for management of inhibits and their controls during spacecraft buildup and testing during IT at GSFC and at the launch range in Japan. The Safety Inhibit Timeline Tool was a pathfinder approach for reviewing software that controls the electrical inhibits. The Safety Inhibit Timeline Tool strengthens the Safety Analysts understanding of the removal of inhibits during the IT process with safety critical software. With this tool, the Safety Analyst can confirm proper safe configuration of a spacecraft during each IT test, track inhibit and software configuration changes, and assess software criticality. In addition to understanding inhibits and controls during IT, the tool allows the Safety Analyst to better communicate to engineers and management the changes in inhibit states with each phase of hardware and software testing and the impact of safety risks. Lessons learned from participating in the GPM campaign at NASA and JAXA will be discussed during this session.

Inhibition of MMPs by alcohols

PubMed Central

Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Hoshika, Tomohiro; Uchiyama, Toshikazu; Tjäderhane, Leo; Breschi, Lorenzo; Mazzoni, Annalisa; Thompson, Jeremy M.; McCracken, Courtney E.; Looney, Stephen W.; Tay, Franklin R.; Pashley, David H.

2011-01-01

Objectives While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. Methods The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 moles/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC50). Results Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose-dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3-heptanol and 1-octanol gave the strongest inhibition. Significance The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID:21676453

HDAC inhibition inhibits brachial plexus avulsion induced neuropathic pain.

PubMed

Zhao, Yingbo; Wu, Tianjian

2018-05-09

Introduction Neuropathic pain induced by brachial plexus avulsion (BPA) is a pathological condition. We hypothesized that inhibition of histone deacetylase (HDAC) could suppress BPA-induced neuropathic pain through inhibition of transient reception potential (TRP) overexpression and protein kinase B (Akt) mediated mammalian target of rapamycin (mTOR) activation. Methods We generated a rat BPA model, administered HDAC inhibitor Tricostatin A (TSA) for 7 days post-surgery and assessed the effects on HDAC expression, Akt phosphorylation, neuroinflammation and mTOR activation. Results TSA treatment alleviated BPA induced mechanical hyperalgesia, suppressed Akt phosphorylation and increased HDAC. We found suppressed pro-inflammatory cytokine levels, TRP cation channel subfamily V member 1 (TRPV1) and TRP melastatin 8 (TRPM8) expression and mTOR activity in TSA treated BPA rats. Discussion Our results suggest that altered HDAC and Akt signaling are involved in BPA-induced neuropathic pain and that inhibition of HDAC could be an effective therapeutic approach in reducing neuropathic pain. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Equol inhibits growth, induces atresia, and inhibits steroidogenesis of mouse antral follicles in vitro

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

Mahalingam, Sharada, E-mail: mahalin2@illinois.edu; Gao, Liying, E-mail: lgao@uiuc.edu; Gonnering, Marni, E-mail: mgonne2@illinois.edu

Equol is a non-steroidal estrogen metabolite produced by microbial conversion of daidzein, a major soy isoflavone, in the gut of some humans and many animal species. Isoflavones and their metabolites can affect endogenous estradiol production, action, and metabolism, potentially influencing ovarian follicle function. However, no studies have examined the effects of equol on intact ovarian antral follicles, which are responsible for sex steroid synthesis and further development into ovulatory follicles. Thus, the present study tested the hypothesis that equol inhibits antral follicle growth, increases follicle atresia, and inhibits steroidogenesis in the adult mouse ovary. To test this hypothesis, antral folliclesmore » isolated from adult CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or equol (600 nM, 6 μM, 36 μM, and 100 μM) for 48 and 96 h. Every 24 h, follicle diameters were measured to monitor growth. At 48 and 96 h, the culture medium was subjected to measurement of hormone levels, and the cultured follicles were subjected to gene expression analysis. Additionally, follicles were histologically evaluated for signs of atresia after 96 h of culture. The results indicate that equol (100 μM) inhibited follicle growth, altered the mRNA levels of bcl2-associated X protein and B cell leukemia/lymphoma 2, and induced follicle atresia. Further, equol decreased the levels of estradiol, testosterone, androstenedione, and progesterone, and it decreased mRNA levels of cholesterol side-chain cleavage, steroid 17-α-hydroxalase, and aromatase. Collectively, these data indicate that equol inhibits growth, increases atresia, and inhibits steroidogenesis of cultured mouse antral follicles. - Highlights: • Equol exposure inhibits antral follicle growth. • Equol exposure increases follicle atresia. • Equol exposure inhibits sex steroid hormone levels. • Equol exposure inhibits mRNA levels of certain steroidogenic enzymes.« less

Lithium inhibits tumor lymphangiogenesis and metastasis through the inhibition of TGFBIp expression in cancer cells

PubMed Central

Maeng, Yong-Sun; Lee, Rina; Lee, Boram; Choi, Seung-il; Kim, Eung Kweon

2016-01-01

Metastasis is the main cause of mortality in cancer patients. Although there are many anti-cancer drugs targeting tumor growth, anti-metastatic agents are rarely developed. Angiogenesis and lymphangiogenesis are crucial for cancer progression; in particular, lymphangiogenesis is pivotal for metastasis in cancer. Here we report that lithium inhibits colon cancer metastasis by blocking lymphangiogenesis. Lithium reduces the expression of transforming growth factor-β-induced protein (TGFBIp) in colon cancer cells by inhibiting Smad3 phosphorylation via GSK3β inactivation. Moreover, lithium inhibits lymphatic endothelial cell migration, which is increased upon TGFBIp expression in tumor cells. Lithium had no significant effect on SW620 tumor growth in vitro and in vivo; however, it inhibited lymphangiogenesis in tumors. In tumor xenografts model, lithium was found to prevent metastasis to the lungs, liver, and lymph nodes by inhibiting TGFBIp-induced tumor lymphangiogenesis. Collectively, our findings demonstrate a novel role of lithium in the inhibition of colon cancer metastasis by blocking TGFBIp expression, and thereby TGFBIp-induced lymphangiogenesis, in primary tumors. PMID:26857144

Inhibition, interference, and conflict in task switching.

PubMed

Costa, Russell E; Friedrich, Frances J

2012-12-01

The role of inhibition in the task-switching process has received increased empirical and theoretical attention in the literature on cognitive control. Many accounts have suggested that inhibition occurs when a conflict must be resolved-for example, when a target stimulus contains features of more than one task. In the two experiments reported here, we used variants of backward inhibition, or N - 2 repetition, designs to examine (1) whether inhibition occurs in the absence of conflict at the stimulus or response level, (2) when in the task-switching process such inhibition may occur, and (3) the potential consequences of inhibition. In Experiment 1, we demonstrate that neither stimulus- nor response-level conflict is necessary for inhibition to occur, while the results of Experiment 2 suggest that inhibition may be associated with a reduction of proactive interference (PI) from a previously performed task. Evidence of inhibition and the reduction of PI both occurred at the task-set level. However, inhibition of specific stimulus values can also occur, but this is clearly separable from task-set inhibition. Both experiments also provided evidence that task-set inhibition can be applied at the time of the new task cue, as opposed to at the onset of the target or at the response stage of the trial. Taken together, the results from these experiments provide insight into when and where in the task-switching process inhibition may occur, as well as into the potential functional benefits that inhibition of task sets may provide.

Self-regulation, ego depletion, and inhibition.

PubMed

Baumeister, Roy F

2014-12-01

Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it. Copyright © 2014 Elsevier Ltd. All rights reserved.

Inhibition of selectin binding

DOEpatents

Nagy, Jon O.; Spevak, Wayne R.; Dasgupta, Falguni; Bertozzi, Caroline

2001-10-09

This invention provides compositions for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, these composition scan be used to palliate certain inflammatory and immunological conditions.

Inhibition of selectin binding

DOEpatents

Nagy, Jon O.; Spevak, Wayne R.; Dasgupta, Falguni; Bertozzi, Caroline

1999-01-01

This invention provides compositions for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, these composition scan be used to palliate certain inflammatory and immunological conditions.

Inhibition of selectin binding

DOEpatents

Nagy, Jon O.; Spevak, Wayne R.; Dasgupta, Falguni; Bertozzi, Carolyn

1999-10-05

This invention provides a system for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, this system can be used to palliate certain inflammatory and immunological conditions.

Fear inhibition in high trait anxiety.

PubMed

Kindt, Merel; Soeter, Marieke

2014-01-01

Trait anxiety is recognized as an individual risk factor for the development of anxiety disorders but the neurobiological mechanisms remain unknown. Here we test whether trait anxiety is associated with impaired fear inhibition utilizing the AX+/BX- conditional discrimination procedure that allows for the independent evaluation of startle fear potentiation and inhibition of fear. Sixty undergraduate students participated in the study--High Trait Anxious: n = 28 and Low Trait Anxious: n = 32. We replicated earlier findings that a transfer of conditioned inhibition for startle responses requires contingency awareness. However, contrary to the fear inhibition hypothesis, our data suggest that high trait anxious individuals show a normal fear inhibition of conditioned startle responding. Only at the cognitive level the high trait anxious individuals showed evidence for impaired inhibitory learning of the threat cue. Together with other findings where impaired fear inhibition was only observed in those PTSD patients who were either high on hyperarousal symptoms or with current anxiety symptoms, we question whether impaired fear inhibition is a biomarker for the development of anxiety disorders.

Reciprocal inhibition of inhibition: A circuit motif for flexible categorization in stimulus selection

PubMed Central

Knudsen, Eric I.

2011-01-01

As a precursor to the selection of a stimulus for gaze and attention, a midbrain network categorizes stimuli into “strongest” and “others.” The categorization tracks flexibly, in real-time, the absolute strength of the strongest stimulus. In this study, we take a first principles approach to computations that are essential for such categorization. We demonstrate that classical feedforward lateral inhibition cannot produce flexible categorization. However, circuits in which the strength of lateral inhibition varies with the relative strength of competing stimuli categorize successfully. One particular implementation - reciprocal inhibition of feedforward lateral inhibition – is structurally the simplest, and it outperforms others in flexibly categorizing rapidly and reliably. Strong predictions of this anatomically supported circuit model are validated by neural responses measured in the owl midbrain. The results demonstrate the extraordinary power of a remarkably simple, neurally grounded circuit motif in producing flexible categorization, a computation fundamental to attention, perception, and decision-making. PMID:22243757

Reciprocal inhibition in writer's cramp.

PubMed

Chen, R S; Tsai, C H; Lu, C S

1995-09-01

We studied the inhibition of median H-reflexes by conditioning stimuli on the radial nerve in 13 patients with writer's cramp, eight of the simple type and five of the dystonic type, and in 14 normal volunteers. The patients and controls were right-handed, and their right arms were studied. Asymptomatic left arms were also studied in nine of 13 patients. In the control group we identified three periods of inhibition, with maximum peaks at conditioning-test intervals of 0 ms (41 +/- 17%), 20 ms (40 +/- 13%), and 100 ms (36 +/- 20%). In the patient group, the amplitudes of inhibition of these three periods in both arms were significantly less than those in the control group. However, there were no significant differences in the amplitudes of inhibition of these three periods between symptomatic and asymptomatic arms. There were also no significant differences between simple and dystonic writer's cramps. Our results indicate that the attenuation of reciprocal inhibition was present not only in symptomatic arms but also in asymptomatic arms of patients with writer's cramp. The defect of reciprocal inhibition in the asymptomatic hand has never been documented. We suggest that the preexistent electrophysiological abnormality may provide an explanation for the development of hand cramp after shifted writing.

Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans.

PubMed

Marney, Annis; Kunchakarra, Siri; Byrne, Loretta; Brown, Nancy J

2010-10-01

Dipeptidyl peptidase-IV inhibitors improve glucose homeostasis in type 2 diabetics by inhibiting degradation of the incretin hormones. Dipeptidyl peptidase-IV inhibition also prevents the breakdown of the vasoconstrictor neuropeptide Y and, when angiotensin-converting enzyme (ACE) is inhibited, substance P. This study tested the hypothesis that dipeptidyl peptidase-IV inhibition would enhance the blood pressure response to acute ACE inhibition. Subjects with the metabolic syndrome were treated with 0 mg of enalapril (n=9), 5 mg of enalapril (n=8), or 10 mg enalapril (n=7) after treatment with sitagliptin (100 mg/day for 5 days and matching placebo for 5 days) in a randomized, cross-over fashion. Sitagliptin decreased serum dipeptidyl peptidase-IV activity (13.08±1.45 versus 30.28±1.76 nmol/mL/min during placebo; P≤0.001) and fasting blood glucose. Enalapril decreased ACE activity in a dose-dependent manner (P<0.001). Sitagliptin lowered blood pressure during enalapril (0 mg; P=0.02) and augmented the hypotensive response to 5 mg of enalapril (P=0.05). In contrast, sitagliptin attenuated the hypotensive response to 10 mg of enalapril (P=0.02). During sitagliptin, but not during placebo, 10 mg of enalapril significantly increased heart rate and plasma norepinephrine concentrations. There was no effect of 0 or 5 mg of enalapril on heart rate or norepinephrine after treatment with either sitagliptin or placebo. Sitagliptin enhanced the dose-dependent effect of enalapril on renal blood flow. In summary, sitagliptin lowers blood pressure during placebo or submaximal ACE inhibition; sitagliptin activates the sympathetic nervous system to diminish hypotension when ACE is maximally inhibited. This study provides the first evidence for an interactive hemodynamic effect of dipeptidyl peptidase-IV and ACE inhibition in humans.

Behavioral inhibition and childhood stuttering

PubMed Central

Choi, Dahye; Conture, Edward G.; Walden, Tedra A.; Lambert, Warren E.; Tumanova, Victoria

2013-01-01

Purpose The purpose of this study was to assess the relation of behavioral inhibition to stuttering and speech/language output in preschool-age children who do (CWS) and do not stutter (CWNS). Method Participants were preschool-age (ages 36 to 68 months), including 26 CWS (22 males) and 28 CWNS (13 males). Participants’ behavioral inhibition (BI) was assessed by measuring the latency to their sixth spontaneous comment during conversation with an unfamiliar experimenter, using methodology developed by Kagan, Reznick, and Gibbons (1989). In addition to these measures of BI, each participant’s stuttered and non-stuttered disfluencies and mean length of utterance (in morphemes) were assessed. Results Among the more salient findings, it was found that (1) there was no significant difference in BI between preschool-age CWS and CWNS as a group, (2) when extremely high versus low inhibited children were selected, there were more CWS with higher BI and fewer CWS with lower BI when compared to their CWNS peers, and (3) more behaviorally inhibited CWS, when compared to less behaviorally inhibited CWS, exhibited more stuttering. Conclusions Findings are taken to suggest that one aspect of temperament (i.e., behavioral inhibition) is exhibited by some preschool-age CWS and that these children stutter more than CWS with lower behavioral inhibition. The present results seem to support continued study of the association between young children’s temperamental characteristics and stuttering, the diagnostic entity (i.e., CWS versus CWNS), as well as stuttering, the behavior (e.g., frequency of stuttered disfluencies). PMID:23773669

Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis.

PubMed

Li, Qingli; Lambrechts, Mark J; Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; Yin, Rutie; Xi, Mingrong; You, Zongbing

2013-01-01

Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose) polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy.

Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis

PubMed Central

Li, Qingli; Lambrechts, Mark J; Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; Yin, Rutie; Xi, Mingrong; You, Zongbing

2013-01-01

Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose) polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy. PMID:23983455

Foxp3+ T cells inhibit antitumor immune memory modulated by mTOR inhibition.

PubMed

Wang, Yanping; Sparwasser, Tim; Figlin, Robert; Kim, Hyung L

2014-04-15

Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3(+) T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3(+) T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients. ©2014 AACR.

Substrate inhibition kinetics of phenol biodegradation

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

Goudar, C.T.; Ganji, S.H.; Pujar, B.G.

Phenol biodegradation was studied in batch experiments using an acclimated inoculum and initial phenol concentrations ranging from 0.1 to 1.3 g/L. Phenol depletion an associated microbial growth were monitored over time to provide information that was used to estimate the kinetics of phenol biodegradation. Phenol inhibited biodegradation at high concentrations, and a generalized substrate inhibition model based on statistical thermodynamics was used to describe the dynamics of microbial growth in phenol. For experimental data obtained in this study, the generalized substrate inhibition model reduced to a form that is analogous to the Andrews equation, and the biokinetic parameters {micro}{sub max},more » maximum specific growth; K{sub s}, saturation constant; and K{sub i}, inhibition constant were estimated as 0.251 h{sup {minus}1}, 0.011 g/L, and 0.348 g/L, respectively, using a nonlinear least squares technique. Given the wide variability in substrate inhibition models used to describe phenol biodegradation, an attempt was made to justify selection of particular model based on theoretical considerations. Phenol biodegradation data from nine previously published studies were used in the generalized substrate inhibition model to determine the appropriate form of the substrate inhibition model. In all nine cases, the generalized substrate inhibition model reduced to a form analogous to the Andrews equation suggesting the suitability of the Andrews equation to describe phenol biodegradation data.« less

Reconciling the role of serotonin in behavioral inhibition and aversion: acute tryptophan depletion abolishes punishment-induced inhibition in humans

PubMed Central

Crockett, Molly J.; Clark, Luke; Robbins, Trevor W.

2009-01-01

The neuromodulator serotonin has been implicated in a large number of affective and executive functions, but its precise contribution to motivation remains unclear. One influential hypothesis has implicated serotonin in aversive processing; another has proposed a more general role for serotonin in behavioral inhibition. Since behavioral inhibition is a pre-potent reaction to aversive outcomes, it has been a challenge to reconcile these two accounts. Here, we show that serotonin is critical for punishment-induced inhibition, but not overall motor response inhibition or reporting aversive outcomes. We used acute tryptophan depletion to temporarily lower brain serotonin in healthy human volunteers as they completed a novel task designed to obtain separate measures of motor response inhibition, punishment-induced inhibition, and sensitivity to aversive outcomes. Following a placebo treatment, participants were slower to respond under punishment conditions, compared to reward conditions. Tryptophan depletion abolished this punishment-induced inhibition, without affecting overall motor response inhibition or the ability to adjust response bias in line with punishment contingencies. The magnitude of reduction in punishment-induced inhibition depended on the degree to which tryptophan depletion reduced plasma tryptophan levels. These findings extend and clarify previous research on the role of serotonin in aversive processing and behavioral inhibition, and fit with current theorizing on serotonin's involvement in predicting aversive outcomes. PMID:19776285

Control of CA3 output by feedforward inhibition despite developmental changes in the excitation-inhibition balance.

PubMed

Torborg, Christine L; Nakashiba, Toshiaki; Tonegawa, Susumu; McBain, Chris J

2010-11-17

In somatosensory cortex, the relative balance of excitation and inhibition determines how effectively feedforward inhibition enforces the temporal fidelity of action potentials. Within the CA3 region of the hippocampus, glutamatergic mossy fiber (MF) synapses onto CA3 pyramidal cells (PCs) provide strong monosynaptic excitation that exhibit prominent facilitation during repetitive activity. We demonstrate in the juvenile CA3 that MF-driven polysynaptic IPSCs facilitate to maintain a fixed EPSC-IPSC ratio during short-term plasticity. In contrast, in young adult mice this MF-driven polysynaptic inhibitory input can facilitate or depress in response to short trains of activity. Transgenic mice lacking the feedback inhibitory loop continue to exhibit both facilitating and depressing polysynaptic IPSCs, indicating that this robust inhibition is not caused by the secondary engagement of feedback inhibition. Surprisingly, eliminating MF-driven inhibition onto CA3 pyramidal cells by blockade of GABA(A) receptors did not lead to a loss of temporal precision of the first action potential observed after a stimulus but triggered in many cases a long excitatory plateau potential capable of triggering repetitive action potential firing. These observations indicate that, unlike other regions of the brain, the temporal precision of single MF-driven action potentials is dictated primarily by the kinetics of MF EPSPs, not feedforward inhibition. Instead, feedforward inhibition provides a robust regulation of CA3 PC excitability across development to prevent excessive depolarization by the monosynaptic EPSP and multiple action potential firings.

A Fusion-Inhibiting Peptide against Rift Valley Fever Virus Inhibits Multiple, Diverse Viruses

PubMed Central

Koehler, Jeffrey W.; Smith, Jeffrey M.; Ripoll, Daniel R.; Spik, Kristin W.; Taylor, Shannon L.; Badger, Catherine V.; Grant, Rebecca J.; Ogg, Monica M.; Wallqvist, Anders; Guttieri, Mary C.; Garry, Robert F.; Schmaljohn, Connie S.

2013-01-01

For enveloped viruses, fusion of the viral envelope with a cellular membrane is critical for a productive infection to occur. This fusion process is mediated by at least three classes of fusion proteins (Class I, II, and III) based on the protein sequence and structure. For Rift Valley fever virus (RVFV), the glycoprotein Gc (Class II fusion protein) mediates this fusion event following entry into the endocytic pathway, allowing the viral genome access to the cell cytoplasm. Here, we show that peptides analogous to the RVFV Gc stem region inhibited RVFV infectivity in cell culture by inhibiting the fusion process. Further, we show that infectivity can be inhibited for diverse, unrelated RNA viruses that have Class I (Ebola virus), Class II (Andes virus), or Class III (vesicular stomatitis virus) fusion proteins using this single peptide. Our findings are consistent with an inhibition mechanism similar to that proposed for stem peptide fusion inhibitors of dengue virus in which the RVFV inhibitory peptide first binds to both the virion and cell membranes, allowing it to traffic with the virus into the endocytic pathway. Upon acidification and rearrangement of Gc, the peptide is then able to specifically bind to Gc and prevent fusion of the viral and endocytic membranes, thus inhibiting viral infection. These results could provide novel insights into conserved features among the three classes of viral fusion proteins and offer direction for the future development of broadly active fusion inhibitors. PMID:24069485

Human milk glycoconjugates that inhibit pathogens.

PubMed

Newburg, D S

1999-02-01

Breast-fed infants have lower incidence of diarrhea, respiratory disease, and otitis media. The protection by human milk has long been attributed to the presence of secretory IgA. However, human milk contains large numbers and amounts of complex carbohydrates, including glycoproteins, glycolipids, glycosaminoglycans, mucins, and especially oligosaccharides. The oligosaccharides comprise the third most abundant solid constituent of human milk, and contain a myriad of structures. Complex carbohydrate moieties of glycoconjugates and oligosaccharides are synthesized by the many glycosyltransferases in the mammary gland; those with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Several examples are reviewed: A fucosyloligosaccharide inhibits the diarrheagenic effect of stable toxin of Escherichia coli. A different fucosyloligosaccharide inhibits infection by Campylobacter jejuni. Binding of Streptococcus pneumoniae and of enteropathogenic E. coli to their respective receptors is inhibited by human milk oligosaccharides. The 46-kD glycoprotein, lactadherin, inhibits rotavirus binding and infectivity. Low levels of lactadherin in human milk are associated with a higher incidence of symptomatic rotavirus in breast-fed infants. A mannosylated glycopeptide inhibits binding by enterohemorrhagic E. coli. A glycosaminoglycan inhibits binding of gp120 to CD4, the first step in HIV infection. Human milk mucin inhibits binding by S-fimbriated E. coli. The ganglioside, GM1, reduces diarrhea production by cholera toxin and labile toxin of E. coli. The neutral glycosphingolipid, Gb3, binds to Shigatoxin. Thus, many complex carbohydrates of human milk may be novel antipathogenic agents, and the milk glycoconjugates and oligosaccharides may be a major source of protection for breastfeeding infants.

Inhibition of return in the archer fish.

PubMed

Gabay, Shai; Leibovich, Tali; Ben-Simon, Avi; Henik, Avishai; Segev, Ronen

2013-01-01

Inhibition of return is the inhibitory tagging of recently attended locations or objects. It was previously suggested that inhibition of return is a foraging facilitator in visual search. Inhibition of return was first discovered in humans and was demonstrated also in monkeys, yet it has never been demonstrated in non-primates. Here we report the presence of inhibition of return in the archer fish, which shoots down prey on overhanging vegetation, using squirts of water spouted from its mouth. Moreover, we find similar attentional effects for fish as for human participants. Our results show that the generation of inhibition of return does not require a fully developed cortex and strengthen the view that inhibition of return functions as a foraging facilitator.

Checkpoint kinase 1 inhibition sensitises transformed cells to dihydroorotate dehydrogenase inhibition

PubMed Central

Arnould, Stéphanie; Rodier, Geneviève; Matar, Gisèle; Vincent, Charles; Pirot, Nelly; Delorme, Yoann; Berthet, Charlène; Buscail, Yoan; Noël, Jean Yohan; Lachambre, Simon; Jarlier, Marta; Bernex, Florence; Delpech, Hélène; Vidalain, Pierre Olivier; Janin, Yves L.; Theillet, Charles; Sardet, Claude

2017-01-01

Reduction in nucleotide pools through the inhibition of mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) has been demonstrated to effectively reduce cancer cell proliferation and tumour growth. The current study sought to investigate whether this antiproliferative effect could be enhanced by combining Chk1 kinase inhibition. The pharmacological activity of DHODH inhibitor teriflunomide was more selective towards transformed mouse embryonic fibroblasts than their primary or immortalised counterparts, and this effect was amplified when cells were subsequently exposed to PF477736 Chk1 inhibitor. Flow cytometry analyses revealed substantial accumulations of cells in S and G2/M phases, followed by increased cytotoxicity which was characterised by caspase 3-dependent induction of cell death. Associating PF477736 with teriflunomide also significantly sensitised SUM159 and HCC1937 human triple negative breast cancer cell lines to dihydroorotate dehydrogenase inhibition. The main characteristic of this effect was the sustained accumulation of teriflunomide-induced DNA damage as cells displayed increased phospho serine 139 H2AX (γH2AX) levels and concentration-dependent phosphorylation of Chk1 on serine 345 upon exposure to the combination as compared with either inhibitor alone. Importantly a similar significant increase in cell death was observed upon dual siRNA mediated depletion of Chk1 and DHODH in both murine and human cancer cell models. Altogether these results suggest that combining DHODH and Chk1 inhibitions may be a strategy worth considering as a potential alternative to conventional chemotherapies. PMID:29221122

Synthetic 8-hydroxydeoxyguanosine inhibited metastasis of pancreatic cancer through concerted inhibitions of ERM and Rho-GTPase.

PubMed

Park, Jong-Min; Han, Young-Min; Jeong, Migyeong; Chung, Myung Hee; Kwon, Chang Il; Ko, Kwang Hyun; Hahm, Ki Baik

2017-09-01

8-hydroxydeoxyguanosine (8-OHdG) is generated consequent to oxidative stress, but its paradoxical anti-oxidative, anti-inflammatory, and anti-mutagenic effects via Rho-GTPase inhibition were noted in various models of inflammation and cancer. Metastasis occurs through cell detachment, epithelial-mesenchymal transition (EMT), and cell migration; during these processes, changes in cell morphology are initiated through Rho-GTPase-dependent actin cytoskeleton polymerization. In this study, we explored the anti-metastatic mechanisms of 8-OHdG in Panc-1 pancreatic cancer cells. 8-OHdG inhibits cell migration by inactivating ERM and Rho-GTPase proteins, and inhibiting focal adhesion kinase (FAK) and matrix metalloproteinases (MMPs). At 15min, 8-OHdG significantly inactivated ERM (p < 0.05) and led to a significant retardation of wound healing; siERM and H1152 (ROCK inhibitor) had similar effects (p < 0.05). However, FAK inhibitor 14, DPI (NOX inhibitor), and NAC (antioxidant) significantly delayed wound healing without inhibiting ERM or CD44 (p < 0.05). In the experiments on cell migration, siERM, siCD44, DPI, and 8-OHdG significantly inhibited MMPs. 8-OHdG significantly decreased DCF-DA activation in Panc-1 pancreatic cancer cells and down-regulated NOXs (nox-1, nox-2, and nox-3). Finally, all of these anti-migration actions of 8-OHdG resulted in significant inhibition of EMT, as evidenced by the up-regulation of ZO-1 and claudin-1 and down-regulation of vimentin. We found significant inhibition of lung metastasis of Panc-1 cells by 8-OHdG. In conclusion, exogenous 8-OHdG had potent anti-metastasis effects mediated by either ERM or Rho GTPase inhibition in metastasis-prone pancreatic cancer cells. Copyright © 2017 Elsevier Inc. All rights reserved.

The Role of Test Context in Latent Inhibition of Conditioned Inhibition: Part of a Search for General Principles of Associative Interference

PubMed Central

Miguez, Gonzalo; Soares, Julia S.; Miller, Ralph R.

2015-01-01

Two lick-suppression experiments with rats assessed interference with behavior indicative of conditioned inhibition by a latent inhibition treatment as a function of test context. We asked what effect the test context has, given identical latent inhibition treatment in Phase 1 and identical conditioned inhibition training in Phase 2. In Experiment 1, an AAA vs. AAB context-shift design determined that latent inhibition treatment in Phase 1 attenuated behavior indicative of conditioned inhibition training administered in Phase 2 regardless of the test context, which could reflect a failure to either acquire or express conditioned inhibition. In Experiment 2, an ABA vs. ABB design found that test performance in Contexts A and B reflected the treatments that had been administered in those contexts (i.e., conditioned inhibition was observed in Context B but not A), which could reflect either context specificity of latent inhibition or context specificity of conditioned inhibition. In either case, latent inhibition of conditioned inhibition training in at least some situations was seen to reflect an expression deficit rather than an acquisition deficit. These data, in conjunction with prior reports, suggest that latent inhibition is relatively specific to the context in which it was administered, whereas conditioned inhibition is specific to its training context only when it is the second learned relationship concerning the target cue. These experiments are part of a larger effort to delineate control by the test context of two-phase associative interference as a function of the nature of target training and the nature of interference training. PMID:25875792

The role of test context in latent inhibition of conditioned inhibition: Part of a search for general principles of associative interference.

PubMed

Miguez, Gonzalo; Soares, Julia S; Miller, Ralph R

2015-09-01

In two lick suppression experiments with rats, we assessed interference with behavior indicative of conditioned inhibition by a latent inhibition treatment as a function of test context. We asked what effect the test context has, given identical latent inhibition treatments in Phase 1 and identical conditioned inhibition trainings in Phase 2. In Experiment 1, an AAA versus AAB context-shift design determined that the latent inhibition treatment in Phase 1 attenuated behavior indicative of the conditioned inhibition training administered in Phase 2, regardless of the test context, which could reflect a failure to either acquire or express conditioned inhibition. In Experiment 2, an ABA versus ABB design showed that test performance in Contexts A and B reflected the treatments that had been administered in those contexts (i.e., conditioned inhibition was observed in Context B but not A), which could reflect either the context specificity of either latent inhibition or conditioned inhibition. In either case, latent inhibition of conditioned inhibition training in at least some situations was seen to reflect an expression deficit rather than an acquisition deficit. These data, in conjunction with prior reports, suggest that latent inhibition is relatively specific to the context in which it was administered, whereas conditioned inhibition is specific to its training context only when it is the second-learned relationship concerning the target cue. These experiments are part of a larger effort to delineate control by the test context of two-phase associative interference, as a function of the nature of target training and the nature of interference training.

Inhibition by somatostatin (growth-hormone release-inhibiting hormone, GH-RIH) of gastric acid and pepsin and G-cell release of gastrin.

PubMed Central

Barros D'sa, A A; Bloom, S R; Baron, J H

1978-01-01

Somatostatin (cyclic growth-hormone release-inhibiting hormone--GH-RIH) was infused into dogs with gastric fistulae. Somatostatin inhibited gastric acid response to four gastric stimulants--insulin, food, histamine, and pentagastrin. Histamine- and pentagastrin-stimulated pepsins were inhibited similarly to inhibition of acid. Somatostatin inhibited the gastrin response to insulin and food. PMID:348581

Dissociations of cognitive inhibition, response inhibition, and emotional interference: Voxelwise ALE meta-analyses of fMRI studies.

PubMed

Hung, Yuwen; Gaillard, Schuyler L; Yarmak, Pavel; Arsalidou, Marie

2018-06-19

Inhibitory control is the stopping of a mental process with or without intention, conceptualized as mental suppression of competing information because of limited cognitive capacity. Inhibitory control dysfunction is a core characteristic of many major psychiatric disorders. Inhibition is generally thought to involve the prefrontal cortex; however, a single inhibitory mechanism is insufficient for interpreting the heterogeneous nature of human cognition. It remains unclear whether different dimensions of inhibitory processes-specifically cognitive inhibition, response inhibition, and emotional interference-rely on dissociated neural systems. We conducted systematic meta-analyses of fMRI studies in the BrainMap database supplemented by PubMed using whole-brain activation likelihood estimation. A total of 66 study experiments including 1,447 participants and 987 foci revealed that while the left anterior insula was concordant in all inhibitory dimensions, cognitive inhibition reliably activated specific dorsal frontal inhibitory system, engaging dorsal anterior cingulate, dorsolateral prefrontal cortex, and parietal areas, whereas emotional interference reliably implicated a ventral inhibitory system, involving the ventral surface of the inferior frontal gyrus and the amygdala. Response inhibition showed concordant clusters in the fronto-striatal system, including the dorsal anterior cingulate region and extended supplementary motor areas, the dorsal and ventral lateral prefrontal cortex, basal ganglia, midbrain regions, and parietal regions. We provide an empirically derived dimensional model of inhibition characterizing neural systems underlying different aspects of inhibitory mechanisms. This study offers a fundamental framework to advance current understanding of inhibition and provides new insights for future clinical research into disorders with different types of inhibition-related dysfunctions. © 2018 Wiley Periodicals, Inc.

Dihydrotestosterone inhibits hair growth in mice by inhibiting insulin-like growth factor-I production in dermal papillae.

PubMed

Zhao, Juan; Harada, Naoaki; Okajima, Kenji

2011-10-01

We demonstrated that insulin-like growth factor-I (IGF-I) production in dermal papillae was increased and hair growth was promoted after sensory neuron stimulation in mice. Although the androgen metabolite dihydrotestosterone (DHT) inhibits hair growth by negatively modulating growth-regulatory effects of dermal papillae, relationship between androgen metabolism and IGF-I production in dermal papillae is not fully understood. We examined whether DHT inhibits IGF-I production by inhibiting sensory neuron stimulation, thereby preventing hair growth in mice. Effect of DHT on sensory neuron stimulation was examined using cultured dorsal root ganglion (DRG) neurons isolated from mice. DHT inhibits calcitonin gene-related peptide (CGRP) release from cultured DRG neurons. The non-steroidal androgen-receptor antagonist flutamide reversed DHT-induced inhibition of CGRP release. Dermal levels of IGF-I and IGF-I mRNA, and the number of IGF-I-positive fibroblasts around hair follicles were increased at 6h after CGRP administration. DHT administration for 3weeks decreased dermal levels of CGRP, IGF-I, and IGF-I mRNA in mice. Immunohistochemical expression of IGF-I and the number of proliferating cells in hair follicles were decreased and hair re-growth was inhibited in animals administered DHT. Co-administration of flutamide and CGRP reversed these changes induced by DHT administration. These observations suggest that DHT may decrease IGF-I production in dermal papillae by inhibiting sensory neuron stimulation through interaction with the androgen receptor, thereby inhibiting hair growth in mice. Copyright © 2011 Elsevier Ltd. All rights reserved.

Characterization of acetylcholinesterase-inhibition by itopride.

PubMed

Iwanaga, Y; Kimura, T; Miyashita, N; Morikawa, K; Nagata, O; Itoh, Z; Kondo, Y

1994-11-01

Itopride is a gastroprokinetic benzamide derivative. This agent inhibited both electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE). The IC50 of itopride with AChE (2.04 +/- 0.27 microM) was, however, 100-fold less than that with BuChE, whereas in the case of neostigmine with AChE (11.3 +/- 3.4 nM), it was 10-fold less. The recovery of AChE activity inhibited by 10(-7) M neostigmine was partial, but that inhibited by up to 3 x 10(-5) M itopride was complete when the reaction mixture was subjected to ultrafiltration. Double reciprocal plots of the experimental data showed that both Km and Vmax were affected by itopride, suggesting that the inhibition is a "mixed" type, although primarily being an uncompetitive one. The inhibitory effect of itopride on cholinesterase (ChE) activity in guinea pig gastrointestine was much weaker than that on pure AChE. However, in the presence of a low dose of diisopropyl fluorophosphate, just enough to inhibit BuChE but not AChE, the IC50s of itopride against ChE activities were found to be about 0.5 microM. In conclusion, itopride exerts reversible and a "mixed" type of inhibition preferably against AChE. The IC50 of itopride for electric eel and guinea pig gastrointestinal AChE inhibition was 200 times and 50 times as large as that of neostigmine, respectively.

Apoptosis-inducing and apoptosis-preventing functions of poliovirus.

PubMed Central

Tolskaya, E A; Romanova, L I; Kolesnikova, M S; Ivannikova, T A; Smirnova, E A; Raikhlin, N T; Agol, V I

1995-01-01

Data showing that an apoptotic reaction (the exit into the cytoplasm and nucleolytic internucleosomal degradation of chromosomal DNA, compaction and fragmentation of chromatin, cellular shrinkage, and cytoplasmic blebbing) developed in a subline of HeLa-S3 cells upon nonpermissive poliovirus infection with either a guanidine-sensitive poliovirus in the presence of guanidine, a guanidine-dependent mutant in the absence of guanidine, or certain temperature-sensitive mutants at a restrictive temperature are presented. Essentially, no apoptotic reaction occurred upon permissive infection of these cells. Both permissive and nonpermissive infections resulted in the inhibition of host protein synthesis. Actinomycin D or cycloheximide also elicited a rapid apoptotic reaction in uninfected cells. However, preinfection or coinfection with poliovirus prevented the apoptotic response to the addition of actinomycin D, and preinfection blocked cycloheximide-induced apoptosis as well. These data fit a model in which the cells used are prepared to develop apoptosis, with their viability due to the presence of certain short-lived mRNA and protein species. Poliovirus infection turns on two oppositely directed sets of reactions. On the one hand, the balance is driven toward apoptosis, probably via the shutoff of host macromolecular synthesis. On the other hand, viral protein exhibits antiapoptotic activity, thereby preventing premature cell death. To our knowledge, this is the first description of an antiapoptotic function for an RNA virus. PMID:7529330

RNA-processing proteins regulate Mec1/ATR activation by promoting generation of RPA-coated ssDNA.

PubMed

Manfrini, Nicola; Trovesi, Camilla; Wery, Maxime; Martina, Marina; Cesena, Daniele; Descrimes, Marc; Morillon, Antonin; d'Adda di Fagagna, Fabrizio; Longhese, Maria Pia

2015-02-01

Eukaryotic cells respond to DNA double-strand breaks (DSBs) by activating a checkpoint that depends on the protein kinases Tel1/ATM and Mec1/ATR. Mec1/ATR is activated by RPA-coated single-stranded DNA (ssDNA), which arises upon nucleolytic degradation (resection) of the DSB. Emerging evidences indicate that RNA-processing factors play critical, yet poorly understood, roles in genomic stability. Here, we provide evidence that the Saccharomyces cerevisiae RNA decay factors Xrn1, Rrp6 and Trf4 regulate Mec1/ATR activation by promoting generation of RPA-coated ssDNA. The lack of Xrn1 inhibits ssDNA generation at the DSB by preventing the loading of the MRX complex. By contrast, DSB resection is not affected in the absence of Rrp6 or Trf4, but their lack impairs the recruitment of RPA, and therefore of Mec1, to the DSB. Rrp6 and Trf4 inactivation affects neither Rad51/Rad52 association nor DSB repair by homologous recombination (HR), suggesting that full Mec1 activation requires higher amount of RPA-coated ssDNA than HR-mediated repair. Noteworthy, deep transcriptome analyses do not identify common misregulated gene expression that could explain the observed phenotypes. Our results provide a novel link between RNA processing and genome stability. © 2014 The Authors.

α-Lipoic acid inhibits the migration and invasion of breast cancer cells through inhibition of TGFβ signaling.

PubMed

Tripathy, Joytirmay; Tripathy, Anindita; Thangaraju, Muthusamy; Suar, Mrutyunjay; Elangovan, Selvakumar

2018-05-23

Invasion and metastasis are the main cause of mortality in breast cancer. Hence, novel therapeutic interventions with high specificity toward invasion and metastasis are necessary. α-Lipoic acid showed antiproliferative and cytotoxic effects on several cancers including breast cancer. However, the effect of lipoic acid on breast cancer metastasis remains unclear. In the present study, we examined the effects of lipoic acid on the migration and invasion of MDA-MB-231 and 4 T1 breast cancer cells. Our data showed that lipoic acid effectively inhibited the colony forming ability of highly invasive MDA-MB-231 and 4 T1 cells. Moreover, the nontoxic concentrations of lipoic acid significantly reduced the migration of breast cancer cells. Lipoic acid also inhibited the TGFβ-induced angiopoietin-like 4 (ANGPTL4) expression and reduced the activity of matrix metalloproteinase-9 (MMP-9), an enzyme involved in invasion and metastasis, in both the cell lines. The inhibition of cell migration by lipoic acid is accompanied by the downregulation of FAK, ERK1/2 and AKT phosphorylation, and inhibition of nuclear translocation of β-catenin. Our data demonstrated that lipoic acid inhibited the migration and invasion of metastatic breast cancer cells at least in part through inhibiting ERK1/2 and AKT signaling. Thus, our findings show that the inhibition of TGFβ signaling is a potential mechanism for the anti-invasive effects of lipoic acid. Copyright © 2017. Published by Elsevier Inc.

Inhibiting prenylation augments chemotherapy efficacy in renal cell carcinoma through dual inhibition on mitochondrial respiration and glycolysis.

PubMed

Huang, Jiangrong; Yang, Xiaoyu; Peng, Xiaochun; Huang, Wei

2017-11-18

Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines. Combination of pitavastatin and paclitaxel is significantly more effective than pitavastatin or paclitaxel alone as shown by both in vitro cell culture system and in vivo RCC xenograft model. Importantly, pitavastatin treatment inhibits mitochondrial respiration via suppressing mitochondrial complex I and II enzyme activities. Interestingly, different from mitochondrial inhibitor phenformin that inhibits mitochondrial respiration but activates glycolytic rate in RCC cells, pitavastatin significantly decreases glycolytic rate. The dual inhibitory action of pitavastatin on mitochondrial respiration and glycolysis results in remarkable energy depletion and oxidative stress in RCC cells. In addition, inhibition of prenylation by depleting Isoprenylcysteine carboxylmethyltransferase (Icmt) also mimics the inhibitory effects of pitavastatin in RCC cells. Our work demonstrates the previously unappreciated association between prenylation inhibition and energy metabolism in RCC, which can be therapeutically exploited, likely in tumors that largely rely on energy metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin

PubMed Central

Verespy III, Stephen; Mehta, Akul Y.; Afosah, Daniel; Al-Horani, Rami A.; Desai, Umesh R.

2016-01-01

Allosteric partial inhibition of soluble, monomeric proteases can offer major regulatory advantages, but remains a concept on paper to date; although it has been routinely documented for receptors and oligomeric proteins. Thrombin, a key protease of the coagulation cascade, displays significant conformational plasticity, which presents an attractive opportunity to discover small molecule probes that induce sub-maximal allosteric inhibition. We synthesized a focused library of some 36 sulfated coumarins to discover two agents that display sub-maximal efficacy (~50%), high potency (<500 nM) and high selectivity for thrombin (>150-fold). Michaelis-Menten, competitive inhibition, and site-directed mutagenesis studies identified exosite 2 as the site of binding for the most potent sulfated coumarin. Stern-Volmer quenching of active site-labeled fluorophore suggested that the allosteric regulators induce intermediate structural changes in the active site as compared to those that display ~80–100% efficacy. Antithrombin inactivation of thrombin was impaired in the presence of the sulfated coumarins suggesting that allosteric partial inhibition arises from catalytic dysfunction of the active site. Overall, sulfated coumarins represent first-in-class, sub-maximal inhibitors of thrombin. The probes establish the concept of allosteric partial inhibition of soluble, monomeric proteins. This concept may lead to a new class of anticoagulants that are completely devoid of bleeding. PMID:27053426

Inhibition of cellulases by phenols

USDA-ARS?s Scientific Manuscript database

The inhibition of enzymes by the end products that they make is a well-known phenomenon. Another form of inhibition is manifested by the decrease in hydrolysis of pretreated cellulosic material as the concentration of solid biomass material increases, even though the ratio of enzyme to cellulose is...

Oxidized quercetin inhibits α-synuclein fibrillization.

PubMed

Zhu, Min; Han, Shubo; Fink, Anthony L

2013-04-01

α-Synucein is a small (14 kDa), abundant, intrinsically disordered presynaptic protein, whose aggregation is believed to be a critical step in Parkinson's disease (PD). Oxidative stress is reported to be a risk factor for dopamine cell degeneration in PD. Flavonoids are suggested to be important antioxidant against oxidative stress. Flavonoids were reported to inhibit fibrillization and disaggregate the preformed fibrils of α-synucein, but the molecular mechanism was still not clear. Quercetin, a well-recognized flavonoid antioxidant, was tested for its inhibition of α-synucein aggregation by thioflavin T assay, light scattering measurement, size-exclusion high performance liquid chromatography, atomic force microscopy, etc. The pre-incubated quercetin exhibited a noticeably stronger inhibition behavior to the fibril formation than that of the freshly prepared. The inhibition is significant in the presence of ortho- and para-benzenediol isomers and inconsiderable in the presence of meta-isomer. The oxidized quercetin species (i.e., chalcantrione, benzyfuranone, quercetinchinone, and other derivatives) cause stronger inhibition than quercetin does because of the elevated polarity and hydrophilicity. Presence of quercetin disaggregates α-synucein fibrils, rather than oligomers and amorphous aggregations. Instead of the antioxidant activity, the 1:1 covalent binding of quercetin with α-synucein, and the increased hydophilicity of the covalently modified α-synucein oligomers or monomers, account for the inhibition of α-synucein fibrillation. Clarification of the molecular mechanism of the inhibition and disaggregation may help to screen safer and more effective flavonoid therapeutic in combating PD. Copyright © 2012. Published by Elsevier B.V.

Tangeretin inhibits extracellular-signal-regulated kinase (ERK) phosphorylation.

PubMed

Van Slambrouck, Séverine; Parmar, Virinder S; Sharma, Sunil K; De Bondt, Bart; Foré, Fleur; Coopman, Peter; Vanhoecke, Barbara W; Boterberg, Tom; Depypere, Herman T; Leclercq, Guy; Bracke, Marc E

2005-03-14

Tangeretin is a methoxyflavone from citrus fruits, which inhibits growth of human mammary cancer cells and cytolysis by natural killer cells. Attempting to unravel the flavonoid's action mechanism, we found that it inhibited extracellular-signal-regulated kinases 1/2 (ERK1/2) phosphorylation in a dose- and time-dependent way. In human T47D mammary cancer cells this inhibition was optimally observed after priming with estradiol. The spectrum of the intracellular signalling kinase inhibition was narrow and comparison of structural congeners showed that inhibition of ERK phosphorylation was not unique for tangeretin. Our data add tangeretin to the list of small kinase inhibitors with a restricted intracellular inhibition profile.

Kindergarteners’ Self-Reported Social Inhibition and Observed Social Reticence: Moderation by Adult-Reported Social Inhibition and Social Anxiety Disorder Symptoms

PubMed Central

Kiel, Elizabeth J.; Buss, Kristin A.; Molitor, Joseph G.

2014-01-01

Prevention of later anxiety problems would best be accomplished by identifying at-risk children early in development. For example, children who develop Social Anxiety Disorder (SAD) may show social withdrawal in the form of social inhibition (i.e., shyness with unfamiliar adults and peers) at school entry. Although the use of children’s perceptions of their own social inhibition would provide insight into early risk, the utility of young children’s self-reports remains unclear. The current study examined whether children deemed more extreme on social inhibition or social anxiety by adult report provided self-report of social inhibition that related to observed social reticence in the laboratory. Participants included 85 kindergarten children (36 female, 49 male), their parents, and their teachers. Moderation analyses revealed that children’s self-reported social inhibition related significantly to observed social reticence under the conditions of high parent-reported social inhibition, high teacher-reported social inhibition, and high SAD symptoms. These results suggest that the most inhibited children are aware of their behavior and can report it in a meaningfully way as young as kindergarten age. PMID:25113397

Can Arousal Modulate Response Inhibition?

ERIC Educational Resources Information Center

Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

2015-01-01

The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

A speculated cause of respiratory inhibition in infants.

PubMed

Minowa, Hideki; Arai, Ikuyo; Yasuhara, Hajime; Ebisu, Reiko; Ohgitani, Ayako

2018-10-01

In our previous studies, we documented that threatened premature labor and asymmetrical intrauterine growth restriction were risk factors for respiratory inhibition. The goal of this study was to determine the cause of respiratory inhibition by considering perinatal risk factors. We examined 1497 infants with a gestational age of 36 weeks or greater. All infants were monitored using pulse oximetry and examined via cranial sonography. Respiratory inhibition was defined as severe hypoxemia caused by respiratory inhibition immediately after crying or gastroesophageal reflux or as a respiratory pause during feeding. We examined the relationships between respiratory inhibition and perinatal factors and speculated on the cause of respiratory inhibition. The median gestational age, birth weight, Apgar score at 1 min, and Apgar score at 5 min of the subjects were 38.9 weeks, 2930 g, 8.0 points, and 9.0 points, respectively. Respiratory inhibition was observed in 422 infants. Lateral ventricle enlargement and increased echogenicity in the ganglionic eminence were observed in 417 and 516 infants, respectively. Respiratory inhibition was significantly correlated with shorter gestational periods, twin pregnancies, lateral ventricle enlargement, and increased echogenicity in the ganglionic eminence. We speculate that umbilical cord compression is a major cause of respiratory inhibition.

BST2/Tetherin Inhibition of Alphavirus Exit

PubMed Central

Ooi, Yaw Shin; Dubé, Mathieu; Kielian, Margaret

2015-01-01

Alphaviruses such as chikungunya virus (CHIKV) and Semliki Forest virus (SFV) are small enveloped RNA viruses that bud from the plasma membrane. Tetherin/BST2 is an interferon-induced host membrane protein that inhibits the release of many enveloped viruses via direct tethering of budded particles to the cell surface. Alphaviruses have highly organized structures and exclude host membrane proteins from the site of budding, suggesting that their release might be insensitive to tetherin inhibition. Here, we demonstrated that exogenously-expressed tetherin efficiently inhibited the release of SFV and CHIKV particles from host cells without affecting virus entry and infection. Alphavirus release was also inhibited by the endogenous levels of tetherin in HeLa cells. While rubella virus (RuV) and dengue virus (DENV) have structural similarities to alphaviruses, tetherin inhibited the release of RuV but not DENV. We found that two recently identified tetherin isoforms differing in length at the N-terminus exhibited distinct capabilities in restricting alphavirus release. SFV exit was efficiently inhibited by the long isoform but not the short isoform of tetherin, while both isoforms inhibited vesicular stomatitis virus exit. Thus, in spite of the organized structure of the virus particle, tetherin specifically blocks alphavirus release and shows an interesting isoform requirement. PMID:25912717

Equol inhibits growth, induces atresia, and inhibits steroidogenesis of mouse antral follicles in vitro

PubMed Central

Mahalingam, Sharada; Gao, Liying; Gonnering, Marni; Helferich, William; Flaws, Jodi A.

2016-01-01

Equol is a non-steroidal estrogen metabolite produced by microbial conversion of daidzein, a major soy isoflavone, in the gut of some humans and many animal species. Isoflavones and their metabolites can affect endogenous estradiol production, action, and metabolism, potentially influencing ovarian follicle function. However, no studies have examined the effects of equol on intact ovarian antral follicles, which are responsible for sex steroid synthesis and further development into ovulatory follicles. Thus, the present study tested the hypothesis that equol inhibits antral follicle growth, increases follicle atresia, and inhibits steroidogenesis in the adult mouse ovary. To test this hypothesis, antral follicles isolated from adult CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or equol (600 nM, 6 μM, 36 μM, 100 μM) for 48 and 96 h. Every 24 h, follicle diameters were measured to monitor growth. At 48 and 96 h, the culture medium was subjected to measurement of hormone levels, and the cultured follicles were subjected to gene expression analysis. Additionally, follicles were histologically evaluated for signs of atresia after 96 h of culture. The results indicate that equol (100 μM) inhibited follicle growth, altered the mRNA levels of bcl2-associated X protein and B cell leukemia/lymphoma 2, and induced follicle atresia. Further, equol decreased the levels of estradiol, testosterone, androstenedione, and progesterone, and it decreased mRNA levels of cholesterol side-chain cleavage, steroid 17-α-hydroxalase, and aromatase. Collectively, these data indicate that equol inhibits growth, increases atresia, and inhibits steroidogenesis of cultured mouse antral follicles. PMID:26876617

Pharmacologic inhibition of lactate production prevents myofibroblast differentiation.

PubMed

Kottmann, Robert Matthew; Trawick, Emma; Judge, Jennifer L; Wahl, Lindsay A; Epa, Amali P; Owens, Kristina M; Thatcher, Thomas H; Phipps, Richard P; Sime, Patricia J

2015-12-01

Myofibroblasts are one of the primary cell types responsible for the accumulation of extracellular matrix in fibrosing diseases, and targeting myofibroblast differentiation is an important therapeutic strategy for the treatment of pulmonary fibrosis. Transforming growth factor-β (TGF-β) has been shown to be an important inducer of myofibroblast differentiation. We previously demonstrated that lactate dehydrogenase and its metabolic product lactic acid are important mediators of myofibroblast differentiation, via acid-induced activation of latent TGF-β. Here we explore whether pharmacologic inhibition of LDH activity can prevent TGF-β-induced myofibroblast differentiation. Primary human lung fibroblasts from healthy patients and those with pulmonary fibrosis were treated with TGF-β and or gossypol, an LDH inhibitor. Protein and RNA were analyzed for markers of myofibroblast differentiation and extracellular matrix generation. Gossypol inhibited TGF-β-induced expression of the myofibroblast marker α-smooth muscle actin (α-SMA) in a dose-dependent manner in both healthy and fibrotic human lung fibroblasts. Gossypol also inhibited expression of collagen 1, collagen 3, and fibronectin. Gossypol inhibited LDH activity, the generation of extracellular lactic acid, and the rate of extracellular acidification in a dose-dependent manner. Furthermore, gossypol inhibited TGF-β bioactivity in a dose-dependent manner. Concurrent treatment with an LDH siRNA increased the ability of gossypol to inhibit TGF-β-induced myofibroblast differentiation. Gossypol inhibits TGF-β-induced myofibroblast differentiation through inhibition of LDH, inhibition of extracellular accumulation of lactic acid, and inhibition of TGF-β bioactivity. These data support the hypothesis that pharmacologic inhibition of LDH may play an important role in the treatment of pulmonary fibrosis. Copyright © 2015 the American Physiological Society.

Influence of transcutaneous electrical nerve stimulation conditions on disynaptic reciprocal Ia inhibition and presynaptic inhibition in healthy adults.

PubMed

Takeda, Kazuya; Tanabe, Shigeo; Koyama, Soichiro; Ushiroyama, Kosuke; Naoi, Yuki; Motoya, Ikuo; Sakurai, Hiroaki; Kanada, Yoshikiyo

2017-03-01

This study investigated the influence of stimulus conditions of transcutaneous electrical nerve stimulation (TENS) on disynaptic reciprocal Ia inhibition (RI) and presynaptic inhibition (D1 inhibition) in healthy adults. Eight healthy participants received TENS (stimulus frequencies of 50, 100, and 200 Hz) over the deep peroneal nerve and tibialis anterior (TA) muscle in the resting condition for 30 min. At pre- and post-intervention, the RI from the TA to the soleus (SOL) and D1 inhibition of the SOL alpha motor neuron were assessed by evoked electromyography. The results showed that RI was not changed by TENS at any stimulus frequency condition. Conversely, D1 inhibition was significantly changed by TENS regardless of the stimulus frequency. The present results and previous studies pertaining to RI suggest that the resting condition might strongly influence the lack of pre- vs. post-intervention change in the RI. Regarding the D1 inhibition, the present results suggest that the effect of TENS might be caused by post-tetanic potentiation. The knowledge gained from the present study might contribute to a better understanding of fundamental studies of TENS in healthy adults and its clinical application for stroke survivors.

Atorvastatin inhibits insulin synthesis by inhibiting the Ras/Raf/ERK/CREB pathway in INS-1 cells

PubMed Central

Sun, Hongxi; Li, Yu; Sun, Bei; Hou, Ningning; Yang, Juhong; Zheng, Miaoyan; Xu, Jie; Wang, Jingyu; Zhang, Yi; Zeng, Xianwei; Shan, Chunyan; Chang, Bai; Chen, Liming; Chang, Baocheng

2016-01-01

Abstract Backround: Type 2 diabetes has become a global epidemic disease. Atorvastatin has become a cornerstone in the prevention and treatment of atherosclerosis. However, increasing evidence showed that statins can dose-dependently increase the risk of diabetes mellitus. The mechanism is not clear. Objective: The Ras complex pathway (Ras/Raf/extracellular signal-regulated kinase [ERK]/cAMP response element-binding protein [CREB]) is the major pathway that regulates the gene transcription. Except for the inhibition of cholesterol synthesis by inhibiting the 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-COA) reductase, statins can also downregulate the phosphorylation of a series of downstream substrates including the key proteins of the Ras complex pathway, therefore may inhibit the insulin syntheses in pancreatic beta cells. In our study, we investigated the inhibitory effect and the underlying mechanism of atorvastatin on insulin synthesis in rat islets. Methods: Islets were isolated from Wistar rats and cultured in Roswell Park Memorial Institute (RPMI)-1640 medium. The insulin content in the medium was measured by radioimmunoassay before and after the treatment of 50 μM atorvastatin. Effect of atorvastatin on the expression of insulin message Ribonucleic acid (mRNA) in pancreatic islet beta cells was also detected using quantitative real-time polymerase chain reaction. Western blotting was used to explore the possible role of the Ras complex pathway (Ras/Raf/ERK/CREB) in atorvastatin-inhibited insulin synthesis. The effects of atorvastatin on the binding of nuclear transcription factor p-CREB with CRE in INS-1 cells were examined via chromatin immunoprecipitation assay. Results: Compared with the control group, the insulin level decreased by 27.1% at 24 hours after atorvastatin treatment. Atorvastatin inhibited insulin synthesis by decreasing insulin mRNA expression of pancreatic islet beta cells. The activities of Ras, Raf-1, and p-CREB in the Ras complex

Task Inhibition and Response Inhibition in Older vs. Younger Adults: A Diffusion Model Analysis

PubMed Central

Schuch, Stefanie

2016-01-01

Differences in inhibitory ability between older (64–79 years, N = 24) and younger adults (18–26 years, N = 24) were investigated using a diffusion model analysis. Participants performed a task-switching paradigm that allows assessing n−2 task repetition costs, reflecting inhibitory control on the level of tasks, as well as n−1 response-repetition costs, reflecting inhibitory control on the level of responses. N−2 task repetition costs were of similar size in both age groups. Diffusion model analysis revealed that for both younger and older adults, drift rate parameters were smaller in the inhibition condition relative to the control condition, consistent with the idea that persisting task inhibition slows down response selection. Moreover, there was preliminary evidence for task inhibition effects in threshold separation and non-decision time in the older, but not the younger adults, suggesting that older adults might apply different strategies when dealing with persisting task inhibition. N−1 response-repetition costs in mean RT were larger in older than younger adults, but in mean error rates tended to be larger in younger than older adults. Diffusion-model analysis revealed longer non-decision times in response repetitions than response switches in both age groups, consistent with the idea that motor processes take longer in response repetitions than response switches due to persisting response inhibition of a previously executed response. The data also revealed age-related differences in overall performance: Older adults responded more slowly and more accurately than young adults, which was reflected by a higher threshold separation parameter in diffusion model analysis. Moreover, older adults showed larger non-decision times and higher variability in non-decision time than young adults, possibly reflecting slower and more variable motor processes. In contrast, overall drift rate did not differ between older and younger adults. Taken together

Inhibiting cancer cell hallmark features through nuclear export inhibition.

PubMed

Sun, Qingxiang; Chen, Xueqin; Zhou, Qiao; Burstein, Ezra; Yang, Shengyong; Jia, Da

2016-01-01

Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

Hypnotic suggestibility, cognitive inhibition, and dissociation.

PubMed

Dienes, Zoltán; Brown, Elizabeth; Hutton, Sam; Kirsch, Irving; Mazzoni, Giuliana; Wright, Daniel B

2009-12-01

We examined two potential correlates of hypnotic suggestibility: dissociation and cognitive inhibition. Dissociation is the foundation of two of the major theories of hypnosis and other theories commonly postulate that hypnotic responding is a result of attentional abilities (including inhibition). Participants were administered the Waterloo-Stanford Group Scale of Hypnotic Susceptibility, Form C. Under the guise of an unrelated study, 180 of these participants also completed: a version of the Dissociative Experiences Scale that is normally distributed in non-clinical populations; a latent inhibition task, a spatial negative priming task, and a memory task designed to measure negative priming. The data ruled out even moderate correlations between hypnotic suggestibility and all the measures of dissociation and cognitive inhibition overall, though they also indicated gender differences. The results are a challenge for existing theories of hypnosis.

Inhibition of Retinoblastoma Protein Inactivation

DTIC Science & Technology

2016-09-01

Retinoblastoma protein, E2F transcription factor, high throughput screen, drug discovery, x-ray crystallography 16. SECURITY CLASSIFICATION OF: 17...developed a method to perform fragment based screening by x-ray crystallography . 2.0 KEYWORDS Retinoblastoma (Rb) pathway, E2F transcription factor...cancer, cell-cycle inhibition, activation, modulation, inhibition, high throughput screening, fragment-based screening, x-ray crystallography

Inhibition of Retinoblastoma Protein Inactivation

DTIC Science & Technology

2017-11-01

SUBJECT TERMS cell cycle, Retinoblastoma protein, E2F transcription factor, high throughput screen, drug discovery, x-ray crystallography 16. SECURITY...screening by x-ray crystallography . 2.0 KEYWORDS Retinoblastoma (Rb) pathway, E2F transcription factor, cancer, cell-cycle inhibition, activation...modulation, inhibition, high throughput screening, fragment-based screening, x-ray crystallography . 3.0 ACCOMPLISHMENTS Summary: We

Effects of Inhibition Conditions on Anammox process

NASA Astrophysics Data System (ADS)

Xie, Haitao; Ji, Dandan; Zang, Lihua

2017-12-01

Anaerobic ammonium oxidation (Anammox) is a very suitable process for the treatment of nitrogen-rich wastewater, which is a promising new biological nitrogen removal process, and has a good application prospects. However, the Anammox process is inhibited by many factors, which hinders the process improvement and the application of the Anammox process. Such as organic,temperature,salts,heavy metals, phosphates, sulfides, pH and other inhibitors are usually present in practical applications. We have reviewed the previous researches on the inhibition of Anammox processes. The effect of the substrate on the anaerobic oxide is mainly caused by free ammonia or nitrite nitrogen. Most heavy metals inhibit Anammox growth and activity. The inhibition of organic matter depends on the content of organic matter and species. High salinity inhibits Anammox activity. Dissolved oxygen allows the flora to be in a balanced state. The optimum pH and temperature, as well as other factors, can provide a good growth environment for Anammox. The knowledge of inhibition on Anammox will help prevent the application and improvement of the Anammox process.

Post-Stop-Signal Adjustments: Inhibition Improves Subsequent Inhibition

ERIC Educational Resources Information Center

Bissett, Patrick G.; Logan, Gordon D.

2012-01-01

Performance in the stop-signal paradigm involves a balance between going and stopping, and one way that this balance is struck is through shifting priority away from the go task, slowing responses after a stop signal, and improving the probability of inhibition. In 6 experiments, the authors tested whether there is a corresponding shift in…

Temporal Dynamics of Proactive and Reactive Motor Inhibition

PubMed Central

Liebrand, Matthias; Pein, Inga; Tzvi, Elinor; Krämer, Ulrike M.

2017-01-01

Proactive motor inhibition refers to endogenous preparatory mechanisms facilitating action inhibition, whereas reactive motor inhibition is considered to be a sudden stopping process triggered by external signals. Previous studies were inconclusive about the temporal dynamics of involved neurocognitive processes during proactive and reactive motor control. Using electroencephalography (EEG), we investigated the time-course of proactive and reactive inhibition, measuring event-related oscillations and event-related potentials (ERPs). Participants performed in a cued go/nogo paradigm with cues indicating whether the motor response might or might not have to be inhibited. Based on the dual mechanisms of control (DMC) framework by Braver, we investigated the role of attentional effects, motor preparation in the sensorimotor cortex and prefrontal cognitive control mechanisms, separating effects before and after target onset. In the cue-target interval, proactive motor inhibition was associated with increased attention, reflected in reduced visual alpha power and an increased contingent negative variation (CNV). At the same time, motor inhibition was modulated by reduced sensorimotor beta power. After target onset, proactive inhibition resulted in an increased N1, indicating allocation of attention towards relevant stimuli, increased prefrontal beta power and a modulation of sensorimotor mu activity. As in previous studies, reactive stopping of motor actions was associated with increased prefrontal beta power and increased sensorimotor beta activity. The results stress the relevance of attentional mechanisms for proactive inhibition and speak for different neurocognitive mechanisms being involved in the early preparation for and in later implementation of motor inhibition. PMID:28496405

Altered cortical processing of motor inhibition in schizophrenia.

PubMed

Lindberg, Påvel G; Térémetz, Maxime; Charron, Sylvain; Kebir, Oussama; Saby, Agathe; Bendjemaa, Narjes; Lion, Stéphanie; Crépon, Benoît; Gaillard, Raphaël; Oppenheim, Catherine; Krebs, Marie-Odile; Amado, Isabelle

2016-12-01

Inhibition is considered a key mechanism in schizophrenia. Short-latency intracortical inhibition (SICI) in the motor cortex is reduced in schizophrenia and is considered to reflect locally deficient γ-aminobutyric acid (GABA)-ergic modulation. However, it remains unclear how SICI is modulated during motor inhibition and how it relates to neural processing in other cortical areas. Here we studied motor inhibition Stop signal task (SST) in stabilized patients with schizophrenia (N = 28), healthy siblings (N = 21) and healthy controls (n = 31) matched in general cognitive status and educational level. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) were used to investigate neural correlates of motor inhibition. SST performance was similar in patients and controls. SICI was modulated by the task as expected in healthy controls and siblings but was reduced in patients with schizophrenia during inhibition despite equivalent motor inhibition performance. fMRI showed greater prefrontal and premotor activation during motor inhibition in schizophrenia. Task-related modulation of SICI was higher in subjects who showed less inhibition-related activity in pre-supplementary motor area (SMA) and cingulate motor area. An exploratory genetic analysis of selected markers of inhibition (GABRB2, GAD1, GRM1, and GRM3) did not explain task-related differences in SICI or cortical activation. In conclusion, this multimodal study provides direct evidence of a task-related deficiency in SICI modulation in schizophrenia likely reflecting deficient GABA-A related processing in motor cortex. Compensatory activation of premotor areas may explain similar motor inhibition in patients despite local deficits in intracortical processing. Task-related modulation of SICI may serve as a useful non-invasive GABAergic marker in development of therapeutic strategies in schizophrenia. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structural and functional bases of inhibited temperament.

PubMed

Clauss, Jacqueline A; Seay, April L; VanDerKlok, Ross M; Avery, Suzanne N; Cao, Aize; Cowan, Ronald L; Benningfield, Margaret M; Blackford, Jennifer Urbano

2014-12-01

Children born with an inhibited temperament are at heightened risk for developing anxiety, depression and substance use. Inhibited temperament is believed to have a biological basis; however, little is known about the structural brain basis of this vulnerability trait. Structural MRI scans were obtained from 84 (44 inhibited, 40 uninhibited) young adults. Given previous findings of amygdala hyperactivity in inhibited individuals, groups were compared on three measures of amygdala structure. To identify novel substrates of inhibited temperament, a whole brain analysis was performed. Functional activation and connectivity were examined across both groups. Inhibited adults had larger amygdala and caudate volume and larger volume predicted greater activation to neutral faces. In addition, larger amygdala volume predicted greater connectivity with subcortical and higher order visual structures. Larger caudate volume predicted greater connectivity with the basal ganglia, and less connectivity with primary visual and auditory cortex. We propose that larger volume in these salience detection regions may result in increased activation and enhanced connectivity in response to social stimuli. Given the strong link between inhibited temperament and risk for psychiatric illness, novel therapeutics that target these brain regions and related neural circuits have the potential to reduce rates of illness in vulnerable individuals. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Selective serotonin reuptake inhibition modulates response inhibition in Parkinson’s disease

PubMed Central

Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R.; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L.; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

2014-01-01

Impulsivity is common in Parkinson’s disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic ‘overdose’ and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson’s disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson’s disease (46–76 years old, 11 male, Hoehn and Yahr stage 1.5–3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54–74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson’s disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson’s Disease Rating Scale

Spatially confined polymer chains: implications of chromatin fibre flexibility and peripheral anchoring on telomere telomere interaction

NASA Astrophysics Data System (ADS)

Gehlen, L. R.; Rosa, A.; Klenin, K.; Langowski, J.; Gasser, S. M.; Bystricky, K.

2006-04-01

We simulate the extension of spatially confined chromatin fibres modelled as polymer chains and examine the effect of the flexibility of the fibre and its degree of freedom. The developed formalism was used to analyse experimental data of telomere-telomere distances in living yeast cells in the absence of confining factors as identified by the proteins Sir4 and yKu70. Our analysis indicates that intrinsic properties of the chromatin fibre, in particular its elastic properties and flexibility, can influence the juxtaposition of the telomeric ends of chromosomes. However, measurements in intact yeast cells showed that the telomeres of chromosomes 3 and 6 come even closer together than the parameters of constraint imposed on the simulations would predict. This juxtaposition was specific to telomeres on one contiguous chromosome and overrode a tendency for separation that is imposed by anchoring.

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

PubMed Central

Jiang, Li-Bo; Meng, De-Hua; Lee, Soo-Min; Liu, Shu-Hao; Xu, Qin-Tong; Wang, Yang; Zhang, Jian

2016-01-01

Osteoarthritis is a disease with inflammatory and catabolic imbalance in cartilage. Dihydroartemisinin (DHA), a natural and safe anti-malarial agent, has been reported to inhibit inflammation, but its effects on chondrocytes have yet to be elucidated. We investigated the effects of DHA on catabolism in chondrocytes. Viability of SD rats chondrocytes was analyzed. Autophagy levels were determined via expression of autophagic markers LC3 and ATG5, GFP-LC3 analysis, acridine orange staining, and electron microscopy. ATG5 siRNA induced autophagic inhibition. Catabolic gene and chemokine expression was evaluated using qPCR. The NF-κB inhibitor SM7368 and p65 over-expression were used to analyze the role of NF-κB pathway in autophagic activation. A concentration of 1 μM DHA without cytotoxicity increased LC3-II and ATG5 levels as well as autophagosomal numbers in chondrocytes. DHA inhibited TNF-α-induced expression of MMP-3 and -9, ADAMTS5, CCL-2 and -5, and CXCL1, which was reversed by autophagic inhibition. TNF-α-stimulated nuclear translocation and degradation of the p65 and IκBα proteins, respectively, were attenuated in DHA-treated chondrocytes. NF-κB inhibition activated autophagy in TNF-α-treated chondrocytes, but p65 over-expression reduced the autophagic response to DHA. These results indicate that DHA might suppress the levels of catabolic and inflammatory factors in chondrocytes by promoting autophagy via NF-κB pathway inhibition. PMID:27941926

Pseudomonas aeruginosa inhibits the growth of Cryptococcus species.

PubMed

Rella, Antonella; Yang, Mo Wei; Gruber, Jordon; Montagna, Maria Teresa; Luberto, Chiara; Zhang, Yong-Mei; Del Poeta, Maurizio

2012-06-01

Pseudomonas aeruginosa is a ubiquitous and opportunistic bacterium that inhibits the growth of different microorganisms, including Gram-positive bacteria and fungi such as Candida spp. and Aspergillus fumigatus. In this study, we investigated the interaction between P. aeruginosa and Cryptococcus spp. We found that P. aeruginosa PA14 and, to a lesser extent, PAO1 significantly inhibited the growth of Cryptococcus spp. The inhibition of growth was observed on solid medium by the visualization of a zone of inhibition of yeast growth and in liquid culture by viable cell counting. Interestingly, such inhibition was only observed when P. aeruginosa and Cryptococcus were co-cultured. Minimal inhibition was observed when cell-cell contact was prevented using a separation membrane, suggesting that cell contact is required for inhibition. Using mutant strains of Pseudomonas quinoline signaling, we showed that P. aeruginosa inhibited the growth of Cryptococcus spp. by producing antifungal molecules pyocyanin, a redox-active phenazine, and 2-heptyl-3,4-dihydroxyquinoline (PQS), an extracellular quorum-sensing signal. Because both P. aeruginosa and Cryptococcus neoformans are commonly found in lung infections of immunocompromised patients, this study may have important implication for the interaction of these microbes in both an ecological and a clinical point of view.

Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

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

Jan, Yi-Hua; Richardson, Jason R., E-mail: jricha3@eohsi.rutgers.edu; Baker, Angela A.

Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling,more » a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.« less

Molecular mechanisms of DNA repair inhibition by caffeine

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

Selby, C.P.; Sancar, A.

1990-05-01

Caffeine potentiates the mutagenic and lethal effects of genotoxic agents. It is thought that this is due, at least in some organisms, to inhibition of DNA repair. However, direct evidence for inhibition of repair enzymes has been lacking. Using purified Escherichia coli DNA photolyase and (A)BC excinuclease, we show that the drug inhibits photoreactivation and nucleotide excision repair by two different mechanisms. Caffeine inhibits photoreactivation by interfering with the specific binding of photolyase to damaged DNA, and it inhibits nucleotide excision repair by promoting nonspecific binding of the damage-recognition subunit, UvrA, of (A)BC excinuclease. A number of other intercalators, includingmore » acriflavin and ethidium bromide, appear to inhibit the excinuclease by a similar mechanism--that is, by trapping the UvrA subunit in nonproductive complexes on undamaged DNA.« less

Inhibition of cortiocosteroidogenesis by delta-9-tetrahydrocannabinol.

PubMed

Warner, W; Harris, L S; Carchman, R A

1977-12-01

ACTH, cholera toxin, cyclic AMP but not pregnenolone-induced steroidogenesis in Y-1 functional mouse adrenal tumor cells was significantly inhibited by delta-9-tetrahydrocannabinol, cannabidiol, and cannabinol. The inhibition of steroidogenesis could not be correlated with a general depression in cell function or viability. The data suggest that cannabinoids inhibit corticosteroidogenesis at a site between the synthesis of cAMP and of pregnenolone.

STIR: Assessing and Training Response Inhibition Abilities

DTIC Science & Technology

2014-07-30

Oct-2013 30-Jun-2014 Approved for Public Release; Distribution Unlimited Final Report: STIR: Assessing and Training Response Inhibition Abilities The...Office P.O. Box 12211 Research Triangle Park, NC 27709-2211 Civilian casualties, response inhibition, cognitive training REPORT DOCUMENTATION PAGE...Assessing and Training Response Inhibition Abilities Report Title Shooting a firearm involves a complex series of actions, and each action depends on a

In vitro evaluation of single- and multi-strain probiotics: Inter-species inhibition between probiotic strains, and inhibition of pathogens.

PubMed

Chapman, C M C; Gibson, G R; Rowland, I

2012-08-01

Many studies comparing the effects of single- and multi-strain probiotics on pathogen inhibition compare treatments with different concentrations. They also do not examine the possibility of inhibition between probiotic strains with a mixture. We tested the ability of 14 single-species probiotics to inhibit each other using a cross-streak assay, and agar spot test. We then tested the ability of 15 single-species probiotics and 5 probiotic mixtures to inhibit Clostridium difficile, Escherichia coli and S. typhimurium, using the agar spot test. Testing was done with mixtures created in two ways: one group contained component species incubated together, the other group of mixtures was made using component species which had been incubated separately, equalised to equal optical density, and then mixed in equal volumes. Inhibition was observed for all combinations of probiotics, suggesting that when used as such there may be inhibition between probiotics, potentially reducing efficacy of the mixture. Significant inter-species variation was seen against each pathogen. When single species were tested against mixtures, the multi-species preparations displayed significantly (p < 0.05 or less) greater inhibition of pathogens in 12 out of 24 cases. Despite evidence that probiotic species will inhibit each other when incubated together in vitro, in many cases a probiotic mixture was more effective at inhibiting pathogens than its component species when tested at approximately equal concentrations of biomass. This suggests that using a probiotic mixture might be more effective at reducing gastrointestinal infections, and that creating a mixture using species with different effects against different pathogens may have a broader spectrum of action that a single provided by a single strain. Copyright © 2012 Elsevier Ltd. All rights reserved.

Inhibition of cholinesterases by fluoride in vitro

PubMed Central

Cimasoni, Giorgio

1966-01-01

1. Series of colorimetric dynamic assays allowed the study of the inhibition of cholinesterases by F− ions in vitro, by using, as sources of enzyme, whole human blood, human serum, homogenized rat brain and two preparations of red blood cells (human and bovine) whose enzymic purity was ascertained. 2. The first evidence of inhibition of human serum pseudocholinesterase by fluoride was noticed at 15–25μm-fluoride. Ten times as much fluoride was needed to start inhibition of acetylcholinesterase of the red blood cells. 3. The action of fluoride on the enzymic reaction was immediate. The reversibility of the inhibition was shown by dialysis and dilution. 4. Kinetic measurements showed that the inhibition under study was not dependent on the substrate concentration and was of the uncompetitive type, similar to that observed in the presence of a heavy metal (cadmium). 5. The activity of serum cholinesterase did not change in the absence of Mg2+ and Ca2+ ions. Fluoride was shown to inhibit the enzyme in the absence of these ions as well as of phosphate. 6. Fluoride could inhibit cholinesterases in the presence of three different substrates and had no action on the non-enzymic hydrolysis. 7. It is thought that the halide is bound reversibly to the enzyme molecule, with the probable exclusion of the active site, but no firm conclusion could be reached on this point. PMID:6007454

Regulation of spatial selectivity by crossover inhibition.

PubMed

Cafaro, Jon; Rieke, Fred

2013-04-10

Signals throughout the nervous system diverge into parallel excitatory and inhibitory pathways that later converge on downstream neurons to control their spike output. Converging excitatory and inhibitory synaptic inputs can exhibit a variety of temporal relationships. A common motif is feedforward inhibition, in which an increase (decrease) in excitatory input precedes a corresponding increase (decrease) in inhibitory input. The delay of inhibitory input relative to excitatory input originates from an extra synapse in the circuit shaping inhibitory input. Another common motif is push-pull or "crossover" inhibition, in which increases (decreases) in excitatory input occur together with decreases (increases) in inhibitory input. Primate On midget ganglion cells receive primarily feedforward inhibition and On parasol cells receive primarily crossover inhibition; this difference provides an opportunity to study how each motif shapes the light responses of cell types that play a key role in visual perception. For full-field stimuli, feedforward inhibition abbreviated and attenuated responses of On midget cells, while crossover inhibition, though plentiful, had surprisingly little impact on the responses of On parasol cells. Spatially structured stimuli, however, could cause excitatory and inhibitory inputs to On parasol cells to increase together, adopting a temporal relation very much like that for feedforward inhibition. In this case, inhibitory inputs substantially abbreviated a cell's spike output. Thus inhibitory input shapes the temporal stimulus selectivity of both midget and parasol ganglion cells, but its impact on responses of parasol cells depends strongly on the spatial structure of the light inputs.

AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers

PubMed Central

Diao, Lixia; Tong, Pan; Fan, Youhong; Carey, Jason PW; Bui, Tuyen N.; Warner, Steve; Heymach, John V; Hunt, Kelly K; Wang, Jing

2016-01-01

Epithelial to mesenchymal transition (EMT) is associated with a wide range of changes in cancer cells, including stemness, chemo- and radio-resistance and metastasis. The mechanistic role of upstream mediators of EMT has not yet been well characterized. Recently, we showed that non-small cell lung cancers (NSCLCs) that have undergone EMT overexpress AXL, a receptor tyrosine kinase. AXL is also overexpressed in a subset of triple-negative breast cancers (TNBCs) and head and neck squamous cell carcinomas (HNSCCs) and its overexpression has been associated with more aggressive tumor behavior and linked to resistance to chemotherapy, radiation, and targeted therapy. Since the DNA repair pathway is also altered in patient tumor specimens overexpressing AXL, it is hypothesized that modulation of AXL in cells that have undergone EMT will sensitize them to agents targeting the DNA repair pathway. Downregulation or inhibition of AXL directly reversed the EMT phenotype, led to decreased expression of DNA repair genes and diminished efficiency of homologous recombination (HR) and RAD51 foci formation. As a result, AXL inhibition caused a state of HR-deficiency in the cells, making them sensitive to inhibition of the DNA repair protein, PARP1. AXL inhibition synergized with PARP inhibition, leading to apoptotic cell death. AXL expression also associated positively with markers of DNA repair across TNBC, HNSCC and NSCLC patient cohorts. PMID:27671334

Stanniocalcin-2 Inhibits Mammalian Growth by Proteolytic Inhibition of the Insulin-like Growth Factor Axis*

PubMed Central

Jepsen, Malene R.; Kløverpris, Søren; Mikkelsen, Jakob H.; Pedersen, Josefine H.; Füchtbauer, Ernst-Martin; Laursen, Lisbeth S.; Oxvig, Claus

2015-01-01

Mammalian stanniocalcin-2 (STC2) is a secreted polypeptide widely expressed in developing and adult tissues. However, although transgenic expression in mice is known to cause severe dwarfism, and targeted deletion of STC2 causes increased postnatal growth, its precise biological role is still unknown. We found that STC2 potently inhibits the proteolytic activity of the growth-promoting metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). Proteolytic inhibition requires covalent binding of STC2 to PAPP-A and is mediated by a disulfide bond, which involves Cys-120 of STC2. Binding of STC2 prevents PAPP-A cleavage of insulin-like growth factor-binding protein (IGFBP)-4 and hence release within tissues of bioactive IGF, required for normal growth. Concordantly, we show that STC2 efficiently inhibits PAPP-A-mediated IGF receptor signaling in vitro and that transgenic mice expressing a mutated variant of STC2, STC2(C120A), which is unable to inhibit PAPP-A, grow like wild-type mice. Our work identifies STC2 as a novel proteinase inhibitor and a previously unrecognized extracellular component of the IGF system. PMID:25533459

Nonsteroidal anti-inflammatory drugs inhibit gastric peroxidase activity.

PubMed

Banerjee, R K

1990-06-20

The peroxidase activity of the mitochondrial fraction of rat gastric mucosa was inhibited with various nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro. Indomethacin was found to be more effective than phenylbutazone (PB) or acetylsalicylic acid (ASA). Mouse gastric peroxidase was also very sensitive to indomethacin inhibition. Indomethacin has no significant effect on submaxillary gland peroxidase activity of either of the species studied. Purified rat gastric peroxidase activity was inhibited 75% with 0.15 mM indomethacin showing half-maximal inhibition at 0.04 mM. The inhibition could be withdrawn by increasing the concentration of iodide but not by H2O2. NSAIDs inhibit gastric peroxidase activity more effectively at acid pH (pH 5.2) than at neutral pH. Spectral studies showed a bathochromic shift of the Soret band of the enzyme with indomethacin indicating its interaction at or near the heme part of the enzyme.

The IFITMs Inhibit Zika Virus Replication.

PubMed

Savidis, George; Perreira, Jill M; Portmann, Jocelyn M; Meraner, Paul; Guo, Zhiru; Green, Sharone; Brass, Abraham L

2016-06-14

Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses. Copyright © 2016. Published by Elsevier Inc.

Nonspecific Inhibition of the Motor System during Response Preparation

PubMed Central

Sias, Ana; Labruna, Ludovica; Ivry, Richard B.

2015-01-01

Motor system excitability is transiently inhibited during the preparation of responses. Previous studies have attributed this inhibition to the operation of two mechanisms, one hypothesized to help resolve competition between alternative response options, and the other to prevent premature response initiation. By this view, inhibition should be restricted to task-relevant muscles. Although this prediction is supported in one previous study (Duque et al., 2010), studies of stopping ongoing actions suggest that some forms of motor inhibition may be widespread (Badry et al., 2009). This motivated us to conduct a series of transcranial magnetic stimulation (TMS) experiments to examine in detail the specificity of preparatory inhibition in humans. Motor-evoked potentials were inhibited in task-irrelevant muscles during response preparation, even when the muscles were contralateral and not homologous to the responding effector. Inhibition was also observed in both choice and simple response task conditions, with and without a preparatory interval. Control experiments ruled out that this inhibition is due to expectancy of TMS or a possible need to cancel the prepared response. These findings suggest that motor inhibition during response preparation broadly influences the motor system and likely reflects a process that occurs whenever a response is selected. We propose a reinterpretation of the functional significance of preparatory inhibition, one by which inhibition reduces noise to enhance signal processing and modulates the gain of a selected response. SIGNIFICANCE STATEMENT Motor preparation entails the recruitment of excitatory and inhibitory neural mechanisms. The current experiments address the specificity of inhibitory mechanisms, asking whether preparatory inhibition affects task-irrelevant muscles. Participants prepared a finger movement to be executed at the end of a short delay period. Transcranial magnetic stimulation over primary motor cortex provided an

Structure–inhibition relationship of ginsenosides towards UDP-glucuronosyltransferases (UGTs)

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

Fang, Zhong-Ze; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of Sciences and The first Affiliated Hospital of Liaoning Medical University, No.457, Zhongshan Road, Dalian 116023; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892

The wide utilization of ginseng provides the high risk of herb–drug interaction (HDI) with many clinical drugs. The inhibition of ginsenosides towards drug-metabolizing enzymes (DMEs) has been regarded as an important reason for herb–drug interaction (HDI). Compared with the deep studies on the ginsenosides' inhibition towards cytochrome P450 (CYP), the inhibition of ginsenosides towards the important phase II enzymes UDP-glucuronosyltransferases (UGTs) remains to be unclear. The present study aims to evaluate the inhibition behavior of ginsenosides towards important UGT isoforms located in the liver and intestine using in vitro methods. The recombinant UGT isoform-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employedmore » as in vitro probe reaction. The results showed that structure-dependent inhibition existed for the inhibition of ginsenosides towards UGT isoforms. To clarify the possibility of in vivo herb–drug interaction induced by this kind of inhibition, the ginsenoside Rg{sub 3} was selected as an example, and the inhibition kinetic type and parameters (K{sub i}) were determined. Rg{sub 3} competitively inhibited UGT1A7, 2B7 and 2B15-catalyzed 4-MU glucuronidation reaction, and exerted noncompetitive inhibition towards UGT1A8-catalyzed 4-MU glucuronidation. The inhibition parameters (K{sub i} values) were calculated to be 22.6, 7.9, 1.9, and 2.0 μM for UGT1A7, 1A8, 2B7 and 2B15. Using human maximum plasma concentration of Rg{sub 3} (400 ng/ml (0.5 μM)) after intramuscular injection of 60 mg Rg{sub 3}, the area under the plasma concentration-time curve (AUC) was extrapolated to increase by 2.2%, 6.3%, 26.3%, and 25% for the co-administered drugs completely undergoing the metabolism catalyzed by UGT1A7, 1A8, 2B7 and 2B15, respectively. All these results indicated that the ginsenosides' inhibition towards UGT isoforms might be an important reason for ginseng–drug interaction. - Highlights: ► Structure-dependent inhibition

Anesthetic agent-specific effects on synaptic inhibition.

PubMed

MacIver, M Bruce

2014-09-01

Anesthetics enhance γ-aminobutyric acid (GABA)-mediated inhibition in the central nervous system. Different agents have been shown to act on tonic versus synaptic GABA receptors to different degrees, but it remains unknown whether different forms of synaptic inhibition are also differentially engaged. With this in mind, we tested the hypothesis that different types of GABA-mediated synapses exhibit different anesthetic sensitivities. The present study compared effects produced by isoflurane, halothane, pentobarbital, thiopental, and propofol on paired-pulse GABAA receptor-mediated synaptic inhibition. Effects on glutamate-mediated facilitation were also studied. Synaptic responses were measured in rat hippocampal brain slices. Orthodromic paired-pulse stimulation was used to assess anesthetic effects on either glutamate-mediated excitatory inputs or GABA-mediated inhibitory inputs to CA1 neurons. Antidromic stimulation was used to assess anesthetic effects on CA1 background excitability. Agents were studied at equieffective concentrations for population spike depression to compare their relative degree of effect on synaptic inhibition. Differing degrees of anesthetic effect on paired-pulse facilitation at excitatory glutamate synapses were evident, and blocking GABA inhibition revealed a previously unseen presynaptic action for pentobarbital. Although all 5 anesthetics depressed synaptically evoked excitation of CA1 neurons, the involvement of enhanced GABA-mediated inhibition differed considerably among agents. Single-pulse inhibition was enhanced by propofol, thiopental, and pentobarbital, but only marginally by halothane and isoflurane. In contrast, isoflurane enhanced paired-pulse inhibition strongly, as did thiopental, but propofol, pentobarbital, and halothane were less effective. These observations support the idea that different GABA synapses use receptors with differing subunit compositions and that anesthetics exhibit differing degrees of selectivity for

Caffeine inhibition of aflatoxin production: mode of action.

PubMed Central

Buchanan, R L; Hoover, D G; Jones, S B

1983-01-01

Evaluation of caffeine and a number of related methylxanthines indicated that the ability of the compound to inhibit growth and aflatoxin production by Aspergillus parasiticus is highly specific and does not involve an inhibition of cyclic AMP phosphodiesterase. Supplementation of the culture medium with purine bases, nucleosides, and nucleotides suggested that the inhibition of fungal growth could be partially overcome by adenine or guanine but that the purines had little effect on the inhibition of aflatoxin production. Likewise, increasing the levels of trace minerals did not overcome the inhibition of toxin production. Electron microscopic evaluation of caffeine-treated and -untreated cultures indicated that the compound produced observable changes in the ultrastructure of the fungus. Images PMID:6316853

Expressive Inhibition Following Interpersonal Trauma: An Analysis of Reported Function

PubMed Central

Clapp, Joshua D.; Jones, Judiann M.; Jaconis, Maryanne; Olsen, Shira A.; Woodward, Matthew J.; Beck, J. Gayle

2014-01-01

Existing research indicates veterans with PTSD may deliberately inhibit the expression of emotion. However, the degree to which inhibition generalizes to other trauma populations and the specific reasons survivors with PTSD inhibit expression remains unclear. The present study looked to evaluate expressive inhibition among survivors of intimate partner violence (N = 74), to determine reasons for inhibition in this population, and to examine whether any justifications for inhibition are unique to individuals with PTSD. The frequency and intensity of inhibition scores were similar to those noted in previous research although no differences were observed across women with and without PTSD. Self-reported justifications for inhibition indicated five general themes: Concern for others, Mistrust/fear of exploitation, Perception of others as indifferent/uncaring, Control/Experiential avoidance, and Situation-specific inhibition. Only mistrust/exploitation motives were uniquely associated with PTSD. Whereas expressive inhibition may be elevated within help-seeking samples, individuals who develop PTSD appear to hold unique reasons for restricting emotional expression. PMID:24507632

Comparison of Alcohol Impairment of Behavioral and Attentional Inhibition

PubMed Central

Weafer, Jessica; Fillmore, Mark T.

2012-01-01

Background Despite the wealth of studies demonstrating the impairing effects of alcohol on behavioral inhibition, less is known regarding effects of the drug on attentional inhibition (i.e., the ability to ignore distracting stimuli in the environment in order to focus attention on relevant information). The current study examined alcohol impairment of both behavioral and attentional inhibition, as well as potential associations between the two mechanisms of inhibitory control. Methods Men (n = 27) and women (n = 21) performed a measure of behavioral inhibition (cued go/no-go task) and a measure of attentional inhibition (delayed ocular return task) following three doses of alcohol: 0.65 g/kg, 0.45 g/kg, and 0.0 g/kg (placebo). Results Alcohol impaired both behavioral and attentional inhibition relative to placebo; however, correlational analyses revealed no associations between measures of behavioral and attentional inhibition following any dose. Additionally, men committed more inhibitory failures on the behavioral inhibition task, whereas women committed more inhibitory failures on the attentional inhibition task. Conclusions These findings suggest that behavioral and attentional inhibition are equally sensitive to the impairing effects of alcohol, yet represent distinct components of inhibitory control. Additionally, the observed gender differences in control of behavior and attention could have important implications regarding negative consequences associated with alcohol-induced disinhibition in men and women. PMID:22673197

Comparison of alcohol impairment of behavioral and attentional inhibition.

PubMed

Weafer, Jessica; Fillmore, Mark T

2012-11-01

Despite the wealth of studies demonstrating the impairing effects of alcohol on behavioral inhibition, less is known regarding effects of the drug on attentional inhibition (i.e., the ability to ignore distracting stimuli in the environment in order to focus attention on relevant information). The current study examined alcohol impairment of both behavioral and attentional inhibition, as well as potential associations between the two mechanisms of inhibitory control. Men (n=27) and women (n=21) performed a measure of behavioral inhibition (cued go/no-go task) and a measure of attentional inhibition (delayed ocular return task) following three doses of alcohol: 0.65 g/kg, 0.45 g/kg, and 0.0 g/kg (placebo). Alcohol impaired both behavioral and attentional inhibition relative to placebo; however, correlational analyses revealed no associations between measures of behavioral and attentional inhibition following any dose. Additionally, men committed more inhibitory failures on the behavioral inhibition task, whereas women committed more inhibitory failures on the attentional inhibition task. These findings suggest that behavioral and attentional inhibition are equally sensitive to the impairing effects of alcohol, yet represent distinct components of inhibitory control. Additionally, the observed gender differences in control of behavior and attention could have important implications regarding negative consequences associated with alcohol-induced disinhibition in men and women. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors

PubMed Central

Mulcahy Levy, Jean M; Zahedi, Shadi; Griesinger, Andrea M; Morin, Andrew; Davies, Kurtis D; Aisner, Dara L; Kleinschmidt-DeMasters, BK; Fitzwalter, Brent E; Goodall, Megan L; Thorburn, Jacqueline; Amani, Vladimir; Donson, Andrew M; Birks, Diane K; Mirsky, David M; Hankinson, Todd C; Handler, Michael H; Green, Adam L; Vibhakar, Rajeev; Foreman, Nicholas K; Thorburn, Andrew

2017-01-01

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors. DOI: http://dx.doi.org/10.7554/eLife.19671.001 PMID:28094001

Inhibition of chrysin on xanthine oxidase activity and its inhibition mechanism.

PubMed

Lin, Suyun; Zhang, Guowen; Liao, Yijing; Pan, Junhui

2015-11-01

Chrysin, a bioactive flavonoid, was investigated for its potential to inhibit the activity of xanthine oxidase (XO), a key enzyme catalyzing xanthine to uric acid and finally causing gout. The kinetic analysis showed that chrysin possessed a strong inhibition on XO ability in a reversible competitive manner with IC50 value of (1.26±0.04)×10(-6)molL(-1). The results of fluorescence titrations indicated that chrysin bound to XO with high affinity, and the interaction was predominately driven by hydrogen bonds and van der Waals forces. Analysis of circular dichroism demonstrated that chrysin induced the conformational change of XO with increases in α-helix and β-sheet and reductions in β-turn and random coil structures. Molecular simulation revealed that chrysin interacted with the amino acid residues Leu648, Phe649, Glu802, Leu873, Ser876, Glu879, Arg880, Phe1009, Thr1010, Val1011 and Phe1013 located within the active cavity of XO. The mechanism of chrysin on XO activity may be the insertion of chrysin into the active site occupying the catalytic center of XO to avoid the entrance of xanthine and causing conformational changes in XO. Furthermore, the interaction assays indicated that chrysin and its structural analog apigenin exhibited an additive effect on inhibition of XO. Copyright © 2015 Elsevier B.V. All rights reserved.

Inhibition of AMPK catabolic action by GSK3

PubMed Central

Suzuki, Tsukasa; Bridges, Dave; Nakada, Daisuke; Skiniotis, Georgios; Morrison, Sean J.; Lin, Jiandie; Saltiel, Alan R.; Inoki, Ken

2013-01-01

SUMMARY AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic and activating catabolic processes. While AMPK activation has been extensively studied, mechanisms that inhibit AMPK remain elusive. Here we report that glycogen synthase kinase 3 (GSK3) inhibits AMPK function. GSK3 forms a stable complex with AMPK through interactions with the AMPK β regulatory subunit and phosphorylates the AMPK α catalytic subunit. This phosphorylation enhances the accessibility of the activation loop of the α subunit to phosphatases, thereby inhibiting AMPK kinase activity. Surprisingly, PI3K-Akt signaling, which is a major anabolic signaling and normally inhibits GSK3 activity, promotes GSK3 phosphorylation and inhibition of AMPK, thus revealing how AMPK senses anabolic environments in addition to cellular energy levels. Consistently, disrupting GSK3 function within the AMPK complex sustains higher AMPK activity and cellular catabolic processes even under anabolic conditions, indicating that GSK3 acts as a critical sensor for anabolic signaling to regulate AMPK. PMID:23623684

A novel taspine analog, HMQ1611, inhibits growth of non-small cell lung cancer by inhibiting angiogenesis

PubMed Central

LU, WEN; DAI, BINGLING; MA, WEINA; ZHANG, YANMIN

2012-01-01

In the present study, we investigated the antitumor activity of HMQ1611, a novel synthetic taspine derivative, in vivo and evaluated associated potential antiangiogenesis mechanisms. The proliferation of A549 cells was examined by WST-1 assay in vitro. Tube formation and lung tissue vessel models were used to observe the antiangiogenic activity of HMQ1611. In addition, vascular enodthelial growth factor (VEGF) secretion and KDR kinase activities were measured by ELISA and the HTRF®KinEASE™-TK assay. In vivo, the antitumor activity was assessed by implantation of A549 cells in athymic mice. The results showed that HMQ1611 inhibited A549 cell proliferation and VEGF secretion, while it significantly inhibited tube formation and tissue vascularization. Furthermore, HMQ1611 inhibited A549 xenograft tumor growth. In conclusion, the results of our study suggest that HMQ1611 has latent properties for the inhibition of angiogenesis which are involved in its antitumor activity. PMID:23162661

A novel taspine analog, HMQ1611, inhibits growth of non-small cell lung cancer by inhibiting angiogenesis.

PubMed

Lu, Wen; Dai, Bingling; Ma, Weina; Zhang, Yanmin

2012-11-01

In the present study, we investigated the antitumor activity of HMQ1611, a novel synthetic taspine derivative, in vivo and evaluated associated potential antiangiogenesis mechanisms. The proliferation of A549 cells was examined by WST-1 assay in vitro. Tube formation and lung tissue vessel models were used to observe the antiangiogenic activity of HMQ1611. In addition, vascular enodthelial growth factor (VEGF) secretion and KDR kinase activities were measured by ELISA and the HTRF(®)KinEASE(™)-TK assay. In vivo, the antitumor activity was assessed by implantation of A549 cells in athymic mice. The results showed that HMQ1611 inhibited A549 cell proliferation and VEGF secretion, while it significantly inhibited tube formation and tissue vascularization. Furthermore, HMQ1611 inhibited A549 xenograft tumor growth. In conclusion, the results of our study suggest that HMQ1611 has latent properties for the inhibition of angiogenesis which are involved in its antitumor activity.

A Qualitative Approach to Enzyme Inhibition

ERIC Educational Resources Information Center

Waldrop, Grover L.

2009-01-01

Most general biochemistry textbooks present enzyme inhibition by showing how the basic Michaelis-Menten parameters K[subscript m] and V[subscript max] are affected mathematically by a particular type of inhibitor. This approach, while mathematically rigorous, does not lend itself to understanding how inhibition patterns are used to determine the…

Expressive inhibition following interpersonal trauma: an analysis of reported function.

PubMed

Clapp, Joshua D; Jones, Judiann M; Jaconis, Maryanne; Olsen, Shira A; Woodward, Matthew J; Beck, J Gayle

2014-03-01

Existing research indicates veterans with posttraumatic stress disorder (PTSD) may deliberately inhibit the expression of emotion. However, the degree to which inhibition generalizes to other trauma populations and the specific reasons survivors with PTSD inhibit expression remains unclear. The present study looked to evaluate expressive inhibition among survivors of intimate partner violence (N = 74), to determine reasons for inhibition in this population, and to examine whether any justifications for inhibition are unique to individuals with PTSD. The frequency and intensity of inhibition scores were similar to those noted in previous research although no differences were observed across women with and without PTSD. Self-reported justifications for inhibition indicated five general themes: Concern for others, Mistrust/fear of exploitation, Perception of others as indifferent/uncaring, Control/Experiential avoidance, and Situation-specific inhibition. Only mistrust/exploitation motives were uniquely associated with PTSD. Whereas expressive inhibition may be elevated within help-seeking samples, individuals who develop PTSD appear to hold unique reasons for restricting emotional expression. Copyright © 2013 Elsevier Ltd. All rights reserved.

The inhibition capacities of children with mathematical disabilities.

PubMed

Censabella, Sandrine; Noël, Marie-Pascale

2008-01-01

Several authors have argued that mathematical disabilities might result from difficulties in inhibiting irrelevant information. The present study addresses this issue by assessing three inhibition functions in 40 ten-year-old children: suppression of irrelevant information from working memory, inhibition of prepotent responses, and interference control. We found no significant differences between children with math disabilities and typically achieving controls, or between children with arithmetic facts disabilities and children with above-average arithmetic facts skills. These findings, along with other empirical evidence and with theoretical considerations, cast doubt on the inhibition deficit hypothesis.

Response inhibition in motor conversion disorder.

PubMed

Voon, Valerie; Ekanayake, Vindhya; Wiggs, Edythe; Kranick, Sarah; Ameli, Rezvan; Harrison, Neil A; Hallett, Mark

2013-05-01

Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P < .001) compared with healthy volunteers, which remained significant after Bonferroni correction for multiple comparisons and after controlling for attention, sustained attention, depression, and anxiety. There were no significant differences in other cognitive measures. We highlight a specific deficit in motor response inhibition that may play a role in impaired inhibition of unwanted movement such as the excessive and aberrant movements seen in motor conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups. © 2013 Movement Disorder Society. Copyright © 2013 Movement Disorder Society.

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.

The development of children's inhibition: does parenting matter?

PubMed

Roskam, Isabelle; Stievenart, Marie; Meunier, Jean-Christophe; Noël, Marie-Pascale

2014-06-01

Whereas a large body of research has investigated the maturation of inhibition in relation to the prefrontal cortex, far less research has been devoted to environmental factors that could contribute to inhibition improvement. The aim of the current study was to test whether and to what extent parenting matters for inhibition development from 2 to 8years of age. Data were collected from 421 families, with 348 mother-child dyads and 342 father-child dyads participating. Children's inhibition capacities and parenting behaviors were assessed in a three-wave longitudinal data collection. The main analyses examined the impact of parenting on the development of children's inhibition capacities. They were conducted using a multilevel modeling (MLM) framework. The results lead to the conclusion that both mothers and fathers contribute through their child-rearing behavior to their children's executive functioning, even when controlling for age-related improvement (maturation) and important covariates such as gender, verbal IQ, and place of enrollment. More significant relations between children's inhibition development and parenting were displayed for mothers than for fathers. More precisely, parenting behaviors that involve higher monitoring, lower discipline, inconsistency and negative controlling, and a positive parenting style are associated with good development of inhibition capacities in children. Copyright © 2014 Elsevier Inc. All rights reserved.

Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity.

PubMed

Thupari, J N; Pinn, M L; Kuhajda, F P

2001-07-13

Inhibition of fatty acid synthase (FAS) induces apoptosis in human breast cancer cells in vitro and in vivo without toxicity to proliferating normal cells. We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apoptosis. In this study we further investigated the role of malonyl-CoA during FAS inhibition. We have found that: [i] inhibition of FAS with cerulenin causes carnitine palmitoyltransferase-1 (CPT-1) inhibition and fatty acid oxidation inhibition in MCF-7 human breast cancer cells likely mediated by elevation of malonyl-CoA; [ii] cerulenin cytotoxicity is due to the nonphysiological state of increased malonyl-CoA, decreased fatty acid oxidation, and decreased fatty acid synthesis; and [iii] the cytotoxic effect of cerulenin can be mimicked by simultaneous inhibition of CPT-1, with etomoxir, and fatty acid synthesis with TOFA, an acetyl-CoA carboxylase (ACC) inhibitor. This study identifies CPT-1 and ACC as two new potential targets for cancer chemotherapy. Copyright 2001 Academic Press.

Anesthetic Agent-Specific Effects on Synaptic Inhibition

PubMed Central

MacIver, M. Bruce

2014-01-01

Background Anesthetics enhance gamma-aminobutyric acid (GABA)-mediated inhibition in the central nervous system. Different agents have been shown to act on tonic versus synaptic GABA receptors to different degrees, but it remains unknown whether different forms of synaptic inhibition are also differentially engaged. With this in mind, we tested the hypothesis that different types of GABA-mediated synapses exhibit different anesthetic sensitivities. The present study compared effects produced by isoflurane, halothane, pentobarbital, thiopental and propofol on paired pulse GABAA receptor-mediated synaptic inhibition. Effects on glutamate-mediated facilitation were also studied. Methods Synaptic responses were measured in rat hippocampal brain slices. Orthodromic paired pulse stimulation was used to assess anesthetic effects on either glutamate-mediated excitatory inputs or GABA-mediated inhibitory inputs to CA1 neurons. Antidromic stimulation was used to assess anesthetic effects on CA1 background excitability. Agents were studied at equi-effective concentrations for population spike depression to compare their relative degree of effect on synaptic inhibition. Results Differing degrees of anesthetic effect on paired pulse facilitation at excitatory glutamate synapses were evident, and blocking GABA inhibition revealed a previously unseen presynaptic action for pentobarbital. Although all five anesthetics depressed synaptically evoked excitation of CA1 neurons, the involvement of enhanced GABA-mediated inhibition differed considerably among agents. Single pulse inhibition was enhanced by propofol, thiopental and pentobarbital, but only marginally by halothane and isoflurane. In contrast, isoflurane enhanced paired pulse inhibition strongly, as did thiopental, but propofol, pentobarbital and halothane were less effective. Conclusions These observations support the idea that different GABA synapses use receptors with differing subunit compositions, and that anesthetics

Neural and behavioral mechanisms of proactive and reactive inhibition

PubMed Central

Meyer, Heidi C.

2016-01-01

Response inhibition is an important component of adaptive behavior. Substantial prior research has focused on reactive inhibition, which refers to the cessation of a motor response that is already in progress. More recently, a growing number of studies have begun to examine mechanisms underlying proactive inhibition, whereby preparatory processes result in a response being withheld before it is initiated. It has become apparent that proactive inhibition is an essential component of the overall ability to regulate behavior and has implications for the success of reactive inhibition. Moreover, successful inhibition relies on learning the meaning of specific environmental cues that signal when a behavioral response should be withheld. Proactive inhibitory control is mediated by stopping goals, which reflect the desired outcome of inhibition and include information about how and when inhibition should be implemented. However, little is known about the circuits and cellular processes that encode and represent features in the environment that indicate the necessity for proactive inhibition or how these representations are implemented in response inhibition. In this article, we will review the brain circuits and systems involved in implementing inhibitory control through both reactive and proactive mechanisms. We also comment on possible cellular mechanisms that may contribute to inhibitory control processes, noting that substantial further research is necessary in this regard. Furthermore, we will outline a number of ways in which the temporal dynamics underlying the generation of the proactive inhibitory signal may be particularly important for parsing out the neurobiological correlates that contribute to the learning processes underlying various aspects of inhibitory control. PMID:27634142

Astragalus polysaccharides inhibits PCV2 replication by inhibiting oxidative stress and blocking NF-κB pathway.

PubMed

Xue, Hongxia; Gan, Fang; Zhang, Zheqian; Hu, Junfa; Chen, Xingxiang; Huang, Kehe

2015-11-01

Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated disease (PCVAD). Astragalus polysaccharide (APS), as one kind of biological macromolecule extracted from Astragalus, has antiviral activities. This study was undertaken to explore the effect of APS on PCV2 replication in vitro and the underlying mechanisms. Our results showed that adding APS before PCV2 infection decreased significantly PCV2 DNA copies, the number of infected cells, MDA level, ROS level and NF-κB activation in PK15 cells and increased significantly GSH contents and SOD activity compared to control without APS. Oxidative stress induced by BSO could eliminate the effect of PCV2 replication inhibition by APS. LPS, as a NF-κB activator, could attenuate the effect of PCV2 replication inhibition by APS. BAY 11-7082, as a NF-κB inhibitor, could increase the effect of PCV2 replication inhibition by APS. In conclusion, APS inhibits PCV2 replication by decreasing oxidative stress and the activation of NF-κB signaling pathway, which suggests that APS might be employed for the prevention of PCV2 infection. Copyright © 2015 Elsevier B.V. All rights reserved.

Exogenously triggered response inhibition in developmental stuttering.

PubMed

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

2018-06-01

The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition. Copyright © 2018 Elsevier Inc. All rights reserved.

The Antiviral Drug Arbidol Inhibits Zika Virus.

PubMed

Fink, Susan L; Vojtech, Lucia; Wagoner, Jessica; Slivinski, Natalie S J; Jackson, Konner J; Wang, Ruofan; Khadka, Sudip; Luthra, Priya; Basler, Christopher F; Polyak, Stephen J

2018-06-12

There are many emerging and re-emerging globally prevalent viruses for which there are no licensed vaccines or antiviral medicines. Arbidol (ARB, umifenovir), used clinically for decades in several countries as an anti-influenza virus drug, inhibits many other viruses. In the current study, we show that ARB inhibits six different isolates of Zika virus (ZIKV), including African and Asian lineage viruses in multiple cell lines and primary human vaginal and cervical epithelial cells. ARB protects against ZIKV-induced cytopathic effects. Time of addition studies indicate that ARB is most effective at suppressing ZIKV when added to cells prior to infection. Moreover, ARB inhibits pseudoviruses expressing the ZIKV Envelope glycoprotein. Thus, ARB, a broadly acting anti-viral agent with a well-established safety profile, inhibits ZIKV, likely by blocking viral entry.

Inhibited interferon production after space flight

NASA Technical Reports Server (NTRS)

Sonnenfeld, G.; Gould, C. L.; Williams, J.; Mandel, A. D.

1988-01-01

Several studies have been performed in our laboratories indicating that interferon production may be impaired in rodents after space flight. Using an antiorthostatic suspension model that simulates some of the effects of microgravity seen during space flight, we have shown that interferon-alpha/beta production was inhibited. The inhibition was not due solely to the stress of suspension. The inhibited interferon production was transient, as suspended animals returned to normal caging recovered the ability to produce interferon. Antiorthostatic suspension of mice also resulted in a loss of resistance to infection with the diabetogenic strain of encephalomyocarditis virus, which correlated with the drop in interferon production. In rats flown in US Space Shuttle mission SL-3, interferon-gamma production was inhibited severely when spleen cells were challenged with concanavalin-A upon return to earth. In contrast, interleukin-3 production by these cells was normal. These results suggest that immune responses may be altered after antiorthostatic modeling or space flight, and the resistance to viral infections may be especially affected.

Structure of a thermophilic F1-ATPase inhibited by an ε-subunit: deeper insight into the ε-inhibition mechanism.

PubMed

Shirakihara, Yasuo; Shiratori, Aya; Tanikawa, Hiromi; Nakasako, Masayoshi; Yoshida, Masasuke; Suzuki, Toshiharu

2015-08-01

F1-ATPase (F1) is the catalytic sector in F(o)F1-ATP synthase that is responsible for ATP production in living cells. In catalysis, its three catalytic β-subunits undergo nucleotide occupancy-dependent and concerted open-close conformational changes that are accompanied by rotation of the γ-subunit. Bacterial and chloroplast F1 are inhibited by their own ε-subunit. In the ε-inhibited Escherichia coli F1 structure, the ε-subunit stabilizes the overall conformation (half-closed, closed, open) of the β-subunits by inserting its C-terminal helix into the α3β3 cavity. The structure of ε-inhibited thermophilic F1 is similar to that of E. coli F1, showing a similar conformation of the ε-subunit, but the thermophilic ε-subunit stabilizes another unique overall conformation (open, closed, open) of the β-subunits. The ε-C-terminal helix 2 and hook are conserved between the two structures in interactions with target residues and in their positions. Rest of the ε-C-terminal domains are in quite different conformations and positions, and have different modes of interaction with targets. This region is thought to serve ε-inhibition differently. For inhibition, the ε-subunit contacts the second catches of some of the β- and α-subunits, the N- and C-terminal helices, and some of the Rossmann fold segments. Those contacts, as a whole, lead to positioning of those β- and α- second catches in ε-inhibition-specific positions, and prevent rotation of the γ-subunit. Some of the structural features are observed even in IF1 inhibition in mitochondrial F1. © 2015 FEBS.

Feedforward somatosensory inhibition is normal in cervical dystonia.

PubMed

Ferrè, Elisa R; Ganos, Christos; Bhatia, Kailash P; Haggard, Patrick

2015-03-01

Insufficient cortical inhibition is a key pathophysiological finding in dystonia. Subliminal sensory stimuli were reported to transiently inhibit somatosensory processing. Here we investigated whether such subliminal feedforward inhibition is reduced in patients with cervical dystonia. Sixteen cervical dystonia patients and 16 matched healthy controls performed a somatosensory detection task. We measured the drop in sensitivity to detect a threshold-level digital nerve shock when it was preceded by a subliminal conditioning shock, compared to when it was not. Subliminal conditioning shocks reduced sensitivity to threshold stimuli to a similar extent in both patients and controls, suggesting that somatosensory subliminal feedforward inhibition is normal in cervical dystonia. Somatosensory feedforward inhibition was normal in this group of cervical dystonia patients. Our results qualify previous concepts of a general dystonic deficit in sensorimotor inhibitory processing. Copyright © 2015 Elsevier Ltd. All rights reserved.

Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab.

PubMed

Sun, Chaonan; Han, Chuyang; Jiang, Yuanjun; Han, Ning; Zhang, Miao; Li, Guang; Qiao, Qiao

2017-01-01

The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER) homeostatic state and result in ER stress (ERS), subsequently causing resistance to radiation and drugs. Whether the ERS pathway is involved in radioresistance after administration of cetuximab has not been reported. Herein, we show that cetuximab could increase the radiosensitivity of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the radiation-induced activation of the ERS signalling pathway IRE1α/ATF6-GRP78 in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB) repair and autophagy. More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal carcinoma patients (P<0.05). Overall, the results of this study show that radioresistance after EGFR inhibition by cetuximab is mediated by the ERS signalling pathway IRE1α/ATF6-GRP78. This suppression was consequently unable to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma cells, which conferred resistance to radiotherapy and cetuximab. These results suggest that the cooperative effects of radiotherapy and cetuximab could be further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma patients.

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer: inhibition of the metastasis-inducer Snail and induction of the metastasis-suppressor RKIP.

PubMed

Baritaki, Stavroula; Huerta-Yepez, Sara; Sahakyan, Anna; Karagiannides, Iordanis; Bakirtzi, Kyriaki; Jazirehi, Ali; Bonavida, Benjamin

2010-12-15

The role of nitric oxide (NO) in cancer has been controversial and is based on the levels of NO and the responsiveness of the tumor type. It remains unclear whether NO can inhibit the epithelial to mesenchymal transition (EMT) in cancer cells. EMT induction is mediated, in part, by the constitutive activation of the metastasis-inducer transcription factor, Snail and EMT can be inhibited by the metastasis-suppressor Raf-1 kinase inhibitor protein (RKIP) and E-cadherin. Snail is transcriptionally regulated by NF-κB and in turn, Snail represses RKIP transcription. Hence, we hypothesized that high levels of NO, that inhibit NF-κB activity, may also inhibit Snail and induce RKIP and leading to inhibition of EMT. We show that treatment of human prostate metastatic cell lines with the NO donor, DETANONOate, inhibits EMT and reverses both the mesenchymal phenotype and the cell invasive properties. Further, treatment with DETANONOate inhibits Snail expression and DNA-binding activity in parallel with the upregulation of RKIP and E-cadherin protein levels. The pivotal roles of Snail inhibition and RKIP induction in DETANONOate-mediated inhibition of EMT were corroborated by both Snail silencing by siRNA and by ectopic expression of RKIP. The in vitro findings were validated in vivo in mice bearing PC-3 xenografts and treated with DETANONOate. The present findings show, for the first time, the novel role of high subtoxic concentrations of NO in the inhibition of EMT. Thus, NO donors may exert therapeutic activities in the reversal of EMT and metastasis.

Cognitive inhibition in students with and without dyslexia and dyscalculia.

PubMed

Wang, Li-Chih; Tasi, Hung-Ju; Yang, Hsien-Ming

2012-01-01

The present study presents a comparison of the cognitive inhibition abilities of dyslexic, dyscalculic, and control students. The participants were 45 dyslexic students, 45 dyscalculic students, and 45 age-, gender-, and IQ-matched control students. The major evaluation tools included six cognitive inhibition tasks which were restructured during principal component analysis into three categories: graph inhibition, number inhibition, and word inhibition. Comparisons of the 3 groups of students revealed that in graph inhibition, dyscalculic students performed worst of the 3 groups, with dyslexic students also performing worse than control students in this category. For number inhibition, the control students' performances were equal to those of dyslexic students, with both groups performing better than dyscalculic students. For word inhibition, control students' performances were equal to those of dyscalculic students; both groups had shorter response times and lower incorrect rates than dyslexic students. These results suggest the complexity of the different cognitive inhibition abilities displayed by dyslexic, dyscalculic, and control students. However, some regular patterns occurred. Copyright © 2012 Elsevier Ltd. All rights reserved.

Polysulfonate suramin inhibits Zika virus infection.

PubMed

Tan, Chee Wah; Sam, I-Ching; Chong, Wei Lim; Lee, Vannajan Sanghiran; Chan, Yoke Fun

2017-07-01

Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition. Suramin, an FDA-approved anti-parasitic drug, inhibits ZIKV infection with 3-5 log 10  PFU viral reduction with IC 50 value of ∼2.5-5 μg/ml (1.93 μM-3.85 μM). A time-of-drug-addition study revealed that suramin remains potent even when administrated at 1-24 hpi. Suramin inhibits ZIKV infection by preventing viral adsorption, entry and replication. Molecular dynamics simulation revealed stronger interaction of suramin with ZIKV NS3 helicase than with the envelope protein. Suramin warrants further investigation as a potential antiviral candidate for ZIKV infection. Heparan sulfate (HS) is a cellular attachment receptor for multiple flaviviruses. However, no direct ZIKV-heparin interaction was observed in heparin-binding analysis, and downregulate or removal of cellular HS with sodium chlorate or heparinase I/III did not inhibit ZIKV infection. This indicates that cell surface HS is not utilized by ZIKV as an attachment receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

Characterization of 16S rRNA Processing with Pre-30S Subunit Assembly Intermediates from E. coli.

PubMed

Smith, Brian A; Gupta, Neha; Denny, Kevin; Culver, Gloria M

2018-06-08

Ribosomal RNA (rRNA) is a major component of ribosomes and is fundamental to the process of translation. In bacteria, 16S rRNA is a component of the small ribosomal subunit and plays a critical role in mRNA decoding. rRNA maturation entails the removal of intervening spacer sequences contained within the pre-rRNA transcript by nucleolytic enzymes. Enzymatic activities involved in maturation of the 5'-end of 16S rRNA have been identified, but those involved in 3'-end maturation of 16S rRNA are more enigmatic. Here, we investigate molecular details of 16S rRNA maturation using purified in vivo-formed small subunit (SSU) assembly intermediates (pre-SSUs) from wild-type Escherichia coli that contain precursor 16S rRNA (17S rRNA). Upon incubation of pre-SSUs with E. coli S100 cell extracts or purified enzymes implicated in 16S rRNA processing, the 17S rRNA is processed into additional intermediates and mature 16S rRNA. These results illustrate that exonucleases RNase R, RNase II, PNPase, and RNase PH can process the 3'-end of pre-SSUs in vitro. However, the endonuclease YbeY did not exhibit nucleolytic activity with pre-SSUs under these conditions. Furthermore, these data demonstrate that multiple pathways facilitate 16S rRNA maturation with pre-SSUs in vitro, with the dominant pathways entailing complete processing of the 5'-end of 17S rRNA prior to 3'-end maturation or partial processing of the 5'-end with concomitant processing of the 3'-end. These results reveal the multifaceted nature of SSU biogenesis and suggest that E. coli may be able to escape inactivation of any one enzyme by using an existing complementary pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

Benzonatate inhibition of voltage-gated sodium currents.

PubMed

Evans, M Steven; Maglinger, G Benton; Fletcher, Anita M; Johnson, Stephen R

2016-02-01

Benzonatate was FDA-approved in 1958 as an antitussive. Its mechanism of action is thought to be anesthesia of vagal sensory nerve fibers that mediate cough. Vagal sensory neurons highly express the Nav1.7 subtype of voltage-gated sodium channels, and inhibition of this channel inhibits the cough reflex. Local anesthetics inhibit voltage-gated sodium channels, but there are no reports of whether benzonatate affects these channels. Our hypothesis is that benzonatate inhibits Nav1.7 voltage-gated sodium channels. We used whole cell voltage clamp recording to test the effects of benzonatate on voltage-gated sodium (Na(+)) currents in two murine cell lines, catecholamine A differentiated (CAD) cells, which express primarily Nav1.7, and N1E-115, which express primarily Nav1.3. We found that, like local anesthetics, benzonatate strongly and reversibly inhibits voltage-gated Na(+) channels. Benzonatate causes both tonic and phasic inhibition. It has greater effects on channel inactivation than on activation, and its potency is much greater at depolarized potentials, indicating inactivated-state-specific effects. Na(+) currents in CAD cells and N1E-115 cells are similarly affected, indicating that benzonatate is not Na(+) channel subtype-specific. Benzonatate is a mixture of polyethoxy esters of 4-(butylamino) benzoic acid having varying degrees of hydrophobicity. We found that Na(+) currents are inhibited most potently by a benzonatate fraction containing the 9-ethoxy component. Detectable effects of benzonatate occur at concentrations as low as 0.3 μM, which has been reported in humans. We conclude that benzonatate has local anesthetic-like effects on voltage-gated sodium channels, including Nav1.7, which is a possible mechanism for cough suppression by the drug. Copyright © 2015 Elsevier Ltd. All rights reserved.

Long-term neprilysin inhibition - implications for ARNIs.

PubMed

Campbell, Duncan J

2017-03-01

Neprilysin has a major role in both the generation and degradation of bioactive peptides. LCZ696 (valsartan/sacubitril, Entresto), the first of the new ARNI (dual-acting angiotensin-receptor-neprilysin inhibitor) drug class, contains equimolar amounts of valsartan, an angiotensin-receptor blocker, and sacubitril, a prodrug for the neprilysin inhibitor LBQ657. LCZ696 reduced blood pressure more than valsartan alone in patients with hypertension. In the PARADIGM-HF study, LCZ696 was superior to the angiotensin-converting enzyme inhibitor enalapril for the treatment of heart failure with reduced ejection fraction, and LCZ696 was approved by the FDA for this purpose in 2015. This approval was the first for chronic neprilysin inhibition. The many peptides metabolized by neprilysin suggest many potential consequences of chronic neprilysin inhibitor therapy, both beneficial and adverse. Moreover, LBQ657 might inhibit enzymes other than neprilysin. Chronic neprilysin inhibition might have an effect on angio-oedema, bronchial reactivity, inflammation, and cancer, and might predispose to polyneuropathy. Additionally, inhibition of neprilysin metabolism of amyloid-β peptides might have an effect on Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy. Much of the evidence for possible adverse consequences of chronic neprilysin inhibition comes from studies in animal models, and the relevance of this evidence to humans is unknown. This Review summarizes current knowledge of neprilysin function and possible consequences of chronic neprilysin inhibition that indicate a need for vigilance in the use of neprilysin inhibitor therapy.

Stachytarpheta cayennensis extract inhibits promastigote and amastigote growth in Leishmania amazonensis via parasite arginase inhibition.

PubMed

Maquiaveli, Claudia do Carmo; Oliveira E Sá, Amanda Maria; Vieira, Paulo Cezar; da Silva, Edson Roberto

2016-11-04

Stachytarpheta cayennensis is a plant that is traditionally used to treat tegumentary leishmaniasis and as an anti-inflammatory agent. This study aimed to evaluate the action of S. cayennensis extracts on the Leishmania (Leishmania) amazonensis arginase enzyme. S. cayennensis was collected from the Brazilian Amazon region. Aqueous extracts were fractionated with n-butanol. The leishmanicidal effects of the n-butanolic fraction (BUF) were evaluated in L. (L.) amazonensis promastigotes and amastigotes. BUF was tested against recombinant arginase from both L. (L.) amazonensis and macrophage arginase. Promastigote cultures and infected macrophage cultures were supplemented with L-ornithine to verify arginase inhibition. NMR analysis was used to identify the major components of BUF. BUF showed an EC 50 of 51 and 32µg/mL against promastigotes and amastigotes of L. (L.) amazonensis, respectively. BUF contains a mixture of verbascoside and isoverbascoside (7:3 ratio) and is a potent L. (L.) amazonensis arginase inhibitor (IC 50 =1.2µg/mL), while macrophage arginase was weakly inhibited (IC 50 >1000µg/mL). The inhibition of arginase by BUF in promastigotes and amastigotes could be demonstrated by culture media supplementation with L-ornithine, a product of the hydrolysis of L-arginine by arginase. Leishmanicidal effects of the S. cayennensis BUF fraction on L. (L.) amazonensis are associated with selective parasite arginase inhibition. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Saccharin and Cyclamate Inhibit Binding of Epidermal Growth Factor

NASA Astrophysics Data System (ADS)

Lee, L. S.

1981-02-01

The binding of 125I-labeled mouse epidermal growth factor (EGF) to 18 cell lines, including HeLa (human carcinoma), MDCK (dog kidney cells), HTC (rat hepatoma), K22 (rat liver), HF (human foreskin), GM17 (human skin fibroblasts), XP (human xeroderma pigmentosum fibroblasts), and 3T3-L1 (mouse fibroblasts), was inhibited by saccharin and cyclamate. The human cells were more sensitive to inhibition by these sweeteners than mouse or rat cells. EGF at doses far above the physiological levels reversed the inhibition in rodent cells but not in HeLa cells. In HeLa cells, the doses of saccharin and cyclamate needed for 50% inhibition were 3.5 and 9.3 mg/ml, respectively. Glucose, 2-deoxyglucose, sucrose, and xylitol did not inhibit EGF binding. Previous studies have shown that phorbol esters, strongly potent tumor promoters, also inhibit EGF binding to tissue culture cells. To explain the EGF binding inhibition by such greatly dissimilar molecules as phorbol esters, saccharin, and cyclamate, it is suggested that they operate through the activation of a hormone response control unit.

Inhibition in motor imagery: a novel action mode switching paradigm.

PubMed

Rieger, Martina; Dahm, Stephan F; Koch, Iring

2017-04-01

Motor imagery requires that actual movements are prevented (i.e., inhibited) from execution. To investigate at what level inhibition takes place in motor imagery, we developed a novel action mode switching paradigm. Participants imagined (indicating only start and end) and executed movements from start buttons to target buttons, and we analyzed trial sequence effects. Trial sequences depended on current action mode (imagination or execution), previous action mode (pure blocks/same mode, mixed blocks/same mode, or mixed blocks/other mode), and movement sequence (action repetition, hand repetition, or hand alternation). Results provided evidence for global inhibition (indicated by switch benefits in execution-imagination (E-I)-sequences in comparison to I-I-sequences), effector-specific inhibition (indicated by hand repetition costs after an imagination trial), and target inhibition (indicated by target repetition benefits in I-I-sequences). No evidence for subthreshold motor activation or action-specific inhibition (inhibition of the movement of an effector to a specific target) was obtained. Two (global inhibition and effector-specific inhibition) of the three observed mechanisms are active inhibition mechanisms. In conclusion, motor imagery is not simply a weaker form of execution, which often is implied in views focusing on similarities between imagination and execution.

Inhibition-of-return at multiple locations in visual space.

PubMed

Wright, R D; Richard, C M

1996-09-01

Inhibition-of-return is thought to be a visual search phenomenon characterized by delayed responses to targets presented at recently cued or recently fixated locations. We studied this inhibition effect following the simultaneous presentation of multiple location cues. The results indicated that response inhibition can be associated with as many as four locations at the same time. This suggests that a purely oculomotor account of inhibition-of-return is oversimplified. In short, although oculomotor processes appear to play a role in inhibition-of-return they may not tell the whole story about how it occurs because we can only program and execute eye movements to one location at a time.

E-cadherin in contact inhibition and cancer.

PubMed

Mendonsa, Alisha M; Na, Tae-Young; Gumbiner, Barry M

2018-05-21

E-cadherin is a key component of the adherens junctions that are integral in cell adhesion and maintaining epithelial phenotype of cells. Homophilic E-cadherin binding between cells is important in mediating contact inhibition of proliferation when cells reach confluence. Loss of E-cadherin expression results in loss of contact inhibition and is associated with increased cell motility and advanced stages of cancer. In this review we discuss the role of E-cadherin and its downstream signaling in regulation of contact inhibition and the development and progression of cancer.

Cellobionic acid inhibition of cellobiohydrolase I and cellobiose dehydrogenase

USDA-ARS?s Scientific Manuscript database

End-product inhibition by cellobiose and glucose is a rate-limiting factor in cellulose hydrolysis by cellulases. While cellobiose and glucose inhibition have been extensively investigated, cellobionate inhibition has been minimally studied despite the discovery that accessory proteins such as cello...

Inhibition of Photophosphorylation by Kaempferol 1

PubMed Central

Arntzen, Charles J.; Falkenthal, Scott V.; Bobick, Sandra

1974-01-01

Kaempferol, a naturally occurring flavonol, inhibited coupled electron transport and both cyclic and noncyclic photophosphorylation in isolated pea (Pisum sativum) chloroplasts. Over a concentration range which gave marked inhibition of ATP synthesis, there was no effect on basal or uncoupled electron flow or light-induced proton accumulation by isolated thylakoids. It is suggested that kaempferol acts as an energy transfer inhibitor. PMID:16658695

Terbinafine inhibits gap junctional intercellular communication.

PubMed

Lee, Ju Yeun; Yoon, Sei Mee; Choi, Eun Ju; Lee, Jinu

2016-09-15

Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca(2+) concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. Copyright © 2016 Elsevier Inc. All rights reserved.

Thalamic inhibition: diverse sources, diverse scales

PubMed Central

Halassa, Michael M.; Acsády, László

2016-01-01

The thalamus is the major source of cortical inputs shaping sensation, action and cognition. Thalamic circuits are targeted by two major inhibitory systems: the thalamic reticular nucleus (TRN) and extra-thalamic inhibitory (ETI) inputs. A unifying framework of how these systems operate is currently lacking. Here, we propose that TRN circuits are specialized to exert thalamic control at different spatiotemporal scales. Local inhibition of thalamic spike rates prevails during attentional selection whereas global inhibition more likely during sleep. In contrast, the ETI (arising from basal ganglia, zona incerta, anterior pretectum and pontine reticular formation) provides temporally-precise and focal inhibition, impacting spike timing. Together, these inhibitory systems allow graded control of thalamic output, enabling thalamocortical operations to dynamically match ongoing behavioral demands. PMID:27589879

Crystal structure of a Fanconi anemia-associated nuclease homolog bound to 5' flap DNA: basis of interstrand cross-link repair by FAN1

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

Gwon, Gwang Hyeon; Kim, Youngran; Liu, Yaqi

2014-10-15

Fanconi anemia (FA) is an autosomal recessive genetic disorder caused by defects in any of 15 FA genes responsible for processing DNA interstrand cross-links (ICLs). The ultimate outcome of the FA pathway is resolution of cross-links, which requires structure-selective nucleases. FA-associated nuclease 1 (FAN1) is believed to be recruited to lesions by a monoubiquitinated FANCI–FANCD2 (ID) complex and participates in ICL repair. Here, we determined the crystal structure of Pseudomonas aeruginosa FAN1 (PaFAN1) lacking the UBZ (ubiquitin-binding zinc) domain in complex with 5' flap DNA. All four domains of the right-hand-shaped PaFAN1 are involved in DNA recognition, with each domainmore » playing a specific role in bending DNA at the nick. The six-helix bundle that binds the junction connects to the catalytic viral replication and repair (VRR) nuclease (VRR nuc) domain, enabling FAN1 to incise the scissile phosphate a few bases distant from the junction. The six-helix bundle also inhibits the cleavage of intact Holliday junctions. PaFAN1 shares several conserved features with other flap structure-selective nucleases despite structural differences. A clamping motion of the domains around the wedge helix, which acts as a pivot, facilitates nucleolytic cleavage. The PaFAN1 structure provides insights into how archaeal Holliday junction resolvases evolved to incise 5' flap substrates and how FAN1 integrates with the FA complex to participate in ICL repair.« less

Evidence that N-acetylcysteine inhibits TNF-alpha-induced cerebrovascular endothelin-1 upregulation via inhibition of mitogen- and stress-activated protein kinase.

PubMed

Sury, Matthias D; Frese-Schaper, Manuela; Mühlemann, Miranda K; Schulthess, Fabienne T; Blasig, Ingolf E; Täuber, Martin G; Shaw, Sidney G; Christen, Stephan

2006-11-01

N-acetylcysteine (NAC) is neuroprotective in animal models of acute brain injury such as caused by bacterial meningitis. However, the mechanism(s) by which NAC exerts neuroprotection is unclear. Gene expression of endothelin-1 (ET-1), which contributes to cerebral blood flow decline in acute brain injury, is partially regulated by reactive oxygen species, and thus a potential target of NAC. We therefore examined the effect of NAC on tumor necrosis factor (TNF)-alpha-induced ET-1 production in cerebrovascular endothelial cells. NAC dose dependently inhibited TNF-alpha-induced preproET-1 mRNA upregulation and ET-1 protein secretion, while upregulation of inducible nitric oxide synthase (iNOS) was unaffected. Intriguingly, NAC had no effect on the initial activation (i.e., IkappaB degradation, nuclear p65 translocation, and Ser536 phosphorylation) of NF-kappaB by TNF-alpha. However, transient inhibition of NF-kappaB DNA binding suggested that NAC may inhibit ET-1 upregulation by inhibiting (a) parallel pathway(s) necessary for full transcriptional activation of NF-kappaB-mediated ET-1 gene expression. Similar to NAC, the MEK1/2 inhibitor U0126, the p38 inhibitor SB203580, and the protein kinase inhibitor H-89 selectively inhibited ET-1 upregulation without affecting nuclear p65 translocation, suggesting that NAC inhibits ET-1 upregulation via inhibition of mitogen- and stress-activated protein kinase (MSK). Supporting this notion, cotreatment with NAC inhibited the TNF-alpha-induced rise in MSK1 and MSK2 kinase activity, while siRNA knock-down experiments showed that MSK2 is the predominant isoform involved in TNF-alpha-induced ET-1 upregulation.

3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis.

PubMed

Xian, Shu-Lin; Cao, Wei; Zhang, Xiao-Dong; Lu, Yun-Fei

2015-02-01

Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro . However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It was identified that 3-BrPA exhibited strong inhibitory effects upon xenograft tumor growth in nude mice. In addition, the antitumor function of 3-BrPA exhibited a dose-effect association, which was similar to that of the chemotherapeutic agent, 5-fluorouracil. Furthermore, 3-BrPA exhibited low toxicity in the blood, liver and kidneys of the nude mice. The present study hypothesized that the inhibitory effect of 3-BrPA is achieved through the inhibition of hexokinase activity, which leads to the downregulation of B-cell lymphoma 2 (Bcl-2) expression, the upregulation of Bcl-2-associated X protein expression and the subsequent activation of caspase-3. These data suggest that 3-BrPA may be a novel therapy for the treatment of gastric cancer.

Inhibition of ethylene production by cobaltous ion. [Beans, apples

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

Lau, O.L; Yang, S.F.

1976-07-01

The effect of Co/sup 2 +/ on ethylene production by mung bean (Phaseolus aureus Roxb.) and by apple tissues was studied. Co/sup 2 +/, depending on concentrations applied, effectively inhibited ethylene production by both tissues. It also strongly inhibited the ethylene production induced by IAA, kinetin, IAA plus kinetin, Ca/sup 2 +/, kinetin plus Ca/sup 2 +/, or Cu/sup 2 +/ treatments in mung bean hypocotyl segments. While Co/sup 2 +/ greatly inhibited ethylene production, it had little effect on the respiration of apple tissue, indicating that Co/sup 2 +/ does not exert its inhibitory effect as a general metabolicmore » inhibitor. Ni/sup 2 +/, which belongs to the same group as Co/sup 2 +/ in the periodic table, also markedly curtailed both the basal and the induced ethylene production by apple and mung bean hypocotyl tissues. In a system in which kinetin and Ca/sup 2 +/ were applied together, kinetin greatly enhanced Ca/sup 2 +/ uptake, thus enhancing ethylene production. Co/sup 2 +/, however, slightly inhibited the uptake of Ca/sup 2 +/ but appreciably inhibited ethylene production, either in the presence or in the absence of kinetin. Tracer experiments using apple tissue indicated that Co/sup 2 +/ strongly inhibited the in vivo conversion of L-(U--/sup 14/C)methionine to /sup 14/C-ethylene. These data suggested that Co/sup 2 +/ inhibited ethylene production by inhibiting the conversion of methionine to ethylene, a common step which is required for ethylene formation by higher plants. Co/sup 2 +/ is known to promote elongation, leaf expansion, and hook opening in excised plant parts in response to applied auxins or cytokinins.Since ethylene is known to inhibit those growth phenomena, it is suggested that Co/sup 2 +/ exerts its promotive effect, at least in part, by inhibiting ethylene formation.« less

N-acetylcysteine inhibits endothelial cell invasion and angiogenesis.

PubMed

Cai, T; Fassina, G; Morini, M; Aluigi, M G; Masiello, L; Fontanini, G; D'Agostini, F; De Flora, S; Noonan, D M; Albini, A

1999-09-01

The thiol N-acetylcysteine (NAC) is a chemopreventive agent that acts through a variety of mechanisms and can prevent in vivo carcinogenesis. We have previously shown that NAC inhibits invasion and metastasis of malignant cells as well as tumor take. Neovascularization is critical for tumor mass expansion and metastasis formation. We investigated whether a target of the anti-cancer activity of NAC could be the inhibition of the tumor angiogenesis-associated phenotype in vitro and in vivo using the potent angiogenic mixture of Kaposi's sarcoma cell products as a stimulus. Two endothelial (EAhy926 and human umbilical vein endothelial [HUVE]) cell lines were utilized in a panel of assays to test NAC ability in inhibiting chemotaxis, invasion, and gelatinolytic activity in vitro. NAC treatment of EAhy926 and HUVE cells in vitro dose-dependently reduced their ability to invade a reconstituted basement membrane, an indicator of endothelial cell activation. Invasion of HUVE cells was inhibited with an ID50 of 0.24 mM NAC, whereas inhibition of chemotaxis required a 10 fold higher doses, indicating that invasion is a preferential target. NAC inhibited the enzymatic activity and conversion to active forms of the gelatinase produced by endothelial cells. The matrigel in vivo assay was used for the evaluation of angiogenesis; NAC strongly inhibited neovascularization of the matrigel sponges in response to Kaposi's sarcoma cell products. NAC prevented angiogenesis while preserving endothelial cells, implying that it could be safely used as an anti-angiogenic treatment.

Terbinafine inhibits gap junctional intercellular communication

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

Lee, Ju Yeun, E-mail: whitewndus@naver.com

Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca{sup 2+} concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibitsmore » GJIC with a so far unknown mechanism of action. - Highlights: • In vitro pharmacological studies were performed on FRT-Cx43 and LN215 cells. • Terbinafine inhibits gap junctional intercellular communication in both cell lines. • The inhibitory effect of terbinafine is reversible and dose-dependent. • Treatment of terbinafine does not alter Cx43 phosphorylation or cytosolic Ca{sup 2+} concentration. • Inhibition of squalene epoxidase is not involved in this new effect of terbinafine.« less

Lactate dehydrogenase activity is inhibited by methylmalonate in vitro.

PubMed

Saad, Laura O; Mirandola, Sandra R; Maciel, Evelise N; Castilho, Roger F

2006-04-01

Methylmalonic acidemia (MMAemia) is an inherited metabolic disorder of branched amino acid and odd-chain fatty acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A. Systemic and neurological manifestations in this disease are thought to be associated with the accumulation of methylmalonate (MMA) in tissues and biological fluids with consequent impairment of energy metabolism and oxidative stress. In the present work we studied the effect of MMA and two other inhibitors of mitochondrial respiratory chain complex II (malonate and 3-nitropropionate) on the activity of lactate dehydrogenase (LDH) in tissue homogenates from adult rats. MMA potently inhibited LDH-catalyzed conversion of lactate to pyruvate in liver and brain homogenates as well as in a purified bovine heart LDH preparation. LDH was about one order of magnitude less sensitive to inhibition by MMA when catalyzing the conversion of pyruvate to lactate. Kinetic studies on the inhibition of brain LDH indicated that MMA inhibits this enzyme competitively with lactate as a substrate (K (i)=3.02+/-0.59 mM). Malonate and 3-nitropropionate also strongly inhibited LDH-catalyzed conversion of lactate to pyruvate in brain homogenates, while no inhibition was observed by succinate or propionate, when present in concentrations of up to 25 mM. We propose that inhibition of the lactate/pyruvate conversion by MMA contributes to lactate accumulation in blood, metabolic acidemia and inhibition of gluconeogenesis observed in patients with MMAemia. Moreover, the inhibition of LDH in the central nervous system may also impair the lactate shuttle between astrocytes and neurons, compromising neuronal energy metabolism.

Inhibition of airway surface fluid absorption by cholinergic stimulation

PubMed Central

Joo, Nam Soo; Krouse, Mauri E.; Choi, Jae Young; Cho, Hyung-Ju; Wine, Jeffrey J.

2016-01-01

In upper airways airway surface liquid (ASL) depth and clearance rates are both increased by fluid secretion. Secretion is opposed by fluid absorption, mainly via the epithelial sodium channel, ENaC. In static systems, increased fluid depth activates ENaC and decreased depth inhibits it, suggesting that secretion indirectly activates ENaC to reduce ASL depth. We propose an alternate mechanism in which cholinergic input, which causes copious airway gland secretion, also inhibits ENaC-mediated absorption. The conjoint action accelerates clearance, and the increased transport of mucus out of the airways restores ASL depth while cleansing the airways. We were intrigued by early reports of cholinergic inhibition of absorption by airways in some species. To reinvestigate this phenomenon, we studied inward short-circuit currents (Isc) in tracheal mucosa from human, sheep, pig, ferret, and rabbit and in two types of cultured cells. Basal Isc was inhibited 20–70% by the ENaC inhibitor, benzamil. Long-lasting inhibition of ENaC-dependent Isc was also produced by basolateral carbachol in all preparations except rabbit and the H441 cell line. Atropine inhibition produced a slow recovery or prevented inhibition if added before carbachol. The mechanism for inhibition was not determined and is most likely multi-factorial. However, its physiological significance is expected to be increased mucus clearance rates in cholinergically stimulated airways. PMID:26846701

Role of GABAergic inhibition in hippocampal network oscillations.

PubMed

Mann, Edward O; Paulsen, Ole

2007-07-01

Physiological rhythmic activity in cortical circuits relies on GABAergic inhibition to balance excitation and control spike timing. With a focus on recent experimental progress in the hippocampus, here we review the mechanisms by which synaptic inhibition can control the precise timing of spike generation, by way of effects of GABAergic events on membrane conductance ('shunting' inhibition) and membrane potential ('hyperpolarizing' inhibition). Synaptic inhibition itself can be synchronized by way of interactions within networks of GABAergic neurons, and by excitatory neurons. The importance of GABAergic mechanisms for generation of cortical rhythms is now well established. What remains to be resolved is how such inhibitory control of spike timing can be harnessed for long-range fast synchronization, and the relevance of these mechanisms to network function. This review is part of the INMED/TINS special issue Physiogenic and pathogenic oscillations: the beauty and the beast, based on presentations at the annual INMED/TINS symposium (http://inmednet.com).

Basal forebrain neuronal inhibition enables rapid behavioral stopping

PubMed Central

Mayse, Jeffrey D.; Nelson, Geoffrey M.; Avila, Irene; Gallagher, Michela; Lin, Shih-Chieh

2015-01-01

Cognitive inhibitory control, the ability to rapidly suppress responses inappropriate for the context, is essential for flexible and adaptive behavior. While most studies on inhibitory control have focused on the fronto-basal-ganglia circuit, here we explore a novel hypothesis and show that rapid behavioral stopping is enabled by neuronal inhibition in the basal forebrain (BF). In rats performing the stop signal task, putative noncholinergic BF neurons with phasic bursting responses to the go signal were inhibited nearly completely by the stop signal. The onset of BF neuronal inhibition was tightly coupled with and temporally preceded the latency to stop, the stop signal reaction time. Artificial inhibition of BF activity in the absence of the stop signal was sufficient to reproduce rapid behavioral stopping. These results reveal a novel subcortical mechanism of rapid inhibitory control by the BF, which provides bidirectional control over the speed of response generation and inhibition. PMID:26368943

Halenaquinone inhibits RANKL-induced osteoclastogenesis.

PubMed

Tsukamoto, Sachiko; Takeuchi, Tomoharu; Kawabata, Tetsuro; Kato, Hikaru; Yamakuma, Michiko; Matsuo, Kanae; El-Desoky, Ahmed H; Losung, Fitje; Mangindaan, Remy E P; de Voogd, Nicole J; Arata, Yoichiro; Yokosawa, Hideyoshi

2014-11-15

Halenaquinone was isolated from the marine sponge Petrosia alfiani as an inhibitor of osteoclastogenic differentiation of murine RAW264 cells. It inhibited the RANKL (receptor activator of nuclear factor-κB ligand)-induced upregulation of TRAP (tartrate-resistant acid phosphatase) activity as well as the formation of multinuclear osteoclasts. In addition, halenaquinone substantially suppressed RANKL-induced IκB degradation and Akt phosphorylation. Thus, these results suggest that halenaquinone inhibits RANKL-induced osteoclastogenesis at least by suppressing the NF-κB and Akt signaling pathways. Copyright © 2014 Elsevier Ltd. All rights reserved.

Action spectra for photosynthetic inhibition

NASA Technical Reports Server (NTRS)

Caldwell, M. M.; Flint, S.; Camp, L. B.

1981-01-01

The ultraviolet action spectrum for photosynthesis inhibition was determined to fall between that of the general DNA action spectrum and the generalized plant action spectrum. The characteristics of this action spectrum suggest that a combination of pronounced increase in effectiveness with decreasing wavelength, substantial specificity for the UV-B waveband, and very diminished response in the UV-A waveband result in large radiation amplification factors when the action spectra are used as weighting functions. Attempted determination of dose/response relationships for leaf disc inhibition provided inconclusive data from which to deconvolute an action spectrum.

Homo Economicus Belief Inhibits Trust

PubMed Central

Xin, Ziqiang; Liu, Guofang

2013-01-01

As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners’ benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals’ homo economicus belief and inhibit their trust. It seems that people’s increasing homo economicus belief may serve as one cause of the worldwide decline of trust. PMID:24146907

Inhibition of UDP-glucuronosyltransferases (UGTs) by phthalate monoesters.

PubMed

Du, Zuo; Cao, Yun-Feng; Li, Sai-Nan; Hu, Cui-Min; Fu, Zhi-Wei; Huang, Chun-Ting; Sun, Xiao-Yu; Liu, Yong-Zhe; Yang, Kun; Fang, Zhong-Ze

2018-04-01

Phthalate monoesters are important metabolites of phthalate esters (PAEs) which have been extensively utilized in industry. This study aims to investigate the inhibition of phthalate monoesters on the activity of various isoforms of UDP-glucuronosyltransferases (UGTs), trying to elucidate the toxicity mechanism of environmental endocrine disruptors from the new perspectives. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was employed to evaluate 8 kinds of phthalate monoesters on 11 sorts of main human UGT isoforms. 100 μM phthalate monoesters exhibited negligible inhibition towards the activity of UGT1A1, UGT1A3, UGT1A6, UGT1A8, UGT1A10, UGT2B4, UGT2B7, UGT2B15 and UGT2B17. The activity of UGT1A7 was strongly inhibited by monoethylhexyl phthalate (MEHP), but slightly inhibited by all the other phthalate monoesters. UGT1A9 was broadly inhibited by monobenzyl phthalate (MBZP), monocyclohexyl phthalate (MCHP), MEHP, monohexyl phthalate (MHP) and monooctyl phthalate (MOP), respectively. MEHP exhibited competitive inhibition towards UGT1A7, and MBZP, MCHP, MEHP, MHP and MOP showed competitive inhibition towards UGT1A9. The inhibition kinetic parameters (K i ) were calculated to be 11.25 μM for MEHP-UGT1A7, and 2.13, 0.09, 1.17, 7.47, 0.16 μM for MBZP-UGT1A9, MCHP-UGT1A9, MEHP-UGT1A9, MHP-UGT1A9, MOP-UGT1A9, respectively. Molecular docking indicated that both hydrogen bonds formation and hydrophobic interactions significantly contributed to the interaction between phthalate monoesters and UGT isoforms. All these information will be beneficial for understanding the adverse effects of PAEs. Copyright © 2018 Elsevier Ltd. All rights reserved.

Protons inhibit anoctamin 1 by competing with calcium.

PubMed

Chun, Hyeyeon; Cho, Hawon; Choi, Jimi; Lee, Jesun; Kim, Sung Min; Kim, Hyungsup; Oh, Uhtaek

2015-11-01

Cl(-) efflux through Ca(2+)-activated Cl(-) channels (CaCCs) in secretory epithelial cells plays a key role in the regulation of fluid secretion. The fluid and electrolyte secretion is closely related to intracellular pH. CaCCs have been known to be inhibited by intracellular acid. However, the molecular mechanism for the inhibition remains unknown. Anoctamin 1 (ANO1) is a Ca(2+)-activated Cl(-) channel that mediates numerous physiological functions including fluid secretion in secretory epithelia. However, little is known about whether ANO1 can be modulated by change of intracellular pH. Here, we demonstrate that Ca(2+)-induced activation of ANO1 and its homolog ANO2 are strongly inhibited by intracellular acid. Intracellular acid caused a rightward shift of the concentration-response curve of Ca(2+) in activating ANO1 and ANO2. To identify the location of the acid-induced inhibition, mutations were made on each of all histidine residues in cytoplasmic part of ANO1. However, none of the His-mutant showed the reduction in the acid-induced inhibition. Furthermore, mutation on Glu- or Asp-residues in the multiple acidic-amino acid regions was ineffective in blocking the acid-induced inhibition. Because the Ca(2+)-binding site of a fungal anoctamin (nhTMEM16) was uncovered by crystallography, mutagenesis was performed in this region. Surprisingly, mutations at Glu, Asp or Asn residues in the hydrophobic core that are known to be essential for Ca(2+)-induced activation of ANO1 blocked the acid-induced inhibition. These results suggest that protons interfere with Ca(2+) at the Ca(2+) binding site of ANO1. These findings provide a molecular mechanism underlying the acid-induced inhibition of ANO1, which may contribute to control fluid and electrolyte secretion in the secretory epithelia. Copyright © 2015. Published by Elsevier Ltd.

Quorum Sensing Inhibition, Relevance to Periodontics

PubMed Central

Yada, Sudheer; Kamalesh, B; Sonwane, Siddharth; Guptha, Indra; Swetha, R K

2015-01-01

Quorum sensing helps bacteria to communicate with each other and in coordinating their behavior. Many diseases of human beings, plants, and animals are mediated by quorum sensing. Various approaches are being tried to inhibit this communication to control the diseases caused by bacteria. Periodontal pathogens also communicate through quorum sensing and new approaches to treat periodontal disease using quorum sensing inhibition need to explored. PMID:25709373

Cadmium ion inhibition of quorum signalling in Chromobacterium violaceum.

PubMed

Thornhill, Starla G; Kumar, Manish; Vega, Leticia M; McLean, Robert J C

2017-10-01

Single-celled bacteria are capable of acting as a community by sensing and responding to population density via quorum signalling. Quorum signalling in Chromobacterium violaceum, mediated by the luxI/R homologue, cviI/R, regulates a variety of phenotypes including violacein pigmentation, virulence and biofilm formation. A number of biological and organic molecules have been described as quorum signalling inhibitors but, to date, metal-based inhibitors have not been widely tested. In this study, we show that quorum sensing is inhibited in C. violaceum in the presence of sub-lethal concentrations of cadmium salts. Notable Cd 2+ -inhibition was seen against pigmentation, motility, chitinase production and biofilm formation. Cd-inhibition of quorum-signalling genes occurred at the level of transcription. There was no direct inhibition of chitinase activity by Cd 2+ at the concentrations tested. Addition of the cognate quorum signals, N-hexanoyl homoserine lactone or N-decanoyl homoserine lactone, even at concentrations in excess of physiological levels, did not reverse the inhibition, suggesting that Cd-inhibition of quorum signaling is irreversible. This study represents the first description of heavy metal-based quorum inhibition in C. violaceum.

Factors Impacting the Child with Behavioral Inhibition

ERIC Educational Resources Information Center

Hornbuckle, Suzanne R.

2010-01-01

Various factors influence the developmental course of the behaviorally inhibited child. These factors include reciprocating, contextual factors, such as the child's own traits, the environment, the maternal characteristics, and the environment. Behaviorally inhibited children show physiological and behavioral signs of fear and anxiety when…

Macrophage migration inhibition test in untreated syphilis.

PubMed

Bowszyc, J

1975-01-01

Two modifications of macrophage migration inhibition test, one of George and Vaughan and the other one of Svejcar, were performed on a total of 78 cases of untreated syphilis at various stages. As specific antigens were used: Treponema Pallidum ultrasonate and cardiolipin. Inhibition of migration was observed in 87 percent patients with primary syphillis and in all patients with late and late congenital syphilis. After improving and standardisation of the technique of Treponema Pallidum antigen-the migration inhibition test may be recommended as a specific in vitro-test for detection of cell mediated immunity in syphilis.

Inhibition of PTEN and activation of Akt by menadione.

PubMed

Yoshikawa, Kyoko; Nigorikawa, Kiyomi; Tsukamoto, Mariko; Tamura, Namiko; Hazeki, Kaoru; Hazeki, Osamu

2007-04-01

Menadione (vitamin K(3)) has been shown to activate Erk in several cell lines. This effect has been shown to be due to the activation of EGF receptors (EGFR) as a result of inhibition of some protein tyrosine phosphatases. In the present study, we examined the effects of menadione on Akt in Chinese hamster ovary cells. The phosphorylation of Akt by menadione was not inhibited by AG1478, an inhibitor of EGFR. Menadione inhibited the lipid phosphatase activity of PTEN in a cell-free system. In an intact cell system, menadione inhibited the effect of transfected PTEN on Akt. Thus, one mechanism of its action was considered the accelerated activation of Akt through inhibition of PTEN. This was not the sole mechanism responsible for the EGFR-independent activation of Akt, because menadione attenuated the rate of Akt dephosphorylation even in PTEN-null PC3 cells. The decelerated inactivation of Akt, probably through inhibition of some tyrosine phosphatases, was considered another mechanism of its action.

Engineered kinesin motor proteins amenable to small-molecule inhibition

PubMed Central

Engelke, Martin F.; Winding, Michael; Yue, Yang; Shastry, Shankar; Teloni, Federico; Reddy, Sanjay; Blasius, T. Lynne; Soppina, Pushpanjali; Hancock, William O.; Gelfand, Vladimir I.; Verhey, Kristen J.

2016-01-01

The human genome encodes 45 kinesin motor proteins that drive cell division, cell motility, intracellular trafficking and ciliary function. Determining the cellular function of each kinesin would benefit from specific small-molecule inhibitors. However, screens have yielded only a few specific inhibitors. Here we present a novel chemical-genetic approach to engineer kinesin motors that can carry out the function of the wild-type motor yet can also be efficiently inhibited by small, cell-permeable molecules. Using kinesin-1 as a prototype, we develop two independent strategies to generate inhibitable motors, and characterize the resulting inhibition in single-molecule assays and in cells. We further apply these two strategies to create analogously inhibitable kinesin-3 motors. These inhibitable motors will be of great utility to study the functions of specific kinesins in a dynamic manner in cells and animals. Furthermore, these strategies can be used to generate inhibitable versions of any motor protein of interest. PMID:27045608

Ibogaine and the inhibition of acetylcholinesterase.

PubMed

Alper, Kenneth; Reith, Maarten E A; Sershen, Henry

2012-02-15

Ibogaine is a psychoactive monoterpine indole alkaloid extracted from the root bark of Tabernanthe iboga Baill. that is used globally in medical and nonmedical settings to treat drug and alcohol addiction, and is of interest as an ethnopharmacological prototype for experimental investigation and pharmaceutical development. The question of whether ibogaine inhibits acetylcholinesterase (AChE) is of pharmacological and toxicological significance. AChE activity was evaluated utilizing reaction with Ellman's reagent with physostigmine as a control. Ibogaine inhibited AChE with an IC(50) of 520±40 μM. Ibogaine's inhibition of AChE is physiologically negligible, and does not appear to account for observations of functional effects in animals and humans that might otherwise suggest the possible involvement of pathways linked to muscarinic acetylcholine transmission. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Growth inhibition of Saccharomyces cerevisiae by the immunosuppressant leflunomide is due to the inhibition of uracil uptake via Fur4p.

PubMed

Fujimura, H

1998-10-01

The immunosuppressant leflunomide inhibits cytokine-stimulated proliferation of lymphoid cells in vitro and also inhibits the growth of the eukaryotic microorganism Saccharomyces cerevisiae. To elucidate the molecular mechanism of action of the drug, two yeast genes which suppress the anti-proliferative effect when present in multiple copies were cloned and designated MLF1 and MLF2 for multicopy suppressor of leflunomide sensitivity. DNA sequencing analysis revealed that the MLF1 gene is identical to the FUR4 gene, which encodes a uracil permease and functions to import uracil efficiently. The MLF2 was found to be identical to the URA3 gene. Excess exogenous uracil also overcomes the anti-proliferative effect of leflunomide on yeast cells. Uracil prototrophy also conferred resistance to leflunomide. Uracil uptake was inhibited by leflunomide. Thus, the growth inhibition by leflunomide seen in a S. cerevisiae ura3 auxotroph is due to the inhibition of the entry of exogenous uracil via the Fur4 uracil permease.

Tone-Inhibiting Insoles Enhance the Reciprocal Inhibition of Ankle Plantarflexors of Subjects With Hemiparesis After Stroke: An Electromyographic Study.

PubMed

Takahashi, Nobushige; Takahashi, Hidetoshi; Takahashi, Osamu; Ushijima, Ryosuke; Umebayashi, Rie; Nishikawa, Junji; Okajima, Yasutomo

2018-02-01

Spasticity is a common sequela of upper motor neuron pathology, such as cerebrovascular diseases and cerebral palsy. Intervention for spasticity of the ankle plantarflexors in physical therapy may include tone-inhibiting casting and/or orthoses for the ankle and foot. However, the physiological mechanism of tone reduction by such orthoses remains unclarified. To investigate the electrophysiologic effects of tone-inhibiting insoles in stroke subjects with hemiparesis by measuring changes in reciprocal Ia inhibition (RI) in the ankle plantarflexor. An interventional before-after study. Acute stroke unit or ambulatory rehabilitation clinic of a university hospital in Japan. Ten subjects (47-84 years) with hemiparesis and 10 healthy male control subjects (31-59 years) were recruited. RI of the spastic soleus in response to the electrical stimulation of the deep peroneal nerve was evaluated by stimulus-locked averaging of rectified electromyography (EMG) of the soleus while subjects were standing. The magnitude of RI, defined as the ratio of the lowest to the baseline amplitude of the rectified EMG at approximately 40 milliseconds after stimulation, was measured while subjects were standing with and without the tone-inhibiting insole on the hemiparesis side. Enhancement of EMG reduction with the tone-inhibiting insole was significant (P < .05) in the subjects with hemiparesis, whereas no significant changes were found in controls. Tone-inhibiting insoles enhanced RI of the soleus in subjects after stroke, which might enhance standing stability by reducing unfavorable ankle plantarflexion tone. III. Copyright © 2018 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

PKA and Epac synergistically inhibit smooth muscle cell proliferation

PubMed Central

Hewer, Richard C.; Sala-Newby, Graciela B.; Wu, Yih-Jer; Newby, Andrew C.; Bond, Mark

2011-01-01

Cyclic AMP signalling promotes VSMC quiescence in healthy vessels and during vascular healing following injury. Cyclic AMP inhibits VSMC proliferation via mechanisms that are not fully understood. We investigated the role of PKA and Epac signalling on cAMP-induced inhibition of VSMC proliferation. cAMP-mediated growth arrest was PKA-dependent. However, selective PKA activation with 6-Benzoyl-cAMP did not inhibit VSMC proliferation, indicating a requirement for additional pathways. Epac activation using the selective cAMP analogue 8-CPT-2′-O-Me-cAMP, did not affect levels of hyperphosphorylated Retinoblastoma (Rb) protein, a marker of G1-S phase transition, or BrdU incorporation, despite activation of the Epac-effector Rap1. However, 6-Benzoyl-cAMP and 8-CPT-2′-O-Me-cAMP acted synergistically to inhibit Rb-hyperphosphorylation and BrdU incorporation, indicating that both pathways are required for growth inhibition. Consistent with this, constitutively active Epac increased Rap1 activity and synergised with 6-Benzoyl-cAMP to inhibit VSMC proliferation. PKA and Epac synergised to inhibit phosphorylation of ERK and JNK. Induction of stellate morphology, previously associated with cAMP-mediated growth arrest, was also dependent on activation of both PKA and Epac. Rap1 inhibition with Rap1GAP or siRNA silencing did not negate forskolin-induced inhibition of Rb-hyperphosphorylation, BrdU incorporation or stellate morphology. This data demonstrates for the first time that Epac synergises with PKA via a Rap1-independent mechanism to mediate cAMP-induced growth arrest in VSMC. This work highlights the role of Epac as a major player in cAMP-dependent growth arrest in VSMC. PMID:20971121

Retrieval-Induced Inhibition in Short-Term Memory.

PubMed

Kang, Min-Suk; Choi, Joongrul

2015-07-01

We used a visual illusion called motion repulsion as a model system for investigating competition between two mental representations. Subjects were asked to remember two random-dot-motion displays presented in sequence and then to report the motion directions for each. Remembered motion directions were shifted away from the actual motion directions, an effect similar to the motion repulsion observed during perception. More important, the item retrieved second showed greater repulsion than the item retrieved first. This suggests that earlier retrieval exerted greater inhibition on the other item being held in short-term memory. This retrieval-induced motion repulsion could be explained neither by reduced cognitive resources for maintaining short-term memory nor by continued inhibition between short-term memory representations. These results indicate that retrieval of memory representations inhibits other representations in short-term memory. We discuss mechanisms of retrieval-induced inhibition and their implications for the structure of memory. © The Author(s) 2015.

Neural Correlates of Central Inhibition during Physical Fatigue

PubMed Central

Tanaka, Masaaki; Ishii, Akira; Watanabe, Yasuyoshi

2013-01-01

Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG). Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs) in the posterior cingulated cortex (PCC), with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue. PMID:23923034

Doxycycline inhibits leukemic cell migration via inhibition of matrix metalloproteinases and phosphorylation of focal adhesion kinase

PubMed Central

WANG, CHUNHUAI; XIANG, RU; ZHANG, XIANGZHONG; CHEN, YUNXIAN

2015-01-01

Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel® matrix-coated Transwell® chamber assays; leukemic cell lines treated with doxycycline (1 µg/ml) or anti-β1-integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)-2 and MMP-9 expression. Furthermore, incubation with blocking anti-β1-integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia. PMID:26004127

Cortisol inhibits CSF2 and CSF3 via DNA methylation and inhibits invasion in first-trimester trophoblast cells

PubMed Central

Smith, Arianna; Witte, Elizabeth; McGee, Devin; Knott, Jason; Narang, Kavita; Racicot, Karen

2018-01-01

Problem Heightened maternal stress affects trophoblast function and increases risk for adverse pregnancy outcomes. Methods of Study Studies were performed using the first-trimester trophoblast cell line, Sw.71. Cytokines were quantified using qPCR and ELISA. Epigenetic regulation of cytokines was characterized by inhibiting histone deacetylation (1 μmol/L suberoylanilide hydroxamic acid [SAHA]) or methylation (5 μmol/L 5-azacytidine), or with chromatin immunoprecipitation (ChIP) with a pan-acetyl histone-3 antibody. Invasion assays used Matrigel chambers. Results Cortisol inhibited expression of CSF2 (GM-CSF) and CSF3 (G-CSF) in trophoblast cells. Cortisol-associated inhibition was dependent on DNA methylation and was not affected by acetylation. There was also a modest decrease in trophoblast invasion, not dependent on loss of CSFs. Conclusion In first-trimester trophoblast cells, the physiological glucocorticoid, cortisol, inhibited two cytokines with roles in placental development and decreased trophoblast invasion. Cortisol-associated changes in trophoblast function could increase the risk for immune-mediated abortion or other adverse pregnancy outcomes. PMID:28846166

Salicylic acid inhibits enzymatic browning of fresh-cut Chinese chestnut (Castanea mollissima) by competitively inhibiting polyphenol oxidase.

PubMed

Zhou, Dan; Li, Lin; Wu, Yanwen; Fan, Junfeng; Ouyang, Jie

2015-03-15

The inhibitory effect and associated mechanisms of salicylic acid (SA) on the browning of fresh-cut Chinese chestnut were investigated. Shelled and sliced chestnuts were immersed in different concentrations of an SA solution, and the browning of the chestnut surface and interior were inhibited. The activities of polyphenol oxidase (PPO) and peroxidase (POD) extracted from chestnuts were measured in the presence and absence of SA. SA at concentrations higher than 0.3g/L delayed chestnut browning by significantly inhibiting the PPO activity (P<0.01), and the POD activity was not significantly affected (P>0.05). The binding and inhibition modes of SA with PPO and POD, determined by AUTODOCK 4.2 and Lineweaver-Burk plots, respectively, established SA as a competitive inhibitor of PPO. Copyright © 2014 Elsevier Ltd. All rights reserved.

Optimal Decision Making in Neural Inhibition Models

ERIC Educational Resources Information Center

van Ravenzwaaij, Don; van der Maas, Han L. J.; Wagenmakers, Eric-Jan

2012-01-01

In their influential "Psychological Review" article, Bogacz, Brown, Moehlis, Holmes, and Cohen (2006) discussed optimal decision making as accomplished by the drift diffusion model (DDM). The authors showed that neural inhibition models, such as the leaky competing accumulator model (LCA) and the feedforward inhibition model (FFI), can mimic the…

Inhibition of trypsin by condensed tannins and wine.

PubMed

Gonçalves, Rui; Soares, Susana; Mateus, Nuno; de Freitas, Victor

2007-09-05

Phenolic compounds are abundant vegetable secondary metabolites in the human diet. The ability of procyanidin oligomers and wine polyphenols to inhibit trypsin activity was studied using a versatile and reliable in vitro method. The hydrolysis of the chromogenic substrate N-benzoyl-d,l-arginine-p-nitroanilide (BApNA) by trypsin was followed by spectrophotometry in the presence and absence of condensed tannins and wine. A clear relationship between the degree of polymerization of procyanidins and enzymatic inhibition was observed. Trypsin activity inhibition was also detected in several types of wine. In general, the inhibition increased with the concentration of phenolic compounds in wines. These results may be relevant when considering these compounds as antinutritional factors, thereby contributing to a reduced absorption of nutrients.

Thymol inhibits Staphylococcus aureus internalization into bovine mammary epithelial cells by inhibiting NF-κB activation.

PubMed

Wei, Zhengkai; Zhou, Ershun; Guo, Changming; Fu, Yunhe; Yu, Yuqiang; Li, Yimeng; Yao, Minjun; Zhang, Naisheng; Yang, Zhengtao

2014-01-01

Bovine mastitis is one of the most costly and prevalent diseases in the dairy industry and is characterised by inflammatory and infectious processes. Staphylococcus aureus (S. aureus), a Gram-positive organism, is a frequent cause of subclinical, chronic mastitis. Thymol, a monocyclic monoterpene compound isolated from Thymus vulgaris, has been reported to have antibacterial properties. However, the effect of thymol on S. aureus internalization into bovine mammary epithelial cells (bMEC) has not been investigated. In this study, we evaluated the effect of thymol on S. aureus internalization into bMEC, the expression of tracheal antimicrobial peptide (TAP) and β-defensin (BNBD5), and the inhibition of NF-κB activation in bMEC infected with S. aureus. Our results showed that thymol (16-64 μg/ml) could reduce the internalization of S. aureus into bMEC and down-regulate the mRNA expression of TAP and BNBD5 in bMEC infected with S. aureus. In addition, thymol was found to inhibit S. aureus-induced nitric oxide (NO) production in bMEC and suppress S. aureus-induced NF-κB activation in a dose-dependent manner. In conclusion, these results indicated that thymol inhibits S. aureus internalization into bMEC by inhibiting NF-κB activation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Parenting Predictors of Delay Inhibition in Socioeconomically Disadvantaged Preschoolers

PubMed Central

Merz, Emily C.; Landry, Susan H.; Zucker, Tricia A.; Barnes, Marcia A.; Assel, Michael; Taylor, Heather B.; Lonigan, Christopher J.; Phillips, Beth M.; Clancy-Menchetti, Jeanine; Eisenberg, Nancy; Spinrad, Tracy L.; Valiente, Carlos; de Villiers, Jill; Consortium, the School Readiness Research

2016-01-01

This study examined longitudinal associations between specific parenting factors and delay inhibition in socioeconomically disadvantaged preschoolers. At Time 1, parents and 2- to 4-year-old children (mean age = 3.21 years; N = 247) participated in a videotaped parent-child free play session, and children completed delay inhibition tasks (gift delay-wrap, gift delay-bow, and snack delay tasks). Three months later, at Time 2, children completed the same set of tasks. Parental responsiveness was coded from the parent-child free play sessions, and parental directive language was coded from transcripts of a subset of 127 of these sessions. Structural equation modeling was used, and covariates included age, gender, language skills, parental education, and Time 1 delay inhibition. Results indicated that in separate models, Time 1 parental directive language was significantly negatively associated with Time 2 delay inhibition, and Time 1 parental responsiveness was significantly positively associated with Time 2 delay inhibition. When these parenting factors were entered simultaneously, Time 1 parental directive language significantly predicted Time 2 delay inhibition whereas Time 1 parental responsiveness was no longer significant. Findings suggest that parental language that modulates the amount of autonomy allotted the child may be an important predictor of early delay inhibition skills. PMID:27833461

Simulating cholinesterase inhibition in birds caused by dietary insecticide exposure

USGS Publications Warehouse

Corson, M.S.; Mora, M.A.; Grant, W.E.

1998-01-01

We describe a stochastic simulation model that simulates avian foraging in an agricultural landscape to evaluate factors affecting dietary insecticide exposure and to predict post-exposure cholinesterase (ChE) inhibition. To evaluate the model, we simulated published field studies and found that model predictions of insecticide decay and ChE inhibition reasonably approximated most observed results. Sensitivity analysis suggested that foraging location usually influenced ChE inhibition more than diet preferences or daily intake rate. Although organophosphorus insecticides usually caused greater inhibition than carbamate insecticides, insecticide toxicity appeared only moderately important. When we simulated impact of heavy insecticide applications during breeding seasons of 15 wild bird species, mean maximum ChE inhibition in most species exceeded 20% at some point. At this level of inhibition, birds may experience nausea and/or may exhibit minor behavioral changes. Simulated risk peaked in April–May and August–September and was lowest in July. ChE inhibition increased with proportion of vegetation in the diet. This model, and ones like it, may help predict insecticide exposure of and sublethal ChE inhibition in grassland animals, thereby reducing dependence of ecological risk assessments on field studies alone.

TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer.

PubMed

Solberg, Nina T; Waaler, Jo; Lund, Kaja; Mygland, Line; Olsen, Petter A; Krauss, Stefan

2018-03-01

Overactivation of the WNT/β-CATENIN signaling axis is a common denominator in colorectal cancer. Currently, there is no available WNT inhibitor in clinical practice. Although TANKYRASE (TNKS) inhibitors have been proposed as promising candidates, there are many colorectal cancer models that do not respond positively to TNKS inhibition in vitro and in vivo Therefore, a combinatorial therapeutic approach combining a TNKS inhibitor (G007-LK) with PI3K (BKM120) and EGFR (erlotinib) inhibitors in colorectal cancer was investigated. The data demonstrate that TNKS inhibition enhances the effect of PI3K and EGFR inhibition in the TNKS inhibitor-sensitive COLO320DM, and in the nonsensitive HCT-15 cell line. In both cell lines, combined TNKS/PI3K/EGFR inhibition is more effective at reducing growth than a dual TNKS/MEK inhibition. TNKS/PI3K/EGFR inhibition affected in a context-dependent manner components of the WNT/β-CATENIN, AKT/mTOR, EGFR, and RAS signaling pathways. TNKS/PI3K/EGFR inhibition also efficiently reduced growth of both COLO320DM and HCT-15 tumor xenografts in vivo At the highest doses, tumor xenograft growth was halted without affecting the body weight of the tested animals. Implications: Combining TNKS inhibitors with PI3K and EGFR inhibition may expand the therapeutic arsenal against colorectal cancers. Mol Cancer Res; 16(3); 543-53. ©2017 AACR . ©2017 American Association for Cancer Research.

Inhibition of Glycoprotein VI Clustering by Collagen as a Mechanism of Inhibiting Collagen-Induced Platelet Responses: The Example of Losartan

PubMed Central

Jiang, Peng; Loyau, Stéphane; Tchitchinadze, Maria; Ropers, Jacques; Jondeau, Guillaume; Jandrot-Perrus, Martine

2015-01-01

Exposure of platelets to collagen triggers the formation of a platelet clot. Pharmacological agents capable of inhibiting platelet activation by collagen are thus of potential therapeutic interest. Thrombus formation is initiated by the interaction of the GPIb-V-IX complex with collagen-bound vWF, while GPVI interaction with collagen triggers platelet activation that is reinforced by ADP and thromboxane A2. Losartan is an angiotensin II (Ang II) type I receptor (AT1R) antagonist proposed to have an antiplatelet activity via the inhibition of both the thromboxane A2 (TXA2) receptor (TP) and the glycoprotein VI (GPVI). Here, we characterized in vitro the effects of losartan at different doses on platelet responses: losartan inhibited platelet aggregation and secretion induced by 1 μg.mL-1 and 10 μg.mL-1 of collagen with an IC50 of ~ 6 μM. Losartan inhibited platelet responses induced by the GPVI specific collagen related peptide but not by the α2β1 specific peptide. However, losartan did not inhibit the binding of recombinant GPVI to collagen, which is not in favor of a simple competition. Indeed, the clustering of GPVI observed in flow cytometry and using the Duolink methodology, was inhibited by losartan. The impact of a therapeutic dose of losartan (100 mg/day) on platelet responses was analyzed ex vivo in a double blind study. No statistically significant differences were observed between losartan-treated (n=25) and non-treated (n=30) patients in terms of collagen and U46619-induced platelet activation. These data indicate that in treated patients, losartan does not achieve a measurable antiplatelet effect but provide the proof of concept that inhibiting collagen-induced GPVI clustering is of pharmacological interest to obtain an antithrombotic efficacy. Trial Registration ClinicalTrials.gov NCT00763893 PMID:26052700

Inhibition of metallopeptidases by flavonoids and related compounds.

PubMed

Bormann, H; Melzig, M F

2000-02-01

To elucidate possible mechanisms of activity in medicinal plants containing flavonoids, the inhibitory potency of twenty flavones, flavonols, flavanones, phenylacrylic acids and various hydroxylated phenylacetic acids on the activity of neutral endopeptidase (NEP; EC 3.4.24.11), angiotensin-converting enzyme (ACE; EC 3.4.15.1) and aminopeptidase N (APN; EC 3.4.11.2) was investigated in vitro. The screening generally resulted that inhibition of these enzymes requires free hydroxyl groups at the flavone molecule. Flavone and methoxylated compounds (sinensetin) were without effects. Flavonoids with free hydroxyl functions in position 3',4' and 5,7 inhibited the activity of NEP (quercetin, luteolin, fisetin), with myricetin (IC50 = 42 microM) as strongest inhibitor. Inhibition of ACE and APN did not depend on this class of compounds and substitution pattern. E.g. 3,4-dihydroxyphenylacetic acid and 4-methylcatechol (urinary metabolites of flavonoids) also inhibited both APN and ACE activity, but not NEP activity. The results demonstrate that some of the pharmacological activities of flavonoids might be related to the inhibition of metallopeptidases responsible for the splitting of regulatory neuropeptides.

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer

PubMed Central

Baritaki, Stavroula; Huerta-Yepez, Sara; Sahakyan, Anna; Karagiannides, Iordanis; Bakirtzi, Kyriaki; Jazirehi, Ali R

2010-01-01

The role of nitric oxide (NO) in cancer has been controversial and is based on the levels of NO and the responsiveness of the tumor type. It remains unclear whether NO can inhibit the epithelial to mesenchymal transition (EMT) in cancer cells. EMT induction is mediated, in part, by the constitutive activation of the metastasis-inducer transcription factor, Snail and EMT can be inhibited by the metastasis-suppressors Raf-1 kinase inhibitor protein (RKIP) and E-cadherin. Snail is transcriptionally regulated by NFκB and in turn, Snail represses RKIP transcription. Hence, we hypothesized that high levels of NO, that inhibit NFκB activity, may also inhibit Snail, induce RKIP and leading to inhibition of EMT. We show that treatment of human prostate metastatic cell lines with the NO donor, DETANONOate, inhibits EMT and reverses both the mesenchymal phenotype and the cell invasive properties. Further, treatment with DETANONOate inhibits Snail expression and DNA-binding activity in parallel with the upregulation of RKIP and E-cadherin protein levels. The pivotal roles of Snail inhibition and RKIP induction in DETANONOate-mediated inhibition of EMT were corroborated by both Snail silencing by siRNA and by ectopic expression of RKIP. The in vitro findings were validated in vivo in mice bearing PC-3 xenografts treated with DETANONOate. The present findings show, for the first time, the novel role of high, yet, subtoxic concentrations of NO in the inhibition of EMT. Thus, NO donors may exert therapeutic activities in the reversal of EMT and metastasis. PMID:21150329

Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression.

PubMed

Feng, Shu; Shao, Longjiang; Yu, Wendong; Gavine, Paul; Ittmann, Michael

2012-07-15

Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer.

Sex differences in emotional contexts modulation on response inhibition.

PubMed

Ramos-Loyo, Julieta; Angulo-Chavira, Armando; Llamas-Alonso, Luis A; González-Garrido, Andrés A

2016-10-01

The aim of the present study was to explore sex differences in the effects that emotional contexts exert on the temporal course of response inhibition using event-related potentials (ERP). Participants performed a Go-NoGo response inhibition task under 3 context conditions: with 1) neutral background stimuli, and 2) pleasant, and 3) unpleasant emotional contexts. No sex differences were found in relation to accuracy. Women showed higher N2NoGo amplitudes than men in both emotional contexts; whereas during inhibition men tended to show higher P3NoGo amplitudes than women in the unpleasant context. Both groups experienced a relevant effect of the presence of the unpleasant context during inhibition processing, as shown by the enhancement of the N2NoGo amplitudes in frontal regions compared to results from the neutral and pleasant conditions. In addition, women showed differences between the pleasant and unpleasant contexts, with the latter inducing higher amplitude values. Only in men did inhibition accuracy correlate with higher N2NoGo and lower P3NoGo amplitudes in the emotional context conditions. These findings suggest that when an inhibition task is performed in an emotionally-neutral background context no sex differences are observed in either accuracy or ERP components. However, when the emotional context was introduced -especially the unpleasant one- some gender differences did become evident. The higher N2NoGo amplitude at the presence of the unpleasant context may reflect an effect on attention and conflict monitoring. In addition, results suggest that during earlier processing stages, women invested more resources to process inhibition than men. Furthermore, men who invested more neural resources during earlier stages showed better response inhibition than those who did it during later processing stages, more closely-related to cognitive and motor inhibition processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Btk inhibition treats TLR7/IFN driven murine lupus.

PubMed

Bender, Andrew T; Pereira, Albertina; Fu, Kai; Samy, Eileen; Wu, Yin; Liu-Bujalski, Lesley; Caldwell, Richard; Chen, Yi-Ying; Tian, Hui; Morandi, Federica; Head, Jared; Koehler, Ursula; Genest, Melinda; Okitsu, Shinji L; Xu, Daigen; Grenningloh, Roland

2016-03-01

Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors. In vitro studies using primary human macrophages revealed that Btk inhibition can block activation by immune complexes and TLR7 which contributes to tissue damage in SLE. Overall, our results provide translational insight into how Btk inhibition may provide benefit to a variety of SLE patients by affecting both BCR and FcR signaling. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Inhibition of Microorganisms by Topical Anesthetics

PubMed Central

Kleinfeld, Jerome; Ellis, Philip P.

1967-01-01

The effect of various topical anesthetics and their preservatives on the growth of Pseudomonas aeruginosa, Staphyloccoccus albus, and Candida albicans was investigated. The topical anesthetics were proparacaine HCl, tetracaine HCl, cocaine HCl, and benoxinate HCl. The preservatives were chlorobutanol and butyl p-hydroxybenzoate. Proparacaine inhibited C. albicans but not P. aeruginosa or S. albus. All three test organisms were inhibited to varying degrees by tetracaine, benoxinate, cocaine, chlorobutanol, and butyl p-hydroxybenzoate. PMID:16349737

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

Inhibition of vaccinia virus maturation by zinc chloride.

PubMed Central

Katz, E; Margalith, E

1981-01-01

Zinc chloride (0.1 mM) inhibited by 96.4% the growth of vaccinia virus in HeLa cells. Approximately 50% inhibition in formation of particles that sedimented in sucrose gradients similarly to vaccinia virions occurred in the presence of zinc ions. Whereas the synthesis of the viral deoxyribonucleic acid was not affected by zinc chloride, a decrease in the overall synthesis of viral polypeptides and inhibition of the cleavage of precursors to the core polypeptides were observed. Images PMID:7347557

Hili Inhibits HIV Replication in Activated T Cells.

PubMed

Peterlin, B Matija; Liu, Pingyang; Wang, Xiaoyun; Cary, Daniele; Shao, Wei; Leoz, Marie; Hong, Tian; Pan, Tao; Fujinaga, Koh

2017-06-01

P-element-induced wimpy-like (Piwil) proteins restrict the replication of mobile genetic elements in the germ line. They are also expressed in many transformed cell lines. In this study, we discovered that the human Piwil 2 (Hili) protein can also inhibit HIV replication, especially in activated CD4 + T cells that are the preferred target cells for this virus in the infected host. Although resting cells did not express Hili, its expression was rapidly induced following T cell activation. In these cells and transformed cell lines, depletion of Hili increased levels of viral proteins and new viral particles. Further studies revealed that Hili binds to tRNA. Some of the tRNAs represent rare tRNA species, whose codons are overrepresented in the viral genome. Targeting tRNA Arg (UCU) with an antisense oligonucleotide replicated effects of Hili and also inhibited HIV replication. Finally, Hili also inhibited the retrotransposition of the endogenous intracysternal A particle (IAP) by a similar mechanism. Thus, Hili joins a list of host proteins that inhibit the replication of HIV and other mobile genetic elements. IMPORTANCE Piwil proteins inhibit the movement of mobile genetic elements in the germ line. In their absence, sperm does not form and male mice are sterile. This inhibition is thought to occur via small Piwi-interacting RNAs (piRNAs). However, in some species and in human somatic cells, Piwil proteins bind primarily to tRNA. In this report, we demonstrate that human Piwil proteins, especially Hili, not only bind to select tRNA species, including rare tRNAs, but also inhibit HIV replication. Importantly, T cell activation induces the expression of Hili in CD4 + T cells. Since Hili also inhibited the movement of an endogenous retrovirus (IAP), our finding shed new light on this intracellular resistance to exogenous and endogenous retroviruses as well as other mobile genetic elements. Copyright © 2017 American Society for Microbiology.

Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: inhibiting viral replication and decreasing viral entry.

PubMed

Yang, Shu; Xu, Miao; Lee, Emily M; Gorshkov, Kirill; Shiryaev, Sergey A; He, Shihua; Sun, Wei; Cheng, Yu-Shan; Hu, Xin; Tharappel, Anil Mathew; Lu, Billy; Pinto, Antonella; Farhy, Chen; Huang, Chun-Teng; Zhang, Zirui; Zhu, Wenjun; Wu, Yuying; Zhou, Yi; Song, Guang; Zhu, Heng; Shamim, Khalida; Martínez-Romero, Carles; García-Sastre, Adolfo; Preston, Richard A; Jayaweera, Dushyantha T; Huang, Ruili; Huang, Wenwei; Xia, Menghang; Simeonov, Anton; Ming, Guoli; Qiu, Xiangguo; Terskikh, Alexey V; Tang, Hengli; Song, Hongjun; Zheng, Wei

2018-01-01

The re-emergence of Zika virus (ZIKV) and Ebola virus (EBOV) poses serious and continued threats to the global public health. Effective therapeutics for these maladies is an unmet need. Here, we show that emetine, an anti-protozoal agent, potently inhibits ZIKV and EBOV infection with a low nanomolar half maximal inhibitory concentration (IC 50 ) in vitro and potent activity in vivo. Two mechanisms of action for emetine are identified: the inhibition of ZIKV NS5 polymerase activity and disruption of lysosomal function. Emetine also inhibits EBOV entry. Cephaeline, a desmethyl analog of emetine, which may be better tolerated in patients than emetine, exhibits a similar efficacy against both ZIKV and EBOV infections. Hence, emetine and cephaeline offer pharmaceutical therapies against both ZIKV and EBOV infection.

Ciclopirox olamine inhibits mTORC1 signaling by activation of AMPK.

PubMed

Zhou, Hongyu; Shang, Chaowei; Wang, Min; Shen, Tao; Kong, Lingmei; Yu, Chunlei; Ye, Zhennan; Luo, Yan; Liu, Lei; Li, Yan; Huang, Shile

2016-09-15

Ciclopirox olamine (CPX), an off-patent antifungal agent, has recently been identified as a potential anticancer agent. The mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation and survival. Little is known about whether and how CPX executes its anticancer action by inhibiting mTOR. Here we show that CPX inhibited the phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), two downstream effector molecules of mTOR complex 1 (mTORC1), in a spectrum of human tumor cells, indicating that CPX inhibits mTORC1 signaling. Using rhabdomyosarcoma cells as an experimental model, we found that expression of constitutively active mTOR (E2419K) conferred resistance to CPX inhibition of cell proliferation, suggesting that CPX inhibition of mTORC1 contributed to its anticancer effect. In line with this, treatment with CPX inhibited tumor growth and concurrently suppressed mTORC1 signaling in RD xenografts. Mechanistically, CPX inhibition of mTORC1 was neither via inhibition of IGF-I receptor or phosphoinositide 3-kinase (PI3K), nor by activation of phosphatase and tensin homolog (PTEN). Instead, CPX inhibition of mTORC1 was attributed to activation of AMP-activated protein kinase (AMPK)-tuberous sclerosis complexes (TSC)/raptor pathways. This is supported by the findings that CPX activated AMPK; inhibition of AMPK with Compound C or ectopic expression of dominant negative AMPKα partially prevented CPX from inhibiting mTORC1; silencing TSC2 attenuated CPX inhibition of mTORC1; and CPX also increased AMPK-mediated phosphorylation of raptor (S792). Therefore, the results indicate that CPX exerts the anticancer effect by activating AMPK, resulting in inhibition of mTORC1 signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

Chirality Influence of Zaltoprofen Towards UDP-Glucuronosyltransferases (UGTs) Inhibition Potential.

PubMed

Jia, Lin; Hu, Cuimin; Wang, Haina; Liu, Yongzhe; Liu, Xin; Zhang, Yan-Yan; Li, Wei; Wang, Li-Xuan; Cao, Yun-Feng; Fang, Zhong-Ze

2015-06-01

Zaltoprofen (ZLT) is a nonsteroidal antiinflammation drug, and has been clinically employed to treat rheumatoid arthritis, osteoarthritis, and other chronic inflammatory pain conditions. The present study aims to investigate the chirality influence of zaltoprofen towards the inhibition potential towards UDP-glucuronosyltransferases (UGTs) isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation system was employed to investigate the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards UGT isoforms. The inhibition difference capability was observed for the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards UGT1A8 and UGT2B7, but not for other tested UGT isoforms. (R)-zaltoprofen exhibited noncompetitive inhibition towards UGT1A8 and competitive inhibition towards UGT2B7. The inhibition kinetic parameters were calculated to be 35.3 μM and 19.2 μM for UGT1A8 and UGT2B7. (R)-zaltoprofen and (S)-zaltoprofen exhibited a different inhibition type towards UGT1A7. Based on the reported maximum plasma concentration of (R)-zaltoprofen in vivo, a high drug-drug interaction between (R)-zaltoprofen and the drugs mainly undergoing UGT1A7, UGT1A8, and UGT2B7-catalyzed glucuronidation was indicated. © 2015 Wiley Periodicals, Inc.

Inhibition-Based Biomarkers for Autism Spectrum Disorder.

PubMed

Levin, April R; Nelson, Charles A

2015-07-01

Autism spectrum disorder (ASD) is a behaviorally defined and heterogeneous disorder. Biomarkers for ASD offer the opportunity to improve prediction, diagnosis, stratification by severity and subtype, monitoring over time and in response to interventions, and overall understanding of the underlying biology of this disorder. A variety of potential biomarkers, from the level of genes and proteins to network-level interactions, is currently being examined. Many of these biomarkers relate to inhibition, which is of particular interest because in many cases ASD is thought to be a disorder of imbalance between excitation and inhibition. Abnormalities in inhibition at the cellular level lead to emergent properties in networks of neurons. These properties take into account a more complete genetic and cellular background than findings at the level of individual genes or cells, and are able to be measured in live humans, offering additional potential as diagnostic biomarkers and predictors of behaviors. In this review we provide examples of how altered inhibition may inform the search for ASD biomarkers at multiple levels, from genes to cells to networks.

Mirror-touch synaesthesia: Difficulties inhibiting the other.

PubMed

Santiesteban, Idalmis; Bird, Geoffrey; Tew, Oliver; Cioffi, Maria Cristina; Banissy, Michael J

2015-10-01

Individuals with mirror touch synaesthesia (MTS) experience touch on their own body when observing others being touched. A recent account proposes that such rare experiences could be linked to impairment in self-other representations. Here we tested participants with MTS on a battery of social cognition tests and found that compared to non-synaesthete controls, the MTS group showed impairment in imitation-inhibition but not in visual perspective taking or theory of mind. Although all of these socio-cognitive abilities rely on the control of self-other representations, they differ as to whether the self, or the other, should be preferentially represented. For imitation-inhibition, representations of the other should be inhibited and self-representations should be enhanced, whereas the opposite is true for visual perspective taking and theory of mind. These findings suggest that MTS is associated with a specific deficit in inhibiting representation of other individuals and shed light on the fractionability of processes underlying typical social cognition. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cortical organization of inhibition-related functions and modulation by psychopathology

PubMed Central

Warren, Stacie L.; Crocker, Laura D.; Spielberg, Jeffery M.; Engels, Anna S.; Banich, Marie T.; Sutton, Bradley P.; Miller, Gregory A.; Heller, Wendy

2013-01-01

Individual differences in inhibition-related functions have been implicated as risk factors for a broad range of psychopathology, including anxiety and depression. Delineating neural mechanisms of distinct inhibition-related functions may clarify their role in the development and maintenance of psychopathology. The present study tested the hypothesis that activity in common and distinct brain regions would be associated with an ecologically sensitive, self-report measure of inhibition and a laboratory performance measure of prepotent response inhibition. Results indicated that sub-regions of DLPFC distinguished measures of inhibition, whereas left inferior frontal gyrus and bilateral inferior parietal cortex were associated with both types of inhibition. Additionally, co-occurring anxiety and depression modulated neural activity in select brain regions associated with response inhibition. Results imply that specific combinations of anxiety and depression dimensions are associated with failure to implement top-down attentional control as reflected in inefficient recruitment of posterior DLPFC and increased activation in regions associated with threat (MTG) and worry (BA10). Present findings elucidate possible neural mechanisms of interference that could help explain executive control deficits in psychopathology. PMID:23781192

Cortical organization of inhibition-related functions and modulation by psychopathology.

PubMed

Warren, Stacie L; Crocker, Laura D; Spielberg, Jeffery M; Engels, Anna S; Banich, Marie T; Sutton, Bradley P; Miller, Gregory A; Heller, Wendy

2013-01-01

Individual differences in inhibition-related functions have been implicated as risk factors for a broad range of psychopathology, including anxiety and depression. Delineating neural mechanisms of distinct inhibition-related functions may clarify their role in the development and maintenance of psychopathology. The present study tested the hypothesis that activity in common and distinct brain regions would be associated with an ecologically sensitive, self-report measure of inhibition and a laboratory performance measure of prepotent response inhibition. Results indicated that sub-regions of DLPFC distinguished measures of inhibition, whereas left inferior frontal gyrus and bilateral inferior parietal cortex were associated with both types of inhibition. Additionally, co-occurring anxiety and depression modulated neural activity in select brain regions associated with response inhibition. Results imply that specific combinations of anxiety and depression dimensions are associated with failure to implement top-down attentional control as reflected in inefficient recruitment of posterior DLPFC and increased activation in regions associated with threat (MTG) and worry (BA10). Present findings elucidate possible neural mechanisms of interference that could help explain executive control deficits in psychopathology.

Naringin suppresses the development of glioblastoma by inhibiting FAK activity.

PubMed

Li, Jinjiang; Dong, Yushu; Hao, Guangzhi; Wang, Bao; Wang, Julei; Liang, Yong; Liu, Yangyang; Zhen, Endi; Feng, Dayun; Liang, Guobiao

2017-01-01

As the most common and lethal primary malignant brain cancer, glioblastoma is hard to timely diagnose and sensitive therapeutic monitoring. It is essential to develop new and effective drugs for glioblastoma multiform. Naringin belongs to citrus flavonoids and was found to display strong anti-inflammatory, antioxidant and antitumor activities. In this report, we found that naringin can specifically inhibit the kinase activity of FAK and suppress the FAK p-Try397 and its downstream pathway in glioblastoma cells. Our study showed out that naringin can inhibit cell proliferation by inhibiting FAK/cyclin D1 pathway, promote cell apoptosis through influencing FAK/bads pathway, at the same time, it can also inhibit cell invasion and metastasis by inhibiting the FAK/mmps pathway. All these showed that naringin exerts the anti-tumor effects in U87 MG by inhibiting the kinase activity of FAK.

Inhibition of Microbial Lipases by Fatty Acids

PubMed Central

Smith, J. L.; Alford, John A.

1966-01-01

Addition of lard or sodium oleate to the medium used for lipase production by Pseudomonas fragi resulted in a decreased accumulation of lipase in the culture supernatant fluid without affecting cell growth. The production and activity of lipase was inhibited by lard, sodium oleate, and the salts of other unsaturated fatty acids. Some divalent cations, Tweens, lecithin, and bovine serum prevented oleate inhibition, but did not reverse it. Similar inhibitory actions were observed with Geotrichum candidum lipase, but not with a staphylococcal lipase or pancreatic lipase. A protective effect by protein in crude enzyme preparations is indicated. The ability of oleate to lower surface tension does not appear to be related to its ability to inhibit lipase. PMID:5970458

Obligate intracellular bacterium Ehrlichia inhibiting mitochondrial activity

PubMed Central

Liu, Yan; Zhang, Zhikai; Jiang, Yongquan; Zhang, Lihong; Popov, Vsevolod L.; Zhang, Jianzhi; Walker, David H.; Yu, Xue-jie

2010-01-01

Ehrlichia are obligately intracellular bacteria that reside in a vacuole in the cytoplasm of phagocytes. We determined by confocal microscopy the interaction between Ehrlichia and mitochondria in DH82 cells to investigate the mechanism of Ehrlichia survival inside the phagocyte. The most remarkable finding of our study was that Ehrlichia morulae interacted with mitochondria and inhibited mitochondrial metabolism,. We showed that in E. chaffeensis-infected DH82 cells, mitochondria did not incorporate BrdU and transcriptional level of the mitochondrial gene NADPH2 was significantly reduced, indicating the inhibition of mitochondrial metabolism. This study demonstrates that Ehrlichia are able to inhibit mitochondrial activities, and it opens up a new avenue for the study of Ehrlichia pathogenesis. PMID:21070861

"Don׳t" versus "won׳t": principles, mechanisms, and intention in action inhibition.

PubMed

Ridderinkhof, K Richard; van den Wildenberg, Wery P M; Brass, Marcel

2014-12-01

The aim of the present review is to provide a theoretical analysis of the role of intentions in inhibition. We will first outline four dimensions along which inhibition can be categorized: intentionality, timing, specificity, and the nature of the to-be-inhibited action. Next, we relate the concept of inhibition to theories of intentional action. In particular, we integrate ideomotor theory with motor control theories that involve predictive forward modeling of the consequences of one׳s action, and evaluate how the dimensional classification of inhibition fits into such an integrative approach. Furthermore, we will outline testable predictions that derive from this novel hypothesis of ideomotor inhibition. We then discuss the viability of the ideomotor inhibition hypothesis and our classification in view of the available evidence on the neural mechanisms of action inhibition, indicating that sensorimotor and ideomotor inhibition engages largely overlapping networks with additional recruitment of dFMC for ideomotor inhibition. Copyright © 2014 Elsevier Ltd. All rights reserved.

Inhibition: Mental Control Process or Mental Resource?

ERIC Educational Resources Information Center

Im-Bolter, Nancie; Johnson, Janice; Ling, Daphne; Pascual-Leone, Juan

2015-01-01

The current study tested 2 models of inhibition in 45 children with language impairment and 45 children with normally developing language; children were aged 7 to 12 years. Of interest was whether a model of inhibition as a mental-control process (i.e., executive function) or as a mental resource would more accurately reflect the relations among…

Differences between endogenous and exogenous emotion inhibition in the human brain.

PubMed

Kühn, Simone; Haggard, Patrick; Brass, Marcel

2014-05-01

The regulation of emotions is an integral part of our mental health. It has only recently been investigated using brain imaging techniques. In most studies, participants are instructed by a cue to inhibit a specific emotional reaction. The aim of the present study was to investigate the alternative situation where a person decides to inhibit an emotion as an act of endogenous self-control. Healthy participants viewed highly arousing pictures with negative valence. In the endogenous condition, participants could freely choose on each trial to inhibit or feel the emotions elicited by the picture. In an exogenous condition, a visual cue instructed them to either feel or inhibit the emotion elicited by the picture. Participants' subjective ratings of intensity of experienced emotion showed an interaction effect between source of control (endogenous/exogenous) and feel/inhibit based on a stronger modulation between feel and inhibition for the endogenous compared to the exogenous condition. Endogenous inhibition of emotions was associated with dorso-medial prefrontal cortex activation, whereas exogenous inhibition was found associated with lateral prefrontal cortex activation. Thus, the brain regions for both endogenous and exogenous inhibition of emotion are highly similar to those for inhibition of motor actions in Brass and Haggard (J Neurosci 27:9141-9145, 2007), Kühn et al. (Hum Brain Mapp 30:2834-2843, 2009). Functional connectivity analyses showed that dorsofrontomedial cortex exerts greater control onto pre-supplementary motor area during endogenous inhibition compared to endogenous feel. This functional dissociation between an endogenous, fronto-medial and an exogenous, fronto-lateral inhibition centre has important implications for our understanding of emotion regulation in health and psychopathology.

gp-91 mediates histone deacetylase inhibition-induced cardioprotection

PubMed Central

Zhao, Ting C; Zhang, Ling X; Cheng, Guangmao; Liu, Jun T

2010-01-01

We have recently shown that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia and reperfusion (I/R) injury. The mechanism by which HDAC inhibition induces cardioprotection remains unknown. We sought to investigate whether the genetic disruption of gp-91, a subunit of NADPH-oxidase, would mitigate cardioprotection of HDAC inhibition. Wild-type and gp-91−/− mice were treated with a potent inhibitor of HDACs, trichostatin A (TSA, 0.1mg/kg, i.p.). Twenty-four hours later, the perfused hearts were subjected to 30 min of ischemia and 30 min of reperfusion. HDAC inhibition in wild-type mice produced marked improvements in ventricular functional recovery and the reduction of infarct size. TSA-induced cardioprotection was eliminated with genetic deletion of gp91. Notably, Western blot and immunostaining displayed a significant increase in gp-91 in myocardium following HDAC inhibition, which resulted in a mildly subsequent increase in the production of reactive oxygen species (ROS). The pretreatment of H9c2 cardiomyoblasts with TSA (50 nmol/L) decreased cell necrosis and increased viability in response to simulated ischemia (SI), which was abrogated by the transfection of cells with gp-91 siRNA, but not by scrambled siRNA. Furthermore, treatment of PLB-985 gp91+/+cells with TSA increased the resistance to SI, which also diminished with genetic disruption of gp91 in gp91phox-deficient PLB-985 cells. TSA treatment inhibited the increased active caspase-3 in H9c2 cardiomyoblasts and PLB-985 gp91+/+cells exposed to SI, which were prevented by knockdown of gp-91 by siRNA. These results suggest that a cascade consisting of gp-91 and HDAC inhibition plays an essential role in orchestrating the cardioprotective effect. PMID:20433879

Nickel Inhibits Mitochondrial Fatty Acid Oxidation

PubMed Central

Uppala, Radha; McKinney, Richard W.; Brant, Kelly A.; Fabisiak, James P.; Goetzman, Eric S.

2015-01-01

Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation—the pathway by which fatty acids are catabolized for energy—in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with L-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 hr), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. PMID:26051273

Neprilysin inhibition in chronic kidney disease

PubMed Central

Judge, Parminder; Haynes, Richard; Landray, Martin J.; Baigent, Colin

2015-01-01

Despite current practice, patients with chronic kidney disease (CKD) are at increased risk of progression to end-stage renal disease and cardiovascular events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin–angiotensin system (RAS), which could act as a potentially beneficial counter-regulatory system in states of RAS activation such as chronic heart failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn. However, one such agent (omapatrilat) showed promise of NEP/RAS inhibition in treating CKD in animal models, producing greater reductions in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with isolated RAS inhibition. A new class of drug called angiotensin receptor neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown substantial benefits in trials in hypertension and HF. In CKD, HF is common due to a range of mechanisms including hypertension and structural heart disease (including left ventricular hypertrophy), suggesting that ARNi could benefit patients with CKD by both retarding the progression of CKD (hence delaying the need for renal replacement therapy) and reducing the risk of cardiovascular disease. LCZ696 is now being studied in a CKD population. PMID:25140014

Inhibiting Metal Oxide Atomic Layer Deposition: Beyond Zinc Oxide

DOE PAGES

Sampson, Matthew D.; Emery, Jonathan D.; Pellin, Michael J.; ...

2017-04-05

The atomic layer deposition (ALD) of several metal oxides is selectivity inhibited on alkanethiol self-assembled monolayers (SAMs) on Au and the eventual nucleation mechanism is investigated. The inhibition ability of the SAM is significantly improved by the in situ H 2-plasma pretreatment of the Au substrate prior to gas-phase deposition of a long-chain alkanethiol, 1-dodecanethiol (DDT). This more rigorous surface preparation inhibits even aggressive oxide ALD precursors, including trimethylaluminum and water, for at least 20 cycles. We study the effect that ALD precursor purge times, growth temperature, alkanethiol chain length, alkanethiol deposition time, and plasma treatment time have on Almore » 2O 3 ALD inhibition. This is the first example of Al 2O 3 ALD inhibition from a vapor-deposited SAM. Inhibition of Al 2O 3, ZnO, and MnO ALD processes are compared, revealing the versatility of this selective surface treatment. As a result, atomic force microscopy (AFM) and grazing incidence x-ray fluorescence (GIXRF) further reveals insight into the mechanism by which the well-defined surface chemistry of ALD may eventually be circumvented to allow metal oxide nucleation and growth on SAM-modified surfaces.« less

Inhibition of Mycobacterium tuberculosis Methionine Aminopeptidases by Bengamide Derivatives

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

Lu, Jing-Ping; Yuan, Xiu-Hua; Yuan, Hai

Methionine aminopeptidase (MetAP) carries out an essential function of protein N-terminal processing in many bacteria and is a promising target for the development of novel antitubercular agents. Natural bengamides potently inhibit the proliferation of mammalian cells by targeting MetAP enzymes, and the X-ray crystal structure of human type 2 MetAP in complex with a bengamide derivative reveals the key interactions at the active site. By preserving the interactions with the conserved residues inside the binding pocket while exploring the differences between bacterial and human MetAPs around the binding pocket, seven bengamide derivatives were synthesized and evaluated for inhibition of MtMetAP1amore » and MtMetAP1c in different metalloforms, inhibition of M. tuberculosis growth in replicating and non-replicating states, and inhibition of human K562 cell growth. Potent inhibition of MtMetAP1a and MtMetAP1c and modest growth inhibition of M. tuberculosis were observed for some of these derivatives. Crystal structures of MtMetAP1c in complex with two of the derivatives provided valuable structural information for improvement of these inhibitors for potency and selectivity.« less

Cocaine inhibition of nicotinic acetylcholine receptors influences dopamine release

PubMed Central

Acevedo-Rodriguez, Alexandra; Zhang, Lifen; Zhou, Fuwen; Gong, Suzhen; Gu, Howard; De Biasi, Mariella; Zhou, Fu-Ming; Dani, John A.

2014-01-01

Nicotinic acetylcholine receptors (nAChRs) potently regulate dopamine (DA) release in the striatum and alter cocaine's ability to reinforce behaviors. Since cocaine is a weak nAChR inhibitor, we hypothesized that cocaine may alter DA release by inhibiting the nAChRs in DA terminals in the striatum and thus contribute to cocaine's reinforcing properties primarily associated with the inhibition of DA transporters. We found that biologically relevant concentrations of cocaine can mildly inhibit nAChR-mediated currents in midbrain DA neurons and consequently alter DA release in the dorsal and ventral striatum. At very high concentrations, cocaine also inhibits voltage-gated Na channels in DA neurons. Furthermore, our results show that partial inhibition of nAChRs by cocaine reduces evoked DA release. This diminution of DA release via nAChR inhibition more strongly influences release evoked at low or tonic stimulation frequencies than at higher (phasic) stimulation frequencies, particularly in the dorsolateral striatum. This cocaine-induced shift favoring phasic DA release may contribute to the enhanced saliency and motivational value of cocaine-associated memories and behaviors. PMID:25237305

Inhibiting Metal Oxide Atomic Layer Deposition: Beyond Zinc Oxide

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

Sampson, Matthew D.; Emery, Jonathan D.; Pellin, Michael J.

The atomic layer deposition (ALD) of several metal oxides is selectivity inhibited on alkanethiol self-assembled monolayers (SAMs) on Au and the eventual nucleation mechanism is investigated. The inhibition ability of the SAM is significantly improved by the in situ H 2-plasma pretreatment of the Au substrate prior to gas-phase deposition of a long-chain alkanethiol, 1-dodecanethiol (DDT). This more rigorous surface preparation inhibits even aggressive oxide ALD precursors, including trimethylaluminum and water, for at least 20 cycles. We study the effect that ALD precursor purge times, growth temperature, alkanethiol chain length, alkanethiol deposition time, and plasma treatment time have on Almore » 2O 3 ALD inhibition. This is the first example of Al 2O 3 ALD inhibition from a vapor-deposited SAM. Inhibition of Al 2O 3, ZnO, and MnO ALD processes are compared, revealing the versatility of this selective surface treatment. As a result, atomic force microscopy (AFM) and grazing incidence x-ray fluorescence (GIXRF) further reveals insight into the mechanism by which the well-defined surface chemistry of ALD may eventually be circumvented to allow metal oxide nucleation and growth on SAM-modified surfaces.« less

Inhibition of bacterial quorum sensing by vanilla extract.

PubMed

Choo, J H; Rukayadi, Y; Hwang, J-K

2006-06-01

The purpose of this study was to search for a novel quorum sensing inhibitor and analyse its inhibitory activity. Quorum sensing inhibition was monitored using the Tn-5 mutant, Chromobacterium violaceum CV026. Vanilla beans (Vanilla planifolia Andrews) were extracted using 75% (v/v) aqueous methanol and added to C. violaceum CV026 cultures. Inhibitory activity was measured by quantifying violacein production using a spectrophotometer. The results have revealed that vanilla extract significantly reduced violacein production in a concentration-dependent manner, indicating inhibition of quorum sensing. Vanilla, a widely used spice and flavour, can inhibit bacterial quorum sensing. The results suggest that the intake of vanilla-containing food materials might promote human health by inhibiting quorum sensing and preventing bacterial pathogenesis. Further studies are required to isolate specific substances from vanilla extract acting as quorum sensing inhibitors.

Caffeine inhibition of aflatoxin synthesis: probable site of action.

PubMed Central

Buchanan, R L; Lewis, D F

1984-01-01

Aflatoxin production by pregrown cultures of Aspergillus parasiticus was completely inhibited by incorporation of 2 mg of caffeine per ml into the medium. This was accompanied by a decrease in glucose utilization and an inhibition of oxygen uptake and carbon dioxide evolution. Enzyme analyses indicated no significant differences in specific activities on glucose-6-phosphate dehydrogenase, mannitol dehydrogenase, phosphofructokinase, fructose 1,6-diphosphatase, pyruvate kinase, or malate dehydrogenase. Glucose uptake kinetics indicated a linear dose-related inhibition of glucose uptake. It appears likely that caffeine inhibits aflatoxin synthesis by restricting the uptake of carbohydrates which are ultimately used by the mold to synthesize this family of mycotoxins. PMID:6331311

Inhibition of hepatic lipogenesis by 2-tetradecylglycidic acid.

PubMed

McCune, S A; Nomura, T; Harris, R A

1979-10-01

2-Tetradecylglycidic acid (TDGA), a hypoglycemic agent, has been found to be a very effective inhibitor of de novo fatty acid synthesis by isolated hepatocytes. A comparison was made between the effectiveness of TDGA and 5-(tetradecyloxy)-2-furoic acid (TOFA), a hypolipidemic agent, on the metabolic processes of isolated hepatocytes. These compounds are structurally related and both inhibit fatty acid synthesis; however, they have opposite effects from each other on the oxidation and esterification of fatty acids. TDGA inhibits whereas TOFA stimulates fatty acid oxidation. TDGA stimulates whereas TOFA inhibits fatty acid esterification.

Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition.

PubMed

Binion, D G; Otterson, M F; Rafiee, P

2008-11-01

Angiogenesis, the growth of new blood vessels, is a critical homeostatic mechanism which regulates vascular populations in response to physiological requirements and pathophysiological demand, including chronic inflammation and cancer. The importance of angiogenesis in gastrointestinal chronic inflammation and cancer has been defined, as antiangiogenic therapy has demonstrated benefit in models of inflammatory bowel disease and colon cancer treatment. Curcumin is a natural product undergoing evaluation for the treatment of chronic inflammation, including inflammatory bowel disease (IBD). The effect of curcumin on human intestinal angiogenesis is not defined. The antiangiogenic effect of curcumin on in vitro angiogenesis was examined using primary cultures of human intestinal microvascular endothelial cells (HIMECs), stimulated with vascular endothelial growth factor (VEGF). Curcumin inhibited proliferation, cell migration and tube formation in HIMECs induced by VEGF. Activation of HIMECs by VEGF resulted in enhanced expression of cyclo-oxygenase-2 (COX-2) mRNA, protein and prostaglandin E(2) (PGE(2)) production. Pretreatment of HIMECs with 10 microM curcumin as well as 1 microM NS398, a selective inhibitor of COX-2, resulted in inhibition of COX-2 at the mRNA and protein level and PGE(2) production. Similarly COX-2 expression in HIMECs was significantly inhibited by Jun N-terminal kinase (JNK; SP600125) and p38 mitogen-activated protein kinase (MAPK; SB203580) inhibitors and was reduced by p44/42 MAPK inhibitor (PD098059). Taken together, these data demonstrate an important role for COX-2 in the regulation of angiogenesis in HIMECs via MAPKs. Moreover, curcumin inhibits microvascular endothelial cell angiogenesis through inhibition of COX-2 expression and PGE(2) production, suggesting that this natural product possesses antiangiogenic properties, which warrants further investigation as adjuvant treatment of IBD and cancer.

Species-Associated Differences in the Inhibition of Propofol Glucuronidation by Magnolol

PubMed Central

Yang, Lu; Zhu, Liangliang; Ge, Guangbo; Xiao, Ling; Wu, Yan; Liang, Sicheng; Cao, Yunfeng; Yang, Ling; Wang, Dong

2014-01-01

Magnolol, a major active constituent in herbal medicine, potently inhibits propofol glucuronidation in human liver microsomes, with inhibition constants in the nanomolar range. This study was conducted to investigate magnolol-induced inhibition of propofol glucuronidation in liver microsomes from Swiss–Hauschka mice, Sprague–Dawley rats, Chinese Bama pigs, and cynomolgus macaques. Results indicated that magnolol (10 μM) inhibited propofol glucuronidation in liver microsomes from Bama pigs and cynomolgus macaques but not in those from mice or rats. Data from liver microsomes from Bama pigs indicated a competitive inhibition mechanism, with a Ki of 1.7 μM. In contrast to that of pig liver microsomes, the inhibition of microsomes from cynomolgus macaques followed a noncompetitive mechanism, with a Ki of 3.4 μM. In summary, this study indicates that magnolol-induced inhibition of propofol glucuronidation varies substantially among species, and the Ki values determined by using liver microsomes from various experimental animal species far exceed that for human liver microsomes. The inhibition of propofol glucuronidation by magnolol in liver microsomes from all animal species tested was significantly lower than the inhibition previously demonstrated in human liver microsomes. Hepatic microsomes from Swiss–Hauschka mice, Sprague–Dawley rats, Chinese Bama pigs, and cynomolgus macaques are not effective models of the inhibition of glucuronidation induced by magnolol in humans. PMID:25199099

Species-associated differences in the inhibition of propofol glucuronidation by magnolol.

PubMed

Yang, Lu; Zhu, Liangliang; Ge, Guangbo; Xiao, Ling; Wu, Yan; Liang, Sicheng; Cao, Yunfeng; Yang, Ling; Wang, Dong

2014-07-01

Magnolol, a major active constituent in herbal medicine, potently inhibits propofol glucuronidation in human liver microsomes, with inhibition constants in the nanomolar range. This study was conducted to investigate magnolol-induced inhibition of propofol glucuronidation in liver microsomes from Swiss-Hauschka mice, Sprague-Dawley rats, Chinese Bama pigs, and cynomolgus macaques. Results indicated that magnolol (10 μM) inhibited propofol glucuronidation in liver microsomes from Bama pigs and cynomolgus macaques but not in those from mice or rats. Data from liver microsomes from Bama pigs indicated a competitive inhibition mechanism, with a Ki of 1.7 μM. In contrast to that of pig liver microsomes, the inhibition of microsomes from cynomolgus macaques followed a noncompetitive mechanism, with a Ki of 3.4 μM. In summary, this study indicates that magnolol-induced inhibition of propofol glucuronidation varies substantially among species, and the Ki values determined by using liver microsomes from various experimental animal species far exceed that for human liver microsomes. The inhibition of propofol glucuronidation by magnolol in liver microsomes from all animal species tested was significantly lower than the inhibition previously demonstrated in human liver microsomes. Hepatic microsomes from Swiss-Hauschka mice, Sprague-Dawley rats, Chinese Bama pigs, and cynomolgus macaques are not effective models of the inhibition of glucuronidation induced by magnolol in humans.

Inhibition of MAO by fractions and constituents of hypericum extract.

PubMed

Bladt, S; Wagner, H

1994-10-01

The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as pure substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition.

High molecular weight polysaccharide that binds and inhibits virus

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

Konowalchuk, Thomas W.; Konowalchuk, Jack

This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods of inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further includes methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

High molecular weight polysaccharide that binds and inhibits virus

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

Konowalchuk, Thomas W

This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods on inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells.

PubMed

Ge, Peng-Fei; Zhang, Ji-Zhou; Wang, Xiao-Fei; Meng, Fan-Kai; Li, Wen-Chen; Luan, Yong-Xin; Ling, Feng; Luo, Yi-Nan

2009-07-01

The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Recent studies suggest that proteasome inhibitors may reduce tumor growth and activate autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the effect of autophagy on the destiny of glioma cells remains unclear. In this study, we sought to investigate whether inhibition of the proteasome can induce autophagy and the effects of autophagy on the fate of human SHG-44 glioma cells. The proteasome inhibitor MG-132 was used to induce autophagy in SHG-44 glioma cells, and the effect of autophagy on the survival of SHG-44 glioma cells was investigated using an autophagy inhibitor 3-MA. Cell viability was measured by MTT assay. Apoptosis and cell cycle were detected by flow cytometry. The expression of autophagy related proteins was determined by Western blot. MG-132 inhibited cell proliferation, induced cell death and cell cycle arrest at G(2)/M phase, and activated autophagy in SHG-44 glioma cells. The expression of autophagy-related Beclin-1 and LC3-I was significantly up-regulated and part of LC3-I was converted into LC3-II. However, when SHG-44 glioma cells were co-treated with MG-132 and 3-MA, the cells became less viable, but cell death and cell numbers at G(2)/M phase increased. Moreover, the accumulation of acidic vesicular organelles was decreased, the expression of Beclin-1 and LC3 was significantly down-regulated and the conversion of LC3-II from LC3-I was also inhibited. Inhibition of the proteasome can induce autophagy in human SHG-44 glioma cells, and inhibition of autophagy increases cell death. This discovery may shed new light on the effect of autophagy on modulating the fate of SHG-44 glioma cells.Acta Pharmacologica Sinica (2009) 30: 1046-1052; doi: 10.1038/aps.2009.71.

The membrane effects, and sensitivity to strychnine, of neural inhibition of the Mauthner cell, and its inhibition by glycine and GABA

PubMed Central

Diamond, J.; Roper, S.; Yasargil, G. M.

1973-01-01

1. Anionic conductance changes in Mauthner neurones of goldfish were measured during synaptically evoked inhibition and inhibition caused by iontophoretic application of the putative inhibitory transmitters glycine and γ-aminobutyric acid (GABA). 2. The effects of either amino acid were indistinguishable from those of the neural inhibitory transmitter(s). The membrane permeability during the neural or drug response was increased to Br-, Cl-, I-, SCN-, NO3-, ClO3-, and formate (HCOO-), but not to HCO3-, BrO3-, IO3-, SO4-, HPO4-, H2PO4-, acetate and citrate. 3. Strychnine was injected intramuscularly, iontophoretically, or applied topically to the exposed brain in order to compare quantitatively its ability to prevent inhibition evoked by synaptic activation and by pharmacological means. Inhibitions were measured by the increase in membrane conductance. 4. Strychnine, at concentrations just adequate to block completely the late collateral inhibition (LCI) and crossed VIII nerve inhibition, had little effect on the pharmacological inhibition caused by glycine, and sometimes there was no detectable effect at all. In one experiment even a local iontophoretic application of strychnine in a sufficient dose to diffuse over the cell and block the LCI almost completely, merely halved the effect of a small dose of glycine applied to the same localized region of the membrane. 5. Higher concentrations of strychnine than those necessary to block synaptically evoked inhibition would reduce the effect of glycine but not that of GABA. The evidence indicated that any apparent effect of strychnine upon GABA could be explained by displacement of the GABA-containing iontophoretic pipette. 6. The glycine-blocking action of iontophoretic pulses of strychnine was of relatively very slow onset and long duration compared to the effects of pulses of glycine and GABA. 7. These findings can be interpreted as either (1) strychnine has a presynaptic action, preventing the release of inhibitory

AOP description: Acetylcholinesterase inhibition

EPA Science Inventory

This adverse outcome pathway (AOP) leverages existing knowledge in the open literature to describe the linkage between inhibition of acetylcholinesterase (AChE) and the subsequent mortality resulting from impacts at cholinergic receptors. The AOP takes a chemical category approa...

Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces atresia, and inhibits steroid hormone production in cultured mouse antral follicles

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

Hannon, Patrick R., E-mail: phannon2@illinois.edu; Brannick, Katherine E., E-mail: kbran@illinois.edu; Wang, Wei, E-mail: Wei.Wang2@covance.com

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental toxicant found in consumer products that causes ovarian toxicity. Antral follicles are the functional ovarian units and must undergo growth, survival from atresia, and proper regulation of steroidogenesis to ovulate and produce hormones. Previous studies have determined that DEHP inhibits antral follicle growth and decreases estradiol levels in vitro; however, the mechanism by which DEHP elicits these effects is unknown. The present study tested the hypothesis that DEHP directly alters regulators of the cell cycle, apoptosis, and steroidogenesis to inhibit antral follicle functionality. Antral follicles from adult CD-1 mice were cultured with vehiclemore » control or DEHP (1–100 μg/ml) for 24–96 h to establish the temporal effects of DEHP on the follicle. Following 24–96 h of culture, antral follicles were subjected to gene expression analysis, and media were subjected to measurements of hormone levels. DEHP increased the mRNA levels of cyclin D2, cyclin dependent kinase 4, cyclin E1, cyclin A2, and cyclin B1 and decreased the levels of cyclin-dependent kinase inhibitor 1A prior to growth inhibition. Additionally, DEHP increased the mRNA levels of BCL2-associated agonist of cell death, BCL2-associated X protein, BCL2-related ovarian killer protein, B-cell leukemia/lymphoma 2, and Bcl2-like 10, leading to an increase in atresia. Further, DEHP decreased the levels of progesterone, androstenedione, and testosterone prior to the decrease in estradiol levels, with decreased mRNA levels of side-chain cleavage, 17α-hydroxylase-17,20-desmolase, 17β-hydroxysteroid dehydrogenase, and aromatase. Collectively, DEHP directly alters antral follicle functionality by inhibiting growth, inducing atresia, and inhibiting steroidogenesis. - Highlights: • DEHP inhibits antral follicle growth by dysregulating cell cycle regulators. • DEHP induces antral follicle atresia by dysregulating apoptosis regulators

Urea inhibits NaK2Cl cotransport in human erythrocytes.

PubMed Central

Lim, J; Gasson, C; Kaji, D M

1995-01-01

We examined the effect of urea on NaK2Cl cotransport in human erythrocytes. In erythrocytes from nine normal subjects, the addition of 45 mM urea, a concentration commonly encountered in uremic subjects, inhibited NaK2Cl cotransport by 33 +/- 7%. Urea inhibited NaK2Cl cotransport reversibly, and in a concentration-dependent fashion with half-maximal inhibition at 63 +/- 10 mM. Acute cell shrinkage increased, and acute cell swelling decreased NaK2Cl cotransport in human erythrocytes. Okadaic acid (OA), a specific inhibitor of protein phosphatase 1 and 2A, increased NaK2Cl cotransport by nearly 80%, suggesting an important role for these phosphatases in the regulation of NaK2Cl cotransport. Urea inhibited bumetanide-sensitive K influx even when protein phosphatases were inhibited with OA, suggesting that urea acted by inhibiting a kinase. In cells subjected to shrinking and OA pretreatment, maneuvers expected to increase the net phosphorylation, urea inhibited cotransport only minimally, suggesting that urea acted by causing a net dephosphorylation of the cotransport protein, or some key regulatory protein. The finding that concentrations of urea found in uremic subjects inhibited NaK2Cl cotransport, a widespread transport pathway with important physiological functions, suggests that urea is not only a marker for accumulation of other uremic toxins, but may be a significant uremic toxin itself. PMID:7593597

Collective and single cell behavior in epithelial contact inhibition.

PubMed

Puliafito, Alberto; Hufnagel, Lars; Neveu, Pierre; Streichan, Sebastian; Sigal, Alex; Fygenson, D Kuchnir; Shraiman, Boris I

2012-01-17

Control of cell proliferation is a fundamental aspect of tissue physiology central to morphogenesis, wound healing, and cancer. Although many of the molecular genetic factors are now known, the system level regulation of growth is still poorly understood. A simple form of inhibition of cell proliferation is encountered in vitro in normally differentiating epithelial cell cultures and is known as "contact inhibition." The study presented here provides a quantitative characterization of contact inhibition dynamics on tissue-wide and single cell levels. Using long-term tracking of cultured Madin-Darby canine kidney cells we demonstrate that inhibition of cell division in a confluent monolayer follows inhibition of cell motility and sets in when mechanical constraint on local expansion causes divisions to reduce cell area. We quantify cell motility and cell cycle statistics in the low density confluent regime and their change across the transition to epithelial morphology which occurs with increasing cell density. We then study the dynamics of cell area distribution arising through reductive division, determine the average mitotic rate as a function of cell size, and demonstrate that complete arrest of mitosis occurs when cell area falls below a critical value. We also present a simple computational model of growth mechanics which captures all aspects of the observed behavior. Our measurements and analysis show that contact inhibition is a consequence of mechanical interaction and constraint rather than interfacial contact alone, and define quantitative phenotypes that can guide future studies of molecular mechanisms underlying contact inhibition.

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.

Momilactone B Inhibits Ketosis In Vitro by Regulating the ANGPTL3-LPL Pathway and Inhibiting HMGCS2.

PubMed

Kang, Dong Young; S P, Nipin; Darvin, Pramod; Joung, Youn Hee; Byun, Hyo Joo; Do, Chang Hee; Park, Kyung Do; Park, Mi Na; Cho, Kwang Hyun; Yang, Young Mok

2017-07-03

Ketogenesis is the production of ketone bodies, which provide energy when the body lacks glucose. Under ketogenic conditions, the body switches from primarily carbohydrate to fat metabolism to maintain energy balance. However, accumulation of high levels of ketone bodies in the blood results in ketosis. Treating ketosis with natural substances is preferable, because they are unlikely to cause side-effects. Momilactone B is an active compound isolated from Korean rice. Based on previous studies, we hypothesized that momilactone B could inhibit ketosis. We constructed an in vitro ketosis model by glucose starvation. We used this model to test the anti-ketosis effects of momilactone B. A primary target for treating ketosis is angiopoietin-like-3 (ANGPTL3), which modulates lipoprotein metabolism by inhibiting lipoprotein lipase (LPL), a multifunctional enzyme that breaks down stored fat to produce triglycerides. We showed that momilactone B could regulate the ANGPTL3-LPL pathway. However, a strong anti-ketosis candidate drug should also inhibit ketogenesis. Ketogenesis can be suppressed by inhibiting the expression of 3-hydroxy-3-methylglutaryl-CoA synthase-2 (HMGCS2), a mitochondrial enzyme that converts acetyl-CoA to ketone bodies. We found that momilactone B suppressed the expression of HMGCS2 through the increased expression of STAT5b. We also elucidated the relationship of STAT5b to ANGPTL3 and LPL expression.

Influence of supraliminal reward information on unconsciously triggered response inhibition.

PubMed

Diao, Liuting; Ding, Cody; Qi, Senqing; Zeng, Qinghong; Huang, Bo; Xu, Mengsi; Fan, Lingxia; Yang, Dong

2014-01-01

Although executive functions (e.g., response inhibition) are often thought to interact consciously with reward, recent studies have demonstrated that they can also be triggered by unconscious stimuli. Further research has suggested a close relationship between consciously and unconsciously triggered response inhibition. To date, however, the effect of reward on unconsciously triggered response inhibition has not been explored. To address this issue, participants in this study performed runs of a modified Go/No-Go task during which they were exposed to both high and low value monetary rewards presented both supraliminally and subliminally. Participants were informed that they would earn the reward displayed if they responded correctly to each trial of the run. According to the results, when rewards were presented supraliminally, a greater unconsciously triggered response inhibition was observed for high-value rewards than for low-value rewards. In contrast, when rewards were presented subliminally, no enhanced unconsciously triggered response inhibition was observed. Results revealed that supraliminal and subliminal rewards have distinct effects on unconsciously triggered response inhibition. These findings have important implications for extending our understanding of the relationship between reward and response inhibition.

Methylene Blue Inhibits Caspases by Oxidation of the Catalytic Cysteine.

PubMed

Pakavathkumar, Prateep; Sharma, Gyanesh; Kaushal, Vikas; Foveau, Bénédicte; LeBlanc, Andrea C

2015-09-24

Methylene blue, currently in phase 3 clinical trials against Alzheimer Disease, disaggregates the Tau protein of neurofibrillary tangles by oxidizing specific cysteine residues. Here, we investigated if methylene blue can inhibit caspases via the oxidation of their active site cysteine. Methylene blue, and derivatives, azure A and azure B competitively inhibited recombinant Caspase-6 (Casp6), and inhibited Casp6 activity in transfected human colon carcinoma cells and in serum-deprived primary human neuron cultures. Methylene blue also inhibited recombinant Casp1 and Casp3. Furthermore, methylene blue inhibited Casp3 activity in an acute mouse model of liver toxicity. Mass spectrometry confirmed methylene blue and azure B oxidation of the catalytic Cys163 cysteine of Casp6. Together, these results show a novel inhibitory mechanism of caspases via sulfenation of the active site cysteine. These results indicate that methylene blue or its derivatives could (1) have an additional effect against Alzheimer Disease by inhibiting brain caspase activity, (2) be used as a drug to prevent caspase activation in other conditions, and (3) predispose chronically treated individuals to cancer via the inhibition of caspases.

Methylene Blue Inhibits Caspases by Oxidation of the Catalytic Cysteine

PubMed Central

Pakavathkumar, Prateep; Sharma, Gyanesh; Kaushal, Vikas; Foveau, Bénédicte; LeBlanc, Andrea C.

2015-01-01

Methylene blue, currently in phase 3 clinical trials against Alzheimer Disease, disaggregates the Tau protein of neurofibrillary tangles by oxidizing specific cysteine residues. Here, we investigated if methylene blue can inhibit caspases via the oxidation of their active site cysteine. Methylene blue, and derivatives, azure A and azure B competitively inhibited recombinant Caspase-6 (Casp6), and inhibited Casp6 activity in transfected human colon carcinoma cells and in serum-deprived primary human neuron cultures. Methylene blue also inhibited recombinant Casp1 and Casp3. Furthermore, methylene blue inhibited Casp3 activity in an acute mouse model of liver toxicity. Mass spectrometry confirmed methylene blue and azure B oxidation of the catalytic Cys163 cysteine of Casp6. Together, these results show a novel inhibitory mechanism of caspases via sulfenation of the active site cysteine. These results indicate that methylene blue or its derivatives could (1) have an additional effect against Alzheimer Disease by inhibiting brain caspase activity, (2) be used as a drug to prevent caspase activation in other conditions, and (3) predispose chronically treated individuals to cancer via the inhibition of caspases. PMID:26400108

Influence of Supraliminal Reward Information on Unconsciously Triggered Response Inhibition

PubMed Central

Diao, Liuting; Ding, Cody; Qi, Senqing; Zeng, Qinghong; Huang, Bo; Xu, Mengsi; Fan, Lingxia; Yang, Dong

2014-01-01

Although executive functions (e.g., response inhibition) are often thought to interact consciously with reward, recent studies have demonstrated that they can also be triggered by unconscious stimuli. Further research has suggested a close relationship between consciously and unconsciously triggered response inhibition. To date, however, the effect of reward on unconsciously triggered response inhibition has not been explored. To address this issue, participants in this study performed runs of a modified Go/No-Go task during which they were exposed to both high and low value monetary rewards presented both supraliminally and subliminally. Participants were informed that they would earn the reward displayed if they responded correctly to each trial of the run. According to the results, when rewards were presented supraliminally, a greater unconsciously triggered response inhibition was observed for high-value rewards than for low-value rewards. In contrast, when rewards were presented subliminally, no enhanced unconsciously triggered response inhibition was observed. Results revealed that supraliminal and subliminal rewards have distinct effects on unconsciously triggered response inhibition. These findings have important implications for extending our understanding of the relationship between reward and response inhibition. PMID:25268227

Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices.

PubMed

de Diego, Carlos; González-Torres, Luis; Núñez, José María; Centurión Inda, Raúl; Martin-Langerwerf, David A; Sangio, Antonio D; Chochowski, Piotr; Casasnovas, Pilar; Blazquéz, Julio C; Almendral, Jesús

2018-03-01

Angiotensin-neprilysin inhibition compared to angiotensin inhibition decreased sudden cardiac death in patients with reduced ejection fraction heart failure (rEFHF). The precise mechanism remains unclear. The purpose of this study was to explore the effect of angiotensin-neprilysin inhibition on ventricular arrhythmias compared to angiotensin inhibition in rEFHF patients with an implantable cardioverter-defibrillator (ICD) and remote monitoring. We prospectively included 120 patients with ICD and (1) New York Heart Association functional class ≥II; (2) left ventricular ejection fraction ≤40%; and (3) remote monitoring. For 9 months, patients received 100% angiotensin inhibition with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), beta-blockers, and mineraloid antagonist. Subsequently, ACEi or ARB was changed to sacubitril-valsartan in all patients, who were followed for 9 months. Appropriate shocks, nonsustained ventricular tachycardia (NSVT), premature ventricular contraction (PVC) burden, and biventricular pacing percentage were analyzed. Patients were an average age of 69 ± 8 years and had mean left ventricular ejection fraction of 30.4% ± 4% (82% ischemic). Use of beta-blockers (98%), mineraloid antagonist (97%) and antiarrhythmic drugs was similar before and after sacubitril-valsartan. Sacubitril-valsartan significantly decreased NSVT episodes (5.4 ± 0.5 vs 15 ± 1.7 in angiotensin inhibition; P <.002), sustained ventricular tachycardia, and appropriate ICD shocks (0.8% vs 6.7% in angiotensin inhibition; P <.02). PVCs per hour decreased after sacubitril-valsartan (33 ± 12 vs 78 ± 15 in angiotensin inhibition; P <.0003) and was associated with increased biventricular pacing percentage (from 95% ± 6% to 98.8% ± 1.3%; P <.02). Angiotensin-neprilysin inhibition decreased ventricular arrhythmias and appropriate ICD shocks in rEFHF patients under home monitoring compared to angiotensin inhibition. Copyright © 2017

Input-Specific NMDAR-Dependent Potentiation of Dendritic GABAergic Inhibition.

PubMed

Chiu, Chiayu Q; Martenson, James S; Yamazaki, Maya; Natsume, Rie; Sakimura, Kenji; Tomita, Susumu; Tavalin, Steven J; Higley, Michael J

2018-01-17

Preservation of a balance between synaptic excitation and inhibition is critical for normal brain function. A number of homeostatic cellular mechanisms have been suggested to play a role in maintaining this balance, including long-term plasticity of GABAergic inhibitory synapses. Many previous studies have demonstrated a coupling of postsynaptic spiking with modification of perisomatic inhibition. Here, we demonstrate that activation of NMDA-type glutamate receptors leads to input-specific long-term potentiation of dendritic inhibition mediated by somatostatin-expressing interneurons. This form of plasticity is expressed postsynaptically and requires both CaMKIIα and the β2 subunit of the GABA-A receptor. Importantly, this process may function to preserve dendritic inhibition, as genetic deletion of NMDAR signaling results in a selective weakening of dendritic inhibition. Overall, our results reveal a new mechanism for linking excitatory and inhibitory input in neuronal dendrites and provide novel insight into the homeostatic regulation of synaptic transmission in cortical circuits. Copyright © 2017 Elsevier Inc. All rights reserved.

Inhibition of cyclooxygenase-independent platelet aggregation by sodium salicylate.

PubMed

Violi, F; Alessandri, C; Praticò, D; Guzzo, A; Ghiselli, A; Balsano, F

1989-06-15

The effect of acetylsalicylic acid (ASA) on platelet aggregation (PA) and thromboxane A2 (TxA2) formation was investigated in vitro and ex vivo after 1 g or 300 mg ASA administration to healthy subjects. 50-100 microM ASA inhibited PA by single aggregating agent such as platelet aggregating factor (PAF) or epinephrine and reduced to less than or equal to 5% of control platelet TxB2 formation, but did not influence PA by epinephrine plus PAF. The latter was inhibited by increasing ASA concentration. In samples incubated with 100 microM ASA and stimulated with epinephrine plus PAF, PA could be inhibited by the addition of 100-300 microM sodium salicylate. After 300 mg-1 g ASA administration to healthy subjects, the inhibition of PA by epinephrine plus PAF was more marked by highest doses of ASA. This study suggests that aspirin inhibits PA with a cyclooxygenase-independent mechanism; this effect is mediated, at least in vitro, by salicylic acid.

The Effectiveness of Reward and Punishment Contingencies on Response Inhibition

ERIC Educational Resources Information Center

Costantini, Arthur F.; Hoving, Kenneth L.

1973-01-01

The relative effectiveness of reward and punishment on the development of response inhibition was evaluated developmentally with kindergarteners and second graders. Removal of positive reinforcers was apparently more effective than reward in producing inhibiting at both age levels. Transfer of inhibition training was also evaluated. (DP)

Magnolol inhibits LPS-induced inflammatory response in uterine epithelial cells : magnolol inhibits LPS-induced inflammatory response.

PubMed

Luo, Jia; Xu, Yanwen; Zhang, Minfang; Gao, Ling; Fang, Cong; Zhou, Canquan

2013-10-01

Endometritis is an inflammation of the uterine lining that is commonly initiated at parturition. The uterine epithelial cells play an important role in defending against invading pathogens. Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been shown to have anti-inflammatory effects. The aim of this study was to investigate the anti-inflammatory effect of magnolol in modifying lipopolysaccharide (LPS)-induced signal pathways in mouse uterine epithelial cells. We found that magnolol inhibited TNF-α and IL-6 production in LPS-stimulated mouse uterine epithelial cells. We also found that magnolol inhibited LPS-induced NF-κB activation, IκBα degradation, phosphorylation of ERK, JNK, and P38. Furthermore, magnolol could significantly inhibit the expression of TLR4 stimulating by LPS. These results suggest that magnolol exerts an anti-inflammatory property by downregulating the expression of TLR4 upregulated by LPS, thereby attenuating TLR4-mediated NF-κB and MAPK signaling and the release of pro-inflammatory cytokines. These findings suggest that magnolol may be a therapeutic agent against endometritis.

Method for inhibiting oxidation of metal sulfide-containing material

DOEpatents

Elsetinow, Alicia; Borda, Michael J.; Schoonen, Martin A.; Strongin, Daniel R.

2006-12-26

The present invention provides means for inhibiting the oxidation of a metal sulfide-containing material, such as ore mine waste rock or metal sulfide taiulings, by coating the metal sulfide-containing material with an oxidation-inhibiting two-tail lipid coating (12) thereon, thereby inhibiting oxidation of the metal sulfide-containing material in acid mine drainage conditions. The lipids may be selected from phospholipids, sphingolipids, glycolipids and combinations thereof.

Impaired face recognition is associated with social inhibition

PubMed Central

Avery, Suzanne N; VanDerKlok, Ross M; Heckers, Stephan; Blackford, Jennifer U

2016-01-01

Face recognition is fundamental to successful social interaction. Individuals with deficits in face recognition are likely to have social functioning impairments that may lead to heightened risk for social anxiety. A critical component of social interaction is how quickly a face is learned during initial exposure to a new individual. Here, we used a novel Repeated Faces task to assess how quickly memory for faces is established. Face recognition was measured over multiple exposures in 52 young adults ranging from low to high in social inhibition, a core dimension of social anxiety. High social inhibition was associated with a smaller slope of change in recognition memory over repeated face exposure, indicating participants with higher social inhibition showed smaller improvements in recognition memory after seeing faces multiple times. We propose that impaired face learning is an important mechanism underlying social inhibition and may contribute to, or maintain, social anxiety. PMID:26776300

Threat interferes with response inhibition.

PubMed

Hartikainen, Kaisa M; Siiskonen, Anna R; Ogawa, Keith H

2012-05-09

A potential threat, such as a spider, captures attention and engages executive functions to adjust ongoing behavior and avoid danger. We and many others have reported slowed responses to neutral targets in the context of emotional distractors. This behavioral slowing has been explained in the framework of attentional competition for limited resources with emotional stimuli prioritized. Alternatively, slowed performance could reflect the activation of avoidance/freezing-type motor behaviors associated with threat. Although the interaction of attention and emotion has been widely studied, little is known on the interaction between emotion and executive functions. We studied how threat-related stimuli (spiders) interact with executive performance and whether the interaction profile fits with a resource competition model or avoidance/freezing-type motor behaviors. Twenty-one young healthy individuals performed a Go-NoGo visual discrimination reaction time (RT) task engaging several executive functions with threat-related and emotionally neutral distractors. The threat-related distractors had no effect on the RT or the error rate in the Go trials. The NoGo error rate, reflecting failure in response inhibition, increased significantly because of threat-related distractors in contrast to neutral distractors, P less than 0.05. Thus, threat-related distractors temporarily impaired response inhibition. Threat-related distractors associated with increased commission errors and no effect on RT does not suggest engagement of avoidance/freezing-type motor behaviors. The results fit in the framework of the resource competition model. A potential threat calls for evaluation of affective significance as well as inhibition of undue emotional reactivity. We suggest that these functions tax executive resources and may render other executive functions, such as response inhibition, temporarily compromised when the demands for resources exceed availability.

Evaluation of alpha- amylase inhibition by Urtica dioica and Juglans regia extracts.

PubMed

Rahimzadeh, Mahsa; Jahanshahi, Samaneh; Moein, Soheila; Moein, Mahmood Reza

2014-06-01

One strategy for the treatment of diabetes is inhibition of pancreatic α- amylase. Plants contains different chemical constituents with potential for inhibition of α-amylase and hence maybe used as therapeutic. Urtica dioica and Juglans regia Linn were tested for α-amylase inhibition. Different concentrations of leaf aqueous extracts were incubated with enzyme substrate solution and the activity of enzyme was measured. For determination of the type of inhibition, Dixon plot was depicted. Acarbose was used as the standard inhibitor. Both plant extracts showed time and concentration dependent inhibition of α-amylase. 60% inhibition was seen with 2 mg/ml of U. dioica and 0.4 mg/ml of J. regia aqueous extract. Dixon plots revealed the type of α-amylase inhibition by these two extracts as competitive inhibition. Determination of the type of α-amylase inhibition by these plant extracts could provide by successful use of plant chemicals as drug targets.

Evaluation of alpha- amylase inhibition by Urtica dioica and Juglans regia extracts

PubMed Central

Rahimzadeh, Mahsa; Jahanshahi, Samaneh; Moein, Soheila; Moein, Mahmood Reza

2014-01-01

Objective(s): One strategy for the treatment of diabetes is inhibition of pancreatic α- amylase. Plants contains different chemical constituents with potential for inhibition of α-amylase and hence maybe used as therapeutic. Materials and Methods: Urtica dioica and Juglans regia Linn were tested for α-amylase inhibition. Different concentrations of leaf aqueous extracts were incubated with enzyme substrate solution and the activity of enzyme was measured. For determination of the type of inhibition, Dixon plot was depicted. Acarbose was used as the standard inhibitor. Results: Both plant extracts showed time and concentration dependent inhibition of α-amylase. 60% inhibition was seen with 2 mg/ml of U. dioica and 0.4 mg/ml of J. regia aqueous extract. Dixon plots revealed the type of α-amylase inhibition by these two extracts as competitive inhibition. Conclusion: Determination of the type of α-amylase inhibition by these plant extracts could provide by successful use of plant chemicals as drug targets. PMID:25140210

Plumbagin inhibits cytokinesis in Bacillus subtilis by inhibiting FtsZ assembly--a mechanistic study of its antibacterial activity.

PubMed

Bhattacharya, Anusri; Jindal, Bhavya; Singh, Parminder; Datta, Anindya; Panda, Dulal

2013-09-01

The assembly of FtsZ plays a central role in construction of the cytokinetic Z-ring that orchestrates bacterial cell division. A naturally occurring naphthoquinone, plumbagin, is known to exhibit antibacterial properties against several types of bacteria. In this study, plumbagin was found to perturb formation of the Z-ring in Bacillus subtilis 168 cells and to cause elongation of these cells without an apparent effect on nucleoid segregation, indicating that it may inhibit FtsZ assembly. Furthermore, it bound to purified B. subtilis FtsZ (BsFtsZ) with a dissociation constant of 20.7 ± 5.6 μM, and inhibited the assembly and GTPase activity of BsFtsZ in vitro. Interestingly, plumbagin did not inhibit either the assembly or GTPase activity of Escherichia coli FtsZ (EcFtsZ) in vitro. Using docking analysis, a putative plumbagin-binding site on BsFtsZ was identified, and the analysis indicated that hydrophobic interactions and hydrogen bonds predominate. Based on the in silico analysis, two variants of BsFtsZ, namely D199A and V307R, were constructed to explore the binding interaction of plumbagin and BsFtsZ. The effects of plumbagin on the assembly and GTPase activity of the variant BsFtsZ proteins in vitro indicated that the residues D199 and V307 may be involved in the binding of plumbagin to BsFtsZ. The results suggest that plumbagin inhibits bacterial proliferation by inhibiting the assembly of FtsZ, and provide insight into the binding site of plumbagin on BsFtsZ, which may help in the design of potent FtsZ-targeted antibacterial agents. © 2013 FEBS.

Comparing Context Specificity of Extinction and Latent Inhibition

PubMed Central

Miller, Ralph R.; Laborda, Mario A.; Polack, Cody W.; Miguez, Gonzalo

2015-01-01

Exposure to a cue alone either before (i.e., latent inhibition treatment) or after (i.e., extinction) the cue is paired with an unconditioned stimulus (US) results in attenuated conditioned responding to the cue. Here we report two experiments in which potential parallels between the context specificity of the effects of extinction and latent inhibition treatments were directly compared in a lick suppression preparation with rats. The reversed ordering of conditioning and nonreinforcement in extinction and latent inhibition designs allowed us to examine the effect of training order on the context specificity of what is learned given phasic reinforcement and nonreinforcement of a target cue. Experiment 1 found that when CS conditioning and CS nonreinforcement were administered in the same context, both extinction and latent inhibition treatments had reduced impact on test performance relative to excitatory conditioning when testing occurred outside the treatment context. Similarly, Experiment 2 found that when conditioning was administered in one context and nonreinforcement was administered in a second context, the effects of both extinction and latent inhibition treatments were attenuated when testing occurred in a neutral context relative to the context in which the CS was nonreinforced. The observed context specificity of extinction and latent inhibition treatments have both been previously reported, but not in a single experiment under otherwise identical conditions. The results of the two experiments convergently suggest that memory of nonreinforcement becomes context dependent after a cue is both reinforced and nonreinforced independent of the order of training. PMID:26100525

Inhibition of trypanosomal cysteine proteinases by their propeptides.

PubMed

Lalmanach, G; Lecaille, F; Chagas, J R; Authié, E; Scharfstein, J; Juliano, M A; Gauthier, F

1998-09-25

The ability of the prodomains of trypanosomal cysteine proteinases to inhibit their active form was studied using a set of 23 overlapping 15-mer peptides covering the whole prosequence of congopain, the major cysteine proteinase of Trypanosoma congolense. Three consecutive peptides with a common 5-mer sequence YHNGA were competitive inhibitors of congopain. A shorter synthetic peptide consisting of this 5-mer sequence flanked by two Ala residues (AYHNGAA) also inhibited purified congopain. No residue critical for inhibition was identified in this sequence, but a significant improvement in Ki value was obtained upon N-terminal elongation. Procongopain-derived peptides did not inhibit lysosomal cathepsins B and L but did inhibit native cruzipain (from Dm28c clone epimastigotes), the major cysteine proteinase of Trypanosoma cruzi, the proregion of which also contains the sequence YHNGA. The positioning of the YHNGA inhibitory sequence within the prosegment of trypanosomal proteinases is similar to that covering the active site in the prosegment of cysteine proteinases, the three-dimensional structure of which has been resolved. This strongly suggests that trypanosomal proteinases, despite their long C-terminal extension, have a prosegment that folds similarly to that in related mammal and plant cysteine proteinases, resulting in reverse binding within the active site. Such reverse binding could also occur for short procongopain-derived inhibitory peptides, based on their resistance to proteolysis and their ability to retain inhibitory activity after prolonged incubation. In contrast, homologous peptides in related cysteine proteinases did not inhibit trypanosomal proteinases and were rapidly cleaved by these enzymes.

Lipid-Lowering Pharmaceutical Clofibrate Inhibits Human Sweet Taste

PubMed Central

Kochem, Matthew

2017-01-01

T1R2-T1R3 is a heteromeric receptor that binds sugars, high potency sweeteners, and sweet taste blockers. In rodents, T1R2-T1R3 is largely responsible for transducing sweet taste perception. T1R2-T1R3 is also expressed in non-taste tissues, and a growing body of evidence suggests that it helps regulate glucose and lipid metabolism. It was previously shown that clofibric acid, a blood lipid-lowering drug, binds T1R2-T1R3 and inhibits its activity in vitro. The purpose of this study was to determine whether clofibric acid inhibits sweetness perception in humans and is, therefore, a T1R2-T1R3 antagonist in vivo. Fourteen participants rated the sweetness intensity of 4 sweeteners (sucrose, sucralose, Na cyclamate, acesulfame K) across a broad range of concentrations. Each sweetener was prepared in solution neat and in mixture with either clofibric acid or lactisole. Clofibric acid inhibited sweetness of every sweetener. Consistent with competitive binding, inhibition by clofibric acid was diminished with increasing sweetener concentration. This study provides in vivo evidence that the lipid-lowering drug clofibric acid inhibits sweetness perception and is, therefore, a T1R carbohydrate receptor inhibitor. Our results are consistent with previous in vitro findings. Given that T1R2-T1R3 may in part regulate glucose and lipid metabolism, future studies should investigate the metabolic effects of T1R inhibition. PMID:27742692

Osthole inhibits bone metastasis of breast cancer

PubMed Central

Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

2017-01-01

Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potential mechanism of this inhibition. In the murine model of breast cancer osseous metastasis, mice that received osthole developed significantly less bone metastases and displayed decreased tumor burden when compared with mice in the control group. Osthole inhibited breast cancer cell growth, migration, and invasion, and induced apoptosis of breast cancer cells. Additionally, it also regulated OPG/RANKL signals in the interactions between bone cells (osteoblasts and osteoclasts) and cancer cells. Besides, it also inhibited TGF-β/Smads signaling in breast cancer metastasis to bone in MDA-231BO cells. The results of this study suggest that osthole has real potential as a therapeutic candidate in the treatment of breast cancer patients with bone metastases. PMID:28938572

Importance of multi-P450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude and prediction from in vitro data

PubMed Central

Isoherranen, Nina; Lutz, Justin D; Chung, Sophie P; Hachad, Houda; Levy, Rene H; Ragueneau-Majlessi, Isabelle

2012-01-01

Drugs that are mainly cleared by a single enzyme are considered more sensitive to drug-drug interactions (DDIs) than drugs cleared by multiple pathways. However, whether this is true when a drug cleared by multiple pathways is co-administered with an inhibitor of multiple P450 enzymes (multi-P450 inhibition) is not known. Mathematically, simultaneous equipotent inhibition of two elimination pathways that each contributes half of the drug clearance is equal to equipotent inhibition of a single pathway that clears the drug. However, simultaneous strong or moderate inhibition of two pathways by a single inhibitor is perceived as an unlikely scenario. The aim of this study was (i) to identify P450 inhibitors currently in clinical use that can inhibit more than one clearance pathway of an object drug in vivo, and (ii) to evaluate the magnitude and predictability of DDIs caused by these multi-P450 inhibitors. Multi-P450 inhibitors were identified using the Metabolism and Transport Drug Interaction Database™. A total of 38 multi-P450 inhibitors, defined as inhibitors that increased the AUC or decreased the clearance of probes of two or more P450’s, were identified. Seventeen (45 %) multi-P450 inhibitors were strong inhibitors of at least one P450 and an additional 12 (32 %) were moderate inhibitors of one or more P450s. Only one inhibitor (fluvoxamine) was a strong inhibitor of more than one enzyme. Fifteen of the multi-P450 inhibitors also inhibit drug transporters in vivo, but such data are lacking on many of the inhibitors. Inhibition of multiple P450 enzymes by a single inhibitor resulted in significant (>2-fold) clinical DDIs with drugs that are cleared by multiple pathways such as imipramine and diazepam while strong P450 inhibitors resulted in only weak DDIs with these object drugs. The magnitude of the DDIs between multi-P450 inhibitors and diazepam, imipramine and omeprazole could be predicted using in vitro data with similar accuracy as probe substrate

Inhibition of Snl6 expression for biofuel production

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

Bart, Rebecca; Chern, Mawsheng; Ronald, Pamela

The invention provides compositions and methods for inhibiting the expression of the gene Snl6 in plants. Plants with inhibited expression of Snl6 have use in biofuel production, e.g., by increasing the amount of soluble sugar that can be extracted from the plant.

Curcumin synergizes with resveratrol to inhibit colon cancer.

PubMed

Majumdar, Adhip P N; Banerjee, Sanjeev; Nautiyal, Jyoti; Patel, Bhaumik B; Patel, Vaishali; Du, Jianhua; Yu, Yingjie; Elliott, Althea A; Levi, Edi; Sarkar, Fazlul H

2009-01-01

Development and progression of many malignancies, including colorectal cancer, are associated with activation of multiple signaling pathways. Therefore, inhibition of these signaling pathways with noncytotoxic natural products represents a logical preventive and/or therapeutic approach for colon cancer. Curcumin and resveratrol, both of which inhibit the growth of transformed cells and colon carcinogenesis, were selected to examine whether combining them would be an effective preventive and/or therapeutic strategy for colon cancer. Indeed, the combination of curcumin and resveratrol was found to be more effective in inhibiting growth of p53-positive (wt) and p53-negative colon cancer HCT-116 cells in vitro and in vivo in SCID xenografts of colon cancer HCT-116 (wt) cells than either agent alone. Analysis by Calcusyn software showed synergism between curcumin and resveratrol. The inhibition of tumors in response to curcumin and/or resveratrol was associated with the reduction in proliferation and stimulation of apoptosis accompanied by attenuation of NF-kappaB activity. In vitro studies have further demonstrated that the combinatorial treatment caused a greater inhibition of constitutive activation of EGFR and its family members as well as IGF-1R. Our current data suggest that the combination of curcumin and resveratrol could be an effective preventive/therapeutic strategy for colon cancer.

IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

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

Ohshima-Hosoyama, Sachiko; Hosoyama, Tohru; Nelon, Laura D.

2010-09-03

Research highlights: {yields} Igf1r is overexpressed and activated in a Sonic Hedgehog driven model of medulloblastoma. {yields} Picropodophyllin targets and abrogates IGF signaling in medulloblastoma. {yields} Picropodophyllin inhibits medulloblastoma tumor cell growth by induction of apoptosis. -- Abstract: The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression.more » We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.« less

Inhibition of autophagy prevents cadmium-induced prostate carcinogenesis.

PubMed

Pal, Deeksha; Suman, Suman; Kolluru, Venkatesh; Sears, Sophia; Das, Trinath P; Alatassi, Houda; Ankem, Murali K; Freedman, Jonathan H; Damodaran, Chendil

2017-06-27

Cadmium, an established carcinogen, is a risk factor for prostate cancer. Induction of autophagy is a prerequisite for cadmium-induced transformation and metastasis. The ability of Psoralidin (Pso), a non-toxic, orally bioavailable compound to inhibit cadmium-induced autophagy to prevent prostate cancer was investigated. Psoralidin was studied using cadmium-transformed prostate epithelial cells (CTPE), which exhibit high proliferative, invasive and colony forming abilities. Gene and protein expression were evaluated by qPCR, western blot, immunohistochemistry and immunofluorescence. Xenograft models were used to study the chemopreventive effects in vivo. Cadmium-transformed prostate epithelial cells were treated with Pso resulting in growth inhibition, without causing toxicity to normal prostate epithelial cells (RWPE-1). Psoralidin-treatment of CTPE cells inhibited the expression of Placenta Specific 8, a lysosomal protein essential for autophagosome and autolysosome fusion, which resulted in growth inhibition. Additionally, Pso treatment caused decreased expression of pro-survival signalling proteins, NFκB and Bcl2, and increased expression of apoptotic genes. In vivo, Pso effectively suppressed CTPE xenografts growth, without any observable toxicity. Tumours from Pso-treated animals showed decreased autophagic morphology, mesenchymal markers expression and increased epithelial protein expression. These results confirm that inhibition of autophagy by Pso plays an important role in the chemoprevention of cadmium-induced prostate carcinogenesis.

Inhibition of insulin amyloid fibrillation by Morin hydrate.

PubMed

Patel, Palak; Parmar, Krupali; Das, Mili

2018-03-01

We report here the inhibition of amyloid fibrillation of human insulin in vitro by Morin hydrate, a naturally occurring small molecule. Using spectroscopic assays and transmission electron microscopy, we found that Morin hydrate effectively inhibits insulin amyloid fibrillation in a dose dependent manner with more than 80% inhibition occurring even at only a 1:1 concentration. As suggested by fluorescence spectroscopic titration studies, Morin hydrate binds to insulin with a fairly strong affinity of -26.436kJmol -1 . Circular dichroism (CD) spectroscopy was used to analyse structural changes of insulin in the presence of Morin hydrate demonstrating the ability of Morin hydrate to bind with the native monomeric protein and/or its near native state, intermediate oligomeric species and amyloid fibrils. Based on computational docking and molecular dynamics study, we propose that Morin hydrate binds to residues having greater aggregation propensity and prevent structural and/or conformational changes leading to amyloid fibrillation. Morin hydrate should also bind to fibrils by hydrogen bonding and/or hydrophobic forces throughout the surface, stabilize them and inhibit the release of oligomeric species which could be nuclei or template for further fibrillation. Overall results provide an insight into the mechanism of inhibition of insulin amyloid fibrillation by Morin hydrate. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibited solid propellant composition containing beryllium hydride

NASA Technical Reports Server (NTRS)

Thompson, W. W. (Inventor)

1978-01-01

An object of this invention is to provide a composition of beryllium hydride and carboxy-terminated polybutadiene which is stable. Another object of this invention is to provide a method for inhibiting the reactivity of beryllium hydride toward carboxy-terminated polybutadiene. It was found that a small amount of lecithin inhibits the reaction of beryllium hydride with the acid groups in carboxy terminated polybutadiene.

Nickel inhibits mitochondrial fatty acid oxidation.

PubMed

Uppala, Radha; McKinney, Richard W; Brant, Kelly A; Fabisiak, James P; Goetzman, Eric S

2015-08-07

Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation-the pathway by which fatty acids are catabolized for energy-in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with l-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 h), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

On the dependence of response inhibition processes on sensory modality.

PubMed

Bodmer, Benjamin; Beste, Christian

2017-04-01

The ability to inhibit responses is a central sensorimotor function but only recently the importance of sensory processes for motor inhibition mechanisms went more into the research focus. In this regard it is elusive, whether there are differences between sensory modalities to trigger response inhibition processes. Due to functional neuroanatomical considerations strong differences may exist, for example, between the visual and the tactile modality. In the current study we examine what neurophysiological mechanisms as well as functional neuroanatomical networks are modulated during response inhibition. Therefore, a Go/NoGo-paradigm employing a novel combination of visual, tactile, and visuotactile stimuli was used. The data show that the tactile modality is more powerful than the visual modality to trigger response inhibition processes. However, the tactile modality loses its efficacy to trigger response inhibition processes when being combined with the visual modality. This may be due to competitive mechanisms leading to a suppression of certain sensory stimuli and the response selection level. Variations in sensory modalities specifically affected conflict monitoring processes during response inhibition by modulating activity in a frontal parietal network including the right inferior frontal gyrus, anterior cingulate cortex and the temporoparietal junction. Attentional selection processes are not modulated. The results suggest that the functional neuroanatomical networks involved in response inhibition critically depends on the nature of the sensory input. Hum Brain Mapp 38:1941-1951, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

The somatotopy of tic inhibition: Where and how much?

PubMed

Ganos, Christos; Bongert, Jens; Asmuss, Luisa; Martino, Davide; Haggard, Patrick; Münchau, Alexander

2015-08-01

Tics are the hallmark feature of Tourette syndrome. The basic phenomenological and neurophysiological characteristics of tics have been widely investigated. Interestingly, the spatial distribution of tics across different body parts has received little attention. No previous study has investigated whether the capacity for voluntary tic inhibition also varies across body parts. We analyzed video sequences of 26 adolescents with Tourette syndrome in a "tic freely" condition, and in a "voluntary tic inhibition" condition, to obtain absolute tic counts for different body parts. Two measures of the spatial distribution of tics were then analyzed. Linear regression analyses were employed to investigate the relation between the contribution of each body part to overall tic behavior and the ability to inhibit tics in that body part, averaged over our patient group. Tic distribution across patients showed a characteristic somatotopic pattern, with the face most strongly represented. A significant negative relation was found between the ability to inhibit tics and pooled tic frequency across body parts. The body parts that exhibited the fewest tics were the ones for which tic inhibition was most effective. Our data are consistent with the idea that tic recruitment order reflects a "tic generator" spreading across a somatotopic map in the brain. Voluntary tic inhibition did not simply cause a proportional reduction of tics in each body part. Rather, the least affected body parts showed most effective voluntary tic inhibition. The results are discussed in terms of signal and noise within cortical-subcortical motor loops. © 2015 International Parkinson and Movement Disorder Society.

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation.

PubMed

Strempel, Sebastian; Schroeder, Christoph; Hemmersbach, Ruth; Boese, Andrea; Tank, Jens; Diedrich, André; Heer, Martina; Luft, Friedrich C; Jordan, Jens

2008-03-01

Sympathetically mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness. Norepinephrine transporter (NET) inhibition prevents neurally mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. We performed a double-blind, randomized, placebo-controlled crossover study in 11 healthy men (26 +/- 1 yr, body mass index 24 +/- 1 kg/m2), who ingested the selective NET inhibitor reboxetine (4 mg) or matching placebo 25, 13, and 1 h before testing on separate days. We monitored heart rate, blood pressure, and thoracic impedance in three different body positions (supine, seated, standing) and during a graded centrifuge run (incremental steps of 0.5 g for 3 min each, up to a maximal vertical acceleration load of 3 g). NET inhibition increased supine blood pressure and heart rate. With placebo, blood pressure increased in the seated position and was well maintained during standing. However, with NET inhibition, blood pressure decreased in the seated and standing position. During hypergravitation, blood pressure increased in a graded fashion with placebo. With NET inhibition, the increase in blood pressure during hypergravitation was profoundly diminished. Conversely, the tachycardic responses to sitting, standing, and hypergravitation all were greatly increased with NET inhibition. In contrast to our expectation, short-term NET inhibition did not improve tolerance to hypergravitation. Redistribution of sympathetic activity to the heart or changes in baroreflex responses could explain the excessive tachycardia that we observed.

ATP depletion inhibits glucocorticoid-induced thymocyte apoptosis.

PubMed Central

Stefanelli, C; Bonavita, F; Stanic', I; Farruggia, G; Falcieri, E; Robuffo, I; Pignatti, C; Muscari, C; Rossoni, C; Guarnieri, C; Caldarera, C M

1997-01-01

In quiescent thymocytes, mitochondrial de-energization was not correlated to apoptotic death. In fact, thymocytes treated with oligomycin, a highly specific inhibitor of ATP synthase, alone or with atractyloside to block ATP translocation from the cytoplasm, were alive, even if their mitochondria were depolarized, as revealed by flow cytometry after Rhodamine 123 staining. Furthermore, oligomycin was a powerful inhibitor of apoptosis induced in rat thymocytes by dexamethasone and, to a lesser extent, by the calcium ionophore A23187 and etoposide, but was without effect when apoptosis was induced by staurosporine, and increased cell death in mitogen-treated thymocytes. The inhibition of apoptosis was confirmed by morphological criteria, inhibition of inter-nucleosomal DNA fragmentation and inhibition of the loss of membrane integrity. The anti-apoptotic effect of oligomycin in cells treated with A23187 or etoposide was correlated to the inhibition of protein synthesis, while inhibition of apoptosis induced by dexamethasone, already evident at an oligomycin concentration of 10 ng/ml, was instead strictly correlated to the effect exerted on the cellular ATP level. Thymocyte apoptosis triggered by dexamethasone was blocked or delayed by inhibitors of respiratory-chain uncouplers, inhibitors of ATP synthase and antioxidants: a lasting protection from dexamethasone-induced apoptosis was always correlated to a drastic and rapid reduction in ATP level (31-35% of control), while a delay in the death process was characterized by a moderate decrease in ATP (73-82% of control). Oligomycin inhibited the specific binding of radioactive corticosteroid to thymocyte nuclei, confirming the inhibitory effect of ATP depletion on glucocorticoid binding and suggesting that ATP depletion is a common mediator of the anti-apoptotic action of different effectors in glucocorticoid-induced apoptosis. In conclusion, the reported data indicate that ATP may act as a cellular modulator of some

Expanded RNA-binding activities of mammalian Argonaute 2

PubMed Central

Tan, Grace S.; Garchow, Barry G.; Liu, Xuhang; Yeung, Jennifer; Morris, John P.; Cuellar, Trinna L.; McManus, Michael T.; Kiriakidou, Marianthi

2009-01-01

Mammalian Argonaute 2 (Ago2) protein associates with microRNAs (miRNAs) or small interfering RNAs (siRNAs) forming RNA-induced silencing complexes (RISCs/miRNPs). In the present work, we characterize the RNA-binding and nucleolytic activity of recombinant mouse Ago2. Our studies show that recombinant mouse Ago2 binds efficiently to miRNAs forming active RISC. Surprisingly, we find that recombinant mouse Ago2 forms active RISC using pre-miRNAs or long unstructured single stranded RNAs as guides. Furthermore, we demonstrate that, in vivo, endogenous human Ago2 binds directly to pre-miRNAs independently of Dicer, and that Ago2:pre-miRNA complexes are found both in the cytoplasm and in the nucleus of human cells. PMID:19808937

Cognitive Control Reflects Context Monitoring, Not Motoric Stopping, in Response Inhibition

PubMed Central

Chatham, Christopher H.; Claus, Eric D.; Kim, Albert; Curran, Tim; Banich, Marie T.; Munakata, Yuko

2012-01-01

The inhibition of unwanted behaviors is considered an effortful and controlled ability. However, inhibition also requires the detection of contexts indicating that old behaviors may be inappropriate – in other words, inhibition requires the ability to monitor context in the service of goals, which we refer to as context-monitoring. Using behavioral, neuroimaging, electrophysiological and computational approaches, we tested whether motoric stopping per se is the cognitively-controlled process supporting response inhibition, or whether context-monitoring may fill this role. Our results demonstrate that inhibition does not require control mechanisms beyond those involved in context-monitoring, and that such control mechanisms are the same regardless of stopping demands. These results challenge dominant accounts of inhibitory control, which posit that motoric stopping is the cognitively-controlled process of response inhibition, and clarify emerging debates on the frontal substrates of response inhibition by replacing the centrality of controlled mechanisms for motoric stopping with context-monitoring. PMID:22384038

Combined autophagy and proteasome inhibition

PubMed Central

Vogl, Dan T; Stadtmauer, Edward A; Tan, Kay-See; Heitjan, Daniel F; Davis, Lisa E; Pontiggia, Laura; Rangwala, Reshma; Piao, Shengfu; Chang, Yunyoung C; Scott, Emma C; Paul, Thomas M; Nichols, Charles W; Porter, David L; Kaplan, Janeen; Mallon, Gayle; Bradner, James E; Amaravadi, Ravi K

2014-01-01

The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy. PMID:24991834

The ammonium sulfate inhibition of human angiogenin.

PubMed

Chatzileontiadou, Demetra S M; Tsirkone, Vicky G; Dossi, Kyriaki; Kassouni, Aikaterini G; Liggri, Panagiota G V; Kantsadi, Anastassia L; Stravodimos, George A; Balatsos, Nikolaos A A; Skamnaki, Vassiliki T; Leonidas, Demetres D

2016-09-01

In this study, we investigate the inhibition of human angiogenin by ammonium sulfate. The inhibitory potency of ammonium sulfate for human angiogenin (IC50 = 123.5 ± 14.9 mm) is comparable to that previously reported for RNase A (119.0 ± 6.5 mm) and RNase 2 (95.7 ± 9.3 mm). However, analysis of two X-ray crystal structures of human angiogenin in complex with sulfate anions (in acidic and basic pH environments, respectively) indicates an entirely distinct mechanism of inhibition. While ammonium sulfate inhibits the ribonucleolytic activity of RNase A and RNase 2 by binding to the active site of these enzymes, sulfate anions bind only to peripheral substrate anion-binding subsites of human angiogenin, and not to the active site. © 2016 Federation of European Biochemical Societies.

Lewis Carroll: a study of mathematical inhibition.

PubMed

Keller, E F

1980-01-01

Carroll's mathematical abilities appear to have been severely constrained--subject simultaneously to inhibition and distortion. Through an analysis of his informal commentary on his relation to mathematical puzzles I have attempted to understand and explain the nature of these inhibitions and distortions. Particular attention to his metaphor of the "mental bun," and his use of this metaphor, has led me to conclude that the mathematical puzzle served, for Carroll, distinctly fetishistic functions. This interpretation dovetails with Greenacre's early intuition about the prevalence in his literary work of fantasies and preoccupations reminescent of clinical experience with fetishism. The connection argued here between inhibitions and distortions in the sexual and intellectual realms suggests, as a domain for further inquiry, the possibility of a more general investigation into the role of sexual fantasies in intellectual activities.

[Breast-feeding (part II): Lactation inhibition--Guidelines for clinical practice].

PubMed

Marcellin, L; Chantry, A A

2015-12-01

Provide guidelines for clinical use of non-pharmacological and pharmacological treatments of inhibition of lactation and the management of the weaning. Systematically review of the literature between 1972 and May 2015 from the databases Medline, Google Scholar, Cochrane Library, and the international recommendations about inhibition of lactation with establishment of levels of evidence (LE) and grades of recommendation. The available data on the effectiveness of non-pharmacological measures are limited, with very low levels of evidence that fail to make recommendations (Professional consensus). Pharmacological treatments for inhibition of lactation should not be given routinely to women who do not wish to breast-feed (Professional consensus). For women aware of the risks of pharmacological treatments of inhibition of lactation, lisuride and cabergolin are the preferred drugs (Professional consensus). Because of potentially serious adverse effects, bromocriptin is contraindicated in inhibiting lactation (Professional consensus). Available data on management of lactation weaning fail to provide recommendation and no treatment is recommended (Professional consensus). Bromocriptin is contraindicated in the treatment of inhibiting lactation. Women who do not wish to breast-feed have to be informed of the benefits and disadvantages of the pharmacological treatment for inhibition of lactation. Copyright © 2015. Published by Elsevier Masson SAS.

Strong G-Protein-Mediated Inhibition of Sodium Channels.

PubMed

Mattheisen, Glynis B; Tsintsadze, Timur; Smith, Stephen M

2018-05-29

Voltage-gated sodium channels (VGSCs) are strategically positioned to mediate neuronal plasticity because of their influence on action potential waveform. VGSC function may be strongly inhibited by local anesthetic and antiepileptic drugs and modestly modulated via second messenger pathways. Here, we report that the allosteric modulators of the calcium-sensing receptor (CaSR) cinacalcet, calindol, calhex, and NPS 2143 completely inhibit VGSC current in the vast majority of cultured mouse neocortical neurons. This form of VGSC current block persisted in CaSR-deficient neurons, indicating a CaSR-independent mechanism. Cinacalcet-mediated blockade of VGSCs was prevented by the guanosine diphosphate (GDP) analog GDPβs, indicating that G-proteins mediated this effect. Cinacalcet inhibited VGSCs by increasing channel inactivation, and block was reversed by prolonged hyperpolarization. Strong cinacalcet inhibition of VGSC currents was also present in acutely isolated mouse cortical neurons. These data identify a dynamic signaling pathway by which G-proteins regulate VGSC current to indirectly modulate central neuronal excitability. Published by Elsevier Inc.

Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

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

Cho, Yoon Sun; Jung, Hye Jin; Seok, Seung Hyeok

2013-04-19

Highlights: ► This is the first functional characterization of UQCRB in vivo model. ► Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ► UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levelsmore » in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases.« less

Impaired face recognition is associated with social inhibition.

PubMed

Avery, Suzanne N; VanDerKlok, Ross M; Heckers, Stephan; Blackford, Jennifer U

2016-02-28

Face recognition is fundamental to successful social interaction. Individuals with deficits in face recognition are likely to have social functioning impairments that may lead to heightened risk for social anxiety. A critical component of social interaction is how quickly a face is learned during initial exposure to a new individual. Here, we used a novel Repeated Faces task to assess how quickly memory for faces is established. Face recognition was measured over multiple exposures in 52 young adults ranging from low to high in social inhibition, a core dimension of social anxiety. High social inhibition was associated with a smaller slope of change in recognition memory over repeated face exposure, indicating participants with higher social inhibition showed smaller improvements in recognition memory after seeing faces multiple times. We propose that impaired face learning is an important mechanism underlying social inhibition and may contribute to, or maintain, social anxiety. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Emotional content modulates response inhibition and perceptual processing.

PubMed

Yang, Suyong; Luo, Wenbo; Zhu, Xiangru; Broster, Lucas S; Chen, Taolin; Li, Jinzhen; Luo, Yuejia

2014-11-01

In this study, event-related potentials were used to investigate the effect of emotion on response inhibition. Participants performed an emotional go/no-go task that required responses to human faces associated with a "go" valence (i.e., emotional, neutral) and response inhibition to human faces associated with a "no-go" valence. Emotional content impaired response inhibition, as evidenced by decreased response accuracy and N2 amplitudes in no-go trials. More importantly, emotional expressions elicited larger N170 amplitudes than neutral expressions, and this effect was larger in no-go than in go trials, indicating that the perceptual processing of emotional expression had priority in inhibitory trials. In no-go trials, correlation analysis showed that increased N170 amplitudes were associated with decreased N2 amplitudes. Taken together, our findings suggest that emotional content impairs response inhibition due to the prioritization of emotional content processing. Copyright © 2014 Society for Psychophysiological Research.

Curine inhibits mast cell-dependent responses in mice.

PubMed

Ribeiro-Filho, Jaime; Leite, Fagner Carvalho; Costa, Hermann Ferreira; Calheiros, Andrea Surrage; Torres, Rafael Carvalho; de Azevedo, Carolina Trindade; Martins, Marco Aurélio; Dias, Celidarque da Silva; Bozza, Patrícia T; Piuvezam, Márcia Regina

2014-09-11

Curine is a bisbenzylisoquinoline alkaloid and the major constituent isolated from Chondrodendron platyphyllum, a plant that is used to treat inflammatory diseases in Brazilian folk medicine. This study investigates the effectiveness of curine on mast cell-dependent responses in mice. To induce mast cell-dependent responses, Swiss mice were subcutaneously sensitized with ovalbumin (OVA-12 μg/mouse) and Al(OH)3 in a 0.9% NaCl solution. Fifteen days later, the animals were challenged with OVA through different pathways. Alternatively, the animals were injected with compound 48/80 or histamine, and several parameters, including anaphylaxis, itching, edema and inflammatory mediator production, were analyzed. Promethazine, cromoglycate, and verapamil were used as control drugs, and all of the treatments were performed 1h before the challenges. Curine pre-treatment significantly inhibited the scratching behavior and the paw edema induced by either compound 48/80 or OVA, and this protective effect was comparable in magnitude with those associated with treatment with either cromoglycate or verapamil. In contrast, curine was a weak inhibitor of histamine-induced paw edema, which was completely inhibited by promethazine. Curine and verapamil significantly inhibited pleural protein extravasations and prostaglandin D2 (PGD2) and cysteinyl leukotrienes (CysLTs) production following allergen-induced pleurisy. Furthermore, like verapamil, curine inhibited the anaphylactic shock caused by either compound 48/80 or an allergen. In in vitro settings, these treatments also inhibited degranulation as well as PGD2 and CysLT production through IgE-dependent activation of the mast cell lineage RBL-2H3. Curine significantly inhibited immediate allergic reactions through mechanisms more related to mast cell stabilization and activation inhibition than interference with the pro-inflammatory effects of mast cell products. These findings are in line with the hypothesis that the alkaloid

Global Precipitation Measurement (GPM) Safety Inhibit Timeline Tool

NASA Technical Reports Server (NTRS)

Dion, Shirley

2012-01-01

The Global Precipitation Measurement (GPM) Observatory is a joint mission under the partnership by National Aeronautics and Space Administration (NASA) and the Japan Aerospace Exploration Agency (JAXA), Japan. The NASA Goddard Space Flight Center (GSFC) has the lead management responsibility for NASA on GPM. The GPM program will measure precipitation on a global basis with sufficient quality, Earth coverage, and sampling to improve prediction of the Earth's climate, weather, and specific components of the global water cycle. As part of the development process, NASA built the spacecraft (built in-house at GSFC) and provided one instrument (GPM Microwave Imager (GMI) developed by Ball Aerospace) JAXA provided the launch vehicle (H2-A by MHI) and provided one instrument (Dual-Frequency Precipitation Radar (DPR) developed by NTSpace). Each instrument developer provided a safety assessment which was incorporated into the NASA GPM Safety Hazard Assessment. Inhibit design was reviewed for hazardous subsystems which included the High Gain Antenna System (HGAS) deployment, solar array deployment, transmitter turn on, propulsion system release, GMI deployment, and DPR radar turn on. The safety inhibits for these listed hazards are controlled by software. GPM developed a "pathfinder" approach for reviewing software that controls the electrical inhibits. This is one of the first GSFC in-house programs that extensively used software controls. The GPM safety team developed a methodology to document software safety as part of the standard hazard report. As part of this process a new tool "safety inhibit time line" was created for management of inhibits and their controls during spacecraft buildup and testing during 1& Tat GSFC and at the Range in Japan. In addition to understanding inhibits and controls during 1& T the tool allows the safety analyst to better communicate with others the changes in inhibit states with each phase of hardware and software testing. The tool was very

PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner.

PubMed

Lehrke, Michael; Kahles, Florian; Makowska, Anna; Tilstam, Pathricia V; Diebold, Sebastian; Marx, Judith; Stöhr, Robert; Hess, Katharina; Endorf, Elizabeth B; Bruemmer, Dennis; Marx, Nikolaus; Findeisen, Hannes M

2015-04-01

Phosphodiesterase 4 (PDE4) activity mediates cAMP-dependent smooth muscle cell (SMC) activation following vascular injury. In this study we have investigated the effects of specific PDE4 inhibition with roflumilast on SMC proliferation and inflammatory activation in vitro and neointima formation following guide wire-induced injury of the femoral artery in mice in vivo. In vitro, roflumilast did not affect SMC proliferation, but diminished TNF-α induced expression of the vascular cell adhesion molecule 1 (VCAM-1). Specific activation of the cAMP effector Epac, but not PKA activation mimicked the effects of roflumilast on VCAM-1 expression. Consistently, the reduction of VCAM-1 expression was rescued following inhibition of Epac. TNF-α induced NFκB p65 translocation and VCAM-1 promoter activity were not altered by roflumilast in SMCs. However, roflumilast treatment and Epac activation repressed the induction of the activating epigenetic histone mark H3K4me2 at the VCAM-1 promoter, while PKA activation showed no effect. Furthermore, HDAC inhibition blocked the inhibitory effect of roflumilast on VCAM-1 expression. Both, roflumilast and Epac activation reduced monocyte adhesion to SMCs in vitro. Finally, roflumilast treatment attenuated femoral artery intima-media ratio by more than 50% after 4weeks. In summary, PDE4 inhibition regulates VCAM-1 through a novel Epac-dependent mechanism, which involves regulatory epigenetic components and reduces neointima formation following vascular injury. PDE4 inhibition and Epac activation might represent novel approaches for the treatment of vascular diseases, including atherosclerosis and in-stent restenosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Overcoming PCR Inhibition During DNA-Based Gut Content Analysis of Ants.

PubMed

Penn, Hannah J; Chapman, Eric G; Harwood, James D

2016-10-01

Generalist predators play an important role in many terrestrial systems, especially within agricultural settings, and ants (Hymenoptera: Formicidae) often constitute important linkages of these food webs, as they are abundant and influential in these ecosystems. Molecular gut content analysis provides a means of delineating food web linkages of ants based on the presence of prey DNA within their guts. Although this method can provide insight, its use on ants has been limited, potentially due to inhibition when amplifying gut content DNA. We designed a series of experiments to determine those ant organs responsible for inhibition and identified variation in inhibition among three species (Tetramorium caespitum (L.), Solenopsis invicta Buren, and Camponotus floridanus (Buckley)). No body segment, other than the gaster, caused significant inhibition. Following dissection, we determined that within the gaster, the digestive tract and crop cause significant levels of inhibition. We found significant differences in the frequency of inhibition between the three species tested, with inhibition most evident in T. caespitum The most effective method to prevent inhibition before DNA extraction was to exude crop contents and crop structures onto UV-sterilized tissue. However, if extracted samples exhibit inhibition, addition of bovine serum albumin to PCR reagents will overcome this problem. These methods will circumvent gut content inhibition within selected species of ants, thereby allowing more detailed and reliable studies of ant food webs. As little is known about the prevalence of this inhibition in other species, it is recommended that the protocols in this study are used until otherwise shown to be unnecessary. © The Authors 2016. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Preparation and swelling inhibition of cation glucoside to montmorillonite

NASA Astrophysics Data System (ADS)

Song, Shaofu; Liu, Jurong; Guo, Gang; Huang, Lei; Qu, Chentun; Li, Bianqin; Chen, Gang

2017-06-01

In this work, a cation glucoside (CG) was synthesized with glucose and glycidyl trimethyl ammonium chloride (GTA) and used as montmorillonite (MMT) swelling inhibiter. The inhibition of CG was investigated by MMT linear expansion test and mud ball immersing test. The results showed that the CG has a good inhibition to the hydration swelling and dispersion of MMT. Under the same condition, the linear expansion rate of MMT in CG solution is much lower that of methylglucoside and the hydration expansion degree of the mud ball in the CG solution was significantly inhibited. The characterizations of physic-chemical properties of particle, analysized by thermogravimetric analysis and scanning electron microscopy, revealed that CG play great role to prevent water from absorb and keep MMT in large particle size.

VISUALIZATION-BASED ANALYSIS FOR A MIXED-INHIBITION BINARY PBPK MODEL: DETERMINATION OF INHIBITION MECHANISM

EPA Science Inventory

A physiologically-based pharmacokinetic (PBPK) model incorporating mixed enzyme inhibition was used to determine the mechanism of metabolic interactions occurring during simultaneous exposures to the organic solvents chloroform and trichloroethylene (TCE). Visualization-based se...

Distractor Inhibition: Principles of Operation during Selective Attention

ERIC Educational Resources Information Center

Wyatt, Natalie; Machado, Liana

2013-01-01

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…

Reversible Inhibition of Spore Germination by Alcohols 1

PubMed Central

Trujillo, Ralph; Laible, Nancy

1970-01-01

Low levels of alcohols have been found to inhibit the process of spore germination. The extent of germination is dependent upon the concentration of alcohol present in the germinating medium. This inhibition is reversible since removal of the alcohol from the spore environment allows germination to proceed. PMID:4993360

“Off with the Old”: Mindfulness Practice Improves Backward Inhibition

PubMed Central

Greenberg, Jonathan; Reiner, Keren; Meiran, Nachshon

2013-01-01

Mindfulness practice has been linked to reduced depressive rumination and described as involving inhibition of information that has been relevant in the past and is no longer relevant in the present moment. Backward inhibition (BI) is considered to be one of the purest measures of task set inhibition, and impaired BI has been linked to depressive rumination. BI was contrasted with Competitor Rule Suppression (CRS), which is another phenomenon observed in task switching, yet one which involves episodic memory tagging of information that is currently conflicting rather than active inhibition. Although similar at baseline level, a randomly assigned group (n = 38) who underwent an eight session mindfulness training program exhibited improved BI but not CRS compared to a waiting list group (n = 38). Findings indicate that mindfulness improves the specific component of task set inhibition, which has previously been linked to reduced rumination. Implications regarding the potential role of task set inhibition in mediating between mindfulness and reduced rumination, as well as the role of mindfulness in “being in the present moment” are discussed. PMID:23335909

Prevention of 5-Fluorouracil-Caused Growth Inhibition in Sordaria fimicola

PubMed Central

Schoen, Howard F.; Berech, John

1977-01-01

Growth (dry weight accumulation) of Sordaria fimicola in standing liquid culture (sucrose-nitrate-salts-vitamins) is inhibited by the presence of 5 μM 5-fluorouracil in the medium. This inhibition is completely prevented by uracil, deoxyuridine, and 5-bromouracil, partly prevented (40 to 90% of growth observed without 5-fluorouracil) by uridine, thymidine, and 5-bromodeoxyuridine, and slightly prevented by trifluorothymine, cytosine, cytidine, deoxycytidine, and 5-methylcytosine (all at 0.5 to 1 mM). Thymidine and thymine riboside were without any apparent effect. Growth is also inhibited by 0.2 mM 6-azauracil, and this inhibition was completely prevented by uracil and uridine, partly prevented by deoxyuridine, 5-bromouracil, cytidine, and 5-methylcytosine, and slightly prevented by thymine, thymidine, 5-bromodeoxyuridine, cytosine, and deoxycytidine. The data suggest that the observed inhibition of growth by 5-fluorouracil is due to inhibition of both ribonucleic acid and deoxyribonucleic acid synthesis. The data also allow inferences concerning pyrimidine interconversions in S. fimicola; i.e., thymine can be anabolized to thymidylic acid without first being demethylated, although demethylation appears to occur also. PMID:848926

Prevention of 5-fluorouracil-caused growth inhibition in Sordaria fimicola.

PubMed

Schoen, H F; Berech, J

1977-02-01

Growth (dry weight accumulation) of Sordaria fimicola in standing liquid culture (sucrose-nitrate-salts-vitamins) is inhibited by the presence of 5 muM 5-fluorouracil in the medium. This inhibition is completely prevented by uracil, deoxyuridine, and 5-bromouracil, partly prevented (40 to 90% of growth observed without 5-fluorouracil) by uridine, thymidine, and 5-bromodeoxyuridine, and slightly prevented by trifluorothymine, cytosine, cytidine, deoxycytidine, and 5-methylcytosine (all at 0.5 to 1 mM). Thymidine and thymine riboside were without any apparent effect. Growth is also inhibited by 0.2 mM 6-azauracil, and this inhibition was completely prevented by uracil and uridine, partly prevented by deoxyuridine, 5-bromouracil, cytidine, and 5-methylcytosine, and slightly prevented by thymine, thymidine, 5-bromodeoxyuridine, cytosine, and deoxycytidine. The data suggest that the observed inhibition of growth by 5-fluorouracil is due to inhibition of both ribonucleic acid and deoxyribonucleic acid synthesis. The data also allow inferences concerning pyrimidine interconversions in S. fimicola; i.e., thymine can be anabolized to thymidylic acid without first being demethylated, although demethylation appears to occur also.

Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival

PubMed Central

2012-01-01

Background The current treatment regimen for glioma patients is surgery, followed by radiation therapy plus temozolomide (TMZ), followed by 6 months of adjuvant TMZ. Despite this aggressive treatment regimen, the overall survival of all surgically treated GBM patients remains dismal, and additional or different therapies are required. Depending on the cancer type, SPARC has been proposed both as a therapeutic target and as a therapeutic agent. In glioma, SPARC promotes invasion via upregulation of the p38 MAPK/MAPKAPK2/HSP27 signaling pathway, and promotes tumor cell survival by upregulating pAKT. As HSP27 and AKT interact to regulate the activity of each other, we determined whether inhibition of HSP27 was better than targeting SPARC as a therapeutic approach to inhibit both SPARC-induced glioma cell invasion and survival. Results Our studies found the following. 1) SPARC increases the expression of tumor cell pro-survival and pro-death protein signaling in balance, and, as a net result, tumor cell survival remains unchanged. 2) Suppressing SPARC increases tumor cell survival, indicating it is not a good therapeutic target. 3) Suppressing HSP27 decreases tumor cell survival in all gliomas, but is more effective in SPARC-expressing tumor cells due to the removal of HSP27 inhibition of SPARC-induced pro-apoptotic signaling. 4) Suppressing total AKT1/2 paradoxically enhanced tumor cell survival, indicating that AKT1 or 2 are poor therapeutic targets. 5) However, inhibiting pAKT suppresses tumor cell survival. 6) Inhibiting both HSP27 and pAKT synergistically decreases tumor cell survival. 7) There appears to be a complex feedback system between SPARC, HSP27, and AKT. 8) This interaction is likely influenced by PTEN status. With respect to chemosensitization, we found the following. 1) SPARC enhances pro-apoptotic signaling in cells exposed to TMZ. 2) Despite this enhanced signaling, SPARC protects cells against TMZ. 3) This protection can be reduced by inhibiting p

IGFBP-3, hypoxia and TNF-{alpha} inhibit adiponectin transcription

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

Zappala, Giovanna, E-mail: zappalag@mail.nih.gov; Rechler, Matthew M.; Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

2009-05-15

The thiazolidinedione rosiglitazone, an agonist ligand for the nuclear receptor PPAR-{gamma}, improves insulin sensitivity in part by stimulating transcription of the insulin-sensitizing adipokine adiponectin. It activates PPAR-{gamma}-RXR-{alpha} heterodimers bound to PPAR-{gamma} response elements in the adiponectin promoter. Rosiglitazone-stimulated adiponectin protein synthesis in 3T3-L1 mouse adipocytes has been shown to be inhibited by IGFBP-3, which can be induced by hypoxia and the proinflammatory cytokine, TNF-{alpha}, two inhibitors of adiponectin transcription. The present study demonstrates that IGFBP-3, the hypoxia-mimetic agent cobalt chloride, and TNF-{alpha} inhibit rosiglitazone-induced adiponectin transcription in mouse embryo fibroblasts that stably express PPAR-{gamma}2. Native IGFBP-3 can bind RXR-{alpha} andmore » inhibited rosiglitazone stimulated promoter activity, whereas an IGFBP-3 mutant that does not bind RXR-{alpha} did not. These results suggest that IGFBP-3 may mediate the inhibition of adiponectin transcription by hypoxia and TNF-{alpha}, and that IGFBP-3 binding to RXR-{alpha} may be required for the observed inhibition.« less

VISUALIZATION-BASED ANALYSIS FOR A MIXED-INHIBITION BINARY PBPK MODEL: DETERMINATION OF INHIBITION MECHANISM

EPA Science Inventory

A physiologically-based pharmacokinetic (PBPK) model incorporating mixed enzyme inhibition was used to determine mechanism of the metabolic interactions occurring during simultaneous inhalation exposures to the organic solvents chloroform and trichloroethylene (TCE).

V...

The effect of vagus nerve stimulation on response inhibition.

PubMed

Schevernels, Hanne; van Bochove, Marlies E; De Taeye, Leen; Bombeke, Klaas; Vonck, Kristl; Van Roost, Dirk; De Herdt, Veerle; Santens, Patrick; Raedt, Robrecht; Boehler, C Nico

2016-11-01

In the current study, we explored whether vagus nerve stimulation (VNS) in patients with epilepsy, which is believed to increase norepinephrine (NE) levels via activation of the locus coeruleus, would positively affect response inhibition. Moreover, we tried to identify the dynamics of the underlying neural processes by investigating event-related potentials (ERPs) and pupil size. Patients performed a stop-signal task once when stimulation was switched on and once when it was switched off. We found a correlational pattern suggesting that patients who clinically benefit more from VNS treatment also show a larger behavioral advantage, in terms of faster response inhibition, when the vagus nerve is being stimulated. Event-related potential (ERP) results suggested more pronounced reactive inhibition when stimulation was switched on, independent of the individual amount of seizure reduction. Transient go-locked pupil size was increased from go trials to successful stop trials to unsuccessful stop trials but without displaying a clear VNS effect, which however, might relate to limited sensitivity. We conclude that VNS likely has a positive effect on response inhibition, at least in patients with epilepsy that benefit clinically from the treatment, presumably relating to enhancements of response-inhibition mechanisms and, therefore, identify enhanced response inhibition as a possible cognitive benefit of VNS. Copyright © 2016 Elsevier Inc. All rights reserved.

A tiered approach to evaluate an iodine recycling inhibition ...

EPA Pesticide Factsheets

The enzyme iodotyrosine deiodinase (dehalogenase, IYD) catalyzes iodide recycling and promotes iodide retention in thyroid follicular cells. Loss of function or chemical inhibition of IYD reduces thyroid hormone synthesis, which leads to insufficiency in tissues and subsequent negative developmental consequences. Iodide recycling by IYD is especially critical for low iodine diets and low iodine environments, including most freshwater ecosystems. We developed a putative adverse outcome pathway for IYD inhibition in amphibians and evaluated IYD inhibition with a tiered approach: 1) development of an in vitro IYD enzyme inhibition assay for chemical screening of compounds of interest to the US EPA, 2) ex vivo thyroid culture to establish thyroglobulin iodination as a biomarker of IYD inhibition, and 3) in vivo bioassays to characterize an organismal adverse outcome and test essentiality of IYD activity. An in vitro colorimetric assay was developed to measure activity of recombinant human IYD enzyme in a 96-well format, establishing the feasibility of medium to high throughput screening of chemicals for IYD inhibition. In ex vivo thyroid culture studies, thyroxine (T4), monoiodotyrosine (MIT), and diiodotyrosine (DIT) were quantified in individual thyroid glands and the media using a ultrahigh performance LC-MS/MS. In vivo exposure of developing Xenopus laevis to a suspected IYD inhibitor (3-L-nitro-tyrosine) resulted in markedly delayed metamorphosis and glandular

Attachment, Behavioral Inhibition, and Anxiety in Preschool Children.

ERIC Educational Resources Information Center

Shamir-Essakow, Galia; Ungerer, Judy A.; Rapee, Ronald M.

2005-01-01

This study examined the association between insecure attachment, behavioral inhibition, and anxiety in an at risk sample of preschool children. The relationship between maternal anxiety and child anxiety was also assessed. Participants were 104 children aged 3-4 years who were assessed for behavioral inhibition and mother-child attachment (using…

Men in the Triangle: Grief, Inhibition, and Defense

ERIC Educational Resources Information Center

Clayton, Robert E.

2015-01-01

Inhibition of emotional experience is a widely acknowledged characteristic of many Western-raised men. While this affective inhibition may impact men chronically in many ways, it becomes particularly salient when men are bereaved or otherwise grieving and are unable fully to experience normative emotional responses to loss. This article briefly…

Digestion products of the PH20 hyaluronidase inhibit remyelination.

PubMed

Preston, Marnie; Gong, Xi; Su, Weiping; Matsumoto, Steven G; Banine, Fatima; Winkler, Clayton; Foster, Scott; Xing, Rubing; Struve, Jaime; Dean, Justin; Baggenstoss, Bruce; Weigel, Paul H; Montine, Thomas J; Back, Stephen A; Sherman, Larry S

2013-02-01

Oligodendrocyte progenitor cells (OPCs) recruited to demyelinating lesions often fail to mature into oligodendrocytes (OLs) that remyelinate spared axons. The glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions and has been implicated in the failure of OPC maturation and remyelination. We tested the hypothesis that OPCs in demyelinating lesions express a specific hyaluronidase, and that digestion products of this enzyme inhibit OPC maturation. Mouse OPCs grown in vitro were analyzed for hyaluronidase expression and activity. Gain of function studies were used to define the hyaluronidases that blocked OPC maturation. Mouse and human demyelinating lesions were assessed for hyaluronidase expression. Digestion products from different hyaluronidases and a hyaluronidase inhibitor were tested for their effects on OPC maturation and functional remyelination in vivo. OPCs demonstrated hyaluronidase activity in vitro and expressed multiple hyaluronidases, including HYAL1, HYAL2, and PH20. HA digestion by PH20 but not other hyaluronidases inhibited OPC maturation into OLs. In contrast, inhibiting HA synthesis did not influence OPC maturation. PH20 expression was elevated in OPCs and reactive astrocytes in both rodent and human demyelinating lesions. HA digestion products generated by the PH20 hyaluronidase but not another hyaluronidase inhibited remyelination following lysolecithin-induced demyelination. Inhibition of hyaluronidase activity lead to increased OPC maturation and promoted increased conduction velocities through lesions. We determined that PH20 is elevated in demyelinating lesions and that increased PH20 expression is sufficient to inhibit OPC maturation and remyelination. Pharmacological inhibition of PH20 may therefore be an effective way to promote remyelination in multiple sclerosis and related conditions. Copyright © 2012 American Neurological Association.

Timing of growth inhibition following shoot inversion in Pharbitis nil

NASA Technical Reports Server (NTRS)

Abdel-Rahman, A. M.; Cline, M. G.

1989-01-01

Shoot inversion in Pharbitis nil results in the enhancement of ethylene production and in the inhibition of elongation in the growth zone of the inverted shoot. The initial increase in ethylene production previously was detected within 2 to 2.75 hours after inversion. In the present study, the initial inhibition of shoot elongation was detected within 1.5 to 4 hours with a weighted mean of 2.4 hours. Ethylene treatment of upright shoots inhibited elongation in 1.5 hours. A cause and effect relationship between shoot inversion-enhanced ethylene production and inhibition of elongation cannot be excluded.

IN VITRO CONAZOLE EXPOSURE INHIBITS TESTOSTERONE PRODUCTION IN THE ADULT AND NEONATAL RAT TESTIS THROUGH THE INHIBITION OF CYP17 ACTIVITY

EPA Science Inventory

IN VITRO CONAZOLE EXPOSURE INHIBITS TESTOSTERONE PRODUCTION IN THE ADULT AND NEONATAL RAT TESTIS THROUGH THE INHIBITION OF CYP17 ACTIVITY

Chad R. Blystone1, David J. Dix2, and John C. Rockett2
1Department of Environmental and Molecular Toxicology, NC State University, R...

LYATK1 potently inhibits LPS-mediated pro-inflammatory response

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

Xi, Feng; Liu, Yuan; Wang, Xiujuan

Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-β-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS-induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine productionmore » was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFκB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings. - Highlights: • LYTAK1 inhibits LPS-induced pro-inflammatory cytokine production in RAW 264.7 cells. • The effect by LYTAK1 is more potent than other known TAK1 inhibitors. • LYTAK1 inhibits LPS-induced cytokine production in primary macrophages/monocytes. • LYTAK1 inhibits LPS-induced TAK1-NFκB and MAPK activation in macrophages/monocytes. • LYTAK1 gavage inhibits LPS-induced endotoxin shock and cytokine production in mice.« less

Hawthorn extract inhibits human isolated neutrophil functions.

PubMed

Dalli, Ernesto; Milara, Javier; Cortijo, Julio; Morcillo, Esteban J; Cosín-Sales, Juan; Sotillo, José Francisco

2008-06-01

Hawthorn extract is a popular herbal medicine given as adjunctive treatment for chronic heart failure. In contrast to the cardiac properties of hawthorn extract, its anti-inflammatory effect has been scarcely investigated. This study examines the effects of a dry extract of leaves and flowers of Crataegus laevigata on various functional outputs of human neutrophils in vitro. Incubation of human neutrophils obtained from peripheral blood of healthy donors with C. laevigata extract (0.75-250 microg/ml) inhibited N-formyl-Met-Leu-Phe (FMLP)-induced superoxide anion generation, elastase release and chemotactic migration with potency values of 43.6, 21.9, and 31.6 microg/ml, respectively. By contrast, serum-opsonized zymosan-induced phagocytosis was unaltered by plant extract. C. laevigata extract (125 microg/ml) reduced FMLP-induced leukotriene B(4) production and lipopolysaccharide-induced generation of tumour necrosis factor-alpha and interleukin-8. Extract inhibited FMLP-induced intracellular calcium signal with potency of 17.4 microg/ml. Extract also markedly inhibited the extracellular calcium entry into calcium-depleted neutrophils, and the thapsigargin-induced intracellular calcium response. In conclusion, C. laevigata extract inhibited various functional outputs of activated human neutrophils which may be relevant to the pathophysiology of cardiac failure.

Multiparameter analysis of activated sludge inhibition by nickel, cadmium, and cobalt.

PubMed

Hernandez-Martinez, Gabriel R; Ortiz-Alvarez, Daniela; Perez-Roa, Michael; Urbina-Suarez, Nestor Andres; Thalasso, Frederic

2018-06-05

Activated sludge processes are often inhibited by nickel, cadmium, and cobalt. The inhibitory effect of these heavy metals on a synthetic wastewater treatment process was tested through pulse microrespirometry; i.e., pulse of substrate injected in a microreactor system. The inhibitory effect was tested under different conditions including the heavy metals, substrate and biomass concentrations, and exposure time. The inhibitory effect was quantified by the percentage of inhibition, half saturation constant (K S ), inhibition constant (K I ), and maximum oxygen uptake rate (OUR max ). The results indicated that, in a range of concentration from 0 to 40 mg L -1 , the three heavy metals exerted an uncompetitive and incomplete inhibitory effect, with a maximum inhibition of 67, 57, and 53% for Ni, Co, and Cd, respectively. An increase of the biomass concentration by 620% resulted in a decrease of the inhibition by 47 and 69% for Co and Cd, respectively, while no effect was observed on Ni inhibition. An increase of the substrate concentration by 87% resulted in an increase of the inhibition by 24, 70, and 47% for Ni, Co and Cd, respectively. In the case of nickel and cadmium, an increase in the exposure time to the heavy metals also increased the inhibition. Copyright © 2018 Elsevier B.V. All rights reserved.

Inhibition of parathyroid hormone release by maitotoxin, a calcium channel activator

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

Fitzpatrick, L.A.; Yasumoto, T.; Aurbach, G.D.

1989-01-01

Maitotoxin, a toxin derived from a marine dinoflagellate, is a potent activator of voltage-sensitive calcium channels. To further test the hypothesis that inhibition of PTH secretion by calcium is mediated via a calcium channel we studied the effect of maitotoxin on dispersed bovine parathyroid cells. Maitotoxin inhibited PTH release in a dose-dependent fashion, and inhibition was maximal at 1 ng/ml. Chelation of extracellular calcium by EGTA blocked the inhibition of PTH by maitotoxin. Maitotoxin enhanced the effects of the dihydropyridine calcium channel agonist (+)202-791 and increased the rate of radiocalcium uptake in parathyroid cells. Pertussis toxin, which ADP-ribosylates and inactivatesmore » a guanine nucleotide regulatory protein that interacts with calcium channels in the parathyroid cell, did not affect the inhibition of PTH secretion by maitotoxin. Maitotoxin, by its action on calcium channels allows entry of extracellular calcium and inhibits PTH release. Our results suggest that calcium channels are involved in the release of PTH. Inhibition of PTH release by maitotoxin is not sensitive to pertussis toxin, suggesting that maitotoxin may act distal to the site interacting with a guanine nucleotide regulatory protein, or maitotoxin could interact with other ions or second messengers to inhibit PTH release.« less

Thiopental inhibits nitric oxide production in rat aorta.

PubMed

Castillo, C; Asbun, J; Escalante, B; Villalón, C M; López, P; Castillo, E F

1999-12-01

We studied whether thiopental affects endothelial nitric oxide dependent vasodilator responses and nitrite production (an indicator of nitric oxide production) elicited by acetylcholine, histamine, and A23187 in rat aorta (artery in which nitric oxide is the main endothelial relaxant factor). In addition, we evaluated the barbiturate effect on nitric oxide synthase (NOS) activity in both rat aorta and kidney homogenates. Thiopental (10-100 microg/mL) reversibly inhibited the endothelium-dependent relaxation elicited by acetylcholine, histamine, and A23187. On the contrary, this anesthetic did not modify the endothelium-independent but cGMP-dependent relaxation elicited by sodium nitroprusside (1 nM - 1 microM) and nitroglycerin (1 nM - 1 microM), thus excluding an effect of thiopental on guanylate cyclase of vascular smooth muscle. Thiopental (100 microg/mL) inhibited both basal (87.8+/-14.3%) and acetylcholine- or A23187-stimulated (78.6+/-3.9 and 39.7+/-5.6%, respectively) production of nitrites in aortic rings. In addition the barbiturate inhibited (100 microg/mL) the NOS (45+/-4 and 42.8+/-9%) in aortic and kidney homogenates, respectively (measured as 14C-labeled citrulline production). In conclusion, thiopental inhibition of endothelium-dependent relaxation and nitrite production in aortic rings strongly suggests an inhibitory effect on NOS. Thiopental inhibition of the NOS provides further support to this contention.

Inhibition of cardiac sodium currents by toluene exposure

PubMed Central

Cruz, Silvia L; Orta-Salazar, Gerardo; Gauthereau, Marcia Y; Millan-Perez Peña, Lourdes; Salinas-Stefanón, Eduardo M

2003-01-01

Toluene is an industrial solvent widely used as a drug of abuse, which can produce sudden sniffing death due to cardiac arrhythmias. In this paper, we tested the hypothesis that toluene inhibits cardiac sodium channels in Xenopus laevis oocytes transfected with Nav1.5 cDNA and in isolated rat ventricular myocytes. In oocytes, toluene inhibited sodium currents (INa+) in a concentration-dependent manner, with an IC50 of 274 μM (confidence limits: 141–407μM). The inhibition was complete, voltage-independent, and slowly reversible. Toluene had no effect on: (i) the shape of the I–V curves; (ii) the reversal potential of Na+; and (iii) the steady-state inactivation. The slow recovery time constant from inactivation of INa+ decreased with toluene exposure, while the fast recovery time constant remained unchanged. Block of INa+ by toluene was use- and frequency-dependent. In rat cardiac myocytes, 300 μM toluene inhibited the sodium current (INa+) by 62%; this inhibition was voltage independent. These results suggest that toluene binds to cardiac Na+ channels in the open state and unbinds either when channels move between inactivated states or from an inactivated to a closed state. The use- and frequency-dependent block of INa+ by toluene might be responsible, at least in part, for its arrhythmogenic effect. PMID:14534149

Glitazones inhibit human monoamine oxidase but their anti-inflammatory actions are not mediated by VAP-1/semicarbazide-sensitive amine oxidase inhibition.

PubMed

Carpéné, Christian; Bizou, Mathilde; Tréguer, Karine; Hasnaoui, Mounia; Grès, Sandra

2015-09-01

Glitazones are peroxisome proliferator-activated receptor gamma (PPARγ) agonists widely used as antidiabetic drugs also known as thiazolidinediones. Most of them exert other effects such as anti-inflammatory actions via mechanisms supposed to be independent from PPARγ activation (e.g., decreased plasma monocyte chemoattractant protein-1 (MCP-1) levels). Recently, pioglitazone has been shown to inhibit the B form of monoamine oxidase (MAO) in mouse, while rosiglitazone and troglitazone were described as non-covalent inhibitors of both human MAO A and MAO B. Since molecules interacting with MAO might also inhibit semicarbazide-sensitive amine oxidase (SSAO), known as vascular adhesion protein-1 (VAP-1), and since VAP-1/SSAO inhibitors exhibit anti-inflammatory activity, our aim was to elucidate whether VAP-1/SSAO inhibition could be a mechanism involved in the anti-inflammatory behaviour of glitazones. To this aim, MAO and SSAO activities were measured in human subcutaneous adipose tissue biopsies obtained from overweight women undergoing plastic surgery. The production of hydrogen peroxide, an end-product of amine oxidase activity, was determined in tissue homogenates using a fluorometric method. The oxidation of 1 mM tyramine was inhibited by pargyline and almost resistant to semicarbazide, therefore predominantly MAO-dependent. Rosiglitazone was more potent than pioglitazone in inhibiting tyramine oxidation. By contrast, benzylamine oxidation was only abolished by semicarbazide: hence SSAO-mediated. Pioglitazone hampered SSAO activity only when tested at 1 mM while rosiglitazone was inefficient. However, rosiglitazone exhibited anti-inflammatory activity in human adipocytes by limiting MCP-1 expression. Our observations rule out any involvement of VAP-1/SSAO inhibition and subsequent limitation of leukocyte extravasation in the anti-inflammatory action of glitazones.

Distractor inhibition: Evidence from lateralized readiness potentials.

PubMed

Pramme, Lisa; Dierolf, Angelika M; Naumann, Ewald; Frings, Christian

2015-08-01

The present study investigated distractor inhibition on the level of stimulus representation. In a sequential distractor-to-distractor priming task participants had to respond to target letters flanked by distractor digits. Reaction time and stimulus-locked lateralized readiness potentials (S-LRPs) of probe responses were measured. Distractor-target onset asynchrony was varied. For RTs responses to probe targets were faster in the case of prime-distractor repetition compared to distractor changes indicating distractor inhibition. Benefits in RTs and the latency of S-LRP onsets for distractor repetition were also modulated by distractor-target onset asynchrony. For S-LRPs distractor inhibition was only present with a simultaneous onset of distractors and target. The results confirm previous results indicating inhibitory mechanisms of object-based selective attention on the level of distractor representations. Copyright © 2015 Elsevier Inc. All rights reserved.

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

Developmental consequences of behavioral inhibition: a model in rhesus monkeys (Macaca mulatta).

PubMed

Chun, Katie; Capitanio, John P

2016-11-01

In children, behavioral inhibition is characterized by a disposition to withdraw in the presence of strangers and novel situations. Later in life, behavioral inhibition can result in an increased risk for anxiety and depression and a decrease in social behavior. We selected rhesus monkeys that, during infancy, showed evidence of behavioral inhibition in response to separation, and contrasted them with non-inhibited peers. To understand the development of behavioral inhibition at juvenile age, we collected behavioral data in response to relocation; in response to a human intruder challenge; and in naturalistic outdoor field corrals. At 4 years of age (young adulthood), we again collected behavioral data in the outdoor field corrals to understand the adult social consequences of behavioral inhibition. We also included sex, dominance rank, and number of available kin in our analyses. Finally, to understand the consistency in behavior in behaviorally inhibited animals, we conducted exploratory analyses contrasting behaviorally inhibited animals that showed high vs. low durations of non-social behaviors as adults. At juvenile age, behaviorally inhibited animals continued to show behavioral differences in the novel testing room and during the human intruder challenge, generally showing evidence of greater anxiety and emotionality compared to non-inhibited controls. In their outdoor corrals, behaviorally inhibited juveniles spent more time alone and less time in proximity and grooming with mother and other adult females. In young adulthood, we found that behavioral inhibition was not related to time spent alone. We did find that duration of time alone in adulthood was related to time alone exhibited as juveniles; sex, dominance rank, or the number of kin were not influential in adult non-social duration, either as main effects or as moderators. Finally, exploratory analyses revealed that behaviorally inhibited females that were more sociable (less time spent alone) as

Peptide bioregulators inhibit apoptosis.

PubMed

Khavinson, V K; Kvetnoii, I M

2000-12-01

The effects of peptide bioregulators epithalon and vilon on the dynamics of irradiation-induced apoptotic death of spleen lymphocytes in rats indicate that these agents inhibit physiologically programmed cell death. The antiapoptotic effect of vilon was more pronounced, which corroborates the concept on tissue-specific effect of peptide bioregulators.

MicroRNA-1271 inhibits proliferation and promotes apoptosis of multiple myeloma cells through inhibiting smoothened-mediated Hedgehog signaling pathway.

PubMed

Xu, Zhengwei; Huang, Chen; Hao, Dingjun

2017-02-01

MicroRNAs (miRNAs) have emerged as important regulators in multiple myeloma (MM). miR-1271 is a tumor suppressor in many cancer types. However, the biological role of miR-1271 in MM remains unclear. In the present study, we elucidated the biological role of miR-1271 in MM. Results showed that miR-1271 was significantly decreased in primary MM cells from MM patients and MM cell lines. Overexpression of miR-1271 inhibited proliferation and promoted apoptosis of MM cells. Conversely, suppression of miR-1271 showed the opposite effect. Bioinformatics algorithm analysis predicted that smoothened (SMO), the activator of Hedgehog (HH) signaling pathway, was a direct target of miR-1271 that was experimentally verified by a dual-luciferase reporter assay. Furthermore, overexpression of miR-1271 inhibited SMO expression and HH signaling pathway. Conversely, the restoration of SMO expression markedly abolished the effect of miR-1271 overexpression on cell proliferation, apoptosis and HH signaling pathway in MM cells. Taken together, the present study suggests that miR-1271 functions as a tumor suppressor that inhibits proliferation and promotes apoptosis of MM cells through inhibiting SMO-mediated HH signaling pathway. This finding implies that miR-1271 is a potential therapeutic target for the treatment of MM.

Jasmonic Acid Enhances Al-Induced Root Growth Inhibition.

PubMed

Yang, Zhong-Bao; He, Chunmei; Ma, Yanqi; Herde, Marco; Ding, Zhaojun

2017-02-01

Phytohormones such as ethylene and auxin are involved in the regulation of the aluminum (Al)-induced root growth inhibition. Although jasmonate (JA) has been reported to play a crucial role in the regulation of root growth and development in response to environmental stresses through interplay with ethylene and auxin, its role in the regulation of root growth response to Al stress is not yet known. In an attempt to elucidate the role of JA, we found that exogenous application of JA enhanced the Al-induced root growth inhibition. Furthermore, phenotype analysis with mutants defective in either JA biosynthesis or signaling suggests that JA is involved in the regulation of Al-induced root growth inhibition. The expression of the JA receptor CORONATINE INSENSITIVE1 (COI1) and the key JA signaling regulator MYC2 was up-regulated in response to Al stress in the root tips. This process together with COI1-mediated Al-induced root growth inhibition under Al stress was controlled by ethylene but not auxin. Transcriptomic analysis revealed that many responsive genes under Al stress were regulated by JA signaling. The differential responsive of microtubule organization-related genes between the wild-type and coi1-2 mutant is consistent with the changed depolymerization of cortical microtubules in coi1 under Al stress. In addition, ALMT-mediated malate exudation and thus Al exclusion from roots in response to Al stress was also regulated by COI1-mediated JA signaling. Together, this study suggests that root growth inhibition is regulated by COI1-mediated JA signaling independent from auxin signaling and provides novel insights into the phytohormone-mediated root growth inhibition in response to Al stress. © 2017 American Society of Plant Biologists. All Rights Reserved.

α2 Adrenergic receptor-mediated inhibition of thermogenesis.

PubMed

Madden, Christopher J; Tupone, Domenico; Cano, Georgina; Morrison, Shaun F

2013-01-30

α2 adrenergic receptor (α2-AR) agonists have been used as antihypertensive agents, in the management of drug withdrawal, and as sedative analgesics. Since α2-AR agonists also influence the regulation of body temperature, we explored their potential as antipyretic agents. This study delineates the central neural substrate for the inhibition of rat brown adipose tissue (BAT) and shivering thermogenesis by α2-AR agonists. Nanoinjection of the α2-AR agonist clonidine (1.2 nmol) into the rostral raphe pallidus area (rRPa) inhibited BAT sympathetic nerve activity (SNA) and BAT thermogenesis. Subsequent nanoinjection of the α2-AR antagonist idazoxan (6 nmol) into the rRPa reversed the clonidine-evoked inhibition of BAT SNA and BAT thermogenesis. Systemic administration of the α2-AR agonists dexmedetomidine (25 μg/kg, i.v.) and clonidine (100 μg/kg, i.v.) inhibited shivering EMGs, BAT SNA, and BAT thermogenesis, effects that were reversed by nanoinjection of idazoxan (6 nmol) into the rRPa. Dexmedetomidine (100 μg/kg, i.p.) prevented and reversed lipopolysaccharide-evoked (10 μg/kg, i.p.) thermogenesis in free-behaving rats. Cholera toxin subunit b retrograde tracing from rRPa and pseudorabies virus transynaptic retrograde tracing from BAT combined with immunohistochemistry for catecholaminergic biosynthetic enzymes revealed the ventrolateral medulla as the source of catecholaminergic input to the rRPa and demonstrated that these catecholaminergic neurons are synaptically connected to BAT. Photostimulation of ventrolateral medulla neurons expressing the PRSx8-ChR2-mCherry lentiviral vector inhibited BAT SNA via activation of α2-ARs in the rRPa. These results indicate a potent inhibition of BAT and shivering thermogenesis by α2-AR activation in the rRPa, and suggest a therapeutic potential of α2-AR agonists for reducing potentially lethal elevations in body temperature during excessive fever.

Alpha-2 adrenergic receptor-mediated inhibition of thermogenesis

PubMed Central

Madden, Christopher J.; Tupone, Domenico; Cano, Georgina; Morrison, Shaun F.

2013-01-01

Alpha2-adrenergic receptor (α2-AR) agonists have been use as anti-hypertensive agents, in the management of drug withdrawal, and as sedative analgesics. Since α2-AR agonists also influence the regulation of body temperature, we explored their potential as antipyretic agents. This study delineates the central neural substrate for the inhibition of rat brown adipose tissue (BAT) and shivering thermogenesis by α2-AR agonists. Nanoinjection of the α2-AR agonist, clonidine (1.2 nmol), into the rostral raphe pallidus (rRPa) inhibited BAT sympathetic nerve activity (SNA) and BAT thermogenesis. Subsequent nanoinjection of the α2-AR antagonist, idazoxan (6nmol) into the rRPa reversed the clonidine-evoked inhibition of BAT SNA and BAT thermogenesis. Systemic administration of the α2-AR agonists, dexmedetomidine (25ug/kg, iv) or clonidine (100ug/kg, iv) inhibited shivering EMGs, BAT SNA and BAT thermogenesis effects that were reversed by nanoinjection of idazoxan (6nmol) into the rRPa. Dexmedetomidine (100µg/kg, ip) prevented and reversed lipopolysaccharide (10µg/kg ip)-evoked thermogenesis in free-behaving rats. Cholera toxin subunit b retrograde tracing from rRPa and pseudorabies virus transynaptic retrograde tracing from BAT combined with immunohistochemistry for catecholaminergic biosynthetic enzymes revealed the ventrolateral medulla as the source of catecholaminergic input to the rRPa and demonstrated that these catecholaminergic neurons are synaptically connected to BAT. Photostimulation of VLM neurons expressing of the PRSx8-ChR2-mCherry lentiviral vector inhibited BAT SNA via activation of α2-ARs in the rRPa. These results indicate a potent inhibition of BAT and shivering thermogenesis by α2-AR activation in the rRPa, and suggest a therapeutic potential of α2-AR agonists for reducing potentially-lethal elevations in body temperature during excessive fever. PMID:23365239

Novel Antimicrobial Peptides That Inhibit Gram Positive Bacterial Exotoxin Synthesis

PubMed Central

Merriman, Joseph A.; Nemeth, Kimberly A.; Schlievert, Patrick M.

2014-01-01

Gram-positive bacteria, such as Staphylococcus aureus, cause serious human illnesses through combinations of surface virulence factors and secretion of exotoxins. Our prior studies using the protein synthesis inhibitor clindamycin and signal transduction inhibitors glycerol monolaurate and α-globin and β-globin chains of hemoglobin indicate that their abilities to inhibit exotoxin production by S. aureus are separable from abilities to inhibit growth of the organism. Additionally, our previous studies suggest that inhibition of exotoxin production, in absence of ability to kill S. aureus and normal flora lactobacilli, will prevent colonization by pathogenic S. aureus, while not interfering with lactobacilli colonization. These disparate activities may be important in development of novel anti-infective agents that do not alter normal flora. We initiated studies to explore the exotoxin-synthesis-inhibition activity of hemoglobin peptides further to develop potential agents to prevent S. aureus infections. We tested synthesized α-globin chain peptides, synthetic variants of α-globin chain peptides, and two human defensins for ability to inhibit exotoxin production without significantly inhibiting S. aureus growth. All of these peptides were weakly or not inhibitory to bacterial growth. However, the peptides were inhibitory to exotoxin production with increasing activity dependent on increasing numbers of positively-charged amino acids. Additionally, the peptides could be immobilized on agarose beads or have amino acid sequences scrambled and still retain exotoxin-synthesis-inhibition. The peptides are not toxic to human vaginal epithelial cells and do not inhibit growth of normal flora L. crispatus. These peptides may interfere with plasma membrane signal transduction in S. aureus due to their positive charges. PMID:24748386

Inhibition properties of propolis extracts to some clinically important enzymes.

PubMed

Baltas, Nimet; Yildiz, Oktay; Kolayli, Sevgi

2016-01-01

The present study was conducted to envisage inhibition effects of propolis on the crucial enzymes, urease, xanthine oxidase (XO) and acetylcholinesterase (AChE). Some of the antioxidant properties of the propolis samples were determined using the total phenolic content (TPE) and total flavonoids in the eight different ethanolic propolis extracts (EPE) samples. Inhibition values of the enzymes were expressed as inhibition concentration (IC 50 ; mg/mL or μg/mL) causing 50% inhibition of the enzymes with donepezil, acetohydroxamic acid and allopurinol as reference inhibitors. All the propolis extracts exhibited variable inhibition effects on these enzymes, but the higher the phenolic contents the lower the inhibitions values (IC 50 = 0.074 to 1.560 mg/mL). IC 50 values of the P5 propolis sample having the highest TPE, obtained from Zonguldak, for AChE, urease and XO were 0.081 ± 0.009, 0.080 ± 0.006 and 0.074 ± 0.011 μg/mL, respectively. The EPE proved to be a good source of inhibitor agents that can be used as natural inhibitors to serve human health.

Prostaglandin E1 inhibits endocytosis in the β-cell endocytosis.

PubMed

Zhao, Ying; Fang, Qinghua; Straub, Susanne G; Lindau, Manfred; Sharp, Geoffrey W G

2016-06-01

Prostaglandins inhibit insulin secretion in a manner similar to that of norepinephrine (NE) and somatostatin. As NE inhibits endocytosis as well as exocytosis, we have now examined the modulation of endocytosis by prostaglandin E1 (PGE1). Endocytosis following exocytosis was recorded by whole-cell patch clamp capacitance measurements in INS-832/13 cells. Prolonged depolarizing pulses producing a high level of Ca(2+) influx were used to stimulate maximal exocytosis and to deplete the readily releasable pool (RRP) of granules. This high Ca(2+) influx eliminates the inhibitory effect of PGE1 on exocytosis and allows specific characterization of the inhibitory effect of PGE1 on the subsequent compensatory endocytosis. After stimulating exocytosis, endocytosis was apparent under control conditions but was inhibited by PGE1 in a Pertussis toxin-sensitive (PTX)-insensitive manner. Dialyzing a synthetic peptide mimicking the C-terminus of the α-subunit of the heterotrimeric G-protein Gz into the cells blocked the inhibition of endocytosis by PGE1, whereas a control-randomized peptide was without effect. These results demonstrate that PGE1 inhibits endocytosis and Gz mediates the inhibition. © 2016 Society for Endocrinology.

Lignocellulosic hydrolysate inhibitors selectively inhibit/deactivate cellulase performance.

PubMed

Mhlongo, Sizwe I; den Haan, Riaan; Viljoen-Bloom, Marinda; van Zyl, Willem H

2015-12-01

In this study, we monitored the inhibition and deactivation effects of various compounds associated with lignocellulosic hydrolysates on individual and combinations of cellulases. Tannic acid representing polymeric lignin residues strongly inhibited cellobiohydrolase 1 (CBH1) and β-glucosidase 1 (BGL1), but had a moderate inhibitory effect on endoglucanase 2 (EG2). Individual monomeric lignin residues had little or no inhibitory effect on hydrolytic enzymes. However, coniferyl aldehyde and syringaldehyde substantially decreased the activity of CBH1 and deactivated BGL1. Acetic and formic acids also showed strong inhibition of BGL1 but not CBH1 and EG2, whereas tannic, acetic and formic acid strongly inhibited a combination of CBH1 and EG2 during Avicel hydrolysis. Diminishing enzymatic hydrolysis is largely a function of inhibitor concentration and the enzyme-inhibitor relationship, rather than contact time during the hydrolysis process (i.e. deactivation). This suggests that decreased rates of hydrolysis during the enzymatic depolymerisation of lignocellulosic hydrolysates may be imparted by other factors related to substrate crystallinity and accessibility. Copyright © 2015 Elsevier Inc. All rights reserved.

Amiloride Derivatives Inhibit Coxsackievirus B3 RNA Replication▿

PubMed Central

Harrison, David N.; Gazina, Elena V.; Purcell, Damian F.; Anderson, David A.; Petrou, Steven

2008-01-01

Amiloride derivatives are known blockers of the cellular Na+/H+ exchanger and the epithelial Na+ channel. More recent studies demonstrate that they also inhibit ion channels formed by a number of viral proteins. We previously reported that 5-(N-ethyl-N-isopropyl)amiloride (EIPA) modestly inhibits intracellular replication and, to a larger extent, release of human rhinovirus 2 (HRV2) (E. V. Gazina, D. N. Harrison, M. Jefferies, H. Tan, D. Williams, D. A. Anderson and S. Petrou, Antiviral Res. 67:98-106, 2005). Here, we demonstrate that amiloride and EIPA strongly inhibit coxsackievirus B3 (CVB3) RNA replication and do not inhibit CVB3 release, in contrast to our previous findings on HRV2. Passaging of plasmid-derived CVB3 in the presence of amiloride generated mutant viruses with amino acid substitutions in position 299 or 372 of the CVB3 polymerase. Introduction of either of these mutations into the CVB3 plasmid produced resistance to amiloride and EIPA, suggesting that they act as inhibitors of CVB3 polymerase, a novel mechanism of antiviral activity for these compounds. PMID:18032495

Enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7.

PubMed

Fang, Zhong-Ze; Wang, Haina; Cao, Yun-Feng; Sun, Dong-Xue; Wang, Li-Xuan; Hong, Mo; Huang, Ting; Chen, Jian-Xing; Zeng, Jia

2015-03-01

UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)-carprofen and (S)-carprofen towards multiple UGT isoforms. The results showed that (S)-carprofen exhibited stronger inhibition potential than (R)-carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R)-carprofen and (S)-carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)-carprofen and (R)-carprofen towards UGT2B7. A Lineweaver-Burk plot showed that both (S)-carprofen and (R)-carprofen exhibited competitive inhibition towards UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameter (Ki ) was calculated to be 7.0 μM and 31.1 μM for (S)-carprofen and (R)-carprofen, respectively. Based on the standard for drug-drug interaction, the threshold for (S)-carprofen and (R)-carprofen to induce a drug-drug interaction is 0.7 μM and 3.1 μM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)-carprofen and (R)-carprofen to possibly induce the drug-drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)-carprofen is more important than (R)-carprofen to avoid a possible drug-drug interaction between carprofen and the drugs mainly undergoing UGT2B7-catalyzed metabolism. © 2014 Wiley Periodicals, Inc.

Boric acid inhibits human prostate cancer cell proliferation.

PubMed

Barranco, Wade T; Eckhert, Curtis D

2004-12-08

The role of boron in biology includes coordinated regulation of gene expression in mixed bacterial populations and the growth and proliferation of higher plants and lower animals. Here we report that boric acid, the dominant form of boron in plasma, inhibits the proliferation of prostate cancer cell lines, DU-145 and LNCaP, in a dose-dependent manner. Non-tumorigenic prostate cell lines, PWR-1E and RWPE-1, and the cancer line PC-3 were also inhibited, but required concentrations higher than observed human blood levels. Studies using DU-145 cells showed that boric acid induced a cell death-independent proliferative inhibition, with little effect on cell cycle stage distribution and mitochondrial function.

Inhibition of oxidative drug metabolism by orphenadrine: in vitro and in vivo evidence for isozyme-specific complexation of cytochrome P-450 and inhibition kinetics.

PubMed

Reidy, G F; Mehta, I; Murray, M

1989-05-01

The anti-parkinsonian agent orphenadrine has been shown to form an in vitro metabolic intermediate (MI) complex in hepatic microsomes isolated from phenobarbital (PB)-treated rats. The present study was undertaken to assess the cytochrome P-450 isozyme specificity of inhibition and MI complexation. Spectral studies with untreated and PB-induced rat hepatic microsomes confirmed earlier reports on the selectivity of P-450 complexation by orphenadrine; MI complex formation was only observed with PB-induced microsomes. Inhibition studies with the P-450 substrates androst-4-ene-3,17-dione (androstenedione) and 7-pentoxyresorufin revealed selective inhibition of P-450 PB-B/D-associated monooxygenase activity. Thus, in microsomes from untreated male rats, orphenadrine failed to significantly inhibit (less than 50% inhibition up to a concentration of 300 microM) any of the major pathways of P-450-associated androstenedione metabolism. Preincubation of these microsomal fractions with orphenadrine and NADPH was not associated with increased inhibition of androstenedione metabolism. However, in PB-induced microsomes, P-450 PB-B/D-specific androstenedione 16 beta-hydroxylase activity was significantly and selectively inhibited (IC50 = 90 microM). Preincubation of orphenadrine with NADPH-supplemented PB-induced microsomes for 2, 4, or 8 min before androstenedione addition resulted in increased inhibition toward 16 beta-hydroxylase activity, lowering the observed IC50 to 6.6, 0.47, and 0.06 microM), respectively. Preincubation did not affect the selectivity of inhibition. In the absence of preincubation, orphenadrine appeared to be a potent mixed (competitive/noncompetitive)-type inhibitor of P-450 PB-B/D-associated pentoxyresorufin O-depentylation (Ki = 3.8 microM). Preincubation of orphenadrine with NADPH-supplemented microsomal fractions for 4 min resulted in a 30-fold lowering of the apparent inhibitor constant (Ki = 0.13 microM) and a change in the apparent inhibition

Cooperation for Better Inhibiting.

PubMed

Novoa, Eva Maria; Ribas de Pouplana, Lluís

2015-06-18

Cladosporin is an antimalarial drug that acts as an ATP-mimetic to selectively inhibit Plasmodium lysyl-tRNA synthetase. Using multiple crystal structures, Fang et al. (2015) reveal in this issue of Chemistry & Biology the fascinating mechanism responsible for cladosporin selectivity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity.

PubMed

Markowicz-Piasecka, Magdalena; Sikora, Joanna; Mateusiak, Łukasz; Mikiciuk-Olasik, Elżbieta; Huttunen, Kristiina M

2017-01-01

The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer's disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35  μ mol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC 50  = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC 50  = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC 50  = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

High Concentrations of Tranexamic Acid Inhibit Ionotropic Glutamate Receptors.

PubMed

Lecker, Irene; Wang, Dian-Shi; Kaneshwaran, Kirusanthy; Mazer, C David; Orser, Beverley A

2017-07-01

The antifibrinolytic drug tranexamic acid is structurally similar to the amino acid glycine and may cause seizures and myoclonus by acting as a competitive antagonist of glycine receptors. Glycine is an obligatory co-agonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Thus, it is plausible that tranexamic acid inhibits NMDA receptors by acting as a competitive antagonist at the glycine binding site. The aim of this study was to determine whether tranexamic acid inhibits NMDA receptors, as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate subtypes of ionotropic glutamate receptors. Tranexamic acid modulation of NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate receptors was studied using whole cell voltage-clamp recordings of current from cultured mouse hippocampal neurons. Tranexamic acid rapidly and reversibly inhibited NMDA receptors (half maximal inhibitory concentration = 241 ± 45 mM, mean ± SD; 95% CI, 200 to 281; n = 5) and shifted the glycine concentration-response curve for NMDA-evoked current to the right. Tranexamic acid also inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (half maximal inhibitory concentration = 231 ± 91 mM; 95% CI, 148 to 314; n = 5 to 6) and kainate receptors (half maximal inhibitory concentration = 90 ± 24 mM; 95% CI, 68 to 112; n = 5). Tranexamic acid inhibits NMDA receptors likely by reducing the binding of the co-agonist glycine and also inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors. Receptor blockade occurs at high millimolar concentrations of tranexamic acid, similar to the concentrations that occur after topical application to peripheral tissues. Glutamate receptors in tissues including bone, heart, and nerves play various physiologic roles, and tranexamic acid inhibition of these receptors may contribute to adverse drug effects.

Curcumin directly inhibits the transport activity of GLUT1

PubMed Central

Gunnink, Leesha K.; Alabi, Ola D.; Kuiper, Benjamin D.; Gunnink, Stephen M.; Schuiteman, Sam J.; Strohbehn, Lauren E.; Hamilton, Kathryn E.; Wrobel, Kathryn E.; Louters, Larry L.

2016-01-01

Curcumin, a major ingredient in turmeric, has a long history of medicinal applications in a wide array of maladies including treatment for diabetes and cancer. Seemingly counterintuitive to the documented hypoglycemic effects of curcumin, however, a recent report indicates that curcumin directly inhibits glucose uptake in adipocytes. The major glucose transporter in adipocytes is GLUT4. Therefore, this study investigates the effects of curcumin in cell lines where the major transporter is GLUT1. We report that curcumin has an immediate inhibitory effect on basal glucose uptake in L929 fibroblast cells with a maximum inhibition of 80% achieved at 75 μM curcumin. Curcumin also blocks activation of glucose uptake by azide, glucose deprivation, hydroxylamine, or phenylarsine oxide. Inhibition does not increase with exposure time and the inhibitory effects reverse within an hour. Inhibition does not appear to involve a reaction between curcumin and the thiol side chain of a cysteine residue since neither prior treatment of cells with iodoacetamide nor curcumin with cysteine alters curcumin’s inhibitory effects. Curcumin is a mixed inhibitor reducing the Vmax of 2DG transport by about half with little effect on the Km. The inhibitory effects of curcumin are not additive to the effects of cytochalasin B and 75 μM curcumin actually reduces specific cytochalasin B binding by 80%. Taken together, the data suggest that curcumin binds directly to GLUT1 at a site that overlaps with the cytochalasin B binding site and thereby inhibits glucose transport. A direct inhibition of GLUT proteins in intestinal epithelial cells would likely reduce absorption of dietary glucose and contribute to a hypoglycemic effect of curcumin. Also, inhibition of GLUT1 activity might compromise cancer cells that overexpress GLUT1 and be another possible mechanism for the documented anticancer effects of curcumin. PMID:27039889

Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex.

PubMed

Sheehan, J P; Lan, H C

1998-09-01

Systemic administration of ISIS 2302, a 20-mer antisense phosphorothioate oligonucleotide targeting human intercellular adhesion molecule-1 mRNA, causes prolongation of plasma clotting times in both monkey and human studies. The anticoagulant effects of ISIS 2302 were investigated with both in vitro coagulation assays in human plasma and purified enzyme systems. At high oligonucleotide plasma concentrations (>100 microgram/mL), prolongation of the prothrombin and thrombin times was observed. In a thrombin time assay using purified components, high concentrations of ISIS 2302 inhibited thrombin clotting activity both by stimulating inhibition by heparin cofactor II and directly competing with fibrinogen for binding to anion binding exosite I. In contrast, low concentrations of ISIS 2302 (<100 microgram/mL) showed a selective, linear prolongation of the activated partial thromboplastin time (PTT). The rate limiting effect of 50 microgram/mL ISIS 2302, which prolonged the PTT to 1.5 times control, was identified by sequential modification of the clotting assay. Delaying addition of oligonucleotide until after contact activation failed to correct prolongation of the PTT. The calcium-dependent steps of the intrinsic pathway were individually assessed by adding sufficient activated coagulation factor to correct the PTT in plasma deficient in that specific factor. Addition of factor XIa, IXa, VIIIa, or Va failed to correct the PTT in the presence of ISIS 2302. In contrast, 0.2 nmol/L factor Xa corrected prolongation of the PTT in factor X-deficient plasma with or without oligonucleotide present. ISIS 2302 (50 microgram/mL) did not prolong a modified Russel viper venom time, suggesting no significant inhibition of prothrombinase. Thus, 50 microgram/mL ISIS 2302 prolonged the PTT by selectively inhibiting intrinsic tenase activity. ISIS 2302 showed partial inhibition of intrinsic tenase activity (to approximately 35% of control) at clinically relevant oligonucleotide

Phosphatidic acid inhibits ceramide 1-phosphate-stimulated macrophage migration.

PubMed

Ouro, Alberto; Arana, Lide; Rivera, Io-Guané; Ordoñez, Marta; Gomez-Larrauri, Ana; Presa, Natalia; Simón, Jorge; Trueba, Miguel; Gangoiti, Patricia; Bittman, Robert; Gomez-Muñoz, Antonio

2014-12-15

Ceramide 1-phosphate (C1P) was recently demonstrated to potently induce cell migration. This action could only be observed when C1P was applied exogenously to cells in culture, and was inhibited by pertussis toxin. However, the mechanisms involved in this process are poorly understood. In this work, we found that phosphatidic acid (PA), which is structurally related to C1P, displaced radiolabeled C1P from its membrane-binding site and inhibited C1P-stimulated macrophage migration. This effect was independent of the saturated fatty acid chain length or the presence of a double bond in each of the fatty acyl chains of PA. Treatment of RAW264.7 macrophages with exogenous phospholipase D (PLD), an enzyme that produces PA from membrane phospholipids, also inhibited C1P-stimulated cell migration. Likewise, PA or exogenous PLD inhibited C1P-stimulated extracellularly regulated kinases (ERK) 1 and 2 phosphorylation, leading to inhibition of cell migration. However, PA did not inhibit C1P-stimulated Akt phosphorylation. It is concluded that PA is a physiological regulator of C1P-stimulated macrophage migration. These actions of PA may have important implications in the control of pathophysiological functions that are regulated by C1P, including inflammation and various cellular processes associated with cell migration such as organogenesis or tumor metastasis. Copyright © 2014 Elsevier Inc. All rights reserved.

Inhibition of HIV infection by caerin 1 antimicrobial peptides.

PubMed

VanCompernolle, Scott; Smith, Patricia B; Bowie, John H; Tyler, Michael J; Unutmaz, Derya; Rollins-Smith, Louise A

2015-09-01

The major mode of transmission of the human immunodeficiency virus (HIV) is by sexual intercourse. In the effort to halt the spread of HIV, one measure that holds great promise is the development of effective microbicides that can prevent transmission. Previously we showed that several amphibian antimicrobial peptides (AMPs) completely inhibit HIV infection of T cells while maintaining good viability of the T cell targets. These peptides also inhibited the transfer of HIV by dendritic cells (DCs) to T cells when added up to 8h after virus exposure. Here we report on the anti-HIV activity of 18 additional structurally related caerin 1 family peptides in comparison with our previous best candidate caerin 1.9. Nine peptides were equally effective or more effective in the inhibition of T cell infection and disruption of the HIV envelope as caerin 1.9. Of those nine peptides, three peptides (caerin 1.2, caerin 1.10, and caerin 1.20) exhibited excellent inhibition of HIV infectivity at low concentrations (12-25μM) and limited toxicity against target T cells and endocervical epithelial cells. There was a direct correlation between the effectiveness of the peptides in disruption of the viral envelope and their capacity to inhibit infection. Thus, several additional caerin 1 family peptides inhibit HIV infection have limited toxicity for vaginal epithelial cells, and would be good candidates for inclusion in microbicide formulations. Copyright © 2015 Elsevier Inc. All rights reserved.

Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1 in Cells

PubMed Central

Zhang, Feiran; Bhat, Shridhar; Gabelli, Sandra B.; Chen, Xiaochun; Miller, Michelle S.; Nacev, Benjamin A.; Cheng, Yim Ling; Meyers, David J.; Tenney, Karen; Shim, Joong Sup; Crews, Phillip; Amzel, L. Mario; Ma, Dawei; Liu, Jun O.

2013-01-01

Methionine aminopeptidases (MetAPs) which remove the initiator methionine from nascent peptides are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1–4). But all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1–4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells. PMID:23634668

Stereoselective effects of MDMA on inhibition of monoamine uptake

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

Steele, T.D.; Nichols, D.E.; Yim, G.K.W.

1986-03-05

The R(-)-isomers of hallucinogenic phenylisopropylamines are most active, whereas the S(+)-enantiomers of amphetamine (AMPH) and methylenedioxymethamphetamine (MDMA) are more potent centrally. To determine if MDMA exhibits stereoselective effects at the biochemical level that resemble either those of amphetamine or the potent hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM), the ability of the isomers of MDMA, AMPH and DOM to inhibit uptake of radiolabelled monoamines into synaptosomes was measured. AMPH was more potent than MDMA in inhibiting uptake of /sup 3/H-norepinephrine (NE) into hypothalamic synaptosomes and /sup 3/H-dopamine (DA) into striatal synaptosomes. The S(+)-isomer was more active in each case. MDMA was more potent thanmore » AMPH in inhibiting uptake of /sup 3/H-serotonin (5-HT) into hippocampal synaptosomes and exhibited a high degree of stereoselectivity, in favor of the S(+)-isomer. DOM showed only minimal activity in inhibiting uptake of any monoamine (IC/sub 50/ > 10/sup -5/M). These results suggest that MDMA exhibits stereoselective effects similar to those of amphetamine on monoamine uptake inhibition, a parameter that is unrelated to the mechanism of action of the hallucinogen DOM.« less

Inhibition of polymorphonuclear leukocyte function by Legionella pneumophila exoproducts.

PubMed

Sahney, N N; Lambe, B C; Summersgill, J T; Miller, R D

1990-08-01

Total exoproducts (relative molecular mass greater than 10,000) from wild-type strains of Legionella pneumophila markedly inhibited human polymorphonuclear leukocyte (PMN) superoxide anion generation, at sub-lethal concentrations, in response to four stimuli [1.7, 0, 0.6 and 3.4% of control for zymosan activated particles (ZAP), phorbol myristate acetate (PMA), calcium ionophore (A 23187), and formyl-methionyl-leucyl-phenylalanine (fMLP), respectively]. PMN chemotaxis towards fMLP and spontaneous migration, were also dramatically inhibited (2.8 and 2.9% of buffer-treated controls, respectively). In contrast, total exoproducts from the cas-1 strain of L. pneumophila, a protease-deficient mutant generated by ethyl methane sulfonate mutagenesis, failed to inhibit PMN superoxide production in response to ZAP and PMA and only partially inhibited PMN response to A 23187 and fMLP. PMN spontaneous migration was unaffected by treatment with total exoproducts from the mutant, while directed chemotaxis was partially inhibited (51.4%). These data demonstrated that L. pneumophila total exoproducts, primarily protease had significant inhibitory effects on normal PMN function and may play an important contributory role in the pathogenesis of legionnaire's disease.

The precarious couple effect: verbally inhibited men + critical, disinhibited women = bad chemistry.

PubMed

Swann, William B; Rentfrow, Peter J; Gosling, Samuel D

2003-12-01

When critical, verbally disinhibited women are paired with verbally inhibited men, relationship quality suffers, rendering the relationship precarious. This effect theoretically emerges when (a). verbally disinhibited women pair with relatively inhibited men (man-more-inhibited couples) and (b). the disinhibition of women in man-more-inhibited couples amplifies women's criticalness and alienates men. Three studies (Ns=437, 300, and 564) provided evidence that relationship quality suffered in man-more-inhibited couples; a 4th study (N=168) showed that the criticalness of women in man-more-inhibited couples did indeed undermine relationship quality. Implications for understanding the impact of gender expectations on relationships and for integrating behavioral and personological approaches to close relationships are discussed.

High-mobility group box 1 inhibits HCO3− absorption in the medullary thick ascending limb through RAGE-Rho-ROCK-mediated inhibition of basolateral Na+/H+ exchange

PubMed Central

Watts, Bruns A.; George, Thampi; Badalamenti, Andrew

2016-01-01

High-mobility group box 1 (HMGB1) is a nuclear protein released extracellularly in response to infection or injury, where it activates immune responses and contributes to the pathogenesis of kidney dysfunction in sepsis and sterile inflammatory disorders. Recently, we demonstrated that HMGB1 inhibits HCO3− absorption in perfused rat medullary thick ascending limbs (MTAL) through a basolateral receptor for advanced glycation end products (RAGE)-dependent pathway that is additive to Toll-like receptor 4 (TLR4)-ERK-mediated inhibition by LPS (Good DW, George T, Watts BA III. Am J Physiol Renal Physiol 309: F720–F730, 2015). Here, we examined signaling and transport mechanisms that mediate inhibition by HMGB1. Inhibition of HCO3− absorption by HMGB1 was eliminated by the Rho-associated kinase (ROCK) inhibitor Y27632 and by a specific inhibitor of Rho, the major upstream activator of ROCK. HMGB1 increased RhoA and ROCK1 activity. HMGB1-induced ROCK1 activation was eliminated by the RAGE antagonist FPS-ZM1 and by inhibition of Rho. The Rho and ROCK inhibitors had no effect on inhibition of HCO3− absorption by bath LPS. Inhibition of HCO3− absorption by HMGB1 was eliminated by bath amiloride, 0 Na+ bath, and the F-actin stabilizer jasplakinolide, three conditions that selectively prevent inhibition of MTAL HCO3− absorption mediated through NHE1. HMGB1 decreased basolateral Na+/H+ exchange activity through activation of ROCK. We conclude that HMGB1 inhibits HCO3− absorption in the MTAL through a RAGE-RhoA-ROCK1 signaling pathway coupled to inhibition of NHE1. The HMGB1-RAGE-RhoA-ROCK1 pathway thus represents a potential target to attenuate MTAL dysfunction during sepsis and other inflammatory disorders. HMGB1 and LPS inhibit HCO3− absorption through different receptor signaling and transport mechanisms, which enables these pathogenic mediators to act directly and independently to impair MTAL function. PMID:27358052

Belief Inhibition in Children's Reasoning: Memory-Based Evidence

ERIC Educational Resources Information Center

Steegen, Sara; Neys, Wim De

2012-01-01

Adult reasoning has been shown as mediated by the inhibition of intuitive beliefs that are in conflict with logic. The current study introduces a classic procedure from the memory field to investigate belief inhibition in 12- to 17-year-old reasoners. A lexical decision task was used to probe the memory accessibility of beliefs that were cued…

Inhibiting poly(ADP-ribosylation) improves axon regeneration.

PubMed

Byrne, Alexandra B; McWhirter, Rebecca D; Sekine, Yuichi; Strittmatter, Stephen M; Miller, David M; Hammarlund, Marc

2016-10-04

The ability of a neuron to regenerate its axon after injury depends in part on its intrinsic regenerative potential. Here, we identify novel intrinsic regulators of axon regeneration: poly(ADP-ribose) glycohodrolases (PARGs) and poly(ADP-ribose) polymerases (PARPs). PARGs, which remove poly(ADP-ribose) from proteins, act in injured C. elegans GABA motor neurons to enhance axon regeneration. PARG expression is regulated by DLK signaling, and PARGs mediate DLK function in enhancing axon regeneration. Conversely, PARPs, which add poly(ADP-ribose) to proteins, inhibit axon regeneration of both C. elegans GABA neurons and mammalian cortical neurons. Furthermore, chemical PARP inhibitors improve axon regeneration when administered after injury. Our results indicate that regulation of poly(ADP-ribose) levels is a critical function of the DLK regeneration pathway, that poly-(ADP ribosylation) inhibits axon regeneration across species, and that chemical inhibition of PARPs can elicit axon regeneration.

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

Inhibition of gravitropism in oat coleoptiles by calcium chelation

NASA Technical Reports Server (NTRS)

Roux, S. J.

1984-01-01

Some cellular event necessary for gravitropism is inhibited by EGTA without interferring with the overall growth. Calcium relieves this inhibition and demonstrates both that inhibition is reversible and was probably due to a reduction in the ability to free calcium required for one or more at the transduction steps of gravitropism. At the near neutral pH used, EGTA is charged and would not be expected to readily cross the membrane. One of its primary effects, then, is probably the bringing of free calcium in the apoplastic space exterior to the cell membranes.

Quercetin inhibits hexose transport in a human diploid fibroblast

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

Salter, D.W.; Custead-Jones, S.; Cook, J.S.

1978-01-01

The flavonol quercetin, a phloretin analog, inhibits transport of 2-deoxyglucose and 3-O-methylglucose in a cultured human diploid fibroblast. This inhibition is related to transport itself and not to the reported effects of flavonoids on membrane-bound ATPases. From concentration-inhibition curves at several pH's we conclude that uncharged (acid) quercetin (pH = 7.65) is the inhibitory form of the molecule (K/sub I/ = 10 ..mu..m). Quercetin, unlike phloretin, is rapidly degraded in 0.1 N NaOH; the degradation products are weakly inhibitory to hexose transport.

Boric acid and boronic acids inhibition of pigeonpea urease.

PubMed

Reddy, K Ravi Charan; Kayastha, Arvind M

2006-08-01

Urease from the seeds of pigeonpea was competitively inhibited by boric acid, butylboronic acid, phenylboronic acid, and 4-bromophenylboronic acid; 4-bromophenylboronic acid being the strongest inhibitor, followed by boric acid > butylboronic acid > phenylboronic acid, respectively. Urease inhibition by boric acid is maximal at acidic pH (5.0) and minimal at alkaline pH (10.0), i.e., the trigonal planar B(OH)3 form is a more effective inhibitor than the tetrahedral B(OH)4 -anionic form. Similarly, the anionic form of phenylboronic acid was least inhibiting in nature.

Contrasting neural effects of aging on proactive and reactive response inhibition.

PubMed

Bloemendaal, Mirjam; Zandbelt, Bram; Wegman, Joost; van de Rest, Ondine; Cools, Roshan; Aarts, Esther

2016-10-01

Two distinct forms of response inhibition may underlie observed deficits in response inhibition in aging. We assessed whether age-related neurocognitive impairments in response inhibition reflect deficient reactive inhibition (outright stopping) or also deficient proactive inhibition (anticipatory response slowing), which might be particularly evident with high information load. We used functional magnetic resonance imaging in young (n = 25, age range 18-32) and older adults (n = 23, 61-74) with a stop-signal task. Relative to young adults, older adults exhibited impaired reactive inhibition (i.e., longer stop-signal reaction time) and increased blood oxygen level-dependent (BOLD) signal for successful versus unsuccessful inhibition in the left frontal cortex and cerebellum. Furthermore, older adults also exhibited impaired proactive slowing, but only as a function of information load. This load-dependent behavioral deficit was accompanied by a failure to increase blood oxygen level-dependent (BOLD) signal under high information load in lateral frontal cortex, presupplementary motor area and striatum. Our findings suggest that inhibitory deficits in older adults are caused both by reduced stopping abilities and by diminished preparation capacity during information overload. Copyright © 2016 Elsevier Inc. All rights reserved.

Method for inhibiting gum formation in liquid hydrocarbon mediums

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

Reid, D.K.

1990-07-17

This patent describes a method of inhibiting the formation of gum and sediment in a liquid hydrocarbonaceous medium. It comprises: adding to the medium an inhibiting amount of an alkyl 1,2-dihydroquinoline or polymerized alkyl 1,2-dihydroquinoline.

Maribavir Inhibits Epstein-Barr Virus Transcription through the EBV Protein Kinase

PubMed Central

Whitehurst, Christopher B.; Sanders, Marcia K.; Law, Mankit; Wang, Fu-Zhang; Xiong, Jie; Dittmer, Dirk P.

2013-01-01

Maribavir (MBV) inhibits Epstein-Barr virus (EBV) replication and the enzymatic activity of the viral protein kinase BGLF4. MBV also inhibits expression of multiple EBV transcripts during EBV lytic infection. Here we demonstrate, with the use of a BGLF4 knockout virus, that effects of MBV on transcription take place primarily through inhibition of BGLF4. MBV inhibits viral genome copy numbers and infectivity to levels similar to and exceeding levels produced by BGLF4 knockout virus. PMID:23449792

FRONTO-STRIATAL FUNCTIONAL CONNECTIVITY DURING RESPONSE INHIBITION IN ALCOHOL DEPENDENCE

PubMed Central

Courtney, Kelly E.; Ghahremani, Dara G.; Ray, Lara A.

2013-01-01

Poor response inhibition has been implicated in the development of alcohol dependence, yet little is known about how neural pathways underlying cognitive control are affected in this disorder. Moreover, endogenous opioid levels may impact the functionality of inhibitory control pathways. This study investigated the relationship between alcohol dependence severity and functional connectivity of fronto-striatal networks during response inhibition in an alcohol dependent sample. A secondary aim of this study was to test the moderating effect of a functional polymorphism (A118G) of the µ-opioid receptor (OPRM1) gene. Twenty individuals with alcohol dependence (6 females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing a Stop Signal Task (SST). The relationship between alcohol dependence severity and functional connectivity within fronto-striatal networks important for response inhibition was assessed using psychophysiological interaction (PPI) analyses. Analyses revealed greater alcohol dependence severity associated with weaker functional connectivity between the putamen and prefrontal regions (e.g., the anterior insula, anterior cingulate, and medial prefrontal cortex) during response inhibition. Further, the OPRM1 genotype was associated with differential response inhibition-related functional connectivity. This study demonstrates that individuals with more severe alcohol dependence exhibit less frontal connectivity with the striatum, a component of cognitive control networks important for response inhibition. These findings suggest that the fronto-striatal pathway underlying response inhibition is weakened as alcoholism progresses. PMID:23240858

Voluntary inhibition of pain avoidance behavior: an fMRI study.

PubMed

Lynn, Margaret T; Demanet, Jelle; Krebs, Ruth M; Van Dessel, Pieter; Brass, Marcel

2016-04-01

Behavioral inhibition has classically been considered to rely upon a neural network centered at the right inferior frontal cortex [rIFC; Aron et al. (8:170-177, 2004; 18:177-185, 2014)]. However, the vast majority of inhibition studies have entailed exogenous stop signals instructing participants to withhold responding. More recent work has begun to examine the neural underpinnings of endogenous inhibition, revealing a distinct cortical basis in the dorsal fronto-median cortex [dFMC; Brass and Haggard (27:9141-9145, 2007); Kühn et al. (30:2834-3843, 2009)]. Yet, contrary to everyday experiences of voluntary behavioral suppression, the paradigms employed to investigate action inhibition have thus far been somewhat artificial, and involve little persuasive motivation to act. Accordingly, the present fMRI study seeks to compare and contrast intentional with instructed inhibition in a novel pain paradigm that recruits 'hot' incentive response systems. Participants received increasing thermal stimulation to their inner wrists, and were required to occasionally withhold their natural impulse to withdraw from the compelling pain sensation at peak temperature, in both instructed and free-choice conditions. Consistent with previous research, we observed inhibition-related activity in the dFMC and the rIFC. However, these regions displayed equivalent activation levels for both inhibition types. These data extend previous research by demonstrating that under ecologically valid conditions with a strong motivation to act, both stopping networks operate in concert to enable suppression of unwanted behavior.

A QSAR Model for Thyroperoxidase Inhibition and Screening ...

EPA Pesticide Factsheets

Thyroid hormones (THs) are critical modulators of a wide range of biological processes from neurodevelopment to metabolism. Well regulated levels of THs are critical during development and even moderate changes in maternal or fetal TH levels produce irreversible neurological deficits in children. The enzyme thyroperoxidase (TPO) plays a key role in the synthesis of THs. Inhibition of TPO by xenobiotics leads to decreased TH synthesis and, depending on the degree of synthesis inhibition, may result in adverse developmental outcomes. Recently, a high-throughput screening assay for TPO inhibition (AUR-TPO) was developed and used to screen the ToxCast Phase I and II chemicals. In the present study, we used the results from the AUR-TPO screening to develop a Quantitative Structure-Activity Relationship (QSAR) model for TPO inhibition in Leadscope®. The training set consisted of 898 discrete organic chemicals: 134 positive and 764 negative for TPO inhibition. A 10 times two-fold 50% cross-validation of the model was performed, yielding a balanced accuracy of 78.7% within its defined applicability domain. More recently, an additional ~800 chemicals from the US EPA Endocrine Disruption Screening Program (EDSP21) were screened using the AUR-TPO assay. This data was used for external validation of the QSAR model, demonstrating a balanced accuracy of 85.7% within its applicability domain. Overall, the cross- and external validations indicate a model with a high predictiv

Inhibition Potentiates the Synchronizing Action of Electrical Synapses

PubMed Central

Pfeuty, Benjamin; Golomb, David; Mato, Germán; Hansel, David

2007-01-01

In vivo and in vitro experimental studies have found that blocking electrical interactions connecting GABAergic interneurons reduces oscillatory activity in the γ range in cortex. However, recent theoretical works have shown that the ability of electrical synapses to promote or impede synchrony, when alone, depends on their location on the dendritic tree of the neurons, the intrinsic properties of the neurons and the connectivity of the network. The goal of the present paper is to show that this versatility in the synchronizing ability of electrical synapses is greatly reduced when the neurons also interact via inhibition. To this end, we study a model network comprising two-compartment conductance-based neurons interacting with both types of synapses. We investigate the effect of electrical synapses on the dynamical state of the network as a function of the strength of the inhibition. We find that for weak inhibition, electrical synapses reinforce inhibition-generated synchrony only if they promote synchrony when they are alone. In contrast, when inhibition is sufficiently strong, electrical synapses improve synchrony even if when acting alone they would stabilize asynchronous firing. We clarify the mechanism underlying this cooperative interplay between electrical and inhibitory synapses. We show that it is relevant in two physiologically observed regimes: spike-to-spike synchrony, where neurons fire at almost every cycle of the population oscillations, and stochastic synchrony, where neurons fire irregularly and at a rate which is substantially lower than the frequency of the global population rhythm. PMID:18946530

Dual effect of chloramphenicol peptides on ribosome inhibition.

PubMed

Bougas, Anthony; Vlachogiannis, Ioannis A; Gatos, Dimitrios; Arenz, Stefan; Dinos, George P

2017-05-01

Chloramphenicol peptides were recently established as useful tools for probing nascent polypeptide chain interaction with the ribosome, either biochemically, or structurally. Here, we present a new 10mer chloramphenicol peptide, which exerts a dual inhibition effect on the ribosome function affecting two distinct areas of the ribosome, namely the peptidyl transferase center and the polypeptide exit tunnel. According to our data, the chloramphenicol peptide bound on the chloramphenicol binding site inhibits the formation of both acetyl-phenylalanine-puromycin and acetyl-lysine-puromycin, showing, however, a decreased peptidyl transferase inhibition compared to chloramphenicol-mediated inhibition per se. Additionally, we found that the same compound is a strong inhibitor of green fluorescent protein synthesis in a coupled in vitro transcription-translation assay as well as a potent inhibitor of lysine polymerization in a poly(A)-programmed ribosome, showing that an additional inhibitory effect may exist. Since chemical protection data supported the interaction of the antibiotic with bases A2058 and A2059 near the entrance of the tunnel, we concluded that the extra inhibition effect on the synthesis of longer peptides is coming from interactions of the peptide moiety of the drug with residues comprising the ribosomal tunnel, and by filling up the tunnel and blocking nascent chain progression through the restricted tunnel. Therefore, the dual interaction of the chloramphenicol peptide with the ribosome increases its inhibitory effect and opens a new window for improving the antimicrobial potency of classical antibiotics or designing new ones.

Amygdala-cingulate intrinsic connectivity is associated with degree of social inhibition

PubMed Central

Blackford, Jennifer Urbano; Clauss, Jacqueline A.; Avery, Suzanne N.; Cowan, Ronald L.; Benningfield, Margaret M.; VanDerKlok, Ross M.

2014-01-01

The tendency to approach or avoid novel people is a fundamental human behavior and is a core dimension of social anxiety. Resting state fMRI was used to test for an association between social inhibition and intrinsic connectivity in 40 young adults ranging from low to high in social inhibition. Higher levels of social inhibition were associated with specific patterns of reduced amygdala-cingulate cortex connectivity. Connectivity was reduced between the superficial amygdala and the rostral cingulate cortex and between the centromedial amygdala and the dorsal anterior cingulate cortex. Social inhibition also modulated connectivity in several well-established intrinsic networks; higher social inhibition correlated with reduced connectivity with default mode and dorsal attention networks and enhanced connectivity in salience and executive control networks. These findings provide important preliminary evidence that social inhibition reflects differences in the underlying intrinsic connectivity of the brain in the absence of social stimuli or stressors. PMID:24534162

DSGOST inhibits tumor growth by blocking VEGF/VEGFR2-activated angiogenesis.

PubMed

Choi, Hyeong Sim; Lee, Kangwook; Kim, Min Kyoung; Lee, Kang Min; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong-Gyu

2016-04-19

Tumor growth requires a process called angiogenesis, a new blood vessel formation from pre-existing vessels, as newly formed vessels provide tumor cells with oxygen and nutrition. Danggui-Sayuk-Ga-Osuyu-Saenggang-Tang (DSGOST), one of traditional Chinese medicines, has been widely used in treatment of vessel diseases including Raynaud's syndrome in Northeast Asian countries including China, Japan and Korea. Therefore, we hypothesized that DSGOST might inhibit tumor growth by targeting newly formed vessels on the basis of its historical prescription. Here, we demonstrate that DSGOST inhibits tumor growth by inhibiting VEGF-induced angiogenesis. DSGOST inhibited VEGF-induced angiogenic abilities of endothelial cells in vitro and in vivo, which resulted from its inhibition of VEGF/VEGFR2 interaction. Furthermore, DSGOST attenuated pancreatic tumor growth in vivo by reducing angiogenic vessel numbers, while not affecting pancreatic tumor cell viability. Thus, our data conclude that DSGOST inhibits VEGF-induced tumor angiogenesis, suggesting a new indication for DSGOST in treatment of cancer.

Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

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

Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan

2012-11-30

Highlights: Black-Right-Pointing-Pointer Salinomycin inhibits preadipocyte differentiation into adipocytes. Black-Right-Pointing-Pointer Salinomycin inhibits transcriptional regulation of adipogenesis. Black-Right-Pointing-Pointer Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics mightmore » have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor {gamma}. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.« less

Zinc-mediated Allosteric Inhibition of Caspase-6*

PubMed Central

Velázquez-Delgado, Elih M.; Hardy, Jeanne A.

2012-01-01

Zinc and caspase-6 have independently been implicated in several neurodegenerative disorders. Depletion of zinc intracellularly leads to apoptosis by an unknown mechanism. Zinc inhibits cysteine proteases, including the apoptotic caspases, leading to the hypothesis that zinc-mediated inhibition of caspase-6 might contribute to its regulation in a neurodegenerative context. Using inductively coupled plasma optical emission spectroscopy, we observed that caspase-6 binds one zinc per monomer, under the same conditions where the zinc leads to complete loss of enzymatic activity. To understand the molecular details of zinc binding and inhibition, we performed an anomalous diffraction experiment above the zinc edge. The anomalous difference maps showed strong 5σ peaks, indicating the presence of one zinc/monomer bound at an exosite distal from the active site. Zinc was not observed bound to the active site. The zinc in the exosite was liganded by Lys-36, Glu-244, and His-287 with a water molecule serving as the fourth ligand, forming a distorted tetrahedral ligation sphere. This exosite appears to be unique to caspase-6, as the residues involved in zinc binding were not conserved across the caspase family. Our data suggest that binding of zinc at the exosite is the primary route of inhibition, potentially locking caspase-6 into the inactive helical conformation. PMID:22891250

N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor.

PubMed

Stamler, J; Mendelsohn, M E; Amarante, P; Smick, D; Andon, N; Davies, P F; Cooke, J P; Loscalzo, J

1989-09-01

Recent evidence suggests that endothelium-derived relaxing factor exhibits properties of nitric oxide. Like nitric oxide, it inhibits platelet function and mediates its effects by elevating intracellular cyclic GMP. In this study we have investigated the role of reduced thiol in the mechanism of action of endothelium-derived relaxing factor on platelets. Bovine aortic endothelial cells were grown on microcarrier beads and pretreated with aspirin before use. Endothelial cells stimulated with bradykinin or exposed to stirred medium expressed a dose-dependent inhibition of platelet aggregation that was potentiated by the reduced thiol, N-acetylcysteine. Endothelial cell-mediated platelet inhibition was attenuated by methylene blue. Inhibition of platelet aggregation by endothelial cells was associated with a rise in platelet intracellular cyclic GMP, an effect that was enhanced by N-acetylcysteine. These data show that 1) the reduced thiol N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor and 2) this effect is associated with increasing intracellular platelet cyclic GMP levels.

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.

Antiangiogenic and Antitumor Effects of Src Inhibition in Ovarian Carcinoma

PubMed Central

Han, Liz Y.; Landen, Charles N.; Trevino, Jose G.; Halder, Jyotsnabaran; Lin, Yvonne G.; Kamat, Aparna A.; Kim, Tae-Jin; Merritt, William M.; Coleman, Robert L.; Gershenson, David M.; Shakespeare, William C.; Wang, Yihan; Sundaramoorth, Raji; Metcalf, Chester A.; Dalgarno, David C.; Sawyer, Tomi K.; Gallick, Gary E.; Sood, Anil K.

2011-01-01

Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma. PMID:16951177

Selected Phytochemicals and Culinary Plant Extracts Inhibit Fructose Uptake in Caco-2 Cells.

PubMed

Lee, Yurim; Lim, Yeni; Kwon, Oran

2015-09-18

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

The Ability To Activate and Inhibit Speeded Responses: Separate Developmental Trends.

ERIC Educational Resources Information Center

Band, Guido P. H.; van der Molen, Maurits W.; Overtoom, Carin C. E.; Verbaten, Marinus N.

2000-01-01

Compared 5-, 8-, and 11-year-olds and young adults on 6 speeded performance tasks, 4 requiring an inhibition of response activation. Analyzed reaction and inhibition times; found support for hypothesis of generalized developmental changes in response activation, but revealed less pronounced development of inhibition. Concluded that a nonselective…

Wnt signaling inhibits CTL memory programming

PubMed Central

Xiao, Zhengguo; Sun, Zhifeng; Smyth, Kendra; Li, Lei

2013-01-01

Induction of functional CTLs is one of the major goals for vaccine development and cancer therapy. Inflammatory cytokines are critical for memory CTL generation. Wnt signaling is important for CTL priming and memory formation, but its role in cytokine-driven memory CTL programming is unclear. We found that wnt signaling inhibited IL-12-driven CTL activation and memory programming. This impaired memory CTL programming was attributed to up-regulation of eomes and down-regulation of T-bet. Wnt signaling suppressed the mTOR pathway during CTL activation, which was different to its effects on other cell types. Interestingly, the impaired memory CTL programming by wnt was partially rescued by mTOR inhibitor rapamycin. In conclusion, we found that crosstalk between wnt and the IL-12 signaling inhibits T-bet and mTOR pathways and impairs memory programming which can be recovered in part by rapamycin. In addition, direct inhibition of wnt signaling during CTL activation does not affect CTL memory programming. Therefore, wnt signaling may serve as a new tool for CTL manipulation in autoimmune diseases and immune therapy for certain cancers. PMID:23911398

Reversal of androgen inhibition of estrogen-activated sexual behavior by cholinergic agents.

PubMed

Dohanich, G P; Cada, D A

1989-12-01

Androgens have been found to inhibit lordosis activated by estrogen treatment of ovariectomized female rats. In the present experiments, dihydrotestosterone propionate (200 micrograms for 3 days) inhibited the incidence of lordosis in ovariectomized females treated with estradiol benzoate (1 microgram for 3 days). This inhibition of lordosis was reversed 15 min after bilateral intraventricular infusion of physostigmine (10 micrograms/cannula), an acetylcholinesterase inhibitor, or carbachol (0.5 microgram/cannula), a cholinergic receptor agonist. This reversal of inhibition appears to be mediated by cholinergic muscarinic receptors since pretreatment with scopolamine (4 mg/kg, ip), a muscarinic receptor blocker, prevented the reversal of androgen inhibition by physostigmine. These results indicate that androgens may inhibit estrogen-activated lordosis through interference with central cholinergic muscarinic mechanisms.

CC-chemokine class inhibition attenuates pathological angiogenesis while preserving physiological angiogenesis.

PubMed

Ridiandries, Anisyah; Tan, Joanne T M; Ravindran, Dhanya; Williams, Helen; Medbury, Heather J; Lindsay, Laura; Hawkins, Clare; Prosser, Hamish C G; Bursill, Christina A

2017-03-01

Increasing evidence shows that CC-chemokines promote inflammatory-driven angiogenesis, with little to no effect on hypoxia-mediated angiogenesis. Inhibition of the CC-chemokine class may therefore affect angiogenesis differently depending on the pathophysiological context. We compared the effect of CC-chemokine inhibition in inflammatory and physiological conditions. In vitro , the broad-spectrum CC-chemokine inhibitor "35K" inhibited inflammatory-induced endothelial cell proliferation, migration, and tubulogenesis, with more modest effects in hypoxia. In vivo , adenoviruses were used to overexpress 35K (Ad35K) and GFP (AdGFP, control virus). Plasma chemokine activity was suppressed by Ad35K in both models. In the periarterial femoral cuff model of inflammatory-driven angiogenesis, overexpression of 35K inhibited adventitial neovessel formation compared with control AdGFP-infused mice. In contrast, 35K preserved neovascularization in the hindlimb ischemia model and had no effect on physiological neovascularization in the chick chorioallantoic membrane assay. Mechanistically, 2 key angiogenic proteins (VEGF and hypoxia-inducible factor-1α) were conditionally regulated by 35K, such that expression was inhibited in inflammation but was unchanged in hypoxia. In conclusion, CC-chemokine inhibition by 35K suppresses inflammatory-driven angiogenesis while preserving physiological ischemia-mediated angiogenesis via conditional regulation of VEGF and hypoxia-inducible factor-1α. CC-chemokine inhibition may be an alternative therapeutic strategy for suppressing diseases associated with inflammatory angiogenesis without inducing the side effects caused by global inhibition.- Ridiandries, A., Tan, J. T. M., Ravindran, D., Williams, H., Medbury, H. J., Lindsay, L., Hawkins, C., Prosser, H. C. G., Bursill, C. A. CC-chemokine class inhibition attenuates pathological angiogenesis while preserving physiological angiogenesis. © FASEB.

Functional mechanisms involved in the internal inhibition of taboo words.

PubMed

Severens, Els; Kühn, Simone; Hartsuiker, Robert J; Brass, Marcel

2012-04-01

The present study used functional magnetic resonance imaging to investigate brain processes associated with the inhibition of socially undesirable speech. It is tested whether the inhibition of undesirable speech is solely related to brain areas associated with classical stop signal tasks or rather also involves brain areas involved in endogenous self-control. During the experiment, subjects had to do a SLIP task, which was designed to elicit taboo or neutral spoonerisms. Here we show that the internal inhibition of taboo words activates the right inferior frontal gyrus, an area that has previously been associated with externally triggered inhibition. This finding strongly suggests that external social rules become internalized and act as a stop-signal.

Functional mechanisms involved in the internal inhibition of taboo words

PubMed Central

Kühn, Simone; Hartsuiker, Robert J.; Brass, Marcel

2012-01-01

The present study used functional magnetic resonance imaging to investigate brain processes associated with the inhibition of socially undesirable speech. It is tested whether the inhibition of undesirable speech is solely related to brain areas associated with classical stop signal tasks or rather also involves brain areas involved in endogenous self-control. During the experiment, subjects had to do a SLIP task, which was designed to elicit taboo or neutral spoonerisms. Here we show that the internal inhibition of taboo words activates the right inferior frontal gyrus, an area that has previously been associated with externally triggered inhibition. This finding strongly suggests that external social rules become internalized and act as a stop-signal. PMID:21609970

Striatal GABA-MRS predicts response inhibition performance and its cortical electrophysiological correlates.

PubMed

Quetscher, Clara; Yildiz, Ali; Dharmadhikari, Shalmali; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Dydak, Ulrike; Beste, Christian

2015-11-01

Response inhibition processes are important for performance monitoring and are mediated via a network constituted by different cortical areas and basal ganglia nuclei. At the basal ganglia level, striatal GABAergic medium spiny neurons are known to be important for response selection, but the importance of the striatal GABAergic system for response inhibition processes remains elusive. Using a novel combination of behavior al, EEG and magnetic resonance spectroscopy (MRS) data, we examine the relevance of the striatal GABAergic system for response inhibition processes. The study shows that striatal GABA levels modulate the efficacy of response inhibition processes. Higher striatal GABA levels were related to better response inhibition performance. We show that striatal GABA modulate specific subprocesses of response inhibition related to pre-motor inhibitory processes through the modulation of neuronal synchronization processes. To our knowledge, this is the first study providing direct evidence for the relevance of the striatal GABAergic system for response inhibition functions and their cortical electrophysiological correlates in humans.

Physiological markers of motor inhibition during human behavior

PubMed Central

Duque, Julie; Greenhouse, Ian; Labruna, Ludovica; Ivry, Richard B.

2017-01-01

Transcranial magnetic stimulation (TMS) studies in humans have shown that many behaviors engage processes that suppress excitability within the corticospinal tract. Inhibition of the motor output pathway has been extensively studied in the context of action stopping, where a planned movement needs to be abruptly aborted. Recent TMS work has also revealed markers of motor inhibition during the preparation of movement. Here, we review the evidence for motor inhibition during action stopping and action preparation, focusing on studies that have used TMS to monitor changes in the excitability of the corticospinal pathway. We discuss how these physiological results have motivated theoretical models of how the brain selects actions, regulates movement initiation and execution, and switches from one state to another. PMID:28341235

Response inhibition under alcohol: effects of cognitive and motivational conflict.

PubMed

Fillmore, M T; Vogel-Sprott, M

2000-03-01

This experiment tested the effect of cognitive and motivational conflict on response inhibition under alcohol. Fifty-six male social drinkers were randomly assigned to one of eight groups (n = 8). Four pairs of groups received 0.62 g/kg of alcohol, or a placebo, and each pair performed a go/stop choice reaction time task under one of four conflict conditions. One condition (C) produced cognitive conflict by presenting "go" and "stop" signals in the task. Another condition (IR) added motivational conflict by administering an equal monetary reward for inhibiting responses to stop-signals, and for responding to go-signals. The remaining two conditions resolved the motivational conflict by administering the monetary reward only for inhibitions (I), or only for responses (R). Compared with placebo, alcohol reduced inhibitions (i.e., impaired inhibitory control) under cognitive conflict (C; p = .041) and under motivational conflict (IR; p = .012). No significant effect of alcohol on inhibitions was observed in conditions where conflict was resolved (i.e., I and R). The study shows that alcohol can reduce the ability to inhibit a response. However, impaired inhibitory control is not an inevitable outcome of the drug action, because it can be counteracted by the consequences of behavior in the situation.

Intraglomerular inhibition shapes the strength and temporal structure of glomerular output

PubMed Central

Shao, Zuoyi; Puche, Adam C.; Liu, Shaolin

2012-01-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MCs) and external tufted cells (ETCs). ETCs, in turn, provide feedforward excitatory input to MCs. MC and ETCs are also regulated by inhibition: intraglomerular and interglomerular inhibitory circuits act at MC and ETC apical dendrites; granule cells (GCs) inhibit MC lateral dendrites via the MC→GC→MC circuit. We investigated the contribution of intraglomerular inhibition to MC and ETCs responses to ON input. ON input evokes initial excitation followed by early, strongly summating inhibitory postsynaptic currents (IPSCs) in MCs; this is followed by prolonged, intermittent IPSCs. The N-methyl-d-aspartate receptor antagonist dl-amino-5-phosphovaleric acid, known to suppress GABA release by GCs, reduced late IPSCs but had no effect on early IPSCs. In contrast, selective intraglomerular block of GABAA receptors eliminated all early IPSCs and caused a 5-fold increase in ON-evoked MC spiking and a 10-fold increase in response duration. ETCs also receive intraglomerular inhibition; blockade of inhibition doubled ETC spike responses. By reducing ETC excitatory drive and directly inhibiting MCs, intraglomerular inhibition is a key factor shaping the strength and temporal structure of MC responses to sensory input. Sensory input generates an intraglomerular excitation-inhibition sequence that limits MC spike output to a brief temporal window. Glomerular circuits may dynamically regulate this input-output window to optimize MC encoding across sniff-sampled inputs. PMID:22592311

Intraglomerular inhibition shapes the strength and temporal structure of glomerular output.

PubMed

Shao, Zuoyi; Puche, Adam C; Liu, Shaolin; Shipley, Michael T

2012-08-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MCs) and external tufted cells (ETCs). ETCs, in turn, provide feedforward excitatory input to MCs. MC and ETCs are also regulated by inhibition: intraglomerular and interglomerular inhibitory circuits act at MC and ETC apical dendrites; granule cells (GCs) inhibit MC lateral dendrites via the MC→GC→MC circuit. We investigated the contribution of intraglomerular inhibition to MC and ETCs responses to ON input. ON input evokes initial excitation followed by early, strongly summating inhibitory postsynaptic currents (IPSCs) in MCs; this is followed by prolonged, intermittent IPSCs. The N-methyl-d-aspartate receptor antagonist dl-amino-5-phosphovaleric acid, known to suppress GABA release by GCs, reduced late IPSCs but had no effect on early IPSCs. In contrast, selective intraglomerular block of GABA(A) receptors eliminated all early IPSCs and caused a 5-fold increase in ON-evoked MC spiking and a 10-fold increase in response duration. ETCs also receive intraglomerular inhibition; blockade of inhibition doubled ETC spike responses. By reducing ETC excitatory drive and directly inhibiting MCs, intraglomerular inhibition is a key factor shaping the strength and temporal structure of MC responses to sensory input. Sensory input generates an intraglomerular excitation-inhibition sequence that limits MC spike output to a brief temporal window. Glomerular circuits may dynamically regulate this input-output window to optimize MC encoding across sniff-sampled inputs.

Active inhibition of herpes simplex virus type 1-induced cell fusion

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

Bzik, D.J.; Person, S.; Read, G.S.

1982-01-01

Previous studies have demonstrated that syn mutant-infected cells fuse less well with nonsyncytial virus-infected cells than with uninfected cells, a phenomenon defined as function inhibition. The present study characterizes the kinetics as well as the requirements for expression of fusion inhibition. Initially, the capacity of sparse syn mutant-infected cells to fuse with uninfected surrounding cells was determined throughout infection. Of seven syn mutants examined, including representatives with alterations in two different viral genes that affect cell fusion, all showed an increase in fusion capacity up to 12 hr after infection and a decrease at later times. Fusion inhibition was examinedmore » in experiments employing sparse syn20-infected cells which had been incubated to a maximum fusion capacity; it was shown that surrounding cells infected with KOS, the parent of syn20, began to inhibit fusion by the syn20-infected cells at about 4 hr after infection, and that the maximum ability to inhibit fusion was attained at about 6 hr after infection. The metabolic blocking agents actinomycin D (RNA), cycloheximide (protein), 2-deoxyglucose, and tunicamycin (glycoslyation of glycoproteins) all showed the ability to inhibit the expression of fusion inhibition by KOS-infected cells if added shortly after infection. It is concluded that fusion inhibition is an active process that requires the synthesis of RNA, proteins, and glycoproteins. 17 references, 3 figures, 2 tables.« less

Nitric oxide inhibits calpain-mediated proteolysis of talin in skeletal muscle cells

NASA Technical Reports Server (NTRS)

Koh, T. J.; Tidball, J. G.

2000-01-01

We tested the hypothesis that nitric oxide can inhibit cytoskeletal breakdown in skeletal muscle cells by inhibiting calpain cleavage of talin. The nitric oxide donor sodium nitroprusside prevented many of the effects of calcium ionophore on C(2)C(12) muscle cells, including preventing talin proteolysis and release into the cytosol and reducing loss of vinculin, cell detachment, and loss of cellular protein. These results indicate that nitric oxide inhibition of calpain protected the cells from ionophore-induced proteolysis. Calpain inhibitor I and a cell-permeable calpastatin peptide also protected the cells from proteolysis, confirming that ionophore-induced proteolysis was primarily calpain mediated. The activity of m-calpain in a casein zymogram was inhibited by sodium nitroprusside, and this inhibition was reversed by dithiothreitol. Previous incubation with the active site-targeted calpain inhibitor I prevented most of the sodium nitroprusside-induced inhibition of m-calpain activity. These data suggest that nitric oxide inhibited m-calpain activity via S-nitrosylation of the active site cysteine. The results of this study indicate that nitric oxide produced endogenously by skeletal muscle and other cell types has the potential to inhibit m-calpain activity and cytoskeletal proteolysis.

Stability and social-behavioral consequences of toddlers' inhibited temperament and parenting behaviors.

PubMed

Rubin, Kenneth H; Burgess, Kim B; Hastings, Paul D

2002-01-01

A prospective longitudinal design was employed to ascertain whether different types of behavioral inhibition (i.e., traditional, peer-social) were stable from toddler to preschool age, and whether inhibited temperament and/or parenting style would predict children's subsequent social and behavioral problems. At Time 1, 108 toddlers (54 males, 54 females) and their mothers were observed in the Traditional Inhibition Paradigm and in a toddler-peer session; then at age 4 years, 88 children were observed with unfamiliar peers, and maternal ratings of psychological functioning were obtained. How mothers and their toddlers interacted was also observed. Results revealed meaningful connections between toddler inhibition, maternal intrusive control and derision, and nonsocial behaviors at age 4. Both forms of toddler inhibition predicted socially reticent behavior during free play at 4 years. If mothers demonstrated relatively high frequencies of intrusive control and/or derisive comments, then the association between their toddlers' peer inhibition and 4-year social reticence was significant and positive; whereas if mothers were neither intrusive nor derisive, then toddlers' peer inhibition and 4-year reticence were not significantly associated. Thus, maternal behaviors moderated the relation between toddlers' peer inhibition and preschoolers' social reticence.

Comparing the context specificity of extinction and latent inhibition.

PubMed

Miller, Ralph R; Laborda, Mario A; Polack, Cody W; Miguez, Gonzalo

2015-12-01

Exposure to a cue alone either before (i.e., latent inhibition treatment) or after (i.e., extinction) the cue is paired with an unconditioned stimulus results in attenuated conditioned responding to the cue. Here we report two experiments in which potential parallels between the context specificity of the effects of extinction and latent inhibition treatments were directly compared in a lick suppression preparation with rats. The reversed ordering of conditioning and nonreinforcement in extinction and latent inhibition designs allowed us to examine the effect of training order on the context specificity of what is learned given phasic reinforcement and nonreinforcement of a target cue. Experiment 1 revealed that when conditioned-stimulus (CS) conditioning and CS nonreinforcement were administered in the same context, both extinction and latent inhibition treatments had reduced impacts on test performance, relative to excitatory conditioning when testing occurred outside the treatment context. Similarly, Experiment 2 showed that when conditioning was administered in one context and nonreinforcement was administered in a second context, the effects of both extinction and latent inhibition treatments were attenuated when testing occurred in a neutral context, relative to the context in which the CS was nonreinforced. The observed context specificity of extinction and latent inhibition treatments has been previously reported in both cases, but not in a single experiment under otherwise identical conditions. The results of the two experiments convergently suggest that memory of nonreinforcement becomes context dependent after a cue is both reinforced and nonreinforced, independent of the order of training.

Magnolol Inhibits the Growth of Non-Small Cell Lung Cancer via Inhibiting Microtubule Polymerization.

PubMed

Shen, Jia; Ma, Hailin; Zhang, Tiancheng; Liu, Hui; Yu, Linghua; Li, Guosheng; Li, Huishuang; Hu, Meichun

2017-01-01

The tubulin/microtubule system, which is an integral component of the cytoskeleton, plays an essential role in mitosis. Targeting mitotic progression by disturbing microtubule dynamics is a rational strategy for cancer treatment. Microtubule polymerization assay was performed to examine the effect of Magnolol (a novel natural phenolic compound isolated from Magnolia obovata) on cellular microtubule polymerization in human non-small cell lung cancer (NSCLC) cells. Cell cycle analysis, mitotic index assay, cell proliferation assay, colony formation assay, western blotting analysis of cell cycle regulators, Annexin V-FITC/PI staining, and live/dead viability staining were carried out to investigate the Magnolol's inhibitory effect on proliferation and viability of NSCLS cells in vitro. Xenograft model of human A549 NSCLC tumor was used to determine the Magnolol's efficacy in vivo. Magnolol treatment effectively inhibited cell proliferation and colony formation of NSCLC cells. Further study proved that Magnolol induced the mitotic phase arrest and inhibited G2/M progression in a dose-dependent manner, which were mechanistically associated with expression alteration of a series of cell cycle regulators. Furthermore, Magnolol treatment disrupted the cellular microtubule organization via inhibiting the polymerization of microtubule. We also found treatment with NSCLC cells with Magnolol resulted in apoptosis activation through a p53-independent pathway, and autophgy induction via down-regulation of the Akt/mTOR pathway. Finally, Magnolol treatment significantly suppressed the NSCLC tumor growth in mouse xenograft model in vivo. These findings identify Magnolol as a promising candidate with anti-microtubule polymerization activity for NSCLC treatment. © 2017 The Author(s). Published by S. Karger AG, Basel.

Quantitative NTCP Pharmacophore and Lack of Association between DILI and NTCP Inhibition

PubMed Central

Dong, Zhongqi; Ekins, Sean; Polli, James E.

2014-01-01

The human sodium taurocholate cotransporting polypeptide (NTCP) is a hepatic bile acid transporter. Inhibition of NTCP uptake may potentially also prevent hepatitis B virus (HBV) infection. The first objective was to develop a quantitative pharmacophore for NTCP inhibition. Recent studies showed that hepatotoxic drugs could inhibit bile acid uptake into hepatocytes, without inhibiting canalicular efflux, and cause bile acid elevation in plasma. Hence, a second objective was to examine whether NTCP inhibition is associated with drug induced liver injury (DILI). Twenty-seven drugs from our previous study were used as the training set to develop a quantitative pharmacophore. From secondary screening from a drug database, six retrieved drugs and three drugs not retrieved by the model were tested for NTCP inhibition. Tertiary screening involved drugs known to cause DILI and not cause DILI. Overall, ninety-four drugs were assessed for hepatotoxicity and were assessed relative to NTCP inhibition. The quantitative pharmacophore possessed one hydrogen bond acceptor, one hydrogen bond donor, a hydrophobic feature, and excluded volumes. From 94 drugs, NTCP inhibitors and non-inhibitors were approximately equally distributed across the drugs of most DILI concern, less DILI concern, and no DILI concern, indicating no relationship between NTCP inhibition and DILI risk. Hence, an approach to treat HBV via NTCP inhibition is not expected to be associated with DILI. PMID:25220493

Quantitative NTCP pharmacophore and lack of association between DILI and NTCP Inhibition.

PubMed

Dong, Zhongqi; Ekins, Sean; Polli, James E

2015-01-23

The human sodium taurocholate cotransporting polypeptide (NTCP) is a hepatic bile acid transporter. Inhibition of NTCP uptake may potentially also prevent hepatitis B virus (HBV) infection. The first objective was to develop a quantitative pharmacophore for NTCP inhibition. Recent studies showed that hepatotoxic drugs could inhibit bile acid uptake into hepatocytes, without inhibiting canalicular efflux, and cause bile acid elevation in plasma. Hence, a second objective was to examine whether NTCP inhibition is associated with drug induced liver injury (DILI). Twenty-seven drugs from our previous study were used as the training set to develop a quantitative pharmacophore. From secondary screening from a drug database, six retrieved drugs and three drugs not retrieved by the model were tested for NTCP inhibition. Tertiary screening involved drugs known to cause DILI and not cause DILI. Overall, ninety-four drugs were assessed for hepatotoxicity and were assessed relative to NTCP inhibition. The quantitative pharmacophore possessed one hydrogen bond acceptor, one hydrogen bond donor, a hydrophobic feature, and excluded volumes. From 94 drugs, NTCP inhibitors and non-inhibitors were approximately equally distributed across the drugs of most DILI concern, less DILI concern, and no DILI concern, indicating no relationship between NTCP inhibition and DILI risk. Hence, an approach to treat HBV via NTCP inhibition is not expected to be associated with DILI. Copyright © 2014 Elsevier B.V. All rights reserved.

Mechanism of acetaminophen inhibition of cyclooxygenase isoforms.

PubMed

Ouellet, M; Percival, M D

2001-03-15

Acetaminophen has similar analgesic and antipyretic properties to nonsteroidal antiinflammatory drugs (NSAIDs), which act via inhibition of cyclooxygenase enzymes. However, unlike NSAIDs, acetaminophen is at best weakly antiinflammatory. The mechanism by which acetaminophen exerts its therapeutic action has yet to be fully determined, as under most circumstances, acetaminophen is a very weak cyclooxygenase inhibitor. The potency of acetaminophen against both purified ovine cyclooxygenase-1 (oCOX-1) and human cyclooxygenase-2 (hCOX-2) was increased approximately 30-fold by the presence of glutathione peroxidase and glutathione to give IC50 values of 33 microM and 980 microM, respectively. Acetaminophen was found to be a good reducing agent of both oCOX-1 and hCOX-2. The results are consistent with a mechanism of inhibition of acetaminophen in which it acts to reduce the active oxidized form of COX to the resting form. Inhibition would therefore be more effective under conditions of low peroxide concentration, consistent with the known tissue selectivity of acetaminophen.

Exploiting oleuropein for inhibiting collagen fibril formation.

PubMed

Bharathy, H; Fathima, N Nishad

2017-08-01

Collagen fibrils accumulate in excessive amounts and impair the normal functioning of the organ; therefore it stimulates the interest for identifying the compounds that could prevent the formation of fibrils. Herein, inhibition of self-assembly of collagen using oleuropein has been studied. The changes in the physico-chemical characteristics of collagen on interaction with increasing concentration of oleuropein has been studied using techniques like viscosity, UV-vis, CD and FT-IR. The inhibitory effect of oleuropein on fibril formation of collagen was proved using SEM. Circular dichroism and FT-IR spectra elucidates the alterations in the secondary structure of collagen suggesting non-covalent interactions between oleuropein and collagen. The decreased rate of collagen fibril formation also confirms the inhibition in the self-assembly of collagen. Hence, our study suggests that inhibition of the self-assembly process using oleuropein may unfold new avenues to treat fibrotic diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibition of melanogenesis by Xanthium strumarium L.

PubMed

Li, Hailan; Min, Young Sil; Park, Kyoung-Chan; Kim, Dong-Seok

2012-01-01

Xanthium strumarium L. (Asteraceae) is traditionally used in Korea to treat skin diseases. In this study, we investigated the effects of a X. strumarium stem extract on melanin synthesis. It inhibited melanin synthesis in a concentration-dependent manner, but it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme, and instead downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase expression. MITF, the master regulator of pigmentation, is a target of the Wnt signaling pathway, which includes glycogen synthase kinase 3β (GSK3β) and β-catenin. Hence, the influence of X. strumarium stem extract on GSK3β and β-catenin was further investigated. X. strumarium induced GSK3β phosphorylation (inactivation), but the level of β-catenin did not change. Moreover, a specific GSK3β inhibitor restored X. strumarium-induced melanin reduction. Hence, we suggest that X. strumarium inhibits melanin synthesis through downregulation of tyrosinase via GSK3β phosphorylation.

Inhibition of Titanium In Fuming Nitric Acid

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

RITTENHOUSE, J. B.; PAPP, C. A.

1958-06-01

Storage tests were conducted to determine the effectiveness of oxygen in inhibiting the corrosion reaction of titanium in fuming nitric acid (FNA). In these tests, which were of 28 days duration at a temperature of 30 C, the samples investigated were ½-inch squares (0.020 inch thick) of commercially pure titanium (75A) and a binary 8 percent-manganese alloy (C110M). The specimens were stored in Teflon-lined aluminum pressure vessels at 50 percent ullage. The pressure vessels were of the following types: vented to the atmosphere, sealed with air in the vapor space, sealed with oxygen atmosphere in the vapor space, and equippedmore » for a 1-ml/minute oxygen flow through the vapor space. Finally, results of the investigation indicated no inhibition of titanium corrosion by oxygen, but confirmed the inhibiting effect of a water content of 1 to 2 percent by weight in the FNA.« less

Inhibiting poly(ADP-ribosylation) improves axon regeneration

PubMed Central

Byrne, Alexandra B; McWhirter, Rebecca D; Sekine, Yuichi; Strittmatter, Stephen M; Miller, David M; Hammarlund, Marc

2016-01-01

The ability of a neuron to regenerate its axon after injury depends in part on its intrinsic regenerative potential. Here, we identify novel intrinsic regulators of axon regeneration: poly(ADP-ribose) glycohodrolases (PARGs) and poly(ADP-ribose) polymerases (PARPs). PARGs, which remove poly(ADP-ribose) from proteins, act in injured C. elegans GABA motor neurons to enhance axon regeneration. PARG expression is regulated by DLK signaling, and PARGs mediate DLK function in enhancing axon regeneration. Conversely, PARPs, which add poly(ADP-ribose) to proteins, inhibit axon regeneration of both C. elegans GABA neurons and mammalian cortical neurons. Furthermore, chemical PARP inhibitors improve axon regeneration when administered after injury. Our results indicate that regulation of poly(ADP-ribose) levels is a critical function of the DLK regeneration pathway, that poly-(ADP ribosylation) inhibits axon regeneration across species, and that chemical inhibition of PARPs can elicit axon regeneration. DOI: http://dx.doi.org/10.7554/eLife.12734.001 PMID:27697151

Inhibition of NEDD4 inhibits cell growth and invasion and induces cell apoptosis in bladder cancer cells.

PubMed

Wen, Wu; Li, Jingying; Wang, Longwang; Xing, Yifei; Li, Xuechao; Ruan, Hailong; Xi, Xiaoqing; Xiong, Jianhua; Kuang, Renrui

2017-08-18

The neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) plays a pivotal oncogenic role in various types of human cancers. However, the function of NEDD4 in bladder cancer has not been fully investigated. In the present study, we aim to explore whether NEDD4 governs cell proliferation, apoptosis, migration, and invasion in bladder cancer cells. Our results showed that downregulation of NEDD4 suppressed cell proliferation in bladder cancer cells. Moreover, we found that inhibition of NEDD4 significantly induced cell apoptosis. Furthermore, downregulation of NEDD4 retarded cell migration and invasion. Notably, overexpression of NEDD4 enhanced cell growth and inhibited apoptosis. Consistently, upregulation of NEDD4 promoted cell migration and invasion in bladder cancer cells. Mechanically, our Western blotting results revealed that downregulation of NEDD4 activated PTEN and inhibited Notch-1 expression, whereas upregulation of NEDD4 reduced PTEN level and increased Notch-1 level in bladder cancer cells. Our findings indicated that NEDD4 exerts its oncogenic function partly due to regulation of PTEN and Notch-1 in bladder cancer cells. These results further revealed that targeting NEDD4 could be a useful approach for the treatment of bladder cancer.

RAAS inhibition and cardiorenal syndrome.

PubMed

Onuigbo, Macaulay Amechi C

2014-01-01

The consensus conference on cardio-renal syndromes (2008) defined 'cardio-renal syndromes' as 'disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other' and identified five subtypes of the syndromes. Various pathophysiologic mechanisms underlie cardiorenal syndrome including hemodynamic derangements, reduced cardiac output leading to impaired renal perfusion, reduced stroke volume, raised atrial filling pressures, elevated atrial pressures, sodium and water retention, venous congestion, right ventricular dysfunction and venous hypertension causing increased renal venous pressure, intra-abdominal hypertension, various neurohormonal adaptations including activation of the renin-angiotensin-aldosterone system, adaptive activation of the sympathetic nervous system, cytokine release and oxidative stress. Although there are standardized clinical guidelines for the management of heart failure, and chronic kidney disease, respectively, there are no similar consensus clinical guidelines for the management of the cardiorenal syndromes. RAAS inhibition is advocated in treating systolic heart failure. There is evidence that RAAS inhibition is also useful in cardiorenal syndrome. However, RAAS inhibition, while potentially useful in the management of cardiorenal syndrome, is not the 'magic bullet', is sometimes limited by adverse renal events, is not applicable to all patients, and must be applied by physicians with due diligence and caution. Nevertheless, a more comprehensive multidisciplinary multipronged approach to managing patients with cardiorenal syndrome is even more pragmatic and commonsense given the multiple mechanisms and pathogenetic pathways implicated in the causation and perpetuation of cardiorenal syndrome.

Behavioural and computational varieties of response inhibition in eye movements.

PubMed

Cutsuridis, Vassilis

2017-04-19

Response inhibition is the ability to override a planned or an already initiated response. It is the hallmark of executive control as its deficits favour impulsive behaviours, which may be detrimental to an individual's life. This article reviews behavioural and computational guises of response inhibition. It focuses only on inhibition of oculomotor responses. It first reviews behavioural paradigms of response inhibition in eye movement research, namely the countermanding and antisaccade paradigms, both proven to be useful tools for the study of response inhibition in cognitive neuroscience and psychopathology. Then, it briefly reviews the neural mechanisms of response inhibition in these two behavioural paradigms. Computational models that embody a hypothesis and/or a theory of mechanisms underlying performance in both behavioural paradigms as well as provide a critical analysis of strengths and weaknesses of these models are discussed. All models assume the race of decision processes. The decision process in each paradigm that wins the race depends on different mechanisms. It has been shown that response latency is a stochastic process and has been proven to be an important measure of the cognitive control processes involved in response stopping in healthy and patient groups. Then, the inhibitory deficits in different brain diseases are reviewed, including schizophrenia and obsessive-compulsive disorder. Finally, new directions are suggested to improve the performance of models of response inhibition by drawing inspiration from successes of models in other domains.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'. © 2017 The Author(s).

Na/K ATPase inhibition by digitalis-like factors in neonates

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

Bottorff, M.B.; Songu-Mize, E.; Hoon, T.J.

1986-03-01

At the authors institution, 48% of neonates < 1 month of age had false-positive digoxin immunoassay determinations while not receiving digoxin, presumably due to an endogenous digoxin-like immunoreactive substance (DLIS) in the plasma. Plasma from 3 neonates positive for DLIS by fluorescence polarization immunoassay (FPIA) was evaluated for inhibitory activity on human red blood cell (RBC) Na/K ATPase. Neonatal plasma aliquots containing DLIS concentrations (conc) of 0.24, 0.37, 0.43, 0.49 and 0.61 ng/ml (3.07 - 7.81 x 10/sup -10/M) were incubated with human RBC and /sup 86/Rb in order to measure /sup 86/Rb uptake inhibition with respect to DLIS negativemore » neonatal plasma. /sup 86/Rb uptake inhibition by digoxin-spiked human serum (1.07 x 10/sup -10/ - 4.57 x 10/sup -6/M) was also measured. Percent inhibition vs. log molar conc plots for DLIS and digoxin were compared. DLIS inhibited Na/K ATPase in a linear fashion over the range studied. Comparing the linear portions of the conc-inhibition curves for digoxin and DLIS, the molar conc of digoxin producing 40% inhibition of /sup 86/Rb uptake is 333 times greater than the molar conc of DLIS producing similar inhibition. Therefore, DLIS in neonatal serum as measured by FPIA has approximately 300 times greater inhibitory activity than digoxin. The presence of circulating DLIS may reflect an adaptive or maladaptive response to some, as yet unknown, process early in life.« less

Blue light does not inhibit nodulation in Sesbania rostrata.

PubMed

Shimomura, Aya; Arima, Susumu; Hayashi, Makoto; Maymon, Maskit; Hirsch, Ann M; Suzuki, Akihiro

2017-01-02

Earlier, we reported that root nodulation was inhibited by blue light irradiation of Lotus japonicus. Because some legumes do not establish nodules exclusively on underground roots, we investigated whether nodule formation in Sesbania rostrata, which forms both root and "stem" nodules following inoculation with Azorhizobium caulinodans, is inhibited by blue light as are L. japonicus nodules. We found that neither S. rostrata nodulation nor nitrogen fixation was inhibited by blue light exposure. Moreover, although A. caulinodans proliferation was not affected by blue light irradiation, bacterial survival was decreased. Therefore, blue light appears to impose different responses depending on the legume-rhizobial symbiosis.

Complement inhibiting properties of dragon's blood from Croton draco.

PubMed

Tsacheva, Ivanka; Rostan, Joerg; Iossifova, Tania; Vogler, Bernhard; Odjakova, Mariela; Navas, Hernan; Kostova, Ivanka; Kojouharova, Michaela; Kraus, Wolfgang

2004-01-01

The latex of Croton draco, its extracts and several latex components have been investigated for their influence on both classical (CP) and alternative (AP) activation pathways of the complement system using a hemolytic assay. The best inhibition was found for the classical pathway. The latex, ethyl acetate and ethyl ether extracts exhibited extremely high inhibition on the CP (94, 90 and 77%, respectively) at a concentration of 1 mg/ml. The flavonoid myricitrin, the alkaloid taspine and the cyclopeptides P1 and P2 showed high inhibition on CP (83, 91, 78 and 63%, respectively) at a concentration of 0.9 mM.

Aminophylline preferentially inhibits chloroethylclonidine-insensitive alpha-adrenoceptor-mediated contractions in rat aorta.

PubMed

Duarte, J; Pérez-Vizcaíno, F; Zarzuelo, A; Jiménez, J; Tamargo, J

1993-11-01

1. In rat thoracic aortae, contractions induced by methoxamine were inhibited by chloroethylclonidine, whereas oxymetazoline-induced contractions, which were more dependent on Ca(2+)-entry, were insensitive to chloroethylclonidine. 2. Aminophylline inhibited the contractions and 45Ca(2+)-uptake induced by both methoxamine and oxymetazoline. However, oxymetazoline-induced contractions were more sensitive to inhibition by aminophylline and D600. 3. Thus, the partial selectivity of aminophylline for the chloroethylclonidine-resistant, highly dependent on extracellular Ca2+, oxymetazoline-mediated responses may be explained by a preferential inhibition of agonist-induced Ca2+ entry as compared to inhibition of other transduction pathways.

Interneuron-mediated inhibition synchronizes neuronal activity during slow oscillation.

PubMed

Chen, Jen-Yung; Chauvette, Sylvain; Skorheim, Steven; Timofeev, Igor; Bazhenov, Maxim

2012-08-15

The signature of slow-wave sleep in the electroencephalogram (EEG) is large-amplitude fluctuation of the field potential, which reflects synchronous alternation of activity and silence across cortical neurons. While initiation of the active cortical states during sleep slow oscillation has been intensively studied, the biological mechanisms which drive the network transition from an active state to silence remain poorly understood. In the current study, using a combination of in vivo electrophysiology and thalamocortical network simulation, we explored the impact of intrinsic and synaptic inhibition on state transition during sleep slow oscillation. We found that in normal physiological conditions, synaptic inhibition controls the duration and the synchrony of active state termination. The decline of interneuron-mediated inhibition led to asynchronous downward transition across the cortical network and broke the regular slow oscillation pattern. Furthermore, in both in vivo experiment and computational modelling, we revealed that when the level of synaptic inhibition was reduced significantly, it led to a recovery of synchronized oscillations in the form of seizure-like bursting activity. In this condition, the fast active state termination was mediated by intrinsic hyperpolarizing conductances. Our study highlights the significance of both intrinsic and synaptic inhibition in manipulating sleep slow rhythms.

Interneuron-mediated inhibition synchronizes neuronal activity during slow oscillation

PubMed Central

Chen, Jen-Yung; Chauvette, Sylvain; Skorheim, Steven; Timofeev, Igor; Bazhenov, Maxim

2012-01-01

The signature of slow-wave sleep in the electroencephalogram (EEG) is large-amplitude fluctuation of the field potential, which reflects synchronous alternation of activity and silence across cortical neurons. While initiation of the active cortical states during sleep slow oscillation has been intensively studied, the biological mechanisms which drive the network transition from an active state to silence remain poorly understood. In the current study, using a combination of in vivo electrophysiology and thalamocortical network simulation, we explored the impact of intrinsic and synaptic inhibition on state transition during sleep slow oscillation. We found that in normal physiological conditions, synaptic inhibition controls the duration and the synchrony of active state termination. The decline of interneuron-mediated inhibition led to asynchronous downward transition across the cortical network and broke the regular slow oscillation pattern. Furthermore, in both in vivo experiment and computational modelling, we revealed that when the level of synaptic inhibition was reduced significantly, it led to a recovery of synchronized oscillations in the form of seizure-like bursting activity. In this condition, the fast active state termination was mediated by intrinsic hyperpolarizing conductances. Our study highlights the significance of both intrinsic and synaptic inhibition in manipulating sleep slow rhythms. PMID:22641778

Inhibition during response preparation is sensitive to response complexity

PubMed Central

Saks, Dylan; Hoang, Timothy; Ivry, Richard B.

2015-01-01

Motor system excitability is transiently suppressed during the preparation of movement. This preparatory inhibition is hypothesized to facilitate response selection and initiation. Given that demands on selection and initiation processes increase with movement complexity, we hypothesized that complexity would influence preparatory inhibition. To test this hypothesis, we probed corticospinal excitability during a delayed-response task in which participants were cued to prepare right- or left-hand movements of varying complexity. Single-pulse transcranial magnetic stimulation was applied over right primary motor cortex to elicit motor evoked potentials (MEPs) from the first dorsal interosseous (FDI) of the left hand. MEP suppression was greater during the preparation of responses involving coordination of the FDI and adductor digiti minimi relative to easier responses involving only the FDI, independent of which hand was cued to respond. In contrast, this increased inhibition was absent when the complex responses required sequential movements of the two muscles. Moreover, complexity did not influence the level of inhibition when the response hand was fixed for the trial block, regardless of whether the complex responses were performed simultaneously or sequentially. These results suggest that preparatory inhibition contributes to response selection, possibly by suppressing extraneous movements when responses involve the simultaneous coordination of multiple effectors. PMID:25717168

Dual inhibition of acetylcholinesterase and butyrylcholinesterase enzymes by allicin

PubMed Central

Kumar, Suresh

2015-01-01

Objectives: The brain of mammals contains two major form of cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The dual inhibition of these enzymes is considered as a promising strategy for the treatment of neurological disorder such as Alzheimer's disease (AD), senile dementia, ataxia, and myasthenia gravis. The present study was undertaken to explore the anticholinesterase inhibition property of allicin. Materials and Methods: An assessment of cholinesterase inhibition was carried out by Ellman's assay. Results: The present study demonstrates allicin, a major ingredient of crushed garlic (Allium sativum L.) inhibited both AChE and BuChE enzymes in a concentration-dependent manner. For allicin, the IC50 concentration was 0.01 mg/mL (61.62 μM) for AChE and 0.05 ± 0.018 mg/mL (308.12 μM) for BuChE enzymes. Conclusions: Allicin shows a potential to ameliorate the decline of cognitive function and memory loss associated with AD by inhibiting cholinesterase enzymes and upregulate the levels of acetylcholine (ACh) in the brain. It can be used as a new lead to target AChE and BuChE to upregulate the level of ACh which will be useful in alleviating the symptoms associated with AD. PMID:26288480

PTEN-mediated ERK1/2 inhibition and paradoxical cellular proliferation following Pnck overexpression

PubMed Central

Deb, Tushar B; Barndt, Robert J; Zuo, Annie H; Sengupta, Surojeet; Coticchia, Christine M; Johnson, Michael D

2014-01-01

Pregnancy upregulated non-ubiquitous calmodulin kinase (Pnck), a novel calmodulin kinase, is significantly overexpressed in breast and renal cancers. We present evidence that at high cell density, overexpression of Pnck in HEK 293 cells inhibits serum-induced extracellular signal-regulated kinase (ERK1/ERK2) activation. ERK1/2 inhibition is calcium-dependent and Pnck kinase activity is required for ERK1/2 inhibition, since expression of a kinase-dead (K44A) and a catalytic loop phosphorylation mutant (T171A) Pnck protein is unable to inhibit ERK 1/2 activity. Ras is constitutively active at high cell density, and Pnck does not alter Ras activation, suggesting that Pnck inhibition of ERK1/2 activity is independent of Ras activity. Pnck inhibition of serum-induced ERK1/2 activity is lost in cells in which phosphatase and tensin homolog (PTEN) is suppressed, suggesting that Pnck inhibition of ERK1/2 activity is mediated by PTEN. Overexpression of protein phosphatase-active but lipid phosphatase-dead PTEN protein inhibits ERK1/2 activity in control cells and enhances Pnck-mediated ERK1/2 inhibition, suggesting that Pnck increases availability of protein phosphatase active PTEN for ERK1/2 inhibition. Pnck is a stress-responsive kinase; however, serum-induced p38 MAP kinase activity is also downregulated by Pnck in a Pnck kinase- and PTEN-dependent manner, similar to ERK1/2 inhibition. Pnck overexpression increases proliferation, which is inhibited by PTEN knockdown, implying that PTEN acts as a paradoxical promoter of proliferation in ERK1/2 and p38 MAP kinase phosphorylation-inhibited, Pnck-overexpressing cells. Overall, these data reveal a novel function of Pnck in the regulation of ERK1/2 and p38 MAP kinase activity and cell proliferation, which is mediated by paradoxical PTEN functions. The possible biological implications of these data are discussed. PMID:24552815

Gradient microfluidics enables rapid bacterial growth inhibition testing.

PubMed

Li, Bing; Qiu, Yong; Glidle, Andrew; McIlvenna, David; Luo, Qian; Cooper, Jon; Shi, Han-Chang; Yin, Huabing

2014-03-18

Bacterial growth inhibition tests have become a standard measure of the adverse effects of inhibitors for a wide range of applications, such as toxicity testing in the medical and environmental sciences. However, conventional well-plate formats for these tests are laborious and provide limited information (often being restricted to an end-point assay). In this study, we have developed a microfluidic system that enables fast quantification of the effect of an inhibitor on bacteria growth and survival, within a single experiment. This format offers a unique combination of advantages, including long-term continuous flow culture, generation of concentration gradients, and single cell morphology tracking. Using Escherichia coli and the inhibitor amoxicillin as one model system, we show excellent agreement between an on-chip single cell-based assay and conventional methods to obtain quantitative measures of antibiotic inhibition (for example, minimum inhibition concentration). Furthermore, we show that our methods can provide additional information, over and above that of the standard well-plate assay, including kinetic information on growth inhibition and measurements of bacterial morphological dynamics over a wide range of inhibitor concentrations. Finally, using a second model system, we show that this chip-based systems does not require the bacteria to be labeled and is well suited for the study of naturally occurring species. We illustrate this using Nitrosomonas europaea, an environmentally important bacteria, and show that the chip system can lead to a significant reduction in the period required for growth and inhibition measurements (<4 days, compared to weeks in a culture flask).

Vanadate inhibition of stomatal opening in epidermal peels of Commelina communis

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

Schwartz, A.; Illan, N.; Assmann, S.M.

There are conflicting reports on the effectiveness of the plasmamembrane H{sup +} ATPase inhibitor, vanadate, in inhibiting stomatal opening. We have observed that vanadate inhibited light-stimulated stomatal opening in epidermal peels of Commelina communis only at KCl concentrations lower than 50 mM. When KCl was replaced with n-methylglucamine chloride, vanadate was still ineffective at high salt concentrations. However, in the absence of Cl{sup {minus}}, when KOH was buffered with V{sub 2}O{sub 5}, vanadate inhibition of stomatal opening occurred even at high salt concentrations (K{sup +} = 70 mM). An inhibitor of anion uptake, anthracene-9-carboxylic acid (200 {mu}M), partially prevented vanadatemore » inhibition of stomatal opening; other inhibitors (DIDS, SITS, Zn{sup 2+}) were ineffective. These results suggest that inhibition of stomatal opening by vanadate requires its entry into guard cells through an anion uptake system. Decreasing vanadate inhibition at high Cl{sup {minus}}/vanadate ratios may result from competition between vanadate and Cl{sup {minus}} for a common uptake mechanism.« less

Contact Inhibition: Also a Control for Cell Proliferation in Unicellular Algae?

PubMed

Costas, E; Aguilera, A; Gonzalez-Gil, S; López-Rodas, V

1993-02-01

According to traditional views, the proliferation of unicellular algae is controlled primarily by environmental conditions. But as in mammalian cells, other biological mechanisms, such as growth factors, cellular aging, and contact inhibition, might also control algal proliferation. Here we ask whether contact inhibition regulates growth in several species of unicellular algae as it does in mammalian cells. Laboratory cultures of the dinoflagellate Prorocentrum lima (Ehrenberg) Dodge show contact inhibition at low cell density, so this would be an autocontrol mechanism of cell proliferation that could also act in natural populations of P. lima. But, Synechocystis spp., Phaeodactylum tricornutum (Bohlin), Skeletonema costatum (Greville), and Tetraselmis spp. do not exhibit contact inhibition in laboratory cultures because they are able to grow at high cellular density. Apparently their growth is limited by nutrient depletion or catabolite accumulation instead of contact inhibition. Spirogyra insignis (Hassall) Kutz, Prorocentrum triestinum Schiller, and Alexandrium tamarense (Halim) Balech show a complex response, as they are able to grow in both low and high cell density medium. These results suggest that contact inhibition is more adaptative in benthic unicellular algae.

Inhibition of Acetoclastic Methanogenesis in Crude Oil- and Creosote-Contaminated Groundwater

USGS Publications Warehouse

Warren, E.; Bekins, B.A.; Godsy, E.M.; Smith, V.K.

2003-01-01

The inhibition of acetoclastic methanogenesis in crude oil- and creosote-contaminated groundwater was studied. The crude oil and water-soluble components of creosote contributed to the inhibition of acetoclastic methanogens. Acetoclastic methanogenesis was much more susceptible to the toxic inhibition of crude oil and creosote than either hydrogen- or formate-utilizing methanogenesis. The effect of this toxic inhibition was apparent in the population of the methanogenic trophic groups near nonaqueous crude oil at the Bemidji, MN, site. At a crude oil-contaminated site, numbers of acetoclastic methanogens found close to crude oil were 100 times fewer than those of hydrogen- and formate-utilizing methanogens. In laboratory toxicity assays, crude oil collected from the site inhibited methane production from acetate but not from formate or hydrogen. Toxicity assays with aqueous creosote extract completely inhibited acetate utilization over the range of tested dilutions but only mildly affected formate and hydrogen utilization. Wastewater reactor studies indicated that this toxicity would result in a decrease in the biodegradation rate of contaminants at sites where toxic compounds are present.

Inhibition of noradrenaline release by lysergic acid diethylamide

PubMed Central

Hughes, J.

1973-01-01

Lysergic acid diethylamide (LSD) inhibits the release of labelled noradrenaline from the guinea-pig vas deferens during intramural nerve stimulation and causes a corresponding reduction in the contractions of the smooth muscle. These effects of LSD are most prominent at low stimulus frequencies and they are prevented by treatment with phentolamine. It is concluded that LSD inhibits noradrenaline release by interacting with presynaptic α-adrenoceptors. PMID:4788042

Inhibition of intra-Golgi transport in vitro by mitotic kinase.

PubMed

Stuart, R A; Mackay, D; Adamczewski, J; Warren, G

1993-02-25

It has previously been shown that exocytic and endocytic membrane traffic are inhibited in mitotic mammalian cells. Here we have used a cell-free intra-Golgi transport assay supplemented with heterologous cytosols to mimic this effect in vitro. Cytosols with high histone kinase activity, made either from mitotic cells or by cyclin A treatment of interphase cells, inhibited intra-Golgi transport by up to 75%. Inhibition of transport was reversed by the kinase inhibitor staurosporine or by reduction in ATP levels leading to inactivation of histone kinase. The data indicate that cell cycle control of intra-Golgi transport is due to a reversible modification of cytosol, and this assay system may be used to study the molecular mechanism of mitotic transport inhibition in mammalian cells.

Glycinergic inhibition tunes coincidence detection in the auditory brainstem

PubMed Central

Myoga, Michael H.; Lehnert, Simon; Leibold, Christian; Felmy, Felix; Grothe, Benedikt

2014-01-01

Neurons in the medial superior olive (MSO) detect microsecond differences in the arrival time of sounds between the ears (interaural time differences or ITDs), a crucial binaural cue for sound localization. Synaptic inhibition has been implicated in tuning ITD sensitivity, but the cellular mechanisms underlying its influence on coincidence detection are debated. Here we determine the impact of inhibition on coincidence detection in adult Mongolian gerbil MSO brain slices by testing precise temporal integration of measured synaptic responses using conductance-clamp. We find that inhibition dynamically shifts the peak timing of excitation, depending on its relative arrival time, which in turn modulates the timing of best coincidence detection. Inhibitory control of coincidence detection timing is consistent with the diversity of ITD functions observed in vivo and is robust under physiologically relevant conditions. Our results provide strong evidence that temporal interactions between excitation and inhibition on microsecond timescales are critical for binaural processing. PMID:24804642

Genetic separation of phototropism from blue light inhibition of hypocotyl elongation on Arabidopsis

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

Liscum, E.; Young, J.C.; Hangarter, R.P.

1991-05-01

Phototropism and inhibition of stem elongation occur in response to blue light-induced inhibition of cell elongation. However, phototropism is a low fluence response and inhibition of hypocotyl elongation is a high irradiance response. The authors have isolated several mutant lines of Arabidopsis which lack blue light-induced inhibition of hypocotyl elongation but retain normal phototropic functions. In addition, a mutant line which completely lacks the phototropic response retains normal blue light-induced inhibition of hypocotyl elongation. F1 progeny of crosses between these two mutant classes exhibited wild-type phototropism and inhibition of hypocotyl elongation in response to blue light stimuli. In the F2more » generation, one in sixteen seedlings were double mutants lacking both phototropism and blue light-induced hypocotyl growth inhibition. These studies conclusively show that blue light-induced phototropism and hypocotyl growth inhibition function through genetically distinct signal transduction or response systems.« less

Frontal white matter damage impairs response inhibition in children following traumatic brain injury.

PubMed

Lipszyc, Jonathan; Levin, Harvey; Hanten, Gerri; Hunter, Jill; Dennis, Maureen; Schachar, Russell

2014-05-01

Inhibition, the ability to suppress inappropriate cognitions or behaviors, can be measured using computer tasks and questionnaires. Inhibition depends on the frontal cortex, but the role of the underlying white matter (WM) is unclear. We assessed the specific impact of frontal WM damage on inhibition in 29 children with moderate-to-severe traumatic brain injury (15 with and 14 without frontal WM damage), 21 children with orthopedic injury, and 29 population controls. We used the Stop Signal Task to measure response inhibition, the Behavior Rating Inventory of Executive Function to assess everyday inhibition, and T2 fluid-attenuated inversion recovery magnetic resonance imaging to identify lesions. Children with frontal WM damage had impaired response inhibition compared with all other groups and poorer everyday inhibition than the orthopedic injury group. Frontal WM lesions most often affected the superior frontal gyrus. These results provide evidence for the critical role of frontal WM in inhibition.

Clofibrate inhibits the umami-savory taste of glutamate

PubMed Central

Kochem, Matthew

2017-01-01

In humans, umami taste can increase the palatability of foods rich in the amino acids glutamate and aspartate and the 5’-ribonucleotides IMP and GMP. Umami taste is transduced, in part, by T1R1-T1R3, a heteromeric G-protein coupled receptor. Umami perception is inhibited by sodium lactisole, which binds to the T1R3 subunit in vitro. Lactisole is structurally similar to the fibrate drugs. Clofibric acid, a lipid lowering drug, also binds the T1R3 subunit in vitro. The purpose of this study was to determine whether clofibric acid inhibits the umami taste of glutamate in human subjects. Ten participants rated the umami taste intensity elicited by 20 mM monosodium glutamate (MSG) mixed with varying concentrations of clofibric acid (0 to 16 mM). In addition, fourteen participants rated the effect of 1.4 mM clofibric acid on umami enhancement by 5’ ribonucleotides. Participants were instructed to rate perceived intensity using a general Labeled Magnitude Scale (gLMS). Each participant was tested in triplicate. Clofibric acid inhibited umami taste intensity from 20 mM MSG in a dose dependent manner. Whereas MSG neat elicited “moderate” umami taste intensity, the addition of 16 mM clofibric acid elicited only “weak” umami intensity on average, and in some subjects no umami taste was elicited. We further show that 1.4 mM clofibric acid suppressed umami enhancement from GMP, but not from IMP. This study provides in vivo evidence that clofibric acid inhibits glutamate taste perception, presumably via T1R1-T1R3 inhibition, and lends further evidence that the T1R1-T1R3 receptor is the principal umami receptor in humans. T1R receptors are expressed extra-orally throughout the alimentary tract and in regulatory organs and are known to influence glucose and lipid metabolism. Whether clofibric acid as a lipid-lowering drug affects human metabolism, in part, through T1R inhibition warrants further examination. PMID:28248971

Clofibrate inhibits the umami-savory taste of glutamate.

PubMed

Kochem, Matthew; Breslin, Paul A S

2017-01-01

In humans, umami taste can increase the palatability of foods rich in the amino acids glutamate and aspartate and the 5'-ribonucleotides IMP and GMP. Umami taste is transduced, in part, by T1R1-T1R3, a heteromeric G-protein coupled receptor. Umami perception is inhibited by sodium lactisole, which binds to the T1R3 subunit in vitro. Lactisole is structurally similar to the fibrate drugs. Clofibric acid, a lipid lowering drug, also binds the T1R3 subunit in vitro. The purpose of this study was to determine whether clofibric acid inhibits the umami taste of glutamate in human subjects. Ten participants rated the umami taste intensity elicited by 20 mM monosodium glutamate (MSG) mixed with varying concentrations of clofibric acid (0 to 16 mM). In addition, fourteen participants rated the effect of 1.4 mM clofibric acid on umami enhancement by 5' ribonucleotides. Participants were instructed to rate perceived intensity using a general Labeled Magnitude Scale (gLMS). Each participant was tested in triplicate. Clofibric acid inhibited umami taste intensity from 20 mM MSG in a dose dependent manner. Whereas MSG neat elicited "moderate" umami taste intensity, the addition of 16 mM clofibric acid elicited only "weak" umami intensity on average, and in some subjects no umami taste was elicited. We further show that 1.4 mM clofibric acid suppressed umami enhancement from GMP, but not from IMP. This study provides in vivo evidence that clofibric acid inhibits glutamate taste perception, presumably via T1R1-T1R3 inhibition, and lends further evidence that the T1R1-T1R3 receptor is the principal umami receptor in humans. T1R receptors are expressed extra-orally throughout the alimentary tract and in regulatory organs and are known to influence glucose and lipid metabolism. Whether clofibric acid as a lipid-lowering drug affects human metabolism, in part, through T1R inhibition warrants further examination.

Vibration-evoked reciprocal inhibition between human wrist muscles.

PubMed

Cody, F W; Plant, T

1989-01-01

Reciprocal inhibition of the voluntarily contracting wrist extensor (extensor carpi radialis, ECR) evoked by proprioceptive afferent input from the flexor (flexor carpi radialis, FCR), was studied in healthy human subjects. Vibration of the FCR tendon was used to elicit Ia-dominated afferent discharge whilst inhibition of ECR was assessed as the reduction in asynchronous, on-going EMG. A small early phase of inhibition (I1) was evident in 25% of trials. The latency (ca. 25 ms) of this component suggested that it was mediated by an Ia oligosynaptic. possibly 'classical' disynaptic, inhibitory pathway. A later and apparently separate phase of reduced activity (I2, ca. 40 ms) was, however, far more consistently observed (96% of trials) and of greater magnitude. The I2 component was usually followed, some 20 ms later, by a phase of elevated activity (E1, 72% trials). Reductions in simultaneously recorded net extensor torque commenced at about 60 ms following the onset of flexor tendon vibration, i.e. some 20 ms after the main I2 EMG component. These mechanical responses must have almost exclusively resulted from reciprocal inhibition of extensor EMG since vibration of the relaxed FCR evoked minimal excitatory flexor activity. The reflex pattern, in any individual subject, was relatively unaffected by altering the duration of the vibration train between one and nineteen cycles (125 Hz). This suggests that the entire response complex resulted largely from the initial afferent volley. The sizes of both the I1 and I2 reductions in ECR activity increased with increasing voluntary extensor contraction so that their depths remained constant proportions of background EMG. Very similar results were obtained when reciprocal inhibition of FCR was produced by vibration of the belly of ECR. Thus, reciprocal inhibition between wrist muscles is mainly expressed as a rather stereotyped, short duration reduction in EMG whose depth is determined by the pre-existing level of motor

Cadmium inhibits the protein degradation of Sml1 by inhibiting the phosphorylation of Sml1 in Saccharomyces cerevisiae

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

Baek, In-Joon; Kang, Hyun-Jun; Chang, Miwha

Highlights: Black-Right-Pointing-Pointer Cd inhibits Sml1-p formation. Black-Right-Pointing-Pointer Cd affects cell cycle. Black-Right-Pointing-Pointer Cd inhibits Sml1 ubiquitination. -- Abstract: Cadmium is a toxic metal, and the mechanism of cadmium toxicity in living organisms has been well studied. Here, we used Saccharomyces cerevisiae as a model system to examine the detailed molecular mechanism of cell growth defects caused by cadmium. Using a plate assay of a yeast deletion mutant collection, we found that deletion of SML1, which encodes an inhibitor of Rnr1, resulted in cadmium resistance. Sml1 protein levels increased when cells were treated with cadmium, even though the mRNA levels ofmore » SML1 remained unchanged. Using northern and western blot analyses, we found that cadmium inhibited Sml1 degradation by inhibiting Sml1 phosphorylation. Sml1 protein levels increased when cells were treated with cadmium due to disruption of the dependent protein degradation pathway. Furthermore, cadmium promoted cell cycle progression into the G2 phase. The same result was obtained using cells in which SML1 was overexpressed. Deletion of SML1 delayed cell cycle progression. These results are consistent with Sml1 accumulation and with growth defects caused by cadmium stress. Interestingly, although cadmium treatment led to increase Sml1 levels, intracellular dNTP levels also increased because of Rnr3 upregulation due to cadmium stress. Taken together, these results suggest that cadmium specifically affects the phosphorylation of Sml1 and that Sml1 accumulates in cells.« less

A Model of Motor Inhibition for a Complex Skill: Baseball Batting

ERIC Educational Resources Information Center

Gray, Rob

2009-01-01

The ability to inhibit an ongoing action in response to a signal from the environment is important for many perceptual-motor actions. This paper examines a particular example of this behavior: attempting to inhibit or "check" a swing in baseball batting. A model of motor inhibition in batting is proposed. In the model there are three different…

Impairment of manual but not saccadic response inhibition following acute alcohol intoxication.

PubMed

Campbell, Anne Eileen; Chambers, Christopher D; Allen, Christopher P G; Hedge, Craig; Sumner, Petroc

2017-12-01

Alcohol impairs response inhibition; however, it remains contested whether such impairments affect a general inhibition system, or whether affected inhibition systems are embedded in, and specific to, each response modality. Further, alcohol-induced impairments have not been disambiguated between proactive and reactive inhibition mechanisms, and nor have the contributions of action-updating impairments to behavioural 'inhibition' deficits been investigated. Forty Participants (25 female) completed both a manual and a saccadic stop-signal reaction time (SSRT) task before and after a 0.8g/kg dose of alcohol and, on a separate day, before and after a placebo. Blocks in which participants were required to ignore the signal to stop or make an additional 'dual' response were included to obtain measures of proactive inhibition as well as updating of attention and action. Alcohol increased manual but not saccadic SSRT. Proactive inhibition was weakly reduced by alcohol, but increases in the reaction times used to baseline this contrast prevent clear conclusions regarding response caution. Finally, alcohol also increased secondary dual response times of the dual task uniformly as a function of the delay between tasks, indicating an effect of alcohol on action-updating or execution. The modality-specific effects of alcohol favour the theory that response inhibition systems are embedded within response modalities, rather than there existing a general inhibition system. Concerning alcohol, saccadic control appears relatively more immune to disruption than manual control, even though alcohol affects saccadic latency and velocity. Within the manual domain, alcohol affects multiple types of action updating, not just inhibition. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Magnesium inhibition of ryanodine-receptor calcium channels: evidence for two independent mechanisms.

PubMed

Laver, D R; Baynes, T M; Dulhunty, A F

1997-04-01

The gating of ryanodine receptor calcium release channels (RyRs) depends on myoplasmic Ca2+ and Mg2+ concentrations. RyRs from skeletal and cardiac muscle are activated by microm Ca2+ and inhibited by mm Ca2+ and Mg2+. 45Ca2+ release from skeletal SR vesicles suggests two mechanisms for Mg2+-inhibition (Meissner, Darling & Eveleth, 1986, Biochemistry 25:236-244). The present study investigates the nature of these mechanisms using measurements of single-channel activity from cardiac- and skeletal RyRs incorporated into planar lipid bilayers. Our measurements of Mg2+- and Ca2+-dependent gating kinetics confirm that there are two mechanisms for Mg2+ inhibition (Type I and II inhibition) in skeletal and cardiac RyRs. The mechanisms operate concurrently, are independent and are associated with different parts of the channel protein. Mg2+ reduces Po by competing with Ca2+ for the activation site (Type-I) or binding to more than one, and probably two low affinity inhibition sites which do not discriminate between Ca2+ and Mg2+ (Type-II). The relative contributions of the two inhibition mechanisms to the total Mg2+ effect depend on cytoplasmic [Ca2+] in such a way that Mg2+ inhibition has the properties of Types-I and II inhibition at low and high [Ca2+] respectively. Both mechanisms are equally important when [Ca2+] = 10 microm in cardiac RyRs or 1 microm in skeletal RyRs. We show that Type-I inhibition is not the sole mechanism responsible for Mg2+ inhibition, as is often assumed, and we discuss the physiological implications of this finding.

The Deakin/Graeff hypothesis: focus on serotonergic inhibition of panic

PubMed Central

Paul, Evan D.; Johnson, Philip L.; Shekhar, Anantha; Lowry, Christopher A.

2014-01-01

The Deakin/Graeff hypothesis proposes that different subpopulations of serotonergic neurons through topographically organized projections to forebrain and brainstem structures modulate the response to acute and chronic stressors, and that dysfunction of these neurons increases vulnerability to affective and anxiety disorders, including Panic Disorder. We outline evidence supporting the existence of a serotonergic system originally discussed by Deakin/Graeff that is implicated in the inhibition of panic-like behavioral and physiological responses. Evidence supporting this panic inhibition system comes from the following observations: 1) serotonergic neurons located in the ‘ventrolateral dorsal raphe nucleus (DRVL) as well as the ventrolateral periaqueductal gray (VLPAG) inhibit dorsal periaqueductal gray-elicited panic-like responses; 2) chronic, but not acute, antidepressant treatment potentiates serotonin’s panicolytic effect; 3) contextual fear activates a central nucleus of the amygdala-DRVL/VLPAG circuit implicated in mediating freezing and inhibiting panic-like escape behaviors; 4) DRVL/VLPAG serotonergic neurons are central chemoreceptors and modulate the behavioral and cardiorespiratory response to panicogenic agents such as sodium lactate and CO2. Implications of the panic inhibition system are discussed. PMID:24661986

Lactobacillus plantarum lipoteichoic acid inhibits biofilm formation of Streptococcus mutans

PubMed Central

Ahn, Ki Bum; Baik, Jung Eun; Park, Ok-Jin; Yun, Cheol-Heui

2018-01-01

Dental caries is a biofilm-dependent oral disease and Streptococcus mutans is the known primary etiologic agent of dental caries that initiates biofilm formation on tooth surfaces. Although some Lactobacillus strains inhibit biofilm formation of oral pathogenic bacteria, the molecular mechanisms by which lactobacilli inhibit bacterial biofilm formation are not clearly understood. In this study, we demonstrated that Lactobacillus plantarum lipoteichoic acid (Lp.LTA) inhibited the biofilm formation of S. mutans on polystyrene plates, hydroxyapatite discs, and dentin slices without affecting the bacterial growth. Lp.LTA interferes with sucrose decomposition of S. mutans required for the production of exopolysaccharide, which is a main component of biofilm. Lp.LTA also attenuated the biding of fluorescein isothiocyanate-conjugated dextran to S. mutans, which is known to have a high affinity to exopolysaccharide on S. mutans. Dealanylated Lp.LTA did not inhibit biofilm formation of S. mutans implying that D-alanine moieties in the Lp.LTA structure were crucial for inhibition. Collectively, these results suggest that Lp.LTA attenuates S. mutans biofilm formation and could be used to develop effective anticaries agents. PMID:29420616

Ankyrin-G Inhibits Endocytosis of Cadherin Dimers.

PubMed

Cadwell, Chantel M; Jenkins, Paul M; Bennett, Vann; Kowalczyk, Andrew P

2016-01-08

Dynamic regulation of endothelial cell adhesion is central to vascular development and maintenance. Furthermore, altered endothelial adhesion is implicated in numerous diseases. Therefore, normal vascular patterning and maintenance require tight regulation of endothelial cell adhesion dynamics. However, the mechanisms that control junctional plasticity are not fully understood. Vascular endothelial cadherin (VE-cadherin) is an adhesive protein found in adherens junctions of endothelial cells. VE-cadherin mediates adhesion through trans interactions formed by its extracellular domain. Trans binding is followed by cis interactions that laterally cluster the cadherin in junctions. VE-cadherin is linked to the actin cytoskeleton through cytoplasmic interactions with β- and α-catenin, which serve to increase adhesive strength. Furthermore, p120-catenin binds to the cytoplasmic tail of cadherin and stabilizes it at the plasma membrane. Here we report that induced cis dimerization of VE-cadherin inhibits endocytosis independent of both p120 binding and trans interactions. However, we find that ankyrin-G, a protein that links membrane proteins to the spectrin-actin cytoskeleton, associates with VE-cadherin and inhibits its endocytosis. Ankyrin-G inhibits VE-cadherin endocytosis independent of p120 binding. We propose a model in which ankyrin-G associates with and inhibits the endocytosis of VE-cadherin cis dimers. Our findings support a novel mechanism for regulation of VE-cadherin endocytosis through ankyrin association with cadherin engaged in lateral interactions. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Inhibition effects of furfural on alcohol dehydrogenase, aldehyde dehydrogenase and pyruvate dehydrogenase.

PubMed Central

Modig, Tobias; Lidén, Gunnar; Taherzadeh, Mohammad J

2002-01-01

The kinetics of furfural inhibition of the enzymes alcohol dehydrogenase (ADH; EC 1.1.1.1), aldehyde dehydrogenase (AlDH; EC 1.2.1.5) and the pyruvate dehydrogenase (PDH) complex were studied in vitro. At a concentration of less than 2 mM furfural was found to decrease the activity of both PDH and AlDH by more than 90%, whereas the ADH activity decreased by less than 20% at the same concentration. Furfural inhibition of ADH and AlDH activities could be described well by a competitive inhibition model, whereas the inhibition of PDH was best described as non-competitive. The estimated K(m) value of AlDH for furfural was found to be about 5 microM, which was lower than that for acetaldehyde (10 microM). For ADH, however, the estimated K(m) value for furfural (1.2 mM) was higher than that for acetaldehyde (0.4 mM). The inhibition of the three enzymes by 5-hydroxymethylfurfural (HMF) was also measured. The inhibition caused by HMF of ADH was very similar to that caused by furfural. However, HMF did not inhibit either AlDH or PDH as severely as furfural. The inhibition effects on the three enzymes could well explain previously reported in vivo effects caused by furfural and HMF on the overall metabolism of Saccharomyces cerevisiae, suggesting a critical role of these enzymes in the observed inhibition. PMID:11964178

Febuxostat Inhibition of Endothelial-Bound XO: Implications for Targeting Vascular ROS Production

PubMed Central

Malik, Umair Z.; Hundley, Nicholas J.; Romero, Guillermo; Radi, Rafael; Freeman, Bruce A.; Tarpey, Margaret M.; Kelley, Eric E.

2011-01-01

Xanthine oxidase (XO) is a critical source of reactive oxygen species (ROS) that contribute to vascular inflammation. Binding of XO to vascular endothelial cell glycosaminoglycans (GAGs) results in significant resistance to inhibition by traditional pyrazolopyrimidine-based inhibitors such as allopurinol. Therefore, we compared the extent of XO inhibition (free and GAG-bound) by allopurinol to febuxostat, a newly approved nonpurine XO-specific inhibitor. In solution, febuxostat was 1000 fold more potent than allopurinol inhibition of XO-dependent uric acid formation (IC50 = 1.8 nM vs. 2.9 μM). Association of XO with heparin-Sepharose 6B (HS6B-XO) had minimal effect on inhibition of uric acid formation by febuxostat (IC50 = 4.4 nM) while further limiting the effect of allopurinol (IC50 = 64 μM). Kinetic analysis of febuxostat inhibition revealed Ki values of 0.96 nM (free) and 0.92 nM (HS6B-XO), confirming equivalent inhibition for both free and GAG-immobilized enzyme. When XO was bound to endothelial cell GAGs, complete enzyme inhibition was observed with 25 nM febuxostat, while no more than 80% inhibition was seen with either allopurinol or oxypurinol, even at concentrations above those tolerated clinically. The superior potency for inhibition of endothelium-associated XO is predictive of a significant role for febuxostat in investigating pathological states where XO-derived ROS are contributive and traditional XO inhibitors are only slightly effective. PMID:21554948

Physiological Markers of Motor Inhibition during Human Behavior.

PubMed

Duque, Julie; Greenhouse, Ian; Labruna, Ludovica; Ivry, Richard B

2017-04-01

Transcranial magnetic stimulation (TMS) studies in humans have shown that many behaviors engage processes that suppress excitability within the corticospinal tract. Inhibition of the motor output pathway has been extensively studied in the context of action stopping, where a planned movement needs to be abruptly aborted. Recent TMS work has also revealed markers of motor inhibition during the preparation of movement. Here, we review the evidence for motor inhibition during action stopping and action preparation, focusing on studies that have used TMS to monitor changes in the excitability of the corticospinal pathway. We discuss how these physiological results have motivated theoretical models of how the brain selects actions, regulates movement initiation and execution, and switches from one state to another. Copyright © 2017 Elsevier Ltd. All rights reserved.

Selective mutism and temperament: the silence and behavioral inhibition to the unfamiliar.

PubMed

Gensthaler, Angelika; Khalaf, Sally; Ligges, Marc; Kaess, Michael; Freitag, Christine M; Schwenck, Christina

2016-10-01

Behavioral inhibition (BI) is a suspected precursor of selective mutism. However, investigations on early behavioral inhibition of children with selective mutism are lacking. Children aged 3-18 with lifetime selective mutism (n = 109), social phobia (n = 61), internalizing behavior (n = 46) and healthy controls (n = 118) were assessed using the parent-rated Retrospective Infant Behavioral Inhibition (RIBI) questionnaire. Analyses showed that children with lifetime selective mutism and social phobia were more inhibited as infants and toddlers than children of the internalizing and healthy control groups, who displayed similar low levels of behavioral inhibition. Moreover, behavioral inhibition was higher in infants with lifetime selective mutism than in participants with social phobia according to the Total BI score (p = 0.012) and the Shyness subscale (p < 0.001). Infant behavioral inhibition, particularly towards social stimuli, is a temperamental feature associated with a lifetime diagnosis of selective mutism. Results yield first evidence of the recently hypothesized temperamental origin of selective mutism. Children at risk should be screened for this debilitating child psychiatric condition.

Evidence Inhibition Responds Reactively to the Salience of Distracting Information during Focused Attention

PubMed Central

Wyatt, Natalie; Machado, Liana

2013-01-01

Along with target amplification, distractor inhibition is regarded as a major contributor to selective attention. Some theories suggest that the strength of inhibitory processing is proportional to the salience of the distractor (i.e., inhibition reacts to the distractor intensity). Other theories suggest that the strength of inhibitory processing does not depend on the salience of the distractor (i.e., inhibition does not react to the distractor intensity). The present study aimed to elucidate the relationship between the intensity of a distractor and its subsequent inhibition during focused attention. A flanker task with a variable distractor-target stimulus-onset asynchrony (SOA) was used to measure both distractor interference and distractor inhibition. We manipulated the intensity of the distractor in two separate ways, by varying its distance from the target (Experiment 1) and by varying its brightness (Experiment 2). The results indicate that more intense distractors were associated with both increased interference and stronger distractor inhibition. The latter outcome provides novel support for the reactive inhibition hypothesis, which posits that inhibition reacts to the strength of distractor input, such that more salient distractors elicit stronger inhibition. PMID:23646147

Sticky Plans: Inhibition and Binding during Serial-Task Control

ERIC Educational Resources Information Center

Mayr, Ulrich

2009-01-01

Recent evidence suggests substantial response-time costs associated with lag-2 repetitions of tasks within explicitly controlled task sequences [Koch, I., Philipp, A. M., Gade, M. (2006). Chunking in task sequences modulates task inhibition. "Psychological Science," 17, 346-350; Schneider, D. W. (2007). Task-set inhibition in chunked task…

The Affective Consequences of Cognitive Inhibition: Devaluation or Neutralization?

ERIC Educational Resources Information Center

Frischen, Alexandra; Ferrey, Anne E.; Burt, Dustin H. R.; Pistchik, Meghan; Fenske, Mark J.

2012-01-01

Affective evaluations of previously ignored visual stimuli are more negative than those of novel items or prior targets of attention or response. This has been taken as evidence that inhibition has negative affective consequences. But inhibition could act instead to attenuate or "neutralize" preexisting affective salience, predicting opposite…

SGLT2 inhibition in the diabetic kidney – an update

PubMed Central

Novikov, Aleksandra; Vallon, Volker

2016-01-01

Purpose of review The sodium glucose cotransporter SGLT2 reabsorbs most of the glucose filtered by the kidneys. SGLT2 inhibitors reduce glucose reabsorption thereby lowering blood glucose levels and have been approved as new anti-hyperglycemic drugs. While the therapeutic strategy is very promising, many questions remain. Recent findings Using validated antibodies SGLT2 expression was localized to the brush border of the early proximal tubule in human kidney and was found upregulated in genetic murine models of type 1 and 2 diabetes. SGLT2 may functionally interact with the Na/H exchanger NHE3 in the proximal tubule. SGLT1-mediated reabsorption explains the fractional glucose reabsorption of 40–50% during SGLT2 inhibition. SGLT2 is expressed on pancreatic alpha cells where its inhibition induces glucagon secretion. SGLT2 inhibition lowers GFR in hyperfiltering diabetic patients consistent with the tubular hypothesis of diabetic hyperfiltration. New data indicate a potential of SGLT2 inhibition for renal medullary hypoxia and ketoacidosis, but also for blood glucose effect-dependent and independent nephroprotective actions, renal gluconeogenesis inhibition, reduction in cardiovascular mortality, and cancer therapy. Summary The findings expand and refine our understanding of SGLT2 and its inhibition, have relevance for clinical practice, and will help interpret ongoing clinical trials on the long-term safety and cardiovascular effects of SGLT2 inhibitors. PMID:26575393

Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation.

PubMed

Huggenberger, Reto; Ullmann, Stefan; Proulx, Steven T; Pytowski, Bronislaw; Alitalo, Kari; Detmar, Michael

2010-09-27

The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin 14 (K14)-VEGF-A transgenic (Tg) mouse model of chronic cutaneous inflammation. Although treatment with an anti-VEGFR-2 antibody inhibited skin inflammation, epidermal hyperplasia, inflammatory infiltration, and angiogenesis, systemic inhibition of VEGFR-3, surprisingly, increased inflammatory edema formation and inflammatory cell accumulation despite inhibition of lymphangiogenesis. Importantly, chronic Tg delivery of the lymphangiogenic factor VEGF-C to the skin of K14-VEGF-A mice completely inhibited development of chronic skin inflammation, epidermal hyperplasia and abnormal differentiation, and accumulation of CD8 T cells. Similar results were found after Tg delivery of mouse VEGF-D that only activates VEGFR-3 but not VEGFR-2. Moreover, intracutaneous injection of recombinant VEGF-C156S, which only activates VEGFR-3, significantly reduced inflammation. Although lymphatic drainage was inhibited in chronic skin inflammation, it was enhanced by Tg VEGF-C delivery. Together, these results reveal an unanticipated active role of lymphatic vessels in controlling chronic inflammation. Stimulation of functional lymphangiogenesis via VEGFR-3, in addition to antiangiogenic therapy, might therefore serve as a novel strategy to treat chronic inflammatory disorders of the skin and possibly also other organs.

Posterior insular cortex is necessary for conditioned inhibition of fear.

PubMed

Foilb, Allison R; Flyer-Adams, Johanna G; Maier, Steven F; Christianson, John P

2016-10-01

Veridical detection of safety versus danger is critical to survival. Learned signals for safety inhibit fear, and so when presented, reduce fear responses produced by danger signals. This phenomenon is termed conditioned inhibition of fear. Here, we report that CS+/CS- fear discrimination conditioning over 5 days in rats leads the CS- to become a conditioned inhibitor of fear, as measured by the classic tests of conditioned inhibition: summation and retardation of subsequent fear acquisition. We then show that NMDA-receptor antagonist AP5 injected to posterior insular cortex (IC) before training completely prevented the acquisition of a conditioned fear inhibitor, while intra-AP5 to anterior and medial IC had no effect. To determine if the IC contributes to the recall of learned fear inhibition, injections of the GABAA agonist muscimol were made to posterior IC before a summation test. This resulted in fear inhibition per se, which obscured inference to the effect of IC inactivation with recall of the safety cue. Control experiments sought to determine if the role of the IC in conditioned inhibition learning could be reduced to simpler fear discrimination function, but fear discrimination and recall were unaffected by AP5 or muscimol, respectively, in the posterior IC. These data implicate a role of posterior IC in the learning of conditioned fear inhibitors. Copyright © 2016 Elsevier Inc. All rights reserved.

Posterior insular cortex is necessary for conditioned inhibition of fear

PubMed Central

Foilb, Allison R.; Flyer-Adams, Johanna G.; Maier, Steven F.; Christianson, John P.

2016-01-01

Veridical detection of safety versus danger is critical to survival. Learned signals for safety inhibit fear, and so when presented, reduce fear responses produced by danger signals. This phenomenon is termed conditioned inhibition of fear. Here, we report that CS+/CS− fear discrimination conditioning over 5 days in rats leads the CS− to become a conditioned inhibitor of fear, as measured by the classic tests of conditioned inhibition: summation and retardation of subsequent fear acquisition. We then show that NMDA-receptor antagonist AP5 injected to posterior insular cortex (IC) before training completely prevented the acquisition of a conditioned fear inhibitor, while intra-AP5 to anterior and medial IC had no effect. To determine if the IC contributes to the recall of learned fear inhibition, injections of the GABAA agonist muscimol were made to posterior IC before a summation test. This resulted in fear inhibition per se, which obscured inference to the effect of IC inactivation with recall of the safety cue. Control experiments sought to determine if the role of the IC in conditioned inhibition learning could be reduced to simpler fear discrimination function, but fear discrimination and recall were unaffected by AP5 or muscmiol, respectively, in the posterior IC. These data implicate a role of posterior IC in the learning of conditioned fear inhibitors. PMID:27523750

THE INHIBITION OF CYPRIDINA LUMINESCENCE BY LIGHT

PubMed Central

Harvey, E. Newton

1925-01-01

The luminescence of Cypridina luciferin-luciferase solution is inhibited by illumination from a carbon arc of 15,000 foot candles in between 1 and 2 seconds. The blue to violet rays are the effective ones, the limits lying somewhere around 4,600 Å. u. to 3,800 Å. u. The luciferin, not the luciferase, is the substance affected by the light. The effect is partially reversible in the dark. The chemiluminescences obtained by oxidizing phosphorus, lophin, and chlorphenylmagnesium bromide are not inhibited by light under the above conditions. PMID:19872169

Aspergillus ficuum phytase activity is inhibited by cereal grain components.

PubMed

Bekalu, Zelalem Eshetu; Madsen, Claus Krogh; Dionisio, Giuseppe; Brinch-Pedersen, Henrik

2017-01-01

In the current study, we report for the first time that grain components of barley, rice, wheat and maize can inhibit the activity of Aspergillus ficuum phytase. The phytase inhibition is dose dependent and varies significantly between cereal species, between cultivars of barley and cultivars of wheat and between Fusarium graminearum infected and non-infected wheat grains. The highest endpoint level of phytase activity inhibition was 90%, observed with grain protein extracts (GPE) from F. graminearum infected wheat. Wheat GPE from grains infected with F. graminearum inhibits phytase activity significantly more than GPE from non-infected grains. For four barley cultivars studied, the IC50 value ranged from 0.978 ± 0.271 to 3.616 ± 0.087 mg×ml-1. For two non-infected wheat cultivars investigated, the IC50 values were varying from 2.478 ± 0.114 to 3.038 ± 0.097 mg×ml-1. The maize and rice cultivars tested gaveIC50 values on 0.983 ± 0.205 and 1.972 ± 0.019 mg×ml-1, respectively. After purifying the inhibitor from barley grains via Superdex G200, an approximately 30-35 kDa protein was identified. No clear trend for the mechanism of inhibition could be identified via Michaelis-Menten kinetics and Lineweaver-Burk plots. However, testing of the purified phytase inhibitor together with the A. ficuum phytase and the specific protease inhibitors pepstatin A, E64, EDTA and PMSF revealed that pepstatin A repealed the phytase inhibition. This indicates that the observed inhibition of A. ficuum phytase by cereal grain extracts is caused by protease activity of the aspartic proteinase type.

Aspergillus ficuum phytase activity is inhibited by cereal grain components

PubMed Central

Bekalu, Zelalem Eshetu; Madsen, Claus Krogh; Dionisio, Giuseppe

2017-01-01

In the current study, we report for the first time that grain components of barley, rice, wheat and maize can inhibit the activity of Aspergillus ficuum phytase. The phytase inhibition is dose dependent and varies significantly between cereal species, between cultivars of barley and cultivars of wheat and between Fusarium graminearum infected and non-infected wheat grains. The highest endpoint level of phytase activity inhibition was 90%, observed with grain protein extracts (GPE) from F. graminearum infected wheat. Wheat GPE from grains infected with F. graminearum inhibits phytase activity significantly more than GPE from non-infected grains. For four barley cultivars studied, the IC50 value ranged from 0.978 ± 0.271 to 3.616 ± 0.087 mg×ml-1. For two non-infected wheat cultivars investigated, the IC50 values were varying from 2.478 ± 0.114 to 3.038 ± 0.097 mg×ml-1. The maize and rice cultivars tested gaveIC50 values on 0.983 ± 0.205 and 1.972 ± 0.019 mg×ml-1, respectively. After purifying the inhibitor from barley grains via Superdex G200, an approximately 30–35 kDa protein was identified. No clear trend for the mechanism of inhibition could be identified via Michaelis-Menten kinetics and Lineweaver-Burk plots. However, testing of the purified phytase inhibitor together with the A. ficuum phytase and the specific protease inhibitors pepstatin A, E64, EDTA and PMSF revealed that pepstatin A repealed the phytase inhibition. This indicates that the observed inhibition of A. ficuum phytase by cereal grain extracts is caused by protease activity of the aspartic proteinase type. PMID:28472144

Thrombin-inhibiting nanoparticles rapidly constitute versatile and detectable anticlotting surfaces

NASA Astrophysics Data System (ADS)

Wheatley Myerson, Jacob; He, Li; Allen, John Stacy; Williams, Todd; Lanza, Gregory; Tollefsen, Douglas; Caruthers, Shelton; Wickline, Samuel

2014-09-01

Restoring an antithrombotic surface to suppress ongoing thrombosis is an appealing strategy for treatment of acute cardiovascular disorders such as erosion of atherosclerotic plaque. An antithrombotic surface would present an alternative to systemic anticoagulation with attendant risks of bleeding. We have designed thrombin-targeted nanoparticles (NPs) that bind to sites of active clotting to extinguish local thrombin activity and inhibit platelet deposition while exhibiting only transient systemic anticoagulant effects. Perfluorocarbon nanoparticles (PFC NP) were functionalized with thrombin inhibitors (either D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone or bivalirudin) by covalent attachment of more than 15 000 inhibitors to each PFC NP. Fibrinopeptide A (FPA) ELISA demonstrated that thrombin-inhibiting NPs prevented cleavage of fibrinogen by both free and clot-bound thrombin. Magnetic resonance imaging (MRI) confirmed that a layer of thrombin-inhibiting NPs prevented growth of clots in vitro. Thrombin-inhibiting NPs were administered in vivo to C57BL6 mice subjected to laser injury of the carotid artery. NPs significantly delayed thrombotic occlusion of the artery, whereas an equivalent bolus of free inhibitor was ineffective. For thrombin-inhibiting NPs, only a short-lived (˜10 min) systemic effect on bleeding time was observed, despite prolonged clot inhibition. Imaging and quantification of in vivo antithrombotic NP layers was demonstrated by MRI of the PFC NP. 19F MRI confirmed colocalization of particles with arterial thrombi, and quantitative 19F spectroscopy demonstrated specific binding and retention of thrombin-inhibiting NPs in injured arteries. The ability to rapidly form and image a new antithrombotic surface in acute vascular syndromes while minimizing risks of bleeding would permit a safer method of passivating active lesions than current systemic anticoagulant regimes.

The contribution of forward masking to saccadic inhibition of return.

PubMed

Souto, David; Born, Sabine; Kerzel, Dirk

2018-03-08

Inhibition of return is the name typically given to the prolonged latency of motor responses directed to a previously cued target location. There is intense debate about the origins of this effect and its function, but most take for granted (despite lack of evidence) that it depends little on forward masking. Therefore, we re-examined the role of forward masking in inhibition of return. Forward masking was indexed by slower saccadic reaction times (SRTs) when the target orientation repeated the cue orientation at the same location. We confirmed effects of orientation repetition in the absence of an attentional bias when cues were presented on both sides of fixation (bilateral presentation). The effect of orientation repetition was reduced with high target contrast, consistent with a low-level origin such as contrast gain control in early visual areas. When presenting cues on only one side of fixation (unilateral presentation), we obtained inhibition of return with longer cue-target intervals and facilitation with targets presented shortly after the cue. The effect of orientation repetition was reduced when facilitation was observed, but was as strong as with bilateral cues when inhibition of return was observed. Therefore, forward masking may contribute to the inhibition of return effect by delaying reaction times to repeated features at the same location, but is not a principal cause of inhibition of return; in agreement with previous views. The saccadic inhibition of return effect is a reaction-time cost when responding to a pre-cued location. Additional object updating costs are typically invoked to explain reaction-time costs observed when cue and target have the same shape. Yet, lower-level, forward masking of the target by the cue can not be ruled out. Importantly, we show an effect of orientation repetition that is consistent with low-level forward masking rather than object updating costs and that does not interact with inhibition of return.

Auxin-induced ethylene triggers abscisic acid biosynthesis and growth inhibition.

PubMed

Hansen, H; Grossmann, K

2000-11-01

The growth-inhibiting effects of indole-3-acetic acid (IAA) at high concentration and the synthetic auxins 7-chloro-3-methyl-8-quinolinecarboxylic acid (quinmerac), 2-methoxy-3,6-dichlorobenzoic acid (dicamba), 4-amino-3,6, 6-trichloropicolinic acid (picloram), and naphthalene acetic acid, were investigated in cleavers (Galium aparine). When plants were root treated with 0.5 mM IAA, shoot epinasty and inhibition of root and shoot growth developed during 24 h. Concomitantly, 1-aminocyclopropane-1-carboxylic acid (ACC) synthase activity, and ACC and ethylene production were transiently stimulated in the shoot tissue within 2 h, followed by increases in immunoreactive (+)-abscisic acid (ABA) and its precursor xanthoxal (xanthoxin) after 5 h. After 24 h of treatment, levels of xanthoxal and ABA were elevated up to 2- and 24-fold, relative to control, respectively. In plants treated with IAA, 7-chloro-3-methyl-8-quinolinecarboxylic acid, naphthalene acetic acid, 2-methoxy-3,6-dichlorobenzoic acid, and 4-amino-3,6,6-trichloropicolinic acid, levels of ethylene, ACC, and ABA increased in close correlation with inhibition of shoot growth. Aminoethoxyvinyl-glycine and cobalt ions, which inhibit ethylene synthesis, decreased ABA accumulation and growth inhibition, whereas the ethylene-releasing ethephon promoted ABA levels and growth inhibition. In accordance, tomato mutants defective in ethylene perception (never ripe) did not produce the xanthoxal and ABA increases and growth inhibition induced by auxins in wild-type plants. This suggests that auxin-stimulated ethylene triggers ABA accumulation and the consequent growth inhibition. Reduced catabolism most probably did not contribute to ABA increase, as indicated by immunoanalyses of ABA degradation and conjugation products in shoot tissue and by pulse experiments with [(3)H]-ABA in cell suspensions of G. aparine. In contrast, studies using inhibitors of ABA biosynthesis (fluridone, naproxen, and tungstate), ABA

Advanced Glycation End Products Inhibit the Proliferation of Human Umbilical Vein Endothelial Cells by Inhibiting Cathepsin D.

PubMed

Li, Yuan; Chang, Ye; Ye, Ning; Dai, Dongxue; Chen, Yintao; Zhang, Naijin; Sun, Guozhe; Sun, Yingxian

2017-02-17

We aimed to investigate the effect of advanced glycation end products (AGEs) on the proliferation and migration ability of human umbilical vein endothelial cells (HUVECs). Cell proliferation was detected by methyl thiazolyl tetrazolium (MTT) assay, real-time cell analyzer and 5-Ethynyl-2'-deoxyuridine (EdU) staining. Cell migration was detected by wound-healing and transwell assay. AGEs significantly inhibited the proliferation and migration of HUVECs in a time-and dose-dependent way. Western blotting revealed that AGEs dramatically increased the expression of microtubule-associated protein 1 light chain 3 (LC3) II/I and p62. Immunofluorescence of p62 and acridine orange staining revealed that AGEs significantly increased the expression of p62 and the accumulation of autophagic vacuoles, respectively. Chloroquine (CQ) could further promote the expression of LC3 II/I and p62, increase the accumulation of autophagic vacuoles and promote cell injury induced by AGEs. In addition, AGEs reduced cathepsin D (CTSD) expression in a time-dependent way. Overexpression of wild-type CTSD significantly decreased the ratio of LC 3 II/I as well as p62 accumulation induced by AGEs, but overexpression of catalytically inactive mutant CTSD had no such effects. Only overexpression of wild-type CTSD could restore the proliferation of HUVECs inhibited by AGEs. However, overexpression of both wild-type CTSD and catalytically inactive mutant CTSD could promote the migration of HUVECs inhibited by AGEs. Collectively, our study found that AGEs inhibited the proliferation and migration in HUVECs and promoted autophagic flux, which in turn played a protective role against AGEs-induced cell injury. CTSD, in need of its catalytic activity, may promote proliferation in AGEs-treated HUVECs independent of the autophagy-lysosome pathway. Meanwhile, CTSD could improve the migration of AGEs-treated HUVECs regardless of its enzymatic activity.

Advanced Glycation End Products Inhibit the Proliferation of Human Umbilical Vein Endothelial Cells by Inhibiting Cathepsin D

PubMed Central

Li, Yuan; Chang, Ye; Ye, Ning; Dai, Dongxue; Chen, Yintao; Zhang, Naijin; Sun, Guozhe; Sun, Yingxian

2017-01-01

We aimed to investigate the effect of advanced glycation end products (AGEs) on the proliferation and migration ability of human umbilical vein endothelial cells (HUVECs). Cell proliferation was detected by methyl thiazolyl tetrazolium (MTT) assay, real-time cell analyzer and 5-Ethynyl-2′-deoxyuridine (EdU) staining. Cell migration was detected by wound-healing and transwell assay. AGEs significantly inhibited the proliferation and migration of HUVECs in a time-and dose-dependent way. Western blotting revealed that AGEs dramatically increased the expression of microtubule-associated protein 1 light chain 3 (LC3) II/I and p62. Immunofluorescence of p62 and acridine orange staining revealed that AGEs significantly increased the expression of p62 and the accumulation of autophagic vacuoles, respectively. Chloroquine (CQ) could further promote the expression of LC3 II/I and p62, increase the accumulation of autophagic vacuoles and promote cell injury induced by AGEs. In addition, AGEs reduced cathepsin D (CTSD) expression in a time-dependent way. Overexpression of wild-type CTSD significantly decreased the ratio of LC 3 II/I as well as p62 accumulation induced by AGEs, but overexpression of catalytically inactive mutant CTSD had no such effects. Only overexpression of wild-type CTSD could restore the proliferation of HUVECs inhibited by AGEs. However, overexpression of both wild-type CTSD and catalytically inactive mutant CTSD could promote the migration of HUVECs inhibited by AGEs. Collectively, our study found that AGEs inhibited the proliferation and migration in HUVECs and promoted autophagic flux, which in turn played a protective role against AGEs-induced cell injury. CTSD, in need of its catalytic activity, may promote proliferation in AGEs-treated HUVECs independent of the autophagy-lysosome pathway. Meanwhile, CTSD could improve the migration of AGEs-treated HUVECs regardless of its enzymatic activity. PMID:28218663

N2 and P3 modulation during partial inhibition in a modified go/nogo task.

PubMed

Nguyen, An T; Moyle, Jonson J; Fox, Allison M

2016-09-01

The neural response following the partial inhibition of responses can provide insight into the processes underlying response inhibition. We examined the N2 and P3 on trials where participants correctly responded to go stimuli, successfully inhibited their response to nogo stimuli, and nogo trials where they initiated but did not complete their response (partial inhibitions) in an adult sample (N=24, M(age)=21.17, SD(age)=3.52). An enhanced and delayed N2 was observed on partially inhibited compared to successfully inhibited nogo trials. Further analysis showed that this modulation was error-related. An enhanced central P3 was observed following successful inhibitions compared to correct go trials, but not following partial inhibitions. The results suggest that the central P3 enhancement is specific to the complete and successful inhibition of responses. Therefore, the absence of a central P3 on partial inhibitions could reflect insufficient inhibition or a monitored failure in inhibiting the response. Although, our findings provide support for the role of P3 in response inhibition, it raises questions about the processes involved in the subsequent inhibition or correction of the erroneous response. Further research examining the neural response following both partial and unsuccessful inhibitions could provide insight regarding these processes. Copyright © 2016 Elsevier B.V. All rights reserved.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models.

PubMed

Jandial, Rahul; Neman, Josh; Lim, Punnajit P; Tamae, Daniel; Kowolik, Claudia M; Wuenschell, Gerald E; Shuck, Sarah C; Ciminera, Alexandra K; De Jesus, Luis R; Ouyang, Ching; Chen, Mike Y; Termini, John

2018-01-30

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S -( p -bromobenzyl) glutathione dicyclopentyl ester ( p- BrBzGSH(Cp)₂) increased levels of the DNA-AGE N ²-1-(carboxyethyl)-2'-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p -BrBzGSH(Cp)₂ exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

PubMed Central

Jandial, Rahul; Neman, Josh; Tamae, Daniel; Kowolik, Claudia M.; Wuenschell, Gerald E.; Ciminera, Alexandra K.; De Jesus, Luis R.; Ouyang, Ching; Chen, Mike Y.

2018-01-01

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S-(p-bromobenzyl) glutathione dicyclopentyl ester (p-BrBzGSH(Cp)2) increased levels of the DNA-AGE N2-1-(carboxyethyl)-2′-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp)2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors. PMID:29385725

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.

Inhibition of Prevotella and Capnocytophaga immunoglobulin A1 proteases by human serum.

PubMed

Frandsen, E V; Kjeldsen, M; Kilian, M

1997-07-01

Oral Prevotella and Capnocytophaga species, regularly isolated from periodontal pockets and associated with extraoral infections, secret specific immunoglobulin A1 (IgA1) proteases cleaving human IgA1 in the hinge region into intact Fab and Fc fragments. To investigate whether these enzymes are subject to inhibition in vivo in humans, we tested 34 sera from periodontally diseased and healthy individuals in an enzyme-linked immunosorbent assay for the presence and titers of inhibition of seven Prevotella and Capnocytophaga proteases. All or nearly all of the sera inhibited the IgA1 protease activity of Prevotella buccae, Prevotella oris, and Prevotella loescheii. A minor proportion of the sera inhibited Prevotella buccalis, Prevotella denticola, and Prevotella melaninogenica IgA1 proteases, while no sera inhibited Capnocytophaga ochracea IgA1 protease. All inhibition titers were low, ranging from 5 to 55, with titer being defined as the reciprocal of the dilution of serum causing 50% inhibition of one defined unit of protease activity. No correlation between periodontal disease status and the presence, absence, or titer of inhibition was observed. The nature of the low titers of inhibition in all sera of the IgA1 proteases of P. buccae, P. oris, and P. loescheii was further examined. In size exclusion chromatography, inhibitory activity corresponded to the peak volume of IgA. Additional inhibition of the P. oris IgA1 protease was found in fractions containing both IgA and IgG. Purification of the IgG fractions of five sera by passage of the sera on a protein G column resulted in recovery of inhibitory IgG antibodies against all three IgA1 proteases, with the highest titer being for the P. oris enzyme. These finding indicate that inhibitory activity is associated with enzyme-neutralizing antibodies.

Inhibition of Prevotella and Capnocytophaga immunoglobulin A1 proteases by human serum.

PubMed Central

Frandsen, E V; Kjeldsen, M; Kilian, M

1997-01-01

Oral Prevotella and Capnocytophaga species, regularly isolated from periodontal pockets and associated with extraoral infections, secret specific immunoglobulin A1 (IgA1) proteases cleaving human IgA1 in the hinge region into intact Fab and Fc fragments. To investigate whether these enzymes are subject to inhibition in vivo in humans, we tested 34 sera from periodontally diseased and healthy individuals in an enzyme-linked immunosorbent assay for the presence and titers of inhibition of seven Prevotella and Capnocytophaga proteases. All or nearly all of the sera inhibited the IgA1 protease activity of Prevotella buccae, Prevotella oris, and Prevotella loescheii. A minor proportion of the sera inhibited Prevotella buccalis, Prevotella denticola, and Prevotella melaninogenica IgA1 proteases, while no sera inhibited Capnocytophaga ochracea IgA1 protease. All inhibition titers were low, ranging from 5 to 55, with titer being defined as the reciprocal of the dilution of serum causing 50% inhibition of one defined unit of protease activity. No correlation between periodontal disease status and the presence, absence, or titer of inhibition was observed. The nature of the low titers of inhibition in all sera of the IgA1 proteases of P. buccae, P. oris, and P. loescheii was further examined. In size exclusion chromatography, inhibitory activity corresponded to the peak volume of IgA. Additional inhibition of the P. oris IgA1 protease was found in fractions containing both IgA and IgG. Purification of the IgG fractions of five sera by passage of the sera on a protein G column resulted in recovery of inhibitory IgG antibodies against all three IgA1 proteases, with the highest titer being for the P. oris enzyme. These finding indicate that inhibitory activity is associated with enzyme-neutralizing antibodies. PMID:9220164

Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome

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

Ahmad, Israr; Muneer, Kashiff M.; Tamimi, Iman A.

2013-07-01

The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β and IL-18 secretion. The NLRP3 (NACHT, LRR, and pyrin domain-containing protein 3) inflammasome is constitutively assembled and activated in human melanoma cells. We have examined the inhibitory effect of thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone), a major ingredient of black seed obtained from the plant Nigella sativa on metastatic human (A375) and mouse (B16F10) melanoma cell lines. We have assessed whether thymoquinone inhibits metastasis of melanoma cells by targeting NLRP3 subunit of inflammasomes. Using an in vitro cell migration assay, we found that thymoquinone inhibited the migration of both humanmore » and mouse melanoma cells. The inhibitory effect of thymoquinone on metastasis was also observed in vivo in B16F10 mouse melanoma model. The inhibition of migration of melanoma cells by thymoquinone was accompanied by a decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by thymoquinone resulted in inhibition of IL-1β and IL-18. Treatment of mouse melanoma cells with thymoquinone also inhibited NF-κB activity. Furthermore, inhibition of reactive oxygen species (ROS) by thymoquinone resulted in partial inactivation of NLRP3 inflammasome. Thus, thymoquinone exerts its inhibitory effect on migration of human and mouse melanoma cells by inhibition of NLRP3 inflammasome. Thus, our results indicate that thymoquinone can be a potential immunotherapeutic agent not only as an adjuvant therapy for melanoma, but also, in the control and prevention of metastatic melanoma. - Highlights: • Thymoquinone causes inhibition of migration of melanoma cells. • Thymoquinone causes inhibition of metastasis in vivo. • Thymoquinone causes inhibition of migration by activation of NLRP3 inflammasome.« less

Anxiety Impacts Cognitive Inhibition in Remitted Anorexia Nervosa.

PubMed

Ely, Alice V; Wierenga, Christina E; Kaye, Walter H

2016-07-01

Eating disorders are complex psychiatric disorders, associated with alterations in neural and cognitive functioning. Research suggests inhibition and set-shifting deficits in anorexia nervosa (AN), but less is known about the persistence of these deficits after recovery, or their relationship to comorbid psychiatric symptoms. Women aged 19-45 remitted from AN (RAN, N = 47) and controls (CW, N = 24) completed the Delis-Kaplan Executive Function System Color-Word Interference Test. It was hypothesized that RAN, and those with higher anxiety or depression, would demonstrate worse Inhibition and Switching task performance than CW. Differences in performance between groups trended toward significance on Inhibition Ratio (p = 0.08) but were nonsignificant on Inhibition/Switching Ratio (p = 0.93). A model including State Anxiety and diagnosis revealed a significant independent effect of State Anxiety (p = 0.026), but not of diagnosis nor their interaction. Regressing State Anxiety on Color-Word Interference Test Inhibition among just the RAN group was significant [β = 0.37, t(46) = 2.63, p = 0.012] but among just CW was not (p = 0.54). Interference control for neutral stimuli is influenced by anxiety in women with a history of AN. Anxiety is linked with greater symptom severity among AN individuals, and state anxiety may account for larger deficits seen on tasks using disorder-specific stimuli. Future research is warranted to elucidate the nature of neuropsychological deficits in eating disorders. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

Improving response inhibition in Parkinson's disease with atomoxetine.

PubMed

Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

2015-04-15

Dopaminergic drugs remain the mainstay of Parkinson's disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Patients with Parkinson's disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson's disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson's disease. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Psychosis-proneness and neural correlates of self-inhibition in theory of mind.

PubMed

van der Meer, Lisette; Groenewold, Nynke A; Pijnenborg, Marieke; Aleman, André

2013-01-01

Impaired Theory of Mind (ToM) has been repeatedly reported as a feature of psychotic disorders. ToM is crucial in social interactions and for the development of social behavior. It has been suggested that reasoning about the belief of others, requires inhibition of the self-perspective. We investigated the neural correlates of self-inhibition in nineteen low psychosis prone (PP) and eighteen high PP subjects presenting with subclinical features. High PP subjects have a more than tenfold increased risk of developing a schizophrenia-spectrum disorder. Brain activation was measured with functional Magnetic Resonance Imaging during a ToM task differentiating between self-perspective inhibition and belief reasoning. Furthermore, to test underlying inhibitory mechanisms, we included a stop-signal task. We predicted worse behavioral performance for high compared to low PP subjects on both tasks. Moreover, based on previous neuroimaging results, different activation patterns were expected in the inferior frontal gyrus (IFG) in high versus low PP subjects in self-perspective inhibition and simple response inhibition. Results showed increased activation in left IFG during self-perspective inhibition, but not during simple response inhibition, for high PP subjects as compared to low PP subjects. High and low PP subjects showed equal behavioral performance. The results suggest that at a neural level, high PP subjects need more resources for inhibiting the self-perspective, but not for simple motor response inhibition, to equal the performance of low PP subjects. This may reflect a compensatory mechanism, which may no longer be available for patients with schizophrenia-spectrum disorders resulting in ToM impairments.

Psychosis-Proneness and Neural Correlates of Self-Inhibition in Theory of Mind

PubMed Central

van der Meer, Lisette; Groenewold, Nynke A.; Pijnenborg, Marieke; Aleman, André

2013-01-01

Impaired Theory of Mind (ToM) has been repeatedly reported as a feature of psychotic disorders. ToM is crucial in social interactions and for the development of social behavior. It has been suggested that reasoning about the belief of others, requires inhibition of the self-perspective. We investigated the neural correlates of self-inhibition in nineteen low psychosis prone (PP) and eighteen high PP subjects presenting with subclinical features. High PP subjects have a more than tenfold increased risk of developing a schizophrenia-spectrum disorder. Brain activation was measured with functional Magnetic Resonance Imaging during a ToM task differentiating between self-perspective inhibition and belief reasoning. Furthermore, to test underlying inhibitory mechanisms, we included a stop-signal task. We predicted worse behavioral performance for high compared to low PP subjects on both tasks. Moreover, based on previous neuroimaging results, different activation patterns were expected in the inferior frontal gyrus (IFG) in high versus low PP subjects in self-perspective inhibition and simple response inhibition. Results showed increased activation in left IFG during self-perspective inhibition, but not during simple response inhibition, for high PP subjects as compared to low PP subjects. High and low PP subjects showed equal behavioral performance. The results suggest that at a neural level, high PP subjects need more resources for inhibiting the self-perspective, but not for simple motor response inhibition, to equal the performance of low PP subjects. This may reflect a compensatory mechanism, which may no longer be available for patients with schizophrenia-spectrum disorders resulting in ToM impairments. PMID:23874445

Nitric oxide-mediated inhibition of taurocholate uptake involves S-nitrosylation of NTCP.

PubMed

Schonhoff, Christopher M; Ramasamy, Umadevi; Anwer, M Sawkat

2011-02-01

The sodium-taurocholate (TC) cotransporting polypeptide (NTCP) facilitates bile formation by mediating sinusoidal Na(+)-TC cotransport. During sepsis-induced cholestasis, there is a decrease in NTCP-dependent uptake of bile acids and an increase in nitric oxide (NO) levels in hepatocytes. In rat hepatocytes NO inhibits Na(+)-dependent uptake of taurocholate. The aim of this study was to extend these findings to human NTCP and to further investigate the mechanism by which NO inhibits TC uptake. Using a human hepatoma cell line stably expressing NTCP (HuH-NTCP), we performed experiments with the NO donors sodium nitroprusside and S-nitrosocysteine and demonstrated that NO inhibits TC uptake in these cells. Kinetic analyses revealed that NO significantly decreased the V(max) but not the K(m) of TC uptake by NTCP, indicating noncompetitive inhibition. NO decreased the amount of NTCP in the plasma membrane, providing a molecular mechanism for the noncompetitive inhibition of TC uptake. One way that NO can modify protein function is through a posttranslational modification known as S-nitrosylation: the binding of NO to cysteine thiols. Using a biotin switch technique we observed that NTCP is S-nitrosylated under conditions in which NO inhibits TC uptake. Moreover, dithiothreitol reversed NO-mediated inhibition of TC uptake and S-nitrosylation of NTCP, indicating that NO inhibits TC uptake via modification of cysteine thiols. In addition, NO treatment led to a decrease in Ntcp phosphorylation. Taken together these results indicate that the inhibition of TC uptake by NO involves S-nitrosylation of NTCP.

Cohort-Sequential Study of Conflict Inhibition during Middle Childhood

ERIC Educational Resources Information Center

Rollins, Leslie; Riggins, Tracy

2017-01-01

This longitudinal study examined developmental changes in conflict inhibition and error correction in three cohorts of children (5, 7, and 9 years of age). At each point of assessment, children completed three levels of Luria's tapping task (1980), which requires the inhibition of a dominant response and maintenance of task rules in working…

46 CFR 154.1740 - Vinyl chloride: Inhibiting and inerting.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 5 2010-10-01 2010-10-01 false Vinyl chloride: Inhibiting and inerting. 154.1740... Operating Requirements § 154.1740 Vinyl chloride: Inhibiting and inerting. When a vessel is carrying vinyl chloride, the master shall ensure that: (a) Section 154.1818 is met; or (b) Section 154.1710 is met, and...

DNA methyltransferase inhibitor CDA-II inhibits myogenic differentiation

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

Chen, Zirong; Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610; Jin, Guorong

2012-06-08

Highlights: Black-Right-Pointing-Pointer CDA-II inhibits myogenic differentiation in a dose-dependent manner. Black-Right-Pointing-Pointer CDA-II repressed expression of muscle transcription factors and structural proteins. Black-Right-Pointing-Pointer CDA-II inhibited proliferation and migration of C2C12 myoblasts. -- Abstract: CDA-II (cell differentiation agent II), isolated from healthy human urine, is a DNA methyltransferase inhibitor. Previous studies indicated that CDA-II played important roles in the regulation of cell growth and certain differentiation processes. However, it has not been determined whether CDA-II affects skeletal myogenesis. In this study, we investigated effects of CDA-II treatment on skeletal muscle progenitor cell differentiation, migration and proliferation. We found that CDA-II blocked differentiationmore » of murine myoblasts C2C12 in a dose-dependent manner. CDA-II repressed expression of muscle transcription factors, such as Myogenin and Mef2c, and structural proteins, such as myosin heavy chain (Myh3), light chain (Mylpf) and MCK. Moreover, CDA-II inhibited C1C12 cell migration and proliferation. Thus, our data provide the first evidence that CDA-II inhibits growth and differentiation of muscle progenitor cells, suggesting that the use of CDA-II might affect skeletal muscle functions.« less

Cysteine-independent activation/inhibition of heme oxygenase-2

PubMed Central

Vukomanovic, Dragic; Rahman, Mona N.; Maines, Mahin D.; Ozolinš, Terence RS; Szarek, Walter A.; Jia, Zongchao; Nakatsu, Kanji

2016-01-01

Reactive thiols of cysteine (cys) residues in proteins play a key role in transforming chemical reactivity into a biological response. The heme oxygenase-2 (HO-2) isozyme contains two cys residues that have been implicated in binding of heme and also the regulation of its activity. In this paper, we address the question of a role for cys residues for the HO-2 inhibitors or activators designed in our laboratory. We tested the activity of full length recombinant human heme oxygenase-2 (FL-hHO-2) and its analog in which cys265 and cys282 were both replaced by alanine to determine the effect on activation by menadione (MD) and inhibition by QC-2350. Similar inhibition by QC-2350 and almost identical activation by MD was observed for both recombinant FL-hHO-2s. Our findings are interpreted to mean that thiols of FL-hHO-2s are not involved in HO-2 activation or inhibition by the compounds that have been designed and identified by us. Activation or inhibition of HO-2 by our compounds should be attributed to a mechanism other than altering binding affinity of HO-2 for heme through cys265 and cys282. PMID:27826418

Cysteine-independent activation/inhibition of heme oxygenase-2.

PubMed

Vukomanovic, Dragic; Rahman, Mona N; Maines, Mahin D; Ozolinš, Terence Rs; Szarek, Walter A; Jia, Zongchao; Nakatsu, Kanji

2016-03-01

Reactive thiols of cysteine (cys) residues in proteins play a key role in transforming chemical reactivity into a biological response. The heme oxygenase-2 (HO-2) isozyme contains two cys residues that have been implicated in binding of heme and also the regulation of its activity. In this paper, we address the question of a role for cys residues for the HO-2 inhibitors or activators designed in our laboratory. We tested the activity of full length recombinant human heme oxygenase-2 (FL-hHO-2) and its analog in which cys265 and cys282 were both replaced by alanine to determine the effect on activation by menadione (MD) and inhibition by QC-2350. Similar inhibition by QC-2350 and almost identical activation by MD was observed for both recombinant FL-hHO-2s. Our findings are interpreted to mean that thiols of FL-hHO-2s are not involved in HO-2 activation or inhibition by the compounds that have been designed and identified by us. Activation or inhibition of HO-2 by our compounds should be attributed to a mechanism other than altering binding affinity of HO-2 for heme through cys265 and cys282.

Fluoxetine regulates cell growth inhibition of interferon-α.

PubMed

Lin, Yu-Min; Yu, Bu-Chin; Chiu, Wen-Tai; Sun, Hung-Yu; Chien, Yu-Chieh; Su, Hui-Chen; Yen, Shu-Yang; Lai, Hsin-Wen; Bai, Chyi-Huey; Young, Kung-Chia; Tsao, Chiung-Wen

2016-10-01

Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.

Inhibition of polyomavirus ori-dependent DNA replication by mSin3B.

PubMed

Xie, An-Yong; Folk, William R

2002-12-01

When tethered in cis to DNA, the transcriptional corepressor mSin3B inhibits polyomavirus (Py) ori-dependent DNA replication in vivo. Histone deacetylases (HDACs) appear not to be involved, since tethering class I and class II HDACs in cis does not inhibit replication and treating the cells with trichostatin A does not specifically relieve inhibition by mSin3B. However, the mSin3B L59P mutation that impairs mSin3B interaction with N-CoR/SMRT abrogates inhibition of replication, suggesting the involvement of N-CoR/SMRT. Py large T antigen interacts with mSin3B, suggesting an HDAC-independent mechanism by which mSin3B inhibits DNA replication.

Toddler Inhibited Temperament, Maternal Cortisol Reactivity and Embarrassment, and Intrusive Parenting

PubMed Central

Kiel, Elizabeth J.; Buss, Kristin A.

2013-01-01

The relevance of parenting behavior to toddlers’ development necessitates a better understanding of the influences on parents during parent-child interactions. Toddlers’ inhibited temperament may relate to parenting behaviors, such as intrusiveness, that predict outcomes later in childhood. The conditions under which inhibited temperament relates to intrusiveness, however, remain understudied. A multi-method approach would acknowledge that several levels of processes determine mothers’ experiences during situations in which they witness their toddlers interacting with novelty. As such, the current study examined maternal cortisol reactivity and embarrassment about shyness as moderators of the relation between toddlers’ inhibited temperament and maternal intrusive behavior. Participants included 92 24-month-olds toddlers and their mothers. Toddlers’ inhibited temperament and maternal intrusiveness were measured observationally in the laboratory. Mothers supplied saliva samples at the beginning of the laboratory visit and 20 minutes after observation. Maternal cortisol reactivity interacted with inhibited temperament in relation to intrusive behavior, such that mothers with higher levels of cortisol reactivity were observed to be more intrusive with more highly inhibited toddlers. Embarrassment related to intrusive behavior as a main effect. These results highlight the importance of considering child characteristics and psychobiological processes in relation to parenting behavior. PMID:23750532

Activity inhibition on municipal activated sludge by single-walled carbon nanotubes

NASA Astrophysics Data System (ADS)

Parise, Alex; Thakor, Harshrajsinh; Zhang, Xiaoqi

2014-01-01

The objective of this study was to evaluate the respiratory activity inhibition of activated sludge used in a typical wastewater treatment plant by single-walled carbon nanotubes (SWCNTs) with different length and functionality. Four types of SWCNTs were evaluated: short, functionalized short, long, and functionalized long. Based on the effective concentration (EC50) values obtained, we determined that functionalized SWCNTs resulted in a higher microbial respiratory inhibition than non-functionalized nanotubes, and long SWCNTs gave a higher microbial respiratory inhibition than their short counterparts. Among the four types of SWCNTs studied, functionalized long exhibited the highest respiration inhibition. Scanning electron microscopy imaging indicates that the long SWCNTs dispersed more favorably after sonication than the short variety. The findings demonstrated that the toxicity of CNTs (exhibited by respiratory inhibition) is related to their physical properties; the length and functionality of SWCNTs affected the toxicity of SWCNTs in a mixed-cultured biologic system.

Production of monoclonal antibody inhibiting dipeptidylaminopeptidase IV activity of Porphyromonas gingivalis.

PubMed

Teshirogi, K; Hayakawa, M; Ikemi, T; Abiko, Y

2003-06-01

Porphyromonas gingivalis is a Gram-negative anaerobic bacterial species implicated as an important pathogen in the development of adult periodontitis. We previously cloned a gene encoding dipeptydilaminopeptidase IV (DAPIV) from P. gingivalis. In the present study, for immunological diagnosis and development of passive immunization, we produced a mouse monoclonal antibody (MAb) capable of inhibiting the DAPIV activity of P. gingivalis using highly purified recombinant DAPIV as an immunogen. The constructed MAb, designated as MAb-Pg-DAP-1, significantly inhibited DAPIV activity in P. gingivalis, as well as slightly inhibited that in other gram-negative bacteria such as Porphyromonas endodontalis and Prevotella loesheii, whereas no inhibition was seen in the gram-positive bacteria Streptococcus mutans and Actinomyces viscosus. Furthermore, the MAb did not inhibit DAPIV enzyme activity in human serum. This novel MAb may be useful for the development of immunological diagnosis capability and in passive immunization.

Measuring Feedforward Inhibition and Its Impact on Local Circuit Function.

PubMed

Hull, Court

2017-05-01

This protocol describes a series of approaches to measure feedforward inhibition in acute brain slices from the cerebellar cortex. Using whole-cell voltage and current clamp recordings from Purkinje cells in conjunction with electrical stimulation of the parallel fibers, these methods demonstrate how to measure the relationship between excitation and inhibition in a feedforward circuit. This protocol also describes how to measure the impact of feedforward inhibition on Purkinje cell excitability, with an emphasis on spike timing. © 2017 Cold Spring Harbor Laboratory Press.

Stability and Social-Behavioral Consequences of Toddlers' Inhibited Temperament and Parenting Behaviors.

ERIC Educational Resources Information Center

Rubin, Kenneth H.; Burgess, Kim B.; Hastings, Paul D.

2002-01-01