Review of Natural Compounds for Potential Skin Cancer Treatment

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Tawona N. Chinembiri

2014-08-01

Full Text Available Most anti-cancer drugs are derived from natural resources such as marine, microbial and botanical sources. Cutaneous malignant melanoma is the most aggressive form of skin cancer, with a high mortality rate. Various treatments for malignant melanoma are available, but due to the development of multi-drug resistance, current or emerging chemotherapies have a relatively low success rates. This emphasizes the importance of discovering new compounds that are both safe and effective against melanoma. In vitro testing of melanoma cell lines and murine melanoma models offers the opportunity for identifying mechanisms of action of plant derived compounds and extracts. Common anti-melanoma effects of natural compounds include potentiating apoptosis, inhibiting cell proliferation and inhibiting metastasis. There are different mechanisms and pathways responsible for anti-melanoma actions of medicinal compounds such as promotion of caspase activity, inhibition of angiogenesis and inhibition of the effects of tumor promoting proteins such as PI3-K, Bcl-2, STAT3 and MMPs. This review thus aims at providing an overview of anti-cancer compounds, derived from natural sources, that are currently used in cancer chemotherapies, or that have been reported to show anti-melanoma, or anti-skin cancer activities. Phytochemicals that are discussed in this review include flavonoids, carotenoids, terpenoids, vitamins, sulforaphane, some polyphenols and crude plant extracts.

Effect of DSPE-PEG on compound action potential, injury potential and ion concentration following compression in ex vivo spinal cord.

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Wang, Aihua; Huo, Xiaolin; Zhang, Guanghao; Wang, Xiaochen; Zhang, Cheng; Wu, Changzhe; Rong, Wei; Xu, Jing; Song, Tao

2016-05-04

It has been shown that polyethylene glycol (PEG) can reseal membrane disruption on the spinal cord, but only high concentrations of PEG have been shown to have this effect. Therefore, the effect of PEG is somewhat limited, and it is necessary to investigate a new approach to repair spinal cord injury. This study assesses the ability of 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly (ethylene glycol)) 2000] (DSPE-PEG) to recover physiological function and attenuate the injury-induced influx of extracellular ions in ex vivo spinal cord injury. Isolated spinal cords were subjected to compression injury and treated with PEG or DSPE-PEG immediately after injury. The compound action potential (CAP) was recorded before and after injury to assess the functional recovery. Furthermore, injury potential, the difference in gap potentials before and after compression, and the concentration of intracellular ions were used to evaluate the effect of DSPE-PEG on reducing ion influx. Data showed that the injury potential and ion concentration of the untreated, PEG and DSPE-PEG group, without significant difference among them, are remarkably higher than those of the intact group. Moreover, the CAP recovery of the DSPE-PEG and PEG treated spinal cords was significantly greater than that of the untreated spinal cords. The level of CAP recovery in the DSPE-PEG and PEG treated groups was the same, but the concentration of DSPE-PEG used was much lower than the concentration of PEG. These results suggest that instant application of DSPE-PEG could effectively repair functional disturbance in SCI at a much lower concentration than PEG. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Herbal Remedies for Coccidiosis Control: A Review of Plants, Compounds, and Anticoccidial Actions

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Thangarasu Muthamilselvan

2016-01-01

Full Text Available Coccidiosis is the bane of the poultry industry causing considerable economic loss. Eimeria species are known as protozoan parasites to cause morbidity and death in poultry. In addition to anticoccidial chemicals and vaccines, natural products are emerging as an alternative and complementary way to control avian coccidiosis. In this review, we update recent advances in the use of anticoccidial phytoextracts and phytocompounds, which cover 32 plants and 40 phytocompounds, following a database search in PubMed, Web of Science, and Google Scholar. Four plant products commercially available for coccidiosis are included and discussed. We also highlight the chemical and biological properties of the plants and compounds as related to coccidiosis control. Emphasis is placed on the modes of action of the anticoccidial plants and compounds such as interference with the life cycle of Eimeria, regulation of host immunity to Eimeria, growth regulation of gut bacteria, and/or multiple mechanisms. Biological actions, mechanisms, and prophylactic/therapeutic potential of the compounds and extracts of plant origin in coccidiosis are summarized and discussed.

Re-modeling Chara action potential: II. The action potential form under salinity stress

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Mary Jane Beilby

2017-04-01

Full Text Available In part I we established Thiel-Beilby model of the Chara action potential (AP. In part II the AP is investigated in detail at the time of saline stress. Even very short exposure of salt-sensitive Chara cells to artificial pond water with 50 mM NaCl (Saline APW modified the AP threshold and drastically altered the AP form. Detailed modeling of 14 saline APs from 3 cells established that both the Ca2+ pump and the Ca2+ channels on internal stores seem to be affected, with the changes sometimes cancelling and sometimes re-enforcing each other, leading to APs with long durations and very complex forms. The exposure to salinity offers further insights into AP mechanism and suggests future experiments. The prolonged APs lead to greater loss of chloride and potassium ions, compounding the effects of saline stress.

Investigating a Potential Auxin-Related Mode of Hormetic/Inhibitory Action of the Phytotoxin Parthenin.

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Belz, Regina G

2016-01-01

Parthenin is a metabolite of Parthenium hysterophorus and is believed to contribute to the weed's invasiveness via allelopathy. Despite the potential of parthenin to suppress competitors, low doses stimulate plant growth. This biphasic action was hypothesized to be auxin-like and, therefore, an auxin-related mode of parthenin action was investigated using two approaches: joint action experiments with Lactuca sativa, and dose-response experiments with auxin/antiauxin-resistant Arabidopsis thaliana genotypes. The joint action approach comprised binary mixtures of subinhibitory doses of the auxin 3-indoleacetic acid (IAA) mixed with parthenin or one of three reference compounds [indole-3-butyric acid (IBA), 2,3,5-triiodobenzoic acid (TIBA), 2-(p-chlorophenoxy)-2-methylpropionic acid (PCIB)]. The reference compounds significantly interacted with IAA at all doses, but parthenin interacted only at low doses indicating that parthenin hormesis may be auxin-related, in contrast to its inhibitory action. The genetic approach investigated the response of four auxin/antiauxin-resistant mutants and a wildtype to parthenin or two reference compounds (IAA, PCIB). The responses of mutant plants to the reference compounds confirmed previous reports, but differed from the responses observed for parthenin. Parthenin stimulated and inhibited all mutants independent of resistance. This provided no indication for an auxin-related action of parthenin. Therefore, the hypothesis of an auxin-related inhibitory action of parthenin was rejected in two independent experimental approaches, while the hypothesis of an auxin-related stimulatory effect could not be rejected.

A survey of synthetic and natural phytotoxic compounds and phytoalexins as potential antimalarial compounds.

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Bajsa, Joanna; Singh, Kshipra; Nanayakkara, Dhammika; Duke, Stephen Oscar; Rimando, Agnes Mamaril; Evidente, Antonio; Tekwani, Babu Lal

2007-09-01

The apicomplexan parasites pathogens such as Plasmodium spp. possess an apicoplast, a plastid organelle similar to those of plants. The apicoplast has some essential plant-like metabolic pathways and processes, making these parasites susceptible to inhibitors of these functions. The main objective of this paper is to determine if phytotoxins with plastid target sites are more likely to be good antiplasmodial compounds than are those with other modes of action. The antiplasmodial activities of some compounds with established phytotoxic action were determined in vitro on a chloroquine (CQ) sensitive (D6, Sierra Leone) strain of Plasmodium falciparum. In this study, we provide in vitro activities of almost 50 such compounds, as well as a few phytoalexins against P. falciparum. Endothall, anisomycin, and cerulenin had sufficient antiplasmodial action to be considered as new lead antimalarial structures. Some derivatives of fusicoccin possessed markedly improved antiplasmodial action than the parent compound. Our results suggest that phytotoxins with plastid targets may not necessarily be better antiplasmodials than those that act at other molecular sites. The herbicides, phytotoxins and the phytoalexins reported here with significant antiplasmodial activity may be useful probes for identification of new antimalarial drug targets and may also be used as new lead structures for new antiplasmodial drug discovery.

Botanical compounds and their regulation of nuclear receptor action: the case of traditional Chinese medicine.

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Li, Ling; Bonneton, François; Chen, Xiao Yong; Laudet, Vincent

2015-02-05

Nuclear receptors (NRs) are major pharmacological targets that allow an access to the mechanisms controlling gene regulation. As such, some NRs were identified as biological targets of active compounds contained in herbal remedies found in traditional medicines. We aim here to review this expanding literature by focusing on the informative articles regarding the mechanisms of action of traditional Chinese medicines (TCMs). We exemplified well-characterized TCM action mediated by NR such as steroid receptors (ER, GR, AR), metabolic receptors (PPAR, LXR, FXR, PXR, CAR) and RXR. We also provided, when possible, examples from other traditional medicines. From these, we draw a parallel between TCMs and phytoestrogens or endocrine disrupting chemicals also acting via NR. We define common principle of action and highlight the potential and limits of those compounds. TCMs, by finely tuning physiological reactions in positive and negative manners, could act, in a subtle but efficient way, on NR sensors and their transcriptional network. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Therapeutic potential of bryophytes and derived compounds against cancer

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Abhijit Dey

2015-08-01

Full Text Available Bryophytes, taxonomically placed between the algae and the pteridophytes, are divided into three classes such as Liverworts, Hornworts and Mosses. Indigenous use involves this small group of plants to treat various diseases. Bryophytes have been investigated pharmacologically for active biomolecules. Several constituents with therapeutic potential have been isolated, characterized and investigated for antibacterial, antifungal, antiviral, antioxidative, antiinflamatory and anticancerous efficacy. The present review deals with the literature covering the anticancerous potential of bryophytes. Apart from the examples of the compounds and the containing bryophyte genera, the authors have tried to include the examples of cancer cell lines on which the efficacy have been tested and the mode of action of certain cytotoxic agents. Crude extracts and isolated compounds from bryophytes were found to possess potent cytotoxic properties. Different types of terpenoids and bibenzyls have been reported among the most potent cytotoxic compounds. Most of these compounds were found to induce apoptosis by activating a number of genes and enzymes. Biochemical markers such as DNA fragmentation, nuclear condensation, proteolysis of poly (ADP-ribose polymerase, activation of caspases, inhibition of antiapoptotic nuclear transcriptional factor-kappaB, activation of p38 mitogen-activated protein kinase etc. have been found to be associated with apoptotic and necrotic response. This review summarizes recent scientific findings and suggests further investigations to evaluate the cytotoxic efficacy of bryophytes.

Electrically evoked compound action potentials artefact rejection by independent component analysis: procedure automation.

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Akhoun, Idrick; McKay, Colette; El-Deredy, Wael

2015-01-15

Independent-components-analysis (ICA) successfully separated electrically-evoked compound action potentials (ECAPs) from the stimulation artefact and noise (ECAP-ICA, Akhoun et al., 2013). This paper shows how to automate the ECAP-ICA artefact cancellation process. Raw-ECAPs without artefact rejection were consecutively recorded for each stimulation condition from at least 8 intra-cochlear electrodes. Firstly, amplifier-saturated recordings were discarded, and the data from different stimulus conditions (different current-levels) were concatenated temporally. The key aspect of the automation procedure was the sequential deductive source categorisation after ICA was applied with a restriction to 4 sources. The stereotypical aspect of the 4 sources enables their automatic classification as two artefact components, a noise and the sought ECAP based on theoretical and empirical considerations. The automatic procedure was tested using 8 cochlear implant (CI) users and one to four stimulus electrodes. The artefact and noise sources were successively identified and discarded, leaving the ECAP as the remaining source. The automated ECAP-ICA procedure successfully extracted the correct ECAPs compared to standard clinical forward masking paradigm in 22 out of 26 cases. ECAP-ICA does not require extracting the ECAP from a combination of distinct buffers as it is the case with regular methods. It is an alternative that does not have the possible bias of traditional artefact rejections such as alternate-polarity or forward-masking paradigms. The ECAP-ICA procedure bears clinical relevance, for example as the artefact rejection sub-module of automated ECAP-threshold detection techniques, which are common features of CI clinical fitting software. Copyright © 2014. Published by Elsevier B.V.

Adjuvant effects and antiserum action potentiation by a (herbal) compound 2-hydroxy-4-methoxy benzoic acid isolated from the root extract of the Indian medicinal plant 'sarsaparilla' (Hemidesmus indicus R. Br.).

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Alam, M I; Gomes, A

1998-10-01

The adjuvant effect and antiserum potentiation of a compound 2-hydroxy-4-methoxy benzoic acid were explored in the present investigation. This compound, isolated and purified from the Indian medicinal plant Hemidesmus indicus R. Br, possessed antisnake venom activity. Rabbits immunized with Vipera russellii venom in the presence and absence of the compound along with Freund's complete adjuvant, produced a precipitating band in immunogel diffusion and immunogel electrophoresis. The venom neutralizing capacity of this antiserum showed positive adjuvant effects as evident by the higher neutralization capacity (lethal and hemorrhage) when compared with the antiserum raised with venom alone. The pure compound potentiated the lethal action neutralization of venom by commercial equine polyvalent snake venom antiserum in experimental models. These observations raised the possibility of the use of chemical antagonists (from herbs) against snake bite, which may provide a better protection in presence of antiserum, especially in the rural parts of India.

Assessing the Electrode-Neuron Interface with the Electrically Evoked Compound Action Potential, Electrode Position, and Behavioral Thresholds.

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DeVries, Lindsay; Scheperle, Rachel; Bierer, Julie Arenberg

2016-06-01

Variability in speech perception scores among cochlear implant listeners may largely reflect the variable efficacy of implant electrodes to convey stimulus information to the auditory nerve. In the present study, three metrics were applied to assess the quality of the electrode-neuron interface of individual cochlear implant channels: the electrically evoked compound action potential (ECAP), the estimation of electrode position using computerized tomography (CT), and behavioral thresholds using focused stimulation. The primary motivation of this approach is to evaluate the ECAP as a site-specific measure of the electrode-neuron interface in the context of two peripheral factors that likely contribute to degraded perception: large electrode-to-modiolus distance and reduced neural density. Ten unilaterally implanted adults with Advanced Bionics HiRes90k devices participated. ECAPs were elicited with monopolar stimulation within a forward-masking paradigm to construct channel interaction functions (CIF), behavioral thresholds were obtained with quadrupolar (sQP) stimulation, and data from imaging provided estimates of electrode-to-modiolus distance and scalar location (scala tympani (ST), intermediate, or scala vestibuli (SV)) for each electrode. The width of the ECAP CIF was positively correlated with electrode-to-modiolus distance; both of these measures were also influenced by scalar position. The ECAP peak amplitude was negatively correlated with behavioral thresholds. Moreover, subjects with low behavioral thresholds and large ECAP amplitudes, averaged across electrodes, tended to have higher speech perception scores. These results suggest a potential clinical role for the ECAP in the objective assessment of individual cochlear implant channels, with the potential to improve speech perception outcomes.

Effects of estragole on the compound action potential of the rat sciatic nerve

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J.H. Leal-Cardoso

2004-08-01

Full Text Available Estragole, a relatively nontoxic terpenoid ether, is an important constituent of many essential oils with widespread applications in folk medicine and aromatherapy and known to have potent local anesthetic activity. We investigated the effects of estragole on the compound action potential (CAP of the rat sciatic nerve. The experiments were carried out on sciatic nerves dissected from Wistar rats. Nerves, mounted in a moist chamber, were stimulated at a frequency of 0.2 Hz, with electric pulses of 50-100-µs duration at 10-20 V, and evoked CAP were monitored on an oscilloscope and recorded on a computer. CAP control parameters were: peak-to-peak amplitude (PPA, 9.9 ± 0.55 mV (N = 15, conduction velocity, 92.2 ± 4.36 m/s (N = 15, chronaxy, 45.6 ± 3.74 µs (N = 5, and rheobase, 3.9 ± 0.78 V (N = 5. Estragole induced a dose-dependent blockade of the CAP. At 0.6 mM, estragole had no demonstrable effect. At 2.0 and 6.0 mM estragole, PPA was significantly reduced at the end of 180-min exposure of the nerve to the drug to 85.6 ± 3.96 and 13.04 ± 1.80% of control, respectively. At 4.0 mM, estragole significantly altered PPA, conduction velocity, chronaxy, and rheobase (P <= 0.05, ANOVA; N = 5 to 49.3 ± 6.21 and 77.7 ± 3.84, 125.9 ± 10.43 and 116.7 ± 4.59%, of control, respectively. All of these effects developed slowly and were reversible upon a 300-min wash-out. The data show that estragole dose-dependently blocks nerve excitability.

Action recognition using mined hierarchical compound features.

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Gilbert, Andrew; Illingworth, John; Bowden, Richard

2011-05-01

The field of Action Recognition has seen a large increase in activity in recent years. Much of the progress has been through incorporating ideas from single-frame object recognition and adapting them for temporal-based action recognition. Inspired by the success of interest points in the 2D spatial domain, their 3D (space-time) counterparts typically form the basic components used to describe actions, and in action recognition the features used are often engineered to fire sparsely. This is to ensure that the problem is tractable; however, this can sacrifice recognition accuracy as it cannot be assumed that the optimum features in terms of class discrimination are obtained from this approach. In contrast, we propose to initially use an overcomplete set of simple 2D corners in both space and time. These are grouped spatially and temporally using a hierarchical process, with an increasing search area. At each stage of the hierarchy, the most distinctive and descriptive features are learned efficiently through data mining. This allows large amounts of data to be searched for frequently reoccurring patterns of features. At each level of the hierarchy, the mined compound features become more complex, discriminative, and sparse. This results in fast, accurate recognition with real-time performance on high-resolution video. As the compound features are constructed and selected based upon their ability to discriminate, their speed and accuracy increase at each level of the hierarchy. The approach is tested on four state-of-the-art data sets, the popular KTH data set to provide a comparison with other state-of-the-art approaches, the Multi-KTH data set to illustrate performance at simultaneous multiaction classification, despite no explicit localization information provided during training. Finally, the recent Hollywood and Hollywood2 data sets provide challenging complex actions taken from commercial movie sequences. For all four data sets, the proposed hierarchical

Promising Potential of Dietary (Poly)Phenolic Compounds in the Prevention and Treatment of Diabetes Mellitus.

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Dias, Tania R; Alves, Marco G; Casal, Susana; Oliveira, Pedro F; Silva, Branca M

2017-01-01

The incidence of diabetes mellitus (DM) is reaching alarming proportions worldwide, particularly because it is increasingly affecting younger people. This reflects the sedentary lifestyle and inappropriate dietary habits, especially due to the advent of processed foods in modern societies. Thus, unsurprisingly, the first medical recommendation to patients with clinically evident DM is the alteration in their eating behaviour, particularly regarding carbohydrates and total energy intake. Despite individual and cultural preferences, human diet makes available a large amount of phytochemicals with therapeutic potential. Phenolic compounds are the most abundant class of phytochemicals in edible plants, fruits and beverages. These compounds have strong antioxidant and anti-inflammatory activities that have been associated with specific features of their chemical structure. Among others, such properties make them promising antidiabetic agents and several mechanisms of action have already been proposed. Herein, we discuss the recent findings on the potential of dietary phenolic compounds for the prevention and/or treatment of (pre)diabetes, and associated complications. A broad range of studies supports the innate potential of phenolic compounds to protect against DM-associated deleterious effects. Their antidiabetic activity has been demonstrated by: i) regulation of carbohydrate metabolism; ii) improvement of glucose uptake; iii) protection of pancreatic β-cells; iv) enhancement of insulin action and v) regulation of crucial signalling pathways to cell homeostasis. Dietary phenolic compounds constitute an easy, safe and cost-effective way to combat the worrying scenario of DM. The interesting particularities of phenolic compounds reinforce the implementation of a (poly)phenolic-rich nutritional regime, not only for (pre)diabetic patients, but also for non-diabetic people. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Multi-class Mode of Action Classification of Toxic Compounds Using Logic Based Kernel Methods.

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Lodhi, Huma; Muggleton, Stephen; Sternberg, Mike J E

2010-09-17

Toxicity prediction is essential for drug design and development of effective therapeutics. In this paper we present an in silico strategy, to identify the mode of action of toxic compounds, that is based on the use of a novel logic based kernel method. The technique uses support vector machines in conjunction with the kernels constructed from first order rules induced by an Inductive Logic Programming system. It constructs multi-class models by using a divide and conquer reduction strategy that splits multi-classes into binary groups and solves each individual problem recursively hence generating an underlying decision list structure. In order to evaluate the effectiveness of the approach for chemoinformatics problems like predictive toxicology, we apply it to toxicity classification in aquatic systems. The method is used to identify and classify 442 compounds with respect to the mode of action. The experimental results show that the technique successfully classifies toxic compounds and can be useful in assessing environmental risks. Experimental comparison of the performance of the proposed multi-class scheme with the standard multi-class Inductive Logic Programming algorithm and multi-class Support Vector Machine yields statistically significant results and demonstrates the potential power and benefits of the approach in identifying compounds of various toxic mechanisms. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Genome-wide fitness test and mechanism-of-action studies of inhibitory compounds in Candida albicans.

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Deming Xu

2007-06-01

Full Text Available Candida albicans is a prevalent fungal pathogen amongst the immunocompromised population, causing both superficial and life-threatening infections. Since C. albicans is diploid, classical transmission genetics can not be performed to study specific aspects of its biology and pathogenesis. Here, we exploit the diploid status of C. albicans by constructing a library of 2,868 heterozygous deletion mutants and screening this collection using 35 known or novel compounds to survey chemically induced haploinsufficiency in the pathogen. In this reverse genetic assay termed the fitness test, genes related to the mechanism of action of the probe compounds are clearly identified, supporting their functional roles and genetic interactions. In this report, chemical-genetic relationships are provided for multiple FDA-approved antifungal drugs (fluconazole, voriconazole, caspofungin, 5-fluorocytosine, and amphotericin B as well as additional compounds targeting ergosterol, fatty acid and sphingolipid biosynthesis, microtubules, actin, secretion, rRNA processing, translation, glycosylation, and protein folding mechanisms. We also demonstrate how chemically induced haploinsufficiency profiles can be used to identify the mechanism of action of novel antifungal agents, thereby illustrating the potential utility of this approach to antifungal drug discovery.

Action Mechanism of Iridoid Compounds on Guinea-pig Right Atrium Specimens

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齊藤, 久美子; 酒井 淳一; 堀田 芳弘

2016-01-01

　We examined the actions of iridoid compounds (aucubin (Auc), geniposidic acid (GA)) and a noniridoid compound (chlorogenic acid (CA)) contained in Eucommia leaves [1] [2], which show blood pressure-lowering effects, on the heart using right atrial specimens isolated from guinea pigs. These 3 compounds showed negative inotropic effects (NIE) and negative chronotropic effects (NCE) at a final concentration of 10 －5 or 10 －4 M in an experiment using right atrial specimens. Furthermore, pretreat...

Simulation of action potential propagation in plants.

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Sukhov, Vladimir; Nerush, Vladimir; Orlova, Lyubov; Vodeneev, Vladimir

2011-12-21

Action potential is considered to be one of the primary responses of a plant to action of various environmental factors. Understanding plant action potential propagation mechanisms requires experimental investigation and simulation; however, a detailed mathematical model of plant electrical signal transmission is absent. Here, the mathematical model of action potential propagation in plants has been worked out. The model is a two-dimensional system of excitable cells; each of them is electrically coupled with four neighboring ones. Ion diffusion between excitable cell apoplast areas is also taken into account. The action potential generation in a single cell has been described on the basis of our previous model. The model simulates active and passive signal transmission well enough. It has been used to analyze theoretically the influence of cell to cell electrical conductivity and H(+)-ATPase activity on the signal transmission in plants. An increase in cell to cell electrical conductivity has been shown to stimulate an increase in the length constant, the action potential propagation velocity and the temperature threshold, while the membrane potential threshold being weakly changed. The growth of H(+)-ATPase activity has been found to induce the increase of temperature and membrane potential thresholds and the reduction of the length constant and the action potential propagation velocity. Copyright © 2011 Elsevier Ltd. All rights reserved.

Developmental impairment of compound action potential in the optic nerve of myelin mutant taiep rats.

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Roncagliolo, Manuel; Schlageter, Carol; León, Claudia; Couve, Eduardo; Bonansco, Christian; Eguibar, José R

2006-01-05

The taiep rat is a myelin mutant with an initial hypomyelination, followed by a progressive demyelination of the CNS. The neurological correlates start with tremor, followed by ataxia, immobility episodes, epilepsy and paralysis. The optic nerve, an easily-isolable central tract fully myelinated by oligodendrocytes, is a suitable preparation to evaluate the developmental impairment of central myelin. We examined the ontogenic development of optic nerve compound action potentials (CAP) throughout the first 6 months of life of control and taiep rats. Control optic nerves (ON) develop CAPs characterized by three waves. Along the first month, the CAPs of taiep rats showed a delayed maturation, with lower amplitudes and longer latencies than controls; at P30, the conduction velocity has only a third of the normal value. Later, as demyelination proceeds, the conduction velocity of taiep ONs begins to decrease and CAPs undergo a gradual temporal dispersion. CAPs of control and taiep showed differences in their pharmacological sensitivity to TEA and 4-AP, two voltage dependent K+ channel-blockers. As compared with TEA, 4-AP induced a significant increase of the amplitudes and a remarkable broadening of CAPs. After P20, unlike controls, the greater sensitivity to 4-AP exhibited by taiep ONs correlates with the detachment and retraction of paranodal loops suggesting that potassium conductances could regulate the excitability as demyelination of CNS axons progresses. It is concluded that the taiep rat, a long-lived mutant, provides a useful model to study the consequences of partial demyelination and the mechanisms by which glial cells regulate the molecular organization and excitability of axonal membranes during development and disease.

Characterization of Cochlear, Vestibular and Cochlear-Vestibular Electrically Evoked Compound Action Potentials in Patients with a Vestibulo-Cochlear Implant

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T. A. K. Nguyen

2017-11-01

Full Text Available The peripheral vestibular system is critical for the execution of activities of daily life as it provides movement and orientation information to motor and sensory systems. Patients with bilateral vestibular hypofunction experience a significant decrease in quality of life and have currently no viable treatment option. Vestibular implants could eventually restore vestibular function. Most vestibular implant prototypes to date are modified cochlear implants to fast-track development. These use various objective measurements, such as the electrically evoked compound action potential (eCAP, to supplement behavioral information. We investigated whether eCAPs could be recorded in patients with a vestibulo-cochlear implant. Specifically, eCAPs were successfully recorded for cochlear and vestibular setups, as well as for mixed cochlear-vestibular setups. Similarities and slight differences were found for the recordings of the three setups. These findings demonstrated the feasibility of eCAP recording with a vestibulo-cochlear implant. They could be used in the short term to reduce current spread and avoid activation of non-targeted neurons. More research is warranted to better understand the neural origin of vestibular eCAPs and to utilize them for clinical applications.

Application of optical action potentials in human induced pluripotent stem cells-derived cardiomyocytes to predict drug-induced cardiac arrhythmias.

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Lu, H R; Hortigon-Vinagre, M P; Zamora, V; Kopljar, I; De Bondt, A; Gallacher, D J; Smith, G

2017-09-01

Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as new and human-relevant source in vitro model for cardiac safety assessment that allow us to investigate a set of 20 reference drugs for predicting cardiac arrhythmogenic liability using optical action potential (oAP) assay. Here, we describe our examination of the oAP measurement using a voltage sensitive dye (Di-4-ANEPPS) to predict adverse compound effects using hiPS-CMs and 20 cardioactive reference compounds. Fluorescence signals were digitized at 10kHz and the records subsequently analyzed off-line. Cells were exposed to 30min incubation to vehicle or compound (n=5/dose, 4 doses/compound) that were blinded to the investigating laboratory. Action potential parameters were measured, including rise time (T rise ) of the optical action potential duration (oAPD). Significant effects on oAPD were sensitively detected with 11 QT-prolonging drugs, while oAPD shortening was observed with I Ca -antagonists, I Kr -activator or ATP-sensitive K + channel (K ATP )-opener. Additionally, the assay detected varied effects induced by 6 different sodium channel blockers. The detection threshold for these drug effects was at or below the published values of free effective therapeutic plasma levels or effective concentrations by other studies. The results of this blinded study indicate that OAP is a sensitive method to accurately detect drug-induced effects (i.e., duration/QT-prolongation, shortening, beat rate, and incidence of early after depolarizations) in hiPS-CMs; therefore, this technique will potentially be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase. Copyright © 2017 Elsevier Inc. All rights reserved.

Impedance and electrically evoked compound action potential (ECAP drop within 24 hours after cochlear implantation.

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Joshua Kuang-Chao Chen

Full Text Available Previous animal study revealed that post-implantation electrical detection levels significantly declined within days. The impact of cochlear implant (CI insertion on human auditory pathway in terms of impedance and electrically evoked compound action potential (ECAP variation within hours after surgery remains unclear, since at this time frequency mapping can only commence weeks after implantation due to factors associated with wound conditions. The study presented our experiences with regards to initial switch-on within 24 hours, and thus the findings about the milieus inside cochlea within the first few hours after cochlear implantation in terms of impedance/ECAP fluctuations. The charts of fifty-four subjects with profound hearing impairment were studied. A minimal invasive approach was used for cochlear implantation, characterized by a small skin incision (≈ 2.5 cm and soft techniques for cochleostomy. Impedance/ECAP was measured intro-operatively and within 24 hours post-operatively. Initial mapping within 24 hours post-operatively was performed in all patients without major complications. Impedance/ECAP became significantly lower measured within 24 hours post-operatively as compared with intra-operatively (p<0.001. There were no differences between pre-operative and post-operative threshold for air-conduction hearing. A significant drop of impedance/ECAP in one day after cochlear implantation was revealed for the first time in human beings. Mechanisms could be related to the restoration of neuronal sensitivity to the electrical stimulation, and/or the interaction between the matrix enveloping the electrodes and the electrical stimulation of the initial switch-on. Less wound pain/swelling and soft techniques both contributed to the success of immediate initial mapping, which implied a stable micro-environment inside the cochlea despite electrodes insertion. Our research invites further studies to correlate initial impedance/ECAP changes

Establishment of alternative potency test for botulinum toxin type A using compound muscle action potential (CMAP) in rats.

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Torii, Yasushi; Goto, Yoshitaka; Nakahira, Shinji; Ginnaga, Akihiro

2014-11-01

The biological activity of botulinum toxin type A has been evaluated using the mouse intraperitoneal (ip) LD50 test. This method requires a large number of mice to precisely determine toxin activity, and, as such, poses problems with regard to animal welfare. We previously developed a compound muscle action potential (CMAP) assay using rats as an alternative method to the mouse ip LD50 test. In this study, to evaluate this quantitative method of measuring toxin activity using CMAP, we assessed the parameters necessary for quantitative tests according to ICH Q2 (R1). This assay could be used to evaluate the activity of the toxin, even when inactive toxin was mixed with the sample. To reduce the number of animals needed, this assay was set to measure two samples per animal. Linearity was detected over a range of 0.1-12.8 U/mL, and the measurement range was set at 0.4-6.4 U/mL. The results for accuracy and precision showed low variability. The body weight was selected as a variable factor, but it showed no effect on the CMAP amplitude. In this study, potency tests using the rat CMAP assay of botulinum toxin type A demonstrated that it met the criteria for a quantitative analysis method. Copyright © 2014 Elsevier Ltd. All rights reserved.

Rebelling against the (Insulin Resistance: A Review of the Proposed Insulin-Sensitizing Actions of Soybeans, Chickpeas, and Their Bioactive Compounds

Directory of Open Access Journals (Sweden)

Jaime L. Clark

2018-03-01

Full Text Available Insulin resistance is a major risk factor for diseases such as type 2 diabetes and metabolic syndrome. Current methods for management of insulin resistance include pharmacological therapies and lifestyle modifications. Several clinical studies have shown that leguminous plants such as soybeans and pulses (dried beans, dried peas, chickpeas, lentils are able to reduce insulin resistance and related type 2 diabetes parameters. However, to date, no one has summarized the evidence supporting a mechanism of action for soybeans and pulses that explains their ability to lower insulin resistance. While it is commonly assumed that the biological activities of soybeans and pulses are due to their antioxidant activities, these bioactive compounds may operate independent of their antioxidant properties and, thus, their ability to potentially improve insulin sensitivity via alternative mechanisms needs to be acknowledged. Based on published studies using in vivo and in vitro models representing insulin resistant states, the proposed mechanisms of action for insulin-sensitizing actions of soybeans, chickpeas, and their bioactive compounds include increasing glucose transporter-4 levels, inhibiting adipogenesis by down-regulating peroxisome proliferator-activated receptor-γ, reducing adiposity, positively affecting adipokines, and increasing short-chain fatty acid-producing bacteria in the gut. Therefore, this review will discuss the current evidence surrounding the proposed mechanisms of action for soybeans and certain pulses, and their bioactive compounds, to effectively reduce insulin resistance.

Involvement of transient receptor potential A1 channel in algesic and analgesic actions of the organic compound limonene.

Science.gov (United States)

Kaimoto, T; Hatakeyama, Y; Takahashi, K; Imagawa, T; Tominaga, M; Ohta, T

2016-08-01

TRPA1 is a Ca-permeable nonselective cation channel expressed in sensory neurons and acts as a nocisensor. Recent reports show that some monoterpenes, a group of naturally occurring organic compounds, modulate TRP channel activity. Here, we report that limonene, being contained in citrus fruits and mushrooms, shows a unique bimodal action on TRPA1 channel. We examine the effects of limonene on sensory neurons from wild-type, TRPV1- and TRPA1-gene-deficient mice and on heterologously expressed channels in vitro. Molecular determinants were identified with using mutated channels. Cellular excitability is monitored with ratiometric Ca imaging. Nociceptive and analgesic actions of limonene are also examined in vivo. In wild-type mouse sensory neurons, limonene increased the intracellular Ca(2+) concentration ([Ca(2+) ]i ), which was inhibited by selective inhibitors of TRPA1 but not TRPV1. Limonene-responsive neurons highly corresponded to TRPA1 agonist-sensitive ones. Limonene failed to stimulate sensory neurons from the TRPA1 (-/-) mouse. Heterologously expressed mouse TRPA1 was activated by limonene. Intraplantar injection of limonene elicited acute pain, which was significantly less in TRPA1 (-/-) mice. Systemic administration of limonene reduced nociceptive behaviours evoked by H2 O2 . In both heterologously and endogenously expressed TRPA1, a low concentration of limonene significantly inhibited H2 O2 -induced TRPA1 activation. TRPA1 activation by limonene was abolished in H2 O2 -insensitive cysteine-mutated channels. Topically applied limonene stimulates TRPA1, resulting in elicitation of acute pain, but its systemic application inhibits nociception induced by oxidative stress. Because limonene is a safe compound, it may be utilized for pain control due to its inhibition of TRPA1 channels. What does this study add: Limonene, a monoterpene in essential oils of various plants, has been known for its antitumor and anti-inflammatory properties. However, molecular

Molecular Mechanisms of Breast Cancer Metastasis and Potential Anti-metastatic Compounds.

Science.gov (United States)

Tungsukruthai, Sucharat; Petpiroon, Nalinrat; Chanvorachote, Pithi

2018-05-01

Throughout the world, breast cancer is among the major causes of cancer-related death and is the most common cancer found in women. The development of cancer molecular knowledge has surpassed the novel concept of cancer biology and unraveled principle targets for anticancer drug developments and treatment strategies. Metastatic breast cancer cells acquire their aggressive features through several mechanisms, including augmentation of survival, proliferation, tumorigenicity, and motility-related cellular pathways. Clearly, natural product-derived compounds have since long been recognized as an important source for anticancer drugs, several of which have been shown to have promising anti-metastasis activities by suppressing key molecular features supporting such cell aggressiveness. This review provides the essential details of breast cancer, the molecular-based insights into metastasis, as well as the effects and mechanisms of potential compounds for breast cancer therapeutic approaches. As the abilities of cancer cells to invade and metastasize are addressed as the hallmarks of cancer, compounds possessing anti-metastatic effects, together with their defined molecular drug action could benefit the development of new drugs as well as treatment strategies. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Intraoperative cochlear nerve mapping with the mobile cochlear nerve compound action potential tracer in vestibular schwannoma surgery.

Science.gov (United States)

Watanabe, Nobuyuki; Ishii, Takuya; Fujitsu, Kazuhiko; Kaku, Shogo; Ichikawa, Teruo; Miyahara, Kosuke; Okada, Tomu; Tanino, Shin; Uriu, Yasuhiro; Murayama, Yuichi

2018-05-18

OBJECTIVE The authors describe the usefulness and limitations of the cochlear nerve compound action potential (CNAP) mobile tracer (MCT) that they developed to aid in cochlear nerve mapping during vestibular schwannoma surgery (VSS) for hearing preservation. METHODS This MCT device requires no more than 2 seconds for stable placement on the nerve to obtain the CNAP and thus is able to trace the cochlear nerve instantaneously. Simultaneous bipolar and monopolar recording is possible. The authors present the outcomes of 18 consecutive patients who underwent preoperative useful hearing (defined as class I or II of the Gardner-Robertson classification system) and underwent hearing-preservation VSS with the use of the MCT. Mapping was considered successful when it was possible to detect and trace the cochlear nerve. RESULTS Mapping of the cochlear nerve was successful in 13 of 18 patients (72.2%), and useful hearing was preserved in 11 patients (61.1%). Among 8 patients with large tumors (Koos grade 3 or 4), the rate of successful mapping was 62.5% (5 patients). The rate of hearing preservation in patients with large tumors was 50% (4 patients). CONCLUSIONS In addition to microsurgical presumption of the arrangement of each nerve, frequent probing on and around an unidentified nerve and comparison of each waveform are advisable with the use of both more sensitive monopolar and more location-specific bipolar MCT. MCT proved to be useful in cochlear nerve mapping and may consequently be helpful in hearing preservation. The authors discuss some limitations and problems with this device.

HIV-1 pseudovirus neutralisation by a natural compound: a potential microbicide

CSIR Research Space (South Africa)

Van den Berg, N

2011-02-01

Full Text Available . The mode of action of the compound is, however, yet to be determined. The aim is to develop a microbicide based on an indigenous plant for people infected with HIV-1. The compound will also be screened against other HIV-1 subtypes to test the neutralisation...

Closure Report for Corrective Action Unit 566: EMAD Compound, Nevada National Security Site, Nevada with ROTC-1, Revision 0

Energy Technology Data Exchange (ETDEWEB)

Mark Krauss

2011-06-01

This Closure Report (CR) presents information supporting the closure of Corrective Action Unit (CAU) 566: EMAD Compound, Nevada National Security Site, Nevada. Corrective Action Unit 566 comprises Corrective Action Site (CAS) 25-99-20, EMAD Compound, located within Area 25 of the Nevada National Security Site. The purpose of this CR is to provide documentation supporting the completed corrective actions and provide data confirming that the closure objectives for CAU 566 were met. To achieve this, the following actions were performed: • Review the current site conditions, including the concentration and extent of contamination. • Implement any corrective actions necessary to protect human health and the environment. • Properly dispose of corrective action and investigation wastes. • Document Notice of Completion and closure of CAU 566 issued by the Nevada Division of Environmental Protection. From October 2010 through May 2011, closure activities were performed as set forth in the Streamlined Approach for Environmental Restoration Plan for CAU 566: EMAD Compound, Nevada National Security Site, Nevada. The purposes of the activities as defined during the data quality objectives process were as follows: • Determine whether contaminants of concern (COCs) are present. • If COCs are present, determine their nature and extent, implement appropriate corrective actions, and properly dispose of wastes. Analytes detected during the closure activities were evaluated against final action levels (FALs) to determine COCs for CAU 566. Assessment of the data from collected soil samples, and from radiological and visual surveys of the site, indicates the FALs were exceeded for polychlorinated biphenyls (PCBs), semivolatile organic compounds (SVOCs), and radioactivity. Corrective actions were implemented to remove the following: • Radiologically contaminated soil assumed greater than FAL at two locations • Radiologically contaminated soil assumed greater than FAL with

Screening action potentials: The power of light

Directory of Open Access Journals (Sweden)

Lars eKaestner

2011-07-01

Full Text Available Action potentials reflect the concerted activity of all electrogenic constituents in the plasma membrane during the excitation of a cell. Therefore, the action potential is an integrated readout and a promising parameter to detect electrophysiological failures or modifications thereof in diagnosis as well as in drug screens. Cellular action potentials can be recorded by optical approaches. To fulfill the pre-requirements to scale up for e.g. pharmacological screens the following preparatory work has to be provided: (i model cells under investigation need to represent target cells in the best possible manner; (ii optical sensors that can be either small molecule dyes or genetically encoded potential probes need to provide a reliable readout with minimal interaction with the naive behavior of the cells and (iii devices need to be capable to stimulate the cells, read out the signals with the appropriate speed as well as provide the capacity for a sufficient throughput. Here we discuss several scenarios for all three categories in the field of cardiac physiology and pharmacology and provide a perspective to use the power of light in screening cardiac action potentials.

Monophasic action potentials and activation recovery intervals as measures of ventricular action potential duration: experimental evidence to resolve some controversies

NARCIS (Netherlands)

Coronel, Ruben; de Bakker, Jacques M. T.; Wilms-Schopman, Francien J. G.; Opthof, Tobias; Linnenbank, André C.; Belterman, Charly N.; Janse, Michiel J.

2006-01-01

BACKGROUND: Activation recovery intervals (ARIs) and monophasic action potential (MAP) duration are used as measures of action potential duration in beating hearts. However, controversies exist concerning the correct way to record MAPs or calculate ARIs. We have addressed these issues

Effects of Various Antiepileptics Used to Alleviate Neuropathic Pain on Compound Action Potential in Frog Sciatic Nerves: Comparison with Those of Local Anesthetics

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Yuhei Uemura

2014-01-01

Full Text Available Antiepileptics used for treating neuropathic pain have various actions including voltage-gated Na+ and Ca2+ channels, glutamate-receptor inhibition, and GABAA-receptor activation, while local anesthetics are also used to alleviate the pain. It has not been fully examined yet how nerve conduction inhibitions by local anesthetics differ in extent from those by antiepileptics. Fast-conducting compound action potentials (CAPs were recorded from frog sciatic nerve fibers by using the air-gap method. Antiepileptics (lamotrigine and carbamazepine concentration dependently reduced the peak amplitude of the CAP (IC50=0.44 and 0.50 mM, resp.. Carbamazepine analog oxcarbazepine exhibited an inhibition smaller than that of carbamazepine. Antiepileptic phenytoin (0.1 mM reduced CAP amplitude by 15%. On the other hand, other antiepileptics (gabapentin, sodium valproate, and topiramate at 10 mM had no effect on CAPs. The CAPs were inhibited by local anesthetic levobupivacaine (IC50=0.23 mM. These results indicate that there is a difference in the extent of nerve conduction inhibition among antiepileptics and that some antiepileptics inhibit nerve conduction with an efficacy similar to that of levobupivacaine or to those of other local anesthetics (lidocaine, ropivacaine, and cocaine as reported previously. This may serve to know a contribution of nerve conduction inhibition in the antinociception by antiepileptics.

Small-conductance calcium-activated potassium (SK) channels contribute to action potential repolarization in human atria

DEFF Research Database (Denmark)

Skibsbye, Lasse; Poulet, Claire; Diness, Jonas Goldin

2014-01-01

(+) currents by ∼15% and prolonged action potential duration (APD), but no effect was observed in myocytes from AF patients. In trabeculae muscle strips from right atrial appendages of SR patients, both compounds increased APD and effective refractory period, and depolarized the resting membrane potential......, while only NS8593 induced these effects in tissue from AF patients. SK channel inhibition did not alter any electrophysiological parameter in human interventricular septum tissue. CONCLUSIONS: SK channels are present in human atria where they participate in repolarization. SK2 and SK3 were down...

Optical mapping of optogenetically shaped cardiac action potentials

Science.gov (United States)

Park, Sarah A.; Lee, Shin-Rong; Tung, Leslie; Yue, David T.

2014-01-01

Light-mediated silencing and stimulation of cardiac excitability, an important complement to electrical stimulation, promises important discoveries and therapies. To date, cardiac optogenetics has been studied with patch-clamp, multielectrode arrays, video microscopy, and an all-optical system measuring calcium transients. The future lies in achieving simultaneous optical acquisition of excitability signals and optogenetic control, both with high spatio-temporal resolution. Here, we make progress by combining optical mapping of action potentials with concurrent activation of channelrhodopsin-2 (ChR2) or halorhodopsin (eNpHR3.0), via an all-optical system applied to monolayers of neonatal rat ventricular myocytes (NRVM). Additionally, we explore the capability of ChR2 and eNpHR3.0 to shape action-potential waveforms, potentially aiding the study of short/long QT syndromes that result from abnormal changes in action potential duration (APD). These results show the promise of an all-optical system to acquire action potentials with precise temporal optogenetics control, achieving a long-sought flexibility beyond the means of conventional electrical stimulation. PMID:25135113

Life cycle responses of the midge Chironomus riparius to compounds with different modes of action.

NARCIS (Netherlands)

Marinkovic, M.; Verweij, R.A.; Nummerdor, G.A.; Jonker, M.J.; Kraak, M.H.S.; Admiraal, W.

2011-01-01

Compounds with different modes of action may affect life cycles of biota differently. The aim of the present study was therefore to investigate the impact of four chemicals with different modes of action, including the essential metal copper, the nonessential metal cadmium, the organometal

Life cycle responses of the midge Chironomus riparius to compounds with different modes of action

NARCIS (Netherlands)

Marinkovic, M.; Verweij, R.A.; Nummerdor, G.A.; Jonker, M.J.; Kraak, M.H.S.; Admiraal, W.

2011-01-01

Compounds with different modes of action may affect life cycles of biota differently. The aim of the present study was therefore to investigate the impact of four chemicals with different modes of action, including the essential metal copper, the nonessential metal cadmium, the organometal

Catalytic properties of niobium compounds

International Nuclear Information System (INIS)

Tanabe, K.; Iizuka, T.

1983-04-01

The catalytic activity and selectivity of niobium compounds including oxides, salts, organometallic compounds and others are outlined. The application of these compounds as catalysts to diversified reactions is reported. The nature and action of niobium catalysts are characteristic and sometimes anomalous, suggesting the necessity of basic research and the potential use as catalysts for important processes in the chemical industry. (Author) [pt

Is action potential threshold lowest in the axon?

NARCIS (Netherlands)

Kole, Maarten H. P.; Stuart, Greg J.

2008-01-01

Action potential threshold is thought to be lowest in the axon, but when measured using conventional techniques, we found that action potential voltage threshold of rat cortical pyramidal neurons was higher in the axon than at other neuronal locations. In contrast, both current threshold and voltage

Action potential propagation: ion current or intramembrane electric field?

Science.gov (United States)

Martí, Albert; Pérez, Juan J; Madrenas, Jordi

2018-01-01

The established action potential propagation mechanisms do not satisfactorily explain propagation on myelinated axons given the current knowledge of biological channels and membranes. The flow across ion channels presents two possible effects: the electric potential variations across the lipid bilayers (action potential) and the propagation of an electric field through the membrane inner part. The proposed mechanism is based on intra-membrane electric field propagation, this propagation can explain the action potential saltatory propagation and its constant delay independent of distance between Ranvier nodes in myelinated axons.

Selective effects of an octopus toxin on action potentials

Science.gov (United States)

Dulhunty, Angela; Gage, Peter W.

1971-01-01

1. A lethal, water soluble toxin (Maculotoxin, MTX) with a molecular weight less than 540, can be extracted from the salivary glands of an octopus (Hapalochlaena maculosa). 2. MTX blocks action potentials in sartorius muscle fibres of toads without affecting the membrane potential. Delayed rectification is not inhibited by the toxin. 3. At low concentrations (10-6-10-5 g/ml.) MTX blocks action potentials only after a certain number have been elicited. The number of action potentials, which can be defined accurately, depends on the concentration of MTX and the concentration of sodium ions in the extracellular solution. 4. The toxin has no post-synaptic effect at the neuromuscular junction and it is concluded that it blocks neuromuscular transmission by inhibiting action potentials in motor nerve terminals. PMID:4330930

Quadratic adaptive algorithm for solving cardiac action potential models.

Science.gov (United States)

Chen, Min-Hung; Chen, Po-Yuan; Luo, Ching-Hsing

2016-10-01

An adaptive integration method is proposed for computing cardiac action potential models accurately and efficiently. Time steps are adaptively chosen by solving a quadratic formula involving the first and second derivatives of the membrane action potential. To improve the numerical accuracy, we devise an extremum-locator (el) function to predict the local extremum when approaching the peak amplitude of the action potential. In addition, the time step restriction (tsr) technique is designed to limit the increase in time steps, and thus prevent the membrane potential from changing abruptly. The performance of the proposed method is tested using the Luo-Rudy phase 1 (LR1), dynamic (LR2), and human O'Hara-Rudy dynamic (ORd) ventricular action potential models, and the Courtemanche atrial model incorporating a Markov sodium channel model. Numerical experiments demonstrate that the action potential generated using the proposed method is more accurate than that using the traditional Hybrid method, especially near the peak region. The traditional Hybrid method may choose large time steps near to the peak region, and sometimes causes the action potential to become distorted. In contrast, the proposed new method chooses very fine time steps in the peak region, but large time steps in the smooth region, and the profiles are smoother and closer to the reference solution. In the test on the stiff Markov ionic channel model, the Hybrid blows up if the allowable time step is set to be greater than 0.1ms. In contrast, our method can adjust the time step size automatically, and is stable. Overall, the proposed method is more accurate than and as efficient as the traditional Hybrid method, especially for the human ORd model. The proposed method shows improvement for action potentials with a non-smooth morphology, and it needs further investigation to determine whether the method is helpful during propagation of the action potential. Copyright © 2016 Elsevier Ltd. All rights

In Vitro Wound Healing Potential and Identification of Bioactive Compounds from Moringa oleifera Lam

Directory of Open Access Journals (Sweden)

Abubakar Amali Muhammad

2013-01-01

Full Text Available Moringa oleifera Lam. (M. oleifera from the monogeneric family Moringaceae is found in tropical and subtropical countries. The present study was aimed at exploring the in vitro wound healing potential of M. oleifera and identification of active compounds that may be responsible for its wound healing action. The study included cell viability, proliferation, and wound scratch test assays. Different solvent crude extracts were screened, and the most active crude extract was further subjected to differential bioguided fractionation. Fractions were also screened and most active aqueous fraction was finally obtained for further investigation. HPLC and LC-MS/MS analysis were used for identification and confirmation of bioactive compounds. The results of our study demonstrated that aqueous fraction of M. oleifera significantly enhanced proliferation and viability as well as migration of human dermal fibroblast (HDF cells compared to the untreated control and other fractions. The HPLC and LC-MS/MS studies revealed kaempferol and quercetin compounds in the crude methanolic extract and a major bioactive compound Vicenin-2 was identified in the bioactive aqueous fraction which was confirmed with standard Vicenin-2 using HPLC and UV spectroscopic methods. These findings suggest that bioactive fraction of M. oleifera containing Vicenin-2 compound may enhance faster wound healing in vitro.

Vanadium Compounds as PTP Inhibitors

Directory of Open Access Journals (Sweden)

Elsa Irving

2017-12-01

Full Text Available Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs and protein tyrosine phosphatases (PTPs. Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti-cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential.

Modeling of action potential generation in NG108-15 cells.

Science.gov (United States)

Molnar, Peter; Hickman, James J

2014-01-01

In order to explore the possibility of identifying toxins based on their effect on the shape of action potentials, we created a computer model of the action potential generation in NG108-15 cells (a neuroblastoma/glioma hybrid cell line). To generate the experimental data for model validation, voltage-dependent sodium, potassium and high-threshold calcium currents, as well as action potentials, were recorded from NG108-15 cells with conventional whole-cell patch-clamp methods. Based on the classic Hodgkin-Huxley formalism and the linear thermodynamic description of the rate constants, ion-channel parameters were estimated using an automatic fitting method. Utilizing the established parameters, action potentials were generated using the Hodgkin-Huxley formalism and were fitted to the recorded action potentials. To demonstrate the applicability of the method for toxin detection and discrimination, the effect of tetrodotoxin (a sodium channel blocker) and tefluthrin (a pyrethroid that is a sodium channel opener) were studied. The two toxins affected the shape of the action potentials differently, and their respective effects were identified based on the predicted changes in the fitted parameters.

Neurotoxic effects of perfluoroalkylated compounds: mechanisms of action and environmental relevance.

Science.gov (United States)

Mariussen, Espen

2012-09-01

Perfluoroalkylated compounds (PFCs) are used in fire-fighting foams, treatment of clothes, carpets and leather products, and as lubricants, pesticides, in paints and medicine. Recent developments in chemical analysis have revealed that fluorinated compounds have become ubiquitously spread and are regarded as a potential threats to the environment. Due to the carbon-fluorine bond, which has a very high bond strength, these chemicals are extremely persistent towards degradation and some PFCs have a potential for bioaccumulation in organisms. Of particular concern has been the developmental toxicity of PFOS and PFOA, which has been manifested in rodent studies as high mortality of prenatally exposed newborn rats and mice within 24 h after delivery. The nervous system appears to be one of the most sensitive targets of environmental contaminants. The serious developmental effects of PFCs have lead to the upcoming of studies that have investigated neurotoxic effects of these substances. In this review the major findings of the neurotoxicity of the main PFCs and their suggested mechanisms of action are presented. The neurotoxic effects are discussed in light of other toxic effects of PFCs to indicate the significance of PFCs as neurotoxicants. The main findings are that PFCs may induce neurobehavioral effects, particularly in developmentally exposed animals. The effects are, however, subtle and inconclusive and are often induced at concentrations where other toxic effects also are expected. Mechanistic studies have shown that PFCs may affect the thyroid system, influence the calcium homeostasis, protein kinase C, synaptic plasticity and cellular differentiation. Compared to other environmental toxicants the human blood levels of PFCs are high and of particular concern is that susceptible groups may be exposed to a cocktail of substances that in combination reach harmful concentrations.

The Action of Chain Extenders in Nylon-6, PET, and Model Compounds

NARCIS (Netherlands)

Loontjens, T.; Pauwels, K.; Derks, F.; Neilen, M.; Sham, C.K.; Serné, M.

1997-01-01

The action of two complementary chain extenders is studied in model systems as well as in poly(ethylene terephthalate) (PET) and nylon–6. Chain extenders are low molecular weight compounds that can be used to increase the molecular weight of polymers in a short time. The reaction must preferably be

A physical action potential generator: design, implementation and evaluation.

Science.gov (United States)

Latorre, Malcolm A; Chan, Adrian D C; Wårdell, Karin

2015-01-01

The objective was to develop a physical action potential generator (Paxon) with the ability to generate a stable, repeatable, programmable, and physiological-like action potential. The Paxon has an equivalent of 40 nodes of Ranvier that were mimicked using resin embedded gold wires (Ø = 20 μm). These nodes were software controlled and the action potentials were initiated by a start trigger. Clinically used Ag-AgCl electrodes were coupled to the Paxon for functional testing. The Paxon's action potential parameters were tunable using a second order mathematical equation to generate physiologically relevant output, which was accomplished by varying the number of nodes involved (1-40 in incremental steps of 1) and the node drive potential (0-2.8 V in 0.7 mV steps), while keeping a fixed inter-nodal timing and test electrode configuration. A system noise floor of 0.07 ± 0.01 μV was calculated over 50 runs. A differential test electrode recorded a peak positive amplitude of 1.5 ± 0.05 mV (gain of 40x) at time 196.4 ± 0.06 ms, including a post trigger delay. The Paxon's programmable action potential like signal has the possibility to be used as a validation test platform for medical surface electrodes and their attached systems.

Chronological changes in the eighth cranial nerve compound action potential (CAP) in experimental endolymphatic hydrops: the effects of altering the polarity of click sounds.

Science.gov (United States)

Morizono, Tetsuo; Kondo, Tsuyoshi; Yamano, Takafumi; Miyagi, Morimichi; Shiraishi, Kimio

2009-02-01

Using a guinea pig model of experimental endolymphatic hydrops, click sounds of altered polarity showed different latencies and amplitudes in hydropic compared with normal cochleae. Latency changes appeared as early as 1 week after endolymphatic obstruction. This method can help diagnose endolymphatic hydrops. The goal of the study was to develop an objective electrophysiological diagnosis of endolymphatic hydrops. Endolymphatic hydrops were created surgically in guinea pigs. The latency and the amplitude of the eighth cranial nerve compound action potential (CAP) for click sounds of altered polarity were measured up to 8 weeks after the surgery. At early stages after surgery, the latency for condensation clicks became longer, and at later stages the latencies for both condensation and rarefaction became longer. The discrepancy in the latencies for rarefaction and condensation click sounds (rarefaction minus condensation) became larger by the first week after surgery, but no further discrepancy occurred thereafter. Compared with latency changes, amplitude changes in the CAP were rapid and progressive following surgery, suggesting ongoing damage to hair cells.

Prediction of Thorough QT study results using action potential simulations based on ion channel screens.

Science.gov (United States)

Mirams, Gary R; Davies, Mark R; Brough, Stephen J; Bridgland-Taylor, Matthew H; Cui, Yi; Gavaghan, David J; Abi-Gerges, Najah

2014-01-01

Detection of drug-induced pro-arrhythmic risk is a primary concern for pharmaceutical companies and regulators. Increased risk is linked to prolongation of the QT interval on the body surface ECG. Recent studies have shown that multiple ion channel interactions can be required to predict changes in ventricular repolarisation and therefore QT intervals. In this study we attempt to predict the result of the human clinical Thorough QT (TQT) study, using multiple ion channel screening which is available early in drug development. Ion current reduction was measured, in the presence of marketed drugs which have had a TQT study, for channels encoded by hERG, CaV1.2, NaV1.5, KCNQ1/MinK, and Kv4.3/KChIP2.2. The screen was performed on two platforms - IonWorks Quattro (all 5 channels, 34 compounds), and IonWorks Barracuda (hERG & CaV1.2, 26 compounds). Concentration-effect curves were fitted to the resulting data, and used to calculate a percentage reduction in each current at a given concentration. Action potential simulations were then performed using the ten Tusscher and Panfilov (2006), Grandi et al. (2010) and O'Hara et al. (2011) human ventricular action potential models, pacing at 1Hz and running to steady state, for a range of concentrations. We compared simulated action potential duration predictions with the QT prolongation observed in the TQT studies. At the estimated concentrations, simulations tended to underestimate any observed QT prolongation. When considering a wider range of concentrations, and conventional patch clamp rather than screening data for hERG, prolongation of ≥5ms was predicted with up to 79% sensitivity and 100% specificity. This study provides a proof-of-principle for the prediction of human TQT study results using data available early in drug development. We highlight a number of areas that need refinement to improve the method's predictive power, but the results suggest that such approaches will provide a useful tool in cardiac safety

Components of action potential repolarization in cerebellar parallel fibres.

Science.gov (United States)

Pekala, Dobromila; Baginskas, Armantas; Szkudlarek, Hanna J; Raastad, Morten

2014-11-15

Repolarization of the presynaptic action potential is essential for transmitter release, excitability and energy expenditure. Little is known about repolarization in thin, unmyelinated axons forming en passant synapses, which represent the most common type of axons in the mammalian brain's grey matter.We used rat cerebellar parallel fibres, an example of typical grey matter axons, to investigate the effects of K(+) channel blockers on repolarization. We show that repolarization is composed of a fast tetraethylammonium (TEA)-sensitive component, determining the width and amplitude of the spike, and a slow margatoxin (MgTX)-sensitive depolarized after-potential (DAP). These two components could be recorded at the granule cell soma as antidromic action potentials and from the axons with a newly developed miniaturized grease-gap method. A considerable proportion of fast repolarization remained in the presence of TEA, MgTX, or both. This residual was abolished by the addition of quinine. The importance of proper control of fast repolarization was demonstrated by somatic recordings of antidromic action potentials. In these experiments, the relatively broad K(+) channel blocker 4-aminopyridine reduced the fast repolarization, resulting in bursts of action potentials forming on top of the DAP. We conclude that repolarization of the action potential in parallel fibres is supported by at least three groups of K(+) channels. Differences in their temporal profiles allow relatively independent control of the spike and the DAP, whereas overlap of their temporal profiles provides robust control of axonal bursting properties.

Detrended fluctuation analysis of compound action potentials re-corded in the cutaneous nerves of diabetic rats

International Nuclear Information System (INIS)

Quiroz-González, Salvador; Rodríguez-Torres, Erika Elizabeth; Segura-Alegría, Bertha; Pereira-Venegas, Javier; Lopez-Gomez, Rosa Estela; Jiménez-Estrada, Ismael

2016-01-01

Highlights: • Fractal analysis of compound action potentials (CAP) evoked in diabetic nerves. • Diabetic rats showed an increment in the chaotic behavior of CAP responses. • Diabetes provokes impaired transmission of sensory information in rats. - Abstract: The electrophysiological alterations in nerves due to diabetes are classically studied in relation to their instantaneous frequency, conduction velocity and amplitude. However, analysis of amplitude variability may reflect the occurrence of feedback loop mechanisms that adjust the output as a function of its previous activity could indicate fractal dynamics. We assume that a peripheral neuropathy, such as that evoked by diabetes, the inability to maintain a steady flow of sensory information is reflected as a breakdown of the long range power-law correlation of CAP area fluctuation from cutaneous nerves. To test this, we first explored in normal rats whether fluctuations in the trial-to-trial CAP area showed a self-similar behavior or fractal structure by means of detrended fluctuations analysis (DFA), and Poincare plots. In addition, we determine whether such CAP fluctuations varied by diabetes induction. Results showed that CAP area fluctuation of SU nerves evoked in normal rats present a long term correlation and self-similar organization (fractal behavior) from trial to trial stimulation as evidenced by DFA of CAP areas. However, CAPs recorded in diabetic nerves exhibited significant reductions in area, larger duration and increased area variability and different Poincare plots than control nerves. The Hurst exponent value determined with the DFA method from a series of 2000 CAPs evoked in diabetic SU nerves was smaller than in control nerves. It is proposed that in cutaneous nerves of normal rats variability of the CAP area present a long term correlation and self-similar organization (fractal behavior), and reflect the ability to maintain a steady flow of sensory information through cutaneous nerves

Modes of Action of Microbially-Produced Phytotoxins

Science.gov (United States)

Duke, Stephen O.; Dayan, Franck E.

2011-01-01

Some of the most potent phytotoxins are synthesized by microbes. A few of these share molecular target sites with some synthetic herbicides, but many microbial toxins have unique target sites with potential for exploitation by the herbicide industry. Compounds from both non-pathogenic and pathogenic microbes are discussed. Microbial phytotoxins with modes of action the same as those of commercial herbicides and those with novel modes of action of action are covered. Examples of the compounds discussed are tentoxin, AAL-toxin, auscaulitoxin aglycone, hydantocidin, thaxtomin, and tabtoxin. PMID:22069756

Studies on the Action Potential From a Thermodynamic Perspective

DEFF Research Database (Denmark)

Wang, Tian

and nerves with ganglia. (2) Attempts have been made to measure the temperature change associated with an action potential as well as an oscillation reaction (Briggs-Rauscher reaction) that shares the adiabatic feature. It turns out that some practical issues need to be solved for the temperature measurement...... of the nerve impulses, while the measured temperature change during the oscillation reaction suggests that there are a reversible adiabatic process and a dissipative process. (3) Local anesthetic e↵ect on nerves is studied. Local anesthetic lidocaine causes a significant stimulus threshold shift of the action......Nerve impulse, also called action potential, has mostly been considered as a pure electrical phenomenon. However, changes in dimensions, e.g. thickness and length, and in temperature along with action potentials have been observed, which indicates that the nerve is a thermodynamic system. The work...

Curcumin as a potential protective compound against cardiac diseases.

Science.gov (United States)

Jiang, Shuai; Han, Jing; Li, Tian; Xin, Zhenlong; Ma, Zhiqiang; Di, Wencheng; Hu, Wei; Gong, Bing; Di, Shouyin; Wang, Dongjin; Yang, Yang

2017-05-01

Curcumin, which was first used 3000 years ago as an anti-inflammatory agent, is a well-known bioactive compound derived from the active ingredient of turmeric (Curcuma longa). Previous research has demonstrated that curcumin has immense therapeutic potential in a variety of diseases via anti-oxidative, anti-apoptotic, and anti-inflammatory pathways. Cardiac diseases are the leading cause of mortality worldwide and cause considerable harm to human beings. Numerous studies have suggested that curcumin exerts a protective role in the human body whereas its actions in cardiac diseases remain elusive and poorly understood. On the basis of the current evidence, we first give a brief introduction of cardiac diseases and curcumin, especially regarding the effects of curcumin in embryonic heart development. Secondly, we analyze the basic roles of curcumin in pathways that are dysregulated in cardiac diseases, including oxidative stress, apoptosis, and inflammation. Thirdly, actions of curcumin in different cardiac diseases will be discussed, as will relevant clinical trials. Eventually, we would like to discuss the existing controversial opinions and provide a detailed analysis followed by the remaining obstacles, advancement, and further prospects of the clinical application of curcumin. The information compiled here may serve as a comprehensive reference of the protective effects of curcumin in the heart, which is significant to the further research and design of curcumin analogs as therapeutic options for cardiac diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Wireless cardiac action potential transmission with ultrasonically inserted silicon microprobes

International Nuclear Information System (INIS)

Shen, C J; Ramkumar, A; Lal, A; Gilmour, R F Jr

2011-01-01

This paper reports on the integration of ultrasonically inserted horn-shaped cardiac probes with wireless transmission of 3D cardiac action potential measurement for applications in ex vivo preparations such as monitoring the onset of ventricular fibrillation. Ultrasonically inserted silicon horn probes permit reduced penetration force during insertion, allowing silicon, a brittle material, to penetrate cardiac tissue. The probes also allow recording from multiple sites that are lithographically defined. An application-specific integrated circuit has been designed with a 40 dB amplifying stage and a frequency modulating oscillator at 95 MHz to wirelessly transmit the recorded action potentials. This ultrasonically inserted microprobe wireless system demonstrates the initial results in wireless monitoring of 3D action potential propagation, and the extraction of parameters of interest including the action potential duration and diastolic interval

Numerical investigation of action potential transmission in plants

Directory of Open Access Journals (Sweden)

Mariusz Pietruszka

2014-01-01

Full Text Available In context of a fairly concise review of recent literature and well established experimental results we reconsider the problem of action potential propagating steadily down the plant cell(s. Having adopted slightly modified Hodgkin-Huxley set of differential equations for the action potential we carried out the numerical investigation of these equations in the course of time. We argue that the Hodgkin-Huxley-Katz model for the nerve impulse can be used to describe the phenomena which take place in plants - this point of view seems to be plausible since the mechanisms involving active ionic transport across membranes from the mathematical point of view are similar. Besides, we compare in a qualitative way our theoretical outcomes with typical experimental results for the action potentials which arise as the reaction of plants to electrical, mechanical and light stimuli. Moreover, we point out the relevance of the sequence of events during the pulse with the appropriate ionic fluxes.

A Systems Biology Approach to Understanding the Mechanisms of Action of an Alternative Anticancer Compound in Comparison to Cisplatin

Science.gov (United States)

Wright, Elise P.; Padula, Matthew P.; Higgins, Vincent J.; Aldrich-Wright, Janice R.; Coorssen, Jens R.

2014-01-01

Many clinically available anticancer compounds are designed to target DNA. This commonality of action often yields overlapping cellular response mechanisms and can thus detract from drug efficacy. New compounds are required to overcome resistance mechanisms that effectively neutralise compounds like cisplatin and those with similar chemical structures. Studies have shown that 56MESS is a novel compound which, unlike cisplatin, does not covalently bind to DNA, but is more toxic to many cell lines and active against cisplatin-resistant cells. Furthermore, a transcriptional study of 56MESS in yeast has implicated iron and copper metabolism as well as the general yeast stress response following challenge with 56MESS. Beyond this, the cytotoxicity of 56MESS remains largely uncharacterised. Here, yeast was used as a model system to facilitate a systems-level comparison between 56MESS and cisplatin. Preliminary experiments indicated that higher concentrations than seen in similar studies be used. Although a DNA interaction with 56MESS had been theorized, this work indicated that an effect on protein synthesis/ degradation was also implicated in the mechanism(s) of action of this novel anticancer compound. In contrast to cisplatin, the different mechanisms of action that are indicated for 56MESS suggest that this compound could overcome cisplatin resistance either as a stand-alone treatment or a synergistic component of therapeutics. PMID:28250393

Perturbation analysis of spontaneous action potential initiation by stochastic ion channels

KAUST Repository

Keener, James P.; Newby, Jay M.

2011-01-01

A stochastic interpretation of spontaneous action potential initiation is developed for the Morris-Lecar equations. Initiation of a spontaneous action potential can be interpreted as the escape from one of the wells of a double well potential

State and location dependence of action potential metabolic cost in cortical pyramidal neurons.

Science.gov (United States)

Hallermann, Stefan; de Kock, Christiaan P J; Stuart, Greg J; Kole, Maarten H P

2012-06-03

Action potential generation and conduction requires large quantities of energy to restore Na(+) and K(+) ion gradients. We investigated the subcellular location and voltage dependence of this metabolic cost in rat neocortical pyramidal neurons. Using Na(+)/K(+) charge overlap as a measure of action potential energy efficiency, we found that action potential initiation in the axon initial segment (AIS) and forward propagation into the axon were energetically inefficient, depending on the resting membrane potential. In contrast, action potential backpropagation into dendrites was efficient. Computer simulations predicted that, although the AIS and nodes of Ranvier had the highest metabolic cost per membrane area, action potential backpropagation into the dendrites and forward propagation into axon collaterals dominated energy consumption in cortical pyramidal neurons. Finally, we found that the high metabolic cost of action potential initiation and propagation down the axon is a trade-off between energy minimization and maximization of the conduction reliability of high-frequency action potentials.

Antimicrobial compounds targeting Gram-negative bacteria in food: Their mode of action and combinational effects

DEFF Research Database (Denmark)

Hyldgaard, Morten

2015-01-01

compromising food shelf-life or safety. Natural antimicrobial compounds have therefore gained increased interest as a label-friendly alternative that can be added directly to food products. Although natural antimicrobials constitute an interesting source of compounds, it is often not understood how...... they interact with bacterial cells to exert their mechanism of inhibition or killing. Furthermore, natural antimicrobials are often not potent enough as single compounds, and may cause unwanted sensory side-effects, which limit the quantities that can be applied to food. These problems might be circumvented...... by combining antimicrobials to decrease the concentrations needed without compromising their antimicrobial activity. The work described in this dissertation presents two projects concerning the mechanism of action of selected natural antimicrobial compounds primarily against Gram-negative bacteria, and two...

Antifouling potential of Nature-inspired sulfated compounds

Science.gov (United States)

Almeida, Joana R.; Correia-da-Silva, Marta; Sousa, Emília; Antunes, Jorge; Pinto, Madalena; Vasconcelos, Vitor; Cunha, Isabel

2017-02-01

Natural products with a sulfated scaffold have emerged as antifouling agents with low or nontoxic effects to the environment. In this study 13 sulfated polyphenols were synthesized and tested for antifouling potential using the anti-settlement activity of mussel (Mytilus galloprovincialis) plantigrade post-larvae and bacterial growth inhibition towards four biofilm-forming bacterial strains. Results show that some of these Nature-inspired compounds were bioactive, particularly rutin persulfate (2), 3,6-bis(β-D-glucopyranosyl) xanthone persulfate (6), and gallic acid persulfate (12) against the settlement of plantigrades. The chemical precursors of sulfated compounds 2 and 12 were also tested for anti-settlement activity and it was possible to conclude that bioactivity is associated with sulfation. While compound 12 showed the most promising anti-settlement activity (EC50 = 8.95 μg.mL-1), compound 2 also caused the higher level of growth inhibition in bacteria Vibrio harveyi (EC20 = 12.5 μg.mL-1). All the three bioactive compounds 2, 6, and 12 were also found to be nontoxic to the non target species Artemia salina ( 1000 μg.mL-1). This study put forward the relevance of synthesizing non-natural sulfated small molecules to generate new nontoxic antifouling agents.

Investigations into the analysis of the rate of decay of the compound action potentials recorded from the rat sciatic nerve after death: significance for the prediction of the post-mortem period.

Science.gov (United States)

Nokes, L D; Daniel, D; Flint, T; Barasi, S

1991-01-01

There have been a number of papers that have reported the investigations of electrical stimulation of muscle groups in order to determine the post-mortem period. To the authors knowledge, no techniques have been described that analyse the compound action potentials (CAP) of various nerve fibre groups after death. This paper reports the monitoring of both the amplitude and latency changes of the CAP recorded from a stimulated rat sciatic nerve after death. Initial results suggest that the method my be useful in determining the early post-mortem period within 1 or 2 h after death. It may also be of use in measuring nerve conduction delay in various pathological conditions that can affect the neural network; for example diabetes.

Active action potential propagation but not initiation in thalamic interneuron dendrites

Science.gov (United States)

Casale, Amanda E.; McCormick, David A.

2012-01-01

Inhibitory interneurons of the dorsal lateral geniculate nucleus of the thalamus modulate the activity of thalamocortical cells in response to excitatory input through the release of inhibitory neurotransmitter from both axons and dendrites. The exact mechanisms by which release can occur from dendrites are, however, not well understood. Recent experiments using calcium imaging have suggested that Na/K based action potentials can evoke calcium transients in dendrites via local active conductances, making the back-propagating action potential a candidate for dendritic neurotransmitter release. In this study, we employed high temporal and spatial resolution voltage-sensitive dye imaging to assess the characteristics of dendritic voltage deflections in response to Na/K action potentials in interneurons of the mouse dorsal lateral geniculate nucleus. We found that trains or single action potentials elicited by somatic current injection or local synaptic stimulation led to action potentials that rapidly and actively back-propagated throughout the entire dendritic arbor and into the fine filiform dendritic appendages known to release GABAergic vesicles. Action potentials always appeared first in the soma or proximal dendrite in response to somatic current injection or local synaptic stimulation, and the rapid back-propagation into the dendritic arbor depended upon voltage-gated sodium and TEA-sensitive potassium channels. Our results indicate that thalamic interneuron dendrites integrate synaptic inputs that initiate action potentials, most likely in the axon initial segment, that then back-propagate with high-fidelity into the dendrites, resulting in a nearly synchronous release of GABA from both axonal and dendritic compartments. PMID:22171033

Synthesis of esters of morpholino-4-carbothionothiolic acid as compounds of potential radioprotective action

Energy Technology Data Exchange (ETDEWEB)

Strzelczyk, M.; Kucharski, A. (Wojskowa Akademia Medyczna, Lodz (Poland))

1979-01-01

The compounds of the group of dithiocarbaminianes as complexing compounds are of importance in radioprotection. Present paper concerns the synthesis of 19, as yet undescribed dithiocarbaminianes esters of morpholino-4-carbothionothiolic acid. They were obtained in the reaction of the potassium salt of the mentioned acid with adequate alkyl or alkyloaryl halogenatas. Potassium salt of the morpholino-4-carbothionothiolic acid was obtained in the reaction of morpholine with carbon disulphite in the presence of potassium hydroxide. Obtaining of the pure potassium salt of the mentioned acid enabled the accurate calculation of the used substarate in further reactions and conduction of reaction in different solvents. Phenyloalkyl, phenacyl and morpholino-4-carbonyloalkyl esters were obtained. Their chemical structure was confirmed by elementary and spectral infrared analysis.

Longitudinal changes of nerve conduction velocity, distal motor latency, compound motor action potential duration, and skin temperature during prolonged exposure to cold in a climate chamber.

Science.gov (United States)

Maetzler, Walter; Klenk, Jochen; Becker, Clemens; Zscheile, Julia; Gabor, Kai-Steffen; Lindemann, Ulrich

2012-09-01

Changes of nerve conduction velocity (NCV), distal motor latency (DML), compound motor action potential (CMAP) duration, and skin temperature with regard to cold have been investigated by use of ice packs or cold water baths, but not after cooling of environmental temperature which has higher ecological validity. The aim of this study was to investigate these parameters during cooled room temperature. NCV, DML, and CMAP duration of the common fibular nerve, and skin temperature were measured in 20 healthy young females during exposure to 15°C room temperature, coming from 25°C room. We found that NCV decreased and DML increased linearly during 45 min observation time, in contrast to CMAP duration and skin temperature which changes followed an exponential curve. To the best of our knowledge, this is the first study investigating changes of these parameters during exposure to environmental cold. The results may pilot some new hypotheses and studies on physiological and pathological changes of the peripheral nervous system and skin to environmental cold, e.g., in elderly with peripheral neuropathies.

[Effect of pulse magnetic field on distribution of neuronal action potential].

Science.gov (United States)

Zheng, Yu; Cai, Di; Wang, Jin-Hai; Li, Gang; Lin, Ling

2014-08-25

The biological effect on the organism generated by magnetic field is widely studied. The present study was aimed to observe the change of sodium channel under magnetic field in neurons. Cortical neurons of Kunming mice were isolated, subjected to 15 Hz, 1 mT pulse magnetic stimulation, and then the currents of neurons were recorded by whole-cell patch clamp. The results showed that, under magnetic stimulation, the activation process of Na(+) channel was delayed, and the inactivation process was accelerated. Given the classic three-layer model, the polarization diagram of cell membrane potential distribution under pulse magnetic field was simulated, and it was found that the membrane potential induced was associated with the frequency and intensity of magnetic field. Also the effect of magnetic field-induced current on action potential was simulated by Hodgkin-Huxley (H-H) model. The result showed that the generation of action potential was delayed, and frequency and the amplitudes were decreased when working current was between -1.32 μA and 0 μA. When the working current was higher than 0 μA, the generation frequency of action potential was increased, and the change of amplitudes was not obvious, and when the working current was lower than -1.32 μA, the time of rising edge and amplitudes of action potential were decreased drastically, and the action potential was unable to generate. These results suggest that the magnetic field simulation can affect the distribution frequency and amplitude of action potential of neuron via sodium channel mediation.

Intraoperative observation of changes in cochlear nerve action potentials during exposure to electromagnetic fields generated by mobile phones.

Science.gov (United States)

Colletti, Vittorio; Mandalà, Marco; Manganotti, Paolo; Ramat, Stefano; Sacchetto, Luca; Colletti, Liliana

2011-07-01

The rapid spread of devices generating electromagnetic fields (EMF) has raised concerns as to the possible effects of this technology on humans. The auditory system is the neural organ most frequently and directly exposed to electromagnetic activity owing to the daily use of mobile phones. In recent publications, a possible correlation between mobile phone usage and central nervous system tumours has been detected. Very recently a deterioration in otoacoustic emissions and in the auditory middle latency responses after intensive and long-term magnetic field exposure in humans has been demonstrated. To determine with objective observations if exposure to mobile phone EMF affects acoustically evoked cochlear nerve compound action potentials, seven patients suffering from Ménière's disease and undergoing retrosigmoid vestibular neurectomy were exposed to the effects of mobile phone placed over the craniotomy for 5 min. All patients showed a substantial decrease in amplitude and a significant increase in latency of cochlear nerve compound action potentials during the 5 min of exposure to EMF. These changes lasted for a period of around 5 min after exposure. The possibility that EMF can produce relatively long-lasting effects on cochlear nerve conduction is discussed and analysed in light of contrasting previous literature obtained under non-surgical conditions. Limitations of this novel approach, including the effects of the anaesthetics, craniotomy and surgical procedure, are presented in detail.

Dynamics of action potential initiation in the GABAergic thalamic reticular nucleus in vivo.

Science.gov (United States)

Muñoz, Fabián; Fuentealba, Pablo

2012-01-01

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold.

Natural compounds with herbicidal activity

Directory of Open Access Journals (Sweden)

Mariano Fracchiolla

2007-12-01

Full Text Available Research about phytotoxic activity of natural compounds could lead both to find new herbicidal active ingredients and to plan environmental friendly weed control strategies. Particularly, living organisms could be a source of compounds that are impossible, for their complexity, to synthesize artificially. More over, they could have alternative sites of action respect to the known chemical herbicides and, due to their origin, they should be more environmental safe. Many living organism, such as bacteria, fungi, insects, lichens and plants, are able to produce bioactive compounds. They generally are secondary metabolites or simply waste molecules. In this paper we make a review about these compounds, highlighting potential and constraints.

Natural compounds with herbicidal activity

Directory of Open Access Journals (Sweden)

Pasquale Montemurro

2011-02-01

Full Text Available Research about phytotoxic activity of natural compounds could lead both to find new herbicidal active ingredients and to plan environmental friendly weed control strategies. Particularly, living organisms could be a source of compounds that are impossible, for their complexity, to synthesize artificially. More over, they could have alternative sites of action respect to the known chemical herbicides and, due to their origin, they should be more environmental safe. Many living organism, such as bacteria, fungi, insects, lichens and plants, are able to produce bioactive compounds. They generally are secondary metabolites or simply waste molecules. In this paper we make a review about these compounds, highlighting potential and constraints.

The DBI action, higher-derivative supergravity, and flattening inflaton potentials

International Nuclear Information System (INIS)

Bielleman, Sjoerd; Ibáñez, Luis E.; Pedro, Francisco G.; Valenzuela, Irene; Wieck, Clemens

2016-01-01

In string theory compactifications it is common to find an effective Lagrangian for the scalar fields with a non-canonical kinetic term. We study the effective action of the scalar position moduli of Type II Dp-branes. In many instances the kinetic terms are in fact modified by a term proportional to the scalar potential itself. This can be linked to the appearance of higher-dimensional supersymmetric operators correcting the Kähler potential. We identify the supersymmetric dimension-eight operators describing the α"′ corrections captured by the D-brane Dirac-Born-Infeld action. Our analysis then allows an embedding of the D-brane moduli effective action into an N=1 supergravity formulation. The effects of the potential-dependent kinetic terms may be very important if one of the scalars is the inflaton, since they lead to a flattening of the scalar potential. We analyze this flattening effect in detail and compute its impact on the CMB observables for single-field inflation with monomial potentials.

Design, synthesis, antiviral activity and mode of action of phenanthrene-containing N-heterocyclic compounds inspired by the phenanthroindolizidine alkaloid antofine.

Science.gov (United States)

Yu, Xiuling; Wei, Peng; Wang, Ziwen; Liu, Yuxiu; Wang, Lizhong; Wang, Qingmin

2016-02-01

The phenanthroindolizidine alkaloid antofine and its analogues have excellent antiviral activity against tobacco mosaic virus (TMV). To simplify the structure and the synthesis of the phenanthroindolizidine alkaloid, a series of phenanthrene-containing N-heterocyclic compounds (compounds 1 to 33) were designed and synthesised, based on the intermolecular interaction of antofine and TMV RNA, and systematically evaluated for their anti-TMV activity. Most of these compounds exhibited good to reasonable anti-TMV activity. The optimum compounds 5, 12 and 21 displayed higher activity than the lead compound antofine and commercial ribavirin. Compound 12 was chosen for field trials of antiviral efficacy against TMV, and was found to exhibit better activity than control plant virus inhibitors. Compounds 5 and 12 were chosen for mode of action studies. The changes in fluorescence intensity of compounds 5 and 12 on separated TMV RNA showed that these small molecules can also bind to TMV RNA, but the mode is very different from that of antofine. The compounds combining phenanthrene and an N-heterocyclic ring could maintain the anti-TMV activity of phenanthroindolizidines, but their modes of action are different from that of antofine. The present study lays a good foundation for us to find more efficient anti-plant virus reagents. © 2015 Society of Chemical Industry.

Intracellular Diagnostics: Hunting for the Mode of Action of Redox-Modulating Selenium Compounds in Selected Model Systems

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Dominika Mániková

2014-08-01

Full Text Available Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-chemical causes thereof, are often only poorly understood. A combination of the nematode- and yeast-based assays provides a powerful platform to investigate a possible biological activity of a new compound and also to explore the “redox link” which may exist between its activity on the one side and its chemistry on the other. Here, we will demonstrate the usefulness of this platform for screening several selenium and tellurium compounds for their activity and action. We will also show how the nematode-based assay can be used to obtain information on compound uptake and distribution inside a multicellular organism, whilst the yeast-based system can be employed to explore possible intracellular mechanisms via chemogenetic screening and intracellular diagnostics. Whilst none of these simple and easy-to-use assays can ultimately substitute for in-depth studies in human cells and animals, these methods nonetheless provide a first glimpse on the possible biological activities of new compounds and offer direction for more complicated future investigations. They may also uncover some rather unpleasant biochemical actions of certain compounds, such as the ability of the trace element supplement selenite to induce DNA strand breaks.

Reconstruction of action potential of repolarization in patients with congenital long-QT syndrome

International Nuclear Information System (INIS)

Kandori, Akihiko; Shimizu, Wataru; Yokokawa, Miki; Kamakura, Shiro; Miyatake, Kunio; Murakami, Masahiro; Miyashita, Tsuyoshi; Ogata, Kuniomi; Tsukada, Keiji

2004-01-01

A method for reconstructing an action potential during the repolarization period was developed. This method uses a current distribution-plotted as a current-arrow map (CAM)-calculated using magnetocardiogram (MCG) signals. The current arrows are summarized during the QRS complex period and subtracted during the ST-T wave period in order to reconstruct the action-potential waveform. To ensure the similarity between a real action potential and the reconstructed action potential using CAM, a monophasic action potential (MAP) and an MCG of the same patient with type-I long-QT syndrome were measured. Although the MAP had one notch that was associated with early afterdepolarization (EAD), the reconstructed action potential had two large and small notches. The small notch timing agreed with the occurrence of the EAD in the MAP. On the other hand, the initiation time of an abnormal current distribution coincides with the appearance timing of the first large notch, and its end time coincides with that of the second small notch. These results suggest that a simple reconstruction method using a CAM based on MCG data can provide a similar action-potential waveform to a MAP waveform without having to introduce a catheter

Triorganotin as a compound with potential reproductive toxicity in mammals

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V.S. Delgado Filho

2011-09-01

Full Text Available Organotin compounds are typical environmental contaminants and suspected endocrine-disrupting substances, which cause irreversible sexual abnormality in female mollusks, called "imposex". However, little is known about the capability of triorganotin compounds, such as tributyltin and triphenyltin, to cause disorders in the sexual development and reproductive functions of mammals, including humans and rodents. Moreover, these compounds can act as potential competitive inhibitors of aromatase enzyme and other steroidogenic enzymes, affecting the reproductive capacity of male and female mammals. In this review, we discuss the cellular, biochemical, and molecular mechanisms by which triorganotin compounds induce adverse effects in the mammalian reproductive function.

Effect of an educational game on university students' learning about action potentials.

Science.gov (United States)

Luchi, Kelly Cristina Gaviao; Montrezor, Luís Henrique; Marcondes, Fernanda K

2017-06-01

The aim of this study was to evaluate the effect of an educational game that is used for teaching the mechanisms of the action potentials in cell membranes. The game was composed of pieces representing the intracellular and extracellular environments, ions, ion channels, and the Na + -K + -ATPase pump. During the game activity, the students arranged the pieces to demonstrate how the ions move through the membrane in a resting state and during an action potential, linking the ion movement with a graph of the action potential. To test the effect of the game activity on student understanding, first-year dental students were given the game to play at different times in a series of classes teaching resting membrane potential and action potentials. In all experiments, students who played the game performed better in assessments. According to 98% of the students, the game supported the learning process. The data confirm the students' perception, indicating that the educational game improved their understanding about action potentials. Copyright © 2017 the American Physiological Society.

Active compounds from cyanobacteria and microalgae: properties and potential applications in biomedicine

Directory of Open Access Journals (Sweden)

Alexey Llopiz

2016-05-01

Full Text Available Cyanobacteria and microalgae are source of many chemicals substances with potential applications on biopharmaceutical industry. Many structures have been characterized in these organism, such as: peptides, proteins, carbohydrates, terpenoids, polyinsatured fatty acids, flavonoids, phenolic compounds, vitamins, porfirins and other organic substances. Chemicals structures of isolated compounds are diverse and it depends of microalgae habitats. Pharmacological activities located in microalgae are bactericides, immunomodulatory, antioxidants, cytoprotective, fungicides and antivirals. These properties may possible the potential treatment of many diseases including autoimmunes disorders, tumoral, and infectious process. In this review are presented and discussed some elements associated to chemical structure and biological activities around of compounds with potential uses as biopharmaceuticals.

Inducing repetitive action potential firing in neurons via synthesized photoresponsive nanoscale cellular prostheses.

Science.gov (United States)

Lu, Siyuan; Madhukar, Anupam

2013-02-01

Recently we reported an analysis that examined the potential of synthesized photovoltaic functional abiotic nanosystems (PVFANs) to modulate membrane potential and activate action potential firing in neurons. Here we extend the analysis to delineate the requirements on the electronic energy levels and the attendant photophysical properties of the PVFANs to induce repetitive action potential under continuous light, a capability essential for the proposed potential application of PVFANs as retinal cellular prostheses to compensate for loss of photoreceptors. We find that repetitive action potential firing demands two basic characteristics in the electronic response of the PVFANs: an exponential dependence of the PVFAN excited state decay rate on the membrane potential and a three-state system such that, following photon absorption, the electron decay from the excited state to the ground state is via intermediate state(s) whose lifetime is comparable to the refractory time following an action potential. In this study, the potential of synthetic photovoltaic functional abiotic nanosystems (PVFANs) is examined under continuous light to modulate membrane potential and activate action potential firing in neurons with the proposed potential application of PVFANs as retinal cellular prostheses. Copyright © 2013 Elsevier Inc. All rights reserved.

A phantom axon setup for validating models of action potential recordings.

Science.gov (United States)

Rossel, Olivier; Soulier, Fabien; Bernard, Serge; Guiraud, David; Cathébras, Guy

2016-08-01

Electrode designs and strategies for electroneurogram recordings are often tested first by computer simulations and then by animal models, but they are rarely implanted for long-term evaluation in humans. The models show that the amplitude of the potential at the surface of an axon is higher in front of the nodes of Ranvier than at the internodes; however, this has not been investigated through in vivo measurements. An original experimental method is presented to emulate a single fiber action potential in an infinite conductive volume, allowing the potential of an axon to be recorded at both the nodes of Ranvier and the internodes, for a wide range of electrode-to-fiber radial distances. The paper particularly investigates the differences in the action potential amplitude along the longitudinal axis of an axon. At a short radial distance, the action potential amplitude measured in front of a node of Ranvier is two times larger than in the middle of two nodes. Moreover, farther from the phantom axon, the measured action potential amplitude is almost constant along the longitudinal axis. The results of this new method confirm the computer simulations, with a correlation of 97.6 %.

Minocycline inhibits D-amphetamine-elicited action potential bursts in a central snail neuron.

Science.gov (United States)

Chen, Y-H; Lin, P-L; Wong, R-W; Wu, Y-T; Hsu, H-Y; Tsai, M-C; Lin, M-J; Hsu, Y-C; Lin, C-H

2012-10-25

Minocycline is a second-generation tetracycline that has been reported to have powerful neuroprotective properties. In our previous studies, we found that d-amphetamine (AMPH) elicited action potential bursts in an identifiable RP4 neuron of the African snail, Achatina fulica Ferussac. This study sought to determine the effects of minocycline on the AMPH-elicited action potential pattern changes in the central snail neuron, using the two-electrode voltage clamping method. Extracellular application of AMPH at 300 μM elicited action potential bursts in the RP4 neuron. Minocycline dose-dependently (300-900 μM) inhibited the action potential bursts elicited by AMPH. The inhibitory effects of minocycline on AMPH-elicited action potential bursts were restored by forskolin (50 μM), an adenylate cyclase activator, and by dibutyryl cAMP (N(6),2'-O-Dibutyryladenosine 3',5'-cyclic monophosphate; 1mM), a membrane-permeable cAMP analog. Co-administration of forskolin (50 μM) plus tetraethylammonium chloride (TEA; 5mM) or co-administration of TEA (5mM) plus dibutyryl cAMP (1mM) also elicited action potential bursts, which were prevented and inhibited by minocycline. In addition, minocycline prevented and inhibited forskolin (100 μM)-elicited action potential bursts. Notably, TEA (50mM)-elicited action potential bursts in the RP4 neuron were not affected by minocycline. Minocycline did not affect steady-state outward currents of the RP4 neuron. However, minocycline did decrease the AMPH-elicited steady-state current changes. Similarly, minocycline decreased the effects of forskolin-elicited steady-state current changes. Pretreatment with H89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride; 10 μM), a protein kinase A inhibitor, inhibited AMPH-elicited action potential bursts and decreased AMPH-elicited steady-state current changes. These results suggest that the cAMP-protein kinase A signaling pathway and the steady-state current are involved in

Antimicrobial activity of some potential active compounds against ...

African Journals Online (AJOL)

Antimicrobial activities of six potential active compounds (acetic acid, chitosan, catechin, gallic acid, lysozyme, and nisin) at the concentration of 500 g/ml against the growth of Escherichia coli, Staphylococcus aureus, Listeria innocua, and Saccharomyces cerevisiae were determined. Lysozyme showed the highest ...

[Patterns of action potential firing in cortical neurons of neonatal mice and their electrophysiological property].

Science.gov (United States)

Furong, Liu; Shengtian, L I

2016-05-25

To investigate patterns of action potential firing in cortical heurons of neonatal mice and their electrophysiological properties. The passive and active membrane properties of cortical neurons from 3-d neonatal mice were observed by whole-cell patch clamp with different voltage and current mode. Three patterns of action potential firing were identified in response to depolarized current injection. The effects of action potential firing patterns on voltage-dependent inward and outward current were found. Neurons with three different firing patterns had different thresholds of depolarized current. In the morphology analysis of action potential, the three type neurons were different in rise time, duration, amplitude and threshold of the first action potential evoked by 80 pA current injection. The passive properties were similar in three patterns of action potential firing. These results indicate that newborn cortical neurons exhibit different patterns of action potential firing with different action potential parameters such as shape and threshold.

Triangulation of the monophasic action potential causes flattening of the electrocardiographic T-wave

DEFF Research Database (Denmark)

Bhuiyan, Tanveer Ahmed; Graff, Claus; Thomsen, Morten Bækgaard

2012-01-01

of the action potential under the effect of the IKr blocker sertindole and associated these changes to concurrent changes in the morphology of electrocardiographic T-waves in dogs. We show that, under the effect of sertindole, the peak changes in the morphology of action potentials occur at time points similar......It has been proposed that triangulation on the cardiac action potential manifests as a broadened, more flat and notched T-wave on the ECG but to what extent such morphology characteristics are indicative of triangulation is more unclear. In this paper, we have analyzed the morphological changes...... to those observed for the peak changes in T-wave morphology on the ECG. We further show that the association between action potential shape and ECG shape is dose-dependent and most prominent at the time corresponding to phase 3 of the action potential....

Prolonged action potential duration in cardiac ablation of PDK1 mice.

Science.gov (United States)

Han, Zhonglin; Jiang, Yu; Yang, Zhongzhou; Cao, Kejiang; Wang, Dao W

2015-01-01

The involvement of the AGC protein kinase family in regulating arrhythmia has drawn considerable attention, but the underlying mechanisms are still not clear. The aim of this study is to explore the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1), one of upstream protein kinases of the AGC protein kinase family, in the pathogenesis of dysregulated electrophysiological basis. PDK1(F/F) αMHC-Cre mice and PDK1(F/F) mice were divided into experiment group and control group. Using patch clamping technology, we explored action potential duration in both groups, and investigated the functions of transient outward potassium channel and L-type Ca(2+) channel to explain the abnormal action potential duration. Significant prolongation action potential duration was found in mice with PDK1 deletion. Further, the peak current of transient outward potassium current and L-type Ca(2+) current were decreased by 84% and 49% respectively. In addition, dysregulation of channel kinetics lead to action potential duration prolongation further. In conclusion, we have demonstrated that PDK1 participates in action potential prolongation in cardiac ablation of PDK1 mice. This effect is likely to be mediated largely through downregulation of transient outward potassium current. These findings indicate the modulation of the PDK1 pathway could provide a new mechanism for abnormal electrophysiological basis.

Potential Antifreeze Compounds in Present-Day Martian Seepage Groundwater

Directory of Open Access Journals (Sweden)

Jiin-Shuh Jean

2008-01-01

Full Text Available Is the recently found seepage groundwater on Mars pure H2O, or mixed with salts and other antifreeze compounds? Given the surface conditions of Mars, it is unlikely that pure water could either exist in its liquid state or have shaped Mars¡¦ fluid erosional landforms (gullies, channels, and valley networks. More likely is that Mars¡¦ seepage groundwater contains antifreeze and salt compounds that resist freezing and suppress evaporation. This model better accounts for Mars¡¦ enigmatic surface erosion. This paper suggests 17 antifreeze compounds potentially present in Martian seepage groundwater. Given their liquid state and physical properties, triethylene glycol, diethylene glycol, ethylene glycol, and 1,3-propylene glycol are advanced as the most likely candidate compounds. This paper also explores how a mixing of glycol or glycerol with salts in the Martian seepage groundwater may have lowered water¡¦s freezing point and raised its boiling point, with consequences that created fluid gully and channel erosion. Ethylene glycol and related hydrocarbon compounds have been identified in Martian and other interstellar meteorites. We suggest that these compounds and their proportions to water be included for detection in future explorations.

Quantitative determination of biological activity of botulinum toxins utilizing compound muscle action potentials (CMAP), and comparison of neuromuscular transmission blockage and muscle flaccidity among toxins.

Science.gov (United States)

Torii, Yasushi; Goto, Yoshitaka; Takahashi, Motohide; Ishida, Setsuji; Harakawa, Tetsuhiro; Sakamoto, Takashi; Kaji, Ryuji; Kozaki, Shunji; Ginnaga, Akihiro

2010-01-01

The biological activity of various types of botulinum toxin has been evaluated using the mouse intraperitoneal LD(50) test (ip LD(50)). This method requires a large number of mice to precisely determine toxin activity, and so has posed a problem with regard to animal welfare. We have used a direct measure of neuromuscular transmission, the compound muscle action potential (CMAP), to evaluate the effect of different types of botulinum neurotoxin (NTX), and we compared the effects of these toxins to evaluate muscle relaxation by employing the digit abduction scoring (DAS) assay. This method can be used to measure a broad range of toxin activities the day after administration. Types A, C, C/D, and E NTX reduced the CMAP amplitude one day after administration at below 1 ip LD(50), an effect that cannot be detected using the mouse ip LD(50) assay. The method is useful not only for measuring toxin activity, but also for evaluating the characteristics of different types of NTX. The rat CMAP test is straightforward, highly reproducible, and can directly determine the efficacy of toxin preparations through their inhibition of neuromuscular transmission. Thus, this method may be suitable for pharmacology studies and the quality control of toxin preparations. Copyright 2009 Elsevier Ltd. All rights reserved.

Eugenia uniflora L. Essential Oil as a Potential Anti-Leishmania Agent: Effects on Leishmania amazonensis and Possible Mechanisms of Action

OpenAIRE

Rodrigues, Klinger Antonio da Franca; Amorim, Layane Val?ria; de Oliveira, Jamylla Mirck Guerra; Dias, Clarice Noleto; Moraes, Denise Fernandes Coutinho; Andrade, Eloisa Helena de Aguiar; Maia, Jose Guilherme Soares; Carneiro, Sabrina Maria Portela; Carvalho, Fernando A?cio de Amorim

2013-01-01

Eugenia uniflora L. is a member of the Myrtaceae family and is commonly known as Brazilian cherry tree. In this study, we evaluated the chemical composition of Eugenia uniflora L. essential oil (EuEO) by using gas chromatography-mass spectrometry (GC-MS) and assessed its anti-Leishmania activity. We also explored the potential mechanisms of action and cytotoxicity of EuEO. Thirty-two compounds were identified, which constituted 92.65% of the total oil composition. The most abundant components...

Fiber Optic Detection of Action Potentials in Axons

National Research Council Canada - National Science Library

Smela, Elisabeth

2006-01-01

In prior exploratory research, we had designed a fiber optic sensor utilizing a long period Bragg grating for the purpose of detecting action potentials in axons optically, through a change in index...

TRH regulates action potential shape in cerebral cortex pyramidal neurons.

Science.gov (United States)

Rodríguez-Molina, Víctor; Patiño, Javier; Vargas, Yamili; Sánchez-Jaramillo, Edith; Joseph-Bravo, Patricia; Charli, Jean-Louis

2014-07-07

Thyrotropin releasing hormone (TRH) is a neuropeptide with a wide neural distribution and a variety of functions. It modulates neuronal electrophysiological properties, including resting membrane potential, as well as excitatory postsynaptic potential and spike frequencies. We explored, with whole-cell patch clamp, TRH effect on action potential shape in pyramidal neurons of the sensorimotor cortex. TRH reduced spike and after hyperpolarization amplitudes, and increased spike half-width. The effect varied with dose, time and cortical layer. In layer V, 0.5µM of TRH induced a small increase in spike half-width, while 1 and 5µM induced a strong but transient change in spike half-width, and amplitude; after hyperpolarization amplitude was modified at 5µM of TRH. Cortical layers III and VI neurons responded intensely to 0.5µM TRH; layer II neurons response was small. The effect of 1µM TRH on action potential shape in layer V neurons was blocked by G-protein inhibition. Inhibition of the activity of the TRH-degrading enzyme pyroglutamyl peptidase II (PPII) reproduced the effect of TRH, with enhanced spike half-width. Many cortical PPII mRNA+ cells were VGLUT1 mRNA+, and some GAD mRNA+. These data show that TRH regulates action potential shape in pyramidal cortical neurons, and are consistent with the hypothesis that PPII controls its action in this region. Copyright © 2014 Elsevier B.V. All rights reserved.

Microelectrode array measurement of potassium ion channel remodeling on the field action potential duration in rapid atrial pacing rabbits model.

Science.gov (United States)

Sun, Juan; Yan, Huang; Wugeti, Najina; Guo, Yujun; Zhang, Ling; Ma, Mei; Guo, Xingui; Jiao, Changan; Xu, Wenli; Li, Tianqi

2015-01-01

Atrial fibrillation (AF) arises from abnormalities in atrial structure and electrical activity. Microelectrode arrays (MEA) is a real-time, nondestructive measurement of the resting and action potential signal, from myocardial cells, to the peripheral circuit of electrophysiological activity. This study examined the field action potential duration (fAPD) of the right atrial appendage (RAA) by MEA in rapid atrial pacing (RAP) in the right atrium of rabbits. In addition, this study also investigated the effect of potassium ion channel blockers on fAPD. 40 New Zealand white rabbits of either sex were randomly divided into 3 groups: 1) the control, 2) potassium ion channel blocker (TEA, 4-Ap and BaCl2), and 3) amiodarone groups. The hearts were quickly removed and right atrial appendage sectioned (slice thickness 500 μm). Each slice was perfused with Tyrode's solution and continuously stimulated for 30 minutes. Sections from the control group were superfused with Tyrode's solution for 10 minutes, while the blocker groups and amiodarone were both treated with their respective compounds for 10 minutes each. The fAPD of RAA and action field action potential morphology were measured using MEA. In non-pace (control) groups, fAPD was 188.33 ± 18.29 ms after Tyrode's solution superfusion, and 173.91 ± 6.83 ms after RAP. In pace/potassium ion channel groups, TEA and BaCl2 superfusion prolonged atrial field action potential (fAPD) (control vs blocker: 176.67 ± 8.66 ms vs 196.11 ± 10.76 ms, 182.22 ± 12.87 ms vs 191.11 ± 13.09 ms with TEA and BaCl2 superfusion, respectively, P action potential in animal heart slices. After superfusing potassium ion channel blockers, fAPD was prolonged. These results suggest that Ito, IKur and IK1 remodel and mediate RAP-induced atrial electrical remodeling. Amiodarone alter potassium ion channel activity (Ito, IKur, IK1 and IKs), shortening fAPD.

Voltage-gated sodium channel expression and action potential generation in differentiated NG108-15 cells.

Science.gov (United States)

Liu, Jinxu; Tu, Huiyin; Zhang, Dongze; Zheng, Hong; Li, Yu-Long

2012-10-25

The generation of action potential is required for stimulus-evoked neurotransmitter release in most neurons. Although various voltage-gated ion channels are involved in action potential production, the initiation of the action potential is mainly mediated by voltage-gated Na+ channels. In the present study, differentiation-induced changes of mRNA and protein expression of Na+ channels, Na+ currents, and cell membrane excitability were investigated in NG108-15 cells. Whole-cell patch-clamp results showed that differentiation (9 days) didn't change cell membrane excitability, compared to undifferentiated state. But differentiation (21 days) induced the action potential generation in 45.5% of NG108-15 cells (25/55 cells). In 9-day-differentiated cells, Na+ currents were mildly increased, which was also found in 21-day differentiated cells without action potential. In 21-day differentiated cells with action potential, Na+ currents were significantly enhanced. Western blot data showed that the expression of Na+ channels was increased with differentiated-time dependent manner. Single-cell real-time PCR data demonstrated that the expression of Na+ channel mRNA was increased by 21 days of differentiation in NG108-15 cells. More importantly, the mRNA level of Na+ channels in cells with action potential was higher than that in cells without action potential. Differentiation induces expression of voltage-gated Na+ channels and action potential generation in NG108-15 cells. A high level of the Na+ channel density is required for differentiation-triggered action potential generation.

Membrane, action, and oscillatory potentials in simulated protocells

Science.gov (United States)

Syren, R. M.; Fox, S. W.; Przybylski, A. T.; Stratten, W. P.

1982-01-01

Electrical membrane potentials, oscillations, and action potentials are observed in proteinoid microspheres impaled with (3 M KCl) microelectrodes. Although effects are of greater magnitude when the vesicles contain glycerol and natural or synthetic lecithin, the results in the purely synthetic thermal protein structures are substantial, attaining 20 mV amplitude in some cases. The results add the property of electrical potential to the other known properties of proteinoid microspheres, in their role as models for protocells.

Introducing the Action Potential to Psychology Students

Science.gov (United States)

Simon-Dack, Stephanie L.

2014-01-01

For this simple active learning technique for teaching, students are assigned "roles" and act out the process of the action potential (AP), including the firing threshold, ion-specific channels for ions to enter and leave the cell, diffusion, and the refractory period. Pre-post test results indicated that students demonstrated increased…

Perturbation analysis of spontaneous action potential initiation by stochastic ion channels

KAUST Repository

Keener, James P.

2011-07-01

A stochastic interpretation of spontaneous action potential initiation is developed for the Morris-Lecar equations. Initiation of a spontaneous action potential can be interpreted as the escape from one of the wells of a double well potential, and we develop an asymptotic approximation of the mean exit time using a recently developed quasistationary perturbation method. Using the fact that the activating ionic channel\\'s random openings and closings are fast relative to other processes, we derive an accurate estimate for the mean time to fire an action potential (MFT), which is valid for a below-threshold applied current. Previous studies have found that for above-threshold applied current, where there is only a single stable fixed point, a diffusion approximation can be used. We also explore why different diffusion approximation techniques fail to estimate the MFT. © 2011 American Physical Society.

Action potentials in retinal ganglion cells are initiated at the site of maximal curvature of the extracellular potential.

Science.gov (United States)

Eickenscheidt, Max; Zeck, Günther

2014-06-01

The initiation of an action potential by extracellular stimulation occurs after local depolarization of the neuronal membrane above threshold. Although the technique shows remarkable clinical success, the site of action and the relevant stimulation parameters are not completely understood. Here we identify the site of action potential initiation in rabbit retinal ganglion cells (RGCs) interfaced to an array of extracellular capacitive stimulation electrodes. We determine which feature of the extracellular potential governs action potential initiation by simultaneous stimulation and recording RGCs interfaced in epiretinal configuration. Stimulation electrodes were combined to areas of different size and were presented at different positions with respect to the RGC. Based on stimulation by electrodes beneath the RGC soma and simultaneous sub-millisecond latency measurement we infer axonal initiation at the site of maximal curvature of the extracellular potential. Stimulation by electrodes at different positions along the axon reveals a nearly constant threshold current density except for a narrow region close to the cell soma. These findings are explained by the concept of the activating function modified to consider a region of lower excitability close to the cell soma. We present a framework how to estimate the site of action potential initiation and the stimulus required to cross threshold in neurons tightly interfaced to capacitive stimulation electrodes. Our results underscore the necessity of rigorous electrical characterization of the stimulation electrodes and of the interfaced neural tissue.

Alteration of neural action potential patterns by axonal stimulation: the importance of stimulus location.

Science.gov (United States)

Crago, Patrick E; Makowski, Nathaniel S

2014-10-01

Stimulation of peripheral nerves is often superimposed on ongoing motor and sensory activity in the same axons, without a quantitative model of the net action potential train at the axon endpoint. We develop a model of action potential patterns elicited by superimposing constant frequency axonal stimulation on the action potentials arriving from a physiologically activated neural source. The model includes interactions due to collision block, resetting of the neural impulse generator, and the refractory period of the axon at the point of stimulation. Both the mean endpoint firing rate and the probability distribution of the action potential firing periods depend strongly on the relative firing rates of the two sources and the intersite conduction time between them. When the stimulus rate exceeds the neural rate, neural action potentials do not reach the endpoint and the rate of endpoint action potentials is the same as the stimulus rate, regardless of the intersite conduction time. However, when the stimulus rate is less than the neural rate, and the intersite conduction time is short, the two rates partially sum. Increases in stimulus rate produce non-monotonic increases in endpoint rate and continuously increasing block of neurally generated action potentials. Rate summation is reduced and more neural action potentials are blocked as the intersite conduction time increases. At long intersite conduction times, the endpoint rate simplifies to being the maximum of either the neural or the stimulus rate. This study highlights the potential of increasing the endpoint action potential rate and preserving neural information transmission by low rate stimulation with short intersite conduction times. Intersite conduction times can be decreased with proximal stimulation sites for muscles and distal stimulation sites for sensory endings. The model provides a basis for optimizing experiments and designing neuroprosthetic interventions involving motor or sensory stimulation.

Determination of cable parameters in skeletal muscle fibres during repetitive firing of action potentials

Science.gov (United States)

Riisager, Anders; Duehmke, Rudy; Nielsen, Ole Bækgaard; Huang, Christopher L; Pedersen, Thomas Holm

2014-01-01

Recent studies in rat muscle fibres show that repetitive firing of action potentials causes changes in fibre resting membrane conductance (Gm) that reflect regulation of ClC-1 Cl− and KATP K+ ion channels. Methodologically, these findings were obtained by inserting two microelectrodes at close proximity in the same fibres enabling measurements of fibre input resistance (Rin) in between action potential trains. Since the fibre length constant (λ) could not be determined, however, the calculation of Gm relied on the assumptions that the specific cytosolic resistivity (Ri) and muscle fibre volume remained constant during the repeated action potential firing. Here we present a three-microelectrode technique that enables determinations of multiple cable parameters in action potential-firing fibres including Rin and λ as well as waveform and conduction velocities of fully propagating action potentials. It is shown that in both rat and mouse extensor digitorum longus (EDL) fibres, action potential firing leads to substantial changes in both muscle fibre volume and Ri. The analysis also showed, however, that regardless of these changes, rat and mouse EDL fibres both exhibited initial decreases in Gm that were eventually followed by a ∼3-fold, fully reversible increase in Gm after the firing of 1450–1800 action potentials. Using this three-electrode method we further show that the latter rise in Gm was closely associated with excitation failures and loss of action potential signal above −20 mV. PMID:25128573

Super agonist actions of clothianidin and related compounds on the SAD beta 2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes.

Science.gov (United States)

Ihara, Makoto; Matsuda, Kazuhiko; Shimomura, Masaru; Sattelle, David B; Komai, Koichiro

2004-03-01

To compare the actions of clothianidin, a neonicotinoid acting on insect nicotinic acetylcholine receptors, and related compounds with that of imidacloprid, the compounds were tested on the Drosophila SAD-chicken beta2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. The maximum response of the SAD beta 2 nicotinic receptor to clothianidin was larger than that observed for acetylcholine. Ring breakage of the imidazolidine ring of imidacloprid resulting in the generation of a guanidine group was critical for this super agonist action.

Across-site patterns of electrically evoked compound action potential amplitude-growth functions in multichannel cochlear implant recipients and the effects of the interphase gap.

Science.gov (United States)

Schvartz-Leyzac, Kara C; Pfingst, Bryan E

2016-11-01

Electrically evoked compound action potential (ECAP) measures of peak amplitude, and amplitude-growth function (AGF) slope have been shown to reflect characteristics of cochlear health (primarily spiral ganglion density) in anesthetized cochlear-implanted guinea pigs. Likewise, the effect of increasing the interphase gap (IPG) in each of these measures also reflects SGN density in the implanted guinea pig. Based on these findings, we hypothesize that suprathreshold ECAP measures, and also how they change as the IPG is increased, have the potential to be clinically applicable in human subjects. However, further work is first needed in order to determine the characteristics of these measures in humans who use cochlear implants. The current study examined across-site patterns of suprathreshold ECAP measures in 10 bilaterally-implanted, adult cochlear implant users. Results showed that both peak amplitude and slope of the AGF varied significantly from electrode to electrode in ear-specific patterns across the subjects' electrode arrays. As expected, increasing the IPG on average increased the peak amplitude and slope. Across ears, there was a significant, negative correlation between the slope of the ECAP AGF and the duration of hearing loss. Across-site patterns of ECAP peak amplitude and AGF slopes were also compared with common ground impedance values and significant correlations were observed in some cases, depending on the subject and condition. The results of this study, coupled with previous studies in animals, suggest that it is feasible to measure the change in suprathreshold ECAP measures as the IPG increases on most electrodes. Further work is needed to investigate the relationship between these measures and cochlear implant outcomes, and determine how these measures might be used when programming a cochlear-implant processor. Published by Elsevier B.V.

Potential Signatures of Semi-volatile Compounds Associated With Nuclear Processing

Energy Technology Data Exchange (ETDEWEB)

Probasco, Kathleen M.; Birnbaum, Jerome C.; Maughan, A. D.

2002-06-01

Semi-volatile chemicals associated with nuclear processes (e.g., the reprocessing of uranium to produce plutonium for nuclear weapons, or the separation of actinides from processing waste streams), can provide sticky residues or signatures that will attach to piping, ducting, soil, water, or other surface media. Volatile compounds, that are more suitable for electro-optical sensing, have been well studied. However, the semi-volatile compounds have not been well documented or studied. A majority of these semi-volatile chemicals are more robust than typical gaseous or liquid chemicals and can have lifetimes of several weeks, months, or years in the environment. However, large data gaps exist concerning these potential signature compounds and more research is needed to fill these data gaps so that important signature information is not overlooked or discarded. This report investigates key semi-volatile compounds associated with nuclear separations, identifies available chemical and physical properties, and discusses the degradation products that would result from hydrolysis, radiolysis and oxidation reactions on these compounds.

Improving Cardiac Action Potential Measurements: 2D and 3D Cell Culture.

Science.gov (United States)

Daily, Neil J; Yin, Yue; Kemanli, Pinar; Ip, Brian; Wakatsuki, Tetsuro

2015-11-01

Progress in the development of assays for measuring cardiac action potential is crucial for the discovery of drugs for treating cardiac disease and assessing cardiotoxicity. Recently, high-throughput methods for assessing action potential using induced pluripotent stem cell (iPSC) derived cardiomyocytes in both two-dimensional monolayer cultures and three-dimensional tissues have been developed. We describe an improved method for assessing cardiac action potential using an ultra-fast cost-effective plate reader with commercially available dyes. Our methods improve dramatically the detection of the fluorescence signal from these dyes and make way for the development of more high-throughput methods for cardiac drug discovery and cardiotoxicity.

Site of cochlear stimulation and its effect on electrically evoked compound action potentials using the MED-EL standard electrode array

Directory of Open Access Journals (Sweden)

Helbig Silke

2009-12-01

Full Text Available Abstract Background The standard electrode array for the MED-EL MAESTRO cochlear implant system is 31 mm in length which allows an insertion angle of approximately 720°. When fully inserted, this long electrode array is capable of stimulating the most apical region of the cochlea. No investigation has explored Electrically Evoked Compound Action Potential (ECAP recordings in this region with a large number of subjects using a commercially available cochlear implant system. The aim of this study is to determine if certain properties of ECAP recordings vary, depending on the stimulation site in the cochlea. Methods Recordings of auditory nerve responses were conducted in 67 subjects to demonstrate the feasibility of ECAP recordings using the Auditory Nerve Response Telemetry (ART™ feature of the MED-EL MAESTRO system software. These recordings were then analyzed based on the site of cochlear stimulation defined as basal, middle and apical to determine if the amplitude, threshold and slope of the amplitude growth function and the refractory time differs depending on the region of stimulation. Results Findings show significant differences in the ECAP recordings depending on the stimulation site. Comparing the apical with the basal region, on average higher amplitudes, lower thresholds and steeper slopes of the amplitude growth function have been observed. The refractory time shows an overall dependence on cochlear region; however post-hoc tests showed no significant effect between individual regions. Conclusions Obtaining ECAP recordings is also possible in the most apical region of the cochlea. However, differences can be observed depending on the region of the cochlea stimulated. Specifically, significant higher ECAP amplitude, lower thresholds and steeper amplitude growth function slopes have been observed in the apical region. These differences could be explained by the location of the stimulating electrode with respect to the neural tissue

Multiple modes of action potential initiation and propagation in mitral cell primary dendrite

DEFF Research Database (Denmark)

Chen, Wei R; Shen, Gongyu Y; Shepherd, Gordon M

2002-01-01

recordings with computational modeling to analyze action-potential initiation and propagation in the primary dendrite. In response to depolarizing current injection or distal olfactory nerve input, fast Na(+) action potentials were recorded along the entire length of the primary dendritic trunk. With weak......-to-moderate olfactory nerve input, an action potential was initiated near the soma and then back-propagated into the primary dendrite. As olfactory nerve input increased, the initiation site suddenly shifted to the distal primary dendrite. Multi-compartmental modeling indicated that this abrupt shift of the spike......-initiation site reflected an independent thresholding mechanism in the distal dendrite. When strong olfactory nerve excitation was paired with strong inhibition to the mitral cell basal secondary dendrites, a small fast prepotential was recorded at the soma, which indicated that an action potential was initiated...

Ionic channels underlying the ventricular action potential in zebrafish embryo.

Science.gov (United States)

Alday, Aintzane; Alonso, Hiart; Gallego, Monica; Urrutia, Janire; Letamendia, Ainhoa; Callol, Carles; Casis, Oscar

2014-06-01

Over the last years zebrafish has become a popular model in the study of cardiac physiology, pathology and pharmacology. Recently, the application of the 3Rs regulation and the characteristics of the embryo have reduced the use of adult zebrafish use in many studies. However, the zebrafish embryo cardiac physiology is poorly characterized since most works have used indirect techniques and direct recordings of cardiac action potential and ionic currents are scarce. In order to optimize the zebrafish embryo model, we used electrophysiological, pharmacological and immunofluorescence tools to identify the characteristics and the ionic channels involved in the ventricular action potentials of zebrafish embryos. The application of Na(+) or T-type Ca(+2) channel blockers eliminated the cardiac electrical activity, indicating that the action potential upstroke depends on Na(+) and T-type Ca(+2) currents. The plateau phase depends on L-type Ca(+2) channels since it is abolished by specific blockade. The direct channel blockade indicates that the action potential repolarization and diastolic potential depends on ERG K(+) channels. The presence in the embryonic heart of the Nav1.5, Cav1.2, Cav3.2 and ERG channels was also confirmed by immunofluorescence, while the absence of effect of specific blockers and immunostaining indicate that two K(+) repolarizing currents present in human heart, Ito and IKs, are absent in the embryonic zebrafish heart. Our results describe the ionic channels present and its role in the zebrafish embryo heart and support the use of zebrafish embryos to study human diseases and their use for drug testing. Copyright © 2014 Elsevier Ltd. All rights reserved.

Decoupling Action Potential Bias from Cortical Local Field Potentials

Directory of Open Access Journals (Sweden)

Stephen V. David

2010-01-01

Full Text Available Neurophysiologists have recently become interested in studying neuronal population activity through local field potential (LFP recordings during experiments that also record the activity of single neurons. This experimental approach differs from early LFP studies because it uses high impendence electrodes that can also isolate single neuron activity. A possible complication for such studies is that the synaptic potentials and action potentials of the small subset of isolated neurons may contribute disproportionately to the LFP signal, biasing activity in the larger nearby neuronal population to appear synchronous and cotuned with these neurons. To address this problem, we used linear filtering techniques to remove features correlated with spike events from LFP recordings. This filtering procedure can be applied for well-isolated single units or multiunit activity. We illustrate the effects of this correction in simulation and on spike data recorded from primary auditory cortex. We find that local spiking activity can explain a significant portion of LFP power at most recording sites and demonstrate that removing the spike-correlated component can affect measurements of auditory tuning of the LFP.

Warm Body Temperature Facilitates Energy Efficient Cortical Action Potentials

Science.gov (United States)

Yu, Yuguo; Hill, Adam P.; McCormick, David A.

2012-01-01

The energy efficiency of neural signal transmission is important not only as a limiting factor in brain architecture, but it also influences the interpretation of functional brain imaging signals. Action potential generation in mammalian, versus invertebrate, axons is remarkably energy efficient. Here we demonstrate that this increase in energy efficiency is due largely to a warmer body temperature. Increases in temperature result in an exponential increase in energy efficiency for single action potentials by increasing the rate of Na+ channel inactivation, resulting in a marked reduction in overlap of the inward Na+, and outward K+, currents and a shortening of action potential duration. This increase in single spike efficiency is, however, counterbalanced by a temperature-dependent decrease in the amplitude and duration of the spike afterhyperpolarization, resulting in a nonlinear increase in the spike firing rate, particularly at temperatures above approximately 35°C. Interestingly, the total energy cost, as measured by the multiplication of total Na+ entry per spike and average firing rate in response to a constant input, reaches a global minimum between 37–42°C. Our results indicate that increases in temperature result in an unexpected increase in energy efficiency, especially near normal body temperature, thus allowing the brain to utilize an energy efficient neural code. PMID:22511855

Warm body temperature facilitates energy efficient cortical action potentials.

Directory of Open Access Journals (Sweden)

Yuguo Yu

Full Text Available The energy efficiency of neural signal transmission is important not only as a limiting factor in brain architecture, but it also influences the interpretation of functional brain imaging signals. Action potential generation in mammalian, versus invertebrate, axons is remarkably energy efficient. Here we demonstrate that this increase in energy efficiency is due largely to a warmer body temperature. Increases in temperature result in an exponential increase in energy efficiency for single action potentials by increasing the rate of Na(+ channel inactivation, resulting in a marked reduction in overlap of the inward Na(+, and outward K(+, currents and a shortening of action potential duration. This increase in single spike efficiency is, however, counterbalanced by a temperature-dependent decrease in the amplitude and duration of the spike afterhyperpolarization, resulting in a nonlinear increase in the spike firing rate, particularly at temperatures above approximately 35°C. Interestingly, the total energy cost, as measured by the multiplication of total Na(+ entry per spike and average firing rate in response to a constant input, reaches a global minimum between 37-42°C. Our results indicate that increases in temperature result in an unexpected increase in energy efficiency, especially near normal body temperature, thus allowing the brain to utilize an energy efficient neural code.

Corrective Action Investigation Plan for Corrective Action Unit 543: Liquid Disposal Units, Nevada Test Site, Nevada: Revision 0

Energy Technology Data Exchange (ETDEWEB)

U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office

2004-05-03

The general purpose of this Corrective Action Investigation Plan is to ensure that adequate data are collected to provide sufficient and reliable information to identify, evaluate, and select technically viable corrective action alternatives (CAAs) for Corrective Action Unit (CAU) 543: Liquid Disposal Units, Nevada Test Site (NTS), Nevada. Located in Areas 6 and 15 on the NTS, CAU 543 is comprised of a total of seven corrective action sites (CASs), one in Area 6 and six in Area 15. The CAS in Area 6 consists of a Decontamination Facility and its components which are associated with decontamination of equipment, vehicles, and materials related to nuclear testing. The six CASs in Area 15 are located at the U.S. Environmental Protection Agency Farm and are related to waste disposal activities at the farm. Sources of possible contamination at Area 6 include potentially contaminated process waste effluent discharged through a process waste system, a sanitary waste stream generated within buildings of the Decon Facility, and radiologically contaminated materials stored within a portion of the facility yard. At Area 15, sources of potential contamination are associated with the dairy operations and the animal tests and experiments involving radionuclide uptake. Identified contaminants of potential concern include volatile organic compounds, semivolatile organic compounds, petroleum hydrocarbons, pesticides, herbicides, polychlorinated biphenyls, metals, and radionuclides. Three corrective action closure alternatives - No Further Action, Close in Place, or Clean Closure - will be recommended for CAU 543 based on an evaluation of all the data quality objective-related data. Field work will be conducted following approval of the plan. The results of the field investigation will support a defensible evaluation of CAAs that will be presented in the Corrective Action Decision Document.

Theoretical study of ionization and one-electron oxidation potentials of N-heterocyclic compounds.

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Sviatenko, Liudmyla K; Gorb, Leonid; Hill, Frances C; Leszczynski, Jerzy

2013-05-15

A number of density functionals was utilized to predict gas-phase adiabatic ionization potentials (IPs) for nitrogen-rich heterocyclic compounds. Various solvation models were applied to the calculation of difference in free energies of solvation of oxidized and reduced forms of heterocyclic compounds in acetonitrile (AN) for correct reproduction of their standard oxidation potentials. We developed generally applicable protocols that could successfully predict the gas-phase adiabatic ionization potentials of nitrogen-rich heterocyclic compounds and their standard oxidation potentials in AN. This approach is supported by a MPW1K/6-31+G(d) level of theory which uses SMD(UA0) approximation for estimation of solvation energy of neutral molecules and PCM(UA0) model for ionized ones. The mean absolute derivation (MAD) and root mean square error (RMSE) of the current theoretical models for IP are equal to 0.22 V and 0.26, respectively, and for oxidation potentials MAD = 0.13 V and RMSE = 0.17. Copyright © 2013 Wiley Periodicals, Inc.

Corrective Action Investigation Plan for Corrective Action Unit 428: Area 3 Septic Waste Systems 1 and 5, Tonopah Test Range, Nevada

International Nuclear Information System (INIS)

ITLV

1999-01-01

and Recovery Act characteristic volatile organic compounds, semivolatile organic compounds, and metals. A limited number of samples will be analyzed for gamma- emitting radionuclides and isotopic uranium from four of the septic tanks and if radiological field screening levels are exceeded. Additional samples will be analyzed for geotechnical and hydrological properties and a bioassessment may be performed. The technical approach for investigating this Corrective Action Unit consists of the following activities: Perform video surveys of the discharge and outfall lines. Collect samples of material in the septic tanks. Conduct exploratory trenching to locate and inspect subsurface components. Collect subsurface soil samples in areas of the collection system including the septic tanks and outfall end of distribution boxes. Collect subsurface soil samples underlying the leachfield distribution pipes via trenching. Collect surface and near- surface samples near potential locations of the Acid Sewer Outfall if Septic Waste System 5 Leachfield cannot be located. Field screen samples for volatile organic compounds, total petroleum hydrocarbons, and radiological activity. Drill boreholes and collect subsurface soil samples if required. Analyze samples for total volatile organic compounds, total semivolatile organic compounds, total Resource Conservation and Recovery Act metals, and total petroleum hydrocarbons (oil/ diesel range organics). Limited number of samples will be analyzed for gamma- emitting radionuclides and isotopic uranium from particular septic tanks and if radiological field screening levels are exceeded. Collect samples from native soils beneath the distribution system and analyze for geotechnical/ hydrologic parameters. Collect and analyze bioassessment samples at the discretion of the Site Supervisor if total petroleum hydrocarbons exceed field- screening levels

Potential of Lichen Compounds as Antidiabetic Agents with Antioxidative Properties: A Review

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Karunaratne, Veranja

2017-01-01

The advancement in the knowledge of potent antioxidants has uncovered the way for greater insight in the treatment of diabetic complications. Lichens are a rich resource of novel bioactive compounds and their antioxidant potential is well documented. Herein we review the antidiabetic potential of lichens which have received considerable attention, in the recent past. We have correlated the antidiabetic and the antioxidant potential of lichen compounds. The study shows a good accordance between antioxidant and antidiabetic activity of lichens and points out the need to look into gathering the scarce and scattered data on biological activities for effective utilization. The review establishes that the lichen extracts, especially of Parmotrema sp. and Ramalina sp. have shown promising potential in both antidiabetic and antioxidant assays. Ubiquitous compounds, namely, zeorin, methylorsellinate, methyl-β-orcinol carboxylate, methyl haematommate, lecanoric acid, salazinic acid, sekikaic acid, usnic acid, gyrophoric acid, and lobaric acid have shown promising potential in both antidiabetic as well as antioxidant assays highlighting their potential for effective treatment of diabetic mellitus and its associated complications. The available compilation of this data provides the future perspectives and highlight the need for further studies of this potent herbal source to harvest more beneficial therapeutic antidiabetic drugs. PMID:28491237

Direct detection of a single evoked action potential with MRS in Lumbricus terrestris.

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Poplawsky, Alexander J; Dingledine, Raymond; Hu, Xiaoping P

2012-01-01

Functional MRI (fMRI) measures neural activity indirectly by detecting the signal change associated with the hemodynamic response following brain activation. In order to alleviate the temporal and spatial specificity problems associated with fMRI, a number of attempts have been made to detect neural magnetic fields (NMFs) with MRI directly, but have thus far provided conflicting results. In this study, we used MR to detect axonal NMFs in the median giant fiber of the earthworm, Lumbricus terrestris, by examining the free induction decay (FID) with a sampling interval of 0.32 ms. The earthworm nerve cords were isolated from the vasculature and stimulated at the threshold of action potential generation. FIDs were acquired shortly after the stimulation, and simultaneous field potential recordings identified the presence or absence of single evoked action potentials. FIDs acquired when the stimulus did not evoke an action potential were summed as background. The phase of the background-subtracted FID exhibited a systematic change, with a peak phase difference of (-1.2 ± 0.3) × 10(-5) radians occurring at a time corresponding to the timing of the action potential. In addition, we calculated the possible changes in the FID magnitude and phase caused by a simulated action potential using a volume conductor model. The measured phase difference matched the theoretical prediction well in both amplitude and temporal characteristics. This study provides the first evidence for the direct detection of a magnetic field from an evoked action potential using MR. Copyright © 2011 John Wiley & Sons, Ltd.

Lichen-derived compounds show potential for central nervous system therapeutics.

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Reddy, R Gajendra; Veeraval, Lenin; Maitra, Swati; Chollet-Krugler, Marylène; Tomasi, Sophie; Dévéhat, Françoise Lohézic-Le; Boustie, Joël; Chakravarty, Sumana

2016-11-15

Natural products from lichens are widely investigated for their biological properties, yet their potential as central nervous system (CNS) therapeutic agents is less explored. The present study investigated the neuroactive properties of selected lichen compounds (atranorin, perlatolic acid, physodic acid and usnic acid), for their neurotrophic, neurogenic and acetylcholine esterase (AChE) activities. Neurotrophic activity (neurite outgrowth) was determined using murine neuroblastoma Neuro2A cells. A MTT assay was performed to assess the cytotoxicity of compounds at optimum neurotrophic activity. Neuro2A cells treated with neurotrophic lichen compounds were used for RT-PCR to evaluate the induction of genes that code for the neurotrophic markers BDNF and NGF. Immunoblotting was used to assess acetyl H3 and H4 levels, the epigenetic markers associated with neurotrophic and/or neurogenic activity. The neurogenic property of the compounds was determined using murine hippocampal primary cultures. AChE inhibition activity was performed using a modified Ellman's esterase method. Lichen compounds atranorin, perlatolic acid, physodic acid and (+)-usnic acid showed neurotrophic activity in a preliminary cell-based screening based on Neuro2A neurite outgrowth. Except for usnic acid, no cytotoxic effects were observed for the two depsides (atranorin and perlatolic acid) and the alkyl depsidone (physodic acid). Perlatolic acid appears to be promising, as it also exhibited AChE inhibition activity and potent proneurogenic activity. The neurotrophic lichen compounds (atranorin, perlatolic acid, physodic acid) modulated the gene expression of BDNF and NGF. In addition, perlatolic acid showed increased protein levels of acetyl H3 and H4 in Neuro2A cells. These lichen depsides and depsidones showed neuroactive properties in vitro (Neuro2A cells) and ex vivo (primary neural stem or progenitor cells), suggesting their potential to treat CNS disorders. Copyright © 2016 Elsevier Gmb

A fast Na+/Ca2+-based action potential in a marine diatom.

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Alison R Taylor

Full Text Available BACKGROUND: Electrical impulses in animals play essential roles in co-ordinating an array of physiological functions including movement, secretion, environmental sensing and development. Underpinning many of these electrical signals is a fast Na+-based action potential that has been fully characterised only in cells associated with the neuromuscular systems of multicellular animals. Such rapid action potentials are thought to have evolved with the first metazoans, with cnidarians being the earliest representatives. The present study demonstrates that a unicellular protist, the marine diatom Odontella sinensis, can also generate a fast Na+/Ca2+ based action potential that has remarkably similar biophysical and pharmacological properties to invertebrates and vertebrate cardiac and skeletal muscle cells. METHODOLOGY/PRINCIPAL FINDINGS: The kinetic, ionic and pharmacological properties of the rapid diatom action potential were examined using single electrode current and voltage clamp techniques. Overall, the characteristics of the fast diatom currents most closely resemble those of vertebrate and invertebrate muscle Na+/Ca2+ currents. CONCLUSIONS/SIGNIFICANCE: This is the first demonstration of voltage-activated Na+ channels and the capacity to generate fast Na+-based action potentials in a unicellular photosynthetic organism. The biophysical and pharmacological characteristics together with the presence of a voltage activated Na+/Ca2+ channel homologue in the recently sequenced genome of the diatom Thalassiosira pseudonana, provides direct evidence supporting the hypothesis that this rapid signalling mechanism arose in ancestral unicellular eukaryotes and has been retained in at least two phylogenetically distant lineages of eukaryotes; opisthokonts and the stramenopiles. The functional role of the fast animal-like action potential in diatoms remains to be elucidated but is likely involved in rapid environmental sensing of these widespread and

Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves.

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Klein, Amanda H; Vyshnevska, Alina; Hartke, Timothy V; De Col, Roberto; Mankowski, Joseph L; Turnquist, Brian; Bosmans, Frank; Reeh, Peter W; Schmelz, Martin; Carr, Richard W; Ringkamp, Matthias

2017-05-17

Voltage-gated sodium (Na V ) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine Na V channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (Na V 1.1-Na V 1.4, Na V 1.6-Na V 1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (Na V 1.8 and Na V 1.9) inhibited by millimolar concentrations, with Na V 1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different Na V channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys ( Macaca nemestrina ). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and Na V 1.9 -/- mice. In nerves from Na V 1.8 -/- mice, TTX-r C-CAPs could not be detected. These data indicate that Na V 1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of Na V 1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of Na V 1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin. SIGNIFICANCE STATEMENT It is unclear whether individual sodium channel isoforms exert differential roles in action potential conduction along the axonal membrane of nociceptive, unmyelinated peripheral nerve

Channel sialic acids limit hERG channel activity during the ventricular action potential.

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Norring, Sarah A; Ednie, Andrew R; Schwetz, Tara A; Du, Dongping; Yang, Hui; Bennett, Eric S

2013-02-01

Activity of human ether-a-go-go-related gene (hERG) 1 voltage-gated K(+) channels is responsible for portions of phase 2 and phase 3 repolarization of the human ventricular action potential. Here, we questioned whether and how physiologically and pathophysiologically relevant changes in surface N-glycosylation modified hERG channel function. Voltage-dependent hERG channel gating and activity were evaluated as expressed in a set of Chinese hamster ovary (CHO) cell lines under conditions of full glycosylation, no sialylation, no complex N-glycans, and following enzymatic deglycosylation of surface N-glycans. For each condition of reduced glycosylation, hERG channel steady-state activation and inactivation relationships were shifted linearly by significant depolarizing ∼9 and ∼18 mV, respectively. The hERG window current increased significantly by 50-150%, and the peak shifted by a depolarizing ∼10 mV. There was no significant change in maximum hERG current density. Deglycosylated channels were significantly more active (20-80%) than glycosylated controls during phases 2 and 3 of action potential clamp protocols. Simulations of hERG current and ventricular action potentials corroborated experimental data and predicted reduced sialylation leads to a 50-70-ms decrease in action potential duration. The data describe a novel mechanism by which hERG channel gating is modulated through physiologically and pathophysiologically relevant changes in N-glycosylation; reduced channel sialylation increases hERG channel activity during the action potential, thereby increasing the rate of action potential repolarization.

Evaluating the mutagenic potential of aerosol organic compounds using informatics-based screening

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Decesari, Stefano; Kovarich, Simona; Pavan, Manuela; Bassan, Arianna; Ciacci, Andrea; Topping, David

2018-02-01

Whilst general policy objectives to reduce airborne particulate matter (PM) health effects are to reduce exposure to PM as a whole, emerging evidence suggests that more detailed metrics associating impacts with different aerosol components might be needed. Since it is impossible to conduct toxicological screening on all possible molecular species expected to occur in aerosol, in this study we perform a proof-of-concept evaluation on the information retrieved from in silico toxicological predictions, in which a subset (N = 104) of secondary organic aerosol (SOA) compounds were screened for their mutagenicity potential. An extensive database search showed that experimental data are available for 13 % of the compounds, while reliable predictions were obtained for 82 %. A multivariate statistical analysis of the compounds based on their physico-chemical, structural, and mechanistic properties showed that 80 % of the compounds predicted as mutagenic were grouped into six clusters, three of which (five-membered lactones from monoterpene oxidation, oxygenated multifunctional compounds from substituted benzene oxidation, and hydroperoxides from several precursors) represent new candidate groups of compounds for future toxicological screenings. These results demonstrate that coupling model-generated compositions to in silico toxicological screening might enable more comprehensive exploration of the mutagenic potential of specific SOA components.

A Parametric Computational Model of the Action Potential of Pacemaker Cells.

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Ai, Weiwei; Patel, Nitish D; Roop, Partha S; Malik, Avinash; Andalam, Sidharta; Yip, Eugene; Allen, Nathan; Trew, Mark L

2018-01-01

A flexible, efficient, and verifiable pacemaker cell model is essential to the design of real-time virtual hearts that can be used for closed-loop validation of cardiac devices. A new parametric model of pacemaker action potential is developed to address this need. The action potential phases are modeled using hybrid automaton with one piecewise-linear continuous variable. The model can capture rate-dependent dynamics, such as action potential duration restitution, conduction velocity restitution, and overdrive suppression by incorporating nonlinear update functions. Simulated dynamics of the model compared well with previous models and clinical data. The results show that the parametric model can reproduce the electrophysiological dynamics of a variety of pacemaker cells, such as sinoatrial node, atrioventricular node, and the His-Purkinje system, under varying cardiac conditions. This is an important contribution toward closed-loop validation of cardiac devices using real-time heart models.

Tetracycline compounds with non-antimicrobial organ protective properties: possible mechanisms of action

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Griffin, Michael O.; Ceballos, Guillermo; Villarreal, Francisco

2010-01-01

Tetracyclines were developed as a result of the screening of soil samples for antibiotics. The firstt of these compounds, chlortetracycline, was introduced in 1947. Tetracyclines were found to be highly effective against various pathogens including rickettsiae, as well as both gram-positive and gram-negative bacteria, thus becoming the first class of broad spectrum antibiotics. Many other interesting properties, unrelated to their antibiotic activity, have been identified for tetracyclines which have led to widely divergent experimental and clinical uses. For example, tetracyclines are also an effective anti-malarial drug. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Another tetracycline, doxycycline is known to exert anti-protease activities. Doxycycline can inhibit matrix metalloproteinases which contribute to tissue destruction activities in diseases such as periodontitis. A large body of literature has provided additional evidence for the “beneficial” actions of tetracyclines, including their ability to act as reactive oxygen species scavengers and anti-inflammatory agents. This review provides a summary of tetracycline’s multiple mechanisms of action as a means to understand their beneficial effects. PMID:20951211

Cell-type-dependent action potentials and voltage-gated currents in mouse fungiform taste buds.

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Kimura, Kenji; Ohtubo, Yoshitaka; Tateno, Katsumi; Takeuchi, Keita; Kumazawa, Takashi; Yoshii, Kiyonori

2014-01-01

Taste receptor cells fire action potentials in response to taste substances to trigger non-exocytotic neurotransmitter release in type II cells and exocytotic release in type III cells. We investigated possible differences between these action potentials fired by mouse taste receptor cells using in situ whole-cell recordings, and subsequently we identified their cell types immunologically with cell-type markers, an IP3 receptor (IP3 R3) for type II cells and a SNARE protein (SNAP-25) for type III cells. Cells not immunoreactive to these antibodies were examined as non-IRCs. Here, we show that type II cells and type III cells fire action potentials using different ionic mechanisms, and that non-IRCs also fire action potentials with either of the ionic mechanisms. The width of action potentials was significantly narrower and their afterhyperpolarization was deeper in type III cells than in type II cells. Na(+) current density was similar in type II cells and type III cells, but it was significantly smaller in non-IRCs than in the others. Although outwardly rectifying current density was similar between type II cells and type III cells, tetraethylammonium (TEA) preferentially suppressed the density in type III cells and the majority of non-IRCs. Our mathematical model revealed that the shape of action potentials depended on the ratio of TEA-sensitive current density and TEA-insensitive current one. The action potentials of type II cells and type III cells under physiological conditions are discussed. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Imaging Action Potential in Single Mammalian Neurons by Tracking the Accompanying Sub-Nanometer Mechanical Motion.

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Yang, Yunze; Liu, Xian-Wei; Wang, Hui; Yu, Hui; Guan, Yan; Wang, Shaopeng; Tao, Nongjian

2018-03-28

Action potentials in neurons have been studied traditionally by intracellular electrophysiological recordings and more recently by the fluorescence detection methods. Here we describe a label-free optical imaging method that can measure mechanical motion in single cells with a sub-nanometer detection limit. Using the method, we have observed sub-nanometer mechanical motion accompanying the action potential in single mammalian neurons by averaging the repeated action potential spikes. The shape and width of the transient displacement are similar to those of the electrically recorded action potential, but the amplitude varies from neuron to neuron, and from one region of a neuron to another, ranging from 0.2-0.4 nm. The work indicates that action potentials may be studied noninvasively in single mammalian neurons by label-free imaging of the accompanying sub-nanometer mechanical motion.

Noise Enhances Action Potential Generation in Mouse Sensory Neurons via Stochastic Resonance.

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Onorato, Irene; D'Alessandro, Giuseppina; Di Castro, Maria Amalia; Renzi, Massimiliano; Dobrowolny, Gabriella; Musarò, Antonio; Salvetti, Marco; Limatola, Cristina; Crisanti, Andrea; Grassi, Francesca

2016-01-01

Noise can enhance perception of tactile and proprioceptive stimuli by stochastic resonance processes. However, the mechanisms underlying this general phenomenon remain to be characterized. Here we studied how externally applied noise influences action potential firing in mouse primary sensory neurons of dorsal root ganglia, modelling a basic process in sensory perception. Since noisy mechanical stimuli may cause stochastic fluctuations in receptor potential, we examined the effects of sub-threshold depolarizing current steps with superimposed random fluctuations. We performed whole cell patch clamp recordings in cultured neurons of mouse dorsal root ganglia. Noise was added either before and during the step, or during the depolarizing step only, to focus onto the specific effects of external noise on action potential generation. In both cases, step + noise stimuli triggered significantly more action potentials than steps alone. The normalized power norm had a clear peak at intermediate noise levels, demonstrating that the phenomenon is driven by stochastic resonance. Spikes evoked in step + noise trials occur earlier and show faster rise time as compared to the occasional ones elicited by steps alone. These data suggest that external noise enhances, via stochastic resonance, the recruitment of transient voltage-gated Na channels, responsible for action potential firing in response to rapid step-wise depolarizing currents.

Pathology and prognosis of proximal-type cervical spondylotic amyotrophy: new assessment using compound muscle action potentials of deltoid and biceps brachii muscles.

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Imajo, Yasuaki; Kato, Yoshihiko; Kanchiku, Tsukasa; Suzuki, Hidenori; Taguchi, Toshihiko

2011-04-01

Case studies of patients with cervical spondylotic amyotrophy (CSA) used compound muscle action potentials (CMAPs) of deltoid and biceps brachii muscles. To discuss pathology and prognosis from the magnetic resonance imaging (MRI) and CMAPs of deltoid and biceps brachii muscles. CSA is a rare type of cervical spondylotic disorder. Selective lesions in ventral nerve roots (VNR) or anterior horns (AH) have been proposed to explain the pathology of CSA, but these are not well understood. Conservative therapy was performed in 21 patients with the proximal-type CSA. Patients were classified into two groups: 13 with incomplete recovery of deltoid and biceps brachii muscle strength (Group 1) and 8 with complete recovery (Group 2). All underwent MRI. Erb-point-stimulated CMAPs were recorded in the deltoid and biceps. Measurements of CMAPs included negative-peak amplitude from the baseline to peak. The percentage amplitude of CMAPs was calculated in contrast to the opposite side. Sagittal T2-weighted MRI showed spinal cord compression in all patients from Group 1 and in four patients from Group 2. Deltoid muscle CMAPs: Three patients from Group 1 and all eight patients from Group 2 had a CMAPs' amplitude on the normal side that was greater than 10 mV. Biceps brachii muscle CMAPs: four patients from Group 1 and four patients from Group 2 had a CMAPs' amplitude on the normal side that was greater than 10 mV. Patients with a CMAPs amplitude on the normal side that exceeded 10 mV had no impingement of the AH. A CMAPs' amplitude that exceeded 10 mV on the normal side and a CMAPs' amplitude of more than 50% on the affected side compared with the normal side indicated slight involvement of VNR. These patients were able to fully recover function.

Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties.

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Casale, Amanda E; Foust, Amanda J; Bal, Thierry; McCormick, David A

2015-11-25

The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two of the largest cortical interneuron subtypes in the mouse: fast-spiking interneurons, which are typically basket or chandelier neurons; and somatostatin containing interneurons, which are typically regular spiking Martinotti cells. We found that fast-spiking and somatostatin-expressing interneurons differed in their electrophysiological characteristics along their entire dendrosomatoaxonal extent. The action potentials generated in the somata and axons, including axon collaterals, of somatostatin-expressing interneurons are significantly broader than those generated in the same compartments of fast-spiking inhibitory interneurons. In addition, action potentials back-propagated into the dendrites of somatostatin-expressing interneurons much more readily than fast-spiking interneurons. Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin-expressing interneurons also depend on BK Ca(2+)-activated K(+) channels. These results indicate that the two broad classes of interneurons studied here have expressly different subcellular physiological properties, allowing them to perform unique computational roles in cortical circuit operations. Neurons in the cerebral cortex are of two major types: excitatory and inhibitory. The proper balance of excitation and inhibition in the brain is critical for its operation. Neurons contain three main

Potential Compounds for Oral Cancer Treatment: Resveratrol, Nimbolide, Lovastatin, Bortezomib, Vorinostat, Berberine, Pterostilbene, Deguelin, Andrographolide, and Colchicine.

Directory of Open Access Journals (Sweden)

Saurabh Bundela

Full Text Available Oral cancer is one of the main causes of cancer-related deaths in South-Asian countries. There are very limited treatment options available for oral cancer. Research endeavors focused on discovery and development of novel therapies for oral cancer, is necessary to control the ever rising oral cancer related mortalities. We mined the large pool of compounds from the publicly available compound databases, to identify potential therapeutic compounds for oral cancer. Over 84 million compounds were screened for the possible anti-cancer activity by custom build SVM classifier. The molecular targets of the predicted anti-cancer compounds were mined from reliable sources like experimental bioassays studies associated with the compound, and from protein-compound interaction databases. Therapeutic compounds from DrugBank, and a list of natural anti-cancer compounds derived from literature mining of published studies, were used for building partial least squares regression model. The regression model thus built, was used for the estimation of oral cancer specific weights based on the molecular targets. These weights were used to compute scores for screening the predicted anti-cancer compounds for their potential to treat oral cancer. The list of potential compounds was annotated with corresponding physicochemical properties, cancer specific bioactivity evidences, and literature evidences. In all, 288 compounds with the potential to treat oral cancer were identified in the current study. The majority of the compounds in this list are natural products, which are well-tolerated and have minimal side-effects compared to the synthetic counterparts. Some of the potential therapeutic compounds identified in the current study are resveratrol, nimbolide, lovastatin, bortezomib, vorinostat, berberine, pterostilbene, deguelin, andrographolide, and colchicine.

Potential Compounds for Oral Cancer Treatment: Resveratrol, Nimbolide, Lovastatin, Bortezomib, Vorinostat, Berberine, Pterostilbene, Deguelin, Andrographolide, and Colchicine

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Bundela, Saurabh; Sharma, Anjana; Bisen, Prakash S.

2015-01-01

Oral cancer is one of the main causes of cancer-related deaths in South-Asian countries. There are very limited treatment options available for oral cancer. Research endeavors focused on discovery and development of novel therapies for oral cancer, is necessary to control the ever rising oral cancer related mortalities. We mined the large pool of compounds from the publicly available compound databases, to identify potential therapeutic compounds for oral cancer. Over 84 million compounds were screened for the possible anti-cancer activity by custom build SVM classifier. The molecular targets of the predicted anti-cancer compounds were mined from reliable sources like experimental bioassays studies associated with the compound, and from protein-compound interaction databases. Therapeutic compounds from DrugBank, and a list of natural anti-cancer compounds derived from literature mining of published studies, were used for building partial least squares regression model. The regression model thus built, was used for the estimation of oral cancer specific weights based on the molecular targets. These weights were used to compute scores for screening the predicted anti-cancer compounds for their potential to treat oral cancer. The list of potential compounds was annotated with corresponding physicochemical properties, cancer specific bioactivity evidences, and literature evidences. In all, 288 compounds with the potential to treat oral cancer were identified in the current study. The majority of the compounds in this list are natural products, which are well-tolerated and have minimal side-effects compared to the synthetic counterparts. Some of the potential therapeutic compounds identified in the current study are resveratrol, nimbolide, lovastatin, bortezomib, vorinostat, berberine, pterostilbene, deguelin, andrographolide, and colchicine. PMID:26536350

A Simple Assay to Screen Antimicrobial Compounds Potentiating the Activity of Current Antibiotics

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Junaid Iqbal

2013-01-01

Full Text Available Antibiotic resistance continues to pose a significant problem in the management of bacterial infections, despite advances in antimicrobial chemotherapy and supportive care. Here, we suggest a simple, inexpensive, and easy-to-perform assay to screen antimicrobial compounds from natural products or synthetic chemical libraries for their potential to work in tandem with the available antibiotics against multiple drug-resistant bacteria. The aqueous extract of Juglans regia tree bark was tested against representative multiple drug-resistant bacteria in the aforementioned assay to determine whether it potentiates the activity of selected antibiotics. The aqueous extract of J. regia bark was added to Mueller-Hinton agar, followed by a lawn of multiple drug-resistant bacteria, Salmonella typhi or enteropathogenic E. coli. Next, filter paper discs impregnated with different classes of antibiotics were placed on the agar surface. Bacteria incubated with extract or antibiotics alone were used as controls. The results showed a significant increase (>30% in the zone of inhibition around the aztreonam, cefuroxime, and ampicillin discs compared with bacteria incubated with the antibiotics/extract alone. In conclusion, our assay is able to detect either synergistic or additive action of J. regia extract against multiple drug-resistant bacteria when tested with a range of antibiotics.

Synthesis, SAR and pharmacological characterization of novel anthraquinone cation compounds as potential anticancer agents.

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Zheng, Yanyan; Zhu, Li; Fan, Lulu; Zhao, Wenna; Wang, Jianlong; Hao, Xianxiao; Zhu, Yunhui; Hu, Xiufang; Yuan, Yaofeng; Shao, Jingwei; Wang, Wenfeng

2017-01-05

Emodin, a natural anthraquinone derivative isolated from Rheum palmatum L., has been demonstrated to exhibit good anti-cancer effect. In this study, a series of novel quaternary ammonium salts of emodin, anthraquinone and anthrone were synthesized and their anticancer activities were tested in vitro. The effects of emodin quaternary ammonium salts on cell viability, apoptosis, intracellular ROS, and mitochondrial membrane potential were investigated in A375, BGC-823, HepG2 and HELF cells. The results demonstrated that compound 4a induced morphological changes and decreased cell viability. Apoptosis triggered by compound 4a was visualized using DAPI staining and Annexin V-FITC/PI staining. Compound 4a-induced apoptosis of A375 cells were showed to be associated with the dissipation of mitochondrial membrane potential (ΔΨm) as a result of the up-regulation of P53 and Caspase-3. When cancer cells were treated with emodin derivative, their ability to generate reactive oxygen species (ROS) rose significantly and the mitochondrial membrane potential decreased. Additionally, confocal microscopy assay confirmed that compound 4a was primarily located in the mitochondria of A375 cells. These results suggested that compound 4a has the potential for use in cancer therapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Action potential bursts in central snail neurons elicited by paeonol: roles of ionic currents

Science.gov (United States)

Chen, Yi-hung; Lin, Pei-lin; Hsu, Hui-yu; Wu, Ya-ting; Yang, Han-yin; Lu, Dah-yuu; Huang, Shiang-suo; Hsieh, Ching-liang; Lin, Jaung-geng

2010-01-01

Aim: To investigate the effects of 2′-hydroxy-4′-methoxyacetophenone (paeonol) on the electrophysiological behavior of a central neuron (right parietal 4; RP4) of the giant African snail (Achatina fulica Ferussac). Methods: Intracellular recordings and the two-electrode voltage clamp method were used to study the effects of paeonol on the RP4 neuron. Results: The RP4 neuron generated spontaneous action potentials. Bath application of paeonol at a concentration of ≥500 μmol/L reversibly elicited action potential bursts in a concentration-dependent manner. Immersing the neurons in Co2+-substituted Ca2+-free solution did not block paeonol-elicited bursting. Pretreatment with the protein kinase A (PKA) inhibitor KT-5720 or the protein kinase C (PKC) inhibitor Ro 31-8220 did not affect the action potential bursts. Voltage-clamp studies revealed that paeonol at a concentration of 500 μmol/L had no remarkable effects on the total inward currents, whereas paeonol decreased the delayed rectifying K+ current (IKD) and the fast-inactivating K+ current (IA). Application of 4-aminopyridine (4-AP 5 mmol/L), an inhibitor of IA, or charybdotoxin 250 nmol/L, an inhibitor of the Ca2+-activated K+ current (IK(Ca)), failed to elicit action potential bursts, whereas tetraethylammonium chloride (TEA 50 mmol/L), an IKD blocker, successfully elicited action potential bursts. At a lower concentration of 5 mmol/L, TEA facilitated the induction of action potential bursts elicited by paeonol. Conclusion: Paeonol elicited a bursting firing pattern of action potentials in the RP4 neuron and this activity relates closely to the inhibitory effects of paeonol on the IKD. PMID:21042287

Selective activation of heteromeric SK channels contributes to action potential repolarization in mouse atrial myocytes.

Science.gov (United States)

Hancock, Jane M; Weatherall, Kate L; Choisy, Stéphanie C; James, Andrew F; Hancox, Jules C; Marrion, Neil V

2015-05-01

Activation of small conductance calcium-activated potassium (SK) channels is proposed to contribute to repolarization of the action potential in atrial myocytes. This role is controversial, as these cardiac SK channels appear to exhibit an uncharacteristic pharmacology. The objectives of this study were to resolve whether activation of SK channels contributes to atrial action potential repolarization and to determine the likely subunit composition of the channel. The effect of 2 SK channel inhibitors was assessed on outward current evoked in voltage clamp and on action potential duration in perforated patch and whole-cell current clamp recording from acutely isolated mouse atrial myocytes. The presence of SK channel subunits was assessed using immunocytochemistry. A significant component of outward current was reduced by the SK channel blockers apamin and UCL1684. Block by apamin displayed a sensitivity indicating that this current was carried by homomeric SK2 channels. Action potential duration was significantly prolonged by UCL1684, but not by apamin. This effect was accompanied by an increase in beat-to-beat variability and action potential triangulation. This pharmacology was matched by that of expressed heteromeric SK2-SK3 channels in HEK293 cells. Immunocytochemistry showed that atrial myocytes express both SK2 and SK3 channels with an overlapping expression pattern. Only proposed heteromeric SK2-SK3 channels are physiologically activated to contribute to action potential repolarization, which is indicated by the difference in pharmacology of evoked outward current and prolongation of atrial action potential duration. The effect of blocking this channel on the action potential suggests that SK channel inhibition during cardiac function has the potential to be proarrhythmic. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Modelling in vivo action potential propagation along a giant axon.

Science.gov (United States)

George, Stuart; Foster, Jamie M; Richardson, Giles

2015-01-01

A partial differential equation model for the three-dimensional current flow in an excitable, unmyelinated axon is considered. Where the axon radius is significantly below a critical value R(crit) (that depends upon intra- and extra-cellular conductivity and ion channel conductance) the resistance of the intracellular space is significantly higher than that of the extracellular space, such that the potential outside the axon is uniformly small whilst the intracellular potential is approximated by the transmembrane potential. In turn, since the current flow is predominantly axial, it can be shown that the transmembrane potential is approximated by a solution to the one-dimensional cable equation. It is noted that the radius of the squid giant axon, investigated by (Hodgkin and Huxley 1952e), lies close to R(crit). This motivates us to apply the three-dimensional model to the squid giant axon and compare the results thus found to those obtained using the cable equation. In the context of the in vitro experiments conducted in (Hodgkin and Huxley 1952e) we find only a small difference between the wave profiles determined using these two different approaches and little difference between the speeds of action potential propagation predicted. This suggests that the cable equation approximation is accurate in this scenario. However when applied to the it in vivo setting, in which the conductivity of the surrounding tissue is considerably lower than that of the axoplasm, there are marked differences in both wave profile and speed of action potential propagation calculated using the two approaches. In particular, the cable equation significantly over predicts the increase in the velocity of propagation as axon radius increases. The consequences of these results are discussed in terms of the evolutionary costs associated with increasing the speed of action potential propagation by increasing axon radius.

7 CFR 1945.19 - Reporting potential natural disasters and initial actions.

Science.gov (United States)

2010-01-01

... 7 Agriculture 13 2010-01-01 2009-01-01 true Reporting potential natural disasters and initial... Assistance-General § 1945.19 Reporting potential natural disasters and initial actions. (a) Purpose. The purpose of reporting potential natural disasters is to provide a systematic procedure for rapid reporting...

Toxicological perspectives on perfluorinated compounds in avian species

Energy Technology Data Exchange (ETDEWEB)

Giesy, J.; Jones, P. [Michigan State Univ., East Lansing, MI (United States)

2004-09-15

Perfluorinated chemicals have been widely used in commerce for the last few decades. Until recently little was known about their environmental fate and even less was known about their potential environmental effects. Since Giesy and co-workers first demonstrated the widespread occurrence of perfluorooctane sulfonic acid (PFOS) in wildlife there has been renewed interest in determining the biological and possible ecological effects of these compounds. The assessment of possible effects of these chemicals has been hampered by a limited understanding of their mode of action and by a lack of toxicological data for wildlife species. Here we summarize recently obtained toxicological studies available for perfluorinated compounds (PFCs) in two avian species and use this information and environmental concentration data to evaluate the potential for environmental risk that these compounds pose.

A three-stage-integrative approach for the identification of potential hepatotoxic compounds from botanical products.

Science.gov (United States)

Jin, Yecheng; Zhao, Xiaoping; Zhang, Yufeng; Li, Xiang; Nie, Xiaojing; Wang, Yi; Fan, Xiaohui

2011-05-01

With the increasing use of herbal medicines and dietary supplements, intensive concerns about their potential toxicities have been raised. Screening and identifying the toxic compounds from these botanical products composed by hundreds of components have become a critical but challenging problem. In this study, 3 methods, including fraction separation, an in-house-developed fluorescein diacetate-based automatic microscopy screening (FAMS) platform, and liquid chromatography-mass spectrometry-based compounds identification were integrated within the Three-Stage-Integrative (TSI) approach for the identification of potential hepatotoxicants from botanical products. The sensitivity and linear range of FAMS assay was validated and compared with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay by previously reported hepatotoxic compounds. The success of TSI approach was further demonstrated by its application to Fructus aristolochiae. Aristolochic acid IVa and aristolodione were tentatively identified to be potential hepatotoxicants in this plant. These applications suggested that our TSI approach provides an effective tool for identifying potential toxic compounds from botanical products.

Understanding the Electrical Behavior of the Action Potential in Terms of Elementary Electrical Sources

Science.gov (United States)

Rodriguez-Falces, Javier

2015-01-01

A concept of major importance in human electrophysiology studies is the process by which activation of an excitable cell results in a rapid rise and fall of the electrical membrane potential, the so-called action potential. Hodgkin and Huxley proposed a model to explain the ionic mechanisms underlying the formation of action potentials. However,…

Action potential-independent and pharmacologically unique vesicular serotonin release from dendrites

Science.gov (United States)

Colgan, Lesley A.; Cavolo, Samantha L.; Commons, Kathryn G.; Levitan, Edwin S.

2012-01-01

Serotonin released within the dorsal raphe nucleus (DR) induces feedback inhibition of serotonin neuron activity and consequently regulates mood-controlling serotonin release throughout the forebrain. Serotonin packaged in vesicles is released in response to action potentials by the serotonin neuron soma and terminals, but the potential for release by dendrites is unknown. Here three-photon (3P) microscopy imaging of endogenous serotonin in living rat brain slice, immunofluorescence and immuno-gold electron microscopy detection of VMAT2 (vesicular monoamine transporter 2) establish the presence of vesicular serotonin within DR dendrites. Furthermore, activation of glutamate receptors is shown to induce vesicular serotonin release from dendrites. However, unlike release from the soma and terminals, dendritic serotonin release is independent of action potentials, relies on L-type Ca2+ channels, is induced preferentially by NMDA, and displays distinct sensitivity to the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. The unique control of dendritic serotonin release has important implications for DR physiology and the antidepressant action of SSRIs, dihydropyridines and NMDA receptor antagonists. PMID:23136413

Marine Pharmacology in 2012–2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

Directory of Open Access Journals (Sweden)

Alejandro M. S. Mayer

2017-08-01

Full Text Available The peer-reviewed marine pharmacology literature from 2012 to 2013 was systematically reviewed, consistent with the 1998–2011 reviews of this series. Marine pharmacology research from 2012 to 2013, conducted by scientists from 42 countries in addition to the United States, reported findings on the preclinical pharmacology of 257 marine compounds. The preclinical pharmacology of compounds isolated from marine organisms revealed antibacterial, antifungal, antiprotozoal, antituberculosis, antiviral and anthelmitic pharmacological activities for 113 marine natural products. In addition, 75 marine compounds were reported to have antidiabetic and anti-inflammatory activities and affect the immune and nervous system. Finally, 69 marine compounds were shown to display miscellaneous mechanisms of action which could contribute to novel pharmacological classes. Thus, in 2012–2013, the preclinical marine natural product pharmacology pipeline provided novel pharmacology and lead compounds to the clinical marine pharmaceutical pipeline, and contributed significantly to potentially novel therapeutic approaches to several global disease categories.

The monophasic action potential upstroke: a means of characterizing local conduction.

Science.gov (United States)

Levine, J H; Moore, E N; Kadish, A H; Guarnieri, T; Spear, J F

1986-11-01

The upstrokes of monophasic action potentials (MAPs) recorded with an extracellular pressure electrode were characterized in isolated canine tissue preparations in vitro. The characteristics of the MAP upstroke were compared with those of the local action potential foot as well as with the characteristics of approaching electrical activation during uniform and asynchronous conduction. The upstroke of the MAP was exponential during uniform conduction. The time constant of rise of the MAP upstroke (TMAP) correlated with that of the action potential foot (Tfoot): TMAP + 1.01 Tfoot + 0.50; r2 = .80. Furthermore, changes in Tfoot with alterations in cycle length were associated with similar changes in TMAP: Tfoot = 1.06 TMAP - 0.11; r2 = .78. In addition, TMAP and Tfoot both deviated from exponential during asynchronous activation; the inflections that developed in the MAP upstroke correlated in time with intracellular action potential upstrokes that were asynchronous in onset in these tissues. Finally, the field of view of the MAP was determined and was found to be dependent in part on tissue architecture and the space constant. Specifically, the field of view of the MAP was found to be greater parallel compared with transverse to fiber orientation (6.02 +/- 1.74 vs 3.03 +/- 1.10 mm; p less than .01). These data suggest that the MAP upstroke may be used to define and characterize local electrical activation. The relatively large field of view of the MAP suggests that this technique may be a sensitive means to record focal membrane phenomena in vivo.

Effects of tacrolimus on action potential configuration and transmembrane ion currents in canine ventricular cells.

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Szabó, László; Szentandrássy, Norbert; Kistamás, Kornél; Hegyi, Bence; Ruzsnavszky, Ferenc; Váczi, Krisztina; Horváth, Balázs; Magyar, János; Bányász, Tamás; Pál, Balázs; Nánási, Péter P

2013-03-01

Tacrolimus is a commonly used immunosuppressive agent which causes cardiovascular complications, e.g., hypertension and hypertrophic cardiomyopathy. In spite of it, there is little information on the cellular cardiac effects of the immunosuppressive agent tacrolimus in larger mammals. In the present study, therefore, the concentration-dependent effects of tacrolimus on action potential morphology and the underlying ion currents were studied in canine ventricular cardiomyocytes. Standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques were applied in myocytes enzymatically dispersed from canine ventricular myocardium. Tacrolimus (3-30 μM) caused a concentration-dependent reduction of maximum velocity of depolarization and repolarization, action potential amplitude, phase-1 repolarization, action potential duration, and plateau potential, while no significant change in the resting membrane potential was observed. Conventional voltage clamp experiments revealed that tacrolimus concentrations ≥3 μM blocked a variety of ion currents, including I(Ca), I(to), I(K1), I(Kr), and I(Ks). Similar results were obtained under action potential voltage clamp conditions. These effects of tacrolimus developed rapidly and were fully reversible upon washout. The blockade of inward currents with the concomitant shortening of action potential duration in canine myocytes is the opposite of those observed previously with tacrolimus in small rodents. It is concluded that although tacrolimus blocks several ion channels at higher concentrations, there is no risk of direct interaction with cardiac ion channels when applying tacrolimus in therapeutic concentrations.

Consequences of Converting Graded to Action Potentials upon Neural Information Coding and Energy Efficiency

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Sengupta, Biswa; Laughlin, Simon Barry; Niven, Jeremy Edward

2014-01-01

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na+ and K+ channels, with generator potential and graded potential models lacking voltage-gated Na+ channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na+ channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a ‘footprint’ in the generator potential that obscures incoming signals. These three processes reduce information rates by ∼50% in generator potentials, to ∼3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation. PMID:24465197

Calcium-Induced calcium release during action potential firing in developing inner hair cells.

Science.gov (United States)

Iosub, Radu; Avitabile, Daniele; Grant, Lisa; Tsaneva-Atanasova, Krasimira; Kennedy, Helen J

2015-03-10

In the mature auditory system, inner hair cells (IHCs) convert sound-induced vibrations into electrical signals that are relayed to the central nervous system via auditory afferents. Before the cochlea can respond to normal sound levels, developing IHCs fire calcium-based action potentials that disappear close to the onset of hearing. Action potential firing triggers transmitter release from the immature IHC that in turn generates experience-independent firing in auditory neurons. These early signaling events are thought to be essential for the organization and development of the auditory system and hair cells. A critical component of the action potential is the rise in intracellular calcium that activates both small conductance potassium channels essential during membrane repolarization, and triggers transmitter release from the cell. Whether this calcium signal is generated by calcium influx or requires calcium-induced calcium release (CICR) is not yet known. IHCs can generate CICR, but to date its physiological role has remained unclear. Here, we used high and low concentrations of ryanodine to block or enhance CICR to determine whether calcium release from intracellular stores affected action potential waveform, interspike interval, or changes in membrane capacitance during development of mouse IHCs. Blocking CICR resulted in mixed action potential waveforms with both brief and prolonged oscillations in membrane potential and intracellular calcium. This mixed behavior is captured well by our mathematical model of IHC electrical activity. We perform two-parameter bifurcation analysis of the model that predicts the dependence of IHCs firing patterns on the level of activation of two parameters, the SK2 channels activation and CICR rate. Our data show that CICR forms an important component of the calcium signal that shapes action potentials and regulates firing patterns, but is not involved directly in triggering exocytosis. These data provide important insights

Selective effects of potassium elevations on glutamate signaling and action potential conduction in hippocampus.

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Meeks, Julian P; Mennerick, Steven

2004-01-07

High-frequency synaptic transmission is depressed by moderate rises in the extracellular potassium concentration ([K+]o). Previous reports have indicated that depression of action potential signaling may underlie the synaptic depression. Here, we investigated the specific contribution of K+-induced action potential changes to synaptic depression. We found that glutamatergic transmission in the hippocampal area CA1 was significantly depressed by 8-10 mM [K+]o, but that GABAergic transmission remained intact. Riluzole, a drug that slows recovery from inactivation of voltage-gated sodium channels (NaChs), interacts with subthreshold [K+]o to depress afferent volleys and EPSCs strongly. Thus, elevated [K+]o likely depresses synapses by slowing NaCh recovery from inactivation. It is unclear from previous studies whether [K+]o-induced action potential depression is caused by changes in initiation, reliability, or waveform. We investigated these possibilities explicitly. [K+]o-induced afferent volley depression was independent of stimulus strength, suggesting that changes in action potential initiation do not explain [K+]o-induced depression. Measurements of action potentials from single axons revealed that 8 mM [K+]o increased conduction failures in a subpopulation of fibers and depressed action potential amplitude in all fibers. Together, these changes quantitatively account for the afferent volley depression. We estimate that conduction failure explains more than half of the synaptic depression observed at 8 mM [K+]o, with the remaining depression likely explained by waveform changes. These mechanisms of selective sensitivity of glutamate release to [K+]o accumulation represent a unique neuromodulatory mechanism and a brake on runaway excitation.

ToxAlerts: a Web server of structural alerts for toxic chemicals and compounds with potential adverse reactions.

Science.gov (United States)

Sushko, Iurii; Salmina, Elena; Potemkin, Vladimir A; Poda, Gennadiy; Tetko, Igor V

2012-08-27

The article presents a Web-based platform for collecting and storing toxicological structural alerts from literature and for virtual screening of chemical libraries to flag potentially toxic chemicals and compounds that can cause adverse side effects. An alert is uniquely identified by a SMARTS template, a toxicological endpoint, and a publication where the alert was described. Additionally, the system allows storing complementary information such as name, comments, and mechanism of action, as well as other data. Most importantly, the platform can be easily used for fast virtual screening of large chemical datasets, focused libraries, or newly designed compounds against the toxicological alerts, providing a detailed profile of the chemicals grouped by structural alerts and endpoints. Such a facility can be used for decision making regarding whether a compound should be tested experimentally, validated with available QSAR models, or eliminated from consideration altogether. The alert-based screening can also be helpful for an easier interpretation of more complex QSAR models. The system is publicly accessible and tightly integrated with the Online Chemical Modeling Environment (OCHEM, http://ochem.eu). The system is open and expandable: any registered OCHEM user can introduce new alerts, browse, edit alerts introduced by other users, and virtually screen his/her data sets against all or selected alerts. The user sets being passed through the structural alerts can be used at OCHEM for other typical tasks: exporting in a wide variety of formats, development of QSAR models, additional filtering by other criteria, etc. The database already contains almost 600 structural alerts for such endpoints as mutagenicity, carcinogenicity, skin sensitization, compounds that undergo metabolic activation, and compounds that form reactive metabolites and, thus, can cause adverse reactions. The ToxAlerts platform is accessible on the Web at http://ochem.eu/alerts, and it is constantly

Anaesthetics stop diverse plant organ movements, affect endocytic vesicle recycling and ROS homeostasis, and block action potentials in Venus flytraps.

Science.gov (United States)

Yokawa, K; Kagenishi, T; Pavlovic, A; Gall, S; Weiland, M; Mancuso, S; Baluška, F

2017-12-11

Anaesthesia for medical purposes was introduced in the 19th century. However, the physiological mode of anaesthetic drug actions on the nervous system remains unclear. One of the remaining questions is how these different compounds, with no structural similarities and even chemically inert elements such as the noble gas xenon, act as anaesthetic agents inducing loss of consciousness. The main goal here was to determine if anaesthetics affect the same or similar processes in plants as in animals and humans. A single-lens reflex camera was used to follow organ movements in plants before, during and after recovery from exposure to diverse anaesthetics. Confocal microscopy was used to analyse endocytic vesicle trafficking. Electrical signals were recorded using a surface AgCl electrode. Mimosa leaves, pea tendrils, Venus flytraps and sundew traps all lost both their autonomous and touch-induced movements after exposure to anaesthetics. In Venus flytrap, this was shown to be due to the loss of action potentials under diethyl ether anaesthesia. The same concentration of diethyl ether immobilized pea tendrils. Anaesthetics also impeded seed germination and chlorophyll accumulation in cress seedlings. Endocytic vesicle recycling and reactive oxygen species (ROS) balance, as observed in intact Arabidopsis root apex cells, were also affected by all anaesthetics tested. Plants are sensitive to several anaesthetics that have no structural similarities. As in animals and humans, anaesthetics used at appropriate concentrations block action potentials and immobilize organs via effects on action potentials, endocytic vesicle recycling and ROS homeostasis. Plants emerge as ideal model objects to study general questions related to anaesthesia, as well as to serve as a suitable test system for human anaesthesia. © The Authors 2017. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Potential of Fruit Wastes as Natural Resources of Bioactive Compounds

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Wen-Hua Ling

2012-07-01

Full Text Available Fruit wastes are one of the main sources of municipal waste. In order to explore the potential of fruit wastes as natural resources of bioactive compounds, the antioxidant potency and total phenolic contents (TPC of lipophilic and hydrophilic components in wastes (peel and seed of 50 fruits were systematically evaluated. The results showed that different fruit residues had diverse antioxidant potency and the variation was very large. Furthermore, the main bioactive compounds were identified and quantified, and catechin, cyanidin 3-glucoside, epicatechin, galangin, gallic acid, homogentisic acid, kaempferol, and chlorogenic acid were widely found in these residues. Especially, the values of ferric-reducing antioxidant power (FRAP, trolox equivalent antioxidant capacity (TEAC and TPC in the residues were higher than in pulps. The results showed that fruit residues could be inexpensive and readily available resources of bioactive compounds for use in the food and pharmaceutical industries.

Protective Actions of 17β-Estradiol and Progesterone on Oxidative Neuronal Injury Induced by Organometallic Compounds

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Yasuhiro Ishihara

2015-01-01

Full Text Available Steroid hormones synthesized in and secreted from peripheral endocrine glands pass through the blood-brain barrier and play a role in the central nervous system. In addition, the brain possesses an inherent endocrine system and synthesizes steroid hormones known as neurosteroids. Increasing evidence shows that neuroactive steroids protect the central nervous system from various harmful stimuli. Reports show that the neuroprotective actions of steroid hormones attenuate oxidative stress. In this review, we summarize the antioxidative effects of neuroactive steroids, especially 17β-estradiol and progesterone, on neuronal injury in the central nervous system under various pathological conditions, and then describe our recent findings concerning the neuroprotective actions of 17β-estradiol and progesterone on oxidative neuronal injury induced by organometallic compounds, tributyltin, and methylmercury.

Oxidative stress protection by newly synthesized nitrogen compounds with pharmacological potential.

Science.gov (United States)

Silva, João P; Areias, Filipe M; Proença, Fernanda M; Coutinho, Olga P

2006-02-09

In this study we used new nitrogen compounds obtained by organic synthesis whose structure predicted an antioxidant potential and then an eventual development as molecules of pharmacological interest in diseases involving oxidative stress. The compounds, identified as FMA4, FMA5, FMA7 and FMA8 differ in the presence of hydroxyl groups located in the C-3 and/or C-4 position of a phenolic unit, which is possibly responsible for their free radicals' buffering capacity. Data from the DPPH discoloration method confirm the high antiradical efficiency of the compounds. The results obtained with cellular models (L929 and PC12) show that they are not toxic and really protect from membrane lipid peroxidation induced by the ascorbate-iron oxidant pair. The level of protection correlates with the drug's lipophilic profile and is sometimes superior to trolox and equivalent to that observed for alpha-tocopherol. The compounds FMA4 and FMA7 present also a high protection from cell death evaluated in the presence of a staurosporine apoptotic stimulus. That protection results in a significant reduction of caspase-3 activity induced by staurosporine which by its turn seems to result from a protection observed in the membrane receptor pathway (caspase-8) together with a protection observed in the mitochondrial pathway (caspase-9). Taken together the results obtained with the new compounds, with linear chains, open up perspectives for their use as therapeutical agents, namely as antioxidants and protectors of apoptotic pathways. On the other hand the slight pro-oxidant profile obtained with the cyclic structures suggests a different therapeutic potential that is under current investigation.

Dynamics of the inward rectifier K+ current during the action potential of guinea pig ventricular myocytes

OpenAIRE

Ibarra, J.; Morley, G.E.; Delmar, M.

1991-01-01

The potassium selective, inward rectifier current (IK1) is known to be responsible for maintaining the resting membrane potential of quiescent ventricular myocytes. However, the contribution of this current to the different phases of the cardiac action potential has not been adequately established. In the present study, we have used the action potential clamp (APC) technique to characterize the dynamic changes of a cesium-sensitive (i.e., Ik1) current which occur during the action potential. ...

Restitution slope is principally determined by steady-state action potential duration.

Science.gov (United States)

Shattock, Michael J; Park, Kyung Chan; Yang, Hsiang-Yu; Lee, Angela W C; Niederer, Steven; MacLeod, Kenneth T; Winter, James

2017-06-01

The steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF. Experiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM - to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope. Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on

[Effects of dauricine on action potentials and slow inward currents of guinea pig ventricular papillary muscles].

Science.gov (United States)

Li, S N; Zhang, K Y

1992-11-01

Effects of dauricine (Dau) on the action potentials (AP), the slow action potentials (SAP), and the slow inward currents (Isi) of guinea pig ventricular papillary muscles were observed by means of intracellular microelectrode and single sucrose gap voltage clamp technique. In the early stage, Dau shortened action potential duration 100 (APD100) and effective refractory period (ERP) (ERP/APD ERP, and APD20, significantly decreased action potential amplitude (APA), maximum velocity (Vmax), and overshot (OS) (ERP/APD > 1; P SAP induced by isoprenaline (P < 0.01), and remarkably inhibited Isi (P < 0.01). The results suggested that Dau exerted an inhibitory effect on Na+, Ca2+, and K+ channels.

Evaluation of the Slope of Amplitude Growth Function Changes of the Electrically Evoked Action Potential in Three Months after Receiving the Device in Children with Cochlear Implant

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Ali Reza Pourjavid

2012-04-01

Full Text Available Objective: In neural response telemetry, intracochlear electrodes stimulate the auditory nerve and record the neural responses. The electrical stimulation is sent to the auditory nerve by an electrode and the resulted response, called electrically evoked compound action potential, is recorded by an adjacent electrode. The most important clinical applications of this test are evaluation and monitoring the intra and postoperative responses of auditory nerve and help to primary setting of speech processor. The aim of this study was evaluating the potential's slope of amplitude growth function changes three monthes after receiving the devise in pediatric cochlear implant recipients. Materials & Methods: This longitudinal study evaluated the potentials' slope of amplitude growth function changes in four given electrodes in four sessions after receiving the devise by approximately one month's intervals in all of the children who implanted in Amir Alam and Hazrat-e-Rasoul hospitals in 2007, July to December. Friedman test was used to analyse the results. Results: Electrically evoked compound action potential's mean slope of each electrode was more in later sessions relative to first session, while there was significant difference between the 1st and the other electrodes’ responses in every session (P<0.05. Conclusion: The reliabiliy of the responses results in more assurance of clinician to fit the speech processor for along time. Better responses in apical electrodes may lead to develope an effective coding strategy.

Metabolic responses of Eisenia fetida after sub-lethal exposure to organic contaminants with different toxic modes of action

Energy Technology Data Exchange (ETDEWEB)

McKelvie, Jennifer R.; Wolfe, David M.; Celejewski, Magda A. [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail Toronto, ON M1C 1A4 (Canada); Alaee, Mehran [Environment Canada, 867 Lakeshore Rd., P.O. Box 5050, Burlington, ON L7R 4A6 (Canada); Simpson, Andre J. [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail Toronto, ON M1C 1A4 (Canada); Simpson, Myrna J., E-mail: myrna.simpson@utoronto.ca [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail Toronto, ON M1C 1A4 (Canada)

2011-12-15

Nuclear magnetic resonance (NMR) - based metabolomics has the potential to identify toxic responses of contaminants within a mixture in contaminated soil. This study evaluated the metabolic response of Eisenia fetida after exposure to an array of organic compounds to determine whether contaminant-specific responses could be identified. The compounds investigated in contact tests included: two pesticides (carbaryl and chlorpyrifos), three pharmaceuticals (carbamazephine, estrone and caffeine), two persistent organohalogens (Aroclor 1254 and PBDE 209) and two industrial compounds (nonylphenol and dimethyl phthalate). Control and contaminant-exposed metabolic profiles were distinguished using principal component analysis and potential contaminant-specific biomarkers of exposure were found for several contaminants. These results suggest that NMR-based metabolomics offers considerable promise for differentiating between the different toxic modes of action (MOA) associated with sub-lethal toxicity to earthworms. - Highlights: > NMR-based earthworm metabolomic analysis of the toxic mode of action of various environmental contaminants. > Organic chemicals with different toxic modes of action resulted in varied metabolomic responses for E. fetida. > NMR-based metabolomics differentiates between the different modes of action associated with sub-lethal toxicity. - {sup 1}H NMR metabolomics was used to identify potential biomarkers of organic contaminant exposure in Eisenia fetida earthworms.

Position-dependent patterning of spontaneous action potentials in immature cochlear inner hair cells.

Science.gov (United States)

Johnson, Stuart L; Eckrich, Tobias; Kuhn, Stephanie; Zampini, Valeria; Franz, Christoph; Ranatunga, Kishani M; Roberts, Terri P; Masetto, Sergio; Knipper, Marlies; Kros, Corné J; Marcotti, Walter

2011-06-01

Spontaneous action potential activity is crucial for mammalian sensory system development. In the auditory system, patterned firing activity has been observed in immature spiral ganglion and brain-stem neurons and is likely to depend on cochlear inner hair cell (IHC) action potentials. It remains uncertain whether spiking activity is intrinsic to developing IHCs and whether it shows patterning. We found that action potentials were intrinsically generated by immature IHCs of altricial rodents and that apical IHCs showed bursting activity as opposed to more sustained firing in basal cells. We show that the efferent neurotransmitter acetylcholine fine-tunes the IHC's resting membrane potential (V(m)), and as such is crucial for the bursting pattern in apical cells. Endogenous extracellular ATP also contributes to the V(m) of apical and basal IHCs by triggering small-conductance Ca(2+)-activated K(+) (SK2) channels. We propose that the difference in firing pattern along the cochlea instructs the tonotopic differentiation of IHCs and auditory pathway.

Position-dependent patterning of spontaneous action potentials in immature cochlear inner hair cells

Science.gov (United States)

Johnson, Stuart L.; Eckrich, Tobias; Kuhn, Stephanie; Zampini, Valeria; Franz, Christoph; Ranatunga, Kishani M.; Roberts, Terri P.; Masetto, Sergio; Knipper, Marlies; Kros, Corné J.; Marcotti, Walter

2011-01-01

Spontaneous action potential activity is crucial for mammalian sensory system development. In the auditory system, patterned firing activity has been observed in immature spiral ganglion cells and brain-stem neurons and is likely to depend on cochlear inner hair cell (IHC) action potentials. It remains uncertain whether spiking activity is intrinsic to developing IHCs and whether it shows patterning. We found that action potentials are intrinsically generated by immature IHCs of altricial rodents and that apical IHCs exhibit bursting activity as opposed to more sustained firing in basal cells. We show that the efferent neurotransmitter ACh, by fine-tuning the IHC’s resting membrane potential (Vm), is crucial for the bursting pattern in apical cells. Endogenous extracellular ATP also contributes to the Vm of apical and basal IHCs by activating SK2 channels. We hypothesize that the difference in firing pattern along the cochlea instructs the tonotopic differentiation of IHCs and auditory pathway. PMID:21572434

Resveratrol exhibits a strong cytotoxic activity in cultured cells and has an antiviral action against polyomavirus: potential clinical use

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Galati Gaspare

2009-07-01

Full Text Available Abstract Background Resveratrol is a non flavonoid polyphenol compound present in many plants and fruits and, at especially high concentrations, in the grape berries of Vitis vinifera. This compound has a strong bioactivity and its cytoprotective action has been demonstrated, however at high concentrations the drug exhibits also an effective anti-proliferative action. We recently showed its ability to abolish the effects of oxidative stress in cultured cells. In this work we assayed the bioactivity of resveratrol as antiproliferative and antiviral drug in cultured fibroblasts. Studies by other Authors showed that this natural compound inhibits the proliferation of different viruses such as herpes simplex, varicella-zoster and influenza A. The results presented here show an evident toxic activity of the drug at high concentrations, on the other hand at sub-cytotoxic concentrations, resveratrol can effectively inhibit the synthesis of polyomavirus DNA. A possible interpretation is that, due to the damage caused by resveratrol to the plasma membrane, the transfer of the virus from the endoplasmic reticulum to the nucleus, may be hindered thus inhibiting the production of viral DNA. Methods The mouse fibroblast line 3T6 and the human tumor line HL60 were used throughout the work. Cell viability and vital cell count were assessed respectively, by the MTT assay and Trypan Blue staining. Cytotoxic properties and evaluation of viral DNA production by agarose gel electrophoresis were performed according to standard protocols. Results Our results show a clear dose dependent both cytotoxic and antiviral effect of resveratrol respectively at high and low concentrations. The cytotoxic action is exerted towards a stabilized cell-line (3T6 as well as a tumor-line (HL60. Furthermore the antiviral action is evident after the phase of virion entry, therefore data suggest that the drug acts during the synthesis of the viral progeny DNA. Conclusion Resveratrol is

Effects of Acetylcholine and Noradrenalin on Action Potentials of Isolated Rabbit Sinoatrial and Atrial Myocytes

Science.gov (United States)

Verkerk, Arie O.; Geuzebroek, Guillaume S. C.; Veldkamp, Marieke W.; Wilders, Ronald

2012-01-01

The autonomic nervous system controls heart rate and contractility through sympathetic and parasympathetic inputs to the cardiac tissue, with acetylcholine (ACh) and noradrenalin (NA) as the chemical transmitters. In recent years, it has become clear that specific Regulators of G protein Signaling proteins (RGS proteins) suppress muscarinic sensitivity and parasympathetic tone, identifying RGS proteins as intriguing potential therapeutic targets. In the present study, we have identified the effects of 1 μM ACh and 1 μM NA on the intrinsic action potentials of sinoatrial (SA) nodal and atrial myocytes. Single cells were enzymatically isolated from the SA node or from the left atrium of rabbit hearts. Action potentials were recorded using the amphotericin-perforated patch-clamp technique in the absence and presence of ACh, NA, or a combination of both. In SA nodal myocytes, ACh increased cycle length and decreased diastolic depolarization rate, whereas NA decreased cycle length and increased diastolic depolarization rate. Both ACh and NA increased maximum upstroke velocity. Furthermore, ACh hyperpolarized the maximum diastolic potential. In atrial myocytes stimulated at 2 Hz, both ACh and NA hyperpolarized the maximum diastolic potential, increased the action potential amplitude, and increased the maximum upstroke velocity. Action potential duration at 50 and 90% repolarization was decreased by ACh, but increased by NA. The effects of both ACh and NA on action potential duration showed a dose dependence in the range of 1–1000 nM, while a clear-cut frequency dependence in the range of 1–4 Hz was absent. Intermediate results were obtained in the combined presence of ACh and NA in both SA nodal and atrial myocytes. Our data uncover the extent to which SA nodal and atrial action potentials are intrinsically dependent on ACh, NA, or a combination of both and may thus guide further experiments with RGS proteins. PMID:22754533

The action of sennosides and related compounds on human colon and rectum 1

Science.gov (United States)

Hardcastle, J. D.; Wilkins, J. L.

1970-01-01

The direct action of intraluminal senna and related compounds on the human colon and rectum has been investigated. Motility was recorded by balloon kymography with recording units inserted into well established transverse colostomies or into the rectum. The motility of the colon was not changed by intraluminal senna glycosides but the introduction of senna previously incubated with faeces or Esch. coli stimulated the colon to peristalt. The peristalsis was similar to that stimulated by rheinanthrone, an oxanthrone produced by chemical hydrolysis and reduction of senna. Both activated senna and rheinanthrone appeared to act in the colon by contact stimulation. No peristaltic response was stimulated in the rectum, either with activated senna or with rheinanthrone. PMID:4929273

Implementing participatory action research in Lithuania: potential and challenges

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Gabija Jarašiūnaitė

2015-12-01

Full Text Available Participatory action research is a quite new approach to research in Lithuania. The aim of an article was to disscuss the potential and challenges of participatory action research while implementing it in Lithuanian organizations. The qualitative approach was chosen for the study using the method of Focus groups. 20 researchers from social and biomedicine sciences from six institutions of High education in Lithuania participated in the study. The results of the study showed that participatory action reasearch is seen as an approach with many possibilities because of a wide range of used methods, constant interactions with research participants and the lenght of the research process. Researchers value the possibility to access organization at the begining, during research process and evaluate the effectiveness of the changes after the process. The research challenges are associated with the competence of a researcher including his/her sensitivity during process, ability to involve active participation of organization members in the ongoing process by creating safe and trusting environment. Some specific challenges associated with Lithuanian organizations are organizations‘ tiredness of researches and lack of faith of the benefits of researches because of some previous experiences. Keywords: Participatory Action Research, Organization, Lithuania.

RXP-E: a connexin43-binding peptide that prevents action potential propagation block

DEFF Research Database (Denmark)

Lewandowski, Rebecca; Procida, Kristina; Vaidyanathan, Ravi

2008-01-01

. Separately, RXP-E was concatenated to a cytoplasmic transduction peptide (CTP) for cytoplasmic translocation (CTP-RXP-E). The effect of RXP-E on action potential propagation was assessed by high-resolution optical mapping in monolayers of neonatal rat ventricular myocytes, containing approximately 20......% of randomly distributed myofibroblasts. In contrast to control experiments, when heptanol (2 mmol/L) was added to the superfusate of monolayers loaded with CTP-RXP-E, action potential propagation was maintained, albeit at a slower velocity. Similarly, intracellular acidification (pH(i) 6.2) caused a loss...... of action potential propagation in control monolayers; however, propagation was maintained in CTP-RXP-E-treated cells, although at a slower rate. Patch-clamp experiments revealed that RXP-E did not prevent heptanol-induced block of sodium currents, nor did it alter voltage dependence or amplitude of Kir2...

ACTION-SPACE CLUSTERING OF TIDAL STREAMS TO INFER THE GALACTIC POTENTIAL

Energy Technology Data Exchange (ETDEWEB)

Sanderson, Robyn E.; Helmi, Amina [Kapteyn Astronomical Institute, P.O. Box 800, 9700 AV Groningen (Netherlands); Hogg, David W., E-mail: robyn@astro.columbia.edu [Center for Cosmology and Particle Physics, Department of Physics, New York University, 4 Washington Place, New York, NY 10003 (United States)

2015-03-10

We present a new method for constraining the Milky Way halo gravitational potential by simultaneously fitting multiple tidal streams. This method requires three-dimensional positions and velocities for all stars to be fit, but does not require identification of any specific stream or determination of stream membership for any star. We exploit the principle that the action distribution of stream stars is most clustered when the potential used to calculate the actions is closest to the true potential. Clustering is quantified with the Kullback-Leibler Divergence (KLD), which also provides conditional uncertainties for our parameter estimates. We show, for toy Gaia-like data in a spherical isochrone potential, that maximizing the KLD of the action distribution relative to a smoother distribution recovers the input potential. The precision depends on the observational errors and number of streams; using K III giants as tracers, we measure the enclosed mass at the average radius of the sample stars accurate to 3% and precise to 20%-40%. Recovery of the scale radius is precise to 25%, biased 50% high by the small galactocentric distance range of stars in our mock sample (1-25 kpc, or about three scale radii, with mean 6.5 kpc). 20-25 streams with at least 100 stars each are required for a stable confidence interval. With radial velocities (RVs) to 100 kpc, all parameters are determined with ∼10% accuracy and 20% precision (1.3% accuracy for the enclosed mass), underlining the need to complete the RV catalog for faint halo stars observed by Gaia.

Neuronal oscillations enhance stimulus discrimination by ensuring action potential precision

DEFF Research Database (Denmark)

Schaefer, Andreas T; Angelo, Kamilla; Spors, Hartwig

2006-01-01

generated membrane potential oscillations dramatically improve action potential (AP) precision by removing the membrane potential variance associated with jitter-accumulating trains of APs. This increased AP precision occurred irrespective of cell type and--at oscillation frequencies ranging from 3 to 65 Hz......Although oscillations in membrane potential are a prominent feature of sensory, motor, and cognitive function, their precise role in signal processing remains elusive. Here we show, using a combination of in vivo, in vitro, and theoretical approaches, that both synaptically and intrinsically......, membrane potential oscillations dramatically enhance the discriminatory capabilities of individual neurons and networks of cells and provide one attractive explanation for their abundance in neurophysiological systems....

A herbicide structure-activity analysis of the antimalarial lead compound MMV007978 against Arabidopsis thaliana.

Science.gov (United States)

Corral, Maxime G; Leroux, Julie; Tresch, Stefan; Newton, Trevor; Stubbs, Keith A; Mylne, Joshua S

2018-07-01

To fight herbicide-resistant weeds, new herbicides are needed; particularly ones with new modes of action. Building on the revelation that many antimalarial drugs are herbicidal, here we focus on the Medicines for Malaria Venture antimalarial lead compound MMV007978 that has herbicidal activity against the model plant Arabidopsis thaliana. Twenty-two variations of the lead compound thiophenyl motif revealed that change was tolerated provided ring size and charge were retained. MMV007978 was active against select monocot and dicot weeds, and physiological profiling indicated that its mode of action is related to germination and cell division. Of interest is the fact that the compound has a profile that is currently not found among known herbicides. We demonstrate that the antimalarial compound MMV007978 is also herbicidal and that exploiting lead compounds that are often understudied could lead to the identification of interesting herbicidal scaffolds. Further structural investigation of MMV007978 could provide improved herbicidal chemistries with a potential new mode of action. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

Benefits of Nut Consumption on Insulin Resistance and Cardiovascular Risk Factors: Multiple Potential Mechanisms of Actions

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Yoona Kim

2017-11-01

Full Text Available Epidemiological and clinical studies have indicated that nut consumption could be a healthy dietary strategy to prevent and treat type 2 diabetes (T2DM and related cardiovascular disease (CVD. The objective of this review is to examine the potential mechanisms of action of nuts addressing effects on glycemic control, weight management, energy balance, appetite, gut microbiota modification, lipid metabolism, oxidative stress, inflammation, endothelial function and blood pressure with a focus on data from both animal and human studies. The favourable effects of nuts could be explained by the unique nutrient composition and bioactive compounds in nuts. Unsaturated fatty acids (monounsaturated fatty acids and polyunsaturated fatty acids present in nuts may play a role in glucose control and appetite suppression. Fiber and polyphenols in nuts may also have an anti-diabetic effect by altering gut microbiota. Nuts lower serum cholesterol by reduced cholesterol absorption, inhibition of HMG-CoA reductase and increased bile acid production by stimulation of 7-α hydroxylase. Arginine and magnesium improve inflammation, oxidative stress, endothelial function and blood pressure. In conclusion, nuts contain compounds that favourably influence glucose homeostasis, weight control and vascular health. Further investigations are required to identify the most important mechanisms by which nuts decrease the risk of T2DM and CVD.

The Crystal Structures of Potentially Tautomeric Compounds

Science.gov (United States)

Furmanova, Nina G.

1981-08-01

Data on the structures of potentially proto-, metallo-, and carbono-tropic compounds, obtained mainly by X-ray diffraction, are surveyed. The results of neutron and electron diffraction studies have also been partly used. It is shown that a characteristic feature of all the systems considered is the formation of hydrogen or secondary bonds ensuring the contribution of both possible tautomeric forms to the structure. Systematic consideration of the experimental data leads to the conclusion that there is a close relation between the crystal structure and the dynamic behaviour of the molecules in solution and that secondary and hydrogen bonds play a significant role in the tautomeric transition. The bibliography includes 152 references.

Action Potential Dynamics in Fine Axons Probed with an Axonally Targeted Optical Voltage Sensor.

Science.gov (United States)

Ma, Yihe; Bayguinov, Peter O; Jackson, Meyer B

2017-01-01

The complex and malleable conduction properties of axons determine how action potentials propagate through extensive axonal arbors to reach synaptic terminals. The excitability of axonal membranes plays a major role in neural circuit function, but because most axons are too thin for conventional electrical recording, their properties remain largely unexplored. To overcome this obstacle, we used a genetically encoded hybrid voltage sensor (hVOS) harboring an axonal targeting motif. Expressing this probe in transgenic mice enabled us to monitor voltage changes optically in two populations of axons in hippocampal slices, the large axons of dentate granule cells (mossy fibers) in the stratum lucidum of the CA3 region and the much finer axons of hilar mossy cells in the inner molecular layer of the dentate gyrus. Action potentials propagated with distinct velocities in each type of axon. Repetitive firing broadened action potentials in both populations, but at an intermediate frequency the degree of broadening differed. Repetitive firing also attenuated action potential amplitudes in both mossy cell and granule cell axons. These results indicate that the features of use-dependent action potential broadening, and possible failure, observed previously in large nerve terminals also appear in much finer unmyelinated axons. Subtle differences in the frequency dependences could influence the propagation of activity through different pathways to excite different populations of neurons. The axonally targeted hVOS probe used here opens up the diverse repertoire of neuronal processes to detailed biophysical study.

Corrective Action Investigation Plan for Corrective Action Unit 232: Area 25 Sewage Lagoons, Nevada Test Site, Nevada, Revision 0

International Nuclear Information System (INIS)

1999-01-01

The Corrective Action Investigation Plan for Corrective Action Unit 232, Area 25 Sewage Lagoons, has been developed in accordance with the Federal Facility Agreement and Consent Order that was agreed to by the U.S. Department of Energy, Nevada Operations Office; the State of Nevada Division of Environmental Protection; and the U. S. Department of Defense. Corrective Action Unit 232 consists of Corrective Action Site 25-03-01, Sewage Lagoon. Corrective Action Unit 232, Area 25 Sewage Lagoons, received sanitary effluent from four buildings within the Test Cell ''C'' Facility from the mid-1960s through approximately 1996. The Test Cell ''C'' Facility was used to develop nuclear propulsion technology by conducting nuclear test reactor studies. Based on the site history collected to support the Data Quality Objectives process, contaminants of potential concern include volatile organic compounds, semivolatile organic compounds, Resource Conservation and Recovery Act metals, petroleum hydrocarbons, polychlorinated biphenyls, pesticides, herbicides, gamma emitting radionuclides, isotopic plutonium, isotopic uranium, and strontium-90. A detailed conceptual site model is presented in Section 3.0 and Appendix A of this Corrective Action Investigation Plan. The conceptual model serves as the basis for the sampling strategy. Under the Federal Facility Agreement and Consent Order, the Corrective Action Investigation Plan will be submitted to the Nevada Division of Environmental Protection for approval. Field work will be conducted following approval of the plan. The results of the field investigation will support a defensible evaluation of corrective action alternatives in the Corrective Action Decision Document

Corrective Action Investigation Plan for Corrective Action Unit 232: Area 25 Sewage Lagoons, Nevada Test Site, Nevada, Revision 0

Energy Technology Data Exchange (ETDEWEB)

USDOE/NV

1999-05-01

The Corrective Action Investigation Plan for Corrective Action Unit 232, Area 25 Sewage Lagoons, has been developed in accordance with the Federal Facility Agreement and Consent Order that was agreed to by the U.S. Department of Energy, Nevada Operations Office; the State of Nevada Division of Environmental Protection; and the U. S. Department of Defense. Corrective Action Unit 232 consists of Corrective Action Site 25-03-01, Sewage Lagoon. Corrective Action Unit 232, Area 25 Sewage Lagoons, received sanitary effluent from four buildings within the Test Cell ''C'' Facility from the mid-1960s through approximately 1996. The Test Cell ''C'' Facility was used to develop nuclear propulsion technology by conducting nuclear test reactor studies. Based on the site history collected to support the Data Quality Objectives process, contaminants of potential concern include volatile organic compounds, semivolatile organic compounds, Resource Conservation and Recovery Act metals, petroleum hydrocarbons, polychlorinated biphenyls, pesticides, herbicides, gamma emitting radionuclides, isotopic plutonium, isotopic uranium, and strontium-90. A detailed conceptual site model is presented in Section 3.0 and Appendix A of this Corrective Action Investigation Plan. The conceptual model serves as the basis for the sampling strategy. Under the Federal Facility Agreement and Consent Order, the Corrective Action Investigation Plan will be submitted to the Nevada Division of Environmental Protection for approval. Field work will be conducted following approval of the plan. The results of the field investigation will support a defensible evaluation of corrective action alternatives in the Corrective Action Decision Document.

Arsenic Trioxide Modulates the Central Snail Neuron Action Potential

Directory of Open Access Journals (Sweden)

Guan-Ling Lu

2009-09-01

Conclusion: As2O3 at 10 mM elicits BoPs in central snail neurons and this effect may relate to the PLC activity of the neuron, rather than protein kinase A activity, or calcium influxes of the neuron. As2O3 at higher concentration irreversibly abolishes the spontaneous action potentials of the neuron.

Action potentials and ion conductances in wild-type and CALHM1-knockout type II taste cells

Science.gov (United States)

Saung, Wint Thu; Foskett, J. Kevin

2017-01-01

Taste bud type II cells fire action potentials in response to tastants, triggering nonvesicular ATP release to gustatory neurons via voltage-gated CALHM1-associated ion channels. Whereas CALHM1 regulates mouse cortical neuron excitability, its roles in regulating type II cell excitability are unknown. In this study, we compared membrane conductances and action potentials in single identified TRPM5-GFP-expressing circumvallate papillae type II cells acutely isolated from wild-type (WT) and Calhm1 knockout (KO) mice. The activation kinetics of large voltage-gated outward currents were accelerated in cells from Calhm1 KO mice, and their associated nonselective tail currents, previously shown to be highly correlated with ATP release, were completely absent in Calhm1 KO cells, suggesting that CALHM1 contributes to all of these currents. Calhm1 deletion did not significantly alter resting membrane potential or input resistance, the amplitudes and kinetics of Na+ currents either estimated from action potentials or recorded from steady-state voltage pulses, or action potential threshold, overshoot peak, afterhyperpolarization, and firing frequency. However, Calhm1 deletion reduced the half-widths of action potentials and accelerated the deactivation kinetics of transient outward currents, suggesting that the CALHM1-associated conductance becomes activated during the repolarization phase of action potentials. NEW & NOTEWORTHY CALHM1 is an essential ion channel component of the ATP neurotransmitter release mechanism in type II taste bud cells. Its contribution to type II cell resting membrane properties and excitability is unknown. Nonselective voltage-gated currents, previously associated with ATP release, were absent in cells lacking CALHM1. Calhm1 deletion was without effects on resting membrane properties or voltage-gated Na+ and K+ channels but contributed modestly to the kinetics of action potentials. PMID:28202574

Population of computational rabbit-specific ventricular action potential models for investigating sources of variability in cellular repolarisation.

Directory of Open Access Journals (Sweden)

Philip Gemmell

Full Text Available Variability is observed at all levels of cardiac electrophysiology. Yet, the underlying causes and importance of this variability are generally unknown, and difficult to investigate with current experimental techniques. The aim of the present study was to generate populations of computational ventricular action potential models that reproduce experimentally observed intercellular variability of repolarisation (represented by action potential duration and to identify its potential causes. A systematic exploration of the effects of simultaneously varying the magnitude of six transmembrane current conductances (transient outward, rapid and slow delayed rectifier K(+, inward rectifying K(+, L-type Ca(2+, and Na(+/K(+ pump currents in two rabbit-specific ventricular action potential models (Shannon et al. and Mahajan et al. at multiple cycle lengths (400, 600, 1,000 ms was performed. This was accomplished with distributed computing software specialised for multi-dimensional parameter sweeps and grid execution. An initial population of 15,625 parameter sets was generated for both models at each cycle length. Action potential durations of these populations were compared to experimentally derived ranges for rabbit ventricular myocytes. 1,352 parameter sets for the Shannon model and 779 parameter sets for the Mahajan model yielded action potential duration within the experimental range, demonstrating that a wide array of ionic conductance values can be used to simulate a physiological rabbit ventricular action potential. Furthermore, by using clutter-based dimension reordering, a technique that allows visualisation of multi-dimensional spaces in two dimensions, the interaction of current conductances and their relative importance to the ventricular action potential at different cycle lengths were revealed. Overall, this work represents an important step towards a better understanding of the role that variability in current conductances may play in

Population of computational rabbit-specific ventricular action potential models for investigating sources of variability in cellular repolarisation.

Science.gov (United States)

Gemmell, Philip; Burrage, Kevin; Rodriguez, Blanca; Quinn, T Alexander

2014-01-01

Variability is observed at all levels of cardiac electrophysiology. Yet, the underlying causes and importance of this variability are generally unknown, and difficult to investigate with current experimental techniques. The aim of the present study was to generate populations of computational ventricular action potential models that reproduce experimentally observed intercellular variability of repolarisation (represented by action potential duration) and to identify its potential causes. A systematic exploration of the effects of simultaneously varying the magnitude of six transmembrane current conductances (transient outward, rapid and slow delayed rectifier K(+), inward rectifying K(+), L-type Ca(2+), and Na(+)/K(+) pump currents) in two rabbit-specific ventricular action potential models (Shannon et al. and Mahajan et al.) at multiple cycle lengths (400, 600, 1,000 ms) was performed. This was accomplished with distributed computing software specialised for multi-dimensional parameter sweeps and grid execution. An initial population of 15,625 parameter sets was generated for both models at each cycle length. Action potential durations of these populations were compared to experimentally derived ranges for rabbit ventricular myocytes. 1,352 parameter sets for the Shannon model and 779 parameter sets for the Mahajan model yielded action potential duration within the experimental range, demonstrating that a wide array of ionic conductance values can be used to simulate a physiological rabbit ventricular action potential. Furthermore, by using clutter-based dimension reordering, a technique that allows visualisation of multi-dimensional spaces in two dimensions, the interaction of current conductances and their relative importance to the ventricular action potential at different cycle lengths were revealed. Overall, this work represents an important step towards a better understanding of the role that variability in current conductances may play in experimentally

Potential use of bitter melon (Momordica charantia) derived compounds as antidiabetics: In silico and in vivo studies.

Science.gov (United States)

Elekofehinti, Olusola Olalekan; Ariyo, Esther Opeyemi; Akinjiyan, Moses Orimoloye; Olayeriju, Olanrewaju Sam; Lawal, Akeem Olalekan; Adanlawo, Isaac Gbadura; Rocha, Joao Batista Teixeira

2018-05-12

Momordica charantia (bitter lemon) belongs to the cucurbitaceae family which has been extensively used in traditional medicines for the cure of various ailments such as cancer and diabetes. The underlying mechanism of M. charantia to maintain glycemic control was investigated. GLP-1 and DPP-4 gene modulation by M. charantia (5-20% inclusion in rats diet) was investigated in vivo by RT-PCR and possible compounds responsible for diabetic action predicted through in silico approach. Phytochemicalss previously characterized from M. charantia were docked into glucacon like peptide-1 receptor (GLP-1r), dipeptidyl peptidase (DPP4) and Takeda-G-protein-receptor-5 (TGR5) predicted using Autodock Vina. The results of the in silico suggests momordicosides D (ligand for TGR5), cucurbitacin (ligand for GLP-1r) and charantin (ligand for DPP-4) as the major antidiabetic compounds in bitter lemon leaf. M. charantia increased the expression of GLP-1 by about 295.7% with concomitant decreased in expression of DPP-4 by 87.2% with 20% inclusion in rat's diet. This study suggests that the mechanism underlying the action of these compounds is through activation of TGR5 and GLP-1 receptor with concurrent inhibition of DPP4. This study confirmed the use of this plant in diabetes management and the possible bioactive compounds responsible for its antidiabetic property are charantin, cucurbitacin and momordicoside D and all belong to the class of saponins. Copyright © 2018 Elsevier B.V. All rights reserved.

State and location dependence of action potential metabolic cost in cortical pyramidal neurons

NARCIS (Netherlands)

Hallermann, Stefan; de Kock, Christiaan P. J.; Stuart, Greg J.; Kole, Maarten H. P.

2012-01-01

Action potential generation and conduction requires large quantities of energy to restore Na+ and K+ ion gradients. We investigated the subcellular location and voltage dependence of this metabolic cost in rat neocortical pyramidal neurons. Using Na+/K+ charge overlap as a measure of action

State and location dependence of action potential metabolic cost in cortical pyramidal neurons

NARCIS (Netherlands)

Hallermann, S.; de Kock, C.P.J.; Stuart, G.J.; Kole, M.H.

2012-01-01

Action potential generation and conduction requires large quantities of energy to restore Na + and K + ion gradients. We investigated the subcellular location and voltage dependence of this metabolic cost in rat neocortical pyramidal neurons. Using Na +K + charge overlap as a measure of action

Corrective Action Decision Document/Closure Report for Corrective Action Unit 232: Area 25 Sewage Lagoons, Nevada Test Site, Nevada

International Nuclear Information System (INIS)

US Department of Energy Nevada Operations Office

1999-01-01

This Corrective Action Decision Document/Closure Report (CADD/CR) has been prepared for Corrective Action Unit (CAU) 232, Area 25 Sewage Lagoons, in accordance with the Federal Facility Agreement and Consent Order. Located at the Nevada Test Site in Nevada, approximately 65 miles northwest of Las Vegas, CAU 232 is comprised of Corrective Action Site 25-03-01, Sewage Lagoon. This CADD/CR identifies and rationalizes the U.S. Department of Energy, Nevada Operations Office's (DOE/NV's) recommendation that no corrective action is deemed necessary for CAU 232. The Corrective Action Decision Document and Closure Report have been combined into one report because sample data collected during the July 1999 corrective action investigation (CAI) activities disclosed no evidence of contamination at the site. Contaminants of potential concern (COPCs) addressed during the CAI included total volatile organic compounds, total semivolatile organic compounds, total Resource Conservation and Recovery Act metals, total pesticides, total herbicides, total petroleum hydrocarbons (gasoline and diesel/oil range), polychlorinated biphenyls, isotopic uranium, isotopic plutonium, strontium-90, and gamma-emitting radionuclides. The data confirmed that none of the COPCs identified exceeded preliminary action levels outlined in the CAIP; therefore, no corrective actions were necessary for CAU 232. After the CAI, best management practice activities were completed and included installation of a fence and signs to limit access to the lagoons, cementing Manhole No. 2 and the diverter box, and closing off influent and effluent ends of the sewage lagoon piping. As a result of the CAI, the DOE/NV recommended that: (1) no further actions were required; (2) no Corrective Action Plan would be required; and (3) no use restrictions were required to be placed on the CAU

Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes.

Science.gov (United States)

Kistamás, Kornél; Szentandrássy, Norbert; Hegyi, Bence; Ruzsnavszky, Ferenc; Váczi, Krisztina; Bárándi, László; Horváth, Balázs; Szebeni, Andrea; Magyar, János; Bányász, Tamás; Kecskeméti, Valéria; Nánási, Péter P

2013-06-15

Despite its widespread therapeutical use there is little information on the cellular cardiac effects of the antidiabetic drug pioglitazone in larger mammals. In the present study, therefore, the concentration-dependent effects of pioglitazone on ion currents and action potential configuration were studied in isolated canine ventricular myocytes using standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques. Pioglitazone decreased the maximum velocity of depolarization and the amplitude of phase-1 repolarization at concentrations ≥3 μM. Action potentials were shortened by pioglitazone at concentrations ≥10 μM, which effect was accompanied with significant reduction of beat-to-beat variability of action potential duration. Several transmembrane ion currents, including the transient outward K(+) current (Ito), the L-type Ca(2+) current (ICa), the rapid and slow components of the delayed rectifier K(+) current (IKr and IKs, respectively), and the inward rectifier K(+) current (IK1) were inhibited by pioglitazone under conventional voltage clamp conditions. Ito was blocked significantly at concentrations ≥3 μM, ICa, IKr, IKs at concentrations ≥10 μM, while IK1 at concentrations ≥30 μM. Suppression of Ito, ICa, IKr, and IK1 has been confirmed also under action potential voltage clamp conditions. ATP-sensitive K(+) current, when activated by lemakalim, was effectively blocked by pioglitazone. Accordingly, action potentials were prolonged by 10 μM pioglitazone when the drug was applied in the presence of lemakalim. All these effects developed rapidly and were readily reversible upon washout. In conclusion, pioglitazone seems to be a harmless agent at usual therapeutic concentrations. Copyright © 2013 Elsevier B.V. All rights reserved.

Natural Compounds as Regulators of the Cancer Cell Metabolism

Directory of Open Access Journals (Sweden)

Claudia Cerella

2013-01-01

Full Text Available Even though altered metabolism is an “old” physiological mechanism, only recently its targeting became a therapeutically interesting strategy and by now it is considered an emerging hallmark of cancer. Nevertheless, a very poor number of compounds are under investigation as potential modulators of cell metabolism. Candidate agents should display selectivity of action towards cancer cells without side effects. This ideal favorable profile would perfectly overlap the requisites of new anticancer therapies and chemopreventive strategies as well. Nature represents a still largely unexplored source of bioactive molecules with a therapeutic potential. Many of these compounds have already been characterized for their multiple anticancer activities. Many of them are absorbed with the diet and therefore possess a known profile in terms of tolerability and bioavailability compared to newly synthetized chemical compounds. The discovery of important cross-talks between mediators of the most therapeutically targeted aberrancies in cancer (i.e., cell proliferation, survival, and migration and the metabolic machinery allows to predict the possibility that many anticancer activities ascribed to a number of natural compounds may be due, in part, to their ability of modulating metabolic pathways. In this review, we attempt an overview of what is currently known about the potential of natural compounds as modulators of cancer cell metabolism.

Antibacterial compounds of Canadian honeys target bacterial cell wall inducing phenotype changes, growth inhibition and cell lysis that resemble action of β-lactam antibiotics.

Directory of Open Access Journals (Sweden)

Katrina Brudzynski

Full Text Available Honeys show a desirable broad spectrum activity against Gram-positive and negative bacteria making antibacterial activity an intrinsic property of honey and a desirable source for new drug development. The cellular targets and underlying mechanism of action of honey antibacterial compounds remain largely unknown. To facilitate the target discovery, we employed a method of phenotypic profiling by directly comparing morphological changes in Escherichia coli induced by honeys to that of ampicillin, the cell wall-active β-lactam of known mechanism of action. Firstly, we demonstrated the purity of tested honeys from potential β-lactam contaminations using quantitative LC-ESI-MS. Exposure of log-phase E. coli to honey or ampicillin resulted in time- and concentration-dependent changes in bacterial cell shape with the appearance of filamentous phenotypes at sub-inhibitory concentrations and spheroplasts at the MBC. Cell wall destruction by both agents, clearly visible on microscopic micrographs, was accompanied by increased permeability of the lipopolysaccharide outer membrane as indicated by fluorescence-activated cell sorting (FACS. More than 90% E. coli exposed to honey or ampicillin became permeable to propidium iodide. Consistently with the FACS results, both honey-treated and ampicillin-treated E. coli cells released lipopolysaccharide endotoxins at comparable levels, which were significantly higher than controls (p<0.0001. E. coli cells transformed with the ampicillin-resistance gene (β-lactamase remained sensitive to honey, displayed the same level of cytotoxicity, cell shape changes and endotoxin release as ampicillin-sensitive cells. As expected, β-lactamase protected the host cell from antibacterial action of ampicillin. Thus, both honey and ampicillin induced similar structural changes to the cell wall and LPS and that this ability underlies antibacterial activities of both agents. Since the cell wall is critical for cell growth and

Conduction velocity of action potentials measured from unidimensional latency-topography in human and frog skeletal muscle fibers.

Science.gov (United States)

Homma, S; Nakajima, Y; Hayashi, K; Toma, S

1986-01-01

Conduction of an action potential along skeletal muscle fibers was graphically displayed by unidimensional latency-topography, UDLT. Since the slopes of the equipotential line were linear and the width of the line was constant, it was possible to calculate conduction velocity from the slope. To determine conduction direction of the muscle action potential elicited by electric stimulation applied directly to the muscle, surface recording electrodes were placed on a two-dimensional plane over a human muscle. Thus a bi-dimensional topography was obtained. Then, twelve or sixteen surface electrodes were placed linearly along the longitudinal direction of the action potential conduction which was disclosed by the bi-dimensional topography. Thus conduction velocity of muscle action potential in man, calculated from the slope, was for m. brachioradialis, 3.9 +/- 0.4 m/s; for m. biceps brachii, 3.6 +/- 0.2 m/s; for m. sternocleidomastoideus, 3.6 +/- 0.4 m/s. By using a tungsten microelectrode to stimulate the motor axons, a convex-like equipotential line of an action potential in UDLT was obtained from human muscle fibers. Since a similar pattern of UDLT was obtained from experiments on isolated frog muscles, in which the muscle action potential was elicited by stimulating the motor axon, it was assumed that the maximum of the curve corresponds to the end-plate region, and that the slopes on both sides indicate bi-directional conduction of the action potential.

Metabolic responses of Eisenia fetida after sub-lethal exposure to organic contaminants with different toxic modes of action

International Nuclear Information System (INIS)

McKelvie, Jennifer R.; Wolfe, David M.; Celejewski, Magda A.; Alaee, Mehran; Simpson, Andre J.; Simpson, Myrna J.

2011-01-01

Nuclear magnetic resonance (NMR) - based metabolomics has the potential to identify toxic responses of contaminants within a mixture in contaminated soil. This study evaluated the metabolic response of Eisenia fetida after exposure to an array of organic compounds to determine whether contaminant-specific responses could be identified. The compounds investigated in contact tests included: two pesticides (carbaryl and chlorpyrifos), three pharmaceuticals (carbamazephine, estrone and caffeine), two persistent organohalogens (Aroclor 1254 and PBDE 209) and two industrial compounds (nonylphenol and dimethyl phthalate). Control and contaminant-exposed metabolic profiles were distinguished using principal component analysis and potential contaminant-specific biomarkers of exposure were found for several contaminants. These results suggest that NMR-based metabolomics offers considerable promise for differentiating between the different toxic modes of action (MOA) associated with sub-lethal toxicity to earthworms. - Highlights: → NMR-based earthworm metabolomic analysis of the toxic mode of action of various environmental contaminants. → Organic chemicals with different toxic modes of action resulted in varied metabolomic responses for E. fetida. → NMR-based metabolomics differentiates between the different modes of action associated with sub-lethal toxicity. - 1 H NMR metabolomics was used to identify potential biomarkers of organic contaminant exposure in Eisenia fetida earthworms.

Fish oil curtails the human action potential dome in a heterogeneous manner: Implication for arrhythmogenesis

NARCIS (Netherlands)

Verkerk, Arie O.; den Ruijter, Hester M.; de Jonge, Nicolaas; Coronel, Ruben

2009-01-01

Omega-3 polyunsaturated fatty acids (omega3-PUFAs) from fish oil modulate various ion channels, including the L-type calcium current (I(Ca,L)). As a result, fish oil shortens the cardiac action potential and may cause a loss of the dome of the action potential (AP). Under conditions of increased

Potential for ion-induced nucleation of volatile organic compounds by radon decay in indoor environments

International Nuclear Information System (INIS)

Daisey, J.M.

1991-11-01

There is considerable interest in the ''unattached'' fraction of radon progeny in indoor air because of its significance to the estimation of the risks of radon exposure. Because of its high mobility in air, the unattached fraction is more efficiently deposited in the respiratory tract. Variation in the diameter of the ''unattached'' fraction and in its diffusion coefficient can be due to clustering of other atmospheric species around the 218 PoO 2 + ion. The purpose of this study was to investigate the potential for the formation of clusters of vapor phase organic compounds, found in indoor air, around the 218 PoO 2 + ion and to determine which were most likely to form clusters. A secondary purpose was to provide a compilation of measurements of indoor organic compounds for future experiments and theoretical calculations by the radon research community. The classical charged liquid droplet theory (Thomson equation) was used to estimate the Gibbs free energy of ion-induced nucleation and to provide an indication of the indoor organic compounds most likely to undergo ion-induced nucleation. Forty-four volatile and semi-volatile organic compounds out of the more than 300 which have been reported in indoor air were investigated. Water vapor was included for comparison. The results indicate that there is a potential for the formation of clusters of organic compounds around the 218 PoO 2 + ion. The compounds with the greatest potential for cluster formation are the volatile oxidized hydrocarbons (e.g., n-butanol, phenol, hexanal, nonanal, benzaldehyde, the ketones and the acetates) and the semi-volatile organic compounds (pentachlorophenol, nicotine, chlordane, chlorpyrifos)

Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour.

Science.gov (United States)

Trenor, Beatriz; Cardona, Karen; Saiz, Javier; Noble, Denis; Giles, Wayne

2017-11-01

In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the action potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs). © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle

DEFF Research Database (Denmark)

Jensen, Ask Schou; Pennisi, Cristian Pablo; Sevcencu, Cristian

2015-01-01

with (+)-thioridazine. In this study we for the first time investigate the cardiotoxicity of the isolated thioridazine enantiomers and show their effects on ventricular repolarization. The effects of (+)-thioridazine, (-)-thioridazine, and racemate on the rabbit ventricular action potential duration (APD) were...... investigated in a randomized controlled blinded experiment. Action potentials were measured in papillary muscles isolated from 21 female rabbits, and the drug effect on 90% APD in comparison with control (DeltaDelta-APD90) was evaluated. Increasing concentrations of (+)-thioridazine and the racemate caused...

Marine Compounds with Therapeutic Potential in Gram-Negative Sepsis

Directory of Open Access Journals (Sweden)

Irina Yermak

2013-06-01

Full Text Available This paper concerns the potential use of compounds, including lipid A, chitosan, and carrageenan, from marine sources as agents for treating endotoxemic complications from Gram-negative infections, such as sepsis and endotoxic shock. Lipid A, which can be isolated from various species of marine bacteria, is a potential antagonist of bacterial endotoxins (lipopolysaccharide (LPSs. Chitosan is a widespread marine polysaccharide that is derived from chitin, the major component of crustacean shells. The potential of chitosan as an LPS-binding and endotoxin-neutralizing agent is also examined in this paper, including a discussion on the generation of hydrophobic chitosan derivatives to increase the binding affinity of chitosan to LPS. In addition, the ability of carrageenan, which is the polysaccharide of red alga, to decrease the toxicity of LPS is discussed. We also review data obtained using animal models that demonstrate the potency of carrageenan and chitosan as antiendotoxin agents.

Recovery of Action Potentials and Twitches after K-contractures in Frog Skeletal Muscle(Physiology)

OpenAIRE

Atsuko, Suzuki; Ibuki, Shirakawa; Kazunari, Noguchi; Hirohiko, Kishi; Haruo, Sugi; Department of Physiology, School of Medicine, Teikyo University:(Present office)Department of Physical Therapy, Health Science University; Department of Physiology, School of Medicine, Teikyo University; Department of Physiology, School of Medicine, Teikyo University; Department of Physiology, School of Medicine, Teikyo University; Department of Physiology, School of Medicine, Teikyo University

2004-01-01

To give information about intracellular Ca^ translocation during and after K-contractures in vertebrate skeletal muscle fibers, we examined recovery of action potentials and twitches after interruption and spontaneous relaxation of K-contractures at low temperature (3℃) that greatly reduced the rate of Ca^ reuptake by the sarcoplasmic reticulum. On membrane repolarization interrupting K-contractures, the amplitude of both action potentials and twitches recovered quickly, while the falling pha...

Surface deformation during an action potential in pearled cells

Science.gov (United States)

Mussel, Matan; Fillafer, Christian; Ben-Porath, Gal; Schneider, Matthias F.

2017-11-01

Electric pulses in biological cells (action potentials) have been reported to be accompanied by a propagating cell-surface deformation with a nanoscale amplitude. Typically, this cell surface is covered by external layers of polymer material (extracellular matrix, cell wall material, etc.). It was recently demonstrated in excitable plant cells (Chara braunii) that the rigid external layer (cell wall) hinders the underlying deformation. When the cell membrane was separated from the cell wall by osmosis, a mechanical deformation, in the micrometer range, was observed upon excitation of the cell. The underlying mechanism of this mechanical pulse has, to date, remained elusive. Herein we report that Chara cells can undergo a pearling instability, and when the pearled fragments were excited even larger and more regular cell shape changes were observed (˜10 -100 μ m in amplitude). These transient cellular deformations were captured by a curvature model that is based on three parameters: surface tension, bending rigidity, and pressure difference across the surface. In this paper these parameters are extracted by curve-fitting to the experimental cellular shapes at rest and during excitation. This is a necessary step to identify the mechanical parameters that change during an action potential.

Onset Dynamics of Action Potentials in Rat Neocortical Neurons and Identified Snail Neurons: Quantification of the Difference

OpenAIRE

Volgushev, Maxim; Malyshev, Aleksey; Balaban, Pavel; Chistiakova, Marina; Volgushev, Stanislav; Wolf, Fred

2008-01-01

The generation of action potentials (APs) is a key process in the operation of nerve cells and the communication between neurons. Action potentials in mammalian central neurons are characterized by an exceptionally fast onset dynamics, which differs from the typically slow and gradual onset dynamics seen in identified snail neurons. Here we describe a novel method of analysis which provides a quantitative measure of the onset dynamics of action potentials. This method captures the...

The Use of Plant Antimicrobial Compounds for Food Preservation

Science.gov (United States)

Hintz, Tana; Matthews, Karl K.

2015-01-01

Foodborne disease is a global issue with significant impact on human health. With the growing consumer demand for natural preservatives to replace chemical compounds, plant antimicrobial compounds must be thoroughly investigated for their potential to serve as biopreservatives. This review paper will focus on the plant-derived products as antimicrobial agents for use in food preservation and to control foodborne pathogens in foods. Structure, modes of action, stability, and resistance to these plant compounds will be discussed as well as their application in food industries and possible technologies by which they can be delivered. Benefits as well as challenges, such as the need for further research for implementation and governmental regulation, will be highlighted. PMID:26539472

Scaling of the quark-antiquark potential and improved actions in SU(2) lattice gauge theory

International Nuclear Information System (INIS)

Montvay, I.; Gutbrod, F.

1983-11-01

The scaling behaviour of the quark-antiquark potential is investigated by a high statistics Monte Carlo calculation in SU(2) lattice gauge theory. Besides the standard one-plaquette action we also use Symanzik's tree-level improved action and Wilson's block-spin improved action. No significant differences between Symanzik's action and the standard action have been observed. For small β Wilson's action scales differently. The string tension value chi extracted from the data corresponds to Λsub(latt) = (0.018 +- 0.001) √chi for the one-plaquette action. (orig.)

Diosgenin, 4-hydroxyisoleucine, and fiber from fenugreek: mechanisms of actions and potential effects on metabolic syndrome.

Science.gov (United States)

Fuller, Scott; Stephens, Jacqueline M

2015-03-01

Metabolic syndrome and its complications continue to rise in prevalence and show no signs of abating in the immediate future. Therefore, the search for effective treatments is a high priority in biomedical research. Products derived from botanicals have a time-honored history of use in the treatment of metabolic diseases including type 2 diabetes. Trigonella foenum-graecum, commonly known as fenugreek, is an annual herbaceous plant that has been a staple of traditional herbal medicine in many cultures. Although fenugreek has been studied in both clinical and basic research settings, questions remain about its efficacy and biologic mechanisms of action. Diosgenin, 4-hydroxyisoleucine, and the fiber component of the plant are the most intensively studied bioactive constituents present in fenugreek. These compounds have been demonstrated to exert beneficial effects on several physiologic markers including glucose tolerance, inflammation, insulin action, liver function, blood lipids, and cardiovascular health. Although insights into the molecular mechanisms underlying the favorable effects of fenugreek have been gained, we still do not have definitive evidence establishing its role as a therapeutic agent in metabolic disease. This review aims to summarize the currently available evidence on the physiologic effects of the 3 best-characterized bioactive compounds of fenugreek, with particular emphasis on biologic mechanisms of action relevant in the context of metabolic syndrome. © 2015 American Society for Nutrition.

Antimicrobial activity of GN peptides and their mode of action

DEFF Research Database (Denmark)

Mojsoska, Biljana; Nielsen, Hanne Mørck; Jenssen, Håvard

2016-01-01

peptides due to their characteristics as naturally derived compounds with antimicrobial activity. In this study, we aimed at characterizing the mechanism of action of a small set of in silico optimized peptides. Following determination of peptide activity against E. coli, S. aureus, and P. aeruginosa......Increasing prevalence of bacteria that carries resistance towards conventional antibiotics has prompted the investigation into new compounds for bacterial intervention to ensure efficient infection control in the future. One group of potential lead structures for antibiotics is antimicrobial...

Urocortin2 prolongs action potential duration and modulates potassium currents in guinea pig myocytes and HEK293 cells.

Science.gov (United States)

Yang, Li-Zhen; Zhu, Yi-Chun

2015-07-05

We previously reported that activation of corticotropin releasing factor receptor type 2 by urocortin2 up-regulates both L-type Ca(2+) channels and intracellular Ca(2+) concentration in ventricular myocytes and plays an important role in cardiac contractility and arrhythmogenesis. This study goal was to further test the hypothesis that urocortin2 may modulate action potentials as well as rapidly and slowly activating delayed rectifier potassium currents. With whole cell patch-clamp techniques, action potentials and slowly activating delayed rectifier potassium currents were recorded in isolated guinea pig ventricular myocytes, respectively. And rapidly activating delayed rectifier potassium currents were tested in hERG-HEK293 cells. Urocortin2 produced a time- and concentration-dependent prolongation of action potential duration. The EC50 values of action potential duration and action potential duration at 90% of repolarization were 14.73 and 24.3nM respectively. The prolongation of action potential duration of urocortin2 was almost completely or partly abolished by H-89 (protein kinase A inhibitor) or KB-R7943 (Na(+)/Ca(2+) exchange inhibitor) pretreatment respectively. And urocortin2 caused reduction of rapidly activating delayed rectifier potassium currents in hERG-HEK293 cells. In addition, urocortin2 slowed the rate of slowly activating delayed rectifier potassium channel activation, and rightward shifted the threshold of slowly activating delayed rectifier potassium currents to more positive potentials. Urocortin2 prolonged action potential duration via activation of protein kinase A and Na(+)/ Ca(2+) exchange in isolated guinea pig ventricular myocytes in a time- and concentration- dependent manner. In hERG-HEK293 cells, urocortin2 reduced rapidly activating delayed rectifier potassium current density which may contribute to action potential duration prolongation. Copyright © 2015 Elsevier B.V. All rights reserved.

Automated grouping of action potentials of human embryonic stem cell-derived cardiomyocytes.

Science.gov (United States)

Gorospe, Giann; Zhu, Renjun; Millrod, Michal A; Zambidis, Elias T; Tung, Leslie; Vidal, Rene

2014-09-01

Methods for obtaining cardiomyocytes from human embryonic stem cells (hESCs) are improving at a significant rate. However, the characterization of these cardiomyocytes (CMs) is evolving at a relatively slower rate. In particular, there is still uncertainty in classifying the phenotype (ventricular-like, atrial-like, nodal-like, etc.) of an hESC-derived cardiomyocyte (hESC-CM). While previous studies identified the phenotype of a CM based on electrophysiological features of its action potential, the criteria for classification were typically subjective and differed across studies. In this paper, we use techniques from signal processing and machine learning to develop an automated approach to discriminate the electrophysiological differences between hESC-CMs. Specifically, we propose a spectral grouping-based algorithm to separate a population of CMs into distinct groups based on the similarity of their action potential shapes. We applied this method to a dataset of optical maps of cardiac cell clusters dissected from human embryoid bodies. While some of the nine cell clusters in the dataset are presented with just one phenotype, the majority of the cell clusters are presented with multiple phenotypes. The proposed algorithm is generally applicable to other action potential datasets and could prove useful in investigating the purification of specific types of CMs from an electrophysiological perspective.

Potential use of DNA adducts to detect mutagenic compounds in soil

International Nuclear Information System (INIS)

Hua Guoxiong; Lyons, Brett; Killham, Ken; Singleton, Ian

2009-01-01

In this study, three different soils with contrasting features, spiked with 300 mg benzo[a]pyrene (BaP)/kg dry soil, were incubated at 20 deg. C and 60% water holding capacity for 540 days. At different time points, BaP and DNA were extracted and quantified, and DNA adducts were quantified by 32 P-postlabelling. After 540 days incubation, 69.3, 81.6 and 83.2% of initial BaP added remained in Cruden Bay, Boyndie and Insch soils, respectively. Meanwhile, a significantly different amount of DNA-BaP adducts were found in the three soils exposed to BaP over time. The work demonstrates the concept that DNA adducts can be detected on DNA extracted from soil. Results suggest the technique is not able to directly reflect bioavailability of BaP transformation products. However, this new method provides a potential way to detect mutagenic compounds in contaminated soil and to assess the outcomes of soil remediation. - A novel DNA adduct assay may provide a potential technique to detect mutagenic compounds in contaminated soil

Toxicology of perfluorinated compounds

Energy Technology Data Exchange (ETDEWEB)

Stahl, Thorsten [Hessian State Laboratory, Wiesbaden (Germany); Mattern, Daniela; Brunn, Hubertus [Hessian State Laboratory, Giessen (Germany)

2011-12-15

Perfluorinated compounds [PFCs] have found a wide use in industrial products and processes and in a vast array of consumer products. PFCs are molecules made up of carbon chains to which fluorine atoms are bound. Due to the strength of the carbon/fluorine bond, the molecules are chemically very stable and are highly resistant to biological degradation; therefore, they belong to a class of compounds that tend to persist in the environment. These compounds can bioaccumulate and also undergo biomagnification. Within the class of PFC chemicals, perfluorooctanoic acid and perfluorosulphonic acid are generally considered reference substances. Meanwhile, PFCs can be detected almost ubiquitously, e.g., in water, plants, different kinds of foodstuffs, in animals such as fish, birds, in mammals, as well as in human breast milk and blood. PFCs are proposed as a new class of 'persistent organic pollutants'. Numerous publications allude to the negative effects of PFCs on human health. The following review describes both external and internal exposures to PFCs, the toxicokinetics (uptake, distribution, metabolism, excretion), and the toxicodynamics (acute toxicity, subacute and subchronic toxicities, chronic toxicity including carcinogenesis, genotoxicity and epigenetic effects, reproductive and developmental toxicities, neurotoxicity, effects on the endocrine system, immunotoxicity and potential modes of action, combinational effects, and epidemiological studies on perfluorinated compounds). (orig.)

The different intracellular action potentials of fast and slow muscle fibres = Différences entre les potentiels d'action intracellulaires de fibres musculaires rapides et lentes

NARCIS (Netherlands)

Wallinga, W.; Gielen, Frans L.H.; Wirtz, Peter; de Jong, Paul; Broenink, Johannes F.

1985-01-01

The time course of the intracellular action potential was studied quantitatively, because it is an important factor in the generation of electromyographic signals. In in vivo preparations of the m. EDL and m. soleus of the rat single motor units were stimulated and intracellular action potentials

The Potential of Deweyan-Inspired Action Research

Science.gov (United States)

Stark, Jody L.

2014-01-01

In its broadest sense, pragmatism could be said to be the philosophical orientation of all action research. Action research is characterized by research, action, and participation grounded in democratic principles and guided by the aim of social improvement. Furthermore, action research is an active process of inquiry that does not admit…

Acetylcholinesterase in Biofouling Species: Characterization and Mode of Action of Cyanobacteria-Derived Antifouling Agents.

Science.gov (United States)

Almeida, Joana R; Freitas, Micaela; Cruz, Susana; Leão, Pedro N; Vasconcelos, Vitor; Cunha, Isabel

2015-07-24

Effective and ecofriendly antifouling (AF) compounds have been arising from naturally produced chemicals. The objective of this study is to use cyanobacteria-derived agents to investigate the role of acetylcholinesterase (AChE) activity as an effect and/or mode of action of promising AF compounds, since AChE inhibitors were found to inhibit invertebrate larval settlement. To pursue this objective, in vitro quantification of AChE activity under the effect of several cyanobacterial strain extracts as potential AF agents was performed along with in vivo AF (anti-settlement) screening tests. Pre-characterization of different cholinesterases (ChEs) forms present in selected tissues of important biofouling species was performed to confirm the predominance of AChE, and an in vitro AF test using pure AChE activity was developed. Eighteen cyanobacteria strains were tested as source of potential AF and AChE inhibitor agents. Results showed effectiveness in selecting promising eco-friendly AF agents, allowing the understanding of the AF biochemical mode of action induced by different compounds. This study also highlights the potential of cyanobacteria as source of AF agents towards invertebrate macrofouling species.

Acetylcholinesterase in Biofouling Species: Characterization and Mode of Action of Cyanobacteria-Derived Antifouling Agents

Directory of Open Access Journals (Sweden)

Joana R. Almeida

2015-07-01

Full Text Available Effective and ecofriendly antifouling (AF compounds have been arising from naturally produced chemicals. The objective of this study is to use cyanobacteria-derived agents to investigate the role of acetylcholinesterase (AChE activity as an effect and/or mode of action of promising AF compounds, since AChE inhibitors were found to inhibit invertebrate larval settlement. To pursue this objective, in vitro quantification of AChE activity under the effect of several cyanobacterial strain extracts as potential AF agents was performed along with in vivo AF (anti-settlement screening tests. Pre-characterization of different cholinesterases (ChEs forms present in selected tissues of important biofouling species was performed to confirm the predominance of AChE, and an in vitro AF test using pure AChE activity was developed. Eighteen cyanobacteria strains were tested as source of potential AF and AChE inhibitor agents. Results showed effectiveness in selecting promising eco-friendly AF agents, allowing the understanding of the AF biochemical mode of action induced by different compounds. This study also highlights the potential of cyanobacteria as source of AF agents towards invertebrate macrofouling species.

RESEARCH REGARDING THE POTENTIAL ACTIVITY OF SOME HETEROCYCLIC COMPOUNDS ON PLANTS GROWTH AND DEVELOPMENT

Directory of Open Access Journals (Sweden)

OANA-IRINA PATRICIU

2017-06-01

Full Text Available It is well known that growth and morphogenesis of plant tissue cultures can be improved by small amounts of some organic compounds. Heterocyclic compounds such as chromanones and thiazoles derivatives, valuable because of their potential biological activities, have also been reported as pesticides, herbicides and plant-growth regulators. In the present study, different concentrations of chromanones and thiazoles derivatives were employed to evaluate their effects on plantlets growth of Ocimum basilicum L. and Echinacea purpurea L. The studied compounds were proved to be growth inhibitors at high concentrations. A growth stimulation effect was registered at low concentration.

Chemical Compounds Toxic to Invertebrates Isolated from Marine Cyanobacteria of Potential Relevance to the Agricultural Industry

KAUST Repository

Essack, Magbubah

2014-10-29

In spite of advances in invertebrate pest management, the agricultural industry is suffering from impeded pest control exacerbated by global climate changes that have altered rain patterns to favour opportunistic breeding. Thus, novel naturally derived chemical compounds toxic to both terrestrial and aquatic invertebrates are of interest, as potential pesticides. In this regard, marine cyanobacterium-derived metabolites that are toxic to both terrestrial and aquatic invertebrates continue to be a promising, but neglected, source of potential pesticides. A PubMed query combined with hand-curation of the information from retrieved articles allowed for the identification of 36 cyanobacteria-derived chemical compounds experimentally confirmed as being toxic to invertebrates. These compounds are discussed in this review.

Chemical Compounds Toxic to Invertebrates Isolated from Marine Cyanobacteria of Potential Relevance to the Agricultural Industry

KAUST Repository

Essack, Magbubah; Alzubaidy, Hanin S.; Bajic, Vladimir B.; Archer, John A.C.

2014-01-01

In spite of advances in invertebrate pest management, the agricultural industry is suffering from impeded pest control exacerbated by global climate changes that have altered rain patterns to favour opportunistic breeding. Thus, novel naturally derived chemical compounds toxic to both terrestrial and aquatic invertebrates are of interest, as potential pesticides. In this regard, marine cyanobacterium-derived metabolites that are toxic to both terrestrial and aquatic invertebrates continue to be a promising, but neglected, source of potential pesticides. A PubMed query combined with hand-curation of the information from retrieved articles allowed for the identification of 36 cyanobacteria-derived chemical compounds experimentally confirmed as being toxic to invertebrates. These compounds are discussed in this review.

Chemical Compounds Toxic to Invertebrates Isolated from Marine Cyanobacteria of Potential Relevance to the Agricultural Industry

Science.gov (United States)

Essack, Magbubah; Alzubaidy, Hanin S.; Bajic, Vladimir B.; Archer, John A. C.

2014-01-01

In spite of advances in invertebrate pest management, the agricultural industry is suffering from impeded pest control exacerbated by global climate changes that have altered rain patterns to favour opportunistic breeding. Thus, novel naturally derived chemical compounds toxic to both terrestrial and aquatic invertebrates are of interest, as potential pesticides. In this regard, marine cyanobacterium-derived metabolites that are toxic to both terrestrial and aquatic invertebrates continue to be a promising, but neglected, source of potential pesticides. A PubMed query combined with hand-curation of the information from retrieved articles allowed for the identification of 36 cyanobacteria-derived chemical compounds experimentally confirmed as being toxic to invertebrates. These compounds are discussed in this review. PMID:25356733

Antimalarial activity of compounds comprising a primary benzene sulfonamide fragment.

Science.gov (United States)

Andrews, Katherine T; Fisher, Gillian M; Sumanadasa, Subathdrage D M; Skinner-Adams, Tina; Moeker, Janina; Lopez, Marie; Poulsen, Sally-Ann

2013-11-15

Despite the urgent need for effective antimalarial drugs with novel modes of action no new chemical class of antimalarial drug has been approved for use since 1996. To address this, we have used a rational approach to investigate compounds comprising the primary benzene sulfonamide fragment as a potential new antimalarial chemotype. We report the in vitro activity against Plasmodium falciparum drug sensitive (3D7) and resistant (Dd2) parasites for a panel of fourteen primary benzene sulfonamide compounds. Our findings provide a platform to support the further evaluation of primary benzene sulfonamides as a new antimalarial chemotype, including the identification of the target of these compounds in the parasite. Copyright © 2013 Elsevier Ltd. All rights reserved.

Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

Science.gov (United States)

Yang, Yang; Ang, Wei; Long, Haiyue; Chang, Ying; Li, Zicheng; Zhou, Liangxue; Yang, Tao; Deng, Yong; Luo, Youfu

2016-10-01

A scaffold-hopping strategy toward Agomelatine based on in silico screening and knowledge analysis was employed to design novel antidepressant agents. A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (6a-1, 6a-2, 6a-9) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound 6a-1 also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects in vivo. The forced swim test (FST) results revealed that compound 6a-1 remarkably reduced the immobility time of rats and the open field test (OFT) results indicated a better general locomotor activity of the rats treated with compound 6a-1 than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound 6a-1 can significantly reduce PC12 cell apoptosis by up-regulation of GSH and down-regulation of ROS in corticosterone-induced lesion of PC12 cells. Meanwhile, the down-regulation of calcium ion concentration and up-regulation of BDNF level in PC12 cells may account for the neuroprotective effects. Furthermore, compound 6a-1 can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data in vivo indicated compound 6a-1 exhibited less hepatotoxicity than Agomelatine.

Role of action potential configuration and the contribution of Ca2+ and K+ currents to isoprenaline-induced changes in canine ventricular cells

Science.gov (United States)

Szentandrássy, N; Farkas, V; Bárándi, L; Hegyi, B; Ruzsnavszky, F; Horváth, B; Bányász, T; Magyar, J; Márton, I; Nánási, PP

2012-01-01

BACKGROUND AND PURPOSE Although isoprenaline (ISO) is known to activate several ion currents in mammalian myocardium, little is known about the role of action potential morphology in the ISO-induced changes in ion currents. Therefore, the effects of ISO on action potential configuration, L-type Ca2+ current (ICa), slow delayed rectifier K+ current (IKs) and fast delayed rectifier K+ current (IKr) were studied and compared in a frequency-dependent manner using canine isolated ventricular myocytes from various transmural locations. EXPERIMENTAL APPROACH Action potentials were recorded with conventional sharp microelectrodes; ion currents were measured using conventional and action potential voltage clamp techniques. KEY RESULTS In myocytes displaying a spike-and-dome action potential configuration (epicardial and midmyocardial cells), ISO caused reversible shortening of action potentials accompanied by elevation of the plateau. ISO-induced action potential shortening was absent in endocardial cells and in myocytes pretreated with 4-aminopyridine. Application of the IKr blocker E-4031 failed to modify the ISO effect, while action potentials were lengthened by ISO in the presence of the IKs blocker HMR-1556. Both action potential shortening and elevation of the plateau were prevented by pretreatment with the ICa blocker nisoldipine. Action potential voltage clamp experiments revealed a prominent slowly inactivating ICa followed by a rise in IKs, both currents increased with increasing the cycle length. CONCLUSIONS AND IMPLICATIONS The effect of ISO in canine ventricular cells depends critically on action potential configuration, and the ISO-induced activation of IKs– but not IKr– may be responsible for the observed shortening of action potentials. PMID:22563726

Phytogenic Compounds as Alternatives to In-Feed Antibiotics: Potentials and Challenges in Application

Directory of Open Access Journals (Sweden)

Chengbo Yang

2015-03-01

Full Text Available This article summarizes current experimental knowledge on the efficacy, possible mechanisms and feasibility in the application of phytogenic products as feed additives for food-producing animals. Phytogenic compounds comprise a wide range of plant-derived natural bioactive compounds and essential oils are a major group. Numerous studies have demonstrated that phytogenic compounds have a variety of functions, including antimicrobial/antiviral, antioxidative and anti-inflammation effects and improvement in the palatability of feed and gut development/health. However, the mechanisms underlying their functions are still largely unclear. In the past, there has been a lack of consistency in the results from both laboratory and field studies, largely due to the varied composition of products, dosages, purities and growing conditions of animals used. The minimal inhibitory concentration (MIC of phytogenic compounds required for controlling enteric pathogens may not guarantee the best feed intake, balanced immunity of animals and cost-effectiveness in animal production. The lipophilic nature of photogenic compounds also presents a challenge in effective delivery to the animal gut and this can partially be resolved by microencapsulation and combination with other compounds (synergistic effect. Interestingly, the effects of photogenic compounds on anti-inflammation, gut chemosensing and possible disruption of bacterial quorum sensing could explain a certain number of studies with different animal species for the better production performance of animals that have received phytogenic feed additives. It is obvious that phytogenic compounds have good potential as an alternative to antibiotics in feed for food animal production and the combination of different phytogenic compounds appears to be an approach to improve the efficacy and safety of phytogenic compounds in the application. It is our expectation that the recent development of high-throughput and �

Incorporated fish oil fatty acids prevent action potential shortening induced by circulating fish oil fatty acids

Directory of Open Access Journals (Sweden)

Hester M Den Ruijter

2010-11-01

Full Text Available Increased consumption of fatty fish, rich in omega-3 polyunsaturated fatty acids (3-PUFAs reduces the severity and number of arrhythmias. Long term 3-PUFA-intake modulates the activity of several cardiac ion channels leading to cardiac action potential shortening. Circulating 3-PUFAs in the bloodstream and incorporated 3-PUFAs in the cardiac membrane have a different mechanism to shorten the action potential. It is, however, unknown whether circulating 3-PUFAs in the bloodstream enhance or diminish the effects of incorporated 3-PUFAs. In the present study, we address this issue. Rabbits were fed a diet rich in fish oil (3 or sunflower oil (9, as control for 3 weeks. Ventricular myocytes were isolated by enzymatic dissociation and action potentials were measured using the perforated patch clamp technique in the absence and presence of acutely administered 3-PUFAs. Plasma of 3 fed rabbits contained more free eicosapentaenoic acid (EPA and isolated myocytes of 3 fed rabbits contained higher amounts of both EPA and docosahexaenoic acid (DHA in their sarcolemma compared to control. In the absence of acutely administered fatty acids, 3 myocytes had a shorter action potential with a more negative plateau than 9 myocytes. In the 9 myocytes, but not in the 3 myocytes, acute administration of a mixture of EPA+DHA shortened the action potential significantly. From these data we conclude that incorporated 3-PUFAs into the sarcolemma and acutely administered 3 fatty acids do not have a cumulative effect on action potential duration and morphology. As a consequence, patients with a high cardiac 3-PUFA status will probably not benefit from short term 3 supplementation as an antiarrhythmic therapy.

Multiple Actions of Rotenone, an Inhibitor of Mitochondrial Respiratory Chain, on Ionic Currents and Miniature End-Plate Potential in Mouse Hippocampal (mHippoE-14 Neurons

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Chin-Wei Huang

2018-05-01

Full Text Available Background/Aims: Rotenone (Rot is known to suppress the activity of complex I in the mitochondrial chain reaction; however, whether this compound has effects on ion currents in neurons remains largely unexplored. Methods: With the aid of patch-clamp technology and simulation modeling, the effects of Rot on membrane ion currents present in mHippoE-14 cells were investigated. Results: Addition of Rot produced an inhibitory action on the peak amplitude of INa with an IC50 value of 39.3 µM; however, neither activation nor inactivation kinetics of INa was changed during cell exposure to this compound. Addition of Rot produced little or no modifications in the steady-state inactivation curve of INa. Rot increased the amplitude of Ca2+-activated Cl- current in response to membrane depolarization with an EC50 value of 35.4 µM; further addition of niflumic acid reversed Rot-mediated stimulation of this current. Moreover, when these cells were exposed to 10 µM Rot, a specific population of ATP-sensitive K+ channels with a single-channel conductance of 18.1 pS was measured, despite its inability to alter single-channel conductance. Under current clamp condition, the frequency of miniature end-plate potentials in mHippoE-14 cells was significantly raised in the presence of Rot (10 µM with no changes in their amplitude and time course of rise and decay. In simulated model of hippocampal neurons incorporated with chemical autaptic connection, increased autaptic strength to mimic the action of Rot was noted to change the bursting pattern with emergence of subthreshold potentials. Conclusions: The Rot effects presented herein might exert a significant action on functional activities of hippocampal neurons occurring in vivo.

ER Stress-Mediated Signaling: Action Potential and Ca(2+) as Key Players.

Science.gov (United States)

Bahar, Entaz; Kim, Hyongsuk; Yoon, Hyonok

2016-09-15

The proper functioning of the endoplasmic reticulum (ER) is crucial for multiple cellular activities and survival. Disturbances in the normal ER functions lead to the accumulation and aggregation of unfolded proteins, which initiates an adaptive response, the unfolded protein response (UPR), in order to regain normal ER functions. Failure to activate the adaptive response initiates the process of programmed cell death or apoptosis. Apoptosis plays an important role in cell elimination, which is essential for embryogenesis, development, and tissue homeostasis. Impaired apoptosis can lead to the development of various pathological conditions, such as neurodegenerative and autoimmune diseases, cancer, or acquired immune deficiency syndrome (AIDS). Calcium (Ca(2+)) is one of the key regulators of cell survival and it can induce ER stress-mediated apoptosis in response to various conditions. Ca(2+) regulates cell death both at the early and late stages of apoptosis. Severe Ca(2+) dysregulation can promote cell death through apoptosis. Action potential, an electrical signal transmitted along the neurons and muscle fibers, is important for conveying information to, from, and within the brain. Upon the initiation of the action potential, increased levels of cytosolic Ca(2+) (depolarization) lead to the activation of the ER stress response involved in the initiation of apoptosis. In this review, we discuss the involvement of Ca(2+) and action potential in ER stress-mediated apoptosis.

Perfluorinated Compounds: Emerging POPs with Potential Immunotoxicity

Science.gov (United States)

Perfluorinated compounds (PFCs) have been recognized as an important class of environmental contaminants commonly detected in blood samples of both wildlife and humans. These compounds have been in use for more than 60 years as surface treatment chemicals, polymerization aids, an...

Antibacterial free fatty acids: activities, mechanisms of action and biotechnological potential.

Science.gov (United States)

Desbois, Andrew P; Smith, Valerie J

2010-02-01

Amongst the diverse and potent biological activities of free fatty acids (FFAs) is the ability to kill or inhibit the growth of bacteria. The antibacterial properties of FFAs are used by many organisms to defend against parasitic or pathogenic bacteria. Whilst their antibacterial mode of action is still poorly understood, the prime target of FFA action is the cell membrane, where FFAs disrupt the electron transport chain and oxidative phosphorylation. Besides interfering with cellular energy production, FFA action may also result from the inhibition of enzyme activity, impairment of nutrient uptake, generation of peroxidation and auto-oxidation degradation products or direct lysis of bacterial cells. Their broad spectrum of activity, non-specific mode of action and safety makes them attractive as antibacterial agents for various applications in medicine, agriculture and food preservation, especially where the use of conventional antibiotics is undesirable or prohibited. Moreover, the evolution of inducible FFA-resistant phenotypes is less problematic than with conventional antibiotics. The potential for commercial or biomedical exploitation of antibacterial FFAs, especially for those from natural sources, is discussed.

Carcinogenicity assessment of water-soluble nickel compounds.

Science.gov (United States)

Goodman, Julie E; Prueitt, Robyn L; Dodge, David G; Thakali, Sagar

2009-01-01

IARC is reassessing the human carcinogenicity of nickel compounds in 2009. To address the inconsistencies among results from studies of water-soluble nickel compounds, we conducted a weight-of-evidence analysis of the relevant epidemiological, toxicological, and carcinogenic mode-of-action data. We found the epidemiological evidence to be limited, in that some, but not all, data suggest that exposure to soluble nickel compounds leads to increased cancer risk in the presence of certain forms of insoluble nickel. Although there is no evidence that soluble nickel acts as a complete carcinogen in animals, there is limited evidence that suggests it may act as a tumor promoter. The mode-of-action data suggest that soluble nickel compounds will not be able to cause genotoxic effects in vivo because they cannot deliver sufficient nickel ions to nuclear sites of target cells. Although the mode-of-action data suggest several possible non-genotoxic effects of the nickel ion, it is unclear whether soluble nickel compounds can elicit these effects in vivo or whether these effects, if elicited, would result in tumor promotion. The mode-of-action data equally support soluble nickel as a promoter or as not being a causal factor in carcinogenesis at all. The weight of evidence does not indicate that soluble nickel compounds are complete carcinogens, and there is only limited evidence that they could act as tumor promoters.

Aqueous extract of Psidium guajava leaves: phenolic compounds and inhibitory potential on digestive enzymes

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ANDERSON A. SIMÃO

Full Text Available ABSTRACT Leaves of Psidium guajava L. (guava have been widely used in the popular way for prevention and treatment of various diseases. Thus, the objective of this study was to evaluate the inhibitory potential of leaves aqueous extract from three cultivars of P. guajava (Pedro Sato, Paluma and Século XXI on α-amylase, α-glycosidase, lipase, and trypsin enzymes, in the presence or not of simulated gastric fluid and to determine the content of phenolic compounds by high performance liquid chromatography. All cultivars presented the same composition in phenolic compounds, but in different proportions. The compounds identified are gallic acid, epigallocatechin gallate, syringic acid, o-coumaric acid, resveratrol, quercetin, and catechin (which was the major compound in all the cultivars evaluated. In the absence of simulated gastric fluid, it was observed different inhibitions exercised by the leaves aqueous extracts from three cultivars of P. guajava on each enzyme. In presence of simulated gastric fluid, all cultivars showed increase in the inhibition of lipase and α-glycosidase, and decrease in inhibition of α-amylase and trypsin enzymes. These results indicate that P. guajava leaves aqueous extracts from all cultivars evaluated possess potential of use as an adjuvant in the treatment of obesity and other dyslipidemias.

Aqueous extract of Psidium guajava leaves: phenolic compounds and inhibitory potential on digestive enzymes.

Science.gov (United States)

Simão, Anderson A; Marques, Tamara R; Marcussi, Silvana; Corrêa, Angelita D

2017-01-01

Leaves of Psidium guajava L. (guava) have been widely used in the popular way for prevention and treatment of various diseases. Thus, the objective of this study was to evaluate the inhibitory potential of leaves aqueous extract from three cultivars of P. guajava (Pedro Sato, Paluma and Século XXI) on α-amylase, α-glycosidase, lipase, and trypsin enzymes, in the presence or not of simulated gastric fluid and to determine the content of phenolic compounds by high performance liquid chromatography. All cultivars presented the same composition in phenolic compounds, but in different proportions. The compounds identified are gallic acid, epigallocatechin gallate, syringic acid, o-coumaric acid, resveratrol, quercetin, and catechin (which was the major compound in all the cultivars evaluated). In the absence of simulated gastric fluid, it was observed different inhibitions exercised by the leaves aqueous extracts from three cultivars of P. guajava on each enzyme. In presence of simulated gastric fluid, all cultivars showed increase in the inhibition of lipase and α-glycosidase, and decrease in inhibition of α-amylase and trypsin enzymes. These results indicate that P. guajava leaves aqueous extracts from all cultivars evaluated possess potential of use as an adjuvant in the treatment of obesity and other dyslipidemias.

Corrective Action Investigation Plan for Corrective Action Unit 230: Area 22 Sewage Lagoons and Corrective Action Unit 320: Area 22 Desert Rock Airport Strainer Box, Nevada Test Site, Nevada

International Nuclear Information System (INIS)

1999-01-01

This Corrective Action Investigation Plan contains the U.S. Department of Energy, Nevada Operation Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 230/320 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 230 consists of Corrective Action Site (CAS) 22-03-01, Sewage Lagoon; while CAU 320 consists of CAS 22-99-01, Strainer Box. These CAUs are referred to as CAU 230/320 or the Sewage Lagoons Site. The Sewage Lagoons Site also includes an Imhoff tank, sludge bed, and associated buried sewer piping. Located in Area 22, the site was used between 1951 to 1958 for disposal of sanitary sewage effluent from the historic Camp Desert Rock Facility at the Nevada Test Site in Nevada. Based on site history, the contaminants of potential concern include volatile organic compounds (VOCs), semivolatile organic compounds, total petroleum hydrocarbons (TPH), and radionuclides. Vertical migration is estimated to be less than 12 feet below ground surface, and lateral migration is limited to the soil immediately adjacent to or within areas of concern. The proposed investigation will involve a combination of field screening for VOCs and TPH using the direct-push method and excavation using a backhoe to gather soil samples for analysis. Gamma spectroscopy will also be conducted for waste management purposes. Sampling locations will be biased to suspected worst-case areas including the nearby sludge bed, sewage lagoon inlet(s) and outlet(s), disturbed soil surrounding the lagoons, surface drainage channel south of the lagoons, and the area near the Imhoff tank. The results of this field investigation will support a defensible evaluation of corrective action alternatives in the corrective action decision document

Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids

Science.gov (United States)

Covey, Dan P.; Bunner, Kendra D.; Schuweiler, Douglas R.; Cheer, Joseph F.; Garris, Paul A.

2018-01-01

The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

Science.gov (United States)

Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

2016-06-01

The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

Fokker-action principle for a system of particles interacting through a linear potential

International Nuclear Information System (INIS)

Rivacoba, A.

1984-01-01

A Fokker-action principle for a system of scalar particles interacting through their time-symmetric relativistic generalization of linear potential is obtained. From this action, motion equations and conservation laws for the total energy and angular momentum of the system, in which field contributions are included, are derived. These equations are exactly applied to the problem suggested by Schild of two particles moving in circular concentric orbits

Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy

NARCIS (Netherlands)

Kole, Maarten H. P.; Letzkus, Johannes J.; Stuart, Greg J.

2007-01-01

Action potentials are binary signals that transmit information via their rate and temporal pattern. In this context, the axon is thought of as a transmission line, devoid of a role in neuronal computation. Here, we show a highly localized role of axonal Kv1 potassium channels in shaping the action

Determination of one-electron reduction potentials of some radiosensitive compounds by pulse radiolysis

International Nuclear Information System (INIS)

Zuo Zhihua; Yao Side; Li Hucheng; Lin Nianyun; Jin Yizun

1994-01-01

One-electron reduction potential (E 7 1 ) is one of the important parameters of radiosensitive compound with high electron affinity. In this work one-electron reduction potentials of some radiosensitizers, such as Miso, 911, CMNa, SMU-1, SMU-2, SMD, SNN, S 3 and BSO, were determined pulse radiolytically by using anthraquinone-2-sulfate (AQS), duroquinone (DQ) and methyl viologen (MV 2+ ) as references

Potential of chromatin modifying compounds for the treatment of Alzheimer's disease.

Science.gov (United States)

Karagiannis, Tom C; Ververis, Katherine

2012-01-01

Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.

Potential of chromatin modifying compounds for the treatment of Alzheimer's disease

Directory of Open Access Journals (Sweden)

Tom C. Karagiannis

2012-02-01

Full Text Available Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.

Application of Emergency Action Levels from Potential Release at Research Reactor HANARO

International Nuclear Information System (INIS)

Kim, Jongsoo; Lee, Goan Yub; Lee, Hae Choi; Kim, Bong Suk

2014-01-01

Execution of the protective action promptly is possible that Emergency Action Levels (EALs) must be established for a radiological release from nuclear facility. The EALs for electric power reactor are already developed and applied to recognize an emergency situation rapidly. Recently the IAEA published the safety report including the EALs for research reactor. This paper describes the EALs to apply for a potential release pathway at the research reactor HANARO. The results of table 1 and 2 will be higher than actual because the weather condition in real situation is difference. However, the EALs applying the potential stack release, ground release and site can be useful for research reactor HANARO making the emergency declaration. The EALs at the site boundary of the table 3 can be applied to protect the off-site public

Evaluating the Potential Bioactivity of a Novel Compound ER1626

OpenAIRE

Wang, Lijun; Zeng, Yanyan; Wang, Tianling; Liu, Hongyi; Xiao, Hong; Xiang, Hua

2014-01-01

Background ER1626, a novel compound, is a derivate of indeno-isoquinoline ketone. This study was designed to evaluate the biological activity and potential anti-tumor mechanism of ER1626. Method MTT assay, scratch assay and flow cytometry were used to determine cell proliferation, cell migration and cell cycle distribution as well as cell apoptosis on human breast cancer MCF-7 cells and endometrial cancer Ishikawa cells. We also explored the antiangiogenic effect of ER1626 on HUVEC cells and ...

Theobroma cacao: Review of the Extraction, Isolation, and Bioassay of Its Potential Anti-cancer Compounds

Science.gov (United States)

Baharum, Zainal; Akim, Abdah Md; Hin, Taufiq Yap Yun; Hamid, Roslida Abdul; Kasran, Rosmin

2016-01-01

Plants have been a good source of therapeutic agents for thousands of years; an impressive number of modern drugs used for treating human diseases are derived from natural sources. The Theobroma cacao tree, or cocoa, has recently garnered increasing attention and become the subject of research due to its antioxidant properties, which are related to potential anti-cancer effects. In the past few years, identifying and developing active compounds or extracts from the cocoa bean that might exert anti-cancer effects have become an important area of health- and biomedicine-related research. This review provides an updated overview of T. cacao in terms of its potential anti-cancer compounds and their extraction, in vitro bioassay, purification, and identification. This article also discusses the advantages and disadvantages of the techniques described and reviews the processes for future perspectives of analytical methods from the viewpoint of anti-cancer compound discovery. PMID:27019680

Dynamic Action Potential Restitution Contributes to Mechanical Restitution in Right Ventricular Myocytes From Pulmonary Hypertensive Rats.

Science.gov (United States)

Hardy, Matthew E L; Pervolaraki, Eleftheria; Bernus, Olivier; White, Ed

2018-01-01

We investigated the steepened dynamic action potential duration (APD) restitution of rats with pulmonary artery hypertension (PAH) and right ventricular (RV) failure and tested whether the observed APD restitution properties were responsible for negative mechanical restitution in these myocytes. PAH and RV failure were provoked in male Wistar rats by a single injection of monocrotaline (MCT) and compared with saline-injected animals (CON). Action potentials were recorded from isolated RV myocytes at stimulation frequencies between 1 and 9 Hz. Action potential waveforms recorded at 1 Hz were used as voltage clamp profiles (action potential clamp) at stimulation frequencies between 1 and 7 Hz to evoke rate-dependent currents. Voltage clamp profiles mimicking typical CON and MCT APD restitution were applied and cell shortening simultaneously monitored. Compared with CON myocytes, MCT myocytes were hypertrophied; had less polarized diastolic membrane potentials; had action potentials that were triggered by decreased positive current density and shortened by decreased negative current density; APD was longer and APD restitution steeper. APD90 restitution was unchanged by exposure to the late Na + -channel blocker (5 μM) ranolazine or the intracellular Ca 2+ buffer BAPTA. Under AP clamp, stimulation frequency-dependent inward currents were smaller in MCT myocytes and were abolished by BAPTA. In MCT myocytes, increasing stimulation frequency decreased contraction amplitude when depolarization duration was shortened, to mimic APD restitution, but not when depolarization duration was maintained. We present new evidence that the membrane potential of PAH myocytes is less stable than normal myocytes, being more easily perturbed by external currents. These observations can explain increased susceptibility to arrhythmias. We also present novel evidence that negative APD restitution is at least in part responsible for the negative mechanical restitution in PAH myocytes. Thus

Sensitivity to structure in action sequences: An infant event-related potential study.

Science.gov (United States)

Monroy, Claire D; Gerson, Sarah A; Domínguez-Martínez, Estefanía; Kaduk, Katharina; Hunnius, Sabine; Reid, Vincent

2017-05-06

Infants are sensitive to structure and patterns within continuous streams of sensory input. This sensitivity relies on statistical learning, the ability to detect predictable regularities in spatial and temporal sequences. Recent evidence has shown that infants can detect statistical regularities in action sequences they observe, but little is known about the neural process that give rise to this ability. In the current experiment, we combined electroencephalography (EEG) with eye-tracking to identify electrophysiological markers that indicate whether 8-11-month-old infants detect violations to learned regularities in action sequences, and to relate these markers to behavioral measures of anticipation during learning. In a learning phase, infants observed an actor performing a sequence featuring two deterministic pairs embedded within an otherwise random sequence. Thus, the first action of each pair was predictive of what would occur next. One of the pairs caused an action-effect, whereas the second did not. In a subsequent test phase, infants observed another sequence that included deviant pairs, violating the previously observed action pairs. Event-related potential (ERP) responses were analyzed and compared between the deviant and the original action pairs. Findings reveal that infants demonstrated a greater Negative central (Nc) ERP response to the deviant actions for the pair that caused the action-effect, which was consistent with their visual anticipations during the learning phase. Findings are discussed in terms of the neural and behavioral processes underlying perception and learning of structured action sequences. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mesoionic Compounds

Indian Academy of Sciences (India)

Organic Chemistry. Kamatak University,. Dharwad. Her research interests are synthesis, reactions and synthetic utility of sydnones. She is currently working on electrochemical and insecticidal/antifungal activities for some of these compounds. Keywords. Aromaticity, mesoionic hetero- cycles, sydnones, tandem re- actions.

Application of mass spectrometric techniques to delineate the modes-of-action of anticancer metallodrugs

NARCIS (Netherlands)

Hartinger, Christian G.; Groessl, Michael; Meier, Samuel M.; Casini, Angela; Dyson, Paul J.

2013-01-01

Mass spectrometry (MS) has emerged as an important tool for studying anticancer metallodrugs in complex biological samples and for characterising their interactions with biomolecules and potential targets on a molecular level. The exact modes-of-action of these coordination compounds and especially

Activation of Mechanosensitive Transient Receptor Potential/Piezo Channels in Odontoblasts Generates Action Potentials in Cocultured Isolectin B4-negative Medium-sized Trigeminal Ganglion Neurons.

Science.gov (United States)

Sato, Masaki; Ogura, Kazuhiro; Kimura, Maki; Nishi, Koichi; Ando, Masayuki; Tazaki, Masakazu; Shibukawa, Yoshiyuki

2018-04-27

Various stimuli to the dentin surface elicit dentinal pain by inducing dentinal fluid movement causing cellular deformation in odontoblasts. Although odontoblasts detect deformation by the activation of mechanosensitive ionic channels, it is still unclear whether odontoblasts are capable of establishing neurotransmission with myelinated A delta (Aδ) neurons. Additionally, it is still unclear whether these neurons evoke action potentials by neurotransmitters from odontoblasts to mediate sensory transduction in dentin. Thus, we investigated evoked inward currents and evoked action potentials form trigeminal ganglion (TG) neurons after odontoblast mechanical stimulation. We used patch clamp recordings to identify electrophysiological properties and record evoked responses in TG neurons. We classified TG cells into small-sized and medium-sized neurons. In both types of neurons, we observed voltage-dependent inward currents. The currents from medium-sized neurons showed fast inactivation kinetics. When mechanical stimuli were applied to odontoblasts, evoked inward currents were recorded from medium-sized neurons. Antagonists for the ionotropic adenosine triphosphate receptor (P2X 3 ), transient receptor potential channel subfamilies, and Piezo1 channel significantly inhibited these inward currents. Mechanical stimulation to odontoblasts also generated action potentials in the isolectin B 4 -negative medium-sized neurons. Action potentials in these isolectin B 4 -negative medium-sized neurons showed a short duration. Overall, electrophysiological properties of neurons indicate that the TG neurons with recorded evoked responses after odontoblast mechanical stimulation were myelinated Aδ neurons. Odontoblasts established neurotransmission with myelinated Aδ neurons via P2X 3 receptor activation. The results also indicated that mechanosensitive TRP/Piezo1 channels were functionally expressed in odontoblasts. The activation of P2X 3 receptors induced an action potential

Mode of action of alginic acid compound in the reduction of gastroesophageal reflux

International Nuclear Information System (INIS)

Malmud, L.S.; Charkes, N.D.; Littlefield, J.; Reilley, J.; Stern, H.; Rosenberg, R.; Fisher, R.S.

1979-01-01

This study was designed to evaluate quantitatively the mode of action of alginic acid compound (AAC) in the treatment of patients with symptomatic gastroesophageal reflux. Gastroesophageal scintigraphy using an orally administered Tc-99m sulfur colloid solution was used to demonstrate that AAC decreased significantly the gastroesophageal reflux index from (9.9 +- 1.3)% to (6.5 +- 0.8)% (p < 0.05). No alteration of lower esophageal sphincter pressure was observed. After AAC was suitably labeled with Sr-87m, a dual-nuclide scintigraphic technique was used to show that most (< 75%) of the AAC was located in the upper half of the stomach in both normal subjects and patients with gastroesophageal reflux. In those subjects in whom reflux did occur after treatment with AAC, the Sr-87m-AAC refluxed into the esophagus preferentially compared with the liquid containing Tc-99m sulfur colloid. These findings suggest that AAC diminishes gastroesophageal reflux by means of its foaming, floating, and viscous properties

Effects of vitamin D compounds on renal and intestinal Ca2+ transport proteins in 25-hydroxyvitamin D3-1alpha-hydroxylase knockout mice.

NARCIS (Netherlands)

Hoenderop, J.G.J.; Kemp, J.W.C.M. van der; Urben, C.M.; Strugnell, S.A.; Bindels, R.J.M.

2004-01-01

BACKGROUND: Vitamin D compounds are used clinically to control secondary hyperparathyroidism (SHPT) due to renal failure. Newer vitamin D compounds retain the suppressive action of 1,25(OH)(2)D(3) on the parathyroid glands and may have less Ca(2+)-mobilizing activity, offering potentially safer

Corrective Action Investigation Plan for Corrective Action Unit 410: Waste Disposal Trenches, Tonopah Test Range, Nevada, Revision No.:0

International Nuclear Information System (INIS)

2002-01-01

This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 410 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 410 is located on the Tonopah Test Range (TTR), which is included in the Nevada Test and Training Range (formerly the Nellis Air Force Range) approximately 140 miles northwest of Las Vegas, Nevada. This CAU is comprised of five Corrective Action Sites (CASs): TA-19-002-TAB2, Debris Mound; TA-21-003-TANL, Disposal Trench; TA-21-002-TAAL, Disposal Trench; 09-21-001-TA09, Disposal Trenches; 03-19-001, Waste Disposal Site. This CAU is being investigated because contaminants may be present in concentrations that could potentially pose a threat to human health and/or the environment, and waste may have been disposed of with out appropriate controls. Four out of five of these CASs are the result of weapons testing and disposal activities at the TTR, and they are grouped together for site closure based on the similarity of the sites (waste disposal sites and trenches). The fifth CAS, CAS 03-19-001, is a hydrocarbon spill related to activities in the area. This site is grouped with this CAU because of the location (TTR). Based on historical documentation and process know-ledge, vertical and lateral migration routes are possible for all CASs. Migration of contaminants may have occurred through transport by infiltration of precipitation through surface soil which serves as a driving force for downward migration of contaminants. Land-use scenarios limit future use of these CASs to industrial activities. The suspected contaminants of potential concern which have been identified are volatile organic compounds; semivolatile organic compounds; high explosives; radiological constituents including depleted uranium

Ionization Potentials of Chemical Warfare Agents and Related Compounds Determined with Density Functional Theory

National Research Council Canada - National Science Library

Wright, J

2000-01-01

...) agents at contaminated sites. Reported herein are theoretical ionization potentials for CW agents and their related compounds calculated using density functional theory at the B3LYP/6-311+G(2d,p) level of theory...

76 FR 21938 - Potential Environmental Impacts of the Proposed Runway 13 Extension and Associated Actions for...

Science.gov (United States)

2011-04-19

... DEPARTMENT OF TRANSPORTATION Federal Aviation Administration Potential Environmental Impacts of the Proposed Runway 13 Extension and Associated Actions for the Devils Lake Regional Airport in Devils Lake, ND AGENCY: Federal Aviation Administration (FAA), Department of Transportation (DOT). ACTION...

Quantitative analysis of single muscle fibre action potentials recorded at known distances

NARCIS (Netherlands)

Albers, B.A.; Put, J.H.M.; Wallinga, W.; Wirtz, P.

1989-01-01

In vivo records of single fibre action potentials (SFAPs) have always been obtained at unknown distance from the active muscle fibre. A new experimental method has been developed enabling the derivation of the recording distance in animal experiments. A single fibre is stimulated with an

The Potential of Phytomelatonin as a Nutraceutical

Directory of Open Access Journals (Sweden)

Marino B. Arnao

2018-01-01

Full Text Available Phytomelatonin (plant melatonin is chemically related to the amino acid tryptophan and has many diverse properties. Phytomelatonin is an interesting compound due to its outstanding actions at the cellular and physiological level, especially its protective effect in plants exposed to diverse stress situations, while its vegetable origin offers many opportunities because it is a natural compound. We present an overview of its origin, its action in plants in general (particularly in plant species with high levels of phytomelatonin, and its possibilities for use as a nutraceutical with particular attention paid to the beneficial effects that it may have in human health. The differences between synthetic melatonin and phytomelatonin, according to its origin and purity, are presented. Finally, the current market for phytomelatonin and its limits and potentials are discussed.

Action of fluor and its compounds on plants

Energy Technology Data Exchange (ETDEWEB)

Kluczynski, B

1976-01-01

This paper contains a brief synthesis of data available from the literature and experimental studies on the influence of fluor and its compounds on plants. The basic part of the paper consists of a list of 301 plants (separately for trees and shrubs and separately for other plants) the resistance of which to fluor compounds has been estimated. The information on resistance has been collected either from field observations or from cabin studies (artificial gassing of plants). The plants have been assigned to three classes: resistant, medium resistant and susceptible. When the resistance has been reported on a more detailed scale than a 3 point one, the data was compressed with some approximation to these three classes. In the list only plants are included with a definite specific or varietal name.

A novel method for beef potentiator preparation and identification of its characteristic aroma compounds.

Science.gov (United States)

Gao, Xianli; Yan, Shuang; Yang, Bao; Lu, Jian; Jin, Zhao

2014-06-01

Beef potentiator (BP) is the most popular savoury flavour and regarded as the soul of the modern food industry. In this work, BP was prepared by a novel method with Aspergillus oryzae and Aspergillus niger (BPSF). Three other BPs prepared using commercial enzymes (Protamex, Flavourzyme and papain; BPCEs) were used as controls to investigate its aroma characteristics and related compounds. Sensory evaluation showed that BPSF possessed more favourable and distinctive sauce-like, meat-like, roast and alcoholic attributes when compared with BPCEs. Significantly higher contents (peak areas) and proportions of pyrazines, pyrroles, sulfurous compounds and alcohols in BPSF were responsible for its sensory characteristics, and most of these aroma compounds were derived from microbial metabolism during beef koji preparation and the Maillard reaction. BP prepared by synergistic fermentation with A. oryzae and A. niger is a potential alternative for BP preparation. © 2013 Society of Chemical Industry.

Outcome producing potential influences twelve-month-olds' interpretation of a novel action as goal-directed.

Science.gov (United States)

Biro, Szilvia; Verschoor, Stephan; Coalter, Esther; Leslie, Alan M

2014-11-01

Learning about a novel, goal-directed action is a complex process. It requires identifying the outcome of the action and linking the action to its outcome for later use in new situations to predict the action or to anticipate its outcome. We investigated the hypothesis that linking a novel action to a salient change in the environment is critical for infants to assign a goal to the novel action. We report a study in which we show that 12-month-old infants, who were provided with prior experience with a novel action accompanied with a salient visible outcome in one context, can interpret the same action as goal-directed even in the absence of the outcome in another context. Our control condition shows that prior experience with the action, but without the salient effect, does not lead to goal-directed interpretation of the novel action. We also found that, for the case of 9-month-olds infants, prior experience with the outcome producing potential of the novel action does not facilitate a goal-directed interpretation of the action. However, this failure was possibly due to difficulties with generalizing the learnt association to another context rather than with linking the action to its outcome. Copyright © 2014 Elsevier Inc. All rights reserved.

Role of action potential configuration and the contribution of C²⁺a and K⁺ currents to isoprenaline-induced changes in canine ventricular cells.

Science.gov (United States)

Szentandrássy, N; Farkas, V; Bárándi, L; Hegyi, B; Ruzsnavszky, F; Horváth, B; Bányász, T; Magyar, J; Márton, I; Nánási, P P

2012-10-01

Although isoprenaline (ISO) is known to activate several ion currents in mammalian myocardium, little is known about the role of action potential morphology in the ISO-induced changes in ion currents. Therefore, the effects of ISO on action potential configuration, L-type Ca²⁺ current (I(Ca)), slow delayed rectifier K⁺ current (I(Ks)) and fast delayed rectifier K⁺ current (I(Kr)) were studied and compared in a frequency-dependent manner using canine isolated ventricular myocytes from various transmural locations. Action potentials were recorded with conventional sharp microelectrodes; ion currents were measured using conventional and action potential voltage clamp techniques. In myocytes displaying a spike-and-dome action potential configuration (epicardial and midmyocardial cells), ISO caused reversible shortening of action potentials accompanied by elevation of the plateau. ISO-induced action potential shortening was absent in endocardial cells and in myocytes pretreated with 4-aminopyridine. Application of the I(Kr) blocker E-4031 failed to modify the ISO effect, while action potentials were lengthened by ISO in the presence of the I(Ks) blocker HMR-1556. Both action potential shortening and elevation of the plateau were prevented by pretreatment with the I(Ca) blocker nisoldipine. Action potential voltage clamp experiments revealed a prominent slowly inactivating I(Ca) followed by a rise in I(Ks) , both currents increased with increasing the cycle length. The effect of ISO in canine ventricular cells depends critically on action potential configuration, and the ISO-induced activation of I(Ks) - but not I(Kr) - may be responsible for the observed shortening of action potentials. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

The Mode of Action of Isocyanide in Three Aquatic Organisms, Balanus amphitrite, Bugula neritina and Danio rerio

KAUST Repository

Zhang, Yi-Fan; Kitano, Yoshikazu; Nogata, Yasuyuki; Zhang, Yu; Qian, Pei-Yuan

2012-01-01

Isocyanide is a potential antifouling compound in marine environments. In this study, we investigated its mode of action in three aquatic organisms. Two of them, the bryozoan Bugula neritina and the barnacle Balanus amphitrite, are major marine

A dual potassium channel activator improves repolarization reserve and normalizes ventricular action potentials

DEFF Research Database (Denmark)

Calloe, Kirstine; Di Diego, José M; Hansen, Rie Schultz

2016-01-01

in cultured canine cardiac myocytes and determined whether a dual K(+) current activator can normalize K(+) currents and restore action potential (AP) configuration. METHODS AND RESULTS: Ventricular myocytes were isolated and cultured for up to 48h. Current and voltage clamp recordings were made using patch...... of EADs. Our results suggest a potential benefit of K(+) current activators under conditions of reduced repolarization reserve including heart failure....

New compounds as potential radio diagnosticians Alzheimer

International Nuclear Information System (INIS)

Rivera Marrero, S.; Sablón Carrazana, M.; Bencomo Martinez, A.; Merceron Martínez, D.; Jimenez Martín, J.; Pérez Perera, R.; Díaz García, O.; Rodríguez Tanty, Ch.; Prats Capote, A.; Perera Pintado, A; Fernández Maza, L.; Balcerzyk, M; Fernández Gómez, I.; Parrado Gallego, Á; León Chaviano, S.; Acosta Medina, E.

2016-01-01

Alzheimer's disease (AD) is the most common cause of dementia in Cuba and all over the World. According to demographic trends it has been called the epidemic of the century. It is characterized by the presence of neuropathological brain deposits: senile plaques, formed by neurofibrillary tangles (NT) and deposits of β-amyloid protein (Aß). Aß plaques could appear even 20 years before the establishment of first clinical symptoms of the disease. The aim of this study was to synthesize new naphthalene derivatives, feasible to be labeled with radionuclides emitters of either gamma radiation or positrons. These labeled compounds should be able to cross blood–brain barrier (BBB) in healthy and AD transgenic animals. As a result of this work, several synthetic precursors were synthesized, which were labeled with iodine-131, carbon-11 and fluorine-18 with a satisfactory radiochemical purity. The corresponding non-radioactive control compounds were also synthesized.In in vitro and in silico studies, obtained compounds showed affinity for the β-amyloid protein. According to SPECT and PET-CT images in healthy laboratory animals, obtained labeled compounds crossed BBB in a bi-directional way without any sign of brain uptake.Furthermore, evaluation of the biodistribution of the [ 18 F] -2- (3-fluoropropyl) -6-methoxynaphthalene ([[ 18 F] Amyloid® was performed in healthy animals.[[ 18 F]Amylovis crossed blood brain barrier. Renal and hepatic pathways were the main excretion routes. On the other hand, in transgenic mice with AD, its uptake and its retention time were higher in comparison with healthy mice. Immunohistochemistry and Congo red staining of control and transgenic mice brain slices were performed to identify β-amyloid plaques.Conclusions: Obtained compounds were able to bi-directionally cross BBB.[[ 18 F]Amylovis® could be a promising PET radiotracer for amyloid plaques visualization. (author)

Action potential propagation recorded from single axonal arbors using multi-electrode arrays.

Science.gov (United States)

Tovar, Kenneth R; Bridges, Daniel C; Wu, Bian; Randall, Connor; Audouard, Morgane; Jang, Jiwon; Hansma, Paul K; Kosik, Kenneth S

2018-04-11

We report the presence of co-occurring extracellular action potentials (eAPs) from cultured mouse hippocampal neurons among groups of planar electrodes on multi-electrode arrays (MEAs). The invariant sequences of eAPs among co-active electrode groups, repeated co-occurrences and short inter-electrode latencies are consistent with action potential propagation in unmyelinated axons. Repeated eAP co-detection by multiple electrodes was widespread in all our data records. Co-detection of eAPs confirms they result from the same neuron and allows these eAPs to be isolated from all other spikes independently of spike sorting algorithms. We averaged co-occurring events and revealed additional electrodes with eAPs that would otherwise be below detection threshold. We used these eAP cohorts to explore the temperature sensitivity of action potential propagation and the relationship between voltage-gated sodium channel density and propagation velocity. The sequence of eAPs among co-active electrodes 'fingerprints' neurons giving rise to these events and identifies them within neuronal ensembles. We used this property and the non-invasive nature of extracellular recording to monitor changes in excitability at multiple points in single axonal arbors simultaneously over several hours, demonstrating independence of axonal segments. Over several weeks, we recorded changes in inter-electrode propagation latencies and ongoing changes in excitability in different regions of single axonal arbors. Our work illustrates how repeated eAP co-occurrences can be used to extract physiological data from single axons with low electrode density MEAs. However, repeated eAP co-occurrences leads to over-sampling spikes from single neurons and thus can confound traditional spike-train analysis.

Towards integrated environmental quality objectives for several compounds with a potential for secondary poisoning

NARCIS (Netherlands)

Plassche EJ van de; ACT; VW/RWS-DGW; AIDE

1994-01-01

Values are derived which can be used to set integrated environmental quality objectives (limit and target values) for 25 compounds with a potential for secondary poisoning. First, Maximum Permissible Concentrations (MPs) and Negligible Concentrations (NCs) are derived for water, sediment and soil

The human ether-a-go-go-related gene (hERG) current inhibition selectively prolongs action potential of midmyocardial cells to augment transmural dispersion.

Science.gov (United States)

Yasuda, C; Yasuda, S; Yamashita, H; Okada, J; Hisada, T; Sugiura, S

2015-08-01

The majority of drug induced arrhythmias are related to the prolongation of action potential duration following inhibition of rapidly activating delayed rectifier potassium current (I(Kr)) mediated by the hERG channel. However, for arrhythmias to develop and be sustained, not only the prolongation of action potential duration but also its transmural dispersion are required. Herein, we evaluated the effect of hERG inhibition on transmural dispersion of action potential duration using the action potential clamp technique that combined an in silico myocyte model with the actual I(Kr) measurement. Whole cell I(Kr) current was measured in Chinese hamster ovary cells stably expressing the hERG channel. The measured current was coupled with models of ventricular endocardial, M-, and epicardial cells to calculate the action potentials. Action potentials were evaluated under control condition and in the presence of 1, 10, or 100 μM disopyramide, an hERG inhibitor. Disopyramide dose-dependently increased the action potential durations of the three cell types. However, action potential duration of M-cells increased disproportionately at higher doses, and was significantly different from that of epicardial and endocardial cells (dispersion of repolarization). By contrast, the effects of disopyramide on peak I(Kr) and instantaneous current-voltage relation were similar in all cell types. Simulation study suggested that the reduced repolarization reserve of M-cell with smaller amount of slowly activating delayed rectifier potassium current levels off at longer action potential duration to make such differences. The action potential clamp technique is useful for studying the mechanism of arrhythmogenesis by hERG inhibition through the transmural dispersion of repolarization.

Anti-addiction Drug Ibogaine Prolongs the Action Potential in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Science.gov (United States)

Rubi, Lena; Eckert, Daniel; Boehm, Stefan; Hilber, Karlheinz; Koenig, Xaver

2017-04-01

Ibogaine is a plant alkaloid used as anti-addiction drug in dozens of alternative medicine clinics worldwide. Recently, alarming reports of life-threatening cardiac arrhythmias and cases of sudden death associated with the ingestion of ibogaine have accumulated. Using whole-cell patch clamp recordings, we assessed the effects of ibogaine and its main metabolite noribogaine on action potentials in human ventricular-like cardiomyocytes derived from induced pluripotent stem cells. Therapeutic concentrations of ibogaine and its long-lived active metabolite noribogaine significantly retarded action potential repolarization in human cardiomyocytes. These findings represent the first experimental proof that ibogaine application entails a cardiac arrhythmia risk for humans. In addition, they explain the clinically observed delayed incidence of cardiac adverse events several days after ibogaine intake. We conclude that therapeutic concentrations of ibogaine retard action potential repolarization in the human heart. This may give rise to a prolongation of the QT interval in the electrocardiogram and cardiac arrhythmias.

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

Science.gov (United States)

Swedberg, Michael D B

2016-01-01

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit

Corrective Action Investigation Plan for Corrective Action Unit 409: Other Waste Sites, Tonopah Test Range, Nevada (Rev. 0)

International Nuclear Information System (INIS)

2000-01-01

This Corrective Action Investigation Plan contains the U.S. Department of Energy, Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 409 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 409 consists of three Corrective Action Sites (CASs): TA-53-001-TAB2, Septic Sludge Disposal Pit No.1; TA-53-002-TAB2, Septic Sludge Disposal Pit No.2; and RG-24-001-RGCR, Battery Dump Site. The Septic Sludge Disposal Pits are located near Bunker Two, close to Area 3, on the Tonopah Test Range. The Battery Dump Site is located at the abandoned Cactus Repeater Station on Cactus Peak. The Cactus Repeater Station was a remote, battery-powered, signal repeater station. The two Septic Sludge Disposal Pits were suspected to be used through the late 1980s as disposal sites for sludge from septic tanks located in Area 3. Based on site history collected to support the Data Quality Objectives process, contaminants of potential concern are the same for the disposal pits and include: volatile organic compounds (VOCs), semivolatile organic compounds, total petroleum hydrocarbons (TPHs) as gasoline- and diesel-range organics, polychlorinated biphenyls, Resource Conservation and Recovery Act metals, and radionuclides (including plutonium and depleted uranium). The Battery Dump Site consists of discarded lead-acid batteries and associated construction debris, placing the site in a Housekeeping Category and, consequently, no contaminants are expected to be encountered during the cleanup process. The corrective action the at this CAU will include collection of discarded batteries and construction debris at the Battery Dump Site for proper disposal and recycling, along with photographic documentation as the process progresses. The corrective action for the remaining CASs involves the collection of background radiological data through borings drilled at

Action Research’s Potential to Foster Institutional Change for Urban Water Management

Directory of Open Access Journals (Sweden)

Dimitrios Zikos

2013-04-01

Full Text Available The paper discusses the potential of action research to meet the challenges entailed in institutional design for urban water management. Our overall aim is to briefly present action research and discuss its methodological merits with regard to the challenges posed by the different conceptual bases for extrapolating the effects of institutional design on institutional change. Thus, our aim is to explore how Action Research meets the challenge of scoping the field in an open fashion for determining the appropriate mechanisms of institutional change and supporting the emerging of new water institutions. To accomplish this aim, we select the Water Framework Directive (WFD as an illustrative driving force requiring changes in water management practices and implying the need for the emergence of new institutions. We employ a case of urban water management in the Volos Metropolitan Area, part of the Thessaly region in Greece, where a Pilot River Basin Plan was implemented. By applying action research and being involved in a long process of interaction between stakeholders, we examine the emergence of new institutions dealing with urban water management under the general principles of the major driving force for change: the WFD.

Event-related potential effects of superior action anticipation in professional badminton players.

Science.gov (United States)

Jin, Hua; Xu, Guiping; Zhang, John X; Gao, Hongwei; Ye, Zuoer; Wang, Pin; Lin, Huiyan; Mo, Lei; Lin, Chong-De

2011-04-04

The ability to predict the trajectory of a ball based on the opponent's body kinematics has been shown to be critical to high-performing athletes in many sports. However, little is known about the neural correlates underlying such superior ability in action anticipation. The present event-related potential study compared brain responses from professional badminton players and non-player controls when they watched video clips of badminton games and predicted a ball's landing position. Replicating literature findings, the players made significantly more accurate judgments than the controls and showed better action anticipation. Correspondingly, they showed enlarged amplitudes of two ERP components, a P300 peaking around 350ms post-stimulus with a parietal scalp distribution and a P2 peaking around 250ms with a posterior-occipital distribution. The P300 effect was interpreted to reflect primed access and/or directing of attention to game-related memory representations in the players facilitating their online judgment of related actions. The P2 effect was suggested to reflect some generic learning effects. The results identify clear neural responses that differentiate between different levels of action anticipation associated with sports expertise. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Action Learning: Avoiding Conflict or Enabling Action

Science.gov (United States)

Corley, Aileen; Thorne, Ann

2006-01-01

Action learning is based on the premise that action and learning are inextricably entwined and it is this potential, to enable action, which has contributed to the growth of action learning within education and management development programmes. However has this growth in action learning lead to an evolution or a dilution of Revan's classical…

Bioavailability of dietary phenolic compounds: Review

Directory of Open Access Journals (Sweden)

Erick Gutiérrez-Grijalva Paul Gutiérrez-Grijalva

2015-12-01

Full Text Available Phenolic compounds are ubiquitous in plant-based foods. High dietary intake of fruits, vegetables and cereals is related to a decreased rate in chronic diseases. Phenolic compounds are thought to be responsible, at least in part, for those health effects. Nonetheless, phenolic compounds bioaccessibility and biotransformation is often not considered in these studies; thus, a precise mechanism of action of phenolic compounds is not known. In this review we aim to present a comprehensive knowledge of the metabolic processes through which phenolic compounds go after intake.

Properties of tritium and its compounds

International Nuclear Information System (INIS)

Belovodskij, L.F.; Gaevoj, V.K.; Grishmanovskij, V.I.

1985-01-01

Ways of tritium preparation and different aspects of its application are considered. Physicochemical properties of this isotope and some compounds of it - tritium oxides, lithium, titanium, zirconium, uranium tritides, tritium organic compounds - are discussed. In particular, diffusion of tritium and its oxide through different materials, tritium oxidation processes, decomposition of tritium-containing compounds under the action of self-radiation are considered. Main radiobiological tritium properties are described

Beat-to-beat variability of cardiac action potential duration: underlying mechanism and clinical implications.

Science.gov (United States)

Nánási, Péter P; Magyar, János; Varró, András; Ördög, Balázs

2017-10-01

Beat-to-beat variability of cardiac action potential duration (short-term variability, SV) is a common feature of various cardiac preparations, including the human heart. Although it is believed to be one of the best arrhythmia predictors, the underlying mechanisms are not fully understood at present. The magnitude of SV is basically determined by the intensity of cell-to-cell coupling in multicellular preparations and by the duration of the action potential (APD). To compensate for the APD-dependent nature of SV, the concept of relative SV (RSV) has been introduced by normalizing the changes of SV to the concomitant changes in APD. RSV is reduced by I Ca , I Kr , and I Ks while increased by I Na , suggesting that ion currents involved in the negative feedback regulation of APD tend to keep RSV at a low level. RSV is also influenced by intracellular calcium concentration and tissue redox potential. The clinical implications of APD variability is discussed in detail.

Antiviral Screening of Multiple Compounds against Ebola Virus.

Science.gov (United States)

Dowall, Stuart D; Bewley, Kevin; Watson, Robert J; Vasan, Seshadri S; Ghosh, Chandradhish; Konai, Mohini M; Gausdal, Gro; Lorens, James B; Long, Jason; Barclay, Wendy; Garcia-Dorival, Isabel; Hiscox, Julian; Bosworth, Andrew; Taylor, Irene; Easterbrook, Linda; Pitman, James; Summers, Sian; Chan-Pensley, Jenny; Funnell, Simon; Vipond, Julia; Charlton, Sue; Haldar, Jayanta; Hewson, Roger; Carroll, Miles W

2016-10-27

In light of the recent outbreak of Ebola virus (EBOV) disease in West Africa, there have been renewed efforts to search for effective antiviral countermeasures. A range of compounds currently available with broad antimicrobial activity have been tested for activity against EBOV. Using live EBOV, eighteen candidate compounds were screened for antiviral activity in vitro. The compounds were selected on a rational basis because their mechanisms of action suggested that they had the potential to disrupt EBOV entry, replication or exit from cells or because they had displayed some antiviral activity against EBOV in previous tests. Nine compounds caused no reduction in viral replication despite cells remaining healthy, so they were excluded from further analysis (zidovudine; didanosine; stavudine; abacavir sulphate; entecavir; JB1a; Aimspro; celgosivir; and castanospermine). A second screen of the remaining compounds and the feasibility of appropriateness for in vivo testing removed six further compounds (ouabain; omeprazole; esomeprazole; Gleevec; D-LANA-14; and Tasigna). The three most promising compounds (17-DMAG; BGB324; and NCK-8) were further screened for in vivo activity in the guinea pig model of EBOV disease. Two of the compounds, BGB324 and NCK-8, showed some effect against lethal infection in vivo at the concentrations tested, which warrants further investigation. Further, these data add to the body of knowledge on the antiviral activities of multiple compounds against EBOV and indicate that the scientific community should invest more effort into the development of novel and specific antiviral compounds to treat Ebola virus disease.

Antiviral Screening of Multiple Compounds against Ebola Virus

Directory of Open Access Journals (Sweden)

Stuart D. Dowall

2016-10-01

Full Text Available In light of the recent outbreak of Ebola virus (EBOV disease in West Africa, there have been renewed efforts to search for effective antiviral countermeasures. A range of compounds currently available with broad antimicrobial activity have been tested for activity against EBOV. Using live EBOV, eighteen candidate compounds were screened for antiviral activity in vitro. The compounds were selected on a rational basis because their mechanisms of action suggested that they had the potential to disrupt EBOV entry, replication or exit from cells or because they had displayed some antiviral activity against EBOV in previous tests. Nine compounds caused no reduction in viral replication despite cells remaining healthy, so they were excluded from further analysis (zidovudine; didanosine; stavudine; abacavir sulphate; entecavir; JB1a; Aimspro; celgosivir; and castanospermine. A second screen of the remaining compounds and the feasibility of appropriateness for in vivo testing removed six further compounds (ouabain; omeprazole; esomeprazole; Gleevec; D-LANA-14; and Tasigna. The three most promising compounds (17-DMAG; BGB324; and NCK-8 were further screened for in vivo activity in the guinea pig model of EBOV disease. Two of the compounds, BGB324 and NCK-8, showed some effect against lethal infection in vivo at the concentrations tested, which warrants further investigation. Further, these data add to the body of knowledge on the antiviral activities of multiple compounds against EBOV and indicate that the scientific community should invest more effort into the development of novel and specific antiviral compounds to treat Ebola virus disease.

Distribution and potential ecological risk of 50 phenolic compounds in three rivers in Tianjin, China.

Science.gov (United States)

Zhong, Wenjue; Wang, Donghong; Wang, Zijian

2018-04-01

Phenolic compounds widely exist in the surface water of many countries; however, few studies have simultaneously analyzed and evaluated broad-spectrum phenolic compounds in various components of the water environment. Therefore this study analyzed the distribution and potential ecological risk of 50 phenolic compounds in the surface water, sediment and suspended particulate matter of three important rivers in Tianjin, the main heavy industry city with high pollution in China. The qualitative results show that phenolic pollution existed extensively in the three rivers and the kinds of phenolic compounds in the water were relatively higher than in both sediment and suspended particulate matter. The quantitative results show that the phenolic pollution in the wet-season samples was serious than dry-season samples. Meanwhile, total concentrations of phenolic compounds in three components from the Dagu Drainage River (DDR) were all much higher than those in the Beitang Drainage River (BDR) and Yongdingxin River (YDXR). The highest total concentrations of phenolic compounds in three components all appeared in wet-season samples in DDR, and the highest total concentration was 1354 μg/L in surface water, 719 μg/kg dw in suspended particulate matter and 2937 μg/kg dw in sediment, respectively. The ecological risk of phenolic compounds in surface water was evaluated using the quotient method, and phenolic compounds with risk quotient (RQ) > 1 (RQ > 0.3 for YDXR) were identified as priority pollutants. Five kinds of phenolic compounds were identified as priority phenolic compounds in BDR, and the order of risk was 2-cresol > 2,4-xylenol > 2-sec-butylphenol > 2-naphthol > 3-cresol. Six kinds of phenolic compounds were identified as priority phenolic compounds in DDR, and the order of risk was 2-naphthol > p-chloro-m-xylenol > 4-cresol > 3-cresol > 2,4-xylenol > 2,3,6-Trimethylphenol. In YDXR, only phenol, 2-naphthol and 2,4-xylenol were identified as

Effect of an Educational Game on University Students' Learning about Action Potentials

Science.gov (United States)

Luchi, Kelly Cristina Gaviao; Montrezor, Luís Henrique; Marcondes, Fernanda K.

2017-01-01

The aim of this study was to evaluate the effect of an educational game that is used for teaching the mechanisms of the action potentials in cell membranes. The game was composed of pieces representing the intracellular and extracellular environments, ions, ion channels, and the Na+-K+-ATPase pump. During the game activity, the students arranged…

Action potential conduction between a ventricular cell model and an isolated ventricular cell

NARCIS (Netherlands)

Wilders, R.; Kumar, R.; Joyner, R. W.; Jongsma, H. J.; Verheijck, E. E.; Golod, D.; van Ginneken, A. C.; Goolsby, W. N.

1996-01-01

We used the Luo and Rudy (LR) mathematical model of the guinea pig ventricular cell coupled to experimentally recorded guinea pig ventricular cells to investigate the effects of geometrical asymmetry on action potential propagation. The overall correspondence of the LR cell model with the recorded

Pathological prolongation of action potential duration as a cause of the reduced alpha-adrenoceptor-mediated negative inotropy in streptozotocin-induced diabetic mice myocardium.

Science.gov (United States)

Kanae, Haruna; Hamaguchi, Shogo; Wakasugi, Yumi; Kusakabe, Taichi; Kato, Keisuke; Namekata, Iyuki; Tanaka, Hikaru

2017-11-01

Effect of pathological prolongation of action potential duration on the α-adrenoceptor-mediated negative inotropy was studied in streptozotocin-induced diabetic mice myocardium. In streptozotocin-treated mouse ventricular myocardium, which had longer duration of action potential than that in control mice, the negative inotropic response induced by phenylephrine was smaller than that in control mice. 4-Aminopyridine prolonged the action potential duration and decreased the negative inotropy in control mice. Cromakalim shortened the action potential duration and increased the negative inotropy in streptozotocin-treated mice. These results suggest that the reduced α-adrenoceptor-mediated inotropy in the diabetic mouse myocardium is partly due to its prolonged action potential. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Teachers in Action Research: Assumptions and Potentials

Science.gov (United States)

Li, Yuen-Ling

2008-01-01

Research literature has long indicated that action research may stimulate practitioners themselves to actively evaluate the quality of their practice. This study is designed to report the use of action research for the development of early years professional practice by analyzing the pre-project and the post-project video-filmed teaching events.…

Study of antineoplastic action of novel isomeric derivatives of 4-thiazolidinone

Directory of Open Access Journals (Sweden)

М. R. Fil

2014-12-01

Full Text Available Pyrazole- and aryl-substituted derivatives of 4-thiazolidinone belong to a perspective group of compounds with potential antitumor action. Earlier, we have demonstrated high toxicity in vitro of several 4-thiazolidinones derivatives towards tumor cell lines. To further enhance the antitumor activity of novel 4-thiazolidinones, their chemical scaffold was optimized, and new pyrazole-thiazolidinones were synthesized. That allowed us to combine in one molecule the potential pharmacophore centres of previously tested compounds. As a result, “hybrid” 4-thiazolidinones exhibit higher toxicity in vitro toward tumor cells of various origin. The molecular mechanisms of antineoplastic activity of these compounds and intensity of induction of apoptosis strongly depended on the position of the substituent in the thiazolidinone cycle. In particular, Les-3661 compound, containing pyrazoline fragment in the 4th position of thiazolidinone core, exhibits 14 times higher cytotoxic activity towards tumor cells (LC50 = 3 µM in comparison to its 2-substituted isomer Les-3713 (LC50 = 42 µM. It is demonstrated that in terms of underlying molecular mechanisms for cytotoxic effect the Les-3661 compound induced caspase-8 and caspase-9 dependent mixed-type of apoptosis, while Les-3713 induced apoptosis mediated only by the caspase-8.

An Excel‐based implementation of the spectral method of action potential alternans analysis

Science.gov (United States)

Pearman, Charles M.

2014-01-01

Abstract Action potential (AP) alternans has been well established as a mechanism of arrhythmogenesis and sudden cardiac death. Proper interpretation of AP alternans requires a robust method of alternans quantification. Traditional methods of alternans analysis neglect higher order periodicities that may have greater pro‐arrhythmic potential than classical 2:1 alternans. The spectral method of alternans analysis, already widely used in the related study of microvolt T‐wave alternans, has also been used to study AP alternans. Software to meet the specific needs of AP alternans analysis is not currently available in the public domain. An AP analysis tool is implemented here, written in Visual Basic for Applications and using Microsoft Excel as a shell. This performs a sophisticated analysis of alternans behavior allowing reliable distinction of alternans from random fluctuations, quantification of alternans magnitude, and identification of which phases of the AP are most affected. In addition, the spectral method has been adapted to allow detection and quantification of higher order regular oscillations. Analysis of action potential morphology is also performed. A simple user interface enables easy import, analysis, and export of collated results. PMID:25501439

From screen to target: insights and approaches into the development of anti-virulence compounds

Directory of Open Access Journals (Sweden)

Katherine SH Beckham

2014-09-01

Full Text Available The detailed understanding of host-pathogen interactions provides exciting opportunities to interfere with the infection process. Anti-virulence compounds aim to modulate or pacify pathogenesis by reducing expression of critical virulence determinants. In particular, prevention of attachment by inhibiting adhesion mechanisms has been the subject of intense research. Whilst it has proven relatively straightforward to develop robust screens for potential antivirulence compounds, understanding their precise mode of action has proven much more challenging. In this review we illustrate this challenge from our own experiences working with the salicylidene acylhydrazide group of compounds. We aim to provide a useful perspective to guide researchers interested in this field and to avoid some of the obvious pitfalls.

Corrective Action Investigation Plan for Corrective Action Unit 490: Station 44 Burn Area, Tonopah Test Range, Nevada (with Record of Technical Change No.1)

International Nuclear Information System (INIS)

2000-01-01

question of whether or not potentially hazardous wastes were generated at three of the four CASs within CAU 490, and whether or not potentially hazardous and radioactive wastes were generated at the fourth CAS in CAU 490 (CAS 09-54-001-09L2). Suspected CAS-specific COPCs include volatile organic compounds, semivolatile organic compounds, total petroleum hydrocarbons, polychlorinated biphenyls, pesticides, explosives, and uranium and plutonium isotopes. The results of this field investigation will support a defensible evaluation of corrective action alternatives in the corrective action decision document

Corrective Action Investigation Plan for Corrective Action Unit 490: Station 44 Burn Area, Tonopah Test Range, Nevada (with Record of Technical Change No.1)

Energy Technology Data Exchange (ETDEWEB)

U.S. Department of Energy, Nevada Operations Office

2000-06-09

the question of whether or not potentially hazardous wastes were generated at three of the four CASs within CAU 490, and whether or not potentially hazardous and radioactive wastes were generated at the fourth CAS in CAU 490 (CAS 09-54-001-09L2). Suspected CAS-specific COPCs include volatile organic compounds, semivolatile organic compounds, total petroleum hydrocarbons, polychlorinated biphenyls, pesticides, explosives, and uranium and plutonium isotopes. The results of this field investigation will support a defensible evaluation of corrective action alternatives in the corrective action decision document.

Ventricular filling slows epicardial conduction and increases action potential duration in an optical mapping study of the isolated rabbit heart

Science.gov (United States)

Sung, Derrick; Mills, Robert W.; Schettler, Jan; Narayan, Sanjiv M.; Omens, Jeffrey H.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

2003-01-01

INTRODUCTION: Mechanical stimulation can induce electrophysiologic changes in cardiac myocytes, but how mechanoelectric feedback in the intact heart affects action potential propagation remains unclear. METHODS AND RESULTS: Changes in action potential propagation and repolarization with increased left ventricular end-diastolic pressure from 0 to 30 mmHg were investigated using optical mapping in isolated perfused rabbit hearts. With respect to 0 mmHg, epicardial strain at 30 mmHg in the anterior left ventricle averaged 0.040 +/- 0.004 in the muscle fiber direction and 0.032 +/- 0.006 in the cross-fiber direction. An increase in ventricular loading increased average epicardial activation time by 25%+/- 3% (P action potential duration at 20% repolarization (APD20) but did at 80% repolarization (APD80), from 179 +/- 7 msec to 207 +/- 5 msec (P action potential duration by a load-dependent mechanism that may not involve stretch-activated channels.

Gene expression profiling in Ishikawa cells: A fingerprint for estrogen active compounds

International Nuclear Information System (INIS)

Boehme, Kathleen; Simon, Stephanie; Mueller, Stefan O.

2009-01-01

Several anthropogenous and naturally occurring substances, referred to as estrogen active compounds (EACs), are able to interfere with hormone and in particular estrogen receptor signaling. EACs can either cause adverse health effects in humans and wildlife populations or have beneficial effects on estrogen-dependent diseases. The aim of this study was to examine global gene expression profiles in estrogen receptor (ER)-proficient Ishikawa plus and ER-deficient Ishikawa minus endometrial cancer cells treated with selected well-known EACs (Diethylstilbestrol, Genistein, Zearalenone, Resveratrol, Bisphenol A and o,p'-DDT). We also investigated the effect of the pure antiestrogen ICI 182,780 (ICI) on the expression patterns caused by these compounds. Transcript levels were quantified 24 h after compound treatment using Illumina BeadChip Arrays. We identified 87 genes with similar expression changes in response to all EAC treatments in Ishikawa plus. ICI lowered the magnitude or reversed the expression of these genes, indicating ER dependent regulation. Apart from estrogenic gene regulation, Bisphenol A, o,p'-DDT, Zearalenone, Genistein and Resveratrol displayed similarities to ICI in their expression patterns, suggesting mixed estrogenic/antiestrogenic properties. In particular, the predominant antiestrogenic expression response of Resveratrol could be clearly distinguished from the other test compounds, indicating a distinct mechanism of action. Divergent gene expression patterns of the phytoestrogens, as well as weaker estrogenic gene expression regulation determined for the anthropogenous chemicals Bisphenol A and o,p'-DDT, warrants a careful assessment of potential detrimental and/or beneficial effects of EACs. The characteristic expression fingerprints and the identified subset of putative marker genes can be used for screening chemicals with an unknown mode of action and for predicting their potential to exert endocrine disrupting effects

The activity of spontaneous action potentials in developing hair cells is regulated by Ca(2+-dependence of a transient K+ current.

Directory of Open Access Journals (Sweden)

Snezana Levic

Full Text Available Spontaneous action potentials have been described in developing sensory systems. These rhythmic activities may have instructional roles for the functional development of synaptic connections. The importance of spontaneous action potentials in the developing auditory system is underpinned by the stark correlation between the time of auditory system functional maturity, and the cessation of spontaneous action potentials. A prominent K(+ current that regulates patterning of action potentials is I(A. This current undergoes marked changes in expression during chicken hair cell development. Although the properties of I(A are not normally classified as Ca(2+-dependent, we demonstrate that throughout the development of chicken hair cells, I(A is greatly reduced by acute alterations of intracellular Ca(2+. As determinants of spike timing and firing frequency, intracellular Ca(2+ buffers shift the activation and inactivation properties of the current to more positive potentials. Our findings provide evidence to demonstrate that the kinetics and functional expression of I(A are tightly regulated by intracellular Ca(2+. Such feedback mechanism between the functional expression of I(A and intracellular Ca(2+ may shape the activity of spontaneous action potentials, thus potentially sculpting synaptic connections in an activity-dependent manner in the developing cochlea.

Voltage Gated Calcium Channel Activation by Backpropagating Action Potentials Downregulates NMDAR Function

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Anne-Kathrin Theis

2018-04-01

Full Text Available The majority of excitatory synapses are located on dendritic spines of cortical glutamatergic neurons. In spines, compartmentalized Ca2+ signals transduce electrical activity into specific long-term biochemical and structural changes. Action potentials (APs propagate back into the dendritic tree and activate voltage gated Ca2+ channels (VGCCs. For spines, this global mode of spine Ca2+ signaling is a direct biochemical feedback of suprathreshold neuronal activity. We previously demonstrated that backpropagating action potentials (bAPs result in long-term enhancement of spine VGCCs. This activity-dependent VGCC plasticity results in a large interspine variability of VGCC Ca2+ influx. Here, we investigate how spine VGCCs affect glutamatergic synaptic transmission. We combined electrophysiology, two-photon Ca2+ imaging and two-photon glutamate uncaging in acute brain slices from rats. T- and R-type VGCCs were the dominant depolarization-associated Ca2+conductances in dendritic spines of excitatory layer 2 neurons and do not affect synaptic excitatory postsynaptic potentials (EPSPs measured at the soma. Using two-photon glutamate uncaging, we compared the properties of glutamatergic synapses of single spines that express different levels of VGCCs. While VGCCs contributed to EPSP mediated Ca2+ influx, the amount of EPSP mediated Ca2+ influx is not determined by spine VGCC expression. On a longer timescale, the activation of VGCCs by bAP bursts results in downregulation of spine NMDAR function.

Mechanism of action of a pestivirus antiviral compound

Science.gov (United States)

Baginski, Scott G.; Pevear, Daniel C.; Seipel, Marty; Sun, Siu Chi Chang; Benetatos, Christopher A.; Chunduru, Srinivas K.; Rice, Charles M.; Collett, Marc S.

2000-01-01

We report here the discovery of a small molecule inhibitor of pestivirus replication. The compound, designated VP32947, inhibits the replication of bovine viral diarrhea virus (BVDV) in cell culture at a 50% inhibitory concentration of approximately 20 nM. VP32947 inhibits both cytopathic and noncytopathic pestiviruses, including isolates of BVDV-1, BVDV-2, border disease virus, and classical swine fever virus. However, the compound shows no activity against viruses from unrelated virus groups. Time of drug addition studies indicated that VP32947 acts after virus adsorption and penetration and before virus assembly and release. Analysis of viral macromolecular synthesis showed VP32947 had no effect on viral protein synthesis or polyprotein processing but did inhibit viral RNA synthesis. To identify the molecular target of VP32947, we isolated drug-resistant (DR) variants of BVDV-1 in cell culture. Sequence analysis of the complete genomic RNA of two DR variants revealed a single common amino acid change located within the coding region of the NS5B protein, the viral RNA-dependent RNA polymerase. When this single amino acid change was introduced into an infectious clone of drug-sensitive wild-type (WT) BVDV-1, replication of the resulting virus was resistant to VP32947. The RNA-dependent RNA polymerase activity of the NS5B proteins derived from WT and DR viruses expressed and purified from recombinant baculovirus-infected insect cells confirmed the drug sensitivity of the WT enzyme and the drug resistance of the DR enzyme. This work formally validates NS5B as a target for antiviral drug discovery and development. The utility of VP32947 and similar compounds for the control of pestivirus diseases, and for hepatitis C virus drug discovery efforts, is discussed. PMID:10869440

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility.

Science.gov (United States)

Devenyi, Ryan A; Ortega, Francis A; Groenendaal, Willemijn; Krogh-Madsen, Trine; Christini, David J; Sobie, Eric A

2017-04-01

Arrhythmias result from disruptions to cardiac electrical activity, although the factors that control cellular action potentials are incompletely understood. We combined mathematical modelling with experiments in heart cells from guinea pigs to determine how cellular electrical activity is regulated. A mismatch between modelling predictions and the experimental results allowed us to construct an improved, more predictive mathematical model. The balance between two particular potassium currents dictates how heart cells respond to perturbations and their susceptibility to arrhythmias. Imbalances of ionic currents can destabilize the cardiac action potential and potentially trigger lethal cardiac arrhythmias. In the present study, we combined mathematical modelling with information-rich dynamic clamp experiments to determine the regulation of action potential morphology in guinea pig ventricular myocytes. Parameter sensitivity analysis was used to predict how changes in ionic currents alter action potential duration, and these were tested experimentally using dynamic clamp, a technique that allows for multiple perturbations to be tested in each cell. Surprisingly, we found that a leading mathematical model, developed with traditional approaches, systematically underestimated experimental responses to dynamic clamp perturbations. We then re-parameterized the model using a genetic algorithm, which allowed us to estimate ionic current levels in each of the cells studied. This unbiased model adjustment consistently predicted an increase in the rapid delayed rectifier K + current and a drastic decrease in the slow delayed rectifier K + current, and this prediction was validated experimentally. Subsequent simulations with the adjusted model generated the clinically relevant prediction that the slow delayed rectifier is better able to stabilize the action potential and suppress pro-arrhythmic events than the rapid delayed rectifier. In summary, iterative coupling of

Identification of a potential superhard compound ReCN

International Nuclear Information System (INIS)

Fan, Xiaofeng; Li, M.M.; Singh, David J.; Jiang, Qing; Zheng, W.T.

2015-01-01

Highlights: • We identify a new ternary compound ReCN with theoretical calculation. • The ternary compound ReCN is with two stable structures with P63mc and P3m1. • ReCN is a semiconductor from the calculation of electronic structures. • ReCN is found to possess the outstanding mechanical properties. • ReCN may be synthesized relatively easily. - Abstract: We identify a new ternary compound, ReCN and characterize its properties including structural stability and indicators of hardness using first principles calculations. We find that there are two stable structures with space groups P63mc (HI) and P3m1 (HII), in which there are no C–C and N–N bonds. Both structures, H1 and III are elastically and dynamically stable. The electronic structures show that ReCN is a semiconductor, although the parent compounds, ReC 2 and ReN 2 are both metallic. ReCN is found to possess the outstanding mechanical properties with the large bulk modulus, shear modulus and excellent ideal strengths. In addition, ReCN may perhaps be synthesized relatively easily because it becomes thermodynamic stable with respect to decomposition at very low pressures

NS5806 partially restores action potential duration but fails to ameliorate calcium transient dysfunction in a computational model of canine heart failure

DEFF Research Database (Denmark)

Maleckar, Mary M; Lines, Glenn T; Koivumäki, Jussi T

2014-01-01

AIMS: The study investigates how increased Ito, as mediated by the activator NS5806, affects excitation-contraction coupling in chronic heart failure (HF). We hypothesized that restoring spike-and-dome morphology of the action potential (AP) to a healthy phenotype would be insufficient to restore...... the intracellular Ca(2) (+) transient (CaT), due to HF-induced remodelling of Ca(2+) handling. METHODS AND RESULTS: An existing mathematical model of the canine ventricular myocyte was modified to incorporate recent experimental data from healthy and failing myocytes, resulting in models of both healthy and HF...... ionic processes with a focus on calcium transients (CaT), how these were altered in HF across the ventricular wall, and the subsequent effects of varying compound concentration in HF. Heart failure model variants recapitulated a characteristic increase in AP duration (APD) in the disease...

Action of certain chemical compounds on radiation haemolysis of erythrocytes

International Nuclear Information System (INIS)

Kolesnikov, Yu.A.; Shulgina, M.A.; Yartsev, E.I.; Novoseltseva, S.D.; Bogatyrev, G.P.

1975-01-01

A radioprotective action of a number of protective chemicals on radiation haemolysis of erythrocytes has been studied. S-bearing radioprotectors, serotonin and arginine possess the highest radioprotective activity. The same radioprotectors delivered to the medium after irradiation do not influence the development of the post-irradiation haemolysis. Certain amino acids, namely proline, serine and taurine have a pronounced radio-protective action when given to the medium after irradiation, taurine producing the strongest effect on the development of radiation haemolysis. The mechanism of action of these substances is unrelated to the increased osmotic pressure of the medium and might be explained by normalization of the functional state of cytomembranes and processes of cell metabolism

Bitropic D3 Dopamine Receptor Selective Compounds as Potential Antipsychotics.

Science.gov (United States)

Luedtke, Robert R; Rangel-Barajas, Claudia; Malik, Mahinder; Reichert, David E; Mach, R H

2015-01-01

Neuropsychiatric disorders represent a substantial social and health care issue. The National Institutes of Health estimates that greater than 2 million adults suffer from neuropsychiatric disorders in the USA. These individuals experience symptoms that can include auditory hallucinations, delusions, unrealistic beliefs and cognitive dysfunction. Although antipsychotic medications are available, suboptimal therapeutic responses are observed for approximately one-third of patients. Therefore, there is still a need to explore new pharmacotherapeutic strategies for the treatment of neuropsychiatric disorders. Many of the medications that are used clinically to treat neuropsychiatric disorders have a pharmacological profile that includes being an antagonist at D2-like (D2, D3 and D4) dopamine receptor subtypes. However, dopamine receptor subtypes are involved in a variety of neuronal circuits that include movement coordination, cognition, emotion, affect, memory and the regulation of prolactin. Consequently, antagonism at D2-like receptors can also contribute to some of the adverse side effects associated with the long-term use of antipsychotics including the a) adverse extrapyramidal symptoms associated with the use of typical antipsychotics and b) metabolic side effects (weight gain, hyperglycemia, increased risk of diabetes mellitus, dyslipidemia and gynecomastia) associated with atypical antipsychotic use. Preclinical studies suggest that D3 versus D2 dopamine receptor selective compounds might represent an alternative strategy for the treatment of the symptoms of schizophrenia. In this review we discuss a) how bitropic Nphenylpiperazine D3 dopamine receptor selective compounds have been developed by modification of the primary (orthosteric) and secondary (allosteric or modulatory) pharmacophores to optimize D3 receptor affinity and D2/D3 binding selectivity ratios and b) the functional selectivity of these compounds. Examples of how these compounds might be

Pharmaceutical Compounds in Wastewater: Wetland Treatment as a Potential Solution

OpenAIRE

White, John R.; Belmont, Marco A.; Metcalfe, Chris D.

2006-01-01

Pharmaceutical compounds are being released into the aquatic environment through wastewater discharge around the globe. While there is limited removal of these compounds within wastewater treatment plants, wetland treatment might prove to be an effective means to reduce the discharge of the compounds into the environment. Wetlands can promote removal of these pharmaceutical compounds through a number of mechanisms including photolysis, plant uptake, microbial degradation, and sorption to the ...

Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins.

Directory of Open Access Journals (Sweden)

Natalya Panova

Full Text Available The advantages offered by established antibiotics in the treatment of infectious diseases are endangered due to the increase in the number of antibiotic-resistant bacterial strains. This leads to a need for new antibacterial compounds. Recently, we discovered a series of compounds termed lipophosphonoxins (LPPOs that exhibit selective cytotoxicity towards Gram-positive bacteria that include pathogens and resistant strains. For further development of these compounds, it was necessary to identify the mechanism of their action and characterize their interaction with eukaryotic cells/organisms in more detail. Here, we show that at their bactericidal concentrations LPPOs localize to the plasmatic membrane in bacteria but not in eukaryotes. In an in vitro system we demonstrate that LPPOs create pores in the membrane. This provides an explanation of their action in vivo where they cause serious damage of the cellular membrane, efflux of the cytosol, and cell disintegration. Further, we show that (i LPPOs are not genotoxic as determined by the Ames test, (ii do not cross a monolayer of Caco-2 cells, suggesting they are unable of transepithelial transport, (iii are well tolerated by living mice when administered orally but not peritoneally, and (iv are stable at low pH, indicating they could survive the acidic environment in the stomach. Finally, using one of the most potent LPPOs, we attempted and failed to select resistant strains against this compound while we were able to readily select resistant strains against a known antibiotic, rifampicin. In summary, LPPOs represent a new class of compounds with a potential for development as antibacterial agents for topical applications and perhaps also for treatment of gastrointestinal infections.

Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins.

Science.gov (United States)

Panova, Natalya; Zborníková, Eva; Šimák, Ondřej; Pohl, Radek; Kolář, Milan; Bogdanová, Kateřina; Večeřová, Renata; Seydlová, Gabriela; Fišer, Radovan; Hadravová, Romana; Šanderová, Hana; Vítovská, Dragana; Šiková, Michaela; Látal, Tomáš; Lovecká, Petra; Barvík, Ivan; Krásný, Libor; Rejman, Dominik

2015-01-01

The advantages offered by established antibiotics in the treatment of infectious diseases are endangered due to the increase in the number of antibiotic-resistant bacterial strains. This leads to a need for new antibacterial compounds. Recently, we discovered a series of compounds termed lipophosphonoxins (LPPOs) that exhibit selective cytotoxicity towards Gram-positive bacteria that include pathogens and resistant strains. For further development of these compounds, it was necessary to identify the mechanism of their action and characterize their interaction with eukaryotic cells/organisms in more detail. Here, we show that at their bactericidal concentrations LPPOs localize to the plasmatic membrane in bacteria but not in eukaryotes. In an in vitro system we demonstrate that LPPOs create pores in the membrane. This provides an explanation of their action in vivo where they cause serious damage of the cellular membrane, efflux of the cytosol, and cell disintegration. Further, we show that (i) LPPOs are not genotoxic as determined by the Ames test, (ii) do not cross a monolayer of Caco-2 cells, suggesting they are unable of transepithelial transport, (iii) are well tolerated by living mice when administered orally but not peritoneally, and (iv) are stable at low pH, indicating they could survive the acidic environment in the stomach. Finally, using one of the most potent LPPOs, we attempted and failed to select resistant strains against this compound while we were able to readily select resistant strains against a known antibiotic, rifampicin. In summary, LPPOs represent a new class of compounds with a potential for development as antibacterial agents for topical applications and perhaps also for treatment of gastrointestinal infections.

Extraction and evaluation of bioactive compounds with antioxidant potential from green arabica coffee extract

Directory of Open Access Journals (Sweden)

Simona PATRICHE

2015-12-01

Full Text Available During the last decade researches concerning the essential role of coffee in health and disease prevention showed an increased development. In the present study we obtained extracts from three green Arabica coffee varieties which demonstrated a significant antioxidant potential due to the presence in their composition of two bioactive compounds, caffeine and chlorogenic acids. The content and antioxidant activity of bioactive compounds were evaluated by qualitative and quantitative analyses using spectrophotometric and chromatography methods. The chlorogenic acid was found in high concentrations, being followed by gallic, p-coumaric and ferulic acids. The highest caffeine contents were found in the green coffee extracts of the Supremo–Columbia and Top Quality–Kenya products.

Mode of action of Organotins in Immune cells

NARCIS (Netherlands)

Hendriksen, P.J.M.; Schmeits, P.C.J.; Loveren, van H.; Shao, J.; Peijnenburg, A.A.C.M.

2015-01-01

This chapter focuses mainly on the effects of organotin compounds in various human and animal models and describes the research performed to elucidate the immunotoxic mechanism of action of organotin compounds. Both dibutyltin (DBT) and tributyltins (TBT) organotin compounds can cause atrophy of the

Quinolinic Carboxylic Acid Derivatives as Potential Multi-target Compounds for Neurodegeneration: Monoamine Oxidase and Cholinesterase Inhibition.

Science.gov (United States)

Khan, Nehal A; Khan, Imtiaz; Abid, Syed M A; Zaib, Sumera; Ibrar, Aliya; Andleeb, Hina; Hameed, Shahid; Iqbal, Jamshed

2018-01-01

Parkinson's disease (PD), a debilitating and progressive disorder, is among the most challenging and devastating neurodegenerative diseases predominantly affecting the people over 60 years of age. To confront PD, an advanced and operational strategy is to design single chemical functionality able to control more than one target instantaneously. In this endeavor, for the exploration of new and efficient inhibitors of Parkinson's disease, we synthesized a series of quinoline carboxylic acids (3a-j) and evaluated their in vitro monoamine oxidase and cholinesterase inhibitory activities. The molecular docking and in silico studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. Moreover, molecular properties were calculated to evaluate the druglikeness of the compounds. The biological evaluation results revealed that the tested compounds were highly potent against monoamine oxidase (A & B), 3c targeted both the isoforms of MAO with IC50 values of 0.51 ± 0.12 and 0.51 ± 0.03 µM, respectively. The tested compounds also demonstrated high and completely selective inhibitory action against acetylcholinesterase (AChE) with IC50 values ranging from 4.36 to 89.24 µM. Among the examined derivatives, 3i was recognized as the most potent inhibitor of AChE with an IC50 value of 4.36 ± 0.12 ±µM. The compounds appear to be promising inhibitors and could be used for the future development of drugs targeting neurodegenerative disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Content and evolution of potential furfural compounds in commercial milk-based infant formula powder after opening the packet.

Science.gov (United States)

Chávez-Servín, Jorge L; de la Torre Carbot, Karina; García-Gasca, Teresa; Castellote, Ana I; López-Sabater, M Carmen

2015-01-01

Potential furfural compounds were examined by RP-HPLC-DAD in 20 commercial milk-based powdered infant formula (IF) brands from local markets from Paris, France; DF, Mexico; Copenhagen, Denmark; England, UK; and Barcelona, Spain. We traced the evolution of these compounds after the packets had been opened at 0, 30 and 70 days of storage at room temperature (≈25 °C; minimum 23 °C and maximum 25.5 °C). All formula brands were analysed during the first 3-5 months of their shelf life. The mean values of all IFs for potential 5-hydroxymethyl-2-furaldehyde (HMF)+2-furaldehyde (F) were 1115.2 μg/100 g (just opened), 1157.6 μg/100 g (30 days) and 1344.5 μg/100 g of product (70 days). In general, slight increases of potential furfural contents were observed in most of the studied IFs, which suggests that the Maillard reaction increases after opening the packets. The main furfural compound found was HMF, as expected. The range of potential HMF consumed for an infant about 6 months old feeding only on formula was estimated between 0.63 mg and 3.25 mg per day. Copyright © 2014 Elsevier Ltd. All rights reserved.

Corrective Action Investigation Plan for Corrective Action Unit 252: Area 25 Engine Test Stand 1 Decontamination Pad, Nevada Test Site, Nevada

Energy Technology Data Exchange (ETDEWEB)

U.S. Department of Energy, Nevada Operations Office

1999-08-20

This Corrective Action Investigation Plan contains the U.S. Department of Energy, Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit 252 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 252 consists of Corrective Action Site (CAS) 25-07-02, Engine Test Stand-1 (ETS-1) Decontamination Pad. Located in Area 25 at the intersection of Road H and Road K at the Nevada Test Site, ETS-1 was designed for use as a mobile radiation checkpoint and for vehicle decontamination. The CAS consists of a concrete decontamination pad with a drain, a gravel-filled sump, two concrete trailer pads, and utility boxes. Constructed in 1966, the ETS-1 facility was part of the Nuclear Rocket Development Station (NRDS) complex and used to test nuclear rockets. The ETS-1 Decontamination Pad and mobile radiation check point was built in 1968. The NRDS complex ceased primary operations in 1973. Based on site history, the focus of the field investigation activities will be to determine if any primary contaminants of potential concern (COPCs) (including radionuclides, total volatile organic compounds, total semivolatile organic compounds, total petroleum hydrocarbons as diesel-range organics, Resource Conservation and Recovery Act metals, total pesticides, and polychlorinated biphenyls) are present at this site. Vertical extent of migration of suspected vehicle decontamination effluent COPCs is expected to be less than 12 feet below ground surface. Lateral extent of migration of COPCs is expected to be limited to the sump area or near the northeast corner of the decontamination pad. Using a biased sampling approach, near-surface and subsurface sampling will be conducted at the suspected worst-case areas including the sump and soil near the northeast corner of the decontamination pad. The results of this field investigation will support a defensible e

Identification of a compound isolated from German chamomile (Matricaria chamomilla) with dermal sensitization potential

International Nuclear Information System (INIS)

Avonto, Cristina; Rua, Diego; Lasonkar, Pradeep B.; Chittiboyina, Amar G.; Khan, Ikhlas A.

2017-01-01

German chamomile is one of the most popular herbal ingredients used in cosmetics and personal care products. Allergic skin reactions following topical application of German chamomile have been occasionally reported, although it is not fully understood which of the chemical constituents is responsible for this adverse effect. In the present work, three candidate sensitizers were isolated from German chamomile based on activity-guided fractionation of chamomile extracts tested using the in vitro KeratinoSens™ assay. The compounds were identified as the polyacetylene tonghaosu (1), and both trans- and cis-glucomethoxycinnamic acids (2 and 3). These three compounds were classified as non- to weakly reactive using in chemico methods; however, aged tonghaosu was found to be more reactive when compared to freshly isolated tonghaosu. The polyacetylene (1) constituent was determined to be chemically unstable, generating a small electrophilic spirolactone, 1,6-dioxaspiro[4.4]non-3-en-2-one (4), upon aging. This small lactone (4) was strongly reactive in both in chemico HTS- and NMR-DCYA methods and further confirmed as a potential skin sensitizer by Local Lymph Node Assay (LLNA). - Highlights: • Fractions of German chamomile tested positive in the KeratinoSens™ assay. • Three compounds containing structural alerts were isolated and tested with in chemico methods. • The polyacetylene tonghaosu was found to be unstable and categorized as potential pre-hapten. • A degradation product of tonghaosu tested as positive dermal sensitizer in animal studies.

Identification of a compound isolated from German chamomile (Matricaria chamomilla) with dermal sensitization potential

Energy Technology Data Exchange (ETDEWEB)

Avonto, Cristina [National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, MS 38677 (United States); Rua, Diego [The Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, MD 20740 (United States); Lasonkar, Pradeep B.; Chittiboyina, Amar G. [National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, MS 38677 (United States); Khan, Ikhlas A., E-mail: ikhan@olemiss.edu [National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, MS 38677 (United States); Division of Pharmacognosy, Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, MS 38677 (United States)

2017-03-01

German chamomile is one of the most popular herbal ingredients used in cosmetics and personal care products. Allergic skin reactions following topical application of German chamomile have been occasionally reported, although it is not fully understood which of the chemical constituents is responsible for this adverse effect. In the present work, three candidate sensitizers were isolated from German chamomile based on activity-guided fractionation of chamomile extracts tested using the in vitro KeratinoSens™ assay. The compounds were identified as the polyacetylene tonghaosu (1), and both trans- and cis-glucomethoxycinnamic acids (2 and 3). These three compounds were classified as non- to weakly reactive using in chemico methods; however, aged tonghaosu was found to be more reactive when compared to freshly isolated tonghaosu. The polyacetylene (1) constituent was determined to be chemically unstable, generating a small electrophilic spirolactone, 1,6-dioxaspiro[4.4]non-3-en-2-one (4), upon aging. This small lactone (4) was strongly reactive in both in chemico HTS- and NMR-DCYA methods and further confirmed as a potential skin sensitizer by Local Lymph Node Assay (LLNA). - Highlights: • Fractions of German chamomile tested positive in the KeratinoSens™ assay. • Three compounds containing structural alerts were isolated and tested with in chemico methods. • The polyacetylene tonghaosu was found to be unstable and categorized as potential pre-hapten. • A degradation product of tonghaosu tested as positive dermal sensitizer in animal studies.

Potential anticancer properties of bioactive compounds of Gymnema sylvestre and its biofunctionalized silver nanoparticles.

Science.gov (United States)

Arunachalam, Kantha Deivi; Arun, Lilly Baptista; Annamalai, Sathesh Kumar; Arunachalam, Aarrthy M

2015-01-01

Gymnema sylvestre is an ethno-pharmacologically important medicinal plant used in many polyherbal formulations for its potential health benefits. Silver nanoparticles (SNPs) were biofunctionalized using aqueous leaf extracts of G. sylvestre. The anticancer properties of the bioactive compounds and the biofunctionalized SNPs were compared using the HT29 human adenoma colon cancer cell line. The preliminary phytochemical screening for bioactive compounds from aqueous extracts revealed the presence of alkaloids, triterpenes, flavonoids, steroids, and saponins. Biofunctionalized SNPs were synthesized using silver nitrate and characterized by ultraviolet-visible spectroscopy, scanning electron microscopy, energy-dispersive X-ray analysis, Fourier transform infrared spectroscopy, and X-ray diffraction for size and shape. The characterized biofunctionalized G. sylvestre were tested for its in vitro anticancer activity against HT29 human colon adenocarcinoma cells. The biofunctionlized G. sylvestre SNPs showed the surface plasmon resonance band at 430 nm. The scanning electron microscopy images showed the presence of spherical nanoparticles of various sizes, which were further determined using the Scherrer equation. In vitro cytotoxic activity of the biofunctionalized green-synthesized SNPs (GSNPs) indicated that the sensitivity of HT29 human colon adenocarcinoma cells for cytotoxic drugs is higher than that of Vero cell line for the same cytotoxic agents and also higher than the bioactive compound of the aqueous extract. Our results show that the anticancer properties of the bioactive compounds of G. sylvestre can be enhanced through biofunctionalizing the SNPs using the bioactive compounds present in the plant extract without compromising their medicinal properties.

Potential physiological effects of pharmaceutical compounds in Atlantic salmon (Salmo salar) implied by transcriptomic analysis.

Science.gov (United States)

Hampel, Miriam; Alonso, Esteban; Aparicio, Irene; Bron, James E; Santos, Juan Luis; Taggart, John B; Leaver, Michael J

2010-05-01

environmentally relevant concentrations of the selected pharmaceutical compounds acetaminophen, carbamazepine, and atenolol produced differences in the expression of 659, 700, and 480 candidate genes, respectively. KEGG annotation numbers (KO annotations) were obtained for between 26.57% and 33.33% of these differently expressed genes per treatment in comparison to non-exposure conditions. Pathways that showed to be induced did not always follow previously reported targets or metabolic routes for the employed treatments; however, several other pathways have been found (four or more features) to be significantly induced. Energy-related pathways have been altered under exposure in all the selected treatments, indicating a possible energy budget leakage due to additional processes resulting from the exposure to environmental contaminants. Observed induction of pathways may indicate additional processes involved in the mode of action of the selected pharmaceuticals which may not have been detected with conventional methods like quantitative PCR in which only suspected features are analyzed punctually for effects. The employment of novel high-throughput screening techniques in combination with global pathway analysis methods, even if the organism is not completely annotated, allows the examination of a much broader range of candidates for potential effects of exposure at the gene level. The continuously growing number of annotations of representative species relevant for environmental quality testing is facilitating pathway analysis processes for not completely annotated organisms. KEGG has shown to be a useful tool for the analysis of induced pathways from data generated by microarray techniques with the selected pharmaceutical contaminants acetaminophen, carbamazepine, and atenolol, but further studies have to be carried out in order to determine if a similar expression pattern in terms of fold change quantity and pathways is observed after long-term exposure. Together with the

An Excel-based implementation of the spectral method of action potential alternans analysis.

Science.gov (United States)

Pearman, Charles M

2014-12-01

Action potential (AP) alternans has been well established as a mechanism of arrhythmogenesis and sudden cardiac death. Proper interpretation of AP alternans requires a robust method of alternans quantification. Traditional methods of alternans analysis neglect higher order periodicities that may have greater pro-arrhythmic potential than classical 2:1 alternans. The spectral method of alternans analysis, already widely used in the related study of microvolt T-wave alternans, has also been used to study AP alternans. Software to meet the specific needs of AP alternans analysis is not currently available in the public domain. An AP analysis tool is implemented here, written in Visual Basic for Applications and using Microsoft Excel as a shell. This performs a sophisticated analysis of alternans behavior allowing reliable distinction of alternans from random fluctuations, quantification of alternans magnitude, and identification of which phases of the AP are most affected. In addition, the spectral method has been adapted to allow detection and quantification of higher order regular oscillations. Analysis of action potential morphology is also performed. A simple user interface enables easy import, analysis, and export of collated results. © 2014 The Author. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

New methodology for Ozone Depletion Potentials of short-lived compounds: n-Propyl bromide as an example

Science.gov (United States)

Wuebbles, Donald J.; Patten, Kenneth O.; Johnson, Matthew T.; Kotamarthi, Rao

2001-07-01

A number of the compounds proposed as replacements for substances controlled under the Montreal Protocol have extremely short atmospheric lifetimes, on the order of days to a few months. An important example is n-propyl bromide (also referred to as 1-bromopropane, CH2BrCH2CH3 or simplified as 1-C3H7Br or nPB). This compound, useful as a solvent, has an atmospheric lifetime of less than 20 days due to its reaction with hydroxyl. Because nPB contains bromine, any amount reaching the stratosphere has the potential to affect concentrations of stratospheric ozone. The definition of Ozone Depletion Potentials (ODP) needs to be modified for such short-lived compounds to account for the location and timing of emissions. It is not adequate to treat these chemicals as if they were uniformly emitted at all latitudes and longitudes as normally done for longer-lived gases. Thus, for short-lived compounds, policymakers will need a table of ODP values instead of the single value generally provided in past studies. This study uses the MOZART2 three-dimensional chemical-transport model in combination with studies with our less computationally expensive two-dimensional model to examine potential effects of nPB on stratospheric ozone. Multiple facets of this study examine key questions regarding the amount of bromine reaching the stratosphere following emission of nPB. Our most significant findings from this study for the purposes of short-lived replacement compound ozone effects are summarized as follows. The degradation of nPB produces a significant quantity of bromoacetone which increases the amount of bromine transported to the stratosphere due to nPB. However, much of that effect is not due to bromoacetone itself, but instead to inorganic bromine which is produced from tropospheric oxidation of nPB, bromoacetone, and other degradation products and is transported above the dry and wet deposition processes of the model. The MOZART2 nPB results indicate a minimal correction of the

Corrective Action Investigation Plan for Corrective Action Unit 410: Waste Disposal Trenches, Tonopah Test Range, Nevada, Revision 0 (includes ROTCs 1, 2, and 3)

Energy Technology Data Exchange (ETDEWEB)

NNSA/NV

2002-07-16

This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 410 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 410 is located on the Tonopah Test Range (TTR), which is included in the Nevada Test and Training Range (formerly the Nellis Air Force Range) approximately 140 miles northwest of Las Vegas, Nevada. This CAU is comprised of five Corrective Action Sites (CASs): TA-19-002-TAB2, Debris Mound; TA-21-003-TANL, Disposal Trench; TA-21-002-TAAL, Disposal Trench; 09-21-001-TA09, Disposal Trenches; 03-19-001, Waste Disposal Site. This CAU is being investigated because contaminants may be present in concentrations that could potentially pose a threat to human health and/or the environment, and waste may have been disposed of with out appropriate controls. Four out of five of these CASs are the result of weapons testing and disposal activities at the TTR, and they are grouped together for site closure based on the similarity of the sites (waste disposal sites and trenches). The fifth CAS, CAS 03-19-001, is a hydrocarbon spill related to activities in the area. This site is grouped with this CAU because of the location (TTR). Based on historical documentation and process know-ledge, vertical and lateral migration routes are possible for all CASs. Migration of contaminants may have occurred through transport by infiltration of precipitation through surface soil which serves as a driving force for downward migration of contaminants. Land-use scenarios limit future use of these CASs to industrial activities. The suspected contaminants of potential concern which have been identified are volatile organic compounds; semivolatile organic compounds; high explosives; radiological constituents including depleted

Molecular Docking Analysis of Ginger Active Compound on Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1

Directory of Open Access Journals (Sweden)

Fifteen Aprila Fajrin

2018-02-01

Full Text Available Ginger had been reported to ameliorate painful diabetic neuropathy (PDN in an animal model. Gingerol and shogaol were active compounds of ginger that potentially act on transient receptor potential cation channel subfamily V member 1 (TRPV1, a key receptor in PDN. This study aims to predict the binding of gingerol and shogaol to TRPV1 using an in silico model. The ligands of the docking study were 3 chemical compounds of each gingerol and shogaol, i.e. 6-shogaol, 8-shogaol, 10-shogaol, 6-gingerol, 8 gingerol and 10-gingerol. Capsaicin, a TRPV1 agonist, was used as a native ligand. The TRPV1 structure was taken from Protein Data Bank (ID 3J9J. The docking analysis was performed using Autodock Vina. The result showed that among the ginger active compounds, 6-shogaol had the strongest binding energy (-7.10 kcal/mol to TRPV1. The 6-shogaol lacked the potential hydrogen bond to Ile265 of TRPV1 protein, which capsacin had. However, it's binding energy towards TRPV1 was not significantly different compared to capsaicin. Therefore, 6-shogaol had potential to be developed as a treatment for PDN.

Pharmaceutical Compounds in Wastewater: Wetland Treatment as a Potential Solution

Directory of Open Access Journals (Sweden)

John R. White

2006-01-01

Full Text Available Pharmaceutical compounds are being released into the aquatic environment through wastewater discharge around the globe. While there is limited removal of these compounds within wastewater treatment plants, wetland treatment might prove to be an effective means to reduce the discharge of the compounds into the environment. Wetlands can promote removal of these pharmaceutical compounds through a number of mechanisms including photolysis, plant uptake, microbial degradation, and sorption to the soil. We review relevant laboratory research on these various mechanisms and provide data on the few studies that have examined wetland removal. There is a need to document the degree to which various pharmaceutical compounds are removed in full-scale treatment wetlands, as there is a paucity of data on overall pharmaceutical removal rates.

Phytochemical Analysis, Identification and Quantification of Antibacterial Active Compounds in Betel Leaves, Piper betle Methanolic Extract.

Science.gov (United States)

Syahidah, A; Saad, C R; Hassan, M D; Rukayadi, Y; Norazian, M H; Kamarudin, M S

2017-01-01

The problems of bacterial diseases in aquaculture are primarily controlled by antibiotics. Medicinal plants and herbs which are seemed to be candidates of replacements for conventional antibiotics have therefore gained increasing interest. Current study was performed to investigate the presence of phytochemical constituents, antibacterial activities and composition of antibacterial active compounds in methanolic extract of local herb, Piper betle . Qualitative phytochemical analysis was firstly carried out to determine the possible active compounds in P. betle leaves methanolic extract. The antibacterial activities of major compounds from this extract against nine fish pathogenic bacteria were then assessed using TLC-bioautography agar overlay assay and their quantity were determined simultaneously by HPLC method. The use of methanol has proved to be successful in extracting numerous bioactive compounds including antibacterial compounds. The TLC-bioautography assay revealed the inhibitory action of two compounds which were identified as hydroxychavicol and eugenol. The $-caryophyllene however was totally inactive against all the tested bacterial species. In this study, the concentration of hydroxychavicol in extract was found to be 374.72±2.79 mg g-1, while eugenol was 49.67±0.16 mg g-1. Based on these findings, it could be concluded that hydroxychavicol and eugenol were the responsible compounds for the promising antibacterial activity of P. betle leaves methanolic extract. This inhibitory action has significantly correlated with the amount of the compounds in extract. Due to its potential, the extract of P. betle leaves or it compounds can be alternative source of potent natural antibacterial agents for aquaculture disease management.

Synthesis and evaluation of antimalarial properties of novel 4-aminoquinoline hybrid compounds.

Science.gov (United States)

Fisher, Gillian M; Tanpure, Rajendra P; Douchez, Antoine; Andrews, Katherine T; Poulsen, Sally-Ann

2014-10-01

Pharmacophore hybridization has recently been employed in the search for antimalarial lead compounds. This approach chemically links two pharmacophores, each with their own antimalarial activity and ideally with different modes of action, into a single hybrid molecule with the goal to improve therapeutic properties. In this paper, we report the synthesis of novel 7-chloro-4-aminoquinoline/primary sulfonamide hybrid compounds. The chlorinated 4-aminoquinoline scaffold is the core structure of chloroquine, an established antimalarial drug, while the primary sulfonamide functional group has a proven track record of efficacy and safety in many clinically used drugs and was recently shown to exhibit some antimalarial activity. The activity of the hybrid compounds was determined against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. While the hybrid compounds had lower antimalarial activity when compared to chloroquine, they demonstrated a number of interesting structure-activity relationship (SAR) trends including the potential to overcome the resistance profile of chloroquine. © 2014 John Wiley & Sons A/S.

Action potential generation requires a high sodium channel density in the axon initial segment

NARCIS (Netherlands)

Kole, Maarten H. P.; Ilschner, Susanne U.; Kampa, Björn M.; Williams, Stephen R.; Ruben, Peter C.; Stuart, Greg J.

2008-01-01

The axon initial segment ( AIS) is a specialized region in neurons where action potentials are initiated. It is commonly assumed that this process requires a high density of voltage-gated sodium ( Na(+)) channels. Paradoxically, the results of patch-clamp studies suggest that the Na(+) channel

Herbal Therapies for Type 2 Diabetes Mellitus: Chemistry, Biology, and Potential Application of Selected Plants and Compounds

Directory of Open Access Journals (Sweden)

Cicero L. T. Chang

2013-01-01

Full Text Available Diabetes mellitus has been recognized since antiquity. It currently affects as many as 285 million people worldwide and results in heavy personal and national economic burdens. Considerable progress has been made in orthodox antidiabetic drugs. However, new remedies are still in great demand because of the limited efficacy and undesirable side effects of current orthodox drugs. Nature is an extraordinary source of antidiabetic medicines. To date, more than 1200 flowering plants have been claimed to have antidiabetic properties. Among them, one-third have been scientifically studied and documented in around 460 publications. In this review, we select and discuss blood glucose-lowering medicinal herbs that have the ability to modulate one or more of the pathways that regulate insulin resistance, β-cell function, GLP-1 homeostasis, and glucose (reabsorption. Emphasis is placed on phytochemistry, anti-diabetic bioactivities, and likely mechanism(s. Recent progress in the understanding of the biological actions, mechanisms, and therapeutic potential of compounds and extracts of plant origin in type 2 diabetes is summarized. This review provides a source of up-to-date information for further basic and clinical research into herbal therapy for type 2 diabetes. Emerging views on therapeutic strategies for type 2 diabetes are also discussed.

Antimicrobial azobenzene compounds and their potential use in biomaterials

Science.gov (United States)

Sessa, L.; Concilio, S.; Iannelli, P.; De Santis, F.; Porta, A.; Piotto, S.

2016-04-01

We recently synthesized a class of active compounds with azobenzene structure [1] and lowest in silico toxicity values. The antimicrobial activity of these molecules and their thermal stability are very promising and indicate that they may have interesting and therapeutically significant applications. This work aims to develop new materials with antibacterial and antifungal activity inserting different percentages of synthetic antimicrobial azo compounds in commercial polymer matrices. We realized thin films using solvent casting and melt compounding techniques. The obtained materials retained the proprieties of the pure matrices. This means that azo dye dissolved in the matrix does not influence the thermal behavior and the morphology of the material. Tested films exhibited the capability to inhibit biofilms formation of S. aureus and C. albicans. Spectrophotometric investigation of the azo compound released from the polymer matrices confirmed that the realized materials might be interesting for biomedical tools, antibacterial surfaces, and films for active packaging.

mechanism of action

African Journals Online (AJOL)

known as azidothymidine) in 1987. Fourteen agents are available for general use in South Africa. Several newer compounds are in preclinical development or have ... Site of action penetration. AlJ. Thymidine. Zidovudine. Retrovir. Intracellularly;. Good activated Tcells. d4T. Thymidine. Stavudine. Zerit. Intracellularly;. Good.

Potentiating action of propofol at GABAA receptors of retinal bipolar cells

DEFF Research Database (Denmark)

Yue, Lan; Xie, An; Bruzik, Karol S

2011-01-01

Purpose. Propofol (2,6-diisopropyl phenol), a widely used systemic anesthetic, is known to potentiate GABA(A) receptor activity in a number of CNS neurons and to produce changes in electroretinographically recorded responses of the retina. However, little is known about propofol's effects...... on specific retinal neurons. The authors investigated the action of propofol on GABA-elicited membrane current responses of retinal bipolar cells, which have both GABA(A) and GABA(C) receptors. Methods. Single, enzymatically dissociated bipolar cells obtained from rat retina were treated with propofol...... + propofol) led to a progressive increase in peak response amplitude and, at higher propofol concentrations, additional changes that included a prolonged time course of response recovery. Pre-exposure of the cell to perfusing propofol typically enhanced the rate of development of potentiation produced...

Melatonin potentiates the anticonvulsant action of phenobarbital in neonatal rats.

Science.gov (United States)

Forcelli, Patrick A; Soper, Colin; Duckles, Anne; Gale, Karen; Kondratyev, Alexei

2013-12-01

Phenobarbital is the most commonly utilized drug for neonatal seizures. However, questions regarding safety and efficacy of this drug make it particularly compelling to identify adjunct therapies that could boost therapeutic benefit. One potential adjunct therapy is melatonin. Melatonin is used clinically in neonatal and pediatric populations, and moreover, it exerts anticonvulsant actions in adult rats. However, it has not been previously evaluated for anticonvulsant effects in neonatal rats. Here, we tested the hypothesis that melatonin would exert anticonvulsant effects, either alone, or in combination with phenobarbital. Postnatal day (P)7 rats were treated with phenobarbital (0-40mg/kg) and/or melatonin (0-80mg/kg) prior to chemoconvulsant challenge with pentylenetetrazole (100mg/kg). We found that melatonin significantly potentiated the anticonvulsant efficacy of phenobarbital, but did not exert anticonvulsant effects on its own. These data provide additional evidence for the further examination of melatonin as an adjunct therapy in neonatal/pediatric epilepsy. Copyright © 2013 Elsevier B.V. All rights reserved.

Cyanobacteria as a Source for Novel Anti-Leukemic Compounds.

Science.gov (United States)

Humisto, Anu; Herfindal, Lars; Jokela, Jouni; Karkman, Antti; Bjørnstad, Ronja; Choudhury, Romi R; Sivonen, Kaarina

2016-01-01

Cyanobacteria are an inspiring source of bioactive secondary metabolites. These bioactive agents are a diverse group of compounds which are varying in their bioactive targets, the mechanisms of action, and chemical structures. Cyanobacteria from various environments, especially marine benthic cyanobacteria, are found to be rich sources for the search for novel bioactive compounds. Several compounds with anticancer activities have been discovered from cyanobacteria and some of these have succeeded to enter the clinical trials. Varying anticancer agents are needed to overcome increasing challenges in cancer treatments. Different search methods are used to reveal anticancer compounds from natural products, but cell based methods are the most common. Cyanobacterial bioactive compounds as agents against acute myeloid leukemia are not well studied. Here we examined our new results combined with previous studies of anti-leukemic compounds from cyanobacteria with emphasis to reveal common features in strains producing such activity. We report that cyanobacteria harbor specific anti-leukemic compounds since several studied strains induced apoptosis against AML cells but were inactive against non-malignant cells like hepatocytes. We noted that particularly benthic strains from the Baltic Sea, such as Anabaena sp., were especially potential AML apoptosis inducers. Taken together, this review and re-analysis of data demonstrates the power of maintaining large culture collections for the search for novel bioactivities, and also how anti-AML activity in cyanobacteria can be revealed by relatively simple and low-cost assays.

In Vitro and Ex Vivo Chemopreventive Action of Mauritia flexuosa Products

Directory of Open Access Journals (Sweden)

Joilane Alves Pereira-Freire

2018-01-01

Full Text Available Mauritia flexuosa (Arecaceae, known as “Buriti,” is a Brazilian palm tree with high economic potential for local communities. Herein, we investigated the phytochemistry profile and antioxidant potential of M. flexuosa fruits and determined the bioaccessibility of phenolic compounds. Peels revealed upper values for phenols, flavonoids, carotenoids, tannins, and ascorbic acid when compared to the pulps and endocarps. All samples showed capacity to scavenger free radicals (0.5, 1.0, 2.0, 4.0, and 8.0 mg/mL but peels presented higher scavenger action in all methods explored. Phenolic compounds identified by HPLC displayed reduced bioaccessibility after in vitro simulated gastrointestinal digestion for pulp (38.7%, peel (18.7%, and endocarp (22.3% extracts (P<0.05. Buriti fruits also protected rat blood cells against lysis induced by peroxyl radicals. We demonstrated the promising chemopreventive potentialities of M. flexuosa fruits and their by-products and peels with higher quantities of bioactive compounds and phenolic substances before and after in vitro bioaccessibility investigation. In Brazil, these parts are discarded or underused, mainly as feed for ruminant animals. Consequently, it is extremely important to explore nutritional characteristics of these by-products for human/livestock foods and to install biofriendly techniques and sustainable biotechnology handling of natural resources.

Changes in time and frequency related aspects of motor unit action potentials during fatigue

NARCIS (Netherlands)

Wallinga, W.; Bouwens, Jeroen S.; Baten, Christian T.M.

1996-01-01

During fatigue the shape of motor unit action potentials (MUAPs) change. Characteristics of the MUAPs described before concern several time related aspects. No attention has been given to the frequency spectrum changes of MUAPS. The median frequency of MUAPS has now been determined for motor units

Map-based model of the cardiac action potential

International Nuclear Information System (INIS)

Pavlov, Evgeny A.; Osipov, Grigory V.; Chan, C.K.; Suykens, Johan A.K.

2011-01-01

A simple computationally efficient model which is capable of replicating the basic features of cardiac cell action potential is proposed. The model is a four-dimensional map and demonstrates good correspondence with real cardiac cells. Various regimes of cardiac activity, which can be reproduced by the proposed model, are shown. Bifurcation mechanisms of these regimes transitions are explained using phase space analysis. The dynamics of 1D and 2D lattices of coupled maps which model the behavior of electrically connected cells is discussed in the context of synchronization theory. -- Highlights: → Recent experimental-data based models are complicated for analysis and simulation. → The simplified map-based model of the cardiac cell is constructed. → The model is capable for replication of different types of cardiac activity. → The spatio-temporal dynamics of ensembles of coupled maps are investigated. → Received data are analyzed in context of biophysical processes in the myocardium.

Map-based model of the cardiac action potential

Energy Technology Data Exchange (ETDEWEB)

Pavlov, Evgeny A., E-mail: genie.pavlov@gmail.com [Department of Computational Mathematics and Cybernetics, Nizhny Novgorod State University, 23, Gagarin Avenue, 603950 Nizhny Novgorod (Russian Federation); Osipov, Grigory V. [Department of Computational Mathematics and Cybernetics, Nizhny Novgorod State University, 23, Gagarin Avenue, 603950 Nizhny Novgorod (Russian Federation); Chan, C.K. [Institute of Physics, Academia Sinica, 128 Sec. 2, Academia Road, Nankang, Taipei 115, Taiwan (China); Suykens, Johan A.K. [K.U. Leuven, ESAT-SCD/SISTA, Kasteelpark Arenberg 10, B-3001 Leuven (Heverlee) (Belgium)

2011-07-25

A simple computationally efficient model which is capable of replicating the basic features of cardiac cell action potential is proposed. The model is a four-dimensional map and demonstrates good correspondence with real cardiac cells. Various regimes of cardiac activity, which can be reproduced by the proposed model, are shown. Bifurcation mechanisms of these regimes transitions are explained using phase space analysis. The dynamics of 1D and 2D lattices of coupled maps which model the behavior of electrically connected cells is discussed in the context of synchronization theory. -- Highlights: → Recent experimental-data based models are complicated for analysis and simulation. → The simplified map-based model of the cardiac cell is constructed. → The model is capable for replication of different types of cardiac activity. → The spatio-temporal dynamics of ensembles of coupled maps are investigated. → Received data are analyzed in context of biophysical processes in the myocardium.

Oxidative shift in tissue redox potential increases beat-to-beat variability of action potential duration.

Science.gov (United States)

Kistamás, Kornél; Hegyi, Bence; Váczi, Krisztina; Horváth, Balázs; Bányász, Tamás; Magyar, János; Szentandrássy, Norbert; Nánási, Péter P

2015-07-01

Profound changes in tissue redox potential occur in the heart under conditions of oxidative stress frequently associated with cardiac arrhythmias. Since beat-to-beat variability (short term variability, SV) of action potential duration (APD) is a good indicator of arrhythmia incidence, the aim of this work was to study the influence of redox changes on SV in isolated canine ventricular cardiomyocytes using a conventional microelectrode technique. The redox potential was shifted toward a reduced state using a reductive cocktail (containing dithiothreitol, glutathione, and ascorbic acid) while oxidative changes were initiated by superfusion with H2O2. Redox effects were evaluated as changes in "relative SV" determined by comparing SV changes with the concomitant APD changes. Exposure of myocytes to the reductive cocktail decreased SV significantly without any detectable effect on APD. Application of H2O2 increased both SV and APD, but the enhancement of SV was the greater, so relative SV increased. Longer exposure to H2O2 resulted in the development of early afterdepolarizations accompanied by tremendously increased SV. Pretreatment with the reductive cocktail prevented both elevation in relative SV and the development of afterdepolarizations. The results suggest that the increased beat-to-beat variability during an oxidative stress contributes to the generation of cardiac arrhythmias.

Ionic electrodeposition of II-VI and III-V compounds. III. Computer simulation of quasi-rest potentials for M/sub 1/X/sub 1/ compounds analogous to CdTe

International Nuclear Information System (INIS)

Engelken, R.D.

1987-01-01

The quasi-rest potential (QRP) has been proposed as a key quantity in characterizing compound semiconductor (e.g. CdTe) electrodeposition. This article expands the modeling/simulation representative of Cd/sub x/Te in chemical equilibrium to calculate two ''QRP's'': E/sub M/1/sub /, the mixed potential occurring immediately after current interruption and before any relaxation in double layer ion concentration and significant ion exchange/surface stoichiometry change occur, and E/sub M/2/sub /, another mixed potential occurring after the double layer ion concentrations have relaxed to their bulk values but still before any significant surface composition change occurs. Significant predictions include existence of a dramatic negative transition in QRP, with negative-going deposition potential, centered on the potential of perfect stoichiometry (PPS), inequality, in general, between the PPS and E/sub M/1/sub / unless the deposit remains in equilibrium with the electrolyte (no ion exchange at open circuit), negligible sensitivity of QRP-E curves to the activity coefficient parameter implying the importance of the PPS in characterizing compound deposition, and disappearance of the transition structure for sufficiently positive Gibbs free energies

Recovery of valuable nitrogen compounds from agricultural liquid wastes: potential possibilities, bottlenecks and future technological challenges.

NARCIS (Netherlands)

Rulkens, W.H.; Klapwijk, A.; Willers, H.C.

1998-01-01

Agricultural liquid livestock wastes are an important potential source of valuable nitrogen-containing compounds such as ammonia and proteins. Large volumetric quantities of these wastes are produced in areas with a high livestock production density. Much technological research has been carried out

Comparison of Two Old Phytochemicals versus Two Newly Researched Plant-Derived Compounds: Potential for Brain and Other Relevant Ailments

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Chun-Mei Wang

2014-01-01

Full Text Available Among hundreds of formulae of Chinese herbal prescriptions and recently extracted active components from the herbs, some of which had demonstrated their functions on nervous system. For the last decade or more, Gingko biloba and Polygala tenuifolia were widely studied for their beneficial effects against damage to the brain. Two compounds extracted from Apium graveolens and Rhizoma coptidis, butylphthalide and berberine, respectively, received much attention recently as potential neuroprotective agents. In this review, the two traditionally used herbs and the two relatively new compounds will be discussed with regard to their potential advantages in alleviating brain and other relevant ailments.

Profiling of the Tox21 Chemical Collection for Mitochondrial Function to Identify Compounds that Acutely Decrease Mitochondrial Membrane Potential

Science.gov (United States)

Attene-Ramos, Matias S.; Huang, Ruili; Michael, Sam; Witt, Kristine L.; Richard, Ann; Tice, Raymond R.; Simeonov, Anton; Austin, Christopher P.

2014-01-01

Background: Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of disorders including cancer, diabetes, and neurodegenerative and cardiovascular diseases. Understanding whether different environmental chemicals and druglike molecules impact mitochondrial function represents an initial step in predicting exposure-related toxicity and defining a possible role for such compounds in the onset of various diseases. Objectives: We sought to identify individual chemicals and general structural features associated with changes in mitochondrial membrane potential (MMP). Methods: We used a multiplexed [two end points in one screen; MMP and adenosine triphosphate (ATP) content] quantitative high throughput screening (qHTS) approach combined with informatics tools to screen the Tox21 library of 10,000 compounds (~ 8,300 unique chemicals) at 15 concentrations each in triplicate to identify chemicals and structural features that are associated with changes in MMP in HepG2 cells. Results: Approximately 11% of the compounds (913 unique compounds) decreased MMP after 1 hr of treatment without affecting cell viability (ATP content). In addition, 309 compounds decreased MMP over a concentration range that also produced measurable cytotoxicity [half maximal inhibitory concentration (IC50) in MMP assay/IC50 in viability assay ≤ 3; p Tice RR, Simeonov A, Austin CP, Xia M. 2015. Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. Environ Health Perspect 123:49–56; http://dx.doi.org/10.1289/ehp.1408642 PMID:25302578

Plasma biomarkers in juvenile marine fish provide evidence for endocrine modulation potential of organotin compounds.

Science.gov (United States)

Min, Byung Hwa; Kim, Bo-Mi; Kim, Moonkoo; Kang, Jung-Hoon; Jung, Jee-Hyun; Rhee, Jae-Sung

2018-08-01

Organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), have been widely used to control marine fouling. Here, we show that organotin stimulation reduces the hormone levels in the plasma of two economically important aquaculture fish. Blood plasma samples were collected from juvenile red seabream and black rockfish exposed to environmentally realistic concentrations of TBT and TPT for 14 days. The levels of two plasma biomarkers, namely the yolk protein precursor vitellogenin (VTG) and the sex steroid 17β-estradiol (E2), were measured to determine the endocrine disrupting potential of the organotin compounds. Both organotin compounds were dose-dependently accumulated in the blood of two fish. Exposure to waterborne TBT and TBT significantly decreased the plasma VTG levels in both the juvenile fish in a dose-dependent manner. In contrast, the treatment with E2, a well-known VTG inducer, significantly increased the plasma VTG levels in both the fish. In addition, the mRNA levels of vtg were also downregulated in the liver tissues of both the fish at 100 and/or 1000 ng L -1 of TBT or TPT exposure. The plasma E2 titers were significantly suppressed at 100 and/or 1000 ng L -1 of TBT or TPT exposure for 14 days compared to their titer in the control. Since estrogen directly regulates vtg gene expression and VTG synthesis, our results reveal the endocrine disrupting potential of organotin compounds, and subsequently the endocrine modulation at early stage of fish can trigger further fluctuations in sexual differentiation, maturation, sex ration or egg production. In addition, the results demonstrate their effects on non-target organisms, particularly on animals reared in aquaculture and fisheries. Copyright © 2018 Elsevier Inc. All rights reserved.

Heteromeric Kv7.2/7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons.

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Battefeld, Arne; Tran, Baouyen T; Gavrilis, Jason; Cooper, Edward C; Kole, Maarten H P

2014-03-05

Rapid energy-efficient signaling along vertebrate axons is achieved through intricate subcellular arrangements of voltage-gated ion channels and myelination. One recently appreciated example is the tight colocalization of K(v)7 potassium channels and voltage-gated sodium (Na(v)) channels in the axonal initial segment and nodes of Ranvier. The local biophysical properties of these K(v)7 channels and the functional impact of colocalization with Na(v) channels remain poorly understood. Here, we quantitatively examined K(v)7 channels in myelinated axons of rat neocortical pyramidal neurons using high-resolution confocal imaging and patch-clamp recording. K(v)7.2 and 7.3 immunoreactivity steeply increased within the distal two-thirds of the axon initial segment and was mirrored by the conductance density estimates, which increased from ~12 (proximal) to 150 pS μm(-2) (distal). The axonal initial segment and nodal M-currents were similar in voltage dependence and kinetics, carried by K(v)7.2/7.3 heterotetramers, 4% activated at the resting membrane potential and rapidly activated with single-exponential time constants (~15 ms at 28 mV). Experiments and computational modeling showed that while somatodendritic K(v)7 channels are strongly activated by the backpropagating action potential to attenuate the afterdepolarization and repetitive firing, axonal K(v)7 channels are minimally recruited by the forward-propagating action potential. Instead, in nodal domains K(v)7.2/7.3 channels were found to increase Na(v) channel availability and action potential amplitude by stabilizing the resting membrane potential. Thus, K(v)7 clustering near axonal Na(v) channels serves specific and context-dependent roles, both restraining initiation and enhancing conduction of the action potential.

Compound-Specific Isotopic Analysis of Meteoritic Amino Acids as a Tool for Evaluating Potential Formation Pathways

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Elsila, Jamie E.; Burton, Aaron S.; Callahan, Michael C.; Charnley, Steven B.; Glavin, Daniel P.; Dworkin, Jason P.

2012-01-01

Measurements of stable hydrogen, carbon, and nitrogen isotopic ratios (delta D, delta C-13, delta N-15) of organic compounds can reveal information about their origin and formation pathways. Several formation mechanisms and environments have been postulated for the amino acids detected in carbonaceous chondrites. As each proposed mechanism utilizes different precursor molecules, the isotopic signatures of the resulting amino acids may point towards the most likely of these proposed pathways. The technique of gas chromatography coupled with mass spectrometry and isotope ratio mass spectrometry provides compound-specific structural and isotopic information from a single splitless injection, enhancing the amount of information gained from small amounts of precious samples such as carbonaceous chondrites. We have applied this technique to measure the compound-specific C, N, and H isotopic ratios of amino acids from seven CM and CR carbonaceous chondrites. We are using these measurements to evaluate predictions of expected isotopic enrichments from potential formation pathways and environments, leading to a better understanding of the origin of these compounds.

Glycyrrhetinic acid and E.resveratroloside act as potential plant derived compounds against dopamine receptor D3 for Parkinson’s disease: a pharmacoinformatics study

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Mirza MU

2014-12-01

Full Text Available Muhammad Usman Mirza,1 A Hammad Mirza,2 Noor-Ul-Huda Ghori,3 Saba Ferdous4 1Centre for Research in Molecular Medicine, The University of Lahore, Lahore, Pakistan; 2Department of Bioscience, COMSATS Institute of Information Technology, Sahiwal, Pakistan; 3Atta-ur-Rehman School of Applied Biosciences, National University of Science and Technology, Islamabad, Pakistan; 4Institute of Structural and Molecular Biology, University College London, UK Abstract: Parkinson’s disease (PD is caused by loss in nigrostriatal dopaminergic neurons and is ranked as the second most common neurodegenerative disorder. Dopamine receptor D3 is considered as a potential target in drug development against PD because of its lesser side effects and higher degree of neuro-protection. One of the prominent therapies currently available for PD is the use of dopamine agonists which mimic the natural action of dopamine in the brain and stimulate dopamine receptors directly. Unfortunately, use of these pharmacological therapies such as bromocriptine, apomorphine, and ropinirole provides only temporary relief of the disease symptoms and is frequently linked with insomnia, anxiety, depression, and agitation. Thus, there is a need for an alternative treatment that not only hinders neurodegeneration, but also has few or no side effects. Since the past decade, much attention has been given to exploitation of phytochemicals and their use in alternative medicine research. This is because plants are a cheap, indispensable, and never ending resource of active compounds that are beneficial against various diseases. In the current study, 40 active phytochemicals against PD were selected through literature survey. These ligands were docked with dopamine receptor D3 using AutoDock and AutoDockVina. Binding energies were compared to docking results of drugs approved by the US Food and Drug Administration against PD. The compounds were further analyzed for their absorption, distribution

Deciphering the mode of action of clinically relevant next generation c2 corrector compounds GLPG2737 and GLPG3221

NARCIS (Netherlands)

Peters, F.; Sahasrabudhe, P.; Gross-Wilde, H.; Kleizen, Bertrand; Conrath, K.; Braakman, I.

2017-01-01

The current therapeutic strategy to repair cystic fibrosis-causing defects in the chloride channel CFTR is to develop novel and better correctors (to improve folding) and potentiators (to improve function). Galapagos- AbbVie identified C2 correctors by high-throughput compound screening and Med Chem

Phenolic compounds, antioxidant potential and antiproliferative potential of 10 common edible flowers from China assessed using a simulated in vitro digestion-dialysis process combined with cellular assays.

Science.gov (United States)

Huang, Weisu; Mao, Shuqin; Zhang, Liuquan; Lu, Baiyi; Zheng, Lufei; Zhou, Fei; Zhao, Yajing; Li, Maiquan

2017-11-01

Phenolic compounds could be sensitive to digestive conditions, thus a simulated in vitro digestion-dialysis process and cellular assays was used to determine phenolic compounds and antioxidant and antiproliferative potentials of 10 common edible flowers from China and their functional components. Gallic acid, ferulic acid, and rutin were widely present in these flowers, which demonstrated various antioxidant capacities (DPPH, ABTS, FRAP and CAA values) and antiproliferative potentials measured by the MTT method. Rosa rugosa, Paeonia suffruticosa and Osmanthus fragrans exhibited the best antioxidant and antiproliferative potentials against HepG2, A549 and SGC-7901 cell lines, except that Osmanthus fragrans was not the best against SGC-7901 cells. The in vitro digestion-dialysis process decreased the antioxidant potential by 33.95-90.72% and the antiproliferative potential by 13.22-87.15%. Following the in vitro digestion-dialysis process, phenolics were probably responsible for antioxidant (R 2 = 0.794-0.924, P digestion and dialysis along with the reduction of phenolics. Nevertheless, they still had considerable antioxidant and antiproliferative potential, which merited further investigation in in vivo studies. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Anticancer and cytotoxic compounds from seashells of the Persian Gulf

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Iraj Nabipour

2009-12-01

Full Text Available Background: Pre-clinical studies for isolation and purification of marine compounds continued at an active pace since the last decade. Today, more than 60% of the anticancer drugs commercially available are of naturally origin thus the sea is a very favorable bed for the discovery of novel anticancer agents. Methods: A total of known 611 seashells species in the Persian Gulf were investigated for synonymy in OBIS database. Then, all the species, including their synonymy were searched in PubMed databse to find their isolated bioactive agents. Results: From 611 known seashells in the Persian Gulf, 172 genera/species had bioactive compounds. Anticancer agents were isolated and purified for 8 genera. These compounds had various structures they were polypeptide, polysaccharide, glycoprotein, alkaloid, cerebroside, and cembranoid which had different mechanism of actions including induction of apoptosis, destroying the skeletal structures of the cells, immune bioactivity and inhibition of topoisomerase I. Spisulosine is the only anticancer agent which is currently under clinical trial. Conclusions: Although, the known seashells from the Persian Gulf have potential anticancer and cytotoxic compounds but a very few investigations had been reported. Further investigations for isolation and purification on bioactive compounds from seashells of the Persian Gulf is recommended.

PHARMACOLOGICAL AND MEDICINAL CHEMISTRY ASPECTS OF CANNABIS COMPOUNDS

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T. Cotelea

2011-12-01

Full Text Available The current communication includes a general overview of the scientific interest and medicianl chemistry aspects of Cannabis compounds. It relates to metabolism, pharmacological action and phisico-chemical analysis of these compounds, as well as of some isomers differing in spatial arrangement of functional groups.

Comment on "Penetration of Action Potentials During Collision in the Median and Lateral Giant Axons of Invertebrates"

DEFF Research Database (Denmark)

Berg, Rune W.; Stauning, Marius Tving; Sorensen, Jakob Balslev

2017-01-01

The action potential (AP) is an electrical impulse elicited by depolarization of the neuronal membrane from the resting membrane potential (around − 70 mV). It propagates along the axon, allowing for rapid and distant communication. Recently, it was claimed that two APs traveling in opposite...

Identification of Secondary Metabolite Gene Clusters in the Pseudovibrio Genus Reveals Encouraging Biosynthetic Potential toward the Production of Novel Bioactive Compounds

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Lynn M. Naughton

2017-08-01

Full Text Available Increased incidences of antimicrobial resistance and the emergence of pan-resistant ‘superbugs’ have provoked an extreme sense of urgency amongst researchers focusing on the discovery of potentially novel antimicrobial compounds. A strategic shift in focus from the terrestrial to the marine environment has resulted in the discovery of a wide variety of structurally and functionally diverse bioactive compounds from numerous marine sources, including sponges. Bacteria found in close association with sponges and other marine invertebrates have recently gained much attention as potential sources of many of these novel bioactive compounds. Members of the genus Pseudovibrio are one such group of organisms. In this study, we interrogate the genomes of 21 Pseudovibrio strains isolated from a variety of marine sources, for the presence, diversity and distribution of biosynthetic gene clusters (BGCs. We expand on results obtained from antiSMASH analysis to demonstrate the similarity between the Pseudovibrio-related BGCs and those characterized in other bacteria and corroborate our findings with phylogenetic analysis. We assess how domain organization of the most abundant type of BGCs present among the isolates (Non-ribosomal peptide synthetases and Polyketide synthases may influence the diversity of compounds produced by these organisms and highlight for the first time the potential for novel compound production from this genus of bacteria, using a genome guided approach.

Coffee contains cholinomimetic compound distinct from caffeine. I: Purification and chromatographic analysis.

Science.gov (United States)

Tse, S Y

1991-07-01

Both regular and decaffeinated coffees were found to have cholinomimetic actions when tested in urethane-anesthetized rats. These actions were distinct from those of caffeine and reversible by atropine. The bioactive fraction was purified from alcoholic extracts of instant decaffeinated coffee by liquid column chromatography and preparative TLC. The purified compound showed similar pharmacological actions as the starting material. Chromatographic behavior was further characterized by analytical TLC and HPLC. Chromatographic analyses of extracts of green coffee beans and roasted ground coffees showed that the cardioactive compound was only present in roasted coffees. Similar analyses of other commonly consumed beverages, including teas and cocoa, showed that this compound was not present in beverages besides coffee.

4-Phenylphenalenones as a template for new photodynamic compounds against Mycosphaerella fijiensis.

Science.gov (United States)

Hidalgo, William; Cano, Marisol; Arbelaez, Manuela; Zarrazola, Edwin; Gil, Jesús; Schneider, Bernd; Otálvaro, Felipe

2016-04-01

Evaluation of 4-phenylphenalenones and structural analogues against the fungal pathogen Mycosphaerella fijiensis (causal agent of black sigatoka disease in bananas) under light-controlled conditions uncovered some key structural features for the design of photodynamic compounds. Structure-activity relationship analysis revealed the importance of a chromophoric aryl-ketone and a steroidomimetic structural motif in the activity of the assayed compounds. The results pointed to 1,2-dihydro-3H-naphtho[2',1':3,4]cyclohepta[1,2-b]furan-3-one, which displayed an activity in the range of propiconazole but with photodynamic behaviour. The present work demonstrates that 1,2-dihydro-3H-naphtho[2',1':3,4]cyclohepta[1,2-b]heterocyclic-3-one derivatives can be used as potential lead compounds for the development of fungicides, relying on a dual mode of action. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

Spatial and frequency domain ring source models for the single muscle fiber action potential

DEFF Research Database (Denmark)

Henneberg, Kaj-åge; R., Plonsey

1994-01-01

In the paper, single-fibre models for the extracellular action potential are developed that will allow the potential to the evaluated at an arbitrary field point in the extracellular space. Fourier-domain models are restricted in that they evaluate potentials at equidistant points along a line...... parallel to the fibre axis. Consequently, they cannot easily evaluate the potential at the boundary nodes of a boundary-element electrode model. The Fourier-domain models employ axial-symmetric ring source models, and thereby provide higher accuracy that the line source model, where the source is lumped...... including anisotropy show that the spatial models require extreme care in the integration procedure owing to the singularity in the weighting functions. With adequate sampling, the spatial models can evaluate extracellular potentials with high accuracy....

In situ imaging and proteome profiling indicate andrographolide is a highly promiscuous compound

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Li, Lin; Wijaya, Hadhi; Samanta, Sanjay; Lam, Yulin; Yao, Shao Q.

2015-06-01

Natural products represent an enormous source of pharmacologically useful compounds, and are often used as the starting point in modern drug discovery. Many biologically interesting natural products are however not being pursued as potential drug candidates, partly due to a lack of well-defined mechanism-of-action. Traditional in vitro methods for target identification of natural products based on affinity protein enrichment from crude cellular lysates cannot faithfully recapitulate protein-drug interactions in living cells. Reported herein are dual-purpose probes inspired by the natural product andrographolide, capable of both reaction-based, real-time bioimaging and in situ proteome profiling/target identification in live mammalian cells. Our results confirm that andrographolide is a highly promiscuous compound and engaged in covalent interactions with numerous previously unknown cellular targets in cell type-specific manner. We caution its potential therapeutic effects should be further investigated in detail.

Coupled iterated map models of action potential dynamics in a one-dimensional cable of cardiac cells

International Nuclear Information System (INIS)

Wang Shihong; Xie Yuanfang; Qu Zhilin

2008-01-01

Low-dimensional iterated map models have been widely used to study action potential dynamics in isolated cardiac cells. Coupled iterated map models have also been widely used to investigate action potential propagation dynamics in one-dimensional (1D) coupled cardiac cells, however, these models are usually empirical and not carefully validated. In this study, we first developed two coupled iterated map models which are the standard forms of diffusively coupled maps and overcome the limitations of the previous models. We then determined the coupling strength and space constant by quantitatively comparing the 1D action potential duration profile from the coupled cardiac cell model described by differential equations with that of the coupled iterated map models. To further validate the coupled iterated map models, we compared the stability conditions of the spatially uniform state of the coupled iterated maps and those of the 1D ionic model and showed that the coupled iterated map model could well recapitulate the stability conditions, i.e. the spatially uniform state is stable unless the state is chaotic. Finally, we combined conduction into the developed coupled iterated map model to study the effects of coupling strength on wave stabilities and showed that the diffusive coupling between cardiac cells tends to suppress instabilities during reentry in a 1D ring and the onset of discordant alternans in a periodically paced 1D cable

From the Test Tube to the Treatment Room: Fundamentals of Boron-containing Compounds and their Relevance to Dermatology.

Science.gov (United States)

Del Rosso, James Q; Plattner, Jacob J

2014-02-01

The development of new drug classes and novel molecules that are brought to the marketplace has been a formidable challenge, especially for dermatologic drugs. The relative absence of new classes of antimicrobial agents is also readily apparent. Several barriers account for slow drug development, including regulatory changes, added study requirements, commercial pressures to bring drugs to market quickly by developing new generations of established compounds, and the greater potential for failure and higher financial risk when researching new drug classes. In addition, the return on investment is usually much lower with dermatologic drugs as compared to the potential revenue from "blockbuster" drugs for cardiovascular or gastrointestinal disease, hypercholesterolemia, and mood disorders. Nevertheless, some researchers are investigating new therapeutic platforms, one of which is boron-containing compounds. Boron-containing compounds offer a wide variety of potential applications in dermatology due to their unique physical and chemical properties, with several in formal phases of development. Tavaborole, a benzoxaborole compound, has been submitted to the United States Food and Drug Administration for approval for treatment of onychomycosis. This article provides a thorough overview of the history of boron-based compounds in medicine, their scientific rationale, physiochemical and pharmacologic properties, and modes of actions including therapeutic targets. A section dedicated to boron-based compounds in development for treatment of various skin disorders is also included.

Identification of a novel compound (β-sesquiphellandrene) from turmeric (Curcuma longa) with anticancer potential: comparison with curcumin.

Science.gov (United States)

Tyagi, Amit Kumar; Prasad, Sahdeo; Yuan, Wei; Li, Shiyou; Aggarwal, Bharat B

2015-12-01

Considering that as many as 80% of the anticancer drugs have their roots in natural products derived from traditional medicine, we examined compounds other than curcumin from turmeric (Curcuma longa) that could exhibit anticancer potential. Present study describes the isolation and characterization of another turmeric-derived compound, β-sesquiphellandrene (SQP) that exhibits anticancer potential comparable to that of curcumin. We isolated several compounds from turmeric, including SQP, α-curcumene, ar-turmerone, α-turmerone, β-turmerone, and γ-turmerone, only SQP was found to have antiproliferative effects comparable to those of curcumin in human leukemia, multiple myeloma, and colorectal cancer cells. While lack of the NF-κB-p65 protein had no effect on the activity of SQP, lung cancer cells that expressed p53 were more susceptible to the cytotoxic effect of SQP than were cells that lacked p53 expression. SQP was also found to be highly effective in suppressing cancer cell colony formation and inducing apoptosis, as shown by assays of intracellular esterase activity, plasma membrane integrity, and cell-cycle phase. SQP was found to induce cytochrome c release and activate caspases that lead to poly ADP ribose polymerase cleavage. SQP exposure was associated with downregulation of cell survival proteins such cFLIP, Bcl-xL, Bcl-2, c-IAP1, and survivin. Furthermore, SQP was found to be synergistic with the chemotherapeutic agents velcade, thalidomide and capecitabine. Overall, our results indicate that SQP has anticancer potential comparable to that of curcumin.

Copaifera langsdorffii: evaluation of potential gastroprotective of extract and isolated compounds obtained from leaves

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Marivane Lemos

Full Text Available AbstractGastric ulcer is a prevalent gastrointestinal disease, and the drugs currently used in the treatment produce several adverse effects. In this context, the search for new therapeutic antiulcer agents is essential, and medicinal plants have great potential. Here, we investigated the gastroprotective properties of Copaifera langsdorffii Desf., Fabaceae, hydroalcoholic extract obtained from leaves and its isolated compounds. The phytochemistry studies and the compounds isolations were performed using chromatographic and spectroscopic methodologies. The hydroalcoholic extract was evaluated using ethanol/HCl, non-steroidal anti-inflammatory drug, stress-induced-ulcer and chronic ulcer-model. The effects on gastric content volume, pH, total acidity and mucus stomach production were evaluated in the pylorus ligated-model. The C. langsdorffii extract obtained from leaves (50, 250 or 500 mg/kg reduced the injured area compared to control group in all experiments. The extract showed a significant decrease in the total gastric juice acidity and an increase in mucus production (500 mg/kg when compared to vehicle. Among isolated compounds (30 mg/kg α-humulene, β-caryophyllene and caryophyllene oxide showed greater gastroprotective activity in the ethanol/HCl induced ulcer model. The data herein obtained shown that C. langsdorffii leaves extract and isolated compounds from it, presented gastroprotective properties in different animal models of gastric ulcer. These effects may be associated with the ability of the extract to decrease gastric secretion and increase the mucus production.

Medical Applications and Toxicities of Gallium Compounds

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Christopher R. Chitambar

2010-05-01

Full Text Available Over the past two to three decades, gallium compounds have gained importance in the fields of medicine and electronics. In clinical medicine, radioactive gallium and stable gallium nitrate are used as diagnostic and therapeutic agents in cancer and disorders of calcium and bone metabolism. In addition, gallium compounds have displayed anti-inflammatory and immunosuppressive activity in animal models of human disease while more recent studies have shown that gallium compounds may function as antimicrobial agents against certain pathogens. In a totally different realm, the chemical properties of gallium arsenide have led to its use in the semiconductor industry. Gallium compounds, whether used medically or in the electronics field, have toxicities. Patients receiving gallium nitrate for the treatment of various diseases may benefit from such therapy, but knowledge of the therapeutic index of this drug is necessary to avoid clinical toxicities. Animals exposed to gallium arsenide display toxicities in certain organ systems suggesting that environmental risks may exist for individuals exposed to this compound in the workplace. Although the arsenic moiety of gallium arsenide appears to be mainly responsible for its pulmonary toxicity, gallium may contribute to some of the detrimental effects in other organs. The use of older and newer gallium compounds in clinical medicine may be advanced by a better understanding of their mechanisms of action, drug resistance, pharmacology, and side-effects. This review will discuss the medical applications of gallium and its mechanisms of action, the newer gallium compounds and future directions for development, and the toxicities of gallium compounds in current use.

The real-time link between person perception and action: brain potential evidence for dynamic continuity.

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Freeman, Jonathan B; Ambady, Nalini; Midgley, Katherine J; Holcomb, Phillip J

2011-01-01

Using event-related potentials, we investigated how the brain extracts information from another's face and translates it into relevant action in real time. In Study 1, participants made between-hand sex categorizations of sex-typical and sex-atypical faces. Sex-atypical faces evoked negativity between 250 and 550 ms (N300/N400 effects), reflecting the integration of accumulating sex-category knowledge into a coherent sex-category interpretation. Additionally, the lateralized readiness potential revealed that the motor cortex began preparing for a correct hand response while social category knowledge was still gradually evolving in parallel. In Study 2, participants made between-hand eye-color categorizations as part of go/no-go trials that were contingent on a target's sex. On no-go trials, although the hand did not actually move, information about eye color partially prepared the motor cortex to move the hand before perception of sex had finalized. Together, these findings demonstrate the dynamic continuity between person perception and action, such that ongoing results from face processing are immediately and continuously cascaded into the motor system over time. The preparation of action begins based on tentative perceptions of another's face before perceivers have finished interpreting what they just saw. © 2010 Psychology Press, an imprint of the Taylor & Francis Group, an Informa business

Potential of volatile compounds produced by fungi to influence sensory quality of coffee beverage

DEFF Research Database (Denmark)

Iamanaka, B. T.; Teixeira, A. A.; Teixeira, A. R. R.

2014-01-01

Fungi are known producers of a large number of volatile compounds (VCs). Several VCs such as 2,4,6 trichloroanisole (TCA), geosmin and terpenes have been found in coffee beverages, and these compounds can be responsible for off-flavor development. However, few studies have related the fungal...... contamination of coffee with the sensory characteristics of the beverage. The aim of this research was to investigate the production of VCs by fungi isolated from coffee and their potential as modifiers of the sensory coffee beverage quality. Three species were isolated from coffee from the southwest of São...... Paulo state and selected for the study: Penicillium brevicompactum, Aspergillus luchuensis (belonging to section Nigri) and Penicillium sp. nov. (related to Penicillium crustosum). VCs produced by the fungal inoculated in raw coffee beans were extracted and tentatively identified by SPME...

The potential of compounds isolated from Xylaria spp. as antifungal agents against anthracnose.

Science.gov (United States)

Elias, Luciana M; Fortkamp, Diana; Sartori, Sérgio B; Ferreira, Marília C; Gomes, Luiz H; Azevedo, João L; Montoya, Quimi V; Rodrigues, André; Ferreira, Antonio G; Lira, Simone P

2018-03-31

Anthracnose is a crop disease usually caused by fungi in the genus Colletotrichum or Gloeosporium. These are considered one of the main pathogens, causing significant economic losses, such as in peppers and guarana. The current forms of control include the use of resistant cultivars, sanitary pruning and fungicides. However, even with the use of some methods of controlling these cultures, the crops are not free of anthracnose. Additionally, excessive application of fungicides increases the resistance of pathogens to agrochemicals and cause harm to human health and the environment. In order to find natural antifungal agents against guarana anthracnose, endophytic fungi were isolated from Amazon guarana. The compounds piliformic acid and cytochalasin D were isolated by chromatographic techniques from two Xylaria spp., guided by assays with Colletotrichum gloeosporioides. The isolated compounds were identified by spectrometric techniques, as NMR and mass spectrometry. This is the first report that piliformic acid and cytochalasin D have antifungal activity against C. gloeosporioides with MIC 2.92 and 2.46μmolmL -1 respectively. Captan and difenoconazole were included as positive controls (MIC 16.63 and 0.02μmolmL -1 , respectively). Thus, Xylaria species presented a biotechnological potential and production of different active compounds which might be promising against anthracnose disease. Copyright © 2018 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

Modulation of leptin resistance by food compounds.

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Aragonès, Gerard; Ardid-Ruiz, Andrea; Ibars, Maria; Suárez, Manuel; Bladé, Cinta

2016-08-01

Leptin is mainly secreted by white adipose tissue and regulates energy homeostasis by inhibiting food intake and stimulating energy expenditure through its action in neuronal circuits in the brain, particularly in the hypothalamus. However, hyperleptinemia coexists with the loss of responsiveness to leptin in common obese conditions. This phenomenon has been defined as leptin resistance and the restoration of leptin sensitivity is considered to be a useful strategy to treat obesity. This review summarizes the existing literature on potentially valuable nutrients and food components to reverse leptin resistance. Notably, several food compounds, such as teasaponins, resveratrol, celastrol, caffeine, and taurine among others, are able to restore the leptin signaling in neurons by overexpressing anorexigenic peptides (proopiomelanocortin) and/or repressing orexigenic peptides (neuropeptide Y/agouti-related peptide), thus decreasing food intake. Additionally, some nutrients, such as vitamins A and D, can improve leptin transport through the blood-brain barrier. Therefore, food components can improve leptin resistance by acting at different levels of the leptin pathway; moreover, some compounds are able to target more than one feature of leptin resistance. However, systematic studies are necessary to define the actual effectiveness of each compound. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Morphological Characterization of the Action Potential Initiation Segment in GnRH Neuron Dendrites and Axons of Male Mice.

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Herde, Michel K; Herbison, Allan E

2015-11-01

GnRH neurons are the final output neurons of the hypothalamic network controlling fertility in mammals. In the present study, we used ankyrin G immunohistochemistry and neurobiotin filling of live GnRH neurons in brain slices from GnRH-green fluorescent protein transgenic male mice to examine in detail the location of action potential initiation in GnRH neurons with somata residing at different locations in the basal forebrain. We found that the vast majority of GnRH neurons are bipolar in morphology, elaborating a thick (primary) and thinner (secondary) dendrite from opposite poles of the soma. In addition, an axon-like process arising predominantly from a proximal dendrite was observed in a subpopulation of GnRH neurons. Ankyrin G immunohistochemistry revealed the presence of a single action potential initiation zone ∼27 μm in length primarily in the secondary dendrite of GnRH neurons and located 30 to 140 μm distant from the cell soma, depending on the type of process and location of the cell body. In addition to dendrites, the GnRH neurons with cell bodies located close to hypothalamic circumventricular organs often elaborated ankyrin G-positive axon-like structures. Almost all GnRH neurons (>90%) had their action potential initiation site in a process that initially, or ultimately after a hairpin loop, was coursing in the direction of the median eminence. These studies indicate that action potentials are initiated in different dendritic and axonal compartments of the GnRH neuron in a manner that is dependent partly on the neuroanatomical location of the cell body.

Mechanisms of action of fungi and bacteria used as biofertilizers in agricultural soils : a systematic review

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Sara Paulina Restrepo-Correa

2017-05-01

Full Text Available Phosphorus, nitrogen, iron and potassium are some compounds necessary for plant growth and development; chemical fertilizers used to increase concentration significantly affect the environment and soil ecosystems. According to the scientific literature, microorganisms with biofertilizer potential have demonstrated various mechanisms of action to solubilize these compounds and thus meet the requirements of plants. This systematic review collects scientific information that describes the mechanisms of action of microbial fertilizers in agricultural soils, published between 2004 and 2014, in three different databases; ScienceDirect, SpringerLink and Scopus,using the search path (biofertilizer AND (bacteria OR fungi AND (effect OR action OR mechanism. After using different inclusion and exclusion criteria, the search displayed a total of 63 original articles, including six unindexed documents. As a result of the systematic review, it indicates that the production of various organic acids allows soil acidification, facilitating absorption of elements. It was also observed that solubilization of P is the most described mechanism, by obtaining a solubilizing of 726.5 mg/L of P due to P. pseudoalcaligenes

Efeitos do potencial de ação neural sobre a percepção de fala em usuários de implante coclear Influence of evoked compound action potential on speech perception in cochlear implant users

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Mariana Cardoso Guedes

2007-08-01

Full Text Available O Potencial de Ação Composto Evocado Eletricamente reflete a atividade do nervo auditivo, podendo ser registrado através dos eletrodos do implante coclear. A determinação dos elementos neurais estimuláveis pode contribuir para explicar a variabilidade de desempenho entre indivíduos implantados. OBJETIVO: Comparar o desempenho nos testes de percepção da fala entre pacientes que apresentaram e que não apresentaram potencial de ação composto evocado eletricamente no momento intra-operatório. MATERIAL E MÉTODO: Estudo prospectivo no qual 100 indivíduos usuários do implante coclear Nucleus 24 foram divididos em dois grupos de acordo com a presença ou ausência do potencial de ação intra-operatório. Após 6 meses de uso do dispositivo, os resultados dos testes de percepção de fala foram comparados entre os grupos. RESULTADOS: O potencial foi observado em 72% dos pacientes. A percepção no teste de frases em formato aberto foi melhor nos indivíduos com presença de potencial (média 82,8% contra 41,0%, p = 0,005. Houve associação entre ausência do potencial e etiologia da surdez por meningite. CONCLUSÃO: Ausência de potencial neural intraoperatório esteve associada ao pior desempenho na percepção da fala e à etiologia da surdez por meningite. Por outro lado, a presença do potencial de ação intraoperatório sugere ótimo prognóstico.Electrically Evoked Compound Action Potential is a measure of synchronous cochlear nerve fibers activity elicited by electrical stimulation of the cochlear implant. The electrophysiological nerve responses may contribute to explain the variability in individual performance of cochlear implant recipients. AIM: To compare speech perception tests’ performances of cochlear implant users according to the presence or absence of intraoperative neural telemetry responses. MATERIAL AND METHOD: Prospective study design with 100 "Nucleus 24" cochlear implant users divided in two groups according

Towards integrated environmental quality objectives for several compounds with a potential for secondary poisoning

OpenAIRE

van de Plassche EJ; ACT; VW/RWS-DGW; AIDE

1994-01-01

Values are derived which can be used to set integrated environmental quality objectives (limit and target values) for 25 compounds with a potential for secondary poisoning. First, Maximum Permissible Concentrations (MPs) and Negligible Concentrations (NCs) are derived for water, sediment and soil based on direct effects on aquatic and soil organisms using extrapolation methods and on possible adverse effects due to secondary poisoning. Two foodchains are taken into account: an aquatic route (...

Grape Seed Oil Compounds: Biological and Chemical Actions for Health

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Juliano Garavaglia

2016-01-01

Full Text Available Grape seed oil is rich in phenolic compounds, fatty acids, and vitamins, with economic importance to pharmaceutical, cosmetic, and food industry. Its use as an edible oil has also been suggested, especially due to its pleasant sensory characteristics. Grape seed oil has beneficial properties for health that are mainly detected by in vitro studies, such as anti-inflammatory, cardioprotective, antimicrobial, and anticancer properties, and may interact with cellular and molecular pathways. These effects have been related to grape seed oil constituents, mainly tocopherol, linolenic acid, resveratrol, quercetin, procyanidins, carotenoids, and phytosterols. The aim of this article was to briefly review the composition and nutritional aspects of grape seed oil, the interactions of its compounds with molecular and cellular pathways, and its possible beneficial effects on health.

Grape Seed Oil Compounds: Biological and Chemical Actions for Health

Science.gov (United States)

Garavaglia, Juliano; Markoski, Melissa M.; Oliveira, Aline; Marcadenti, Aline

2016-01-01

Grape seed oil is rich in phenolic compounds, fatty acids, and vitamins, with economic importance to pharmaceutical, cosmetic, and food industry. Its use as an edible oil has also been suggested, especially due to its pleasant sensory characteristics. Grape seed oil has beneficial properties for health that are mainly detected by in vitro studies, such as anti-inflammatory, cardioprotective, antimicrobial, and anticancer properties, and may interact with cellular and molecular pathways. These effects have been related to grape seed oil constituents, mainly tocopherol, linolenic acid, resveratrol, quercetin, procyanidins, carotenoids, and phytosterols. The aim of this article was to briefly review the composition and nutritional aspects of grape seed oil, the interactions of its compounds with molecular and cellular pathways, and its possible beneficial effects on health. PMID:27559299

Occurrence of a tetrodotoxin-like compound in the eggs of the venomous blue-ringed octopus (Hapalochlaena maculosa).

Science.gov (United States)

Sheumack, D D; Howden, M E; Spence, I

1984-01-01

A lethal toxin was isolated and partly purified from the eggs of the blue-ringed octopus, Hapalochlaena maculosa. Examination of the toxin by thin layer chromatography, isoelectric focusing and its effects upon the compound nerve action potentials of the toad sciatic nerve gave results that were indistinguishable from those displayed by authentic tetrodotoxin, the toxin present in the venom glands of the octopus.

Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain.

Science.gov (United States)

Lim, Eun Yeong; Kim, Yun Tai

2016-01-01

Neuropathic pain, defined as pain caused by a lesion or disease of the somatosensory nervous system, is characterized by dysesthesia, hyperalgesia, and allodynia. The number of patients with this type of pain has increased rapidly in recent years. Yet, available neuropathic pain medicines have undesired side effects, such as tolerance and physical dependence, and do not fully alleviate the pain. The mechanisms of neuropathic pain are still not fully understood. Injury causes inflammation and immune responses and changed expression and activity of receptors and ion channels in peripheral nerve terminals. Additionally, neuroinflammation is a known factor in the development and maintenance of neuropathic pain. During neuropathic pain development, the C-C motif chemokine receptor 2 (CCR2) acts as an important signaling mediator. Traditional plant treatments have been used throughout the world for treating diseases. We and others have identified food-derived compounds that alleviate neuropathic pain. Here, we review the natural compounds for neuropathic pain relief, their mechanisms of action, and the potential benefits of natural compounds with antagonistic effects on GPCRs, especially those containing CCR2, for neuropathic pain treatment.

Seaweed Bioactive Compounds against Pathogens and Microalgae: Potential Uses on Pharmacology and Harmful Algae Bloom Control.

Science.gov (United States)

Zerrifi, Soukaina El Amrani; El Khalloufi, Fatima; Oudra, Brahim; Vasconcelos, Vitor

2018-02-09

Cyanobacteria are found globally due to their adaptation to various environments. The occurrence of cyanobacterial blooms is not a new phenomenon. The bloom-forming and toxin-producing species have been a persistent nuisance all over the world over the last decades. Evidence suggests that this trend might be attributed to a complex interplay of direct and indirect anthropogenic influences. To control cyanobacterial blooms, various strategies, including physical, chemical, and biological methods have been proposed. Nevertheless, the use of those strategies is usually not effective. The isolation of natural compounds from many aquatic and terrestrial plants and seaweeds has become an alternative approach for controlling harmful algae in aquatic systems. Seaweeds have received attention from scientists because of their bioactive compounds with antibacterial, antifungal, anti-microalgae, and antioxidant properties. The undesirable effects of cyanobacteria proliferations and potential control methods are here reviewed, focusing on the use of potent bioactive compounds, isolated from seaweeds, against microalgae and cyanobacteria growth.

[Effects of 2-(p-dimethylaminostyryl) pyridine methycholide (DSPM-Ci) on ECG, left atrium contractivity and on papillary muscle action potentials].

Science.gov (United States)

Jiang, X Y; Zhou, C M; Li, D M; Zhang, K J

1996-01-01

The effects of DSPM-Cl on ECG in rats, on the dose-effect curve in guinea pig left atria and on the fast action potential (AP), high-K+ depolarized slow action potential (SAP) in guinea pigs papillary muscle were examined electrophysiologically. DSPM-Cl (2 mg.kg-1) showed significant nagative frequency, negative conductivity effect, and prolonged the PP and PR interval. DSPM-CI (30-50 mumol.L-1) was shown to inhibit left atria contractility and shift the concentration-response curve of Iso and CaCl2 to the right with PD2' values of 4.60 and 4.13, respectively. In addition, DSPM-Cl was found to prolong the duration of action potential 90 (APD90) and effective refractory period (ERP), and decrease the maximal upstroke velocity (Vmax) in K(+)-depolarized guinea pigs papillary muscles. The results suggest that, like verpamil, DSPM-Cl might be a calcium antagonist.

The Transformative Potential of Action Research and ICT in the Second Language (L2) Classroom

Science.gov (United States)

Farren, Margaret; Crotty, Yvonne; Kilboy, Laura

2015-01-01

This study shows the transformative potential of action research and information and communications technology (ICT) in the second language (L2) classroom. Two enquiries from teacher-researchers are detailed in the article. Their engagement in a collaborative professional development Masters programme was pivotal in designing and implementing ICT…

A simulation of T-wave alternans vectocardiographic representation performed by changing the ventricular heart cells action potential duration.

Science.gov (United States)

Janusek, D; Kania, M; Zaczek, R; Zavala-Fernandez, H; Maniewski, R

2014-04-01

The presence of T wave alternans (TWA) in the surface ECG signals has been recognized as a marker of electrical instability, and is hypothesized to be related to patients at increased risk for ventricular arrhythmias. In this paper we present a TWA simulation study. The TWA phenomenon was simulated by changing the duration of the ventricular heart cells action potential. The magnitude was calculated in the surface ECG with the use of the time domain method. The spatially concordant TWA, where during one heart beat all ventricular cells display a short-duration action potential and during the next beat they exhibit a long-duration action potential, as well as the discordant TWA, where at least one region is out of phase, was simulated. The vectocardiographic representation was employed. The obtained results showed a high level of T-loop pattern and location disturbances connected to the discordant TWA simulation in contrast to the concordant one. This result may be explained by the spatial heterogeneity of the ventricular repolarization process, which could be higher for the discordant TWA than for the concordant TWA. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Backpropagating Action Potentials Enable Detection of Extrasynaptic Glutamate by NMDA Receptors

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Yu-Wei Wu

2012-05-01

Full Text Available Synaptic NMDA receptors (NMDARs are crucial for neural coding and plasticity. However, little is known about the adaptive function of extrasynaptic NMDARs occurring mainly on dendritic shafts. Here, we find that in CA1 pyramidal neurons, backpropagating action potentials (bAPs recruit shaft NMDARs exposed to ambient glutamate. In contrast, spine NMDARs are “protected,” under baseline conditions, from such glutamate influences by perisynaptic transporters: we detect bAP-evoked Ca2+ entry through these receptors upon local synaptic or photolytic glutamate release. During theta-burst firing, NMDAR-dependent Ca2+ entry either downregulates or upregulates an h-channel conductance (Gh of the cell depending on whether synaptic glutamate release is intact or blocked. Thus, the balance between activation of synaptic and extrasynaptic NMDARs can determine the sign of Gh plasticity. Gh plasticity in turn regulates dendritic input probed by local glutamate uncaging. These results uncover a metaplasticity mechanism potentially important for neural coding and memory formation.

Current developments of coumarin compounds in medicinal chemistry.

Science.gov (United States)

Peng, Xin-Mei; Damu, Guri L V; Zhou, Cheng- He

2013-01-01

Coumarin compounds represent an important type of naturally occurring and synthetic oxygen-containing heterocycles with typical benzopyrone framework. This type of special benzopyrone structure enables its derivatives readily interact with a diversity of enzymes and receptors in organisms through weak bond interactions, thereby exhibit wide potentiality as medicinal drugs. So far, some coumarin-based drugs such as anticoagulant and antineurodegenerative agents have been extensively used in clinic. Coumarin-containing supramolecular medicinal agents as a new increasing expansion of supramolecular chemistry in pharmaceutical science have also been actively investigated in recent years. Coumarin-derived artificial ion receptors, fluorescent probes and biological stains are growing quickly and have a variety of potential applications in monitoring timely enzyme activity, complex biological events as well as accurate pharmacological and pharmacokinetic properties. This review provides a systematic summary and insight of the whole range of medicinal chemistry in the current developments of coumarin compounds as anticoagulant, antineurodegenerative, anticancer, antioxidative, antibacterial, antifungal, antiviral, antiparasitic, antiinflammatory and analgesic, antidiabetic, antidepressive and other bioactive agents as well as supramolecular medicinal drugs, diagnostic agents and pathologic probes, and biological stains. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of coumarinbased medicinal chemistry are also presented.

Increased transient Na+ conductance and action potential output in layer 2/3 prefrontal cortex neurons of the fmr1-/y mouse.

Science.gov (United States)

Routh, Brandy N; Rathour, Rahul K; Baumgardner, Michael E; Kalmbach, Brian E; Johnston, Daniel; Brager, Darrin H

2017-07-01

Layer 2/3 neurons of the prefrontal cortex display higher gain of somatic excitability, responding with a higher number of action potentials for a given stimulus, in fmr1 -/y mice. In fmr1 -/y L2/3 neurons, action potentials are taller, faster and narrower. Outside-out patch clamp recordings revealed that the maximum Na + conductance density is higher in fmr1 -/y L2/3 neurons. Measurements of three biophysically distinct K + currents revealed a depolarizing shift in the activation of a rapidly inactivating (A-type) K + conductance. Realistic neuronal simulations of the biophysical observations recapitulated the elevated action potential and repetitive firing phenotype. Fragile X syndrome is the most common form of inherited mental impairment and autism. The prefrontal cortex is responsible for higher order cognitive processing, and prefrontal dysfunction is believed to underlie many of the cognitive and behavioural phenotypes associated with fragile X syndrome. We recently demonstrated that somatic and dendritic excitability of layer (L) 5 pyramidal neurons in the prefrontal cortex of the fmr1 -/y mouse is significantly altered due to changes in several voltage-gated ion channels. In addition to L5 pyramidal neurons, L2/3 pyramidal neurons play an important role in prefrontal circuitry, integrating inputs from both lower brain regions and the contralateral cortex. Using whole-cell current clamp recording, we found that L2/3 pyramidal neurons in prefrontal cortex of fmr1 -/y mouse fired more action potentials for a given stimulus compared with wild-type neurons. In addition, action potentials in fmr1 -/y neurons were significantly larger, faster and narrower. Voltage clamp of outside-out patches from L2/3 neurons revealed that the transient Na + current was significantly larger in fmr1 -/y neurons. Furthermore, the activation curve of somatic A-type K + current was depolarized. Realistic conductance-based simulations revealed that these biophysical changes in Na

Automatic classification of visual evoked potentials based on wavelet decomposition

Science.gov (United States)

Stasiakiewicz, Paweł; Dobrowolski, Andrzej P.; Tomczykiewicz, Kazimierz

2017-04-01

Diagnosis of part of the visual system, that is responsible for conducting compound action potential, is generally based on visual evoked potentials generated as a result of stimulation of the eye by external light source. The condition of patient's visual path is assessed by set of parameters that describe the time domain characteristic extremes called waves. The decision process is compound therefore diagnosis significantly depends on experience of a doctor. The authors developed a procedure - based on wavelet decomposition and linear discriminant analysis - that ensures automatic classification of visual evoked potentials. The algorithm enables to assign individual case to normal or pathological class. The proposed classifier has a 96,4% sensitivity at 10,4% probability of false alarm in a group of 220 cases and area under curve ROC equals to 0,96 which, from the medical point of view, is a very good result.

Potentiation of E-4031-induced torsade de pointes by HMR1556 or ATX-II is not predicted by action potential short-term variability or triangulation.

Science.gov (United States)

Michael, G; Dempster, J; Kane, K A; Coker, S J

2007-12-01

Torsade de pointes (TdP) can be induced by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether IKs blockade or enhancement of INa could potentiate TdP induced by IKr blockade and to investigate whether short-term variability (STV) or triangulation of action potentials preceded TdP. Experiments were performed in open-chest, pentobarbital-anaesthetized, alpha 1-adrenoceptor-stimulated, male New Zealand White rabbits, which received three consecutive i.v. infusions of either the IKr blocker E-4031 (1, 3 and 10 nmol kg(-1) min(-1)), the IKs blocker HMR1556 (25, 75 and 250 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. In a second study rabbits received either the same doses of E-4031, the INa enhancer, ATX-II (0.4, 1.2 and 4.0 nmol kg(-1)) or both of these drugs. ECGs and epicardial monophasic action potentials were recorded. HMR1556 alone did not cause TdP but increased E-4031-induced TdP from 25 to 80%. ATX-II alone caused TdP in 38% of rabbits, as did E-4031; 75% of rabbits receiving both drugs had TdP. QT intervals were prolonged by all drugs but the extent of QT prolongation was not related to the occurrence of TdP. No changes in STV were detected and triangulation was only increased after TdP occurred. Giving modulators of ion channels in combination substantially increased TdP but, in this model, neither STV nor triangulation of action potentials could predict TdP.

Real time estimation of generation, extinction and flow of muscle fibre action potentials in high density surface EMG.

Science.gov (United States)

Mesin, Luca

2015-02-01

Developing a real time method to estimate generation, extinction and propagation of muscle fibre action potentials from bi-dimensional and high density surface electromyogram (EMG). A multi-frame generalization of an optical flow technique including a source term is considered. A model describing generation, extinction and propagation of action potentials is fit to epochs of surface EMG. The algorithm is tested on simulations of high density surface EMG (inter-electrode distance equal to 5mm) from finite length fibres generated using a multi-layer volume conductor model. The flow and source term estimated from interference EMG reflect the anatomy of the muscle, i.e. the direction of the fibres (2° of average estimation error) and the positions of innervation zone and tendons under the electrode grid (mean errors of about 1 and 2mm, respectively). The global conduction velocity of the action potentials from motor units under the detection system is also obtained from the estimated flow. The processing time is about 1 ms per channel for an epoch of EMG of duration 150 ms. A new real time image processing algorithm is proposed to investigate muscle anatomy and activity. Potential applications are proposed in prosthesis control, automatic detection of optimal channels for EMG index extraction and biofeedback. Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical-genetic profile analysis of five inhibitory compounds in yeast.

Science.gov (United States)

Alamgir, Md; Erukova, Veronika; Jessulat, Matthew; Azizi, Ali; Golshani, Ashkan

2010-08-06

Chemical-genetic profiling of inhibitory compounds can lead to identification of their modes of action. These profiles can help elucidate the complex interactions between small bioactive compounds and the cell machinery, and explain putative gene function(s). Colony size reduction was used to investigate the chemical-genetic profile of cycloheximide, 3-amino-1,2,4-triazole, paromomycin, streptomycin and neomycin in the yeast Saccharomyces cerevisiae. These compounds target the process of protein biosynthesis. More than 70,000 strains were analyzed from the array of gene deletion mutant yeast strains. As expected, the overall profiles of the tested compounds were similar, with deletions for genes involved in protein biosynthesis being the major category followed by metabolism. This implies that novel genes involved in protein biosynthesis could be identified from these profiles. Further investigations were carried out to assess the activity of three profiled genes in the process of protein biosynthesis using relative fitness of double mutants and other genetic assays. Chemical-genetic profiles provide insight into the molecular mechanism(s) of the examined compounds by elucidating their potential primary and secondary cellular target sites. Our follow-up investigations into the activity of three profiled genes in the process of protein biosynthesis provided further evidence concerning the usefulness of chemical-genetic analyses for annotating gene functions. We termed these genes TAE2, TAE3 and TAE4 for translation associated elements 2-4.

QSAR modeling and chemical space analysis of antimalarial compounds

Science.gov (United States)

Sidorov, Pavel; Viira, Birgit; Davioud-Charvet, Elisabeth; Maran, Uko; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

2017-05-01

Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including 3000 molecules tested in one or several of 17 anti- Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.

Do Morphemes Matter when Reading Compound Words with Transposed Letters? Evidence from Eye-Tracking and Event-Related Potentials

Science.gov (United States)

Stites, Mallory C.; Federmeier, Kara D.; Christianson, Kiel

2017-01-01

The current study investigates the online processing consequences of encountering compound words with transposed letters (TLs), to determine if TLs that cross morpheme boundaries are more disruptive to reading than those within a single morpheme, as would be predicted by accounts of obligatory morpho-orthopgrahic decomposition. Two measures of online processing, eye movements and event-related potentials (ERPs), were collected in separate experiments. Participants read sentences containing correctly spelled compound words (cupcake), or compounds with TLs occurring either across morpheme boundaries (cucpake) or within one morpheme (cupacke). Results showed that between- and within-morpheme transpositions produced equal processing costs in both measures, in the form of longer reading times (Experiment 1) and a late posterior positivity (Experiment 2) that did not differ between conditions. Findings converge to suggest that within- and between-morpheme TLs are equally disruptive to recognition, providing evidence against obligatory morpho-orthographic processing and in favor of whole-word access of English compound words during sentence reading. PMID:28791313

Molecular docking and ADME-toxicity studies of potential compounds of medicinal plants grown in Indonesia as an anti-rheumatoid arthritis

Science.gov (United States)

Awaluddin, Rizki; Muhtadi, Wildan Khairi; Chabib, Lutfi; Ikawati, Zullies; Martien, Ronny; Ismail, Hilda

2017-03-01

Rheumatoid arthritis (RA) is an autoimmune disease with recurrent bone destruction around the joints that could lead to permanent joint damage. DMARDs (Disease Modifying Anti-Rheumatoid Drugs) and NSAIDs (Non-Steroid Anti-Inflammatory Drugs) are the RA therapies with many side effects on long term use. Based on the ethnomedicine, there are many plants that could be found in Indonesia that contain the potential compounds as alternative RA therapies. The aim of this study is to assess the potential of compounds of various medicinal plants against multiple proteins that play an important role on RA through the molecular docking study and pharmacokinetic prediction. Hesperidin, EGCG (Epigallocatechin gallate), and mangiferin showed higher activity compared to the other compounds against TACE (TNF-α converting enzyme) which play an important role in the inhibition of TNF-α. Inhibition on it could suppress macrophage cell and T-cell activity by suppressing the regulation of cytokine secretion against inflammation. Furthermore, hesperidin, EGCG, and mangiferin did not show effects on CYP450 (cytochrome P450). Modification of drug delivery system must be done to increase the bioavailability of the compounds. It can be concluded that hesperidin, EGCG, and mangiferin are potential to be developed as an RA therapy with a modification of drug delivery system. This study suggest the encapsulation method using liposome as the drug carrier, which is suitable with the charactheristic of hesperidine, EGCG, and mangiferin.

Candidacidal Action of CF66I, an Antifungal Compound Produced ...

African Journals Online (AJOL)

Erah

terms of efficacy and/or safety is needed. During the search for .... and the formation of interconnected cells. Cell surfaces were wrinkled, and ... roughening and disruption (Fig 3b, 3c and. 3d). In addition, this compound caused the clusters of ...

Neuroprotective and memory-related actions of novel alpha-7 nicotinic agents with different mixed agonist/antagonist properties.

Science.gov (United States)

Meyer, E M; Tay, E T; Zoltewicz, J A; Meyers, C; King, M A; Papke, R L; De Fiebre, C M

1998-03-01

The goals of this study were to develop compounds that were selective and highly efficacious agonists at alpha-7 receptors, while varying in antagonist activity; and to test the hypothesis that these compounds had memory-related and neuroprotective actions associated with both agonist and antagonist alpha-7 receptor activities. Three compounds were identified; E,E-3-(cinnamylidene)anabaseine (3-CA), E,E-3-(2-methoxycinnamylidene) anabaseine (2-MeOCA) and E,E-3-(4-methoxycinnamylidene) anabaseine (4-MeOCA) each displaced [125I]alpha-bungarotoxin binding from rat brain membranes and activated rat alpha-7 receptors in a Xenopus oocyte expression system fully efficaciously. The potency series for binding and receptor activation was 2-MeOCA > 4-MeOCA = 3-CA and 2-MeOCA = 3-CA > 4-MeOCA, respectively. No compound significantly activated oocyte-expressed alpha-4beta-2 receptors. Although each cinnamylidene-anabaseine caused a long-term inhibition of alpha-7 receptors, as measured by ACh-application 5 min later, this inhibition ranged considerably, from less than 20% (3-CA) to 90% (2-MeOCA) at an identical concentration (10 microM). These compounds improved passive avoidance behavior in nucleus basalis lesioned rats, with 2-MeOCA most potent in this respect. In contrast, only 3-CA was neuroprotective against neurite loss during nerve growth factor deprivation in differentiated rat pheochromocytoma (PC12) cells. Choline, an efficacious alpha-7 agonist without antagonist activity, was also protective in this model. These results suggest that the neurite-protective action of alpha-7 receptor agonists may be more sensitive to potential long-term antagonist properties than acute behavioral actions are.

Anti-trypanosomal activities and structural chemical properties of selected compound classes.

Science.gov (United States)

Ponte-Sucre, Alicia; Bruhn, Heike; Schirmeister, Tanja; Cecil, Alexander; Albert, Christian R; Buechold, Christian; Tischer, Maximilian; Schlesinger, Susanne; Goebel, Tim; Fuß, Antje; Mathein, Daniela; Merget, Benjamin; Sotriffer, Christoph A; Stich, August; Krohne, Georg; Engstler, Markus; Bringmann, Gerhard; Holzgrabe, Ulrike

2015-02-01

Potent compounds do not necessarily make the best drugs in the market. Consequently, with the aim to describe tools that may be fundamental for refining the screening of candidates for animal and preclinical studies and further development, molecules of different structural classes synthesized within the frame of a broad screening platform were evaluated for their trypanocidal activities, cytotoxicities against murine macrophages J774.1 and selectivity indices, as well as for their ligand efficiencies and structural chemical properties. To advance into their modes of action, we also describe the morphological and ultrastructural changes exerted by selected members of each compound class on the parasite Trypanosoma brucei. Our data suggest that the potential organelles targeted are either the flagellar pocket (compound 77, N-Arylpyridinium salt; 15, amino acid derivative with piperazine moieties), the endoplasmic reticulum membrane systems (37, bisquaternary bisnaphthalimide; 77, N-Arylpyridinium salt; 68, piperidine derivative), or mitochondria and kinetoplasts (88, N-Arylpyridinium salt; 68, piperidine derivative). Amino acid derivatives with fumaric acid and piperazine moieties (4, 15) weakly inhibiting cysteine proteases seem to preferentially target acidic compartments. Our results suggest that ligand efficiency indices may be helpful to learn about the relationship between potency and chemical characteristics of the compounds. Interestingly, the correlations found between the physico-chemical parameters of the selected compounds and those of commercial molecules that target specific organelles indicate that our rationale might be helpful to drive compound design toward high activities and acceptable pharmacokinetic properties for all compound families.

Structure, solution chemistry, antiproliferative actions and protein binding properties of non-conventional platinum(ii) compounds with sulfur and phosphorus donors

NARCIS (Netherlands)

Mügge, C.; Rothenburger, C.; Beyer, A.; Görls, H.; Gabbiani, C.; Casini, A.; Michelucci, E.; Landini, I.; Nobili, S.; Mini, E.; Messori, L.; Weigand, W.

2011-01-01

Twelve Pt(ii) complexes with cis-PtP2S2 pharmacophores (where P2 refers to two monodentate or one bidentate phosphane ligand and S2 is a dithiolato ligand) were prepared, characterized and evaluated as potential antiproliferative agents. The various compounds were first studied from the structural

Testing antidepressant compounds in a neuropsychological model of drug action

NARCIS (Netherlands)

Cerit, Hilal

2015-01-01

Although much research effort has been put into the development of new antidepressant drugs, the process of developing a drug often fails at the stage of large randomized controlled trials (RCTs) in which an initially promising compound appears to lack efficacy after all. Several experimental

Spatiotemporal distribution of carbonyl compounds in China.

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Ho, K F; Ho, Steven Sai Hang; Huang, R-J; Dai, W T; Cao, J J; Tian, Linwei; Deng, W J

2015-02-01

A sampling campaign was carried out at nine Chinese cities in 2010/2011. Fifteen monocarbonyls (C# = 1-9) were quantified. Temperature is the rate-determining factor of the summertime carbonyl levels. The carbonyl emissions in winter are mainly driven by the primary anthropogenic sources like automobile. A molar ratio of propionaldehyde to nonaldehyde is a barometer of the impact of atmospheric vegetation emission which suggesting that strong vegetation emissions exist in summer and high propionaldehyde abundance is caused by fossil fuel combustion in winter. Potential health risk assessment of formaldehyde and acetaldehyde was conducted and the highest cumulative risks were observed at Chengdu in summer and Wuhan in winter. Because of the strong photochemical reaction and large amount of anthropogenic emissions, high concentrations of carbonyl compounds were observed in Chengdu. The use of ethanol-blended gasoline in Wuhan is the key reason of acetaldehyde emission and action should be taken to avoid potential health risks. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sensitivity of the amplitude of the single muscle fibre action potential to microscopic volume conduction parameters

NARCIS (Netherlands)

Alberts, B.A.; Rutten, Wim; Wallinga, W.; Boom, H.B.K.

1988-01-01

A microscopic model of volume conduction was applied to examine the sensitivity of the single muscle fibre action potential to variations in parameters of the source and of the volume conductor, such as conduction velocity, intracellular conductivity and intracellular volume fraction. The model

Youth Participatory Action Research and Educational Transformation: The Potential of Intertextuality as a Methodological Tool

Science.gov (United States)

Bertrand, Melanie

2016-01-01

In this article, Melanie Bertrand explores the potential of using the concept of intertextuality--which captures the way snippets of written or spoken text from one source become incorporated into other sources--in the study and practice of youth participatory action research (YPAR). Though this collective and youth-centered form of research…

In vitro assessment of antiproliferative action selectivity of dietary isothiocyanates for tumor versus normal human cells

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Konić-Ristić Aleksandra

2016-01-01

Full Text Available Background/Aim. Numerous epidemiological studies have shown beneficial effects of cruciferous vegetables consumption in cancer chemoprevention. Biologically active compounds of different Brassicaceae species with antitumor potential are isothiocyanates, present in the form of their precursors - glucosinolates. The aim of this study was to determine the selectivity of antiproliferative action of dietary isothiocyanates for malignant versus normal cells. Methods. Antiproliferative activity of three isothiocyanates abundant in human diet: sulforaphane, benzyl isothiocyanate (BITC and phenylethyl isothiocyanate, on human cervix carcinoma cell line - HeLa, melanoma cell line - Fem-x, and colon cancer cell line - LS 174, and on peripheral blood mononuclear cells (PBMC, with or without mitogen, were determined by MTT colorimetric assay 72 h after their continuous action. Results. All investigated isothiocyanates inhibited the proliferation of HeLa, Fem-x and LS 174 cells. On all cell lines treated, BITC was the most potent inhibitor of cell proliferation with half-maximum inhibitory concentration (IC50 values of 5.04 mmoL m-3 on HeLa cells, 2.76 mmol m-3 on Fem-x, and 14.30 mmol m-3 on LS 174 cells. Antiproliferative effects on human PBMC were with higher IC50 than on malignant cells. Indexes of selectivity, calculated as a ratio between IC50 values obtained on PBMC and malignant cells, were between 1.12 and 16.57, with the highest values obtained for the action of BITC on melanoma Fem-x cells. Conclusion. Based on its antiproliferative effects on malignant cells, as well as the selectivity of the action to malignant vs normal cells, benzyl isothiocyanate can be considered as a promising candidate in cancer chemoprevention. In general, the safety of investigated compounds, in addition to their antitumor potential, should be considered as an important criterion in cancer chemoprevention. Screening of selectivity is a plausible approach to the evaluation

Role of Nutrients and Phyto-compounds in the Modulation of Antimicrobial Resistance.

Science.gov (United States)

Harakeh, Steve; Khan, Imran; Almasaudi, Saad B; Azhar, Esam I; Al-Jaouni, Soad; Niedzweicki, Aleksandra

2017-01-01

findings of this review confirm that certain compounds can act in synergy with currently used antimicrobials to enhance the potential of antimicrobial agents and thus to reduce the emergence of antimicrobial resistance. Some of these synergies are already being used to enhance the potential of currently used antimicrobial agents. More studies need to be conducted to better understand the mechanism of action of such compounds, and based on the results, new compounds may be sought. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Potential of the octanol-water partition coefficient (logP) to predict the dermal penetration behaviour of amphiphilic compounds in aqueous solutions.

Science.gov (United States)

Korinth, Gintautas; Wellner, Tanja; Schaller, Karl Heinz; Drexler, Hans

2012-11-23

Aqueous amphiphilic compounds may exhibit enhanced skin penetration compared with neat compounds. Conventional models do not predict this percutaneous penetration behaviour. We investigated the potential of the octanol-water partition coefficient (logP) to predict dermal fluxes for eight compounds applied neat and as 50% aqueous solutions in diffusion cell experiments using human skin. Data for seven other compounds were accessed from literature. In total, seven glycol ethers, three alcohols, two glycols, and three other chemicals were considered. Of these 15 compounds, 10 penetrated faster through the skin as aqueous solutions than as neat compounds. The other five compounds exhibited larger fluxes as neat applications. For 13 of the 15 compounds, a consistent relationship was identified between the percutaneous penetration behaviour and the logP. Compared with the neat applications, positive logP were associated with larger fluxes for eight of the diluted compounds, and negative logP were associated with smaller fluxes for five of the diluted compounds. Our study demonstrates that decreases or enhancements in dermal penetration upon aqueous dilution can be predicted for many compounds from the sign of logP (i.e., positive or negative). This approach may be suitable as a first approximation in risk assessments of dermal exposure. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

BK channels regulate spontaneous action potential rhythmicity in the suprachiasmatic nucleus.

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Jack Kent

Full Text Available BACKGROUND: Circadian ( approximately 24 hr rhythms are generated by the central pacemaker localized to the suprachiasmatic nucleus (SCN of the hypothalamus. Although the basis for intrinsic rhythmicity is generally understood to rely on transcription factors encoded by "clock genes", less is known about the daily regulation of SCN neuronal activity patterns that communicate a circadian time signal to downstream behaviors and physiological systems. Action potentials in the SCN are necessary for the circadian timing of behavior, and individual SCN neurons modulate their spontaneous firing rate (SFR over the daily cycle, suggesting that the circadian patterning of neuronal activity is necessary for normal behavioral rhythm expression. The BK K(+ channel plays an important role in suppressing spontaneous firing at night in SCN neurons. Deletion of the Kcnma1 gene, encoding the BK channel, causes degradation of circadian behavioral and physiological rhythms. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that loss of robust behavioral rhythmicity in Kcnma1(-/- mice is due to the disruption of SFR rhythms in the SCN, we used multi-electrode arrays to record extracellular action potentials from acute wild-type (WT and Kcnma1(-/- slices. Patterns of activity in the SCN were tracked simultaneously for up to 3 days, and the phase, period, and synchronization of SFR rhythms were examined. Loss of BK channels increased arrhythmicity but also altered the amplitude and period of rhythmic activity. Unexpectedly, Kcnma1(-/- SCNs showed increased variability in the timing of the daily SFR peak. CONCLUSIONS/SIGNIFICANCE: These results suggest that BK channels regulate multiple aspects of the circadian patterning of neuronal activity in the SCN. In addition, these data illustrate the characteristics of a disrupted SCN rhythm downstream of clock gene-mediated timekeeping and its relationship to behavioral rhythms.

The effect of recording site on extracted features of motor unit action potential.

Science.gov (United States)

Artuğ, N Tuğrul; Goker, Imran; Bolat, Bülent; Osman, Onur; Kocasoy Orhan, Elif; Baslo, M Baris

2016-06-01

Motor unit action potential (MUAP), which consists of individual muscle fiber action potentials (MFAPs), represents the electrical activity of the motor unit. The values of the MUAP features are changed by denervation and reinnervation in neurogenic involvement as well as muscle fiber loss with increased diameter variability in myopathic diseases. The present study is designed to investigate how increased muscle fiber diameter variability affects MUAP parameters in simulated motor units. In order to detect this variation, simulated MUAPs were calculated both at the innervation zone where the MFAPs are more synchronized, and near the tendon, where they show increased temporal dispersion. Reinnervation in neurogenic state increases MUAP amplitude for the recordings at both the innervation zone and near the tendon. However, MUAP duration and the number of peaks significantly increased in a case of myopathy for recordings near the tendon. Furthermore, of the new features, "number of peaks×spike duration" was found as the strongest indicator of MFAP dispersion in myopathy. MUAPs were also recorded from healthy participants in order to investigate the biological counterpart of the simulation data. MUAPs which were recorded near to tendon revealed significantly prolonged duration and decreased amplitude. Although the number of peaks was increased by moving the needle near to tendon, this was not significant. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Control of clustered action potential firing in a mathematical model of entorhinal cortex stellate cells.

Science.gov (United States)

Tait, Luke; Wedgwood, Kyle; Tsaneva-Atanasova, Krasimira; Brown, Jon T; Goodfellow, Marc

2018-07-14

The entorhinal cortex is a crucial component of our memory and spatial navigation systems and is one of the first areas to be affected in dementias featuring tau pathology, such as Alzheimer's disease and frontotemporal dementia. Electrophysiological recordings from principle cells of medial entorhinal cortex (layer II stellate cells, mEC-SCs) demonstrate a number of key identifying properties including subthreshold oscillations in the theta (4-12 Hz) range and clustered action potential firing. These single cell properties are correlated with network activity such as grid firing and coupling between theta and gamma rhythms, suggesting they are important for spatial memory. As such, experimental models of dementia have revealed disruption of organised dorsoventral gradients in clustered action potential firing. To better understand the mechanisms underpinning these different dynamics, we study a conductance based model of mEC-SCs. We demonstrate that the model, driven by extrinsic noise, can capture quantitative differences in clustered action potential firing patterns recorded from experimental models of tau pathology and healthy animals. The differential equation formulation of our model allows us to perform numerical bifurcation analyses in order to uncover the dynamic mechanisms underlying these patterns. We show that clustered dynamics can be understood as subcritical Hopf/homoclinic bursting in a fast-slow system where the slow sub-system is governed by activation of the persistent sodium current and inactivation of the slow A-type potassium current. In the full system, we demonstrate that clustered firing arises via flip bifurcations as conductance parameters are varied. Our model analyses confirm the experimentally suggested hypothesis that the breakdown of clustered dynamics in disease occurs via increases in AHP conductance. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Ionization from short-range potential under action of electromagnetic field of complex configuration

CERN Document Server

Rodionov, V N; Kravtsova, G A

2002-01-01

The transcendental equation for the complex energy is obtained on the basis of the exactly solvable 3D model of the short-acting potential and the Green time function in the intensive electromagnetic field, constituting the combination of the constant magnetic field and the circular-polarization wave field. The electron quasistationary states parameters in the delta-potential with an account of the action of the intensive external field of complex configuration are calculated. The problem on the possibility of stabilizing the bound states decay of the spinor and scalar particles through the intensive magnetic field is clarified. It is established that the obtained results regime the reexamination of the accepted notion on the stabilizing role of the strong magnetic field by the atoms ionization

Understanding the Effectiveness of Natural Compound Mixtures in Cancer through Their Molecular Mode of Action

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Thazin Nwe Aung

2017-03-01

Full Text Available Many approaches to cancer management are often ineffective due to adverse reactions, drug resistance, or inadequate target specificity of single anti-cancer agents. In contrast, a combinatorial approach with the application of two or more anti-cancer agents at their respective effective dosages can achieve a synergistic effect that boosts cytotoxicity to cancer cells. In cancer, aberrant apoptotic pathways allow cells that should be killed to survive with genetic abnormalities, leading to cancer progression. Mutations in apoptotic mechanism arising during the treatment of cancer through cancer progression can consequently lead to chemoresistance. Natural compound mixtures that are believed to have multiple specific targets with minimal acceptable side-effects are now of interest to many researchers due to their cytotoxic and chemosensitizing activities. Synergistic interactions within a drug mixture enhance the search for potential molecular targets in cancer cells. Nonetheless, biased/flawed scientific evidence from natural products can suggest false positive therapeutic benefits during drug screening. In this review, we have taken these factors into consideration when discussing the evidence for these compounds and their synergistic therapeutic benefits in cancer. While there is limited evidence for clinical efficacy for these mixtures, in vitro data suggest that these preparations merit further investigation, both in vitro and in vivo.

Six coordination compounds: mode of cytotoxic action and biological evaluation

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ali aydin

2016-09-01

Full Text Available This study describes the biological and anticancer properties of followed coordination compounds. IR spectra, magnetic properties, thermal analyses and crystal structures of six cyanido-complexes derivatives with [MII(CN4]2- (MII= Ni and Pd and [Co(CN6]3- anions and N-bishydeten (N,N-bis(2-hydroxyethylethylenediamine as a capping ligand have been previously reported. Here, we investigated these complexes denoted as[Ni(N-bishydetenNi(CN4] (C1, [Zn2(N-bishydeten2Ni(CN4] (C2, [Ni(N-bishydetenPd(CN4] (C3, [Cd(N-bishydeten2][Pd(CN4] (C4, [Ni2(N-bishydeten2Co(CN6].3H2O (C5 and K[Cd(N-bishydetenCo(CN6].1.5H2O (C6, which were tested for their anti-proliferative activity against human cervical cancer (HeLa, human colon cancer (HT29, rat glioma (C6 and African green monkey kidney (Vero cell lines. The DNA/BSA binding affinities of these compounds were also elucidated by spectroscopic titrations, displacement experiments and electrophoresis measurements. Studies on cancerous cells revealed that C1, C2, C4 and C6 exhibited significant antitumor activity and inhibited tumor progression in testing cell lines and showed high solubility in the solvent. Absorbance and emission spectra data results revealed that the complexes interact with the DNA via groove binding mode of interaction. Overall, these compounds have been found to demonstrate effective anti-proliferative activity against the cancer cell lines, indicating that they are a potent candidate for preclinical or clinical study.

Regulation of gap junction conductance by calcineurin through Cx43 phosphorylation: implications for action potential conduction.

Science.gov (United States)

Jabr, Rita I; Hatch, Fiona S; Salvage, Samantha C; Orlowski, Alejandro; Lampe, Paul D; Fry, Christopher H

2016-11-01

Cardiac arrhythmias are associated with raised intracellular [Ca 2+ ] and slowed action potential conduction caused by reduced gap junction (GJ) electrical conductance (Gj). Ventricular GJs are composed of connexin proteins (Cx43), with Gj determined by Cx43 phosphorylation status. Connexin phosphorylation is an interplay between protein kinases and phosphatases but the precise pathways are unknown. We aimed to identify key Ca 2+ -dependent phosphorylation sites on Cx43 that regulate cardiac gap junction conductance and action potential conduction velocity. We investigated the role of the Ca 2+ -dependent phosphatase, calcineurin. Intracellular [Ca 2+ ] was raised in guinea-pig myocardium by a low-Na solution or increased stimulation. Conduction velocity and Gj were measured in multicellular strips. Phosphorylation of Cx43 serine residues (S365 and S368) and of the intermediary regulator I1 at threonine35 was measured by Western blot. Measurements were made in the presence and absence of inhibitors to calcineurin, I1 or protein phosphatase-1 and phosphatase-2.Raised [Ca 2 + ] i decreased Gj, reduced Cx43 phosphorylation at S365 and increased it at S368; these changes were reversed by calcineurin inhibitors. Cx43-S368 phosphorylation was reversed by the protein kinase C inhibitor chelerythrine. Raised [Ca 2+ ] i also decreased I1 phosphorylation, also prevented by calcineurin inhibitors, to increase activity of the Ca 2+ -independent phosphatase, PPI. The PP1 inhibitor, tautomycin, prevented Cx43-365 dephosphorylation, Cx43-S368 phosphorylation and Gj reduction in raised [Ca 2+ ] i . PP2A had no role. Conduction velocity was reduced by raised [Ca 2+ ] i and reversed by calcineurin inhibitors. Reduced action potential conduction and Gj in raised [Ca 2+ ] are regulated by calcineurin-dependent Cx43-S365 phosphorylation, leading to Cx43-S368 dephosphorylation. The calcineurin action is indirect, via I1 dephosphorylation and subsequent activation of PP1.

Insulin sensitizing and alpha-glucoamylase inhibitory action of sennosides, rheins and rhaponticin in Rhei Rhizoma.

Science.gov (United States)

Choi, Soo Bong; Ko, Byoung Seob; Park, Seong Kyu; Jang, Jin Sun; Park, Sunmin

2006-01-25

Extracts from Rhei Rhizoma extracts (RR) have been reported to attenuate metabolic disorders such as diabetic nephropathy, hypercholesterolemia and platelet aggregation. With this study we investigated the anti-diabetic action of 70% ethanol RR extract in streptozotocin-induced diabetic mice, and determined the action mechanism of active compounds of RR in vitro. In the diabetic mice, serum glucose levels at fasting and post-prandial states and glucose area under the curve at modified oral glucose tolerance tests were lowered without altering serum insulin levels, indicating that RR contained potential anti-diabetic agents. The fractions fractionated from RR extracts by XAD-4 column revealed that 60%, 80% and 100% methanol fractions enhanced insulin sensitivity and inhibited alpha-glucoamylase activity. The major compounds of these fractions were sennosides, rhein and rhaponticin. Rhaponticin and rhein enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Rhaponticin increased adipocytes with a differentiating effect similar to pioglitazone, but rhein and sennoside B decreased triglyceride accumulation. Sennoside A and B inhibited alpha-glucoamylase activity as much as acarbose. In conclusion, a crude extract of RR improves glucose intolerance by enhancing insulin-stimulated glucose uptake and decreasing carbohydrate digestion via inhibiting alpha-glucoamylase activity. Rhein and rhaponticin are potential candidates for hypoglycemic agents.

Isolation and characterization of antifungal compound from Lactobacillus plantarum KCC-10 from forage silage with potential beneficial properties.

Science.gov (United States)

Valan Arasu, M; Jung, M-W; Ilavenil, S; Jane, M; Kim, D-H; Lee, K-D; Park, H-S; Hur, T-Y; Choi, G-J; Lim, Y-C; Al-Dhabi, N A; Choi, K-C

2013-11-01

The purpose of this study was to isolate, identify and characterize an antifungal compound from Lactobacillus plantarum KCC-10 from forage silage with potential beneficial properties. The 16S rRNA gene-based phylogenetic affiliation was determined using bioinformatic tools and identified as Lactobacillus sp. KCC-10 with 100% sequence similarity to L. plantarum. The antifungal substances were extracted with ethyl acetate from spent medium in which Lactobacillus sp. KCC-10 was cultivated. Antifungal activity was assessed using the broth microdilution technique. The compounds were obtained by eluting the crude extract with various concentrations of solvents followed by chromatographic purification. Based on the infrared, (13) C nuclear magnetic resonance (NMR) and (1) H NMR spectral data, the compound was identified as a phenolic-related antibiotic. The minimum inhibitory concentration of the compound against Aspergillus clavatus, A. oryzae, Botrytis elliptica and Scytalidium vaccinii was 2.5 mg ml(-1) and that against A. fumigatus, A. niger and S. fusca was 5.0 mg ml(-1) , respectively. In addition, Lactobacillus sp. KCC-10 was highly sensitive towards oxgall (0.3%) but grew well in the presence of sodium taurocholate (0.3%). An antimicrobial susceptibility pattern was an intrinsic feature of this strain; thus, consumption does not represent a health risk to humans or animals. Novel L. plantarum KCC-10 with antifungal and potential probiotic properties was characterized for use in animal food. This study revealed that L. plantarum KCC-10 exhibited good antifungal activity similar to that of probiotic Lactobacillus strains. © 2013 The Society for Applied Microbiology.

Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative

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Marcin Mączyński

2018-06-01

Full Text Available This work describes the synthesis of a new series of isoxazole derivatives, their immunosuppressive properties, and the mechanism of action of a representative compound. A new series of N′-substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM1–MM10 was synthesized in reaction of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide with relevant carbonyl compounds. The isoxazole derivatives were tested in several in vitro models using human cells. The compounds inhibited phytohemagglutinin A (PHA-induced proliferation of peripheral blood mononuclear cells (PBMCs to various degrees. The toxicity of the compounds with regard to a reference A549 cell line was also differential. 5-amino-N′-(2,4-dihydroxyphenylmethylidene-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM3 compound was selected for further investigation because of its lack of toxicity and because it had the strongest antiproliferative activity. The compound was shown to inhibit lipopolysaccharide (LPS-induced tumor necrosis factor (TNF α production in human whole blood cell cultures. In the model of Jurkat cells, MM3 elicited strong increases in the expression of caspases, Fas, and NF-κB1, indicating that a proapoptotic action may account for its immunosuppressive action in the studied models.

Implications of an assessment of potential organic contamination of ground water at an inactive uranium mill

International Nuclear Information System (INIS)

Price, J.B.

1986-01-01

Laws and regulations concerning remedial actions at inactive uranium mills explicitly recognize radiological and nonradiological hazards and may implicitly recognize the potential presence of hazardous wastes at these mill sites. Ground-water studies at the sites have placed an increasing emphasis on screening for priority pollutants. The Grand Junction, Colorado, mill site was deemed to have a high potential for the presence of organic compounds in ground water, and was chosen as a prototype for assessing the presence of organic compounds in ground water at inactive sites. Lessons learned from the assessment of organics at the Grand Junction site were used to develop a screening procedure for other inactive mill sites

Protective effects of organoselenium compounds against methylmercury-induced oxidative stress in mouse brain mitochondrial-enriched fractions

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D.F. Meinerz

2011-11-01

Full Text Available We evaluated the potential neuroprotective effect of 1-100 µM of four organoselenium compounds: diphenyl diselenide, 3’3-ditri-fluoromethyldiphenyl diselenide, p-methoxy-diphenyl diselenide, and p-chloro-diphenyl diselenide, against methylmercury-induced mitochondrial dysfunction and oxidative stress in mitochondrial-enriched fractions from adult Swiss mouse brain. Methylmercury (10-100 µM significantly decreased mitochondrial activity, assessed by MTT reduction assay, in a dose-dependent manner, which occurred in parallel with increased glutathione oxidation, hydroperoxide formation (xylenol orange assay and lipid peroxidation end-products (thiobarbituric acid reactive substances, TBARS. The co-incubation with diphenyl diselenide (100 µM completely prevented the disruption of mitochondrial activity as well as the increase in TBARS levels caused by methylmercury. The compound 3’3-ditrifluoromethyldiphenyl diselenide provided a partial but significant protection against methylmercury-induced mitochondrial dysfunction (45.4 ± 5.8% inhibition of the methylmercury effect. Diphenyl diselenide showed a higher thiol peroxidase activity compared to the other three compounds. Catalase blocked methylmercury-induced TBARS, pointing to hydrogen peroxide as a vector during methylmercury toxicity in this model. This result also suggests that thiol peroxidase activity of organoselenium compounds accounts for their protective actions against methylmercury-induced oxidative stress. Our results show that diphenyl diselenide and potentially other organoselenium compounds may represent important molecules in the search for an improved therapy against the deleterious effects of methylmercury as well as other mercury compounds.

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

Science.gov (United States)

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

2016-10-01

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

Evaluating the potential bioactivity of a novel compound ER1626.