Biological Activities of Tetrodotoxin-Producing Enterococcus faecium AD1 Isolated from Puffer Fishes

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Tu Hoang Khue Nguyen

2015-01-01

Full Text Available Puffer fishes were collected from the central sea in Vietnam from spring to summer season. The eggs were incubated in MRS broth that was used to test the toxicity in mice and isolate the lactic acid bacteria community that could produce tetrodotoxin (TTX. Thin layer chromatography (TLC and high performance lipid chromatography (HPLC were used to detect and quantify TTX. As a result, Enterococcus faecium AD1 which was identified by biochemical test and 16S rRNA analysis could produce TTX 0.3 mg/mL when cultured in MRS broth. The bacterium was optimized for TTX production and gave 0.18 mg/mL, 0.07 mg/mL, and 0.15 mg/mL in media prepared from the meat-washing water of freshwater fishes (Pangasius bocourti, Oreochromis sp. and sea fish (Auxis thazard, respectively, that are also hopeful to answer some poisoning cases related to eating fishes. Enterococcus faecium also showed the wide antimicrobial activities on yeast, Gram-negative and -positive bacteria. Extracted exopolysaccharide (EPS that reacted with 2,2-diphenyl-1-picrylhydrazyl to give IC50 at 5 mg/mL equaled 11 mg/mL ascorbic acid which could show effects on Hela-6 and Hep G2 using sulforhodamine B test. Enterococcus faecium can be claimed as a promising source in tetrodotoxin and biological compounds.

Effects of tetrodotoxin and ion replacements on the short-circuit current induced by Escherichiacoli heat stable enterotoxin across small intestine of the gerbil (Gerbillus cheesmani

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Fawzia Yaqoub Al-Balool

2004-03-01

Full Text Available The effects of mucosally added Escherichia coli heat stable enterotoxin (STa 30 ng ml-1 on the basal short-circuit current (Isc in µA cm-2 across stripped and unstripped sheets of jejuna and ilea taken from fed, starved (4 days, water ad lib and undernourished (50% control food intake for 21 days gerbil (Gerbillus cheesmani were investigated. The effect of neurotoxin tetrodotoxin (TTX 10 µM and the effects of replacing chloride by gluconate or the effects of removing bicarbonate from bathing buffers on the maximum increase in Isc induced by STa were also investigated. The maximum increase in Isc which resulted from the addition of STa were significantly higher in jejuna and ilea taken from starved and undernourished gerbils when compared with the fed control both using stripped and unstripped sheets. In the two regions of the small intestine taken from fed and starved animals TTX reduced the maximum increase in Isc induced by STa across unstripped sheets only. Moreover in jejuna and ilea taken from undernourished gerbils TTX reduced significantly the maximum increase in Isc induced by STa across stripped and unstripped sheets. Replacing chloride by gluconate decreased the maximum increase in Isc induced by STa across jejuna and ilea taken from undernourished gerbils only. Removing bicarbonates from bathing buffer decreased the maximum increase in Isc across the jejuna and ilea taken from starved and undernourished gerbils.

Development of standardized methodology for identifying toxins in clinical samples and fish species associated with tetrodotoxin-borne poisoning incidents

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Tai-Yuan Chen

2016-01-01

Full Text Available Tetrodotoxin (TTX is a naturally occurring toxin in food, especially in puffer fish. TTX poisoning is observed frequently in South East Asian regions. In TTX-derived food poisoning outbreaks, the amount of TTX recovered from suspicious fish samples or leftovers, and residual levels from biological fluids of victims are typically trace. However, liquid chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry methods have been demonstrated to qualitatively and quantitatively determine TTX in clinical samples from victims. Identification and validation of the TTX-originating seafood species responsible for a food poisoning incident is needed. A polymerase chain reaction-based method on mitochondrial DNA analysis is useful for identification of fish species. This review aims to collect pertinent information available on TTX-borne food poisoning incidents with a special emphasis on the analytical methods employed for TTX detection in clinical laboratories as well as for the identification of TTX-bearing species.

Occurrence of tetrodotoxin-binding high molecular weight substances in the body fluid of shore crab (Hemigrapsus sanguineus).

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Shiomi, K; Yamaguchi, S; Kikuchi, T; Yamamori, K; Matsui, T

1992-12-01

The shore crab (Hemigrapsus sanguineus) is highly resistant to tetrodotoxin (TTX) although it contains no detectable amount of TTX (less than 5 MU/g, where 1 MU is defined as the amount of TTX killing a 20 g mouse in 30 min). Its body fluid was examined for neutralizing effects against the lethal activity of TTX. When the mixture of the body fluid and TTX was injected i.p. into mice, the lethal activity of TTX was significantly reduced; 1 ml of the body fluid was evaluated to neutralize 3.6-4.0 MU of TTX. Higher neutralizing activity (7.2-12.5 MU/ml of the body fluid) was exhibited by i.v. administration of the body fluid into mice before or after i.p. challenge of TTX. The lethal effect of paralytic shellfish poisons was not counteracted by the body fluid. Analysis by gel filtration on Sepharose 6B revealed that the body fluid contained TTX-binding high mol. wt substances (> 2,000,000) responsible for the neutralizing activity of the body fluid against TTX, which accounts for the high resistibility of the crab to TTX. When the crude toxin extracted from the liver of puffer (Takifugu niphobles) was mixed with the body fluid and chromatographed on Sepharose 6B, almost pure TTX was obtained from the fractions containing the TTX-binding high mol. wt substances, suggesting that the TTX-binding high mol. wt substances could be useful in purification of TTX from biological samples.

Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses

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Jorge Lago

2015-10-01

Full Text Available Tetrodotoxin (TTX is a potent neurotoxin responsible for many human intoxications and fatalities each year. The origin of TTX is unknown, but in the pufferfish, it seems to be produced by endosymbiotic bacteria that often seem to be passed down the food chain. The ingestion of contaminated pufferfish, considered the most delicious fish in Japan, is the usual route of toxicity. This neurotoxin, reported as a threat to human health in Asian countries, has spread to the Pacific and Mediterranean, due to the increase of temperature waters worldwide. TTX, for which there is no known antidote, inhibits sodium channel producing heart failure in many cases and consequently death. In Japan, a regulatory limit of 2 mg eq TTX/kg was established, although the restaurant preparation of “fugu” is strictly controlled by law and only chefs qualified are allowed to prepare the fish. Due to its paralysis effect, this neurotoxin could be used in the medical field as an analgesic to treat some cancer pains.

Tetrodotoxin – Distribution and Accumulation in Aquatic Organisms, and Cases of Human Intoxication

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Osamu Arakawa

2008-05-01

Full Text Available Many pufferfish of the family Tetraodontidae possess a potent neurotoxin, tetrodotoxin (TTX. In marine pufferfish species, toxicity is generally high in the liver and ovary, whereas in brackish water and freshwater species, toxicity is higher in the skin. In 1964, the toxin of the California newt was identified as TTX as well, and since then TTX has been detected in a variety of other organisms. TTX is produced primarily by marine bacteria, and pufferfish accumulate TTX via the food chain that begins with these bacteria. Consequently, pufferfish become non-toxic when they are fed TTX-free diets in an environment in which the invasion of TTX-bearing organisms is completely shut off. Although some researchers claim that the TTX of amphibians is endogenous, we believe that it also has an exogenous origin, i.e., from organisms consumed as food. TTX-bearing animals are equipped with a high tolerance to TTX, and thus retain or accumulate TTX possibly as a biologic defense substance. There have been many cases of human intoxication due to the ingestion of TTX-bearing pufferfish, mainly in Japan, China, and Taiwan, and several victims have died. Several cases of TTX intoxication due to the ingestion of small gastropods, including some lethal cases, were recently reported in China and Taiwan, revealing a serious public health issue.

Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50 and No Observed Adverse Effect Level (NOAEL

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Paula Abal

2017-02-01

Full Text Available Tetrodotoxin (TTX is starting to appear in molluscs from the European waters and is a hazard to seafood consumers. This toxin blocks sodium channels resulting in neuromuscular paralysis and even death. As a part of the risk assessment process leading to a safe seafood level for TTX, oral toxicity data are required. In this study, a 4-level Up and Down Procedure was designed in order to determine for the first time the oral lethal dose 50 (LD50 and the No Observed Adverse Effect Level (NOAEL in mice by using an accurate well-characterized TTX standard.

Difference in Uptake of Tetrodotoxin and Saxitoxins into Liver Tissue Slices among Pufferfish, Boxfish and Porcupinefish

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Yuji Nagashima

2018-01-01

Full Text Available Although pufferfish of the family Tetraodontidae contain high levels of tetrodotoxin (TTX mainly in the liver, some species of pufferfish, boxfish of the family Ostraciidae, and porcupinefish of the family Diodontidae do not. To clarify the mechanisms, uptake of TTX and saxitoxins (STXs into liver tissue slices of pufferfish, boxfish and porcupinefish was examined. Liver tissue slices of the pufferfish (toxic species Takifugu rubripes and non-toxic species Lagocephalus spadiceus, L. cheesemanii and Sphoeroides pachygaster incubated with 50 µM TTX accumulated TTX (0.99–1.55 µg TTX/mg protein after 8 h, regardless of the toxicity of the species. In contrast, in liver tissue slices of boxfish (Ostracion immaculatus and porcupinefish (Diodon holocanthus, D. liturosus, D. hystrix and Chilomycterus reticulatus, TTX content did not increase with incubation time, and was about 0.1 µg TTX/mg protein. When liver tissue slices were incubated with 50 µM STXs for 8 h, the STXs content was <0.1 µg STXs/mg protein, irrespective of the fish species. These findings indicate that, like the toxic species of pufferfish T. rubripes, non-toxic species such as L. spadiceus, L. cheesemanii and S. pachygaster, potentially take up TTX into the liver, while non-toxic boxfish and porcupinefish do not take up either TTX or STXs.

A tetrodotoxin-binding protein in the hemolymph of shore crab Hemigrapsus sanguineus: purification and properties.

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Nagashima, Yuji; Yamamoto, Kazuhiko; Shimakura, Kuniyoshi; Shiomi, Kazuo

2002-06-01

The shore crab Hemigrapsus sanguineus hemolymph contains soluble proteins that bind tetrodotoxin (TTX) and are responsible for high resistance of the crab to TTX. The TTX-binding protein was purified from the hemolymph by ultrafiltration, lectin affinity chromatography and gel filtration HPLC. The purified protein gave only one band in native-polyacrylamide gel electrophoresis (PAGE), confirming its homogeneity. Its molecular weight was estimated to be about 400k by gel filtration HPLC, while it was estimated to be about 82k under non-reducing conditions and about 72 and 82k under reducing conditions by SDS-PAGE, indicating that the TTX-binding protein was composed of at least two distinct subunits. The TTX-binding protein was an acidic glycoprotein with pI 3.5, abundant in Asp and Glu but absent in Trp, and contained 6% reducing sugar and 12% amino sugar. The protein selectively bound to TTX, with a neutralizing ability of 6.7 mouse unit TTX/mg protein, but not to paralytic shellfish poisoning toxins. However, its neutralizing activity was almost lost by treatments with enzymes (protease XIV, thermolysin, trypsin, amyloglucosidase and alpha-amylase) and denaturing agents (1% SDS, 1% dithiothreitol, 8 M urea and 6 M guanidine hydrochloride), suggesting the involvement of both proteinaceous and sugar moieties in the binding to TTX and the importance of the steric conformation of the TTX-binding protein. Copright 2002 Elsevier Science Ltd.

Tetrodotoxin Detection by a Surface Plasmon Resonance Sensor in Pufferfish Matrices and Urine

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Allen D. Taylor

2011-01-01

Full Text Available Tetrodotoxin (TTX poisoning is most commonly associated with consumption of pufferfish. TTX is a low molecular weight (~319 Da neurotoxin that selectively blocks voltage-sensitive Na+-gated ion channels. The standard method accepted worldwide for monitoring TTX toxicity in food matrices is the mouse bioassay. Ethical concerns from live animal testing, low sample throughput, and analytical inaccuracies have led to the need for an alternative method. We have previously established that surface plasmon resonance (SPR sensors can quantify TTX in aqueous buffer samples by an antibody-based inhibition assay. In this paper, we report the extension of the assay for the detection of TTX in both clinical- and food-relevant matrices. The assay was optimized for application to three relevant complex matrices: pufferfish liver extract, pufferfish muscle extract, and human urine. Matrix effects are discussed and calibration curves are presented. Naturally contaminated pufferfish liver and muscle extracts were analyzed by the SPR method, and the data is compared to liquid-chromatography electrospray-ionization multiple reactions monitoring mass spectrometry (LC/ESI/MRM/MS data. Ten samples, including three from a poisoning incident, two control monkfish samples, and five toxic pufferfish samples, were analyzed using this method, and the data is compared to LC/ESI/MRM/MS analysis of the samples.

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

Urinary Excretion of Tetrodotoxin Modeled in a Porcine Renal Proximal Tubule Epithelial Cell Line, LLC-PK1

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Takuya Matsumoto

2017-07-01

Full Text Available This study examined the urinary excretion of tetrodotoxin (TTX modeled in a porcine renal proximal tubule epithelial cell line, LLC-PK1. Time course profiles of TTX excretion and reabsorption across the cell monolayers at 37 °C showed that the amount of TTX transported increased linearly for 60 min. However, at 4 °C, the amount of TTX transported was approximately 20% of the value at 37 °C. These results indicate that TTX transport is both a transcellular and carrier-mediated process. Using a transport inhibition assay in which cell monolayers were incubated with 50 µM TTX and 5 mM of a transport inhibitor at 37 °C for 30 min, urinary excretion was significantly reduced by probenecid, tetraethylammonium (TEA, l-carnitine, and cimetidine, slightly reduced by p-aminohippuric acid (PAH, and unaffected by 1-methyl-4-phenylpyridinium (MPP+, oxaliplatin, and cefalexin. Renal reabsorption was significantly reduced by PAH, but was unaffected by probenecid, TEA and l-carnitine. These findings indicate that TTX is primarily excreted by organic cation transporters (OCTs and organic cation/carnitine transporters (OCTNs, partially transported by organic anion transporters (OATs and multidrug resistance-associated proteins (MRPs, and negligibly transported by multidrug and toxic compound extrusion transporters (MATEs.

Tetrodotoxin detection and species identification of pufferfish in retail roasted fish fillet by DNA barcoding in China.

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Li, Nan; Shen, Qing; Wang, Jiahui; Han, Chunhui; Ji, Rong; Li, Fengqin; Jiang, Tao

2015-01-01

This study identifies the pufferfish species and detects tetrodotoxin (TTX) in roasted fish fillet samples collected in Beijing, Qingdao and Xiamen, China. The cytochrome c oxidase I (COI) gene was used as the target gene for identification of the pufferfish species in the samples. Enzyme-linked immunosorbent assay (ELISA) screened the TTX levels in samples that had been detected as containing pufferfish by DNA barcode. A total of 125 samples were identified by DNA barcodes; 32 (26%) samples contained pufferfish composition and, among them, 26 (81%) were the highly toxic species Lagocephalus lunaris. All 32 samples containing the pufferfish composition were positive for TTX with levels ranging from 100 to 63,800 ng g(-1). Most of the 32 samples contained the highly toxic L. lunaris. Based on the results, we suggest that the monitoring of roasted fish fillet should be strengthened and the processing procedures should be standardised to minimise TTX poisoning caused by pufferfish.

Tetrodotoxin-Bupivacaine-Epinephrine Combinations for Prolonged Local Anesthesia

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Christina Bognet

2011-12-01

Full Text Available Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL solutions, with or without epinephrine 5 µg/mL (1:200,000 in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 µM and epinephrine 5 µg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain (P < 0.001 or bupivacaine 0.25% with epinephrine 5 µg/mL (P < 0.001. Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 µg/mL appear promising for prolonged duration of local anesthesia.

Of poisons and parasites-the defensive role of tetrodotoxin against infections in newts.

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Johnson, Pieter T J; Calhoun, Dana M; Stokes, Amber N; Susbilla, Calvin B; McDevitt-Galles, Travis; Briggs, Cheryl J; Hoverman, Jason T; Tkach, Vasyl V; de Roode, Jacobus C

2018-02-24

Classical research on animal toxicity has focused on the role of toxins in protection against predators, but recent studies suggest these same compounds can offer a powerful defense against parasites and infectious diseases. Newts in the genus Taricha are brightly coloured and contain the potent neurotoxin, tetrodotoxin (TTX), which is hypothesized to have evolved as a defense against vertebrate predators such as garter snakes. However, newt populations often vary dramatically in toxicity, which is only partially explained by predation pressure. The primary aim of this study was to evaluate the relationships between TTX concentration and infection by parasites. By systematically assessing micro- and macroparasite infections among 345 adult newts (sympatric populations of Taricha granulosa and T. torosa), we detected 18 unique taxa of helminths, fungi, viruses and protozoans. For both newt species, per-host concentrations of TTX, which varied from undetectable to >60 μg/cm 2 skin, negatively predicted overall parasite richness as well as the likelihood of infection by the chytrid fungus, Batrachochytrium dendrobatidis, and ranavirus. No such effect was found on infection load among infected hosts. Despite commonly occurring at the same wetlands, T. torosa supported higher parasite richness and average infection load than T. granulosa. Host body size and sex (females > males) tended to positively predict infection levels in both species. For hosts in which we quantified leucocyte profiles, total white blood cell count correlated positively with both parasite richness and total infection load. By coupling data on host toxicity and infection by a broad range of micro- and macroparasites, these results suggest that-alongside its effects on predators-tetrodotoxin may help protect newts against parasitic infections, highlighting the importance of integrative research on animal chemistry, immunological defenses and natural enemy ecology. © 2018 The Authors. Journal

Preliminary Results on the Evaluation of the Occurrence of Tetrodotoxin Associated to Marine Vibrio spp. in Bivalves from the Galician Rias (Northwest of Spain

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Jose Manuel Leão

2018-03-01

Full Text Available Tetrodotoxins (TTX are a potent group of natural neurotoxins putatively produced by symbiotic microorganisms and affecting the aquatic environment. These neurotoxins have been recently found in some species of bivalves and gastropods along the European Coasts (Greece, UK, and The Netherlands linked to the presence of high concentrations of Vibrio, in particular Vibrio parahaemolyticus. This study is focused on the evaluation of the presence of Vibrio species and TTX in bivalves (mussels, oysters, cockles, clams, scallops, and razor clams from Galician Rias (northwest of Spain. The detection and isolation of the major Vibrio spp. and other enterobacterial populations have been carried out with the aim of screening for the presence of the pathways genes, poliketide synthase (PKS and non-ribosomal peptide synthetase (NRPS possibly involved in the biosynthesis of these toxins. Samples containing Vibrio spp. were analyzed by biochemical (API20E-galery and genetic tests (PCR-RT. These samples were then screened for TTX toxicity by a neuroblastoma cell-based assay (N2a and the presence of TTX was further confirmed by LC-MS/MS. TTX was detected in two infaunal samples. This is the first confirmation of the presence of TTX in bivalve molluscs from the Galician Rias.

Toxic Marine Puffer Fish in Thailand Seas and Tetrodotoxin They Contained

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Hisao Kurazono

2011-10-01

Full Text Available A total of 155 puffers caught from two of Thailand’s seas, the Gulf of Siam and the Andaman seas, during April to July 2010 were included in this study. Among 125 puffers from the Gulf of Siam, 18 were Lagocephalus lunaris and 107 were L. spadiceus which were the same two species found previously in 2000–2001. Thirty puffers were collected from the Andaman seas, 28 Tetraodon nigroviridis and two juvenile Arothron reticularis; the two new species totally replaced the nine species found previously in 1992–1993. Conventional mouse bioassay was used to determine the toxicity in all fish tissue extracts, i.e., liver, reproductive tissue, digestive tissue and muscle. One of each of the species L. lunaris and L. spadiceus (5.56 and 0.93%, respectively were toxic. All 28 T. nigroviridis and 2 A. reticularis (100% from the Andaman seas were toxic. The toxicity scores in T. nigroviridis tissues were much higher than in the respective tissues of the other three fish species. Liquid chromatography/tandem mass spectrometry (LC-MS/MS revealed that the main toxic principle was tetrodotoxin (TTX. This study is the first to report TTX in L. spadiceus. Our findings raised a concern for people, not only Thais but also inhabitants of other countries situated on the Andaman coast; consuming puffers of the Andaman seas is risky due to potential TTX intoxication.

Parallel evolution of tetrodotoxin resistance in three voltage-gated sodium channel genes in the garter snake Thamnophis sirtalis.

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McGlothlin, Joel W; Chuckalovcak, John P; Janes, Daniel E; Edwards, Scott V; Feldman, Chris R; Brodie, Edmund D; Pfrender, Michael E; Brodie, Edmund D

2014-11-01

Members of a gene family expressed in a single species often experience common selection pressures. Consequently, the molecular basis of complex adaptations may be expected to involve parallel evolutionary changes in multiple paralogs. Here, we use bacterial artificial chromosome library scans to investigate the evolution of the voltage-gated sodium channel (Nav) family in the garter snake Thamnophis sirtalis, a predator of highly toxic Taricha newts. Newts possess tetrodotoxin (TTX), which blocks Nav's, arresting action potentials in nerves and muscle. Some Thamnophis populations have evolved resistance to extremely high levels of TTX. Previous work has identified amino acid sites in the skeletal muscle sodium channel Nav1.4 that confer resistance to TTX and vary across populations. We identify parallel evolution of TTX resistance in two additional Nav paralogs, Nav1.6 and 1.7, which are known to be expressed in the peripheral nervous system and should thus be exposed to ingested TTX. Each paralog contains at least one TTX-resistant substitution identical to a substitution previously identified in Nav1.4. These sites are fixed across populations, suggesting that the resistant peripheral nerves antedate resistant muscle. In contrast, three sodium channels expressed solely in the central nervous system (Nav1.1-1.3) showed no evidence of TTX resistance, consistent with protection from toxins by the blood-brain barrier. We also report the exon-intron structure of six Nav paralogs, the first such analysis for snake genes. Our results demonstrate that the molecular basis of adaptation may be both repeatable across members of a gene family and predictable based on functional considerations. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Activity deprivation induces neuronal cell death: mediation by tissue-type plasminogen activator.

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Eldi Schonfeld-Dado

Full Text Available Spontaneous activity is an essential attribute of neuronal networks and plays a critical role in their development and maintenance. Upon blockade of activity with tetrodotoxin (TTX, neurons degenerate slowly and die in a manner resembling neurodegenerative diseases-induced neuronal cell death. The molecular cascade leading to this type of slow cell death is not entirely clear. Primary post-natal cortical neurons were exposed to TTX for up to two weeks, followed by molecular, biochemical and immunefluorescence analysis. The expression of the neuronal marker, neuron specific enolase (NSE, was down-regulated, as expected, but surprisingly, there was a concomitant and striking elevation in expression of tissue-type plasminogen activator (tPA. Immunofluorescence analysis indicated that tPA was highly elevated inside affected neurons. Transfection of an endogenous tPA inhibitor, plasminogen activator inhibitor-1 (PAI-1, protected the TTX-exposed neurons from dying. These results indicate that tPA is a pivotal player in slowly progressing activity deprivation-induced neurodegeneration.

Tetrodotoxin and paralytic shellfish poisons in gastropod species from Vietnam analyzed by high-performance liquid chromatography and liquid chromatography–tandem mass spectrometry

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Hsiao-Chin Jen

2014-06-01

Full Text Available Among marine toxins, tetrodotoxin (TTX and paralytic shellfish poisons (PSPs are known as notorious neurotoxins that induce serious food poisoning incidents in the Southeast Asia region. The aim of this study was to investigate whether TTX and PSP toxins are important issues of seafood safety. Paralytic toxicity was observed in mice exposed to 34 specimens from five species of gastropods using a PSP bioassay. Five species of gastropods, Natica vitellus, Natica tumidus, Oliva hirasei, Oliva lignaria, and Oliva annulata, were collected from the coastal seawaters in Nha Trang City, Vietnam, between August 2007 and October 2007. The average lethal potency of gastropod specimens was 90 ± 40 (mean ± standard deviation mouse units (MU for N. vitellus, 64 ± 19 MU for N. tumidus, 42 ± 28 MU for O. hirasei, 51 ± 17 MU for O. lignaria, and 39 ± 18 MU for O. annulata. All toxic extracts from the sample species were clarified using a C18 Sep-Pak solid-phase extraction column and a microcentrifuge filter prior to analysis. High-performance liquid chromatography coupled with fluorescence detection indicated that the toxins of the olive shell (O. hirasei, O. lignaria, and O. annulata were mainly composed of saxitoxin (STX (73–82%, gonyautoxin (GTX 2, 3 (12–22%, and minor levels of TTX (5–6%. The toxins of N. vitellus and N. tumidus were mainly composed of STX (76–81% and GTX 1, 4 (19–24%. Furthermore, liquid chromatography–tandem mass spectrometry analysis was used to verify the identity of the PSPs and TTX. Our evidence shows that these gastropods have novel toxin profiles.

Simultaneous identification and quantification of tetrodotoxin in fresh pufferfish and pufferfish-based products using immunoaffinity columns and liquid chromatography/quadrupole-linear ion trap mass spectrometry

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Guo, Mengmeng; Wu, Haiyan; Jiang, Tao; Tan, Zhijun; Zhao, Chunxia; Zheng, Guanchao; Li, Zhaoxin; Zhai, Yuxiu

2017-07-01

In this study, we established a comprehensive method for simultaneous identification and quantification of tetrodotoxin (TTX) in fresh pufferfish tissues and pufferfish-based products using liquid chromatography/quadrupole-linear ion trap mass spectrometry (LC-QqLIT-MS). TTX was extracted by 1% acetic acid-methanol, and most of the lipids were then removed by freezing lipid precipitation, followed by purification and concentration using immunoaffinity columns (IACs). Matrix effects were substantially reduced due to the high specificity of the IACs, and thus, background interference was avoided. Quantitation analysis was therefore performed using an external calibration curve with standards prepared in mobile phase. The method was evaluated by fortifying samples at 1, 10, and 100 ng/g, respectively, and the recoveries ranged from 75.8%-107%, with a relative standard deviation of less than 15%. The TTX calibration curves were linear over the range of 1-1 000 μg/L, with a detection limit of 0.3 ng/g and a quantification limit of 1 ng/g. Using this method, samples can be further analyzed using an information-dependent acquisition (IDA) experiment, in the positive mode, from a single liquid chromatography-tandem mass spectrometry injection, which can provide an extra level of confirmation by matching the full product ion spectra acquired for a standard sample with those from an enhanced product ion (EPI) library. The scheduled multiple reaction monitoring method enabled TTX to be screened for, and TTX was positively identified using the IDA and EPI spectra. This method was successfully applied to analyze a total of 206 samples of fresh pufferfish tissues and pufferfish-based products. The results from this study show that the proposed method can be used to quantify and identify TTX in a single run with excellent sensitivity and reproducibility, and is suitable for the analysis of complex matrix pufferfish samples.

Pufferfish Saxitoxin and Tetrodotoxin Binding Protein (PSTBP Analogues in the Blood Plasma of the Pufferfish Arothron nigropunctatus, A. hispidus, A. manilensis, and Chelonodon patoca

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Mari Yotsu-Yamashita

2018-06-01

Full Text Available Pufferfish saxitoxin and tetrodotoxin (TTX binding protein (PSTBP is a glycoprotein that we previously isolated from the blood plasma of the pufferfish Takifugu pardalis; this protein was also detected in seven species of the genus Takifugu. We proposed that PSTBP is a carrier protein for TTX in pufferfish; however, PSTBP had not yet been found in genera other than Takifugu. In this study, we investigated the presence of PSTBP-like proteins in the toxic pufferfish Arothron nigropunctatus, A. hispidus, A. manilensis, and Chelonodon patoca. On the basis of ultrafiltration experiments, TTX was found to be present and partially bound to proteins in the plasma of these pufferfish, and Western blot analyses with anti-PSTBP antibody revealed one or two bands per species. The observed decreases in molecular mass following deglycosylation with glycopeptidase F suggest that these positive proteins are glycoproteins. The molecular masses of the deglycosylated proteins detected in the three Arothron species were larger than that of PSTBP in the genus Takifugu, whereas the two bands detected in C. patoca had molecular masses similar to that of tributyltin-binding protein-2 (TBT-bp2. The N-terminal amino acid sequences of 23–29 residues of these detected proteins were all homologous with those of PSTBP and TBT-bp2.

Diversity and Biosynthetic Potential of Culturable Microbes Associated with Toxic Marine Animals

Science.gov (United States)

Chau, Rocky; Kalaitzis, John A.; Wood, Susanna A.; Neilan, Brett A.

2013-01-01

Tetrodotoxin (TTX) is a neurotoxin that has been reported from taxonomically diverse organisms across 14 different phyla. The biogenic origin of tetrodotoxin is still disputed, however, TTX biosynthesis by host-associated bacteria has been reported. An investigation into the culturable microbial populations from the TTX-associated blue-ringed octopus Hapalochlaena sp. and sea slug Pleurobranchaea maculata revealed a surprisingly high microbial diversity. Although TTX was not detected among the cultured isolates, PCR screening identifiedsome natural product biosynthesis genes putatively involved in its assembly. This study is the first to report on the microbial diversity of culturable communities from H. maculosa and P. maculata and common natural product biosynthesis genes from their microbiota. We also reassess the production of TTX reported from three bacterial strains isolated from the TTX-containing gastropod Nassarius semiplicatus. PMID:23917066

Diversity and Biosynthetic Potential of Culturable Microbes Associated with Toxic Marine Animals

Directory of Open Access Journals (Sweden)

Brett A. Neilan

2013-08-01

Full Text Available Tetrodotoxin (TTX is a neurotoxin that has been reported from taxonomically diverse organisms across 14 different phyla. The biogenic origin of tetrodotoxin is still disputed, however, TTX biosynthesis by host-associated bacteria has been reported. An investigation into the culturable microbial populations from the TTX-associated blue-ringed octopus Hapalochlaena sp. and sea slug Pleurobranchaea maculata revealed a surprisingly high microbial diversity. Although TTX was not detected among the cultured isolates, PCR screening identifiedsome natural product biosynthesis genes putatively involved in its assembly. This study is the first to report on the microbial diversity of culturable communities from H. maculosa and P. maculata and common natural product biosynthesis genes from their microbiota. We also reassess the production of TTX reported from three bacterial strains isolated from the TTX-containing gastropod Nassarius semiplicatus.

Conditional intrinsic voltage oscillations in mature vertebrate neurons undergo specific changes in culture

DEFF Research Database (Denmark)

Guertin, Pierre A; Hounsgaard, Jørn

2006-01-01

cord of adult turtles maintainable for several weeks in culture conditions. N-methyl-D-aspartate (NMDA)-induced-tetrodotoxin (TTX)-resistant voltage oscillations in motoneurons were approximately 10 times faster in culture than in acute preparations. Oscillations in culture were abolished by NMDA...

In vivo neurochemical characterization of clothianidin induced striatal dopamine release.

Science.gov (United States)

Faro, L R F; Oliveira, I M; Durán, R; Alfonso, M

2012-12-16

Clothianidin (CLO) is a neonicotinoid insecticide with selective action on nicotinic acetylcholine receptors. The aim of this study was to determine the neurochemical basis for CLO-induced striatal dopamine release using the microdialysis technique in freely moving and conscious rats. Intrastriatal administration of CLO (3.5mM), produced an increase in both spontaneous (2462 ± 627% with respect to basal values) and KCl-evoked (4672 ± 706% with respect to basal values) dopamine release. This effect was attenuated in Ca(2+)-free medium, and was prevented in reserpine pre-treated animals or in presence of tetrodotoxin (TTX). To investigate the involvement of dopamine transporter (DAT), the effect of CLO was observed in presence of nomifensine. The coadministration of CLO and nomifensine produced an additive effect on striatal dopamine release. The results suggest that the effect of CLO on striatal dopamine release is predominantly mediated by an exocytotic mechanism, Ca(2+), vesicular and TTX-dependent and not by a mechanism mediated by dopamine transporter. Published by Elsevier Ireland Ltd.

Suppression of neurotoxic lesion-induced seizure activity: evidence for a permanent role for the hippocampus in contextual memory.

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Fraser T Sparks

Full Text Available Damage to the hippocampus (HPC using the excitotoxin N-methyl-D-aspartate (NMDA can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX, a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours or remote (5 weeks time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories.

Co-expression of the transcription factors CEH-14 and TTX-1 regulates AFD neuron-specific genes gcy-8 and gcy-18 in C. elegans.

Science.gov (United States)

Kagoshima, Hiroshi; Kohara, Yuji

2015-03-15

A wide variety of cells are generated by the expression of characteristic sets of genes, primarily those regulated by cell-specific transcription. To elucidate the mechanism regulating cell-specific gene expression in a highly specialized cell, AFD thermosensory neuron in Caenorhabditis elegans, we analyzed the promoter sequences of guanylyl cyclase genes, gcy-8 and gcy-18, exclusively expressed in AFD. In this study, we showed that AFD-specific expression of gcy-8 and gcy-18 requires the co-expression of homeodomain proteins, CEH-14/LHX3 and TTX-1/OTX1. We observed that mutation of ttx-1 or ceh-14 caused a reduction in the expression of gcy-8 and gcy-18 and that the expression was completely lost in double mutants. This synergy effect was also observed with other AFD marker genes, such as ntc-1, nlp-21and cng-3. Electrophoretic mobility shift assays revealed direct interaction of CEH-14 and TTX-1 proteins with gcy-8 and gcy-18 promoters in vitro. The binding sites of CEH-14 and TTX-1 proteins were confirmed to be essential for AFD-specific expression of gcy-8 and gcy-18 in vivo. We also demonstrated that forced expression of CEH-14 and TTX-1 in AWB chemosensory neurons induced ectopic expression of gcy-8 and gcy-18 reporters in this neuron. Finally, we showed that the regulation of gcy-8 and gcy-18 expression by ceh-14 and ttx-1 is evolutionally conserved in five Caenorhabditis species. Taken together, ceh-14 and ttx-1 expression determines the fate of AFD as terminal selector genes at the final step of cell specification. Copyright © 2015 Elsevier Inc. All rights reserved.

Calcimimetic R568 inhibits tetrodotoxin-sensitive colonic electrolyte secretion and reduces c-fos expression in myenteric neurons.

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Sun, Xiangrong; Tang, Lieqi; Winesett, Steven; Chang, Wenhan; Cheng, Sam Xianjun

2018-02-01

Calcium-sensing receptor (CaSR) is expressed on neurons of both submucosal and myenteric plexuses of the enteric nervous system (ENS) and the CaSR agonist R568 inhibited Cl - secretion in intestine. The purpose of this study was to localize the primary site of action of R568 in the ENS and to explore how CaSR regulates secretion through the ENS. Two preparations of rat proximal and distal colon were used. The full-thickness preparation contained both the submucosal and myenteric plexuses, whereas for the "stripped" preparation the myenteric plexus with the muscle layers was removed. Both preparations were mounted onto Ussing chambers and Cl - secretory responses were compared by measuring changes in short circuit current (I sc ). Two tissue-specific CaSR knockouts (i.e., neuron-specific vs. enterocyte-specific) were generated to compare the effect of R568 on expression of c-fos protein in myenteric neurons by immunocytochemistry. In full-thickness colons, tetrodotoxin (TTX) inhibited I sc , both in proximal and distal colons. A nearly identical inhibition was produced by R568. However, in stripped preparations, while the effect of TTX on I sc largely remained, the effect of R568 was nearly completely eliminated. In keeping with this, R568 reduced c-fos protein expression only in myenteric neurons of wild type mice and mutant mice that contained CaSR in neurons (i.e., villin Cre/Casr flox/flox mice), but not in myenteric neurons of nestin Cre/Casr flox/flox mice in which neuronal cell CaSR was eliminated. These results indicate that R568 exerts its anti-secretory effects predominantly via CaSR-mediated inhibition of neuronal activity in the myenteric plexus. Published by Elsevier Inc.

Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs.

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Sitges, M; Sanchez-Tafolla, B M; Chiu, L M; Aldana, B I; Guarneros, A

2011-10-01

4-Aminopyridine (4-AP) is a convulsing agent that in vivo preferentially releases Glu, the most important excitatory amino acid neurotransmitter in the brain. Here the ionic dependence of 4-AP-induced Glu release and the effects of several of the most common antiepileptic drugs (AEDs) and of the new potential AED, vinpocetine on 4-AP-induced Glu release were characterized in hippocampus isolated nerve endings pre-loaded with labelled Glu ([3H]Glu). 4-AP-induced [3H]Glu release was composed by a tetrodotoxin (TTX) sensitive and external Ca2+ dependent fraction and a TTX insensitive fraction that was sensitive to the excitatory amino acid transporter inhibitor, TBOA. The AEDs: carbamazepine, phenytoin, lamotrigine and oxcarbazepine at the highest dose tested only reduced [3H]Glu release to 4-AP between 50-60%, and topiramate was ineffective. Vinpocetine at a much lower concentration than the above AEDs, abolished [3H]Glu release to 4-AP. We conclude that the decrease in [3H]Glu release linked to the direct blockade of presynaptic Na+ channels, may importantly contribute to the anticonvulsant actions of all the drugs tested here (except topiramate); and that the significantly greater vinpocetine effect in magnitude and potency on [3H]Glu release when excitability is exacerbated like during seizures, may involve the increase additionally exerted by vinpocetine in some K+ channels permeability. Copyright © 2011 Elsevier B.V. All rights reserved.

Extracted tetrodotoxin from puffer fish Lagocephalus lagocephalus ...

African Journals Online (AJOL)

Jane

2011-08-03

Aug 3, 2011 ... severe physiological damage caused by puffer fish intoxication, therapy ... accumulates in TTX-bearing animals when ingesting toxic organisms as .... on the “absorptivity micromolar extinction coefficient” of NADH at. 340 nm.

Possible mechanisms of action of Gymnodinium breve toxin at the mammalian neuromuscular junction.

Science.gov (United States)

Shinnick-Gallagher, P.

1980-01-01

1 The mechanism of action of a crude fraction of Gymnodinium breve toxin (GBTX) was investigated by intracellular recording techniques in the rat phrenic nerve diaphragm preparation. 2 GBTX (2 micrograms/ml) decreased the input resistance of the muscle membrane concomitantly with a depolarization of the resting membrane potential. 3 A low sodium solution reversed or prevented a GBTX-induced membrane depolarization. 4 Tetrodotoxin (TTX) antagonized a GBTX-induced increase in miniature endplate potential (m.e.p.p.) frequency and repolarized a GBTX-depolarized membrane. Pretreatment with TTX prevented GBTX effects. 5 GBTX reversibly reduced depolarizations produced by bath applied acetylcholine (ACh). The membrane depolarization was not responsible for the depression of ACh responses. 6 These findings suggest that GBTX increases m.e.p.p. frequency and depolarizes the resting membrane potential by increasing sodium permeability. The reduction of ACh-induced depolarizations suggests that GBTX may be acting at some site on the ACh receptor. PMID:7190452

[Study on tetrodotoxin detection and toxic puffer fish identification of roasted fish fillet at the retail in Beijing and Qingdao].

Science.gov (United States)

Shen, Qing; Jiang, Tao; Li, Nan; Wang, Jiahui; Han, Chunhui; Zhang, Jing; Xu, Jin; Zhang, Dongfeng; Li, Fengqin

2014-11-01

The roasted fish fillet sample at the retail collected in Beijing and Qingdao were detected for TTX, and the TTX positive samples was analyzed for fish species identification. TTX was tested by EUSA method and the cytochrome c oxidase I (COI) genome of TTX-positive samples was extracted and identified by DNA barcode. Totally, 90 samples were tested by EUSA and 58 (64.4%) samples were positive for TTX with the levels ranging from 0.10 mg/kg to 63.81 mg/kg. Among the TTX positive samples, 24 (41.3%) were identified containing toxic puffer fish and 21 (87.5%) were Lagocephalus lunaris, the highly toxic puffer fish. Some roasted fish fillet samples obtained from the retail in two cities were positive for TTX and contained toxic puffer fish. Based on these results, we suggest that roasted fish fillet producers should prevent toxic puffer fish from mixing in the raw material and the I regulators should strengthen the TTX surveillance and product labeling supervision of roasted fish fillet.

A resistant predator and its toxic prey: persistence of newt toxin leads to poisonous (not venomous) snakes.

Science.gov (United States)

Williams, Becky L; Brodie, Edmund D; Brodie, Edmund D

2004-10-01

The common garter snake (Thamnophis sirtalis) preys upon the rough-skinned newt (Taricha granulosa), which contains the neurotoxin tetrodotoxin (TTX) in the skin. TTX is toxic, large quantities are present in a newt, and highly resistant snakes have the ability to ingest multiple newts; subsequently snakes harbor significant amounts of active toxin in their own tissues after consuming a newt. Snakes harbor TTX in the liver for 1 mo or more after consuming just one newt, and at least 7 wk after consuming a diet of newts. Three weeks after eating one newt, snakes contained an average of 42 microg of TTX in the liver. This amount could severely incapacitate or kill avian predators, and mammalian predators may be negatively affected as well.

Long-term nicotine exposure dampens LPS-induced nerve-mediated airway hyperreactivity in murine airways.

Science.gov (United States)

Xu, Yuan; Cardell, Lars-Olaf

2017-09-01

Nicotine is a major component of cigarette smoke. It causes addiction and is used clinically to aid smoke cessation. The aim of the present study is to investigate the effect of nicotine on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and to explore the potential involvement of neuronal mechanisms behind nicotine's effects in murine models in vivo and in vitro. BALB/c mice were exposed to nicotine in vivo via subcutaneous Alzet osmotic minipumps containing nicotine tartate salt solution (24 mg·kg -1 ·day -1 ) for 28 days. LPS (0.1 mg/ml, 20 µl) was administered intranasally for 3 consecutive days during the end of this period. Lung functions were measured with flexiVent. For the in vitro experiments, mice tracheae were organcultured with either nicotine (10 μM) or vehicle (DMSO, 0.1%) for 4 days. Contractile responses of the tracheal segments were measured in myographs following electric field stimulation (EFS; increasing frequencies of 0.2 to 12.8 Hz) before and after incubation with 10 µg/ml LPS for 1 h. Results showed that LPS induced AHR to methacholine in vivo and increased contractile responses to EFS in vitro. Interestingly, long-term nicotine exposure markedly dampened this LPS-induced AHR both in vitro and in vivo. Tetrodotoxin (TTX) inhibited LPS-induced AHR but did not further inhibit nicotine-suppressed AHR in vivo. In conclusion, long-term nicotine exposure dampened LPS-induced AHR. The effect of nicotine was mimicked by TTX, suggesting the involvement of neuronal mechanisms. This information might be used for evaluating the long-term effects of nicotine and further exploring of how tobacco products interact with bacterial airway infections. Copyright © 2017 the American Physiological Society.

Dynamic changes in glucose metabolism of living rat brain slices induced by hypoxia and neurotoxic chemical-loading revealed by positron autoradiography

International Nuclear Information System (INIS)

Omata, N.; Fujibayashi, Y.; Waki, A.; Sadato, N.; Yano, R.; Yoshimoto, M.; Yonekura, Y.; Murata, T.; Yoshida, S.

1999-01-01

Fresh rat brain slices were incubated with 2-deoxy-2-[ 18 F]-fluoro-D-glucose ([ 18 F]FDG) in oxygenated Krebs-Ringer solution at 36 degree C, and serial two-dimensional time-resolved images of [ 18 F]FDG uptake were obtained from these specimens on imaging plates. The fractional rate constant (= k3*) of [ 18 F]FDG proportional to the cerebral glucose metabolic rate (CMRglc) was evaluated by applying the Gjedde-Patlak graphical method to the image data. With hypoxia loading (oxygen deprivation) or glucose metabolism inhibitors acting on oxidative phosphorylation, the k3* value increased dramatically suggesting enhanced glycolysis. After relieving hypoxia ≤10-min, the k3* value returned to the pre-loading level. In contrast, with ≥20-min hypoxia only partial or no recovery was observed, indicating that irreversible neuronal damage had been induced. However, after loading with tetrodotoxin (TTX), the k3* value also decreased but returned to the pre-loading level even after 70-min TTX-loading, reflecting a transient inhibition of neuronal activity. This technique provides a new means of quantifying dynamic changes in the regional CMRglc in living brain slices in response to various interventions such as hypoxia and neurotoxic chemical-loading as well as determining the viability and prognosis of brain tissues. (author)

Time-Dependent Decline in Multifocal Electroretinogram Requires Faster Recording Procedures in Anesthetized Pigs

DEFF Research Database (Denmark)

Sørensen, Nina Buus; Christiansen, Anders Tolstrup; Kjær, Troels Wesenberg

2017-01-01

between the 3-minute and the prolonged mfERG recordings for conventional amplitudes and the global-flash direct response. The global flash-induced component significantly decreases with prolonged mfERG recordings. CONCLUSIONS: A 3-minute mfERG recording and a single stimulation protocol is sufficient...... injection of tetrodotoxin (TTX) was given and the mfERG was rerecorded as described above. Data were analyzed using mixed models in SAS statistical software. RESULTS: Propofol significantly decreases the conventional and global-flash amplitudes over time. The only significant effect of isoflurane...... is a decrease in the global-flash amplitudes. At 15 minutes after TTX injection several of the mfERG amplitudes are significantly decreased. There is a linear correlation between the conventional P1 and the global-flash DR mfERG-amplitude (R2 = 0.82, slope = 0.72, P

Different role of TTX-sensitive voltage-gated sodium channel (NaV 1) subtypes in action potential initiation and conduction in vagal airway nociceptors.

Science.gov (United States)

Kollarik, M; Sun, H; Herbstsomer, R A; Ru, F; Kocmalova, M; Meeker, S N; Undem, B J

2018-04-15

The action potential initiation in the nerve terminals and its subsequent conduction along the axons of afferent nerves are not necessarily dependent on the same voltage-gated sodium channel (Na V 1) subunits. The action potential initiation in jugular C-fibres within airway tissues is not blocked by TTX; nonetheless, conduction of action potentials along the vagal axons of these nerves is often dependent on TTX-sensitive channels. This is not the case for nodose airway Aδ-fibres and C-fibres, where both action potential initiation and conduction is abolished by TTX or selective Na V 1.7 blockers. The difference between the initiation of action potentials within the airways vs. conduction along the axons should be considered when developing Na V 1 blocking drugs for topical application to the respiratory tract. The action potential (AP) initiation in the nerve terminals and its subsequent AP conduction along the axons do not necessarily depend on the same subtypes of voltage-gated sodium channels (Na V 1s). We evaluated the role of TTX-sensitive and TTX-resistant Na V 1s in vagal afferent nociceptor nerves derived from jugular and nodose ganglia innervating the respiratory system. Single cell RT-PCR was performed on vagal afferent neurons retrogradely labelled from the guinea pig trachea. Almost all of the jugular neurons expressed the TTX-sensitive channel Na V 1.7 along with TTX-resistant Na V 1.8 and Na V 1.9. Tracheal nodose neurons also expressed Na V 1.7 but, less frequently, Na V 1.8 and Na V 1.9. Na V 1.6 were expressed in ∼40% of the jugular and 25% of nodose tracheal neurons. Other Na V 1 α subunits were only rarely expressed. Single fibre recordings were made from the vagal nodose and jugular nerve fibres innervating the trachea or lung in the isolated perfused vagally-innervated preparations that allowed for selective drug delivery to the nerve terminal compartment (AP initiation) or to the desheathed vagus nerve (AP conduction). AP initiation in

Activation of mGluR5 induces spike afterdepolarization and enhanced excitability in medium spiny neurons of the nucleus accumbens by modulating persistent Na+ currents

Science.gov (United States)

D’Ascenzo, Marcello; Podda, Maria Vittoria; Fellin, Tommaso; Azzena, Gian Battista; Haydon, Philip; Grassi, Claudio

2009-01-01

The involvement of metabotropic glutamate receptors type 5 (mGluR5) in drug-induced behaviours is well-established but limited information is available on their functional roles in addiction-relevant brain areas like the nucleus accumbens (NAc). This study demonstrates that pharmacological and synaptic activation of mGluR5 increases the spike discharge of medium spiny neurons (MSNs) in the NAc. This effect was associated with the appearance of a slow afterdepolarization (ADP) which, in voltage-clamp experiments, was recorded as a slowly inactivating inward current. Pharmacological studies showed that ADP was elicited by mGluR5 stimulation via G-protein-dependent activation of phospholipase C and elevation of intracellular Ca2+ levels. Both ADP and spike aftercurrents were significantly inhibited by the Na+ channel-blocker, tetrodotoxin (TTX). Moreover, the selective blockade of persistent Na+ currents (INaP), achieved by NAc slice pre-incubation with 20 nm TTX or 10 μm riluzole, significantly reduced the ADP amplitude, indicating that this type of Na+ current is responsible for the mGluR5-dependent ADP. mGluR5 activation also produced significant increases in INaP, and the pharmacological blockade of this current prevented the mGluR5-induced enhancement of spike discharge. Collectively, these data suggest that mGluR5 activation upregulates INaP in MSNs of the NAc, thereby inducing an ADP that results in enhanced MSN excitability. Activation of mGluR5 will significantly alter spike firing in MSNs in vivo, and this effect could be an important mechanism by which these receptors mediate certain aspects of drug-induced behaviours. PMID:19433572

Association between tetrodotoxin resistant channels and lipid rafts regulates sensory neuron excitability.

Directory of Open Access Journals (Sweden)

Alessandro Pristerà

Full Text Available Voltage-gated sodium channels (VGSCs play a key role in the initiation and propagation of action potentials in neurons. Na(V1.8 is a tetrodotoxin (TTX resistant VGSC expressed in nociceptors, peripheral small-diameter neurons able to detect noxious stimuli. Na(V1.8 underlies the vast majority of sodium currents during action potentials. Many studies have highlighted a key role for Na(V1.8 in inflammatory and chronic pain models. Lipid rafts are microdomains of the plasma membrane highly enriched in cholesterol and sphingolipids. Lipid rafts tune the spatial and temporal organisation of proteins and lipids on the plasma membrane. They are thought to act as platforms on the membrane where proteins and lipids can be trafficked, compartmentalised and functionally clustered. In the present study we investigated Na(V1.8 sub-cellular localisation and explored the idea that it is associated with lipid rafts in nociceptors. We found that Na(V1.8 is distributed in clusters along the axons of DRG neurons in vitro and ex vivo. We also demonstrated, by biochemical and imaging studies, that Na(V1.8 is associated with lipid rafts along the sciatic nerve ex vivo and in DRG neurons in vitro. Moreover, treatments with methyl-β-cyclodextrin (MβCD and 7-ketocholesterol (7KC led to the dissociation between rafts and Na(V1.8. By calcium imaging we demonstrated that the lack of association between rafts and Na(V1.8 correlated with impaired neuronal excitability, highlighted by a reduction in the number of neurons able to conduct mechanically- and chemically-evoked depolarisations. These findings reveal the sub-cellular localisation of Na(V1.8 in nociceptors and highlight the importance of the association between Na(V1.8 and lipid rafts in the control of nociceptor excitability.

Maculotoxin: a neurotoxin from the venom glands of the octopus Hapalochlaena maculosa identified as tetrodotoxin.

Science.gov (United States)

Sheumack, D D; Howden, M E; Spence, I; Quinn, R J

1978-01-13

Maculotoxin, a potent neurotoxin isolated from the posterior salivary glands of the blue-ringed octopus. Hapalochlaena maculosa, has now been identified as tetrodotoxin. This is the first reported case in which tetrodotoxin has been found to occur in a venom.

Intoxication following minor stabs from the spines of a porcupine fish.

NARCIS (Netherlands)

Gorcum, Teetske F van; Janse, Max; Leenders, Marianne E C; Vries, Irma de; Meulenbelt, Jan

2006-01-01

We report an unusual intoxication by tetrodotoxin (TTX). A curator of an aquarium sustained minor punctures in his finger from the spines of a porcupine fish during an autopsy of a dead porcupine fish. He developed paresthesias, numbness, paresis, dizziness and headache. The death of the fish might

Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V.

Directory of Open Access Journals (Sweden)

Bryan D Moyer

Full Text Available Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM-8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S channels in mouse dorsal root ganglia (DRG neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage-sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi-electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both

The LIM and POU homeobox genes ttx-3 and unc-86 act as terminal selectors in distinct cholinergic and serotonergic neuron types.

Science.gov (United States)

Zhang, Feifan; Bhattacharya, Abhishek; Nelson, Jessica C; Abe, Namiko; Gordon, Patricia; Lloret-Fernandez, Carla; Maicas, Miren; Flames, Nuria; Mann, Richard S; Colón-Ramos, Daniel A; Hobert, Oliver

2014-01-01

Transcription factors that drive neuron type-specific terminal differentiation programs in the developing nervous system are often expressed in several distinct neuronal cell types, but to what extent they have similar or distinct activities in individual neuronal cell types is generally not well explored. We investigate this problem using, as a starting point, the C. elegans LIM homeodomain transcription factor ttx-3, which acts as a terminal selector to drive the terminal differentiation program of the cholinergic AIY interneuron class. Using a panel of different terminal differentiation markers, including neurotransmitter synthesizing enzymes, neurotransmitter receptors and neuropeptides, we show that ttx-3 also controls the terminal differentiation program of two additional, distinct neuron types, namely the cholinergic AIA interneurons and the serotonergic NSM neurons. We show that the type of differentiation program that is controlled by ttx-3 in different neuron types is specified by a distinct set of collaborating transcription factors. One of the collaborating transcription factors is the POU homeobox gene unc-86, which collaborates with ttx-3 to determine the identity of the serotonergic NSM neurons. unc-86 in turn operates independently of ttx-3 in the anterior ganglion where it collaborates with the ARID-type transcription factor cfi-1 to determine the cholinergic identity of the IL2 sensory and URA motor neurons. In conclusion, transcription factors operate as terminal selectors in distinct combinations in different neuron types, defining neuron type-specific identity features.

Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats.

Science.gov (United States)

He, Wan-You; Zhang, Bin; Xiong, Qing-Ming; Yang, Cheng-Xiang; Zhao, Wei-Cheng; He, Jian; Zhou, Jun; Wang, Han-Bing

2016-04-21

The mammalian target of rapamycin (mTOR) is a key regulator of mRNA translation and protein synthesis, and it is specifically inhibited by rapamycin. In chronic pain conditions, mTOR-mediated local protein synthesis is crucial for neuronal hyperexcitability and synaptic plasticity. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 plays a major role in action potential initiation and propagation and cellular excitability in DRG (dorsal root ganglion) neurons. In this study, we investigated if mTOR modulates the phosphorylation of Nav1.8 that is associated with neuronal hyperexcitability and behavioral hypersensitivity in STZ-induced diabetic rats. Painful diabetic neuropathy (PDN) was induced in Sprague-Dawley rats by intraperitoneal injection with streptozotocin (STZ) at 60mg/kg. After the onset of PDN, the rats received daily intrathecal administrations of rapamycin (1μg, 3μg, or 10μg/day) for 7 days; other diabetic rats received the same volumes of dimethyl sulfoxide (DMSO). Herein, we demonstrate a marked increase in protein expression of total mTOR and phospho-mTOR (p-mTOR) together with the up-regulation of phosphor-Nav1.8 (p-Nav1.8) prior to the mechanical withdrawal threshold reaching a significant reduction in dorsal root ganglions (DRGs). Furthermore, the intrathecal administration of rapamycin, inhibiting the activity of mTOR, suppressed the phosphorylation of DRG Nav1.8, reduced the TTX-R current density, heightened the voltage threshold for activation and lowered the voltage threshold for inactivation and relieved mechanical hypersensitivity in diabetic rats. An intrathecal injection (i.t.) of rapamycin inhibited the phosphorylation and enhanced the functional availability of DRG Nav1.8 attenuated STZ-induced hyperalgesia. These results suggest that rapamycin is a potential therapeutic intervention for clinical PDN. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of (−-Gallocatechin-3-Gallate on Tetrodotoxin-Resistant Voltage-Gated Sodium Channels in Rat Dorsal Root Ganglion Neurons

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Jian-Min Jiang

2013-05-01

Full Text Available The (−-gallocatechin-3-gallate (GCG concentration in some tea beverages can account for as much as 50% of the total catechins. It has been shown that catechins have analgesic properties. Voltage-gated sodium channels (Nav mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant compared to other isoforms and functionally linked to nociception. In this study, the effects of GCG on tetrodotoxin-resistant Na+ currents were investigated in rat primary cultures of dorsal root ganglion neurons via the whole-cell patch-clamp technique. We found that 1 μM GCG reduced the amplitudes of peak current density of tetrodotoxin-resistant Na+ currents significantly. Furthermore, the inhibition was accompanied by a depolarizing shift of the activation voltage and a hyperpolarizing shift of steady-state inactivation voltage. The percentage block of GCG (1 μM on tetrodotoxin-resistant Na+ current was 45.1% ± 1.1% in 10 min. In addition, GCG did not produce frequency-dependent block of tetrodotoxin-resistant Na+ currents at stimulation frequencies of 1 Hz, 2 Hz and 5 Hz. On the basis of these findings, we propose that GCG may be a potential analgesic agent.

Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes Na(V)1.9, Na(V)1.7 and Na(V)1.1

Czech Academy of Sciences Publication Activity Database

Touška, Filip; Sattler, S.; Malsch, P.; Lewis, R. J.; Reeh, P. W.; Zimmermann, K.

2017-01-01

Roč. 15, č. 9 (2017), č. článku 269. ISSN 1660-3397 Institutional support: RVO:67985823 Keywords : voltage-gated calcium channels * calcitonin-gene related peptide * tetrodotoxin * TTX * P-CTX-1 * TRPA1 * TRPC5 * neuropathic pain * neurogenic inflammation Subject RIV: FH - Neurology OBOR OECD: Neurosciences (including psychophysiology Impact factor: 3.503, year: 2016

Acute Cocaine Exposure elicits rises in calcium in Arousal Related Laterodorsal Tegmental Neurons

DEFF Research Database (Denmark)

Lambert, Mads; Ipsen, Theis; Kohlmeier, Kristi Anne

2017-01-01

Cocaine has strong reinforcing properties, which underlie its high addiction potential. Reinforcement of use of addictive drugs is associated with rises in dopamine (DA) in mesoaccumbal circuitry. Excitatory afferent input to mesoaccumbal circuitry sources from the laterodorsal tegmental nucleus...... (LDT). Chronic, systemic cocaine exposure has been shown to have cellular effects on LDT cells, but acute actions of local application have never been demonstrated. Using calcium imaging, we show that acute application of cocaine to mouse brain slices induces calcium spiking in cells of the LDT....... Spiking was attenuated by tetrodotoxin (TTX) and low calcium solutions, and abolished by prior exhaustion of intracellular calcium stores. Further, DA receptor antagonists reduced these transients, whereas DA induced rises with similar spiking kinetics. Amphetamine, which also results in elevated levels...

Marine Biotoxins: Occurrence, Toxicity, and Detection Methods

Science.gov (United States)

Asakawa, M.

2017-04-01

This review summarizes the role of marine organisms as vectors of marine biotoxins, and discusses the need for surveillance to protect public health and ensure the quality of seafood. I Paralytic shellfish poison (PSP) and PSP-bearing organisms-PSP is produced by toxic dinoflagellates species belonging to the genera Alexandrium, Gymnodinium, and Pyrodinium. Traditionally, PSP monitoring programs have only considered filter-feeding molluscs that concentrate these toxic algae, however, increasing attention is now being paid to higher-order predators that carry PSP, such as carnivorous gastropods and crustaceans. II. Tetrodotoxin (TTX) and TTX-bearing organisms - TTX is the most common natural marine toxin that causes food poisonings in Japan, and poses a serious public health risk. TTX was long believed to be present only in pufferfish. However, TTX was detected in the eggs of California newt Taricha torosa in 1964, and since then it has been detected in a wide variety of species belonging to several different phyla. In this study, the main toxic components in the highly toxic ribbon worm Cephalothrix simula and the greater blue-ringed octopus Hapalochlaena lunulata from Japan were purified and analysed.

Rare processes with top quarks: FCNCs, tt+X, tttt, t+X

CERN Document Server

Li, Yichen; The ATLAS collaboration

2018-01-01

The latest ATLAS and CMS searches or measurements of rare processes with top quarks, including FCNCs, tt+X, tttt, and t+X, are presented. FCNC branching ratio limits are pushed to new low, with some of them even reaching the expected limits for some BSMs. Associated production of W/Z/photon with a pair of top quarks are established and their cross sections are measured. The evidence of associated production of Z boson with a top quark is found. While there is no evidence for the four top quark production yet.

Tetrodotoxin as a Tool to Elucidate Sensory Transduction Mechanisms: The Case for the Arterial Chemoreceptors of the Carotid Body

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Constancio Gonzalez

2011-12-01

Full Text Available Carotid bodies (CBs are secondary sensory receptors in which the sensing elements, chemoreceptor cells, are activated by decreases in arterial PO2 (hypoxic hypoxia. Upon activation, chemoreceptor cells (also known as Type I and glomus cells increase their rate of release of neurotransmitters that drive the sensory activity in the carotid sinus nerve (CSN which ends in the brain stem where reflex responses are coordinated. When challenged with hypoxic hypoxia, the physiopathologically most relevant stimulus to the CBs, they are activated and initiate ventilatory and cardiocirculatory reflexes. Reflex increase in minute volume ventilation promotes CO2 removal from alveoli and a decrease in alveolar PCO2 ensues. Reduced alveolar PCO2 makes possible alveolar and arterial PO2 to increase minimizing the intensity of hypoxia. The ventilatory effect, in conjunction the cardiocirculatory components of the CB chemoreflex, tend to maintain an adequate supply of oxygen to the tissues. The CB has been the focus of attention since the discovery of its nature as a sensory organ by de Castro (1928 and the discovery of its function as the origin of ventilatory reflexes by Heymans group (1930. A great deal of effort has been focused on the study of the mechanisms involved in O2 detection. This review is devoted to this topic, mechanisms of oxygen sensing. Starting from a summary of the main theories evolving through the years, we will emphasize the nature and significance of the findings obtained with veratridine and tetrodotoxin (TTX in the genesis of current models of O2-sensing.

Vasoactive intestinal peptide and electrical activity influence neuronal survival

International Nuclear Information System (INIS)

Brenneman, D.E.; Eiden, L.E.

1986-01-01

Blockage of electrical activity in dissociated spinal cord cultures results in a significant loss of neurons during a critical period in development. Decreases in neuronal cell numbers and 125 I-labeled tetanus toxin fixation produced by electrical blockage with tetrodotoxin (TTX) were prevented by addition of vasoactive intestinal peptide (VIP) to the nutrient medium. The most effective concentration of VIP was 0.1 nM. At higher concentrations, the survival-enhancing effect of VIP on TTX-treated cultures was attenuated. Addition of the peptide alone had no significant effect on neuronal cell counts or tetanus toxin fixation. With the same experimental conditions, two closely related peptides, PHI-27 (peptide, histidyl-isoleucine amide) and secretin, were found not to increase the number of neurons in TTX-treated cultures. Interference with VIP action by VIP antiserum resulted in neuronal losses that were not significantly different from those observed after TTX treatment. These data indicate that under conditions of electrical blockade a neurotrophic action of VIP on neuronal survival can be demonstrated

Adaptive evolution of the vertebrate skeletal muscle sodium channel

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Jian Lu

2011-01-01

Full Text Available Tetrodotoxin (TTX is a highly potent neurotoxin that blocks the action potential by selectively binding to voltage-gated sodium channels (Na v. The skeletal muscle Na v (Na v1.4 channels in most pufferfish species and certain North American garter snakes are resistant to TTX, whereas in most mammals they are TTX-sensitive. It still remains unclear as to whether the difference in this sensitivity among the various vertebrate species can be associated with adaptive evolution. In this study, we investigated the adaptive evolution of the vertebrate Na v1.4 channels. By means of the CODEML program of the PAML 4.3 package, the lineages of both garter snakes and pufferfishes were denoted to be under positive selection. The positively selected sites identified in the p-loop regions indicated their involvement in Na v1.4 channel sensitivity to TTX. Most of these sites were located in the intracellular regions of the Na v1.4 channel, thereby implying the possible association of these regions with the regulation of voltage-sensor movement.

Cholera Toxin Induces Sustained Hyperexcitability in Myenteric, but Not Submucosal, AH Neurons in Guinea Pig Jejunum

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Joel C. Bornstein

2017-04-01

Full Text Available Background and Aims: Cholera toxin (CT-induced hypersecretion requires activation of secretomotor pathways in the enteric nervous system (ENS. AH neurons, which have been identified as a population of intrinsic sensory neurons (ISNs, are a source of excitatory input to the secretomotor pathways. We therefore examined effects of CT in the intestinal lumen on myenteric and submucosal AH neurons.Methods: Isolated segments of guinea pig jejunum were incubated for 90 min with saline plus CT (12.5 μg/ml or CT + neurotransmitter antagonist, or CT + tetrodotoxin (TTX in their lumen. After washing CT away, submucosal or myenteric plexus preparations were dissected keeping circumferentially adjacent mucosa intact. Submucosal AH neurons were impaled adjacent to intact mucosa and myenteric AH neurons were impaled adjacent to, more than 5 mm from, and in the absence of intact mucosa. Neuronal excitability was monitored by injecting 500 ms current pulses through the recording electrode.Results: After CT pre-treatment, excitability of myenteric AH neurons adjacent to intact mucosa (n = 29 was greater than that of control neurons (n = 24, but submucosal AH neurons (n = 33, control n = 27 were unaffected. CT also induced excitability increases in myenteric AH neurons impaled distant from the mucosa (n = 6 or in its absence (n = 5. Coincubation with tetrodotoxin or SR142801 (NK3 receptor antagonist, but not SR140333 (NK1 antagonist or granisetron (5-HT3 receptor antagonist prevented the increased excitability induced by CT. Increased excitability was associated with a reduction in the characteristic AHP and an increase in the ADP of these neurons, but not a change in the hyperpolarization-activated inward current, Ih.Conclusions: CT increases excitability of myenteric, but not submucosal, AH neurons. This is neurally mediated and depends on NK3, but not 5-HT3 receptors. Therefore, CT may act to amplify the secretomotor response to CT via an increase in the

Toxin and species identification of toxic octopus implicated into food poisoning in Taiwan.

Science.gov (United States)

Wu, Ya-Jung; Lin, Chun-Lan; Chen, Chien-Hung; Hsieh, Cheng-Hong; Jen, Hsiao-Chin; Jian, Shi-Jie; Hwang, Deng-Fwu

2014-12-01

A food poisoning incident due to ingestion of unknown octopus occurred in Taipei in December, 2010. The serum and urine from victims (male 38 and 43 years old) were collected, determined the toxicity, and identified tetrodotoxin (TTX) by high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). It was found that only urine contained the trace of TTX. Then, two retained specimen (one without blue ring in the skin and another with small blue ring in the skin) were collected from victims and examined for the toxicity and toxin. Meanwhile, 6 specimens of octopus without blue ring in the skin and 4 specimens of octopus with blue ring in the skin were re-collected from the market. Both retained octopus samples were found to contain TTX. However, re-collected market's octopus without blue ring in the skin did not show to contain TTX the and was identified as Octopus aegina by using the analysis of cytochrome b gene (Cyt b) and cytochrome c oxidase subunit I gene (COI). Only octopus with blue ring in the skin contained TTX and was identified as Hapalochlaena fasciata by using the analysis of Cyt b and COI. Therefore, this octopus food poisoning was caused by toxic octopus H. fasciata and the causative agent was TTX. Copyright © 2014 Elsevier Ltd. All rights reserved.

Anti-tumor activity of tetrodotoxin extracted from the Masked Puffer ...

African Journals Online (AJOL)

Anti-tumor activity of tetrodotoxins extracted from the skin of the Masked Puffer fish (Arothron diadematus) from the Red Sea was evaluated using the Ehrlich ascite carcinoma tumor model in mice. Activity was assessed using a variety of cellular and liver biochemical parameters. Experimental mice were divided into 4 equal ...

Potential Threats Posed by Tetrodotoxins in UK Waters: Examination of Detection Methodology Used in Their Control

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Andrew D. Turner

2015-12-01

Full Text Available Tetrodotoxin is a neurotoxin responsible for many human fatalities, most commonly following the consumption of pufferfish. Whilst the source of the toxin has not been conclusively proven, it is thought to be associated with various species of marine bacteria. Whilst the toxins are well studied in fish and gastropods, in recent years, there have been a number of reports of tetrodotoxin occurring in bivalve shellfish, including those harvested from the UK and other parts of Europe. This paper reviews evidence concerning the prevalence of tetrodotoxins in the UK together with methodologies currently available for testing. Biological, biomolecular and chemical methods are reviewed, including recommendations for further work. With the recent development of quantitative chromatographic methods for these and other hydrophilic toxins, as well as the commercial availability of rapid testing kits, there are a number of options available to ensure consumers are protected against this threat.

Topical Drug Formulations for Prolonged Corneal Anesthesia

Science.gov (United States)

Wang, Liqiang; Shankarappa, Sahadev A.; Tong, Rong; Ciolino, Joseph B.; Tsui, Jonathan H.; Chiang, Homer H.; Kohane, Daniel S.

2013-01-01

Purpose Ocular local anesthetics (OLA’s) currently used in routine clinical practice for corneal anesthesia are short acting and their ability to delay corneal healing makes them unsuitable for long-term use. In this study, we examined the effect on the duration of corneal anesthesia of the site-1 sodium channel blocker tetrodotoxin (TTX), applied with either proparacaine or the chemical permeation enhancer OTAB. The effect of test solutions on corneal healing was also studied. Methods Solutions of TTX, proparacaine, and OTAB, singly or in combination were applied topically to the rat cornea. The blink response, an indirect measure of corneal sensitivity, was recorded using a Cochet-Bonnet esthesiometer, and the duration of corneal anesthesia calculated. The effect of test compounds on the rate of corneal epithelialization was studied in vivo following corneal debridement. Results Combination of TTX and proparacaine resulted in corneal anesthesia that was 8–10 times longer in duration than that from either drug administered alone, while OTAB did not prolong anesthesia. The rate of corneal healing was moderately delayed following co-administration of TTX and proparacaine. Conclusion Co-administration of TTX and proparacaine significantly prolonged corneal anesthesia but in view of delayed corneal re-epithelialization, caution is suggested in use of the combination. PMID:23615270

Tetrodotoxin poisoning caused by Goby fish consumption in southeast China: a retrospective case series analysis

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Jie You

2015-01-01

Full Text Available OBJECTIVES: To investigate an unusual outbreak of tetrodotoxin poisoning in Leizhou, southeast China, a case series analysis was conducted to identify the source of illness. METHODS: A total of 22 individuals experienced symptoms of poisoning, including tongue numbness, dizziness, nausea and limb numbness and weakness. Two toxic species, Amoya caninus and Yongeichthys nebulosus, were morphologically identified from the batches of gobies consumed by the patients. Tetrodotoxin levels in the blood and Goby fish samples were detected using liquid chromatography-tandem mass spectrometry. RESULTS: The tetrodotoxin levels in the remaining cooked Goby fish were determined to be 2090.12 µg/kg. For Amoya caninus, the toxicity levels were 1858.29 µg/kg in the muscle and 1997.19 µg/kg in the viscera and for Yongeichthys nebulosus, they were 2783.00 µg/kg in the muscle and 2966.21 µg/kg in the viscera. CONCLUSION: This outbreak demonstrates an underestimation of the risk of Goby fish poisoning. Furthermore, the relationships among the toxic species, climates and marine algae present should be clarified in the future.

Identification of tetrodotoxin and fish species in a dried dressed fish fillet implicated in food poisoning.

Science.gov (United States)

Hwang, Deng-Fwu; Hsieh, Yu-Wen; Shiu, Yu-Cheng; Chen, Shu-Kong; Cheng, Chao-An

2002-02-01

There were five victims of neurotoxic food poisoning from a dried dressed fish fillet in Changhua County, Taiwan, in February 2000. The toxicity of the dried dressed fish fillets was 243 mouse units per g according to a tetrodotoxin bioassay. The partially purified toxin was identified as tetrodotoxin and anhydrotetrodotoxin. The sequence of the 376-nucleotide region in the cytochrome b gene of the mitochondrial DNA exhibited the same genotype as that of the toxic puffer fish Lagocephalus lunaris. The same single restriction site for Hinfl was found in the polymerase chain reaction (PCR) products from the dried dressed fish fillet and the muscle of L. lunaris, yielding two DNA fragments of 170 and 206 bp. However, no restriction site for Hinfl was found in the PCR products from other toxic puffer fishes, including Takifugu niphobles, Takifugu oblongus, and Takifugu rubripes. Therefore, the species of the dried dressed fish fillet was identified as L. lunaris and its causative agent was identified as tetrodotoxin.

Ethanolic extract of Aconiti Brachypodi Radix attenuates nociceptive pain probably via inhibition of voltage-dependent Na⁺ channel.

Science.gov (United States)

Ren, Wei; Yuan, Lin; Li, Jun; Huang, Xian-Ju; Chen, Su; Zou, Da-Jiang; Liu, Xiangming; Yang, Xin-Zhou

2012-01-01

Aconiti Brachypodi Radix, belonging to the genus of Aconitum (Family Ranunculaceae), are used clinically as anti-rheumatic, anti-inflammatory and anti-nociceptive in traditional medicine of China. However, its mechanism and influence on nociceptive threshold are unknown and need further investigation. The analgesic effects of ethanolic extract of Aconiti Brachypodi Radix (EABR) were thus studied in vivo and in vitro. Three pain models in mice were used to assess the effect of EABR on nociceptive threshold. In vitro study was conducted to clarify the modulation of the extract on the tetrodotoxin-sensitive (TTX-S) sodium currents in rat's dorsal root ganglion (DRG) neurons using whole-cell patch clamp technique. The results showed that EABR (5-20 mg/kg, i.g.) could produce dose-dependent analgesic effect on hot-plate tests as well as writhing response induced by acetic acid. In addition, administration of 2.5-10 mg/kg EABR (i.g.) caused significant decrease in pain responses in the first and second phases of formalin test without altering the PGE₂ production in the hind paw of the mice. Moreover, EABR (10 µg/ml -1 mg/ml) could suppress TTX-S voltage-gated sodium currents in a dose-dependent way, indicating the underlying electrophysiological mechanism of the analgesic effect of the folk plant medicine. Collectively, our results indicated that EABR has analgesic property in three pain models and useful influence on TTX-S sodium currents in DRG neurons, suggesting that the interference with pain messages caused by the modulation of EABR on TTX-S sodium currents in DRG neurones may explain some of its analgesic effect.

Dorsal root potential produced by a TTX-insensitive micro-circuitry in the turtle spinal cord

DEFF Research Database (Denmark)

Russo, R E; Delgado-Lezama, R; Hounsgaard, J

2000-01-01

1, The mechanisms underlying the dorsal root potential (DRP) were studied in transverse slices of turtle spinal cord. DRPs were evoked by stimulating one filament in a dorsal root and were recorded from another such filament. 2. The DRP evoked at supramaximal stimulus intensity was reduced....... 5. Our results show that part of the DRP is generated by a TTX-resistant, probably non-spiking micro-circuit with separate components mediated by GABA and glutamate....

Synthetic Ciguatoxins Selectively Activate Nav1.8-derived Chimeric Sodium Channels Expressed in HEK293 Cells*

Science.gov (United States)

Yamaoka, Kaoru; Inoue, Masayuki; Miyazaki, Keisuke; Hirama, Masahiro; Kondo, Chie; Kinoshita, Eiji; Miyoshi, Hiroshi; Seyama, Issei

2009-01-01

The synthetic ciguatoxin CTX3C has been shown to activate tetrodotoxin (TTX)-sensitive sodium channels (Nav1.2, Nav1.4, and Nav1.5) by accelerating activation kinetics and shifting the activation curve toward hyperpolarization (Yamaoka, K., Inoue, M., Miyahara, H., Miyazaki, K., and Hirama, M. (2004) Br. J. Pharmacol. 142, 879–889). In this study, we further explored the effects of CTX3C on the TTX-resistant sodium channel Nav1.8. TTX-resistant channels have been shown to be involved in transducing pain and related sensations (Akopian, A. N., Sivilotti, L., and Wood, J. N. (1996) Nature 379, 257–262). Thus, we hypothesized that ciguatoxin-induced activation of the Nav1.8 current would account for the neurological symptoms of ciguatera poisoning. We found that 0.1 μm CTX3C preferentially affected the activation process of the Nav1.8 channel compared with those of the Nav1.2 and Nav1.4 channels. Importantly, without stimulation, 0.1 μm CTX3C induced a large leakage current (IL). The conductance of the IL calculated relative to the maximum conductance (Gmax) was 10 times larger than that of Nav1.2 or Nav1.4. To determine the molecular domain of Nav1.8 responsible for conferring higher sensitivity to CTX3C, we made two chimeric constructs from Nav1.4 and Nav1.8. Chimeras containing the N-terminal half of Nav1.8 exhibited a large response similar to wild-type Nav1.8, indicating that the region conferring high sensitivity to ciguatoxin action is located in the D1 or D2 domains. PMID:19164297

Constraint shapes convergence in tetrodotoxin-resistant sodium channels of snakes.

Science.gov (United States)

Feldman, Chris R; Brodie, Edmund D; Brodie, Edmund D; Pfrender, Michael E

2012-03-20

Natural selection often produces convergent changes in unrelated lineages, but the degree to which such adaptations occur via predictable genetic paths is unknown. If only a limited subset of possible mutations is fixed in independent lineages, then it is clear that constraint in the production or function of molecular variants is an important determinant of adaptation. We demonstrate remarkably constrained convergence during the evolution of resistance to the lethal poison, tetrodotoxin, in six snake species representing three distinct lineages from around the globe. Resistance-conferring amino acid substitutions in a voltage-gated sodium channel, Na(v)1.4, are clustered in only two regions of the protein, and a majority of the replacements are confined to the same three positions. The observed changes represent only a small fraction of the experimentally validated mutations known to increase Na(v)1.4 resistance to tetrodotoxin. These results suggest that constraints resulting from functional tradeoffs between ion channel function and toxin resistance led to predictable patterns of evolutionary convergence at the molecular level. Our data are consistent with theoretical predictions and recent microcosm work that suggest a predictable path is followed during an adaptive walk along a mutational landscape, and that natural selection may be frequently constrained to produce similar genetic outcomes even when operating on independent lineages.

Presynaptic calcium signalling in cerebellar mossy fibres

DEFF Research Database (Denmark)

Thomsen, Louiza Bohn; Jörntell, Henrik; Midtgaard, Jens

2010-01-01

Whole-cell recordings were obtained from mossy fibre terminals in adult turtles in order to characterize the basic membrane properties. Calcium imaging of presynaptic calcium signals was carried out in order to analyse calcium dynamics and presynaptic GABA B inhibition. A tetrodotoxin (TTX......)-sensitive fast Na(+) spike faithfully followed repetitive depolarizing pulses with little change in spike duration or amplitude, while a strong outward rectification dominated responses to long-lasting depolarizations. High-threshold calcium spikes were uncovered following addition of potassium channel blockers....... Calcium imaging using Calcium-Green dextran revealed a stimulus-evoked all-or-none TTX-sensitive calcium signal in simple and complex rosettes. All compartments of a complex rosette were activated during electrical activation of the mossy fibre, while individual simple and complex rosettes along an axon...

Effects of Silodosin and Tamsulosin on the Seminal Vesicle Contractile Response.

Science.gov (United States)

Hayashi, Tokumasa; Takeya, Mitsue; Nakamura, Kei-ichiro; Matsuoka, Kei

2016-01-01

To understand the mechanisms underlying ejaculation dysfunction caused by α1A-adrenocetor (AR) antagonists, the effects of α1A-AR antagonists on the contractile responses of the seminal vesicle were investigated. Isolated seminal vesicles from guinea pigs were cannulated and pressurized, and the changes in the intraluminal pressure were recorded. Periodic applications of electrical stimulation (ES) caused biphasic increase in the intraluminal pressure, that is, initial and subsequent contractions. The effects of silodosin and tamsulosin, α1A-AR antagonists, on the contractile responses were examined. The ES-induced biphasic contractions were blocked by tetrodotoxin (TTX). Silodosin and tamsulosin suppressed the initial contractions in a dose-dependent manner, while also exerting various inhibitory effects on the subsequent contractions. Increases in the intraluminal pressure facilitated spontaneous phasic contractions. The spontaneous contractions were not affected by TTX or α1A-AR antagonists, but were abolished by nifedipine. The initial contractions triggered by neuronal excitations were suppressed by silodosin and tamsulosin, suggesting that the ejaculation dysfunction may be attributed to the α1A-AR antagonist-mediated suppression of nerve-evoked contractions in the seminal vesicle. The subsequent contractions may be induced by mechanical stimulation associated with the initial, nerve-evoked contractions. Alternatively, other transmitters may be involved to various degrees in the neuromuscular transmission of the seminal vesicle. © 2014 Wiley Publishing Asia Pty Ltd.

Early metabolic responses to lithium/pilocarpine-induced status epilepticus in rat brain.

Science.gov (United States)

Imran, Imran; Hillert, Markus H; Klein, Jochen

2015-12-01

lithium-pilocarpine ('Pilo') administration, and extracellular metabolites were measured by microdialysis. Seizures caused several-fold increases in lactate levels which were attenuated by diazepam ('Diaz'), ketamine, atropine and tetrodotoxin (TTX). Indicators of oxidative stress and membrane damage were also increased during seizures. Omission of calcium and pregabalin, a calcium channel blocker, reduced cellular damage induced by SE. © 2015 International Society for Neurochemistry.

Native pyroglutamation of huwentoxin-IV: a post-translational modification that increases the trapping ability to the sodium channel.

Science.gov (United States)

Rong, Mingqiang; Duan, Zhigui; Chen, Juliang; Li, Jianglin; Xiao, Yuchen; Liang, Songping

2013-01-01

Huwentoxin-IV (HWTX-IV), a tetrodotoxin-sensitive (TTX-s) sodium channel antagonist, is found in the venom of the Chinese spider Ornithoctonus huwena. A naturally modified HWTX-IV (mHWTX-IV), having a molecular mass 18 Da lower than HWTX-IV, has also been isolated from the venom of the same spider. By a combination of enzymatic fragmentation and MS/MS de novo sequencing, mHWTX-IV has been shown to have the same amino acid sequence as that of HWTX-IV, except that the N-terminal glutamic acid replaced by pyroglutamic acid. mHWTX-IV inhibited tetrodotoxin-sensitive voltage-gated sodium channels of dorsal root ganglion neurons with an IC50 nearly equal to native HWTX-IV. mHWTX-IV showed the same activation and inactivation kinetics seen for native HWTX-IV. In contrast with HWTX-IV, which dissociates at moderate voltage depolarization voltages (+50 mV, 180000 ms), mHWTX-IV inhibition of TTX-sensitive sodium channels is not reversed by strong depolarization voltages (+200 mV, 500 ms). Recovery of Nav1.7current was voltage-dependent and was induced by extreme depolarization in the presence of HWTX-IV, but no obvious current was elicited after application of mHWTX-IV. Our data indicate that the N-terminal modification of HWTX-IV gives the peptide toxin a greater ability to trap the voltage sensor in the sodium channel. Loss of a negative charge, caused by cyclization at the N-terminus, is a possible reason why the modified toxin binds much stronger. To our knowledge, this is the first report of a pyroglutamic acid residue in a spider toxin; this modification seems to increase the trapping ability of the voltage sensor in the sodium channel.

Native pyroglutamation of huwentoxin-IV: a post-translational modification that increases the trapping ability to the sodium channel.

Directory of Open Access Journals (Sweden)

Mingqiang Rong

Full Text Available Huwentoxin-IV (HWTX-IV, a tetrodotoxin-sensitive (TTX-s sodium channel antagonist, is found in the venom of the Chinese spider Ornithoctonus huwena. A naturally modified HWTX-IV (mHWTX-IV, having a molecular mass 18 Da lower than HWTX-IV, has also been isolated from the venom of the same spider. By a combination of enzymatic fragmentation and MS/MS de novo sequencing, mHWTX-IV has been shown to have the same amino acid sequence as that of HWTX-IV, except that the N-terminal glutamic acid replaced by pyroglutamic acid. mHWTX-IV inhibited tetrodotoxin-sensitive voltage-gated sodium channels of dorsal root ganglion neurons with an IC50 nearly equal to native HWTX-IV. mHWTX-IV showed the same activation and inactivation kinetics seen for native HWTX-IV. In contrast with HWTX-IV, which dissociates at moderate voltage depolarization voltages (+50 mV, 180000 ms, mHWTX-IV inhibition of TTX-sensitive sodium channels is not reversed by strong depolarization voltages (+200 mV, 500 ms. Recovery of Nav1.7current was voltage-dependent and was induced by extreme depolarization in the presence of HWTX-IV, but no obvious current was elicited after application of mHWTX-IV. Our data indicate that the N-terminal modification of HWTX-IV gives the peptide toxin a greater ability to trap the voltage sensor in the sodium channel. Loss of a negative charge, caused by cyclization at the N-terminus, is a possible reason why the modified toxin binds much stronger. To our knowledge, this is the first report of a pyroglutamic acid residue in a spider toxin; this modification seems to increase the trapping ability of the voltage sensor in the sodium channel.

Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes NaV1.9, NaV1.7 and NaV1.1

Directory of Open Access Journals (Sweden)

Filip Touska

2017-08-01

Full Text Available Ciguatoxins (CTXs are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1 into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP from nerve terminals. In this study, we used mouse and rat skin preparations and enzyme-linked immunosorbent assays (ELISA to study the molecular mechanism by which P-CTX-1 induces CGRP release. We show that P-CTX-1 induces CGRP release more effectively in mouse as compared to rat skin, exhibiting EC50 concentrations in the low nanomolar range. P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP ion channels. In contrast, lidocaine and tetrodotoxin (TTX reduce CGRP release by 53–75%, with the remaining fraction involving L-type and T-type voltage-gated calcium channels (VGCC. Using transgenic mice, we revealed that the TTX-resistant voltage-gated sodium channel (VGSC NaV1.9, but not NaV1.8 or NaV1.7 alone and the combined activation of the TTX-sensitive VGSC subtypes NaV1.7 and NaV1.1 carry the largest part of the P-CTX-1-caused CGRP release of 42% and 34%, respectively. Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera that may help in the identification of potential therapeutics.

Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes NaV1.9, NaV1.7 and NaV1.1

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Touska, Filip; Sattler, Simon; Malsch, Philipp; Lewis, Richard J.; Zimmermann, Katharina

2017-01-01

Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals. In this study, we used mouse and rat skin preparations and enzyme-linked immunosorbent assays (ELISA) to study the molecular mechanism by which P-CTX-1 induces CGRP release. We show that P-CTX-1 induces CGRP release more effectively in mouse as compared to rat skin, exhibiting EC50 concentrations in the low nanomolar range. P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels. In contrast, lidocaine and tetrodotoxin (TTX) reduce CGRP release by 53–75%, with the remaining fraction involving L-type and T-type voltage-gated calcium channels (VGCC). Using transgenic mice, we revealed that the TTX-resistant voltage-gated sodium channel (VGSC) NaV1.9, but not NaV1.8 or NaV1.7 alone and the combined activation of the TTX-sensitive VGSC subtypes NaV1.7 and NaV1.1 carry the largest part of the P-CTX-1-caused CGRP release of 42% and 34%, respectively. Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera that may help in the identification of potential therapeutics. PMID:28867800

Synthetic ciguatoxins selectively activate Nav1.8-derived chimeric sodium channels expressed in HEK293 cells.

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Yamaoka, Kaoru; Inoue, Masayuki; Miyazaki, Keisuke; Hirama, Masahiro; Kondo, Chie; Kinoshita, Eiji; Miyoshi, Hiroshi; Seyama, Issei

2009-03-20

The synthetic ciguatoxin CTX3C has been shown to activate tetrodotoxin (TTX)-sensitive sodium channels (Na(v)1.2, Na(v)1.4, and Na(v)1.5) by accelerating activation kinetics and shifting the activation curve toward hyperpolarization (Yamaoka, K., Inoue, M., Miyahara, H., Miyazaki, K., and Hirama, M. (2004) Br. J. Pharmacol. 142, 879-889). In this study, we further explored the effects of CTX3C on the TTX-resistant sodium channel Na(v)1.8. TTX-resistant channels have been shown to be involved in transducing pain and related sensations (Akopian, A. N., Sivilotti, L., and Wood, J. N. (1996) Nature 379, 257-262). Thus, we hypothesized that ciguatoxin-induced activation of the Na(v)1.8 current would account for the neurological symptoms of ciguatera poisoning. We found that 0.1 mum CTX3C preferentially affected the activation process of the Na(v)1.8 channel compared with those of the Na(v)1.2 and Na(v)1.4 channels. Importantly, without stimulation, 0.1 mum CTX3C induced a large leakage current (I (L)). The conductance of the I (L) calculated relative to the maximum conductance (G (max)) was 10 times larger than that of Na(v)1.2 or Na(v)1.4. To determine the molecular domain of Na(v)1.8 responsible for conferring higher sensitivity to CTX3C, we made two chimeric constructs from Na(v)1.4 and Na(v)1.8. Chimeras containing the N-terminal half of Na(v)1.8 exhibited a large response similar to wild-type Na(v)1.8, indicating that the region conferring high sensitivity to ciguatoxin action is located in the D1 or D2 domains.

Hypercapnic vasodilatation in isolated rat basilar arteries is exerted via low pH and does not involve nitric oxide synthase stimulation or cyclic GMP production

DEFF Research Database (Denmark)

You, J P; Wang, Qian; Zhang, W

1994-01-01

this relaxation by 54% and 70%, respectively. The effect of L-NOARG was completely reversed by L-arginine. Blockade of nerve excitation with tetrodotoxin (TTX) had no affect on the 15% CO2 elicited vasodilatation. Measurements of cGMP in vessel segments showed no significant increase in cGMP content in response...... to hypercapnia. L-NOARG and MB, but not TTX, significantly reduced the basal cGMP content in cerebral vessels. Adding 1.5% halothane to the incubation medium did not result in a significant increase in cGMP content. Lowering the pH by cumulative application of 0.12 M HCl resulted in relaxation identical...... elicits vasodilatation of isolated rat basilar arteries by a mechanism independent of nitric oxide synthase (NOS) activity. The markedly reduced basal cGMP levels in cerebral vessels by L-NOARG and MB suggest that there exists a basal NO formation in the cerebral vessel wall....

Mechanism of S100b release from rat cortical slices determined under basal and stimulated conditions.

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Gürsoy, Murat; Büyükuysal, R Levent

2010-03-01

Incubation of rat cortical slices in a medium that was not containing oxygen and glucose (oxygen-glucose deprivation, OGD) caused a 200% increase in the release of S100B. However, when slices were transferred to a medium containing oxygen and glucose (reoxygenation conditions, or REO), S100B release reached 500% of its control value. Neither inhibition of nitric oxide (NO) synthase by L-NAME nor addition of the NO donors sodium nitroprussid (SNP) or hydroxylamine (HA) to the medium altered basal S100B release. Similarly, the presence of SNP, HA or NO precursor L: -arginine in the medium, or inhibition of NO synthase by L-NAME also failed to alter OGD- and REO-induced S100B outputs. Moreover, individual inhibition of PKC, PLA(2) or PLC all failed to attenuate the S100B release determined under control condition or enhanced by either OGD or REO. Blockade of calcium channels with verapamil, chelating the Ca(+2) ions with BAPTA or blockade of sodium channels with tetrodotoxin (TTX) did not alter OGD- and REO-induced S100B release. In contrast to the pharmacologic manipulations mentioned above, glutamate and alpha-ketoglutarate added at high concentrations to the medium prevented both OGD- and REO-induced S100B outputs. These results indicate that neither NO nor the activation of PKC, PLA(2) or PLC seem to be involved in basal or OGD- and REO-induced S100B outputs. Additionally, calcium and sodium currents that are sensitive to verapamil and TTX, respectively, are unlikely to contribute to the enhanced S100B release observed under these conditions.

Differential Effects of Inactivation of Discrete Regions of Medial Prefrontal Cortex on Memory Consolidation of Moderate and Intense Inhibitory Avoidance Training

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María E. Torres-García

2017-11-01

Full Text Available It has been found that the medial prefrontal cortex (mPFC is involved in memory encoding of aversive events, such as inhibitory avoidance (IA training. Dissociable roles have been described for different mPFC subregions regarding various memory processes, wherein the anterior cingulate cortex (ACC, prelimbic cortex (PL, and infralimbic cortex (IL are involved in acquisition, retrieval, and extinction of aversive events, respectively. On the other hand, it has been demonstrated that intense training impedes the effects on memory of treatments that typically interfere with memory consolidation. The aim of this work was to determine if there are differential effects on memory induced by reversible inactivation of neural activity of ACC, PL, or IL produced by tetrodotoxin (TTX in rats trained in IA using moderate (1.0 mA and intense (3.0 mA foot-shocks. We found that inactivation of ACC has no effects on memory consolidation, regardless of intensity of training. PL inactivation impairs memory consolidation in the 1.0 mA group, while no effect on consolidation was produced in the 3.0 mA group. In the case of IL, a remarkable amnestic effect in LTM was observed in both training conditions. However, state-dependency can explain the amnestic effect of TTX found in the 3.0 mA IL group. In order to circumvent this effect, TTX was injected into IL immediately after training (thus avoiding state-dependency. The behavioral results are equivalent to those found after PL inactivation. Therefore, these findings provide evidence that PL and IL, but not ACC, mediate LTM of IA only in moderate training.

Pacific ciguatoxin-1b effect over Na+ and K+ currents, inositol 1,4,5-triphosphate content and intracellular Ca2+ signals in cultured rat myotubes

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Hidalgo, Jorge; Liberona, José Luis; Molgó, Jordi; Jaimovich, Enrique

2002-01-01

The action of the main ciguatoxin involved in ciguatera fish poisoning in the Pacific region (P-CTX-1b) was studied in myotubes originated from rat skeletal muscle cells kept in primary culture. The effect of P-CTX-1b on sodium currents at short times of exposure (up to 1 min) showed a moderate increase in peak Na+ current. During prolonged exposures, P-CTX-1b decreased the peak Na+ current. This action was always accompanied by an increase of leakage currents, tail currents and outward Na+ currents, resulting in an intracellular Na+ accumulation. This effect is blocked by prior exposure to tetrodotoxin (TTX) and becomes evident only after washout of TTX. Low to moderate concentrations of P-CTX-1b (2–5 nM) partially blocked potassium currents in a manner that was dependent on the membrane potential. P-CTX-1b (2–12 nM) caused a small membrane depolarization (3–5 mV) and an increase in the frequency of spontaneous action potential discharges that reached in general low frequencies (0.1–0.5 Hz). P-CTX-1b (10 nM) caused a transient increase of intracellular inositol 1,4,5-trisphosphate (IP3) mass levels, which was blocked by TTX. In the presence of P-CTX-1b (10 nM) and in the absence of external Ca2+, the intracellular Ca2+ levels show a transient increase in the cytoplasm as well as in the nuclei. The time course of this effect may reflect the action of IP3 over internal stores activated by P-CTX-1b-induced membrane depolarization. PMID:12429578

Mechanism of palytoxin-induced [3H]norepinephrine release from a rat pheochromocytoma cell line

International Nuclear Information System (INIS)

Tatsumi, M.; Takahashi, M.; Ohizumi, Y.

1984-01-01

Palytoxin, isolated from the zoanthid Palytoha species, is one of the most potent marine toxins. Palytoxin caused a release of [ 3 H]norepinephrine from clonal rat pheochromocytoma cells in a concentration-dependent manner. This releasing action of palytoxin was markedly inhibited or abolished by Co 2+ or Ca 2+ -free medium, but was not modified by tetrodotoxin. The release of [ 3 H]norepinephrine induced by a low concentration of palytoxin was abolished in sodium-free medium and increased as the external Na+ concentrations were increased, but the release induced by a high concentration was unaffected by varying the concentration of external Na + . The release of [ 3 H]norepinephrine induced by both concentrations of palytoxin increased with increasing Ca 2+ concentrations. Palytoxin caused a concentration-dependent increase in 22 Na and 45 Ca influxes into pheochromocytoma cells. The palytoxin-induced 45 Ca influx was markedly inhibited by Co 2+ , whereas the palytoxin-induced 22 Na influx was not affected by tetrodotoxin. These results suggest that in pheochromocytoma cells the [ 3 H]norepinephrine release induced by lower concentrations of palytoxin is primarily brought about by increasing tetrodotoxin-insensitive Na + permeability across the cell membrane, whereas that induced by higher concentrations is mainly caused by a direct increase in Ca 2+ influx into them

NMDA receptor antagonist-enhanced high frequency oscillations: are they generated broadly or regionally specific?

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Olszewski, Maciej; Dolowa, Wioleta; Matulewicz, Pawel; Kasicki, Stefan; Hunt, Mark J

2013-12-01

Systemic administration of NMDA receptor antagonists, used to model schizophrenia, increase the power of high-frequency oscillations (130-180Hz, HFO) in a variety of neuroanatomical and functionally distinct brain regions. However, it is unclear whether HFO are independently and locally generated or instead spread from a distant source. To address this issue, we used local infusion of tetrodotoxin (TTX) to distinct brain areas to determine how accurately HFO recorded after injection of NMDAR antagonists reflect the activity actually generated at the electrode tip. Changes in power were evaluated in local field potentials (LFPs) recorded from the nucleus accumbens (NAc), prefrontal cortex and caudate and in electrocorticograms (ECoGs) from visual and frontal areas. HFO recorded in frontal and visual cortices (ECoGs) or in the prefrontal cortex, caudate (LFPs) co-varied in power and frequency with observed changes in the NAc. TTX infusion to the NAc immediately and profoundly reduced the power of accumbal HFO which correlated with changes in HFO recorded in distant cortical sites. In contrast, TTX infusion to the prefrontal cortex did not change HFO power recorded locally, although gamma power was reduced. A very similar result was found after TTX infusion to the caudate. These findings raise the possibility that the NAc is an important neural generator. Our data also support existing studies challenging the idea that high frequencies recorded in LFPs are necessarily generated at the recording site. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Orexins control intestinal glucose transport by distinct neuronal, endocrine, and direct epithelial pathways.

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Ducroc, Robert; Voisin, Thierry; El Firar, Aadil; Laburthe, Marc

2007-10-01

Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OxA) and orexin B (OxB) on intestinal glucose transport in the rat. Injection of orexins led to a decrease in the blood glucose level in oral glucose tolerance tests (OGTTs). Effects of orexins on glucose entry were analyzed in Ussing chambers using the Na(+)-dependent increase in short-circuit current (Isc) to quantify jejunal glucose transport. The rapid and marked increase in Isc induced by luminal glucose was inhibited by 10 nmol/l OxA or OxB (53 and 59%, respectively). Response curves to OxA and OxB were not significantly different with half-maximal inhibitory concentrations at 0.9 and 0.4 nmol/l, respectively. On the one hand, OxA-induced inhibition of Isc was reduced by the neuronal blocker tetrodotoxin (TTX) and by a cholecystokinin (CCK) 2R antagonist, indicating involvement of neuronal and endocrine CCK-releasing cells. The OX(1)R antagonist SB334867 had no effect on OxA-induced inhibition, which is likely to occur via a neuronal and/or endocrine OX(2)R. On the other hand, SB334867 induced a significant right shift of the concentration-effect curve for OxB. This OxB-preferring OX(1)R pathway was not sensitive to TTX or to CCKR antagonists, suggesting that OxB may act directly on enterocytic OX(1)R. These distinct effects of OxA and OxB are consistent with the expression of OX(1)R and OX(2)R mRNA in the epithelial and nonepithelial tissues, respectively. Our data delineate a new function for orexins as inhibitors of intestinal glucose absorption and provide a new basis for orexin-induced short-term control of energy homeostasis.

Effect of 670-nm Light-Emitting Diode Light On Neuronal Cultures

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Wong-Riley, Margaret T. T.; Whelan, Harry T.

2002-01-01

Light close to and within the near infrared range has documented benefits for promoting wound healing in human and animal studies. Our preliminary results using light-emitting diodes (LEDs) in this range have also demonstrated two-to five-fold increases in growth-phase-specific DNA synthesis in normal fibroblasts, muscle cells, osteoblasts, and mucosal epithelial cells in tissue cultures. However, the mechanisms of action of such light on cells are poorly understood. We hypothesized that the therapeutic effects of such light result from the stimulation of cellular events associated with increases in cytochrome oxidase activity. As a first step in testing our hypothesis, we subjected primary neuronal cultures to impulse blockade by tetrodotoxin (TTX), a voltage-dependent sodium channel blocker, and applied LED light at 670 nm to determine if it could partially or fully reverse the reduction of cytochrome oxidase activity by TTX. The wavelength and parameters were previously tested to be beneficial for wound healing.

Voltage-gated Na+ currents in human dorsal root ganglion neurons

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Zhang, Xiulin; Priest, Birgit T; Belfer, Inna; Gold, Michael S

2017-01-01

Available evidence indicates voltage-gated Na+ channels (VGSCs) in peripheral sensory neurons are essential for the pain and hypersensitivity associated with tissue injury. However, our understanding of the biophysical and pharmacological properties of the channels in sensory neurons is largely based on the study of heterologous systems or rodent tissue, despite evidence that both expression systems and species differences influence these properties. Therefore, we sought to determine the extent to which the biophysical and pharmacological properties of VGSCs were comparable in rat and human sensory neurons. Whole cell patch clamp techniques were used to study Na+ currents in acutely dissociated neurons from human and rat. Our results indicate that while the two major current types, generally referred to as tetrodotoxin (TTX)-sensitive and TTX-resistant were qualitatively similar in neurons from rats and humans, there were several differences that have important implications for drug development as well as our understanding of pain mechanisms. DOI: http://dx.doi.org/10.7554/eLife.23235.001 PMID:28508747

The effects of nidopallium caudolaterale inactivation on serial-order behaviour in pigeons (Columba livia).

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Johnston, Melissa Jane; Clarkson, Andrew N; Gowing, Emma K; Scarf, Damian; Colombo, Mike

2018-06-06

Serial-order behaviour is the ability to complete a sequence of responses in a predetermined order to achieve a reward. In birds, serial-order behaviour is thought to be impaired by damage to the nidopallium caudolaterale (NCL). In the current study, we examined the role of the NCL in serial-order behaviour by training pigeons on a 4-item serial-order task and a go/no-go discrimination task. Following training, pigeons were received infusions of 1μl of either tetrodotoxin (TTX) or saline. Saline infusions had no impact on serial-order behaviour whereas TTX infusions resulted in a significant decrease in performance. The serial-order impairments, however, were not the results of errors of any specific error at any specific list item. With respect to the go/no-go discrimination task, saline infusions also had no impact on performance whereas TTX infusions impaired pigeons' discrimination abilities. Given the impairments on the go/no-go discrimination task, which does not require processing of serial-order information, we tentatively conclude that damage to the NCL does not impair serial-order behaviour per se, but rather results in a more generalised impairment that may impact performance across a range of tasks.

Effects of curcumin on TTX-R sodium currents of dorsal root ganglion neurons in type 2 diabetic rats with diabetic neuropathic pain.

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Meng, Bo; Shen, Lu-Lu; Shi, Xiao-Ting; Gong, Yong-Sheng; Fan, Xiao-Fang; Li, Jun; Cao, Hong

2015-09-25

Type 2 diabetic mellitus (T2DM) has reached pandemic status and shows no signs of abatement. Diabetic neuropathic pain (DNP) is generally considered to be one of the most common complications of T2DM, which is also recognized as one of the most difficult types of pain to treat. As one kind of peripheral neuropathic pain, DNP manifests typical chronic neuralgia symptoms, including hyperalgesia, allodynia, autotomy, and so on. The injured dorsal root ganglion (DRG) is considered as the first stage of the sensory pathway impairment, whose neurons display increased frequency of action potential generation and increased spontaneous activities. These are mainly due to the changed properties of voltage-gated sodium channels (VGSCs) and the increased sodium currents, especially TTX-R sodium currents. Curcumin, one of the most important phytochemicals from turmeric, has been demonstrated to effectively prevent and/or ameliorate diabetic mellitus and its complications including DNP. The present study demonstrates that the TTX-R sodium currents of small-sized DRG neurons isolated from DNP rats are significantly increased. Such abnormality can be efficaciously ameliorated by curcumin. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Purification of a myotoxin from the toadfish Thalassophryne maculosa (Günter) venom.

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Sosa-Rosales, J I; D'Suze, G; Salazar, V; Fox, J; Sevcik, C

2005-02-01

Venom was milked by gently pressing the base of the opercular and dorsal fin spines. Three fractions were obtained by molecular exclusion high pressure liquid chromatography (HPLC) (Protein Pak 125SW, Millipore Corporation) column, but only the last one with 22.7 min retention time (rt) was biological active (TmPP-22.7). This fraction was rechromatographed on reversed phase HPLC chlorobutylsilane columns (C4, Vydac) nine fractions were obtained, but only one (TmC4-47.2) with 47.2 min rt was biologically active. MALD-TOF mass analysis was carried out on two samples of TmC-47.2 and the results were 15,161.36 and 15,154.70 a.m.u., respectively. Raw venom (1040 microg/ml) depolarised frog (Hyla crepitans) muscle irreversibly from -85 (-88, -81) mV (n=20, median and its 95% CI) to -18 (-24, -15) mV (n=24). The biological activity in TmPP-22.7 (38 microg/ml), which depolarised muscle fibres from -79 (-82, -76) mV (n=20) to -63 (-69 -57) mV (n=24). The depolarising fraction was TmC4-47.2 (50 microg/ml) which depolarised muscles from -87 (91, -82) mV (n=33) to -63 (-76 -51) mV (n=53); the depolarising effect at this concentration was completely reversed on washing with normal saline for 2 h. Muscles treated with 1 microM tetrodotoxin (TTX) were depolarised from -80 (-85, -72) mV (n=49) to -44 (-56, -31) mV (n=44) when 100 microg/ml TmC4-47.2 were applied with TTX; washing 130 min with 1 microM TTX repolarised to -59 (-69, -50) mV (n=25). We also present evidence that TmC4-47.2 induces myonecrosis in mice.

Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons

International Nuclear Information System (INIS)

Birinyi-Strachan, Liesl C.; Gunning, Simon J.; Lewis, Richard J.; Nicholson, Graham M.

2005-01-01

The present study investigated the actions of the polyether marine toxin Pacific ciguatoxin-1 (P-CTX-1) on neuronal excitability in rat dorsal root ganglion (DRG) neurons using patch-clamp recording techniques. Under current-clamp conditions, bath application of 2-20 nM P-CTX-1 caused a rapid, concentration-dependent depolarization of the resting membrane potential in neurons expressing tetrodotoxin (TTX)-sensitive voltage-gated sodium (Na v ) channels. This action was completely suppressed by the addition of 200 nM TTX to the external solution, indicating that this effect was mediated through TTX-sensitive Na v channels. In addition, P-CTX-1 also prolonged action potential and afterhyperpolarization (AHP) duration. In a subpopulation of neurons, P-CTX-1 also produced tonic action potential firing, an effect that was not accompanied by significant oscillation of the resting membrane potential. Conversely, in neurons expressing TTX-resistant Na v currents, P-CTX-1 failed to alter any parameter of neuronal excitability examined in this study. Under voltage-clamp conditions in rat DRG neurons, P-CTX-1 inhibited both delayed-rectifier and 'A-type' potassium currents in a dose-dependent manner, actions that occurred in the absence of alterations to the voltage dependence of activation. These actions appear to underlie the prolongation of the action potential and AHP, and contribute to repetitive firing. These data indicate that a block of potassium channels contributes to the increase in neuronal excitability, associated with a modulation of Na v channel gating, observed clinically in response to ciguatera poisoning

Correlation of Respiratory Activity of Contralateral Diaphragm Muscles for Evaluation of Recovery Following Hemiparesis

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Dow, Douglas E.; Zhan, Wen-Zhi; Sieck, Gary C.; Mantilla, Carlos B.

2014-01-01

Respiration is impaired by disruption of the central drive for inspiration to the diaphragm muscle (DIAm). Some function may recover involving nerve regeneration, reinnervation or neuroplasticity. A research animal model involves inducing hemiparesis of the DIAm and monitoring any recovery under different conditions. Methods to accurately track the level of functional recovery are needed. In this study, an algorithm was developed and tested to quantify the relative amount of electromyogram (EMG) activity that temporally correlated for an experimental (EXP) hemi-DIAm with its intact contralateral hemi-DIAm. An average rectified value (ARV) trace was calculated. A template was formed of the ARV trace of the intact hemi-DIAm, with higher positive values corresponding with periods of inspirations and lower negative values corresponding with quiet periods. This template was multiplied by the EXP ARV trace to reward (more positive) periods of correlating activity, and punish (more negative) periods of high activity on the EXP side that corresponded with quiet periods on the intact side. The average integrated value was the index of correlating contralateral activity (ICCA). A negative ICCA value indicated no net correlation of activity, and a positive value indicated a net correlation of activity. The algorithm was tested on rats having the conditions of control or hemi-paresis induced by denervatation (DNV), tetrodotoxin administration (TTX) or cervical spinal hemi-section (SH). Control had high positive ICCA values, and DNV had negative values. TTX maintained negative ICCA values at 3, 7 and 14 days, indicating a lack of functional recovery. SH maintained negative values at 3 and 7 days, but a subset had positive values at 14 days indicating some functional recovery. PMID:19965125

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.

Toxicity and Molecular Identification of Green Toadfish Lagocephalus lunaris Collected from Kyushu Coast, Japan

Directory of Open Access Journals (Sweden)

Yuji Nagashima

2011-01-01

Full Text Available Green toadfish Lagocephalus lunaris inhabits tropical and subtropical seas and contains high tetrodotoxin (TTX levels in the muscle as well as liver and gonad. In 2008 to 2009, food poisoning due to ingesting L. lunais occurred in Western Japan. Five specimens of green toadfish caught in Kyushu coast, Japan, were analyzed for toxicity, toxins, and species identification. All five specimens were toxic by bioassay. Comparing the maximum toxicity in tissues, ovary contained the most toxin (1810 mouse unit [MU]/g, followed by liver (341 MU/g, muscle (135 MU/g, skin (79 MU/g, and intestine (72 MU/g. Liquid chromatography/mass spectrometry analysis revealed that TTX was the major toxin. Nucleotide sequence analysis of the 16S rRNA gene fragment of muscle mitochondrial DNA indicated that partial sequences of PCR products of four specimens were identical with that of L. lunaris. The sequence of one specimen was indistinguishable from that of the brown-backed toadfish Lagocephalus wheeleri, a nontoxic species.

Distribution of TTX-sensitive voltage-gated sodium channels in primary sensory endings of mammalian muscle spindles.

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Carrasco, Dario I; Vincent, Jacob A; Cope, Timothy C

2017-04-01

Knowledge of the molecular mechanisms underlying signaling of mechanical stimuli by muscle spindles remains incomplete. In particular, the ionic conductances that sustain tonic firing during static muscle stretch are unknown. We hypothesized that tonic firing by spindle afferents depends on sodium persistent inward current (INaP) and tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. The NaV 1.6 isoform was selected for both its capacity to produce INaP and for its presence in other mechanosensors that fire tonically. The present study shows that NaV 1.6 immunoreactivity (IR) is concentrated in heminodes, presumably where tonic firing is generated, and we were surprised to find NaV 1.6 IR strongly expressed also in the sensory terminals, where mechanotransduction occurs. This spatial pattern of NaV 1.6 IR distribution was consistent for three mammalian species (rat, cat, and mouse), as was tonic firing by primary spindle afferents. These findings meet some of the conditions needed to establish participation of INaP in tonic firing by primary sensory endings. The study was extended to two additional NaV isoforms, selected for their sensitivity to TTX, excluding TTX-resistant NaV channels, which alone are insufficient to support firing by primary spindle endings. Positive immunoreactivity was found for NaV 1.1 , predominantly in sensory terminals together with NaV 1.6 and for NaV 1.7 , mainly in preterminal axons. Differential distribution in primary sensory endings suggests specialized roles for these three NaV isoforms in the process of mechanosensory signaling by muscle spindles. NEW & NOTEWORTHY The molecular mechanisms underlying mechanosensory signaling responsible for proprioceptive functions are not completely elucidated. This study provides the first evidence that voltage-gated sodium channels (NaVs) are expressed in the spindle primary sensory ending, where NaVs are found at every site

Regulation of Na(+)/K(+)-ATPase by neuron-specific transcription factor Sp4: implication in the tight coupling of energy production, neuronal activity and energy consumption in neurons.

Science.gov (United States)

Johar, Kaid; Priya, Anusha; Wong-Riley, Margaret T T

2014-02-01

A major source of energy demand in neurons is the Na(+)/K(+)-ATPase pump that restores the ionic gradient across the plasma membrane subsequent to depolarizing neuronal activity. The energy comes primarily from mitochondrial oxidative metabolism, of which cytochrome c oxidase (COX) is a key enzyme. Recently, we found that all 13 subunits of COX are regulated by specificity (Sp) factors, and that the neuron-specific Sp4, but not Sp1 or Sp3, regulates the expression of key glutamatergic receptor subunits as well. The present study sought to test our hypothesis that Sp4 also regulates Na(+)/K(+)-ATPase subunit genes in neurons. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutational analysis, over-expression, and RNA interference studies, we found that Sp4, with minor contributions from Sp1 and Sp3, functionally regulate the Atp1a1, Atp1a3, and Atp1b1 subunit genes of Na(+)/K(+)-ATPase in neurons. Transcripts of all three genes were up-regulated by depolarizing KCl stimulation and down-regulated by the impulse blocker tetrodotoxin (TTX), indicating that their expression was activity-dependent. Silencing of Sp4 blocked the up-regulation of these genes induced by KCl, whereas over-expression of Sp4 rescued them from TTX-induced suppression. The effect of silencing or over-expressing Sp4 on primary neurons was much greater than those of Sp1 or Sp3. The binding sites of Sp factors on these genes are conserved among mice, rats and humans. Thus, Sp4 plays an important role in the transcriptional coupling of energy generation and energy consumption in neurons. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Ciguatoxin enhances quantal transmitter release from frog motor nerve terminals.

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Molgó, J.; Comella, J. X.; Legrand, A. M.

1990-01-01

1. Ciguatoxin (CTX), a marine toxin produced by the benthic dinoflagellate Gambierdiscus toxicus, is responsible for a complex endemic disease in man known as ciguatera fish poisoning. In the present study we have investigated the effects of purified CTX extracted for Gymnothorax javanicus moray-eel liver on frog isolated neuromuscular preparations with conventional electrophysiological techniques. 2. CTX (1-2.5 nM) applied to cutaneous pectoris nerve-muscle preparations induced, after a short delay, spontaneous fibrillations of the muscle fibres that could be suppressed with 1 microM tetrodotoxin (TTX) or by formamide to uncouple excitation-contraction. 3. In preparations treated with formamide, CTX (1-2.5 nM) caused either spontaneous or repetitive muscle action potentials (up to frequencies of 60-100 Hz) in response to a single nerve stimulus. Recordings performed at extrajunctional regions of the muscle membrane revealed that during the repetitive firing a prolongation of the repolarizing phase of the action potential occurred. At junctional sites the repetitive action potentials were triggered by repetitive endplate potentials (e.p.ps). 4. CTX (2.5 nM) caused a TTX-sensitive depolarization of the muscle membrane. 5. In junctions equilibrated in solutions containing high Mg2+ + low Ca2+, addition of CTX (1.5 nM) first induced an average increase of 239 +/- 36% in the mean quantal content of e.p.ps. Subsequently CTX reduced and finally blocked nerve-evoked transmitter release irreversibly. 6. CTX (1.5-2.5 nM) increased the frequency of miniature endplate potentials (m.e.p.ps) in junctions bathed either in normal Ringer, low Ca2(+)-high Mg2+ medium or in a nominally Ca2(+)-free solution containing EGTA.2+ Extensive washing with toxin-free solutions did not reverse the effect.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1972891

Toxicity of puffer fish: two species (Lagocephalus laevigatus, linaeus 1766 and Sphoeroides spengleri, Bloch 1785 from the Southeastern Brazilian coast

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J. S. Oliveira

2003-01-01

Full Text Available In Brazil, where puffer fish are considered poisonous, there are few documented cases on human consumption and consequent poisoning. In this study, toxicity of two puffer fish species from the Brazilian coast was examined. Specimens of Sphoeroides spengleri and Lagocephalus laevigatus were caught in São Sebastião Channel (North coast of São Paulo State, Brazil between January 1996 and May 1997. Acidic ethanol extracts from muscle and skin plus viscera were tested for mice acute toxicity using the standard method of Kawabata. Polar extracts of S. spengleri showed high toxicity up to 946 MU/g. Extracts from L. laevigatus showed very low levels of toxicity, never exceeding 1.7 MU/g. All extracts from both species blocked amielinic nerve fiber evoked impulses of crustacean legs; this effect reverted on washing similar to the standard tetrodotoxin TTX. The aqueous extract solutions were partially purified using an ionic exchange column (Amberlit GC-50 followed by treatment with activated charcoal (Norit-A. The presence of TTX and their analogs in the semi-purified extracts were confirmed by HPLC and mass spectrometry (MALDI-TOF.

Conduction velocity is regulated by sodium channel inactivation in unmyelinated axons innervating the rat cranial meninges.

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De Col, Roberto; Messlinger, Karl; Carr, Richard W

2008-02-15

Axonal conduction velocity varies according to the level of preceding impulse activity. In unmyelinated axons this typically results in a slowing of conduction velocity and a parallel increase in threshold. It is currently held that Na(+)-K(+)-ATPase-dependent axonal hyperpolarization is responsible for this slowing but this has long been equivocal. We therefore examined conduction velocity changes during repetitive activation of single unmyelinated axons innervating the rat cranial meninges. In direct contradiction to the currently accepted postulate, Na(+)-K(+)-ATPase blockade actually enhanced activity-induced conduction velocity slowing, while the degree of velocity slowing was curtailed in the presence of lidocaine (10-300 microm) and carbamazepine (30-500 microm) but not tetrodotoxin (TTX, 10-80 nm). This suggests that a change in the number of available sodium channels is the most prominent factor responsible for activity-induced changes in conduction velocity in unmyelinated axons. At moderate stimulus frequencies, axonal conduction velocity is determined by an interaction between residual sodium channel inactivation following each impulse and the retrieval of channels from inactivation by a concomitant Na(+)-K(+)-ATPase-mediated hyperpolarization. Since the process is primarily dependent upon sodium channel availability, tracking conduction velocity provides a means of accessing relative changes in the excitability of nociceptive neurons.

Substance P stimulates the opossum sphincter of Oddi in vitro.

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Parodi, J E; Cho, N; Zenilman, M E; Barteau, J A; Soper, N J; Becker, J M

1990-09-01

We have previously shown that substance P (SP) regulates sphincter of Oddi (SO) motility in vivo. However, its mechanism of action remains unclear. Our aim was to develop an in vitro model to measure spikeburst (SB) an contractile frequency (CMC) of the SO and to characterize further SP effects. In 16 opossums, SO rings were excised, mounted within a Kreb's tissue bath with bipolar electrodes and force transducers, allowed to equilibrate, and exposed to increasing SP concentrations with washout between each test solution. Spikeburst and CMC frequencies were recorded on a polygraph, quantitated, expressed as differences before and during SP, and statistically analyzed with Student's test. Although SP induced a significant concentration-dependent increase in phasic SB frequency and CMC, the amplitude of concentrations was not affected by SP. A close correlation was found between basal and SP-stimulated SB and CMC, suggesting myoelectric and mechanical coupling. Previous exposure of SO to SP antagonist [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP significantly decreased the response to SP. Tetrodotoxin (TTX), did not affect the delta CMC response to SP. In conclusion an in vitro preparation was developed to study the effect of SP on the SO. Substance P increased SB and CMC of the SO in a concentration-dependent fashion, thus acting as a stimulatory peptide. Perfusion of SO rings with SP antagonist had no effect on basal CMC but significantly inhibited the action of SP in a competitive manner. The effect of SP was not altered by TTX. These data suggest that the action of SP on the SO is primarily myogenic.

Regulation of the sodium-potassium pump in cultured rat skeletal myotubes by intracellular sodium ions

International Nuclear Information System (INIS)

Brodie, C.; Sampson, S.R.

1989-01-01

The properties of the Na-K pump and some of the factors controlling its amount and function were studied in rat myotubes in culture. The number of Na-K pump sites was quantified by measuring the amount of [ 3 H]ouabain bound to whole-cell preparations. Activity of the pump was determined by measurement of ouabain-sensitive 86 Rb-uptake and component of membrane potential. Chronic treatment of myotubes with tetrodotoxin (TTX), which lowers [Na]i, decreased the number of Na-K pumps, the ouabain-sensitive 86Rb uptake, and the size of the electrogenic pump component of Em. In contrast, chronic treatment with either ouabain or veratridine, which increases [Na+]i, resulted in an elevated level of Na-K pump sites. This effect was blocked by inhibitors of protein synthesis. Neither rates of degradation nor affinity of pump sites in cells treated with TTX, veratridine, or ouabain differred from those in control cells. The number and activity of Na-K pump sites were unaffected by chronic elevation in [Ca]i or chronic depolarization. We conclude that alterations in the level in intracellular Na ions play the major role in regulation of Na-K pump synthesis in cultured mammalian skeletal muscle

Recent memory for socially transmitted food preferences in rats does not depend on the hippocampus.

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Thapa, Rajat; Sparks, Fraser T; Hanif, Wahab; Gulbrandsen, Tine; Sutherland, Robert J

2014-10-01

The standard model of systems consolidation holds that the hippocampus (HPC) is involved only in the initial storage and retrieval of a memory. With time hippocampal-neocortical interactions slowly strengthen the neocortical memory, ultimately enabling retrieval of the memory without the HPC. Key support for this idea comes from experiments measuring memory recall in the socially-transmitted food preference (STFP) task in rats. HPC damage within a day or two of STFP learning can abolish recall, but similar damage five or more days after learning has no effect. We hypothesize that disruption of cellular consolidation outside the HPC could contribute to the amnesia with recent memories, perhaps playing a more important role than the loss of HPC. This view predicts that intraHPC infusion of Tetrodotoxin (TTX), which can block conduction of action potentials from the lesion sites, will block the retrograde amnesia in the STFP task. Here we confirm the previously reported retrograde amnesia with neurotoxic HPC damage within the first day after learning, but show that co-administration of TTX with the neurotoxin blocks the retrograde amnesia despite very extensive HPC damage. These results indicate that HPC damage disrupts cellular consolidation of the recent memory elsewhere; STFP memory may not ever depend on the HPC. Copyright © 2014 Elsevier Inc. All rights reserved.

Voltage-dependent inward currents in smooth muscle cells of skeletal muscle arterioles

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Shirokov, Roman E.

2018-01-01

Voltage-dependent inward currents responsible for the depolarizing phase of action potentials were characterized in smooth muscle cells of 4th order arterioles in mouse skeletal muscle. Currents through L-type Ca2+ channels were expected to be dominant; however, action potentials were not eliminated in nominally Ca2+-free bathing solution or by addition of L-type Ca2+ channel blocker nifedipine (10 μM). Instead, Na+ channel blocker tetrodotoxin (TTX, 1 μM) reduced the maximal velocity of the upstroke at low, but not at normal (2 mM), Ca2+ in the bath. The magnitude of TTX-sensitive currents recorded with 140 mM Na+ was about 20 pA/pF. TTX-sensitive currents decreased five-fold when Ca2+ increased from 2 to 10 mM. The currents reduced three-fold in the presence of 10 mM caffeine, but remained unaltered by 1 mM of isobutylmethylxanthine (IBMX). In addition to L-type Ca2+ currents (15 pA/pF in 20 mM Ca2+), we also found Ca2+ currents that are resistant to 10 μM nifedipine (5 pA/pF in 20 mM Ca2+). Based on their biophysical properties, these Ca2+ currents are likely to be through voltage-gated T-type Ca2+ channels. Our results suggest that Na+ and at least two types (T- and L-) of Ca2+ voltage-gated channels contribute to depolarization of smooth muscle cells in skeletal muscle arterioles. Voltage-gated Na+ channels appear to be under a tight control by Ca2+ signaling. PMID:29694371

Effects of excitatory and inhibitory neurotransmission on motor patterns of human sigmoid colon in vitro

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Aulí, M; Martínez, E; Gallego, D; Opazo, A; Espín, F; Martí-Gallostra, M; Jiménez, M; Clavé, P

2008-01-01

Background and purpose: To characterize the in vitro motor patterns and the neurotransmitters released by enteric motor neurons (EMNs) in the human sigmoid colon. Experimental approach: Sigmoid circular strips were studied in organ baths. EMNs were stimulated by electrical field stimulation (EFS) and through nicotinic ACh receptors. Key results: Strips developed weak spontaneous rhythmic contractions (3.67±0.49 g, 2.54±0.15 min) unaffected by the neurotoxin tetrodotoxin (TTX; 1 μM). EFS induced strong contractions during (on, 56%) or after electrical stimulus (off, 44%), both abolished by TTX. Nicotine (1–100 μM) inhibited spontaneous contractions. Latency of off-contractions and nicotine responses were reduced by NG-nitro-L-arginine (1 mM) and blocked after further addition of apamin (1 μM) or the P2Y1 receptor antagonist MRS 2179 (10 μM) and were unaffected by the P2X antagonist NF279 (10 μM) or α-chymotrypsin (10 U mL−1). Amplitude of on- and off-contractions was reduced by atropine (1 μM) and the selective NK2 receptor antagonist Bz-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (1 μM). MRS 2179 reduced the amplitude of EFS on- and off-contractions without altering direct muscular contractions induced by ACh (1 nM–1 mM) or substance P (1 nM–10 μM). Conclusions and implications: Latency of EFS-induced off-contractions and inhibition of spontaneous motility by nicotine are caused by stimulation of inhibitory EMNs coreleasing NO and a purine acting at muscular P2Y1 receptors through apamin-sensitive K+ channels. EFS-induced on- and off-contractions are caused by stimulation of excitatory EMNs coreleasing ACh and tachykinins acting on muscular muscarinic and NK2 receptors. Prejunctional P2Y1 receptors might modulate the activity of excitatory EMNs. P2Y1 and NK2 receptors might be therapeutic targets for colonic motor disorders. PMID:18846038

Mechanisms of CO2/H+ chemoreception by respiratory rhythm generator neurons in the medulla from newborn rats in vitro

Science.gov (United States)

Kawai, Akira; Onimaru, Hiroshi; Homma, Ikuo

2006-01-01

We investigated mechanisms of CO2/H+ chemoreception in the respiratory centre of the medulla by measuring membrane potentials of pre-inspiratory neurons, which are putative respiratory rhythm generators, in the brainstem–spinal cord preparation of the neonatal rat. Neuronal response was tested by changing superfusate CO2 concentration from 2% to 8% at constant HCO3− concentration (26 mm) or by changing pH from 7.8 to 7.2 by reducing HCO3− concentration at constant CO2 (5%). Both respiratory and metabolic acidosis lead to depolarization of neurons with increased excitatory synaptic input and increased burst rate. Respiratory acidosis potentiated the amplitude of the neuronal drive potential. In the presence of tetrodotoxin (TTX), membrane depolarization persisted during respiratory and metabolic acidosis. However, the depolarization was smaller than that before application of TTX, which suggests that some neurons are intrinsically, and others synaptically, chemosensitive to CO2/H+. Application of Ba2+ blocked membrane depolarization by respiratory acidosis, whereas significant depolarization in response to metabolic acidosis still remained after application of Cd2+ and Ba2+. We concluded that the intrinsic responses to CO2/H+changes were mediated by potassium channels during respiratory acidosis, and that some other mechanisms operate during metabolic acidosis. In low-Ca2+, high-Mg2+ solution, an increased CO2 concentration induced a membrane depolarization with a simultaneous increase of the burst rate. Pre-inspiratory neurons could adapt their baseline membrane potential to external CO2/H+ changes by integration of these mechanisms to modulate their burst rates. Thus, pre-inspiratory neurons might play an important role in modulation of respiratory rhythm by central chemoreception in the brainstem–spinal cord preparation. PMID:16469786

Inhibition of Na+ channel currents in rat myoblasts by 4-aminopyridine

International Nuclear Information System (INIS)

Lu Boxun; Liu Linyun; Liao Lei; Zhang Zhihong; Mei Yanai

2005-01-01

Our previous study revealed that 4-aminopyridine (4-AP), a specific blocker of A-type current, could also inhibit inward Na + currents (I Na ) with a state-independent mechanism in rat cerebellar granule cells. In the present study, we report an inhibitory effect of 4-AP on voltage-gated and tetrodotoxin (TTX)-sensitive I Na recorded from cultured rat myoblasts. 4-AP inhibited I Na amplitude in a dose-dependent manner between the concentrations of 0.5 and 10 mM without significant alteration in the activation or inactivation kinetics of the channel. By comparison to the 4-AP-induced inhibitory effect on cerebellum neurons, the inhibitory effect on myoblasts was enhanced through repetitive pulse and inflected by changing frequency. Specifically, the lower the frequency of pulse, the higher the inhibition observed, suggesting that block manner is inversely use-dependent. Moreover, experiments adding 4-AP to the intracellular solution indicate that the inhibitory effects are localized inside the cell. Additionally, 4-AP significantly modifies the properties of steady-state activation and inactivation kinetics of the channel. Our data suggest that the K + channel blocker 4-AP inhibits both neuron and myoblast Na + channels via different mechanisms. These findings may also provide information regarding 4-AP-induced pharmacological and toxicological effects in clinical use and experimental research

Salvia miltiorrhiza Induces Tonic Contraction of the Lower Esophageal Sphincter in Rats via Activation of Extracellular Ca2+ Influx

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Ching-Chung Tsai

2015-08-01

Full Text Available Up to 40% of patients with gastroesophageal reflux disease (GERD suffer from proton pump inhibitor refractory GERD but clinically the medications to strengthen the lower esophageal sphincter (LES to avoid irritating reflux are few in number. This study aimed to examine whether Salvia miltiorrhiza (SM extracts induce tonic contraction of rat LES ex vivo and elucidate the underlying mechanisms. To investigate the mechanism underlying the SM extract-induced contractile effects, rats were pretreated with atropine (a muscarinic receptor antagonist, tetrodotoxin (a sodium channel blocker, nifedipine (a calcium channel blocker, and Ca2+-free Krebs-Henseleit solution with ethylene glycol tetraacetic acid (EGTA, followed by administration of cumulative dosages of SM extracts. SM extracts induced dose-related tonic contraction of the LES, which was unaffected by tetrodotoxin, atropine, or nifedipine. However, the SM extract-induced LES contraction was significantly inhibited by Ca2+-free Krebs-Henseleit solution with EGTA. Next, SM extracts significantly induce extracellular Ca2+ entry into primary LES cells in addition to intracellular Ca2+ release and in a dose-response manner. Confocal fluorescence microscopy showed that the SM extracts consistently induced significant extracellular Ca2+ influx into primary LES cells in a time-dependent manner. In conclusion, SM extracts could induce tonic contraction of LES mainly through the extracellular Ca2+ influx pathway.

Cocaine- and amphetamine-regulated transcript (CART signaling within the paraventricular thalamus modulates cocaine-seeking behaviour.

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Morgan H James

Full Text Available BACKGROUND: Cocaine- and amphetamine-regulated transcript (CART has been demonstrated to play a role in regulating the rewarding and reinforcing effects of various drugs of abuse. A recent study demonstrated that i.c.v. administration of CART negatively modulates reinstatement of alcohol seeking, however, the site(s of action remains unclear. We investigated the paraventricular thalamus (PVT as a potential site of relapse-relevant CART signaling, as this region is known to receive dense innervation from CART-containing hypothalamic cells and to project to a number of regions known to be involved in mediating reinstatement, including the nucleus accumbens (NAC, medial prefrontal cortex (mPFC and basolateral amygdala (BLA. METHODOLOGY/PRINCIPAL FINDINGS: Male rats were trained to self-administer cocaine before being extinguished to a set criterion. One day following extinction, animals received intra-PVT infusions of saline, tetrodotoxin (TTX; 2.5 ng, CART (0.625 µg or 2.5 µg or no injection, followed by a cocaine prime (10 mg/kg, i.p.. Animals were then tested under extinction conditions for one hour. Treatment with either TTX or CART resulted in a significant attenuation of drug-seeking behaviour following cocaine-prime, with the 2.5 µg dose of CART having the greatest effect. This effect was specific to the PVT region, as misplaced injections of both TTX and CART resulted in responding that was identical to controls. CONCLUSIONS/SIGNIFICANCE: We show for the first time that CART signaling within the PVT acts to inhibit drug-primed reinstatement of cocaine seeking behaviour, presumably by negatively modulating PVT efferents that are important for drug seeking, including the NAC, mPFC and BLA. In this way, we identify a possible target for future pharmacological interventions designed to suppress drug seeking.

Guanidinium Toxins and Their Interactions with Voltage-Gated Sodium Ion Channels

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Lorena M. Durán-Riveroll

2017-10-01

Full Text Available Guanidinium toxins, such as saxitoxin (STX, tetrodotoxin (TTX and their analogs, are naturally occurring alkaloids with divergent evolutionary origins and biogeographical distribution, but which share the common chemical feature of guanidinium moieties. These guanidinium groups confer high biological activity with high affinity and ion flux blockage capacity for voltage-gated sodium channels (NaV. Members of the STX group, known collectively as paralytic shellfish toxins (PSTs, are produced among three genera of marine dinoflagellates and about a dozen genera of primarily freshwater or brackish water cyanobacteria. In contrast, toxins of the TTX group occur mainly in macrozoa, particularly among puffer fish, several species of marine invertebrates and a few terrestrial amphibians. In the case of TTX and analogs, most evidence suggests that symbiotic bacteria are the origin of the toxins, although endogenous biosynthesis independent from bacteria has not been excluded. The evolutionary origin of the biosynthetic genes for STX and analogs in dinoflagellates and cyanobacteria remains elusive. These highly potent molecules have been the subject of intensive research since the latter half of the past century; first to study the mode of action of their toxigenicity, and later as tools to characterize the role and structure of NaV channels, and finally as therapeutics. Their pharmacological activities have provided encouragement for their use as therapeutants for ion channel-related pathologies, such as pain control. The functional role in aquatic and terrestrial ecosystems for both groups of toxins is unproven, although plausible mechanisms of ion channel regulation and chemical defense are often invoked. Molecular approaches and the development of improved detection methods will yield deeper understanding of their physiological and ecological roles. This knowledge will facilitate their further biotechnological exploitation and point the way towards

Characterization and evolutionary analysis of tributyltin-binding protein and pufferfish saxitoxin and tetrodotoxin-binding protein genes in toxic and nontoxic pufferfishes.

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Hashiguchi, Y; Lee, J M; Shiraishi, M; Komatsu, S; Miki, S; Shimasaki, Y; Mochioka, N; Kusakabe, T; Oshima, Y

2015-05-01

Understanding the evolutionary mechanisms of toxin accumulation in pufferfishes has been long-standing problem in toxicology and evolutionary biology. Pufferfish saxitoxin and tetrodotoxin-binding protein (PSTBP) is involved in the transport and accumulation of tetrodotoxin and is one of the most intriguing proteins related to the toxicity of pufferfishes. PSTBPs are fusion proteins consisting of two tandem repeated tributyltin-binding protein type 2 (TBT-bp2) domains. In this study, we examined the evolutionary dynamics of TBT-bp2 and PSTBP genes to understand the evolution of toxin accumulation in pufferfishes. Database searches and/or PCR-based cDNA cloning in nine pufferfish species (6 toxic and 3 nontoxic) revealed that all species possessed one or more TBT-bp2 genes, but PSTBP genes were found only in 5 toxic species belonging to genus Takifugu. These toxic Takifugu species possessed two or three copies of PSTBP genes. Phylogenetic analysis of TBT-bp2 and PSTBP genes suggested that PSTBPs evolved in the common ancestor of Takifugu species by repeated duplications and fusions of TBT-bp2 genes. In addition, a detailed comparison of Takifugu TBT-bp2 and PSTBP gene sequences detected a signature of positive selection under the pressure of gene conversion. The complicated evolutionary dynamics of TBT-bp2 and PSTBP genes may reflect the diversity of toxicity in pufferfishes. © 2015 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2015 European Society For Evolutionary Biology.

Differences in the Electrophysiological Properties of Mouse Somatosensory Layer 2/3 Neurons In Vivo and Slice Stem from Intrinsic Sources Rather than a Network-Generated High Conductance State

Science.gov (United States)

2018-01-01

Abstract Synaptic activity in vivo can potentially alter the integration properties of neurons. Using recordings in awake mice, we targeted somatosensory layer 2/3 pyramidal neurons and compared neuronal properties with those from slices. Pyramidal cells in vivo had lower resistance and gain values, as well as broader spikes and increased spike frequency adaptation compared to the same cells in slices. Increasing conductance in neurons using dynamic clamp to levels observed in vivo, however, did not lessen the differences between in vivo and slice conditions. Further, local application of tetrodotoxin (TTX) in vivo blocked synaptic-mediated membrane voltage fluctuations but had little impact on pyramidal cell membrane input resistance and time constant values. Differences in electrophysiological properties of layer 2/3 neurons in mouse somatosensory cortex, therefore, stem from intrinsic sources separate from synaptic-mediated membrane voltage fluctuations. PMID:29662946

Measuring Relative Coupling Strength in Circadian Systems.

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Schmal, Christoph; Herzog, Erik D; Herzel, Hanspeter

2018-02-01

Modern imaging techniques allow the monitoring of circadian rhythms of single cells. Coupling between these single cellular circadian oscillators can generate coherent periodic signals on the tissue level that subsequently orchestrate physiological outputs. The strength of coupling in such systems of oscillators is often unclear. In particular, effects on coupling strength by varying cell densities, by knockouts, and by inhibitor applications are debated. In this study, we suggest to quantify the relative coupling strength via analyzing period, phase, and amplitude distributions in ensembles of individual circadian oscillators. Simulations of different oscillator networks show that period and phase distributions become narrower with increasing coupling strength. Moreover, amplitudes can increase due to resonance effects. Variances of periods and phases decay monotonically with coupling strength, and can serve therefore as measures of relative coupling strength. Our theoretical predictions are confirmed by studying recently published experimental data from PERIOD2 expression in slices of the suprachiasmatic nucleus during and after the application of tetrodotoxin (TTX). On analyzing the corresponding period, phase, and amplitude distributions, we can show that treatment with TTX can be associated with a reduced coupling strength in the system of coupled oscillators. Analysis of an oscillator network derived directly from the data confirms our conclusions. We suggest that our approach is also applicable to quantify coupling in fibroblast cultures and hepatocyte networks, and for social synchronization of circadian rhythmicity in rodents, flies, and bees.

Role of taurine on acid secretion in the rat stomach

Science.gov (United States)

2011-01-01

Background Taurine has chemical structure similar to an inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Previous studies on GABA in the stomach suggest GABAergic neuron is involved in acid secretion, but the effects of taurine are poor understood. Methods The effects of taurine on acid secretion, signal transduction, and localization of taurinergic neurons were determined in the rat stomach using everted whole stomach, RIA kit and immunohistochemical methods. Results We used antibodies against taurine-synthesizing enzyme, cysteine sulfuric acid decarboxylase (CSAD), and taurine. CSAD- and taurine-positive cells were found in the muscle and mucosal layers. Distributions of CSAD- and taurine-positive cells in both mucosal and muscle layers were heterogeneous in the stomach. Taurine at 10-9~10-4 M induced acid secretion, and the maximum secretion was at 10-5 M, 1.6-fold higher than the spontaneous secretion. Taurine-induced acid secretion was completely inhibited by bicuculline and atropine but not by cimetidine, proglumide, or strychnine. Atropine and tetrodotoxin (TTX) completely inhibited the acid secretion induced by low concentrations of taurine and partially inhibited induced by high concentrations. Verapamil, a calcium blocker agent, inhibited acid output elicited by taurine. We assumed all Ca2+ channels involved in the response to these secretagogues were equally affected by verapamil. Intracellular cAMP (adenosine 3', 5'-monophosphat) in the stomach significantly increased with taurine treatment in a dose-dependent manner. High correlation (r=0.859, p taurine concentrations with cAMP was observed. Conclusions Our results demonstrated for the first time in taurine-induced acid secretion due to increase intracellular calcium may act through the A type of GABA receptors, which are mainly located on cholinergic neurons though cAMP pathway and partially on nonneuronal cells in the rat stomach. PMID:21294907

Role of taurine on acid secretion in the rat stomach

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Ho Jau-Der

2011-02-01

Full Text Available Abstract Background Taurine has chemical structure similar to an inhibitory neurotransmitter, γ-aminobutyric acid (GABA. Previous studies on GABA in the stomach suggest GABAergic neuron is involved in acid secretion, but the effects of taurine are poor understood. Methods The effects of taurine on acid secretion, signal transduction, and localization of taurinergic neurons were determined in the rat stomach using everted whole stomach, RIA kit and immunohistochemical methods. Results We used antibodies against taurine-synthesizing enzyme, cysteine sulfuric acid decarboxylase (CSAD, and taurine. CSAD- and taurine-positive cells were found in the muscle and mucosal layers. Distributions of CSAD- and taurine-positive cells in both mucosal and muscle layers were heterogeneous in the stomach. Taurine at 10-9~10-4 M induced acid secretion, and the maximum secretion was at 10-5 M, 1.6-fold higher than the spontaneous secretion. Taurine-induced acid secretion was completely inhibited by bicuculline and atropine but not by cimetidine, proglumide, or strychnine. Atropine and tetrodotoxin (TTX completely inhibited the acid secretion induced by low concentrations of taurine and partially inhibited induced by high concentrations. Verapamil, a calcium blocker agent, inhibited acid output elicited by taurine. We assumed all Ca2+ channels involved in the response to these secretagogues were equally affected by verapamil. Intracellular cAMP (adenosine 3', 5'-monophosphat in the stomach significantly increased with taurine treatment in a dose-dependent manner. High correlation (r=0.859, p Conclusions Our results demonstrated for the first time in taurine-induced acid secretion due to increase intracellular calcium may act through the A type of GABA receptors, which are mainly located on cholinergic neurons though cAMP pathway and partially on nonneuronal cells in the rat stomach.

Clinical and epidemiological study of 27 poisonings caused by ingesting puffer fish (Tetrodontidae in the states of Santa Catarina and Bahia, Brazil Estudo clinico-epidemiológico de 27 envenenamentos causados pela ingestão de baiacus (Tetrodontidae nos estados de Santa Catarina e Bahia, Brasil

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Claudia Carvalho Pestana Silva

2010-02-01

Full Text Available Puffer fish can be poisonous due to the presence of the potent neurotoxins such as Tetrodotoxin (TTX and Saxitoxin (STX found in its tissues. The authors report 27 human poisonings from ingestion of puffer fish in patients treated at Toxicology Centers in the states of Santa Catarina and Bahia, Brazil, between 1984 and January 2009. Poisonings were classified as moderate (52% and severe (33%, two deaths were observed. Early diagnosis is very important to ensure respiratory support.Os baiacus ou peixes-bola podem ser venenosos devido à presença em seus tecidos corporais de Tetrodotoxina e/ou Saxitoxina, ambas potentes neurotoxinas. Os autores relatam 27 envenenamentos por ingestão da carne de baiacus. Os pacientes foram atendidos nos Centros de Toxicologia de Santa Catarina e da Bahia de 1984 a 2009. Os acidentes foram classificados em moderados (52% e graves (33%, havendo dois óbitos. O diagnóstico precoce é fundamental no sentido de garantir suporte ventilatório aos pacientes.

Ca++ dependent bistability induced by serotonin in spinal motoneurons

DEFF Research Database (Denmark)

Hounsgaard, J.; Kiehn, O.

1985-01-01

The plateau potential, responsible for the bistable state of spinal motoneurons, recently described in the decerebrate cat, was suggested to depend on serotonin (Hounsgaard et al. 1984). In an in vitro preparation of the spinal cord of the turtle we now show that serotonin, applied directly...... to the bath, transforms the intrinsic response properties of motoneurons, uncovering a plateau potential and voltage sensitive bistability. The changes induced by serotonin were blocked by Mn++, while the plateau potential and the bistability remained after application of tetrodotoxin. We conclude...... that serotonin controls the expression of a Ca++ dependent plateau potential in motoneurons....

Aspects of dopamine and acetylcholine release induced by glutamate receptors

International Nuclear Information System (INIS)

Paes, Paulo Cesar de Arruda

2002-01-01

The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)

Distinct presynaptic regulation of dopamine release through NMDA receptors in striosome- and matrix-enriched areas of the rat striatum

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Krebs, M.O.; Trovero, F.; Desban, M.; Gauchy, C.; Glowinski, J.; Kemel, M.L. (College de France, Paris (France))

1991-05-01

Striosome- and matrix-enriched striatal zones were defined in coronal and sagittal brain sections of the rat, on the basis of {sup 3}H-naloxone binding to mu-opiate receptors (a striosome-specific marker). Then, using a new in vitro microsuperfusion device, the NMDA (50 microM)-evoked release of newly synthesized {sup 3}H-dopamine ({sup 3}H-DA) was examined in these four striatal areas under Mg(2+)-free conditions. The amplitudes of the responses were different in striosomal (171 +/- 6% and 161 +/- 5% of the spontaneous release) than in matrix areas (223 +/- 6% and 248 +/- 12%), even when glycine (1 or 100 microM) was coapplied (in the presence of 1 microM strychnine). In the four areas, the NMDA-evoked release of {sup 3}H-DA was blocked completely by Mg{sup 2}{sup +} (1 mM) or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801; 1 microM) and almost totally abolished by kynurenate (100 microM). Because the tetrodotoxin (TTX)-resistant NMDA-evoked release of {sup 3}H-DA was similar in striosome- (148 +/- 5% and 152 +/- 6%) or matrix-enriched (161 +/- 5% and 156 +/- 7%) areas, the indirect (TTX-sensitive) component of NMDA-evoked responses, which involves striatal neurons and/or afferent fibers, seems more important in the matrix- than in the striosome-enriched areas. The modulation of DA release by cortical glutamate and/or aspartate-containing inputs through NMDA receptors in the matrix appears thus to be partly distinct from that observed in the striosomes, providing some functional basis for the histochemical striatal heterogeneity.

Histamine facilitates GABAergic transmission in the rat entorhinal cortex: Roles of H1 and H2 receptors, Na+ -permeable cation channels, and inward rectifier K+ channels.

Science.gov (United States)

Cilz, Nicholas I; Lei, Saobo

2017-05-01

In the brain, histamine (HA) serves as a neuromodulator and a neurotransmitter released from the tuberomammillary nucleus (TMN). HA is involved in wakefulness, thermoregulation, energy homeostasis, nociception, and learning and memory. The medial entorhinal cortex (MEC) receives inputs from the TMN and expresses HA receptors (H 1 , H 2 , and H 3 ). We investigated the effects of HA on GABAergic transmission in the MEC and found that HA significantly increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) with an EC 50 of 1.3 µM, but failed to significantly alter sIPSC amplitude. HA-induced increases in sIPSC frequency were sensitive to tetrodotoxin (TTX), required extracellular Ca 2+ , and persisted when GDP-β-S, a G-protein inactivator, was applied postsynaptically via the recording pipettes, indicating that HA increased GABA release by facilitating the excitability of GABAergic interneurons in the MEC. Recordings from local MEC interneurons revealed that HA significantly increased their excitability as determined by membrane depolarization, generation of an inward current at -65 mV, and augmentation of action potential firing frequency. Both H 1 and H 2 receptors were involved in HA-induced increases in sIPSCs and interneuron excitability. Immunohistochemical staining showed that both H 1 and H 2 receptors are expressed on GABAergic interneurons in the MEC. HA-induced depolarization of interneurons involved a mixed ionic mechanism including activation of a Na + -permeable cation channel and inhibition of a cesium-sensitive inward rectifier K + channel, although HA also inhibited the delayed rectifier K + channels. Our results may provide a cellular mechanism, at least partially, to explain the roles of HA in the brain. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

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

Science.gov (United States)

Pearlstein, E; Clarac, F; Cattaert, D

1998-01-23

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

Presynaptic nicotinic α7 and non-α7 receptors stimulate endogenous GABA release from rat hippocampal synaptosomes through two mechanisms of action.

Directory of Open Access Journals (Sweden)

Stefania Zappettini

Full Text Available BACKGROUND: Although converging evidence has suggested that nicotinic acetylcholine receptors (nAChR play a role in the modulation of GABA release in rat hippocampus, the specific involvement of different nAChR subtypes at presynaptic level is still a matter of debate. In the present work we investigated, using selective α7 and α4β2 nAChR agonists, the presence of different nAChR subtypes on hippocampal GABA nerve endings to assess to what extent and through which mechanisms they stimulate endogenous GABA release. METHODOLOGY/FINDINGS: All agonists elicited GABA overflow. Choline (Ch-evoked GABA overflow was dependent to external Ca(2+, but unaltered in the presence of Cd(2+, tetrodotoxin (TTX, dihydro-β-erythroidine (DHβE and 1-(4,4-Diphenyl-3-butenyl-3-piperidinecarboxylic acid hydrochloride SKF 89976A. The effect of Ch was blocked by methyllycaconitine (MLA, α-bungarotoxin (α-BTX, dantrolene, thapsigargin and xestospongin C, suggesting that GABA release might be triggered by Ca(2+ entry into synaptosomes through the α7 nAChR channel with the involvement of calcium from intracellular stores. Additionally, 5-Iodo-A-85380 dihydrochloride (5IA85380 elicited GABA overflow, which was Ca(2+ dependent, blocked by Cd(2+, and significantly inhibited by TTX and DHβE, but unaffected by MLA, SKF 89976A, thapsigargin and xestospongin C and dantrolene. These findings confirm the involvement of α4β2 nAChR in 5IA85380-induced GABA release that seems to occur following membrane depolarization and opening calcium channels. CONCLUSIONS/SIGNIFICANCE: Rat hippocampal synaptosomes possess both α7 and α4β2 nAChR subtypes, which can modulate GABA release via two distinct mechanisms of action. The finding that GABA release evoked by the mixture of sub-maximal concentration of 5IA85380 plus sub-threshold concentrations of Ch was significantly larger than that elicited by the sum of the effects of the two agonists is compatible with the possibility that

Human-induced pluripotent stem cell-derived cardiomyocytes from cardiac progenitor cells: effects of selective ion channel blockade.

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Altomare, Claudia; Pianezzi, Enea; Cervio, Elisabetta; Bolis, Sara; Biemmi, Vanessa; Benzoni, Patrizia; Camici, Giovanni G; Moccetti, Tiziano; Barile, Lucio; Vassalli, Giuseppe

2016-12-01

Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes are likely to revolutionize electrophysiological approaches to arrhythmias. Recent evidence suggests the somatic cell origin of hiPSCs may influence their differentiation potential. Owing to their cardiomyogenic potential, cardiac-stromal progenitor cells (CPCs) are an interesting cellular source for generation of hiPSC-derived cardiomyocytes. The effect of ionic current blockade in hiPSC-derived cardiomyocytes generated from CPCs has not been characterized yet. Human-induced pluripotent stem cell-derived cardiomyocytes were generated from adult CPCs and skin fibroblasts from the same individuals. The effect of selective ionic current blockade on spontaneously beating hiPSC-derived cardiomyocytes was assessed using multi-electrode arrays. Cardiac-stromal progenitor cells could be reprogrammed into hiPSCs, then differentiated into hiPSC-derived cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes of cardiac origin showed higher upregulation of cardiac-specific genes compared with those of fibroblastic origin. Human-induced pluripotent stem cell-derived cardiomyocytes of both somatic cell origins exhibited sensitivity to tetrodotoxin, a blocker of Na +  current (I Na ), nifedipine, a blocker of L-type Ca 2+  current (I CaL ), and E4031, a blocker of the rapid component of delayed rectifier K +  current (I Kr ). Human-induced pluripotent stem cell-derived cardiomyocytes of cardiac origin exhibited sensitivity to JNJ303, a blocker of the slow component of delayed rectifier K +  current (I Ks ). In hiPSC-derived cardiomyocytes of cardiac origin, I Na , I CaL , I Kr , and I Ks were present as tetrodotoxin-, nifedipine-, E4031-, and JNJ303-sensitive currents, respectively. Although cardiac differentiation efficiency was improved in hiPSCs of cardiac vs. non-cardiac origin, no major functional differences were observed between hiPSC-derived cardiomyocytes of different somatic

Evaluation of the effects and mechanisms of action of glufosinate, an organophosphate insecticide, on striatal dopamine release by using in vivo microdialysis in freely moving rats.

Science.gov (United States)

Ferreira Nunes, Brenda V; Durán, Rafael; Alfonso, Miguel; de Oliveira, Iris Machado; Ferreira Faro, Lilian R

2010-10-01

The purpose of the present work was to assess the effects of glufosinate ammonium (GLA), an aminoacid structurally related to glutamate, on in vivo dopamine (DA) release from rat striatum, using brain microdialysis coupled to HPLC-EC. Intrastriatal administration of GLA produced significant concentration-dependent increases in DA levels. At least two mechanisms can be proposed to explain these increases: GLA could be inducing DA release from synaptic vesicles or producing an inhibition of DA transporter (DAT). Thus, we investigated the effects of GLA under Ca(++)-free condition, and after pretreatment with reserpine and TTX. It was observed that the pretreatment with Ca(++)-free Ringer, reserpine or TTX significantly reduced the DA release induced by GLA. Coinfusion of GLA and nomifensine shows that the GLA-induced DA release did not involve the DAT. These results show that GLA-induced striatal DA release is probably mediated by an exocytotic-, Ca(++)-, action potential-dependent mechanism, being independent of DAT.

New insights into neurogenic cyclic motor activity in the isolated guinea-pig colon.

Science.gov (United States)

Costa, M; Wiklendt, L; Keightley, L; Brookes, S J H; Dinning, P G; Spencer, N J

2017-10-01

The contents of the guinea pig distal colon consist of multiple pellets that move anally in a coordinated manner. This row of pellets results in continued distention of the colon. In this study, we have investigated quantitatively the features of the neurally dependent colonic motor patterns that are evoked by constant distension of the full length of guinea-pig colon. Constant distension was applied to the excised guinea-pig by high-resolution manometry catheters or by a series of hooks. Constant distension elicited regular Cyclic Motor Complexes (CMCs) that originated at multiple different sites along the colon and propagated in an oral or anal direction extending distances of 18.3±10.3 cm. CMCs were blocked by tetrodotoxin (TTX; 0.6 μ mol L -1 ), hexamethonium (100 μ mol L -1 ) or hyoscine (1 μ mol L -1 ). Application of TTX in a localized compartment or cutting the gut circumferentially disrupted the spatial continuity of CMCs. Localized smooth muscle contraction was not required for CMC propagation. Shortening the length of the preparations or disruption of circumferential pathways reduced the integrity and continuity of CMCs. CMCs are a distinctive neurally dependent cyclic motor pattern, that emerge with distension over long lengths of the distal colon. They do not require changes in muscle tension or contractility to entrain the neural activity underlying CMC propagation. CMCs are likely to play an important role interacting with the neuromechanical processes that time the propulsion of multiple natural pellets and may be particularly relevant in conditions of impaction or obstruction, where long segments of colon are simultaneously distended. © 2017 John Wiley & Sons Ltd.

Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

NARCIS (Netherlands)

Saigusa, T.; Aono, Y.; Sekino, R.; Uchida, T.; Takada, K.; Oi, Y.; Koshikawa, N.; Cools, A.R.

2009-01-01

Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular

Chronic ciguatoxin treatment induces synaptic scaling through voltage gated sodium channels in cortical neurons.

Science.gov (United States)

Martín, Víctor; Vale, Carmen; Rubiolo, Juan A; Roel, Maria; Hirama, Masahiro; Yamashita, Shuji; Vieytes, Mercedes R; Botana, Luís M

2015-06-15

Ciguatoxins are sodium channels activators that cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents with long-term neurological alterations. In central neurons, chronic perturbations in activity induce homeostatic synaptic mechanisms that adjust the strength of excitatory synapses and modulate glutamate receptor expression in order to stabilize the overall activity. Immediate early genes, such as Arc and Egr1, are induced in response to activity changes and underlie the trafficking of glutamate receptors during neuronal homeostasis. To better understand the long lasting neurological consequences of ciguatera, it is important to establish the role that chronic changes in activity produced by ciguatoxins represent to central neurons. Here, the effect of a 30 min exposure of 10-13 days in vitro (DIV) cortical neurons to the synthetic ciguatoxin CTX 3C on Arc and Egr1 expression was evaluated using real-time polymerase chain reaction approaches. Since the toxin increased the mRNA levels of both Arc and Egr1, the effect of CTX 3C in NaV channels, membrane potential, firing activity, miniature excitatory postsynaptic currents (mEPSCs), and glutamate receptors expression in cortical neurons after a 24 h exposure was evaluated using electrophysiological and western blot approaches. The data presented here show that CTX 3C induced an upregulation of Arc and Egr1 that was prevented by previous coincubation of the neurons with the NaV channel blocker tetrodotoxin. In addition, chronic CTX 3C caused a concentration-dependent shift in the activation voltage of NaV channels to more negative potentials and produced membrane potential depolarization. Moreover, 24 h treatment of cortical neurons with 5 nM CTX 3C decreased neuronal firing and induced synaptic scaling mechanisms, as evidenced by a decrease in the amplitude of mEPSCs and downregulation in the protein level of glutamate receptors that was also prevented by tetrodotoxin

Kainate-induced network activity in the anterior cingulate cortex.

Science.gov (United States)

Shinozaki, R; Hojo, Y; Mukai, H; Hashizume, M; Murakoshi, T

2016-06-14

Anterior cingulate cortex (ACC) plays a pivotal role in higher order processing of cognition, attention and emotion. The network oscillation is considered an essential means for integration of these CNS functions. The oscillation power and coherence among related areas are often dis-regulated in several psychiatric and pathological conditions with a hemispheric asymmetric manner. Here we describe the network-based activity of field potentials recorded from the superficial layer of the mouse ACC in vitro using submerged type recordings. A short activation by kainic acid administration to the preparation induced populational activities ranging over several frequency bands including theta (3-8Hz), alpha (8-12Hz), beta (13-30Hz), low gamma (30-50Hz) and high gamma (50-80Hz). These responses were repeatable and totally abolished by tetrodotoxin, and greatly diminished by inhibitors of ionotropic and metabotropic glutamate receptors, GABAA receptor or gap-junctions. These observations suggest that the kainate-induced network activity can be a useful model of the network oscillation in the ACC circuit. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Immediate x-radiation induced contractions of the isolated guinea pig terminal ileum: the localization of the effect by drugs

Energy Technology Data Exchange (ETDEWEB)

Spruegel, W; Schubert, E; Mitznegg, P; Heim, F [Erlangen-Nuernberg Univ., Erlangen (Germany, F.R.). Pharmakologisches Inst.; Hasl, G; Pauly, H [Erlangen-Nuernberg Univ., Erlangen (Germany, F.R.). Inst. fuer Radiologie

1977-04-01

Tone and motility of the isolated guinea pig ileum were increased by irradiation with a dose of 10 krad. The maximal effect corresponds to that induced by 0.001 ..mu..g/ml acetylcholine or 0.3 ..mu..g/ml nicotine. The pharmacological analysis of this effect performed with acetylcholine and nicotine and several blocking agents including hexamethonium, atropine, tetrodotoxin, diphenhydramine, and verapamil suggests that radiation acts on the postganglionic parasympathetic neuron and the neuromuscular synapse. The mechanism of radiation is likely to consist of both an increased release of acetylcholine from the postganglionic neuron and a sensibilization of the cholinergic receptor site at the smooth muscle cell. The latter effect is thought to result from an increased contractile action induced by acetylcholine or nicotine in the irradiated ileal smooth muscle.

Direct versus indirect actions of ghrelin on hypothalamic NPY neurons.

Science.gov (United States)

Hashiguchi, Hiroshi; Sheng, Zhenyu; Routh, Vanessa; Gerzanich, Volodymyr; Simard, J Marc; Bryan, Joseph

2017-01-01

Assess direct versus indirect action(s) of ghrelin on hypothalamic NPY neurons. Electrophysiology was used to measure ion channel activity in NPY-GFP neurons in slice preparations. Ca2+ imaging was used to monitor ghrelin activation of isolated NPY GFP-labeled neurons. Immunohistochemistry was used to localize Trpm4, SUR1 and Kir6.2 in the hypothalamus. Acylated ghrelin depolarized the membrane potential (MP) of NPY-GFP neurons in brain slices. Depolarization resulted from a decreased input resistance (IR) in ~70% of neurons (15/22) or an increased IR in the remainder (7/22), consistent with the opening or closing of ion channels, respectively. Although tetrodotoxin (TTX) blockade of presynaptic action potentials reduced ghrelin-induced changes in MP and IR, ghrelin still significantly depolarized the MP and decreased IR in TTX-treated neurons, suggesting that ghrelin directly opens cation channel(s) in NPY neurons. In isolated NPY-GFP neurons, ghrelin produced a sustained rise of [Ca2+]c, with an EC50 ~110 pM. Pharmacologic studies confirmed that the direct action of ghrelin was through occupation of the growth hormone secretagogue receptor, GHS-R, and demonstrated the importance of the adenylate cyclase/cAMP/protein kinase A (PKA) and phospholipase C/inositol triphosphate (PLC/IP3) pathways as activators of 5' AMP-activated protein kinase (AMPK). Activation of isolated neurons was not affected by CNQX or TTX, but reducing [Na+]o suppressed activation, suggesting a role for Na+-permeable cation channels. SUR1 and two channel partners, Kir6.2 and Trpm4, were identified immunologically in NPY-GFP neurons in situ. The actions of SUR1 and Trpm4 modulators were informative: like ghrelin, diazoxide, a SUR1 agonist, elevated [Ca2+]c and glibenclamide, a SUR1 antagonist, partially suppressed ghrelin action, while 9-phenanthrol and flufenamic acid, selective Trpm4 antagonists, blocked ghrelin actions on isolated neurons. Ghrelin activation was unaffected by nifedipine and

Aspects of dopamine and acetylcholine release induced by glutamate receptors; Aspectos das liberacoes de dopamina e acetilcolina mediadas por receptores de glutamato

Energy Technology Data Exchange (ETDEWEB)

Paes, Paulo Cesar de Arruda

2002-07-01

The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)

Developmental regulation of voltage-sensitive sodium channels in rat skeletal muscle

International Nuclear Information System (INIS)

Sherman, S.J.

1985-01-01

The developmental regulation of the voltage-sensitive Na + channel in rat skeletal muscle was studied in vivo and in vitro. In triceps surae muscle developing in vivo the development of TTX-sensitive Na + channel occurred primarily during the first three postnatal weeks as determined by the specific binding of [ 3 H]saxitoxin. This development proceeded in two separate phases. The first phase occurs independently of continuing motor neuron innervation and accounts for 60% of the adult density of TTX-sensitive Na + channels. The second phase, which begins about day 11, requires innervation. Muscle cells in primary culture were found to have both TTX-sensitive and insensitive Na + channels. The development of the TTX-sensitive channel, in vitro, paralleled the initial innervation-independent phase of development observed in vivo. The density of TTX-sensitive Na + channels in cultured muscle cells was regulated by electrical activity and cytosolic Ca ++ levels. Pharmacological blockade of the spontaneous electrical activity present in these cells lead to a nearly 2-fold increase in the surface density of TTX-sensitive channels. The turnover time of the TTX-sensitive Na + channel was measured by blocking the incorporation of newly synthesized channels with tunicamycin, an inhibitor of N-linked protein glycosylation. The regulation of channel density by electrical activity, cytosolic Ca ++ levels, and agents affecting cyclic neucleotide levels had no effect on the turnover time of the TTX-sensitive Na + channel, indicating that these regulatory agents instead affect the synthesis of the channel

Analgesic treatment of ciguatoxin-induced cold allodynia.

Science.gov (United States)

Zimmermann, Katharina; Deuis, Jennifer R; Inserra, Marco C; Collins, Lindon S; Namer, Barbara; Cabot, Peter J; Reeh, Peter W; Lewis, Richard J; Vetter, Irina

2013-10-01

Ciguatera, the most common form of nonbacterial ichthyosarcotoxism, is caused by consumption of fish that have bioaccumulated the polyether sodium channel activator ciguatoxin. The neurological symptoms of ciguatera include distressing, often persistent sensory disturbances such as paraesthesias and the pathognomonic symptom of cold allodynia. We show that intracutaneous administration of ciguatoxin in humans elicits a pronounced axon-reflex flare and replicates cold allodynia. To identify compounds able to inhibit ciguatoxin-induced Nav responses, we developed a novel in vitro ciguatoxin assay using the human neuroblastoma cell line SH-SY5Y. Pharmacological characterisation of this assay demonstrated a major contribution of Nav1.2 and Nav1.3, but not Nav1.7, to ciguatoxin-induced Ca2+ responses. Clinically available Nav inhibitors, as well as the Kv7 agonist flupirtine, inhibited tetrodotoxin-sensitive ciguatoxin-evoked responses. To establish their in vivo efficacy, we used a novel animal model of ciguatoxin-induced cold allodynia. However, differences in the efficacy of these compounds to reverse ciguatoxin-induced cold allodynia did not correlate with their potency to inhibit ciguatoxin-induced responses in SH-SY5Y cells or at heterologously expressed Nav1.3, Nav1.6, Nav1.7, or Nav1.8, indicating cold allodynia might be more complex than simple activation of Nav channels. These findings highlight the need for suitable animal models to guide the empiric choice of analgesics, and suggest that lamotrigine and flupirtine could be potentially useful for the treatment of ciguatera. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Upregulation of the sodium channel NaVβ4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local DRG inflammation

Science.gov (United States)

Xie, Wenrui; Tan, Zhi-Yong; Barbosa, Cindy; Strong, Judith A.; Cummins, Theodore R.; Zhang, Jun-Ming

2016-01-01

High frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform NaV1.6 contributes to pain behaviors and spontaneous activity in this model. Among all the isoforms in adult DRG, NaV1.6 is the main carrier of TTX-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons the regulatory β4 subunit is potentially the endogenous blocker. We used in vivo siRNA mediated knockdown of NaVβ4 to examine its role in the DRG inflammation model. NaVβ4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRGs showed that NaVβ4 siRNA blocked the inflammation-induced increase in spontaneous activity of Aβ neurons, and reduced repetitive firing and other measures of excitability. NaVβ4 was preferentially expressed in larger diameter cells; DRG inflammation increased its expression and this was reversed by NaVβ4 siRNA, based on immunohistochemistry and Western blotting. NaVβ4 siRNA also reduced immunohistochemical NaV1.6 expression. Patch clamp recordings of TTX-sensitive Na currents in acutely cultured medium diameter DRG neurons showed that DRG inflammation increased transient and especially resurgent current; effects blocked by NaVβ4 siRNA. NaVβ4 may represent a more specific target for pain conditions that depend on myelinated neurons expressing NaV1.6. PMID:26785322

A novel toxin from Haplopelma lividum selectively inhibits the NA_V1.8 channel and possesses potent analgesic efficacy

DEFF Research Database (Denmark)

Meng, Ping; Huang, Honggang; Wang, Gan

2017-01-01

Spider venoms are a complex mixture of peptides with a large number of neurotoxins targeting ion channels. Although thousands of peptide toxins have been identified from venoms of numerous species of spiders, many unknown species urgently need to be investigated. In this study, a novel sodium...... channel inhibitor, μ-TRTX-Hl1a, was identified from the venom of Haplopelma lividum. It contained eight cysteines and formed a conserved cysteine pattern of ICK motif. μ-TRTX-Hl1a inhibited the TTX-resistant (TTX-r) sodium channel current rather than the TTX-sensitive (TTX-s) sodium channel current...

Enhancement of synaptic transmission induced by BDNF in cultured cortical neurons

Science.gov (United States)

He, Jun; Gong, Hui; Zeng, Shaoqun; Li, Yanling; Luo, Qingming

2005-03-01

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, BDNF has been reported to exert an acute potentiation of synaptic activity and are critically involved in long-term potentiation (LTP). We found that BDNF rapidly induced potentiation of synaptic activity and an increase in the intracellular Ca2+ concentration in cultured cortical neurons. Within minutes of BDNF application to cultured cortical neurons, spontaneous firing rate was dramatically increased as were the frequency and amplitude of excitatory spontaneous postsynaptic currents (EPSCs). Fura-2 recordings showed that BDNF acutely elicited an increase in intracellular calcium concentration ([Ca2+]c). This effect was partially dependent on [Ca2+]o; The BDNF-induced increase in [Ca2+]c can not be completely blocked by Ca2+-free solution. It was completely blocked by K252a and partially blocked by Cd2+ and TTX. The results demonstrate that BDNF can enhances synaptic transmission and that this effect is accompanied by a rise in [Ca2+]c that requires two route: the release of Ca2+ from intracellular calcium stores and influx of extracellular Ca2+ through voltage-dependent Ca2+ channels in cultured cortical neurons.

Brevenal inhibits pacific ciguatoxin-1B-induced neurosecretion from bovine chromaffin cells.

Directory of Open Access Journals (Sweden)

César Mattei

Full Text Available Ciguatoxins and brevetoxins are neurotoxic cyclic polyether compounds produced by dinoflagellates, which are responsible for ciguatera and neurotoxic shellfish poisoning (NSP respectively. Recently, brevenal, a natural compound was found to specifically inhibit brevetoxin action and to have a beneficial effect in NSP. Considering that brevetoxin and ciguatoxin specifically activate voltage-sensitive Na+ channels through the same binding site, brevenal has therefore a good potential for the treatment of ciguatera. Pacific ciguatoxin-1B (P-CTX-1B activates voltage-sensitive Na+ channels and promotes an increase in neurotransmitter release believed to underpin the symptoms associated with ciguatera. However, the mechanism through which slow Na+ influx promotes neurosecretion is not fully understood. In the present study, we used chromaffin cells as a model to reconstitute the sequence of events culminating in ciguatoxin-evoked neurosecretion. We show that P-CTX-1B induces a tetrodotoxin-sensitive rise in intracellular Na+, closely followed by an increase in cytosolic Ca2+ responsible for promoting SNARE-dependent catecholamine secretion. Our results reveal that brevenal and beta-naphtoyl-brevetoxin prevent P-CTX-1B secretagogue activity without affecting nicotine or barium-induced catecholamine secretion. Brevenal is therefore a potent inhibitor of ciguatoxin-induced neurotoxic effect and a potential treatment for ciguatera.

Brevenal inhibits pacific ciguatoxin-1B-induced neurosecretion from bovine chromaffin cells.

Science.gov (United States)

Mattei, César; Wen, Peter J; Nguyen-Huu, Truong D; Alvarez, Martha; Benoit, Evelyne; Bourdelais, Andrea J; Lewis, Richard J; Baden, Daniel G; Molgó, Jordi; Meunier, Frédéric A

2008-01-01

Ciguatoxins and brevetoxins are neurotoxic cyclic polyether compounds produced by dinoflagellates, which are responsible for ciguatera and neurotoxic shellfish poisoning (NSP) respectively. Recently, brevenal, a natural compound was found to specifically inhibit brevetoxin action and to have a beneficial effect in NSP. Considering that brevetoxin and ciguatoxin specifically activate voltage-sensitive Na+ channels through the same binding site, brevenal has therefore a good potential for the treatment of ciguatera. Pacific ciguatoxin-1B (P-CTX-1B) activates voltage-sensitive Na+ channels and promotes an increase in neurotransmitter release believed to underpin the symptoms associated with ciguatera. However, the mechanism through which slow Na+ influx promotes neurosecretion is not fully understood. In the present study, we used chromaffin cells as a model to reconstitute the sequence of events culminating in ciguatoxin-evoked neurosecretion. We show that P-CTX-1B induces a tetrodotoxin-sensitive rise in intracellular Na+, closely followed by an increase in cytosolic Ca2+ responsible for promoting SNARE-dependent catecholamine secretion. Our results reveal that brevenal and beta-naphtoyl-brevetoxin prevent P-CTX-1B secretagogue activity without affecting nicotine or barium-induced catecholamine secretion. Brevenal is therefore a potent inhibitor of ciguatoxin-induced neurotoxic effect and a potential treatment for ciguatera.

Paracrine Maturation and Migration of SH-SY5Y Cells by Dental Pulp Stem Cells.

Science.gov (United States)

Gervois, P; Wolfs, E; Dillen, Y; Hilkens, P; Ratajczak, J; Driesen, R B; Vangansewinkel, T; Bronckaers, A; Brône, B; Struys, T; Lambrichts, I

2017-06-01

Neurological disorders are characterized by neurodegeneration and/or loss of neuronal function, which cannot be adequately repaired by the host. Therefore, there is need for novel treatment options such as cell-based therapies that aim to salvage or reconstitute the lost tissue or that stimulate host repair. The present study aimed to evaluate the paracrine effects of human dental pulp stem cells (hDPSCs) on the migration and neural maturation of human SH-SY5Y neuroblastoma cells. The hDPSC secretome had a significant chemoattractive effect on SH-SY5Y cells as shown by a transwell assay. To evaluate neural maturation, SH-SY5Y cells were first induced toward neuronal cells, after which they were exposed to the hDPSC secretome. In addition, SH-SY5Y cells subjected to the hDPSC secretome showed increased neuritogenesis compared with nonexposed cells. Maturated cells were shown to increase immune reactivity for neuronal markers compared with controls. Ultrastructurally, retinoic acid (RA) signaling and subsequent exposure to the hDPSC secretome induced a gradual rise in metabolic activity and neuronal features such as multivesicular bodies and cytoskeletal elements associated with cellular communication. In addition, electrophysiological recordings of differentiating cells demonstrated a transition toward a neuronal electrophysiological profile based on the maximum tetrodotoxin (TTX)-sensitive, Na + current. Moreover, conditioned medium (CM)-hDPSC-maturated SH-SY5Y cells developed distinct features including, Cd 2+ -sensitive currents, which suggests that CM-hDPSC-maturated SH-SY5Y acquired voltage-gated Ca 2+ channels. The results reported in this study demonstrate the potential of hDPSCs to support differentiation and recruitment of cells with neuronal precursor characteristics in a paracrine manner. Moreover, this in vitro experimental design showed that the widely used SH-SY5Y cell line can improve and simplify the preclinical in vitro research on the molecular

Mechanisms underlying odorant-induced and spontaneous calcium signals in olfactory receptor neurons of spiny lobsters, Panulirus argus.

Science.gov (United States)

Tadesse, Tizeta; Derby, Charles D; Schmidt, Manfred

2014-01-01

We determined if a newly developed antennule slice preparation allows studying chemosensory properties of spiny lobster olfactory receptor neurons under in situ conditions with Ca(2+) imaging. We show that chemical stimuli reach the dendrites of olfactory receptor neurons but not their somata, and that odorant-induced Ca(2+) signals in the somata are sufficiently stable over time to allow stimulation with a substantial number of odorants. Pharmacological manipulations served to elucidate the source of odorant-induced Ca(2+) transients and spontaneous Ca(2+) oscillations in the somata of olfactory receptor neurons. Both Ca(2+) signals are primarily mediated by an influx of extracellular Ca(2+) through voltage-activated Ca(2+) channels that can be blocked by CoCl2 and the L-type Ca(2+) channel blocker verapamil. Intracellular Ca(2+) stores contribute little to odorant-induced Ca(2+) transients and spontaneous Ca(2+) oscillations. The odorant-induced Ca(2+) transients as well as the spontaneous Ca(2+) oscillations depend on action potentials mediated by Na(+) channels that are largely TTX-insensitive but blocked by the local anesthetics tetracaine and lidocaine. Collectively, these results corroborate the conclusion that odorant-induced Ca(2+) transients and spontaneous Ca(2+) oscillations in the somata of olfactory receptor neurons closely reflect action potential activity associated with odorant-induced phasic-tonic responses and spontaneous bursting, respectively. Therefore, both types of Ca(2+) signals represent experimentally accessible proxies of spiking.

Characterization of noradrenaline release in the locus coeruleus of freely moving awake rats by in vivo microdialysis.

Science.gov (United States)

Fernández-Pastor, Begoña; Mateo, Yolanda; Gómez-Urquijo, Sonia; Javier Meana, J

2005-07-01

The origin and regulation of noradrenaline (NA) in the locus coeruleus (LC) is unknown. The neurochemical features of NA overflow (nerve impulse dependence, neurotransmitter synthesis, vesicle storage, reuptake, alpha2-adrenoceptor-mediated regulation) were characterized in the LC. Brain microdialysis was performed in awake rats. Dialysates were analyzed for NA. NA in the LC decreased via local infusion of Ca2+-free medium (-42+/-5%) or the sodium channel blocker tetrodotoxine (TTX) (-47+/-8%) but increased (333+/-40%) via KCl-induced depolarization. The tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (250 mg kg(-1), i.p.) and the vesicle depletory drug reserpine (5 mg kg(-1), i.p.) decreased NA. Therefore, extracellular NA in the LC satisfies the criteria for an impulse flow-dependent vesicular exocytosis of neuronal origin. Local perfusion of the alpha2-adrenoceptor agonist clonidine (0.1-100 microM) decreased NA (E(max)=-79+/-5%) in the LC, whereas the opposite effect (E(max)=268+/-53%) was observed with the alpha2A-adrenoceptor antagonist BRL44408 (0.1-100 microM). This suggests a tonic modulation of NA release through local alpha2A-adrenoceptors. The selective NA reuptake inhibitor desipramine (DMI) (0.1-100 microM) administered into the LC increased NA in the LC (E(max)=223+/-40%) and simultaneously decreased NA in the cingulate cortex, confirming the modulation exerted by NA in the LC on firing activity of noradrenergic cells and on the subsequent NA release in noradrenergic terminals. Synaptic processes underlying NA release in the LC are similar to those in noradrenergic terminal areas. NA in the LC could represent local somatodendritic release, but also the presence of neurotransmitter release from collateral axon terminals.

Tabletop exercise as a tool of evaluating physical protection system

International Nuclear Information System (INIS)

Matsuzawa, Reina

2014-01-01

Evaluation of designed and implemented physical protection system (PPS) is essential for ensuring the effectiveness of PPS. In Japan, nuclear facility operators, which are required to assess performance of PPS, have conducted performance test of PPS element and periodical trainings as well as annual PPS exercise with relevant agencies. In addition to these practical or field efforts, non-field tool for evaluating PPS effectiveness such as tabletop exercise (TTX) can be utilized as it is applied in the USA and other countries. This paper discusses the potential advantage of TTX as an evaluation tool of PPS effectiveness, looking at the characterizations of TTX in comparison to field evaluations, and potential cases where operator would get benefit from TTX especially. (author)

Distinct presynaptic control of dopamine release in striosomal and matrix areas of the cat caudate nucleus

International Nuclear Information System (INIS)

Kemel, M.L.; Desban, M.; Glowinski, J.; Gauchy, C.

1989-01-01

By use of a sensitive in vitro microsuperfusion method, the cholinergic presynaptic control of dopamine release was investigated in a prominent striosome (areas poor in acetylcholinesterase activity) located within the core of cat caudate nucleus and also in adjacent matrix area. The spontaneous release of [ 3 H]dopamine continuously synthesized from [ 3 H]tyrosine in the matrix area was found to be twice that in the striosomal area; the spontaneous and potassium-evoked releases of [ 3 H]dopamine were calcium-dependent in both compartments. With 10 -6 M tetrodotoxin, 5 x 10 -5 M acetylcholine stimulated [ 3 H]dopamine release in both striosomal and matrix areas, effects completely antagonized by atropine, thus showing the involvement of muscarinic receptors located on dopaminergic nerve terminals. Experiments without tetrodotoxin revealed a more complex regulation of dopamine release in the matrix: (i) in contrast to results seen in the striosome, acetylcholine induced only a transient stimulatory effect on matrix dopamine release. (ii) Although 10 -6 M atropine completely abolished the cholinergic stimulatory effect on [ 3 H]dopamine release in striosomal area, delayed and prolonged stimulation of [ 3 H] dopamine release was seen with atropine in the matrix. The latter effect was completely abolished by the nicotinic antagonist pempidine. Therefore, in the matrix, in addition to its direct (tetrodotoxin-insensitive) facilitatory action on [ 3 H]dopamine release, acetylcholine exerts two indirect (tetrodotoxin-sensitive) opposing effects: an inhibition and a stimulation of [ 3 H]dopamine release mediated by muscarinic and nicotinic receptors, respectively

Biophysical properties and computational modeling of calcium spikes in serotonergic neurons of the dorsal raphe nucleus.

Science.gov (United States)

Tuckwell, Henry C

2013-06-01

Serotonergic neurons of the dorsal raphe nuclei, with their extensive innervation of nearly the whole brain have important modulatory effects on many cognitive and physiological processes. They play important roles in clinical depression and other psychiatric disorders. In order to quantify the effects of serotonergic transmission on target cells it is desirable to construct computational models and to this end these it is necessary to have details of the biophysical and spike properties of the serotonergic neurons. Here several basic properties are reviewed with data from several studies since the 1960s to the present. The quantities included are input resistance, resting membrane potential, membrane time constant, firing rate, spike duration, spike and afterhyperpolarization (AHP) amplitude, spike threshold, cell capacitance, soma and somadendritic areas. The action potentials of these cells are normally triggered by a combination of sodium and calcium currents which may result in autonomous pacemaker activity. We here analyse the mechanisms of high-threshold calcium spikes which have been demonstrated in these cells the presence of TTX (tetrodotoxin). The parameters for calcium dynamics required to give calcium spikes are quite different from those for regular spiking which suggests the involvement of restricted parts of the soma-dendritic surface as has been found, for example, in hippocampal neurons. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Human-derived gut microbiota modulates colonic secretion in mice by regulating 5-HT3 receptor expression via acetate production.

Science.gov (United States)

Bhattarai, Yogesh; Schmidt, Bradley A; Linden, David R; Larson, Eric D; Grover, Madhusudan; Beyder, Arthur; Farrugia, Gianrico; Kashyap, Purna C

2017-07-01

Serotonin [5-hydroxytryptamine (5-HT)], an important neurotransmitter and a paracrine messenger in the gastrointestinal tract, regulates intestinal secretion by its action primarily on 5-HT 3 and 5-HT 4 receptors. Recent studies highlight the role of gut microbiota in 5-HT biosynthesis. In this study, we determine whether human-derived gut microbiota affects host secretory response to 5-HT and 5-HT receptor expression. We used proximal colonic mucosa-submucosa preparation from age-matched Swiss Webster germ-free (GF) and humanized (HM; ex-GF colonized with human gut microbiota) mice. 5-HT evoked a significantly greater increase in short-circuit current (Δ I sc ) in GF compared with HM mice. Additionally, 5-HT 3 receptor mRNA and protein expression was significantly higher in GF compared with HM mice. Ondansetron, a 5-HT 3 receptor antagonist, inhibited 5-HT-evoked Δ I sc in GF mice but not in HM mice. Furthermore, a 5-HT 3 receptor-selective agonist, 2-methyl-5-hydroxytryptamine hydrochloride, evoked a significantly higher Δ I sc in GF compared with HM mice. Immunohistochemistry in 5-HT 3A -green fluorescent protein mice localized 5-HT 3 receptor expression to enterochromaffin cells in addition to nerve fibers. The significant difference in 5-HT-evoked Δ I sc between GF and HM mice persisted in the presence of tetrodotoxin (TTX) but was lost after ondansetron application in the presence of TTX. Application of acetate (10 mM) significantly lowered 5-HT 3 receptor mRNA in GF mouse colonoids. We conclude that host secretory response to 5-HT may be modulated by gut microbiota regulation of 5-HT 3 receptor expression via acetate production. Epithelial 5-HT 3 receptor may function as a mediator of gut microbiota-driven change in intestinal secretion. NEW & NOTEWORTHY We found that gut microbiota alters serotonin (5-HT)-evoked intestinal secretion in a 5-HT 3 receptor-dependent mechanism and gut microbiota metabolite acetate alters 5-HT 3 receptor expression in

Cell shape changes induced by cationic anesthetics

Science.gov (United States)

1976-01-01

The effects of local anesthetics on cultivated macrophages were studied in living preparations and recorded in still pictures and time-lapse cine-micrographs. Exposure to 12mM lidocaine or 1.5 mM tetracaine resulted in rounding in 10-15 min. Rounding was characterized by cell contraction, marked increase in retraction fibrils, withdrawal of cell processes, and, in late stages, pulsation-like activity and zeiosis. Cells showed appreciable membrane activity as they rounded. Respreading was complete within 15 min of perfusion in drug-free medium and entailed a marked increase in surface motility over control periods. As many as eight successive cycles of rounding and spreading were obtained with lidocaine without evidence of cell damage. The effects of anesthetics were similar to those observed with EDTA, but ethylene- glycol-bis(beta-aminoethylether)-N, N'-tetraacetic acid-Mg was ineffective. Rounding was also induced by benzocaine, an anesthetic nearly uncharged at pH 7.0. Quaternary (nondischargeable) compounds were of low activity, presumably because they are slow permeants. Lidocaine induced rounding at 10 degrees C and above but was less effective at 5 degrees C and ineffective at 0 degrees C. Rounding by the anesthetic was also obtained in media depleted or Na or enriched with 10 mM Ca or Mg. The latter finding, together with the failure of tetrodotoxin to induce rounding, suggests that the anesthetic effect is unrelated to inhibition of sodium conductance. It is possible that the drugs influence divalent ion fluxes or some component of the contractile cells' machinery, but a metabolic target of action cannot yet be excluded. PMID:814194

Bioterrorism: toxins as weapons.

Science.gov (United States)

Anderson, Peter D

2012-04-01

The potential for biological weapons to be used in terrorism is a real possibility. Biological weapons include infectious agents and toxins. Toxins are poisons produced by living organisms. Toxins relevant to bioterrorism include ricin, botulinum, Clostridium perfrigens epsilson toxin, conotoxins, shigatoxins, saxitoxins, tetrodotoxins, mycotoxins, and nicotine. Toxins have properties of biological and chemical weapons. Unlike pathogens, toxins do not produce an infection. Ricin causes multiorgan toxicity by blocking protein synthesis. Botulinum blocks acetylcholine in the peripheral nervous system leading to muscle paralysis. Epsilon toxin damages cell membranes. Conotoxins block potassium and sodium channels in neurons. Shigatoxins inhibit protein synthesis and induce apoptosis. Saxitoxin and tetrodotoxin inhibit sodium channels in neurons. Mycotoxins include aflatoxins and trichothecenes. Aflatoxins are carcinogens. Trichothecenes inhibit protein and nucleic acid synthesis. Nicotine produces numerous nicotinic effects in the nervous system.

Role of calcium in gonadotropin releasing hormone-induced luteinizing hormone secretion from the bovine pituitary

International Nuclear Information System (INIS)

Kile, J.P.

1986-01-01

The hypothesis was tested that GnRH acts to release LH by increasing calcium uptake by gonadotroph which in turn stimulates calcium-calmodulin activity and results in LH release from bovine pituitary cells as it does in the rat. Pituitary glands of calves (4-10 months of age) were enzymatically dispersed (0.2% collagenase) and grown for 5 days to confluency in multiwell plates (3 x 10 5 /well). Cells treated with GnRH Ca ++ ionophore A23187, and ouabain all produced significant releases of LH release in a pronounced all or none fashion, while thorough washing of the cells with 0.5 mM EGTA in Ca ++ -free media prevented the action of GnRH. GnRH caused a rapid efflux of 45 Ca ++ . Both GnRH-stimulated 45 Ca efflux and LH release could be partially blocked by verapamil GnRH-induced LH release could also be blocked by nifedipine and tetrodotoxin, although these agents did not affect 45 Ca efflux. The calmodulin antagonists calmidazolium and W7 were found to block GnRH induced LH release, as well as LH release induced by theophylline, KC PGE 2 and estradiol. These data indicated that: (1) calcium is required for GnRH action, but extracellular Ca ++ does not regulate LH release; (2) GnRH elevates intracellular Ca ++ by opening both voltage sensitive and receptor mediated Ca ++ channels; (3) activation of calmodulin is one mechanism involved in GnRH-induced LH release

Greater Efficacy of Total Thyroidectomy versus Radioiodine Therapy on Hyperthyroidism and Thyroid-Stimulating Immunoglobulin Levels in Patients with Graves' Disease Previously Treated with Antithyroid Drugs

Science.gov (United States)

Kautbally, Shakeel; Alexopoulou, Orsalia; Daumerie, Chantal; Jamar, François; Mourad, Michel; Maiter, Dominique

2012-01-01

Aims We compared the effects of total thyroidectomy (TTx) and radioiodine (RAI) administration on the course of thyroid hormones and thyroid-stimulating immunoglobulins (TSI) in patients with Graves' disease. Methods We retrospectively studied 80 patients initially treated with antithyroid drugs and requiring either RAI (8.3 ± 1.7 mCi of 131I; n = 40) or TTx (n = 40) as second-line therapy. Results The TTx and RAI groups were not different, except for larger goiter, higher FT3 and more frequent Graves' orbitopathy at diagnosis in the surgery group (p antithyroid drugs. PMID:24783007

Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus

Directory of Open Access Journals (Sweden)

Saba Pierluigi

2005-05-01

Full Text Available Abstract Background Previous studies by our group suggest that extracellular dopamine (DA and noradrenaline (NA may be co-released from noradrenergic nerve terminals in the cerebral cortex. We recently demonstrated that the concomitant release of DA and NA could be elicited in the cerebral cortex by electrical stimulation of the locus coeruleus (LC. This study analyses the effect of both single train and repeated electrical stimulation of LC on NA and DA release in the medial prefrontal cortex (mPFC, occipital cortex (Occ, and caudate nucleus. To rule out possible stressful effects of electrical stimulation, experiments were performed on chloral hydrate anaesthetised rats. Results Twenty min electrical stimulation of the LC, with burst type pattern of pulses, increased NA and DA both in the mPFC and in the Occ. NA in both cortices and DA in the mPFC returned to baseline within 20 min after the end of the stimulation period, while DA in the Occ reached a maximum increase during 20 min post-stimulation and remained higher than baseline values at 220 min post-stimulation. Local perfusion with tetrodotoxin (TTX, 10 μM markedly reduced baseline NA and DA in the mPFC and Occ and totally suppressed the effect of electrical stimulation in both areas. A sequence of five 20 min stimulations at 20 min intervals were delivered to the LC. Each stimulus increased NA to the same extent and duration as the first stimulus, whereas DA remained elevated at the time next stimulus was delivered, so that baseline DA progressively increased in the mPFC and Occ to reach about 130 and 200% the initial level, respectively. In the presence of the NA transport (NAT blocker desipramine (DMI, 100 μM, multiple LC stimulation still increased extracellular NA and DA levels. Electrical stimulation of the LC increased NA levels in the homolateral caudate nucleus, but failed to modify DA level. Conclusion The results confirm and extend that LC stimulation induces a concomitant

Activation of neural cholecystokinin-1 receptors induces relaxation of the isolated rat duodenum which is reduced by nitric oxide synthase inhibitors

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S.R. Martins

2006-02-01

Full Text Available Cholecystokinin (CCK influences gastrointestinal motility, by acting on central and peripheral receptors. The aim of the present study was to determine whether CCK has any effect on isolated duodenum longitudinal muscle activity and to characterize the mechanisms involved. Isolated segments of the rat proximal duodenum were mounted for the recording of isometric contractions of longitudinal muscle in the presence of atropine and guanethidine. CCK-8S (EC50: 39; 95% CI: 4.1-152 nM and cerulein (EC50: 58; 95% CI: 18-281 nM induced a concentration-dependent and tetrodotoxin-sensitive relaxation. Nomeganitro-L-arginine (L-NOARG reduced CCK-8S- and cerulein-induced relaxation (IC50: 5.2; 95% CI: 2.5-18 µM in a concentration-dependent manner. The magnitude of 300 nM CCK-8S-induced relaxation was reduced by 100 µM L-NOARG from 73 ± 5.1 to 19 ± 3.5% in an L-arginine but not D-arginine preventable manner. The CCK-1 receptor antagonists proglumide, lorglumide and devazepide, but not the CCK-2 receptor antagonist L-365,260, antagonized CCK-8S-induced relaxation in a concentration-dependent manner. These findings suggest that CCK-8S and cerulein activate intrinsic nitrergic nerves acting on CCK-1 receptors in order to cause relaxation of the rat duodenum longitudinal muscle.

Transcriptional coupling of synaptic transmission and energy metabolism: role of nuclear respiratory factor 1 in co-regulating neuronal nitric oxide synthase and cytochrome c oxidase genes in neurons.

Science.gov (United States)

Dhar, Shilpa S; Liang, Huan Ling; Wong-Riley, Margaret T T

2009-10-01

Neuronal activity is highly dependent on energy metabolism; yet, the two processes have traditionally been regarded as independently regulated at the transcriptional level. Recently, we found that the same transcription factor, nuclear respiratory factor 1 (NRF-1) co-regulates an important energy-generating enzyme, cytochrome c oxidase, as well as critical subunits of glutamatergic receptors. The present study tests our hypothesis that the co-regulation extends to the next level of glutamatergic synapses, namely, neuronal nitric oxide synthase, which generates nitric oxide as a downstream signaling molecule. Using in silico analysis, electrophoretic mobility shift assay, chromatin immunoprecipitation, promoter mutations, and NRF-1 silencing, we documented that NRF-1 functionally bound to Nos1, but not Nos2 (inducible) and Nos3 (endothelial) gene promoters. Both COX and Nos1 transcripts were up-regulated by depolarizing KCl treatment and down-regulated by TTX-mediated impulse blockade in neurons. However, NRF-1 silencing blocked the up-regulation of both Nos1 and COX induced by KCl depolarization, and over-expression of NRF-1 rescued both Nos1 and COX transcripts down-regulated by TTX. These findings are consistent with our hypothesis that synaptic neuronal transmission and energy metabolism are tightly coupled at the molecular level.

Transient inactivation of the neonatal ventral hippocampus impairs attentional set-shifting behavior

DEFF Research Database (Denmark)

Brooks, Julie M; Pershing, Michelle L; Thomsen, Morten Skøtt

2012-01-01

as adults on an attentional set-shifting task. Performance in this task depends upon the integrity of the PFC and NAC. TTX infusions did not affect the initial acquisition or ability to learn an intra-dimensional shift. However, TTX rats required a greater number of trials than did controls to acquire...

Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients

DEFF Research Database (Denmark)

Arora, Satish; Gude, Einar; Sigurdardottir, Vilborg

2012-01-01

The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated...... NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure....

Chair Report Consultancy Meeting on Nuclear Security Assessment Methodologies (NUSAM) Transport Case Study Working Group

Energy Technology Data Exchange (ETDEWEB)

Shull, Doug [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

2015-08-19

The purpose of the consultancy assignment was to (i) apply the NUSAM assessment methods to hypothetical transport security table top exercise (TTX) analyses and (ii) document its results to working materials of NUSAM case study on transport. A number of working group observations, using the results of TTX methodologies, are noted in the report.

Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling.

Science.gov (United States)

Vetter, Irina; Touska, Filip; Hess, Andreas; Hinsbey, Rachel; Sattler, Simon; Lampert, Angelika; Sergejeva, Marina; Sharov, Anastasia; Collins, Lindon S; Eberhardt, Mirjam; Engel, Matthias; Cabot, Peter J; Wood, John N; Vlachová, Viktorie; Reeh, Peter W; Lewis, Richard J; Zimmermann, Katharina

2012-10-03

Ciguatoxins are sodium channel activator toxins that cause ciguatera, the most common form of ichthyosarcotoxism, which presents with peripheral sensory disturbances, including the pathognomonic symptom of cold allodynia which is characterized by intense stabbing and burning pain in response to mild cooling. We show that intraplantar injection of P-CTX-1 elicits cold allodynia in mice by targeting specific unmyelinated and myelinated primary sensory neurons. These include both tetrodotoxin-resistant, TRPA1-expressing peptidergic C-fibres and tetrodotoxin-sensitive A-fibres. P-CTX-1 does not directly open heterologously expressed TRPA1, but when co-expressed with Na(v) channels, sodium channel activation by P-CTX-1 is sufficient to drive TRPA1-dependent calcium influx that is responsible for the development of cold allodynia, as evidenced by a large reduction of excitatory effect of P-CTX-1 on TRPA1-deficient nociceptive C-fibres and of ciguatoxin-induced cold allodynia in TRPA1-null mutant mice. Functional MRI studies revealed that ciguatoxin-induced cold allodynia enhanced the BOLD (Blood Oxygenation Level Dependent) signal, an effect that was blunted in TRPA1-deficient mice, confirming an important role for TRPA1 in the pathogenesis of cold allodynia.

Mechanism of resveratrol-induced relaxation of the guinea pig fundus.

Science.gov (United States)

Tsai, Ching-Chung; Tey, Shu-Leei; Lee, Ming-Che; Liu, Ching-Wen; Su, Yu-Tsun; Huang, Shih-Che

2018-04-01

Resveratrol is a polyphenolic compound that can be isolated from plants and also is a constituent of red wine. Resveratrol induces relaxation of vascular smooth muscle and may prevent cardiovascular diseases. Impaired gastric accommodation plays an important role in functional dyspepsia and fundic relaxation and is a therapeutic target of functional dyspepsia. Although drugs for fundic relaxation have been developed, these types of drugs are still rare. The purpose of this study was to investigate the relaxant effects of resveratrol in the guinea pig fundus. We studied the relaxant effects of resveratrol in the guinea pig fundus. In addition, we investigated the mechanism of resveratrol-induced relaxation on the guinea pig fundus by using tetraethylammonium (a non-selective potassium channel blocker), apamine (a selective inhibitor of the small conductance calcium-activated potassium channel), iberiotoxin (an inhibitor of large conductance calcium-activated potassium channels), glibenclamide (an ATP-sensitive potassium channel blocker), KT 5720 (a cAMP-dependent protein kinase A inhibitor), KT 5823 (a cGMP-dependent protein kinase G inhibitor), NG-nitro-L-arginine (a competitive inhibitor of nitric oxide synthase), tetrodotoxin (a selective neuronal Na + channel blocker), ω-conotoxin GVIA (a selective neuronal Ca 2+ channel blocker) and G-15 (a G-protein coupled estrogen receptor antagonist). The results of this study showed that resveratrol has potent and dose-dependent relaxant effects on the guinea pig fundic muscle. In addition, the results showed that resveratrol-induced relaxation of the guinea pig fundus occurs through nitric oxide and ATP-sensitive potassium channels. This study provides the first evidence concerning the relaxant effects of resveratrol in the guinea pig fundic muscle strips. Furthermore, resveratrol may be a potential drug to relieve gastrointestinal dyspepsia. Copyright © 2018 Elsevier GmbH. All rights reserved.

Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling

Directory of Open Access Journals (Sweden)

Due Michael R

2012-08-01

not thermal, nociceptive behavioral changes in the rat, which were prevented by pre-treating animals with Compound 15. Unlike TLR4 wild-type mice, TLR4 knockout mice did not exhibit M3G-induced hyperalgesia. As abnormal pain sensitivity is often associated with NaVs, we predicted that M3G acting via the MD-2/TLR4 complex may affect the density and gating of NaVs in sensory neurons. We show that M3G increases tetrodotoxin-sensitive and tetrodotoxin-resistant (NaV1.9 current densities. Conclusions These outcomes provide evidence that M3G may play a role in OIH via the TLR4/MD-2 heterodimer complex and biophysical properties of tetrodotoxin-sensitive and tetrodotoxin-resistant NaV currents.

High Ca2+ Influx During Traumatic Brain Injury Leads to Caspase-1-Dependent Neuroinflammation and Cell Death.

Science.gov (United States)

Abdul-Muneer, P M; Long, Mathew; Conte, Adriano Andrea; Santhakumar, Vijayalakshmi; Pfister, Bryan J

2017-08-01

We investigated the hypothesis that high Ca 2+ influx during traumatic brain injury induces the activation of the caspase-1 enzyme, which triggers neuroinflammation and cell apoptosis in a cell culture model of neuronal stretch injury and an in vivo model of fluid percussion injury (FPI). We first established that stretch injury causes a rapid increase in the intracellular Ca 2+ level, which activates interleukin-converting enzyme caspase-1. The increase in the intracellular Ca 2+ level and subsequent caspase-1 activation culminates into neuroinflammation via the maturation of IL-1β. Further, we analyzed caspase-1-mediated apoptosis by TUNEL staining and PARP western blotting. The voltage-gated sodium channel blocker, tetrodotoxin, mitigated the stretch injury-induced neuroinflammation and subsequent apoptosis by blocking Ca 2+ influx during the injury. The effect of tetrodotoxin was similar to the caspase-1 inhibitor, zYVAD-fmk, in neuronal culture. To validate the in vitro results, we demonstrated an increase in caspase-1 activity, neuroinflammation and neurodegeneration in fluid percussion-injured animals. Our data suggest that neuronal injury/traumatic brain injury (TBI) can induce a high influx of Ca 2+ to the cells that cause neuroinflammation and cell death by activating caspase-1, IL-1β, and intrinsic apoptotic pathways. We conclude that excess IL-1β production and cell death may contribute to neuronal dysfunction and cognitive impairment associated with TBI.

β adrenergic receptor modulation of neurotransmission to cardiac vagal neurons in the nucleus ambiguus.

Science.gov (United States)

Bateman, R J; Boychuk, C R; Philbin, K E; Mendelowitz, D

2012-05-17

β-adrenergic receptors are a class of G protein-coupled receptors that have essential roles in regulating heart rate, blood pressure, and other cardiorespiratory functions. Although the role of β adrenergic receptors in the peripheral nervous system is well characterized, very little is known about their role in the central nervous system despite being localized in many brain regions involved in autonomic activity and regulation. Since parasympathetic activity to the heart is dominated by cardiac vagal neurons (CVNs) originating in the nucleus ambiguus (NA), β adrenergic receptors localized in the NA represent a potential target for modulating cardiac vagal activity and heart rate. This study tests the hypothesis that activation of β adrenergic receptors alters the membrane properties and synaptic neurotransmission to CVNs. CVNs were identified in brainstem slices, and membrane properties and synaptic events were recorded using the whole-cell voltage-clamp technique. The nonselective β agonist isoproterenol significantly decreased inhibitory GABAergic and glycinergic as well as excitatory glutamatergic neurotransmission to CVNs. In addition, the β(1)-selective receptor agonist dobutamine, but not β(2) or β(3) receptor agonists, significantly decreased inhibitory GABAergic and glycinergic and excitatory glutamatergic neurotransmission to CVNs. These decreases in neurotransmission to CVNs persisted in the presence of tetrodotoxin (TTX). These results provide a mechanism by which activation of adrenergic receptors in the brainstem can alter parasympathetic activity to the heart. Likely physiological roles for this adrenergic receptor activation are coordination of parasympathetic-sympathetic activity and β receptor-mediated increases in heart rate upon arousal. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Minocycline enhances inhibitory transmission to substantia gelatinosa neurons of the rat spinal dorsal horn.

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Peng, H-Z; Ma, L-X; Lv, M-H; Hu, T; Liu, T

2016-04-05

Minocycline, a second-generation tetracycline, is well known for its antibiotic, anti-inflammatory, and antinociceptive effects. Modulation of synaptic transmission is one of the analgesic mechanisms of minocycline. Although it has been reported that minocycline may suppress excitatory glutamatergic synaptic transmission, it remains unclear whether it could affect inhibitory synaptic transmission, which also plays a key role in modulating pain signaling. To examine the effect of minocycline on synaptic transmission in rat spinal substantia gelatinosa (SG) neurons, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) using whole-cell patch-clamp recording at a holding potential of 0 mV. Bath application of minocycline significantly increased the frequency but not the amplitude of sIPSCs in a reversible and concentration-dependent manner with an EC50 of 85. The enhancement of inhibitory synaptic transmission produced by minocycline was not affected by the glutamate receptor antagonists CNQX and D-APV or by the voltage-gated sodium channel blocker tetrodotoxin (TTX). Moreover, the potency of minocycline for facilitating sIPSC frequency was the same in both glycinergic and GABAergic sIPSCs without changing their decay phases. However, the facilitatory effect of minocycline on sIPSCs was eliminated in a Ca(2+)-free Krebs solution or by co-administration with calcium channel blockers. In summary, our data demonstrate that baseline inhibitory synaptic transmission in SG neurons is markedly enhanced by minocycline. This may function to decrease the excitability of SG neurons, thus leading to a modulation of nociceptive transmission. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Differential effects of centrally-active antihypertensives on 5-HT1A receptors in rat dorso-lateral septum, rat hippocampus and guinea-pig hippocampus.

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Leishman, D J; Boeijinga, P H; Galvan, M

1994-01-01

1. The electrophysiological responses elicited by 5-hydroxytryptamine1A-(5-HT1A) receptor agonists in rat and guinea-pig CA1 pyramidal neurones and rat dorso-lateral septal neurones were compared in vitro by use of conventional intracellular recording techniques. 2. In the presence of 1 microM tetrodotoxin (TTX), to prevent indirect effects, 5-HT, N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT) hyperpolarized the neurones from rat and guinea-pig brain. 3. The hypotensive drug flesinoxan, a selective 5-HT1A receptor agonist, hyperpolarized neurones in all three areas tested; however, another hypotensive agent with high affinity at 5-HT1A-receptors, 5-methyl-urapidil, hyperpolarized only the neurones in rat hippocampus and septum. 4. In guinea-pig hippocampal neurones, 5-methyl-urapidil behaved as a 5-HT1A-receptor antagonist. 5. The relative efficacies (5-HT = 1) of DP-5-CT, 8-OH-DPAT, flesinoxan and 5-methyl-urapidil at the three sites were: rat hippocampus, 1.09, 0.7, 0.5 and 0.24; rat septum, 0.88, 0.69, 0.82 and 0.7; guinea-pig hippocampus, 1.0, 0.69, 0.89 and 0, respectively. 6. It is concluded that the hypotensive agents flesinoxan and 5-methyl-urapidil appear to have different efficacies at 5-HT1A receptors located in different regions of the rodent brain. Whether these regional and species differences arise from receptor plurality or variability in intracellular transduction mechanisms remains to be elucidated.

Paradoxical effect of salbutamol in a model of acute organophosphates intoxication in guinea pigs: role of substance P release.

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Chávez, Jaime; Segura, Patricia; Vargas, Mario H; Arreola, José Luis; Flores-Soto, Edgar; Montaño, Luis M

2007-04-01

Organophosphates induce bronchoobstruction in guinea pigs, and salbutamol only transiently reverses this effect, suggesting that it triggers additional obstructive mechanisms. To further explore this phenomenon, in vivo (barometric plethysmography) and in vitro (organ baths, including ACh and substance P concentration measurement by HPLC and immunoassay, respectively; intracellular Ca2+) measurement in single myocytes) experiments were performed. In in vivo experiments, parathion caused a progressive bronchoobstruction until a plateau was reached. Administration of salbutamol during this plateau decreased bronchoobstruction up to 22% in the first 5 min, but thereafter airway obstruction rose again as to reach the same intensity as before salbutamol. Aminophylline caused a sustained decrement (71%) of the parathion-induced bronchoobstruction. In in vitro studies, paraoxon produced a sustained contraction of tracheal rings, which was fully blocked by atropine but not by TTX, omega-conotoxin (CTX), or epithelium removal. During the paraoxon-induced contraction, salbutamol caused a temporary relaxation of approximately 50%, followed by a partial recontraction. This paradoxical recontraction was avoided by the M2- or neurokinin-1 (NK1)-receptor antagonists (methoctramine or AF-DX 116, and L-732138, respectively), accompanied by a long-lasting relaxation. Forskolin caused full relaxation of the paraoxon response. Substance P and, to a lesser extent, ACh released from tracheal rings during 60-min incubation with paraoxon or physostigmine, respectively, were significantly increased when salbutamol was administered in the second half of this period. In myocytes, paraoxon did not produce any change in the intracellular Ca2+ basal levels. Our results suggested that: 1) organophosphates caused smooth muscle contraction by accumulation of ACh released through a TTX- and CTX-resistant mechanism; 2) during such contraction, salbutamol relaxation is functionally antagonized by the

Dot immunoassay for the simultaneous determination of postvaccination immunity against pertussis, diphtheria, and tetanus.

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Khramtsov, Pavel; Bochkova, Maria; Timganova, Valeria; Zamorina, Svetlana; Rayev, Mikhail

2017-06-01

A dot immunoassay for simultaneous semiquantitative detection of IgG against tetanus toxoid (Ttx) and diphtheria toxoid (Dtx) and qualitative detection of anti-Bordetella pertussis IgGs in human blood serum using carbon nanoparticles functionalized with streptococcal protein G was developed. Inactivated B. pertussis cells in suspension form were used as an antigen in the immunoassay. Pertussis, tetanus, and diphtheria antigens were separately spotted onto nitrocellulose strips, and then the immunostrips were successively incubated with blood sera and a suspension of carbon nanoparticles. The immunostrips were then scanned with a flatbed scanner, and the images obtained were processed with ImageJ. One hundred fifty-five venous blood serum samples from children vaccinated with diphtheria, tetanus, and whole-cell pertussis (DTwP) vaccine were tested in comparison with a conventional ELISA and agglutination test. The total time required for analysis of 32 serum samples was less than 3 h. Comparison between the results of the dot immunoassay and the corresponding ELISA/agglutination test revealed a high level of agreement (Cohen's kappa between 0.765 and 0.813). The lower limit of quantification was 0.06 IU/ml for anti-Ttx and anti-Dtx. The intra-assay coefficients of variation were less than 15% for anti-Ttx and anti-Dtx and less than 10% for anti-pertussis. The diagnostic sensitivity of detection of the antibody protection level was 93.5% for anti-Ttx [95% confidence interval (CI) 83.5-97.9%], 92.4% for anti-Dtx (95% CI 80.9297.5%), and 90.2% for anti-pertussis (95% CI 75.9-96.8%). The diagnostic specificity was 90.9% for anti-Ttx (95% CI 57.1-99.5%), 85% for anti-Dtx (95% CI 61.1-96.0%), and 89.3% for anti-pertussis (95%CI 80.8-94.5%). The dot immunoassay developed does not require expensive reading equipment, and allows detection of antibodies against three antigens in a single analysis. The immunostrips can be stored for a long time without changes in the

Inhibition of Inactive States of Tetrodotoxin-Sensitive Sodium Channels Reduces Spontaneous Firing of C-Fiber Nociceptors and Produces Analgesia in Formalin and Complete Freund's Adjuvant Models of Pain.

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David J Matson

Full Text Available While genetic evidence shows that the Nav1.7 voltage-gated sodium ion channel is a key regulator of pain, it is unclear exactly how Nav1.7 governs neuronal firing and what biophysical, physiological, and distribution properties of a pharmacological Nav1.7 inhibitor are required to produce analgesia. Here we characterize a series of aminotriazine inhibitors of Nav1.7 in vitro and in rodent models of pain and test the effects of the previously reported "compound 52" aminotriazine inhibitor on the spiking properties of nociceptors in vivo. Multiple aminotriazines, including some with low terminal brain to plasma concentration ratios, showed analgesic efficacy in the formalin model of pain. Effective concentrations were consistent with the in vitro potency as measured on partially-inactivated Nav1.7 but were far below concentrations required to inhibit non-inactivated Nav1.7. Compound 52 also reversed thermal hyperalgesia in the complete Freund's adjuvant (CFA model of pain. To study neuronal mechanisms, electrophysiological recordings were made in vivo from single nociceptive fibers from the rat tibial nerve one day after CFA injection. Compound 52 reduced the spontaneous firing of C-fiber nociceptors from approximately 0.7 Hz to 0.2 Hz and decreased the number of action potentials evoked by suprathreshold tactile and heat stimuli. It did not, however, appreciably alter the C-fiber thresholds for response to tactile or thermal stimuli. Surprisingly, compound 52 did not affect spontaneous activity or evoked responses of Aδ-fiber nociceptors. Results suggest that inhibition of inactivated states of TTX-S channels, mostly likely Nav1.7, in the peripheral nervous system produces analgesia by regulating the spontaneous discharge of C-fiber nociceptors.

Miniature excitatory synaptic currents in cultured hippocampal neurons.

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Finch, D M; Fisher, R S; Jackson, M B

1990-06-04

We performed patch clamp recordings in the whole cell mode from cultured embryonic mouse hippocampal neurons. In bathing solutions containing tetrodotoxin (TTX), the cells showed spontaneous inward currents (SICs) ranging in size from 1 to 100 pA. Several observations indicated that the SICs were miniature excitatory synaptic currents mediated primarily by non-NMDA (N-methyl-D-aspartate) excitatory amino acid receptors: the rising phase of SICs was fast (1 ms to half amplitude at room temperature) and smooth, suggesting unitary events. The SICs were blocked by the broad-spectrum glutamate receptor antagonist gamma-D-glutamylglycine (DGG), but not by the selective NMDA-receptor antagonist D-2-amino-5-phosphonovaleric acid (5-APV). SICs were also blocked by desensitizing concentrations of quisqualate. Incubating cells in tetanus toxin, which blocks exocytotic transmitter release, eliminated SICs. The presence of SICs was consistent with the morphological arrangement of glutamatergic innervation in the cell cultures demonstrated immunohistochemically. Spontaneous outward currents (SOCs) were blocked by bicuculline and presumed to be mediated by GABAA receptors. This is consistent with immunohistochemical demonstration of GABAergic synapses. SIC frequency was increased in a calcium dependent manner by bathing the cells in a solution high in K+, and application of the dihydropyridine L-type calcium channel agonist BAY K 8644 increased the frequency of SICs. Increases in SIC frequency produced by high K+ solutions were reversed by Cd2+ and omega-conotoxin GVIA, but not by the selective L-type channel antagonist nimodipine. This suggested that presynaptic L-type channels were in a gating mode that was not blocked by nimodipine, and/or that another class of calcium channel makes a dominant contribution to excitatory transmitter release.

A systemic evaluation of cardiac differentiation from mRNA reprogrammed human induced pluripotent stem cells.

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Ashish Mehta

Full Text Available Genetically unmodified cardiomyocytes mandated for cardiac regenerative therapy is conceivable by "foot-print free" reprogramming of somatic cells to induced pluripotent stem cells (iPSC. In this study, we report generation of foot-print free hiPSC through messenger RNA (mRNA based reprograming. Subsequently, we characterize cardiomyocytes derived from these hiPSC using molecular and electrophysiological methods to characterize their applicability for regenerative medicine. Our results demonstrate that mRNA-iPSCs differentiate ontogenetically into cardiomyocytes with increased expression of early commitment markers of mesoderm, cardiac mesoderm, followed by cardiac specific transcriptional and sarcomeric structural and ion channel genes. Furthermore, these cardiomyocytes stained positively for sarcomeric and ion channel proteins. Based on multi-electrode array (MEA recordings, these mRNA-hiPSC derived cardiomyocytes responded predictably to various pharmacologically active drugs that target adrenergic, sodium, calcium and potassium channels. The cardiomyocytes responded chronotropically to isoproterenol in a dose dependent manner, inotropic activity of nifidipine decreased spontaneous contractions. Moreover, Sotalol and E-4031 prolonged QT intervals, while TTX reduced sodium influx. Our results for the first time show a systemic evaluation based on molecular, structural and functional properties of cardiomyocytes differentiated from mRNA-iPSC. These results, coupled with feasibility of generating patient-specific iPSCs hold great promise for the development of large-scale generation of clinical grade cardiomyocytes for cardiac regenerative medicine.

Modulation of electrogenic transport processes in the porcine proximal colon by enteric neurotransmitters.

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Pfannkuche, H; Mauksch, A; Gäbel, G

2012-06-01

The aim of our study was to evaluate the involvement of essential pro- and antisecretory neurotransmitters in regulation of secretion in porcine proximal colon. Choline acetyltransferase (ChAT), nitric oxide synthase (NOS), vasoactive intestinal peptide (VIP), substance P (SP), somatostatin (SOM) and neuropeptide Y (NPY) were located immunohistochemically in the epithelium and subepithelial layer. Modulation of epithelial secretion was studied in Ussing chambers. Application of carbachol (CA), sodium nitroprussid (SNP), VIP and SP but not of NPY or SOM resulted in a chloride dependent increase in short circuit current (I(sc) ). I(sc) increase induced by CA, VIP or SNP was not altered by preincubation with tetrodotoxin or indomethacin. In contrast, SP-induced I(sc) increase was diminished by preincubation with tetrodotoxin, indomethacin, L-nitro-arginin-methyl-ester, and atropine but not hexamethonium. Simultaneous application of CA and VIP, or CA and SNP increased the I(sc) stronger as expected. Applying SP/CA led to a smaller increase in I(sc) as calculated. It is concluded that mainly prosecretory neurotransmitters are involved in regulation of colonic secretion. Cross-potentiations of acetylcholine and nitric oxide and acetylcholine and VIP suggest activation of different intracellular cascades. Similar intracellular pathways may be stimulated by acetylcholine and SP, thus preventing an additive effect of the transmitters. © 2011 Blackwell Verlag GmbH.

Noradrenaline decreases spike voltage threshold and induces electrographic sharp waves in turtle medial cortex in vitro.

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Lorenzo, Daniel; Velluti, Julio C

2004-01-01

The noradrenergic modulation of neuronal properties has been described at different levels of the mammalian brain. Although the anatomical characteristics of the noradrenergic system are well known in reptiles, functional data are scarce. In our study the noradrenergic modulation of cortical electrogenesis in the turtle medial cortex was studied in vitro using a combination of field and intracellular recordings. Turtle EEG consists of a low voltage background interspersed by spontaneous large sharp waves (LSWs). Noradrenaline (NA, 5-40 microM) induced (or enhanced) the generation of LSWs in a dose-dependent manner. Pharmacological experiments suggest the participation of alpha and beta receptors in this effect. In medial cortex neurons NA induced a hyperpolarization of the resting potential and a decrease of input resistance. Both effects were observed also after TTX treatment. Noradrenaline increased the response of the cells to depolarizing pulses, resulting in an upward shift of the frequency/current relation. In most cells the excitability change was mediated by a decrease of the spike voltage threshold resulting in the reduction of the amount of depolarization needed to fire the cell (voltage threshold minus resting potential). As opposed to the mechanisms reported in mammalian neurons, no changes in the frequency adaptation or the post-train afterhyperpolarization were observed. The NA effects at the cellular level were not reproduced by noradrenergic agonists. Age- and species-dependent properties in the pharmacology of adrenergic receptors could be involved in this result. Cellular effects of NA in turtle cortex are similar to those described in mammals, although the increase in cellular excitability seems to be mediated by a different mechanism. Copyright 2004 S. Karger AG, Basel

The effects and mechanism of action of methane on ileal motor function.

Science.gov (United States)

Park, Y M; Lee, Y J; Hussain, Z; Lee, Y H; Park, H

2017-09-01

Methane has been associated with constipation-predominant irritable bowel syndrome, slowing intestinal transit time by augmenting contractile activity. However, the precise mechanism underlying this effect remains unclear. Therefore, we investigated the mechanisms underlying the effect of methane on contractile activity, and whether such effects are mediated by nerve impulses or muscular contraction. We connected guinea pig ileal muscle strips to a force/tension transducer and measured amplitudes of contraction in response to electrical field stimulation (EFS; 1, 2, 8, 16 Hz) following methane infusion in the presence of tetradotoxin (TTX), atropine, guanethidine, or GR 113808. We then performed calcium imaging using Oregon Green 488 BAPTA-1 AM in order to visualize changes in calcium fluorescence in response to EFS following methane infusion in the presence of TTX, atropine, or a high K + solution. Methane significantly increased amplitudes of contraction (PMethane-induced increases in amplitude were inhibited when lower-frequency (1, 2 Hz) EFS was applied following atropine infusion (PMethane significantly increased calcium fluorescence, while this increase was attenuated following atropine infusion (Pmethane infusion. The actions of methane on the intestine are influenced by the cholinergic pathway of the enteric nervous system. Our findings support the classification of methane as a gasotransmitter. © 2017 John Wiley & Sons Ltd.

Effect of taurine on calcium accumulation in resting and depolarised insect synaptosomes

Energy Technology Data Exchange (ETDEWEB)

Whitton, P.S.; Nicholson, R.A.; Strang, R.H.

1988-06-01

The effect of taurine (2-aminoethanesulphonic acid) on /sup 45/Ca/sup 2 +/ accumulation in resting and depolarised synaptosomes obtained from the locust Schistocerca americana gregaria was studied. Taurine reduced /sup 45/Ca/sup 2 +/ accumulation in resting synaptosomes, and this effect was more pronounced when synaptosomes were depolarized with either high (K+) or veratridine. Veratridine-induced /sup 45/Ca/sup 2 +/ accumulation was not affected by either gamma-aminobutyric acid or leucine, but was reduced by both verapamil and tetrodotoxin.

Effects of ethanol on voltage-sensitive Na-channels in cultured skeletal muscle: Up-regulation as a result of chronic treatment

International Nuclear Information System (INIS)

Brodie, C.; Sampson, S.R.

1990-01-01

The effects of acute and chronic treatment with ethanol were studied on the number and activity of tetrodotoxin-sensitive Na-channels in cultured rat skeletal muscle. The number of channels was determined by measurements of specific binding of [3H] saxitoxin (STX) in whole cell preparations. Measurements were also made of the frequency and rate of rise of spontaneously occurring action potentials, which are the physiologic expression of Na-channel density. Acute ethanol (37.5-150 mM), while causing depolarization of membrane potential and blockade of electrical activity, was without effect on specific STX binding. Neither methanol, acetaldehyde nor ethylene glycol had significant effects on these properties when given acutely in the same concentrations as ethanol. Chronic ethanol caused dose-related increases in STX binding and action potential properties with maximal levels being attained after 3 days of treatment at a concentration of 150 mM. On removal of ethanol from the culture medium all properties returned to control levels after 48 hr. Both increased external K+ and tetrodotoxin, which up-regulate Na-channels by reducing cytosolic Ca++, potentiated the ethanol-induced increase in Na-channel density. The increase in STX binding was not associated with changes in affinity of the binding sites for the ligand but was completely prevented by treatment with cycloheximide and actinomycin D. The results demonstrate that ethanol interacts with the cell membrane to induce synthesis of STX-binding sites

GABAergic actions on cholinergic laterodorsal tegmental neurons

DEFF Research Database (Denmark)

Kohlmeier, K A; Kristiansen, Uffe

2010-01-01

Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) play a critical role in regulation of behavioral state. Therefore, elucidation of mechanisms that control their activity is vital for understanding of how switching between wakefulness, sleep and anesthetic states is effectuated....... In vivo studies suggest that GABAergic mechanisms within the pons play a critical role in behavioral state switching. However, the postsynaptic, electrophysiological actions of GABA on LDT neurons, as well as the identity of GABA receptors present in the LDT mediating these actions is virtually unexplored...... neurons. Post-synaptic location of GABA(A) receptors was demonstrated by persistence of muscimol-induced inward currents in TTX and low Ca(2+) solutions. THIP, a selective GABA(A) receptor agonist with a preference for d-subunit containing GABA(A) receptors, induced inward currents, suggesting...

Nitrergic Pathway Is the Main Contributing Mechanism in the Human Gastric Fundus Relaxation: An In Vitro Study.

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Yang Won Min

Full Text Available Human gastric fundus relaxation is mediated by intrinsic inhibitory pathway. We investigated the roles of nitrergic and purinergic pathways, two known inhibitory factors in gastric motility, on spontaneous and nerve-evoked contractions in human gastric fundus muscles.Gastric fundus muscle strips (12 circular and 13 longitudinal were obtained from patients without previous gastrointestinal motility disorder who underwent gastrectomy for stomach cancer. Using these specimens, we examined basal tone, peak, amplitude, and frequency of spontaneous contractions, and peak and nadir values under electrical field stimulation (EFS, 150 V, 0.3 ms, 10 Hz, 20 s. To examine responses to purinergic and nitrergic inhibition without cholinergic innervation, atropine (muscarinic antagonist, 1 μM, MRS2500 (a purinergic P2Y1 receptor antagonist, 1 μM, and N-nitro-L-arginine (L-NNA, a nitric oxide synthase inhibitor, 100 μM were added sequentially for spontaneous and electrically-stimulated contractions. Tetrodotoxin was used to confirm any neuronal involvement.In spontaneous contraction, L-NNA increased basal tone and peak in both muscle layers, while amplitude and frequency were unaffected. EFS (up to 10 Hz uniformly induced initial contraction and subsequent relaxation in a frequency-dependent manner. Atropine abolished initial on-contraction and induced only relaxation during EFS. While MRS2500 showed no additional influence, L-NNA reversed relaxation (p = 0.012 in circular muscle, and p = 0.006 in longitudinal muscle. Tetrodotoxin abolished any EFS-induced motor response.The relaxation of human gastric fundus muscle is reduced by nitrergic inhibition. Hence, nitrergic pathway appears to be the main mechanism for the human gastric fundus relaxation.

An N-methyl-D-aspartate receptor mediated large, low-frequency, spontaneous excitatory postsynaptic current in neonatal rat spinal dorsal horn neurons.

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Thomson, L M; Zeng, J; Terman, G W

2006-09-01

Examples of spontaneous oscillating neural activity contributing to both pathological and physiological states are abundant throughout the CNS. Here we report a spontaneous oscillating intermittent synaptic current located in lamina I of the neonatal rat spinal cord dorsal horn. The spontaneous oscillating intermittent synaptic current is characterized by its large amplitude, slow decay time, and low-frequency. We demonstrate that post-synaptic N-methyl-D-aspartate receptors (NMDARs) mediate the spontaneous oscillating intermittent synaptic current, as it is inhibited by magnesium, bath-applied d-2-amino-5-phosphonovalerate (APV), or intracellular MK-801. The NR2B subunit of the NMDAR appears important to this phenomenon, as the NR2B subunit selective NMDAR antagonist, alpha-(4-hydroxphenyl)-beta-methyl-4-benzyl-1-piperidineethanol tartrate (ifenprodil), also partially inhibited the spontaneous oscillating intermittent synaptic current. Inhibition of spontaneous glutamate release by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Gly5] enkephalin-ol (DAMGO) inhibited the spontaneous oscillating intermittent synaptic current frequency. Marked inhibition of spontaneous oscillating intermittent synaptic current frequency by tetrodotoxin (TTX), but not post-synaptic N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314), suggests that the glutamate release important to the spontaneous oscillating intermittent synaptic current is dependent on active neural processes. Conversely, increasing dorsal horn synaptic glutamate release by GABAA or glycine inhibition increased spontaneous oscillating intermittent synaptic current frequency. Moreover, inhibiting glutamate transporters with threo-beta-benzyloxyaspartic acid (DL-TBOA) increased spontaneous oscillating intermittent synaptic current frequency and decay time. A possible functional role of this spontaneous NMDAR

Neuronal and glial release of (3H)GABA from the rat olfactory bulb

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Jaffe, E.H.; Cuello, A.C.

1981-12-01

Neuronal versus glial components of the (3H)gamma-aminobutyric acid ((3H)GABA) release studies were performed with two different microdissected layers of the olfactory bulb of the rat. In some experiments substantia nigra was used as a GABAergic axonal system and the trigeminal ganglia as a peripheral glial model. Spontaneous release of (3H)GABA was always lower in neuronal elements as compared with glial cells. A veratridine-evoked release was observed from the ONL but not from the trigeminal ganglia. Tetrodotoxin (TTX) abolished the veratridine-evoked release from the ONL, which also showed a partial inhibition when high magnesium concentrations were used in a Ca2+-free solution. beta-Alanine was strongly exchanged with (3H)GABA from the ONL of animals with the olfactory nerve lesioned and from animals with no lesion; but only a small heteroexchange was found from the external plexiform layer. The beta-alanine heteroexchange was able to deplete the releasable GABA store from the ONL of lesioned animals. In nonlesioned animals and the external plexiform layer, the veratridine-stimulated release of (3H)GABA was not significantly reduced after the beta-alanine heteroexchange. Stimulation of the (3H)GABA release by high concentrations of potassium elicited a higher release rate from axonal terminals than from dendrites or glia. Neurones and glia showed a similar inhibition of (3H)GABA release when a high magnesium concentration was added to a calcium-free solution. When D-600 was used as a calcium-flux blocker no inhibition of the release was observed in glial cells, whereas an almost complete blockage was found in both neuronal preparations (substantia nigra and EPL). These results provide further evidence for differential release mechanisms of GABA from CNS neurones and glial cells.

5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function.

Science.gov (United States)

Wang, Xin; Dergacheva, Olga; Kamendi, Harriet; Gorini, Christopher; Mendelowitz, David

2007-08-01

Opioids evoke respiratory depression, bradycardia, and reduced respiratory sinus arrhythmia, whereas serotonin (5-HT) agonists stimulate respiration and cardiorespiratory interactions. This study tested whether serotonin agonists can prevent the inhibitory effects of opioids on cardiorespiratory function. Spontaneous and rhythmic inspiratory-related activity and gamma-aminobutyric acid (GABA) neurotransmission to premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus were recorded simultaneously in an in vitro thick slice preparation. The mu-opioid agonist fentanyl inhibited respiratory frequency. The 5-hydroxytryptamine 1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin increased respiratory frequency by itself and also prevented the fentanyl-induced respiratory depression. The 5-hydroxytryptamine 4alpha agonist BIMU-8 did not by itself change inspiratory activity but prevented the mu-opioid-mediated respiratory depression. Both spontaneous and inspiratory-evoked GABAergic neurotransmission to cardiac vagal neurons were inhibited by fentanyl. 8-Hydroxy-2-(di-n-propylamino)tetralin inhibited spontaneous but not inspiratory-evoked GABAergic activity to parasympathetic cardiac neurons. However, 8-hydroxy-2-(di-n-propylamino)tetralin differentially altered the opioid-mediated depression of inspiratory-evoked GABAergic activity but did not change the opioid-induced reduction in spontaneous GABAergic neurotransmission. In contrast, BIMU-8 did not alter GABAergic neurotransmission to cardiac vagal neurons by itself but prevented the fentanyl depression of both spontaneous and inspiratory-elicited GABAergic neurotransmission to cardiac vagal neurons. In the presence of tetrodotoxin, the inhibition of GABAergic inhibitory postsynaptic currents with fentanyl is prevented by coapplication of BIMU-8, indicating that BIMU-8 acts at presynaptic GABAergic terminals to prevent fentanyl-induced depression. These results suggest that activation of 5

PLC-dependent intracellular Ca2+ release was associated with C6-ceramide-induced inhibition of Na+ current in rat granule cells.

Science.gov (United States)

Liu, Zheng; Fei, Xiao-Wei; Fang, Yan-Jia; Shi, Wen-Jie; Zhang, Yu-Qiu; Mei, Yan-Ai

2008-09-01

In this report, the effects of C(6)-ceramide on the voltage-gated inward Na(+) currents (I(Na)), two types of main K(+) current [outward rectifier delayed K(+) current (I(K)) and outward transient K(+) current (I(A))], and cell death in cultured rat cerebellar granule cells were investigated. At concentrations of 0.01-100 microM, ceramide produced a dose-dependent and reversible inhibition of I(Na) without alteration of the steady-state activation and inactivation properties. Treatment with C(2)-ceramide caused a similar inhibitory effect on I(Na). However, dihydro-C(6)-ceramide failed to modulate I(Na). The effect of C(6)-ceramide on I(Na) was abolished by intracellular infusion of the Ca(2+)-chelating agent, 1,2-bis (2-aminophenoxy) ethane-N, N, N9, N9-tetraacetic acid, but was mimicked by application of caffeine. Blocking the release of Ca(2+) from the sarcoplasmic reticulum with ryanodine receptor blocker induced a gradual increase in I(Na) amplitude and eliminated the effect of ceramide on I(Na). In contrast, the blocker of the inositol 1,4,5-trisphosphate-sensitive Ca(2+) receptor did not affect the action of C(6)-ceramide. Intracellular application of GTPgammaS also induced a gradual decrease in I(Na) amplitude, while GDPbetaS eliminated the effect of C(6)-ceramide on I(Na). Furthermore, the C(6)-ceramide effect on I(Na) was abolished after application of the phospholipase C (PLC) blockers and was greatly reduced by the calmodulin inhibitors. Fluorescence staining showed that C(6)-ceramide decreased cell viability and blocking I(Na) by tetrodotoxin did not mimic the effect of C(6)-ceramide, and inhibiting intracellular Ca(2+) release by dantrolene could not decrease the C(6)-ceramide-induced cell death. We therefore suggest that increased PLC-dependent Ca(2+) release through the ryanodine-sensitive Ca(2+) receptor may be responsible for the C(6)-ceramide-induced inhibition of I(Na), which does not seem to be associated with C(6)-ceramide-induced granule

Gastritis caused by ingestion of eggs of puffer fish : a case report

International Nuclear Information System (INIS)

Lee, Dong Ho; Ko, Young Tae

1996-01-01

Tetrodotoxin is a neurotoxin, so gastrointestinal symptoms are very rare; these described in the literature are merely nausea and vomiting. Severe complications in the gastrointestinal tract caused by tetrodotoxin have not been radiologically reported. US and CT show thickening of the gastric wall and contraction of the lumen, and upper gastrointestinal series show shortening, lobulation and irregularity of the lesser and greater curvature of the body and antrum similar to the findings of corrosive gastritis

Gastritis caused by ingestion of eggs of puffer fish : a case report

Energy Technology Data Exchange (ETDEWEB)

Lee, Dong Ho; Ko, Young Tae [Kyunghee Univ. College of Medicine, Seoul (Korea, Republic of)

1996-09-01

Tetrodotoxin is a neurotoxin, so gastrointestinal symptoms are very rare; these described in the literature are merely nausea and vomiting. Severe complications in the gastrointestinal tract caused by tetrodotoxin have not been radiologically reported. US and CT show thickening of the gastric wall and contraction of the lumen, and upper gastrointestinal series show shortening, lobulation and irregularity of the lesser and greater curvature of the body and antrum similar to the findings of corrosive gastritis.

Stimulation of Na+ -K+ -pump currents by epithelial nicotinic receptors in rat colon.

Science.gov (United States)

Bader, Sandra; Lottig, Lena; Diener, Martin

2017-05-01

Acetylcholine-induced epithelial Cl - secretion is generally thought to be mediated by epithelial muscarinic receptors and nicotinic receptors on secretomotor neurons. However, recent data have shown expression of nicotinic receptors by intestinal epithelium and the stimulation of Cl - secretion by nicotine, in the presence of the neurotoxin, tetrodotoxin. Here, we aimed to identify the transporters activated by epithelial nicotinic receptors and to clarify their role in cholinergic regulation of intestinal ion transport. Ussing chamber experiments were performed, using rat distal colon with intact epithelia. Epithelia were basolaterally depolarized to measure currents across the apical membrane. Apically permeabilized tissue was also used to measure currents across the basolateral membrane in the presence of tetrodotoxin. Nicotine had no effect on currents through Cl - channels in the apical membrane or on currents through K + channels in the apical or the basolateral membrane. Instead, nicotine stimulated the Na + -K + -pump as indicated by Na + -dependency and sensitivity of the nicotine-induced current across the basolateral membrane to cardiac steroids. Effects of nicotine were inhibited by nicotinic receptor antagonists such as hexamethonium and mimicked by dimethyl-4-phenylpiperazinium, a chemically different nicotinic agonist. Simultaneous stimulation of epithelial muscarinic and nicotinic receptors led to a strong potentiation of transepithelial Cl - secretion. These results suggest a novel concept for the cholinergic regulation of transepithelial ion transport by costimulation of muscarinic and nicotinic epithelial receptors and a unique role of nicotinic receptors controlling the activity of the Na + -K + -ATPase. © 2017 The British Pharmacological Society.

A crosstalk between Na⁺ channels, Na⁺/K⁺ pump and mitochondrial Na⁺ transporters controls glucose-dependent cytosolic and mitochondrial Na⁺ signals.

Science.gov (United States)

Nita, Iulia I; Hershfinkel, Michal; Lewis, Eli C; Sekler, Israel

2015-02-01

Glucose-dependent cytosolic Na(+) influx in pancreatic islet β cells is mediated by TTX-sensitive Na(+) channels and is propagated into the mitochondria through the mitochondrial Na(+)/Ca(2+) exchanger, NCLX. Mitochondrial Na(+) transients are also controlled by the mitochondrial Na(+)/H(+) exchanger, NHE, while cytosolic Na(+) changes are governed by Na(+)/K(+) ATPase pump. The functional interaction between the Na(+) channels, Na(+)/K(+) ATPase pump and mitochondrial Na(+) transporters, NCLX and NHE, in mediating Na(+) signaling is poorly understood. Here, we combine fluorescent Na(+) imaging, pharmacological inhibition by TTX, ouabain and EIPA, with molecular control of NCLX expression, so as to investigate the crosstalk between Na(+) transporters on both the plasma membrane and the mitochondria. According to our results, glucose-dependent cytosolic Na(+) response was enhanced by ouabain and was followed by a rise in mitochondrial Na(+) signal. Silencing of NCLX expression using siNCLX, did not affect the glucose- or ouabain-dependent cytosolic rise in Na(+). In contrast, the ouabain-dependent rise in mitochondrial Na(+) was strongly suppressed by siNCLX. Furthermore, mitochondrial Na(+) influx rates were accelerated in cells treated with the Na(+)/H(+) exchanger inhibitor, EIPA or by combination of EIPA and ouabain. Similarly, TTX blocked the cytosolic and mitochondrial Na(+) responses, which were enhanced by ouabain or EIPA, respectively. Our results suggest that Na(+)/K(+) ATPase pump controls cytosolic glucose-dependent Na(+) rise, in a manner that is mediated by TTX-sensitive Na(+) channels and subsequent mitochondrial Na(+) uptake via NCLX. Furthermore, these results indicate that mitochondrial Na(+) influx via NCLX is antagonized by Na(+) efflux, which is mediated by the mitochondrial NHE; thus, the duration of mitochondrial Na(+) transients is set by the interplay between these pivotal transporters. Copyright © 2014 Elsevier Ltd. All rights reserved.

LHC experimental sensitivity to CP violating gtt couplings

CERN Document Server

Sjölin, J

2003-01-01

The level of CP violation in pp to tt+X induced by the standard model is known to be below the experimental sensitivity by many orders of magnitude. However, in some effective theories, it is plausible that new CP violating physics could reveal itself as additional non- renormalizable terms in the Lagrangian. Since these should respect the symmetries of the low-energy gauge interaction, violate CP and generate the correct event topology, the set of allowed terms is highly restricted. This analysis gives an estimate of the expected experimental sensitivity to the lowest order effective CP violating gtt interaction term beyond the standard model using simulated data from the ATLAS detector at the LHC. (36 refs).

The chemokine CXCL1/growth related oncogene increases sodium currents and neuronal excitability in small diameter sensory neurons

Directory of Open Access Journals (Sweden)

Wick Dayna M

2008-09-01

Full Text Available Abstract Background Altered Na+ channel expression, enhanced excitability, and spontaneous activity occur in nerve-injury and inflammatory models of pathological pain, through poorly understood mechanisms. The cytokine GRO/KC (growth related oncogene; CXCL1 shows strong, rapid upregulation in dorsal root ganglion in both nerve injury and inflammatory models. Neurons and glia express its receptor (CXCR2. CXCL1 has well-known effects on immune cells, but little is known about its direct effects on neurons. Results We report that GRO/KC incubation (1.5 nM, overnight caused marked upregulation of Na+ currents in acutely isolated small diameter rat (adult sensory neurons in vitro. In both IB4-positive and IB4-negative sensory neurons, TTX-resistant and TTX-sensitive currents increased 2- to 4 fold, without altered voltage dependence or kinetic changes. These effects required long exposures, and were completely blocked by co-incubation with protein synthesis inhibitor cycloheximide. Amplification of cDNA from the neuronal cultures showed that 3 Na channel isoforms were predominant both before and after GRO/KC treatment (Nav 1.1, 1.7, and 1.8. TTX-sensitive isoforms 1.1 and 1.7 significantly increased 2 – 3 fold after GRO/KC incubation, while 1.8 showed a trend towards increased expression. Current clamp experiments showed that GRO/KC caused a marked increase in excitability, including resting potential depolarization, decreased rheobase, and lower action potential threshold. Neurons acquired a striking ability to fire repetitively; IB4-positive cells also showed marked broadening of action potentials. Immunohistochemical labelling confirmed that the CXCR2 receptor was present in most neurons both in dissociated cells and in DRG sections, as previously shown for neurons in the CNS. Conclusion Many studies on the role of chemokines in pain conditions have focused on their rapid and indirect effects on neurons, via release of inflammatory mediators

Increased cholinergic contractions of jejunal smooth muscle caused by a high cholesterol diet are prevented by the 5-HT4 agonist – tegaserod

Directory of Open Access Journals (Sweden)

Shaffer Eldon

2006-02-01

Full Text Available Abstract Background Excess cholesterol in bile and in blood is a major risk factor for the respective development of gallbladder disease and atherosclerosis. This lipid in excess negatively impacts the functioning of other smooth muscles, including the intestine. Serotonin is an important mediator of the contractile responses of the small intestine. Drugs targeting the serotonin receptor are used as prokinetic agents to manage intestinal motor disorders, in particular irritable bowel syndrome. Thus, tegaserod, acting on 5-HT4 receptor, ideally should obviate detrimental effects of excessive cholesterol on gastrointestinal smooth muscle. In this study we examined the effect of tegaserod on cholesterol-induced changes in the contractile responses of intestinal smooth muscle. Methods The effects of a high cholesterol (1% diet on the in vitro contractile responses of jejunal longitudinal smooth muscle from Richardson ground squirrels to the cholinergic agonist carbachol were examined in the presence or absence of tetrodrodotoxin (TTX. Two groups of animals, fed either low (0.03% or high cholesterol rat chow diet, were further divided into two subgroups and treated for 28 days with either vehicle or tegaserod. Results The high cholesterol diet increased, by nearly 2-fold, contractions of the jejunal longitudinal smooth muscle elicited by carbachol. These cholinergic contractions were mediated by muscarinic receptors since they were blocked by scopolamine, a muscarinic receptor antagonist, but not by the nicotinic receptor antagonist, hexamethonium. Tegaserod treatment, which did not affect cholinergic contractions of tissues from low cholesterol fed animals, abrogated the increase caused by the high cholesterol diet. With low cholesterol diet TTX enhanced carbachol-evoked contractions, whereas this action potential blocker did not affect the augmented cholinergic contractions seen with tissues from animals on the high cholesterol diet. Tegaserod

Effects on the sodium channel of some new cardiotonic drugs: the 4-, 5-, and 6-pyridyl-2(1H)-quinolone derivatives

International Nuclear Information System (INIS)

Grima, M.; Beguin, M.F.; Millanvoye-Van Brussel, E.M.; Decker, N.; Schwartz, J.

1988-01-01

To study the action of some new cardiotonic drugs, the 4-, 5-, and 6-pyridyl-2(1H)-quinolone series, on the fast Na+ channel, we compared the effects of eight compounds of this series and milrinone on 22 Na uptake in rat brain synaptosomes and in rat heart muscle cells in culture. The action of tetrodotoxin, a specific Na+ channel blocker, on the positive inotropic effect of these compounds on guinea pig atria was also examined. The new positive inotropic agents enhance 22 Na uptake in synaptosomes in a dose-dependent manner. The activities, expressed as percentage of the maximum activity of protoveratrine B, a classic Na+ channel agonist, reached 70% for milrinone, 60% for compound 7, 57% for compound 6, and less than 50% for the other drugs. For compound 8, but not for milrinone, it was possible to observe a stimulatory effect of the 22 Na uptake on heart muscle cells in culture. Tetrodotoxin (1 and 100 microM) inhibited the stimulatory effects of the inotropic drugs on both preparations. The positive inotropic activities of protoveratrine B, milrinone, and compounds 5 and 8, in guinea pig atria, were inhibited by tetrodotoxin. The affinity and the activity of the other compounds were unchanged in the presence of tetrodotoxin. Our results showed that the stimulation of Na+ influx through the fast Na+ channel might represent a part of the mechanism of action of the inotropic effect of some new cardiotonic drugs

Effects on the sodium channel of some new cardiotonic drugs: the 4-, 5-, and 6-pyridyl-2(1H)-quinolone derivatives

Energy Technology Data Exchange (ETDEWEB)

Grima, M.; Beguin, M.F.; Millanvoye-Van Brussel, E.M.; Decker, N.; Schwartz, J.

1988-09-01

To study the action of some new cardiotonic drugs, the 4-, 5-, and 6-pyridyl-2(1H)-quinolone series, on the fast Na+ channel, we compared the effects of eight compounds of this series and milrinone on /sup 22/Na uptake in rat brain synaptosomes and in rat heart muscle cells in culture. The action of tetrodotoxin, a specific Na+ channel blocker, on the positive inotropic effect of these compounds on guinea pig atria was also examined. The new positive inotropic agents enhance /sup 22/Na uptake in synaptosomes in a dose-dependent manner. The activities, expressed as percentage of the maximum activity of protoveratrine B, a classic Na+ channel agonist, reached 70% for milrinone, 60% for compound 7, 57% for compound 6, and less than 50% for the other drugs. For compound 8, but not for milrinone, it was possible to observe a stimulatory effect of the /sup 22/Na uptake on heart muscle cells in culture. Tetrodotoxin (1 and 100 microM) inhibited the stimulatory effects of the inotropic drugs on both preparations. The positive inotropic activities of protoveratrine B, milrinone, and compounds 5 and 8, in guinea pig atria, were inhibited by tetrodotoxin. The affinity and the activity of the other compounds were unchanged in the presence of tetrodotoxin. Our results showed that the stimulation of Na+ influx through the fast Na+ channel might represent a part of the mechanism of action of the inotropic effect of some new cardiotonic drugs.

Role of neuronal activity in regulating the structure and function of auditory neurons

International Nuclear Information System (INIS)

Born, D.E.

1986-01-01

The role of afferent activity in maintaining neuronal structure and function was investigated in second order auditory neurons in nucleus magnocellularis (NM) of the chicken. The cochlea provides the major excitatory input to NM neurons via the eighth nerve. Removal of the cochlea causes dramatic changes in NM neurons. To determine if the elimination of neuronal activity is responsible for the changes in NM seen after cochlea removal, tetrodotoxin was used block action potentials in the cochlear ganglion cells. Tetrodotoxin injections into the perilymph reliably blocked neuronal activity in the cochlear nerve and NM. Far field recordings of sound-evoked potentials revealed that responses returned within 6 hours. Changes in amino acid incorporation in NM neurons were measured by giving intracardiac injections of 3 H-leucine and preparing tissue for autoradiographic demonstration of incorporated amino acid. Grain counts over individual neurons revealed that a single injection of tetrodotoxin produced a 40% decrease in grain density in ipsilateral NM neurons. It is concluded that neuronal activity plays an important contribution to the maintenance of the normal properties of NM neurons

Effects of peptides derived from dietary proteins on mucus secretion in rat jejunum.

Science.gov (United States)

Claustre, Jean; Toumi, Férial; Trompette, Aurélien; Jourdan, Gérard; Guignard, Henri; Chayvialle, Jean Alain; Plaisancié, Pascale

2002-09-01

The hypothesis that dietary proteins or their hydrolysates may regulate intestinal mucin discharge was investigated in the isolated vascularly perfused rat jejunum using an enzyme-linked immunosorbent assay for rat intestinal mucins. On luminal administration, casein hydrolysate [0.05-5% (wt/vol)] stimulated mucin secretion in rat jejunum (maximal response at 417% of controls). Lactalbumin hydrolysate (5%) also evoked mucin discharge. In contrast, casein, and a mixture of amino acids was without effect. Chicken egg albumin and its hydrolysate or meat hydrolysate also did not modify mucin release. Interestingly, casein hydrolysate-induced mucin secretion was abolished by intra-arterial TTX or naloxone (an opioid antagonist). beta-Casomorphin-7, an opioid peptide released from beta-casein on milk ingestion, induced a strong mucin secretion (response at 563% of controls) that was inhibited by naloxone. Intra-arterial beta-casomorphin-7 also markedly increased mucin secretion (410% of controls). In conclusion, two enzymatic milk protein hydrolysates (casein and lactalbumin hydrolysates) and beta-casomorphin-7, specifically, induced mucin release in rat jejunum. The casein hydrolysate-induced mucin secretion is triggered by a neural pathway and mediated by opioid receptor activation.

Combined Transcriptomic and Proteomic Analysis of the Posterior Salivary Gland from the Southern Blue-Ringed Octopus and the Southern Sand Octopus.

Science.gov (United States)

Whitelaw, Brooke L; Strugnell, Jan M; Faou, Pierre; da Fonseca, Rute R; Hall, Nathan E; Norman, Mark; Finn, Julian; Cooke, Ira R

2016-09-02

This study provides comprehensive proteomic profiles from the venom producing posterior salivary glands of octopus (superorder Octopodiformes) species. A combined transcriptomic and proteomic approach was used to identify 1703 proteins from the posterior salivary gland of the southern blue-ringed octopus, Hapalochlaena maculosa and 1300 proteins from the posterior salivary gland of the southern sand octopus, Octopus kaurna. The two proteomes were broadly similar; clustering of proteins into orthogroups revealed 937 that were shared between species. Serine proteases were particularly diverse and abundant in both species. Other abundant proteins included a large number of secreted proteins, many of which had no known conserved domains, or homology to proteins with known function. On the basis of homology to known venom proteins, 23 putative toxins were identified in H. maculosa and 24 in O. kaurna. These toxins span nine protein families: CAP (cysteine rich secretory proteins, antigen 5, parthenogenesis related), chitinase, carboxylesterase, DNase, hyaluronidase, metalloprotease, phospholipase, serine protease and tachykinin. Serine proteases were responsible for 70.9% and 86.3% of putative toxin expression in H. maculosa and O. kaurna, respectively, as determined using intensity based absolute quantification (iBAQ) measurements. Phylogenetic analysis of the putative toxin serine proteases revealed a similar suite of diverse proteins present in both species. Posterior salivary gland composition of H. maculosa and O. kaurna differ in several key aspects. While O. kaurna expressed the proteinaceous neurotoxin, tachykinin, this was absent from H. maculosa, perhaps reflecting the acquisition of a potent nonproteinaceous neurotoxin, tetrodotoxin (TTX) produced by bacteria in the salivary glands of that species. The dispersal factor, hyaluronidase was particularly abundant in H. maculosa. Chitinase was abundant in both species and is believed to facilitate

Na+,K+-pump stimulation improves contractility in isolated muscles of mice with hyperkalemic periodic paralysis.

Science.gov (United States)

Clausen, Torben; Nielsen, Ole Bækgaard; Clausen, Johannes D; Pedersen, Thomas Holm; Hayward, Lawrence J

2011-07-01

In patients with hyperkalemic periodic paralysis (HyperKPP), attacks of muscle weakness or paralysis are triggered by K(+) ingestion or rest after exercise. Force can be restored by muscle work or treatment with β(2)-adrenoceptor agonists. A missense substitution corresponding to a mutation in the skeletal muscle voltage-gated Na(+) channel (Na(v)1.4, Met1592Val) causing human HyperKPP was targeted into the mouse SCN4A gene (mutants). In soleus muscles prepared from these mutant mice, twitch, tetanic force, and endurance were markedly reduced compared with soleus from wild type (WT), reflecting impaired excitability. In mutant soleus, contractility was considerably more sensitive than WT soleus to inhibition by elevated [K(+)](o). In resting mutant soleus, tetrodotoxin (TTX)-suppressible (22)Na uptake and [Na(+)](i) were increased by 470 and 58%, respectively, and membrane potential was depolarized (by 16 mV, P Na(+),K(+) pump-mediated (86)Rb uptake was 83% larger than in WT. Salbutamol stimulated (86)Rb uptake and reduced [Na(+)](i) both in mutant and WT soleus. Stimulating Na(+),K(+) pumps with salbutamol restored force in mutant soleus and extensor digitorum longus (EDL). Increasing [Na(+)](i) with monensin also restored force in soleus. In soleus, EDL, and tibialis anterior muscles of mutant mice, the content of Na(+),K(+) pumps was 28, 62, and 33% higher than in WT, respectively, possibly reflecting the stimulating effect of elevated [Na(+)](i) on the synthesis of Na(+),K(+) pumps. The results confirm that the functional disorders of skeletal muscles in HyperKPP are secondary to increased Na(+) influx and show that contractility can be restored by acute stimulation of the Na(+),K(+) pumps. Calcitonin gene-related peptide (CGRP) restored force in mutant soleus but caused no detectable increase in (86)Rb uptake. Repeated excitation and capsaicin also restored contractility, possibly because of the release of endogenous CGRP from nerve endings in the isolated

Impaired activity of adherens junctions contributes to endothelial dilator dysfunction in ageing rat arteries.

Science.gov (United States)

Chang, Fumin; Flavahan, Sheila; Flavahan, Nicholas A

2017-08-01

Ageing-induced endothelial dysfunction contributes to organ dysfunction and progression of cardiovascular disease. VE-cadherin clustering at adherens junctions promotes protective endothelial functions, including endothelium-dependent dilatation. Ageing increased internalization and degradation of VE-cadherin, resulting in impaired activity of adherens junctions. Inhibition of VE-cadherin clustering at adherens junctions (function-blocking antibody; FBA) reduced endothelial dilatation in young arteries but did not affect the already impaired dilatation in old arteries. After junctional disruption with the FBA, dilatation was similar in young and old arteries. Src tyrosine kinase activity and tyrosine phosphorylation of VE-cadherin were increased in old arteries. Src inhibition increased VE-cadherin at adherens junctions and increased endothelial dilatation in old, but not young, arteries. Src inhibition did not increase dilatation in old arteries treated with the VE-cadherin FBA. Ageing impairs the activity of adherens junctions, which contributes to endothelial dilator dysfunction. Restoring the activity of adherens junctions could be of therapeutic benefit in vascular ageing. Endothelial dilator dysfunction contributes to pathological vascular ageing. Experiments assessed whether altered activity of endothelial adherens junctions (AJs) might contribute to this dysfunction. Aortas and tail arteries were isolated from young (3-4 months) and old (22-24 months) F344 rats. VE-cadherin immunofluorescent staining at endothelial AJs and AJ width were reduced in old compared to young arteries. A 140 kDa VE-cadherin species was present on the cell surface and in TTX-insoluble fractions, consistent with junctional localization. Levels of the 140 kDa VE-cadherin were decreased, whereas levels of a TTX-soluble 115 kDa VE-cadherin species were increased in old compared to young arteries. Acetylcholine caused endothelium-dependent dilatation that was decreased in old

Na+/K+-ATPase inhibition partially mimics the ethanol-induced increase of the Golgi cell-dependent component of the tonic GABAergic current in rat cerebellar granule cells.

Directory of Open Access Journals (Sweden)

Marvin R Diaz

Full Text Available Cerebellar granule cells (CGNs are one of many neurons that express phasic and tonic GABAergic conductances. Although it is well established that Golgi cells (GoCs mediate phasic GABAergic currents in CGNs, their role in mediating tonic currents in CGNs (CGN-I(tonic is controversial. Earlier studies suggested that GoCs mediate a component of CGN-I(tonic that is present only in preparations from immature rodents. However, more recent studies have detected a GoC-dependent component of CGN-I(tonic in preparations of mature rodents. In addition, acute exposure to ethanol was shown to potentiate the GoC component of CGN-I(tonic and to induce a parallel increase in spontaneous inhibitory postsynaptic current frequency at CGNs. Here, we tested the hypothesis that these effects of ethanol on GABAergic transmission in CGNs are mediated by inhibition of the Na(+/K(+-ATPase. We used whole-cell patch-clamp electrophysiology techniques in cerebellar slices of male rats (postnatal day 23-30. Under these conditions, we reliably detected a GoC-dependent component of CGN-I(tonic that could be blocked with tetrodotoxin. Further analysis revealed a positive correlation between basal sIPSC frequency and the magnitude of the GoC-dependent component of CGN-I(tonic. Inhibition of the Na(+/K(+-ATPase with a submaximal concentration of ouabain partially mimicked the ethanol-induced potentiation of both phasic and tonic GABAergic currents in CGNs. Modeling studies suggest that selective inhibition of the Na(+/K(+-ATPase in GoCs can, in part, explain these effects of ethanol. These findings establish a novel mechanism of action of ethanol on GABAergic transmission in the central nervous system.

Effects of cholera toxin on the potential difference and motor responses induced by distension in the rat proximal small intestine in vivo.

Science.gov (United States)

Kordasti, Shirin; Sapnara, Maria; Thomas, Evan A; Lindstrom, Erik; Forsman, Mikael; Bornstein, Joel C; Sjövall, Henrik

2006-05-01

Cholera toxin (CT) may induce uncontrolled firing in recurrent networks of secretomotor neurons in the submucous plexus. This hypothesis was tested in chloralose-anesthetized rats in vivo. The secretory reflex response to graded intestinal distension was measured with or without prior exposure to luminal CT. The transmural potential difference (PD) was used as a marker for electrogenic chloride secretion. In controls, distension increased PD, and this response was reduced by the neural blocker tetrodotoxin given serosally and the vasoactive intestinal peptide (VIP) receptor antagonist [4Cl-d-Phe(6),Leu(17)]VIP (2 mug.min(-1).kg(-1) iv) but unaffected by the serotonin 5-HT(3) receptor antagonist granisetron, by the nicotinic receptor antagonist hexamethonium, by the muscarinic receptor antagonist atropine, or by the cyclooxygenase inhibitor indomethacin. Basal PD increased significantly with time in CT-exposed segments, an effect blocked by granisetron, by indomethacin, and by [4Cl-d-Phe(6),Leu(17)]VIP but not by hexamethonium or atropine. In contrast, once the increased basal PD produced by CT was established, [4Cl-d-Phe(6),Leu(17)]VIP and indomethacin had no significant effect, whereas granisetron and hexamethonium markedly depressed basal PD. CT significantly reduced the increase in PD produced by distension, an effect reversed by granisetron, indomethacin, and atropine. CT also activated a specific motility response to distension, repeated cluster contractions, but only in animals pretreated with granisetron, indomethacin, or atropine. These data are compatible with the hypothesis that CT induces uncontrolled activity in submucous secretory networks. Development of this state depends on 5-HT(3) receptors, VIP receptors, and prostaglandin synthesis, whereas its maintenance depends on 5-HT(3) and nicotinic receptors but not VIP receptors. The motility effects of CT (probably reflecting myenteric activity) are partially suppressed via a mechanism involving 5-HT(3

Differences in Mode of Action of Cochinchinenin A and B on ...

African Journals Online (AJOL)

HP

1College of Life Science and Bioengineering, Beijing University of ... association between cochinchinenin B and TTX-R sodium channel were ..... Data were expressed as the mean ± SEM. .... Thus at the beginning of the reaction, the drugs.

Regulation of serotonin release from enterochromaffin cells of rat cecum mucosa

International Nuclear Information System (INIS)

Simon, C.; Ternaux, J.P.

1990-01-01

The release of endogenous serotonin or previously taken up tritiated serotonin from isolated strips of rat cecum mucosa containing enterochromaffin cells was studied in vitro. Release of tritiated serotonin was increased by potassium depolarization and was decreased by tetrodotoxin, veratridine and the absence of calcium. Endogenous serotonin was released at a lower rate than tritiated serotonin; endogenous serotonin release was stimulated by potassium depolarization but was unaffected by tetrodotoxin, veratridine or the absence of calcium. Carbachol, norepinephrine, clonidine and isoproterenol decreased release of tritiated serotonin but had less or reverse effect on release of endogenous serotonin. The results suggest two different serotoninergic pools within the enterochromaffin cell population

patient entrance skin doses at minna and ibadan for common

African Journals Online (AJOL)

DR. AMINU

Entrance surface dose from two diagnostic x-ray centers in Nigeria for three common radiological examinations is .... typical ESD values for adult patients for three different ... TTX located in the region of Nigeria where regulatory activities have ...

Urotensin II modulates rapid eye movement sleep through activation of brainstem cholinergic neurons

DEFF Research Database (Denmark)

Huitron-Resendiz, Salvador; Kristensen, Morten Pilgaard; Sánchez-Alavez, Manuel

2005-01-01

administration of UII into the PPT nucleus increases REM sleep without inducing changes in the cortical blood flow. Intracerebroventricular injection of UII enhances both REM sleep and wakefulness and reduces slow-wave sleep 2. Intracerebroventricular, but not local, administration of UII increases cortical...... dorsal tegmental nuclei. This distribution suggests that the UII system is involved in functions regulated by acetylcholine, such as the sleep-wake cycle. Here, we tested the hypothesis that UII influences cholinergic PPT neuron activity and alters rapid eye movement (REM) sleep patterns in rats. Local...... synaptic transmission because it persisted in the presence of TTX and antagonists of ionotropic glutamate, GABA, and glycine receptors. Collectively, these results suggest that UII plays a role in the regulation of REM sleep independently of its cerebrovascular actions by directly activating cholinergic...

Electrically induced release of acetylcholine from denervated Schwann cells.

Science.gov (United States)

Dennis, M J; Miledi, R

1974-03-01

1. Focal electrical stimulation of Schwann cells at the end-plates of denervated frog muscles elicited slow depolarizations of up to 30 mV in the muscle fibres. This response is referred to as a Schwann-cell end-plate potential (Schwann-e.p.p.).2. Repeated stimulation sometimes evoked further Schwann-e.p.p.s, but they were never sustained for more than 30 pulses. Successive e.p.p.s varied in amplitude and time course independently of the stimulus.3. The Schwann-e.p.p.s were reversibly blocked by curare, suggesting that they result from a release of acetylcholine (ACh) by the Schwann cells.4. ACh release by electrical stimulation did not seem to occur in quantal form and was not dependent on the presence of calcium ions in the external medium; nor was it blocked by tetrodotoxin.5. Stimulation which caused release of ACh also resulted in extensive morphological disruption of the Schwann cells, as seen with both light and electron microscopy.6. It is concluded that electrical stimulation of denervated Schwann cells causes break-down of the cell membrane and releases ACh, presumably in molecular form.

Agmatine Modulation of Noradrenergic Neurotransmission in Isolated Rat Blood Vessels.

Science.gov (United States)

Török, Jozef; Zemančíková, Anna

2016-06-30

Agmatine, a vasoactive metabolite of L-arginine, is widely distributed in mammalian tissues including blood vessels. Agmatine binding to imidazoline and α₂-adrenoceptors induces a variety of physiological and pharmacological effects. We investigated the effect of agmatine on contractile responses of the rat pulmonary artery and portal vein induced by electrical stimulation of perivascular nerves and by exogenous adrenergic substances. Experiments were performed on isolated segments of rat main pulmonary artery and its extralobular branches, and portal vein suspended in organ bath containing modified Krebs bicarbonate solution and connected to a force-displacement transducer for isometric tension recording. Electrical field stimulation (EFS) produced tetrodotoxin-sensitive contractile responses of pulmonary artery and portal vein. Besides the well known vasorelaxant actions, we found that agmatine also produced a concentration-dependent inhibition of neurogenic contractions induced by EFS in pulmonary arteries; however, the agmatine treatment did not influence the responses to exogenous noradrenaline. The inhibitory effect on EFS-induced contractions was not abolished by the α₂-adrenoceptor antagonist rauwolscine. In portal vein, in contrast, agmatine increased spontaneous mechanical contractions and enhanced the contractions induced by EFS. The results suggest that agmatine can significantly influence vascular function of pulmonary arteries and portal veins by modulating sympathetically mediated vascular contractions by pre- and postsynaptic mechanisms.

The natural scorpion peptide, BmK NT1 activates voltage-gated sodium channels and produces neurotoxicity in primary cultured cerebellar granule cells.

Science.gov (United States)

Zou, Xiaohan; He, Yuwei; Qiao, Jinping; Zhang, Chunlei; Cao, Zhengyu

2016-01-01

The scorpion Buthus martensii Karsch has been used in Traditional Chinese Medicine to treat neuronal diseases such as neuropathic pain, paralysis and epilepsy for thousands of years. Studies have demonstrated that scorpion venom is the primary active component. Although scorpion venom can effectively attenuate pain in the clinic, it also produces neurotoxic response. In this study, toxicity guided purification led to identify a mammalian toxin termed BmK NT1 comprising of 65 amino acid residues and an amidated C-terminus, a mature peptide encoded by the nucleotide sequence (GenBank No. AF464898). In contract to the recombinant product of the same nucleotide sequence, BmK AGAP, which displayed analgesic and anti-tumor effect, intravenous injection (i.v.) of BmK NT1 produced acute toxicity in mice with an LD50 value of 1.36 mg/kg. In primary cultured cerebellar granule cells, BmK NT1 produced a concentration-dependent cell death with an IC50 value of 0.65 μM (0.41-1.03 μM, 95% Confidence Intervals, 95% CI) which was abolished by TTX, a voltage-gated sodium channel (VGSC) blocker. We also demonstrated that BmK NT1 produced modest sodium influx in cerebellar granule cell cultures with an EC50 value of 2.19 μM (0.76-6.40 μM, 95% CI), an effect similar to VGSC agonist, veratridine. The sodium influx response was abolished by TTX suggesting that BmK NT1-induced sodium influx is solely through activation of VGSC. Considered these data together, we demonstrated that BmK NT1 activated VGSC and produced neurotoxicity in cerebellar granule cell cultures. Copyright © 2015 Elsevier Ltd. All rights reserved.

Marine toxins and their toxicological significance: An overview

Digital Repository Service at National Institute of Oceanography (India)

Sarkar, A.

, Hemolysins-1 and hemolysin-2, saxitoxin, neosaxitoxin, gonyautoxin, tetrodotoxin, ptychodiscus brevis toxin and theonellamide F. According to their mode of action, these toxins are classified into different categories such as cytotoxin, enterotoxin...

Why do insects enter chill coma? Low temperature and high extracellular potassium compromises muscle function in Locusta migratoria

DEFF Research Database (Denmark)

Findsen, Anders; Pedersen, Thomas Holm; Nielsen, Ole Bækgaard

and a frequency of 60 Hz. To explore to what extent loss of force during cold exposure reflects loss of muscle function, all experiments were performed both in the presence and absence of TTX, which selectively inhibits motor nerve function in insects. Maximum tetanic force decreased approximately 75% when...

Characterisation of botulinum toxins type A and B, by matrix-assisted laser desorption ionisation and electrospray mass spectrometry

NARCIS (Netherlands)

Baar, B.L.M. van; Hulst, A.G.; Jong, A.L. de; Wils, E.R.J.

2002-01-01

A method earlier developed for the mass spectrometric (MS) identification of tetanus toxin (TTx) was applied to botulinum toxins type A and B (BTxA and BTxB). Botulinum toxins are extremely neurotoxic bacterial toxins, likely to be used as biological warfare agent. Biologically active BTxA and BTxB

Mechanism of norepinephrine release elicited by renal nerve stimulation, veratridine and potassium chloride in the isolated rat kidney

International Nuclear Information System (INIS)

el-Din, M.M.; Malik, K.U.

1987-01-01

We have investigated the mechanism by which renal nerve stimulation (RNS), veratridine (Vt) and KCl promote release of norepinephrine in the isolated rat kidney perfused with Tyrode's solution and prelabeled with [ 3 H]norepinephrine by examining the overflow of tritium elicited by these stimuli during 1) extracellular Ca++ depletion, 2) alterations in extracellular Na+ concentration and 3) administration of tetrodotoxin, amiloride, LiCl and calcium channel blockers. RNS (1-4 Hz), Vt (15-90 nmol) and KCl (150-500 mumol) produced renal vasoconstriction and enhanced the tritium overflow in a frequency- and concentration-dependent manner, respectively. Omission of Ca++ (1.8 mM) from the perfusion fluid abolished the renal vasoconstriction and the increase in tritium overflow elicited by RNA and KCl and substantially reduced that caused by Vt. Lowering the Na+ concentration in the perfusion medium (from 150 to 25 mM) reduced the overflow of tritium and the renal vasoconstriction caused by RNS (2 Hz) or Vt (45 nmol); the increase in tritium overflow in response to these stimuli was positively correlated with extracellular Na+ (25-150 mM). In contrast, KCl-induced tritium overflow was negatively correlated with extracellular Na+ concentration. Tetrodotoxin (0.3 microM) abolished the effect of RNS and Vt, but not that of KCl, to increase overflow of tritium and to produce renal vasoconstriction. Administration of amiloride (180 microM) enhanced the overflow of tritium but attenuated the associated renal vasoconstriction produced by RNS, Vt and KCl. Replacement of NaCl (75 mM) with equimolar concentration of LiCl enhanced the overflow of tritium elicited by RNS, Vt and KCl; the associated renal vasoconstriction remained unaltered

Effect of in vitro inorganic lead on dopamine release from superfused rat striatal synaptosomes

International Nuclear Information System (INIS)

Minnema, D.J.; Greenland, R.D.; Michaelson, I.A.

1986-01-01

The effect of inorganic lead in vitro in several aspects of [ 3 H]dopamine release from superfused rat striatal synaptosomes was examined. Under conditions of spontaneous release, lead (1-30 microM) induced dopamine release in a concentration-dependent manner. The onset of the lead-induced release was delayed by approximately 15-30 sec. The magnitude of dopamine release induced by lead was increased when calcium was removed from the superfusing buffer. Lead-induced release was unaffected in the presence of putative calcium, sodium, and/or potassium channel blockers (nickel, tetrodotoxin, tetraethylammonium, respectively). Depolarization-evoked dopamine release, produced by a 1-sec exposure to 61 mM potassium, was diminished at calcium concentrations below 0.254 mM. The onset of depolarization-evoked release was essentially immediate following exposure of the synaptosomes to high potassium. The combination of lead (3 or 10 microM) with high potassium reduced the magnitude of depolarization-evoked dopamine release. This depression of depolarization-evoked release by lead was greater in the presence of 0.25 mM than 2.54 mM calcium in the superfusing buffer. These findings demonstrate multiple actions of lead on synaptosomal dopamine release. Lead can induce dopamine release by yet unidentified neuronal mechanisms independent of external calcium. Lead can also reduce depolarization-evoked dopamine release by apparent competition with calcium influx at the neuronal membrane calcium channel

Management of hypocalcemia following total thyroidectomy

International Nuclear Information System (INIS)

Pahuja, D.N.; Patwardhan, U.N.; Samuel, A.M.

1999-01-01

A retrospective analysis of calcemic status of 500 randomly selected patients, who underwent total thyroidectomy (TTx) for differentiated thyroid carcinoma (DTC) was studied. These patients were followed up from a minimum of 2-3 years, to a maximum of 15-20 years, and calcemic status was ascertained at varying times following their surgery and radioiodine ( 131 ) therapy

Chemotherapy modulates specific aspects of cognition parallel to neurogenesis (Commentary on Nokia et al.).

NARCIS (Netherlands)

Lucassen, P.J.

2012-01-01

In this study, we demonstrate capabilities to selectively manipulate dissociated co-cultures of neurons plated in dual-compartment devices. Synaptic receptor antagonists and tetrodotoxin solutions were used to selectively control and study the network-wide burst propagation and cell firing in

Chronic blockade of bioelectric activity in neonatal rat cortex grown in vitro: morphological effects

NARCIS (Netherlands)

Ruijter, J. M.; Baker, R. E.; de Jong, B. M.; Romijn, H. J.

1991-01-01

Culture thickness, numerical density of neurons and neuronal survival were studied in timed series of control and tetrodotoxin-silenced neocortical cultures to provide information on the role of bioelectric activity on neuronal development. In control cultures, culture thickness and number of

The augmenting action of banana tree juice on skeletal muscle contraction.

Science.gov (United States)

Singh, Y N; Dryden, W F

1990-01-01

An extract obtained from juice expressed from the stem of the plantain banana tree (Musa sapientum L., var. paradisiaca) induces twitch augmentation in skeletal muscles. The mechanism of this action was investigated in the mouse hemi-diaphragm preparation. Directly evoked twitches and potassium induced (K+) contractures were both augmented by the extract. Twitch augmentation was partly dependent on extracellular Ca2+. The action on K(+)-contractures was unaffected by tetrodotoxin, but the rate of relaxation was enhanced in the absence of extracellular calcium (0[Ca2+]o). Muscle contracture induced by high concentrations of extract was also augmented in 0[Ca2+]o and in the presence of the Ca2(+)-channel blocking agent, nifedipine. The time course of the contracture was shortened in 0[Ca2+]o, but not by nifedipine. Nifedipine enhanced the augmenting effect of the extract on twitches but shortened the time-course of this action. In addition, a muscle contracture was superimposed on the twitching muscle at higher concentrations of nifedipine. Manganese, on the other hand, reduced or abolished the augmenting action of the extract. The results are consistent with an action of banana tree juice on the molecule responsible for excitation-contraction coupling in skeletal muscle, resulting in a labilization of intracellular Ca2+.

Evidence against nitrergic neuromodulation in the rat vas deferens.

Science.gov (United States)

Ventura, S; Burnstock, G

1997-09-03

Electrical field stimulation (60 V, 1 ms, single pulses or 20 s trains of 1-10 Hz) of the nerve terminals within the rat vas deferens produced biphasic contractions in preparations oriented to measure either longitudinal or circular muscle contractions. In confirmation of earlier reports, these contractions were blocked by tetrodotoxin (1 microM). The initial fast purinergic contraction was dominant in prostatic halves of the vas deferens while the second slower noradrenergic contraction was greater in epididymal halves. Although previous studies have shown nitric oxide synthase immuno-positive nerves in the vas deferens, electrical field stimulation-induced contractions were unaffected by L-arginine, sodium nitroprusside, N-nitro-L-arginine methyl ester (L-NAME) or superoxide dismutase in concentrations up to I mM. In concentrations above 1 mM, L-NAME reduced the size of the field stimulation-induced contractions but this effect could not be reversed by either L-arginine or sodium nitroprusside. Furthermore, L-arginine, sodium nitroprusside and L-NAME did not affect the contractions induced by exogenous application of noradrenaline (10 microM), ATP (1 mM) or BaCl2 (1-10 mM). We conclude that nitric oxide does not act as a neuromodulator in isolated preparations of rat vas deferens.

Dopamine regulation of [3H]acetylcholine release from guinea-pig stomach

International Nuclear Information System (INIS)

Kusunoki, M.; Taniyama, K.; Tanaka, C.

1985-01-01

The involvement of dopamine receptors in cholinergic transmission of guinea-pig stomach was investigated by analyzing the effects of dopamine receptor agonists and antagonists on acetylcholine (ACh) release from this organ. Electrical stimulation (1-20 Hz) of strips of guinea-pig stomach preloaded with [ 3 H] choline induced a [ 3 H]ACh release that was calcium dependent and tetrodotoxin sensitive. Dopamine inhibited this transmural stimulation-induced [ 3 H]ACh release in a concentration-dependent manner (10(-8)-10(-4) M). This effect of dopamine was not altered by 10(-5) M hexamethonium, thereby suggesting that the major dopamine receptors are located on the postganglionic cholinergic neurons. Concentration-response curves for dopamine on [ 3 H]ACh release were inhibited by haloperidol, sulpiride and domperidone but not by prazosin, yohimbine, propranolol and ketanserin. LY 171555, an agonist for the D2 dopamine receptor, but not SKF 38-393, an agonist for the D1 dopamine receptor, to some extent decreased the release of [ 3 H]ACh induced by transmural stimulation. In view of the results, the release of ACh from postganglionic cholinergic neurons is probably required through dopamine receptors antagonized by D2 antagonists but not by adrenergic or serotonin receptor antagonists

Al-Malkiet al., Afr J Tradit Complement Altern Med. (2016) 13(2):25 ...

African Journals Online (AJOL)

user

Background: The aim of the present study was to evaluate in vivo anti-tumor activity of Balanites aegyptiaca fruits extracts in addition to its role in ... includes chemotherapy, immunotherapy, radiotherapy, and surgery in advanced grades and stages. However ..... kidney of mice and the possible protective role of tetrodotoxin.

Differential Alterations in Excitatory and Inhibitory Networks Involving Dentate Granule Cells Following Chronic Treatment with Distinct Classes of NMDAR Antagonists in Hippocampal Slice Cultures

Science.gov (United States)

2010-03-08

Rev. 8-98) Prescribed by ANSI Std Z39-18 Copyright Statement The author herby certitles thaI the use of any copyrighted material in the thesis...synaptic Ras-GTPase activating protein TBI: traumatic brain injury TeNT: tetanus toxin TLE: temporal lobe epilepsy TEA : tetraethylammonium TTX...antagonist QX-314 non membrane permeable sodium channel blocker TEA Kv channel blocker XVI XVII List of compounds and their pharmacological actions

Spannungsaktivierte Natriumkanäle im Corpus luteum des Primaten und ihre Rolle bei der Regulation von Steroidproduktion und Luteolyse

OpenAIRE

Bulling, Andreas

2008-01-01

Im Ovar des Menschen und im Corpus Luteum des Rhesusaffen konnte die mRNA für einen bislang nur im peripheren Nervensystem und in neuroendokrinen Zellen gefundenen spannungsaktivierten Natriumkanal (eNaK, SCN9A) nachgewiesen werden. In kultivierten humanen Granulosaluteinzellen wurden sowohl die Transkriptmenge, als auch die durch depolarisierende Spannungspulse ausgelösten, TTX-sensitiven transienten Ströme durch hCG negativ reguliert. Trotz des gleichzeitigen Vorkommens spannungsaktivierter...

Novel Target for Ameliorating Pain and Other Problems after SCI: Spontaneous Activity in Nociceptors

Science.gov (United States)

2014-10-01

tetrodotoxin-sensitive inward current) carried by Nav1.8 channels. Importantly, we confirmed that Nav1.8 knockdown eliminated the increase in persistent SA...Wei, P., Zhan, S., Zhang, S., McDougall , J.J., King, O.D., Mogil, J.S., 2011. The Rat Grimace Scale: a partially automated method for quantifying pain

Neurotoxic Syndromes in Marine Poisonings a Review

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Gholam Hossein Mohebbi

2014-08-01

Full Text Available Background: Marine neurotoxins as of Marine biotoxins are natural toxins that produced mainly by dinoflagellates, diatoms and several species of invertebrates and fish. Marine poisoning results from the ingestion of marine animals contain these toxins and causes considerable adverse effects. Materials and methods: This review provides some facts about the structures of marine neurotoxins, their molecular target and pharmacology, analytical methods for their detection and quantitation, diagnosis and laboratory testing, clinical manifestations, as well as prevention and treatment, if were obtainable. Furthermore, we focus on marine poisoning and various associated neurological syndromes like ciguatera, tetrodotoxin poisoning, and paralytic shellfish poisoning, after ingestion of the common marine toxins. Results: A number of neurotoxins that prescribed according to their potency (LD50 are: Maitotoxin, Ciguatoxins and Palytoxin, Tetrodotoxin and Saxitoxin, Brevetoxins, Azaspiracid, Yessotoxin, Cooliatoxin, Domoic acid and Conotoxins, Respectively. The primary target of most marine neurotoxins is voltage gated sodium channels and the resulting block of ion conductance through these channels. Moreover, these compounds interact with voltage-gated potassium and calcium channels and modulate the flux of stated ions into many cell types. As well, the target recognized for palytoxin is the Na+- K+ /ATPase. Conclusion: Results of reviewed studies revealed that, the Ciguatera is the commonest syndrome of marine poisoning, but is rarely lethal. Puffer fish poisoning results from the ingestion of fish containing tetrodotoxin and paralytic shellfish poisoning are less common, but have a higher fatality rate than ciguatera. Despite their high toxicity, no much research has been done on some of the toxins, like maitotoxin. In addition, there have remained unknown the pharmacological effects, mechanism of action and molecular target of some toxins such as

G-protein mediates voltage regulation of agonist binding to muscarinic receptors: effects on receptor-Na+ channel interaction

International Nuclear Information System (INIS)

Cohen-Armon, M.; Garty, H.; Sokolovsky, M.

1988-01-01

The authors previous experiments in membranes prepared from rat heart and brain led them to suggest that the binding of agonist to the muscarinic receptors and to the Na + channels is a coupled event mediated by guanine nucleotide binding protein(s) [G-protein(s)]. These in vitro findings prompted us to employ synaptoneurosomes from brain stem tissue to examine (i) the binding properties of [ 3 H] acetylcholine at resting potential and under depolarization conditions in the absence and presence of pertussis toxin; (ii) the binding of [ 3 H]batrachotoxin to Na + channel(s) in the presence of the muscarinic agonists; and (iii) muscarinically induced 22 Na + uptake in the presence and absence of tetrodotoxin, which blocks Na + channels. The findings indicate that agonist binding to muscarinic receptors is voltage dependent, that this process is mediated by G-protein(s), and that muscarinic agonists induce opening of Na + channels. The latter process persists even after pertussis toxin treatment, indicating that it is not likely to be mediated by pertussis toxin sensitive G-protein(s). The system with its three interacting components-receptor, G-protein, and Na + channel-is such that at resting potential the muscarinic receptor induces opening of Na + channels; this property may provide a possible physiological mechanism for the depolarization stimulus necessary for autoexcitation or repetitive firing in heart or brain tissues

Anti-tumor activity of tetrodotoxin extracted from the Masked Puffer ...

African Journals Online (AJOL)

as demonstrated by trypan blue stain (d and f) and after treatment with Annexin V stain (e & g) (X1000). Notice ... hair erection and loss of appetite. ..... effect of vitamin A against carcinogenic effect of 7, 12- DMBA on the liver of albino rat. Egypt.

TRADOC Union List of Periodicals.

Science.gov (United States)

1988-08-01

0161-119. Apr 1986+ TSD 1979+ Cuadernos del Tercer Mundo TTY Mar 1985 - Cuba Internacional TSL 0011-2593 Current 12 issues only Cuban News and Propaganda...Australiir. Journal of Political History TSQ 198 4. Austr ,I] .liiw utl,-cAk Ti& ?r, 1-9913 1963+ Auto Wee!, TRW current issues ori] Aut ob d.\\ TTX...Consumer Guide Auto Series TTH current year onil Consumer Guide Investment Series TTH current year only Consumer News (Publication ceased in 1979) TRW Apr

TRADOC Library and Information Network (TRALINET). Union List of Periodicals (TULIP) (6th Edition)

Science.gov (United States)

1993-12-01

LIST OF PERIODICALS PAGE 87 DECEMBER 1993 AUSTRALIAN OUTLOOK TRC (0004-9913] paper 1963-1989. AUTO WEEK TRW paper Current issue only. AUTOBODY AND...LIST OF PERIODICALS PAGE 100 DECEMBER 1993 BOLETIN DEL FMI TTY paper 1989+ BON APPETIT APF [0006-6990] paper Current two years only TSS paper Jan 1988...Current month only EL DIARIO/LA PRENSA TTY (0742-9428] paper Current month only EL MERCURIO (CHILE) TTY paper Current month only EL MUNDO TTX paper

Presynaptic Glycine Receptors Increase GABAergic Neurotransmission in Rat Periaqueductal Gray Neurons

Directory of Open Access Journals (Sweden)

Kwi-Hyung Choi

2013-01-01

Full Text Available The periaqueductal gray (PAG is involved in the central regulation of nociceptive transmission by affecting the descending inhibitory pathway. In the present study, we have addressed the functional role of presynaptic glycine receptors in spontaneous glutamatergic transmission. Spontaneous EPSCs (sEPSCs were recorded in mechanically dissociated rat PAG neurons using a conventional whole-cell patch recording technique under voltage-clamp conditions. The application of glycine (100 µM significantly increased the frequency of sEPSCs, without affecting the amplitude of sEPSCs. The glycine-induced increase in sEPSC frequency was blocked by 1 µM strychnine, a specific glycine receptor antagonist. The results suggest that glycine acts on presynaptic glycine receptors to increase the probability of glutamate release from excitatory nerve terminals. The glycine-induced increase in sEPSC frequency completely disappeared either in the presence of tetrodotoxin or Cd2+, voltage-gated Na+, or Ca2+ channel blockers, suggesting that the activation of presynaptic glycine receptors might depolarize excitatory nerve terminals. The present results suggest that presynaptic glycine receptors can regulate the excitability of PAG neurons by enhancing glutamatergic transmission and therefore play an important role in the regulation of various physiological functions mediated by the PAG.

State-dependent variation in the inhibitory effect of (D-Ala sup 2 , D-Leu sup 5 )-enkephalin on hippocampal serotonin release in ground squirrels

Energy Technology Data Exchange (ETDEWEB)

Kramarova, L.I.; Lee, T.F.; Cui, Y.; Wang, L.C.H. (Univ. of Alberta, Edmonton (Canada))

1990-01-01

Accumulated evidence has suggested that increased endogenous opioid activities may facilitate the onset of hibernation either directly or possibly through modulation of other neurotransmitter systems. The seasonal change of (D-Ala{sup 2}, D-Leu{sup 5})-enkephalin (DADLE), a {delta} receptor agonist, in modulating K{sup +}-induced ({sup 3}H)-5-hydroxytryptamine (5-HT) release from the hippocampal and hypothalamic slices of euthermic and hibernating Richardsons' ground squirrels was therefore investigated. DADLE had no effect on 5-HT release in the hypothalamic slices but elicited a dose-related inhibition on ({sup 3}H)-5-HT release from the hippocampal slices of the euthermic ground squirrel. The inhibitory effect of DADLE was completely reversed by naloxone, but not by tetrodotoxin. In contrast, DADLE failed to alter the K{sup +}-induced 5-HT release from the hippocampal slices of the hibernating ground squirrel. This state-dependent reduction in responsiveness to an opioid is consistent with the hypothesis that enhanced endogenous opioid activity in the hibernating phase could lead to down regulation of the opioid receptors and minimize its inhibition on hippocampal serotonergic activity. A high 5-HT activity would inhibit midbrain reticular activating system indirectly through non-serotonergic fibers, which in turn facilitate the onset or maintenance of hibernation.

Aβ42 oligomers selectively disrupt neuronal calcium release.

Science.gov (United States)

Lazzari, Cristian; Kipanyula, Maulilio J; Agostini, Mario; Pozzan, Tullio; Fasolato, Cristina

2015-02-01

Accumulation of amyloid-β (Aβ) peptides correlates with aging and progression of Alzheimer's disease (AD). Aβ peptides, which cause early synaptic dysfunctions, spine loss, and memory deficits, also disturb intracellular Ca(2+) homeostasis. By cytosolic and endoplasmic reticulum Ca(2+) measurements, we here define the short-term effects of synthetic Aβ42 on neuronal Ca(2+) dynamics. When applied acutely at submicromolar concentration, as either oligomers or monomers, Aβ42 did not cause Ca(2+) release or Ca(2+) influx. Similarly, 1-hour treatment with Aβ42 modified neither the resting cytosolic Ca(2+) level nor the long-lasting Ca(2+) influx caused by KCl-induced depolarization. In contrast, Aβ42 oligomers, but not monomers, significantly altered Ca(2+) release from stores with opposite effects on inositol 1,4,5-trisphosphate (IP3)- and caffeine-induced Ca(2+) mobilization without alteration of the total store Ca(2+) content. Ca(2+) dysregulation by Aβ42 oligomers involves metabotropic glutamate receptor 5 and requires network activity and the intact exo-endocytotic machinery, being prevented by tetrodotoxin and tetanus toxin. These findings support the idea that Ca(2+) store dysfunction is directly involved in Aβ42 neurotoxicity and represents a potential therapeutic target in AD-like dementia. Copyright © 2015 Elsevier Inc. All rights reserved.

Methods to induce primary and secondary traumatic damage in organotypic hippocampal slice cultures.

Science.gov (United States)

Adamchik, Y; Frantseva, M V; Weisspapir, M; Carlen, P L; Perez Velazquez, J L

2000-04-01

Organotypic brain slice cultures have been used in a variety of studies on neurodegenerative processes [K.M. Abdel-Hamid, M. Tymianski, Mechanisms and effects of intracellular calcium buffering on neuronal survival in organotypic hippocampal cultures exposed to anoxia/aglycemia or to excitotoxins, J. Neurosci. 17, 1997, pp. 3538-3553; D.W. Newell, A. Barth, V. Papermaster, A.T. Malouf, Glutamate and non-glutamate receptor mediated toxicity caused by oxygen and glucose deprivation in organotypic hippocampal cultures, J. Neurosci. 15, 1995, pp. 7702-7711; J.L. Perez Velazquez, M.V. Frantseva, P.L. Carlen, In vitro ischemia promotes glutamate mediated free radical generation and intracellular calcium accumulation in pyramidal neurons of cultured hippocampal slices, J. Neurosci. 23, 1997, pp. 9085-9094; L. Stoppini, L.A. Buchs, D. Muller, A simple method for organotypic cultures of nervous tissue, J. Neurosci. Methods 37, 1991, pp. 173-182; R.C. Tasker, J.T. Coyle, J.J. Vornov, The regional vulnerability to hypoglycemia induced neurotoxicity in organotypic hippocampal culture: protection by early tetrodotoxin or delayed MK 801, J. Neurosci. 12, 1992, pp. 4298-4308.]. We describe two methods to induce traumatic cell damage in hippocampal organotypic cultures. Primary trauma injury was achieved by rolling a stainless steel cylinder (0.9 g) on the organotypic slices. Secondary injury was followed after dropping a weight (0.137 g) on a localised area of the organotypic slice, from a height of 2 mm. The time course and extent of cell death were determined by measuring the fluorescence of the viability indicator propidium iodide (PI) at several time points after the injury. The initial localised impact damage spread 24 and 67 h after injury, cell death being 25% and 54%, respectively, when slices were kept at 37 degrees C. To validate these methods as models to assess neuroprotective strategies, similar insults were applied to slices at relatively low temperatures (30

Neuropathic pain in experimental autoimmune neuritis is associated with altered electrophysiological properties of nociceptive DRG neurons.

Science.gov (United States)

Taha, Omneya; Opitz, Thoralf; Mueller, Marcus; Pitsch, Julika; Becker, Albert; Evert, Bernd Oliver; Beck, Heinz; Jeub, Monika

2017-11-01

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na + current measurements revealed a significant increase of the fast TTX-sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na + currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na + channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals. Copyright © 2017 Elsevier Inc. All rights reserved.

Modulatory effects of taurine on jejunal contractility

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Q.Y. Yao

2014-12-01

Full Text Available Taurine (2-aminoethanesulfonic acid is widely distributed in animal tissues and has diverse pharmacological effects. However, the role of taurine in modulating smooth muscle contractility is still controversial. We propose that taurine (5-80 mM can exert bidirectional modulation on the contractility of isolated rat jejunal segments. Different low and high contractile states were induced in isolated jejunal segments of rats to observe the effects of taurine and the associated mechanisms. Taurine induced stimulatory effects on the contractility of isolated rat jejunal segments at 3 different low contractile states, and inhibitory effects at 3 different high contractile states. Bidirectional modulation was not observed in the presence of verapamil or tetrodotoxin, suggesting that taurine-induced bidirectional modulation is Ca2+ dependent and requires the presence of the enteric nervous system. The stimulatory effects of taurine on the contractility of isolated jejunal segments was blocked by atropine but not by diphenhydramine or by cimetidine, suggesting that muscarinic-linked activation was involved in the stimulatory effects when isolated jejunal segments were in a low contractile state. The inhibitory effects of taurine on the contractility of isolated jejunal segments were blocked by propranolol and L-NG-nitroarginine but not by phentolamine, suggesting that adrenergic β receptors and a nitric oxide relaxing mechanism were involved when isolated jejunal segments were in high contractile states. No bidirectional effects of taurine on myosin phosphorylation were observed. The contractile states of jejunal segments determine taurine-induced stimulatory or inhibitory effects, which are associated with muscarinic receptors and adrenergic β receptors, and a nitric oxide associated relaxing mechanism.

Modulatory effects of taurine on jejunal contractility

Energy Technology Data Exchange (ETDEWEB)

Yao, Q.Y.; Chen, D.P.; Ye, D.M.; Diao, Y.P.; Lin, Y. [Dalian Medical University, Dalian, Liaoning (China)

2014-10-14

Taurine (2-aminoethanesulfonic acid) is widely distributed in animal tissues and has diverse pharmacological effects. However, the role of taurine in modulating smooth muscle contractility is still controversial. We propose that taurine (5-80 mM) can exert bidirectional modulation on the contractility of isolated rat jejunal segments. Different low and high contractile states were induced in isolated jejunal segments of rats to observe the effects of taurine and the associated mechanisms. Taurine induced stimulatory effects on the contractility of isolated rat jejunal segments at 3 different low contractile states, and inhibitory effects at 3 different high contractile states. Bidirectional modulation was not observed in the presence of verapamil or tetrodotoxin, suggesting that taurine-induced bidirectional modulation is Ca{sup 2+} dependent and requires the presence of the enteric nervous system. The stimulatory effects of taurine on the contractility of isolated jejunal segments was blocked by atropine but not by diphenhydramine or by cimetidine, suggesting that muscarinic-linked activation was involved in the stimulatory effects when isolated jejunal segments were in a low contractile state. The inhibitory effects of taurine on the contractility of isolated jejunal segments were blocked by propranolol and L-NG-nitroarginine but not by phentolamine, suggesting that adrenergic β receptors and a nitric oxide relaxing mechanism were involved when isolated jejunal segments were in high contractile states. No bidirectional effects of taurine on myosin phosphorylation were observed. The contractile states of jejunal segments determine taurine-induced stimulatory or inhibitory effects, which are associated with muscarinic receptors and adrenergic β receptors, and a nitric oxide associated relaxing mechanism.

Multivesicular release underlies short term synaptic potentiation independent of release probability change in the supraoptic nucleus.

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Michelle E Quinlan

Full Text Available Magnocellular neurons of the supraoptic nucleus receive glutamatergic excitatory inputs that regulate the firing activity and hormone release from these neurons. A strong, brief activation of these excitatory inputs induces a lingering barrage of tetrodotoxin-resistant miniature EPSCs (mEPSCs that lasts for tens of minutes. This is known to accompany an immediate increase in large amplitude mEPSCs. However, it remains unknown how long this amplitude increase can last and whether it is simply a byproduct of greater release probability. Using in vitro patch clamp recording on acute rat brain slices, we found that a brief, high frequency stimulation (HFS of afferents induced a potentiation of mEPSC amplitude lasting up to 20 min. This amplitude potentiation did not correlate with changes in mEPSC frequency, suggesting that it does not reflect changes in presynaptic release probability. Nonetheless, neither postsynaptic calcium chelator nor the NMDA receptor antagonist blocked the potentiation. Together with the known calcium dependency of HFS-induced potentiation of mEPSCs, our results imply that mEPSC amplitude increase requires presynaptic calcium. Further analysis showed multimodal distribution of mEPSC amplitude, suggesting that large mEPSCs were due to multivesicular glutamate release, even at late post-HFS when the frequency is no longer elevated. In conclusion, high frequency activation of excitatory synapses induces lasting multivesicular release in the SON, which is independent of changes in release probability. This represents a novel form of synaptic plasticity that may contribute to prolonged excitatory tone necessary for generation of burst firing of magnocellular neurons.

Modulatory effects of taurine on jejunal contractility

International Nuclear Information System (INIS)

Yao, Q.Y.; Chen, D.P.; Ye, D.M.; Diao, Y.P.; Lin, Y.

2014-01-01

Taurine (2-aminoethanesulfonic acid) is widely distributed in animal tissues and has diverse pharmacological effects. However, the role of taurine in modulating smooth muscle contractility is still controversial. We propose that taurine (5-80 mM) can exert bidirectional modulation on the contractility of isolated rat jejunal segments. Different low and high contractile states were induced in isolated jejunal segments of rats to observe the effects of taurine and the associated mechanisms. Taurine induced stimulatory effects on the contractility of isolated rat jejunal segments at 3 different low contractile states, and inhibitory effects at 3 different high contractile states. Bidirectional modulation was not observed in the presence of verapamil or tetrodotoxin, suggesting that taurine-induced bidirectional modulation is Ca 2+ dependent and requires the presence of the enteric nervous system. The stimulatory effects of taurine on the contractility of isolated jejunal segments was blocked by atropine but not by diphenhydramine or by cimetidine, suggesting that muscarinic-linked activation was involved in the stimulatory effects when isolated jejunal segments were in a low contractile state. The inhibitory effects of taurine on the contractility of isolated jejunal segments were blocked by propranolol and L-NG-nitroarginine but not by phentolamine, suggesting that adrenergic β receptors and a nitric oxide relaxing mechanism were involved when isolated jejunal segments were in high contractile states. No bidirectional effects of taurine on myosin phosphorylation were observed. The contractile states of jejunal segments determine taurine-induced stimulatory or inhibitory effects, which are associated with muscarinic receptors and adrenergic β receptors, and a nitric oxide associated relaxing mechanism

Modulatory effects of taurine on jejunal contractility

Science.gov (United States)

Yao, Q.Y.; Chen, D.P.; Ye, D.M.; Diao, Y.P.; Lin, Y.

2014-01-01

Taurine (2-aminoethanesulfonic acid) is widely distributed in animal tissues and has diverse pharmacological effects. However, the role of taurine in modulating smooth muscle contractility is still controversial. We propose that taurine (5-80 mM) can exert bidirectional modulation on the contractility of isolated rat jejunal segments. Different low and high contractile states were induced in isolated jejunal segments of rats to observe the effects of taurine and the associated mechanisms. Taurine induced stimulatory effects on the contractility of isolated rat jejunal segments at 3 different low contractile states, and inhibitory effects at 3 different high contractile states. Bidirectional modulation was not observed in the presence of verapamil or tetrodotoxin, suggesting that taurine-induced bidirectional modulation is Ca2+ dependent and requires the presence of the enteric nervous system. The stimulatory effects of taurine on the contractility of isolated jejunal segments was blocked by atropine but not by diphenhydramine or by cimetidine, suggesting that muscarinic-linked activation was involved in the stimulatory effects when isolated jejunal segments were in a low contractile state. The inhibitory effects of taurine on the contractility of isolated jejunal segments were blocked by propranolol and L-NG-nitroarginine but not by phentolamine, suggesting that adrenergic β receptors and a nitric oxide relaxing mechanism were involved when isolated jejunal segments were in high contractile states. No bidirectional effects of taurine on myosin phosphorylation were observed. The contractile states of jejunal segments determine taurine-induced stimulatory or inhibitory effects, which are associated with muscarinic receptors and adrenergic β receptors, and a nitric oxide associated relaxing mechanism. PMID:25387674

Neurokinin-1 receptor activation in globus pallidus

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Lei Chen

2009-10-01

Full Text Available The undecapeptide substance P has been demonstrated to modulate neuronal activity in a number of brain regions by acting on neurokinin-1 receptors. Anatomical studies revealed a moderate level of neurokinin-1 receptor in rat globus pallidus. To determine the electrophysiological effects of neurokinin-1 receptor activation in globus pallidus, whole-cell patch-clamp recordings were performed in the present study. Under current-clamp recordings, neurokinin-1 receptor agonist, [Sar9, Met(O211] substance P (SM-SP at 1 μM, depolarized globus pallidus neurons and increased their firing rate. Consistently, SM-SP induced an inward current under voltage-clamp recording. The depolarization evoked by SM-SP persisted in the presence of tetrodotoxin, glutamate and GABA receptor antagonists, indicating its direct postsynaptic effects. The neurokinin-1 receptor antagonist, SR140333B, could block SM-SP-induced depolarization. Further experiments showed that suppression of potassium conductance was the predominant ionic mechanism of SM-SP-induced depolarization. To determine if neurokinin-1 receptor activation exerts any effects on GABAergic and glutamatergic neurotransmission, the action of SM-SP on synaptic currents was studied. SM-SP significantly increased the frequency of spontaneous inhibitory postsynaptic currents, but only induced a transient increase in the frequency of miniature inhibitory postsynaptic currents. No change was observed in both spontaneous and miniature excitatory postsynaptic currents. Based on the direct excitatory effects of SM-SP on pallidal neurons, we hypothesize that neurokinin-1 receptor activation in globus pallidus may be involved in the beneficial effect of substance P in Parkinson’s disease.

Transcriptomic Analysis of Ciguatoxin-Induced Changes in Gene Expression in Primary Cultures of Mice Cortical Neurons

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Juan Andrés Rubiolo

2018-05-01

Full Text Available Ciguatoxins are polyether marine toxins that act as sodium channel activators. These toxins cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents several symptoms in humans including long-term neurological alterations. Earlier work has shown that both acute and chronic exposure of primary cortical neurons to synthetic ciguatoxin CTX3C have profound impacts on neuronal function. Thus, the present work aimed to identify relevant neuronal genes and metabolic pathways that could be altered by ciguatoxin exposure. To study the effect of ciguatoxins in primary neurons in culture, we performed a transcriptomic analysis using whole mouse genome microarrays, for primary cortical neurons exposed during 6, 24, or 72 h in culture to CTX3C. Here, we have shown that the effects of the toxin on gene expression differ with the exposure time. The results presented here have identified several relevant genes and pathways related to the effect of ciguatoxins on neurons and may assist in future research or even treatment of ciguatera. Moreover, we demonstrated that the effects of the toxin on gene expression were exclusively consequential of its action as a voltage-gated sodium channel activator, since all the effects of CTX3C were avoided by preincubation of the neurons with the sodium channel blocker tetrodotoxin.

Anoxia increases potassium conductance in hippocampal nerve cells.

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Hansen, A J; Hounsgaard, J; Jahnsen, H

1982-07-01

The effect of anoxia on nerve cell function was studied by intra- and extracellular microelectrode recordings from the CA1 and CA3 region in guinea pig hippocampal slices. Hyperpolarization and concomitant reduction of the nerve cell input resistance was observed early during anoxia. During this period the spontaneous activity first disappeared, then the evoked activity gradually disappeared. The hyperpolarization was followed by depolarization and an absence of a measurable input resistance. All the induced changes were reversed when the slice was reoxygenated. Reversal of the electro-chemical gradient for Cl- across the nerve cell membrane did not affect the course of events during anoxia. Aminopyridines blocked the anoxic hyperpolarization and attenuated the decrease of membrane resistance, but had no effect on the later depolarization. Blockers of synaptic transmission. Mn++, Mg++ and of Na+-channels (TTX) were without effect on the nerve cell changes during anoxia. It is suggested that the reduction of nerve cell excitability in anoxia is primarily due to increased K+-conductance. Thus, the nerve cells are hyperpolarized and the input resistance reduced, causing higher threshold and reduction of synaptic potentials. The mechanism of the K+-conductance activation is unknown at present.

Induced Abortion

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... Education & Events Advocacy For Patients About ACOG Induced Abortion Home For Patients Search FAQs Induced Abortion Page ... Induced Abortion FAQ043, May 2015 PDF Format Induced Abortion Special Procedures What is an induced abortion? What ...

Affinity purification of the voltage-sensitive sodium channel from electroplax with resins selective for sialic acid

Energy Technology Data Exchange (ETDEWEB)

James, W.M.; Emerick, M.C.; Agnew, W.S. (Yale Univ. School of medicine, New Haven, CT (USA))

1989-07-11

The voltage-sensitive sodium channel present in the eel (Electrophorus electricus) has an unusually high content of sialic acid, including {alpha}-(2{yields}8)-linked polysialic acid, not found in other electroplax membrane glycopeptides. Lectins from Limax flavus (LFA) and wheat germ (WGA) proved the most effective of 11 lectin resins tried. The most selective resin was prepared from IgM antibodies against Neisseria meningitidis {alpha}-(2{yields}8)-polysialic acid which were affinity purified and coupled to Sepharose 4B. The sodium channel was found to bind to WGA, LFA, and IgM resins and was readily eluted with the appropriate soluble carbohydrates. Experiments with LFA and IgM resins demonstrated binding and unbinding rates and displacement kinetics, which suggest highly specific binding at multiple sites on the sodium channel protein. In preparative-scale purification of protein previously fractionated by anion-exchange chromatography, without stabilizing TTX, high yields were reproducibly obtained. Further, when detergent extracts were prepared from electroplax membranes fractionated by low-speed sedimentation, a single step over the IgM resin provided a 70-fold purification, yielding specific activities of 3,200 pmol of ({sup 3}H)TTX-binding sites/mg of protein and a single polypeptide of {approximately}285,000 Da on SDS-acrylamide gels. No small peptides were observed after this 5-h isolation. The authors describe a cation-dependent stabilization with millimolar levels of monovalent and micromolar levels of divalent species.

Purinergic modulation of adult guinea pig cardiomyocytes in long term cultures and co-cultures with extracardiac or intrinsic cardiac neurones.

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Horackova, M; Huang, M H; Armour, J A

1994-05-01

To determine the capacity of ATP to modify cardiomyocytes directly or indirectly via peripheral autonomic neurones, the effects of various purinergic agents were studied on long term cultures of adult guinea pig ventricular myocytes and their co-cultures with extracardiac (stellate ganglion) or intrinsic cardiac neurones. Ventricular myocytes and cardiac neurones were enzymatically dissociated and plated together or alone (myocytes only). Myocyte cultures were used for experiments after three to six weeks. The electrical and contractile properties of cultured myocytes and myocyte-neuronal networks were investigated. The spontaneous beating frequency of ventricular myocytes co-cultured with stellate ganglion neurones increased by approximately 140% (p under control conditions, but when beta adrenergic receptors of tetrodotoxin sensitive neural responses were blocked, ATP induced greater augmentation (> 100%). In contrast, ATP induced much smaller effects in non-innervated myocyte cultures (approximately 26%, p UTP > MSATP > beta gamma ATP > alpha beta ATP. Adenosine (10(-4) M) attenuated the beating frequency of myocytes in both types of co-culture, while not significantly affecting non-innervated myocyte cultures. The experimental model used in this study showed that extrinsic and intrinsic cardiac neurones which possess P2 receptors can greatly enhance cardiac myocyte contractile rate when activated by ATP. Since adenosine reduced contractile rate in both types of co-cultures while not affecting non-innervated myocytes, it is concluded that some of these neurones possess P1 receptors.

Effects of Levetiracetam, Carbamazepine, Phenytoin, Valproate, Lamotrigine, Oxcarbazepine, Topiramate, Vinpocetine and Sertraline on Presynaptic Hippocampal Na(+) and Ca(2+) Channels Permeability.

Science.gov (United States)

Sitges, María; Chiu, Luz María; Reed, Ronald C

2016-04-01

Ion channels are targets of various antiepileptic drugs. In cerebral presynaptic nerve endings Na(+) and Ca(2+) channels are particularly abundant, as they control neurotransmitter release, including the release of glutamate (Glu), the most concentrated excitatory amino acid neurotransmitter in the brain. Several pre-synaptic channels are implicated in the mechanism of action of the pro-convulsive agent, 4-aminopyridine (4-AP). In the present study the effects of levetiracetam and other established and newer (vinpocetine) anti-epileptic drugs, as well as of the anti-depressant, sertraline on the increase in Ca(2+) induced by 4-AP in hippocampal isolated nerve endings were investigated. Also the effects of some of the anti-seizure drugs on the selective increase in Ca(2+) induced by high K(+), or on the selective increase in Na(+) induced by veratridine were tested. Sertraline and vinpocetine effectively inhibited the rise in Ca(2+) induced by 4-AP, which was dependent on the out-in Na(+) gradient and tetrodotoxin sensitive. Carbamazepine, phenytoin, lamotrigine and oxcarbazepine inhibited the rise in Ca(2+) induced by 4-AP too, but at higher concentrations than sertraline and vinpocetine, whereas levetiracetam, valproic acid and topiramate did not. The three latter antiepileptic drugs also failed in modifying other responses mediated by the activation of brain presynaptic Na(+) or Ca(2+) channels, including Glu release. This indicates that levetiracetam, valproic acid and topiramate mechanisms of action are unrelated with a decrease in presynaptic Na(+) or Ca(2+) channels permeability. It is concluded that depolarized cerebral isolated nerve endings represent a useful tool to unmask potential antiepileptic drugs targeting presynaptic Na(+) and/or Ca(2+) channels in the brain; such as vinpocetine or the anti-depressant sertraline, which high effectiveness to control seizures in the animal in vivo has been demonstrated.

Conducted vasoconstriction in rat mesenteric arterioles: role for dihydropyridine-insensitive Ca(2+) channels

DEFF Research Database (Denmark)

Gustafsson, F; Andreasen, D; Salomonsson, Max

2001-01-01

The aim of this study was to evaluate the role of voltage-operated Ca(2+) channels in the initiation and conduction of vasoconstrictor responses to local micropipette electrical stimulation of rat mesenteric arterioles (28 +/- 1 microm, n = 79) in vivo. Local and conducted (600 microm upstream from...... the pipette) vasoconstriction was not blocked by TTX (1 micromol/l, n = 5), nifedipine, or nimodipine (10 micromol/l, n = 9). Increasing the K(+) concentration of the superfusate to 75 mmol/l did not evoke vasoconstriction, but this depolarizing stimulus reversibly abolished vasoconstrictor responses...

A Common Structural Component for β-Subunit Mediated Modulation of Slow Inactivation in Different KV Channels

DEFF Research Database (Denmark)

Strutz-Seebohm, Nathalie; Henrion, Ulrike; Schmitt, Nicole

2013-01-01

Background/Aims: Potassium channels are tetrameric proteins providing potassium selective passage through lipid embedded proteinaceous pores with highest fidelity. The selectivity results from binding to discrete potassium binding sites and stabilization of a hydrated potassium ion in a central...... internal cavity. The four potassium binding sites, generated by the conserved TTxGYGD signature sequence are formed by the backbone carbonyls of the amino acids TXGYG. Residues KV1.5-Val481, KV4.3-Leu368 and KV7.1- Ile 313 represent the amino acids in the X position of the respective channels. Methods...

Early enriched environment exposure protects spatial memory and accelerates amyloid plaque formation in APP(Swe/PS1(L166P mice.

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Francesca Montarolo

Full Text Available Enriched environment exposure improves several aspects of cognitive performance in Alzheimer's disease patients and in animal models and, although the role of amyloid plaques is questionable, several studies also assessed their response to enriched environment, with contrasting results. Here we report that rearing APP(Swe/PS1(L166P mice in an enriched environment since birth rescued the spatial memory impairment otherwise present at 6 months of age. At the same time, the exposure to the enriched environment caused a transient acceleration of plaque formation, while there was no effect on intracellular staining with the 6E10 antibody, which recognizes β-amyloid, full length amyloid precursor protein and its C-terminal fragments. The anticipation of plaque formation required exposure during early development, suggesting an action within critical periods for circuits formation. On the other hand, chronic neuronal activity suppression by tetrodotoxin decreased the number of plaques without affecting intracellular amyloid. These results indicate that enriched environment exposure since early life has a protective effect on cognitive deterioration although transiently accelerates amyloid deposition. In addition, the effects of the enriched environment might be due to increased neuronal activity, because plaques were reduced by suppression of electrical signaling by tetrodotoxin.

Induced Seismicity

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Keranen, Katie M.; Weingarten, Matthew

2018-05-01

The ability of fluid-generated subsurface stress changes to trigger earthquakes has long been recognized. However, the dramatic rise in the rate of human-induced earthquakes in the past decade has created abundant opportunities to study induced earthquakes and triggering processes. This review briefly summarizes early studies but focuses on results from induced earthquakes during the past 10 years related to fluid injection in petroleum fields. Study of these earthquakes has resulted in insights into physical processes and has identified knowledge gaps and future research directions. Induced earthquakes are challenging to identify using seismological methods, and faults and reefs strongly modulate spatial and temporal patterns of induced seismicity. However, the similarity of induced and natural seismicity provides an effective tool for studying earthquake processes. With continuing development of energy resources, increased interest in carbon sequestration, and construction of large dams, induced seismicity will continue to pose a hazard in coming years.

miR-34b/c Regulates Wnt1 and Enhances Mesencephalic Dopaminergic Neuron Differentiation

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Roberto De Gregorio

2018-04-01

Full Text Available Summary: The differentiation of dopaminergic neurons requires concerted action of morphogens and transcription factors acting in a precise and well-defined time window. Very little is known about the potential role of microRNA in these events. By performing a microRNA-mRNA paired microarray screening, we identified miR-34b/c among the most upregulated microRNAs during dopaminergic differentiation. Interestingly, miR-34b/c modulates Wnt1 expression, promotes cell cycle exit, and induces dopaminergic differentiation. When combined with transcription factors ASCL1 and NURR1, miR-34b/c doubled the yield of transdifferentiated fibroblasts into dopaminergic neurons. Induced dopaminergic (iDA cells synthesize dopamine and show spontaneous electrical activity, reversibly blocked by tetrodotoxin, consistent with the electrophysiological properties featured by brain dopaminergic neurons. Our findings point to a role for miR-34b/c in neuronal commitment and highlight the potential of exploiting its synergy with key transcription factors in enhancing in vitro generation of dopaminergic neurons. : In this article, Bellenchi and colleagues show that the microRNA miR-34b/c is expressed in FACS-purified Pitx3-GFP+ neurons and promotes dopaminergic differentiation by negative modulating Wnt1 and the downstream WNT signaling pathway. Induced dopaminergic cells, expressing miR-34b/c, synthesize dopamine and show the electrophysiological properties featured by brain dopaminergic neurons. Keywords: microRNA, dopamine, mESC, miR34b/c, epiSC, transdifferentiation, Wnt1, Wnt pathway, reprogramming

Neurovascular and Autonomic Dysfunction Associated with Gulf War Illness Pain

Science.gov (United States)

2016-10-01

from nerve agents such as Soman or Tabun ( Gordon et al., 1978; Gall, 1981; Ray et al., 1991; Adler, et al., 1992; Kassa and Vachek, 2002; Kassa and...distribution. Based on distribution normality or non-normality, parametric (Two-sample t-tests) or non- parametric (Mann- Whitney rank sum tests) analyses...sensitive and tetrodotoxin-resistant sodium channels to the insecticide allethrin in rat dorsal root ganglion neurons." Brain Res 627(2): 239-248. Gordon

Regulation of Na(+)/K(+)-ATPase by nuclear respiratory factor 1: implication in the tight coupling of neuronal activity, energy generation, and energy consumption.

Science.gov (United States)

Johar, Kaid; Priya, Anusha; Wong-Riley, Margaret T T

2012-11-23

NRF-1 regulates mediators of neuronal activity and energy generation. NRF-1 transcriptionally regulates Na(+)/K(+)-ATPase subunits α1 and β1. NRF-1 functionally regulates mediators of energy consumption in neurons. NRF-1 mediates the tight coupling of neuronal activity, energy generation, and energy consumption at the molecular level. Energy generation and energy consumption are tightly coupled to neuronal activity at the cellular level. Na(+)/K(+)-ATPase, a major energy-consuming enzyme, is well expressed in neurons rich in cytochrome c oxidase, an important enzyme of the energy-generating machinery, and glutamatergic receptors that are mediators of neuronal activity. The present study sought to test our hypothesis that the coupling extends to the molecular level, whereby Na(+)/K(+)-ATPase subunits are regulated by the same transcription factor, nuclear respiratory factor 1 (NRF-1), found recently by our laboratory to regulate all cytochrome c oxidase subunit genes and some NMDA and AMPA receptor subunit genes. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation, promoter mutational analysis, and real-time quantitative PCR, NRF-1 was found to functionally bind to the promoters of Atp1a1 and Atp1b1 genes but not of the Atp1a3 gene in neurons. The transcripts of Atp1a1 and Atp1b1 subunit genes were up-regulated by KCl and down-regulated by tetrodotoxin. Atp1b1 is positively regulated by NRF-1, and silencing of NRF-1 with small interference RNA blocked the up-regulation of Atp1b1 induced by KCl, whereas overexpression of NRF-1 rescued these transcripts from being suppressed by tetrodotoxin. On the other hand, Atp1a1 is negatively regulated by NRF-1. The binding sites of NRF-1 on Atp1a1 and Atp1b1 are conserved among mice, rats, and humans. Thus, NRF-1 regulates key Na(+)/K(+)-ATPase subunits and plays an important role in mediating the tight coupling between

Permissive effect of dexamethasone on the increase of proenkephalin mRNA induced by depolarization of chromaffin cells

International Nuclear Information System (INIS)

Naranjo, J.R.; Mocchetti, I.; Schwartz, J.P.; Costa, E.

1986-01-01

In cultured bovine chromaffin cells, changes in the dynamic state of enkephalin stores elicited experimentally were studied by measuring cellular proenkephalin mRNA, as well as enkephalin precursors and authentic enkephalin content of cells and culture media. In parallel, tyrosine hydroxylase mRNA and catecholamine cell content were also determined. Low concentrations (0.5-100 pM) of dexamethasone increased the cell contents of proenkephalin mRNA and enkephalin-containing peptides. High concentrations of the hormone(1 μM) were required to increase the cell contents of tyrosine hydroxylase mRNA and catecholamines. Depolarization of the cells with 10 μM veratridine resulted in a depletion of enkephalin and catecholamine stores after 24 hr. The enkephalin, but not the catecholamine, content was restored by 48 hr. An increase in proenkephalin mRNA content might account for the recovery; this increase was curtailed by tetrodotoxin and enhanced by 10 pM dexamethasone. Tyrosine hydroxylase mRNA content was not significantly modified by depolarization, even in the presence of 1 μM dexamethasone. Aldosterone, progesterone, testosterone, or estradiol (1 μM) failed to change proenkephalin mRNA. Hence, dexamethasone appears to exert a specific permissive action on the stimulation of the proenkephalin gene elicited by depolarization. Though the catecholamines and enkephalins are localized in the same chromaffin granules and are coreleased by depolarization, the genes coding for the processes that are rate limiting in the production of these neuromodulators can be differentially regulated

Exercise-Induced Asthma

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... Videos for Educators Search English Español Exercise-Induced Asthma KidsHealth / For Parents / Exercise-Induced Asthma What's in ... Exercise-Induced Asthma Print What Is Exercise-Induced Asthma? Most kids and teens with asthma have symptoms ...

Iodine-131 treatment and chromosomal damage: in vivo dose-effect relationship.

Science.gov (United States)

Erselcan, Taner; Sungu, Selma; Ozdemir, Semra; Turgut, Bulent; Dogan, Derya; Ozdemir, Ozturk

2004-05-01

Although it is well known that radiation induces chromosomal aberrations, there is a lack of information on the in vivo dose-effect relationship in patients receiving iodine-131 treatment, and the results of previous studies are controversial. In this study, the sister chromatid exchange (SCE) method was employed to investigate acute and late chromosomal damage (CD) in the peripheral lymphocytes of 15 patients who received various doses of (131)I (259-3,700 MBq), either for thyrotoxicosis (TTX) or for ablation treatment in differentiated thyroid cancer (DTC). The SCE frequencies in cultured peripheral lymphocytes were determined before treatment (to assess basal SCE frequencies), on the 3rd day (to assess acute SCE frequencies) and 6 months later (to assess late SCE frequencies). The basal, acute and late SCE frequencies (mean+/-SD) were 3.19+/-0.93, 10.83+/-1.72 and 5.75+/-2.06, respectively, in the whole group, and these values differed significantly from each other ( Pdisappearance of damaged lymphocytes from the peripheral circulation in a dose-dependent manner following (131)I treatment. Further studies are therefore needed to clarify the effect of the negative beta value on the biological dosimetry approach in continuous internal low LET radiation, as in the case of (131)I treatment.

Ride comfort analysis with physiological parameters for an e-health train.

Science.gov (United States)

Lee, Youngbum; Shin, Kwangsoo; Lee, Sangjoon; Song, Yongsoo; Han, Sungho; Lee, Myoungho

2009-12-01

Transportation by train has numerous advantages over road transportation, especially with regard to energy efficiency, ecological features, safety, and punctuality. However, the contrast in ride comfort between standard road transportation and train travel has become a competitive issue. The ride comfort enhancement technology of tilting trains (TTX) is a particularly important issue in the development of the Korean high-speed railroad business. Ride comfort is now defined in international standards such as UIC13 and ISO2631. The Korean standards such as KSR9216 mainly address physical parameters such as vibration and noise. In the area of ride comfort, living quality parameter techniques have recently been considered in Korea, Japan, and Europe. This study introduces biological parameters, particularly variations in heart rate, as a more direct measure of comfort. Biological parameters are based on physiological responses rather than on purely external mechanical parameters. Variability of heart rate and other physiological parameters of passengers are measured in a simulation involving changes in the tilting angle of the TTX. This research is a preliminary study for the implementation of an e-health train, which would provide passengers with optimized ride comfort. The e-health train would also provide feedback on altered ride comfort situations that can improve a passenger's experience and provide a healthcare service on the train. The aim of this research was to develop a ride comfort evaluation system for the railway industry, the automobile industry, and the air industry. The degree of tilt correlated with heart rate, fatigue, and unrelieved alertness.

Liberia national disaster preparedness coordination exercise: Implementing lessons learned from the West African disaster preparedness initiative.

Science.gov (United States)

Hamer, Melinda J Morton; Reed, Paul L; Greulich, Jane D; Beadling, Charles W

2017-01-01

In light of the recent Ebola outbreak, there is a critical need for effective disaster management systems in Liberia and other West African nations. To this end, the West Africa Disaster Preparedness Initiative held a disaster management exercise in conjunction with the Liberian national government on November 24-25, 2015. During this tabletop exercise (TTX), interactions within and between the 15 counties and the Liberian national government were conducted and observed to refine and validate the county and national standard operating procedures (SOPs). The exercise took place in three regional locations throughout Liberia: Monrovia, Buchanan, and Bong. The TTX format allowed counties to collaborate utilizing open-source software platforms including Ushahidi, Sahana, QGIS, and KoBoCollect. Four hundred sixty-seven individuals (representing all 15 counties of Liberia) identified as key actors involved with emergency operations and disaster preparedness participated in the exercise. A qualitative survey with open-ended questions was administered to exercise participants to determine needed improvements in the disaster management system in Liberia. Key findings from the exercise and survey include the need for emergency management infrastructure to extend to the community level, establishment of a national disaster management agency and emergency operations center, customized local SOPs, ongoing surveillance, a disaster exercise program, and the need for effective data sharing and hazard maps. These regional exercises initiated the process of validating and refining Liberia's national and county-level SOPs. Liberia's participation in this exercise has provided a foundation for advancing its preparedness, response, and recovery capacities and could provide a template for other countries to use.

Synaptically released zinc triggers metabotropic signaling via a zinc-sensing receptor in the hippocampus.

Science.gov (United States)

Besser, Limor; Chorin, Ehud; Sekler, Israel; Silverman, William F; Atkin, Stan; Russell, James T; Hershfinkel, Michal

2009-03-04

Zn(2+) is coreleased with glutamate from mossy fiber terminals and can influence synaptic function. Here, we demonstrate that synaptically released Zn(2+) activates a selective postsynaptic Zn(2+)-sensing receptor (ZnR) in the CA3 region of the hippocampus. ZnR activation induced intracellular release of Ca(2+), as well as phosphorylation of extracellular-regulated kinase and Ca(2+)/calmodulin kinase II. Blockade of synaptic transmission by tetrodotoxin or CdCl inhibited the ZnR-mediated Ca(2+) rises. The responses mediated by ZnR were largely attenuated by the extracellular Zn(2+) chelator, CaEDTA, and in slices from mice lacking vesicular Zn(2+), suggesting that synaptically released Zn(2+) triggers the metabotropic activity. Knockdown of the expression of the orphan G-protein-coupled receptor 39 (GPR39) attenuated ZnR activity in a neuronal cell line. Importantly, we observed widespread GPR39 labeling in CA3 neurons, suggesting a role for this receptor in mediating ZnR signaling in the hippocampus. Our results describe a unique role for synaptic Zn(2+) acting as the physiological ligand of a metabotropic receptor and provide a novel pathway by which synaptic Zn(2+) can regulate neuronal function.

Regulation of granule cell excitability by a low-threshold calcium spike in turtle olfactory bulb

DEFF Research Database (Denmark)

Pinato, Giulietta; Midtgaard, Jens

2003-01-01

of the cell usually increased their amplitude so that they more easily boosted Na spike initiation. The LTS persisted in the presence of TTX but was antagonized by blockers of T-type calcium channels. The voltage dependence, kinetics, and inactivation properties of the LTS were characteristic of a low......-threshold calcium spike. The threshold of the LTS was slightly above the resting potential but well below the Na spike threshold, and the LTS was often evoked in isolation in normal medium. Tetraethylammonium (TEA) and 4-aminopyridine (4-AP) had only minimal effects on the LTS but revealed the presence of a high...

Purinergic signaling triggers endfoot high-amplitude Ca2+ signals and causes inversion of neurovascular coupling after subarachnoid hemorrhage.

Science.gov (United States)

Pappas, Anthony C; Koide, Masayo; Wellman, George C

2016-11-01

Neurovascular coupling supports brain metabolism by matching focal increases in neuronal activity with local arteriolar dilation. Previously, we demonstrated that an emergence of spontaneous endfoot high-amplitude Ca 2+ signals (eHACSs) caused a pathologic shift in neurovascular coupling from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage model animals. Extracellular purine nucleotides (e.g., ATP) can trigger astrocyte Ca 2+ oscillations and may be elevated following subarachnoid hemorrhage. Here, the role of purinergic signaling in subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling was examined by imaging parenchymal arteriolar diameter and astrocyte Ca 2+ signals in rat brain slices using two-photon fluorescent and infrared-differential interference contrast microscopy. We report that broad-spectrum inhibition of purinergic (P2) receptors using suramin blocked eHACSs and restored vasodilatory neurovascular coupling after subarachnoid hemorrhage. Importantly, eHACSs were also abolished using a cocktail of inhibitors targeting G q -coupled P2Y receptors. Further, activation of P2Y receptors in brain slices from un-operated animals triggered high-amplitude Ca 2+ events resembling eHACSs and disrupted neurovascular coupling. Neither tetrodotoxin nor bafilomycin A1 affected eHACSs suggesting that purine nucleotides are not released by ongoing neurotransmission and/or vesicular release after subarachnoid hemorrhage. These results indicate that purinergic signaling via P2Y receptors contributes to subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling. © The Author(s) 2016.

Activity-dependent intracellular Ca2+ transients in unmyelinated nerve fibres of the isolated adult rat vagus nerve.

Science.gov (United States)

Wächtler, J; Mayer, C; Grafe, P

1998-04-01

Confocal laser scanning microscopy was used to follow changes in the free intracellular calcium concentration ([Ca2+]i) in nerve fibres and adjacent Schwann cells in isolated rat vagus nerves. [Ca2+]i was monitored by the Ca2+-sensitive fluorescent dyes Calcium Green-1 and Fura Red. Intracellular Ca2+ transients were observed during repetitive (1-50 Hz) supramaximal electrical stimulation or by bath application of ATP. Trains of action potentials were more effective at elongated, fibre-like structures of the vagus nerves, whereas ATP-induced Ca2+ transients were found predominantly in regions of Schwann cell bodies. Activity-induced Ca2+ signals were unaffected by pharmacological manipulation of intracellular Ca2+ stores, during long-lasting application of purinergic receptor agonists, or by substitution of extracellular Na+ with Li+. However, they were abolished in the presence of Ca2+-free bathing solution or after the blocking of Ca2+ channels with Cd2+. Ca2+ transients were also observed during Ca2+ action potentials. Such "Ca2+ spikes" were elicited by electrical stimulation in the presence of a combination of tetrodotoxin and K+ channel blockers. These data suggest that voltage-dependent Ca2+ channels, activated during short trains of Na+ action potentials, produce an increase in intra-axonal [Ca2+] of rat vagus nerves. We did not find evidence for activity-dependent Ca2+ transients in the Schwann cells surrounding the unmyelinated axons.

Diet induced thermogenesis

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Westerterp KR

2004-08-01

Full Text Available Objective Daily energy expenditure consists of three components: basal metabolic rate, diet-induced thermogenesis and the energy cost of physical activity. Here, data on diet-induced thermogenesis are reviewed in relation to measuring conditions and characteristics of the diet. Methods Measuring conditions include nutritional status of the subject, physical activity and duration of the observation. Diet characteristics are energy content and macronutrient composition. Results Most studies measure diet-induced thermogenesis as the increase in energy expenditure above basal metabolic rate. Generally, the hierarchy in macronutrient oxidation in the postprandial state is reflected similarly in diet-induced thermogenesis, with the sequence alcohol, protein, carbohydrate, and fat. A mixed diet consumed at energy balance results in a diet induced energy expenditure of 5 to 15 % of daily energy expenditure. Values are higher at a relatively high protein and alcohol consumption and lower at a high fat consumption. Protein induced thermogenesis has an important effect on satiety. In conclusion, the main determinants of diet-induced thermogenesis are the energy content and the protein- and alcohol fraction of the diet. Protein plays a key role in body weight regulation through satiety related to diet-induced thermogenesis.

Exercise-Induced Bronchoconstriction (EIB)

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... Conditions & Treatments ▸ Conditions Dictionary ▸ Exercise-Induced Bronchoconstriction Share | Exercise-Induced Bronchoconstriction (EIB) « Back to A to Z Listing Exercise-Induced Bronchoconstriction, (EIB), often known as exercise-induced ...

Induced pluripotency with endogenous and inducible genes

International Nuclear Information System (INIS)

Duinsbergen, Dirk; Eriksson, Malin; Hoen, Peter A.C. 't; Frisen, Jonas; Mikkers, Harald

2008-01-01

The recent discovery that two partly overlapping sets of four genes induce nuclear reprogramming of mouse and even human cells has opened up new possibilities for cell replacement therapies. Although the combination of genes that induce pluripotency differs to some extent, Oct4 and Sox2 appear to be a prerequisite. The introduction of four genes, several of which been linked with cancer, using retroviral approaches is however unlikely to be suitable for future clinical applications. Towards developing a safer reprogramming protocol, we investigated whether cell types that express one of the most critical reprogramming genes endogenously are predisposed to reprogramming. We show here that three of the original four pluripotency transcription factors (Oct4, Klf4 and c-Myc or MYCER TAM ) induced reprogramming of mouse neural stem (NS) cells exploiting endogenous SoxB1 protein levels in these cells. The reprogrammed neural stem cells differentiated into cells of each germ layer in vitro and in vivo, and contributed to mouse development in vivo. Thus a combinatorial approach taking advantage of endogenously expressed genes and inducible transgenes may contribute to the development of improved reprogramming protocols

2017 Solar Eclipse in Hopkinsville, KY: E/PO Feedback from Two Venues

Science.gov (United States)

Dowling, Timothy E.; Consolmagno, Guy

2017-10-01

Hopkinsville, Kentucky was the largest town in the region of maximum totality for the 21 August 2017 Solar Eclipse, and transformed itself into “Eclipseville” with extensive media attention. Here we give 2 on-the-ground reports on education and public outreach (E/PO) activities from Hopkinsville. One of us (TD) partnered with the Kentucky Division of Emergency Management (KYEM) and was in the Hopkinsville VIP area, and the other (GC) led a series of E/PO events at the Hopkinsville Church of Ss. Peter & Paul, which were nationally advertised in diocesan newspapers. In addition, both of us were interviewed extensively by local and national media before the event. Pre-event planning by KYEM extended for over a year, and culminated in a 6-hour, 12 July 2017 Tabletop Exercise (TTX) run by FEMA. This face-to-face workshop drew over 250 participants, including Kentucky’s Lt. Governor, health and public safety officials at the state-level and from the 21 Kentucky counties in the path of totality, mayors and convention-bureau officials from the affected KY towns, the KY National Guard, the U.S. Depts. of Health and Human Services, Homeland Security, and Transportation, the National Weather Service, the U.S. Coast Guard for riverboat traffic, the U.S. Forest Service, the American Red Cross, representatives from ATT, Verizon and Sprint, and representatives from local universities—it was the largest TTX in Kentucky’s history. Here, we report on E/PO feedback we assembled from the VIP and parochial sites, including the most frequently asked questions, which types of answers seemed to be most effective, and how actual events compared with the large-crowd preparations and planning.

Palytoxin: a new marine toxin from a coelenterate.

Science.gov (United States)

Moore, R E; Scheuer, P J

1971-04-30

Palytoxin has been isolated from the zoanthids "limu-make-o-Hana" (Tentatively identified as Palythoa sp.) as a noncrystalline, chromatographically pure entity. Apart from polypeptide and protein toxins, it is the most highly toxic substance known, with a lethal dose (LD(59)) in mice of 0.15 microgram per kilogram by intravenous injection. Unlike the potent toxins batrachotoxin, saxitoxin, and tetrodotoxin which have molecular weights of 500 or less, palytoxin has an estimated molecular weight of 3300 and contains no repetitive amino acid or sugar units.

Orexins depolarize rostral ventrolateral medulla neurons and increase arterial pressure and heart rate in rats mainly via orexin 2 receptors.

Science.gov (United States)

Huang, Shang-Cheng; Dai, Yu-Wen E; Lee, Yen-Hsien; Chiou, Lih-Chu; Hwang, Ling-Ling

2010-08-01

An injection of orexin A or B into the cisterna magna or the rostral ventrolateral medulla (RVLM), where bulbospinal vasomotor neurons are located, elevated arterial pressure (AP) and heart rate (HR). We examined how orexins affected RVLM neurons to regulate cardiovascular functions by using in vitro recordings of neuronal activity of the RVLM and in vivo measurement of cardiovascular functions in rats. Orexin A and B concentration-dependently depolarized RVLM neurons. At 100 nM, both peptides excited 42% of RVLM neurons. Tetrodotoxin failed to block orexin-induced depolarization. In the presence of N-(2-methyl-6-benzoxazolyl)-N'-1, 5-naphthyridin-4-yl urea (SB-334867), an orexin 1 receptor (OX(1)R) antagonist, orexin A depolarized 42% of RVLM neurons with a smaller, but not significantly different, amplitude (4.9 +/- 0.8 versus 7.2 +/- 1.1 mV). In the presence of (2S)-1- (3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-[(4-pyridinylmethyl)amino]-1-butanone hydrochloride (TCS OX2 29), an orexin 2 receptor (OX(2)R) antagonist, orexin A depolarized 25% of RVLM neurons with a significantly smaller amplitude (1.7 +/- 0.5 mV). Coapplication of both antagonists completely eliminated orexin A-induced depolarization. An OX(2)R agonist, [Ala(11),D-Leu(15)]-orexin B, concentration-dependently depolarized RVLM neurons. Regarding neuronal phenotypes, orexins depolarized 88% of adrenergic, 43% of nonadrenergic, and 36 to 41% of rhythmically firing RVLM neurons. Intracisternal TCS OX2 29 (3 and 10 nmol) suppressed intracisternal orexin A-induced increases of AP and HR, whereas intracisternal SB-334867 (3 and 10 nmol) had no effect on the orexin A-induced increase of HR but suppressed the orexin A-induced pressor response at 10 nmol. We concluded that orexins directly excite RVLM neurons, which include bulbospinal vasomotor neurons, and regulate cardiovascular function mainly via the OX(2)R, with a smaller contribution from the OX(1)R.

Generation of highly purified neural stem cells from human adipose-derived mesenchymal stem cells by Sox1 activation.

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Feng, Nianhua; Han, Qin; Li, Jing; Wang, Shihua; Li, Hongling; Yao, Xinglei; Zhao, Robert Chunhua

2014-03-01

Neural stem cells (NSCs) are ideal candidates in stem cell-based therapy for neurodegenerative diseases. However, it is unfeasible to get enough quantity of NSCs for clinical application. Generation of NSCs from human adipose-derived mesenchymal stem cells (hAD-MSCs) will provide a solution to this problem. Currently, the differentiation of hAD-MSCs into highly purified NSCs with biological functions is rarely reported. In our study, we established a three-step NSC-inducing protocol, in which hAD-MSCs were induced to generate NSCs with high purity after sequentially cultured in the pre-inducing medium (Step1), the N2B27 medium (Step2), and the N2B27 medium supplement with basic fibroblast growth factor and epidermal growth factor (Step3). These hAD-MSC-derived NSCs (adNSCs) can form neurospheres and highly express Sox1, Pax6, Nestin, and Vimentin; the proportion was 96.1% ± 1.3%, 96.8% ± 1.7%, 96.2% ± 1.3%, and 97.2% ± 2.5%, respectively, as detected by flow cytometry. These adNSCs can further differentiate into astrocytes, oligodendrocytes, and functional neurons, which were able to generate tetrodotoxin-sensitive sodium current. Additionally, we found that the neural differentiation of hAD-MSCs were significantly suppressed by Sox1 interference, and what's more, Step1 was a key step for the following induction, probably because it was associated with the initiation and nuclear translocation of Sox1, an important transcriptional factor for neural development. Finally, we observed that bone morphogenetic protein signal was inhibited, and Wnt/β-catenin signal was activated during inducing process, and both signals were related with Sox1 expression. In conclusion, we successfully established a three-step inducing protocol to derive NSCs from hAD-MSCs with high purity by Sox1 activation. These findings might enable to acquire enough autologous transplantable NSCs for the therapy of neurodegenerative diseases in clinic.

Copper Induces Vasorelaxation and Antagonizes Noradrenaline -Induced Vasoconstriction in Rat Mesenteric Artery

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Yu-Chun Wang

2013-11-01

Full Text Available Background/Aims: Copper is an essential trace element for normal cellular function and contributes to critical physiological or pathological processes. The aim of the study was to investigate the effects of copper on vascular tone of rat mesenteric artery and compare the effects of copper on noradrenaline (NA and high K+ induced vasoconstriction. Methods: The rat mesenteric arteries were isolated and the vessel tone was measured by using multi wire myograph system in vitro. Blood pressure of carotid artery in rabbits was measured by using physiological data acquisition and analysis system in vivo. Results: Copper dose-dependently blunted NA-induced vasoconstriction of rat mesenteric artery. Copper-induced vasorelaxation was inhibited when the vessels were pretreated with NG-nitro-L-arginine methyl ester (L-NAME. Copper did not blunt high K+-induced vasoconstriction. Copper preincubation inhibited NA-evoked vasoconstriction and the inhibition was not affected by the presence of L-NAME. Copper preincubation showed no effect on high K+-evoked vasoconstriction. Copper chelator diethyldithiocarbamate trihydrate (DTC antagonized the vasoactivity induced by copper in rat mesenteric artery. In vivo experiments showed that copper injection (iv significantly decreased blood pressure of rabbits and NA or DTC injection (iv did not rescue the copper-induced hypotension and animal death. Conclusion: Copper blunted NA but not high K+-induced vasoconstriction of rat mesenteric artery. The acute effect of copper on NA-induced vasoconstriction was depended on nitric oxide (NO, but the effect of copper pretreatment on NA-induced vasoconstriction was independed on NO, suggesting that copper affected NA-induced vasoconstriction by two distinct mechanisms.

Colonic smooth muscle responses in patients with diverticular disease of the colon: effect of the NK2 receptor antagonist SR48968.

Science.gov (United States)

Maselli, M A; Piepoli, A L; Guerra, V; Caruso, M L; Pezzolla, F; Lorusso, D; Demma, I; De Ponti, F

2004-05-01

Little is known about the pathophysiology of diverticular disease. To compare passive and active stress and the response to carbachol of colonic smooth muscle specimens from patients with diverticular disease and patients with colon cancer. The effect of the NK2 receptor antagonist, SR48968, on electrically evoked contractions of circular muscle was also investigated. Sigmoid colon segments were obtained from 16 patients (51-83 years) undergoing elective sigmoid resection for diverticular disease and 39 patients (50-88 years) undergoing left hemicolectomy for non-obstructive sigmoid colon cancer. Isometric tension was measured on circular or longitudinal taenial muscle. Strips were stretched gradually to Lo (length allowing the development of optimal active tension with carbachol) and were also exposed to increasing carbachol concentrations. The effects of atropine, tetrodotoxin and SR48968 on electrically evoked (supramaximal strength, 0.3 ms, 0.1-10 Hz) contractions of circular strips from 8 patients with diverticular disease and 19 patients with colon cancer were also studied. Both passive and active stress in circular muscle strips obtained from patients with diverticular disease was higher than in patients with colon cancer (P colon cancer, whereas a tetrodotoxin-resistant component was identified in patients with diverticular disease. The changes in both passive and active stress in specimens from patients with diverticular disease may reflect circular smooth muscle dysfunction. Acetylcholine and tachykinins are the main excitatory neurotransmitters mediating electrically evoked contractions in human sigmoid colon circular muscle.

Enhanced stimulus-induced gamma activity in humans during propofol-induced sedation.

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Neeraj Saxena

Full Text Available Stimulus-induced gamma oscillations in the 30-80 Hz range have been implicated in a wide number of functions including visual processing, memory and attention. While occipital gamma-band oscillations can be pharmacologically modified in animal preparations, pharmacological modulation of stimulus-induced visual gamma oscillations has yet to be demonstrated in non-invasive human recordings. Here, in fifteen healthy humans volunteers, we probed the effects of the GABAA agonist and sedative propofol on stimulus-related gamma activity recorded with magnetoencephalography, using a simple visual grating stimulus designed to elicit gamma oscillations in the primary visual cortex. During propofol sedation as compared to the normal awake state, a significant 60% increase in stimulus-induced gamma amplitude was seen together with a 94% enhancement of stimulus-induced alpha suppression and a simultaneous reduction in the amplitude of the pattern-onset evoked response. These data demonstrate, that propofol-induced sedation is accompanied by increased stimulus-induced gamma activity providing a potential window into mechanisms of gamma-oscillation generation in humans.

Detection of zinc translocation into apical dendrite of CA1 pyramidal neuron after electrical stimulation.

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Suh, Sang Won

2009-02-15

Translocation of the endogenous cation zinc from presynaptic terminals to postsynaptic neurons after brain insult has been implicated as a potential neurotoxic event. Several studies have previously demonstrated that a brief electrical stimulation is sufficient to induce the translocation of zinc from presynaptic vesicles into the cytoplasm (soma) of postsynaptic neurons. In the present work I have extended those findings in three ways: (i) providing evidence that zinc translocation occurs into apical dendrites, (ii) presenting data that there is an apparent translocation into apical dendrites when only a zinc-containing synaptic input is stimulated, and (iii) presenting data that there is no zinc translocation into apical dendrite of ZnT3 KO mice following electrical stimulation. Hippocampal slices were preloaded with the "trappable" zinc fluorescent probe, Newport Green. After washout, a single apical dendrite in the stratum radiatum of hippocampal CA1 area was selected and focused on. Burst stimulation (100Hz, 500microA, 0.2ms, monopolar) was delivered to either the adjacent Schaffer-collateral inputs (zinc-containing) or to the adjacent temporo-ammonic inputs (zinc-free) to the CA1 dendrites. Stimulation of the Schaffer collaterals increased the dendritic fluorescence, which was blocked by TTX, low-Ca medium, or the extracellular zinc chelator, CaEDTA. Stimulation of the temporo-ammonic pathway caused no significant rise in the fluorescence. Genetic depletion of vesicular zinc by ZnT3 KO showed no stimulation-induced apical dendrite zinc rise. The present study provides evidence that synaptically released zinc translocates into postsynaptic neurons through the apical dendrites of CA1 pyramidal neurons during physiological synaptic activity.

Laser-induced interactions

International Nuclear Information System (INIS)

Green, W.R.

1979-01-01

This dissertation discusses some of the new ways that lasers can be used to control the energy flow in a medium. Experimental and theoretical considerations of the laser-induced collision are discussed. The laser-induced collision is a process in which a laser is used to selectively transfer energy from a state in one atomic or molecular species to another state in a different species. The first experimental demonstration of this process is described, along with later experiments in which lasers were used to create collisional cross sections as large as 10 - 13 cm 2 . Laser-induced collisions utilizing both a dipole-dipole interaction and dipole-quadrupole interaction have been experimentally demonstrated. The theoretical aspects of other related processes such as laser-induced spin-exchange, collision induced Raman emission, and laser-induced charge transfer are discussed. Experimental systems that could be used to demonstrate these various processes are presented. An experiment which produced an inversion of the resonance line of an ion by optical pumping of the neutral atom is described. This type of scheme has been proposed as a possible method for constructing VUV and x-ray lasers

Diet-induced obesity attenuates fasting-induced hyperphagia.

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Briggs, D I; Lemus, M B; Kua, E; Andrews, Z B

2011-07-01

Obesity impairs arcuate (ARC) neuropeptide Y (NPY)/agouti-releated peptide (AgRP) neuronal function and renders these homeostatic neurones unresponsive to the orexigenic hormone ghrelin. In the present study, we investigated the effect of diet-induced obesity (DIO) on feeding behaviour, ARC neuronal activation and mRNA expression following another orexigenic stimulus, an overnight fast. We show that 9 weeks of high-fat feeding attenuates fasting-induced hyperphagia by suppressing ARC neuronal activation and hypothalamic NPY/AgRP mRNA expression. Thus, the lack of appropriate feeding responses in DIO mice to a fast is caused by failure ARC neurones to recognise and/or respond to orexigenic cues. We propose that fasting-induced hyperphagia is regulated not by homeostatic control of appetite in DIO mice, but rather by changes in the reward circuitry. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

Effects of Hypocretin/Orexin and Major Transmitters of Arousal on Fast Spiking Neurons in Mouse Cortical Layer 6B.

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Wenger Combremont, Anne-Laure; Bayer, Laurence; Dupré, Anouk; Mühlethaler, Michel; Serafin, Mauro

2016-08-01

Fast spiking (FS) GABAergic neurons are thought to be involved in the generation of high-frequency cortical rhythms during the waking state. We previously showed that cortical layer 6b (L6b) was a specific target for the wake-promoting transmitter, hypocretin/orexin (hcrt/orx). Here, we have investigated whether L6b FS cells were sensitive to hcrt/orx and other transmitters associated with cortical activation. Recordings were thus made from L6b FS cells in either wild-type mice or in transgenic mice in which GFP-positive GABAergic cells are parvalbumin positive. Whereas in a control condition hcrt/orx induced a strong increase in the frequency, but not amplitude, of spontaneous synaptic currents, in the presence of TTX, it had no effect at all on miniature synaptic currents. Hcrt/orx effect was thus presynaptic although not by an action on glutamatergic terminals but rather on neighboring cells. In contrast, noradrenaline and acetylcholine depolarized and excited these cells through a direct postsynaptic action. Neurotensin, which is colocalized in hcrt/orx neurons, also depolarized and excited these cells but the effect was indirect. Morphologically, these cells exhibited basket-like features. These results suggest that hcrt/orx, noradrenaline, acetylcholine, and neurotensin could contribute to high-frequency cortical activity through an action on L6b GABAergic FS cells. © The Author 2016. Published by Oxford University Press.

Histamine influences body temperature by acting at H1 and H3 receptors on distinct populations of preoptic neurons.

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Lundius, Ebba Gregorsson; Sanchez-Alavez, Manuel; Ghochani, Yasmin; Klaus, Joseph; Tabarean, Iustin V

2010-03-24

The preoptic area/anterior hypothalamus, a region that contains neurons that control thermoregulation, is the main locus at which histamine affects body temperature. Here we report that histamine reduced the spontaneous firing rate of GABAergic preoptic neurons by activating H3 subtype histamine receptors. This effect involved a decrease in the level of phosphorylation of the extracellular signal-regulated kinase and was not dependent on synaptic activity. Furthermore, a population of non-GABAergic neurons was depolarized, and their firing rate was enhanced by histamine acting at H1 subtype receptors. In our experiments, activation of the H1R receptors was linked to the PLC pathway and Ca(2+) release from intracellular stores. This depolarization persisted in TTX or when fast synaptic potentials were blocked, indicating that it represents a postsynaptic effect. Single-cell reverse transcription-PCR analysis revealed expression of H3 receptors in a population of GABAergic neurons, while H1 receptors were expressed in non-GABAergic cells. Histamine applied in the median preoptic nucleus induced a robust, long-lasting hyperthermia effect that was mimicked by either H1 or H3 histamine receptor subtype-specific agonists. Our data indicate that histamine modulates the core body temperature by acting at two distinct populations of preoptic neurons that express H1 and H3 receptor subtypes, respectively.

Development of inducer-free expression plasmids based on IPTG-inducible promoters for Bacillus subtilis.

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Tran, Dinh Thi Minh; Phan, Trang Thi Phuong; Huynh, Thanh Kieu; Dang, Ngan Thi Kim; Huynh, Phuong Thi Kim; Nguyen, Tri Minh; Truong, Tuom Thi Tinh; Tran, Thuoc Linh; Schumann, Wolfgang; Nguyen, Hoang Duc

2017-07-25

Besides Escherichia coli, Bacillus subtilis is an important bacterial species for the production of recombinant proteins. Recombinant genes are inserted into shuttle expression vectors which replicate in both E. coli and in B. subtilis. The ligation products are first transformed into E. coli cells, analyzed for correct insertions, and the correct recombinant plasmids are then transformed into B. subtilis. A major problem using E. coli cells can be the strong basal level of expression of the recombinant protein which may interfere with the stability of the cells. To minimize this problem, we developed strong expression vectors being repressed in E. coli and inducer-free in B. subtilis. In general, induction of IPTG-inducible expression vectors is determined by the regulatory lacI gene encoding the LacI repressor in combination with the lacO operator on the promoter. To investigate the inducer-free properties of the vectors, we constructed inducer-free expression plasmids by removing the lacI gene and characterized their properties. First, we examined the ability to repress a reporter gene in E. coli, which is a prominent property facilitating the construction of the expression vectors carrying a target gene. The β-galactosidase (bgaB gene) basal levels expressed from Pgrac01-bgaB could be repressed at least twice in the E. coli cloning strain. Second, the inducer-free production of BgaB from four different plasmids with the Pgrac01 promoter in B. subtilis was investigated. As expected, BgaB expression levels of inducer-free constructs are at least 37 times higher than that of the inducible constructs in the absence of IPTG, and comparable to those in the presence of the inducer. Third, using efficient IPTG-inducible expression vectors containing the strong promoter Pgrac100, we could convert them into inducer-free expression plasmids. The BgaB production levels from the inducer-free plasmid in the absence of the inducer were at least 4.5 times higher than that of

Uterine contraction induced by Tanzanian plants used to induce abortion

DEFF Research Database (Denmark)

Nikolajsen, Tine; Nielsen, Frank; Rasch, Vibeke

2011-01-01

Women in Tanzania use plants to induce abortion. It is not known whether the plants have an effect.......Women in Tanzania use plants to induce abortion. It is not known whether the plants have an effect....

Protective immunity to UV radiation-induced skin tumours induced by skin grafts and epidermal cells

International Nuclear Information System (INIS)

Ronald Sluyter; Kylie S Yuen; Gary M Halliday

2001-01-01

There is little evidence that cutaneous dendritic cells (DC), including epidermal Langerhans cells (LC), can induce immunity to UV radiation (UVR)-induced skin tumours. Here, it is shown that cells within skin can induce protective antitumour immunity against a UVR-induced fibrosarcoma. Transplantation of the skin overlying subcutaneous tumours onto naive recipients could induce protective antitumour immunity, probably because the grafting stimulated the tumour Ag-loaded DC to migrate to local lymph nodes. This suggests that cutaneous APC can present tumour Ag to induce protective antitumour immunity. Previously, it has been shown that immunization of mice with MHC class II+ epidermal cells (EC) pulsed with tumour extracts could induce delayed-type hypersensitivity against tumour cells. Here, this same immunization protocol could induce protective immunity against a minimum tumorigenic dose of UVR-induced fibrosarcoma cells, but not higher doses. Epidermal cells obtained from semiallogeneic donors and pulsed with tumour extract could also induce protective immunity. However, presentation of BSA Ag from the culture medium was found to contribute to this result using semiallogeneic EC. The results suggest that LC overlying skin tumours may be able to induce protective immunity to UVR-induced tumours if stimulated to migrate from the skin. Copyright (2001) Australasian Society of Immunology Inc

Blockade of persistent sodium currents contributes to the riluzole-induced inhibition of spontaneous activity and oscillations in injured DRG neurons.

Directory of Open Access Journals (Sweden)

Rou-Gang Xie

Full Text Available In addition to a fast activating and immediately inactivating inward sodium current, many types of excitable cells possess a noninactivating or slowly inactivating component: the persistent sodium current (I(NaP. The I(NaP is found in normal primary sensory neurons where it is mediated by tetrodotoxin-sensitive sodium channels. The dorsal root ganglion (DRG is the gateway for ectopic impulses that originate in pathological pain signals from the periphery. However, the role of I(NaP in DRG neurons remains unclear, particularly in neuropathic pain states. Using in vivo recordings from single medium- and large-diameter fibers isolated from the compressed DRG in Sprague-Dawley rats, we show that local application of riluzole, which blocks the I(NaP, also inhibits the spontaneous activity of A-type DRG neurons in a dose-dependent manner. Significantly, riluzole also abolished subthreshold membrane potential oscillations (SMPOs, although DRG neurons still responded to intracellular current injection with a single full-sized spike. In addition, the I(NaP was enhanced in medium- and large-sized neurons of the compressed DRG, while bath-applied riluzole significantly inhibited the I(NaP without affecting the transient sodium current (I(NaT. Taken together, these results demonstrate for the first time that the I(NaP blocker riluzole selectively inhibits I(NaP and thereby blocks SMPOs and the ectopic spontaneous activity of injured A-type DRG neurons. This suggests that the I(NaP of DRG neurons is a potential target for treating neuropathic pain at the peripheral level.

Blockade of persistent sodium currents contributes to the riluzole-induced inhibition of spontaneous activity and oscillations in injured DRG neurons.

Science.gov (United States)

Xie, Rou-Gang; Zheng, Da-Wei; Xing, Jun-Ling; Zhang, Xu-Jie; Song, Ying; Xie, Ya-Bin; Kuang, Fang; Dong, Hui; You, Si-Wei; Xu, Hui; Hu, San-Jue

2011-04-25

In addition to a fast activating and immediately inactivating inward sodium current, many types of excitable cells possess a noninactivating or slowly inactivating component: the persistent sodium current (I(NaP)). The I(NaP) is found in normal primary sensory neurons where it is mediated by tetrodotoxin-sensitive sodium channels. The dorsal root ganglion (DRG) is the gateway for ectopic impulses that originate in pathological pain signals from the periphery. However, the role of I(NaP) in DRG neurons remains unclear, particularly in neuropathic pain states. Using in vivo recordings from single medium- and large-diameter fibers isolated from the compressed DRG in Sprague-Dawley rats, we show that local application of riluzole, which blocks the I(NaP), also inhibits the spontaneous activity of A-type DRG neurons in a dose-dependent manner. Significantly, riluzole also abolished subthreshold membrane potential oscillations (SMPOs), although DRG neurons still responded to intracellular current injection with a single full-sized spike. In addition, the I(NaP) was enhanced in medium- and large-sized neurons of the compressed DRG, while bath-applied riluzole significantly inhibited the I(NaP) without affecting the transient sodium current (I(NaT)). Taken together, these results demonstrate for the first time that the I(NaP) blocker riluzole selectively inhibits I(NaP) and thereby blocks SMPOs and the ectopic spontaneous activity of injured A-type DRG neurons. This suggests that the I(NaP) of DRG neurons is a potential target for treating neuropathic pain at the peripheral level.

Dexamethasone rapidly increases GABA release in the dorsal motor nucleus of the vagus via retrograde messenger-mediated enhancement of TRPV1 activity.

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Andrei V Derbenev

Full Text Available Glucocorticoids influence vagal parasympathetic output to the viscera via mechanisms that include modulation of neural circuitry in the dorsal vagal complex, a principal autonomic regulatory center. Glucocorticoids can modulate synaptic neurotransmitter release elsewhere in the brain by inducing release of retrograde signalling molecules. We tested the hypothesis that the glucocorticoid agonist dexamethasone (DEX modulates GABA release in the rat dorsal motor nucleus of the vagus (DMV. Whole-cell patch-clamp recordings revealed that DEX (1-10 µM rapidly (i.e. within three minutes increased the frequency of tetrodotoxin-resistant, miniature IPSCs (mIPSCs in 67% of DMV neurons recorded in acutely prepared slices. Glutamate-mediated mEPSCs were also enhanced by DEX (10 µM, and blockade of ionotropic glutamate receptors reduced the DEX effect on mIPSC frequency. Antagonists of type I or II corticosteroid receptors blocked the effect of DEX on mIPSCs. The effect was mimicked by application of the membrane-impermeant BSA-conjugated DEX, and intracellular blockade of G protein function with GDP βS in the recorded cell prevented the effect of DEX. The enhancement of GABA release was blocked by the TRPV1 antagonists, 5'-iodoresiniferatoxin or capsazepine, but was not altered by the cannabinoid type 1 receptor antagonist AM251. The DEX effect was prevented by blocking fatty acid amide hydrolysis or by inhibiting anandamide transport, implicating involvement of the endocannabinoid system in the response. These findings indicate that DEX induces an enhancement of GABA release in the DMV, which is mediated by activation of TRPV1 receptors on afferent terminals. The effect is likely induced by anandamide or other 'endovanilloid', suggesting activation of a local retrograde signal originating from DMV neurons to enhance synaptic inhibition locally in response to glucocorticoids.

Ghrelin is involved in the paracrine communication between neurons and glial cells.

Science.gov (United States)

Avau, B; De Smet, B; Thijs, T; Geuzens, A; Tack, J; Vanden Berghe, P; Depoortere, I

2013-09-01

Ghrelin is the only known peripherally active orexigenic hormone produced by the stomach that activates vagal afferents to stimulate food intake and to accelerate gastric emptying. Vagal sensory neurons within the nodose ganglia are surrounded by glial cells, which are able to receive and transmit chemical signals. We aimed to investigate whether ghrelin activates or influences the interaction between both types of cells. The effect of ghrelin was compared with that of leptin and cholecystokinin (CCK). Cultures of rat nodose ganglia were characterized by immunohistochemistry and the functional effects of peptides, neurotransmitters, and pharmacological blockers were measured by Ca(2+) imaging using Fluo-4-AM as an indicator. Neurons responded to KCl and were immunoreactive for PGP-9.5 whereas glial cells responded to lysophosphatidic acid and had the typical SOX-10-positive nuclear staining. Neurons were only responsive to CCK (31 ± 5%) whereas glial cells responded equally to the applied stimuli: ghrelin (27 ± 2%), leptin (21 ± 2%), and CCK (30 ± 2%). In contrast, neurons stained more intensively for the ghrelin receptor than glial cells. ATP induced [Ca(2+) ]i rises in 90% of the neurons whereas ACh and the NO donor, SIN-1, mainly induced [Ca(2+) ]i changes in glial cells (41 and 51%, respectively). The percentage of ghrelin-responsive glial cells was not affected by pretreatment with suramin, atropine, hexamethonium or 1400 W, but was reduced by l-NAME and by tetrodotoxin. Neurons were shown to be immunoreactive for neuronal NO-synthase (nNOS). Our data show that ghrelin induces Ca(2+) signaling in glial cells of the nodose ganglion via the release of NO originating from the neurons. © 2013 John Wiley & Sons Ltd.

Calcium-dependent smooth muscle excitatory effect elicited by the venom of the hydrocoral Millepora complanata.

Science.gov (United States)

Rojas, Alejandra; Torres, Mónica; Rojas, J Isela; Feregrino, Angélica; Heimer-de la Cotera, Edgar P

2002-06-01

In the present paper, we describe the results obtained from a preliminary pharmacological and biochemical study of the fire coral Millepora complanata, a regular component of coral reefs in the Mexican Caribbean. The protein-containing crude extract obtained from M. complanata (tested from 0.001 to 1000 microg protein/ml) caused a concentration-dependent stimulation of spontaneous contractions of the guinea pig ileum. The extract (EC(50)=11.55+/-2.36 microg/ml) was approximately 12-fold less potent than ionomycin (EC(50)=0.876+/-0.25 microg/ml) and its maximum induced contraction (1mg protein/ml) was equivalent to 68% of the response to 60mM KCl. FPLC size exclusion chromatography of the M. complanta extract afforded 12 primary fractions, of which only FV (containing proteins with molecular weights ranging from 17 to 44 kDa) and FVIII (consisting of peptides with molecular weights lesser than 1.8k Da) elicited an excitatory effect when tested at the EC(50) of the original extract. After incubation in Ca(2+)-free medium, the ileal response to FV and FVIII was significantly reduced. Blockage of L-type Ca(2+) channels with nifedipine (1 microM) inhibited FV and FVIII-evoked contractions. Cd(2+) (10 microM), an unspecific blocker of voltage-activated calcium channels, also antagonized FV and FVIII-induced effects, whereas the Na(+) channel blocker tetrodotoxin (10nM) did not significantly affect FV and FVIII responses. These results suggest that the contractions induced by the bioactive fractions obtained from the crude extract of M. complanata are caused mainly by a direct action on smooth muscle cells, via an increase in Ca(2+) permeability that occurs, at least partly, through L-type voltage-dependent Ca(2+) channels found in the cell membrane of smooth muscle. Copright 2002 Elsevier Science Ltd.

The effects of nicotinic and muscarinic receptor activation on patch-clamped cells in the optic tectum of Rana pipiens.

Science.gov (United States)

Yu, C-J; Debski, E A

2003-01-01

Both nicotinic and muscarinic cholinergic receptors are present in the optic tectum. To begin to understand how the activation of these receptors affects visual activity patterns, we have determined the types of physiological responses induced by their activation. Using tectal brain slices from the leopard frog, we found that application of nicotine (100 microM) evoked long-lasting responses in 60% of patch-clamped tectal cells. Thirty percent of these responses consisted of an increase in spontaneous postsynaptic currents (sPSCs) and had both a glutamatergic and GABAergic component as determined by the use of 6-cyano-7-nitroquinoxaline-2,3-dione (50 microM) and bicuculline (25 microM), respectively. Remaining response types consisted of an inward membrane current (16%) and an increase in sPSCs combined with an inward membrane current (14%). All responses could be elicited in the presence of tetrodotoxin (0.5 microM). Muscarinic receptor-mediated responses, induced by carbachol (100 microM) application after nicotinic receptor desensitization, produced responses in 70% of tectal cells. In contrast to responses elicited by nicotine, carbachol-induced responses could be evoked multiple times without significant decrement. Responses consisted of either an outward current (57%), a decrease in sPSCs (5%) or an increase in sPSCs, with (almost 6%) or without (almost 3%) an outward current. The response elicited by carbachol was not predicted by the response of the cell to nicotine. Our results suggest that nicotinic receptors are found predominantly at presynaptic locations in the optic tectum while muscarinic receptors are most often present at postsynaptic sites. We conclude that both of these receptor types could substantially modulate visual activity by changing either the input to tectal neurons or the level of their response to that input.

Down-regulation of voltage-dependent sodium channels initiated by sodium influx in developing neurons

International Nuclear Information System (INIS)

Dargent, B.; Couraud, F.

1990-01-01

To address the issue of whether regulatory feedback exists between the electrical activity of a neuron and ion-channel density, the authors investigated the effect of Na + -channel activators (scorpion α toxin, batrachotoxin, and veratridine) on the density of Na + channels in fetal rat brain neurons in vitro. A partial but rapid (t 1/2 , 15 min) disappearance of surface Na + channels was observed as measured by a decrease in the specific binding of [ 3 H]saxitoxin and 125 I-labeled scorpion β toxin and a decrease in specific 22 Na + uptake. Moreover, the increase in the number of Na + channels that normally occurs during neuronal maturation in vitro was inhibited by chronic channel activator treatment. The induced disappearance of Na + channels was abolished by tetrodotoxin, was found to be dependent on the external Na + concentration, and was prevented when either choline (a nonpermeant ion) or Li + (a permeant ion) was substituted for Na + . Amphotericin B, a Na + ionophore, and monensin were able to mimick the effect of Na + -channel activators, while a KCl depolarization failed to do this. This feedback regulation seems to be a neuronal property since Na + -channel density in cultured astrocytes was not affected by channel activator treatment or by amphotericin B. The present evidence suggests that an increase in intracellular Na + concentration, whether elicited by Na + -channel activators or mediated by a Na + ionophore, can induce a decrease in surface Na + channels and therefore is involved in down-regulation of Na + -channel density in fetal rat brain neurons in vitro

Intracellular Na(+) and metabolic modulation of Na/K pump and excitability in the rat suprachiasmatic nucleus neurons.

Science.gov (United States)

Wang, Yi-Chi; Yang, Jyh-Jeen; Huang, Rong-Chi

2012-10-01

Na/K pump activity and metabolic rate are both higher during the day in the suprachiasmatic nucleus (SCN) that houses the circadian clock. Here we investigated the role of intracellular Na(+) and energy metabolism in regulating Na/K pump activity and neuronal excitability. Removal of extracellular K(+) to block the Na/K pump excited SCN neurons to fire at higher rates and return to normal K(+) to reactivate the pump produced rebound hyperpolarization to inhibit firing. In the presence of tetrodotoxin to block the action potentials, both zero K(+)-induced depolarization and rebound hyperpolarization were blocked by the cardiac glycoside strophanthidin. Ratiometric Na(+) imaging with a Na(+)-sensitive fluorescent dye indicated saturating accumulation of intracellular Na(+) in response to pump blockade with zero K(+). The Na(+) ionophore monensin also induced Na(+) loading and hyperpolarized the membrane potential, with the hyperpolarizing effect of monensin abolished in zero Na(+) or by pump blockade. Conversely, Na(+) depletion with Na(+)-free pipette solution depolarized membrane potential but retained residual Na/K pump activity. Cyanide inhibition of oxidative phosphorylation blocked the Na/K pump to depolarize resting potential and increase spontaneous firing in most cells, and to raise intracellular Na(+) levels in all cells. Nonetheless, the Na/K pump was incompletely blocked by cyanide but completely blocked by iodoacetate to inhibit glycolysis, indicating the involvement of both oxidative phosphorylation and glycolysis in fueling the Na/K pump. Together, the results indicate the importance of intracellular Na(+) and energy metabolism in regulating Na/K pump activity as well as neuronal excitability in the SCN neurons.

Radiation-induced apoptosis

International Nuclear Information System (INIS)

Ohyama, Harumi

1995-01-01

Apoptosis is an active process of gene-directed cellular self-destruction that can be induced in many cell types via numerous physiological and pathological stimuli. We found that interphasedeath of thymocytes is a typical apoptosis showing the characteristic features of apoptosis including cell shrinkage, chromatin condensation and DNA degradation. Moderate dose of radiation induces extensive apoptosis in rapidly proliferating cell population such as the epithelium of intestinal crypt. Recent reports indicate that the ultimate form of radiation-induced mitotic death in several cells is also apoptosis. One of the hallmarks of apoptosis is the enzymatic internucleosomal degradation of chromatin DNA. We identified an endonuclease responsible for the radiation-induced DNA degradation in rat thymocytes. The death-sparing effects of interrupting RNA and protein synthesis suggested a cell genetic program for apoptosis. Apoptosis of thymocytes initiated by DNA damage, such as radiation and radio mimetic substance, absolutely requires the protein of p53 cancer suppresser gene. The cell death induced by glucocorticoid, or aging, has no such requirement. Expression of oncogene bcl-2 rescues cells from the apoptosis. Massive apoptosis in radiosensitive cells induced by higher dose radiation may be fatal. It is suggested that selective apoptotic elimination of cells would play an important role for protection against carcinogenesis and malformation through removal of cells with unrepaired radiation-induced DNA damages. Data to evaluate the significance of apoptosis in the radiation risk are still poor. Further research should be done in order to clarify the roles of the cell death on the acute and late effects of irradiation. (author)

Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1

Science.gov (United States)

Inserra, Marco C.; Israel, Mathilde R.; Caldwell, Ashlee; Castro, Joel; Deuis, Jennifer R.; Harrington, Andrea M.; Keramidas, Angelo; Garcia-Caraballo, Sonia; Maddern, Jessica; Erickson, Andelain; Grundy, Luke; Rychkov, Grigori Y.; Zimmermann, Katharina; Lewis, Richard J.; Brierley, Stuart M.; Vetter, Irina

2017-01-01

Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (NaV), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on NaV1.1–1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective NaV toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes, an increase in the inactivation time constant was observed only at NaV1.8, while the slope factor of the conductance-voltage curves was significantly increased for NaV1.7 and peak current was significantly increased for NaV1.6. Accordingly, P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, respectively. The contribution of these isoforms to excitability of peripheral C- and A-fibre sensory neurons, confirmed using murine skin and visceral single-fibre recordings, reflects the expression pattern of NaV isoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation. PMID:28225079

Trauma-induced systemic inflammatory response versus exercise-induced immunomodulatory effects.

Science.gov (United States)

Fehrenbach, Elvira; Schneider, Marion E

2006-01-01

Accidental trauma and heavy endurance exercise, both induce a kind of systemic inflammatory response, also called systemic inflammatory response syndrome (SIRS). Exercise-related SIRS is conditioned by hyperthermia and concomitant heat shock responses, whereas trauma-induced SIRS manifests concomitantly with tissue necrosis and immune activation, secondarily followed by fever. Inflammatory cytokines are common denominators in both trauma and exercise, although there are marked quantitative differences. Different anti-inflammatory cytokines may be involved in the control of inflammation in trauma- and exercise-induced stress. Exercise leads to a balanced equilibrium between inflammatory and anti-inflammatory responses. Intermittent states of rest, as well as anti-oxidant capacity, are lacking or minor in trauma but are high in exercising individuals. Regular training may enhance immune competence, whereas trauma-induced SIRS often paves the way for infectious complications, such as sepsis.

Shock-induced electrical activity in polymeric solids. A mechanically induced bond scission model

International Nuclear Information System (INIS)

Graham, R.A.

1979-01-01

When polymeric solids are subjected to high-pressure shock loading, two anomalous electrical phenomena, shock-induced conduction and shock-induced polarization, are observed. The present paper proposes a model of mechanically induced bond scission within the shock front to account for the effects. An experimental study of shock-induced polarization in poly(pyromellitimide) (Vespel SP-1) is reported for shock compressions from 17 to 23% (pressures from 2.5 to 5.4 GPa). Poly(pyromellitimide) is found to be a strong generator of such polarization and the polarization is found to reflect an irreversible or highly hysteretic process. The present measurements are combined with prior measurements to establish a correlation between monomer structure and strength of shock-induced polarization; feeble signals are observed in the simpler monomer repeat units of poly(tetrafluoroethylene) and polyethylene while the strongest signals are observed in more complex monomers of poly(methyl methacrylate) and poly(pyromellitimide). It is also noted that there is an apparent correlation between shock-induced conduction and shock-induced polarization. Such shock-induced electrical activity is also found to be well correlated with the propensity for mechanical bond scission observed in experiments carried out in conventional mechanochemical studies. The bond scission model can account for characteristics observed for electrical activity in shock-loaded polymers and their correlation to monomer structure. Localization of elastic energy within the monomer repeat unit or along the main chain leads to the different propensities for bond scission and resulting shock-induced electrical activity

Apoptosis-inducing factor (Aif1) mediates anacardic acid-induced apoptosis in Saccharomyces cerevisiae.

Science.gov (United States)

Muzaffar, Suhail; Chattoo, Bharat B

2017-03-01

Anacardic acid is a medicinal phytochemical that inhibits proliferation of fungal as well as several types of cancer cells. It induces apoptotic cell death in various cell types, but very little is known about the mechanism involved in the process. Here, we used budding yeast Saccharomyces cerevisiae as a model to study the involvement of some key elements of apoptosis in the anacardic acid-induced cell death. Plasma membrane constriction, chromatin condensation, DNA degradation, and externalization of phosphatidylserine (PS) indicated that anacardic acid induces apoptotic cell death in S. cerevisiae. However, the exogenous addition of broad-spectrum caspase inhibitor Z-VAD-FMK or deletion of the yeast caspase Yca1 showed that the anacardic acid-induced cell death is caspase independent. Apoptosis-inducing factor (AIF1) deletion mutant was resistant to the anacardic acid-induced cell death, suggesting a key role of Aif1. Overexpression of Aif1 made cells highly susceptible to anacardic acid, further confirming that Aif1 mediates anacardic acid-induced apoptosis. Interestingly, instead of the increase in the intracellular reactive oxygen species (ROS) normally observed during apoptosis, anacardic acid caused a decrease in the intracellular ROS levels. Quantitative real-time PCR analysis showed downregulation of the BIR1 survivin mRNA expression during the anacardic acid-induced apoptosis.

Filament-induced remote surface ablation for long range laser-induced breakdown spectroscopy operation

International Nuclear Information System (INIS)

Rohwetter, Ph.; Stelmaszczyk, K.; Woeste, L.; Ackermann, R.; Mejean, G.; Salmon, E.; Kasparian, J.; Yu, J.; Wolf, J.-P.

2005-01-01

We demonstrate laser induced ablation and plasma line emission from a metallic target at distances up to 180 m from the laser, using filaments (self-guided propagation structures ∼ 100 μm in diameter and ∼ 5 x 10 13 W/cm 2 in intensity) appearing as femtosecond and terawatt laser pulses propagating in air. The remarkable property of filaments to propagate over a long distance independently of the diffraction limit opens the frontier to long range operation of the laser-induced breakdown spectroscopy technique. We call this special configuration of remote laser-induced breakdown spectroscopy 'remote filament-induced breakdown spectroscopy'. Our results show main features of filament-induced ablation on the surface of a metallic sample and associated plasma emission. Our experimental data allow us to estimate requirements for the detection system needed for kilometer-range remote filament-induced breakdown spectroscopy experiment

Chemical-induced Vitiligo

Science.gov (United States)

Harris, John E.

2016-01-01

Synopsis Chemical-induced depigmentation of the skin has been recognized for over 75 years, first as an occupational hazard but then extending to those using household commercial products as common as hair dyes. Since their discovery, these chemicals have been used therapeutically in patients with severe vitiligo to depigment their remaining skin and improve their appearance. The importance of recognizing this phenomenon was highlighted during an outbreak of vitiligo in Japan during the summer of 2013, when over 16,000 users of a new skin lightening cosmetic cream developed skin depigmentation at the site of contact with the cream and many in remote areas as well. Depigmenting chemicals appear to be analogs of the amino acid tyrosine that disrupt melanogenesis and result in autoimmunity and melanocyte destruction. Because chemical-induced depigmentation is clinically and histologically indistinguishable from non-chemically induced vitiligo, and because these chemicals appear to induce melanocyte autoimmunity, this phenomenon should be known as “chemical-induced vitiligo”, rather than less accurate terms that have been previously used. PMID:28317525

Pump, sodium, inducer, intermediate size (ISIP) (impeller/inducer/diffuser retrofit)

International Nuclear Information System (INIS)

Paradise, D.R.

1978-01-01

This specification defines the requirements for the Intermediate-Size Inducer Pump (ISIP), which is to be made by replacing the impeller of the FFTF Prototype Pump with a new inducer, impeller, diffuser, seal, and necessary adapter hardware. Subsequent testing requirements of the complete pump assembly are included

Flow-induced and acoustically induced vibration experience in operating gas-cooled reactors

International Nuclear Information System (INIS)

Halvers, L.J.

1977-03-01

An overview has been presented of flow-induced and acoustically induced vibration failures that occurred in the past in gas-cooled graphite-moderated reactors, and the importance of this experience for the Gas-Cooled Fast-Breeder Reactor (GCFR) project has been assessed. Until now only failures in CO 2 -cooled reactors have been found. No problems with helium-cooled reactors have been encountered so far. It is shown that most of the failures occurred because flow-induced and acoustically induced dynamic loads were underestimated, while at the same time not enough was known about the influence of environmental parameters on material behavior. All problems encountered were solved. The comparison of the influence of the gas properties on acoustically induced and flow-induced vibration phenomena shows that the interaction between reactor design and the thermodynamic properties of the primary coolant precludes a general preference for either carbon dioxide or helium. The acoustic characteristics of CO 2 and He systems are different, but the difference in dynamic loadings due to the use of one rather than the other remains difficult to predict. A slight preference for helium seems, however, to be justified

Drug-induced thrombocytopenia

DEFF Research Database (Denmark)

Pedersen-Bjergaard, U; Andersen, M; Hansen, P B

1997-01-01

induced by non-cytotoxic drugs is characterised by heterogeneous clinical picture and recovery is generally rapid. Although corticosteroids seem inefficient, we still recommend that severe symptomatic cases of drug-induced thrombocytopenia are treated as idiopathic thrombocytopenic purpura due...

Review of July 2013 Nuclear Security Insider Threat Exercise November 2013

Energy Technology Data Exchange (ETDEWEB)

Pederson, Ann C. [ORNL; Snow, Catherine L. [ORNL; Townsend, Jeremy [ORNL; Shannon, Michael [ORNL

2013-11-01

This document is a review of the Nuclear Security Insider Threat Exercise which was hosted at ORNL in July 2013. Nuclear security culture and the insider threat are best learned through experience. Culture is inherently difficult to teach, and as such is best learned through modeled behaviors and learning exercise. This TTX, NSITE, is a tool that strives to aid students in learning what an effective (and ineffective) nuclear security culture might look like by simulating dynamic events that strengthen or weaken the nuclear security regime. The goals of NSITE are to stimulate complex thought and discussion and assist decision makers and management in determining the most effective policies and procedures for their country or facility.

Diet induced thermogenesis

NARCIS (Netherlands)

Westerterp, K.R.

2004-01-01

OBJECTIVE: Daily energy expenditure consists of three components: basal metabolic rate, diet-induced thermogenesis and the energy cost of physical activity. Here, data on diet-induced thermogenesis are reviewed in relation to measuring conditions and characteristics of the diet. METHODS: Measuring

Bleomycin-induced pneumonitis

NARCIS (Netherlands)

S. Sleijfer (Stefan)

2001-01-01

textabstractThe cytotoxic agent bleomycin is feared for its induction of sometimes fatal pulmonary toxicity, also known as bleomycin-induced pneumonitis (BIP). The central event in the development of BIP is endothelial damage of the lung vasculature due to bleomycin-induced

Effects of cartap on isolated mouse phrenic nerve diaphragm and its related mechanism.

Science.gov (United States)

Liao, J W; Kang, J J; Liu, S H; Jeng, C R; Cheng, Y W; Hu, C M; Tsai, S F; Wang, S C; Pang, V F

2000-06-01

Cartap, a nereistoxin analogue pesticide, is reported to have no irritation to eyes in rabbits. However, we have demonstrated recently that cartap could actually cause acute death in rabbits via ocular exposure. Our preliminary study with isolated mouse phrenic nerve diaphragms has shown that instead of neuromuscular blockade, cartap caused muscular contracture. The objective of the study was to examine the effect of cartap on the neuromuscular junction in more detail and to investigate its possible underlying mechanism with isolated mouse phrenic nerve diaphragms and sarcoplasmic reticulum (SR) vesicles. Cartap or nereistoxin at various concentrations was added in the organ bath with isolated mouse phrenic nerve diaphragm and both nerve- and muscle-evoked twitches were recorded. Instead of blocking the neuromuscular transmission as nereistoxin did, cartap caused contracture in stimulated or quiescent isolated mouse phrenic nerve diaphragm. Both the cartap-induced muscular contracture force and the time interval to initiate the contracture were dose-dependent. The contracture induced by cartap was not affected by the pretreatment of the diaphragm with the acetylcholine receptor blocker alpha-bungarotoxin; the Na(+) channel blocker tetrodotoxin; or various Ca(2+) channel blockers, NiCl(2), verapamil, and nifedipine. On the contrary, the contracture was significantly inhibited when the diaphragm was pretreated with ryanodine or EGTA containing Ca(2+)-free Krebs solution or in combination. This suggested that both internal and extracellular Ca(2+) might participate in cartap-induced skeletal muscle contracture. Moreover, cartap inhibited the [(3)H]-ryanodine binding to the Ca(2+) release channel of SR in a dose-dependent manner. Additionally, cartap could induce a significant reduction in Ca(2+)-ATPase activity of SR vesicles at a relatively high dose. The results suggested that cartap might cause the influx of extracellular Ca(2+) and the release of internal Ca(2

Modification of the striatal dopaminergic neuron system by carbon monoxide exposure in free-moving rats, as determined by in vivo brain microdialysis

Energy Technology Data Exchange (ETDEWEB)

Hara, Shuichi; Kurosaki, Kunihiko; Kuriiwa, Fumi; Endo, Takahiko [Department of Forensic Medicine, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402 (Japan); Mukai, Toshiji [Department of Legal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-0015 (Japan)

2002-10-01

Acute carbon monoxide (CO) intoxication in humans results in motor deficits, which resemble those in Parkinson's disease, suggesting possible disturbance of the central dopaminergic (DAergic) neuronal system by CO exposure. In the present study, therefore, we explored the effects of CO exposure on the DAergic neuronal system in the striatum of freely moving rats by means of in vivo brain microdialysis. Exposure of rats to CO (up to 0.3%) for 40 min caused an increase in extracellular dopamine (DA) levels and a decrease in extracellular levels of its major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum depending on the CO concentration. Reoxygenation following termination of the CO exposure resulted in a decline of DA to the control level and an overshoot in the recovery of DOPAC and HVA to levels higher than the control. A monoamine oxidase type A (MAO-A) inhibitor, clorgyline, significantly potentiated the CO-induced increase in DA and completely abolished the subsequent overshoot in the recovery of DOPAC and HVA. Tetrodotoxin, a Na{sup +} channel blocker, completely abolished both the CO-induced increase in DA and the overshoot of DOPAC and HVA. A DA uptake inhibitor, nomifensine, strongly potentiated the CO-induced increase in DA without affecting the subsequent overshoot of DOPAC and HVA. Clorgyline further potentiated the effect of nomifensine on the CO-induced increase in DA, although a slight overshoot of DOPAC and HVA appeared. These findings suggest that (1) CO exposure may stimulate Na{sup +}-dependent DA release in addition to suppressing DA metabolism, resulting in a marked increase in extracellular DA in rat striatum, and (2) CO withdrawal and subsequent reoxygenation may enhance the oxidative metabolism, preferentially mediated by MAO-A, of the increased extracellular DA. In the light of the neurotoxicity of DA per se and reactive substances, such as quinones and activated oxygen species

Induced abortion in Taiwan.

Science.gov (United States)

Wang, P D; Lin, R S

1995-04-01

Induced abortion is widely practised in Taiwan; however, it had been illegal until 1985. It was of interest to investigate induced abortion practices in Taiwan after its legalization in 1985 in order to calculate the prevalence rate and ratio of induced abortion to live births and to pregnancies in Taiwan. A study using questionnaires through personal interviews was conducted on more than seventeen thousand women who attended a family planning service in Taipei metropolitan areas between 1991 and 1992. The reproductive history and sexual behaviour of the subjects were especially focused on during the interviews. Preliminary findings showed that 46% of the women had a history of having had an induced abortion. Among them, 54.8% had had one abortion, 29.7% had had two, and 15.5% had had three or more. The abortion ratio was 379 induced abortions per 1,000 live births and 255 per 1,000 pregnancies. The abortion ratio was highest for women younger than 20 years of age, for aboriginal women and for nulliparous women. When logistic regression was used to control for confounding variables, we found that the number of previous live births is the strongest predictor relating to women seeking induced abortion. In addition, a significant positive association exists between increasing number of induced abortions and cervical dysplasia.

Paliperidone palmitate-induced sialorrhoea

Directory of Open Access Journals (Sweden)

Cengiz Cengisiz

2016-03-01

Full Text Available Extrapyramidal, metabolic, and cardiac side effects were reported for atypical antipsychotics; although a few resources show paliperidone-induced sialorrhea, there are no resources that show paliperidone palmitate-induced sialorrhea. In this paper, we present the paliperidone palmitate-induced sialorrhea side effects of a patient who applied on our clinic [Cukurova Med J 2016; 41(0.100: 8-13

Chemical Detection Based on Adsorption-Induced and Photo-Induced Stresses in MEMS Devices

Energy Technology Data Exchange (ETDEWEB)

Datskos, P.G.

1999-04-05

Recently there has been an increasing demand to perform real-time in-situ chemical detection of hazardous materials, contraband chemicals, and explosive chemicals. Currently, real-time chemical detection requires rather large analytical instrumentation that are expensive and complicated to use. The advent of inexpensive mass produced MEMS (micro-electromechanical systems) devices opened-up new possibilities for chemical detection. For example, microcantilevers were found to respond to chemical stimuli by undergoing changes in their bending and resonance frequency even when a small number of molecules adsorb on their surface. In our present studies, we extended this concept by studying changes in both the adsorption-induced stress and photo-induced stress as target chemicals adsorb on the surface of microcantilevers. For example, microcantilevers that have adsorbed molecules will undergo photo-induced bending that depends on the number of absorbed molecules on the surface. However, microcantilevers that have undergone photo-induced bending will adsorb molecules on their surfaces in a distinctly different way. Depending on the photon wavelength and microcantilever material, the microcantilever can be made to bend by expanding or contracting the irradiated surface. This is important in cases where the photo-induced stresses can be used to counter any adsorption-induced stresses and increase the dynamic range. Coating the surface of the microstructure with a different material can provide chemical specificity for the target chemicals. However, by selecting appropriate photon wavelengths we can change the chemical selectivity due to the introduction of new surface states in the MEMS device. We will present and discuss our results on the use of adsorption-induced and photo-induced bending of microcantilevers for chemical detection.

Second-order nonlinearity induced transparency.

Science.gov (United States)

Zhou, Y H; Zhang, S S; Shen, H Z; Yi, X X

2017-04-01

In analogy to electromagnetically induced transparency, optomechanically induced transparency was proposed recently in [Science330, 1520 (2010)SCIEAS0036-807510.1126/science.1195596]. In this Letter, we demonstrate another form of induced transparency enabled by second-order nonlinearity. A practical application of the second-order nonlinearity induced transparency is to measure the second-order nonlinear coefficient. Our scheme might find applications in quantum optics and quantum information processing.

An evaluation of a hubless inducer and a full flow hydraulic turbine driven inducer boost pump

Science.gov (United States)

Lindley, B. K.; Martinson, A. R.

1971-01-01

The purpose of the study was to compare the performance of several configurations of hubless inducers with a hydrodynamically similar conventional inducer and to demonstrate the performance of a full flow hydraulic turbine driven inducer boost pump using these inducers. A boost pump of this type consists of an inducer connected to a hydraulic turbine with a high speed rotor located in between. All the flow passes through the inducer, rotor, and hydraulic turbine, then into the main pump. The rotor, which is attached to the main pump shaft, provides the input power to drive the hydraulic turbine which, in turn, drives the inducer. The inducer, rotating at a lower speed, develops the necessary head to prevent rotor cavitation. The rotor speed is consistent with present main engine liquid hydrogen pump designs and the overall boost pump head rise is sufficient to provide adequate main pump suction head. This system would have the potential for operating at lower liquid hydrogen tank pressures.

Inducible Laryngeal Obstruction: Excessive Dynamic Airway Collapse vs. Inducible Laryngeal Obstruction

Science.gov (United States)

2017-10-20

REPORT TYPE 10/20/2017 Poster 4. TITLE AND SUBTITLE Inducible Laryngeal Obstrnction: Excessive Dynamic Airway Collapse vs. Inducible Laryngeal...REPORT b.ABSTRACT c. THIS PAGE ABSTRACT OF PAGES 3. DATES COVERED (From - To) 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER

Traffic forecasts ignoring induced demand

DEFF Research Database (Denmark)

Næss, Petter; Nicolaisen, Morten Skou; Strand, Arvid

2012-01-01

the model calculations included only a part of the induced traffic, the difference in cost-benefit results compared to the model excluding all induced traffic was substantial. The results show lower travel time savings, more adverse environmental impacts and a considerably lower benefitcost ratio when...... induced traffic is partly accounted for than when it is ignored. By exaggerating the economic benefits of road capacity increase and underestimating its negative effects, omission of induced traffic can result in over-allocation of public money on road construction and correspondingly less focus on other...... performance of a proposed road project in Copenhagen with and without short-term induced traffic included in the transport model. The available transport model was not able to include long-term induced traffic resulting from changes in land use and in the level of service of public transport. Even though...

Effects of scallop shell extract on scopolamine-induced memory impairment and MK801-induced locomotor activity.

Science.gov (United States)

Hasegawa, Yasushi; Inoue, Tatsuro; Kawaminami, Satoshi; Fujita, Miho

2016-07-01

To evaluate the neuroprotective effects of the organic components of scallop shells (scallop shell extract) on memory impairment and locomotor activity induced by scopolamine or 5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine (MK801). Effect of the scallop shell extract on memory impairment and locomotor activity was investigated using the Y-maze test, the Morris water maze test, and the open field test. Scallop shell extract significantly reduced scopolamine-induced short-term memory impairment and partially reduced scopolamine-induced spatial memory impairment in the Morris water maze test. Scallop shell extract suppressed scopolamine-induced elevation of acetylcholine esterase activity in the cerebral cortex. Treatment with scallop shell extract reversed the increase in locomotor activity induced by scopolamine. Scallop shell extract also suppressed the increase in locomotor activity induced by MK801. Our results provide initial evidence that scallop shell extract reduces scopolamine-induced memory impairment and suppresses MK-801-induced hyperlocomotion. Copyright © 2016 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

[Drug induced diarrhea].

Science.gov (United States)

Morard, Isabelle; Hadengue, Antoine

2008-09-03

Diarrhea is a frequent adverse event involving the most frequently antibiotics, laxatives and NSAI. Drug induced diarrhea may be acute or chronic. It may be due to expected, dose dependant properties of the drug, to immuno-allergic or bio-genomic mechanisms. Several pathophysiological mechanisms have been described resulting in osmotic, secretory or inflammatory diarrhea, shortened transit time, or malabsorption. Histopathological lesions sometimes associated with drug induced diarrhea are usually non specific and include ulcerations, inflammatory or ischemic lesions, fibrous diaphragms, microscopic colitis and apoptosis. The diagnosis of drug induced diarrhea, sometimes difficult to assess, relies on the absence of other obvious causes and on the rapid disappearance of the symptoms after withdrawal of the suspected drug.

Differences between Drug-Induced and Contrast Media-Induced Adverse Reactions Based on Spontaneously Reported Adverse Drug Reactions.

Science.gov (United States)

Ryu, JiHyeon; Lee, HeeYoung; Suh, JinUk; Yang, MyungSuk; Kang, WonKu; Kim, EunYoung

2015-01-01

We analyzed differences between spontaneously reported drug-induced (not including contrast media) and contrast media-induced adverse reactions. Adverse drug reactions reported by an in-hospital pharmacovigilance center (St. Mary's teaching hospital, Daejeon, Korea) from 2010-2012 were classified as drug-induced or contrast media-induced. Clinical patterns, frequency, causality, severity, Schumock and Thornton's preventability, and type A/B reactions were recorded. The trends among causality tools measuring drug and contrast-induced adverse reactions were analyzed. Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021%) and 3.9/100,000 (outpatients, 0.004%). The most common adverse drug reaction-associated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast media-induced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p contrast media-induced adverse reactions (56.6%, p = 0.066). Causality patterns differed between the two adverse reaction classes. The World Health Organization-Uppsala Monitoring Centre causality evaluation and Naranjo algorithm results significantly differed from those of the Korean algorithm version II (p contrast media-induced adverse reactions. The World Health Organization-Uppsala Monitoring Centre and Naranjo algorithm causality evaluation afforded similar results.

Troglitazone induced apoptosis via PPARγ activated POX-induced ROS formation in HT29 cells.

Science.gov (United States)

Wang, Jing; Lv, XiaoWen; Shi, JiePing; Hu, XiaoSong; DU, YuGuo

2011-08-01

In order to investigate the potential mechanisms in troglitazone-induced apoptosis in HT29 cells, the effects of PPARγ and POX-induced ROS were explored. [3- (4, 5)-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay, Annexin V and PI staining using FACS, plasmid transfection, ROS formation detected by DCFH staining, RNA interference, RT-PCR & RT-QPCR, and Western blotting analyses were employed to investigate the apoptotic effect of troglitazone and the potential role of PPARγ pathway and POX-induced ROS formation in HT29 cells. Troglitazone was found to inhibit the growth of HT29 cells by induction of apoptosis. During this process, mitochondria related pathways including ROS formation, POX expression and cytochrome c release increased, which were inhibited by pretreatment with GW9662, a specific antagonist of PPARγ. These results illustrated that POX upregulation and ROS formation in apoptosis induced by troglitazone was modulated in PPARγ-dependent pattern. Furthermore, the inhibition of ROS and apoptosis after POX siRNA used in troglitazone-treated HT29 cells indicated that POX be essential in the ROS formation and PPARγ-dependent apoptosis induced by troglitazone. The findings from this study showed that troglitazone-induced apoptosis was mediated by POX-induced ROS formation, at least partly, via PPARγ activation. Copyright © 2011 The Editorial Board of Biomedical and Environmental Sciences. Published by Elsevier B.V. All rights reserved.

P2Y receptor-mediated transient relaxation of rat longitudinal ileum preparations involves phospholipase C activation, intracellular Ca(2+) release and SK channel activation.

Science.gov (United States)

Mader, Felix; Krause, Ludwig; Tokay, Tursonjan; Hakenberg, Oliver W; Köhling, Rüdiger; Kirschstein, Timo

2016-05-01

Purinergic signaling plays a major role in the enteric nervous system, where it governs gut motility through a number of P2X and P2Y receptors. The aim of this study was to investigate the P2Y receptor-mediated motility in rat longitudinal ileum preparations. Ileum smooth muscle strips were prepared from rats, and fixed in an organ bath. Isometric contraction and relaxation responses of the muscle strips were measured with force transducers. Drugs were applied by adding of stock solutions to the organ bath to yield the individual final concentrations. Application of the non-hydrolyzable P2 receptor agonists α,β-Me-ATP or 2-Me-S-ADP (10, 100 μmol/L) dose-dependently elicited a transient relaxation response followed by a sustained contraction. The relaxation response was largely blocked by SK channel blockers apamin (500 nmol/L) and UCL1684 (10 μmol/L), PLC inhibitor U73122 (100 μmol/L), IP3 receptor blocker 2-APB (100 μmol/L) or sarcoendoplasmic Ca(2+) ATPase inhibitor thapsigargin (1 μmol/L), but not affected by atropine, NO synthase blocker L-NAME or tetrodotoxin. Furthermore, α,β-Me-ATP-induced relaxation was suppressed by P2Y1 receptor antagonist MRS2179 (50 μmol/L) or P2Y13 receptor antagonist MRS2211 (100 μmol/L), and was abolished by co-application of the two antagonists, whereas 2-Me-S-ADP-induced relaxation was abolished by P2Y6 receptor antagonist MRS2578 (50 μmol/L). In addition, P2Y1 receptor antagonist MRS2500 (1 μmol/L) not only abolished α,β-Me-ATP-induced relaxation, but also suppressed 2-Me-S-ADP-induced relaxation. P2Y receptor agonist-induced transient relaxation of rat ileum smooth muscle strips is mediated predominantly by P2Y1 receptor, but also by P2Y6 and P2Y13 receptors, and involves PLC, IP3, Ca(2+) release and SK channel activation, but is independent of acetylcholine and NO release.

Taurine activates GABAergic networks in the neocortex of immature mice

Directory of Open Access Journals (Sweden)

Bogdan Aurel Sava

2014-02-01

Full Text Available Although it has been suggested that taurine is the main endogenous neurotransmitter acting on glycine receptors, the implications of glycine receptor-mediated taurine actions on immature neocortical networks have not been addressed yet. To investigate the influence of taurine on the excitability of neuronal networks in the immature neocortex, we performed whole-cell patch-clamp recordings from visually identified pyramidal neurons and interneurons in coronal slices from C57Bl/6 and GAD67-GFP transgenic mice (postnatal days 2-4. In 46 % of the pyramidal neurons bath-application of taurine at concentrations ≥ 300 mM significantly enhanced the frequency of postsynaptic currents (PSCs by 744.3 ± 93.8 % (n = 120 cells. This taurine-induced increase of PSC frequency was abolished by 0.2 mM tetrodotoxine, 1 mM strychnine or 3 mM gabazine, but was unaffected by the glutamatergic antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX and (± R(--3-(2-carboxypiperazine-4-yl-propyl-1-phosphonic acid (CPP, suggesting that taurine specifically activates GABAergic network activity projecting to pyramidal neurons. Cell-attached recordings revealed that taurine enhanced the frequency of action potentials in pyramidal neurons, indicating an excitatory action of the GABAergic PSCs. In order to identify the presynaptic targets of taurine we demonstrate that bath application of taurine induced in GAD67-GFP labeled interneurons an inward current that is mainly mediated by glycine receptors and can generate action potentials in these cells. We conclude from these results that taurine can enhance network excitability in the immature neocortex by selectively activating GABAergic interneurons via interactions with glycine receptors.

Analysis of Spontaneous and Nerve-Evoked Calcium Transients in Intact Extraocular Muscles in Vitro

Science.gov (United States)

Feng, Cheng-Yuan; Hennig, Grant W.; Corrigan, Robert D.; Smith, Terence K.; von Bartheld, Christopher S.

2012-01-01

Extraocular muscles (EOMs) have unique calcium handling properties, yet little is known about the dynamics of calcium events underlying ultrafast and tonic contractions in myofibers of intact EOMs. Superior oblique EOMs of juvenile chickens were dissected with their nerve attached, maintained in oxygenated Krebs buffer, and loaded with fluo-4. Spontaneous and nerve stimulation-evoked calcium transients were recorded and, following calcium imaging, some EOMs were double-labeled with rhodamine-conjugated alpha-bungarotoxin (rhBTX) to identify EOM myofiber types. EOMs showed two main types of spontaneous calcium transients, one slow type (calcium waves with 1/2max duration of 2–12 s, velocity of 25–50 μm/s) and two fast “flash-like” types (Type 1, 30–90 ms; Type 2, 90–150 ms 1/2max duration). Single pulse nerve stimulation evoked fast calcium transients identical to the fast (Type 1) calcium transients. Calcium waves were accompanied by a local myofiber contraction that followed the calcium transient wavefront. The magnitude of calcium-wave induced myofiber contraction far exceeded those of movement induced by nerve stimulation and associated fast calcium transients. Tetrodotoxin eliminated nerve-evoked transients, but not spontaneous transients. Alpha-bungarotoxin eliminated both spontaneous and nerve-evoked fast calcium transients, but not calcium waves, and caffeine increased wave activity. Calcium waves were observed in myofibers lacking spontaneous or evoked fast transients, suggestive of multiply-innervated myofibers, and this was confirmed by double-labeling with rhBTX. We propose that the abundant spontaneous calcium transients and calcium waves with localized contractions that do not depend on innervation may contribute to intrinsic generation of tonic functions of EOMs. PMID:22579493

The endothelin ET(B) receptor agonist [125I]BQ-3020 binds predominantly to nerves in the bovine retractor penis muscle and penile artery.

Science.gov (United States)

Parkkisenniemi, U M; Palkama, A; Virtanen, I; Klinge, E

2000-11-01

Preliminary pharmacological experiments have suggested that in the bovine retractor penis muscle there are relaxation-mediating endothelin ET(B) receptors, at least part of which are located on the inhibitory nitrergic nerves. The present work was undertaken to test this hypothesis by means of receptor autoradiography and additional pharmacological experiments. In the retractor penis muscle and the penile artery, specific binding of the ETB receptor-selective agonist [125I]BQ-3020 took place predominantly to nerve trunks and minor nerve branches. The situation was the same in the dorsal metatarsal artery, that was included as a reference because of its different innervation. Throughout the nerves the silver grains were evenly distributed over the nuclei of Schwann cells and the spaces between them. In the retractor penis there was also a small amount of specific binding to smooth muscle. No specific endothelial binding was observed in any of the tissues examined. The pharmacological studies confirmed that the relaxation of the retractor penis muscle induced by the ET(B) receptor-selective agonist, sarafotoxin S6c, is susceptible to tetrodotoxin as well as to inhibition of nitric oxide synthase. The relaxation was also characterized by inconsistency, weakness and tachyphylaxis. The electrical field stimulation-induced submaximal relaxation of the retractor penis was unaffected by stimulation or blockade of ET(B) receptors. The autoradiography suggests that in all the three bovine tissues studied there are ET(B) receptors located on nerves independently of the type of efferent nerve. The pharmacological experiments do not support the concept that in the bovine retractor penis muscle neuronal ET(B) receptors exert important immediate effects on the functioning of the penile erection-mediating nitrergic nerves.

Effects of endorphins on different parts of the gastrointestinal tract of rat and guinea-pig in vitro.

Science.gov (United States)

Nijkamp, F P; Van Ree, J M

1980-04-01

1 The spasmogenic and spasmolytic effects of beta-lipotropin (LPH) fragments and one analogue were investigated on different parts of the gastro-intestinal tract of guinea-pig and rat in vitro.2 Changes in muscle tone were observed in colon and rectum and to a lesser extent in jejunum and ileum of both species. Rat colon and rectum contracted to the peptides. Guinea-pig colon and rectum relaxed after an initial short-lasting contraction.3 On the rat rectum (D-ala(2))met-enkephalin, leu-enkephalin, gamma-endorphin, alpha-endorphin and beta-LPH 80-91 caused dose-dependent contractions, their ED(50) values being 0.96 x 10(-12) mol, 1.05 x 10(-11) mol, 1.22 x 10(-11) mol, 1.08 x 10(-10) mol, 2.65 x 10(-10) mol and 6.5 x 10(-9) mol, respectively.4 Naloxone dose-dependently shifted the dose-response curve of met-enkephalin to the right. Atropine, hexamethonium, burimamide, mepyramine, propranolol and indomethacin did not influence the response to met-enkephalin.5 In the presence of tetrodotoxin, the ED(50) for met-enkephalin and the maximal contractor response induced by met-enkephalin, appeared to be increased.6 The 5-hydroxytryptamine (5-HT) antagonists, methysergide and cyproheptadine, reduced the contractor response in a non-competitive manner. The alpha-adrenoceptor antagonist phentolamine, in contrast, caused an increase of the maximal response to met-enkephalin of up to 200%. Noradrenergic and tryptaminergic systems, therefore, might be involved in the changes in muscle tone induced by met-enkephalin.7 These results demonstrate that rectum and colon of guinea-pig and rat are very sensitive to opioid-like peptides.

Baby universes with induced gravity

International Nuclear Information System (INIS)

Gao Yihong; Gao Hongbo

1989-01-01

In this paper some quantum effects of baby universes with induced gravity are discussed. It is proved that the interactions between the baby-parent universes are non-local, and argue that the induced low-energy cosmological constant is zero. This argument does not depend on the detail of the induced potential

Geraniin suppresses RANKL-induced osteoclastogenesis in vitro and ameliorates wear particle-induced osteolysis in mouse model

Energy Technology Data Exchange (ETDEWEB)

Xiao, Fei; Zhai, Zanjing; Jiang, Chuan; Liu, Xuqiang; Li, Haowei; Qu, Xinhua [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Ouyang, Zhengxiao [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Department of Orthopaedics, Hunan Provincial Tumor Hospital and Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013 (China); Fan, Qiming; Tang, Tingting [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Qin, An, E-mail: dr.qinan@gmail.com [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Gu, Dongyun, E-mail: dongyungu@gmail.com [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Engineering Research Center of Digital Medicine and Clinical Translation, Ministry of Education of PR China (China); School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030 (China)

2015-01-01

Wear particle-induced osteolysis and subsequent aseptic loosening remains the most common complication that limits the longevity of prostheses. Wear particle-induced osteoclastogenesis is known to be responsible for extensive bone erosion that leads to prosthesis failure. Thus, inhibition of osteoclastic bone resorption may serve as a therapeutic strategy for the treatment of wear particle induced osteolysis. In this study, we demonstrated for the first time that geraniin, an active natural compound derived from Geranium thunbergii, ameliorated particle-induced osteolysis in a Ti particle-induced mouse calvaria model in vivo. We also investigated the mechanism by which geraniin exerts inhibitory effects on osteoclasts. Geraniin inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner, evidenced by reduced osteoclast formation and suppressed osteoclast specific gene expression. Specially, geraniin inhibited actin ring formation and bone resorption in vitro. Further molecular investigation demonstrated geraniin impaired osteoclast differentiation via the inhibition of the RANKL-induced NF-κB and ERK signaling pathways, as well as suppressed the expression of key osteoclast transcriptional factors NFATc1 and c-Fos. Collectively, our data suggested that geraniin exerts inhibitory effects on osteoclast differentiation in vitro and suppresses Ti particle-induced osteolysis in vivo. Geraniin is therefore a potential natural compound for the treatment of wear particle induced osteolysis in prostheses failure. - Highlights: • Geraniin suppresses osteoclasts formation and function in vitro. • Geraniin impairs RANKL-induced nuclear factor-κB and ERK signaling pathway. • Geraniin suppresses osteolysis in vivo. • Geraniin may be used for treating osteoclast related diseases.

Contribution of radiation-induced, nitric oxide-mediated bystander effect to radiation-induced adaptive response.

Science.gov (United States)

Matsumoto, H.; Ohnishi, T.

There has been a recent upsurge of interest in radiation-induced adaptive response and bystander effect which are specific modes in stress response to low-dose low-dose rate radiation Recently we found that the accumulation of inducible nitric oxide NO synthase iNOS in wt p53 cells was induced by chronic irradiation with gamma rays followed by acute irradiation with X-rays but not by each one resulting in an increase in nitrite concentrations of medium It is suggested that the accumulation of iNOS may be due to the depression of acute irradiation-induced p53 functions by pre-chronic irradiation In addition we found that the radiosensitivity of wt p53 cells against acute irradiation with X-rays was reduced after chronic irradiation with gamma rays This reduction of radiosensitivity of wt p53 cells was nearly completely suppressed by the addition of NO scavenger carboxy-PTIO to the medium This reduction of radiosensitivity of wt p53 cells is just radiation-induced adaptive response suggesting that NO-mediated bystander effect may considerably contribute to adaptive response induced by radiation

Vaccination with IL-6 analogues induces autoantibodies to IL-6 and influences experimentally induced inflammation

DEFF Research Database (Denmark)

Galle, Pia; Jensen, Lene; Andersson, Christina

2007-01-01

; yet they appear healthy and do not exhibit overt clinical or laboratory abnormalities. We induced comparable levels of aAb-IL-6 in different mouse strains by vaccination with immunogenic IL-6 analogues. We observed that the induced aAb-IL-6 protected against collagen-induced arthritis and experimental...

Noise-Induced Hearing Loss

Science.gov (United States)

... Home » Health Info » Hearing, Ear Infections, and Deafness Noise-Induced Hearing Loss On this page: What is ... I find additional information about NIHL? What is noise-induced hearing loss? Every day, we experience sound ...

Drug-induced apnea.

Science.gov (United States)

Boutroy, M J

1994-01-01

Drugs have been in the past and will in the future still be liable to induce apnea in neonates, infants and older children. At these different stages of development, the child may be abnormally vulnerable to respiratory disorders and apnea, and doses of drugs, without any abnormal side effects in adult patients, can be harmful in younger subjects. Drugs responsible for apnea during development are numerous, but more than half of the problems are induced by sedatives and hypnotics, among which phenothiazines, barbiturates, benzodiazepines (included transplacentally acquired) and general anesthetics are a few. Other pharmacological families are apnea inducers in the neonatal period and childhood: analgesics and opioid narcotics, agents acting at the levels of neuromuscular function and autonomic ganglia, and cardiovascular agents. The pathogenesis of these apneas depends on the disturbance of any mechanism responsible for the respiratory activity: medullary centers and brain stem structures, afferent influx to CNS, sleep stages, upper airways, lungs and respiratory muscles. At key stages such as birth and infancy, drugs may emphasize the particular sensitivity of the mechanisms responsible for inducing apnea. This might explain unexpected respiratory disorders during development.

Irradiation-Induced Nanostructures

Energy Technology Data Exchange (ETDEWEB)

Birtcher, R.C.; Ewing, R.C.; Matzke, Hj.; Meldrum, A.; Newcomer, P.P.; Wang, L.M.; Wang, S.X.; Weber, W.J.

1999-08-09

This paper summarizes the results of the studies of the irradiation-induced formation of nanostructures, where the injected interstitials from the source of irradiation are not major components of the nanophase. This phenomena has been observed by in situ transmission electron microscopy (TEM) in a number of intermetallic compounds and ceramics during high-energy electron or ion irradiations when the ions completely penetrate through the specimen. Beginning with single crystals, electron or ion irradiation in a certain temperature range may result in nanostructures composed of amorphous domains and nanocrystals with either the original composition and crystal structure or new nanophases formed by decomposition of the target material. The phenomenon has also been observed in natural materials which have suffered irradiation from the decay of constituent radioactive elements and in nuclear reactor fuels which have been irradiated by fission neutrons and other fission products. The mechanisms involved in the process of this nanophase formation are discussed in terms of the evolution of displacement cascades, radiation-induced defect accumulation, radiation-induced segregation and phase decomposition, as well as the competition between irradiation-induced amorphization and recrystallization.

Dioscin induces caspase-independent apoptosis through activation of apoptosis-inducing factor in breast cancer cells.

Science.gov (United States)

Kim, Eun-Ae; Jang, Ji-Hoon; Lee, Yun-Han; Sung, Eon-Gi; Song, In-Hwan; Kim, Joo-Young; Kim, Suji; Sohn, Ho-Yong; Lee, Tae-Jin

2014-07-01

Dioscin, a saponin extracted from the roots of Polygonatum zanlanscianense, shows several bioactivities such as antitumor, antifungal, and antiviral properties. Although, dioscin is already known to induce cell death in variety cancer cells, the molecular basis for dioscin-induced cell death was not definitely known in cancer cells. In this study, we found that dioscin treatment induced cell death in dose-dependent manner in breast cancer cells such as MDA-MB-231, MDA-MB-453, and T47D cells. Dioscin decreased expressions of Bcl-2 and cIAP-1 proteins, which were down-regulated at the transcriptional level. Conversely, Mcl-1 protein level was down-regulated by facilitating ubiquitin/proteasome-mediated Mcl-1 degradation in dioscin-treated cells. Pretreatment with z-VAD fails to attenuate dioscin-induced cell death as well as caspase-mediated events such as cleavages of procaspase-3 and PARP. In addition, dioscin treatment increased the population of annexin V positive cells and induced DNA fragmentation in a dose-dependent manner in MDA-MB-231 cells. Furthermore, apoptosis inducing factor (AIF) was released from the mitochondria and translocated to the nucleus. Suppression in AIF expression by siRNA reduced dioscin-induced apoptosis in MDA-MB-231 cells. Taken together, our results demonstrate that dioscin-induced cell death was mediated via AIF-facilitating caspase-independent pathway as well as down-regulating anti-apoptotic proteins such as Bcl-2, cIAP-1, and Mcl-1 in breast cancer cells.

Diet induced thermogenesis

OpenAIRE

Westerterp KR

2004-01-01

Objective Daily energy expenditure consists of three components: basal metabolic rate, diet-induced thermogenesis and the energy cost of physical activity. Here, data on diet-induced thermogenesis are reviewed in relation to measuring conditions and characteristics of the diet. Methods Measuring conditions include nutritional status of the subject, physical activity and duration of the observation. Diet characteristics are energy content and macronutrient composition. Resu...

Quinine-induced tinnitus in rats.

Science.gov (United States)

Jastreboff, P J; Brennan, J F; Sasaki, C T

1991-10-01

Quinine ingestion reportedly induces tinnitus in humans. To expand our salicylate-based animal model of tinnitus, a series of conditioned suppression experiments was performed on 54 male-pigmented rats using quinine injections to induce tinnitus. Quinine induced changes in both the extent of suppression and recovery of licking, which followed a pattern that paralleled those produced after salicylate injections, and which may be interpreted as the result of tinnitus perception in animals. These changes depended on the dose and time schedule of quinine administration. Additionally, the calcium channel blocker, nimodipine, abolished the quinine-induced effect in a dose-dependent manner.

Chronic lead exposure induces cochlear oxidative stress and potentiates noise-induced hearing loss.

Science.gov (United States)

Jamesdaniel, Samson; Rosati, Rita; Westrick, Judy; Ruden, Douglas M

2018-08-01

Acquired hearing loss is caused by complex interactions of multiple environmental risk factors, such as elevated levels of lead and noise, which are prevalent in urban communities. This study delineates the mechanism underlying lead-induced auditory dysfunction and its potential interaction with noise exposure. Young-adult C57BL/6 mice were exposed to: 1) control conditions; 2) 2 mM lead acetate in drinking water for 28 days; 3) 90 dB broadband noise 2 h/day for two weeks; and 4) both lead and noise. Blood lead levels were measured by inductively coupled plasma mass spectrometry analysis (ICP-MS) lead-induced cochlear oxidative stress signaling was assessed using targeted gene arrays, and the hearing thresholds were assessed by recording auditory brainstem responses. Chronic lead exposure downregulated cochlear Sod1, Gpx1, and Gstk1, which encode critical antioxidant enzymes, and upregulated ApoE, Hspa1a, Ercc2, Prnp, Ccl5, and Sqstm1, which are indicative of cellular apoptosis. Isolated exposure to lead or noise induced 8-12 dB and 11-25 dB shifts in hearing thresholds, respectively. Combined exposure induced 18-30 dB shifts, which was significantly higher than that observed with isolated exposures. This study suggests that chronic exposure to lead induces cochlear oxidative stress and potentiates noise-induced hearing impairment, possibly through parallel pathways. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Research progress of exercise-induced fatigue

Directory of Open Access Journals (Sweden)

Peng-yi DAI

2016-12-01

Full Text Available Exercise-induced fatigue is a comprehensive response to a variety of physiological and biochemical changes in the body, and can affect people's quality of life to different extents. If no timely recovery after occurrence of fatigue, accumulated gradually, it can lead to "burnout", a "overtraining syndrome", "chronic fatigue syndrome", etc., which will cause endocrine disturbance, immune suppression, even physical illness. Exercise-induced fatigue becomes an important factor endangering human health. In recent years, many experts and scholars at home and abroad are committed to the research of exercise-induced fatigue, and have put forward a variety of hypothesis to explain the cause of exercise-induced fatigue. They expect to find out the methods for preventing and eliminating exercise-induced fatigue. This article discusses mainly the pathogenesis, model building, elimination/ relief, etc. of exercise-induced fatigue to point out the research achievements of exercise-induced fatigue and its existing problems. DOI: 10.11855/j.issn.0577-7402.2016.11.14

Interactions of pyrethroid insecticides with GABAA and peripheral-type benzodiazepine receptors

International Nuclear Information System (INIS)

Devaud, L.L.

1988-01-01

Pyrethroid insecticides are potent proconvulsants in the rat. All pyrethroids evincing proconvulsant activity elicited a similar 25-30% maximal reduction of seizure threshold. The Type II pyrethroids were the most potent proconvulsants with 1RαS, cis cypermethrin having an ED 50 value of 6.3 nmol/kg. The proconvulsant activity of both Type I and Type II pyrenthroids was blocked by pretreatment with PK 11195, the peripheral-type benzodiazepine receptor (PTBR) antagonist. In contrast, phenytoin did not antagonize the proconvulsant activity of either deltamethrin or permethrin. Pyrethroids displaced the specific binding of [ 3 H]Ro5-4864 to rat brain membranes with a significant correlation between the log EC 50 values for their activities as proconvulsants and the log IC 50 values for their inhibition of [ 3 H]Ro5-4864 binding. Both Ro5-4864 and pyrethroid insecticides were found to influence specific [ 35 S]TBPS binding in a GABA-dependent manner. PK 11195 and the Type II pyrethroid, deltamethrin antagonized the Ro5-4864-induced modulation of [ 35 S]TBPS binding. Pyrethroid insecticides, Ro5-4864 and veratridine influenced GABA-gated 36 Chloride influx. Moreover, the Type II pyrethroids elicited an increase in 36 chloride influx in the absence of GABA-stimulation. Both of these actions were antagonized by PK 11195 and tetrodotoxin

Terahertz Induced Electromigration

DEFF Research Database (Denmark)

Strikwerda, Andrew; Zalkovskij, Maksim; Iwaszczuk, Krzysztof

2014-01-01

We report the first observation of THz-field-induced electromigration in subwavelength metallic gap structures after exposure to intense single-cycle, sub-picosecond electric field transients of amplitude up to 400 kV/cm.......We report the first observation of THz-field-induced electromigration in subwavelength metallic gap structures after exposure to intense single-cycle, sub-picosecond electric field transients of amplitude up to 400 kV/cm....

Beam induced RF heating

CERN Document Server

Salvant, B; Arduini, G; Assmann, R; Baglin, V; Barnes, M J; Bartmann, W; Baudrenghien, P; Berrig, O; Bracco, C; Bravin, E; Bregliozzi, G; Bruce, R; Bertarelli, A; Carra, F; Cattenoz, G; Caspers, F; Claudet, S; Day, H; Garlasche, M; Gentini, L; Goddard, B; Grudiev, A; Henrist, B; Jones, R; Kononenko, O; Lanza, G; Lari, L; Mastoridis, T; Mertens, V; Métral, E; Mounet, N; Muller, J E; Nosych, A A; Nougaret, J L; Persichelli, S; Piguiet, A M; Redaelli, S; Roncarolo, F; Rumolo, G; Salvachua, B; Sapinski, M; Schmidt, R; Shaposhnikova, E; Tavian, L; Timmins, M; Uythoven, J; Vidal, A; Wenninger, J; Wollmann, D; Zerlauth, M

2012-01-01

After the 2011 run, actions were put in place during the 2011/2012 winter stop to limit beam induced radio frequency (RF) heating of LHC components. However, some components could not be changed during this short stop and continued to represent a limitation throughout 2012. In addition, the stored beam intensity increased in 2012 and the temperature of certain components became critical. In this contribution, the beam induced heating limitations for 2012 and the expected beam induced heating limitations for the restart after the Long Shutdown 1 (LS1) will be compiled. The expected consequences of running with 25 ns or 50 ns bunch spacing will be detailed, as well as the consequences of running with shorter bunch length. Finally, actions on hardware or beam parameters to monitor and mitigate the impact of beam induced heating to LHC operation after LS1 will be discussed.

The ovarian DNA damage repair response is induced prior to phosphoramide mustard-induced follicle depletion, and ataxia telangiectasia mutated inhibition prevents PM-induced follicle depletion

Energy Technology Data Exchange (ETDEWEB)

Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

2016-02-01

Phosphoramide mustard (PM) is an ovotoxic metabolite of cyclophosphamide and destroys primordial and primary follicles potentially by DNA damage induction. The temporal pattern by which PM induces DNA damage and initiation of the ovarian response to DNA damage has not yet been well characterized. This study investigated DNA damage initiation, the DNA repair response, as well as induction of follicular demise using a neonatal rat ovarian culture system. Additionally, to delineate specific mechanisms involved in the ovarian response to PM exposure, utility was made of PKC delta (PKCδ) deficient mice as well as an ATM inhibitor (KU 55933; AI). Fisher 344 PND4 rat ovaries were cultured for 12, 24, 48 or 96 h in medium containing DMSO ± 60 μM PM or KU 55933 (48 h; 10 nM). PM-induced activation of DNA damage repair genes was observed as early as 12 h post-exposure. ATM, PARP1, E2F7, P73 and CASP3 abundance were increased but RAD51 and BCL2 protein decreased after 96 h of PM exposure. PKCδ deficiency reduced numbers of all follicular stages, but did not have an additive impact on PM-induced ovotoxicity. ATM inhibition protected all follicle stages from PM-induced depletion. In conclusion, the ovarian DNA damage repair response is active post-PM exposure, supporting that DNA damage contributes to PM-induced ovotoxicity. - Highlights: • PM exposure induces DNA damage repair gene expression. • Inhibition of ATM prevented PM-induced follicle depletion. • PKCδ deficiency did not impact PM-induced ovotoxicity.

The mode of inotropic action of ciguatoxin on guinea-pig cardiac muscle.

Science.gov (United States)

Seino, A.; Kobayashi, M.; Momose, K.; Yasumoto, T.; Ohizumi, Y.

1988-01-01

1. Ciguatoxin (CTX) caused a dose-dependent increase in the contractile force of the guinea-pig isolated left atria at concentrations ranging from 0.1 to 10 ng ml-1 with the ED50 value of 0.5 ng ml-1. 2. In the atria, tetrodotoxin (5 x 10(-7) M) inhibited markedly the inotropic action of CTX. The inotropic effect of CTX at low concentrations was abolished by practolol (10(-5) M) and reserpine (2 mg kg-1 daily, for 3 days), whereas that of CTX at high concentrations was partially inhibited by both drugs. 3. In single atrial cells, CTX (3 ng ml-1) produced a marked increase in the amplitude of longitudinal contractions. 4. CTX (3 ng ml-1) caused marked prolongation in the falling phase of action potentials of atrial strips without affecting the maximum rate of rise of action potentials and membrane resting potentials. The effect of CTX on action potentials was abolished by tetrodotoxin (10(-6) M). 5. The whole-cell patch-clamp experiments on myocytes revealed that CTX (20 ng ml-1) shifted the current-voltage curve of Na inward currents by 40 mV in the negative direction. CTX caused a small sustained Na inward current even at resting membrane potentials. 6. These results suggest that the inotropic action of lower concentrations of CTX is primarily due to an indirect action via noradrenaline release, whereas that of higher concentrations is caused not only by an indirect action but also by a direct action on voltage-dependent Na channels of cardiac muscle.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3207997

Induced mutations in sesame breeding

International Nuclear Information System (INIS)

Ashri, A.

2001-01-01

The scope of induced mutations in sesame (Sesamum indicum L.) breeding is reviewed. So far in Egypt, India, Iraq, Rep. of Korea, and Sri Lanka, 14 officially released varieties have been developed through induced mutations: 12 directly and 2 through cross breeding (one using the 'dt45' induced mutant from Israel). For another variety released in China there are no details. The induced mutations approach was adopted primarily in order to obtain genetic variability that was not available in the germplasm collection. The mutagens commonly applied have been gamma rays, EMS and sodium azide. Sesame seeds can withstand high mutagen doses, and there are genotypic differences in sensitivity between varieties. The mutants induced in the above named countries and others include better yield, improved seed retention, determinate habit, modified plant architecture and size, more uniform and shorter maturation period, earliness, resistance to diseases, genic male sterility, seed coat color, higher oil content and modified fatty acids composition. Some of the induced mutants have already given rise to improved varieties, the breeding value of other mutants is now being assessed and still others can serve as useful markers in genetic studies and breeding programmes. (author)

Holographic Two-Photon Induced Photopolymerization

Data.gov (United States)

Federal Laboratory Consortium — Holographic two-photon-induced photopolymerization (HTPIP) offers distinct advantages over conventional one-photon-induced photopolymerization and current techniques...

Involvement of inducible nitric oxide synthase in radiation-induced vascular endothelial damage

International Nuclear Information System (INIS)

Hong, Chang-Won; Lee, Joon-Ho; Kim, Suwan; Noh, Jae Myoung; Kim, Young-Mee; Pyo, Hongryull; Lee, Sunyoung

2013-01-01

The use of radiation therapy has been linked to an increased risk of cardiovascular disease. To understand the mechanisms underlying radiation-induced vascular dysfunction, we employed two models. First, we examined the effect of X-ray irradiation on vasodilation in rabbit carotid arteries. Carotid arterial rings were irradiated with 8 or 16 Gy using in vivo and ex vivo methods. We measured the effect of acetylcholine-induced relaxation after phenylephrine-induced contraction on the rings. In irradiated carotid arteries, vasodilation was significantly attenuated by both irradiation methods. The relaxation response was completely blocked by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a potent inhibitor of soluble guanylate cyclase. Residual relaxation persisted after treatment with L-N ω -nitroarginine (L-NA), a non-specific inhibitor of nitric oxide synthase (NOS), but disappeared following the addition of aminoguanidine (AG), a selective inhibitor of inducible NOS (iNOS). The relaxation response was also affected by tetraethylammonium, an inhibitor of endothelium-derived hyperpolarizing factor activity. In the second model, we investigated the biochemical events of nitrosative stress in human umbilical-vein endothelial cells (HUVECs). We measured iNOS and nitrotyrosine expression in HUVECs exposed to a dose of 4 Gy. The expression of iNOS and nitrotyrosine was greater in irradiated HUVECs than in untreated controls. Pretreatment with AG, L-N 6 -(1-iminoethyl) lysine hydrochloride (a selective inhibitor of iNOS), and L-NA attenuated nitrosative stress. While a selective target of radiation-induced vascular endothelial damage was not definitely determined, these results suggest that NO generated from iNOS could contribute to vasorelaxation. These studies highlight a potential role of iNOS inhibitors in ameliorating radiation-induced vascular endothelial damage. (author)

Systemic resistance induced by rhizosphere bacteria

NARCIS (Netherlands)

Loon, L.C. van; Bakker, P.A.H.M.; Pieterse, C.M.J.

1998-01-01

Nonpathogenic rhizobacteria can induce a systemic resistance in plants that is phenotypically similar to pathogen-induced systemic acquired resistance (SAR). Rhizobacteria-mediated induced systemic resistance (ISR) has been demonstrated against fungi, bacteria, and viruses in Arabidopsis, bean,

Induced radioactivity at CERN

CERN Multimedia

1970-01-01

A description of some of the problems and some of the advantages associated with the phenomenon of induced radioactivity at accelerator centres such as CERN. The author has worked in this field for several years and has recently written a book 'Induced Radioactivity' published by North-Holland.

Mastication-induced vertigo and nystagmus.

Science.gov (United States)

Park, Seong-Ho; Kim, Hyo-Jung; Kim, Ji-Soo; Koo, Ja-Won; Oh, Seo Won; Kim, Dong-Uk; Kim, Joon-Tae; Welgampola, Miriam; Deriu, Franca

2014-03-01

Even though trigeminovestibular connections are well established in animals, mastication-induced dizziness has been described only as a vascular steal phenomenon in humans. We determined induction or modulation of nystagmus in two index patients with mastication-induced vertigo, 12 normal controls, and 52 additional patients with peripheral (n = 38, 26 with vestibular neuritis/labyrinthitis and 12 with Meniere's disease) or central (n = 14, 11 with Wallenberg syndrome, two with cerebellar infarction, and one with pontine infarction) vestibulopathy during their acute or compensated phase. Both index patients developed mastication-induced vertigo after near complete resolution of the spontaneous vertigo from presumed acute unilateral peripheral vestibulopathy. The nystagmus and vertigo gradually built up during mastication and dissipated slowly after cessation of mastication. Brain MRI and cerebral angiography were normal in these patients. Mastication did not induce nystagmus in normal controls. However, mastication induced nystagmus in five (24 %) of the 21 patients without spontaneous nystagmus (SN) but with a previous history of a vestibular syndrome, and either increased (21/31, 68 %) or decreased (7/31, 23 %) the SN in almost all the patients (28/31, 90 %) with SN. Mastication may induce significant vertigo and nystagmus in patients with a prior history of acute vestibulopathy. The induction or modulation of nystagmus by mastication in both peripheral and central vestibulopathies supports trigeminal modulation of the vestibular system in human. The gradual build-up and dissipation suggest a role of the velocity storage mechanism in the generation of mastication-induced vertigo and nystagmus.

Mechanistic review of drug-induced steatohepatitis

International Nuclear Information System (INIS)

Schumacher, Justin D.; Guo, Grace L.

2015-01-01

Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. - Highlights: • Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds • Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis. • Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs. • Chemotherapeutics that induce CASH are cationic amphiphilic drugs. • Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.

Mechanistic review of drug-induced steatohepatitis

Energy Technology Data Exchange (ETDEWEB)

Schumacher, Justin D., E-mail: Justin.d.schumacher@rutgers.edu; Guo, Grace L.

2015-11-15

Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. - Highlights: • Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds • Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis. • Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs. • Chemotherapeutics that induce CASH are cationic amphiphilic drugs. • Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.

Full scale measurement of wind induced pressures : 1 configuration of wind induced pressures

NARCIS (Netherlands)

Geurts, C.P.W.; Wijen, H.L.M.

1994-01-01

A research project 10 the spectral characteristics of wind induced pressures is in progress in Eindhoven. This project includes both wind tunnel and full scale measurements. Wind induced pressures are measured in full scale at the main building of Eindhoven University of Technology. This paper

TCDD Induces the Hypoxia-Inducible Factor (HIF-1α Regulatory Pathway in Human Trophoblastic JAR Cells

Directory of Open Access Journals (Sweden)

Tien-Ling Liao

2014-09-01

Full Text Available The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non-hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1α stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS and nitric oxide. TCDD-induced HIF-1α stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K inhibitor or N-acetylcysteine (a ROS scavenger. The augmented HIF-1α stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor γ (PPARγ, PPARγ coactivator-1α, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1α pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development.

Study of vitamin D serum level in patients with epilepsy treated with enzyme-inducing and non enzyme-inducing medications

Directory of Open Access Journals (Sweden)

sima Hashemipour

2014-01-01

Full Text Available Background : Changes of serum minerals and vitamin D have been reported in anticonvulsant drugs user patients. The present study aimed at comparing the changes of serum minerals and vitamin D among two groups of enzyme-inducing and non enzyme-inducing anticonvulsant drug users. Methods: In this study 22 patients treated with enzyme-inducing drugs (carbamazepin, phenytoin, phenobarbital were compared to 25 patients of matched sex, age, and BMI treated with non enzyme-inducing drugs (sodium evaporate, lamotrigine. Serum calcium, phosphate, parathormone, and 25-hydroxy vitamin D were calculated in both groups. Calcium was measured by Calorimetery method. Parathormone and vitamin D were measured using ELISA method. Results: The mean serum vitamin D level was lower in enzyme-inducing than non enzyme-inducing drugs users (15.9±8.3 and 24.2±14.8, P=0.02. Frequency of vitamin D deficiency was higher in enzyme-inducing compared to non enzyme-inducing drugs users, 84% and 48% , respectively (P=0.016. The mean serum calcium level was significantly lower in enzyme-inducing drugs users. (8.7±0.2 vs. 9.0± 0.7, p= 0.05. Four percent in enzyme-inducing group compared to twenty four percent of non enzyme-inducing group had secondary hyperparathyroidism (P=0.016. Conclusion: While vitamin D deficiency is more frequent in enzyme-inducing drug users, secondary hyperparathyroidism is less frequent.

Morphine potentiates seizures induced by GABA antagonists and attenuates seizures induced by electroshock in the rat.

Science.gov (United States)

Foote, F; Gale, K

1983-11-25

In a naloxone-reversible, dose-dependent manner, morphine (10-50 mg/kg i.p.) protected against seizures induced by maximal electroshock and increased the incidence and severity of seizures induced by bicuculline, in rats. Morphine also potentiated seizures induced by isoniazid and by picrotoxin. Thus, opiate activity influences the expression of seizures in contrasting ways depending upon the mode of seizure induction. Since morphine consistently potentiated seizures induced by interference with GABA transmission, it appears that GABAergic systems may be of particular significance for the elucidation of the varied effects of morphine on seizure susceptibility.

Cisplatin-Induced Eosinophilic Pneumonia

Directory of Open Access Journals (Sweden)

Hideharu Ideguchi

2014-01-01

Full Text Available A 67-year-old man suffering from esophageal cancer was admitted to our hospital complaining of dyspnea and hypoxemia. He had been treated with cisplatin, docetaxel, and fluorouracil combined with radiotherapy. Chest computed tomography revealed bilateral ground-glass opacity, and bronchoalveolar lavage fluid showed increased eosinophils. Two episodes of transient eosinophilia in peripheral blood were observed after serial administration of anticancer drugs before the admission, and drug-induced lymphocyte stimulation test to cisplatin was positive. Thus cisplatin-induced eosinophilic pneumonia was suspected, and corticosteroid was effectively administered. To our knowledge, this is the first reported case of cisplatin-induced eosinophilic pneumonia.

The transition time induced narrow linewidth of the electromagnetically induced transparency in caesium vapour

International Nuclear Information System (INIS)

Li Luming; Peng Xiang; Liu Cheng; Guo Hong; Chen Xuzong

2004-01-01

We observed a narrow linewidth (∼60 kHz) in a Doppler-broadened system showing electromagnetically induced transparency in caesium atomic vapour. The transition time induced reduction of the linewidth is illustrated both theoretically and experimentally

Prevalence of exercise-induced bronchoconstriction and exercise-induced laryngeal obstruction in a general adolescent population.

Science.gov (United States)

Johansson, Henrik; Norlander, Katarina; Berglund, Lars; Janson, Christer; Malinovschi, Andrei; Nordvall, Lennart; Nordang, Leif; Emtner, Margareta

2015-01-01

Exercise-induced respiratory symptoms are common among adolescents. Exercise is a known stimulus for transient narrowing of the airways, such as exercise-induced bronchoconstriction (EIB) and exercise-induced laryngeal obstruction (EILO). Our aim was to investigate the prevalence of EIB and EILO in a general population of adolescents. In this cross-sectional study, a questionnaire on exercise-induced dyspnoea was sent to all adolescents born in 1997 and 1998 in Uppsala, Sweden (n=3838). A random subsample of 146 adolescents (99 with self-reported exercise-induced dyspnoea and 47 without this condition) underwent standardised treadmill exercise tests for EIB and EILO. The exercise test for EIB was performed while breathing dry air; a positive test was defined as a decrease of ≥10% in FEV1 from baseline. EILO was investigated using continuous laryngoscopy during exercise. The estimated prevalence of EIB and EILO in the total population was 19.2% and 5.7%, respectively. No gender differences were found. In adolescents with exercise-induced dyspnoea, 39.8% had EIB, 6% had EILO and 4.8% had both conditions. In this group, significantly more boys than girls had neither EIB nor EILO (64.7% vs 38.8%; p=0.026). There were no significant differences in body mass index, lung function, diagnosed asthma or medication between the participants with exercise-induced dyspnoea who had or did not have a positive EIB or EILO test result. Both EIB and EILO are common causes of exercise-induced dyspnoea in adolescents. EILO is equally common among girls and boys and can coexist with EIB. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Delayed brain ischemia tolerance induced by electroacupuncture pretreatment is mediated via MCP-induced protein 1

Science.gov (United States)

2013-01-01

Background Emerging studies have demonstrated that pretreatment with electroacupuncture (EA) induces significant tolerance to focal cerebral ischemia. The present study seeks to determine the involvement of monocyte chemotactic protein-induced protein 1 (MCPIP1), a recently identified novel modulator of inflammatory reactions, in the cerebral neuroprotection conferred by EA pretreatment in the animal model of focal cerebral ischemia and to elucidate the mechanisms of EA pretreatment-induced ischemic brain tolerance. Methods Twenty-four hours after the end of the last EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes in male C57BL/6 mice and MCPIP1 knockout mice. Transcription and expression of MCPIP1 gene was monitored by qRT-PCR, Western blot and immunohistochemistry. The neurobehavioral scores, infarction volumes, proinflammatory cytokines and leukocyte infiltration in brain and NF-κB signaling were evaluated after ischemia/reperfusion. Results MCPIP1 protein and mRNA levels significantly increased specifically in mouse brain undergoing EA pretreatment. EA pretreatment significantly attenuated the infarct volume, neurological deficits, upregulation of proinflammatory cytokines and leukocyte infiltration in the brain of wild-type mice after MCAO compared with that of the non-EA group. MCPIP1-deficient mice failed to evoke EA pretreatment-induced tolerance compared with that of the control MCPIP1 knockout group without EA treatment. Furthermore, the activation of NF-κB signaling was significantly reduced in EA-pretreated wild-type mice after MCAO compared to that of the non-EA control group and MCPIP1-deficient mice failed to confer the EA pretreatment-induced inhibition of NF-κB signaling after MCAO. Conclusions Our data demonstrated that MCPIP1 deficiency caused significant lack of EA pretreatment-induced cerebral protective effects after MCAO compared with the control group and that MCPIP1 is

Characterization of Chemically-Induced Bacterial Ghosts (BGs Using Sodium Hydroxide-Induced Vibrio parahaemolyticus Ghosts (VPGs

Directory of Open Access Journals (Sweden)

Hyun Jung Park

2016-11-01

Full Text Available Acellular bacterial ghosts (BGs are empty non-living bacterial cell envelopes, commonly generated by controlled expression of the cloned lysis gene E of bacteriophage PhiX174. In this study, Vibrio parahaemolyticus ghosts (VPGs were generated by chemically-induced lysis and the method is based on minimum inhibitory concentration (MIC of sodium hydroxide (NaOH, acetic acid, boric acid, citric acid, maleic acid, hydrochloric acid, and sulfuric acid. The MIC values of the respective chemicals were 3.125, 6.25, <50.0, 25.0, 6.25, 1.56, and 0.781 mg/mL. Except for boric acid, the lysis efficiency reached more than 99.99% at 5 min after treatment of all chemicals. Among those chemicals, NaOH-induced VPGs appeared completely DNA-free, which was confirmed by quantitative real-time PCR. Besides, lipopolysaccharides (LPS extracted from the NaOH-induced VPGs showed no distinctive band on SDS-PAGE gel after silver staining. On the other hand, LPS extracted from wild-type bacterial cells, as well as the organic acids-induced VPGs showed triple major bands and LPS extracted from the inorganic acids-induced VPGs showed double bands. It suggests that some surface structures in LPS of the NaOH-induced VPGs may be lost, weakened, or modified by the MIC of NaOH. Nevertheless, Limulus amoebocyte lysate assay revealed that there is no significant difference in endotoxic activity between the NaOH-induced VPGs and wild-type bacterial cells. Macrophages exposed to the NaOH-induced VPGs at 0.5 × 106 CFU/mL showed cell viability of 97.9%, however, the MIC of NaOH did not reduce the cytotoxic effect of wild-type bacterial cells. Like Escherichia coli LPS, the NaOH-induced VPGs are an excellent activator of pro-inflammatory cytokines (IL-1β and iNOS, anti-inflammatory cytokine (IL-10, and dual activities (IL-6 in the stimulated macrophage cells. On the other hand, the induction of TNF-α mRNA was remarkable in the macrophages exposed with wild-type cells. Scanning

Statin-induced autoimmune necrotizing myositis

Directory of Open Access Journals (Sweden)

Katarzyna Ząber

2016-02-01

Full Text Available Myositides comprise a large group of disorders involving limb muscle weakness. In differential diagnosis we have to consider idiopathic myositides, myositides associated with other diseases, and those induced by external factors, e.g. drug-induced. Statins are commonly used drugs, but many patients experience a broad spectrum of adverse effects including symptoms from skeletal muscle. Physicians should pay special attention to patients reporting muscle weakness lasting longer than 12 weeks, despite statin withdrawal, as well as other symptoms: dysphagia, disturbed grip function, elevated creatinine kinase (CK levels and abnormal electromyography. The reported case deals with the problem of differential diagnosis of drug-induced muscle injury, polymyositis with a recently reported myopathy – statin-induced autoimmune necrotizing myositis, related to anti-HMGCR antibodies.

Collision-induced destructive quantum interference

International Nuclear Information System (INIS)

Yang Xihua; Sun Zhenrong; Zhang Shi'an; Ding Liang'en; Wang Zugeng

2005-01-01

We conduct theoretical studies on the collision-induced destructive quantum interference of two-colour two-photon transitions in an open rhomb-type five-level system with a widely separated doublet by the density matrix approach. The effects of the collision-induced decay rates, the ratio of the transition dipole moments and the energy separation of the doublet on the interference are analysed. It is shown that a narrow dip appears in the excitation spectrum due to the collision-induced destructive interference, and that the narrow interference dip still exists even when the collision broadening is comparable to the energy separation of the doublet. The physical origin of the collision-induced destructive quantum interference is analysed in the dressed-atom picture

Molecular mechanisms of induced-mutations

International Nuclear Information System (INIS)

Kato, Takeshi

1985-01-01

The outcome of recent studies on mechanisms of induced-mutations is outlined with particular emphasis on the dependence of recA gene function in Escherichia coli. Genes involved in spontaneous mutation and x-ray- and chemical-induced mutation and genes involved in adaptive response are presented. As for SOS mutagenesis, SOS-induced regulation mechanisms and mutagenic routes are described. Furthermore, specificity of mutagens themselves are discussed in relation to mechanisms of base substitution, frameshift, and deletion mutagenesis. (Namekawa, K.)

Effects of Depilation-Induced Skin Pigmentation and Diet-Induced Fluorescence on In Vivo Fluorescence Imaging

OpenAIRE

Kwon, Sunkuk; Sevick-Muraca, Eva M.

2017-01-01

Near-infrared fluorescence imaging (NIRFI) and far-red fluorescence imaging (FRFI) were used to investigate effects of depilation-induced skin pigmentation and diet-induced background fluorescence on fluorescent signal amplitude and lymphatic contraction frequency in C57BL6 mice. Far-red fluorescent signal amplitude, but not frequency, was affected by diet-induced fluorescence, which was removed by feeding the mice an alfalfa-free diet, and skin pigmentation further impacted the amplitude mea...

Laser-induced nuclear fusion

International Nuclear Information System (INIS)

Jablon, Claude

1977-01-01

Research programs on laser-induced thermonuclear fusion in the United States, in Europe and in USSR are reviewed. The principle of the fusion reactions induced is explained, together with the theoretical effects of the following phenomena: power and type of laser beams, shape and size of the solid target, shock waves, and laser-hydrodynamics coupling problems [fr

Neutron-induced fission cross sections

International Nuclear Information System (INIS)

Weigmann, H.

1991-01-01

In the history of fission research, neutron-induced fission has always played the most important role. The practical importance of neutron-induced fission rests upon the fact that additional neutrons are produced in the fission process, and thus a chain reaction becomes possible. The practical applications of neutron-induced fission will not be discussed in this chapter, but only the physical properties of one of its characteristics, namely (n,f) cross sections. The most important early summaries on the subject are the monograph edited by Michaudon which also deals with the practical applications, the earlier review article on fission by Michaudon, and the review by Bjornholm and Lynn, in which neutron-induced fission receives major attention. This chapter will attempt to go an intermediate way between the very detailed theoretical treatment in the latter review and the cited monograph which emphasizes the applied aspects and the techniques of fission cross-section measurements. The more recent investigations in the field will be included. Section II will survey the properties of cross sections for neutron-induced fission and also address some special aspects of the experimental methods applied in their measurement. Section Ill will deal with the formal theory of neutron-induced nuclear reactions for the resolved resonance region and the region of statistical nuclear reactions. In Section IV, the fission width, or fission transmission coefficient, will be discussed in detail. Section V will deal with the broader structures due to incompletely damped vibrational resonances, and in particular will address the special case of thorium and neighboring isotopes. Finally, Section VI will briefly discuss parity violation effects in neutron-induced fission. 74 refs., 14 figs., 3 tabs

Molecular Surface of JZTX-V (β-Theraphotoxin-Cj2a Interacting with Voltage-Gated Sodium Channel Subtype NaV1.4

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Ji Luo

2014-07-01

Full Text Available Voltage-gated sodium channels (VGSCs; NaV1.1–NaV1.9 have been proven to be critical in controlling the function of excitable cells, and human genetic evidence shows that aberrant function of these channels causes channelopathies, including epilepsy, arrhythmia, paralytic myotonia, and pain. The effects of peptide toxins, especially those isolated from spider venom, have shed light on the structure–function relationship of these channels. However, most of these toxins have not been analyzed in detail. In particular, the bioactive faces of these toxins have not been determined. Jingzhaotoxin (JZTX-V (also known as β-theraphotoxin-Cj2a is a 29-amino acid peptide toxin isolated from the venom of the spider Chilobrachys jingzhao. JZTX-V adopts an inhibitory cysteine knot (ICK motif and has an inhibitory effect on voltage-gated sodium and potassium channels. Previous experiments have shown that JZTX-V has an inhibitory effect on TTX-S and TTX-R sodium currents on rat DRG cells with IC50 values of 27.6 and 30.2 nM, respectively, and is able to shift the activation and inactivation curves to the depolarizing and the hyperpolarizing direction, respectively. Here, we show that JZTX-V has a much stronger inhibitory effect on NaV1.4, the isoform of voltage-gated sodium channels predominantly expressed in skeletal muscle cells, with an IC50 value of 5.12 nM, compared with IC50 values of 61.7–2700 nM for other heterologously expressed NaV1 subtypes. Furthermore, we investigated the bioactive surface of JZTX-V by alanine-scanning the effect of toxin on NaV1.4 and demonstrate that the bioactive face of JZTX-V is composed of three hydrophobic (W5, M6, and W7 and two cationic (R20 and K22 residues. Our results establish that, consistent with previous assumptions, JZTX-V is a Janus-faced toxin which may be a useful tool for the further investigation of the structure and function of sodium channels.

Rosuvastatin-induced pemphigoid.

LENUS (Irish Health Repository)

Murad, Aizuri A

2012-01-01

Statins are widely prescribed medications and very well tolerated. Rosuvastatin is another member of this drug used to treat dyslipidaemia. It is a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase. Immunobullous disease is usually idiopathic but can be drug-induced. Both idiopathic and iatrogenic forms share common clinical and immunohistological features. The authors report a case of pemphigoid induced by rosuvastatin, a commonly prescribed medication. To our knowledge, there is limited report on rosuvastatin associated with pemphigoid in the literature.

Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study

OpenAIRE

Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

2016-01-01

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis act...

Smad7 induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis.

Science.gov (United States)

Halder, Sunil K; Beauchamp, R Daniel; Datta, Pran K

2005-07-01

Smad proteins play a key role in the intracellular signaling of the transforming growth factor beta (TGF-beta) superfamily of extracellular polypeptides that initiate signaling to regulate a wide variety of biological processes. The inhibitory Smad, Smad7, has been shown to function as intracellular antagonists of TGF-beta family signaling and is upregulated in several cancers. To determine the effect of Smad7-mediated blockade of TGF-beta signaling, we have stably expressed Smad7 in a TGF-beta-sensitive, well-differentiated, and non-tumorigenic cell line, FET, that was derived from human colon adenocarcinoma. Smad7 inhibits TGF-beta-induced transcriptional responses by blocking complex formation between Smad 2/3 and Smad4. While Smad7 has no effect on TGF-beta-induced activation of p38 MAPK and ERK, it blocks the phosphorylation of Akt by TGF-beta and enhances TGF-beta-induced phosphorylation of c-Jun. FET cells expressing Smad7 show anchorage-independent growth and enhance tumorigenicity in athymic nude mice. Smad7 blocks TGF-beta-induced growth inhibition by preventing TGF-beta-induced G1 arrest. Smad7 inhibits TGF-beta-mediated downregulation of c-Myc, CDK4, and Cyclin D1, and suppresses the expression of p21(Cip1). As a result, Smad7 inhibits TGF-beta-mediated downregulation of Rb phosphorylation. Furthermore, Smad7 inhibits the apoptosis of these cells. Together, Smad7 may increase the tumorigenicity of FET cells by blocking TGF-beta-induced growth inhibition and by inhibiting apoptosis. Thus, this study provides a mechanism by which a portion of human colorectal tumors may become refractory to tumor-suppressive actions of TGF-beta that might result in increased tumorigenicity.

Physalis minima Leaves Extract Induces Re-Endothelialization in Deoxycorticosterone Acetate-Salt-Induced Endothelial Dysfunction in Rats

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Dian Nugrahenny

2018-02-01

Full Text Available The administration of deoxy-corticosterone acetate (DOCA-salt can induce oxidative stress leading to decrease the bioavailability of nitric oxide (NO, increase senescence of circulating endothelial progenitor cells (EPCs, thus contributing to endothelial dysfunction. This study was aimed to investigate the effects of Physalis minima L. leaves extract on serum NO levels, circulating EPCs number, and histopathology of tail artery endothelial cells in DOCA-salt-induced endothelial dysfunction in rats. Twenty-five male Wistar rats were randomly divided into five groups: rats without any treatment (normal, rats treated with DOCA (10 mg/kgBW s.c. twice weekly and given 0.9% NaCl to drink ad libitum for 6 weeks, and DOCA-salt-induced rats orally supplemented with P. minima leaves extract at doses of 500, 1500, or 2500 mg/kgBW for 4 weeks. Serum NO levels were measured by colorimetry. The number of circulating EPCs (CD34+/CD133+ cells was determined by flow cytometry. The tail artery sections were histologically processed with hematoxylin-eosin staining. DOCA-salt-induced rats showed significantly (p<0.05 decrease in serum NO levels and circulating EPCs number compared to the normal. There was also more detached tail artery endothelial cells in DOCA-salt-induced rats. P. minima leaves extract at a dose of 500 mg/kgBW significantly (p<0.05 increased serum NO level and circulating EPCs number, and also induced an optimal re-endothelialization in DOCA-salt-induced rats. P. minima leave extract dose-dependently increases NO bioavailability contributing to enhanced EPCs mobilization, thereby promoting re-endothelialization in DOCA-salt-induced endothelial dysfunction in rats.

Induced Current Characteristics Due to Laser Induced Plasma and Its Application to Laser Processing Monitoring

International Nuclear Information System (INIS)

Madjid, Syahrun Nur; Idris, Nasrullah; Kurniawan, Koo Hendrik; Kagawa, Kiichiro

2011-01-01

In laser processing, suitable conditions for laser and gas play important role in ensuring a high quality of processing. To determine suitable conditions, we employed the electromagnetic phenomena associated with laser plasma generation. An electrode circuit was utilised to detect induced current due to the fast electrons propelled from the material during laser material processing. The characteristics of induced current were examined by changing parameters such as supplied voltage, laser pulse energy, number of laser shots, and type of ambient gas. These characteristics were compared with the optical emission characteristics. It was shown that the induced current technique proposed in this study is much more sensitive than the optical method in monitoring laser processing, that is to determine the precise focusing condition, and to accurately determine the moment of completion of laser beam penetration. In this study it was also shown that the induced current technique induced by CW CO 2 laser can be applied in industrial material processing for monitoring the penetration completion in a stainless steel plate drilling process.

Self-Reports of Induced Abortion

DEFF Research Database (Denmark)

Rasch, V; Muhammad, H; Urassa, E

2000-01-01

OBJECTIVES: This study estimated the proportion of incomplete abortions that are induced in hospital-based settings in Tanzania. METHODS: A cross-sectional questionnaire study was conducted in 2 phases at 3 hospitals in Tanzania. Phase 1 included 302 patients with a diagnosis of incomplete abortion......, and phase 2 included 823 such patients. RESULTS: In phase 1, in which cases were classified by clinical criteria and information from the patient, 3.9% to 16.1% of the cases were classified as induced abortion. In phase 2, in which the structured interview was changed to an empathetic dialogue...... and previously used clinical criteria were omitted, 30.9% to 60.0% of the cases were classified as induced abortion. CONCLUSIONS: An empathetic dialogue improves the quality of data collected among women with induced abortion....

Diffuse Transcranial Electrical Stimulation (DTES)-induced ...

African Journals Online (AJOL)

Higher voltages were needed to induce convulsion in pretreated animals than in normal animals. It is therefore suggestive that DTES-induced hypermotility can be used as an animal model for testing drugs that can be of advantage in the management of non convulsive (petit mal) status epilepticus (SE), and DTES induced ...

Effect of atorvastatin on hyperglycemia-induced brain oxidative stress and neuropathy induced by diabetes

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Nastaran Faghihi

2015-04-01

Conclusion: The findings of the present study reveal that atorvastatin is able to prevent hyperglycemia-induced diabetic neuropathy and inhibit brain oxidative stress during diabetes. It is probable that reduction of urea is one of the reasons for atorvastatin prevention of hyperglycemia-induced neuropathy.

Characterization of 5-hydroxytryptamine-induced contraction and acetylcholine-induced relaxation in isolated chicken basilar artery.

Science.gov (United States)

Matsumoto, F; Watanabe, Y; Obi, T; Islam, M Z; Yamazaki-Himeno, E; Shiraishi, M; Miyamoto, A

2012-05-01

The aim of the present study was to clarify the responsiveness of the chicken basilar artery to 5-hydroxytryptamine (5-HT) and acetylcholine (ACh) and to characterize the related receptor subtypes in vitro. Basilar arteries were obtained from freshly slaughtered broiler chickens. The 5-HT induced concentration-dependent contraction of the arteries. The concentration-response curves for 5-HT were shifted 30-fold to the right by methiothepin (a 5-HT(1) and 5-HT(2) receptor antagonist) and 3-fold to the right by ketanserin (a 5-HT(2) receptor antagonist). In the presence of ketanserin, the concentration-response curve for 5-HT was shifted 10-fold to the right by methiothepin. The pA(2) value for methiothepin was 8.26. The ACh induced concentration-dependent relaxation under conditions of precontraction by 5-HT. The concentration-response curve for ACh was shifted to the right by atropine [a nonselective muscarinic (M) receptor antagonist] and hexahydro-sila-difenidol hydrochloride, a p-fluoroanalog (pFHHSiD, an M(3) receptor antagonist), but not by pirenzepine (an M(1) receptor antagonist) or methoctramine (an M(2) receptor antagonist). The pA(2) value for pFHHSiD was 7.55. Nω-Nitro-l-arginine (a nitric oxide synthase inhibitor) inhibited ACh-induced relaxation by approximately 50%. These results suggest that 5-HT induces contraction via activation of 5-HT(1) and 5-HT(2) receptors and that ACh induces relaxation via activation of the M(3) receptor. The 5-HT(1) receptor might play a dominant role in 5-HT-induced contraction. One of the factors involved in ACh-induced relaxation is probably nitric oxide released from endothelial cells.

Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

Energy Technology Data Exchange (ETDEWEB)

Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsuneyama, Koichi [Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930‐0194 (Japan); Endo, Shinya [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsukui, Tohru [Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350‐1241 (Japan); Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan)

2012-10-01

Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

International Nuclear Information System (INIS)

Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori; Tsuneyama, Koichi; Endo, Shinya; Tsukui, Tohru; Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

2012-01-01

Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

Induced quantum conformal gravity

International Nuclear Information System (INIS)

Novozhilov, Y.V.; Vassilevich, D.V.

1988-11-01

Quantum gravity is considered as induced by matter degrees of freedom and related to the symmetry breakdown in the low energy region of a non-Abelian gauge theory of fundamental fields. An effective action for quantum conformal gravity is derived where both the gravitational constant and conformal kinetic term are positive. Relation with induced classical gravity is established. (author). 15 refs

Sleep-inducing factors.

Science.gov (United States)

García-García, Fabio; Acosta-Peña, Eva; Venebra-Muñoz, Arturo; Murillo-Rodríguez, Eric

2009-08-01

Kuniomi Ishimori and Henri Piéron were the first researchers to introduce the concept and experimental evidence for a chemical factor that would presumably accumulate in the brain during waking and eventually induce sleep. This substance was named hypnotoxin. Currently, the variety of substances which have been shown to alter sleep includes peptides, cytokines, neurotransmitters and some substances of lipidic nature, many of which are well known for their involvement in other biological activities. In this chapter, we describe the sleep-inducing properties of the vasoactive intestinal peptide, prolactin, adenosine and anandamide.

Mifepristone inhibits MPA-and FGF2-induced mammary tumor growth but not FGF2-induced mammary hyperplasia

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Juan P. Cerliani

2010-12-01

Full Text Available We have previously demonstrated a crosstalk between fibroblast growth factor 2 (FGF2 and progestins inducing experimental breast cancer growth. The aim of the present study was to compare the effects of FGF2 and of medroxyprogesterone acetate (MPA on the mouse mammary glands and to investigate whether the antiprogestin RU486 was able to reverse the MPA- or FGF2-induced effects on both, mammary gland and tumor growth. We demonstrate that FGF2 administered locally induced an intraductal hyperplasia that was not reverted by RU486, suggesting that FGF2-induced effects are progesterone receptor (PR-independent. However, MPA-induced paraductal hyperplasia was reverted by RU486 and a partial agonistic effect was observed in RU486-treated glands. Using C4-HD tumors which only grow in the presence of MPA, we showed that FGF2 administered intratumorally was able to stimulate tumor growth as MPA. The histology of FGF2-treated tumors showed different degrees of gland differentiation. RU486 inhibited both, MPA or FGF2 induced tumor growth. However, only complete regression was observed in MPA-treated tumors. Our results support the hypothesis that stromal FGF2 activates PR inducing hormone independent tumor growth.

Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

International Nuclear Information System (INIS)

Song, Yao; Baba, Tomohisa; Li, Ying-Yi; Furukawa, Kaoru; Tanabe, Yamato; Matsugo, Seiichi; Sasaki, Soichiro; Mukaida, Naofumi

2015-01-01

Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization. - Highlights: • Gemcitabine induced CXCL8 expression in human pancreatic cancer cells. • CXCL8 expression required ROS generation and NF-κB activation. • CXCL8 did not affect in vitro proliferation of human pancreatic cancer cells. • CXCL8 in vivo counteracted gemcitabine by inducing neovascularization

Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

Energy Technology Data Exchange (ETDEWEB)

Song, Yao; Baba, Tomohisa [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan); Li, Ying-Yi [Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Furukawa, Kaoru; Tanabe, Yamato [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan); School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa (Japan); Matsugo, Seiichi [School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa (Japan); Sasaki, Soichiro [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan); Mukaida, Naofumi, E-mail: mukaida@staff.kanazawa-u.ac.jp [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan)

2015-03-06

Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization. - Highlights: • Gemcitabine induced CXCL8 expression in human pancreatic cancer cells. • CXCL8 expression required ROS generation and NF-κB activation. • CXCL8 did not affect in vitro proliferation of human pancreatic cancer cells. • CXCL8 in vivo counteracted gemcitabine by inducing neovascularization.

Fixed point theorems for generalized Lipschitzian semigroups

Directory of Open Access Journals (Sweden)

Jong Soo Jung

2001-01-01

semigroup of K into itself, that is, for s∈G, ‖Tsx−Tsy‖≤as‖x−y‖+bs(‖x−Tsx‖+‖y−Tsy‖+cs(‖x−Tsy‖+‖y−Tsx‖, for x,y∈K where as,bs,cs>0 such that there exists a t1∈G such that bs+cs<1 for all s≽t1. It is proved that if there exists a closed subset C of K such that ⋂sco¯{Ttx:t≽s}⊂C for all x∈K, then with [(α+βp(αp⋅2p−1−1/(cp−2p−1βp⋅Np]1/p<1 has a common fixed point, where α=lim sups(as+bs+cs/(1-bs-cs and β=lim sups(2bs+2cs/(1-bs-cs.

Mitochondrial Swelling Induced by Glutathione

Science.gov (United States)

Lehninger, Albert L.; Schneider, Marion

1959-01-01

Reduced glutathione, in concentrations approximating those occurring in intact rat liver, causes swelling of rat liver mitochondria in vitro which is different in kinetics and extent from that yielded by L-thyroxine. The effect is also given by cysteine, which is more active, and reduced coenzyme A, but not by L-ascorbate, cystine, or oxidized glutathione. The optimum pH is 6.5, whereas thyroxine-induced swelling is optimal at pH 7.5. The GSH-induced swelling is not inhibited by DNP or dicumarol, nor by high concentrations of sucrose, serum albumin, or polyvinylpyrrolidone, in contrast to thyroxine-induced swelling. ATP inhibits the GSH swelling, but ADP and AMP are ineffective. Mn-+ is a very potent inhibitor, but Mg++ is ineffective. Ethylenediaminetetraacetate is also an effective inhibitor of GSH-induced swelling. The respiratory inhibitors amytal and antimycin A do not inhibit the swelling action of GSH, but cyanide does; these findings are consistent with the view that the oxidation-reduction state of the respiratory chain between cytochrome c and oxygen is a determinant of GSH-induced swelling. Reversal of GSH-induced swelling by osmotic means or by ATP in KCl media could not be observed. Large losses of nucleotides and protein occur during the swelling by GSH, suggesting that the action is irreversible. The characteristically drastic swelling action of GSH could be prevented if L-thyroxine was also present in the medium. PMID:13630941

Induced gravity and gauge interactions revisited

International Nuclear Information System (INIS)

Broda, Boguslaw; Szanecki, Michal

2009-01-01

It has been shown that the primary, old-fashioned idea of Sakharov's induced gravity and gauge interactions, in the 'one-loop dominance' version, works astonishingly well yielding phenomenologically reasonable results. As a byproduct, the issue of the role of the UV cutoff in the context of the induced gravity has been reexamined (an idea of self-cutoff induced gravity). As an additional check, the black hole entropy has been used in the place of the action. Finally, it has been explicitly shown that the induced coupling constants of gauge interactions of the standard model assume qualitatively realistic values.

Radiation-induced instability of human genome

International Nuclear Information System (INIS)

Ryabchenko, N.N.; Demina, Eh.A.

2014-01-01

A brief review is dedicated to the phenomenon of radiation-induced genomic instability where the increased level of genomic changes in the offspring of irradiated cells is characteristic. Particular attention is paid to the problems of genomic instability induced by the low-dose radiation, role of the bystander effect in formation of radiation-induced instability, and its relationship with individual radiosensitivity. We believe that in accordance with the paradigm of modern radiobiology the increased human individual radiosensitivity can be formed due to the genome instability onset and is a significant risk factor for radiation-induced cancer

Uridine prevents fenofibrate-induced fatty liver.

Directory of Open Access Journals (Sweden)

Thuc T Le

Full Text Available Uridine, a pyrimidine nucleoside, can modulate liver lipid metabolism although its specific acting targets have not been identified. Using mice with fenofibrate-induced fatty liver as a model system, the effects of uridine on liver lipid metabolism are examined. At a daily dosage of 400 mg/kg, fenofibrate treatment causes reduction of liver NAD(+/NADH ratio, induces hyper-acetylation of peroxisomal bifunctional enzyme (ECHD and acyl-CoA oxidase 1 (ACOX1, and induces excessive accumulation of long chain fatty acids (LCFA and very long chain fatty acids (VLCFA. Uridine co-administration at a daily dosage of 400 mg/kg raises NAD(+/NADH ratio, inhibits fenofibrate-induced hyper-acetylation of ECHD, ACOX1, and reduces accumulation of LCFA and VLCFA. Our data indicates a therapeutic potential for uridine co-administration to prevent fenofibrate-induced fatty liver.

Terbinafine-induced lichenoid drug eruption.

Science.gov (United States)

Zheng, Yue; Zhang, Jie; Chen, Haiyan; Lai, Wei; Maibach, Howard I

2017-03-01

Drug-induced lichen planus has been induced by antibiotics, anticonvulsants, antidiabetics, antimalarials, antitubercular drugs, antihypertensives, psychiatric drugs, chemotherapeutic agents, diuretic, heavy metals, NSAIDs, etc. Terbinafine, an antifungal agent, is widely used for dermatophyte infections and onychomycosis. Cutaneous adverse effects of terbinafine are rarely reported. Here, we report a case of terbinafine-induced lichenoid drug eruption in a 22-year-old who presented with generalized lichenoid eruption 2 weeks after terbinafine initiation of. The body and lip cleared completely after 8 weeks of drug withdrawal; nail change cleared after 12 weeks.

Moderately delayed post-insult treatment with normobaric hyperoxia reduces excitotoxin-induced neuronal degeneration but increases ischemia-induced brain damage

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Haelewyn Benoit

2011-04-01

Full Text Available Abstract Background The use and benefits of normobaric oxygen (NBO in patients suffering acute ischemic stroke is still controversial. Results Here we show for the first time to the best of our knowledge that NBO reduces both NMDA-induced calcium influxes in vitro and NMDA-induced neuronal degeneration in vivo, but increases oxygen and glucose deprivation-induced cell injury in vitro and ischemia-induced brain damage produced by middle cerebral artery occlusion in vivo. Conclusions Taken together, these results indicate that NBO reduces excitotoxin-induced calcium influx and subsequent neuronal degeneration but favors ischemia-induced brain damage and neuronal death. These findings highlight the complexity of the mechanisms involved by the use of NBO in patients suffering acute ischemic stroke.

Interactions between superficial and deep dorsal horn spinal cord neurons in the processing of nociceptive information.

Science.gov (United States)

Petitjean, Hugues; Rodeau, Jean-Luc; Schlichter, Rémy

2012-12-01

In acute rat spinal cord slices, the application of capsaicin (5 μm, 90 s), an agonist of transient receptor potential vanilloid 1 receptors expressed by a subset of nociceptors that project to laminae I-II of the spinal cord dorsal horn, induced an increase in the frequency of spontaneous excitatory and spontaneous inhibitory postsynaptic currents in about half of the neurons in laminae II, III-IV and V. In the presence of tetrodotoxin, which blocks action potential generation and polysynaptic transmission, capsaicin increased the frequency of miniature excitatory postsynaptic currents in only 30% of lamina II neurons and had no effect on the frequency of miniature excitatory postsynaptic currents in laminae III-V or on the frequency of miniature inhibitory postsynaptic currents in laminae II-V. When the communication between lamina V and more superficial laminae was interrupted by performing a mechanical section between laminae IV and V, capsaicin induced an increase in spontaneous excitatory postsynaptic current frequency in laminae II-IV and an increase in spontaneous inhibitory postsynaptic current frequency in lamina II that were similar to those observed in intact slices. However, in laminae III-IV of transected slices, the increase in spontaneous inhibitory postsynaptic current frequency was virtually abolished. Our results indicate that nociceptive information conveyed by transient receptor potential vanilloid 1-expressing nociceptors is transmitted from lamina II to deeper laminae essentially by an excitatory pathway and that deep laminae exert a 'feedback' control over neurons in laminae III-IV by increasing inhibitory synaptic transmission in these laminae. Moreover, we provide evidence that laminae III-IV might play an important role in the processing of nociceptive information in the dorsal horn. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Whisker motor cortex reorganization after superior colliculus output suppression in adult rats.

Science.gov (United States)

Veronesi, Carlo; Maggiolini, Emma; Franchi, Gianfranco

2013-10-01

The effect of unilateral superior colliculus (SC) output suppression on the ipsilateral whisker motor cortex (WMC) was studied at different time points after tetrodotoxin and quinolinic acid injections, in adult rats. The WMC output was assessed by mapping the movement evoked by intracortical microstimulation (ICMS) and by recording the ICMS-evoked electromyographic (EMG) responses from contralateral whisker muscles. At 1 h after SC injections, the WMC showed: (i) a strong decrease in contralateral whisker sites, (ii) a strong increase in ipsilateral whisker sites and in ineffective sites, and (iii) a strong increase in threshold current values. At 6 h after injections, the WMC size had shrunk to 60% of the control value and forelimb representation had expanded into the lateral part of the normal WMC. Thereafter, the size of the WMC recovered, returning to nearly normal 12 h later (94% of control) and persisted unchanged over time (1-3 weeks). The ICMS-evoked EMG response area decreased at 1 h after SC lesion and had recovered its baseline value 12 h later. Conversely, the latency of ICMS-evoked EMG responses had increased by 1 h and continued to increase for as long as 3 weeks following the lesion. These findings provide physiological evidence that SC output suppression persistently withdrew the direct excitatory drive from whisker motoneurons and induced changes in the WMC. We suggest that the changes in the WMC are a form of reversible short-term reorganization that is induced by SC lesion. The persistent latency increase in the ICMS-evoked EMG response suggested that the recovery of basic WMC excitability did not take place with the recovery of normal explorative behaviour. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Hydroxyurea-Induced Replication Stress

Directory of Open Access Journals (Sweden)

Kenza Lahkim Bennani-Belhaj

2010-01-01

Full Text Available Bloom's syndrome (BS displays one of the strongest known correlations between chromosomal instability and a high risk of cancer at an early age. BS cells combine a reduced average fork velocity with constitutive endogenous replication stress. However, the response of BS cells to replication stress induced by hydroxyurea (HU, which strongly slows the progression of replication forks, remains unclear due to publication of conflicting results. Using two different cellular models of BS, we showed that BLM deficiency is not associated with sensitivity to HU, in terms of clonogenic survival, DSB generation, and SCE induction. We suggest that surviving BLM-deficient cells are selected on the basis of their ability to deal with an endogenous replication stress induced by replication fork slowing, resulting in insensitivity to HU-induced replication stress.

Polarization-induced interference within electromagnetically induced transparency for atoms of double-V linkage

Science.gov (United States)

Sun, Yuan; Liu, Chang; Chen, Ping-Xing; Liu, Liang

2018-02-01

People have been paying attention to the role of atoms' complex internal level structures in the research of electromagnetically induced transparency (EIT) for a long time, where the various degenerate Zeeman levels usually generate complex linkage patterns for the atomic transitions. It turns out, with special choices of the atomic states and the atomic transitions' linkage structure, clear signatures of quantum interference induced by the probe and coupling light's polarizations can emerge from a typical EIT phenomena. We propose to study a four-state system with double-V linkage pattern for the transitions and analyze the polarization-induced interference under the EIT condition. We show that such interference arises naturally under mild conditions on the optical field and atom manipulation techniques. Moreover, we construct a variation form of double-M linkage pattern where the polarization-induced interference enables polarization-dependent cross modulation between incident weak lights that can be effective even at the few-photon level. The theme is to gain more insight into the essential question: how can we build a nontrivial optical medium where incident lights experience polarization-dependent nonlinear optical interactions, valid for a wide range of incidence intensities down to the few-photon level?

Induced abortion and subsequent pregnancy duration

DEFF Research Database (Denmark)

Zhou, Wei Jin; Sørensen, Henrik Toft; Olsen, Jørn

1999-01-01

OBJECTIVE: To examine whether induced abortion influences subsequent pregnancy duration. METHODS: Women who had their first pregnancies during 1980, 1981, and 1982 were identified in three Danish national registries. A total of 15,727 women whose pregnancies were terminated by first-trimester ind......OBJECTIVE: To examine whether induced abortion influences subsequent pregnancy duration. METHODS: Women who had their first pregnancies during 1980, 1981, and 1982 were identified in three Danish national registries. A total of 15,727 women whose pregnancies were terminated by first......-trimester induced abortions were compared with 46,026 whose pregnancies were not terminated by induced abortions. All subsequent pregnancies until 1994 were identified by register linkage. RESULTS: Preterm and post-term singleton live births were more frequent in women with one, two, or more previous induced...... abortions. After adjusting for potential confounders and stratifying by gravidity, the odds ratios of preterm singleton live births in women with one, two, or more previous induced abortions were 1.89 (95% confidence interval [CI] 1.70, 2.11), 2.66 (95% CI 2.09, 3.37), and 2.03 (95% CI 1.29, 3...

Drug-induced cholestasis: mechanisms, models, and markers.

Science.gov (United States)

Chatterjee, Sagnik; Annaert, Pieter

2018-04-27

Drug-induced cholestasis is a risk factor in progression of drug candidates, and poses serious health hazard if not detected before going into human. Intrahepatic accumulation of bile acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. The major challenges in obtaining a complete understanding of drug-induced cholestasis lies in the complexity of BA-mediated toxicity mechanisms and the impact of bile acids at different 'targets' such as transporters, enzymes and nuclear receptors. At the same time, it is not trivial to have a relevant in vitro system that recapitulates these features. In addition, lack of sensitive and early preclinical biomarkers, relevant to the clinical situation, complicates proper detection of drug-induced cholestasis. Significant overlap in biomarker signatures between different mechanisms of drug-induced liver injury (DILI) precludes identification of specific mechanisms. Over the last decade the knowledge gaps in drug-induced cholestasis are closing due to growing mechanistic understanding of BA-mediated toxicity at (patho)physiologically relevant BA concentrations. Significant progress has been made in the mechanistic understanding of drug-induced cholestasis and associated toxicity, biomarkers and susceptibility factors. In addition, novel in vitro models are evolving which provide a holistic understanding of processes underlying drug-induced cholestasis. This review summarizes the challenges and recent understandings about drug-induced cholestasis with a potential path forward. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Magnetic-flutter-induced pedestal plasma transport

International Nuclear Information System (INIS)

Callen, J.D.; Hegna, C.C.; Cole, A.J.

2013-01-01

Plasma toroidal rotation can limit reconnection of externally applied resonant magnetic perturbation (RMP) fields δB on rational magnetic flux surfaces. Hence it causes the induced radial perturbations δB ρ to be small there, thereby inhibiting magnetic island formation and stochasticity at the top of pedestals in high (H-mode) confinement tokamak plasmas. However, the δB ρ s induced by RMPs increase away from rational surfaces and are shown to induce significant sinusoidal radial motion (flutter) of magnetic field lines with a radial extent that varies linearly with δB ρ and inversely with distance from the rational surface because of the magnetic shear. This produces a radial electron thermal diffusivity that is (1/2)(δB ρ /B 0 ) 2 times a kinetically derived, electron-collision-induced, magnetic-shear-reduced, effective parallel electron thermal diffusivity in the absence of magnetic stochasticity. These low collisionality flutter-induced transport processes and thin magnetic island effects are shown to be highly peaked in the vicinity of rational surfaces at the top of low collisionality pedestals. However, the smaller but finite level of magnetic-flutter-induced electron heat transport midway between rational surfaces is the primary factor that determines the electron temperature difference between rational surfaces at the pedestal top. The magnetic-flutter-induced non-ambipolar electron density transport can be large enough to push the plasma toward an electron density transport root. Requiring ambipolar density transport is shown to determine the radial electric field, the plasma toroidal rotation (via radial force balance), a reduced electron thermal diffusivity and increased ambipolar density transport in the pedestal. At high collisionality the various flutter effects are less strongly peaked at rational surfaces and generally less significant. They are thus less likely to exhibit flutter-induced resonant behaviour and transition toward an

Magnetic-flutter-induced pedestal plasma transport

Science.gov (United States)

Callen, J. D.; Hegna, C. C.; Cole, A. J.

2013-11-01

Plasma toroidal rotation can limit reconnection of externally applied resonant magnetic perturbation (RMP) fields δB on rational magnetic flux surfaces. Hence it causes the induced radial perturbations δBρ to be small there, thereby inhibiting magnetic island formation and stochasticity at the top of pedestals in high (H-mode) confinement tokamak plasmas. However, the δBρs induced by RMPs increase away from rational surfaces and are shown to induce significant sinusoidal radial motion (flutter) of magnetic field lines with a radial extent that varies linearly with δBρ and inversely with distance from the rational surface because of the magnetic shear. This produces a radial electron thermal diffusivity that is (1/2)(δBρ/B0)2 times a kinetically derived, electron-collision-induced, magnetic-shear-reduced, effective parallel electron thermal diffusivity in the absence of magnetic stochasticity. These low collisionality flutter-induced transport processes and thin magnetic island effects are shown to be highly peaked in the vicinity of rational surfaces at the top of low collisionality pedestals. However, the smaller but finite level of magnetic-flutter-induced electron heat transport midway between rational surfaces is the primary factor that determines the electron temperature difference between rational surfaces at the pedestal top. The magnetic-flutter-induced non-ambipolar electron density transport can be large enough to push the plasma toward an electron density transport root. Requiring ambipolar density transport is shown to determine the radial electric field, the plasma toroidal rotation (via radial force balance), a reduced electron thermal diffusivity and increased ambipolar density transport in the pedestal. At high collisionality the various flutter effects are less strongly peaked at rational surfaces and generally less significant. They are thus less likely to exhibit flutter-induced resonant behaviour and transition toward an electron

Evaluation of nefazodone-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes

Energy Technology Data Exchange (ETDEWEB)

Lee, Sujeong, E-mail: crystalee@gmail.com [Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343 (Korea, Republic of); Lee, Hyang-Ae, E-mail: hyangaelee@gmail.com [Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799 (Korea, Republic of); Human and Environmental Toxicology Program, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350 (Korea, Republic of); Choi, Sung Woo, E-mail: djmaya@snu.ac.kr [Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799 (Korea, Republic of); Kim, Sung Joon, E-mail: sjoonkim@snu.ac.kr [Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799 (Korea, Republic of); Kim, Ki-Suk, E-mail: idkks00@gmail.com [Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343 (Korea, Republic of); Human and Environmental Toxicology Program, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350 (Korea, Republic of)

2016-04-01

The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which express the major cardiac ion channels and recapitulate spontaneous mechanical and electrical activities, may provide a possible solution for the lack of in vitro human-based cardiotoxicity testing models. Cardiotoxicity induced by the antidepressant nefazodone was previously revealed to cause an acquired QT prolongation by hERG channel blockade. To elucidate the cellular mechanisms underlying the cardiotoxicity of nefazodone beyond hERG, its effects on cardiac action potentials (APs) and ion channels were investigated using hiPSC-CMs with whole-cell patch clamp techniques. In a proof of principle study, we examined the effects of cardioactive channel blockers on the electrophysiological profile of hiPSC-CMs in advance of the evaluation of nefazodone. Nefazodone dose-dependently prolonged the AP duration at 90% (APD{sub 90}) and 50% (APD{sub 50}) repolarization, reduced the maximum upstroke velocity (dV/dt{sub max}) and induced early after depolarizations. Voltage-clamp studies of hiPSC-CMs revealed that nefazodone inhibited various voltage-gated ion channel currents including I{sub Kr}, I{sub Ks}, I{sub Na}, and I{sub Ca}. Among them, I{sub Kr} and I{sub Na} showed relatively higher sensitivity to nefazodone, consistent with the changes in the AP parameters. In summary, hiPSC-CMs enabled an integrated approach to evaluate the complex interactions of nefazodone with cardiac ion channels. These results suggest that hiPSC-CMs can be an effective model for detecting drug-induced arrhythmogenicity beyond the current standard assay of heterologously expressed hERG K{sup +} channels. - Highlights: • Nefazodone prolonged APD and decreased upstroke velocity of APs in hiPSC-CMs. • Nefazodone inhibited cardiac ion channels, especially I{sub Kr} and I{sub Na}, in hiPSC-CMs. • Nefazodone-induced AP changes are mainly the result of I{sub Kr} and I{sub Na} inhibition

The role of hypoxia inducible factor-1 alpha in bypassing oncogene-induced senescence.

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Mehtap Kilic Eren

Full Text Available Oncogene induced senescence (OIS is a sustained anti-proliferative response acutely induced in primary cells via activation of mitogenic oncogenes such as Ras/BRAF. This mechanism acts as an initial barrier preventing normal cells transformation into malignant cell. Besides oncogenic activation and DNA damage response (DDR, senescence is modulated by a plethora of other factors, and one of the most important one is oxygen tension of the tissue. The aim of this study was to determine the impact of hypoxia on RasV12-induced senescence in human diploid fibroblasts (HDFs. We showed here that hypoxia prevents execution of oncogene induced senescence (OIS, through a strong down-regulation of senescence hallmarks, such as SA- β-galactosidase, H3K9me3, HP1γ, p53, p21CIP1 and p16INK4a in association with induction of hypoxia inducible factor-1α (HIF-1α. In addition, hypoxia also decreased marks of H-RasV12-induced DDR in both cell lines through down-regulation of ATM/ATR, Chk1 and Chk2 phosphorylation as well as decreased γ-H2AX positivity. Utilizing shRNA system targeting HIF-1α we show that HIF-1α is directly involved in down regulation of p53 and its target p21CIP1 but not p16INK4a. In line with this finding we found that knock down of HIF-1α leads to a strong induction of apoptotic response, but not restoration of senescence in Ras expressing HDFs in hypoxia. This indicates that HIF-1α is an important player in early steps of tumorigenesis, leading to suppression of senescence through its negative regulation of p53 and p21CIP1. In our work we describe a mechanism through which hypoxia and specifically HIF-1α preclude cells from maintaining senescence-driven anti proliferative response. These findings indicate the possible mechanism through which hypoxic environment helps premalignant cells to evade impingement of cellular failsafe pathways.

Congruence properties of induced representations

DEFF Research Database (Denmark)

Mayer, Dieter; Momeni, Arash; Venkov, Alexei

In this paper we study representations of the projective modular group induced from the Hecke congruence group of level 4 with Selberg's character. We show that the well known congruence properties of Selberg's character are equivalent to the congruence properties of the induced representations...

Catecholamine induced cardiomyopathy in pheochromocytoma

Directory of Open Access Journals (Sweden)

Ron Thomas Varghese

2013-01-01

Full Text Available Catecholamine induced cardiomyopathy in the setting of pheochromocytoma is an unusual clinical entity. Earlier studies have reported left ventricular dysfunction in around 10% of subjects with pheochromocytoma. [1] Catecholamine induced vasoconstriction, direct toxic effect of byproducts of catecholamine degradation and direct receptor-mediated mechanisms are thought to contribute to cardiomyopathy in subjects with pheochromocytoma. The presentation remains a diagnostic challenge as patients may already have hypertensive heart disease and acute coronary syndrome on account of uncontrolled secondary hypertension. We report a case of a 42-year-old male, who presented with features of pheochromocytoma induced cardiomyopathy.

Fermion-induced quantum critical points.

Science.gov (United States)

Li, Zi-Xiang; Jiang, Yi-Fan; Jian, Shao-Kai; Yao, Hong

2017-08-22

A unified theory of quantum critical points beyond the conventional Landau-Ginzburg-Wilson paradigm remains unknown. According to Landau cubic criterion, phase transitions should be first-order when cubic terms of order parameters are allowed by symmetry in the Landau-Ginzburg free energy. Here, from renormalization group analysis, we show that second-order quantum phase transitions can occur at such putatively first-order transitions in interacting two-dimensional Dirac semimetals. As such type of Landau-forbidden quantum critical points are induced by gapless fermions, we call them fermion-induced quantum critical points. We further introduce a microscopic model of SU(N) fermions on the honeycomb lattice featuring a transition between Dirac semimetals and Kekule valence bond solids. Remarkably, our large-scale sign-problem-free Majorana quantum Monte Carlo simulations show convincing evidences of a fermion-induced quantum critical points for N = 2, 3, 4, 5 and 6, consistent with the renormalization group analysis. We finally discuss possible experimental realizations of the fermion-induced quantum critical points in graphene and graphene-like materials.Quantum phase transitions are governed by Landau-Ginzburg theory and the exceptions are rare. Here, Li et al. propose a type of Landau-forbidden quantum critical points induced by gapless fermions in two-dimensional Dirac semimetals.

Photobiological implications of melanin photoprotection after UVB-induced tanning of human skin but not UVA-induced tanning.

Science.gov (United States)

Coelho, Sergio G; Yin, Lanlan; Smuda, Christoph; Mahns, Andre; Kolbe, Ludger; Hearing, Vincent J

2015-03-01

Repetitive suberythemal UVA and/or UVB exposures were used to generate comparable UV-induced tans in human skin over the course of 2 weeks. To evaluate the potential photoprotective values of those UVA- and/or UVB- induced tans and to avoid the confounding issue of residual UV-induced DNA damage, we waited 1 week before challenging those areas with a 1.5 MED of UVA+UVB after which we measure DNA damage. The results show that the type of UV used to induce skin pigmentation affects the redistribution of melanin in the skin and/or de novo melanin synthesis. The UVA-induced tans failed to even provide a minimal SPF of 1.5, which suggests that producing a tan with UVA-rich sunlamps prior to a holiday or vacation is completely counterproductive. Published 2014. This article is a US Government work and is in the public domain in the USA.

Overexpression of Hypoxia-Inducible Factor-1α Exacerbates Endothelial Barrier Dysfunction Induced by Hypoxia

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Pei Wang

2013-09-01

Full Text Available Background/Aims: The mechanisms involved in endothelial barrier dysfunction induced by hypoxia are incompletely understood. There is debate about the role of hypoxia-inducible factor-1α (HIF-1α in endothelial barrier disruption. The aim of this study was to investigate the effect of genetic overexpression of HIF-1α on barrier function and the underlying mechanisms in hypoxic endothelial cells. Methods: The plasmid pcDNA3.1/V5-His-HIF-1α was stably transfected into human endothelial cells. The cells were exposed to normoxia or hypoxia. The mRNA and protein expressions of HIF-1α were detected by RT-PCR and Western blot respectively. The barrier function was assessed by measuring the transendothelial electrical resistance (TER. The Western blot analysis was used to determine the protein expression of glucose transporter-1 (GLUT-1, zonular occludens-1 (ZO-1, occludin, and myosin light chain kinase (MLCK in endothelial cells. The mRNA expression of proinflammatory cytokines was detected by qRT-PCR. Results: Genetic overexpression of HIF-1α significantly increased the mRNA and protein expression of HIF-1α in endothelial cells. The overexpression of HIF-1α enhanced the hypoxia-induced increase of HIF-1α and GLUT-1 protein expression. HIF-1α overexpression not only exacerbated hypoxia-induced endothelial barrier dysfunction but also augmented hypoxia-induced up-regulation of MLCK protein expression. HIF-1α overexpression also enhanced IL-1β, IL-6 and TNF-α mRNA expression. Conclusion: We provide evidence that genetic overexpression of HIF-1α aggravates the hypoxia-induced endothelial barrier dysfunction via enhancing the up-regulation of MLCK protein expression caused by hypoxia, suggesting a potential role for HIF-1α in the pathogenesis of endothelial barrier dysfunction in hypoxia.

A K ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans.

Science.gov (United States)

MacDonald, Patrick E; De Marinis, Yang Zhang; Ramracheya, Reshma; Salehi, Albert; Ma, Xiaosong; Johnson, Paul R V; Cox, Roger; Eliasson, Lena; Rorsman, Patrik

2007-06-01

Glucagon, secreted from pancreatic islet alpha cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring beta cells, or to an intrinsic glucose sensing by the alpha cells themselves. We examined hormone secretion and Ca(2+) responses of alpha and beta cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn(2+) signalling was blocked, but was reversed by low concentrations (1-20 muM) of the ATP-sensitive K(+) (KATP) channel opener diazoxide, which had no effect on insulin release or beta cell responses. This effect was prevented by the KATP channel blocker tolbutamide (100 muM). Higher diazoxide concentrations (>/=30 muM) decreased glucagon and insulin secretion, and alpha- and beta-cell Ca(2+) responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (10 muM) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the KATP channel, inhibition of voltage-gated Na(+) (TTX) and N-type Ca(2+) channels (omega-conotoxin), but not L-type Ca(2+) channels (nifedipine), prevented glucagon secretion. Both the N-type Ca(2+) channels and alpha-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an alpha-cell KATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion.

Exercise induced asthma and endogenous opioids.

Science.gov (United States)

Gaillard, R C; Bachman, M; Rochat, T; Egger, D; de Haller, R; Junod, A F

1986-01-01

Concentrations of endogenous opioid peptides in the plasma are increased during exercise and these substances have been implicated in the pathogenesis of asthma induced by chloropropramide and alcohol in diabetic patients. This work was undertaken to determine whether exercise induced asthma might be mediated by endogenous opioids. Plasma beta endorphin, met-enkephalin, and adrenocorticotrophic hormone (ACTH) concentrations were measured in five asthmatic patients and five normal volunteers breathing cold air during exercise. In four of the patients the effect of an infusion of naloxone on FEV1 was also measured during exercise induced asthma. Exercise produced acute bronchoconstriction in all asthmatics, characterised by a fall in FEV1; whereas no change occurred in normal subjects. There was no difference in plasma met-enkephalin, beta endorphin, and ACTH concentration between the two groups. Infusion of naloxone neither prevented nor worsened exercise induced asthma. These data suggest that endogenous opioids probably do not play a part in the development of exercise induced asthma. PMID:2944240

The origin of electromagnetically induced absorption

International Nuclear Information System (INIS)

Park, Jong Dae; Hwang, Sung Tae; Lee, Ho Seong; Park, Sung Jong; Cho, Hyuck; Choi, Won Sik

2000-01-01

Recently, there have been a lot of interests in the coherence superposition of atomic states which are formed by laser fields. Coherent population trapping(CTP), electromagnetically induced transparency(EIT), enhancement of the refractive index without absorption, lasing without inversion(LWI), and electromagnetically induced absorption(EIA) are the examples where coherence effects are important. Previously, the spontaneous transfer of the light-induced coherence from the excited level to the ground one was emphasized for the essential ingredient for electromagnetically induced absorption. In this paper, we have considered a case where linearly polarized coupling laser and probe laser are applied to the same degenerated ground and excited levels. We have solved the master equations for density matrix using time varying Hamiltonian and studied the absorption spectra at various conditions. We demonstrate that EIA can be observed without spontaneous transfer of the light-induced coherence in F g = 1 -> F e = 2 D2 transitions of Hydrogen atoms

Single Low-Dose Radiation Induced Regulation of Keratinocyte Differentiation in Calcium-Induced HaCaT Cells

Science.gov (United States)

Hahn, Hyung Jin; Youn, Hae Jeong; Cha, Hwa Jun; Kim, Karam; An, Sungkwan

2016-01-01

Background We are continually exposed to low-dose radiation (LDR) in the range 0.1 Gy from natural sources, medical devices, nuclear energy plants, and other industrial sources of ionizing radiation. There are three models for the biological mechanism of LDR: the linear no-threshold model, the hormetic model, and the threshold model. Objective We used keratinocytes as a model system to investigate the molecular genetic effects of LDR on epidermal cell differentiation. Methods To identify keratinocyte differentiation, we performed western blots using a specific antibody for involucrin, which is a precursor protein of the keratinocyte cornified envelope and a marker for keratinocyte terminal differentiation. We also performed quantitative polymerase chain reaction. We examined whether LDR induces changes in involucrin messenger RNA (mRNA) and protein levels in calcium-induced keratinocyte differentiation. Results Exposure of HaCaT cells to LDR (0.1 Gy) induced p21 expression. p21 is a key regulator that induces growth arrest and represses stemness, which accelerates keratinocyte differentiation. We correlated involucrin expression with keratinocyte differentiation, and examined the effects of LDR on involucrin levels and keratinocyte development. LDR significantly increased involucrin mRNA and protein levels during calcium-induced keratinocyte differentiation. Conclusion These studies provide new evidence for the biological role of LDR, and identify the potential to utilize LDR to regulate or induce keratinocyte differentiation. PMID:27489424

Andrographolide alleviates imiquimod-induced psoriasis in mice via inducing autophagic proteolysis of MyD88.

Science.gov (United States)

Shao, Fenli; Tan, Tao; Tan, Yang; Sun, Yang; Wu, Xingxin; Xu, Qiang

2016-09-01

Psoriasis is a chronic inflammatory skin disease with excessive activation of toll-like receptors (TLRs), which play important roles in developing psoriasis. Targeting TLR signaling remains a challenge for treating psoriasis. Here, we found that andrographolide (Andro), a small-molecule natural product, alleviated imiquimod- but not interleukin 23 (IL-23)-induced psoriasis in mice with reducing expressions of IL-23 and IL-1β in the skin. The improvement in imiquimod-induced psoriasis by Andro was not observed in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) knockout mice. Furthermore, Andro inhibited mRNA expressions of IL-23, IL-6 and IL-1β but not CD80 and CD86 in bone-marrow derived dendritic cells (BMDCs) treated with lipopolysaccharide (LPS) in a MAP1LC3B-dependent manner. In addition, Andro inhibited imiquimod-induced mRNA expressions of IL-23, IL-6, IL-1β, CD80 and CD86 in BMDCs from mice. Interestingly, Andro induced a degradation of myeloid differentiation factor 88 (MyD88) and blocked the recruitment of TNF receptor-associated factor 6 (TRAF6) to MyD88 upon LPS stimulation in BMDCs from mice. Blockade of autophagic proteolysis using NH4Cl or MAP1LC3B(-/-) BMDCs abolished the Andro-induced MyD88 degradation. In conclusion, Andro controls activation of MyD88-dependent cytokines and alleviates psoriasis in mice via inducing autophagic proteolysis of MyD88, which could be a novel strategy to treat psoriasis. Copyright © 2016 Elsevier Inc. All rights reserved.

UV-induced skin damage

International Nuclear Information System (INIS)

Ichihashi, M.; Ueda, M.; Budiyanto, A.; Bito, T.; Oka, M.; Fukunaga, M.; Tsuru, K.; Horikawa, T.

2003-01-01

Solar radiation induces acute and chronic reactions in human and animal skin. Chronic repeated exposures are the primary cause of benign and malignant skin tumors, including malignant melanoma. Among types of solar radiation, ultraviolet B (290-320 nm) radiation is highly mutagenic and carcinogenic in animal experiments compared to ultraviolet A (320-400 nm) radiation. Epidemiological studies suggest that solar UV radiation is responsible for skin tumor development via gene mutations and immunosuppression, and possibly for photoaging. In this review, recent understanding of DNA damage caused by direct UV radiation and by indirect stress via reactive oxygen species (ROS) and DNA repair mechanisms, particularly nucleotide excision repair of human cells, are discussed. In addition, mutations induced by solar UV radiation in p53, ras and patched genes of non-melanoma skin cancer cells, and the role of ROS as both a promoter in UV-carcinogenesis and an inducer of UV-apoptosis, are described based primarily on the findings reported during the last decade. Furthermore, the effect of UV on immunological reaction in the skin is discussed. Finally, possible prevention of UV-induced skin cancer by feeding or topical use of antioxidants, such as polyphenols, vitamin C, and vitamin E, is discussed

Food-Induced Acute Pancreatitis.

Science.gov (United States)

Manohar, Murli; Verma, Alok K; Upparahalli Venkateshaiah, Sathisha; Goyal, Hemant; Mishra, Anil

2017-12-01

Food allergy, a commonly increasing problem worldwide, defined as an adverse immune response to food. A variety of immune-related effector cells such as mast cells, eosinophils, neutrophils, and T cells are involved in food-related allergic responses categorized as IgE mediated, non-IgE mediated, and mixed (IgE and non-IgE) depending upon underlying immunological mechanisms. The dietary antigens mainly target the gastrointestinal tract including pancreas that gets inflamed due to food allergy and leads acute pancreatitis. Reports indicate several food proteins induce pancreatitis; however, detailed underlying mechanism of food-induced pancreatitis is unexplored. The aim of the review is to understand and update the current scenario of food-induced pancreatitis. A comprehensive literature search of relevant research articles has been performed through PubMed, and articles were chosen based on their relevance to food allergen-mediated pancreatitis. Several cases in the literature indicate that acute pancreatitis has been provoked after the consumption of mustard, milk, egg, banana, fish, and kiwi fruits. Food-induced pancreatitis is an ignored and unexplored area of research. The review highlights the significance of food in the development of pancreatitis and draws the attention of physicians and scientists to consider food allergies as a possible cause for initiation of pancreatitis pathogenesis.

Olfactory-Induced Synesthesias: A Review and Model

Science.gov (United States)

Stevenson, Richard J.; Tomiczek, Caroline

2007-01-01

Recent reviews of synesthesia concentrate upon rare neurodevelopmental examples and exclude common olfactory-induced experiences with which they may profitably be compared. Like the neurodevelopmental synesthesias, odor-induced experiences involve different sensory modalities; are reliable, asymmetric (concurrents cannot induce), and automatic;…

Cowhage-induced itch as an experimental model for pruritus. A comparative study with histamine-induced itch.

Directory of Open Access Journals (Sweden)

Alexandru D P Papoiu

2011-03-01

Full Text Available Histamine is the prototypical pruritogen used in experimental itch induction. However, in most chronic pruritic diseases, itch is not predominantly mediated by histamine. Cowhage-induced itch, on the other hand, seems more characteristic of itch occurring in chronic pruritic diseases.We tested the validity of cowhage as an itch-inducing agent by contrasting it with the classical itch inducer, histamine, in healthy subjects and atopic dermatitis (AD patients. We also investigated whether there was a cumulative effect when both agents were combined.Fifteen healthy individuals and fifteen AD patients were recruited. Experimental itch induction was performed in eczema-free areas on the volar aspects of the forearm, using different itch inducers: histamine, cowhage and their combination thereof. Itch intensity was assessed continuously for 5.5 minutes after stimulus application using a computer-assisted visual analogue scale (COVAS.In both healthy and AD subjects, the mean and peak intensity of itch were higher after the application of cowhage compared to histamine, and were higher after the combined application of cowhage and histamine, compared to histamine alone (p<0.0001 in all cases. Itch intensity ratings were not significantly different between healthy and AD subjects for the same itch inducer used; however AD subjects exhibited a prolonged itch response in comparison to healthy subjects (p<0.001.Cowhage induced a more intense itch sensation compared to histamine. Cowhage was the dominant factor in itch perception when both pathways were stimulated in the same time. Cowhage-induced itch is a suitable model for the study of itch in AD and other chronic pruritic diseases, and it can serve as a new model for testing antipruritic drugs in humans.

Methylphenidate Actively Induces Emergence from General Anesthesia

Science.gov (United States)

Solt, Ken; Cotten, Joseph F.; Cimenser, Aylin; Wong, Kin F.K.; Chemali, Jessica J.; Brown, Emery N.

2011-01-01

Background Although accumulating evidence suggests that arousal pathways in the brain play important roles in emergence from general anesthesia, the roles of monoaminergic arousal circuits are unclear. In this study we tested the hypothesis that methylphenidate (an inhibitor of dopamine and norepinephrine transporters) induces emergence from isoflurane anesthesia. Methods Using adult rats we tested the effect of methylphenidate IV on time to emergence from isoflurane anesthesia. We then performed experiments to test separately for methylphenidate-induced changes in arousal and changes in minute ventilation. A dose-response study was performed to test for methylphenidate–induced restoration of righting during continuous isoflurane anesthesia. Surface electroencephalogram recordings were performed to observe neurophysiological changes. Plethysmography recordings and arterial blood gas analysis were performed to assess methylphenidate-induced changes in respiratory function. Droperidol IV was administered to test for inhibition of methylphenidate's actions. Results Methylphenidate decreased median time to emergence from 280 to 91 s. The median difference in time to emergence without compared to with methylphenidate was 200 [155, 331] s (median, [95% confidence interval]). During continuous inhalation of isoflurane, methylphenidate induced return of righting in a dose-dependent manner, induced a shift in electroencephalogram power from delta to theta, and induced an increase in minute ventilation. Administration of droperidol (0.5 mg/kg IV) prior to methylphenidate (5 mg/kg IV) largely inhibited methylphenidate-induced emergence behavior, electroencephalogram changes, and changes in minute ventilation. Conclusions Methylphenidate actively induces emergence from isoflurane anesthesia by increasing arousal and respiratory drive, possibly through activation of dopaminergic and adrenergic arousal circuits. Our findings suggest that methylphenidate may be clinically

Radiotherapy-Induced Skin Reactions Induce Fibrosis Mediated by TGF-β1 Cytokine

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Cherley Borba Vieira de Andrade

2017-04-01

Full Text Available Purpose: This study aimed to investigate radiation-induced lesions on the skin in an experimental animal model. Methods and Materials: Cutaneous wounds were induced in Wistar rats by 4 MeV energy electron beam irradiation, using a dose rate of 240 cGy/min, for 3 different doses (10 Gy, 40 Gy, and 60 Gy. The skin was observed 5, 10, and 25 days (D after ionizing radiation exposition. Results: Infiltrate inflammatory process was observed in D5 and D10, for the 40 Gy and 60 Gy groups, and a progressive increase of transforming growth factor β1 is associated with this process. It could also be noted a mischaracterization of collagen fibers at the high-dose groups. Conclusion: It was observed that the lesions caused by ionizing radiation in rats were very similar to radiodermatitis in patients under radiotherapy treatment. Advances in Knowledge: This study is important to develop strategies to prevent radiation-induced skin reactions.

Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

Energy Technology Data Exchange (ETDEWEB)

Sharma, Bhupesh, E-mail: drbhupeshresearch@gmail.com; Sharma, P.M.

2013-11-15

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential

Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

International Nuclear Information System (INIS)

Sharma, Bhupesh; Sharma, P.M.

2013-01-01

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential in

Polyphosphate induces matrix metalloproteinase-3-mediated proliferation of odontoblast-like cells derived from induced pluripotent stem cells

Energy Technology Data Exchange (ETDEWEB)

Ozeki, Nobuaki; Hase, Naoko; Yamaguchi, Hideyuki; Hiyama, Taiki; Kawai, Rie [Department of Endodontics, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, Aichi 464-8651 (Japan); Kondo, Ayami [Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto, Chikusa-ku, Nagoya 464-8650 (Japan); Nakata, Kazuhiko [Department of Endodontics, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, Aichi 464-8651 (Japan); Mogi, Makio, E-mail: makio@dpc.agu.ac.jp [Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto, Chikusa-ku, Nagoya 464-8650 (Japan)

2015-05-01

Inorganic polyphosphate [Poly(P)] may represent a physiological source of phosphate and has the ability to induce bone differentiation in osteoblasts. We previously reported that cytokine-induced matrix metalloproteinase (MMP)-3 accelerates the proliferation of purified odontoblast-like cells. In this study, MMP-3 small interfering RNA (siRNA) was transfected into odontoblast-like cells derived from induced pluripotent stem cells to investigate whether MMP-3 activity is induced by Poly(P) and/or is associated with cell proliferation and differentiation into odontoblast-like cells. Treatment with Poly(P) led to an increase in both cell proliferation and additional odontoblastic differentiation. Poly(P)-treated cells showed a small but significant increase in dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1) mRNA expression, which are markers of mature odontoblasts. The cells also acquired additional odontoblast-specific properties including adoption of an odontoblastic phenotype typified by high alkaline phosphatase (ALP) activity and a calcification capacity. In addition, Poly(P) induced expression of MMP-3 mRNA and protein, and increased MMP-3 activity. MMP-3 siRNA-mediated disruption of the expression of these effectors potently suppressed the expression of odontoblastic biomarkers ALP, DSPP, and DMP-1, and blocked calcification. Interestingly, upon siRNA-mediated silencing of MMP-3, we noted a potent and significant decrease in cell proliferation. Using specific siRNAs, we revealed that a unique signaling cascade, Poly(P)→MMP-3→DSPP and/or DMP-1, was intimately involved in the proliferation of odontoblast-like cells. - Highlights: • Polyphosphate increases proliferation of iPS cell-derived odontoblast-like cells. • Polyphosphate-induced MMP-3 results in an increase of cell proliferation. • Induced cell proliferation involves MMP-3, DSPP, and/or DMP-1 sequentially. • Induced MMP-3 also results in an increase of odontoblastic

Cholinergic neurotransmission in human corpus cavernosum. II. Acetylcholine synthesis

International Nuclear Information System (INIS)

Blanco, R.; De Tejada, S.; Goldstein, I.; Krane, R.J.; Wotiz, H.H.; Cohen, R.A.

1988-01-01

Physiological and histochemical evidence indicates that cholinergic nerves may participate in mediating penile erection. Acetylcholine synthesis and release was studied in isolated human corporal tissue. Human corpus cavernosum incubated with [ 3 H]choline accumulated [ 3 H]choline and synthesized [ 3 H]acethylcholine in an concentration-dependent manner. [ 3 H]Acetylcholine accumulation by the tissue was inhibited by hemicholinium-3, a specific antagonist of the high-affinity choline transport in cholinergic nerves. Transmural electrical field stimulation caused release of [ 3 H]acetylcholine which was significantly diminished by inhibiting neurotransmission with calcium-free physiological salt solution or tetrodotoxin. These observations provide biochemical and physiological evidence for the existence of cholinergic innervation in human corpus cavernosum

Therapeutic Benefits of Induced Pluripotent Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension.

Directory of Open Access Journals (Sweden)

Wei-Chun Huang

Full Text Available Pulmonary arterial hypertension (PAH is characterized by progressive increases in vascular resistance and the remodeling of pulmonary arteries. The accumulation of inflammatory cells in the lung and elevated levels of inflammatory cytokines in the bloodstream suggest that inflammation may play a role in PAH. In this study, the benefits of induced pluripotent stem cells (iPSCs and iPSC-conditioned medium (iPSC CM were explored in monocrotaline (MCT-induced PAH rats. We demonstrated that both iPSCs and iPSC CM significantly reduced the right ventricular systolic pressure and ameliorated the hypertrophy of the right ventricle in MCT-induced PAH rats in models of both disease prevention and disease reversal. In the prevention of MCT-induced PAH, iPSC-based therapy led to the decreased accumulation of inflammatory cells and down-regulated the expression of the IL-1β, IL-6, IL-12α, IL-12β, IL-23 and IFNγ genes in lung specimens, which implied that iPSC-based therapy may be involved in the regulation of inflammation. NF-κB signaling is essential to the inflammatory cascade, which is activated via the phosphorylation of the NF-κB molecule. Using the chemical inhibitor specifically blocked the phosphorylation of NF-κB, and in vitro assays of cultured human M1 macrophages implied that the anti-inflammation effect of iPSC-based therapy may contribute to the disturbance of NF-κB activation. Here, we showed that iPSC-based therapy could restore the hemodynamic function of right ventricle with benefits for preventing the ongoing inflammation in the lungs of MCT-induced PAH rats by regulating NF-κB phosphorylation.

Nephroprotective and anti-inflammatory effects of aqueous extract of Melissa officinalis L. on acetaminophen-induced and pleurisy-induced lesions in rats

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Denise Pereira Müzell

2013-06-01

Full Text Available This study assessed the bioactive properties of an aqueous extract of M. officinalis for its anti-inflammatory activity and its protection against hepatic and renal lesions induced by acetaminophen (APAP. Animals pre-treated with the crude extract in pleurisy induced by carrageenan showed a reduction in the amounts of exudate, in the numbers of leukocytes and polymorphonuclear cells. Intragastric administration of the extract for seven days prior to the APAP-induced lesion showed no protective effect on the liver. The treatment with the extract induced an increase of serum aspartate aminotransferase, indicating a rise of toxicity. Contrarily, the same treatment reduced the APAP induced lesion in kidney, with respect to ν-glutamyltransferase. The results suggested that the extract was not hepatoprotective and could lead to an increase in the lesions induced by the APAP. On the other hand, the extract was nephroprotective against the lesions induced by the APAP and showed an anti-inflammatory effect on pleurisy carrageenan-induced.

Radiation- induced aneuploidy in mammalian germ cells

International Nuclear Information System (INIS)

Tease, C.

1989-01-01

The ability of ionizing radiation to induce aneuploidy in mammalian germ cells has been investigated experimentally in the laboratory mouse using a variety of cytogenetic and genetic methods. These studies have provided unambiguous evidence of induced nondisjunction in both male and female germ cells when the effect of irradiation is screened in meiotic cells or preimplantation embryos. In contrast, however, cytogenetic analyses of post-implantation embryos and genetic assays for induced chromosome gains have not found a significant radiation effect. These apparently contradictory findings may be reconciled if (a) radiation induces tertiary rather than primary trisomy, or (b) induces embryo-lethal genetic damage, such as deletions, in addition to numerical anomalies. Either or both of these explanations may account for the apparent loss during gestation of radiation-induced trisomic embryos. Extrapolating from the information so far available, it seems unlikely that environmental exposure to low doses if low dose rate radiation will result in a detectable increase in the rate of aneuploidy in the human population. (author)

Exercise-induced rhabdomyolysis.

Science.gov (United States)

Lee, George

2014-11-03

Exercise-induced rhabdomyolysis, or exertional rhabdomyolysis (ER), is a clinical entity typically considered when someone presents with muscle stiffness, swelling, and pain out of proportion to the expected fatigue post exercise. The diagnosis is confirmed by myoglobinuria, and an elevated serum Creatinine Phosphokinase (CPK) level, usually 10 times the normal range. However, an elevation in CPK is seen in most forms of strenuous exercise, up to 20 times the upper normal range. Therefore, there is no definitive pathologic CPK cut-off. Fortunately the dreaded complication of acute renal failure is rare compared to other forms rhabdomyolysis. We review the risks, diagnosis, clinical course and treatment for exercise- induced rhabdomyolysis.

Sociocultural determinants of induced abortion

International Nuclear Information System (INIS)

Korejo, R.; Noorani, K.J.; Bhutta, S.

2003-01-01

Objective: To determine the frequency of induced abortion and identity the role of sociocultural factors contributing to termination of pregnancy and associated morbidity and mortality in hospital setting. Subjects and Methods: The patients who were admitted for induced abortion were interviewed in privacy. On condition of anonymity they were asked about the age, parity, family setup and relationships, with particular emphasis on sociocultural reasons and factors contributing to induction of abortion. Details of status of abortionist and methods used for termination of pregnancy, the resulting complications and their severity were recorded. Results: Out of total admissions, 57(2.35%) gave history of induced abortion. All women belonged to low socioeconomic class and 59.6% of them were illiterate. Forty-three (75.5%) of these women had never practiced concentration. Twenty-four (42%) were grandmultiparae and did not want more children. In 29 women (50.9%) the decision for abortion had been supported by the husband. In 25 (43.8%) abortion was carried out by Daiyan (traditional midwives). Serious complications like uterine perforation with or without bowel injury were encouraged in 25 (43.8%) of these women. During the study period illegally induced abortion accounted for 6 (10.5%) maternal deaths. Conclusion: Prevalence of poverty, illiteracy, grand multiparity and non-practice of contraception are strong determinants of induced abortion. (author)

Infrared laser-induced chemical reactions

International Nuclear Information System (INIS)

Katayama, Mikio

1978-01-01

The experimental means which clearly distinguishes between infrared ray-induced reactions and thermal reactions has been furnished for the first time when an intense monochromatic light source has been obtained by the development of infrared laser. Consequently, infrared laser-induced chemical reactions have started to develop as one field of chemical reaction researches. Researches of laser-induced chemical reactions have become new means for the researches of chemical reactions since they were highlighted as a new promising technique for isotope separation. Specifically, since the success has been reported in 235 U separation using laser in 1974, comparison of this method with conventional separation techniques from the economic point of view has been conducted, and it was estimated by some people that the laser isotope separation is cheaper. This report briefly describes on the excitation of oscillation and reaction rate, and introduces the chemical reactions induced by CW laser and TEA CO 2 laser. Dependence of reaction yield on laser power, measurement of the absorbed quantity of infrared ray and excitation mechanism are explained. Next, isomerizing reactions are reported, and finally, isotope separation is explained. It was found that infrared laser-induced chemical reactions have the selectivity for isotopes. Since it is evident that there are many examples different from thermal and photo-chemical reactions, future collection of the data is expected. (Wakatsuki, Y.)

Radiation-induced bone neoplasma in facial cranium

Energy Technology Data Exchange (ETDEWEB)

Zomer-Drozda, J; Buraczewska-Lipinska, H; Buraczewski, J [Instytut Onkologii, Warsaw (Poland)

1976-01-01

Radiation-induced bone neoplasms in the region of facial cranium account for about 40% of all radiation-induced tumours of bones, although the number of cases with lesions irradiated in this area is proportionally much lower than the number of cases treated with radiotherapy in other parts of the body. Four personal cases of radiation-induced tumours with complicated course are reported. Attention is called to the value of radiological investigations in the diagnosis of bone diseases and in differential diagnosis of radiation-induced tumours of bones.

Radiation-induced camptocormia and dropped head syndrome. Review and case report of radiation-induced movement disorders

International Nuclear Information System (INIS)

Seidel, Clemens; Kuhnt, Thomas; Kortmann, Rolf-Dieter; Hering, Kathrin

2015-01-01

In recent years, camptocormia and dropped head syndrome (DHS) have gained attention as particular forms of movement disorders. Camptocormia presents with involuntary forward flexion of the thoracolumbar spine that typically increases during walking or standing and may severely impede walking ability. DHS is characterized by weakness of the neck extensors and a consecutive inability to extend the neck; in severe cases the head is fixed in a ''chin to chest position.'' Many diseases may underlie these conditions, and there have been some reports about radiation-induced camptocormia and DHS. A PubMed search with the keywords ''camptocormia,'' ''dropped head syndrome,'' ''radiation-induced myopathy,'' ''radiation-induced neuropathy,'' and ''radiation-induced movement disorder'' was carried out to better characterize radiation-induced movement disorders and the radiation techniques involved. In addition, the case of a patient developing camptocormia 23 years after radiation therapy of a non-Hodgkin's lymphoma of the abdomen is described. In total, nine case series of radiation-induced DHS (n = 45 patients) and - including our case - three case reports (n = 3 patients) about radiogenic camptocormia were retrieved. Most cases (40/45 patients) occurred less than 15 years after radiotherapy involving extended fields for Hodgkin's disease. The use of wide radiation fields including many spinal segments with paraspinal muscles may lead to radiation-induced movement disorders. If paraspinal muscles and the thoracolumbar spine are involved, the clinical presentation can be that of camptocormia. DHS may result if there is involvement of the cervical spine. To prevent these disorders, sparing of the spine and paraspinal muscles is desirable. (orig.) [de

Inducing magneto-electric response in topological insulator

International Nuclear Information System (INIS)

Zeng, Lunwu; Song, Runxia; Zeng, Jing

2013-01-01

Utilizing electric potential and magnetic scalar potential formulas, which contain zero-order Bessel functions of the first kind and the constitutive relations of topological insulators, we obtained the induced magnetic scalar potentials and induced magnetic monopole charges which are induced by a point charge in topological insulators. The results show that infinite image magnetic monopole charges are generated by a point electric charge. The magnitude of the induced magnetic monopole charges are determined not only by the point electric charge, but also by the material parameters. - Highlights: ► Electric potential and magnetic scalar potential which contain zero-order Bessel function of the first kind were derived. ► Boundary conditions of topological insulator were built. ► Induced monopole charges were worked out.

Tsunami Induced Scour Around Monopile Foundations

DEFF Research Database (Denmark)

Fuhrman, David R.; Eltard-Larsen, Bjarke; Baykal, Cüneyt

While the run-up, inundation, and destructive potential of tsunami events has received considerable attention in the literature, the associated interaction with the sea bed i.e. boundary layer dynamics, induced sediment transport, and resultant sea bed morphology, has received relatively little...... specific attention. The present paper aims to further the understanding of tsunami-induced scour, by numerically investigating tsunami-induced flow and scour processes around a monopile structure, representative of those commonly utilized as offshore wind turbine foundations. The simulations are based...... a monopile at model (laboratory) spatial and temporal scales. Therefore, prior to conducting such numerical simulations involving tsunami-induced scour, it is necessary to first establish a methodology for maintaining similarity of model and full field scales. To achieve hydrodynamic similarity we...

Ultrasensitive detection of target analyte-induced aggregation of gold nanoparticles using laser-induced nanoparticle Rayleigh scattering.

Science.gov (United States)

Lin, Jia-Hui; Tseng, Wei-Lung

2015-01-01

Detection of salt- and analyte-induced aggregation of gold nanoparticles (AuNPs) mostly relies on costly and bulky analytical instruments. To response this drawback, a portable, miniaturized, sensitive, and cost-effective detection technique is urgently required for rapid field detection and monitoring of target analyte via the use of AuNP-based sensor. This study combined a miniaturized spectrometer with a 532-nm laser to develop a laser-induced Rayleigh scattering technique, allowing the sensitive and selective detection of Rayleigh scattering from the aggregated AuNPs. Three AuNP-based sensing systems, including salt-, thiol- and metal ion-induced aggregation of the AuNPs, were performed to examine the sensitivity of laser-induced Rayleigh scattering technique. Salt-, thiol-, and metal ion-promoted NP aggregation were exemplified by the use of aptamer-adsorbed, fluorosurfactant-stabilized, and gallic acid-capped AuNPs for probing K(+), S-adenosylhomocysteine hydrolase-induced hydrolysis of S-adenosylhomocysteine, and Pb(2+), in sequence. Compared to the reported methods for monitoring the aggregated AuNPs, the proposed system provided distinct advantages of sensitivity. Laser-induced Rayleigh scattering technique was improved to be convenient, cheap, and portable by replacing a diode laser and a miniaturized spectrometer with a laser pointer and a smart-phone. Using this smart-phone-based detection platform, we can determine whether or not the Pb(2+) concentration exceed the maximum allowable level of Pb(2+) in drinking water. Copyright © 2014 Elsevier B.V. All rights reserved.

Mechanisms of caffeine-induced inhibition of UVB carcinogenesis

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Allan H Conney

2013-06-01

Full Text Available Sunlight-induced nonmelanoma skin cancer is the most prevalent cancer in the United States with more than 2 million cases per year. Several studies have shown an inhibitory effect of caffeine administration on UVB-induced skin cancer in mice, and these studies are paralleled by epidemiology studies that indicate an inhibitory effect of coffee drinking on nonmelanoma skin cancer in humans. Strikingly, decaffeinated coffee consumption had no such inhibitory effect.Mechanism studies indicate that caffeine has a sunscreen effect that inhibits UVB-induced formation of thymine dimers and sunburn lesions in the epidermis of mice. In addition, caffeine administration has a biological effect that enhances UVB-induced apoptosis thereby enhancing the elimination of damaged precancerous cells, and caffeine administration also enhances apoptosis in tumors. Caffeine administration enhances UVB-induced apoptosis by p53-dependent and p53-independent mechanisms. Exploration of the p53-independent effect indicated that caffeine administration enhanced UVB-induced apoptosis by inhibiting the UVB-induced increase in ATR-mediated formation of phospho-Chk1 (Ser345 and abolishing the UVB-induced decrease in cyclin B1 which resulted in caffeine-induced premature and lethal mitosis in mouse skin. In studies with cultured primary human keratinocytes, inhibition of ATR with siRNA against ATR inhibited Chk1 phosphorylation and enhanced UVB-induced apoptosis. Transgenic mice with decreased epidermal ATR function that were irradiated chronically with UVB had 69% fewer tumors at the end of the study compared with irradiated littermate controls with normal ATR function. These results, which indicate that genetic inhibition of ATR (like pharmacologic inhibition of ATR via caffeine inhibits UVB-induced carcinogenesis and supports the concept that ATR-mediated phosphorylation of Chk1 is an important target for caffeine’s inhibitory effect on UVB-induced carcinogenesis.

Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy.

Science.gov (United States)

Reza, Musarrat Maisha; Subramaniyam, Nathiya; Sim, Chu Ming; Ge, Xiaojia; Sathiakumar, Durgalakshmi; McFarlane, Craig; Sharma, Mridula; Kambadur, Ravi

2017-10-24

Exercise induces expression of the myokine irisin, which is known to promote browning of white adipose tissue and has been shown to mediate beneficial effects following exercise. Here we show that irisin induces expression of a number of pro-myogenic and exercise response genes in myotubes. Irisin increases myogenic differentiation and myoblast fusion via activation of IL6 signaling. Injection of irisin in mice induces significant hypertrophy and enhances grip strength of uninjured muscle. Following skeletal muscle injury, irisin injection improves regeneration and induces hypertrophy. The effects of irisin on hypertrophy are due to activation of satellite cells and enhanced protein synthesis. In addition, irisin injection rescues loss of skeletal muscle mass following denervation by enhancing satellite cell activation and reducing protein degradation. These data suggest that irisin functions as a pro-myogenic factor in mice.

Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione.

Science.gov (United States)

Wiraswati, Hesti Lina; Hangen, Emilie; Sanz, Ana Belén; Lam, Ngoc-Vy; Reinhardt, Camille; Sauvat, Allan; Mogha, Ariane; Ortiz, Alberto; Kroemer, Guido; Modjtahedi, Nazanine

2016-11-22

Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion.

[Exercise-induced inspiratory stridor. An important differential diagnosis of exercise-induced asthma].

Science.gov (United States)

Christensen, Pernille; Thomsen, Simon Francis; Rasmussen, Niels; Backer, Vibeke

2007-11-19

Recent studies suggest that exercise-induced inspiratory stridor (EIIS) is an important and often overlooked differential diagnosis of exercise-induced asthma. EIIS is characterised by astma-like symptoms, but differs by inspiratory limitation, fast recovery, and a lack of effect of inhaled bronchodilators. The prevalence of EIIS is reported to be 5-27%, and affects both children and adults. The pathophysiology, the pathogenesis, and the treatment of the condition are not yet clarified. At present, a population-based study is being conducted in order to address these points.

ETHICS IN HEALTH CARE: INDUCEMENT AND HUMAN SUBJECTS

Directory of Open Access Journals (Sweden)

MUNIR HOSSAIN TALUKDER

2011-05-01

Full Text Available Currently, most health researchers or donor organizations considerinducement as a vital part in promoting research. They propose benefits, such as post research free medical treatment, food, insurance facilities, or even cash, in order to meet sufficient number of subjects. So, inducement may influence one to participate in a research. Is it ethical to offer inducement to human subjects? What are the risks in such practice? What will happen if the donor agencies use subjects by hiding possible risks from them? When an inducement can satisfy ethical criteria? The CIOMS, FDA, and other ethical guidelines hold that inducement is unethical because it involves enough risk for voluntary informed consent. Supporting this position, a group of ethicists has argued that inducement undermines voluntariness especially when subjects are poor and vulnerable, and thus, unethical. In contrast to them, others argue that inducement contributes to discover new knowledge which can improve miserable condition of the poor. In their view, an inducement maintains all ethical criteria including subject’s autonomy, and therefore, morally permissible. The paper focuses this debate and analyzes both types ofargument. It examines whether inducement invalidate informed consent.Even if inducement may not violate the basic components of informedconsent, the paper concludes, subjects may claim a prima facie right to enjoy research outcomes.

Glucocorticoid-Induced Leucine Zipper Protects the Retina From Light-Induced Retinal Degeneration by Inducing Bcl-xL in Rats.

Science.gov (United States)

Gu, Ruiping; Tang, Wenyi; Lei, Boya; Ding, Xinyi; Jiang, Cheng; Xu, Gezhi

2017-07-01

The aim of the present study was to investigate the neuroprotective effects of glucocorticoid-induced leucine zipper (GILZ) in a light-induced retinal degeneration model and to explore the underlying mechanisms. Intravitreal injection of recombinant GILZ-overexpressing lentivirus (OE-GILZ-rLV) and short hairpin RNA targeting GILZ recombinant lentivirus (shRNA-GILZ-rLV) was performed to up- and downregulate retinal GILZ, respectively. Three days after stable transduction, rats were exposed to continuous bright light (5000 lux) for 2 days. Retinal function was assessed by full-field electroretinography (ERG), and the retinal structure was examined for photoreceptor survival and death in rats kept under a 12-hour light:2-hour dark cycle following light exposure. The expression levels of retinal Bcl-xL, caspase-9, and caspase-3 were examined by Western blotting or real-time PCR at 1, 3, 5, and 7 days after light exposure. Exposure to bright light downregulated retinal GILZ in parallel with the downregulation of Bcl-xL and the upregulation of active caspase-3. Overexpression of retinal GILZ attenuated the decrease of Bcl-xL and the activation of caspase-9 and caspase-3 at 1, 3, 5, and 7 days after bright light exposure, respectively. GILZ silencing aggravated the downregulation of Bcl-xL induced by bright light exposure. Bright light exposure reduced the amplitude of ERG, increased the number of apoptotic photoreceptor cells, and decreased retinal thickness; and GILZ overexpression could attenuate all these effects. Overexpression of GILZ by OE-GILZ-rLV transduction protected the retina from light-induced cellular damage by activating antiapoptotic pathways.

Agmatine attenuates silica-induced pulmonary fibrosis.

Science.gov (United States)

El-Agamy, D S; Sharawy, M H; Ammar, E M

2014-06-01

There is a large body of evidence that nitric oxide (NO) formation is implicated in mediating silica-induced pulmonary fibrosis. As a reactive free radical, NO may not only contribute to lung parenchymal tissue injury but also has the ability to combine with superoxide and form a highly reactive toxic species peroxynitrite that can induce extensive cellular toxicity in the lung tissues. This study aimed to explore the effect of agmatine, a known NO synthase inhibitor, on silica-induced pulmonary fibrosis in rats. Male Sprague Dawley rats were treated with agmatine for 60 days following a single intranasal instillation of silica suspension (50 mg in 0.1 ml saline/rat). The results revealed that agmatine attenuated silica-induced lung inflammation as it decreased the lung wet/dry weight ratio, protein concentration, and the accumulation of the inflammatory cells in the bronchoalveolar lavage fluid. Agmatine showed antifibrotic activity as it decreased total hydroxyproline content of the lung and reduced silica-mediated lung inflammation and fibrosis in lung histopathological specimen. In addition, agmatine significantly increased superoxide dismutase (p Agmatine also reduced silica-induced overproduction of pulmonary nitrite/nitrate as well as tumor necrosis factor α. Collectively, these results demonstrate the protective effects of agmatine against the silica-induced lung fibrosis that may be attributed to its ability to counteract the NO production, lipid peroxidation, and regulate cytokine effects. © The Author(s) 2014.

The Effects of Acute Stress-Induced Sleep Disturbance on Acoustic Trauma-Induced Tinnitus in Rats

Directory of Open Access Journals (Sweden)

Yiwen Zheng

2014-01-01

Full Text Available Chronic tinnitus is a debilitating condition and often accompanied by anxiety, depression, and sleep disturbance. It has been suggested that sleep disturbance, such as insomnia, may be a risk factor/predictor for tinnitus-related distress and the two conditions may share common neurobiological mechanisms. This study investigated whether acute stress-induced sleep disturbance could increase the susceptibility to acoustic trauma-induced tinnitus in rats. The animals were exposed to unilateral acoustic trauma 24 h before sleep disturbance being induced using the cage exchange method. Tinnitus perception was assessed behaviourally using a conditioned lick suppression paradigm 3 weeks after the acoustic trauma. Changes in the orexin system in the hypothalamus, which plays an important role in maintaining long-lasting arousal, were also examined using immunohistochemistry. Cage exchange resulted in a significant reduction in the number of sleep episodes and acoustic trauma-induced tinnitus with acoustic features similar to a 32 kHz tone at 100 dB. However, sleep disturbance did not exacerbate the perception of tinnitus in rats. Neither tinnitus alone nor tinnitus plus sleep disturbance altered the number of orexin-expressing neurons. The results suggest that acute sleep disturbance does not cause long-term changes in the number of orexin neurons and does not change the perception of tinnitus induced by acoustic trauma in rats.

Collagen-induced arthritis in mice

NARCIS (Netherlands)

Bevaart, Lisette; Vervoordeldonk, Margriet J.; Tak, Paul P.

2010-01-01

Collagen-induced arthritis (CIA) in mice is an animal model for rheumatoid arthritis (RA) and can be induced in DBA/1 and C57BL/6 mice using different protocols. The CIA model can be used to unravel mechanisms involved in the development of arthritis and is frequently used to study the effect of new

X-irradiation-induced emesis in Suncus murinus

International Nuclear Information System (INIS)

Torii, Yoshifumi; Saito, Hiroshi; Matsuki, Norio; Shikita, Mikio.

1993-01-01

X-irradiation-induced emesis was investigated in Suncus murinus, a house musk shrew. Whole body X-irradiation caused emesis, and the calculated ED 50 value that induced emesis in 50% of animals was 429 cGy. At the irradiation dose of 800 cGy all the animals vomited 10.0±2.4 times with a latency of 20.0±2.9 min. The emetogenic effect of X-irradiation was dependent on the part of the body exposed. Abdominal X-irradiation at 1000 cGy caused emesis in all animals studied, whereas the same dose to the head had no emetogenic effect. We investigated several prophylactic methods against X-irradiation-induced emesis. Surgical vagotomy completely inhibited the emesis induced by 800 cGy X-irradiation. Emesis was also prevented by the subcutaneous administration of tropisetron (ICS 205-930, a selective serotonergic 5-HT 3 receptor antagonist) with an ID 50 value of 29 μg/kg. These results suggest that (1) suncus is a useful experimental animal for the study of radiation-induced emesis and the development of prophylactic drugs, (2) serotonin plays an important role in X-irradiation-induced emesis, and (3) X-irradiation-induced emesis is very similar to that caused by cancer chemotherapeutic agents. (author)

Impact of mechanical stress induced in silica vacuum windows on laser-induced damage.

Science.gov (United States)

Gingreau, Clémence; Lanternier, Thomas; Lamaignère, Laurent; Donval, Thierry; Courchinoux, Roger; Leymarie, Christophe; Néauport, Jérôme

2018-04-15

At the interface between vacuum and air, optical windows must keep their optical properties, despite being subjected to mechanical stress. In this Letter, we investigate the impact of such stress on the laser-induced damage of fused silica windows at the wavelength of 351 nm in the nanosecond regime. Different stress values, from 1 to 30 MPa, both tensile and compressive, were applied. No effect of the stress on the laser-induced damage was evidenced.

Effects of calcitonin gene-related peptide on canine cerebral artery strips and the in-vivo vertebral blood flow in dogs.

Science.gov (United States)

Ikegaki, I; Suzuki, Y; Satoh, S; Asano, T; Shibuya, M; Sugita, K

1989-10-01

The effects of calcitonin gene-related peptide (CGRP) on canine cerebral arteries and on vertebral blood flow were investigated in-vivo and in-vitro and the findings compared with the effects of vasoactive intestinal peptide (VIP) and substance P. Administration of CGRP into the vertebral artery caused a dose-dependent and long-lasting increase in blood flow. The in-vivo vasodilatory effects of substance P and VIP were short-lasting. CGRP (0.1 to 100 nmol/l) elicited a concentration-dependent relaxation of the isolated middle cerebral and basilar arteries when the tissues were precontracted by exposure to prostaglandin F2 alpha (PGF2 alpha). This effect was not antagonized by propranolol, atropine, tetrodotoxin, (N-Ac-Tyr1, D-Phe2)-growth hormone-releasing factor(1-29)-NH2 or (D-Pro2, D-Trp7,9) substance P. CGRP also reduced concentration-dependently the contraction of cerebral arteries induced by KCl or 9,11-epithio-11,12-metano-thromboxane A2 (STXA2). Mechanical removal of the endothelium did not abolish the vasodilatory response to CGRP. In PGF2 alpha-contracted canine cerebral arteries, VIP (0.1 to 100 nmol/l) was less potent a vasodilator than CGRP. At low concentrations (0.01 to 1 nmol/l) substance P elicited a rapid and short-lasting relaxation, and in the absence of endothelium this relaxation disappeared. These findings are clear evidence that CGRP modulates vascular tone.

Electrophysiological evidence of increased glycine receptor-mediated phasic and tonic inhibition by blockade of glycine transporters in spinal superficial dorsal horn neurons of adult mice

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Misa Oyama

2017-03-01

Full Text Available To understand the synaptic and/or extrasynaptic mechanisms underlying pain relief by blockade of glycine transporter subtypes GlyT1 and GlyT2, whole-cell recordings were made from dorsal horn neurons in spinal slices from adult mice, and the effects of NFPS and ALX-1393, selective GlyT1 and GlyT2 inhibitors, respectively, on phasic evoked or miniature glycinergic inhibitory postsynaptic currents (eIPSCs or mIPSCs were examined. NFPS and ALX-1393 prolonged the decay phase of eIPSCs without affecting their amplitude. In the presence of tetrodotoxin to record mIPSCs, NFPS and ALX-1393 induced a tonic inward current that was reversed by strychnine. Although NFPS had no statistically significant influences on mIPSCs, ALX-1393 significantly increased their frequency. We then further explored the role of GlyTs in the maintenance of glycinergic IPSCs. To facilitate vesicular release of glycine, repetitive high-frequency stimulation (HFS was applied at 10 Hz for 3 min during continuous recordings of eIPSCs at 0.1 Hz. Prominent suppression of eIPSCs was evident after HFS in the presence of ALX-1393, but not NFPS. Thus, it appears that phasic and tonic inhibition may contribute to the analgesic effects of GlyT inhibitors. However, reduced glycinergic inhibition due to impaired vesicular refilling could hamper the analgesic efficacy of GlyT2 inhibitors.

The psychostimulant modafinil enhances gap junctional communication in cortical astrocytes.

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Liu, Xinhe; Petit, Jean-Marie; Ezan, Pascal; Gyger, Joël; Magistretti, Pierre; Giaume, Christian

2013-12-01

Sleep-wake cycle is characterized by changes in neuronal network activity. However, for the last decade there is increasing evidence that neuroglial interaction may play a role in the modulation of sleep homeostasis and that astrocytes have a critical impact in this process. Interestingly, astrocytes are organized into communicating networks based on their high expression of connexins, which are the molecular constituents of gap junction channels. Thus, neuroglial interactions should also be considered as the result of the interplay between neuronal and astroglial networks. Here, we investigate the effect of modafinil, a wakefulness-promoting agent, on astrocyte gap junctional communication. We report that in the cortex modafinil injection increases the expression of mRNA and protein of connexin 30 but not those of connexin 43, the other major astroglial connexin. These increases are correlated with an enhancement of intercellular dye coupling in cortical astrocytes, which is abolished when neuronal activity is silenced by tetrodotoxin. Moreover, gamma-hydroxybutyric acid, which at a millimolar concentration induces sleep, has an opposite effect on astroglial gap junctions in an activity-independent manner. These results support the proposition that astroglia may play an important role in complex physiological brain functions, such as sleep regulation, and that neuroglial networking interaction is modified during sleep-wake cycle. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'. Copyright © 2013. Published by Elsevier Ltd.

RMP-Flutter-Induced Pedestal Plasma Transport

Energy Technology Data Exchange (ETDEWEB)

Callen, J. D.; Hegna, C., E-mail: callen@engr.wisc.edu [University of Wisconsin, Madison (United States); Cole, A. J. [Columbia University, New York (United States)

2012-09-15

Full text: Plasma toroidal rotation can prevent or limit reconnection of externally applied resonant magnetic perturbation (RMP) fields {delta}B on rational magnetic flux surfaces. Hence, it causes the induced radial perturbations to vanish or be small there, and thereby inhibits magnetic island formation and stochasticity in the edge of high (H-mode) confinement tokamak plasmas. However, the radial component of the spatial magnetic flutter induced by RMP fields off rational surfaces causes a radial electron thermal diffusivity of (1/2)({delta}B{sub p}/B){sup 2} times a magnetic-shear-influenced effective parallel electron thermal diffusivity. The resultant RMP-flutter-induced electron thermal diffusivity can be comparable to experimentally inferred values at the top of H-mode pedestals. This process also causes a factor of about 3 smaller RMP-induced electron density diffusivity there. Because this electron density transport is non-ambipolar, it produces a toroidal torque on the plasma, which is usually in the co-current direction. Kinetic-based cylindrical screw-pinch and toroidal models of these RMP-flutter-induced plasma transport effects have been developed. The RMP-induced increases in these diffusive plasma transport processes are typically spatially inhomogeneous in that they are strongly peaked near the rational surfaces in low collisionality pedestals, which may lead to resonant sensitivities to the local safety factor q. The effects can be large enough to reduce the radially averaged gradients of the electron temperature and density at the top of H-mode edge pedestals, and modify the plasma toroidal rotation and radial electric field there. At high collisionality the various effects are less strongly peaked at rational surfaces and thus less likely to exhibit RMP-induced resonant behavior. These RMP-flutter-induced plasma transport processes provide a new paradigm for developing an understanding of how RMPs modify the pedestal structure to stabilize

M-CSF signals through the MAPK/ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo.

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Jennifer M Curry

Full Text Available BACKGROUND: M-CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors. VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation. Previously, we reported that in vitro M-CSF induces the expression of biologically-active VEGF from human monocytes. METHODOLOGY AND RESULTS: In this study, we demonstrate the molecular mechanism of M-CSF-induced VEGF production. Using a construct containing the VEGF promoter linked to a luciferase reporter, we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M-CSF stimulation. Further analysis revealed that M-CSF induced VEGF through the MAPK/ERK signaling pathway via the transcription factor, Sp1. Thus, inhibition of either ERK or Sp1 suppressed M-CSF-induced VEGF at the mRNA and protein level. M-CSF also induced the nuclear localization of Sp1, which was blocked by ERK inhibition. Finally, mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M-CSF-treated human monocytes. To evaluate the biological significance of M-CSF induced VEGF production, we used an in vivo angiogenesis model to illustrate the ability of M-CSF to recruit mononuclear phagocytes, increase VEGF levels, and enhance angiogenesis. Importantly, the addition of a neutralizing VEGF antibody abolished M-CSF-induced blood vessel formation. CONCLUSION: These data delineate an ERK- and Sp1-dependent mechanism of M-CSF induced VEGF production and demonstrate for the first time the ability of M-CSF to induce angiogenesis via VEGF in vivo.

Inducing magneto-electric response in topological insulator

Energy Technology Data Exchange (ETDEWEB)

Zeng, Lunwu, E-mail: 163.sin@163.com [Jiangsu Key Laboratory for Intelligent Agricultural Equipment, College of Engineering, Nanjing Agricultural University, Nanjing 210031 (China); Song, Runxia [Jiangsu Key Laboratory for Intelligent Agricultural Equipment, College of Engineering, Nanjing Agricultural University, Nanjing 210031 (China); Zeng, Jing [Faculty of Business and Economics, Macquarie University, NSW 2122 (Australia)

2013-02-15

Utilizing electric potential and magnetic scalar potential formulas, which contain zero-order Bessel functions of the first kind and the constitutive relations of topological insulators, we obtained the induced magnetic scalar potentials and induced magnetic monopole charges which are induced by a point charge in topological insulators. The results show that infinite image magnetic monopole charges are generated by a point electric charge. The magnitude of the induced magnetic monopole charges are determined not only by the point electric charge, but also by the material parameters. - Highlights: Black-Right-Pointing-Pointer Electric potential and magnetic scalar potential which contain zero-order Bessel function of the first kind were derived. Black-Right-Pointing-Pointer Boundary conditions of topological insulator were built. Black-Right-Pointing-Pointer Induced monopole charges were worked out.

Inducing Lactation: Breastfeeding for Adoptive Moms

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... Dynamics > Adoption & Foster Care > Inducing Lactation: Breastfeeding for Adoptive Moms Family Life Listen Español Text Size Email Print Share Inducing Lactation: Breastfeeding for Adoptive Moms Page Content Article Body A growing number ...

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

Energy Technology Data Exchange (ETDEWEB)

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

2015-09-25

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

Induced pluripotent stem cell-derived neuron as a human model for testing environmentally induced developmental neurotoxicity

Science.gov (United States)

Induced pluripotent stem cell-derived neurons as a human model for testing environmentally induced developmental neurotoxicity Ingrid L. Druwe1, Timothy J. Shafer2, Kathleen Wallace2, Pablo Valdivia3 ,and William R. Mundy2. 1University of North Carolina, Curriculum in Toxicology...

Multi-property isotropic intermolecular potentials and predicted spectral lineshapes of collision-induced absorption (CIA), collision-induced light scattering (CILS) and collision-induced hyper-Rayleigh scattering (CIHR) for H2sbnd Ne, -Kr and -Xe

Science.gov (United States)

El-Kader, M. S. A.; Godet, J.-L.; Gustafsson, M.; Maroulis, G.

2018-04-01

Quantum mechanical lineshapes of collision-induced absorption (CIA), collision-induced light scattering (CILS) and collision-induced hyper-Rayleigh scattering (CIHR) at room temperature (295 K) are computed for gaseous mixtures of molecular hydrogen with neon, krypton and xenon. The induced spectra are detected using theoretical values for induced dipole moment, pair-polarizability trace and anisotropy, hyper-polarizability and updated intermolecular potentials. Good agreement is observed for all spectra when the literature and the present potentials which are constructed from the transport and thermo-physical properties are used.

Manganese (II) induces chemical hypoxia by inhibiting HIF-prolyl hydroxylase: Implication in manganese-induced pulmonary inflammation

International Nuclear Information System (INIS)

Han, Jeongoh; Lee, Jong-Suk; Choi, Daekyu; Lee, Youna; Hong, Sungchae; Choi, Jungyun; Han, Songyi; Ko, Yujin; Kim, Jung-Ae; Mi Kim, Young; Jung, Yunjin

2009-01-01

Manganese (II), a transition metal, causes pulmonary inflammation upon environmental or occupational inhalation in excess. We investigated a potential molecular mechanism underlying manganese-induced pulmonary inflammation. Manganese (II) delayed HIF-1α protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1α hydroxylation and subsequent von Hippel-Lindau(VHL)-dependent HIF-1α degradation. HPH inhibition by manganese (II) was neutralized significantly by elevated dose of iron. Consistent with this, the induction of cellular HIF-1α protein by manganese (II) was abolished by pretreatment with iron. Manganese (II) induced the HIF-1 target gene involved in pulmonary inflammation, vascular endothelial growth factor (VEGF), in lung carcinoma cell lines. The induction of VEGF was dependent on HIF-1. Manganese-induced VEGF promoted tube formation of HUVEC. Taken together, these data suggest that HIF-1 may be a potential mediator of manganese-induced pulmonary inflammation

Ganoderma lucidum total triterpenes attenuate DLA induced ascites and EAC induced solid tumours in Swiss albino mice.

Science.gov (United States)

Smina, T P; Mathew, J; Janardhanan, K K

2016-04-30

G. lucidum total triterpenes were assessed for its apoptosis-inducing and anti-tumour activities. The ability of the total triterpenes to induce apoptosis was evaluated in Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines. Total triterpenes were found to be highly cytotoxic to DLA and EAC cell lines with IC50 values 5 ± 0.32 and 7.9 ± 0.2 µg/ml respectively. Total triterpenes induced apoptosis in both cell lines which is evident from the DNA fragmentation assay. Anti-tumour activity was accessed using DLA induced solid and EAC induced ascites tumour models in Swiss albino mice. Administration of 10, 50 and 100 mg/kg b. wt. total triterpenes showed 11.86, 27.27 and 40.57% increase in life span of animals in ascites tumour model. Treatment with 10, 50 and 100 mg/kg b. wt. total triterpenes exhibited 76.86, 85.01 and 91.03% inhibition in tumour volume and 67.96, 72.38 and 77.90% inhibition in tumour weight respectively in the solid tumour model. The study reveals the significant dose-dependent anti-tumour activity of total triterpenes in both models. Total triterpenes were more active against the solid tumour than the ascites tumour. The anti-oxidant potential and ability to induce cell-specific apoptosis could be contributing to its anti-tumour activities.

Hydroxychloroquine-induced erythroderma.

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Pai, Sunil B; Sudershan, Bhuvaneshwari; Kuruvilla, Maria; Kamath, Ashwin; Suresh, Pooja K

2017-01-01

Erythroderma is characterized by diffuse erythema and scaling of the skin involving more than 90% of the total body skin surface area. Drug-induced erythroderma has rarely been reported with hydroxychloroquine. We report a case of a 50-year-old female patient, with systemic lupus erythematosus, who developed itchy lesions all over the body 1 month after starting treatment with hydroxychloroquine. Drug-induced erythroderma was suspected. Hydroxychloroquine was withdrawn and the patient was treated with emollients, mid-potency corticosteroids, and oral antihistamines. A biopsy was done which confirmed the diagnosis of erythroderma. She recovered with treatment and was discharged. A careful history and clinical examination to search for potential causative factors will help prevent disabling sequelae in erythroderma.

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

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Wang, Xin; Xu, Mei; Frank, Jacqueline A. [Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536 (United States); Ke, Zun-ji [Department of Biochemistry, Shanghai University of Traditional Chinese Medicine, Shanghai, China 201203 (China); Luo, Jia, E-mail: jialuo888@uky.edu [Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536 (United States); Department of Biochemistry, Shanghai University of Traditional Chinese Medicine, Shanghai, China 201203 (China)

2017-04-01

Thiamine (vitamin B1) deficiency (TD) plays a major role in the etiology of Wernicke's encephalopathy (WE) which is a severe neurological disorder. TD induces selective neuronal cell death, neuroinflammation, endoplasmic reticulum (ER) stress and oxidative stress in the brain which are commonly observed in many aging-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and progressive supranuclear palsy (PSP). However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research is hindered due to the lack of appropriate in vitro models. The neurons derived for the human induced pluripotent stem cells (hiPSCs) provide a relevant and powerful tool for the research in pharmaceutical and environmental neurotoxicity. In this study, we for the first time used human induced pluripotent stem cells (hiPSCs)-derived neurons (iCell neurons) to investigate the mechanisms of TD-induced neurodegeneration. We showed that TD caused a concentration- and duration-dependent death of iCell neurons. TD induced ER stress which was evident by the increase in ER stress markers, such as GRP78, XBP-1, CHOP, ATF-6, phosphorylated eIF2α, and cleaved caspase-12. TD also triggered oxidative stress which was shown by the increase in the expression 2,4-dinitrophenyl (DNP) and 4-hydroxynonenal (HNE). ER stress inhibitors (STF-083010 and salubrinal) and antioxidant N-acetyl cysteine (NAC) were effective in alleviating TD-induced death of iCell neurons, supporting the involvement of ER stress and oxidative stress. It establishes that the iCell neurons are a novel tool to investigate cellular and molecular mechanisms for TD-induced neurodegeneration. - Highlights: • Thiamine deficiency (TD) causes death of human neurons in culture. • TD induces both endoplasmic reticulum (ER) stress and oxidative stress. • Alleviating ER stress and oxidative stress reduces TD-induced

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

International Nuclear Information System (INIS)

Wang, Xin; Xu, Mei; Frank, Jacqueline A.; Ke, Zun-ji; Luo, Jia

2017-01-01

Thiamine (vitamin B1) deficiency (TD) plays a major role in the etiology of Wernicke's encephalopathy (WE) which is a severe neurological disorder. TD induces selective neuronal cell death, neuroinflammation, endoplasmic reticulum (ER) stress and oxidative stress in the brain which are commonly observed in many aging-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and progressive supranuclear palsy (PSP). However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research is hindered due to the lack of appropriate in vitro models. The neurons derived for the human induced pluripotent stem cells (hiPSCs) provide a relevant and powerful tool for the research in pharmaceutical and environmental neurotoxicity. In this study, we for the first time used human induced pluripotent stem cells (hiPSCs)-derived neurons (iCell neurons) to investigate the mechanisms of TD-induced neurodegeneration. We showed that TD caused a concentration- and duration-dependent death of iCell neurons. TD induced ER stress which was evident by the increase in ER stress markers, such as GRP78, XBP-1, CHOP, ATF-6, phosphorylated eIF2α, and cleaved caspase-12. TD also triggered oxidative stress which was shown by the increase in the expression 2,4-dinitrophenyl (DNP) and 4-hydroxynonenal (HNE). ER stress inhibitors (STF-083010 and salubrinal) and antioxidant N-acetyl cysteine (NAC) were effective in alleviating TD-induced death of iCell neurons, supporting the involvement of ER stress and oxidative stress. It establishes that the iCell neurons are a novel tool to investigate cellular and molecular mechanisms for TD-induced neurodegeneration. - Highlights: • Thiamine deficiency (TD) causes death of human neurons in culture. • TD induces both endoplasmic reticulum (ER) stress and oxidative stress. • Alleviating ER stress and oxidative stress reduces TD-induced

Experimental Study on Piezoelectric Energy Harvesting from Vortex-Induced Vibrations and Wake-Induced Vibrations

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Min Zhang

2016-01-01

Full Text Available A rigid circular cylinder with two piezoelectric beams attached on has been tested through vortex-induced vibrations (VIV and wake-induced vibrations (WIV by installing a big cylinder fixed upstream, in order to study the influence of the different flow-induced vibrations (FIV types. The VIV test shows that the output voltage increases with the increases of load resistance; an optimal load resistance exists for the maximum output power. The WIV test shows that the vibration of the small cylinder is controlled by the vortex frequency of the large one. There is an optimal gap of the cylinders that can obtain the maximum output voltage and power. For a same energy harvesting device, WIV has higher power generation capacity; then the piezoelectric output characteristics can be effectively improved.

Induced proteins in human melanomas by γ-ray

International Nuclear Information System (INIS)

Ohnishi, T.; Ihara, M.; Utsumi, H.

1992-01-01

When cells are exposed to environmental stresses such as heat, chemicals, radiation, the cells respond to them by synthesizing a characteristic group of proteins, called stress proteins. There are many famous stress proteins: heat shock proteins and metallothionein. Treated cells have a protective mechanism against these environmental stresses. SOS responses in Escherichia coli are most famous. As the mechanisms, when cells are exposed by many kinds of DNA damage agents, various enzymes are induced after the cleavage of repressor protein LexA by activated RecA enzyme. Thereafter, induced proteins act for DNA repair and mutagenesis. In mammalian cells there are many reports about inducible genes such as O 6 -methylguanine methyltransferase gene. This gene was also inducible by alkylating agents. The difference of radiation sensitivities may be reflected by the contents of repair enzymes(s) or the induced proteins. Therefore, this study aims on the differences in inducible proteins between radiosensitive cells and control cells. Since it was hypothesized that induced proteins concerning to DNA damage repair or the proteins to recognize the damage may exist in the nuclei, induced proteins in nuclei of γ-ray irradiated cells were analyzed. (author). 5 refs., 1 tab

Molecular Mechanisms of Antipsychotic Drug-Induced Diabetes

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Jiezhong Chen

2017-11-01

Full Text Available Antipsychotic drugs (APDs are widely prescribed to control various mental disorders. As mental disorders are chronic diseases, these drugs are often used over a life-time. However, APDs can cause serious glucometabolic side-effects including type 2 diabetes and hyperglycaemic emergency, leading to medication non-compliance. At present, there is no effective approach to overcome these side-effects. Understanding the mechanisms for APD-induced diabetes should be helpful in prevention and treatment of these side-effects of APDs and thus improve the clinical outcomes of APDs. In this review, the potential mechanisms for APD-induced diabetes are summarized so that novel approaches can be considered to relieve APD-induced diabetes. APD-induced diabetes could be mediated by multiple mechanisms: (1 APDs can inhibit the insulin signaling pathway in the target cells such as muscle cells, hepatocytes and adipocytes to cause insulin resistance; (2 APD-induced obesity can result in high levels of free fatty acids (FFA and inflammation, which can also cause insulin resistance. (3 APDs can cause direct damage to β-cells, leading to dysfunction and apoptosis of β-cells. A recent theory considers that both β-cell damage and insulin resistance are necessary factors for the development of diabetes. In high-fat diet-induced diabetes, the compensatory ability of β-cells is gradually damaged, while APDs cause direct β-cell damage, accounting for the severe form of APD-induced diabetes. Based on these mechanisms, effective prevention of APD-induced diabetes may need an integrated approach to combat various effects of APDs on multiple pathways.

Sociocultural determinants of induced abortion.

Science.gov (United States)

Korejo, Razia; Noorani, Khurshid Jehan; Bhutta, Shereen

2003-05-01

To determine the frequency of induced abortion and identify the role of sociocultural factors contributing to termination of pregnancy and associated morbidity and mortality in hospital setting. Prospective observational study. The study was conducted in the Department of Obstetrics and Gynaecology, Jinnah Postgraduate Medical Centre, Karachi from January 1999 to June 2001. The patients who were admitted for induced abortion were interviewed in privacy. On condition of anonymity they were asked about the age, parity, family setup and relationships, with particular emphasis on sociocultural reasons and factors contributing to induction of abortion. Details of status of abortionist and methods used for termination of pregnancy, the resulting complications and their severity were recorded. Out of total admissions, 57(2.35%) gave history of induced abortion. All women belonged to low socioeconomic class and 59.6% of them were illiterate. Forty-three (75.5%) of these women had never practiced contraception. Twenty-four (42%) were grandmultiparae and did not want more children. In 29 women (50.9%) the decision for abortion had been supported by the husband. In 25 women (43.8%) abortion was carried out by Daiyan (traditional midwives). Serious complications like uterine perforation with or without bowel injury were encountered in 25 (43.8%) of these women. During the study period illegally induced abortion accounted for 6 (10.5%) maternal deaths. Prevalence of poverty, illiteracy, grand multiparity and non-practice of contraception are strong determinants of induced abortion.

Rail-induced Traffic in China

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Nan He

2017-11-01

Full Text Available The rapid development of China’s railway has exerted an enormous influence on the intercity passenger transport structure in recent years. However, it has not satisfied the passengers’ travel demand due to induced traffic. This paper is committed to solving such issue, with the aim of satisfying the current travel demand, and of anticipating the demand of the predicted traffic growth over the next 20 to 30 years. The paper has considered the increase in rail passenger kilometres caused by the growth of rail kilometres as rail-induced traffic. Based on the concept and former research of induced traffic, the panel data of 26 provinces and 3 municipalities of China between the year 2000 and 2014 were collected, and the elasticity models (including elasticity-based model, distributed lag model, high-speed rail (HSR elasticity model and rail efficiency model have been constructed. The results show the importance of model formation incorporation of rail-induced traffic. It is better to get the correct value in divided zones with different train frequencies or incorporation rail efficiency in cities or provinces. The lag time and rail types also need to be considered. In summary, the results analysis not only confirms the existence of rail-induced traffic, but also provides substantial recommendations to train operation planning.

Nitric oxide protects macrophages from hydrogen peroxide-induced apoptosis by inducing the formation of catalase.

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Yoshioka, Yasuhiro; Kitao, Tatsuya; Kishino, Takashi; Yamamuro, Akiko; Maeda, Sadaaki

2006-04-15

We investigated the cytoprotective effect of NO on H2O2-induced cell death in mouse macrophage-like cell line RAW264. H2O2-treated cells showed apoptotic features, such as activation of caspase-9 and caspase-3, nuclear fragmentation, and DNA fragmentation. These apoptotic features were significantly inhibited by pretreatment for 24 h with NO donors, sodium nitroprusside and 1-hydroxy-2-oxo-3,3-bis-(2-aminoethyl)-1-triazene, at a low nontoxic concentration. The cytoprotective effect of NO was abrogated by the catalase inhibitor 3-amino-1,2,4-triazole but was not affected by a glutathione synthesis inhibitor, L-buthionine-(S,R)-sulfoximine. NO donors increased the level of catalase and its activity in a concentration-dependent manner. Cycloheximide, a protein synthesis inhibitor, inhibited both the NO-induced increase in the catalase level and the cytoprotective effect of NO. These results indicate that NO at a low concentration protects macrophages from H2O2-induced apoptosis by inducing the production of catalase.

Regulation of radiation-induced protein kinase Cδ activation in radiation-induced apoptosis differs between radiosensitive and radioresistant mouse thymic lymphoma cell lines

International Nuclear Information System (INIS)

Nakajima, Tetsuo; Yukawa, Osami; Tsuji, Hideo; Ohyama, Harumi; Wang, Bing; Tatsumi, Kouichi; Hayata, Isamu; Hama-Inaba, Hiroko

2006-01-01

Protein kinase Cδ (PKCδ) has an important role in radiation-induced apoptosis. The expression and function of PKCδ in radiation-induced apoptosis were assessed in a radiation-sensitive mouse thymic lymphoma cell line, 3SBH5, and its radioresistant variant, XR223. Rottlerin, a PKCδ-specific inhibitor, completely abolished radiation-induced apoptosis in 3SBH5. Radiation-induced PKCδ activation correlated with the degradation of PKCδ, indicating that PKCδ activation through degradation is involved in radiation-induced apoptosis in radiosensitive 3SBH5. In radioresistant XR223, radiation-induced PKCδ activation was lower than that in radiosensitive 3SBH5. Cytosol PKCδ levels in 3SBH5 decreased markedly after irradiation, while those in XR223 did not. There was no apparent change after irradiation in the membrane fractions of either cell type. In addition, basal cytosol PKCδ levels in XR223 were higher than those in 3SBH5. These results suggest that the radioresistance in XR223 to radiation-induced apoptosis is due to a difference in the regulation of radiation-induced PKCδ activation compared to that of 3SBH5. On the other hand, Atm -/- mouse thymic lymphoma cells were more radioresistant to radiation-induced apoptosis than wild-type mouse thymic lymphoma cells. Irradiated wild-type cells, but not Atm -/- cells, had decreased PKCδ levels, indicating that the Atm protein is involved in radiation-induced apoptosis through the induction of PKCδ degradation. The decreased Atm protein levels induced by treatment with Atm small interfering RNA had no effect on radiation-induced apoptosis in 3SBH5 cells. These results suggest that the regulation of radiation-induced PKCδ activation, which is distinct from the Atm-mediated cascade, determines radiation sensitivity in radiosensitive 3SBH5 cells

Pump cavitation and inducer design

International Nuclear Information System (INIS)

Heslenfeld, M.W.; Hes, M. de

2002-01-01

Details of past work on sodium pump development and cavitation studies executed mainly for SNR 300 were reported earlier. Among the requirements for large sodium pumps are long life (200000 hours up to 300000 hours) and small size of impeller and pump, fully meeting the process and design criteria. These criteria are the required 'Q, H, r characteristics' in combination with a low NPSH value and the avoidance of cavitation damage to the pump. The pump designer has to develop a sound hydraulic combination consisting of suction arrangement, impeller design and diffuser. On the other hand the designer is free to choose an optimal pump speed. The pump speed in its turn influences the rotor dynamic pump design and the pump drive. The introduction of the inducer as an integral part of the pump design is based on following advantages: no tip cavitation; (possible) cavitation bubbles move to the open centre due to centrifugal forces on the fluid; the head of the inducer improves the inlet conditions of the impeller. The aim of an inducer is the increase in the suction specific speed (SA value) of a pump whereby the inducer functions as a pressure source improving the impeller inlet conditions. With inducer-impeller combinations values up to SA=15000 are realistic. With the use of an inducer the overall pump sizes can be reduced with Ca. 30%. Pumps commonly available have SA values up to a maximum of ca. 10000. A development programme was executed for SNR 300 in order to reach an increase of the suction specific speed of the impeller from SA 8200 to SA 11000. Further studies to optimize pumps design for the follow up line introduced the 'inducer acting as a pre-impeller' development. This programme was executed in the period 1979-1981. At the FDO premises a scale 1 2.8 inducer impeller combination with a suction specific speed SA=15000 was developed, constructed and tested at the water test rig. This water test rig is equipped with a perspex pipe allowing also visualisation

Differentiation-inducing factor-1 induces cyclin D1 degradation through the phosphorylation of Thr286 in squamous cell carcinoma

International Nuclear Information System (INIS)

Mori, Jun; Takahashi-Yanaga, Fumi; Miwa, Yoshikazu; Watanabe, Yutaka; Hirata, Masato; Morimoto, Sachio; Shirasuna, Kanemitsu; Sasaguri, Toshiyuki

2005-01-01

Differentiation-inducing factors (DIFs) are morphogens which induce cell differentiation in Dictyostelium. We reported that DIF-1 and DIF-3 inhibit proliferation and induce differentiation in mammalian cells. In this study, we investigated the effect of DIF-1 on oral squamous cell carcinoma cell lines NA and SAS, well differentiated and poorly differentiated cell lines, respectively. Although DIF-1 did not induce the expression of cell differentiation makers in these cell lines, it inhibited the proliferation of NA and SAS in a dose-dependent manner by restricting the cell cycle in the G 0 /G 1 phase. DIF-1 induced cyclin D1 degradation, but this effect was prevented by treatment with lithium chloride and SB216763, the inhibitors of glycogen synthase kinase-3β (GSK-3β). Depletion of endogenous GSK-3β by RNA interference also attenuated the effect of DIF-1 on cyclin D1 degradation. Therefore, we investigated the effect of DIF-1 on GSK-3β and found that DIF-1 dephosphorylated GSK-3β on Ser 9 and induced the nuclear translocation of GSK-3β, suggesting that DIF-1 activated GSK-3β. Then, we examined the effect of DIF-1 on cyclin D1 mutants (Thr286Ala, Thr288Ala, and Thr286/288Ala). We revealed that Thr286Ala and Thr286/288Ala mutants were highly resistant to DIF-1-induced degradation compared with wild-type cyclin D1, indicating that the phosphorylation of Thr 286 was critical for cyclin D1 degradation induced by DIF-1. These results suggest that DIF-1 induces degradation of cyclin D1 through the GSK-3β-mediated phosphorylation of Thr 286

Radiation-induced radical ions in calcium sulfite

Science.gov (United States)

Bogushevich, S. E.

2006-07-01

We have used EPR to study the effect of γ radiation on calcium sulfite. We have observed and identified the radiation-induced radical ions SO 2 - (iso) with g = 2.0055 and SO 2 - (orth-1) with g1 = 2.0093, g2 = 2.0051, g3 = 2.0020, identical to the initial and thermally induced SO 2 - respectively, SO 3 - (iso) with g = 2.0031 and SO 3 - (axial) with g⊥ = 2.0040, g∥ = 2.0023, identical to mechanically induced SO 3 - . We have established the participation of radiation-induced radical ions SO 3 - in formation of post-radiation SO 2 - .

Evaluation of induced seismicity forecast models in the Induced Seismicity Test Bench

Science.gov (United States)

Király, Eszter; Gischig, Valentin; Zechar, Jeremy; Doetsch, Joseph; Karvounis, Dimitrios; Wiemer, Stefan

2016-04-01

Induced earthquakes often accompany fluid injection, and the seismic hazard they pose threatens various underground engineering projects. Models to monitor and control induced seismic hazard with traffic light systems should be probabilistic, forward-looking, and updated as new data arrive. Here, we propose an Induced Seismicity Test Bench to test and rank such models. We apply the test bench to data from the Basel 2006 and Soultz-sous-Forêts 2004 geothermal stimulation projects, and we assess forecasts from two models that incorporate a different mix of physical understanding and stochastic representation of the induced sequences: Shapiro in Space (SiS) and Hydraulics and Seismics (HySei). SiS is based on three pillars: the seismicity rate is computed with help of the seismogenic index and a simple exponential decay of the seismicity; the magnitude distribution follows the Gutenberg-Richter relation; and seismicity is distributed in space based on smoothing seismicity during the learning period with 3D Gaussian kernels. The HySei model describes seismicity triggered by pressure diffusion with irreversible permeability enhancement. Our results show that neither model is fully superior to the other. HySei forecasts the seismicity rate well, but is only mediocre at forecasting the spatial distribution. On the other hand, SiS forecasts the spatial distribution well but not the seismicity rate. The shut-in phase is a difficult moment for both models in both reservoirs: the models tend to underpredict the seismicity rate around, and shortly after, shut-in. Ensemble models that combine HySei's rate forecast with SiS's spatial forecast outperform each individual model.

Neogambogic acid prevents silica-induced fibrosis via inhibition of high-mobility group box 1 and MCP-1-induced protein 1

Energy Technology Data Exchange (ETDEWEB)

Zhang, Wei [Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096 (China); Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Zhang, Mei, E-mail: meizhang1717@163.com [Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Wang, Zhongjiang [Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Cheng, Yusi; Liu, Haijun [Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Zhou, Zewei [Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Han, Bing [Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Chen, Baoan [Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Yao, Honghong, E-mail: yaohh@seu.edu.cn [Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096 (China); Chao, Jie, E-mail: chaojie@seu.edu.cn [Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096 (China); Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China)

2016-10-15

Background: Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO{sub 2}); early stages are characterized by alveolar inflammation, and later stages are characterized by progressive lung fibrosis. Mounting evidence indicates that high-mobility group box 1 (HMGB1) is involved in pulmonary fibrosis. Whether neogambogic acid (NGA) inhibits macrophage and fibroblast activation induced by SiO{sub 2} by targeting HMGB1 remains unclear. Methods and results: Experiments using cultured mouse macrophages (RAW264.7 cells) demonstrated that SiO{sub 2} treatment induces the expression of HMGB1 in a time- and dose-dependent manner via mitogen-activated protein kinases (MAPKs) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; in turn, this expression causes macrophage apoptosis and fibroblast activation. Pretreating macrophages with NGA inhibited the HMGB1 expression induced by SiO{sub 2} and attenuated both macrophage apoptosis and fibroblast activation. Moreover, NGA directly inhibited MCP-1-induced protein 1 (MCPIP1) expression, as well as markers of fibroblast activation and migration induced by SiO{sub 2}. Furthermore, the effects of NGA on macrophages and fibroblasts were confirmed in vivo by exposing mice to SiO{sub 2}. Conclusion: NGA can prevent SiO{sub 2}-induced macrophage activation and apoptosis via HMGB1 inhibition and SiO{sub 2}-induced fibrosis via the MCPIP1 pathway. Targeting HMGB1 and MCPIP1 with NGA could provide insights into the potential development of a therapeutic approach for alleviating the inflammation and fibrosis induced by SiO{sub 2}. - Highlights: • The SiO{sub 2} induced HMGB1 in alveolar macrophage and MCPIP1 in fibroblast. • NGA rescued the SiO{sub 2}-induced apoptosis of alveolar macrophages via HMGB1 signaling. • NGA inhibited the fibroblast activation induced by SiO{sub 2} via MCPIP1 signaling. • NGA might represent a potential therapeutic approach for silicosis.

DNA damage-inducible transcript 4 (DDIT4) mediates methamphetamine-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes

International Nuclear Information System (INIS)

Chen, Rui; Wang, Bin; Chen, Ling; Cai, Dunpeng; Li, Bing; Chen, Chuanxiang; Huang, Enping; Liu, Chao; Lin, Zhoumeng; Xie, Wei-Bing; Wang, Huijun

2016-01-01

Methamphetamine (METH) is an amphetamine-like psychostimulant that is commonly abused. Previous studies have shown that METH can induce damages to the nervous system and recent studies suggest that METH can also cause adverse and potentially lethal effects on the cardiovascular system. Recently, we demonstrated that DNA damage-inducible transcript 4 (DDIT4) regulates METH-induced neurotoxicity. However, the role of DDIT4 in METH-induced cardiotoxicity remains unknown. We hypothesized that DDIT4 may mediate METH-induced autophagy and apoptosis in cardiomyocytes. To test the hypothesis, we examined DDIT4 protein expression in cardiomyocytes and in heart tissues of rats exposed to METH with Western blotting. We also determined the effects on METH-induced autophagy and apoptosis after silencing DDIT4 expression with synthetic siRNA with or without pretreatment of a mTOR inhibitor rapamycin in cardiomyocytes using Western blot analysis, fluorescence microscopy and TUNEL staining. Our results showed that METH exposure increased DDIT4 expression and decreased phosphorylation of mTOR that was accompanied with increased autophagy and apoptosis both in vitro and in vivo. These effects were normalized after silencing DDIT4. On the other hand, rapamycin promoted METH-induced autophagy and apoptosis in DDIT4 knockdown cardiomyocytes. These results suggest that DDIT4 mediates METH-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes. - Highlights: • METH exposure increases DDIT4 expression in cardiomyocytes. • DDIT4 mediates METH-induced autophagy and apoptosis in cardiomyocytes. • DDIT4 silencing protects cardiomyocytes against METH-caused autophagy and apoptosis.

DNA damage-inducible transcript 4 (DDIT4) mediates methamphetamine-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes

Energy Technology Data Exchange (ETDEWEB)

Chen, Rui [Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China); Department of Forensic Medicine, Guangdong Medical University, Dongguan 523808 (China); Wang, Bin; Chen, Ling; Cai, Dunpeng; Li, Bing; Chen, Chuanxiang; Huang, Enping [Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China); Liu, Chao [Guangzhou Forensic Science Institute, Guangzhou 510030 (China); Lin, Zhoumeng [Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506 (United States); Xie, Wei-Bing, E-mail: xieweib@126.com [Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China); Wang, Huijun, E-mail: hjwang711@yahoo.cn [Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China)

2016-03-15

Methamphetamine (METH) is an amphetamine-like psychostimulant that is commonly abused. Previous studies have shown that METH can induce damages to the nervous system and recent studies suggest that METH can also cause adverse and potentially lethal effects on the cardiovascular system. Recently, we demonstrated that DNA damage-inducible transcript 4 (DDIT4) regulates METH-induced neurotoxicity. However, the role of DDIT4 in METH-induced cardiotoxicity remains unknown. We hypothesized that DDIT4 may mediate METH-induced autophagy and apoptosis in cardiomyocytes. To test the hypothesis, we examined DDIT4 protein expression in cardiomyocytes and in heart tissues of rats exposed to METH with Western blotting. We also determined the effects on METH-induced autophagy and apoptosis after silencing DDIT4 expression with synthetic siRNA with or without pretreatment of a mTOR inhibitor rapamycin in cardiomyocytes using Western blot analysis, fluorescence microscopy and TUNEL staining. Our results showed that METH exposure increased DDIT4 expression and decreased phosphorylation of mTOR that was accompanied with increased autophagy and apoptosis both in vitro and in vivo. These effects were normalized after silencing DDIT4. On the other hand, rapamycin promoted METH-induced autophagy and apoptosis in DDIT4 knockdown cardiomyocytes. These results suggest that DDIT4 mediates METH-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes. - Highlights: • METH exposure increases DDIT4 expression in cardiomyocytes. • DDIT4 mediates METH-induced autophagy and apoptosis in cardiomyocytes. • DDIT4 silencing protects cardiomyocytes against METH-caused autophagy and apoptosis.

Thymus function in drug-induced lupus.

Science.gov (United States)

Rubin, R L; Salomon, D R; Guerrero, R S

2001-01-01

Autoimmunity develops when a lupus-inducing drug is introduced into the thymus of normal mice, but the relevance of this model to the human disorder is unclear in part because it is widely assumed that the thymus is non-functional in the adult. We compared thymus function in 10 patients with symptomatic procainamide-induced lupus to that in 13 asymptomatic patients who only developed drug-induced autoantibodies. T cell output from the thymus was quantified using a competitive polymerase chain reaction that detects T cell receptor DNA excision circles in peripheral blood lymphocytes. Despite the advanced age of the patient population under study, newly generated T cells were detected in all subjects. Although there was no overall quantitative difference between the symptomatic and asymptomatic patients, we found a positive correlation between the level of T cell receptor excision circles in peripheral lymphocytes and serum IgG anti-chromatin antibody activity in patients with drug-induced lupus. The association between autoantibodies and nascent peripheral T cells supports the requirement for T cells in autoantibody production. Our observations are consistent with findings in mice in which autoreactive T cells derived from drug-induced abnormalities in T cell development in the thymus.

Genetic alterations during radiation-induced carcinogenesis

International Nuclear Information System (INIS)

Kodama, Seiji

1995-01-01

This paper reviews radiation-induced genetic alterations and its carcinogenesis, focusing on the previous in vitro assay outcome. A colony formation assay using Syrian hamster fetal cells and focus formation assay using mouse C3H10T1/2 cells are currently available to find malignant transformation of cells. Such in vitro assays has proposed the hypothesis that radiation-induced carcinogenesis arises from at least two-stage processes; i.e., that an early step induced by irradiation plays an important role in promoting the potential to cause the subsequent mutation. A type of genetic instability induced by radiation results in a persistently elevated frequency of spontaneous mutations, so-called the phenomenon of delayed reproductive death. One possible mechanism by which genetic instability arises has been shown to be due to the development of abnormality in the gene group involved in the maintenance mechanism of genome stability. Another possibility has also been shown to stem from the loss of telomere (the extremities of a chromosome). The importance of search for radiation-induced genetic instability is emphasized in view of the elucidation of carcinogenesis. (N.K.)

Characterization of ion beam induced nanostructures

International Nuclear Information System (INIS)

Ghatak, J.; Satpati, B.; Umananda, M.; Kabiraj, D.; Som, T.; Dev, B.N.; Akimoto, K.; Ito, K.; Emoto, T.; Satyam, P.V.

2006-01-01

Tailoring of nanostructures with energetic ion beams has become an active area of research leading to the fundamental understanding of ion-solid interactions at nanoscale regime and with possible applications in the near future. Rutherford backscattering spectrometry (RBS), high resolution transmission electron microscopy (HRTEM) and asymmetric X-ray Bragg-rocking curve experimental methods have been used to characterize ion-induced effects in nanostructures. The possibility of surface and sub-surface/interface alloying at nano-scale regime, ion-beam induced embedding, crater formation, sputtering yield variations for systems with isolated nanoislands, semi-continuous and continuous films of noble metals (Au, Ag) deposited on single crystalline silicon will be reviewed. MeV-ion induced changes in specified Au-nanoislands on silicon substrate are tracked as a function of ion fluence using ex situ TEM. Strain induced in the bulk silicon substrate surface due to 1.5 MeV Au 2+ and C 2+ ion beam irradiation is determined by using HRTEM and asymmetric Bragg X-ray rocking curve methods. Preliminary results on 1.5 MeV Au 2+ ion-induced effects in nanoislands of Co deposited on silicon substrate will be discussed

Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption.

Science.gov (United States)

van't Hof, R J; Armour, K J; Smith, L M; Armour, K E; Wei, X Q; Liew, F Y; Ralston, S H

2000-07-05

Nitric oxide has been suggested to be involved in the regulation of bone turnover, especially in pathological conditions characterized by release of bone-resorbing cytokines. The cytokine IL-1 is thought to act as a mediator of periarticular bone loss and tissue damage in inflammatory diseases such as rheumatoid arthritis. IL-1 is a potent stimulator of both osteoclastic bone resorption and expression of inducible nitric oxide synthase (iNOS) in bone cells and other cell types. In this study, we investigated the role that the iNOS pathway plays in mediating the bone-resorbing effects of IL-1 by studying mice with targeted disruption of the iNOS gene. Studies in vitro and in vivo showed that iNOS-deficient mice exhibited profound defects of IL-1-induced osteoclastic bone resorption but responded normally to calciotropic hormones such as 1,25 dihydroxyvitamin D3 and parathyroid hormone. Immunohistochemical studies and electrophoretic mobility shift assays performed on bone marrow cocultures from iNOS-deficient mice showed abnormalities in IL-1-induced nuclear translocation of the p65 component of NFkappaB and in NFkappaB-DNA binding, which were reversed by treatment with the NO donor S-nitroso-acetyl penicillamine. These results show that the iNOS pathway is essential for IL-1-induced bone resorption and suggest that the effects of NO may be mediated by modulating IL-1-induced nuclear activation of NFkappaB in osteoclast precursors.

Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption

Science.gov (United States)

van't Hof, R. J.; Armour, K. J.; Smith, L. M.; Armour, K. E.; Wei, X. Q.; Liew, F. Y.; Ralston, S. H.

2000-01-01

Nitric oxide has been suggested to be involved in the regulation of bone turnover, especially in pathological conditions characterized by release of bone-resorbing cytokines. The cytokine IL-1 is thought to act as a mediator of periarticular bone loss and tissue damage in inflammatory diseases such as rheumatoid arthritis. IL-1 is a potent stimulator of both osteoclastic bone resorption and expression of inducible nitric oxide synthase (iNOS) in bone cells and other cell types. In this study, we investigated the role that the iNOS pathway plays in mediating the bone-resorbing effects of IL-1 by studying mice with targeted disruption of the iNOS gene. Studies in vitro and in vivo showed that iNOS-deficient mice exhibited profound defects of IL-1-induced osteoclastic bone resorption but responded normally to calciotropic hormones such as 1,25 dihydroxyvitamin D3 and parathyroid hormone. Immunohistochemical studies and electrophoretic mobility shift assays performed on bone marrow cocultures from iNOS-deficient mice showed abnormalities in IL-1-induced nuclear translocation of the p65 component of NFκB and in NFκB-DNA binding, which were reversed by treatment with the NO donor S-nitroso-acetyl penicillamine. These results show that the iNOS pathway is essential for IL-1-induced bone resorption and suggest that the effects of NO may be mediated by modulating IL-1-induced nuclear activation of NFκB in osteoclast precursors. PMID:10869429

Prevention and Treatment of Noise-Induced Tinnitus

Science.gov (United States)

2014-09-01

Tinnitus PRINCIPAL INVESTIGATOR: Dr. Richard A. Altschuler CONTRACTING ORGANIZATION: University of Michigan REPORT DATE: 2014...3 Ju 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Prevention and Treatment of Noise-Induced Tinnitus 5b. GRANT NUMBER 5c. PROGRAM...prevent or treat noise induced tinnitus . Our studies showed a military relevant small arms fire-like noise will induce tinnitus in approximately 33

Snake antivenom for snake venom induced consumption coagulopathy

OpenAIRE

Maduwage, Kalana; Buckley, Nick A.; Janaka de Silva, H.; Lalloo, David; Isbister, Geoffrey K.

2015-01-01

Background\\ud \\ud Snake venom induced consumption coagulopathy is a major systemic effect of envenoming. Observational studies suggest that antivenom improves outcomes for venom induced consumption coagulopathy in some snakebites and not others. However, the effectiveness of snake antivenom in all cases of venom induced consumption coagulopathy is controversial.\\ud \\ud Objectives\\ud \\ud To assess the effect of snake antivenom as a treatment for venom induced consumption coagulopathy in people...

Induced Pluripotent Stem Cells-Derived Mesenchymal Stem Cells Attenuate Cigarette Smoke-Induced Cardiac Remodeling and Dysfunction

Directory of Open Access Journals (Sweden)

Yingmin Liang

2017-07-01

Full Text Available The strong relationship between cigarette smoking and cardiovascular disease (CVD has been well-documented, but the mechanisms by which smoking increases CVD risk appear to be multifactorial and incompletely understood. Mesenchymal stem cells (MSCs are regarded as an important candidate for cell-based therapy in CVD. We hypothesized that MSCs derived from induced pluripotent stem cell (iPSC-MSCs or bone marrow (BM-MSCs might alleviate cigarette smoke (CS-induced cardiac injury. This study aimed to investigate the effects of BM-MSCs or iPSC-MSCs on CS-induced changes in serum and cardiac lipid profiles, oxidative stress and inflammation as well as cardiac function in a rat model of passive smoking. Male Sprague-Dawley rats were randomly selected for exposure to either sham air (SA as control or 4% CS for 1 h per day for 56 days. On day 29 and 43, human adult BM-MSCs, iPSC-MSCs or PBS were administered intravenously to CS-exposed rats. Results from echocardiography, serum and cardiac lipid profiles, cardiac antioxidant capacity, cardiac pro- and anti-inflammatory cytokines and cardiac morphological changes were evaluated at the end of treatment. iPSC-MSC-treated group showed a greater effect in the improvement of CS-induced cardiac dysfunction over BM-MSCs-treated group as shown by increased percentage left ventricular ejection fraction and percentage fractional shortening, in line with the greater reversal of cardiac lipid abnormality. In addition, iPSC-MSCs administration attenuated CS-induced elevation of cardiac pro-inflammatory cytokines as well as restoration of anti-inflammatory cytokines and anti-oxidative markers, leading to ameliorate cardiac morphological abnormalities. These data suggest that iPSC-MSCs on one hand may restore CS-induced cardiac lipid abnormality and on the other hand may attenuate cardiac oxidative stress and inflammation via inhibition of CS-induced NF-κB activation, leading to improvement of cardiac remodeling and

Induced disease resistance signaling in plants

NARCIS (Netherlands)

Verhagen, B.W.M.; Loon, L.C. van; Pieterse, C.M.J.

2006-01-01

To protect themselves from disease, plants have evolved sophisticated inducible defense mechanisms in which the signal molecules salicylic acid, jasmonic acid and ethylene often play crucial roles. Elucidation of signaling pathways controlling induced disease resistance is a major objective in

Radiation-induced gene expression in human subcutaneous fibroblasts is predictive of radiation-induced fibrosis

DEFF Research Database (Denmark)

Rødningen, Olaug Kristin; Børresen-Dale, Anne-Lise; Alsner, Jan

2008-01-01

BACKGROUND AND PURPOSE: Breast cancer patients show a large variation in normal tissue reactions after ionizing radiation (IR) therapy. One of the most common long-term adverse effects of ionizing radiotherapy is radiation-induced fibrosis (RIF), and several attempts have been made over the last...... years to develop predictive assays for RIF. Our aim was to identify basal and radiation-induced transcriptional profiles in fibroblasts from breast cancer patients that might be related to the individual risk of RIF in these patients. MATERIALS AND METHODS: Fibroblast cell lines from 31 individuals......-treated fibroblasts. Transcriptional differences in basal and radiation-induced gene expression profiles were investigated using 15K cDNA microarrays, and results analyzed by both SAM and PAM. RESULTS: Sixty differentially expressed genes were identified by applying SAM on 10 patients with the highest risk of RIF...

Drug-induced hair loss.

Science.gov (United States)

2016-05-01

Hair loss can have major psychological consequences. It can be due to a wide variety of causes, including hormonal disorders, dietary factors, infections, inflammation, trauma, emotional factors, and cancer. Drugs can also induce hair loss, by interacting with the hair growth cycle. Drug-induced hair loss may be immediate or delayed, sudden or gradual, and diffuse or localised. It is usually reversible after drug discontinuation. The drugs most often implicated in hair loss are anticancer agents, interferon, azole antifungals, lithium, immunosuppressants, and many other drugs belonging to a variety of pharmacological classes.

Cyclophosphamide-induced pulmonary toxicity

International Nuclear Information System (INIS)

Siemann, D.W.; Macler, L.; Penney, D.P.

1986-01-01

Unlike radiation effects, pulmonary toxicity following drug treatments may develop soon after exposure. The dose-response relationship between Cyclophosphamide and lung toxicity was investigated using increased breathing frequency assays used successfully for radiation induced injury. The data indicate that release of protein into the alveolus may play a significant role in Cy induced pulmonary toxicity. Although the mechanism responsible for the increased alveolar protein is as yet not identified, the present findings suggest that therapeutic intervention to inhibit protein release may be an approach to protect the lungs from toxic effects. (UK)

Role of neurotensin in radiation-induced hypothermia in rats

International Nuclear Information System (INIS)

Kandasamy, S.B.; Hunt, W.A.; Harris, A.H.

1991-01-01

The role of neurotensin in radiation-induced hypothermia was examined. Intracerebroventricular (ICV) administration of neurotensin produced dose-dependent hypothermia. Histamine appears to mediate neurotensin-induced hypothermia because the mast cell stabilizer disodium cromoglycate and antihistamines blocked the hypothermic effects of neurotensin. An ICV pretreatment with neurotensin antibody attenuated neurotensin-induced hypothermia, but did not attenuate radiation-induced hypothermia, suggesting that radiation-induced hypothermia was not mediated by neurotensin

Flow-induced vibration -- 1994. PVP-Volume 273

International Nuclear Information System (INIS)

Au-Yang, M.K.; Fujita, K.

1994-01-01

Flow-induced vibration is a subject of practical interest to many engineering disciplines, including the power generation, process, and petrochemical industries. In the nuclear industry, flow-induced vibration reaches a higher level of concern because of safety issues and the huge cost associated with down time and site repair. Not surprisingly, during the last 25 years a tremendous amount of effort has been spent in the study of flow-induced vibration phenomena related to nuclear plant components, notably nuclear steam generator tube banks and nuclear fuel bundles. Yet, in spite of this concentrated effort, the industry is still not free from flow-induced vibration-related problems. This explains why in this volume almost half of the papers address the issue of cross-flow induced vibration in tube bundles, with applications to the nuclear steam generator and nuclear fuel bundles in mind. Unlike 10 or 15 years ago, when flow-induced vibration studies almost always involved experimentation and empirical studies, the advent of high-speed computers has enabled numerical calculation and simulation of this complex phenomenon to take place. Separate abstracts were prepared for 27 papers in this volume

Curvature-Induced Instabilities of Shells

Science.gov (United States)

Pezzulla, Matteo; Stoop, Norbert; Steranka, Mark P.; Bade, Abdikhalaq J.; Holmes, Douglas P.

2018-01-01

Induced by proteins within the cell membrane or by differential growth, heating, or swelling, spontaneous curvatures can drastically affect the morphology of thin bodies and induce mechanical instabilities. Yet, the interaction of spontaneous curvature and geometric frustration in curved shells remains poorly understood. Via a combination of precision experiments on elastomeric spherical shells, simulations, and theory, we show how a spontaneous curvature induces a rotational symmetry-breaking buckling as well as a snapping instability reminiscent of the Venus fly trap closure mechanism. The instabilities, and their dependence on geometry, are rationalized by reducing the spontaneous curvature to an effective mechanical load. This formulation reveals a combined pressurelike term in the bulk and a torquelike term in the boundary, allowing scaling predictions for the instabilities that are in excellent agreement with experiments and simulations. Moreover, the effective pressure analogy suggests a curvature-induced subcritical buckling in closed shells. We determine the critical buckling curvature via a linear stability analysis that accounts for the combination of residual membrane and bending stresses. The prominent role of geometry in our findings suggests the applicability of the results over a wide range of scales.

Cellular Responses to Cisplatin-Induced DNA Damage

Directory of Open Access Journals (Sweden)

Alakananda Basu

2010-01-01

Full Text Available Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. How cells respond to cisplatin-induced DNA damage plays a critical role in deciding cisplatin sensitivity. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death. This paper summarizes our current understandings regarding the mechanisms by which cisplatin induces cell death and the bases of cisplatin resistance. We have discussed various steps, including the entry of cisplatin inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein kinases. An understanding of how various signaling pathways regulate cisplatin-induced cell death should aid in the development of more effective therapeutic strategies for the treatment of cancer.

Hierarchical Bayesian Modeling of Fluid-Induced Seismicity

Science.gov (United States)

Broccardo, M.; Mignan, A.; Wiemer, S.; Stojadinovic, B.; Giardini, D.

2017-11-01

In this study, we present a Bayesian hierarchical framework to model fluid-induced seismicity. The framework is based on a nonhomogeneous Poisson process with a fluid-induced seismicity rate proportional to the rate of injected fluid. The fluid-induced seismicity rate model depends upon a set of physically meaningful parameters and has been validated for six fluid-induced case studies. In line with the vision of hierarchical Bayesian modeling, the rate parameters are considered as random variables. We develop both the Bayesian inference and updating rules, which are used to develop a probabilistic forecasting model. We tested the Basel 2006 fluid-induced seismic case study to prove that the hierarchical Bayesian model offers a suitable framework to coherently encode both epistemic uncertainty and aleatory variability. Moreover, it provides a robust and consistent short-term seismic forecasting model suitable for online risk quantification and mitigation.

Ubiquitin-dependent system controls radiation induced apoptosis

International Nuclear Information System (INIS)

Delic, J.; Magdelenat, H.; Glaisner, S.; Magdelenat, H.; Maciorowski, Z.

1997-01-01

The selective proteolytic pathway, dependent upon 'N-end rule' protein recognition/ubiquitination and on the subsequent proteasome dependent processing of ubiquitin conjugates, operates in apoptosis induced by γ-irradiation. The proteasome inhibitor peptide aldehyde, MG132, efficiently induced apoptosis and was also able (at doses lower than those required for apoptosis induction) to potentiate apoptosis induced by DNA damage. Its specificity is suggested by the induction of the ubiquitin (UbB and UbC) and E1 (ubiquitin activating enzyme) genes and by an altered ubiquitination pattern. More selectively, a di-peptide competitor of the 'N-end rule' of ubiquitin dependent protein processing inhibited radiation induced apoptosis. This inhibition is also followed by an altered ubiquitination pattern and by activation of Poly (ADP-ribose) polymerase (PARP). These data strongly suggest that early apoptosis radiation induced events are controlled by ubiquitin-dependent proteolytic processing. (author)

Mild induced hypothermia

DEFF Research Database (Denmark)

Johansen, Maria E; Jensen, Jens-Ulrik; Bestle, Morten H

2014-01-01

INTRODUCTION: Coagulopathy associates with poor outcome in sepsis. Mild induced hypothermia has been proposed as treatment in sepsis but it is not known whether this intervention worsens functional coagulopathy. MATERIALS AND METHODS: Interim analysis data from an ongoing randomized controlled...... trial; The Cooling And Surviving Septic shock (CASS) study. Patients suffering severe sepsis/septic shock are allocated to either mild induced hypothermia (cooling to 32-34°C for 24hours) or control (uncontrolled temperature). TRIAL REGISTRATION: NCT01455116. Thrombelastography (TEG) is performed three....... At enrollment, 3%, 38%, and 59% had a hypocoagulable, normocoagulable, and hypercoagulable TEG clot strength (MA), respectively. In the hypothermia group, functional coagulopathy improved during the hypothermia phase, measured by R and MA, in patients with hypercoagulation as well as in patients...

Inducible limb-shaking transitory ischemic attacks

DEFF Research Database (Denmark)

Rosenbaum, Sverre; Ovesen, Christian; Futrell, Nancy

2016-01-01

with exercise-induced weakness associated with tremor in his right arm. His left internal carotid artery was occluded at the bifurcation. Administration of statin and antiplatelet did not relieve his symptoms, and his stereotypic, exercise-induced "limb-shaking" episodes persisted. He underwent successful...

Curcumin-induced histone acetylation inhibition improves stress-induced gastric ulcer disease in rats.

Science.gov (United States)

He, Ping; Zhou, Renmin; Hu, Guorui; Liu, Zhifeng; Jin, Yu; Yang, Guang; Li, Mei; Lin, Qian

2015-03-01