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Sample records for transporter inhibitors evidence

  1. The cannabinoid transporter inhibitor OMDM-2 reduces social interaction: Further evidence for transporter-mediated endocannabinoid release.

    Science.gov (United States)

    Seillier, Alexandre; Giuffrida, Andrea

    2018-03-01

    Experimental evidence suggests that the transport of endocannabinoids might work bi-directionally. Accordingly, it is possible that pharmacological blockade of the latter affects not only the re-uptake, but also the release of endocannabinoids, thus preventing them from stimulating CB 1 receptors. We used biochemical, pharmacological, and behavioral approaches to investigate the effects of the transporter inhibitor OMDM-2 on social interaction, a behavioral assay that requires activation of CB 1 receptors. The underlying mechanisms of OMDM-2 were compared with those of the Fatty Acid Amide Hydrolase (FAAH) inhibitor URB597. Systemic administration of OMDM-2 reduced social interaction, but in contrast to URB597-induced social deficit, this effect was not reversed by the TRPV1 antagonist capsazepine. The CB 1 antagonist AM251, which did not affect URB597-induced social withdrawal, exacerbated OMDM-2 effect. In addition, the potent CB 1 agonist CP55,940 reversed OMDM-2-, but not URB597-, induced social withdrawal. Blockade of CB 1 receptor by AM251 reduced social interaction and the cholecystokinin CCK2 antagonist LY225910 reversed this effect. Similarly, OMDM-2-induced social withdrawal was reversed by LY225910, whereas URB597 effect was not. Elevation of endocannabinoid levels by URB597 or JZL184, an inhibitor of 2-AG degradation, failed to reverse OMDM-2-induced social withdrawal, and did not show additive effects on cannabinoid measurements when co-administered with OMDM-2. Taken together, these findings indicate that OMDM-2 impaired social interaction in a manner that is consistent with reduced activation of presynaptic CB 1 receptors. As cannabinoid reuptake inhibitors may impair endocannabinoid release, caution should be taken when using these drugs to enhance endocannabinoid tone in vivo. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence

    Science.gov (United States)

    D'Souza, Deepak Cyril; Singh, Nagendra; Elander, Jacqueline; Carbuto, Michelle; Pittman, Brian; de Haes, Joanna Udo; Sjogren, Magnus; Peeters, Pierre; Ranganathan, Mohini; Schipper, Jacques

    2012-01-01

    Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, -serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors. PMID:22113087

  3. Safety of Sodium-Glucose Co-Transporter 2 Inhibitors during Ramadan Fasting: Evidence, Perceptions and Guidelines

    Directory of Open Access Journals (Sweden)

    Salem A. Beshyah

    2016-06-01

    Full Text Available Sodium-glucose co-transporter 2 (SGLT2 inhibitors are a new glucose-lowering therapy for T2DM with documented benefits on blood glucose, hypertension, weight reduction and long term cardiovascular benefit. They have an inherent osmotic diuretic effect and lead to some volume loss and possible dehydration. There is some concern about the safety of using SGLT2 inhibitors in Muslim type 2 diabetes mellitus (T2DM patients during the fast during Ramadan. Currently, there is a dearth of research data to help guide physicians and reassure patients.  One study confirmed good glycemic control with less risk of hypoglycemia and no marked volume depletion. Data in the elderly and in combination with diuretics are reassuring of their safe to use in Ramadan in general. SGLT2 inhibitor-related diabetic ketoacidosis has not been reported during Ramadan and is unlikely to be relevant. Survey of physicians revealed that the majority felt that SGLT2 inhibitors are generally safe in T2DM patients during Ramadan fasting but should be discontinued in certain high risk patients. Some professional groups with interest in diabetes and Ramadan fasting included SGLT2 inhibitors in their guidelines on management of diabetes during Ramadan. They acknowledged the lack of trial data, recommended caution in high risk groups, advised regular monitoring and emphasized pre-Ramadan patients’ education. In conclusion, currently, knowledge, data and experience with SGLT2 inhibitors in Ramadan are limited. Nonetheless, stable patients with normal kidney function and low risk of dehydration may safely use the SGLT2 inhibitors therapy. Higher risk patients should be observed carefully and managed on individual basis.

  4. Inhibitors of plant hormone transport

    Czech Academy of Sciences Publication Activity Database

    Klíma, Petr; Laňková, Martina; Zažímalová, Eva

    2016-01-01

    Roč. 253, č. 6 (2016), s. 1391-1404 ISSN 0033-183X R&D Projects: GA MŠk(CZ) LD15088 Institutional support: RVO:61389030 Keywords : polar auxin transport * acid-binding protein * gnom arf-gef * equilibrative nucleoside transporter * efflux carrier polarity * plasma-membrane-protein * cultured tobacco cells * arabidopsis-thaliana * gravitropic response * brefeldin-a * Plant hormones * Transport * Inhibitors * Auxin * Cytokinins * Strigolactones * Abscisic acid * Cell biology Subject RIV: ED - Physiology Impact factor: 2.870, year: 2016

  5. Molecular modeling of auxin transport inhibitors

    International Nuclear Information System (INIS)

    Gardner, G.; Black-Schaefer, C.; Bures, M.G.

    1990-01-01

    Molecular modeling techniques have been used to study the chemical and steric properties of auxin transport inhibitors. These bind to a specific site on the plant plasma membrane characterized by its affinity for N-1-naphthylphthalamic acid (NPA). A three-dimensional model was derived from critical features of ligands for the NPA receptor, and a suggested binding conformation is proposed. This model, along with three-dimensional structural searching techniques, was then used to search the Abbott corporate database of chemical structures. Of the 467 compounds that satisfied the search criteria, 77 representative molecules were evaluated for their ability to compete for [ 3 H]NPA binding to corn microsomal membranes. Nineteen showed activity that ranged from 16 to 85% of the maximum NPA binding. Four of the most active of these, from chemical classes not included in the original compound set, also inhibited polar auxin transport through corn coleoptile sections

  6. Screening for Inhibitors of Essential Leishmania Glucose Transporters

    Science.gov (United States)

    2013-07-01

    Leishmania Glucose Transporters PRINCIPAL INVESTIGATOR: Scott M. Landfear, Ph.D. CONTRACTING ORGANIZATION: Oregon Health & Science...COVERED 1 July 2009- 30 June 2013 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Screening for Inhibitors of Essential Leishmania Glucose Transporters 5b...The objective of this project was to identify compounds that selectively inhibit the essential Leishmania glucose transporters and could hence serve

  7. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Tang, H L; Li, D D; Zhang, J J; Hsu, Y H; Wang, T S; Zhai, S D; Song, Y Q

    2016-12-01

    To evaluate the comparative effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on risk of bone fracture in patients with type 2 diabetes mellitus (T2DM). PubMed, EMBASE, CENTRAL and ClinicalTrials.gov were systematically searched from inception to 27 January 2016 to identify randomized controlled trials (RCTs) reporting the outcome of fracture in patients with T2DM treated with SGLT2 inhibitors. Pairwise and network meta-analyses, as well as a cumulative meta-analysis, were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). A total of 38 eligible RCTs (10 canagliflozin, 15 dapagliflozin and 13 empagliflozin) involving 30 384 patients, with follow-ups ranging from 24 to 160 weeks, were included. The fracture event rates were 1.59% in the SGLT2 inhibitor groups and 1.56% in the control groups. The incidence of fracture events was similar among these three SGLT2 inhibitor groups. Compared with placebo, canagliflozin (OR 1.15; 95% CI 0.71-1.88), dapagliflozin (OR 0.68; 95% CI 0.37-1.25) and empagliflozin (OR 0.93; 95% CI 0.74-1.18) were not significantly associated with an increased risk of fracture. Our cumulative meta-analysis indicated the robustness of the null findings with regard to SGLT2 inhibitors. Our meta-analysis based on available RCT data does not support the harmful effect of SGLT2 inhibitors on fractures, although future safety monitoring from RCTs and real-world data with detailed information on bone health is warranted. © 2016 John Wiley & Sons Ltd.

  8. TWISTED DWARF1 Mediates the Action of Auxin Transport Inhibitors on Actin Cytoskeleton Dynamics

    Science.gov (United States)

    Bailly, Aurelien; Zwiewka, Marta; Sovero, Valpuri; Ge, Pei; Aryal, Bibek; Hao, Pengchao; Linnert, Miriam; Burgardt, Noelia Inés; Lücke, Christian; Weiwad, Matthias; Michel, Max; Weiergräber, Oliver H.; Pollmann, Stephan; Azzarello, Elisa; Fukao, Yoichiro; Hoffmann, Céline; Wedlich-Söldner, Roland

    2016-01-01

    Plant growth and architecture is regulated by the polar distribution of the hormone auxin. Polarity and flexibility of this process is provided by constant cycling of auxin transporter vesicles along actin filaments, coordinated by a positive auxin-actin feedback loop. Both polar auxin transport and vesicle cycling are inhibited by synthetic auxin transport inhibitors, such as 1-N-naphthylphthalamic acid (NPA), counteracting the effect of auxin; however, underlying targets and mechanisms are unclear. Using NMR, we map the NPA binding surface on the Arabidopsis thaliana ABCB chaperone TWISTED DWARF1 (TWD1). We identify ACTIN7 as a relevant, although likely indirect, TWD1 interactor, and show TWD1-dependent regulation of actin filament organization and dynamics and that TWD1 is required for NPA-mediated actin cytoskeleton remodeling. The TWD1-ACTIN7 axis controls plasma membrane presence of efflux transporters, and as a consequence act7 and twd1 share developmental and physiological phenotypes indicative of defects in auxin transport. These can be phenocopied by NPA treatment or by chemical actin (de)stabilization. We provide evidence that TWD1 determines downstream locations of auxin efflux transporters by adjusting actin filament debundling and dynamizing processes and mediating NPA action on the latter. This function appears to be evolutionary conserved since TWD1 expression in budding yeast alters actin polarization and cell polarity and provides NPA sensitivity. PMID:27053424

  9. Luminal nucleotides are tonic inhibitors of renal tubular transport

    DEFF Research Database (Denmark)

    Leipziger, Jens Georg

    2011-01-01

    PURPOSE OF REVIEW: Extracellular ATP is an essential local signaling molecule in all organ systems. In the kidney, purinergic signaling is involved in an array of functions and this review highlights those of relevance for renal tubular transport. RECENT FINDINGS: Purinergic receptors are express...... discovered as an important signaling compartment in which local purinergic signaling determines an inhibitory tone for renal tubular transport. Blocking components of this system leads to tubular hyper-absorption, volume retention and elevated blood pressure.......PURPOSE OF REVIEW: Extracellular ATP is an essential local signaling molecule in all organ systems. In the kidney, purinergic signaling is involved in an array of functions and this review highlights those of relevance for renal tubular transport. RECENT FINDINGS: Purinergic receptors are expressed...... in all renal tubular segments and their stimulation generally leads to transport inhibition. Recent evidence has identified the tubular lumen as a restricted space for purinergic signaling. The concentrations of ATP in the luminal fluids are sufficiently high to inflict a tonic inhibition of renal...

  10. Adipocyte glucose transport regulation by eicosanoid precursors and inhibitors

    International Nuclear Information System (INIS)

    Lee, H.C.C.

    1987-01-01

    Glucose uptake and free fatty acid release by adipocytes are increased by catecholamines. The mechanism of the stimulatory action of catecholamines on glucose uptake may be via eicosanoid production from release fatty acids. Rats were fed iso-nutrient diets with high or low safflower oil. After one month, 5 rats per diet group were fed diets with aspirin or without aspirin for 2 days. Isolated adipocytes from epididymal fat pads were incubated at 37 0 C, gassed with 95% O 2 -5% CO 2 in KRB buffer with 3% bovine serum albumin and with or without eicosanoid modifiers; a stimulator (10 -5 M norepinephrine, N), or inhibitors (167 μl of antiserum to prostaglandin E (AntiE) per 1600 μl or 23mM Asp), or combinations of these. At 2-, 5-, and 10-min incubation, samples of incubation mixtures were taken to measure 2-deoxy glucose transport using 3 H-2-deoxy glucose, 14 C-inulin, and liquid scintillation counter

  11. Functional evidence of multidrug resistance transporters (MDR in rodent olfactory epithelium.

    Directory of Open Access Journals (Sweden)

    Adrien Molinas

    Full Text Available P-glycoprotein (Pgp and multidrug resistance-associated protein (MRP1 are membrane transporter proteins which function as efflux pumps at cell membranes and are considered to exert a protective function against the entry of xenobiotics. While evidence for Pgp and MRP transporter activity is reported for olfactory tissue, their possible interaction and participation in the olfactory response has not been investigated.Functional activity of putative MDR transporters was assessed by means of the fluorometric calcein acetoxymethyl ester (calcein-AM accumulation assay on acute rat and mouse olfactory tissue slices. Calcein-AM uptake was measured as fluorescence intensity changes in the presence of Pgp or MRP specific inhibitors. Epifluorescence microscopy measured time course analysis in the olfactory epithelium revealed significant inhibitor-dependent calcein uptake in the presence of each of the selected inhibitors. Furthermore, intracellular calcein accumulation in olfactory receptor neurons was also significantly increased in the presence of either one of the Pgp or MRP inhibitors. The presence of Pgp or MRP1 encoding genes in the olfactory mucosa of rat and mouse was confirmed by RT-PCR with appropriate pairs of species-specific primers. Both transporters were expressed in both newborn and adult olfactory mucosa of both species. To assess a possible involvement of MDR transporters in the olfactory response, we examined the electrophysiological response to odorants in the presence of the selected MDR inhibitors by recording electroolfactograms (EOG. In both animal species, MRPs inhibitors induced a marked reduction of the EOG magnitude, while Pgp inhibitors had only a minor or no measurable effect.The findings suggest that both Pgp and MRP transporters are functional in the olfactory mucosa and in olfactory receptor neurons. Pgp and MRPs may be cellular constituents of olfactory receptor neurons and represent potential mechanisms for modulation

  12. The Monocarboxylate Transporter Inhibitor α-Cyano-4-Hydroxycinnamic Acid Disrupts Rat Lung Branching

    Directory of Open Access Journals (Sweden)

    Sara Granja

    2013-12-01

    Full Text Available Background/Aims: The human embryo develops in a hypoxic environment. In this way, cells have to rely on the glycolytic pathway for energy supply, leading to an intracellular accumulation of monocarboxylates such as lactate and pyruvate. These acids have an important role in cell metabolism and their rapid transport across the plasma membrane is crucial for the maintenance of intracellular pH homeostasis. This transport is mediated by a family of transporters, designated by monocarboxylate transporters (MCTs, namely isoforms 1 and 4. MCT1/4 expression is regulated by the ancillary protein CD147.The general aim of this study was to characterize the expression pattern of MCT1/4, CD147 and the glucose transporter GLUT1 during human fetal lung development and elucidate the role of MCTs in lung development. Methods: The expression pattern of MCT1/4 and GLUT1 was characterized by immunohistochemistry and fetal lung viability and branching were evaluated by exposing rat fetal lung explants to CHC, an inhibitor of MCT activity. Results: Our findings show that all the biomarkers are differently expressed during fetal lung development and that CHC appears to have an inhibitory effect on lung branching and viability, in a dose dependent way. Conclusion: We provide evidence for the role of MCTs in embryo lung development, however to prove the dependence of MCT activity further studies are waranted.

  13. Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors

    DEFF Research Database (Denmark)

    Cao, Jianjing; Slack, Rachel D.; Bakare, Oluyomi M.

    2016-01-01

    The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacolog...

  14. Flavonoids Are Inhibitors of Human Organic Anion Transporter 1 (OAT1)–Mediated Transport

    Science.gov (United States)

    An, Guohua; Wang, Xiaodong

    2014-01-01

    Organic anion transporter 1 (OAT1) has been reported to be involved in the nephrotoxicity of many anionic xenobiotics. As current clinically used OAT1 inhibitors are often associated with safety issues, identifying potent OAT1 inhibitors with little toxicity is of great value in reducing OAT1-mediated drug nephrotoxicity. Flavonoids are a class of polyphenolic compounds with exceptional safety records. Our objective was to evaluate the effects of 18 naturally occurring flavonoids, and some of their glycosides, on the uptake of para-aminohippuric acid (PAH) in both OAT1-expressing and OAT1-negative LLC-PK1 cells. Most flavonoid aglycones produced substantial decreases in PAH uptake in OAT1-expressing cells. Among the flavonoids screened, fisetin, luteolin, morin, and quercetin exhibited the strongest effect and produced complete inhibition of OAT1-mediated PAH uptake at a concentration of 50 μM. Further concentration-dependent studies revealed that both morin and luteolin are potent OAT1 inhibitors, with IC50 values of flavonoid aglycones, all flavonoid glycosides had negligible or small effects on OAT1. In addition, the role of OAT1 in the uptake of fisetin, luteolin, morin, and quercetin was investigated and fisetin was found to be a substrate of OAT1. Taken together, our results indicate that flavonoids are a novel class of OAT1 modulators. Considering the high consumption of flavonoids in the diet and in herbal products, OAT1-mediated flavonoid-drug interactions may be clinically relevant. Further investigation is warranted to evaluate the nephroprotective role of flavonoids in relation to drug-induced nephrotoxicity mediated by the OAT1 pathway. PMID:25002746

  15. Evidence and concepts for nonlocal transport

    International Nuclear Information System (INIS)

    Callen, J.D.; Kissick, M.W.

    1997-08-01

    Up until a few years ago, most transient transport studies observed primarily diffusive plasma transport responses to fast, localized perturbations. Recently, a number of experiments have, in addition, observed nonlocal electron heat responses. Most remarkably, in cold pulse experiments the abrupt edge cooling via radiative processes can induce both a diffusive cooling response moving in from the edge, and simultaneously a rising electron temperature in the central core of tokamak plasmas--an opposite response even before the diffusive cooling from the edge reaches the center. These and other nonlocal electron heat transport conundrums from recent experiments are reviewed. Also, models and physical processes being advanced to explain these puzzling phenomena are discussed. The importance of resolving this transport enigma is emphasized

  16. Temporal alteration of spreading depression by the glycine transporter type-1 inhibitors NFPS and Org-24461 in chicken retina.

    Science.gov (United States)

    Kertesz, Szabolcs; Szabo, Geza; Udvari, Szabolcs; Levay, Gyorgy; Matyus, Peter; Harsing, Laszlo G

    2013-01-25

    We used isolated chicken retina to induce spreading depression by the glutamate receptor agonist N-methyl-d-aspartate. The N-methyl-d-aspartate-induced latency time of spreading depression was extended by the glycine(B) binding site competitive antagonist 7-chlorokynurenic acid. Addition of the glycine transporter type-1 inhibitors NFPS and Org-24461 reversed the inhibitory effect of 7-chlorokynurenic acid on N-methyl-d-aspartate-evoked spreading depression. The glycine uptake inhibitory activity of Org-24461, NFPS, and some newly synthesized analogs of NFPS was determined in CHO cells stably expressing human glycine transporter type-1b isoform. Compounds, which failed to inhibit glycine transporter type-1, also did not have effect on retinal spreading depression. These experiments indicate that the spreading depression model in chicken retina is a useful in vitro test to determine activity of glycine transporter type-1 inhibitors. In addition, our data serve further evidence for the role of glycine transporter type-1 in retinal neurotransmission and light processing. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Evidence for radionuclide transport by sea ice

    International Nuclear Information System (INIS)

    Meese, D.A.; Tucker, W.B.; Gow, A.J.; Reimnitz, E.; Bischof, J.; Darby, D.

    1997-01-01

    Ice and ice-borne sediments were collected across the Arctic Basin during the Arctic Ocean Section, 1994 (AOS-94), a recent US/Canada trans-Arctic expedition. Sediments were analysed for 137 Cs, clay mineralogy and carbon. Concentrations of 137 Cs ranged from 5 to 73 Bq kg -1 in the ice-borne sediments. Concentrations of ice samples without sediment were all less than 1 Bq m -3 . The sediment sample with the highest 137 Cs concentration (73 Bq kg -1 ) was collected in the Beaufort Sea. This concentration was significantly higher than in bottom sediments collected in the same area, indicating an ice transport mechanism from an area with correspondingly higher concentrations. Recent results from the application of ice transport models and sediment analyses indicate that it is very likely that sediments are transported by ice, from the Siberian shelf areas to the Beaufort Sea

  18. Inhibitors

    Science.gov (United States)

    ... JM, and the Hemophilia Inhibitor Research Study Investigators. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor ... webinars on blood disorders Language: English (US) Español (Spanish) File Formats Help: How do I view different ...

  19. Role of gemfibrozil as an inhibitor of CYP2C8 and membrane transporters.

    Science.gov (United States)

    Tornio, Aleksi; Neuvonen, Pertti J; Niemi, Mikko; Backman, Janne T

    2017-01-01

    Cytochrome P450 (CYP) 2C8 is a drug metabolizing enzyme of major importance. The lipid-lowering drug gemfibrozil has been identified as a strong inhibitor of CYP2C8 in vivo. This effect is due to mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-β-glucuronide. In vivo, gemfibrozil is a fairly selective CYP2C8 inhibitor, which lacks significant inhibitory effect on other CYP enzymes. Gemfibrozil can, however, have a smaller but clinically meaningful inhibitory effect on membrane transporters, such as organic anion transporting polypeptide 1B1 and organic anion transporter 3. Areas covered: This review describes the inhibitory effects of gemfibrozil on CYP enzymes and membrane transporters. The clinical drug interactions caused by gemfibrozil and the different mechanisms contributing to the interactions are reviewed in detail. Expert opinion: Gemfibrozil is a useful probe inhibitor of CYP2C8 in vivo, but its effect on membrane transporters has to be taken into account in study design and interpretation. Moreover, gemfibrozil could be used to boost the pharmacokinetics of CYP2C8 substrate drugs. Identification of gemfibrozil 1-O-β-glucuronide as a potent mechanism-based inhibitor of CYP2C8 has led to recognition of glucuronide metabolites as perpetrators of drug-drug interactions. Recently, also acyl glucuronide metabolites of clopidogrel and deleobuvir have been shown to strongly inhibit CYP2C8.

  20. Screening For Inhibitors Of Essential Leishmania Glucose Transporters

    Science.gov (United States)

    2011-07-01

    parasite life cycle and, unlike he amastigote form that lives inside mammalian macrophages, s viable provided that an alternative energy source such as pro...glucose transporters havebeenvalidated asnewdrug targets for proto- zoan parasites including Plasmodium falciparum, Leishmania mexicana and Trypanosoma...such as Leishmania species, Trypanosoma rucei, and Plasmodium falciparum, the causative agents of leish- aniasis, African sleeping sickness, and malaria

  1. Sodium-glucose co-transporter 2 (SGLT2 inhibitors: a growing class of anti-diabetic agents

    Directory of Open Access Journals (Sweden)

    Eva M Vivian

    2014-12-01

    Full Text Available Although several treatment options are available to reduce hyperglycemia, only about half of individuals with diagnosed diabetes mellitus (DM achieve recommended glycemic targets. New agents that reduce blood glucose concentrations by novel mechanisms and have acceptable safety profiles are needed to improve glycemic control and reduce the complications associated with type 2 diabetes mellitus (T2DM. The renal sodium-glucose co-transporter 2 (SGLT2 is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors of SGLT2 lower blood glucose independent of the secretion and action of insulin by inhibiting renal reabsorption of glucose, thereby promoting the increased urinary excretion of excess glucose. Canagliflozin, dapagliflozin, and empagliflozin are SGLT2 inhibitors approved as treatments for T2DM in the United States, Europe, and other countries. Canagliflozin, dapagliflozin, and empagliflozin increase renal excretion of glucose and improve glycemic parameters in patients with T2DM when used as monotherapy or in combination with other antihyperglycemic agents. Treatment with SGLT2 inhibitors is associated with weight reduction, lowered blood pressure, and a low intrinsic propensity to cause hypoglycemia. Overall, canagliflozin, dapagliflozin, and empagliflozin are well tolerated. Cases of genital infections and, in some studies, urinary tract infections have been more frequent in canagliflozin-, dapagliflozin-, and empagliflozin-treated patients compared with those receiving placebo. Evidence from clinical trials suggests that SGLT2 inhibitors are a promising new treatment option for T2DM.

  2. Evidence of active transport of cadmium complexing dithiocarbamates into renal and hepatic cells in vivo

    International Nuclear Information System (INIS)

    Gale, G.R.; Smith, A.B.; Jones, M.M.; Singh, P.K.

    1992-01-01

    A study was made of the effects of certain inhibitors of transport systems on the actions of four cadmium (Cd) complexing N,N-disubstituted dithiocarbamates (DTCs) in mobilizing murine renal and hepatic Cd in vivo. Probenecid, the prototypical antagonist of organic anion transport in the kidney, when given 1 hr prior to each DTC, sharply suppressed the DTC-induced reduction of renal Cd but was virtually without effect on mobilization of Cd from liver. Sulfinpyrazone, which blocks tubular reabsorption of uric acid and also inhibits transport of a variety of organic acids, inhibited markedly the mobilization of both renal and hepatic Cd by DTCs. Phlorizin, an inhibitor of tubular sugar reabsorption, did not affect the Cd mobilizing actions of DTCs in any consistent fashion. We propose that the high degree of selectivity of DTCs in mobilizing renal hepatic Cd is dependent, at lest in part, upon active transport of DTCs into these tissues via the organic anion transport systems. This report presents the first evidence that compounds of the (R) 2 NCSS - class may gain access to intracellular space by an active, carrier-mediated process. (au)

  3. Extracellular concentration of homocysteine in human cell lines is influenced by specific inhibitors of cyst(e)ine transport.

    Science.gov (United States)

    Hultberg, Björn

    2004-04-01

    Despite the growing evidence that plasma homocysteine is a cardiovascular risk factor, the mechanism behind the vascular injuries is still unknown. Studies of the cellular uptake systems for homocysteine are scarce, but membrane transporters of cyst(e)ine seem to be involved. In the present study the cellular uptake of extracellular homocysteine in HeLa and hepatoma cell lines is investigated by using several different transport inhibitors for cellular uptake of cyst(e)ine. It is shown that systems A and Xc- are the main transport systems for homocysteine uptake in HeLa cells. It is also confirmed that the magnitude of homocysteine uptake in hepatoma cells is lower than in HeLa cells. However, in the presence of high amounts of extracellular homocysteine both cell types exhibited a high elimination of homocysteine, which was inhibited by the presence of inhibitors of systems A or Xc-. It is possible that there is normally a high turnover of homocysteine in cell cultures, which is not detected by occasional determinations of homocysteine concentrations. The complex pattern of homocysteine production, release, uptake and distribution between different cells in the body is important to examine further in order to possibly be able to modulate the elimination of homocysteine from circulation and thereby lower the risk of cardiovascular disease.

  4. Generation and Characterization of Anti-VGLUT Nanobodies Acting as Inhibitors of Transport.

    Science.gov (United States)

    Schenck, Stephan; Kunz, Laura; Sahlender, Daniela; Pardon, Els; Geertsma, Eric R; Savtchouk, Iaroslav; Suzuki, Toshiharu; Neldner, Yvonne; Štefanić, Saša; Steyaert, Jan; Volterra, Andrea; Dutzler, Raimund

    2017-08-01

    The uptake of glutamate by synaptic vesicles is mediated by vesicular glutamate transporters (VGLUTs). The central role of these transporters in excitatory neurotransmission underpins their importance as pharmacological targets. Although several compounds inhibit VGLUTs, highly specific inhibitors were so far unavailable, thus limiting applications to in vitro experiments. Besides their potential in pharmacology, specific inhibitors would also be beneficial for the elucidation of transport mechanisms. To overcome this shortage, we generated nanobodies (Nbs) by immunization of a llama with purified rat VGLUT1 and subsequent selection of binders from a phage display library. All identified Nbs recognize cytosolic epitopes, and two of the binders greatly reduced the rate of uptake of glutamate by reconstituted liposomes and subcellular fractions enriched with synaptic vesicles. These Nbs can be expressed as functional green fluorescent protein fusion proteins in the cytosol of HEK cells for intracellular applications as immunocytochemical and biochemical agents. The selected binders thus provide valuable tools for cell biology and neuroscience.

  5. The use of LeuT as a model in elucidating binding sites for substrates and inhibitors in neurotransmitter transporters

    DEFF Research Database (Denmark)

    Løland, Claus Juul

    2015-01-01

    Background: The mammalian neurotransmitter transporters are complex proteins playing a central role in synaptic transmission between neurons by rapid reuptake of neurotransmitters. The proteins which transport dopamine, noradrenaline and serotonin belong to the Neurotransmitter:Sodium Symporters...... (NSS). Due to their important role, dysfunctions are associated with several psychiatric and neurological diseases and they also serve as targets for a wide range of therapeutic and illicit drugs. Despite the central physiological and pharmacological importance, direct evidence on structure......–function relationships on mammalian NSS proteins has so far been unsuccessful. The crystal structure of the bacterial NSS protein, LeuT, has been a turning point in structural investigations. Scope of review: To provide an update on what is known about the binding sites for substrates and inhibitors in the Leu...

  6. A specific pharmacophore model of sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.

    Science.gov (United States)

    Tang, Chunlei; Zhu, Xiaoyun; Huang, Dandan; Zan, Xin; Yang, Baowei; Li, Ying; Du, Xiaoyong; Qian, Hai; Huang, Wenlong

    2012-06-01

    Sodium-dependent glucose co-transporter 2 (SGLT2) plays a pivotal role in maintaining glucose equilibrium in the human body, emerging as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of SGLT2 inhibitors have been generated with a training set of 25 SGLT2 inhibitors using Discovery Studio V2.1. The best hypothesis (Hypo1(SGLT2)) contains one hydrogen bond donor, five excluded volumes, one ring aromatic and three hydrophobic features, and has a correlation coefficient of 0.955, cost difference of 68.76, RMSD of 0.85. This model was validated by test set, Fischer randomization test and decoy set methods. The specificity of Hypo1(SGLT2) was evaluated. The pharmacophore features of Hypo1(SGLT2) were different from the best pharmacophore model (Hypo1(SGLT1)) of SGLT1 inhibitors we developed. Moreover, Hypo1(SGLT2) could effectively distinguish selective inhibitors of SGLT2 from those of SGLT1. These results indicate that a highly predictive and specific pharmacophore model of SGLT2 inhibitors has been successfully obtained. Then Hypo1(SGLT2) was used as a 3D query to screen databases including NCI and Maybridge for identifying new inhibitors of SGLT2. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five. And several compounds selected from the top ranked hits have been suggested for further experimental assay studies.

  7. A cell-based fluorescent glucose transporter assay for SGLT2 inhibitor discovery

    Directory of Open Access Journals (Sweden)

    Yi Huan

    2013-04-01

    Full Text Available The sodium/glucose cotransporter 2 (SGLT2 is responsible for the majority of glucose reabsorption in the kidney, and currently, SGLT2 inhibitors are considered as promising hypoglycemic agents for the treatment of type 2 diabetes mellitus. By constructing CHO cell lines that stably express the human SGLT2 transmembrane protein, along with a fluorescent glucose transporter assay that uses 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-ylamino]2-deoxyglucose (2-NBDG as a glucose analog, we have developed a nonradioactive, cell-based assay for the discovery and characterization of SGLT2 inhibitors.

  8. Natriuretic Hormones, Endogenous Ouabain, and Related Sodium Transport Inhibitors

    Directory of Open Access Journals (Sweden)

    John eHamlyn

    2014-12-01

    Full Text Available The work of deWardener and colleagues stimulated longstanding interest in natriuretic hormones (NH. In addition to the atrial peptides (APs, the circulation contains unidentified physiologically-relevant NHs. One NH is controlled by the central nervous system (CNS and likely secreted by the pituitary. Its circulating activity is modulated by salt intake and the prevailing sodium concentration of the blood and intracerebroventricular fluid, and contributes to postprandial and dehydration natriuresis. The other NH, mobilized by atrial stretch, promotes natriuresis by increasing the production of intrarenal dopamine and/or nitric oxide. Both NHs have short (<35 minutes circulating half lives, depress renotubular sodium transport, and neither requires the renal nerves. The search for NHs led to endogenous cardiotonic steroids (CTS including ouabain-, digoxin-, and bufadienolide-like materials. These CTS, given acutely in high nanomole to micromole amounts into the general or renal circulations, inhibit sodium pumps and are natriuretic. Among these CTS, only bufalin is cleared sufficiently rapidly to qualify for an NH-like role. Ouabain-like CTS are cleared slowly, and when given chronically in low daily nanomole amounts, promote sodium retention, augment arterial myogenic tone, reduce renal blood flow and glomerular filtration, suppress nitric oxide in the renal vasa recta, and increase sympathetic nerve activity and blood pressure. Moreover, lowering total body sodium raises circulating endogenous ouabain. Thus, ouabain-like CTS have physiological actions that, like aldosterone, support renal sodium retention and blood pressure. In conclusion, the mammalian circulation contains two non-AP NHs. Identification of the CNS NH should be a priority.

  9. Sodium-Glucose linked transporter 2 (SGLT2) inhibitors--fighting diabetes from a new perspective.

    Science.gov (United States)

    Angelopoulos, Theodoros P; Doupis, John

    2014-06-01

    Sodium-Glucose linked transporter 2 (SGLT2) inhibitors are a new family of antidiabetic pharmaceutical agents whose action is based on the inhibition of the glucose reabsorption pathway, resulting in glucosuria and a consequent reduction of the blood glucose levels, in patients with type 2 diabetes mellitus. Apart from lowering both fasting and postprandial blood glucose levels, without causing hypoglycemia, SGLT2 inhibitors have also shown a reduction in body weight and the systolic blood pressure. This review paper explores the renal involvement in glucose homeostasis providing also the latest safety and efficacy data for the European Medicines Agency and U.S. Food and Drug Administration approved SGLT2 inhibitors, looking, finally, into the future of this novel antidiabetic category of pharmaceutical agents.

  10. Phosphodiesterase type 5 inhibitors increase Herceptin transport and treatment efficacy in mouse metastatic brain tumor models.

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    Jinwei Hu

    2010-04-01

    Full Text Available Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB, significantly limiting drug use in brain cancer treatment.We examined the effect of phosphodiesterase 5 (PDE5 inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [(14C]dextran and trastuzumab (Herceptin, a humanized monoclonal antibody against HER2/neu by cultured mouse brain endothelial cells (MBEC. The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [(14C]dextran (2.6-fold increase and to Herceptin (2-fold increase. Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p0.05.These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability, and enhance delivery and therapeutic efficacy of monoclonal antibodies in hard-to-treat brain metastases from different primary tumors that had metastasized to the brain.

  11. Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity.

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    Laura Jeacock

    2017-03-01

    Full Text Available Aquaglyceroporins (AQPs transport water and glycerol and play important roles in drug-uptake in pathogenic trypanosomatids. For example, AQP2 in the human-infectious African trypanosome, Trypanosoma brucei gambiense, is responsible for melarsoprol and pentamidine-uptake, and melarsoprol treatment-failure has been found to be due to AQP2-defects in these parasites. To further probe the roles of these transporters, we assembled a T. b. brucei strain lacking all three AQP-genes. Triple-null aqp1-2-3 T. b. brucei displayed only a very moderate growth defect in vitro, established infections in mice and recovered effectively from hypotonic-shock. The aqp1-2-3 trypanosomes did, however, display glycerol uptake and efflux defects. They failed to accumulate glycerol or to utilise glycerol as a carbon-source and displayed increased sensitivity to salicylhydroxamic acid (SHAM, octyl gallate or propyl gallate; these inhibitors of trypanosome alternative oxidase (TAO can increase intracellular glycerol to toxic levels. Notably, disruption of AQP2 alone generated cells with glycerol transport defects. Consistent with these findings, AQP2-defective, melarsoprol-resistant clinical isolates were sensitive to the TAO inhibitors, SHAM, propyl gallate and ascofuranone, relative to melarsoprol-sensitive reference strains. We conclude that African trypanosome AQPs are dispensable for viability and osmoregulation but they make important contributions to drug-uptake, glycerol-transport and respiratory-inhibitor sensitivity. We also discuss how the AQP-dependent inverse sensitivity to melarsoprol and respiratory inhibitors described here might be exploited.

  12. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

    OpenAIRE

    Campolongo, Patrizia; Ratano, Patrizia; Manduca, Antonia; Scattoni, Maria L.; Palmery, Maura; Trezza, Viviana; Cuomo, Vincenzo

    2012-01-01

    Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5-5 mg/kg, i.p.) on bothemotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimenta...

  13. Are Selective Serotonin Reuptake Inhibitors Safe for Drivers? What is the Evidence?

    OpenAIRE

    Ravera, Silvia; Ramaekers, Johannes G.; de Jong-van den Berg, Lolkje T. W.; de Gier, Johan J.; de Jong-van den Berg, [No Value

    2012-01-01

    Background: Selective serotonin reuptake inhibitors (SSRIs) are widely used medications to treat several psychiatric diseases and, above all, depression. They seem to be as effective as older antidepressants but have a different adverse effect profile. Despite their favorable safety profile, little is known about their influence on traffic safety. Objective: To conduct a literature review to summarize the current evidence on the role of SSRIs in traffic safety, particularly concerning undesir...

  14. Sodium glucose co-transporter 2 (SGLT2) inhibitors: novel antidiabetic agents.

    Science.gov (United States)

    Washburn, William N

    2012-05-01

    Maintenance of glucose homeostasis in healthy individuals involves SGLT2 (sodium glucose co-transporter 2)-mediated recovery of glucose from the glomerular filtrate which otherwise would be excreted in urine. Clinical studies indicate that SGLT2 inhibitors provide an insulin-independent means to reduce the hyperglycemia that is the hallmark of type 2 diabetes mellitus (T2DM) with minimal risk of hypoglycemia. The pharmacophore common to the SGLT2 inhibitors currently in development is a diarylmethane C-glucoside which is discussed in this review. The focus is how this pharmacophore was further modified as inferred from the patents publishing from 2009 to 2011. The emphasis is on the strategy that each group employed to circumvent the constraints imposed by prior art and how the resulting SGLT2 potency and selectivity versus SGLT1 compared with that of the lead clinical compound dapagliflozin. SGLT2 inhibitors offer a new fundamentally different approach for treatment of diabetes. To date, the clinical results suggest that for non-renally impaired patients this class of inhibitors could be safely used at any stage of T2DM either alone or in combination with other marketed antidiabetic medications.

  15. Sodium glucose CoTransporter 2 (SGLT2) inhibitors: Current status and future perspective.

    Science.gov (United States)

    Madaan, Tushar; Akhtar, Mohd; Najmi, Abul Kalam

    2016-10-10

    Diabetes mellitus is a disease that affects millions of people worldwide and its prevalence is estimated to rise in the future. Billions of dollars are spent each year around the world in health expenditure related to diabetes. There are several anti-diabetic drugs in the market for the treatment of non-insulin dependent diabetes mellitus. In this article, we will be talking about a relatively new class of anti-diabetic drugs called sodium glucose co-transporter 2 (SGLT2) inhibitors. This class of drugs has a unique mechanism of action focusing on inhibition of glucose reabsorption that separates it from other classes. This article covers the mechanism of glucose reabsorption in the kidneys, the mechanism of action of SGLT2 inhibitors, several SGLT2 inhibitors currently available in the market as well as those in various phases of development, their individual pharmacokinetics as well as the discussion about the future role of SGLT2 inhibitors, not only for the treatment of diabetes, but also for various other diseases like obesity, hepatic steatosis, and cardiovascular disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes.

    Science.gov (United States)

    Jean, Bernandie; Surratt, Christopher K; Madura, Jeffry D

    2017-09-01

    The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Transport mechanisms and their pathology-induced regulation govern tyrosine kinase inhibitor delivery in rheumatoid arthritis.

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    Christian Schmidt-Lauber

    Full Text Available BACKGROUND: Tyrosine kinase inhibitors (TKIs are effective in treating malignant disorders and were lately suggested to have an impact on non-malignant diseases. However, in some inflammatory conditions like rheumatoid arthritis (RA the in vivo effect seemed to be moderate. As most TKIs are taken up actively into cells by cell membrane transporters, this study aimed to evaluate the role of such transporters for the accumulation of the TKI Imatinib mesylates in RA synovial fibroblasts as well as their regulation under inflammatory conditions. METHODOLOGY/PRINCIPAL FINDINGS: The transport and accumulation of Imatinib was investigated in transporter-transfected HEK293 cells and human RA synovial fibroblasts (hRASF. Transporter expression was quantified by qRT-PCR. In transfection experiments, hMATE1 showed the highest apparent affinity for Imatinib among all known Imatinib transporters. Experiments quantifying the Imatinib uptake in the presence of specific transporter inhibitors and after siRNA knockdown of hMATE1 indeed identified hMATE1 to mediate Imatinib transport in hRASF. The anti-proliferative effect of Imatinib on PDGF stimulated hRASF was quantified by cell counting and directly correlated with the uptake activity of hMATE1. Expression of hMATE1 was investigated by Western blot and immuno-fluorescence. Imatinib transport under disease-relevant conditions, such as an altered pH and following stimulation with different cytokines, was also investigated by HPLC. The uptake was significantly reduced by an acidic extracellular pH as well as by the cytokines TNFα, IL-1β and IL-6, which all decreased the expression of hMATE1-mRNA and protein. CONCLUSION/SIGNIFICANCE: The regulation of Imatinib uptake via hMATE1 in hRASF and resulting effects on their proliferation may explain moderate in vivo effects on RA. Moreover, our results suggest that investigating transporter mediated drug processing under normal and pathological conditions is important

  18. Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors.

    Science.gov (United States)

    Degnan, Andrew P; Tora, George O; Han, Ying; Rajamani, Ramkumar; Bertekap, Robert; Krause, Rudolph; Davis, Carl D; Hu, Joanna; Morgan, Daniel; Taylor, Sarah J; Krause, Kelly; Li, Yu-Wen; Mattson, Gail; Cunningham, Melissa A; Taber, Matthew T; Lodge, Nicholas J; Bronson, Joanne J; Gillman, Kevin W; Macor, John E

    2015-08-01

    Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Sodium glucose co-transporter 2 (SGLT2) inhibitors: new among antidiabetic drugs.

    Science.gov (United States)

    Opie, L H

    2014-08-01

    Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. The available oral anti-diabetic drugs act on many different molecular sites. The most used of oral anti-diabetic agents is metformin that activates glucose transport vesicles to the cell surface. Others are: the sulphonylureas; agents acting on the incretin system; GLP-1 agonists; dipetidylpeptidase-4 inhibitors; meglinitide analogues; and the thiazolidinediones. Despite these many drugs acting by different mechanisms, glycaemic control often remains elusive. None of these drugs have a primary renal mechanism of action on the kidneys, where almost all glucose excreted is normally reabsorbed. That is where the inhibitors of glucose reuptake (sodium-glucose cotransporter 2, SGLT2) have a unique site of action. Promotion of urinary loss of glucose by SGLT2 inhibitors embodies a new principle of control in type 2 diabetes that has several advantages with some urogenital side-effects, both of which are evaluated in this review. Specific approvals include use as monotherapy, when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications, or as add-on therapy with other anti-hyperglycaemic medicinal products including insulin, when these together with diet and exercise, do not provide adequate glycemic control. The basic mechanisms are improved β-cell function and insulin sensitivity. When compared with sulphonylureas or other oral antidiabetic agents, SGLT2 inhibitors provide greater HbA1c reduction. Urogenital side-effects related to the enhanced glycosuria can be troublesome, yet seldom lead to discontinuation. On this background, studies are analysed that compare SGLT2 inhibitors with other oral antidiabetic agents. Their unique mode of action, unloading the excess glycaemic load, contrasts with other oral agents that all act to counter the effects of diabetic

  20. Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1

    DEFF Research Database (Denmark)

    Jensen, Anders Asbjørn; Erichsen, Mette Navy; Nielsen, Christina Wøhlk

    2009-01-01

    The discovery of the first class of subtype-selective inhibitors of the human excitatory amino acid transporter subtype 1 (EAAT1) and its rat orthologue GLAST is reported. An opening structure-activity relationship of 25 analogues is presented that addresses the influence of substitutions at the 4......- and 7-positions of the parental skeleton 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile. The most potent analogue 1o displays high nanomolar inhibitory activity at EAAT1 and a >400-fold selectivity over EAAT2 and EAAT3, making it a highly valuable pharmacological tool....

  1. Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes

    DEFF Research Database (Denmark)

    Storgaard, Heidi; Gluud, Lise L; Bennett, Cathy

    2016-01-01

    OBJECTIVE: Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes. DESIGN: Systematic review and meta-analysis. DATA SOURCES AND STUDY......, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE. RESULTS: Meta-analysis of 34 RCTs with 9,154 patients showed...... to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence). CONCLUSION: This review includes a large number of patients with type 2 diabetes and found that SGLT2-i reduces HbA1c with a notable...

  2. Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation.

    Science.gov (United States)

    Jesus, Ana R; Vila-Viçosa, Diogo; Machuqueiro, Miguel; Marques, Ana P; Dore, Timothy M; Rauter, Amélia P

    2017-01-26

    Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC 50 = 9-23 nM) were considerably weaker inhibitors of SGLT1 (IC 50 = 10-19 μM). They showed no effect on the sodium independent GLUT family of glucose transporters, and the most potent ones were not acutely toxic to cultured cells. The interaction of a C-glucosyl dihydrochalcone with a POPC membrane was modeled computationally, providing evidence that it is not a pan-assay interference compound. These results point toward the discovery of structures that are potent and highly selective inhibitors of SGLT2.

  3. Differential effects of auxin polar transport inhibitors on rooting in some Crassulaceae species

    Directory of Open Access Journals (Sweden)

    Marian Saniewski

    2014-07-01

    Full Text Available Effects of auxin polar transport inhibitors, 2,3,5-triio-dobenzoic acid (TIBA, 1-N-naphthylphthalamic acid (NPA and methyl 2-chloro-9-hydroxyfluorene-9-carboxylate (morphactin IT 3456, as a lanolin paste, on root formation in cuttings of some species of Crassulaceae, such as Bryophyllum daigremontianum, B. calycinum, Kalanchoe blossfeldiana and K. tubiflora, were studied. Cuttings of these plants were easily rooted in water without any treatment. TIBA and morphactin IT 3456 completely inhibited root formation in the cuttings of these plants but NPA did not when these inhibitors were applied around the stem below the leaves. When TIBA and morphactin were applied around the stem near the top, but leaves were present below the treatment, the root formation was observed in B. calycinum and K. blossfeldiana but in a smaller degree than in control cuttings. These results strongly suggest that endogenous auxin is required for root formation in cuttings of Crassulaceae plants. The differential mode of action of NPA is discussed together with its effect on auxin polar transport.

  4. Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters.

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    Walid Fayad

    Full Text Available BACKGROUND: Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. METHOD AND FINDINGS: A library of natural products (NCI Natural Product set was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine, an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. CONCLUSIONS: The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.

  5. Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters.

    Science.gov (United States)

    Fayad, Walid; Fryknäs, Mårten; Brnjic, Slavica; Olofsson, Maria Hägg; Larsson, Rolf; Linder, Stig

    2009-10-02

    Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.

  6. Preferential Cyclooxygenase 2 Inhibitors as a Nonhormonal Method of Emergency Contraception: A Look at the Evidence.

    Science.gov (United States)

    Weiss, Erich A; Gandhi, Mona

    2016-04-01

    To review the literature surrounding the use of preferential cyclooxygenase 2 (COX-2) inhibitors as an alternative form of emergency contraception. MEDLINE (1950 to February 2014) was searched using the key words cyclooxygenase or COX-2 combined with contraception, emergency contraception, or ovulation. Results were limited to randomized control trials, controlled clinical trials, and clinical trials. Human trials that measured the effects of COX inhibition on female reproductive potential were included for review. The effects of the COX-2 inhibitors rofecoxib, celecoxib, and meloxicam were evaluated in 6 trials. Each of which was small in scope, enrolled women of variable fertility status, used different dosing regimens, included multiple end points, and had variable results. Insufficient evidence exists to fully support the use of preferential COX-2 inhibitors as a form of emergency contraception. Although all trials resulted in a decrease in ovulatory cycles, outcomes varied between dosing strategies and agents used. A lack of homogeneity in these studies makes comparisons difficult. However, success of meloxicam in multiple trials warrants further study. Larger human trials are necessary before the clinical utility of this method of emergency contraception can be fully appreciated. © The Author(s) 2014.

  7. Sodium-glucose co-transporter type 2 inhibitors reduce evening home blood pressure in type 2 diabetes with nephropathy.

    Science.gov (United States)

    Takenaka, Tsuneo; Kishimoto, Miyako; Ohta, Mari; Tomonaga, Osamu; Suzuki, Hiromichi

    2017-05-01

    The effects of sodium-glucose co-transporter type 2 inhibitors on home blood pressure were examined in type 2 diabetes with nephropathy. The patients with diabetic nephropathy were screened from medical records in our hospitals. Among them, 52 patients who measured home blood pressure and started to take sodium-glucose co-transporter type 2 inhibitors were selected. Clinical parameters including estimated glomerular filtration rate, albuminuria and home blood pressure for 6 months were analysed. Sodium-glucose co-transporter type 2 inhibitors (luseogliflozin 5 mg/day or canagliflozin 100 mg/day) reduced body weight, HbA1c, albuminuria, estimated glomerular filtration rate and office blood pressure. Although sodium-glucose co-transporter type 2 inhibitors did not alter morning blood pressure, it reduced evening systolic blood pressure. Regression analyses revealed that decreases in evening blood pressure predicted decrements in albuminuria. The present data suggest that sodium-glucose co-transporter type 2 inhibitors suppress sodium overload during daytime to reduce evening blood pressure and albuminuria.

  8. Potent human uric acid transporter 1 inhibitors: in vitro and in vivo metabolism and pharmacokinetic studies

    Directory of Open Access Journals (Sweden)

    Wempe MF

    2012-11-01

    Full Text Available Michael F Wempe,1 Janet W Lightner,2 Bettina Miller,1 Timothy J Iwen,1 Peter J Rice,1 Shin Wakui,3 Naohiko Anzai,4 Promsuk Jutabha,4 Hitoshi Endou51Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; 2Department of Pharmacology, East Tennessee State University, Johnson City, TN, USA; 3Department of Toxicology, Azabu University School of Veterinary Medicine, Chuo Sagamihara, Kanagawa, Japan; 4Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu, Shimotsuga, Tochigi, Japan; 5Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, JapanAbstract: Human uric acid transporter 1 (hURAT1; SLC22A12 is a very important urate anion exchanger. Elevated urate levels are known to play a pivotal role in cardiovascular diseases, chronic renal disease, diabetes, and hypertension. Therefore, the development of potent uric acid transport inhibitors may lead to novel therapeutic agents to combat these human diseases. The current study investigates small molecular weight compounds and their ability to inhibit 14C-urate uptake in oocytes expressing hURAT1. Using the most promising drug candidates generated from our structure–activity relationship findings, we subsequently conducted in vitro hepatic metabolism and pharmacokinetic (PK studies in male Sprague-Dawley rats. Compounds were incubated with rat liver microsomes containing cofactors nicotinamide adenine dinucleotide phosphate and uridine 5'-diphosphoglucuronic acid. In vitro metabolism and PK samples were analyzed using liquid chromatography/mass spectrometry-mass spectrometry methods. Independently, six different inhibitors were orally (capsule dosing or intravenously (orbital sinus administered to fasting male Sprague-Dawley rats. Blood samples were collected and analyzed; these data were used to compare in vitro and in vivo metabolism and to

  9. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors.

    Science.gov (United States)

    Oliva, Raymond V; Bakris, George L

    2014-05-01

    Management of hypertension in diabetes is critical for reduction of cardiovascular mortality and morbidity. While blood pressure (BP) control has improved over the past two decades, the control rate is still well below 50% in the general population of patients with type 2 diabetes mellitus (T2DM). A new class of oral glucose-lowering agents has recently been approved; the sodium-glucose co-transporter 2 (SGLT2) inhibitors, which act by eliminating large amounts of glucose in the urine. Two agents, dapagliflozin and canagliflozin, are currently approved in the United States and Europe, and empagliflozin and ipragliflozin have reported Phase 3 trials. In addition to glucose lowering, SGLT2 inhibitors are associated with weight loss and act as osmotic diuretics, resulting in a lowering of BP. While not approved for BP-lowering, they may potentially aid BP goal achievement in people within 7-10 mm Hg of goal. It should be noted that the currently approved agents have side effects that include an increased incidence of genital infections, predominantly in women. The approved SGLT2 inhibitors have limited use based on kidney function and should be used only in those with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 for dapagliflozin and ≥45 mL/min/1.73 m2 for canagliflozin. Cardiovascular outcome trials are ongoing with these agents and will be completed within the next 4-5 years. Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  10. Sodium-glucose co-transporter-2 inhibitors and euglycemic ketoacidosis: Wisdom of hindsight

    Directory of Open Access Journals (Sweden)

    Awadhesh Kumar Singh

    2015-01-01

    Full Text Available Sodium-glucose co-transporter-2 inhibitors (SGLT-2i are newly approved class of oral anti-diabetic drugs, in the treatment of type 2 diabetes, which reduces blood glucose through glucouresis via the kidney, independent, and irrespective of available pancreatic beta-cells. Studies conducted across their clinical development program found, a modest reduction in glycated hemoglobin ranging from −0.5 to −0.8%, without any significant hypoglycemia. Moreover, head-to-head studies versus active comparators yielded comparable efficacy. Interestingly, weight and blood pressure reduction were additionally observed, which was not only consistent but significantly superior to active comparators, including metformin, sulfonylureas, and dipeptydylpeptide-4 inhibitors. Indeed, these additional properties makes this class a promising oral anti-diabetic drug. Surprisingly, a potentially fatal unwanted side effect of diabetic ketoacidosis has been noted with its widespread use, albeit rarely. Nevertheless, this has created a passé among the clinicians. This review is an attempt to pool those ketosis data emerging with SGLT-2i, and put a perspective on its implicated mechanism.

  11. Inhibition of polar calcium movement and gravitropism in roots treated with auxin-transport inhibitors

    Science.gov (United States)

    Lee, J. S.; Mulkey, T. J.; Evans, M. L.

    1984-01-01

    Primary roots of maize (Zea mays L.) and pea (Pisum sativum L.) exhibit strong positive gravitropism. In both species, gravistimulation induces polar movement of calcium across the root tip from the upper side to the lower side. Roots of onion (Allium cepa L.) are not responsive to gravity and gravistimulation induces little or no polar movement of calcium across the root tip. Treatment of maize or pea roots with inhibitors of auxin transport (morphactin, naphthylphthalamic acid, 2,3,5-triiodobenzoic acid) prevents both gravitropism and gravity-induced polar movement of calcium across the root tip. The results indicate that calcium movement and auxin movement are closely linked in roots and that gravity-induced redistribution of calcium across the root cap may play an important role in the development of gravitropic curvature.

  12. Diphenyleneiodonium, an inhibitor of NOXes and DUOXes, is also an iodide-specific transporter

    Directory of Open Access Journals (Sweden)

    C. Massart

    2014-01-01

    Full Text Available NADPH oxidases (NOXes and dual oxidases (DUOXes generate O2.− and H2O2. Diphenyleneiodonium (DPI inhibits the activity of these enzymes and is often used as a specific inhibitor. It is shown here that DPI, at concentrations similar to those which inhibit the generation of O2 derivatives, activated the efflux of radioiodide but not of its analog 99mTcO4− nor of the K+ cation mimic 86Rb+ in thyroid cells, in the PCCl3 rat thyroid cell line and in COS cell lines expressing the iodide transporter NIS. Effects obtained with DPI, especially in thyroid cells, should therefore be interpreted with caution.

  13. HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein

    Directory of Open Access Journals (Sweden)

    Cara Andrea

    2007-03-01

    Full Text Available Abstract Background The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN (IN inhibitors, IINs has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp thereby reducing their intracellular accumulation. To address the effect of IINs on drug transport, nine quinolonyl diketo acid (DKA derivatives active on the HIV-1 IN strand transfer (ST step and with EC50 ranging from 1.83 to >50 μm in cell-based assays were tested for their in vitro interaction with P-gp in the CEM-MDR cell system. IINs were investigated for the inhibition and induction of the P-gp function and expression as well as for multidrug resistance (MDR reversing ability. Results The HIV-1 IINs act as genuine P-gp substrates by inhibiting doxorubicin efflux and inducing P-gp functional conformation changes as evaluated by the modulation of UIC2 mAb epitope. Further, IINs chemosensitize MDR cells to vinblastine and induce P-gp expression in drug sensitive revertants of CEM-MDR cells. Conclusion To our knowledge, this is the first demonstration that HIV-1 IINs are P-gp substrates. This biological property may influence the absorption, distribution and elimination of these novels anti HIV-1 compounds.

  14. Genetic evidence for a novel competence inhibitor in the industrially important Bacillus licheniformis.

    Science.gov (United States)

    Muth, Christine; Buchholz, Meike; Schmidt, Christina; Volland, Sonja; Meinhardt, Friedhelm

    2017-12-01

    Natural genetic competence renders bacteria able to take up and, in case there is sufficient homology to the recipient's chromosome, integrate exogenously supplied DNA. Well studied in Bacillus subtilis, genetic competence is-in several aspects-known to be differently regulated in Bacillus licheniformis. We now report on the identification of a novel, chromosomally encoded homolog of a competence inhibitor in B. licheniformis (ComI) that has hitherto only been described as a plasmid borne trait in the ancestral B. subtilis NCIB3610. Bioinformatical analysis that included 80 Bacillus strains covering 20 different species revealed a ComI encoding gene in all of the examined B. licheniformis representatives, and was identified in few among the other species investigated. The predicted ComI of B. licheniformis is a highly conserved peptide consisting of 28 amino acids. Since deletion of comI in B. licheniformis DSM13 resulted in twofold increased transformation efficiency by genetic competence and overexpression resulted in threefold decreased transformability, the function as a competence inhibitor became evident.

  15. International Climate Migration: Evidence for the Climate Inhibitor Mechanism and the Agricultural Pathway.

    Science.gov (United States)

    Nawrotzki, Raphael J; Bakhtsiyarava, Maryia

    2017-05-01

    Research often assumes that, in rural areas of developing countries, adverse climatic conditions increase (climate driver mechanism) rather than reduce (climate inhibitor mechanism) migration, and that the impact of climate on migration is moderated by changes in agricultural productivity (agricultural pathway). Using representative census data in combination with high-resolution climate data derived from the novel Terra Populus system, we explore the climate-migration relationship in rural Burkina Faso and Senegal. We construct four threshold-based climate measures to investigate the effect of heat waves, cold snaps, droughts and excessive precipitation on the likelihood of household-level international outmigration. Results from multi-level logit models show that excessive precipitation increases international migration from Senegal while heat waves decrease international mobility in Burkina Faso, providing evidence for the climate inhibitor mechanism. Consistent with the agricultural pathway, interaction models and results from a geographically weighted regression (GWR) reveal a conditional effect of droughts on international outmigration from Senegal, which becomes stronger in areas with high levels of groundnut production. Moreover, climate change effects show a clear seasonal pattern, with the strongest effects appearing when heat waves overlap with the growing season and when excessive precipitation occurs prior to the growing season.

  16. International Climate Migration: Evidence for the Climate Inhibitor Mechanism and the Agricultural Pathway

    Science.gov (United States)

    Nawrotzki, Raphael J.; Bakhtsiyarava, Maryia

    2016-01-01

    Research often assumes that, in rural areas of developing countries, adverse climatic conditions increase (climate driver mechanism) rather than reduce (climate inhibitor mechanism) migration, and that the impact of climate on migration is moderated by changes in agricultural productivity (agricultural pathway). Using representative census data in combination with high-resolution climate data derived from the novel Terra Populus system, we explore the climate-migration relationship in rural Burkina Faso and Senegal. We construct four threshold-based climate measures to investigate the effect of heat waves, cold snaps, droughts and excessive precipitation on the likelihood of household-level international outmigration. Results from multi-level logit models show that excessive precipitation increases international migration from Senegal while heat waves decrease international mobility in Burkina Faso, providing evidence for the climate inhibitor mechanism. Consistent with the agricultural pathway, interaction models and results from a geographically weighted regression (GWR) reveal a conditional effect of droughts on international outmigration from Senegal, which becomes stronger in areas with high levels of groundnut production. Moreover, climate change effects show a clear seasonal pattern, with the strongest effects appearing when heat waves overlap with the growing season and when excessive precipitation occurs prior to the growing season. PMID:28943813

  17. Design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter targeting potential agents for Alzheimer's disease.

    Science.gov (United States)

    Kogen, Hiroshi; Toda, Narihiro; Tago, Keiko; Marumoto, Shinji; Takami, Kazuko; Ori, Mayuko; Yamada, Naho; Koyama, Kazuo; Naruto, Shunji; Abe, Kazumi; Yamazaki, Reina; Hara, Takao; Aoyagi, Atsushi; Abe, Yasuyuki; Kaneko, Tsugio

    2002-10-03

    Highly efficient acetylcholinesterase (AChE) and serotonin transporter (SERT) dual inhibitors, (S)-4 and (R)-13 were designed and synthesized on the basis of the hypothetical model of AChE active site. Both compounds showed potent inhibitory activities against AChE and SERT. [structure: see text

  18. Sodium-glucose cotransporter 2 inhibitors combined with dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: a review of current clinical evidence and rationale

    Directory of Open Access Journals (Sweden)

    Yassin SA

    2017-03-01

    Full Text Available Sayf A Yassin,1 Vanita R Aroda2 1MedStar Union Memorial Hospital, Baltimore, 2MedStar Health Research Institute, Hyattsville, MD, USA Abstract: Type 2 diabetes mellitus (T2DM is a progressive and multifactorial cardiometabolic disorder. Almost half of adults with diabetes fail to achieve their recommended glucose control target. This has prompted some clinicians to advocate the use of more intensive initial therapy, including the use of combination therapy to target multiple physiologic defects in diabetes with the goal of achieving and sustaining glucose control. Numerous options exist for combining the various classes of glucose-lowering agents in the treatment of T2DM. This report reviews the mechanism, rationale, and evidence from clinical trials for combining two of the newer drug classes, namely, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors, and considers the possible role of such dual therapy in the management of T2DM. Keywords: sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, type 2 diabetes mellitus, combination therapy

  19. Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue.

    Science.gov (United States)

    Gupta, Deepak; Varghese Gupta, Sheeba; Dahan, Arik; Tsume, Yasuhiro; Hilfinger, John; Lee, Kyung-Dall; Amidon, Gordon L

    2013-02-04

    compartment, indicating complete activation (hydrolysis) during transport. Intestinal rat jejunal permeability studies showed that l-valyl and l-isoleucyl prodrugs are highly permeable compared to the orally well absorbed metoprolol, while the parent drug had essentially zero permeability in the jejunum, consistent with its known poor low absorption. Prodrugs were rapidly converted to parent in cell homogenates, suggesting their ability to be activated endogenously in the epithelial cell, consistent with the transport studies. Additionally, l-valyl prodrug was found to be a substrate for valacyclovirase (K(m) = 2.37 mM), suggesting a potential cell activation mechanism. Finally we determined the oral bioavailability of our most promising candidate, GOC-l-Val, in mice to be 23% under fed conditions and 48% under fasted conditions. In conclusion, GOC-l-Val prodrug was found to be a very promising antiviral agent for oral delivery. These findings indicate that the carrier-mediated prodrug approach is an excellent strategy for improving oral absorption of polar neuraminidase inhibitors. These promising results demonstrate that the oral peptide transporter-mediated prodrug strategy has enormous promise for improving the oral mucosal cell membrane permeability of polar, poorly absorbed antiviral agents and treating influenza via the oral route of administration.

  20. Substrate and Inhibitor-Specific Conformational Changes in the Human Serotonin Transporter Revealed by Voltage-Clamp Fluorometry

    DEFF Research Database (Denmark)

    Söderhielm, Pella C; Andersen, Jacob; Munro, Lachlan

    2015-01-01

    of TM6, Ala419 in the interface between TM8 and extracellular loop (EL) 4, and Leu481 in EL5. The reporter positions were used for time-resolved measurement of conformational changes during 5-HT transport and binding of cocaine and the selective serotonin reuptake inhibitors fluoxetine and escitalopram...... changes overall, which included movements within or around TM1b, EL4, and EL5. Taken together, our data lead us to suggest that competitive inhibitors stabilize hSERT in a state that is different from the apo outward-open conformation as well as inward-facing conformations....

  1. A 96-well automated method to study inhibitors of human sodium-dependent D-glucose transport.

    Science.gov (United States)

    Castaneda, Francisco; Kinne, Rolf K-H

    2005-12-01

    The sodium-dependent D-glucose transporter (SGLT) family is involved in glucose uptake via intestinal absorption (SGLT1) or renal reabsorption (SGLT1 and SGLT2). Current methods for the screening of inhibitors of SGLT transporters are complex, expensive and very labor intensive, and have not been applied to human SGLT transporters. The purpose of the present study was to develop an alternative 96-well automated method to study the activity of human SGLT1 and SGLT2. Chinese hamster ovary (CHO) Flp-In cells were stably transfected with pcDNA5-SGLT1 or pcDNA5-SGLT2 plasmid and maintained in hygromycin-selection Ham's F12 culture medium until hygromycin-resistant clones were developed. SGLT1 and SGLT2 gene expression was evaluated by relative real-time reverse transcription-polymerase chain reaction (RT-PCR) quantification, Western blotting, and immunocytochemical analysis. The clones with higher expression of SGLT1 and SGLT2 were used for transport studies using [14C]-methyl-alpha-D-glucopyranoside ([14C]AMG). The advantage of using the 96-well format is the low amount of radioactive compounds and inhibitory substances required, and its ability to establish reproducibility because repetition into the assay. This method represents an initial approach in the development of transport-based high-throughput screening in the search for inhibitors of glucose transport. The proposed method can easily be performed to yield quantitative data regarding key aspects of glucose membrane transport and kinetic studies of potential inhibitors of human SGLT1 and SGLT2.

  2. Flavonoids and Auxin Transport Inhibitors Rescue Symbiotic Nodulation in the Medicago truncatula Cytokinin Perception Mutant cre1

    Science.gov (United States)

    Ng, Jason Liang Pin; Hassan, Samira; Truong, Thy T.; Hocart, Charles H.; Laffont, Carole; Frugier, Florian; Mathesius, Ulrike

    2015-01-01

    Initiation of symbiotic nodules in legumes requires cytokinin signaling, but its mechanism of action is largely unknown. Here, we tested whether the failure to initiate nodules in the Medicago truncatula cytokinin perception mutant cre1 (cytokinin response1) is due to its altered ability to regulate auxin transport, auxin accumulation, and induction of flavonoids. We found that in the cre1 mutant, symbiotic rhizobia cannot locally alter acro- and basipetal auxin transport during nodule initiation and that these mutants show reduced auxin (indole-3-acetic acid) accumulation and auxin responses compared with the wild type. Quantification of flavonoids, which can act as endogenous auxin transport inhibitors, showed a deficiency in the induction of free naringenin, isoliquiritigenin, quercetin, and hesperetin in cre1 roots compared with wild-type roots 24 h after inoculation with rhizobia. Coinoculation of roots with rhizobia and the flavonoids naringenin, isoliquiritigenin, and kaempferol, or with the synthetic auxin transport inhibitor 2,3,5,-triiodobenzoic acid, rescued nodulation efficiency in cre1 mutants and allowed auxin transport control in response to rhizobia. Our results suggest that CRE1-dependent cytokinin signaling leads to nodule initiation through the regulation of flavonoid accumulation required for local alteration of polar auxin transport and subsequent auxin accumulation in cortical cells during the early stages of nodulation. PMID:26253705

  3. Radiogenic isotope evidence for transatlantic atmospheric dust transport

    Science.gov (United States)

    Kumar, Ashwini; Abouchami, Wafa; Garrison, Virginia H.; Galer, Stephen J. G.; Andreae, Meinrat O.

    2013-04-01

    source origin. These results identify an African source signal, in aerosols from the Virgin Islands and Tobago collected during African dusts incursion, and thus provides evidence for transatlantic dust transport during the spring/summer season. This, in turn, is entirely consistent with 7-day back-trajectory analysis at these locations as well as recent seasonal AOD maps [8]. [1] Prospero et al. (1970) Earth Planet. Sci. Lett. 9, 287-293. [2] Swap et al. (1992) Tellus 44, 133-149. [3] Koren et al. (2006) Environ. Res. Lett. 1, 014005. [4] Ben-Ami et al. (2010) Atmos. Chem. Phys. 10, 7533-7544. [5] Duce & Tindale (1991) Lim Ocean., 36, 1715-1726. [6] Bollhöfer & Rosman (2000) Geochim. Cosmochim. Acta 64, 3251-3262. [7] Abouchami et al. (in prep.) [8] Ridley et al. (2012) J. Geophys. Res. 117, D02202.

  4. Effects of antidiabetic drugs on the incidence of macrovascular complications and mortality in type 2 diabetes mellitus: a new perspective on sodium-glucose co-transporter 2 inhibitors.

    Science.gov (United States)

    Rahelić, Dario; Javor, Eugen; Lucijanić, Tomo; Skelin, Marko

    2017-02-01

    Elevated hemoglobin A 1c (HbA 1c ) values correlate with microvascular and macrovascular complications. Thus, patients with type 2 diabetes mellitus (T2DM) are at an increased risk of developing macrovascular events. Treatment of T2DM should be based on a multifactorial approach because of its evidence regarding reduction of macrovascular complications and mortality in T2DM. It is well known that intensive glucose control reduces the risk of microvascular complications in T2DM, but the effects of antidiabetic drugs on macrovascular complications and mortality in T2DM are less clear. The results of recent trials have demonstrated clear evidence that empagliflozin and liraglutide reduce cardiovascular (CV) and all-cause mortality in T2DM, an effect that is absent in other members of antidiabetic drugs. Empagliflozin is a member of a novel class of antidiabetic drugs, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. Two ongoing randomized clinical trials involving other SGLT2 inhibitors, canagliflozin and dapagliflozin, will provide additional evidence of the beneficial effects of SGLT2 inhibitors in T2DM population. The aim of this paper is to systematically present the latest evidence regarding the usage of antidiabetic drugs, and the reduction of macrovascular complications and mortality. A special emphasis is put on the novel class of antidiabetic drugs, of SGLT2 inhibitors. Key messages Macrovascular complications and mortality are best clinical trial endpoints for evaluating the efficacy of antidiabetic drugs. The first antidiabetic drug that demonstrated a reduction in mortality in the treatment of type 2 diabetes mellitus (T2DM) was empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 inhibitors are novel class of antidiabetic drugs that play a promising role in the treatment of T2DM.

  5. Differential effects of histone deacetylase inhibitors on cellular drug transporters and their implications for using epigenetic modifiers in combination chemotherapy.

    Science.gov (United States)

    Valdez, Benigno C; Li, Yang; Murray, David; Brammer, Jonathan E; Liu, Yan; Hosing, Chitra; Nieto, Yago; Champlin, Richard E; Andersson, Borje S

    2016-09-27

    HDAC inhibitors, DNA alkylators and nucleoside analogs are effective components of combination chemotherapy. To determine a possible mechanism of their synergism, we analyzed the effects of HDAC inhibitors on the expression of drug transporters which export DNA alkylators. Exposure of PEER lymphoma T-cells to 15 nM romidepsin (Rom) resulted in 40%-50% reduction in mRNA for the drug transporter MRP1 and up to ~500-fold increase in the MDR1 mRNA within 32-48 hrs. MRP1 protein levels concomitantly decreased while MDR1 increased. Other HDAC inhibitors - panobinostat, belinostat and suberoylanilide hydroxamic acid (SAHA) - had similar effects on these transporters. The protein level of MRP1 correlated with cellular resistance to busulfan and chlorambucil, and Rom exposure sensitized cells to these DNA alkylators. The decrease in MRP1 correlated with decreased cellular drug export activity, and increased level of MDR1 correlated with increased export of daunorubicin. A similar decrease in the level of MRP1 protein, and increase in MDR1, were observed when mononuclear cells derived from patients with T-cell malignancies were exposed to Rom. Decreased MRP1 and increased MDR1 expressions were also observed in blood mononuclear cells from lymphoma patients who received SAHA-containing chemotherapy in a clinical trial. This inhibitory effect of HDAC inhibitors on the expression of MRP1 suggests that their synergism with DNA alkylating agents is partly due to decreased efflux of these alkylators. Our results further imply the possibility of antagonistic effects when HDAC inhibitors are combined with anthracyclines and other MDR1 drug ligands in chemotherapy.

  6. Inhibitors of the 5-lipoxygenase arachidonic acid pathway induce ATP release and ATP-dependent organic cation transport in macrophages.

    Science.gov (United States)

    da Silva-Souza, Hercules Antônio; Lira, Maria Nathalia de; Costa-Junior, Helio Miranda; da Cruz, Cristiane Monteiro; Vasconcellos, Jorge Silvio Silva; Mendes, Anderson Nogueira; Pimenta-Reis, Gabriela; Alvarez, Cora Lilia; Faccioli, Lucia Helena; Serezani, Carlos Henrique; Schachter, Julieta; Persechini, Pedro Muanis

    2014-07-01

    We have previously described that arachidonic acid (AA)-5-lipoxygenase (5-LO) metabolism inhibitors such as NDGA and MK886, inhibit cell death by apoptosis, but not by necrosis, induced by extracellular ATP (ATPe) binding to P2X7 receptors in macrophages. ATPe binding to P2X7 also induces large cationic and anionic organic molecules uptake in these cells, a process that involves at least two distinct transport mechanisms: one for cations and another for anions. Here we show that inhibitors of the AA-5-LO pathway do not inhibit P2X7 receptors, as judged by the maintenance of the ATPe-induced uptake of fluorescent anionic dyes. In addition, we describe two new transport phenomena induced by these inhibitors in macrophages: a cation-selective uptake of fluorescent dyes and the release of ATP. The cation uptake requires secreted ATPe, but, differently from the P2X7/ATPe-induced phenomena, it is also present in macrophages derived from mice deficient in the P2X7 gene. Inhibitors of phospholipase A2 and of the AA-cyclooxygenase pathway did not induce the cation uptake. The uptake of non-organic cations was investigated by measuring the free intracellular Ca(2+) concentration ([Ca(2+)]i) by Fura-2 fluorescence. NDGA, but not MK886, induced an increase in [Ca(2+)]i. Chelating Ca(2+) ions in the extracellular medium suppressed the intracellular Ca(2+) signal without interfering in the uptake of cationic dyes. We conclude that inhibitors of the AA-5-LO pathway do not block P2X7 receptors, trigger the release of ATP, and induce an ATP-dependent uptake of organic cations by a Ca(2+)- and P2X7-independent transport mechanism in macrophages. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Evidence of fractional transport in point vortex flow

    International Nuclear Information System (INIS)

    Leoncini, Xavier; Kuznetsov, Leonid; Zaslavsky, George M.

    2004-01-01

    Advection properties of passive particles in flows generated by point vortices are considered. Transport properties are anomalous with characteristic transport exponent μ∼1.5. This behavior is linked back to the presence of coherent fractal structures within the flow. A fractional kinetic analysis allows to link the characteristic transport exponent μ to the trapping time exponent γ=1+μ. The quantitative agreement is found for different systems of vortices investigated and a clear signature is obtained of the fractional nature of transport in these flows

  8. Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors

    DEFF Research Database (Denmark)

    Løland, Claus Juul; Desai, Rajeev I; Zou, Mu-Fa

    2007-01-01

    Cocaine exerts its stimulatory effect by inhibiting the dopamine transporter (DAT). However, novel benztropine- and rimcazole-based inhibitors show reduced stimulant effects compared with cocaine, despite higher affinity and selectivity for DAT. To investigate possible mechanisms, we compared...... the extracellular transporter gate is open but inaccessible when it is closed. The data indicated that cocaine analogs bind an open conformation, whereas benztropine and rimcazole analogs bind a closed conformation. Next, we investigated the changes in inhibition potency of [(3)H]dopamine uptake of the compounds...... at a mutant DAT (Y335A) characterized by a global change in the conformational equilibrium. We observed a close relationship between the decrease in potencies of inhibitors at this mutant and cocaine-like responding in rats trained to discriminate cocaine from saline injections. Our data suggest...

  9. Evidence for strange kinetics in Hasegawa-Mima turbulent transport

    International Nuclear Information System (INIS)

    Annibaldi, S.V.; Drury, L.O'C.; Manfredi, G.; Dendy, R.O.

    2000-01-01

    We have studied the transport of test particle ensembles moving in turbulent electrostatic fields governed by the Hasegawa-Mima (HM) equation. As a result of the interplay of the linear dispersive term and the nonlinear term in the HM equation, 'strange kinetics' emerge: the poloidal particle transport undergoes a qualitative transition from diffusive, through supradiffusive, to ballistic. (author). Letter-to-the-editor

  10. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

    Directory of Open Access Journals (Sweden)

    Patrizia eCampolongo

    2012-03-01

    Full Text Available Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5-5 mg/kg, i.p. on bothemotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimental settings, named High Arousal and Low Arousal conditions. The two different experimental conditions influenced emotional reactivity independently of drug administration. Indeed, vehicle-treated rats exposed to the Low Arousal condition spent more time in the centre of the arena than vehicle-treated rats exposed to the High Arousal context. Conversely, the different arousal conditions did not affect the cognitive performances of vehicle-treated animals such as the capability to discriminate a spatial displacement of the objects or an object substitution.AM404 administration did not alter the locomotor activity of the animals exposed to both environmental conditions. Interestingly, AM404 administration increased the emotional reactivity of rats exposed to the High Arousal condition but did not influence emotionality of rats exposed to the Low Arousal condition. Moreover, AM404 administration influenced the cognitive parameters depending on the level of emotional arousal: it impaired the capability of rats exposed to the High Arousal condition to recognize a novel object while it did not induce any impairing effect in rats exposed to the Low Arousal condition.These findings suggest that drugs which enhance the endocannabinoid signalling induce different effects on recognition memory performance depending on the level of emotional arousal induced by the environmental conditions.

  11. A role for accumbal glycine receptors in modulation of dopamine release by the glycine transporter-1 inhibitor Org25935

    Directory of Open Access Journals (Sweden)

    Helga eHöifödt Lidö

    2011-03-01

    Full Text Available AbstractAccumbal glycine modulates basal and ethanol-induced dopamine levels in the nucleus accumbens (nAc as well as voluntary ethanol consumption. Also, systemic administration of the glycine transporter-1 inhibitor Org25935 elevates dopamine levels in nAc, prevents a further ethanol-induced dopamine elevation and robustly and dose-dependently decreases ethanol consumption in rats. Here we investigated whether Org25935 applied locally in nAc modulates dopamine release, and whether accumbal glycine receptors or NMDA receptors are involved in this tentative effect. We also addressed whether Org25935 and ethanol applied locally in nAc interact with dopamine levels, as seen after systemic administration. We used in vivo microdialysis coupled to HPLC-ED in freely moving male Wistar rats to monitor dopamine output in nAc after local perfusion of Org25935 alone, with ethanol, or Org25935-perfusion after pre-treatment with the glycine receptor antagonist strychnine or the NMDA receptor glycine site antagonist L-701.324. Local Org25935 increased extracellular dopamine levels in a subpopulation of rats. Local strychnine, but not systemic L-701.324, antagonized the dopamine-activating effect of Org25935. Ethanol failed to induce a dopamine overflow in the subpopulation responding to Org25935 with a dopamine elevation. The study supports a role for accumbal glycine receptors rather than NMDA receptor signaling in the dopamine-activating effect of Org25935. The results further indicate that the previously reported systemic Org25935-ethanol interaction with regard to accumbal dopamine is localized to the nAc. This adds to the growing evidence for the glycine receptor as an important player in the dopamine reward circuitry and in ethanol’s effects within this system.

  12. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model.

    Directory of Open Access Journals (Sweden)

    Fei Shen

    Full Text Available Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a µ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and µ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid

  13. [Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors in CKD].

    Science.gov (United States)

    Insalaco, Monica; Zanoli, Luca; Rastelli, Stefania; Lentini, Paolo; Rapisarda, Francesco; Fatuzzo, Pasquale; Castellino, Pietro; Granata, Antonio

    2015-01-01

    Among the new drugs used for the treatment of Diabetes Mellitus type 2, sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a promising therapeutic option. Since their ability to lower glucose is proportional to GFR, their effect is reduced in patients with chronic kidney disease (CKD). The antidiabetic mechanism of these drugs is insulin-independent and, therefore, complimentary to that of others antihyperglicaemic agents. Moreover, SGLT2 inhibitors are able to reduce glomerular hyperfiltration, systemic and intraglomerular pressure and uric acid levels, with consequent beneficial effects on the progression of kidney disease in non diabetic patients as well. Only few studies have been performed to evaluate the effects of SGLT2 inhibitors in patients with CKD. Therefore, safety and efficacy of SGLT2 inhibitors should be better clarified in the setting of CKD. In this paper, we will review the use of SGLT2 inhibitors in diabetic patients, including those with CKD.

  14. Estimating the impact of transport efficiency on trade costs: Evidence from Chinese agricultural traders

    OpenAIRE

    Li, Zhigang; Yu, Xiaohua; Zeng, Yinchu

    2011-01-01

    Using a unique survey data on agricultural traders in China in 2004, this study provides direct evidence on significance of interregional transport costs and their key determinants. Our major findings are as follows: (1) the trade barriers within China are dominated by transport-related costs but not artificial barriers, approximated by tolls and fines; (2) Labor and fuels costs are the most significant component of transport costs; (3) road quality is very important for transportation effici...

  15. Are selective serotonin reuptake inhibitors safe for drivers? What is the evidence?

    Science.gov (United States)

    Ravera, Silvia; Ramaekers, Johannes G; de Jong-van den Berg, Lolkje T W; de Gier, Johan J

    2012-05-01

    Selective serotonin reuptake inhibitors (SSRIs) are widely used medications to treat several psychiatric diseases and, above all, depression. They seem to be as effective as older antidepressants but have a different adverse effect profile. Despite their favorable safety profile, little is known about their influence on traffic safety. To conduct a literature review to summarize the current evidence on the role of SSRIs in traffic safety, particularly concerning undesirable effects that could potentially impair fitness to drive, experimental and pharmacoepidemiologic studies on driving impairment, 2 existing categorization systems for driving-impairing medications, and the European legislative procedures for assessing fitness to drive before issuing a driver's license and driving under the influence of medicines. The article search was performed in the following electronic databases: MEDLINE, PsycINFO, ScienceDirect, and SafetyLit. The English-language scientific literature was searched using key words such as SSRIs and psychomotor performance, car crash or traffic accident, and adverse effects. For inclusion in this review, papers had to be full-text articles, refer to possible driving-related adverse effects, and be experimental or pharmacoepidemiologic studies on SSRIs and traffic accident risks. No restrictions concerning publication year were applied. Ten articles were selected as background information on driving-related adverse effects, and 15 articles were selected regarding experimental and pharmacoepidemiologic work. Regarding SSRI adverse effects, the most reported undesirable effects referring to driving impairment were anxiety, agitation, sleep disturbances, headache, increased risk of suicidal behavior, and deliberate self-harm. Regarding the remaining issues addressed in this article, inconsistencies were found between the outcomes of the selected experimental and epidemiologic studies and between the 2 existing categorization systems under

  16. Repositioning of Verrucosidin, a Purported Inhibitor of Chaperone Protein GRP78, as an Inhibitor of Mitochondrial Electron Transport Chain Complex I

    Science.gov (United States)

    Gonzalez, Reyna; Pao, Peng-Wen; Hofman, Florence M.; Chen, Thomas C.; Louie, Stan G.; Pirrung, Michael C.; Schönthal, Axel H.

    2013-01-01

    Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD’s anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose), but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin). However, VCD’s strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion will be discussed. PMID:23755268

  17. Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I.

    Directory of Open Access Journals (Sweden)

    Simmy Thomas

    Full Text Available Verrucosidin (VCD belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78 expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD's anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose, but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin. However, VCD's strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin might act in a similar GRP78-independent fashion will be discussed.

  18. Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3.

    Science.gov (United States)

    Hsueh, Chia-Hsiang; Yoshida, Kenta; Zhao, Ping; Meyer, Timothy W; Zhang, Lei; Huang, Shiew-Mei; Giacomini, Kathleen M

    2016-09-06

    One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD.

  19. In vivo neuronal synthesis and axonal transport of Kunitz protease inhibitor (KPI)-containing forms of the amyloid precursor protein.

    Science.gov (United States)

    Moya, K L; Confaloni, A M; Allinquant, B

    1994-11-01

    We have shown previously that the amyloid precursor protein (APP) is synthesized in retinal ganglion cells and is rapidly transported down the axons, and that different molecular weight forms of the precursor have different developmental time courses. Some APP isoforms contain a Kunitz protease inhibitor (KPI) domain, and APP that lacks the KPI domain is considered the predominant isoform in neurons. We now show that, among the various rapidly transported APPs, a 140-kDa isoform contains the KPI domain. This APP isoform is highly expressed in rapidly growing retinal axons, and it is also prominent in adult axon endings. This 140-kDa KPI-containing APP is highly sulfated compared with other axonally transported isoforms. These results show that APP with the KPI domain is a prominent isoform synthesized in neurons in vivo, and they suggest that the regulation of protease activity may be an important factor during the establishment of neuronal connections.

  20. Sodium-Glucose Linked Transporter-2 Inhibitors in Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    L. Zanoli

    2015-01-01

    Full Text Available SGLT2 inhibitors are new antihyperglycaemic agents whose ability to lower glucose is directly proportional to GFR. Therefore, in chronic kidney disease (CKD the blood glucose lowering effect is reduced. Unlike many current therapies, the mechanism of action of SGLT2 inhibitors is independent of insulin action or beta-cell function. In addition, the mechanism of action of SGLT2 inhibitors is complementary and not alternative to other antidiabetic agents. SGLT2 inhibitors could be potentially effective in attenuating renal hyperfiltration and, consequently, the progression of CKD. Moreover, the reductions in intraglomerular pressure, systemic blood pressure, and uric acid levels induced by SGLT inhibition may potentially be of benefit in CKD subjects without diabetes. However, at present, only few clinical studies were designed to evaluate the effects of SGLT2 inhibitors in CKD. Consequently, safety and potential efficacy beyond blood glucose lowering should be better clarified in CKD. In this paper we provide an updated review of the use of SGLT2 inhibitors in clinical practice, with particular attention on subjects with CKD.

  1. Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport

    Directory of Open Access Journals (Sweden)

    Nadine Ruderisch

    2017-10-01

    Full Text Available Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ antibodies and secretase inhibitors. However, the blood-brain barrier (BBB limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.

  2. Assessment of vandetanib as an inhibitor of various human renal transporters: inhibition of multidrug and toxin extrusion as a possible mechanism leading to decreased cisplatin and creatinine clearance.

    Science.gov (United States)

    Shen, Hong; Yang, Zheng; Zhao, Weiping; Zhang, Yueping; Rodrigues, A David

    2013-12-01

    Vandetanib was evaluated as an inhibitor of human organic anion transporter 1 (OAT1), OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion (MATE1 and MATE2K) transfected (individually) into human embryonic kidney 293 cells (HEK293). Although no inhibition of OAT1 and OAT3 was observed, inhibition of OCT2-mediated uptake of 1-methyl-4-phenylpyridinium (MPP(+)) and metformin was evident (IC(50) of 73.4 ± 14.8 and 8.8 ± 1.9 µM, respectively). However, vandetanib was an even more potent inhibitor of MATE1- and MATE2K-mediated uptake of MPP(+) (IC(50) of 1.23 ± 0.05 and 1.26 ± 0.06 µM, respectively) and metformin (IC(50) of 0.16 ± 0.05 and 0.30 ± 0.09 µM, respectively). Subsequent cytotoxicity studies demonstrated that transport inhibition by vandetanib (2.5 µM) significantly decreased the sensitivity [right shift in concentration of cisplatin giving rise to 50% cell death; IC(50(CN))] of MATE1-HEK and MATE2K-HEK cells to cisplatin [IC(50(CN)) of 1.12 ± 0.13 versus 2.39 ± 0.44 µM; 0.85 ± 0.09 versus 1.99 ± 0.16 µM; P cisplatin nephrotoxicity (reduced cisplatin clearance), in some subjects receiving vandetanib therapy.

  3. Effects of inhibitors of protein synthesis and intracellular transport on the gamma-aminobutyric acid agonist-induced functional differentiation of cultured cerebellar granule cells

    DEFF Research Database (Denmark)

    Belhage, B; Hansen, Gert Helge; Meier, E

    1990-01-01

    The effect of inhibitors of protein synthesis (actinomycin D, cycloheximide), proteases (leupeptin), and intracellular transport (colchicine, monensin) on the gamma-aminobutyric acid (GABA) agonist [4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP)]-induced changes in morphological...... an intracellular and a plasma membrane localization of the receptors. In all experiments cultures treated with THIP alone served as controls. The inhibitors of protein synthesis totally abolished the ability of THIP to induce low-affinity GABA receptors. In contrast, the inhibitors of intracellular transport...

  4. Transendothelial albumin flux: evidence against active transport of albumin

    International Nuclear Information System (INIS)

    Siflinger-Birnboim, A.; Del Vecchio, P.J.; Cooper, J.A.; Malik, A.B.

    1986-01-01

    The authors studied whether albumin is actively transported across cultured pulmonary endothelium by comparing the transendothelial flux of 125 I-albumin from the luminal-to-abluminal side to the flux from the abluminal-to-luminal side. Bovine pulmonary artery endothelial cells were grown to confluence on gelatinized polycarbonated filters separating abluminal from luminal compartments. Each compartment had an albumin concentration of 1 g/100 ml to equalize oncotic pressure gradients. The effect of hydrostatic pressure was eliminated by maintaining an equal level of fluid in both compartments. The transendothelial flux of albumin across the monolayer was measured by placing 125 I-albumin tracer either on the luminal or the abluminal side. Equal fluxes of 125 I-albumin from luminal-to-abluminal side and from abluminal-to-luminal side were observed. The results indicate that the pulmonary endothelium behaves symmetrically for albumin, indicating the absence of active transport of albumin

  5. Glycine transporter dimers: evidence for occurrence in the plasma membrane

    DEFF Research Database (Denmark)

    Bartholomäus, Ingo; Milan-Lobo, Laura; Nicke, Annette

    2008-01-01

    membrane based on hydrodynamic and native gel electrophoretic studies. Here, we used cysteine substitution and oxidative cross-linking to show that of GlyT1 and GlyT2 also form dimeric complexes within the plasma membrane. GlyT oligomerization at the cell surface was confirmed for both GlyT1 and GlyT2......Different Na(+)/Cl(-)-dependent neurotransmitter transporters of the SLC6a family have been shown to form dimers or oligomers in both intracellular compartments and at the cell surface. In contrast, the glycine transporters (GlyTs) GlyT1 and -2 have been reported to exist as monomers in the plasma...

  6. Glycine transporter dimers: evidence for occurrence in the plasma membrane.

    Science.gov (United States)

    Bartholomäus, Ingo; Milan-Lobo, Laura; Nicke, Annette; Dutertre, Sébastien; Hastrup, Hanne; Jha, Alok; Gether, Ulrik; Sitte, Harald H; Betz, Heinrich; Eulenburg, Volker

    2008-04-18

    Different Na(+)/Cl(-)-dependent neurotransmitter transporters of the SLC6a family have been shown to form dimers or oligomers in both intracellular compartments and at the cell surface. In contrast, the glycine transporters (GlyTs) GlyT1 and -2 have been reported to exist as monomers in the plasma membrane based on hydrodynamic and native gel electrophoretic studies. Here, we used cysteine substitution and oxidative cross-linking to show that of GlyT1 and GlyT2 also form dimeric complexes within the plasma membrane. GlyT oligomerization at the cell surface was confirmed for both GlyT1 and GlyT2 by fluorescence resonance energy transfer microscopy. Endoglycosidase treatment and surface biotinylation further revealed that complex-glycosylated GlyTs form dimers located at the cell surface. Furthermore, substitution of tryptophan 469 of GlyT2 by an arginine generated a transporter deficient in dimerization that was retained intracellulary. Based on these results and GlyT structures modeled by using the crystal structure of the bacterial homolog LeuT(Aa), as a template, residues located within the extracellular loop 3 and at the beginning of transmembrane domain 6 are proposed to contribute to the dimerization interface of GlyTs.

  7. Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation.

    Science.gov (United States)

    Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

    2015-06-05

    The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu(406) is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation*

    Science.gov (United States)

    Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

    2015-01-01

    The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu406 is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. PMID:25903124

  9. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria

    Science.gov (United States)

    Chino, Yukihiro; Samukawa, Yoshishige; Sakai, Soichi; Nakai, Yasuhiro; Yamaguchi, Jun-ichi; Nakanishi, Takeo; Tamai, Ikumi

    2014-01-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, SUA and the urinary excretion rate of uric acid (UEUA) were analysed after the oral administration of luseogliflozin, a SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UEUA, suggesting that SUA decreased as a result of the increase in the UEUA. The increase in UEUA was correlated with an increase in urinary d-glucose excretion, but not with the plasma luseogliflozin concentration. Additionally, in vitro transport experiments showed that luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UEUA is likely due to glycosuria, the study focused on the facilitative glucose transporter 9 isoform 2 (GLUT9ΔN, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and d-glucose. It was observed that the efflux of [14C]UA in Xenopus oocytes expressing the GLUT9 isoform 2 was trans-stimulated by 10 mm d-glucose, a high concentration of glucose that existed under SGLT2 inhibition. On the other hand, the uptake of [14C]UA by oocytes was cis-inhibited by 100 mm d-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UEUA could potentially be increased by luseogliflozin-induced glycosuria, with alterations of UA transport activity because of urinary glucose. PMID:25044127

  10. Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Saini, Nipun; Black, Paul N.; Montefusco, David; DiRusso, Concetta C., E-mail: cdirusso2@unl.edu

    2015-09-25

    The inhibition of the fatty acid uptake into non-adipose tissues provides an attractive target for prevention of lipotoxicity leading to obesity-associated non-alcoholic fatty liver disease and type 2 diabetes. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterification with coenzyme A. Here we characterize Grassofermata/CB5, previously identified as a fatty acid uptake inhibitor directed against HsFATP2. The compound was effective in inhibiting the uptake of fatty acids in the low micro-molar range (IC{sub 50} 8–11 μM) and prevented palmitate-mediated lipid accumulation and cell death in cell lines that are models for intestines, liver, muscle and pancreas. In adipocytes, uptake inhibition was less effective (IC{sub 50} 58 μM). Inhibition was specific for long chain fatty acids and was ineffective toward medium chain fatty acids, which are transported by diffusion. Kinetic analysis of Grassofermata-dependent FA transport inhibition verified a non-competitive mechanism. By comparison with Grassofermata, several atypical antipsychotic drugs previously implicated as inhibitors of FA uptake were ineffectual. In mice Grassofermata decreased absorption of {sup 13}C-oleate demonstrating its potential as a therapeutic agent. - Highlights: • Grassofermata is a small compound inhibitor of FATP2. • Uptake inhibition is specific for long chain fatty acids. • Uptake kinetics shows low specificity for adipocytes compared to other cell types. • Inhibition is by a non-competitive mechanism. • Atypical antipsychotics do not inhibit FA uptake by comparison with Grassofermata.

  11. Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity

    International Nuclear Information System (INIS)

    Saini, Nipun; Black, Paul N.; Montefusco, David; DiRusso, Concetta C.

    2015-01-01

    The inhibition of the fatty acid uptake into non-adipose tissues provides an attractive target for prevention of lipotoxicity leading to obesity-associated non-alcoholic fatty liver disease and type 2 diabetes. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterification with coenzyme A. Here we characterize Grassofermata/CB5, previously identified as a fatty acid uptake inhibitor directed against HsFATP2. The compound was effective in inhibiting the uptake of fatty acids in the low micro-molar range (IC 50 8–11 μM) and prevented palmitate-mediated lipid accumulation and cell death in cell lines that are models for intestines, liver, muscle and pancreas. In adipocytes, uptake inhibition was less effective (IC 50 58 μM). Inhibition was specific for long chain fatty acids and was ineffective toward medium chain fatty acids, which are transported by diffusion. Kinetic analysis of Grassofermata-dependent FA transport inhibition verified a non-competitive mechanism. By comparison with Grassofermata, several atypical antipsychotic drugs previously implicated as inhibitors of FA uptake were ineffectual. In mice Grassofermata decreased absorption of 13 C-oleate demonstrating its potential as a therapeutic agent. - Highlights: • Grassofermata is a small compound inhibitor of FATP2. • Uptake inhibition is specific for long chain fatty acids. • Uptake kinetics shows low specificity for adipocytes compared to other cell types. • Inhibition is by a non-competitive mechanism. • Atypical antipsychotics do not inhibit FA uptake by comparison with Grassofermata

  12. Are Selective Serotonin Reuptake Inhibitors Safe for Drivers? What is the Evidence?

    NARCIS (Netherlands)

    Ravera, Silvia; Ramaekers, Johannes G.; de Jong-van den Berg, Lolkje T. W.; de Gier, Johan J.; de Jong-van den Berg, [No Value

    Background: Selective serotonin reuptake inhibitors (SSRIs) are widely used medications to treat several psychiatric diseases and, above all, depression. They seem to be as effective as older antidepressants but have a different adverse effect profile. Despite their favorable safety profile, little

  13. Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy

    International Nuclear Information System (INIS)

    Bakhiya, Nadiya; Arlt, Volker M.; Bahn, Andrew; Burckhardt, Gerhard; Phillips, David H.; Glatt, Hansruedi

    2009-01-01

    Aristolochic acid (AA), present in Aristolochia species, is the major causative agent in the development of severe renal failure and urothelial cancers in patients with AA nephropathy. It may also be a cause of Balkan endemic nephropathy. Epithelial cells of the proximal tubule are the primary cellular target of AA. To study whether organic anion transporters (OATs) expressed in proximal tubule cells are involved in uptake of AA, we used human epithelial kidney (HEK293) cells stably expressing human (h) OAT1, OAT3 or OAT4. AA potently inhibited the uptake of characteristic substrates, p-aminohippurate for hOAT1 and estrone sulfate for hOAT3 and hOAT4. Aristolochic acid I (AAI), the more cytotoxic and genotoxic AA congener, exhibited high affinity for hOAT1 (K i = 0.6 μM) as well as hOAT3 (K i = 0.5 μM), and lower affinity for hOAT4 (K i = 20.6 μM). Subsequently, AAI-DNA adduct formation (investigated by 32 P-postlabelling) was used as a measure of AAI uptake. Significantly higher levels of adducts occurred in hOAT-expressing cells than in control cells: this effect was abolished in the presence of the OAT inhibitor probenecid. In Xenopus laevis oocytes hOAT-mediated efflux of p-aminohippurate was trans-stimulated by extracellular AA, providing further molecular evidence for AA translocation by hOATs. Our study indicates that OATs can mediate the uptake of AA into proximal tubule cells and thereby participate in kidney cell damage by this toxin.

  14. Cytopathological evidence for transport of phytoplasma in infected plants

    Directory of Open Access Journals (Sweden)

    Anna Rudzińska-Langwald

    2014-01-01

    Full Text Available Pleomorphic phytoplasmas were observed in sieve tubes, companion cells and in phloem parenchyma of Tagetes patula L., Helichrysum bracteatum Willd. and Gladiolus sp. L. plants with morphological changes typical for phytoplasma infection. In the pores of the sieve plate phytoplasma cells were seen which suggests that the vertical transport of this pathogen goes in the sieve tubes of infected plants throughout the sieve tube pores. The contact of the sieve tube with the neighbouring cells goes through the plasmodesmata, but no changes of the plasmodesmata were observed in the phloem of infected plants. The size and structure of unchanged plasmodesmata does not allow passing through such big structures like phytoplasma. Instead close contact between phytoplasma cells and vertical sieve tube walls takes place. Damages to the cell wall were observed forming cavities in which the phytoplasma cells were present. The damages of parenchyma and companion cells walls also were seen. In cells where the damages of the walls were observed phytoplasmas were present. The phytoplasma cells were sporadically seen also in the intercellular spaces of parenchyma. These data suggest that horizontal transport depends on damages to the infected plant cell walls caused by the phytoplasma itself.

  15. The effects of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Storgaard, Heidi; Gluud, Lise Lotte; Christensen, Mikkel

    2014-01-01

    INTRODUCTION: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) increase urinary glucose excretion through a reduced renal glucose reabsorption. We plan to perform a systematic review of SGLT-2i for treatment of type 2 diabetes. METHODS AND ANALYSIS: A systematic review with meta-analyses of r......INTRODUCTION: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) increase urinary glucose excretion through a reduced renal glucose reabsorption. We plan to perform a systematic review of SGLT-2i for treatment of type 2 diabetes. METHODS AND ANALYSIS: A systematic review with meta......-analyses of randomised clinical trials on SGLT-2i versus placebo, other oral glucose lowering drugs or insulin for patients with type 2 diabetes will be performed. The primary end point will be the glycated haemoglobin. Secondary end points will include changes in body weight, body mass index, fasting plasma glucose......, plasma cholesterol, kidney and liver blood tests, blood pressure and adverse events. Electronic (the Cochrane Library, MEDLINE, EMBASE and the Science Citation Index) and manual searches will be performed. Meta-analyses will be performed and the results presented as mean differences for continuous...

  16. Analgesic effect of GT-0198, a structurally novel glycine transporter 2 inhibitor, in a mouse model of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Yu Omori

    2015-03-01

    Full Text Available This study was conducted to identify the characteristic pharmacological features of GT-0198 that is phenoxymethylbenzamide derivatives. GT-0198 inhibited the function of glycine transporter 2 (GlyT2 in human GlyT2-expressing HEK293 cells and did not bind various major transporters or receptors of neurotransmitters in a competitive manner. Thus, GT-0198 is considered to be a comparatively selective GlyT2 inhibitor. Intravenous, oral, and intrathecal injections of GT-0198 decreased the pain-related response in a model of neuropathic pain with partial sciatic nerve ligation. This result suggests that GT-0198 has an analgesic effect. The analgesic effect of GT-0198 was abolished by the intrathecal injection of strychnine, a glycine receptor antagonist. Therefore, GT-0198 is considered to exhibit its analgesic effect via the activation of a glycine receptor by glycine following presynaptic GlyT2 inhibition in the spinal cord. In summary, GT-0198 is a structurally novel GlyT2 inhibitor bearing a phenoxymethylbenzamide moiety with in vivo efficacy in behavioral models of neuropathic pain.

  17. Wet-gas transport in the Mediterranean Sea. Selection of a combined kinetic hydrate/corrosion inhibitor system

    Energy Technology Data Exchange (ETDEWEB)

    Zettlitzer, M. [RWE Dea AG, Wietze (Germany); Rozengard, N.; Koeckritz, V. [Technical Univ. Freiberg (Germany); Malt, E. [RWE Dea AG (Egypt)

    2007-09-13

    Raw gas will be collected on a platform in the centre of the field. Due to volume and weight constraints, condensing fluids will not be separated from the gas on the platform so that the raw gas will be transported in three-phase mode (gas, water, and condensate) via a 33 km long pipeline to a gas treatment plant. Under the calculated pipeline pressure of about 100 barg, hydrate formation is - according to the outcome of thermodynamic simulations - to be expected at temperatures of 19 C and below while the pipeline may cool down to about 15 C in winter conditions. Due to logistical, environmental and economic reasons, RWE Dea decided to inhibit hydrate formation with kinetic hydrate inhibitors (KHI). As the gas also contains carbon dioxide, certain corrosivity was forecasted and addition of a corrosion inhibitor turned out to be necessary. Laboratory tests were carried out to confirm the feasibility of the concept and to define the required dosage of KHI. Service companies were contacted and several kinetic hydrate and corrosion inhibitors were screened. Experiments with the different chemicals were performed at the University of Freiberg in a high-pressure cell at the pipeline pressure of 100 barg. Hydrate formation was detected by continuous pressure registration during temperature changes and by observation through a glass window. In order to preselect the chemicals, first tests were performed with pure methane. These tests also served for calibration of the equipment with literature data and especially as an indication for the minimum chemical concentration required. A second test series was performed with synthetic gas in a composition close to that of the field gas under consideration in order to verify the results obtained with methane. Finally, the optimum kinetic hydrate inhibitor was identified as well as the required dosage concentration. Compatibility of KHI and corrosion inhibitor was experimentally proven. A further set of kinetic inhibitor tests with

  18. Unexpected effects of azole transporter inhibitors on antifungal susceptibility in Candida glabrata and other pathogenic Candida species.

    Science.gov (United States)

    Nagayoshi, Yohsuke; Miyazaki, Taiga; Shimamura, Shintaro; Nakayama, Hironobu; Minematsu, Asuka; Yamauchi, Shunsuke; Takazono, Takahiro; Nakamura, Shigeki; Yanagihara, Katsunori; Kohno, Shigeru; Mukae, Hiroshi; Izumikawa, Koichi

    2017-01-01

    The pathogenic fungus Candida glabrata is often resistant to azole antifungal agents. Drug efflux through azole transporters, such as Cdr1 and Cdr2, is a key mechanism of azole resistance and these genes are under the control of the transcription factor Pdr1. Recently, the monoamine oxidase A (MAO-A) inhibitor clorgyline was shown to inhibit the azole efflux pumps, leading to increased azole susceptibility in C. glabrata. In the present study, we have evaluated the effects of clorgyline on susceptibility of C. glabrata to not only azoles, but also to micafungin and amphotericin B, using wild-type and several mutant strains. The addition of clorgyline to the culture media increased fluconazole susceptibility of a C. glabrata wild-type strain, whereas micafungin and amphotericin B susceptibilities were markedly decreased. These phenomena were also observed in other medically important Candida species, including Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida krusei. Expression levels of CDR1, CDR2 and PDR1 mRNAs and an amount of Cdr1 protein in the C. glabrata wild-type strain were highly increased in response to the treatment with clorgyline. However, loss of Cdr1, Cdr2, Pdr1, and a putative clorgyline target (Fms1), which is an ortholog of human MAO-A, or overexpression of CDR1 did not affect the decreased susceptibility to micafungin and amphotericin B in the presence of clorgyline. The presence of other azole efflux pump inhibitors including milbemycin A4 oxime and carbonyl cyanide 3-chlorophenylhydrazone also decreased micafungin susceptibility in C. glabrata wild-type, Δcdr1, Δcdr2, and Δpdr1 strains. These findings suggest that azole efflux pump inhibitors increase azole susceptibility but concurrently induce decreased susceptibility to other classes of antifungals independent of azole transporter functions.

  19. Metabolism of ATP-binding cassette drug transporter inhibitors: complicating factor for multidrug resistance.

    NARCIS (Netherlands)

    Cnubben, N.H.; Wortelboer, H.M.; Zanden, J.J. van; Rietjens, I.M.; Bladeren, P.J. van

    2005-01-01

    Membrane transport proteins belonging to the ATP-binding cassette (ABC) family of transport proteins play a central role in the defence of organisms against toxic compounds, including anticancer drugs. However, for compounds that are designed to display a toxic effect, this defence system diminishes

  20. Detection of inhibitors of Candida albicans Cdr transporters using a diS-C3(3 fluorescence

    Directory of Open Access Journals (Sweden)

    Joanna eSzczepaniak

    2015-03-01

    Full Text Available Candida albicans is a major cause of opportunistic and life-threatening, systemic fungal infections. Hence new antifungal agents, as well as new methods to treat fungal infections, are still needed. The application of inhibitors of drug-efflux pumps may increase the susceptibility of C. albicans to drugs. We developed a new fluorescence method that allows the in vivo activity evaluation of compounds inhibiting of C. albicans transporters. We show that the potentiometric dye 3,3′-dipropylthiacarbocyanine iodide diS-C3(3 is pumped out by both Cdr1 and Cdr2 transporters. The fluorescence labeling with diS-C3(3 enables a real-time observation of the activity of C. albicans Cdr1 and Cdr2 transporters. We demonstrate that enniatin A and beauvericin show different specificities toward these transporters. Enniatin A inhibits diS-C3(3 efflux by Cdr1 while beauvericin inhibits both Cdr1p and Cdr2p.

  1. Evidence for particle transport between alveolar macrophages in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Benson, J.M.; Nikula, K.J.; Guilmette, R.A.

    1995-12-01

    Recent studies at this Institute have focused on determining the role of alveolar macrophages (AMs) in the transport of particles within and form the lung. For those studies, AMs previously labeled using the nuclear stain Hoechst 33342 and polychromatic Fluoresbrite microspheres (1 {mu}m diameter, Polysciences, Inc., Warrington, PA) were instilled into lungs of recipient F344 rats. The fate of the donor particles and the doubly labeled AMs within recipient lungs was followed for 32 d. Within 2-4 d after instillation, the polychromatic microspheres were found in both donor and resident AMs, suggesting that particle transfer occurred between the donor and resident AMs. However, this may also have been an artifact resulting from phagocytosis of the microspheres form dead donor cells or from the fading or degradation of Hoechst 33342 within the donor cells leading to their misidentification as resident AMs. The results support the earlier findings that microspheres in donor AMs can be transferred to resident AMs within 2 d after instillation.

  2. Evidence of a gustatory-vestibular pathway for protein transport.

    Science.gov (United States)

    Gacek, Richard; Lyon, Michael J

    2010-02-01

    To demonstrate anatomically a pathway for protein transport from the palate to the vestibular system. The vestibulofacial anastomosis and associated ganglion cells were identified in a collection of 160 horizontally sectioned human temporal bones that had been stained with hematoxylin and eosin. Wheat germ agglutinin-horseradish peroxidase (HRP) was applied to the greater superficial petrosal nerve in 4 Sprague-Dawley rats. After 30 hours, the rats were killed by intracardiac perfusion, and the seventh and eighth nerves with adjacent brainstem removed. Frozen sections cut at 30 mum through this block were then reacted for HRP, counterstained with neutral red, and mounted on slides for examination in the light microscope. Thirty-two of the 160 human temporal bones contained sections through the vestibulofacial anastomosis and its ganglion. In all cases, the ganglion was incorporated into the vestibular ganglion (VG) adjacent to the nervus intermedius. In all 4 experimental rats, HRP reaction product labeled a small number of ganglion cells in the VG adjacent to the nervus intermedius and facial nerve. These observations support the presence of a pathway from receptors in the palate to the VG.

  3. Discovery of novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus.

    Science.gov (United States)

    Brincat, Jean Pierre; Carosati, Emanuele; Sabatini, Stefano; Manfroni, Giuseppe; Fravolini, Arnaldo; Raygada, Jose L; Patel, Diixa; Kaatz, Glenn W; Cruciani, Gabriele

    2011-01-13

    Four novel inhibitors of the NorA efflux pump of Staphylococcus aureus, discovered through a virtual screening process, are reported. The four compounds belong to different chemical classes and were tested for their in vitro ability to block the efflux of a well-known NorA substrate, as well as for their ability to potentiate the effect of ciprofloxacin (CPX) on several strains of S. aureus, including a NorA overexpressing strain. Additionally, the MIC values of each of the compounds individually are reported. A structure-activity relationship study was also performed on these novel chemotypes, revealing three new compounds that are also potent NorA inhibitors. The virtual screening procedure employed FLAP, a new methodology based on GRID force field descriptors.

  4. Flozins, inhibitors of type 2 renal sodium-glucose co-transporter – not only antihyperglycemic drugs

    Directory of Open Access Journals (Sweden)

    Mizerski Grzegorz

    2015-09-01

    Full Text Available The kidneys play a crucial role in the regulation of the carbohydrate metabolism. In normal physiological conditions, the glucose that filters through the renal glomeruli is subsequently nearly totally reabsorbed in the proximal renal tubules. Two transporters are engaged in this process: sodium-glucose co-transporter type 1 (SGLT1, and sodium-glucose co-transporter type type 2 (SGLT2 - this being located in the luminal membrane of the renal tubular epithelial cells. It was found that the administration of dapagliflozin, a selective SGLT2 inhibitor, in patients with type 2 diabetes, is associated with the reduction of HbA1c concentration by 0.45-1.11%. Additional benefits from the treatment with dapagliflozin are the reduction of arterial blood pressure and a permanent reduction of body weight. This outcome is related to the effect of osmotic diuresis and to the considerable loss of the glucose load by way of urine excretion. Dapagliflozin may be successfully applied in type 2 diabetes monotherapy, as well as in combined therapy (including insulin, where it is equally effective as other oral anti-diabetic drugs. Of note: serious adverse effects of dapagliflozin administration are rarely observed. What is more, episodes of severe hypoglycaemia related with the treatment occur only sporadically, most often in the course of diabetes polytherapy. The most frequent effects of the SGLT2 inhibitors are inseparably associated with the mechanism of their action (the glucuretic effect, and cover urogenital infections with a mild clinical course. At present, clinical trials are being continued of the administration of several subsequent drugs from this group, the most advanced of these being the use of canagliflozin and empagliflozin.

  5. Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

    Science.gov (United States)

    Gluud, Lise L.; Bennett, Cathy; Grøndahl, Magnus F.; Christensen, Mikkel B.; Knop, Filip K.; Vilsbøll, Tina

    2016-01-01

    Objective Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes. Design Systematic review and meta-analysis. Data Sources and Study Selection We included double-blinded, randomised controlled trials (RCTs) evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin, sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through electronic databases and extensive manual searches. Primary outcomes were glycated haemoglobin A1c (HbA1c) levels, serious adverse events, death, severe hypoglycaemia, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE. Results Meta-analysis of 34 RCTs with 9,154 patients showed that SGLT2-i reduced HbA1c compared with placebo (mean difference -0.69%, 95% confidence interval -0.75 to -0.62%). We downgraded the evidence to ‘low quality’ due to variability and evidence of publication bias (P = 0.015). Canagliflozin was associated with the largest reduction in HbA1c (-0.85%, -0.99% to -0.71%). There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine, and exerted beneficial effects on bodyweight, blood pressure, lipids and alanine aminotransferase (moderate to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence). Conclusion

  6. A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease.

    Science.gov (United States)

    Toda, Narihiro; Tago, Keiko; Marumoto, Shinji; Takami, Kazuko; Ori, Mayuko; Yamada, Naho; Koyama, Kazuo; Naruto, Shunji; Abe, Kazumi; Yamazaki, Reina; Hara, Takao; Aoyagi, Atsushi; Abe, Yasuyuki; Kaneko, Tsugio; Kogen, Hiroshi

    2003-10-01

    Alzheimer's disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a previous paper, we found a potential dual inhibitor, 1, of AChE (IC50=101 nM) and SERT (IC50=42 nM), but its AChE inhibition activity was less than donepezil (IC50=10 nM). Here, we report the conformationally restricted (R)-18a considerably enhanced inhibitory activity against AChE (IC50=14 nM) and SERT (IC50=6 nM).

  7. In vivo evaluation of carbon-11-labelled non-sarcosine-based glycine transporter 1 inhibitors in mice and conscious monkeys

    Energy Technology Data Exchange (ETDEWEB)

    Toyohara, Jun [Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan 260-8670 (Japan); Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 173-0022 (Japan); Ishiwata, Kiichi; Sakata, Muneyuki [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 173-0022 (Japan); Wu, Jin [Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan 260-8670 (Japan); Nishiyama, Shingo; Tsukada, Hideo [Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan 434-8601 (Japan); Hashimoto, Kenji, E-mail: hashimoto@faculty.chiba-u.j [Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan 260-8670 (Japan)

    2011-05-15

    Introduction: Glycine transporter 1 (GlyT-1) is an attractive target in positron emission tomography (PET) studies. Here, we report the in vivo evaluation of three carbon-11-labelled non-sarcosine-type GlyT-1 inhibitors - [{sup 11}C]SA1, [{sup 11}C]SA2 and [{sup 11}C]SA3 - as novel PET tracers for GlyT-1. Methods: The regional brain distributions of the three compounds in mice were studied at baseline and under receptor-blockade conditions with co-injection of carrier loading or pretreatment with an excess of selective GlyT-1 inhibitors (ALX-5407 and SSR504734). Metabolic stability was investigated by radio high-performance liquid chromatography. Dynamic PET scans in conscious monkeys were performed with/without selective GlyT-1 inhibitors. Results: The IC{sub 50} values of SA1, SA2 and SA3 were 9.0, 6400 and 39.7 nM, respectively. The regional brain uptakes of [{sup 11}C]SA1 and [{sup 11}C]SA3 in mice were heterogeneous and consistent with the known distribution of GlyT-1. [{sup 11}C]SA2 showed low and homogeneous uptake in the brain. Most radioactivity in the brain was detected in unchanged form, although peripherally these compounds were degraded. Carrier loading decreased the uptake of [{sup 11}C]SA1 in GlyT-1-rich regions. However, similar reductions were not observed with [{sup 11}C]SA3. Pretreatment with ALX-5407 decreased the uptake of [{sup 11}C]SA1 in GlyT-1-rich regions. In the monkey at baseline, regional brain uptake of [{sup 11}C]SA1 was heterogeneous and consistent with the known GlyT-1 distribution. Pretreatment with selective GlyT-1 inhibitors significantly decreased the distribution volume ratio of [{sup 11}C] SA1 in GlyT-1-rich regions. Conclusions: [{sup 11}C]SA1 has the most suitable profile among the three carbon-11-labelled GlyT-1 inhibitors. Lead optimization of [{sup 11}C]SA1 structure will be required to achieve in vivo selective GlyT-1 imaging.

  8. In vivo evaluation of carbon-11-labelled non-sarcosine-based glycine transporter 1 inhibitors in mice and conscious monkeys

    International Nuclear Information System (INIS)

    Toyohara, Jun; Ishiwata, Kiichi; Sakata, Muneyuki; Wu, Jin; Nishiyama, Shingo; Tsukada, Hideo; Hashimoto, Kenji

    2011-01-01

    Introduction: Glycine transporter 1 (GlyT-1) is an attractive target in positron emission tomography (PET) studies. Here, we report the in vivo evaluation of three carbon-11-labelled non-sarcosine-type GlyT-1 inhibitors - [ 11 C]SA1, [ 11 C]SA2 and [ 11 C]SA3 - as novel PET tracers for GlyT-1. Methods: The regional brain distributions of the three compounds in mice were studied at baseline and under receptor-blockade conditions with co-injection of carrier loading or pretreatment with an excess of selective GlyT-1 inhibitors (ALX-5407 and SSR504734). Metabolic stability was investigated by radio high-performance liquid chromatography. Dynamic PET scans in conscious monkeys were performed with/without selective GlyT-1 inhibitors. Results: The IC 50 values of SA1, SA2 and SA3 were 9.0, 6400 and 39.7 nM, respectively. The regional brain uptakes of [ 11 C]SA1 and [ 11 C]SA3 in mice were heterogeneous and consistent with the known distribution of GlyT-1. [ 11 C]SA2 showed low and homogeneous uptake in the brain. Most radioactivity in the brain was detected in unchanged form, although peripherally these compounds were degraded. Carrier loading decreased the uptake of [ 11 C]SA1 in GlyT-1-rich regions. However, similar reductions were not observed with [ 11 C]SA3. Pretreatment with ALX-5407 decreased the uptake of [ 11 C]SA1 in GlyT-1-rich regions. In the monkey at baseline, regional brain uptake of [ 11 C]SA1 was heterogeneous and consistent with the known GlyT-1 distribution. Pretreatment with selective GlyT-1 inhibitors significantly decreased the distribution volume ratio of [ 11 C] SA1 in GlyT-1-rich regions. Conclusions: [ 11 C]SA1 has the most suitable profile among the three carbon-11-labelled GlyT-1 inhibitors. Lead optimization of [ 11 C]SA1 structure will be required to achieve in vivo selective GlyT-1 imaging.

  9. Amino acid derivatives are substrates or non-transported inhibitors of the amino acid transporter PAT2 (slc36a2).

    Science.gov (United States)

    Edwards, Noel; Anderson, Catriona M H; Gatfield, Kelly M; Jevons, Mark P; Ganapathy, Vadivel; Thwaites, David T

    2011-01-01

    The H(+)-coupled amino acid transporter PAT2 (SLC36A2) transports the amino acids proline, glycine, alanine and hydroxyproline. A physiological role played by PAT2 in amino acid reabsorption in the renal proximal tubule is demonstrated by mutations in SLC36A2 that lead to an iminoglycinuric phenotype (imino acid and glycine uria) in humans. A number of proline, GABA and tryptophan derivatives were examined to determine if they function either as transported substrates or non-transported inhibitors of PAT2. The compounds were investigated following heterologous expression of rat PAT2 in Xenopus laevis oocytes. PAT2 function was characterised by: radiotracer uptake and competition (cis-inhibition) studies; radiotracer efflux and trans-stimulation; and measurement of substrate-induced positive inward current by two-electrode voltage-clamp. In general, the proline derivatives appeared to be transported substrates and the relative ability to induce current flow was closely related to the inhibitory effects on PAT2-mediated l-[(3)H]proline uptake. In contrast, certain heterocyclic GABA derivatives (e.g. l-pipecolic acid) were translocated only slowly. Finally, the tryptophan derivatives inhibited PAT2 function but did not undergo transport. l-Proline uptake was inhibited by 5-hydroxy-l-tryptophan (IC(50) 1.6±0.4mM), α-methyl-d,l-tryptophan (3.5±1.5mM), l-tryptophan, 1-methyl-l-tryptophan and indole-3-propionic acid. Although neither 5-hydroxy-l-tryptophan nor α-methyl-d,l-tryptophan were able to elicit inward current in PAT2-expressing oocytes both reduced the current evoked by l-proline. 5-Hydroxy-l-tryptophan and α-methyl-d,l-tryptophan were unable to trans-stimulate l-proline efflux from PAT2-expressing oocytes, confirming that the two compounds act as non-transported blockers of PAT2. These two tryptophan derivatives should prove valuable experimental tools in future investigations of the physiological roles of PAT2. Copyright © 2010 Elsevier B.V. All rights

  10. Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2 inhibitor for the treatment of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Joshua J Neumiller

    2014-06-01

    Full Text Available Type 2 diabetes is increasing in prevalence worldwide, and hyperglycemia is often poorly controlled despite a number of therapeutic options. Unlike previously available agents, sodium-glucose co-transporter 2 (SGLT2 inhibitors offer an insulin-independent mechanism for improving blood glucose levels, since they promote urinary glucose excretion (UGE by inhibiting glucose reabsorption in the kidney. In addition to glucose control, SGLT2 inhibitors are associated with weight loss and blood pressure reductions, and do not increase the risk of hypoglycemia. Empagliflozin is a selective inhibitor of SGLT2, providing dose-dependent UGE increases in healthy volunteers, with up to 90 g of glucose excreted per day. It can be administered orally, and studies of people with renal or hepatic impairment indicated empagliflozin needed no dose adjustment based on pharmacokinetics. In Phase II trials in patients with type 2 diabetes, empagliflozin provided improvements in glycosylated hemoglobin (HbA1c and other measures of glycemic control when given as monotherapy or add-on to metformin, as well as reductions in weight and systolic blood pressure. As add-on to basal insulin, empagliflozin not only improved HbA1c levels but also reduced insulin doses. Across studies, empagliflozin was generally well tolerated with a similar rate of hypoglycemia to placebo; however, patients had a slightly increased frequency of genital infections, but not urinary tract infections, versus placebo. Phase III studies have also reported a good safety profile along with significant improvements in HbA1c, weight and blood pressure, with no increased risk of hypoglycemia versus placebo. Based on available data, it appears that empagliflozin may be a useful option in a range of patients; however, clinical decisions will be better informed by the results of ongoing studies, in particular, a large cardiovascular outcome study (EMPA-REG OUTCOME™.

  11. The effects of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Storgaard, Heidi; Gluud, Lise Lotte; Christensen, Mikkel

    2014-01-01

    INTRODUCTION: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) increase urinary glucose excretion through a reduced renal glucose reabsorption. We plan to perform a systematic review of SGLT-2i for treatment of type 2 diabetes. METHODS AND ANALYSIS: A systematic review with meta......-analyses of randomised clinical trials on SGLT-2i versus placebo, other oral glucose lowering drugs or insulin for patients with type 2 diabetes will be performed. The primary end point will be the glycated haemoglobin. Secondary end points will include changes in body weight, body mass index, fasting plasma glucose...... to the knowledge regarding the beneficial and harmful effects of SGLT-2i in patients with type 2 diabetes. We plan to publish the study irrespective of the results. RESULTS: The study will be disseminated by peer-review publication and conference presentation. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014008960...

  12. A new structural class of subtype-selective inhibitor of cloned excitatory amino acid transporter, EAAT2

    DEFF Research Database (Denmark)

    Bräuner-Osborne, Hans; Hermit, M B; Nielsen, B

    2000-01-01

    We have studied the pharmacological effects of (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and the enantiomers of (RS)-2-amino-3-(3-hydroxy-1,2, 5-thiadiazol-4-yl)propionic acid (TDPA) on cloned human excitatory amino acid transporter subtypes 1, 2 and 3 (EAAT1......-3) expressed in Cos-7 cells. Whereas AMPA and (R)-TDPA were both inactive as inhibitors of [3H]-(R)-aspartic acid uptake on all three EAAT subtypes, (S)-TDPA was shown to selectively inhibit uptake by EAAT2 with a potency equal to that of the endogenous ligand (S)-glutamic acid. (S)-TDPA thus represents a new...

  13. Assessing links between energy consumption, freight transport, and economic growth: evidence from dynamic simultaneous equation models.

    Science.gov (United States)

    Nasreen, Samia; Saidi, Samir; Ozturk, Ilhan

    2018-06-01

    We investigate this study to examine the relationship between economic growth, freight transport, and energy consumption for 63 developing countries over the period of 1990-2016. In order to make the panel data analysis more homogeneous, we apply the income level of countries to divide the global panel into three sub-panels, namely, lower-middle income countries (LMIC), upper-middle income countries (UMIC), and high-income countries (HIC). Using the generalized method of moments (GMM), the results prove evidence of bidirectional causal relationship between economic growth and freight transport for all selected panels and between economic growth and energy consumption for the high- and upper-middle income panels. For the lower-middle income panel, the causality is unidirectional running from energy consumption to economic growth. Also, the results indicate that the relationship between freight transport and energy use is bidirectional for the high-income countries and unidirectional from freight transport to energy consumption for the upper-middle and lower-middle income countries. Empirical evidence demonstrates the importance of energy for economic activity and rejects the neo-classical assumption that energy is neutral for growth. An important policy recommendation is that there is need of advancements in vehicle technology which can reduce energy intensity from transport sector and improve the energy efficiency in transport activity which in turn allows a greater positive role of transport in global economic activity.

  14. Assay for inhibitors of nucleoside transport based upon the use of 5-125I]Iodo-2-deoxyuridine as permeant

    International Nuclear Information System (INIS)

    Mahony, W.B.; Zimmerman, T.P.

    1986-01-01

    5[ 125 I]Iodo-2-deoxyuridine (IdUrd) has been shown to serve as a permeant for the nucleoside transport system of human erythrocytes and to be metabolically inert in these cells. Linear initial velocities were obtained at 20 0 C for 125 IdUrd transport, yielding a K/sub m/ of 73 +/- 18 μM (n = 6). Low-affinity inhibitors of 125 IdUrd transport, such as adenosine (K/sub i/ = 32 +/- 2 μM, n = 2), could be characterized by Michaelis-Menten kinetics. However, high-affinity inhibitors, such as 6-[4-nitrobenzyl)thio]9-β-D-ribofuranosylpurine, caused nonlinear initial velocities when added to the cells simultaneously with 125 IdUrd. Conditions were defined (viz., 20-min pretreatment of cells with test compound followed by 5.0-min incubation with 1.0 μM 125 IdUrd, all at 20 0 C) whereby high-affinity inhibitors of IdUrd transport can be identified and evaluated according to their 50% inhibitory concentrations. The use of 125 IdUrd as permeant greatly expedites the testing of compounds as inhibitors of nucleoside transport by allowing the cell pellets generated in these assays to be monitored directly in a gamma spectrometer, thereby circumventing the solubilization and decolorization of cell pellets required by assays that use 3 H- or 14 C-labeled nucleoside permeants

  15. Mitochondrial genome-knockout cells demonstrate a dual mechanism of action for the electron transport complex I inhibitor mycothiazole.

    Science.gov (United States)

    Meyer, Kirsten J; Singh, A Jonathan; Cameron, Alanna; Tan, An S; Leahy, Dora C; O'Sullivan, David; Joshi, Praneta; La Flamme, Anne C; Northcote, Peter T; Berridge, Michael V; Miller, John H

    2012-04-01

    Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC(50) 0.36-13.8 nM) include HeLa, P815, RAW 264.7, MDCK, HeLa S3, 143B, 4T1, B16, and CD4/CD8 T cells. Insensitive cell lines (IC(50) 12.2-26.5 μM) include HL-60, LN18, and Jurkat. Thus, there is a 34,000-fold difference in sensitivity between HeLa and HL-60 cells. Some sensitive cell lines show a biphasic response, suggesting more than one mechanism of action. Mitochondrial genome-knockout ρ(0) cell lines are insensitive to mycothiazole, supporting a conditional mitochondrial site of action. Mycothiazole is cytostatic rather than cytotoxic in sensitive cells, has a long lag period of about 12 h, and unlike the complex I inhibitor, rotenone, does not cause G(2)/M cell cycle arrest. Mycothiazole decreases, rather than increases the levels of reactive oxygen species after 24 h. It is concluded that the cytostatic inhibitory effects of mycothiazole on mitochondrial electron transport function in sensitive cell lines may depend on a pre-activation step that is absent in insensitive cell lines with intact mitochondria, and that a second lower-affinity cytotoxic target may also be involved in the metabolic and growth inhibition of cells.

  16. Inhibitor mechanisms in the S1 binding site of the dopamine transporter defined by multi-site molecular tethering of photoactive cocaine analogs.

    Science.gov (United States)

    Krout, Danielle; Pramod, Akula Bala; Dahal, Rejwi Acharya; Tomlinson, Michael J; Sharma, Babita; Foster, James D; Zou, Mu-Fa; Boatang, Comfort; Newman, Amy Hauck; Lever, John R; Vaughan, Roxanne A; Henry, L Keith

    2017-10-15

    Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints. Understanding the molecular mechanisms governing the pharmacological inhibition of DAT is therefore key for understanding the requisite interactions for behavioral modulation and addiction. Previously, we leveraged complementary computational docking, mutagenesis, peptide mapping, and substituted cysteine accessibility strategies to identify the specific adduction site and binding pose for the crosslinkable, photoactive cocaine analog, RTI 82, which contains a photoactive azide attached at the 2β position of the tropane pharmacophore. Here, we utilize similar methodology with a different cocaine analog N-[4-(4-azido-3-I-iodophenyl)-butyl]-2-carbomethoxy-3-(4-chlorophenyl)tropane, MFZ 2-24, where the photoactive azide is attached to the tropane nitrogen. In contrast to RTI 82, which crosslinked into residue Phe319 of transmembrane domain (TM) 6, our findings show that MFZ 2-24 adducts to Leu80 in TM1 with modeling and biochemical data indicating that MFZ 2-24, like RTI 82, occupies the central S1 binding pocket with the (+)-charged tropane ring nitrogen coordinating with the (-)-charged carboxyl side chain of Asp79. The superimposition of the tropane ring in the three-dimensional binding poses of these two distinct ligands provides strong experimental evidence for cocaine binding to DAT in the S1 site

  17. Lack of cross-shelf transport of sediments on the western margin of India: Evidence from clay mineralogy

    Digital Repository Service at National Institute of Oceanography (India)

    Ramaswamy, V.; Nair, R.R.

    transported long distances along the shelf, cross-shelf transport appears to be minimal. Confirmatory evidence of qualitative differences in outer and inner shelf clays is provided by sediment trap clay mineralogy on the outer shelf. Clay bound pollutant...

  18. Early Discontinuation of Metformin in Individuals Treated with Inhibitors of Transporters of Metformin

    DEFF Research Database (Denmark)

    Stage, Tore Bjerregaard; Lee, Moa P; Hallas, Jesper

    2016-01-01

    The aim of this study was to examine the risk of early discontinuation of metformin as a proxy for intolerance, associated with use of drugs known to inhibit transporters involved in metformin distribution. We analysed all incident users of metformin in Denmark between 2000 and 2012 (n = 132......,221) and in a cohort of US patients (n = 296,903). Risk of early discontinuation of metformin was assessed using adjusted logistic regression for 28 drugs putatively inhibiting metformin transporters and four negative controls. Increased odds ratio of early discontinuation of metformin was only associated with codeine...... drugs were associated with a decreased risk. These findings indicate that codeine use may be associated with risk of early discontinuation of metformin and could be used as a basis for further investigation....

  19. Evidence-based support for the use of proton pump inhibitors in cancer therapy.

    Science.gov (United States)

    Fais, Stefano

    2015-11-24

    'We can only cure what we can understand first', said Otto H. Warburg, the 1931 Nobel laureate for his discovery on tumor metabolism. Unfortunately, we still don't know too much the mechanisms underlying of cancer development and progression. One of the unsolved mystery includes the strategies that cancer cells adopt to cope with an adverse microenvironment. However, we knew, from the Warburg's discovery, that through their metabolism based on sugar fermentation, cancer cells acidify their microenvironment and this progressive acidification induces a selective pressure, leading to development of very malignant cells entirely armed to survive in the hostile microenvironment generated by their own metabolism. One of the most mechanism to survive to the acidic tumor microenvironment are proton exchangers not allowing intracellular acidification through a continuous elimination of H(+) either outside the cells or within the internal vacuoles. This article wants to comment a translational process through which from the preclinical demonstration that a class of proton pump inhibitors (PPI) exploited worldwide for peptic ulcer treatment and gastroprotection are indeed chemosensitizers as well, we have got to the clinical proof of concept that PPI may well be included in new anti-cancer strategies, and with a solid background and rationale.

  20. Raman Microspectroscopic Evidence for the Metabolism of a Tyrosine Kinase Inhibitor, Neratinib, in Cancer Cells.

    Science.gov (United States)

    Aljakouch, Karim; Lechtonen, Tatjana; Yosef, Hesham K; Hammoud, Mohamad K; Alsaidi, Wissam; Kötting, Carsten; Mügge, Carolin; Kourist, Robert; El-Mashtoly, Samir F; Gerwert, Klaus

    2018-06-11

    Tyrosine kinase receptors are one of the main targets in cancer therapy. They play an essential role in the modulation of growth factor signaling and thereby inducing cell proliferation and growth. Tyrosine kinase inhibitors such as neratinib bind to EGFR and HER2 receptors and exhibit antitumor activity. However, little is known about their detailed cellular uptake and metabolism. Here, we report for the first time the intracellular spatial distribution and metabolism of neratinib in different cancer cells using label-free Raman imaging. Two new neratinib metabolites were detected and fluorescence imaging of the same cells indicate that neratinib accumulates in lysosomes. The results also suggest that both EGFR and HER2 follow the classical endosome lysosomal pathway for degradation. A combination of Raman microscopy, DFT calculations, and LC-MS was used to identify the chemical structure of neratinib metabolites. These results show the potential of Raman microscopy to study drug pharmacokinetics. © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  1. [Competition between branded and generic drugs in Austria: evidence from the market for ACE inhibitors].

    Science.gov (United States)

    Mahlich, J C; Stadler, I

    2012-01-01

    The market for pharmaceuticals in Austria is highly regulated and manufacturers cannot set prices freely after patent expiration of the pioneer drug. We wanted to examine the effect of price regulation on price competition between branded and generic drugs in Austria. We examined the Austrian market for ACE inhibitors and describe competitive dynamics by means of 6 indices. We compared our results with those of Grabowski and Vernon who studied the US market. According to our analysis the competition amongst the producers of generic drugs is not great and consequently, compared to the USA, over time the prices for generic products decrease less and their market share increases less. This is due to a market-oriented system in the USA which waives most regulatory provisions. Our conclusions are in line with the findings by Danzon und Chao (2000) who argue that in a price-regulated market competitive dynamics are less strongly developed. From a politico-economic view, the necessity of price regulations in the pharmaceutical market seems questionable, as price regulations generally also cause other negative effects, such as distorted economic incentives for research and development investments. © Georg Thieme Verlag KG Stuttgart · New York.

  2. Effect of Known Inhibitors of Ion Transport on Pendrin (SLC26A4 Activity in a Human Kidney Cell Line

    Directory of Open Access Journals (Sweden)

    Emanuele Bernardinelli

    2016-05-01

    Full Text Available Background/Aims: Pendrin is a Cl-/I-/HCO3- exchanger playing a fundamental role in controlling blood pressure and airway function, therefore representing an attractive target for the treatment of hypertensive states and respiratory distresses. A review of the literature regarding the ability of some compounds (namely several known inhibitors of ion transport to block pendrin activity revealed discordant findings. These incongruous findings may be due, in part, to the concentration of compound and/or the nature of the model system used in the study. Methods: Pendrin activity was evaluated by measuring pendrin-dependent iodide influx following overexpression of the transporter in a human kidney cell line, in the presence of selected test compounds or the respective vehicles. Results: Pendrin activity was significantly hampered by 0.1 mM 5-nitro-2-[(3-phenylpropylamino]benzoic acid (NPPB, niflumic acid and tenidap, but was resistant to 0.1 mM 4, 4′-diisothiocyano-2, 2′-stilbene-disulfonic acid (DIDS, furosemide and probenecid. Conclusions: The results of the present study indicate that clinically effective non-steroidal anti-inflammatory drugs (niflumic acid and tenidap directly inhibit pendrin activity.

  3. Dihydro-β-agarofurans from the roots of the Australian endemic rainforest tree Maytenus bilocularis act as leucine transport inhibitors.

    Science.gov (United States)

    Wibowo, Mario; Wang, Qian; Holst, Jeff; White, Jonathan M; Hofmann, Andreas; Davis, Rohan A

    2018-04-01

    Phytochemical studies of the roots of the Australian plant, Maytenus bilocularis, resulted in the identification of six previously undescribed dihydro-β-agarofuran sesquiterpenoids, bilocularins D-I, along with three known natural products, namely 1α,2α,6β,15-tetraacetoxy-9β-benzoyloxydihydro-β-agarofuran, pristimerin, and celastrol. The structures of all compounds were characterized via analysis of 1D/2D NMR and MS data. The absolute configuration of bilocularin D was defined by X-ray crystallography analysis. Bilocularins D and G, 1α,2α,6β,15-tetraacetoxy-9β-benzoyloxydihydro-β-agarofuran, and celastrol inhibited leucine transport in the human prostate cancer cell line LNCaP with IC 50 values ranging from 2.5-27.9 μM, which were more potent than the L-type amino acid transporter (LAT) family inhibitor 2-aminobicyclo[2,2,1]-heptane-2-carboxylic acid (BCH). Bilocularins D-F are the first examples of dihydro-β-agarofurans bearing a hydroxyacetate group. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Single-molecule interrogation of a bacterial sugar transporter allows the discovery of an extracellular inhibitor

    Science.gov (United States)

    Kong, Lingbing; Harrington, Leon; Li, Qiuhong; Cheley, Stephen; Davis, Benjamin G.; Bayley, Hagan

    2013-08-01

    Capsular polysaccharides form the outermost protective layer around many Gram-negative bacteria. Antibiotics aimed directly at weakening this layer are not yet available. In pathogenic Escherichia coli E69, a protein, Wza, forms a pore in the outer membrane that transports K30 capsular polysaccharide from its site of synthesis to the outside of the cell. This therefore represents a prospective antibiotic target. Here we test a variety of grommet-like mimics of K30 capsular polysaccharide on wild-type Wza and on mutant open forms of the pore by electrical recording in planar lipid bilayers. The most effective glycomimetic was the unnatural cyclic octasaccharide octakis(6-deoxy-6-amino)cyclomaltooctaose (am8γCD), which blocks the α-helix barrel of Wza, a site that is directly accessible from the external medium. This glycomimetic inhibited K30 polysaccharide transport in live E. coli E69. With the protective outer membrane disrupted, the bacteria can be recognized and killed by the human immune system.

  5. Supraspinal and spinal effects of L-trans-PDC, an inhibitor of glutamate transporter, on the micturition reflex in rats.

    Science.gov (United States)

    Honda, Masashi; Yoshimura, Naoki; Hikita, Katsuya; Hinata, Nobuyuki; Muraoka, Kuniyasu; Saito, Motoaki; Chancellor, Michael B; Takenaka, Atsushi

    2013-09-01

    Glutamate is a major excitatory transmitter in the central nervous system, controlling lower urinary tract function. Five types of glutamate transporters such as GLAST (EAAT1), GLT-1 (EAAT2), EAAC-1 (EAAT3), EAAT4, and EAAT5 have been cloned so far. In the current study we tested whether L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC), a non-selective inhibitor of glutamate transporters that increases endogenous glutamate concentration, can affect the micturition reflex in urethane anesthetized rats. Continuous cystometrograms (CMG, 0.04 ml/min infusion rate) were performed in two groups of urethane-anesthetized rats. A group of 18 rats was used for intrathecal administration of 1-10 µg of L-trans-PDC via an intrathecal catheter. In the second group of 18 rats, 1-10 µg of L-trans-PDC were administered intracerebroventricularly via a catheter inserted into the lateral ventricle. Micturition parameters were recorded and compared before and after drug administration. Intrathecal administration of L-trans-PDC at 1, 3, and 10 µg (n = 6 per dose) increased intercontraction intervals in dose dependent fashion, but did not affect postvoid residual or basal pressure at any doses tested. Intracerebroventricular administration of L-trans-PDC at 1, 3, and 10 µg (n = 6 per dose) also increased intercontraction intervals in dose dependent fashion, but did not affect postvoid residual or basal pressure at any doses tested. The current results show that, in urethane-anesthetized rats, suppression of glutamate transporters by L-trans-PDC has an inhibitory effect on the micturition reflex at supraspinal and spinal sites, possibly via activation of glutamate-mediated inhibitory pathways. Copyright © 2012 Wiley Periodicals, Inc.

  6. Plasminogen activator inhibitor-1 removal using dextran sulphate columns. Evidence of PAI-1 homeostasis.

    LENUS (Irish Health Repository)

    Maher, Vincent M G

    2009-08-01

    Patients with high plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels are prone to develop thrombosis. Lowering PAI-1 levels may offer a therapeutic option and help to better understand PAI-1 metabolism. We examined the effect on plasma PAI-1 levels of LDL-apheresis using dextran sulphate (DS) columns in 12 patients (9 male, 3 female, 49 +\\/- 10 years) with heterozygous familial hypercholesterolaemia and coronary artery disease. One plasma volume equivalent (2.3-4.0 l) was treated during each procedure (at flow rates of 23 +\\/- 2 ml\\/min). Lipids and PAI-1 antigen levels were measured in plasma before and immediately after 19 aphereses (once in 7 patients, twice in 3 patients and three times in 2 patients) and also at 3 and 7 days post apheresis in five of these patients and in the column eluates from 8 of these patients. DS-apheresis reduced plasma cholesterol (50 +\\/- 8%), triglyceride (45 +\\/- 27%), apolipoprotein B (59 +\\/- 10%) and PAI-1 antigen levels from 10.2 +\\/- 5.2 to 6.0 +\\/- 3.1 ng\\/ml (P = 0.005). The PAI-I changes were independent of circadian variation. PAI-I bound to the DS-columns (3.51 +\\/- 1.03 ng\\/ml filtered plasma) and the percent of filtered PAI-1 that was bound correlated inversely (r = -0.81, P < 0.02) with basal PAI-1 levels indicating a high affinity saturable binding process. In four patients, plasma PAI-1 levels post-apheresis were higher than expected based on the amount of PAI-removed by the DS columns. The difference between the expected and actual PAI-1 level post apheresis, reflecting PAI-1 secretion or extracellular redistribution, correlated inversely with basal PAI-1 levels (r = -0.83, P = 0.01). PAI-1 levels returned to baseline pre-apheresis values 7 days post apheresis. PAI-1 antigen may be removed from plasma without adverse effect, resulting temporarily in its extracellular redistribution and restoration to baseline levels over one week. PAI-1 redistribution particularly when baseline pre

  7. Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells

    Science.gov (United States)

    Lai, I-Lu; Chou, Chih-Chien; Lai, Po-Ting; Fang, Chun-Sheng; Shirley, Lawrence A.; Yan, Ribai; Mo, Xiaokui; Bloomston, Mark; Kulp, Samuel K.; Bekaii-Saab, Tanios; Chen, Ching-Shih

    2014-01-01

    Gemcitabine resistance remains a significant clinical challenge. Here, we used a novel glucose transporter (Glut) inhibitor, CG-5, as a proof-of-concept compound to investigate the therapeutic utility of targeting the Warburg effect to overcome gemcitabine resistance in pancreatic cancer. The effects of gemcitabine and/or CG-5 on viability, survival, glucose uptake and DNA damage were evaluated in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cell lines. Mechanistic studies were conducted to determine the molecular basis of gemcitabine resistance and the mechanism of CG-5-induced sensitization to gemcitabine. The effects of CG-5 on gemcitabine sensitivity were investigated in a xenograft tumor model of gemcitabine-resistant pancreatic cancer. In contrast to gemcitabine-sensitive pancreatic cancer cells, the resistant Panc-1 and Panc-1GemR cells responded to gemcitabine by increasing the expression of ribonucleotide reductase M2 catalytic subunit (RRM2) through E2F1-mediated transcriptional activation. Acting as a pan-Glut inhibitor, CG-5 abrogated this gemcitabine-induced upregulation of RRM2 through decreased E2F1 expression, thereby enhancing gemcitabine-induced DNA damage and inhibition of cell survival. This CG-5-induced inhibition of E2F1 expression was mediated by the induction of a previously unreported E2F1-targeted microRNA, miR-520f. The addition of oral CG-5 to gemcitabine therapy caused greater suppression of Panc-1GemR xenograft tumor growth in vivo than either drug alone. Glut inhibition may be an effective strategy to enhance gemcitabine activity for the treatment of pancreatic cancer. PMID:24879635

  8. Evidence for PMAT- and OCT-like biogenic amine transporters in a probiotic strain of Lactobacillus: Implications for interkingdom communication within the microbiota-gut-brain axis.

    Directory of Open Access Journals (Sweden)

    Mark Lyte

    Full Text Available The ability of prokaryotic microbes to produce and respond to neurochemicals that are more often associated with eukaryotic systems is increasingly recognized through the concept of microbial endocrinology. Most studies have described the phenomena of neurochemical production by bacteria, but there remains an incomplete understanding of the mechanisms by which microbe- or host-derived neuroactive substances can be recognized by bacteria. Based on the evolutionary origins of eukaryotic solute carrier transporters, we hypothesized that bacteria may possess an analogous uptake function for neuroactive biogenic amines. Using specific fluorescence-based assays, Lactobacillus salivarius biofilms appear to express both plasma membrane monoamine transporter (PMAT- and organic cation transporter (OCT-like uptake of transporter-specific fluorophores. This phenomenon is not distributed throughout the genus Lactobacillus as L. rhamnosus biofilms did not take up these fluorophores. PMAT probe uptake into L. salivarius biofilms was attenuated by the protonophore CCCP, the cation transport inhibitor decynium-22, and the natural substrates norepinephrine, serotonin and fluoxetine. These results provide the first evidence, to our knowledge, for the existence of PMAT- and OCT-like uptake systems in a bacterium. They also suggest the existence of a hitherto unrecognized mechanism by which a probiotic bacterium may interact with host signals and may provide a means to examine microbial endocrinology-based interactions in health and disease that are part of the larger microbiota-gut-brain axis.

  9. Renal accumulation of [{sup 111}In]DOTATOC in rats: influence of inhibitors of the organic ion transport and diuretics

    Energy Technology Data Exchange (ETDEWEB)

    Stahl, A.R. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nuclear Medicine, Munich (Germany); Universitaetsklinikum Essen, Department of Radiology, Essen (Germany); Wagner, B.; Heemann, U.; Lutz, J. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nephrology, Munich (Germany); Poethko, T.; Perutka, M.; Wester, H.J.; Essler, M.; Schwaiger, M. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nuclear Medicine, Munich (Germany)

    2007-12-15

    Radiation exposure to the kidney limits therapy with radiometal labelled DOTATOC. This study evaluates the organic anion and cation transport (inhibitors: probenecid and cimetidine/dexamethason) as well as diuresis (furosemide and mannitol) regarding renal uptake of [{sup 111}In]DOTATOC. One hundred eight male Fisher rats were injected with [{sup 111}In]DOTATOC via the tail vein. Prior to activity injection a total of 84 rats underwent injection with probenecid vs. sodium chloride 0.9% (48 rats), cimetidine vs. dexamethasone vs. sodium chloride 0.9% (18 rats), and furosemide vs. mannitol vs. sodium chloride 0.9% (18 rats). Rats were sacrificed at predetermined time points up to 48 h after activity injection. Kidneys, adrenal glands, pancreas, spleen, blood, liver, and muscle were harvested and injected activity per gram tissue was determined. Autoradiographic images of the kidneys were acquired in a total of 24 rats. Probenecid led to a reduction in renal uptake by up to 30% while not significantly changing the activity accumulation in the other organs investigated. This reduction was attributable to the renal cortex (ratio cortex/medulla 1.72 vs. 1.99; p = 0.006). Cimetidine and dexamethasone had no effect in any of the organs. Furosemide led to a 44% increase in renal activity accumulation attributable to enhanced renal medullary uptake (ratio cortex/medulla 1.44 versus 1.69; p = 0.006). Mannitol had no effect on renal activity uptake. Inhibition of the organic anion transport by probenecid may help reduce renal uptake regarding therapy with radiometal labelled DOTATOC. The enhancing effect of furosemide may be unfavourable for therapy. The results must be confirmed by human studies. (orig.)

  10. Effects of selected electron transport chain inhibitors on 24-h hydrogen production by Synechocystis sp. PCC 6803.

    Science.gov (United States)

    Burrows, Elizabeth H; Chaplen, Frank W R; Ely, Roger L

    2011-02-01

    One factor limiting biosolar hydrogen (H(2)) production from cyanobacteria is electron availability to the hydrogenase enzyme. In order to optimize 24-h H(2) production this study used Response Surface Methodology and Q2, an optimization algorithm, to investigate the effects of five inhibitors of the photosynthetic and respiratory electron transport chains of Synechocystis sp. PCC 6803. Over 3 days of diurnal light/dark cycling, with the optimized combination of 9.4 mM KCN (3.1 μmol 10(10) cells(-1)) and 1.5 mM malonate (0.5 μmol 10(10) cells(-1)) the H(2) production was 30-fold higher, in EHB-1 media previously optimized for nitrogen (N), sulfur (S), and carbon (C) concentrations (Burrows et al., 2008). In addition, glycogen concentration was measured over 24 h with two light/dark cycling regimes in both standard BG-11 and EHB-1 media. The results suggest that electron flow as well as glycogen accumulation should be optimized in systems engineered for maximal H(2) output. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus.

    Science.gov (United States)

    Scheen, André J

    2015-01-01

    Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12-104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin

  12. Transportation assimilation revisited: New evidence from repeated cross-sectional survey data

    Science.gov (United States)

    2018-01-01

    Background Based on single cross-sectional data, prior research finds evidence of “transportation assimilation” among U.S. immigrants: the length of stay in the U.S. is negatively correlated with public transit use. This paper revisits this question by using repeated cross-sectional data, and examines the trend of transportation assimilation over time. Methods and results Using 1980, 1990, 2000 1% census and 2010 (1%) American Community Survey, I examine the relationship between the length of stay in the U.S. and public transit ridership among immigrants. I first run regressions separately in four data sets: I regress public transit ridership on the length of stay, controlling for other individual and geographic variables. I then compare the magnitudes of the relationship in four regressions. To study how the rate of transportation assimilation changes over time, I pool the data set and regress public transit ridership on the length of stay and its interactions with year dummies to compare the coefficients across surveys. Results confirm the conclusion of transportation assimilation: as the length of stay in the U.S. increases, an immigrant’s public transit use decreases. However, the repeated cross-section analysis suggests the assimilation rate has been decreasing in the past few decades. Conclusions This paper finds evidence of transportation assimilation: immigrants become less likely to ride public transit as the length of stay in the U.S. increases. The assimilation rate, however, has been decreasing over time. This paper finds that the rate of public transit ridership among new immigrants upon arrival, the geographic distribution of immigrants, and the changing demographics of the U.S. immigrants play roles in affecting the trend of transportation assimilation. PMID:29668676

  13. 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

    Directory of Open Access Journals (Sweden)

    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.

  14. 'What works' in reducing sexual harassment and sexual offences on public transport nationally and internationally: a rapid evidence assessment

    OpenAIRE

    Gekoski, Anna; Gray, Jacqueline M.; Horvath, Miranda A. H.; Edwards, Sarah; Emirali, Aliye; Adler, Joanna R.

    2015-01-01

    In Britain, public transport is generally very safe and serious sexual assaults are rare. However, research has found that around 15% of women and girls have been subjected to unwanted sexual behaviour on the London transport network, the vast majority of which goes unreported (Transport for London [TfL], 2013a). This document reports the findings of a rapid evidence assessment, conducted on behalf go the British Transport Police, to identify the main initiatives that are being used to reduce...

  15. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes.

    Science.gov (United States)

    Jabbour, S A; Goldstein, B J

    2008-08-01

    The kidney plays a central role in the regulation of plasma glucose levels, although until recently this has not been widely appreciated or considered a target for therapeutic intervention. The sodium glucose co-transporter type 2 (SGLT2) located in the plasma membrane of cells lining the proximal tubule mediates the majority of renal glucose reabsorption from the tubular fluid, which normally prevents the loss of glucose in the urine. Competitive inhibitors of SGLT2 that provoke the renal excretion of glucose have been discovered, thereby providing a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes. To explore the physiology of SGLT2 action and discuss several SGLT2 inhibitors that have entered early clinical development. All publicly available data were identified by searching the internet for 'SGLT2' and 'SGLT2 inhibitor' through 1 November 2007. Published articles, press releases and abstracts presented at national and international meetings were considered. Sodium glucose co-transporter type 2 inhibition is a novel treatment option for diabetes, which has been studied in preclinical models and a few potent and selective SGLT2 inhibitors have been reported and are currently in clinical development. These agents appear to be safe and generally well tolerated, and will potentially be a beneficial addition to the growing battery of oral antihyperglycaemic agents.

  16. Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects.

    Science.gov (United States)

    D'Souza, Deepak Cyril; Carson, Richard E; Driesen, Naomi; Johannesen, Jason; Ranganathan, Mohini; Krystal, John H

    2018-01-31

    Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with schizophrenia. The dose-related occupancy and target engagement of the GlyT1 inhibitor PF-03463275 were studied to inform optimal dose selection for a clinical trial for cognitive impairments associated with schizophrenia. In substudy 1, the effects of PF-03463275 (10, 20, and 40 mg twice a day) on occupancy of GlyT1 were tested using positron emission tomography and 18 F-MK-6577, and visual long-term potentiation (LTP) in schizophrenia patients (SZs) and healthy control subjects. Furthermore, the capacity of PF-03463275 to attenuate ketamine-induced disruption of working memory-related activation of a "working memory" circuit was tested only in healthy control subjects using functional magnetic resonance imaging. Subsequently, the effects of PF-03463275 (60 mg twice a day) on occupancy of GlyT1 and long-term potentiation were examined only in SZs (substudy 2). PF-03463275 at 10, 20, 40, and 60 mg twice a day produced ∼44%, 61%, 76%, and 83% GlyT1 occupancy, respectively, in SZs with higher ligand binding to GlyT1 in subcortical versus cortical regions. PF-03463275 did not attenuate any ketamine-induced effects but did improve working memory accuracy in healthy control subjects. PF-03463275 increased long-term potentiation only in SZs with peak effects at 40 mg twice a day (∼75% GlyT1 occupancy) and with a profile suggestive of an inverted U dose response. PF-03463275 was well-tolerated. The dose-related GlyT1 occupancy of PF-03463275 is linear. While PF-03463275 did not show evidence of facilitating N-methyl-D-aspartate receptor function in the ketamine assay, it enhanced neuroplasticity in SZs. These findings provide support for a clinical trial to test the ability of PF-03463275 to enhance cognitive remediation toward addressing cognitive impairments associated with schizophrenia. Published by Elsevier Inc.

  17. An Evidence-based Guideline for the air medical transportation of prehospital trauma patients.

    Science.gov (United States)

    Thomas, Stephen H; Brown, Kathleen M; Oliver, Zoë J; Spaite, Daniel W; Lawner, Benjamin J; Sahni, Ritu; Weik, Tasmeen S; Falck-Ytter, Yngve; Wright, Joseph L; Lang, Eddy S

    2014-01-01

    Decisions about the transportation of trauma patients by helicopter are often not well informed by research assessing the risks, benefits, and costs of such transport. The objective of this evidence-based guideline (EBG) is to recommend a strategy for the selection of prehospital trauma patients who would benefit most from aeromedical transportation. A multidisciplinary panel was recruited consisting of experts in trauma, EBG development, and emergency medical services (EMS) outcomes research. Representatives of the Federal Interagency Committee on Emergency Medical Services (FICEMS), the National Highway Traffic Safety Administration (NHTSA) (funding agency), and the Children's National Medical Center (investigative team) also contributed to the process. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to guide question formulation, evidence retrieval, appraisal/synthesis, and formulate recommendations. The process followed the National Evidence-Based Guideline Model Process, which has been approved by the Federal Interagency Committee on EMS and the National EMS Advisory Council. Two strong and three weak recommendations emerged from the process, all supported only by low or very low quality evidence. The panel strongly recommended that the 2011 CDC Guideline for the Field Triage of Injured Patients be used as the initial step in the triage process, and that ground emergency medical services (GEMS) be used for patients not meeting CDC anatomic, physiologic, and situational high-acuity criteria. The panel issued a weak recommendation to use helicopter emergency medical services (HEMS) for higher-acuity patients if there is a time-savings versus GEMS, or if an appropriate hospital is not accessible by GEMS due to systemic/logistical factors. The panel strongly recommended that online medical direction should not be required for activating HEMS. Special consideration was given to the potential need for local

  18. Evaluation of the glycine transporter inhibitor Org 25935 as augmentation to cognitive-behavioral therapy for panic disorder: a multicenter, randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Nations, Kari R; Smits, Jasper A J; Tolin, David F; Rothbaum, Barbara O; Hofmann, Stefan G; Tart, Candyce D; Lee, Allen; Schipper, Jacques; Sjogren, Magnus; Xue, Dixi; Szegedi, Armin; Otto, Michael W

    2012-05-01

    A growing body of evidence supports the efficacy of D-cycloserine (DCS), a partial agonist at the N-methyl-D-aspartate (NMDA) glutamate receptor, as augmentation to cognitive-behavioral therapy (CBT) in the treatment of anxiety disorders. Org 25935 is a glycine transporter 1 inhibitor that acts to increase synaptic glycine levels and enhance NMDA-mediated glutamatergic activity. The aim of this study was to examine the efficacy of a glutamatergic compound other than DCS in a CBT augmentation paradigm. This was a randomized, double-blind, placebo-controlled, parallel-group clinical trial for which participants were recruited from November 2008 through February 2010. Eligible adult patients diagnosed (DSM-IV) with panic disorder with or without agoraphobia (N = 40) were scheduled to receive 5 manualized CBT treatment sessions. Participants were randomly assigned to receive either a dose of Org 25935 (4 mg or 12 mg) or placebo 2 hours prior to the start of CBT sessions 3, 4, and 5. The primary endpoint was symptomatic change as measured by the Panic Disorder Severity Scale (PDSS) 1 week following the last CBT session. Although mean PDSS total scores decreased significantly from baseline to end of treatment in every group, no statistically significant benefit was observed for Org 25935 (4 or 12 mg) over placebo on the primary endpoint or on any secondary efficacy endpoint. Org 25935 showed no safety issues at either dose but was much better tolerated at the 4-mg dose level than at the 12-mg dose level. Org 25935 demonstrated no benefit over placebo in augmenting CBT for panic disorder. Study limitations and implications are discussed. clinicaltrials.gov Identifier: NCT00725725. © Copyright 2012 Physicians Postgraduate Press, Inc.

  19. On the observability of turbulent transport rates by Argo: supporting evidence from an inversion experiment

    Directory of Open Access Journals (Sweden)

    G. Forget

    2015-10-01

    Full Text Available Although estimation of turbulent transport parameters using inverse methods is not new, there is little evaluation of the method in the literature. Here, it is shown that extended observation of the broad-scale hydrography by Argo provides a path to improved estimates of regional turbulent transport rates. Results from a 20-year ocean state estimate produced with the ECCO v4 (Estimating the Circulation and Climate of the Ocean, version 4 non-linear inverse modeling framework provide supporting evidence. Turbulent transport parameter maps are estimated under the constraints of fitting the extensive collection of Argo profiles collected through 2011. The adjusted parameters dramatically reduce misfits to in situ profiles as compared with earlier ECCO solutions. They also yield a clear reduction in the model drift away from observations over multi-century-long simulations, both for assimilated variables (temperature and salinity and independent variables (biogeochemical tracers. Despite the minimal constraints imposed specifically on the estimated parameters, their geography is physically plausible and exhibits close connections with the upper-ocean stratification as observed by Argo. The estimated parameter adjustments furthermore have first-order impacts on upper-ocean stratification and mixed layer depths over 20 years. These results identify the constraint of fitting Argo profiles as an effective observational basis for regional turbulent transport rate inversions. Uncertainties and further improvements of the method are discussed.

  20. Evidence for aquaporin-mediated water transport in nematocytes of the jellyfish Pelagia noctiluca.

    Science.gov (United States)

    Marino, Angela; Morabito, Rossana; La Spada, Giuseppina; Adragna, Norma C; Lauf, Peter K

    2011-01-01

    Nematocytes, the stinging cells of Cnidarians, have a cytoplasm confined to a thin rim. The main cell body is occupied by an organoid, the nematocyst, containing the stinging tubule and venom. Exposed to hypotonic shock, nematocytes initially swell during an osmotic phase (OP) and then undergo regulatory volume decrease (RVD) driven by K(+), Cl(-) and obligatory water extrusion mechanisms. The purpose of this report is to characterize the OP. Nematocytes were isolated by the NaSCN/Ca(2+) method from tentacles of the jellyfish Pelagia noctiluca, collected in the Strait of Messina, Italy. Isolated nematocytes were subjected to hyposmotic shock in 65% artificial seawater (ASW) for 15 min. The selective aquaporin water channel inhibitor HgCl(2) (0.1-25 μM) applied prior to osmotic shock prevented the OP and thus RVD. These effects were attenuated in the presence of 1mM dithiothreitol (DTT), a mercaptide bond reducing agent. AgNO(3) (1 μM) and TEA (tetraethylammonium, 100 μM), also reported to inhibit water transport, did not alter the OP but significantly diminished RVD, suggesting different modes of action for the inhibitors tested. Based on estimates of the nematocyte surface area and volume, and OP duration, a relative water permeability of ~10(-7) cm/sec was calculated and the number of putative aquaporin molecules mediating the OP was estimated. This water permeability is 3-4 orders of magnitude lower in comparison to higher order animals and may constitute an evolutionary advantage for Cnidarian survival. Copyright © 2011 S. Karger AG, Basel.

  1. Evidence for the 'grasshopper' effect and fractionation during long-range atmospheric transport of organic contaminants

    International Nuclear Information System (INIS)

    Gouin, T.; Mackay, D.; Jones, K.C.; Harner, T.; Meijer, S.N.

    2004-01-01

    Although there is indisputable evidence that long-range atmospheric transport (LRAT) of organic contaminants occurs on a global scale, uncertainties remain about the detailed mechanism and extent of this phenomenon as well as the physical-chemical properties which facilitate LRAT. In this study, we discuss how mass balance models and monitoring data can contribute to a fuller understanding of the mechanism and extent of LRAT. Specifically we address the issues of 'grasshopping' or 'hopping' (the extent to which molecules are subject to multiple hops as distinct from a single emission-deposition event) and 'global fractionation' (the differing behavior of chemicals as they are transported). It is shown that simple mass balance models can be used to assist the interpretation of monitoring data while also providing an instrument that can be used to assess the LRAT potential and the extent of hopping that organic substances may experience. The available evidence supports the notion that many persistent organic pollutants experience varying degrees of 'hopping' during their environmental journey and as a consequence become fractionated with distance from source. - Evidence for global scale fractionation and hopping of POPs is reviewed

  2. Ammonia excretion in Caenorhabditis elegans: mechanism and evidence of ammonia transport of the Rhesus protein CeRhr-1

    Science.gov (United States)

    Adlimoghaddam, Aida; Boeckstaens, Mélanie; Marini, Anna-Maria; Treberg, Jason R.; Brassinga, Ann-Karen C.; Weihrauch, Dirk

    2015-01-01

    ABSTRACT The soil-dwelling nematode Caenorhabditis elegans is a bacteriovorous animal, excreting the vast majority of its nitrogenous waste as ammonia (25.3±1.2 µmol gFW−1 day−1) and very little urea (0.21±0.004 µmol gFW−1 day−1). Although these roundworms have been used for decades as genetic model systems, very little is known about their strategy to eliminate the toxic waste product ammonia from their bodies into the environment. The current study provides evidence that ammonia is at least partially excreted via the hypodermis. Starvation reduced the ammonia excretion rates by more than half, whereas mRNA expression levels of the Rhesus protein CeRhr-2, V-type H+-ATPase (subunit A) and Na+/K+-ATPase (α-subunit) decreased correspondingly. Moreover, ammonia excretion rates were enhanced in media buffered to pH 5 and decreased at pH 9.5. Inhibitor experiments, combined with enzyme activity measurements and mRNA expression analyses, further suggested that the excretion mechanism involves the participation of the V-type H+-ATPase, carbonic anhydrase, Na+/K+-ATPase, and a functional microtubule network. These findings indicate that ammonia is excreted, not only by apical ammonia trapping, but also via vesicular transport and exocytosis. Exposure to 1 mmol l−1 NH4Cl caused a 10-fold increase in body ammonia and a tripling of ammonia excretion rates. Gene expression levels of CeRhr-1 and CeRhr-2, V-ATPase and Na+/K+-ATPase also increased significantly in response to 1 mmol l−1 NH4Cl. Importantly, a functional expression analysis showed, for the first time, ammonia transport capabilities for CeRhr-1 in a phylogenetically ancient invertebrate system, identifying these proteins as potential functional precursors to the vertebrate ammonia-transporting Rh-glycoproteins. PMID:25740900

  3. Evidence-based decision making : developing a knowledge base for successful program outcomes in transportation asset management.

    Science.gov (United States)

    2015-12-01

    MAP-21 and AASHTOs framework for transportation asset management (TAM) offer opportunities to use more : rigorous approaches to collect and apply evidence within a TAM context. This report documents the results of a study : funded by the Georgia D...

  4. Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds.

    Directory of Open Access Journals (Sweden)

    Diana Ortiz

    Full Text Available Development of resistance against current antimalarial drugs necessitates the search for novel drugs that interact with different targets and have distinct mechanisms of action. Malaria parasites depend upon high levels of glucose uptake followed by inefficient metabolic utilization via the glycolytic pathway, and the Plasmodium falciparum hexose transporter PfHT, which mediates uptake of glucose, has thus been recognized as a promising drug target. This transporter is highly divergent from mammalian hexose transporters, and it appears to be a permease that is essential for parasite viability in intra-erythrocytic, mosquito, and liver stages of the parasite life cycle. An assay was developed that is appropriate for high throughput screening against PfHT based upon heterologous expression of PfHT in Leishmania mexicana parasites that are null mutants for their endogenous hexose transporters. Screening of two focused libraries of antimalarial compounds identified two such compounds that are high potency selective inhibitors of PfHT compared to human GLUT1. Additionally, 7 other compounds were identified that are lower potency and lower specificity PfHT inhibitors but might nonetheless serve as starting points for identification of analogs with more selective properties. These results further support the potential of PfHT as a novel drug target.

  5. Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation

    DEFF Research Database (Denmark)

    Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch

    2015-01-01

    ) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced...... to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4...

  6. Adverse Effects and Safety of SGLT2 Inhibitor Use among Patients with Type 2 Diabetes: Findings from RCT Evidence

    OpenAIRE

    Tang, Huilin; Zhang, Jingjing; Song, Yiqing

    2017-01-01

    Sodium-glucose cotransporter 2 (SGTL2) inhibitors, a novel class of glucose-lowering agents, act in an insulin-independent manner by increasing urinary glucose excretion. In addition to reduce hyperglycemia, SGTL2 inhibitor exerts beneficial effects on cardiovascular risk factors (e.g., lower blood pressure and enhance weigh loss), which may confer additional health benefits for type 2 diabetes patients. The EMPA-REG OUTCOME trial showed that empagliflozin not only reduced the risk of major a...

  7. Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP 4 and breast cancer resistance protein (BCRP

    Directory of Open Access Journals (Sweden)

    Rhiannon N. Hardwick

    2016-12-01

    Full Text Available Tyrosine and aurora kinases are important effectors in signal transduction pathways that are often involved in aberrant cancer cell growth. Tyrosine (TKI and aurora (AKI kinase inhibitors are anti-cancer agents specifically designed to target such signaling pathways through TKI/AKI binding to the ATP-binding pocket of kinases thereby leading to diminished kinase activity. Some TKIs have been identified as inhibitors of ATP-binding cassette (ABC transporters such as P-glycoprotein and breast cancer resistance protein (BCRP, which are commonly upregulated in malignant cells. TKI/AKIs have been investigated as ABC transporter inhibitors in order to facilitate the accumulation of concomitantly administered chemo-therapeutics within cancer cells. However, ABC transporters are prominently expressed in the liver and other eliminating organs, and their inhibition has been linked to intracellular accumulation of drugs, altered disposition, and toxicity. The potential for TKIs/AKIs to inhibit other important hepatic efflux transporters, particularly multidrug resistance-associated proteins (MRPs, remains unknown. The aim of the current study was to compare the inhibitory potency of 20 selected TKI/AKIs against MRP4 and BCRP through the use of inverted membrane vesicle assays. Relative IC50 values were estimated by determining TKI/AKI inhibition of MRP4-mediated [3H]-dehydroepiandrosterone sulfate uptake and BCRP-mediated [3H]-estrone sulfate uptake. To provide insight to the clinical relevance of TKI/AKI inhibition of ABC efflux transporters, the ratio of the steady-state maximum total plasma concentration (Css to the IC50 for each compound was calculated with Css/IC50 ratio >0.1 deemed potentially clinically relevant. Such analysis identified several potentially clinically relevant inhibitors of MRP4: alisertib, danusertib, erlotinib, lapatinib, neratinib, nilotinib, pazopanib, sorafenib, and tozasertib. The potentially clinically relevant inhibition of

  8. Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis.

    Science.gov (United States)

    Packer, Milton

    2018-06-01

    Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis probably contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin. © 2018 John Wiley & Sons Ltd.

  9. Potent inhibitors of human LAT1 (SLC7A5) transporter based on dithiazole and dithiazine compounds for development of anticancer drugs.

    Science.gov (United States)

    Napolitano, Lara; Scalise, Mariafrancesca; Koyioni, Maria; Koutentis, Panayiotis; Catto, Marco; Eberini, Ivano; Parravicini, Chiara; Palazzolo, Luca; Pisani, Leonardo; Galluccio, Michele; Console, Lara; Carotti, Angelo; Indiveri, Cesare

    2017-11-01

    The LAT1 transporter is acknowledged as a pharmacological target of tumours since it is strongly overexpressed in many human cancers. The purpose of this work was to find novel compounds exhibiting potent and prolonged inhibition of the transporter. To this aim, compounds based on dithiazole and dithiazine scaffold have been screened in the proteoliposome experimental model. Inhibition was tested on the antiport catalysed by hLAT1 as transport of extraliposomal [ 3 H]histidine in exchange with intraliposomal histidine. Out of 59 compounds tested, 8 compounds, showing an inhibition higher than 90% at 100µM concentration, were subjected to dose-response analysis. Two of them exhibited IC 50 lower than 1µM. Inhibition kinetics, performed on the two best inhibitors, indicated a mixed type of inhibition with respect to the substrate. Furthermore, inhibition of the transporter was still present after removal of the compounds from the reaction mixture, but was reversed on addition of dithioerythritol, a S-S reducing agent, indicating the formation of disulfide(s) between the compounds and the protein. Molecular docking of the two best inhibitors on the hLAT1 homology structural model, highlighted interaction with the substrate binding site and formation of a covalent bond with the residue C407. Indeed, the inhibition was impaired in the hLAT1 mutant C407A confirming the involvement of that Cys residue. Treatment of SiHa cells expressing hLAT1 at relatively high level, with the two most potent inhibitors led to cell death which was not observed after treatment with a compound exhibiting very poor inhibitory effect. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Sodium-glucose co-transporter-2 inhibitors, the latest residents on the block: Impact on glycaemic control at a general practice level in England.

    Science.gov (United States)

    Heald, Adrian H; Fryer, Anthony A; Anderson, Simon G; Livingston, Mark; Lunt, Mark; Davies, Mark; Moreno, Gabriela Y C; Gadsby, Roger; Young, Robert J; Stedman, Mike

    2018-03-08

    To determine, using published general practice-level data, how differences in Type 2 diabetes mellitus (T2DM) prescribing patterns relate to glycaemic target achievement levels. Multiple linear regression modelling was used to link practice characteristics and defined daily dose (DDD) of different classes of medication in 2015/2016 and changes between that year and the year 2014/2015 in medication to proportion of patients achieving target glycaemic control (glycated haemoglobin A1c [HbA1c] ≤58 mmol/mol [7.5%]) and proportion of patients at high glycaemic risk (HbA1c >86 mmol/mol [10.0%]) for practices in the National Diabetes Audit with >100 people with T2DM on their register. Overall, HbA1c outcomes were not different between the years studied. Although, in percentage terms, most practices increased their use of sodium-glucose co-transporter-2 (SGLT2) inhibitors (96%), dipeptidyl peptidase-4 (DPP-4) inhibitors (76%) and glucagon-like peptide 1 (GLP-1) analogues (53%), there was wide variation in the use of older and newer therapies. For example, 12% of practices used >200% of the national average for some newer agents. In cross-sectional analysis, greater prescribing of metformin and analogue insulin were associated with a higher proportion of patients achieving HbA1c ≤58 mmol/mol; the use of SGLT2 inhibitors and metformin was associated with a reduced proportion of patients with HbA1c >86 mol/mol; otherwise associations for sulphonylureas, GLP-1 analogues, SGLT2 inhibitors and DPP-4 inhibitors were neutral or negative. In year-on-year analysis there was ongoing deterioration in glycaemic control, which was offset to some extent by increased use of SGLT2 inhibitors and GLP-1 analogues, which were associated with a greater proportion of patients achieving HbA1c levels ≤58 mmol/mol and a smaller proportion of patients with HbA1c levels >86 mmol/mol. SGLT2 inhibitor prescribing was associated with significantly greater improvements than those found

  11. Insights into the molecular mechanism of action of Celastraceae sesquiterpenes as specific, non-transported inhibitors of human P-glycoprotein.

    Science.gov (United States)

    Muñoz-Martínez, Francisco; Reyes, Carolina P; Pérez-Lomas, Antonio L; Jiménez, Ignacio A; Gamarro, Francisco; Castanys, Santiago

    2006-01-01

    Dihydro-beta-agarofuran sesquiterpenes from Celastraceae have been recently shown to bind to human P-glycoprotein (Pgp), functioning as specific, mixed-type inhibitors of its drug transport activity, as well as multidrug resistance (MDR) modulators in vitro. However, nothing is known about whether such compounds are themselves transported by Pgp, or whether they affect Pgp expression as well as its activity, or about the location of their binding site within the protein. We performed transport experiments with a newly synthesized fluorescent sesquiterpene derivative, which retains the anti-Pgp activity of its natural precursor. This probe was poorly transported by Pgp, MRP1, MRP2 and BCRP transporters, compared with classical MDR substrates. Moreover, Pgp did not confer cross-resistance to the most potent dihydro-beta-agarofurans, which did not affect Pgp expression levels in several MDR cell lines. Finally, we observed competitive and non-competitive interactions between one of such dihydro-beta-agarofurans (Mama12) and classical Pgp modulators such as cyclosporin A, verapamil, progesterone, vinblastine and GF120918. These findings suggest that multidrug ABC transporters do not confer resistance to dihydro-beta-agarofurans and could not affect their absorption and biodistribution in the body. Moreover, we mapped their binding site(s) within Pgp, which may prove useful for the rational design of improved modulators based on the structure of dihydro-beta-agarofurans.

  12. Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression.

    Science.gov (United States)

    Degnan, Andrew P; Tora, George O; Huang, Hong; Conlon, David A; Davis, Carl D; Hanumegowda, Umesh M; Hou, Xiaoping; Hsiao, Yi; Hu, Joanna; Krause, Rudolph; Li, Yu-Wen; Newton, Amy E; Pieschl, Rick L; Raybon, Joseph; Rosner, Thorsten; Sun, Jung-Hui; Taber, Matthew T; Taylor, Sarah J; Wong, Michael K; Zhang, Huiping; Lodge, Nicholas J; Bronson, Joanne J; Macor, John E; Gillman, Kevin W

    2016-12-21

    Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.

  13. Skin cancer associated with commonly prescribed drugs: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and statins -weighing the evidence.

    Science.gov (United States)

    Nardone, Beatrice; Orrell, Kelsey A; Vakharia, Paras P; West, Dennis P

    2018-02-01

    Skin cancers, including both malignant melanoma (MM) and nonmelanoma skin cancer (NMSC), are the most commonly diagnosed cancers in the US. The incidence of both MM and NMSC continues to rise. Areas covered: Current evidence for an association between four of the most commonly prescribed classes of drugs in the U.S. and risk for MM and NMSC is reported. Medline was searched (January 2000 to May 2017) for each drug in the classes and for 'basal cell carcinoma', 'squamous cell carcinoma', 'non-melanoma skin cancer', 'skin cancer' and 'melanoma'. Skin cancer risk information was reported for: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins). Expert opinion: Since skin cancer risk is associated with all four classes of these commonly prescribed drugs that represent nearly 20% of the Top 100 drugs in the U.S., these important findings warrant enhanced education, especially for prescribers and those patients at high risk for skin cancer.

  14. Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons.

    Science.gov (United States)

    Avelar, Alicia J; Cao, Jianjing; Newman, Amy Hauck; Beckstead, Michael J

    2017-09-01

    Abuse of psychostimulants like cocaine that inhibit dopamine (DA) reuptake through the dopamine transporter (DAT) represents a major public health issue, however FDA-approved pharmacotherapies have yet to be developed. Recently a class of ligands termed "atypical DAT inhibitors" has gained attention due to their range of effectiveness in increasing extracellular DA levels without demonstrating significant abuse liability. These compounds not only hold promise as therapeutic agents to treat stimulant use disorders but also as experimental tools to improve our understanding of DAT function. Here we used patch clamp electrophysiology in mouse brain slices to explore the effects of two atypical DAT inhibitors (R-modafinil and JHW 007) on the physiology of single DA neurons in the substantia nigra and ventral tegmental area. Despite their commonalities of being DAT inhibitors that lack cocaine-like behavioral profiles, these compounds exhibited surprisingly divergent cellular effects. Similar to cocaine, R-modafinil slowed DA neuron firing in a D2 receptor-dependent manner and rapidly enhanced the amplitude and duration of D2 receptor-mediated currents in the midbrain. In contrast, JHW 007 exhibited little effect on firing, slow DAT blockade, and an unexpected inhibition of D2 receptor-mediated currents that may be due to direct D2 receptor antagonism. Furthermore, pretreatment with JHW 007 blunted the cellular effects of cocaine, suggesting that it may be valuable to investigate similar DAT inhibitors as potential therapeutic agents. Further exploration of these and other atypical DAT inhibitors may reveal important cellular effects of compounds that will have potential as pharmacotherapies for treating cocaine use disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: implications for the emergence and reversal of cancer drug resistance.

    Science.gov (United States)

    Hegedüs, Csilla; Truta-Feles, Krisztina; Antalffy, Géza; Várady, György; Német, Katalin; Ozvegy-Laczka, Csilla; Kéri, György; Orfi, László; Szakács, Gergely; Settleman, Jeffrey; Váradi, András; Sarkadi, Balázs

    2012-08-01

    Human ABCG2 is a plasma membrane glycoprotein that provides physiological protection against xenobiotics. ABCG2 also significantly influences biodistribution of drugs through pharmacological tissue barriers and confers multidrug resistance to cancer cells. Moreover, ABCG2 is the molecular determinant of the side population that is characteristically enriched in normal and cancer stem cells. Numerous tumors depend on unregulated EGFR signaling, thus inhibition of this receptor by small molecular weight inhibitors such as gefitinib, and the novel second generation agents vandetanib, pelitinib and neratinib, is a promising therapeutic option. In the present study, we provide detailed biochemical characterization regarding the interaction of these EGFR inhibitors with ABCG2. We show that ABCG2 confers resistance to gefitinib and pelitinib, whereas the intracellular action of vandetanib and neratinib is unaltered by the presence of the transporter. At higher concentrations, however, all these EGFR inhibitors inhibit ABCG2 function, thereby promoting accumulation of ABCG2 substrate drugs. We also report enhanced expression of ABCG2 in gefitinib-resistant non-small cell lung cancer cells, suggesting potential clinical relevance of ABCG2 in acquired drug resistance. Since ABCG2 has important impact on both the pharmacological properties and anti-cancer efficiencies of drugs, our results regarding the novel EGFR inhibitors should provide useful information about their therapeutic applicability against ABCG2-expressing cancer cells depending on EGFR signaling. In addition, the finding that these EGFR inhibitors efficiently block ABCG2 function may help to design novel drug-combination therapeutic strategies. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. A virtual high-throughput screening approach to the discovery of novel inhibitors of the bacterial leucine transporter, LeuT

    DEFF Research Database (Denmark)

    Simmons, Katie J; Gotfryd, Kamil; Billesbølle, Christian B

    2013-01-01

    Abstract Membrane proteins are intrinsically involved in both human and pathogen physiology, and are the target of 60% of all marketed drugs. During the past decade, advances in the studies of membrane proteins using X-ray crystallography, electron microscopy and NMR-based techniques led to the e...... this is a virtual high-throughput screening (vHTS) technique initially developed for soluble proteins. This paper describes application of this technique to the discovery of inhibitors of the leucine transporter (LeuT), a member of the neurotransmitter:sodium symporter (NSS) family....

  17. [Sodium-glucose co-transporter-2 inhibitors: from the bark of apple trees and familial renal glycosuria to the treatment of type 2 diabetes mellitus].

    Science.gov (United States)

    Mauricio, Dídac

    2013-09-01

    The therapeutic armamentarium for the treatment of hyperglycemia in type 2 diabetes mellitus is still inadequate. We are currently witnessing the introduction of a new mode of hypoglycemic treatment through induction of glycosuria to decrease the availability of the metabolic substrate, i.e. glucose. Clinical trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors are as efficacious as other oral hypoglycemic drugs. This article discusses the basic features of this new treatment concept and the efficacy and safety of this new drug group. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  18. Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level.

    Science.gov (United States)

    Fischer, Jana; Kleinau, Gunnar; Rutz, Claudia; Zwanziger, Denise; Khajavi, Noushafarin; Müller, Anne; Rehders, Maren; Brix, Klaudia; Worth, Catherine L; Führer, Dagmar; Krude, Heiko; Wiesner, Burkhard; Schülein, Ralf; Biebermann, Heike

    2018-06-01

    G-protein-coupled receptors (GPCRs) can constitute complexes with non-GPCR integral membrane proteins, while such interaction has not been demonstrated at a single molecule level so far. We here investigated the potential interaction between the thyrotropin receptor (TSHR) and the monocarboxylate transporter 8 (MCT8), a member of the major facilitator superfamily (MFS), using fluorescence cross-correlation spectroscopy (FCCS). Both the proteins are expressed endogenously on the basolateral plasma membrane of the thyrocytes and are involved in stimulation of thyroid hormone production and release. Indeed, we demonstrate strong interaction between both the proteins which causes a suppressed activation of G q/11 by TSH-stimulated TSHR. Thus, we provide not only evidence for a novel interaction between the TSHR and MCT8, but could also prove this interaction on a single molecule level. Moreover, this interaction forces biased signaling at the TSHR. These results are of general interest for both the GPCR and the MFS research fields.

  19. Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition

    Directory of Open Access Journals (Sweden)

    Jayanthan Aarthi

    2011-12-01

    Full Text Available Abstract Background Currently, Atypical Teratoid Rhabdoid Tumor (AT/RT constitutes one of the most difficult to treat malignancies in pediatrics. Hence, new knowledge of potential targets for therapeutics and the development of novel treatment approaches are urgently needed. We have evaluated the presence of cytokine pathways and the effects of two clinically available multi-tyrosine kinase inhibitors for cytotoxicity, target modulation and drug combinability against AT/RT cell lines. Results AT/RT cell lines expressed measurable quantities of VEGF, FGF, PDGF and SDF-1, although the absolute amounts varied between the cell lines. The targeted receptor tyrosine kinase inhibitor sorafenib inhibited the key signaling molecule Erk, which was activated following the addition of own conditioned media, suggesting the existence of autocrine/paracrine growth stimulatory pathways. The multi-tyrosine kinase inhibitors sorafenib and sunitinib also showed significant growth inhibition of AT/RT cells and their activity was enhanced by combination with the topoisomerase inhibitor, irinotecan. The loss of cytoplasmic NF-kappa-B in response to irinotecan was diminished by sorafenib, providing evidence for a possible benefit for this drug combination. Conclusions In addition to previously described involvement of insulin like growth factor (IGF family of cytokines, a multitude of other growth factors may contribute to the growth and survival of AT/RT cells. However, consistent with the heterogeneous nature of this tumor, quantitative and qualitative differences may exist among different tumor samples. Multi-tyrosine kinase inhibitors appear to have effective antitumor activity against all cell lines studied. In addition, the target modulation studies and drug combinability data provide the groundwork for additional studies and support the evaluation of these agents in future treatment protocols.

  20. Transport and deposition of plutonium in the ocean: Evidence from Gulf of Mexico sediments

    International Nuclear Information System (INIS)

    Scott, M.R.; Salter, P.F.; Halverson, J.E.

    1983-01-01

    A study of sediments in the Gulf of Mexico shows dramatic gradients in Pu content and isotope ratios from the continental shelf to the Sigsbee Abyssal Plain. In terms of predicted direct fallout inventory of Pu, one shelf core contains 745% of the predicted inventory, while abyssal plain sediments contain only 15-20% of the predicted value. Absolute Pu concentrations of shelf sediments are also conspicuously high, up to 110 dpm/kg, compared to 13.5 dpm/kg in Mississippi River suspended sediment. There is no evidence of Pu remobilization in Gulf of Mexico shelf sediments, based on comparison of Pu profiles with Mn/Al and Fe/Al profiles. Horizontal transport of fallout nuclides from the open ocean to removal sites in ocean margin sediments is concluded to be the source of both the high concentrations and high inventories of Pu reported here. The shelf sediments show 240 Pu/ 239 Pu ratios close to 0.179, the average stratospheric fallout value, but the ratios decrease progressively across the Gulf to low values of 0.06 in abyssal plain sediments. The source of low-ratio Pu in deep-water sediments may be debris from low yield tests transported in the troposphere. Alternatively, it may represent a fraction of the Pu from global stratospheric fallout which has been separated in the water column from the remainder of the Pu in the ocean. In either case, the low-ratio material must have been removed rapidly to the sea floor where it composes a major fraction of the Pu in abyssal plain sediments. Pu delivered by global atmospheric fallout from the stratosphere has apparently remained for the most part in the water or has been transported horizontally and removed into shallow-water sediments. (orig.)

  1. The war in Kosovo: Evidence of pollution transport in the Balkans during operation "Allied Force".

    Science.gov (United States)

    Melas, D; Zerefos, C; Rapsomanikis, S; Tsangas, N; Alexandropoulou, A

    2000-01-01

    During the operation "Allied Force" in the spring of 1999, the burning or damaging of industrial and military targets in the Former Republic of Yugoslavia resulted in the release of a large number of chemicals into the atmosphere. The releases contained not only conventional air pollutants, but also Semi-Volatile Organic compounds (SVOs) which are known to be hazardous to health. Under suitable meteorological conditions, these chemicals can be transported across borders over large distances. In this paper, an analysis of measurements and dispersion calculations is presented which provides evidence of pollutant transport from the conflict area to Greece. The measuring program was carried out in Xanthi, Greece and included aerosol sampling and subsequent analysis for the determination of the concentration of SVOs including dioxins, furans, PCBs (PolyChlorinated Biphenyls), PAHs (Polycyclic Aromatic Hydrocarbons) and organic phthalates. This paper focuses on two episodes of organic phthalates that were observed during the conflict period. Pollution measurements are interpreted by means of air trajectories and dispersion calculations. For this purpose, the HYSPLIT_4 (HYbrid Single-Particle Langrangian Integrated Trajectory) modeling system is used to calculate the dispersion of toxic substances.

  2. Treatment options in HR⁺/HER2⁻ advanced breast cancer patients pretreated with nonsteroidal aromatase inhibitors: what does current evidence tell us?

    Science.gov (United States)

    De Placido, Sabino; Pronzato, Paolo

    2015-01-01

    Many postmenopausal women with advanced or metastatic breast cancer (BC) receive nonsteroidal aromatase inhibitors (NSAIs). Virtually all of them experience progression, but may still gain benefit from a different endocrine or targeted agent. We indirectly compare the results of trials on endocrine or targeted treatment in HR(+)/HER2(-) mBC patients who progressed after a prior NSAI therapy. Although with the limitations of any indirect comparison, evidence suggests that only the combination of everolimus and exemestane is associated with a prolonged progression-free survival and a more evident clinical benefit than its comparators. We speculate that prior NSAI therapy can 'per se' individuate patients eligible to everolimus. More robust data from head-to-head trials will provide more grounded evidence on this issue.

  3. Influence of ferrocyanide inhibitors on the transport and crystrallization processes of sodium chloride in porous building materials

    NARCIS (Netherlands)

    Gupta, S.; Terheiden, K.H; Pel, L.; Sawdy - Heritage, A.M.

    2012-01-01

    Salt weathering leads to destruction of many valuable cultural heritage monuments and porous building materials. In order to reduce the impact of this, effective treatment methods are required. The use of crystallization inhibitors to mitigate salt damage has been proposed in the past; however, to

  4. Geological evidence and sediment transport modelling for the 1946 and 1960 tsunamis in Shinmachi, Hilo, Hawaii

    Science.gov (United States)

    Chagué, Catherine; Sugawara, Daisuke; Goto, Kazuhisa; Goff, James; Dudley, Walter; Gadd, Patricia

    2018-02-01

    The Japanese community of Shinmachi, established on low-lying land between downtown Hilo and Waiakea, Hawaii, was obliterated by the 1946 Aleutian tsunami but was rebuilt, only to be destroyed again by the 1960 Chilean tsunami. The aim of this study was to find out if any geological evidence of these well documented events had been preserved in the sedimentary record in Wailoa River State Park, which replaced Shinmachi after the 1960 tsunami. This was achieved by collecting cores in the park and performing sedimentological, chronological and geochemical analyses, the latter also processed by principal component analysis. Sediment transport modelling was carried out for both tsunamis, to infer the source of the sediment and areas of deposition on land. The field survey revealed two distinct units within peat and soil, a thin lower unit composed of weathered basalt fragments within mud (Unit 1) and an upper unit dominated by fine volcanic sand within fine silt exhibiting subtle upward fining and coarsening (Unit 2, consisting of Unit 2A and Unit 2B), although these two anomalous units only occur on the western shore of Waiakea Mill Pond. Analysis with an ITRAX core scanner shows that Unit 1 is characterised by high Mn, Fe, Rb, La and Ce counts, combined with elevated magnetic susceptibility. Based on its chemical and sedimentological characteristics, Unit 1 is attributed to a flood event in Wailoa River that occurred around 1520-1660 CE, most probably as a result of a tropical storm. The sharp lower contact of Unit 2 coincides with the appearance of arsenic, contemporaneous with an increase in Ca, Sr, Si, Ti, K, Zr, Mn, Fe, La and Ce. In this study, As is used as a chronological and source material marker, as it is known to have been released into Wailoa River Estuary and Waiakea Mill Pond by the Canec factory between 1932 and 1963. Thus, not only the chemical and sedimentological evidence but also sediment transport modelling, corroborating the historical record

  5. Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease.

    Science.gov (United States)

    Abe, Yasuyuki; Aoyagi, Atsushi; Hara, Takao; Abe, Kazumi; Yamazaki, Reina; Kumagae, Yoshihiro; Naruto, Shunji; Koyama, Kazuo; Marumoto, Shinji; Tago, Keiko; Toda, Narihiro; Takami, Kazuko; Yamada, Naho; Ori, Mayuko; Kogen, Hiroshi; Kaneko, Tsugio

    2003-09-01

    A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.

  6. Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice

    Science.gov (United States)

    Nguyen, Hai T; Guiard, Bruno P; Bacq, Alexandre; David, Denis J; David, Indira; Quesseveur, Gaël; Gautron, Sophie; Sanchez, Connie; Gardier, Alain M

    2013-01-01

    BACKGROUND AND PURPOSE Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT]ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. EXPERIMENTAL APPROACH This study examined the effects of escitalopram, on both [5-HT]ext and [NA]ext in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT−/−) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]ext, either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT]ext elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT]ext and/or [NA]ext affected the antidepressant-like activity of escitalopram. KEY RESULTS In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT]ext and [NA]ext. As expected, escitalopram failed to increase cortical [5-HT]ext in SERT−/− mice, whereas its neurochemical effects on [NA]ext persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters. CONCLUSIONS AND IMPLICATIONS These experiments suggest that escitalopram enhances, although moderately, cortical [NA]extin vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET). PMID:22233336

  7. Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy

    Directory of Open Access Journals (Sweden)

    Khalid J.H. Alzahrani

    2017-08-01

    Full Text Available Leishmania pyrimidine salvage is replete with opportunities for therapeutic intervention with enzyme inhibitors or antimetabolites. Their uptake into cells depends upon specific transporters; therefore it is essential to establish whether various Leishmania species possess similar pyrimidine transporters capable of drug uptake. Here, we report a comprehensive characterization of pyrimidine transport in L. major and L. mexicana. In both species, two transporters for uridine/adenosine were detected, one of which also transported uracil and the antimetabolites 5-fluoruracil (5-FU and 5F,2′deoxyuridine (5F,2′dUrd, and was designated uridine-uracil transporter 1 (UUT1; the other transporter mediated uptake of adenosine, uridine, 5F,2′dUrd and thymidine and was designated Nucleoside Transporter 1 (NT1. To verify the reported L. donovani model of two NT1-like genes encoding uridine/adenosine transporters, and an NT2 gene encoding an inosine transporter, we cloned the corresponding L. major and L. mexicana genes, expressing each in T. brucei. Consistent with the L. donovani reports, the NT1-like genes of either species mediated the adenosine-sensitive uptake of [3H]-uridine but not of [3H]-inosine. Conversely, the NT2-like genes mediated uptake of [3H]-inosine but not [3H]-uridine. Among pyrimidine antimetabolites tested, 5-FU and 5F,2′dUrd were the most effective antileishmanials; resistance to both analogs was induced in L. major and L. mexicana. In each case it was found that the resistant cells had lost the transport capacity for the inducing drug. Metabolomics analysis found that the mechanism of action of 5-FU and 5F-2′dUrd was similar in both Leishmania species, with major changes in deoxynucleotide metabolism. We conclude that the pyrimidine salvage system is highly conserved in Leishmania species - essential information for the development of pyrimidine-based chemotherapy. Keywords: Leishmania, Pyrimidine metabolism, Uracil

  8. Effect of Sodium-Glucose Co-Transporter 2 Inhibitor, Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes.

    Science.gov (United States)

    Shin, Seok Joon; Chung, Sungjin; Kim, Soo Jung; Lee, Eun-Mi; Yoo, Young-Hye; Kim, Ji-Won; Ahn, Yu-Bae; Kim, Eun-Sook; Moon, Sung-Dae; Kim, Myung-Jun; Ko, Seung-Hyun

    2016-01-01

    Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes. Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue. After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.

  9. Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway

    Science.gov (United States)

    Lorenz, Christian; Dougherty, Thomas J.

    2016-01-01

    ABSTRACT In Gram-negative bacteria, a dedicated machinery consisting of LolABCDE components targets lipoproteins to the outer membrane. We used a previously identified small-molecule inhibitor of the LolCDE complex of Escherichia coli to assess the global transcriptional consequences of interference with lipoprotein transport. Exposure of E. coli to the LolCDE inhibitor at concentrations leading to minimal and significant growth inhibition, followed by transcriptome sequencing, identified a small group of genes whose transcript levels were decreased and a larger group whose mRNA levels increased 10- to 100-fold compared to those of untreated cells. The majority of the genes whose mRNA concentrations were reduced were part of the flagellar assembly pathway, which contains an essential lipoprotein component. Most of the genes whose transcript levels were elevated encode proteins involved in selected cell stress pathways. Many of these genes are involved with envelope stress responses induced by the mislocalization of outer membrane lipoproteins. Although several of the genes whose RNAs were induced have previously been shown to be associated with the general perturbation of the cell envelope by antibiotics, a small subset was affected only by LolCDE inhibition. Findings from this work suggest that the efficiency of the Lol system function may be coupled to a specific monitoring system, which could be exploited in the development of reporter constructs suitable for use for screening for additional inhibitors of lipoprotein trafficking. IMPORTANCE Inhibition of the lipoprotein transport pathway leads to E. coli death and subsequent lysis. Early significant changes in the levels of RNA for a subset of genes identified to be associated with some periplasmic and envelope stress responses were observed. Together these findings suggest that disruption of this key pathway can have a severe impact on balanced outer membrane synthesis sufficient to affect viability. PMID

  10. Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway.

    Science.gov (United States)

    Lorenz, Christian; Dougherty, Thomas J; Lory, Stephen

    2016-12-01

    In Gram-negative bacteria, a dedicated machinery consisting of LolABCDE components targets lipoproteins to the outer membrane. We used a previously identified small-molecule inhibitor of the LolCDE complex of Escherichia coli to assess the global transcriptional consequences of interference with lipoprotein transport. Exposure of E. coli to the LolCDE inhibitor at concentrations leading to minimal and significant growth inhibition, followed by transcriptome sequencing, identified a small group of genes whose transcript levels were decreased and a larger group whose mRNA levels increased 10- to 100-fold compared to those of untreated cells. The majority of the genes whose mRNA concentrations were reduced were part of the flagellar assembly pathway, which contains an essential lipoprotein component. Most of the genes whose transcript levels were elevated encode proteins involved in selected cell stress pathways. Many of these genes are involved with envelope stress responses induced by the mislocalization of outer membrane lipoproteins. Although several of the genes whose RNAs were induced have previously been shown to be associated with the general perturbation of the cell envelope by antibiotics, a small subset was affected only by LolCDE inhibition. Findings from this work suggest that the efficiency of the Lol system function may be coupled to a specific monitoring system, which could be exploited in the development of reporter constructs suitable for use for screening for additional inhibitors of lipoprotein trafficking. Inhibition of the lipoprotein transport pathway leads to E. coli death and subsequent lysis. Early significant changes in the levels of RNA for a subset of genes identified to be associated with some periplasmic and envelope stress responses were observed. Together these findings suggest that disruption of this key pathway can have a severe impact on balanced outer membrane synthesis sufficient to affect viability. Copyright © 2016 Lorenz et al.

  11. Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3).

    Science.gov (United States)

    Liang, Xiaomin; Chien, Huan-Chieh; Yee, Sook Wah; Giacomini, Marilyn M; Chen, Eugene C; Piao, Meiling; Hao, Jia; Twelves, Jolyn; Lepist, Eve-Irene; Ray, Adrian S; Giacomini, Kathleen M

    2015-12-07

    The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters (THTR-1, SLC19A2, and THTR-2, SLC19A3). Our study demonstrated that human THTR-2 (hTHTR-2), SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin (Km = 1.15 ± 0.2 mM) and other cationic compounds (MPP(+) and famotidine). The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug-drug and drug-nutrient interactions.

  12. Gram-scale solution-phase synthesis of selective sodium bicarbonate Co-transport Inhibitor S0859

    DEFF Research Database (Denmark)

    Larsen, Ann Møller; Krogsgaard-Larsen, Niels; Lauritzen, Gitte

    2012-01-01

    Na+-coupled HCO3- transporters (NBCs) mediate the transport of bicarbonate ions across cell membranes and are thus ubiquitous regulators of intracellular pH. NBC dysregulation is associated with a range of diseases; for instance, NBCn1 is strongly up-regulated in a model of ErbB2-dependent breast...

  13. Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties.

    Science.gov (United States)

    Santora, Vincent J; Almos, Theresa A; Barido, Richard; Basinger, Jillian; Bellows, Chris L; Bookser, Brett Carder; Breitenbucher, J Guy; Broadbent, Nicola J; Cabebe, Clifford; Chai, Chih-Kun; Chen, Mi; Chow, Stephine; Chung, De Michael; Crickard, Lindsay; Danks, Anne M; Freestone, Graeme; Gitnick, Dany; Gupta, Varsha; Hoffmaster, Christine; Hudson, Andrew R; Kaplan, Alan P; Kennedy, Michael R; Lee, Dong; Limberis, James; Ly, Kiev; Mak, Chi Ching; Masatsugu, Brittany; Morse, Andrew C; Na, Jim; Neul, David; Nikpur, John; Peters, Marco; Petroski, Robert E; Renick, Joel; Sebring, Kristen; Sevidal, Samantha; Tabatabaei, Ali; Wen, Jenny; Yan, Yingzhuo; Yoder, Zachary W; Zook, Douglas

    2018-06-11

    We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4-c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dosing of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat Novel Object Recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.

  14. Evidence for the prevention of bone loss in elderly and old early non-metastatic breast cancer patients treated with aromatase inhibitors

    DEFF Research Database (Denmark)

    Gunmalm, V.; Jørgensen, N. R.; Abrahamsen, B.

    2017-01-01

    Breast cancer (BC) is the most common cancer amongst women worldwide. Bone health is emerging as an important issue for BC survivors. In this literature study, we focus on agents for preventing bone loss in early non-metastatic estrogen receptor positive BC in treatment with aromatase inhibitors...... (AI) and to assess the evidence for antiresorptive treatment of bone loss in early non-metastatic breast cancer. We included randomized controlled trials (RCT's) comparing: (a) bisphosphonates and control; (b) different bisphosphonates; (c) denosumab and control and (d) bisphosphonates vs. denosumab...... in early non-metastatic BC women in AI treatment. Among antiresorptives, zoledronic acid currently has the highest evidence for prevention of AI associated bone loss in early non-metastatic BC. Data on fracture prevention among all patients, elderly and old is sparse. More randomized controlled studies...

  15. Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy.

    Science.gov (United States)

    Alzahrani, Khalid J H; Ali, Juma A M; Eze, Anthonius A; Looi, Wan Limm; Tagoe, Daniel N A; Creek, Darren J; Barrett, Michael P; de Koning, Harry P

    2017-08-01

    Leishmania pyrimidine salvage is replete with opportunities for therapeutic intervention with enzyme inhibitors or antimetabolites. Their uptake into cells depends upon specific transporters; therefore it is essential to establish whether various Leishmania species possess similar pyrimidine transporters capable of drug uptake. Here, we report a comprehensive characterization of pyrimidine transport in L. major and L. mexicana. In both species, two transporters for uridine/adenosine were detected, one of which also transported uracil and the antimetabolites 5-fluoruracil (5-FU) and 5F,2'deoxyuridine (5F,2'dUrd), and was designated uridine-uracil transporter 1 (UUT1); the other transporter mediated uptake of adenosine, uridine, 5F,2'dUrd and thymidine and was designated Nucleoside Transporter 1 (NT1). To verify the reported L. donovani model of two NT1-like genes encoding uridine/adenosine transporters, and an NT2 gene encoding an inosine transporter, we cloned the corresponding L. major and L. mexicana genes, expressing each in T. brucei. Consistent with the L. donovani reports, the NT1-like genes of either species mediated the adenosine-sensitive uptake of [ 3 H]-uridine but not of [ 3 H]-inosine. Conversely, the NT2-like genes mediated uptake of [ 3 H]-inosine but not [ 3 H]-uridine. Among pyrimidine antimetabolites tested, 5-FU and 5F,2'dUrd were the most effective antileishmanials; resistance to both analogs was induced in L. major and L. mexicana. In each case it was found that the resistant cells had lost the transport capacity for the inducing drug. Metabolomics analysis found that the mechanism of action of 5-FU and 5F-2'dUrd was similar in both Leishmania species, with major changes in deoxynucleotide metabolism. We conclude that the pyrimidine salvage system is highly conserved in Leishmania species - essential information for the development of pyrimidine-based chemotherapy. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights

  16. Modeling the impact of transport energy consumption on CO2 emission in Pakistan: Evidence from ARDL approach.

    Science.gov (United States)

    Danish; Baloch, Muhammad Awais; Suad, Shah

    2018-04-01

    The objective of this research is to examine the relationship between transport energy consumption, economic growth, and carbon dioxide emission (CO 2 ) from transport sector incorporating foreign direct investment and urbanization. This study is carried out in Pakistan by applying autoregressive distributive lag (ARDL) and vector error correction model (VECM) over 1990-2015. The empirical results indicate a strong significant impact of transport energy consumption on CO 2 emissions from the transportation sector. Furthermore, foreign direct investment also contributes to CO 2 emission. Interestingly, the impact of economic growth and urbanization on transport CO 2 emission is statistically insignificant. Overall, transport energy consumption and foreign direct investment are not environmentally friendly. The new empirical evidence from this study provides a complete picture of the determinants of emissions from the transport sector and these novel findings not only help to advance the existing literature but also can be of special interest to the country's policymakers. So, we urge that government needs to focus on promoting the energy efficient means of transportation to improve environmental quality with less adverse influence on economic growth.

  17. Negotiating multisectoral evidence: a qualitative study of knowledge exchange at the intersection of transport and public health

    Directory of Open Access Journals (Sweden)

    Cornelia Guell

    2017-01-01

    Full Text Available Abstract Background For the prevention and control of chronic diseases, two strategies are frequently highlighted: that public health should be evidence based, and that it should develop a multisectoral approach. At the end of a natural experimental study of the health impacts of new transport infrastructure, we took the opportunity of a knowledge exchange forum to explore how stakeholders assessed, negotiated and intended to apply multisectoral evidence in policy and practice at the intersection of transport and health. We aimed to better understand the challenges they faced in knowledge exchange, as well as their everyday experiences with working in multisectoral remits. Methods In 2015, we conducted participant observation during an interactive event with 41 stakeholders from national and local government, the third sector and academia in Cambridge, UK. Formal and informal interactions between stakeholders were recorded in observational field notes. We also conducted 18 semistructured interviews reflecting on the event and on knowledge exchange in general. Results We found that stakeholders negotiated a variety of challenges. First, stakeholders had to negotiate relatively new formal and informal multisectoral remits; and how to reconcile the differing expectations of transport specialists, who tended to emphasise the importance of precedence in guiding action, and health specialists’ concern for the rigour and synthesis of research evidence. Second, research in this field involved complex study designs, and often produced evidence with uncertain transferability to other settings. Third, health outcomes of transport schemes had political traction and were used strategically but not easily translated into cost-benefit ratios. Finally, knowledge exchange meant multiple directions of influence. Stakeholders were concerned that researchers did not always have skills to translate their findings into understandable evidence, and some stakeholders

  18. Transport inhibition of digoxin using several common P-gp expressing cell lines is not necessarily reporting only on inhibitor binding to P-gp.

    Directory of Open Access Journals (Sweden)

    Annie Albin Lumen

    Full Text Available We have reported that the P-gp substrate digoxin required basolateral and apical uptake transport in excess of that allowed by digoxin passive permeability (as measured in the presence of GF120918 to achieve the observed efflux kinetics across MDCK-MDR1-NKI (The Netherlands Cancer Institute confluent cell monolayers. That is, GF120918 inhibitable uptake transport was kinetically required. Therefore, IC50 measurements using digoxin as a probe substrate in this cell line could be due to inhibition of P-gp, of digoxin uptake transport, or both. This kinetic analysis is now extended to include three additional cell lines: MDCK-MDR1-NIH (National Institute of Health, Caco-2 and CPT-B2 (Caco-2 cells with BCRP knockdown. These cells similarly exhibit GF120918 inhibitable uptake transport of digoxin. We demonstrate that inhibition of digoxin transport across these cell lines by GF120918, cyclosporine, ketoconazole and verapamil is greater than can be explained by inhibition of P-gp alone. We examined three hypotheses for this non-P-gp inhibition. The inhibitors can: (1 bind to a basolateral digoxin uptake transporter, thereby inhibiting digoxin's cellular uptake; (2 partition into the basolateral membrane and directly reduce membrane permeability; (3 aggregate with digoxin in the donor chamber, thereby reducing the free concentration of digoxin, with concomitant reduction in digoxin uptake. Data and simulations show that hypothesis 1 was found to be uniformly acceptable. Hypothesis 2 was found to be uniformly unlikely. Hypothesis 3 was unlikely for GF120918 and cyclosporine, but further studies are needed to completely adjudicate whether hetero-dimerization contributes to the non-P-gp inhibition for ketoconazole and verapamil. We also find that P-gp substrates with relatively low passive permeability such as digoxin, loperamide and vinblastine kinetically require basolateral uptake transport over that allowed by +GF120918 passive permeability, while

  19. Evident?

    DEFF Research Database (Denmark)

    Plant, Peter

    2012-01-01

    Quality assurance and evidence in career guidance in Europe are often seen as self-evident approaches, but particular interests lie behind......Quality assurance and evidence in career guidance in Europe are often seen as self-evident approaches, but particular interests lie behind...

  20. Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates.

    Science.gov (United States)

    Baumann, Michael H; Bulling, Simon; Benaderet, Tova S; Saha, Kusumika; Ayestas, Mario A; Partilla, John S; Ali, Syed F; Stockner, Thomas; Rothman, Richard B; Sandtner, Walter; Sitte, Harald H

    2014-05-01

    Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [(3)H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [(3)H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.

  1. Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor.

    Science.gov (United States)

    Kulmatycki, Kenneth; Hanna, Imad; Meyers, Dan; Salunke, Atish; Movva, Aishwarya; Majumdar, Tapan; Natrillo, Adrienne; Vapurcuyan, Arpine; Rebello, Sam; Sunkara, Gangadhar; Chen, Jin

    2015-05-01

    An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 ± 0.95 μM, 3.34 ± 0.64 μM, and 0.973 ± 0.11 μM, respectively. In the presence of steady state pradigastat concentrations, AUC(τ, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(τ, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.

  2. Variability and seasonality of active transportation in USA: evidence from the 2001 NHTS

    Science.gov (United States)

    2011-01-01

    Background Active transportation including walking and bicycling is an important source of physical activity. Promoting active transportation is a challenge for the fields of public health and transportation. Descriptive data on the predictors of active transportation, including seasonal patterns in active transportation in the US as a whole, is needed to inform interventions and policies. Methods This study analyzed monthly variation in active transportation for the US using National Household Travel Survey 2001 data. For each age group of children, adolescents, adults and elderly, logistic regression models were used to identify predictors of the odds of active transportation including gender, race/ethnicity, household income level, geographical region, urbanization level, and month. Results The probability of engaging in active transportation was generally higher for children and adolescents than for adults and the elderly. Active transportation was greater in the lower income groups (except in the elderly), was lower in the South than in other regions of the US, and was greater in areas with higher urbanization. The percentage of people using active transportation exhibited clear seasonal patterns: high during summer months and low during winter months. Children and adolescents were more sensitive to seasonality than other age groups. Women, non-Caucasians, persons with lower household income, who resided in the Midwest or Northeast, and who lived in more urbanized areas had greater seasonal variation. Conclusions These descriptive results suggest that interventions and policies that target the promotion of active transportation need to consider socio-demographic factors and seasonality. PMID:21917136

  3. Alterations in brain extracellular dopamine and glycine levels following combined administration of the glycine transporter type-1 inhibitor Org-24461 and risperidone.

    Science.gov (United States)

    Nagy, Katalin; Marko, Bernadett; Zsilla, Gabriella; Matyus, Peter; Pallagi, Katalin; Szabo, Geza; Juranyi, Zsolt; Barkoczy, Jozsef; Levay, Gyorgy; Harsing, Laszlo G

    2010-12-01

    The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced

  4. Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1.

    Science.gov (United States)

    Rizvi, Syed Mohd Danish; Shaikh, Sibhghatulla; Khan, Mahiuddin; Biswas, Deboshree; Hameed, Nida; Shakil, Shazi

    2014-01-01

    Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters (SERT) to increase the synaptic concentrations of serotonin. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) is responsible for amyloid β plaque formation. Hence it is an interesting target for Alzheimer's disease (AD) therapy. This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named 'Fetzima' with BACE-1 and SERT. Fetzima is chemically known as levomilnacipran. The study has explored a possible link between the treatment of Depression and AD. 'Autodock 4.2' was used for docking study. The free energy of binding (ΔG) values for 'levomilnacipran-SERT' interaction and 'levomilnacipran-BACE1' interaction were found to be -7.47 and -8.25 kcal/mol, respectively. Levomilnacipran was found to interact with S438, known to be the most important amino acid residue of serotonin binding site of SERT during 'levomilnacipran-SERT' interaction. In the case of 'levomilnacipran-BACE1' interaction, levomilnacipran interacted with two very crucial aspartic acid residues of BACE-1, namely, D32 and D228. These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain. Hence, Fetzima (levomilnacipran) might act as a potent dual inhibitor of SERT and BACE-1 and expected to form the basis of a future dual therapy against depression and AD. It is an established fact that development of AD is associated with Major Depressive Disorder. Therefore, the design of new BACE-1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial.

  5. Design, synthesis and structure-activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease.

    Science.gov (United States)

    Toda, Narihiro; Tago, Keiko; Marumoto, Shinji; Takami, Kazuko; Ori, Mayuko; Yamada, Naho; Koyama, Kazuo; Naruto, Shunji; Abe, Kazumi; Yamazaki, Reina; Hara, Takao; Aoyagi, Atsushi; Abe, Yasuyuki; Kaneko, Tsugio; Kogen, Hiroshi

    2003-05-01

    We have designed and synthesized a dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT) as a novel class of treatment drugs for Alzheimer's disease on the basis of a hypothetical model of the AChE active site. Dual inhibitions of AChE and SERT would bring about greater therapeutic effects than AChE inhibition alone and avoid adverse peripheral effects caused by excessive AChE inhibition. Compound (S)-6j exhibited potent inhibitory activities against AChE (IC(50)=101 nM) and SERT (IC(50)=42 nM). Furthermore, (S)-6j showed inhibitory activities of both AChE and SERT in mice brain following oral administration.

  6. L-Cysteine/D,L-homocysteine-regulated ileum motility via system L and B°(,+) transporter: Modification by inhibitors of hydrogen sulfide synthesis and dietary treatments.

    Science.gov (United States)

    Yamane, Satoshi; Nomura, Ryouya; Yanagihara, Madoka; Nakamura, Hiroyuki; Fujino, Hiromichi; Matsumoto, Kenjiro; Horie, Syunji; Murayama, Toshihiko

    2015-10-05

    Previous studies including ours demonstrated that L-cysteine treatments decreased motility in gastrointestinal tissues including the ileum via hydrogen sulfide (H2S), which is formed from sulfur-containing amino acids such as L-cysteine and L-homocysteine. However, the amino acid transport systems involved in L-cysteine/L-homocysteine-induced responses have not yet been elucidated in detail; therefore, we investigated these systems pharmacologically by measuring electrical stimulation (ES)-induced contractions with amino acids in mouse ileum preparations. The treatments with L-cysteine and D,L-homocysteine inhibited ES-induced contractions in ileum preparations from fasted mice, and these responses were decreased by the treatment with 2-aminobicyclo[2.2.1]heptane-2-carboxylate (BCH), an inhibitor of systems L and B°(,+). The results obtained using ileum preparations and a model cell line (PC12 cells) with various amino acids and BCH showed that not only L-cysteine, but also aminooxyacetic acid and D,L-propargylglycine, which act as H2S synthesis inhibitors, appeared to be taken up by these preparations/cells in L and B°(,+) system-dependent manners. The L-cysteine and D,L-homocysteine responses were delayed and abolished, respectively, in ileum preparations from fed mice. Our results suggested that the regulation of ileum motility by L-cysteine and D,L-homocysteine was dependent on BCH-sensitive systems, and varied depending on feeding in mice. Therefore, the effects of aminooxyacetic acid and D,L-propargylglycine on transport systems need to be considered in pharmacological analyses. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Evidence for modified transport due to sheared E x B flows in high-temperature plasmas

    International Nuclear Information System (INIS)

    Groebner, R.J.; Burrell, K.H.; Austin, M.E.

    1994-11-01

    Sheared mass flows are generated in many fluids and are often important for the dynamics of instabilities in these fluids. Similarly, large values of the E x B velocity have been observed in magnetic confinement machines and there is theoretical and experimental evidence that sufficiently large shear in this velocity may stabilize important instabilities. Two examples of this phenomenon have been observed in the DIII-D tokamak. In the first example, sufficient heating power can lead to the L-H transition, a rapid improvement in confinement in the boundary layer of the plasma. For discharges with heating power close to the threshold required to get the transition, changes in the edge radial electric field are observed to occur prior to the transition itself. In the second example, certain classes of discharges with toroidal momentum input from neutral beam injection exhibit a further improvement of confinement in the plasma core leading to a regime called the VH-mode. In both examples, the region of improved confinement is characterized by an increase of shear in the radial electric field E r , reduced levels of turbulence and increases in gradients of temperatures and densities. These observations are consistent with the hypothesis that the improved confinement is caused by an increase in shear of the E x B velocity which leads to a reduction of turbulence. For the VH-mode, the dominant term controlling E r is the toroidal rotation v φ , indicating that the E r profile is controlled by the source and transport of toroidal momentum

  8. Oil Shocks through International Transport Costs: Evidence from U.S. Business Cycles

    OpenAIRE

    Hakan Yilmazkuday

    2011-01-01

    The effects of oil shocks on output volatility through international transport costs are investigated in an open-economy DSGE model. Two versions of the model, with and without international transport costs, are structurally estimated for the U.S. economy by a Bayesian approach for moving windows of ten years. For model selection, the posterior odds ratios of the two versions are compared for each ten-year window. The version with international transport costs is selected during periods of hi...

  9. Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

    Directory of Open Access Journals (Sweden)

    Willias Masocha

    2016-12-01

    Full Text Available Background There is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1 whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP. Methods The reaction latency to thermal stimuli (hot plate test; at 55 °C and cold stimuli (cold plate test; at 4 °C of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min. Results The coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h. Conclusions These results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711’s antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1

  10. Transport and redistribution of Chernobyl fallout radionuclides by fluvial processes: some preliminary evidence

    International Nuclear Information System (INIS)

    Walling, D.E.; Bradley, S.B.

    1988-01-01

    Several measurements of 137 Cs concentrations in suspended sediment transported by the River Severn during the post-Chernobyl period and in recent channel and floodplain deposits along the river emphasise the potential significance of fluvial processes in the transport and concentration of fallout radionuclides. (author)

  11. Evidence synthesis and decision modelling to support complex decisions: stockpiling neuraminidase inhibitors for pandemic influenza usage [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Samuel I. Watson

    2017-03-01

    Full Text Available Objectives: The stockpiling of neuraminidase inhibitor (NAI antivirals as a defence against pandemic influenza is a significant public health policy decision that must be made despite a lack of conclusive evidence from randomised controlled trials regarding the effectiveness of NAIs on important clinical end points such as mortality. The objective of this study was to determine whether NAIs should be stockpiled for treatment of pandemic influenza on the basis of current evidence. Methods: A decision model for stockpiling was designed. Data on previous pandemic influenza epidemiology was combined with data on the effectiveness of NAIs in reducing mortality obtained from a recent individual participant meta-analysis using observational data. Evidence synthesis techniques and a bias modelling method for observational data were used to incorporate the evidence into the model. The stockpiling decision was modelled for adults (≥16 years old and the United Kingdom was used as an example. The main outcome was the expected net benefits of stockpiling in monetary terms. Health benefits were estimated from deaths averted through stockpiling. Results: After adjusting for biases in the estimated effectiveness of NAIs, the expected net benefit of stockpiling in the baseline analysis was £444 million, assuming a willingness to pay of £20,000/QALY ($31,000/QALY. The decision would therefore be to stockpile NAIs. There was a greater probability that the stockpile would not be utilised than utilised. However, the rare but catastrophic losses from a severe pandemic justified the decision to stockpile. Conclusions: Taking into account the available epidemiological data and evidence of effectiveness of NAIs in reducing mortality, including potential biases, a decision maker should stockpile anti-influenza medication in keeping with the postulated decision rule.

  12. Transportation

    National Research Council Canada - National Science Library

    Adams, James; Carr, Ron; Chebl, Maroun; Coleman, Robert; Costantini, William; Cox, Robert; Dial, William; Jenkins, Robert; McGovern, James; Mueller, Peter

    2006-01-01

    ...., trains, ships, etc.) and maximizing intermodal efficiency. A healthy balance must be achieved between the flow of international commerce and security requirements regardless of transportation mode...

  13. SGLT-2 Inhibitors and Cardiovascular Risk

    DEFF Research Database (Denmark)

    Cavender, Matthew A; Norhammar, Anna; Birkeland, Kåre I

    2018-01-01

    BACKGROUND: Prior studies found patients treated with sodium-glucose co-transporter-2 inhibitors (SGLT-2i) had lower rates of death and heart failure (HF). Whether the benefits of SGLT-2i vary based upon the presence of cardiovascular disease (CVD) is unknown. OBJECTIVES: This study sought...... to determine the association between initiation of SGLT-2i therapy and HF or death in patients with and without CVD. METHODS: The CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) study was a multinational, observational study in which adults with type 2 diabetes...... evidence regarding the benefit of SGLT-2i in patients without established CVD. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)....

  14. Scanning ion-selective electrode technique and X-ray microanalysis provide direct evidence of contrasting Na+ transport ability from root to shoot in salt-sensitive cucumber and salt-tolerant pumpkin under NaCl stress.

    Science.gov (United States)

    Lei, Bo; Huang, Yuan; Sun, Jingyu; Xie, Junjun; Niu, Mengliang; Liu, Zhixiong; Fan, Molin; Bie, Zhilong

    2014-12-01

    Grafting onto salt-tolerant pumpkin rootstock can increase cucumber salt tolerance. Previous studies have suggested that this can be attributed to pumpkin roots with higher capacity to limit the transport of Na(+) to the shoot than cucumber roots. However, the mechanism remains unclear. This study investigated the transport of Na(+) in salt-tolerant pumpkin and salt-sensitive cucumber plants under high (200 mM) or moderate (90 mM) NaCl stress. Scanning ion-selective electrode technique showed that pumpkin roots exhibited a higher capacity to extrude Na(+), and a correspondingly increased H(+) influx under 200 or 90 mM NaCl stress. The 200 mM NaCl induced Na(+)/H(+) exchange in the root was inhibited by amiloride (a Na(+)/H(+) antiporter inhibitor) or vanadate [a plasma membrane (PM) H(+) -ATPase inhibitor], indicating that Na(+) exclusion in salt stressed pumpkin and cucumber roots was the result of an active Na(+)/H(+) antiporter across the PM, and the Na(+)/H(+) antiporter system in salt stressed pumpkin roots was sufficient to exclude Na(+) X-ray microanalysis showed higher Na(+) in the cortex, but lower Na(+) in the stele of pumpkin roots than that in cucumber roots under 90 mM NaCl stress, suggesting that the highly vacuolated root cortical cells of pumpkin roots could sequester more Na(+), limit the radial transport of Na(+) to the stele and thus restrict the transport of Na(+) to the shoot. These results provide direct evidence for pumpkin roots with higher capacity to limit the transport of Na(+) to the shoot than cucumber roots. © 2014 Scandinavian Plant Physiology Society.

  15. Hydroxymethylglutaryl-CoA Reductase Inhibitors in Older Persons with Acute Myocardial Infarction: Evidence for an Age–Statin Interaction

    Science.gov (United States)

    Foody, JoAnne Micale; Rathore, Saif S.; Galusha, Deron; Masoudi, Frederick A.; Havranek, Edward P.; Radford, Martha J.; Krumholz, Harlan M.

    2009-01-01

    OBJECTIVES To characterize the relationship between hydroxymethylglutaryl-CoA reductase inhibitors (statins) and outcomes in older persons with acute myocardial infarction (AMI). DESIGN Observational study. SETTING Acute care hospitals in the United States from April 1998 to June 2001. PARTICIPANTS Medicare patients aged 65 and older with a principal discharge diagnosis of AMI (N = 65,020) who did and did not receive a discharge prescription for statins. MEASUREMENTS The primary outcome of interest was all-cause mortality at 3 years after discharge. RESULTS Of 23,013 patients with AMI assessed, 5,513 (24.0%) were receiving a statin at discharge. Nearly 40% of eligible patients (n =8,452) were aged 80 and older, of whom 1,310 (15.5%) were receiving a statin at discharge. In a multivariable model taking into account demographic, clinical, physician and hospital characteristics, and propensity score, discharge statin therapy was associated with significantly lower 3-year mortality (hazard ratio (HR) =0.89 (95% confidence interval (CI) =0.83–0.96)). In an analysis stratified by age, discharge statins were associated with lower mortality in patients younger than 80 (HR =0.84, 95% CI =0.76–0.92) but not in those aged 80 and older (HR =0.97, 95% CI =0.87–1.09). CONCLUSION Statin therapy is associated with lower mortality in older patients with AMI younger than 80 but not in those aged 80 and older, as a group. This finding questions whether statin efficacy data in younger patients can be broadly applied to the very old and indicates the need for further study of this group. PMID:16551308

  16. Human organic cation transporter 2 (hOCT2): Inhibitor studies using S2-hOCT2 cells

    International Nuclear Information System (INIS)

    Chiba, Shoetsu; Ikawa, Toru; Takeshita, Hiroshi; Kanno, Sanae; Nagai, Tomonori; Takada, Meri; Mukai, Toshiji; Wempe, Michael F.

    2013-01-01

    Highly expressed in kidney and located on the basolateral membrane, human organic cation transporter 2 (hOCT2) can transport various compounds (i.e. drugs and toxins) into the proximal tubular cell. Using cultured proximal tubule cells stably expressing hOCT2 (i.e. S2-hOCT2 cells), we sought to probe different compound classes (e.g. analgesics, anti-depressants, anti-psychotics, disinfectant, herbicides, insecticides, local anesthetic, muscarinic acetylcholine receptor antagonist, sedatives, steroid hormone, stimulants and toxins) for their ability to inhibit 14 C-TEA uptake, a prototypical OCT2 substrate. Aconitine, amitriptyline, atropine, chlorpyrifos, diazepam, fenitrothion, haloperidol, lidocaine, malathion, mianserin, nicotine and triazolam significantly inhibited 14 C-TEA uptake; IC 50 values were 59.2, 2.4, 2.0, 20.7, 32.3, 13.2, 32.5, 104.6, 71.1, 17.7, 52.8 and 65.5 μM, respectively. In addition, aconitine, amitriptyline, atropine, chlorpyrifos, fenitrothion, haloperidol, lidocaine, and nicotine displayed competitive inhibition with K i values of 145.6, 2.5, 2.4, 24.8, 16.9, 51.6, 86.8 and 57.7 μM, respectively. These in vitro data support the notion that compounds pertaining to a wide variety of different drug classes have the potential to decrease renal clearance of drugs transported via hOCT2. Consequently, these data warrant additional studies to probe hOCT2 and its role to influence drug pharmacokinetics

  17. Cobenefits of replacing car trips with alternative transportation: a review of evidence and methodological issues.

    Science.gov (United States)

    Xia, Ting; Zhang, Ying; Crabb, Shona; Shah, Pushan

    2013-01-01

    It has been reported that motor vehicle emissions contribute nearly a quarter of world energy-related greenhouse gases and cause nonnegligible air pollution primarily in urban areas. Reducing car use and increasing ecofriendly alternative transport, such as public and active transport, are efficient approaches to mitigate harmful environmental impacts caused by a large amount of vehicle use. Besides the environmental benefits of promoting alternative transport, it can also induce other health and economic benefits. At present, a number of studies have been conducted to evaluate cobenefits from greenhouse gas mitigation policies. However, relatively few have focused specifically on the transport sector. A comprehensive understanding of the multiple benefits of alternative transport could assist with policy making in the areas of transport, health, and environment. However, there is no straightforward method which could estimate cobenefits effect at one time. In this paper, the links between vehicle emissions and air quality, as well as the health and economic benefits from alternative transport use, are considered, and methodological issues relating to the modelling of these cobenefits are discussed.

  18. Cobenefits of Replacing Car Trips with Alternative Transportation: A Review of Evidence and Methodological Issues

    Directory of Open Access Journals (Sweden)

    Ting Xia

    2013-01-01

    Full Text Available It has been reported that motor vehicle emissions contribute nearly a quarter of world energy-related greenhouse gases and cause nonnegligible air pollution primarily in urban areas. Reducing car use and increasing ecofriendly alternative transport, such as public and active transport, are efficient approaches to mitigate harmful environmental impacts caused by a large amount of vehicle use. Besides the environmental benefits of promoting alternative transport, it can also induce other health and economic benefits. At present, a number of studies have been conducted to evaluate cobenefits from greenhouse gas mitigation policies. However, relatively few have focused specifically on the transport sector. A comprehensive understanding of the multiple benefits of alternative transport could assist with policy making in the areas of transport, health, and environment. However, there is no straightforward method which could estimate cobenefits effect at one time. In this paper, the links between vehicle emissions and air quality, as well as the health and economic benefits from alternative transport use, are considered, and methodological issues relating to the modelling of these cobenefits are discussed.

  19. Transportation

    International Nuclear Information System (INIS)

    Anon.

    1998-01-01

    Here is the decree of the thirtieth of July 1998 relative to road transportation, to trade and brokerage of wastes. It requires to firms which carry out a road transportation as well as to traders and to brokers of wastes to declare their operations to the prefect. The declaration has to be renewed every five years. (O.M.)

  20. Seasonal and long-term change in lead deposition in central Japan: evidence for atmospheric transport from continental Asia

    International Nuclear Information System (INIS)

    Bellis, David J.; Satake, Kenichi; Inagaki, Michiko; Zeng, Jiye; Oizumi, Tsuyoshi

    2005-01-01

    Long-range transport of air pollution from continental Asia is currently an important issue concerning the Japanese environment, especially in regions susceptible to acidification due to low buffering capacity, such as Murakami, Niigata prefecture, located on the west coast of central Japan. Evidence for long-range transport was obtained through lead and lead isotopic analysis of 84 archived precipitation filters, showing seasonal changes in lead deposition from May 1999 to May 2002. Lead deposition was highest in winter and spring (November through May) each year and lowest in summer. Computed 72-h back trajectories showed that in winter air masses were predominantly transported from the northwest, passing over northern China and eastern Russia, whilst in summer air masses predominantly originated from the southeast passing over Japan. Lead isotopic analysis showed higher 208 Pb/ 206 Pb during winter, indicating that lead originated from a different source. A plot of 207 Pb/ 206 Pb vs. 208 Pb/ 206 Pb identified a thorogenic component, which is excess 208 Pb compared to a standard lead growth curve, indicative of certain lead ores and coals in continental Asia. The data provided evidence of long-range transport of lead from continental Asia to Japan. Bark pockets included within the trunks of two Japanese cedar trees harvested near Murakami, dating between 1972 and 1982, exhibited lead isotope ratios indicative of Japanese-sourced lead. In contrast, current (2003) bark showed thorogenic ratios, consistent with a relative decline in Japanese-sourced and increase in continental-sourced lead

  1. Common selective serotonin reuptake inhibitor side effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: data from a randomized controlled trial.

    Science.gov (United States)

    Garfield, Lauren D; Dixon, David; Nowotny, Petra; Lotrich, Francis E; Pollock, Bruce G; Kristjansson, Sean D; Doré, Peter M; Lenze, Eric J

    2014-10-01

    Antidepressant side effects are a significant public health issue, associated with poor adherence, premature treatment discontinuation, and, rarely, significant harm. Older adults assume the largest and most serious burden of medication side effects. We investigated the association between antidepressant side effects and genetic variation in the serotonin system in anxious, older adults participating in a randomized, placebo-controlled trial of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Adults (N = 177) aged ≥ 60 years were randomized to active treatment or placebo for 12 weeks. Side effects were assessed using the Udvalg fur Kliniske Undersøgelser side-effect rating scale. Genetic polymorphisms were putative functional variants in the promoters of the serotonin transporter and 1A and 2A receptors (5-HTTLPR [L/S + rs25531], HTR1A rs6295, HTR2A rs6311, respectively). Four significant drug-placebo side-effect differences were found: increased duration of sleep, dry mouth, diarrhea, and diminished sexual desire. Analyses using putative high- versus low-transcription genotype groupings revealed six pharmacogenetic effects: greater dry mouth and decreased sexual desire for the low- and high-expressing serotonin transporter genotypes, respectively, and greater diarrhea with the 1A receptor low-transcription genotype. Diminished sexual desire was experienced significantly more by high-expressing genotypes in the serotonin transporter, 1A, or 2A receptors. There was not a significant relationship between drug concentration and side effects nor a mean difference in drug concentration between low- and high-expressing genotypes. Genetic variation in the serotonin system may predict who develops common SSRI side effects and why. More work is needed to further characterize this genetic modulation and to translate research findings into strategies useful for more personalized patient care. Published by Elsevier Inc.

  2. Effects of Job Accessibility Improved by Public Transport System: Natural Experimental Evidence from the Copenhagen Metro

    DEFF Research Database (Denmark)

    Pons Rotger, Gabriel Angel; Nielsen, Thomas Alexander Sick

    2015-01-01

    This study examines the effect of accessibility to urban jobs via a public transport system on individual earnings and commuting behaviour. The effect of improved public transport based accessibility on these outcomes is determined by exploiting the exogenous variation in access to a public rail ...... with a change in commuting patterns as the improved access to public transport facilitates a shift from employment within the township to better paid jobs in the city centre, as well as in other suburbs of the Copenhagen Metropolitan area...

  3. Effects of Job Accessibility Improved by Public Transport System: Natural Experimental Evidence from the Copenhagen Metro

    DEFF Research Database (Denmark)

    Pons Rotger, Gabriel Angel; Nielsen, Thomas Alexander Sick

    2015-01-01

    This study examines the effect of accessibility to urban jobs via a public transport system on individual earnings and commuting behaviour. The effect of improved public transport based accessibility on these outcomes is determined by exploiting the exogenous variation in access to a public rail...... and Metro system resulting from the construction of a new terminal Metro station connecting southern townships to Copenhagen city centre. The results show that public transport based job accessibility has a positive and permanent effect on individual earnings. The increase in earnings is associated...... with a change in commuting patterns as the improved access to public transport facilitates a shift from employment within the township to better paid jobs in the city centre, as well as in other suburbs of the Copenhagen Metropolitan area...

  4. Moving Low-Carbon Transportation in Xinjiang: Evidence from STIRPAT and Rigid Regression Models

    Directory of Open Access Journals (Sweden)

    Jiefang Dong

    2016-12-01

    Full Text Available With the rapid economic development of the Xinjiang Uygur Autonomous Region, the area’s transport sector has witnessed significant growth, which in turn has led to a large increase in carbon dioxide emissions. As such, calculating of the carbon footprint of Xinjiang’s transportation sector and probing the driving factors of carbon dioxide emissions are of great significance to the region’s energy conservation and environmental protection. This paper provides an account of the growth in the carbon emissions of Xinjiang’s transportation sector during the period from 1989 to 2012. We also analyze the transportation sector’s trends and historical evolution. Combined with the STIRPAT (Stochastic Impacts by Regression on Population, Affluence and Technology model and ridge regression, this study further quantitatively analyzes the factors that influence the carbon emissions of Xinjiang’s transportation sector. The results indicate the following: (1 the total carbon emissions and per capita carbon emissions of Xinjiang’s transportation sector both continued to rise rapidly during this period; their average annual growth rates were 10.8% and 9.1%, respectively; (2 the carbon emissions of the transportation sector come mainly from the consumption of diesel and gasoline, which accounted for an average of 36.2% and 2.6% of carbon emissions, respectively; in addition, the overall carbon emission intensity of the transportation sector showed an “S”-pattern trend within the study period; (3 population density plays a dominant role in increasing carbon dioxide emissions. Population is then followed by per capita GDP and, finally, energy intensity. Cargo turnover has a more significant potential impact on and role in emission reduction than do private vehicles. This is because road freight is the primary form of transportation used across Xinjiang, and this form of transportation has low energy efficiency. These findings have important

  5. Evidence for an ABC-Type Riboflavin Transporter System in Pathogenic Spirochetes

    Science.gov (United States)

    Deka, Ranjit K.; Brautigam, Chad A.; Biddy, Brent A.; Liu, Wei Z.; Norgard, Michael V.

    2013-01-01

    ABSTRACT Bacterial transporter proteins are involved in the translocation of many essential nutrients and metabolites. However, many of these key bacterial transport systems remain to be identified, including those involved in the transport of riboflavin (vitamin B2). Pathogenic spirochetes lack riboflavin biosynthetic pathways, implying reliance on obtaining riboflavin from their hosts. Using structural and functional characterizations of possible ligand-binding components, we have identified an ABC-type riboflavin transport system within pathogenic spirochetes. The putative lipoprotein ligand-binding components of these systems from three different spirochetes were cloned, hyperexpressed in Escherichia coli, and purified to homogeneity. Solutions of all three of the purified recombinant proteins were bright yellow. UV-visible spectra demonstrated that these proteins were likely flavoproteins; electrospray ionization mass spectrometry and thin-layer chromatography confirmed that they contained riboflavin. A 1.3-Å crystal structure of the protein (TP0298) encoded by Treponema pallidum, the syphilis spirochete, demonstrated that the protein’s fold is similar to the ligand-binding components of ABC-type transporters. The structure also revealed other salient details of the riboflavin binding site. Comparative bioinformatics analyses of spirochetal genomes, coupled with experimental validation, facilitated the discovery of this new ABC-type riboflavin transport system(s). We denote the ligand-binding component as riboflavin uptake transporter A (RfuA). Taken together, it appears that pathogenic spirochetes have evolved an ABC-type transport system (RfuABCD) for survival in their host environments, particularly that of the human host. PMID:23404400

  6. A Modified Method for Evaluating Sustainable Transport Solutions Based on AHP and Dempster–Shafer Evidence Theory

    Directory of Open Access Journals (Sweden)

    Luyuan Chen

    2018-04-01

    Full Text Available With the challenge of transportation environment, a large amount of attention is paid to sustainable mobility worldwide, thus bringing the problem of the evaluation of sustainable transport solutions. In this paper, a modified method based on analytical hierarchy process (AHP and Dempster–Shafer evidence theory (D-S theory is proposed for evaluating the impact of transport measures on city sustainability. AHP is adapted to determine the weight of sustainability criteria while D-S theory is used for data fusion of the sustainability assessment. A Transport Sustainability Index (TSI is presented as a primary measure to determine whether transport solutions have a positive impact on city sustainability. A case study of car-sharing is illustrated to show the efficiency of our proposed method. Our modified method has two desirable properties. One is that the BPA is generated with a new modification framework of evaluation levels, which can flexibly manage uncertain information. The other is that the modified method has excellent performance in sensitivity analysis.

  7. Transportation

    National Research Council Canada - National Science Library

    Allshouse, Michael; Armstrong, Frederick Henry; Burns, Stephen; Courts, Michael; Denn, Douglas; Fortunato, Paul; Gettings, Daniel; Hansen, David; Hoffman, D. W; Jones, Robert

    2007-01-01

    .... The ability of the global transportation industry to rapidly move passengers and products from one corner of the globe to another continues to amaze even those wise to the dynamics of such operations...

  8. Ergopeptines bromocriptine and ergovaline and the dopamine type-2 receptor inhibitor domperidone inhibit bovine equilibrative nucleoside transporter 1-like activity.

    Science.gov (United States)

    Miles, Edwena D; Xue, Yan; Strickland, James R; Boling, James A; Matthews, James C

    2011-09-14

    Neotyphodium coenophialum-infected tall fescue contains ergopeptines. Except for interactions with biogenic amine receptors (e.g., dopamine type-2 receptor, D2R), little is known about how ergopeptines affect animal metabolism. The effect of ergopeptines on bovine nucleoside transporters (NT) was evaluated using Madin-Darby bovine kidney (MDBK) cells. Equilibrative NT1 (ENT1)-like activity accounted for 94% of total NT activity. Inhibitory competition (IC(50)) experiments found that this activity was inhibited by both bromocriptine (a synthetic model ergopeptine and D2R agonist) and ergovaline (a predominant ergopeptine of tall fescue). Kinetic inhibition analysis indicated that bromocriptine inhibited ENT1-like activity through a competitive and noncompetitive mechanism. Domperidone (a D2R antagonist) inhibited ENT1 activity more in the presence than in the absence of bromocriptine and displayed an IC(50) value lower than that of bromocriptine or ergovaline, suggesting that inhibition was not through D2R-mediated events. These novel mechanistic findings imply that cattle consuming endophyte-infected tall fescue have reduced ENT1 activity and, thus, impaired nucleoside metabolism.

  9. Does improving Public Transport decrease Car Ownership? Evidence from the Copenhagen Metropolitan Area

    DEFF Research Database (Denmark)

    Mulalic, Ismir; Pilegaard, Ninette; Rouwendal, Jan

    Car ownership is lower in urban areas, which is probably related to the availability of better publict ransport. Better public transport thus may offer the possibility to relieve the many problems (congestion,health, and parking) associated with the presence of cars in urban areas. To investigate...... network whichoffers particularly high quality public transport. Simulations based on the estimated model show that forthe greater Copenhagen area a planned extension of the metro network decreases car ownership by 2-3%.Our results suggest also a substantial increase in the interest for living in areas...

  10. Evidence of transport, sedimentation and coagulation mechanisms in the relaxation of post-volcanic stratospheric aerosols

    Directory of Open Access Journals (Sweden)

    D. Fussen

    2001-09-01

    Full Text Available Spatio-temporal distributions of stratospheric aerosols, measured by the ORA instrument from August 1992 until May 1993, are presented in the latitude range (40° S–40° N. Particle total number density, mode radius and distribution width are derived and interpreted. The respective roles of advection, sedimentation and coagulation are discussed. We also identify clear transport/sedimentation patterns and we show the enhancement of coagulation in stagnation regions. Efficient transport of aerosol particles up to 50 km is suggested.Key words. Atmospheric composition and structure (aerosols and particles; middle atmosphere-composition and chemistry; volcanic effects

  11. The transport of nifurtimox, an anti-trypanosomal drug, in an in vitro model of the human blood-brain barrier: evidence for involvement of breast cancer resistance protein.

    Science.gov (United States)

    Watson, Christopher P; Dogruel, Murat; Mihoreanu, Larisa; Begley, David J; Weksler, Babette B; Couraud, Pierre O; Romero, Ignacio A; Thomas, Sarah A

    2012-02-03

    Human African trypanosomiasis (HAT) is a parasitic disease affecting sub-Saharan Africa. The parasites are able to traverse the blood-brain barrier (BBB), which marks stage 2 (S2) of the disease. Delivery of anti-parasitic drugs across the BBB is key to treating S2 effectively and the difficulty in achieving this goal is likely to be a reason why some drugs require highly intensive treatment regimes to be effective. This study aimed to investigate not only the drug transport mechanisms utilised by nifurtimox at the BBB, but also the impact of nifurtimox-eflornithine combination therapy (NECT) and other anti-HAT drug combination therapies (CTs) on radiolabelled-nifurtimox delivery in an in vitro model of drug accumulation and the human BBB, the hCMEC/D3 cell line. We found that nifurtimox appeared to use several membrane transporters, in particular breast-cancer resistance protein (BCRP), to exit the BBB cells. The addition of eflornithine caused no change in the accumulation of nifurtimox, nor did the addition of clinically relevant doses of the other anti-HAT drugs suramin, nifurtimox or melarsoprol, but a significant increase was observed with the addition of pentamidine. The results provide evidence that anti-HAT drugs are interacting with membrane transporters at the human BBB and suggest that combination with known transport inhibitors could potentially improve their efficacy. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Effects of a glycine transporter-1 inhibitor and D-serine on MK-801-induced immobility in the forced swimming test in rats.

    Science.gov (United States)

    Kawaura, Kazuaki; Koike, Hiroyuki; Kinoshita, Kohnosuke; Kambe, Daiji; Kaku, Ayaka; Karasawa, Jun-ichi; Chaki, Shigeyuki; Hikichi, Hirohiko

    2015-02-01

    Glutamatergic dysfunction, particularly the hypofunction of N-methyl-D-aspartate (NMDA) receptors, is involved in the pathophysiology of schizophrenia. The positive modulation of the glycine site on the NMDA receptor has been proposed as a novel therapeutic approach for schizophrenia. However, its efficacy against negative symptoms, which are poorly managed by current medications, has not been fully addressed. In the present study, the effects of the positive modulation of the glycine site on the NMDA receptor were investigated in an animal model of negative symptoms of schizophrenia. The subchronic administration of MK-801 increased immobility in the forced swimming test in rats without affecting spontaneous locomotor activity. The increased immobility induced by MK-801 was attenuated by the atypical antipsychotic clozapine but not by either the typical antipsychotic haloperidol or the antidepressant imipramine, indicating that the increased immobility induced by subchronic treatment with MK-801 in the forced swimming test may represent a negative symptom of schizophrenia. Likewise, positive modulation of the glycine sites on the NMDA receptor using an agonist for the glycine site, D-serine, and a glycine transporter-1 inhibitor, N-[(3R)-3-([1,1'-biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine hydrochloride (NFPS), significantly reversed the increase in immobility in MK-801-treated rats without reducing the immobility time in vehicle-treated rats. The present results show that the stimulation of the NMDA receptor through the glycine site on the receptor either directly with D-serine or by blocking glycine transporter-1 attenuates the immobility elicited by the subchronic administration of MK-801 and may be potentially useful for the treatment of negative symptoms of schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Polarized sphingolipid transport from the subapical compartment : Evidence for distinct sphingolipid domains

    NARCIS (Netherlands)

    van Ijzendoorn, SCD; Hoekstra, D

    1999-01-01

    In polarized HepG2 cells, the sphingolipids glucosylceramide and sphingomyelin (SM), transported along the reverse transcytotic pathway, are sorted in subapical compartments (SACs), and subsequently targeted to either apical or basolateral plasma membrane domains, respectively. In the present study,

  14. Dynamic linkages between road transport energy consumption, economic growth, and environmental quality: evidence from Pakistan.

    Science.gov (United States)

    Danish; Baloch, Muhammad Awais

    2018-03-01

    The focus of the present research work is to investigate the dynamic relationship between economic growth, road transport energy consumption, and environmental quality. To this end, we rely on time series data for the period 1971 to 2014 in the context of Pakistan. To use sulfur dioxide (SO 2 ) emission from transport sector as a new proxy for measuring environmental quality, the present work employs time series technique ARDL which allows energy consumption from the transport sector, urbanization, and road infrastructure to be knotted by symmetric relationships with SO 2 emissions and economic growth. From the statistical results, we confirm that road infrastructure boosts economic growth. Simultaneously, road infrastructure and urbanization hampers environmental quality and causes to accelerate emission of SO 2 in the atmosphere. Furthermore, economic growth has a diminishing negative impact on total SO 2 emission. Moreover, we did not find any proof of the expected role of transport energy consumption in SO 2 emission. The acquired results directed that care should be taken in the expansion of road infrastructure and green city policies and planning are required in the country.

  15. Evidence for long-range transport of carbon monoxide in the Southern Hemisphere from SCIAMACHY observations

    NARCIS (Netherlands)

    Gloudemans, A.M.S.; Krol, M.C.; Meirink, J.F.; de Laat, A.T.J.; van der Werf, G.R.; Schrijver, H.; van den Broek, M.M.P.; Aben, I.

    2006-01-01

    The SCIAMACHY satellite instrument shows enhanced carbon monoxide (CO) columns in the Southern Hemisphere during the local Spring. Chemistry-transport model simulations using the new GFEDv2 biomass-burning emission database show a similar temporal and spatial CO distribution, indicating that the

  16. Evidence of a sewer vapor transport pathway at the USEPA vapor intrusion research duplex

    Science.gov (United States)

    The role of sewer lines as preferential pathways for vapor intrusion is poorly understood. Although the importance of sewer lines for volatile organic compound (VOC) transport has been documented at a small number of sites with vapor intrusion, sewer lines are not routinely sampl...

  17. Physiological Evidence for Isopotential Tunneling in the Electron Transport Chain of Methane-Producing Archaea.

    Science.gov (United States)

    Duszenko, Nikolas; Buan, Nicole R

    2017-09-15

    Many, but not all, organisms use quinones to conserve energy in their electron transport chains. Fermentative bacteria and methane-producing archaea (methanogens) do not produce quinones but have devised other ways to generate ATP. Methanophenazine (MPh) is a unique membrane electron carrier found in Methanosarcina species that plays the same role as quinones in the electron transport chain. To extend the analogy between quinones and MPh, we compared the MPh pool sizes between two well-studied Methanosarcina species, Methanosarcina acetivorans C2A and Methanosarcina barkeri Fusaro, to the quinone pool size in the bacterium Escherichia coli We found the quantity of MPh per cell increases as cultures transition from exponential growth to stationary phase, and absolute quantities of MPh were 3-fold higher in M. acetivorans than in M. barkeri The concentration of MPh suggests the cell membrane of M. acetivorans , but not of M. barkeri , is electrically quantized as if it were a single conductive metal sheet and near optimal for rate of electron transport. Similarly, stationary (but not exponentially growing) E. coli cells also have electrically quantized membranes on the basis of quinone content. Consistent with our hypothesis, we demonstrated that the exogenous addition of phenazine increases the growth rate of M. barkeri three times that of M. acetivorans Our work suggests electron flux through MPh is naturally higher in M. acetivorans than in M. barkeri and that hydrogen cycling is less efficient at conserving energy than scalar proton translocation using MPh. IMPORTANCE Can we grow more from less? The ability to optimize and manipulate metabolic efficiency in cells is the difference between commercially viable and nonviable renewable technologies. Much can be learned from methane-producing archaea (methanogens) which evolved a successful metabolic lifestyle under extreme thermodynamic constraints. Methanogens use highly efficient electron transport systems and

  18. The rebound effect on road freight transport: Empirical evidence from Portugal

    International Nuclear Information System (INIS)

    Matos, Fernando J.F.; Silva, Francisco J.F.

    2011-01-01

    Because a large proportion of total operating costs for transportation companies goes towards energy, a reduction in energy operating costs, brought about by an increase in fleet fuel efficiency, or an increase in operational efficiency, results in a change in the relative cost of road freight transportation. This fact could result in an increase in the demand for such services. If this is true, the result would be an increase in total fuel consumption. Consequently, that part of the energy savings obtained through the increased energy efficiency would be lost. The existence of a 'Rebound Effect' is especially important in the road freight transportation sector and is crucial for the definition of a national energy policy. In this study, data from the road freight transportation sector in Portugal for the years of 1987 through 2006 was analyzed. It was determined that an increase in energy efficiency did not cause a backfire, but did cause a total direct rebound effect of 24.1%. In addition, fleet operators were more inclined to adopt operational efficiencies than technological fuel efficiencies as a means of increasing the total operational efficiency. - Research highlights: → We estimate a direct rebound effect for road freight transportation in Portugal. → The functional form chosen was a log-log model and the estimation method used was the two stage least squares model. → Increasing energy efficiency by 1% results in a reduction of 0.759% in energy consumption (a direct rebound effect of about 24.1%). → Estimates of reduced fuel consumption without considering the direct rebound effect may be overestimated by about 0.87 million liters of diesel per year for each percentage point increase in energy efficiency.

  19. CoMFA and CoMSIA 3D-QSAR studies on S(6)-(4-nitrobenzyl)mercaptopurine riboside (NBMPR) analogs as inhibitors of human equilibrative nucleoside transporter 1 (hENT1).

    Science.gov (United States)

    Gupte, Amol; Buolamwini, John K

    2009-01-15

    3D-QSAR (CoMFA and CoMSIA) studies were performed on human equlibrative nucleoside transporter (hENT1) inhibitors displaying K(i) values ranging from 10,000 to 0.7nM. Both CoMFA and CoMSIA analysis gave reliable models with q2 values >0.50 and r2 values >0.92. The models have been validated for their stability and robustness using group validation and bootstrapping techniques and for their predictive abilities using an external test set of nine compounds. The high predictive r2 values of the test set (0.72 for CoMFA model and 0.74 for CoMSIA model) reveals that the models can prove to be a useful tool for activity prediction of newly designed nucleoside transporter inhibitors. The CoMFA and CoMSIA contour maps identify features important for exhibiting good binding affinities at the transporter, and can thus serve as a useful guide for the design of potential equilibrative nucleoside transporter inhibitors.

  20. Mineral-produced high-pressure striae and clay polish: Key evidence for nonballistic transport of ejecta from Ries crater

    Science.gov (United States)

    Chao, E.C.T.

    1976-01-01

    Recently discovered mineral-produced, deeply incised striae and mirror-like polish on broken surfaces of limestone fragments from the sedimentary ejecta of the Ries impact crater of southern Germany are described. The striae and polish were produced under high confining pressures during high-velocity nonballistic transport of the ejecta mass within the time span of the cratering event (measured in terms of seconds). The striae on these fragments were produced by scouring by small mineral grains embedded in the surrounding clay matrix, and the polish was formed under the same condition, by movements of relatively fragment-free clay against the fragment surfaces. The occurrence of these striae and polish is key evidence for estimating the distribution and determining the relative importance of nonballistic and ballistic transport of ejecta from the shallow Ries stony meteorite impact crater.

  1. Experimental Evidence of Momentum Transport Induced by an Up-Down Asymmetric Magnetic Equilibrium in Toroidal Plasmas

    International Nuclear Information System (INIS)

    Camenen, Y.; Peeters, A. G.; Casson, F. J.; Hornsby, W. A.; Snodin, A. P.; Szepesi, G.; Bortolon, A.; Duval, B. P.; Federspiel, L.; Karpushov, A. N.; Piras, F.; Sauter, O.

    2010-01-01

    The first experimental evidence of parallel momentum transport generated by the up-down asymmetry of a toroidal plasma is reported. The experiments, conducted in the Tokamak a Configuration Variable, were motivated by the recent theoretical discovery of ion-scale turbulent momentum transport induced by an up-down asymmetry in the magnetic equilibrium. The toroidal rotation gradient is observed to depend on the asymmetry in the outer part of the plasma leading to a variation of the central rotation by a factor of 1.5-2. The direction of the effect and its magnitude are in agreement with theoretical predictions for the eight possible combinations of plasma asymmetry, current, and magnetic field.

  2. SGLT2 inhibitors: are they safe?

    Science.gov (United States)

    Filippas-Ntekouan, Sebastian; Filippatos, Theodosios D; Elisaf, Moses S

    2018-01-01

    Sodium-glucose linked transporter type 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with positive cardiovascular and kidney effects. The aim of this review is to present the safety issues associated with SGLT2 inhibitors. Urogenital infections are the most frequently encountered adverse events, although tend to be mild to moderate and are easily manageable with standard treatment. Although no increased acute kidney injury risk was evident in the major trials, the mechanism of action of these drugs requires caution when they are administered in patients with extracellular volume depletion or with drugs affecting renal hemodynamics. Canagliflozin raised the risk of amputations and the rate of fractures in the CANVAS trial, although more data are necessary before drawing definite conclusions. The risk of euglycemic diabetic ketoacidosis seems to be minimal when the drugs are prescribed properly. Regarding other adverse events, SGLT2 inhibitors do not increase the risk of hypoglycemia even when co-administered with insulin, but a decrease in the dose of sulphonylureas may be needed. The available data do not point to a causative role of SGLT2 inhibitors on malignancy risk, however, these drugs should be used with caution in patients with known hematuria or history of bladder cancer. SGLT2 inhibitors seem to be safe and effective in the treatment of diabetes but more studies are required to assess their long-term safety.

  3. Lack of Contribution of Multidrug Resistance-associated Protein and Organic Anion-transporting Polypeptide to Pharmacokinetics of Regorafenib, a Novel Multi-Kinase Inhibitor, in Rats.

    Science.gov (United States)

    Hotta, Kazuo; Ueyama, Jun; Tatsumi, Yasuaki; Tsukiyama, Ikuto; Sugiura, Yuka; Saito, Hiroko; Matsuura, Katsuhiko; Hasegawa, Takaaki

    2015-09-01

    We investigated whether hepatic multidrug resistance-associated protein 2 (ABCC2) is involved in the hepatobiliary excretion of regorafenib, a novel multi-kinase inhibitor, using Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR) lacking the efflux transporter ABCC2. The involvement of organic anion-transporting polypeptide 1 (OATP1; OATP in humans) and OATP2 in the hepatic uptake of regorafenib and their protein levels in the liver were also investigated in the two rat groups. When regorafenib (5 mg/kg) was administered intravenously, the plasma concentrations of regorafenib were higher in EHBR than those in SD rats. However, the slope of the plasma concentration-time curves was the same for the two groups. Although the apparent biliary clearance of regorafenib in EHBR was lower than that of SD rats, no significant difference in the biliary excretion rate was observed between them, suggesting that regorafenib is not a substrate for ABCC2 and is not excreted into bile by ABCC2. It was also found that the contribution of biliary excretion to the systemic elimination of regorafenib is small. The protein-binding profiles of regorafenib were found to be linear in both rat groups. The binding potency, which was very high in both rat groups (>99.5%), was significantly higher in EHBR than that in SD rats. No significant differences in the plasma concentrations of unbound regorafenib were observed between the two rat groups, suggesting that the differences observed in the pharmacokinetic behaviors of regorafenib between the two rat groups were due to differences in protein-binding. When the protein levels of hepatic OATP1 and OATP2 were measured by immunoblot analysis, the expression of both transporters in EHBR was less than 40% of that in SD rats. The present results suggest that regorafenib is not a substrate for OATP1 and OATP2. These findings suggest the possibility that ABCC2-mediated hepatobiliary excretion and OATP1/OATP2-mediated hepatic uptake do

  4. National Borders and Transport corridors in Europe: Evidence of linkages in the Dublin-Belfast corridor

    DEFF Research Database (Denmark)

    Petrov, Laura Oana; Williams, Brendan; Shahumyan, Harutyun

    2012-01-01

    Europe’s urban life focuses around a major network of cities, which exchange population, goods, and services of every kind both within regions and across borders. By their very nature, urban questions thus have a transnational dimension, and constitute a fruitful area of Euro-pean cooperation...... the population to benefit from essential facilities offered by functional urbanised areas which can include other cities. But, they often exacerbate urban sprawl into new urban areas. Visible impacts of motorway based urban sprawl are apparent in countries or regions with rapid economic growth and in the New....... The growth of urban areas is associated with acces-sibility to transportation routes, and has become the most important factor in landscape and land use change throughout Europe. Apart from providing links between cities, transport corridors are also exten-sions of cities' functionality which allow...

  5. Experimental evidence for anisotropic double exchange interaction driven anisotropic transport in manganite heterostructures

    NARCIS (Netherlands)

    Liao, Zhaoliang; Koster, Gertjan; Huijben, Mark; Rijnders, A.J.H.M.

    2017-01-01

    An anisotropic double exchange interaction driven giant transport anisotropy is demonstrated in a canonic double exchange system of La2/3Sr1/3MnO3 ultrathin films epitaxially grown on NdGaO3 (110) substrates. The oxygen octahedral coupling at the La2/3Sr1/3MnO3/NdGaO3 interface induces a planar

  6. Experimental evidence of off-diagonal transport term and the discrepancy between energy/particle balance and perturbation analyses

    International Nuclear Information System (INIS)

    Nagashima, Keisuke; Fukuda, Takeshi

    1991-12-01

    Evidence of temperature gradient driven particle flux was observed from the sawtooth induced density propagation phenomenon in JT-60. This off-diagonal particle flux was confirmed using the numerical calculation of measured chord integrated electron density. It was shown that the discrepancies between thermal and particle diffusivities estimated from the perturbation method and energy/particle balance analysis can be explained by considering the flux equations with off-diagonal transport terms. These flux equations were compared with the E x B convective fluxes in an electro-static drift wave instability and it was found that the E x B fluxes are consistent with several experimental observations. (author)

  7. Possible evidence for transport of an iron cyanide complex by plants

    International Nuclear Information System (INIS)

    Samiotakis, M.; Ebbs, S.D.

    2004-01-01

    Barley (Hordeum vulgare L.), oat (Avena sativa L.), and wild cane (Sorghum bicolor L.), were exposed to 15 N-labeled ferrocyanide to determine whether these plant species can transport this iron cyanide complex. Plants were treated with ferrocyanide in a nutrient solution that simulated iron cyanide contaminated groundwater and soil solutions. This nutrient solution has been shown to maintain ferrocyanide speciation with minimal dissociation to free cyanide. Following treatment, all three plants showed dramatic enrichments in roots (δ 15 N%o=1000-1500) and shoots (δ 15 N%o=500). Barley and oat showed enrichment primarily in roots while wild cane showed a near equal enrichment in root and shoot tissues. Nitrogen-deficient barley plants treated with ferrocyanide showed a significantly greater 15 N enrichment as compared to nitrogen-sufficient plants. While the results are suggestive of ferrocyanide transport by these plant species, additional study will be required to verify these results. - Results suggest ferrocyanide transport by barley, oat and wild cane

  8. Possible evidence for transport of an iron cyanide complex by plants

    Energy Technology Data Exchange (ETDEWEB)

    Samiotakis, M.; Ebbs, S.D

    2004-01-01

    Barley (Hordeum vulgare L.), oat (Avena sativa L.), and wild cane (Sorghum bicolor L.), were exposed to {sup 15}N-labeled ferrocyanide to determine whether these plant species can transport this iron cyanide complex. Plants were treated with ferrocyanide in a nutrient solution that simulated iron cyanide contaminated groundwater and soil solutions. This nutrient solution has been shown to maintain ferrocyanide speciation with minimal dissociation to free cyanide. Following treatment, all three plants showed dramatic enrichments in roots ({delta} {sup 15}N%o=1000-1500) and shoots ({delta} {sup 15}N%o=500). Barley and oat showed enrichment primarily in roots while wild cane showed a near equal enrichment in root and shoot tissues. Nitrogen-deficient barley plants treated with ferrocyanide showed a significantly greater {sup 15}N enrichment as compared to nitrogen-sufficient plants. While the results are suggestive of ferrocyanide transport by these plant species, additional study will be required to verify these results. - Results suggest ferrocyanide transport by barley, oat and wild cane.

  9. Transportation

    Science.gov (United States)

    2007-01-01

    Faculty ii INDUSTRY TRAVEL Domestic Assistant Deputy Under Secretary of Defense (Transportation Policy), Washington, DC Department of...developed between the railroad and trucking industries. Railroads: Today’s seven Class I freight railroad systems move 42% of the nation’s intercity ...has been successfully employed in London to reduce congestion and observed by this industry study during its travels . It is currently being

  10. Contingency management in substance abuse treatment: a structured review of the evidence for its transportability.

    Science.gov (United States)

    Hartzler, Bryan; Lash, Steve J; Roll, John M

    2012-04-01

    Extant literature on contingency management (CM) transportability, or its transition from academia to community practice, is reviewed. The Consolidated Framework for Implementation Research (CFIR; Damschroder et al., 2009) guides the examination of this material. PsychInfo and Medline database searches identified 27 publications, with reviewed reference lists garnering 22 others. These 49 sources were examined according to CFIR domains of the intervention, outer setting, inner setting, clinicians, and implementation processes. Intervention characteristics were focal in 59% of the identified literature, with less frequent focus on clinicians (34%), inner setting (32%), implementation processes (18%), and outer setting (8%). As intervention characteristics, adaptability and trialability most facilitate transportability whereas non-clinical origin, perceived inefficacy or disadvantages, and costs are impediments. Clinicians with a managerial focus and greater clinic tenure and CM experience are candidates to curry organizational readiness for implementation, and combat staff disinterest or philosophical objection. A clinic's technology comfort, staff continuity, and leadership advocacy are inner setting characteristics that prompt effective implementation. Implementation processes in successful demonstration projects include careful fiscal/logistical planning, role-specific staff engagement, practical adaptation in execution, and evaluation via fidelity-monitoring and cost-effectiveness analyses. Outer setting characteristics-like economic policies and inter-agency networking or competition-are salient, often unrecognized influences. As most implementation constructs are still moving targets, CM transportability is in its infancy and warrants further scientific attention. More effective dissemination may necessitate that future research weight emphasis on external validity, and utilize models of implementation science. Published by Elsevier Ireland Ltd.

  11. Transport processes for Chernobyl-labelled sediments: preliminary evidence from upland mid-Wales

    International Nuclear Information System (INIS)

    Bonnett, P.J.P.; Leeks, G.J.L.; Cambray, R.S.

    1989-01-01

    The nuclear accident at Chernobyl in April 1986 resulted in a significant increase in the inventory of radiocaesium retained in the soil in many regions of the United Kingdom. The deposition of 134 Cs provides a convenient tool for the examination of erosional processes in upland systems. Detailed soil sampling has been undertaken within the Plynlimon experimental catchments to establish the pattern of deposition of Chernobyl-derived radionuclides. The preliminary results of a combined radiometric and mineral magnetic approach to the study of the transport of Chernobyl-labelled sediments and their source areas on these upland catchments in mid-Wales are described. (author)

  12. Long-range spatial dependence in fractured rock. Empirical evidence and implications for tracer transport

    International Nuclear Information System (INIS)

    Painter, S.

    1999-02-01

    Nonclassical stochastic continuum models incorporating long-range spatial dependence are evaluated as models for fractured crystalline rock. Open fractures and fracture zones are not modeled explicitly in this approach. The fracture zones and intact rock are modeled as a single stochastic continuum. The large contrasts between the fracture zones and unfractured rock are accounted for by making use of random field models specifically designed for highly variable systems. Hydraulic conductivity data derived from packer tests in the vicinity of the Aespoe Hard Rock Laboratory form the basis for the evaluation. The Aespoe log K data were found to be consistent with a fractal scaling model based on bounded fractional Levy motion (bfLm), a model that has been used previously to model highly variable sedimentary formations. However, the data are not sufficient to choose between this model, a fractional Brownian motion model for the normal-score transform of log K, and a conventional geostatistical model. Stochastic simulations conditioned by the Aespoe data coupled with flow and tracer transport calculations demonstrate that the models with long-range dependence predict earlier arrival times for contaminants. This demonstrates the need to evaluate this class of models when assessing the performance of proposed waste repositories. The relationship between intermediate-scale and large-scale transport properties in media with long-range dependence is also addressed. A new Monte Carlo method for stochastic upscaling of intermediate-scale field data is proposed

  13. Evidence of thermal transport anisotropy in stable glasses of vapor deposited organic molecules

    Science.gov (United States)

    Ràfols-Ribé, Joan; Dettori, Riccardo; Ferrando-Villalba, Pablo; Gonzalez-Silveira, Marta; Abad, Llibertat; Lopeandía, Aitor F.; Colombo, Luciano; Rodríguez-Viejo, Javier

    2018-03-01

    Vapor deposited organic glasses are currently in use in many optoelectronic devices. Their operation temperature is limited by the glass transition temperature of the organic layers and thermal management strategies become increasingly important to improve the lifetime of the device. Here we report the unusual finding that molecular orientation heavily influences heat flow propagation in glassy films of small molecule organic semiconductors. The thermal conductivity of vapor deposited thin-film semiconductor glasses is anisotropic and controlled by the deposition temperature. We compare our data with extensive molecular dynamics simulations to disentangle the role of density and molecular orientation on heat propagation. Simulations do support the view that thermal transport along the backbone of the organic molecule is strongly preferred with respect to the perpendicular direction. This is due to the anisotropy of the molecular interaction strength that limits the transport of atomic vibrations. This approach could be used in future developments to implement small molecule glassy films in thermoelectric or other organic electronic devices.

  14. Experimental evidence of high pressure decoupling between charge transport and structural dynamics in a protic ionic glass-former.

    Science.gov (United States)

    Wojnarowska, Z; Rams-Baron, M; Knapik-Kowalczuk, J; Połatyńska, A; Pochylski, M; Gapinski, J; Patkowski, A; Wlodarczyk, P; Paluch, M

    2017-08-01

    In this paper the relaxation dynamics of ionic glass-former acebutolol hydrochloride (ACB-HCl) is studied as a function of temperature and pressure by using dynamic light scattering and broadband dielectric spectroscopy. These unique experimental data provide the first direct evidence that the decoupling between the charge transport and structural relaxation exists in proton conductors over a wide T-P thermodynamic space, with the time scale of structural relaxation being constant at the liquid-glass transition (τ α  = 1000 s). We demonstrate that the enhanced proton transport, being a combination of intermolecular H + hopping between cation and anion as well as tautomerization process within amide moiety of ACB molecule, results in a breakdown of the Stokes-Einstein relation at ambient and elevated pressure with the fractional exponent k being pressure dependent. The dT g /dP coefficient, stretching exponent β KWW and dynamic modulus E a /ΔV # were found to be the same regardless of the relaxation processes studied. This is in contrast to the apparent activation volume parameter that is different when charge transport and structural dynamics are considered. These experimental results together with theoretical considerations create new ideas to design efficient proton conductors for potential electrochemical applications.

  15. In vitro, in vivo and ex vivo characterization of ibrutinib: a potent inhibitor of the efflux function of the transporter MRP1

    Science.gov (United States)

    Zhang, Hui; Patel, Atish; Ma, Shao-Lin; Li, Xiao Jie; Zhang, Yun-Kai; Yang, Pei-Qi; Kathawala, Rishil J; Wang, Yi-Jun; Anreddy, Nagaraju; Fu, Li-Wu; Chen, Zhe-Sheng

    2014-01-01

    Background and Purpose The transporter, multidrug resistance protein 1 (MRP1, ABCC1), plays a critical role in the development of multidrug resistance (MDR). Ibrutinib is an inhibitor of Bruton's tyrosine kinase. Here we investigated the reversal effect of ibrutinib on MRP1-mediated MDR. Experimental Approach Cytotoxicity was determined by MTT assay. The expression of protein was detected by Western blot. RT-PCR and Q-PCR were performed to detect the expression of MRP1 mRNA. The intracellular accumulation and efflux of substrates for MRP1 were measured by scintillation counter and flow cytometry. HEK293/MRP1 cell xenografts in nude mice were established to study the effects of ibrutinib in vivo. Key Results Ibrutinib significantly enhanced the cytotoxicity of MRP1 substrates in HEK293/MRP1 and HL60/Adr cells overexpressing MRP1. Furthermore, ibrutinib increased the accumulation of substrates in these MRP1-overexpressing cells by inhibiting the drug efflux function of MRP1. However, mRNA and protein expression of MRP1 remained unaltered after treatment with ibrutinib in MRP1-overexpressing cells. In vivo, ibrutinib enhanced the efficacy of vincristine to inhibit the growth of HEK293/MRP1 tumour xenografts in nude mice. Importantly, ibrutinib also enhances the cytotoxicity of vincristine in primary cultures of leukaemia blasts, derived from patients. Conclusions and Implications Our results indicated that ibrutinib significantly increased the efficacy of the chemotherapeutic agents which were MRP1 substrates, in MRP1-overexpressing cells, in vitro, in vivo and ex vivo. These findings will lead to further studies on the effects of a combination of ibrutinib with chemotherapeutic agents in cancer patients overexpressing MRP1. PMID:25164592

  16. Three-dimensional quantitative structure-activity relationship (3D QSAR) and pharmacophore elucidation of tetrahydropyran derivatives as serotonin and norepinephrine transporter inhibitors

    Science.gov (United States)

    Kharkar, Prashant S.; Reith, Maarten E. A.; Dutta, Aloke K.

    2008-01-01

    Three-dimensional quantitative structure-activity relationship (3D QSAR) using comparative molecular field analysis (CoMFA) was performed on a series of substituted tetrahydropyran (THP) derivatives possessing serotonin (SERT) and norepinephrine (NET) transporter inhibitory activities. The study aimed to rationalize the potency of these inhibitors for SERT and NET as well as the observed selectivity differences for NET over SERT. The dataset consisted of 29 molecules, of which 23 molecules were used as the training set for deriving CoMFA models for SERT and NET uptake inhibitory activities. Superimpositions were performed using atom-based fitting and 3-point pharmacophore-based alignment. Two charge calculation methods, Gasteiger-Hückel and semiempirical PM3, were tried. Both alignment methods were analyzed in terms of their predictive abilities and produced comparable results with high internal and external predictivities. The models obtained using the 3-point pharmacophore-based alignment outperformed the models with atom-based fitting in terms of relevant statistics and interpretability of the generated contour maps. Steric fields dominated electrostatic fields in terms of contribution. The selectivity analysis (NET over SERT), though yielded models with good internal predictivity, showed very poor external test set predictions. The analysis was repeated with 24 molecules after systematically excluding so-called outliers (5 out of 29) from the model derivation process. The resulting CoMFA model using the atom-based fitting exhibited good statistics and was able to explain most of the selectivity (NET over SERT)-discriminating factors. The presence of -OH substituent on the THP ring was found to be one of the most important factors governing the NET selectivity over SERT. Thus, a 4-point NET-selective pharmacophore, after introducing this newly found H-bond donor/acceptor feature in addition to the initial 3-point pharmacophore, was proposed.

  17. Prenatal serotonin reuptake inhibitor (SRI antidepressant exposure and serotonin transporter promoter genotype (SLC6A4 influence executive functions at 6 years of age

    Directory of Open Access Journals (Sweden)

    Whitney eWeikum

    2013-10-01

    Full Text Available Prenatal exposure to serotonin reuptake inhibitor (SRI antidepressants and maternal depression may affect prefrontal cognitive skills (executive functions; EFs including self-control, working memory and cognitive flexibility. We examined long-term effects of prenatal SRI exposure on EFs to determine whether effects are moderated by maternal mood and/or genetic variations in SLC6A4 (a gene that codes for the serotonin transporter [5-HTT] central to the regulation of synaptic serotonin levels and behavior. Children who were exposed to SRIs prenatally (SRI-exposed N=26 and non-exposed (N=38 were studied at age 6 years (M=6.3 SD=0.5 using the Hearts & Flowers task (H&F to assess EFs. Maternal mood was measured during pregnancy (3rd trimester and when the child was age 6 years (Hamilton Depression Scale. Parent reports of child behavior were also obtained (MacArthur Health & Behavior Questionnaire. Parents of prenatally SRI-exposed children reported fewer child externalizing and inattentive (ADHD behaviors. Generalized estimate equation modeling showed a significant 3-way interaction between prenatal SRI exposure, SLC6A4 variant, and maternal mood at the 6-year time-point on H&F accuracy. For prenatally SRI-exposed children, regardless of maternal mood, the H&F accuracy of children with reduced 5HTT expression (a short [S] allele remained stable. Even with increasing maternal depressive symptoms (though all below clinical threshold, EFs of children with at least one short allele were comparable to children with the same genotype whose mothers reported few if any depressive symptoms – in this sense they showed resilience. Children with two long (L alleles were more sensitive to context. When their mothers had few depressive symptoms, LL children showed extremely good EF performance – better than any other group. When their mothers reported more depressive symptoms, LL children’s EF performance was worse than that of any other group.

  18. Muscle symptoms in statin users, associations with cytochrome P450, and membrane transporter inhibitor use: a subanalysis of the USAGE study.

    Science.gov (United States)

    Ito, Matthew K; Maki, Kevin C; Brinton, Eliot A; Cohen, Jerome D; Jacobson, Terry A

    2014-01-01

    Drug interactions have been identified as a risk factor for muscle-related side effects in statin users. The aim was to assess whether use of medications that inhibit cytochrome P450 (CYP450) isozymes, organic anion transporting polypeptide 1B1 (OATP1B1), or P-glycoprotein (P-gp) are associated with muscle-related symptoms among current and former statin users. Persons (n = 10,138) from the Understanding Statin Use in America and Gaps in Education (USAGE) internet survey were categorized about whether they ever reported new or worsening muscle pain while taking a statin (n = 2935) or ever stopped a statin because of muscle pain (n = 1516). Univariate and multivariate logistic regression models were used to assess associations between use of concomitant therapies that inhibit CYP450 isozymes, OATP1B1, P-gp, or a combination and muscle-related outcomes. In multivariate analyses, concomitant use of a CYP450 inhibitor was associated with increased odds for new or worse muscle pain (odds ratio [OR] = 1.42; P statin because of muscle pain (OR = 1.28; P = .037). Concomitant use of medication known to inhibit both OATP1B1 and P-gp was also associated with increased odds (OR = 1.80; P = .030) of ever having stopped a statin because of muscle pain. Concomitant use of medication(s) that inhibit statin metabolism was associated with increased odds of new or worse muscle pain while taking a statin and having previously stopped a statin because of muscle symptoms. These data emphasize the importance of enhancing the capabilities of clinicians and health systems for identifying and reducing statin drug interactions. Copyright © 2014 National Lipid Association. All rights reserved.

  19. Evidence for thyroxine transport by the lung and heart capillary endothelium

    International Nuclear Information System (INIS)

    Heltianu, C.; Dobrila, L.; Antohe, F.; Simionescu, M.

    1989-01-01

    The uptake and transport of carrier-bound thyroxine by the endothelium were investigated by perfusing through the heart and lung of young rats radiolabeled thyroxine bound to prealbumin ([125I]T4Pa) or serum ([125I]T4S). In addition these complexes were tagged to 5-nm gold particles to obtain quantitative (radioassay) and qualitative (autoradiography) data from the same experiment. The complexes (prewarmed at 37 degrees) were perfused in situ at various concentrations (1 to 50 muCi/ml) for time intervals ranging from 5 to 30 min. After thorough washing of the unbound probe, tissue fragments were either measured for total uptake in a gamma counter or processed for electron microscopy autoradiography. The results showed that both the lung and heart take up [125I]T4 complexes by a process that is saturable at low hormone concentration; uptake is completed by free T4 and Pa. In specimens perfused with double-labeled complexes (iodinated and tagged to gold) autoradiography revealed that silver grains and gold particles colocalize predominantly on endothelial plasmalemmal vesicles. The probe appeared first in vesicles open to the capillary lumen (5 min) and further on in vesicles apparently free within the cytoplasm or open to the abluminal front. At 30 min, only silver grains seem to be present in the pericapillary space, on the alveolar epithelial cells, as well as on the nucleus and mitochondria of heart myocytes. The findings suggest that (1) T4Pa uptake by the endothelial cell (EC) is a specific process (possibly via specific binding sites); (2) T4Pa is taken up and transported across capillary EC by plasmalemmal vesicles; (3) in the pericapillary space T4 seems to dissociate from its carrier

  20. Chemical Evidence for Vertical Transport from Magma Chambers to the Surface During Mid-Ocean Ridge Volcanic Eruptions

    Science.gov (United States)

    Sinton, J. M.; Rubin, K. H.

    2009-12-01

    Many mid-ocean ridge eruptions show significant internal chemical heterogeneity; in general, the amount of chemical heterogeneity within eruptions scales with erupted volume. These variations reflect magmatic processes occurring in magma reservoirs prior to or possibly during eruption. For example, systematic variations in Mg# with along-axis distance in the early 90’s Aldo-Kihi (S. EPR near 17.5°S), 1996 N. Gorda, 1993 Co-Axial (Juan de Fuca Ridge), and 1991-2 and 2005-6 9°50’N EPR eruptions is unlikely to be related to fractionation during emplacement, and rather reflects variations in sub-axial magma reservoirs prior to eruption. Such variations are inconsistent with well-mixed sub-axial reservoirs and, in some cases, require relatively long-lived, systematic variations in reservoir temperatures along axis. Chemical heterogeneity within the Aldo-Kihi eruption preserves spatial variations in mantle-derived isotopic and trace element ratios with implications for the temporal and spatial scales of magma injections to the crust and along-axis mixing within shallow reservoirs. These spatial variations are difficult to reconcile with significant (> ~1 km) along-axis magma transport, as are striking correlations of chemical compositions with surface geological discontinuities or seismically imaged sub-axial magma chamber reflectors in the S. Hump (S. EPR), 9°50’N EPR, N. Gorda and 1975-1984 Krafla (N. Iceland) eruptive units. Rather, spatial correlations between surface lava compositions and sub-axial magma chamber properties or long-lived axial morphology suggest that most of the erupted magma was transported nearly vertically from the underlying reservoirs to the surface during these eruptions. In the case of the Krafla eruption, coincident deformation suggests a component of lateral melt migration at depth, despite chemical evidence for vertical transport of erupted lava from more than one chemical reservoir. In addition, along-ridge movement of earthquake

  1. Certolizumab Pegol for Treating Rheumatoid Arthritis Following Inadequate Response to a TNF-α Inhibitor: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

    Science.gov (United States)

    Bermejo, Iñigo; Stevenson, Matt; Archer, Rachel; Stevens, John W; Goka, Edward; Clowes, Mark; Scott, David L; Young, Adam

    2017-11-01

    As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (UCB Pharma) of certolizumab pegol (CZP; Cimzia ® ) to submit evidence of its clinical and cost effectiveness for the treatment of rheumatoid arthritis (RA) following inadequate response to a tumour necrosis factor-α inhibitor (TNFi). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based upon the company's submission to NICE. The clinical effectiveness evidence in the company's submission for CZP was based predominantly on six randomised controlled trials (RCTs) comparing the efficacy of CZP against placebo. The clinical effectiveness review identified no head-to-head evidence on the efficacy of CZP against the comparators within the scope; therefore, the company performed a network meta-analysis (NMA). The company's NMA concluded that CZP had a similar efficacy to that of its comparators. The company submitted a Markov model that assessed the incremental cost effectiveness of CZP versus comparator biologic disease-modifying antirheumatic drugs (bDMARDs) for the treatment of RA from the perspective of the National Health Service for three decision problems, each of which followed an inadequate response to a TNFi. These were (1) a comparison against rituximab (RTX) in combination with methotrexate (MTX); (2) a comparison against bDMARDs when RTX was contraindicated or withdrawn due to an adverse event; and (3) a comparison against bDMARDs when MTX was contraindicated or withdrawn due to an adverse event. Results from the company's economic evaluation showed that CZP resulted in a similar number of quality-adjusted life years (QALYs) produced at similar or lower costs compared with comparator b

  2. Evidence for a pharmacokinetic interaction between eslicarbazepine and rosuvastatin: Potential effects on xenobiotic transporters.

    Science.gov (United States)

    Gidal, Barry E; Mintzer, Scott; Schwab, Matthias; Schutz, Ralph; Kharidia, Jahnavi; Blum, David; Grinnell, Todd; Sunkaraneni, Soujanya

    2017-09-01

    Patients with partial-onset seizures and comorbid cardiovascular disease may concomitantly receive eslicarbazepine acetate (ESL), an antiepileptic drug, and rosuvastatin, an HMG-CoA reductase inhibitor. This study evaluated the effect of multiple-dose ESL on the pharmacokinetic (PK) parameters of a single dose of rosuvastatin in healthy subjects. This was a Phase I, single-center, fixed-sequence, open-label study. Healthy subjects received two treatments, in sequence. Treatment A: a single 40mg oral dose of rosuvastatin on Day 1, followed by a washout period (Days 1-4); treatment B: titration of ESL (400-800mg once daily) on Days 5-18, followed by ESL 1200mg once daily on Days 19-35, with a single dose of rosuvastatin (40mg) on Day 32. Subjects then entered a 2-week follow-up period. Plasma concentrations of rosuvastatin were quantified for PK analyses. Safety and tolerability were assessed throughout the study. Thirty-three healthy subjects were enrolled and 30 completed the study. Mean rosuvastatin (standard deviation) t 1/2 was similar when rosuvastatin was used concomitantly with ESL and when it was used alone (26.5 [16.3]h, and 22.4 [9.5]h, respectively). The geometric least squares mean ratios (90% confidence intervals) of rosuvastatin exposure levels between rosuvastatin used concomitantly with ESL and rosuvastatin used alone were as follows: C max , 64.0% (55.9-73.3%); AUC (0-∞) , 63.0% (57.1-69.4%); and AUC (0-last) , 60.9% (55.2-67.1%). Concomitant use of ESL and rosuvastatin was generally well tolerated. Rosuvastatin exposure was 36-39% lower with steady-state administration of ESL, potentially due to reduced oral bioavailability of rosuvastatin. Consequently, when rosuvastatin is used with ESL, a rosuvastatin dose adjustment may be necessary if a clinically significant change in lipids is noted. Copyright © 2017. Published by Elsevier B.V.

  3. Proton-pump inhibitors adverse effects: a review of the evidence and position statement by the Sociedad Española de Patología Digestiva.

    Science.gov (United States)

    de la Coba Ortiz, Cristóbal; Argüelles Arias, Federico; Martín de Argila de Prados, Carlos; Júdez Gutiérrez, Javier; Linares Rodríguez, Antonio; Ortega Alonso, Aida; Rodríguez de Santiago, Enrique; Rodríguez-Téllez, Manuel; Vera Mendoza, María Isabel; Aguilera Castro, Lara; Álvarez Sánchez, Ángel; Andrade Bellido, Raúl Jesús; Bao Pérez, Fidencio; Castro Fernández, Manuel; Giganto Tomé, Froilán

    2016-04-01

    In the last few years a significant number of papers have related the use of proton-pump inhibitors (PPIs) to potential serious adverse effects that have resulted in social unrest. The goal of this paper was to provide a literature review for the development of an institutional position statement by Sociedad Española de Patología Digestiva (SEPD) regarding the safety of long-term PPI use. A comprehensive review of the literature was performed to draw conclusions based on a critical assessment of the following: a) current PPI indications; b) vitamin B12 deficiency and neurological disorders; c) magnesium deficiency; d) bone fractures; e) enteric infection and pneumonia; f) interactions with thienopyridine derivatives; e) complications in cirrhotic patients. Current PPI indications have remained unchanged for years now, and are well established. A general screening of vitamin B12 levels is not recommended for all patients on a PPI; however, it does seem necessary that magnesium levels be measured at therapy onset, and then monitored in subjects on other drugs that may induce hypomagnesemia. A higher risk for bone fractures is present, even though causality cannot be concluded for this association. The association between PPIs and infection with Clostridium difficile is mild to moderate, and the risk for pneumonia is low. In patients with cardiovascular risk receiving thienopyridines derivatives it is prudent to adequately consider gastrointestinal and cardiovascular risks, given the absence of definitive evidence regardin potential drug-drug interactions; if gastrointestinal risk is found to be moderate or high, effective prevention should be in place with a PPI. PPIs should be cautiously indicated in patients with decompensated cirrhosis. PPIs are safe drugs whose benefits outweigh their potential side effects both short-term and long-term, provided their indication, dosage, and duration are appropriate.

  4. Land Use, Climate and Transport of Nutrients: Evidence Emerging from the Lake Vicocase Study

    Science.gov (United States)

    Recanatesi, F.; Ripa, M. N.; Leone, A.; Luigi, Perini; Luca, Salvati

    2013-08-01

    Soil erosion is a Europe-wide problem, causing both loss of soil fertility and pollution due to nutrient transport into water bodies. This process is particularly important in the Mediterranean area, where the climate, characterised by long periods of drought followed by intense precipitation, favours soil erosion. Research carried out in this field has amply described this process, showing that climate and land use/land cover (LU/LC) are the two main factors regulating this phenomenon. However, the interaction between these factors is complex and experimental research is needed to understand the nutrient loads deriving from different land uses. This paper shows the results of a long-term monitoring project carried out in the Lake Vico basin (central Italy), using high resolution data and runoff samples to determine the phosphorus (P) export from four different LU/LC classes resulting from the same climatic event. The results highlight the fundamental role that LU/LC plays in terms of phosphorus load. Furthermore, the results appear to indicate that the maximum rainfall registered for 30' ( I 30, max), rather than the total quantity of precipitation, has the greatest effect on levels of erosion, and consequently on the migration of nutrients rather than the total quantity of precipitation can affect on erosion and therefore the migration of nutrients. These data could contribute to scientific planning support for land management choices aimed at controlling water pollution from non-point pollution sources.

  5. Gas transport in low-permeability formations: a review of experimental evidence and modeling approaches

    International Nuclear Information System (INIS)

    Marschall, Paul; Keller, Lukas; Lanyon, Bill; Senger, Rainer

    2012-01-01

    This paper presents a review of phenomenological studies on immiscible fluid flow in porous media, clarifies terminology as used by different disciplines and discusses the different modeling approaches. It concludes with a discussion on the transferability of classical two-phase flow concepts on gas transport processes in low-permeability clay-stones. From a phenomenological point of view, advection and diffusion of dissolved species represent the simplest transport mechanisms in a water-saturated porous medium. The propagation of the dissolved species is controlled by the water velocity and its extent is controlled by the hydrodynamic dispersion - a well-known aggregate representation of the mixing processes due to diffusion, Taylor dispersion and tortuosity. Usually, the dissolution of a gaseous species in water is described by Henry's law, the diffusion of the dissolved gas is represented by Fick's law and the viscous losses of the pore water flow in the pore network are expressed by Darcy's law. Two-phase flow conditions occur when gas invades as a separate phase a water-saturated porous medium. This process is often called drainage, because the non-wetting fluid (gas) displaces a wetting fluid (pore water, 'defending' fluid). The propagation of the gas front is controlled by the complex interaction of gravity, viscous forces and capillary forces. Lenormand et al. (1988) conducted two-phase flow experiments for a wide range of capillary numbers Ca and viscosity ratios M. They identified 3 major flow regimes in the C a -M-space, which they coined viscous fingering, capillary fingering and stable displacement. The regime of stable displacement applies for the special case where the invading fluid has a higher viscosity than the defending fluid (e.g. water imbibition in a gas-filled porous medium). Viscous and capillary fingering are associated with instable displacement of a wetting fluid by the non-wetting fluid, giving rise to phenomena such as migration

  6. TRANSPORT PROPERTIES FOR 1-ETHYL-3-METHYLIMIDAZOLIUM n-ALKYL SULFATES: POSSIBLE EVIDENCE OF GROTTHUSS MECHANISM

    International Nuclear Information System (INIS)

    García-Garabal, S.; Vila, J.; Rilo, E.; Domínguez-Pérez, M.; Segade, L.; Tojo, E.; Verdía, P.; Varela, L.M.; Cabeza, O.

    2017-01-01

    The objective of this work was to study the effect of the temperature and the lengthening of the linear alkyl chain of the anion in the transport physical properties of the pure ionic liquids 1-ethyl-3-methyl imidazolium n-alkyl sulphate (being n = 0, 1, 2, 4, 6 and 8). Density, viscosity and electrical conductivities were measured at atmospheric pressure in a wide temperature range. In the bibliography, data existed for these magnitudes for all ionic liquids studied but none of these had information about the electrical conductivity of 1-ethyl-3-methyl imidazolium n-alkyl sulfate whith n = 0, 4, 6 and 8. The experimental results show clearly 1-ethyl-3-methyl imidazolium hydrogen sulphate cannot be considered part of the 1-ethyl-3-methyl imidazolium n-alkyl sulphate family because of its hydrogen bonding ability. Results of density and viscosity behave as expected. However, in the case of the electrical conductivity due to the lack of alkyl chain in the hydrogen sulfate we expected to get extreme values but in practise, we obtained intermediate values between 1-ethyl-3-methyl imidazolium butyl sulphate and 1-ethyl-3-methyl imidazolium hexyl sulphate. This suggests that a Grotthus mechanism exists as result of a protonic current in addition to ionic conductivity, being Waldeńs plot consistent with this idea.

  7. Voltammetric and Mathematical Evidence for Dual Transport Mediation of Serotonin Clearance In Vivo

    Science.gov (United States)

    Wood, Kevin M.; Zeqja, Anisa; Nijhout, H. Frederik; Reed, Michael C.; Best, Janet; Hashemi, Parastoo

    2014-01-01

    The neurotransmitter serotonin underlies many of the brain’s functions. Understanding serotonin neurochemistry is important for improving treatments for neuropsychiatric disorders such as depression. Antidepressants commonly target serotonin clearance via serotonin transporters (SERTs) and have variable clinical effects. Adjunctive therapies, targeting other systems including serotonin autoreceptors, also vary clinically and carry adverse consequences. Fast scan cyclic voltammetry (FSCV) is particularly well suited for studying antidepressant effects on serotonin clearance and autoreceptors by providing real-time chemical information on serotonin kinetics in vivo. However, the complex nature of in vivo serotonin responses makes it difficult to interpret experimental data with established kinetic models. Here, we electrically stimulated the mouse medial forebrain bundle (MFB) to provoke and detect terminal serotonin in the substantia nigra reticulata (SNr). In response to MFB stimulation we found three dynamically distinct serotonin signals. To interpret these signals we developed a computational model that supports two independent serotonin reuptake mechanisms (high affinity, low efficiency reuptake mechanism and low affinity, high efficiency reuptake system) and bolsters an important inhibitory role for the serotonin autoreceptors. Our data and analysis, afforded by the powerful combination of voltammetric and theoretical methods, gives new understanding of the chemical heterogeneity of serotonin dynamics in the brain. This diverse serotonergic matrix likely contributes to clinical variability of antidepressants. PMID:24702305

  8. Contemporary protease inhibitors and cardiovascular risk

    DEFF Research Database (Denmark)

    Lundgren, Jens; Mocroft, Amanda; Ryom, Lene

    2018-01-01

    PURPOSE OF REVIEW: To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations. RECENT FINDINGS: For the two contemporary most frequently used protease inhibitors, darunavir and atazanavir [both pharmacologically boosted...

  9. Geochemical evidence for seasonal controls on the transportation of Holocene loess, Matanuska Valley, southern Alaska, USA

    Science.gov (United States)

    Muhs, Daniel; Budahn, James R.; Skipp, Gary L.; McGeehin, John

    2016-01-01

    Loess is a widespread Quaternary deposit in Alaska and loess accretion occurs today in some regions, such as the Matanuska Valley. The source of loess in the Matanuska Valley has been debated for more than seven decades, with the Knik River and the Matanuska River, both to the east, being the leading candidates and the Susitna River, to the west, as a less favorable source. We report here new stratigraphic, mineralogic, and geochemical data that test the competing hypotheses of these river sources. Loess thickness data are consistent with previous studies that show that a source or sources lay to the east, which rules out the Susitna River as a source. Knik and Matanuska River silts can be distinguished using Sc–Th–La, LaN/YbN vs. Eu/Eu∗, Cr/Sc, and As/Sb. Matanuska Valley loess falls clearly within the range of values for these ratios found in Matanuska River silt. Dust storms from the Matanuska River are most common in autumn, when river discharge is at a minimum and silt-rich point bars are exposed, wind speed from the north is beginning to increase after a low-velocity period in summer, snow depth is still minimal, and soil temperatures are still above freezing. Thus, seasonal changes in climate and hydrology emerge as critical factors in the timing of aeolian silt transport in southern Alaska. These findings could be applicable to understanding seasonal controls on Pleistocene loess accretion in Europe, New Zealand, South America, and elsewhere in North America.

  10. Preliminary evidence of apathetic-like behavior in aged vesicular monoamine transporter 2 deficient mice

    Directory of Open Access Journals (Sweden)

    Aron Baumann

    2016-11-01

    Full Text Available Apathy is considered to be a core feature of Parkinson’s disease (PD and has been associated with a variety of states and symptoms of the disease, such as increased severity of motor symptoms, impaired cognition, executive dysfunction, and dementia. Apart from the high prevalence of apathy in PD, which is estimated to be about 40%, the underlying pathophysiology remains poorly understood and current treatment approaches are unspecific and proved to be only partially effective. In animal models, apathy has been sub-optimally modeled, mostly by means of pharmacological and stress-induced methods, whereby concomitant depressive-like symptoms could not be ruled out. In the context of PD only a few studies on toxin-based models (i.e. 6-OHDA or MPTP claimed to have determined apathetic symptoms in animals. The assessment of apathetic symptoms in more elaborated and multifaceted genetic animal models of PD could help to understand the pathophysiological development of apathy in PD and eventually advance specific treatments for afflicted patients. Here we report the presence of behavioral signs of apathy in 12 months old mice that express only ~5% of the vesicular monoamine transporter 2 (VMAT2. Apathetic-like behavior in VMAT2 deficient (LO mice was evidenced by impaired burrowing and nest building skills, and a reduced preference for sweet solution in the saccharin preference test, while the performance in the forced swimming test was normal. Our preliminary results suggest that VMAT2 deficient mice show an apathetic-like phenotype that might be independent of depressive-like symptoms. Therefore VMAT2 LO mice could be a useful tool to study of the pathophysiological substrates of apathy and to test novel treatment strategies for apathy in the context of PD.

  11. Airborne dust transport to the eastern Pacific Ocean off southern California: Evidence from San Clemente Island

    Science.gov (United States)

    Muhs, D.R.; Budahn, J.; Reheis, M.; Beann, J.; Skipp, G.; Fisher, E.

    2007-01-01

    Islands are natural dust traps, and San Clemente Island, California, is a good example. Soils on marine terraces cut into Miocene andesite on this island are clay-rich Vertisols or Alfisols with vertic properties. These soils are overlain by silt-rich mantles, 5-20 cm thick, that contrast sharply with the underlying clay-rich subsoils. The silt mantles have a mineralogy that is distinct from the island bedrock. Silt mantles are rich in quartz, which is rare in the island andesite. The clay fraction of the silt mantles is dominated by mica, also absent from local andesite, and contrasts with the subsoils, dominated by smectite. Ternary plots of immobile trace elements (Sc-Th-La and Ta-Nd-Cr) show that the island andesite has a composition intermediate between average upper continental crust and average oceanic crust. In contrast, the silt and, to a lesser extent, clay fractions of the silt mantles have compositions closer to average upper continental crust. The silt mantles have particle size distributions similar to loess and Mojave Desert dust, but are coarser than long-range-transported Asian dust. We infer from these observations that the silt mantles are derived from airborne dust from the North American mainland, probably river valleys in the coastal mountains of southern California and/or the Mojave Desert. Although average winds are from the northwest in coastal California, easterly winds occur numerous times of the year when "Santa Ana" conditions prevail, caused by a high-pressure cell centered over the Great Basin. Examination of satellite imagery shows that easterly Santa Ana winds carry abundant dust to the eastern Pacific Ocean and the California Channel Islands. Airborne dust from mainland North America may be an important component of the offshore sediment budget in the easternmost Pacific Ocean, a finding of potential biogeochemical and climatic significance.

  12. Dopamine transporter imaging in clinically unclear cases of parkinsonism and the importance of Scans Without Evidence of Dopaminergic Deficit (SWEDDs

    Directory of Open Access Journals (Sweden)

    Marco A. T. Utiumi

    2012-09-01

    Full Text Available The clinical diagnosis of Parkinson's disease (PD is susceptible to misdiagnosis, especially in the earlier stages of the disease. Recently, in vivo imaging techniques assessing the presynaptic dopamine transporter (DAT have emerged as a useful tool in PD diagnosis, improving its accuracy. OBJECTIVE: It was to illustrate the clinical usefulness of a brain single-photon emission computed tomography (SPECT DAT ligand, and highlight relevant aspects of scans without evidence of dopaminergic deficit (SWEDDs in this context. CASES: We described four representative patients with clinically unclear parkinsonian syndromes who underwent [99mTc]-TRODAT-1 SPECT and reviewed the clinical implications. CONCLUSION: DAT-SPECT is an important, cost-effective, technique for the differential diagnosis of parkinsonian syndromes. Additionally, SWEDD cases present clinical and paraclinical peculiarities that may retrospectively identify them as essential/dystonic tremor. The lack of histopathological data limits further conclusions.

  13. The glutamate transport inhibitor DL-Threo-β-Benzyloxyaspartic acid (DL-TBOA) differentially affects SN38- and oxaliplatin-induced death of drug-resistant colorectal cancer cells

    DEFF Research Database (Denmark)

    Cuesta, Elena Pedraz; Christensen, Sandra; Jensen, Anders A.

    2015-01-01

    affinity glutamate transporters Solute Carrier (SLC)-1A1 and -1A3 (EAAT3, EAAT1) is associated with the resistant phenotypes. Analyses included real-time quantitative PCR, immunoblotting and immunofluorescence analyses, radioactive tracer flux measurements, and biochemical analyses of cell viability...... was undetectable. The changes in SLC1A1 expression were accompanied by parallel changes in DL-Threo-β-Benzyloxyaspartic acid (TBOA)-sensitive, UCPH101-insensitive [(3)H]-D-Aspartate uptake, consistent with increased activity of SLC1A1 (or other family members), yet not of SLC1A3. DL-TBOA co-treatment concentration...... and glutamate transporter activity are altered in SN38-resistant CRC cells. Importantly, the non-selective glutamate transporter inhibitor DL-TBOA reduces chemotherapy-induced p53 induction and augments CRC cell death induced by SN38, while attenuating that induced by oxaliplatin. These findings may point...

  14. Evidence of non-Darcy flow and non-Fickian transport in fractured media at laboratory scale

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    C. Cherubini

    2013-07-01

    Full Text Available During a risk assessment procedure as well as when dealing with cleanup and monitoring strategies, accurate predictions of solute propagation in fractured rocks are of particular importance when assessing exposure pathways through which contaminants reach receptors. Experimental data obtained under controlled conditions such as in a laboratory allow to increase the understanding of the fundamental physics of fluid flow and solute transport in fractures. In this study, laboratory hydraulic and tracer tests have been carried out on an artificially created fractured rock sample. The tests regard the analysis of the hydraulic loss and the measurement of breakthrough curves for saline tracer pulse inside a rock sample of parallelepiped shape (0.60 × 0.40 × 0.08 m. The convolution theory has been applied in order to remove the effect of the acquisition apparatus on tracer experiments. The experimental results have shown evidence of a non-Darcy relationship between flow rate and hydraulic loss that is best described by Forchheimer's law. Furthermore, in the flow experiments both inertial and viscous flow terms are not negligible. The observed experimental breakthrough curves of solute transport have been modeled by the classical one-dimensional analytical solution for the advection–dispersion equation (ADE and the single rate mobile–immobile model (MIM. The former model does not properly fit the first arrival and the tail while the latter, which recognizes the existence of mobile and immobile domains for transport, provides a very decent fit. The carried out experiments show that there exists a pronounced mobile–immobile zone interaction that cannot be neglected and that leads to a non-equilibrium behavior of solute transport. The existence of a non-Darcian flow regime has showed to influence the velocity field in that it gives rise to a delay in solute migration with respect to the predicted value assuming linear flow. Furthermore, the

  15. Dipeptidyl Peptidase-4 Inhibitor Development and Post-authorisation Programme for Vildagliptin - Clinical Evidence for Optimised Management of Chronic Diseases Beyond Type 2 Diabetes.

    Science.gov (United States)

    Strain, William David; Paldánius, Päivi M

    2017-08-01

    The last decade has witnessed the role of dipeptidyl peptidase-4 (DPP-4) inhibitors in producing a conceptual change in early management of type 2 diabetes mellitus (T2DM) by shifting emphasis from a gluco-centric approach to holistically treating underlying pathophysiological processes. DPP-4 inhibitors highlighted the importance of acknowledging hypoglycaemia and weight gain as barriers to optimised care in T2DM. These complications were an integral part of diabetes management before the introduction of DPP-4 inhibitors. During the development of DPP-4 inhibitors, regulatory requirements for introducing new agents underwent substantial changes, with increased emphasis on safety. This led to the systematic collection of adjudicated cardiovascular (CV) safety data, and, where 95% confidence of a lack of harm could not be demonstrated, the standardised CV safety studies. Furthermore, the growing awareness of the worldwide extent of T2DM demanded a more diverse approach to recruitment and participation in clinical trials. Finally, the global financial crisis placed a new awareness on the health economics of diabetes, which rapidly became the most expensive disease in the world. This review encompasses unique developments in the global landscape, and the role DPP-4 inhibitors, specifically vildagliptin, have played in research advancement and optimisation of diabetes care in a diverse population with T2DM worldwide.

  16. Evidence for distinct sodium-, dopamine-, and cocaine-dependent conformational changes in transmembrane segments 7 and 8 of the dopamine transporter

    DEFF Research Database (Denmark)

    Norregaard, Lene; Loland, Claus Juul; Gether, Ulrik

    2003-01-01

    . Inhibitors such as cocaine did not alter the effect of MTSET in M371C. The protection of M371C inactivation by dopamine required Na+. Because dopamine binding is believed to be Na+-independent, this suggests that dopamine induces a transport-associated conformational change that decreases the reactivity of M......371C with MTSET. In contrast to M371C, cocaine decreased the reaction rate of A399C with MTSET, whereas dopamine had no effect. The protection by cocaine can either reflect that Ala-399 lines the cocaine binding crevice or that cocaine induces a conformational change that decreases the reactivity of A...

  17. Proton NMR studies of Cucurbita maxima trypsin inhibitors: Evidence for pH-dependent conformational change and his25 - try27 interaction

    Energy Technology Data Exchange (ETDEWEB)

    Krishnamoorthi, R.; Chanlan Sun Lin; Yuxi Gong (Kansas State Univ., Manhattan (United States)); VanderVelde, D. (Univ. of Kansas, Lawrence (United States)); Hahn, K. (Univ. of Colorado, Denver (United States))

    1992-01-28

    A pH-dependent His25-Tyr27 interaction was demonstrated in the case of Cucurbita maxima trypsin inhibitors (CMTI-I and CMTI-III) by means of nuclear magnetic resonance (NMR) spectroscopy. pH titration, line widths, peak shapes, deuterium exchange kinetics, and two-dimensional nuclear Overhauser effect spectroscopy (NOESY) were employed to characterize a conformational change involving Tyr27, which was shown to be triggered by deprotonation of His25 around pH 6. A hydrogen bond is proposed to be formed between N{sub {epsilon}} of His25 and OH of Tyr27, as a distance between the atoms, His25 N{epsilon} and Tyr25 OH, of 3.02 {angstrom} is consistent with a model built with NOE-derived distance constraints. The presently characterized relative orientations of His25 and Tyr27 are of functional significance, as these residues make contact with the enzyme in the enzyme-inhibitor complex. Furthermore, trypsin assay and inhibitor-binding studies showed that conformations of trypsin and the squash inhibitor complex. Furthermore, trypsin assay and inhibitor-binding studies showed that conformations of trypsin and the squash inhibitor were functionally relevant only in the pH range 6-8. The pK{sub a} of His25 was determined and found to be influenced by Glu9/Lys substitution and by the hydrolysis of the reactive-site peptide bond between Arg5 and Ile6. As these sites are located far (>10 {angstrom}) from His25, the results point out conformational changes that are propagated to a distant site in the protein molecule.

  18. Combined 5-FU and ChoKα inhibitors as a new alternative therapy of colorectal cancer: evidence in human tumor-derived cell lines and mouse xenografts.

    Directory of Open Access Journals (Sweden)

    Ana de la Cueva

    Full Text Available Colorectal cancer (CRC is the third major cause of cancer related deaths in the world. 5-fluorouracil (5-FU is widely used for the treatment of colorectal cancer but as a single-agent renders low response rates. Choline kinase alpha (ChoKα, an enzyme that plays a role in cell proliferation and transformation, has been reported overexpressed in many different tumors, including colorectal tumors. ChoKα inhibitors have recently entered clinical trials as a novel antitumor strategy.ChoKα specific inhibitors, MN58b and TCD-717, have demonstrated a potent antitumoral activity both in vitro and in vivo against several tumor-derived cell line xenografts including CRC-derived cell lines. The effect of ChoKα inhibitors in combination with 5-FU as a new alternative for the treatment of colon tumors has been investigated both in vitro in CRC-tumour derived cell lines, and in vivo in mouse xenografts models. The effects on thymidilate synthase (TS and thymidine kinase (TK1 levels, two enzymes known to play an essential role in the mechanism of action of 5-FU, were analyzed by western blotting and quantitative PCR analysis. The combination of 5-FU with ChoKα inhibitors resulted in a synergistic effect in vitro in three different human colon cancer cell lines, and in vivo against human colon xenografts in nude mice. ChoKα inhibitors modulate the expression levels of TS and TK1 through inhibition of E2F production, providing a rational for its mechanism of action.Our data suggest that both drugs in combination display a synergistic antitumoral effect due to ChoKα inhibitors-driven modulation of the metabolization of 5-FU. The clinical relevance of these findings is strongly supported since TCD-717 has recently entered Phase I clinical trials against solid tumors.

  19. Probing for improved potency and in vivo bioavailability of excitatory amino acid transporter subtype 1 inhibitors UCPH-101 and UCPH-102: Design, synthesis and pharmacological evaluation of substituted 7-biphenyl analogs

    DEFF Research Database (Denmark)

    Erichsen, Mette Norman; Hansen, J; Artacho Ruiz, Jose

    2014-01-01

    Uptake of the major excitatory neurotransmitter in the CNS, (S)-glutamate, is mediated by a family of excitatory amino acid transporters (EAAT). Previously we have explored the structure-activity relationship (SAR) of a series of EAAT1 selective inhibitors, leading to the development of the potent...... were designed, synthesized and characterized pharmacologically at EAAT1-3 in a [(3)H]-D-aspartate uptake assay. Most notably, the potent EAAT1 inhibition displayed of UCPH-101 and UCPH-102 was retained in analog 1d in which the napht-1-yl group in the 7-position of UCPH-102 has been replaced by an o...

  20. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group

    NARCIS (Netherlands)

    Cicardi, M.; Bork, K.; Caballero, T.; Craig, T.; Li, H. H.; Longhurst, H.; Reshef, A.; Zuraw, B.; Werner, Aberer; Aygören-Pürsün, Emel; Banerji, Aleena; Bjorkander, Janne; Boccon-Gibod, Isabelle; Konrad, Bork; Bouillet, Laurence; Bova, Maria; Bowen, Tom; Branco Ferreira, Manuel; Bygum, Anette; Caballero, Teresa; Cancian, Mauro; Castel-Branco, Maria Graça; Cicardi, Marco; Craig, Timothy; de Carolis, Caterina; Mihály, Enikö; Josè, Fabiani; Farkas, Henriette; Gompels, Mark; Gower, Richard; Groffik, Adriane; Grumach, Anete; Guillarte, Mar; Hernandez Landeros, Maria Esthela; Kaplan, Allen; Leibovich, Iris; Li, Henry; Lock, Bob; Longhurst, Hilary; Lumry, William; Malbran, Alejandro; Martinez-Saguer, Immaculada; Campos, Matta; Maurer, Marcus; Moldovan, Dumitru; Montinaro, Vincenzo; Nieto, Sandra; Nordenfelt, Patrik; Obtulovicz, Krystana; Zeerleder, Sacha

    2012-01-01

    Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life-threatening, disabling disease. In the last 2 years, the results of well-designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market.

  1. Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice.

    Science.gov (United States)

    Vilchez, Valery; Turcios, Lilia; Butterfield, David A; Mitov, Mihail I; Coquillard, Cristin L; Brandon, Ja Anthony; Cornea, Virgilius; Gedaly, Roberto; Marti, Francesc

    2017-10-01

    The PI3K/mTOR signaling cascade is fundamental in T-cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T-cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T-cell activities. Substantial adverse effects in long-term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T-cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI-103 and PKI-587 inhibitors interfered IL-2-dependent responses in T-cells. However, in contrast to the inhibitory effects in non-Treg T-cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI-103, and PKI-587 targeted different signaling events and induced different metabolic patterns in primary T-cells. Similar to rapamycin, in vivo administration of PI-103 and PKI-587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T-cells and support their potential as a novel therapeutic option in transplantation. © 2017 Steunstichting ESOT.

  2. SGLT2 inhibitors.

    Science.gov (United States)

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity-Relationship Study

    DEFF Research Database (Denmark)

    Hansen, Stinne Wessel; Erichsen, Mette Norman; Fu, Bingru

    2016-01-01

    in analogues with substantially improved inhibitory potencies at EAAT1 compared to that displayed by the hit, it provided a detailed insight into structural requirements for EAAT1 activity of this scaffold. The discovery of this new class of EAAT1-selective inhibitors not only supplements the currently...

  4. The serotonin transporter polymorphism (5-HTTLPR) and cortisol stress responsiveness: preliminary evidence for a modulating role for sleep quality.

    Science.gov (United States)

    van Dalfsen, Jens H; Markus, C Rob

    2018-05-23

    The short (S) allele of a functional polymorphism (5-HTTLPR) within the promoter region of the serotonin transporter gene (SLC6A4) is found to predispose the risk for stress-related affective disorders relative to the long (L) allele. Evidence suggests that elevated stress reactivity of the hypothalamic-pituitary-adrenal (HPA) axis might underlie this association although there is little understanding about the origin of inconsistent findings. Since inadequate sleep is commonly known to promote HPA stress reactivity, it might well play an important modulating role. The present study tested this hypothesis by investigating whether sleep quality moderates the relationship between 5-HTTLPR and cortisol stress responsiveness. From a large 5-HTTLPR database (n = 771), a sample of healthy male and female participants homozygous for either the 5-HTTLPR S-allele (n = 25) or L-allele (n = 25) were assessed for sleep quality and salivary cortisol secretion during acute laboratory stress. Diminished sleep quality was found to exclusively potentiate cortisol stress reactivity in the homozygous L-allele genotype. Accounting for this 5-HTTLPR-dependent influence enhanced the predictive value of 5-HTTLPR on cortisol stress responsiveness, revealing greater HPA reactivity in S-allele relative to L-allele carriers. Current findings suggest that variations in sleep quality may serve as a confounding factor in the search for genetic differences in stress sensitivity and related affective disorders.

  5. The distribution of the anti-HIV drug, 2'3'-dideoxycytidine (ddC), across the blood-brain and blood-cerebrospinal fluid barriers and the influence of organic anion transport inhibitors.

    Science.gov (United States)

    Gibbs, J E; Thomas, S A

    2002-02-01

    The brain and CSF distribution of the HIV reverse transcriptase inhibitor, 2'3'-dideoxycytidine (ddC), was investigated by the in situ brain perfusion and isolated incubated choroid plexus methods in the guinea pig. Multiple-time brain perfusions indicated that the distribution of [3H]ddC to the brain and CSF was low and the unidirectional rate constant (K(in)) for the brain uptake of this nucleoside analogue (0.52 +/- 0.10 microL/min/g) was not significantly different to that for the vascular marker, [14C]mannitol (0.44 +/- 0.09 microL/min/g). The influence of unlabelled ddC, six organic anion transport inhibitors and 3'-azido 3'-deoxythymidine (AZT) on the CNS uptake of [3H]ddC was examined in situ and in vitro. ddC, probenecid and 2,4-dichlorophenoxyacetic acid altered the distribution of [3H]ddC into the brain and choroid plexuses, indicating that the limited distribution of [3H]ddC was a result of an organic anion efflux transporter, in addition to the low lipophilicity of this drug (octanol-saline partition coefficient, 0.047 +/- 0.001). The CNS distribution was also sensitive to p-aminohippurate and deltorphin II, but not digoxin, suggesting the involvement of organic anion transporters (OAT1/OAT3-like) and organic anion transporting polypeptides (OATP1/OATPA-like). AZT did not effect the accumulation of [3H]ddC, indicating that when these nucleoside analogues are used in anti-HIV combination therapy, the CNS distribution of ddC is unchanged.

  6. Integrating Norm Activation Model and Theory of Planned Behavior to Understand Sustainable Transport Behavior: Evidence from China.

    Science.gov (United States)

    Liu, Yuwei; Sheng, Hong; Mundorf, Norbert; Redding, Colleen; Ye, Yinjiao

    2017-12-18

    With increasing urbanization in China, many cities are facing serious environmental problems due to continuous and substantial increase in automobile transportation. It is becoming imperative to examine effective ways to reduce individual automobile use to facilitate sustainable transportation behavior. Empirical, theory-based research on sustainable transportation in China is limited. In this research, we propose an integrated model based on the norm activation model and the theory of planned behavior by combining normative and rational factors to predict individuals' intention to reduce car use. Data from a survey of 600 car drivers in China's three metropolitan areas was used to test the proposed model and hypotheses. Results showed that three variables, perceived norm of car-transport reduction, attitude towards reduction, and perceived behavior control over car-transport reduction, significantly affected the intention to reduce car-transport. Personal norms mediated the relationship between awareness of consequences of car-transport, ascription of responsibility of car-transport, perceived subjective norm for car-transport reduction, and intention to reduce car-transport. The results of this research not only contribute to theory development in the area of sustainable transportation behavior, but also provide a theoretical frame of reference for relevant policy-makers in urban transport management.

  7. Integrating Norm Activation Model and Theory of Planned Behavior to Understand Sustainable Transport Behavior: Evidence from China

    Directory of Open Access Journals (Sweden)

    Yuwei Liu

    2017-12-01

    Full Text Available With increasing urbanization in China, many cities are facing serious environmental problems due to continuous and substantial increase in automobile transportation. It is becoming imperative to examine effective ways to reduce individual automobile use to facilitate sustainable transportation behavior. Empirical, theory-based research on sustainable transportation in China is limited. In this research, we propose an integrated model based on the norm activation model and the theory of planned behavior by combining normative and rational factors to predict individuals’ intention to reduce car use. Data from a survey of 600 car drivers in China’s three metropolitan areas was used to test the proposed model and hypotheses. Results showed that three variables, perceived norm of car-transport reduction, attitude towards reduction, and perceived behavior control over car-transport reduction, significantly affected the intention to reduce car-transport. Personal norms mediated the relationship between awareness of consequences of car-transport, ascription of responsibility of car-transport, perceived subjective norm for car-transport reduction, and intention to reduce car-transport. The results of this research not only contribute to theory development in the area of sustainable transportation behavior, but also provide a theoretical frame of reference for relevant policy-makers in urban transport management.

  8. Lifting and transport by sea of great stone columns: evidence of traditional methods used in 18th and 19th century building programs as a clue to reconstructing Roman marble transport processes

    Directory of Open Access Journals (Sweden)

    Paolo Barresi

    2017-01-01

    Full Text Available Aim of this paper is to investigate the traditional technologies of lifting and sea transport of large stone blocks (time spent for sea transport, ways of charging and stewing large stone pieces, number of people engaged with evidence from 18th and 19th century Italy, as a key to understand ancient Roman practices. I shall use data from reconstruction of the 5th century Christian basilica of St. Paul at Rome, burnt in 1823, where new granite shafts, mainly from Italian quarries, replaced the Roman ones. Other documentary sources help to understand some details related to heavy transport, otherwise unknown for Roman period. It should be obviously dangerous to induce directly that the same technologies used for lifting and transport of columns in 18th or 19th century were in use also in Roman Imperial age, but the study of such processes can help us to put in the right view our reconstruction of ancient reality.

  9. Sodium glucose co-transporter inhibitors for the management of diabetes mellitus: an opinion paper from the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy.

    Science.gov (United States)

    Clements, Jennifer N; Whitley, Heather P; D'Souza, Jennifer J; Gross, Benjamin; Hess, Rick; Reece, Sara; Gentry, Chad; Shealy, Kayce

    2015-01-01

    Type 2 diabetes mellitus (T2DM) carries a high prevalence in the United States and worldwide. Therefore, the number of medication classes being developed and studied has grown. The individualized management of diabetes is accomplished by evaluating a medication's efficacy, safety, and cost, along with the patient's preference and tolerance to the medication. Sodium glucose co-transporter 2 inhibitors are a new therapeutic class indicated for the treatment of diabetes and have a unique mechanism of action, independent of beta-cell function. The first agent approved by the Food and Drug Administration (FDA) was canagliflozin in March 2013. Two agents - dapagliflozin and empagliflozin - were FDA-approved in January and July 2014, respectively. A clear understanding of the new class is needed to identify its appropriate use in clinical practice. Members of the American College of Clinical Pharmacy Endocrine and Metabolism Practice and Research Network reviewed available literature regarding this therapeutic class. The article addresses the advantages, disadvantages, emerging role, and patient education for sodium glucose co-transporter 2 inhibitors. Key limitations for this article include limited access to clinical trial data not published by the pharmaceutical company and limited data on products produced outside the United States.

  10. Proton NMR studies of Cucurbita maxima trypsin inhibitors: evidence for pH-dependent conformational change and His25-Tyr27 interaction.

    Science.gov (United States)

    Krishnamoorthi, R; Lin, C L; Gong, Y X; VanderVelde, D; Hahn, K

    1992-01-28

    A pH-dependent His25-Tyr27 interaction was demonstrated in the case of Cucurbita maxima trypsin inhibitors (CMTI-I and CMTI-III) by means of nuclear magnetic resonance (NMR) spectroscopy. pH titration, line widths, peak shapes, deuterium exchange kinetics, and two-dimensional nuclear Overhauser effect spectroscopy (NOESY) were employed to characterize a conformational change involving Tyr27, which was shown to be triggered by deprotonation of His25 around pH 6. A hydrogen bond is proposed to be formed between N epsilon of His25 and OH of Tyr27, as a distance between the atoms, His25 N epsilon and Tyr27 OH, of 3.02 A is consistent with a model built with NOE-derived distance constraints. Both the X-ray [Bode, W., Greyling, J.H., Huber, R., Otlewski, J., & Wilusz, T. (1989) FEBS Lett. 242, 282-292] and NMR [Holak, T.A., Gondol, D., Otlewski, J., & Wilusz, T. (1989) J. Mol. Biol. 210, 635-648] structures of CMTI-I at low pH (4.7-5.3) rule out such an interaction between the two aromatic rings, as the ring planes are oriented about 10 A away from each other. The presently characterized relative orientations of His25 and Tyr27 are of functional significance, as these residues make contact with the enzyme in the enzyme-inhibitor complex. Furthermore, trypsin assay and inhibitor-binding studies showed that conformations of trypsin and the squash inhibitor were functionally relevant only in the pH range 6-8. The pKa of His25 was determined and found to be influenced by Glu9/Lys substitution and by the hydrolysis of the reactive-site peptide bond between Arg5 and Ile6.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Proton pump inhibitors for the treatment of patients with erosive esophagitis and gastroesophageal reflux disease: current evidence and safety of dexlansoprazole

    Directory of Open Access Journals (Sweden)

    Mermelstein J

    2016-07-01

    Full Text Available Joseph Mermelstein,1 Alanna Chait Mermelstein,2 Maxwell M Chait,3 1Department of Medicine, Mount Sinai Beth Israel/Icahn School of Medicine, 2Department of Psychiatry, New York Presbyterian Hospital/Weill Cornell Medicine, 3Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA Abstract: Gastroesophageal reflux disease is the most common upper gastroenterology disorder in the US. It is associated with a variety of complications and significantly impacts quality of life. Proton pump inhibitors are the most effective treatment. Dexlansoprazole modified release (MR is a proton pump inhibitor that employs a novel release formulation that prolongs its absorption and allows for more flexibility in dosing. Dexlansoprazole MR can be dosed without regard to food intake or time of day, and once-daily dosing may replace twice-daily dosing of other agents. Dexlansoprazole MR is effective for healing and maintenance of erosive esophagitis, and for the treatment of nonerosive disease, including nocturnal gastroesophageal reflux disease. Dexlansoprazole MR is safe and well tolerated, and can improve quality of life. Keywords: dexlansoprazole, proton pump inhibitors, gastroesophageal reflux disease, erosive esophagitis

  12. Are Chinese Green Transport Policies Effective? A New Perspective from Direct Pollution Rebound Effect, and Empirical Evidence From the Road Transport Sector

    Directory of Open Access Journals (Sweden)

    Lu-Yi Qiu

    2017-03-01

    Full Text Available Air pollution has become a serious challenge in China. Emissions from motor vehicles have been found to be one main sources of air pollution. Although the Chinese government has undertaken numerous green policies to mitigate harmful emissions from road transport sector, it is still uncertain for both policy makers and researchers to know whether the policies are effective in the short and long terms. We propose a new concept of “pollution rebound effect” (PRE to estimate the effectiveness of green traffic policies. We estimate direct air PRE as a measure of the effectiveness of the policies of reducing air pollution from the transport sector based on time-series data from the period 1986–2014. We find that the short-term direct air PRE is −0.4105, and the corresponding long-run PRE is −0.246. The negative results indicate that the direct air PRE does not exist in the road passenger transport sector in China, both in the short term and in the long term during the period 1986–2014. This implies that the Chinese green transport policies are effective in terms of harmful emissions reduction in the transport sector. This research, to the best of our knowledge, is the first attempt to quantify the effectiveness of the green transport policies in the transitional period that China is currently undergoing.

  13. Molecular insights into human monoamine oxidase (MAO) inhibition by 1,4-naphthoquinone: evidences for menadione (vitamin K3) acting as a competitive and reversible inhibitor of MAO.

    Science.gov (United States)

    Coelho Cerqueira, Eduardo; Netz, Paulo Augusto; Diniz, Cristiane; Petry do Canto, Vanessa; Follmer, Cristian

    2011-12-15

    Monoamine oxidase (MAO) catalyzes the oxidative deamination of biogenic and exogenous amines and its inhibitors have therapeutic value for several conditions including affective disorders, stroke, neurodegenerative diseases and aging. The discovery of 2,3,6-trimethyl-1,4-naphthoquinone (TMN) as a nonselective and reversible inhibitor of MAO, has suggested 1,4-naphthoquinone (1,4-NQ) as a potential scaffold for designing new MAO inhibitors. Combining molecular modeling tools and biochemical assays we evaluate the kinetic and molecular details of the inhibition of human MAO by 1,4-NQ, comparing it with TMN and menadione. Menadione (2-methyl-1,4-naphthoquinone) is a multitarget drug that acts as a precursor of vitamin K and an inducer of mitochondrial permeability transition. Herein we show that MAO-B was inhibited competitively by 1,4-NQ (K(i)=1.4 μM) whereas MAO-A was inhibited by non-competitive mechanism (K(i)=7.7 μM). Contrasting with TMN and 1,4-NQ, menadione exhibited a 60-fold selectivity for MAO-B (K(i)=0.4 μM) in comparison with MAO-A (K(i)=26 μM), which makes it as selective as rasagiline. Fluorescence and molecular modeling data indicated that these inhibitors interact with the flavin moiety at the active site of the enzyme. Additionally, docking studies suggest the phenyl side groups of Tyr407 and Tyr444 (for MAO-A) or Tyr398 and Tyr435 (for MAO-B) play an important role in the interaction of the enzyme with 1,4-NQ scaffold through forces of dispersion as verified for menadione, TMN and 1,4-NQ. Taken together, our findings reveal the molecular details of MAO inhibition by 1,4-NQ scaffold and show for the first time that menadione acts as a competitive and reversible inhibitor of human MAO. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Evidence of independent action of neurohypophyseal peptides on osmotic water flow and active sodium transport in the same target organ: studies on RANA esculenta skin and bladder (1961)

    International Nuclear Information System (INIS)

    Bourguet, J.; Maetz, J.

    1961-01-01

    Neurohypophyseal peptides produce on the skin and bladder of certain amphibia simultaneous increases of the passive osmotic permeability to water and active transport of sodium. The present work shows that oxytocin and two of its analogues arginine-8-oxytocin (arginine vasotocin) and lysine-8-oxytocin (lysine vasotocin) may produce the same increase of water permeability, while stimulating in quite different ways the sodium transport. This is the case for both skin and bladder. In other words, there is no correlation between natriferic and hydro-osmotic activities. The results are interpreted as evidence that neurohypophyseal hormones act on not one, as previously assumed, but two targets, inside the same epithelial cell. (author) [fr

  15. Evidence about chlorophyllin can function as an inhibitor or promoter of induced genetic damage by gamma radiation in Drosophila somatic cells

    International Nuclear Information System (INIS)

    Pimentel, A.E.; Cruces, M.P.; Zimmering, S.I.

    2000-01-01

    The irradiation of the individuals that had been feed during 24 hours with a chlorophyllin solution at 5 % was delayed from 0 until 4 days. The protector effect of chlorophyllin persisted by 3 days and it appears to coincide with the stage when stopping the mitotic divisions in the imagal disk. Within of the same cellular population, it was demonstrated that chlorophyllin can function as an inhibitor, in the case of simple stains mwh or a potentiator in the case of twin stains and the flr type stains. It was planned an explanation for these results. (Author)

  16. Role of SGLT2 Inhibitors in Patients with Diabetes Mellitus and Heart Failure.

    Science.gov (United States)

    Verbrugge, Frederik H

    2017-08-01

    This review aims to summarize the evidence on cardiovascular risks and benefits of glucose-lowering drugs in diabetic patients, with a particular focus on the role of sodium-glucose transporter-2 (SGLT-2) inhibitors and their promising potential as a heart failure treatment. The SGLT-2 inhibitor empagliflozin has emerged as the first glucose-lowering drug to lower cardiovascular mortality in diabetes with an unprecedented 38% relative risk reduction. In addition, empagliflozin significantly reduced the rate of heart failure admissions with 35% when compared to placebo in diabetic patients with established atherosclerosis. SGLT-2 inhibitors should be considered as a first-line drug to achieve glycemic control in diabetic patients at high risk for cardiovascular diseases and heart failure in particular. As SGLT-2 inhibitors target different pathophysiological pathways in heart failure, they might even be considered in the broader population without diabetes, but this remains the topic of further study.

  17. Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover.

    Science.gov (United States)

    Hussein, H; Dulin, J; Smanik, L; Drost, W T; Russell, D; Wellman, M; Bertone, A

    2017-08-01

    Our investigations evaluated the effect of VEL-0230, a highly specific irreversible inhibitor of cathepsin K (CatK). The objectives of our study were to determine whether repeated dosing of a CatK inhibitor (CatKI) produced a desired inhibition of the bone resorption biomarker (CTX-1), and document the effect of repeated dosing on bone homeostasis, structure, and dynamics of bone resorption and formation in horses. Twelve young exercising horses were randomized in a prospective, controlled clinical trial and received 4 weekly doses of a CatKI or vehicle. Baseline and poststudy nuclear scintigraphy, blood sampling and analysis of plasma bone biomarkers (CTX-1 and osteocalcin), poststudy bone fluorescent labeling, and bone biopsy were performed. Bone specimens were further processed for microcomputed tomography and bone histomorphometry. Each dose of this CatKI transiently inhibited plasma CTX-1 (reflecting inhibition of bone collagen resorption) and increased bone plasma osteocalcin concentrations, with no detectable adverse effect on normal bone turnover in the face of exercise. Bone morphology, density, and formation rate were not different between control and treated group. Further investigation of CatK inhibition in abnormal bone turnover is required in animals with bone diseases. © 2016 John Wiley & Sons Ltd.

  18. In vitro and in vivo evidences that antioxidant action contributes to the neuroprotective effects of the neuronal nitric oxide synthase and monoamine oxidase-B inhibitor, 7-nitroindazole.

    Science.gov (United States)

    Thomas, Bobby; Saravanan, Karuppagounder S; Mohanakumar, Kochupurackal P

    2008-05-01

    The neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI) is neuroprotective against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Monoamine oxidase (MAO)-B inhibitory action partially contributes to this effect. We tested the hypothesis that 7-NI could be a powerful hydroxyl radical (OH) scavenger, and interferes with oxidative stress caused by MPTP. We measured OH, reduced glutathione (GSH), as well as superoxide dismutase (SOD) and catalase activities in the nucleus caudatus putamen and substantia nigra of Balb/c mice following MPTP and/or 7-NI administration. The nNOS inhibitor caused dose-dependent inhibition in the production of OH in (i) Fenton-like reaction employing ferrous citrate in a cell-free system in test tubes, (ii) in isolated mitochondrial preparation in presence of MPP+, and (iii) in the striatum of mice systemically treated with MPTP. An MPTP-induced depletion of GSH in both the nuclei was blocked by 7-NI, which was dose-dependent (10-50mg/kg), but independent of MAO-B inhibition. The nNOS-mediated recovery of GSH paralleled attenuation of MPTP-induced depletion of striatal dopamine. MPTP-induced increase in the activities of striatal or nigral SOD and catalase were significantly attenuated by 7-NI treatment. These results suggest potent antioxidant action of 7-NI in its neuroprotective effects against MPTP-induced neurotoxicity.

  19. Transport Properties of the Organic Conductor (TMTSF)2BrO4: Evidence of Variable Range Hopping

    DEFF Research Database (Denmark)

    Mortensen, Kell; Jacobsen, Claus Schelde; Bechgaard, Klaus

    1984-01-01

    A study of d.c. and microwave conductivity and thermoelectric power of the organic conductor (TMTSF)2BrO4 is presented. The transport properties are in qualitative agreement with charge transport via variable-range hopping among localized states. The localization is attributed to the anions, which...

  20. New evidence and impact of electron transport non-linearities based on new perturbative inter-modulation analysis

    NARCIS (Netherlands)

    van Berkel, M.; Kobayashi, T.; Igami, H.; Vandersteen, Gerd; Hogeweij, G.M.D.; Tanaka, K.; Tamura, N.; Zwart, Hans; Kubo, S.; Ito, S.; Tsuchiya, H.; de Baar, M.R.

    2017-01-01

    A new methodology to analyze non-linear components in perturbative transport experiments is introduced. The methodology has been experimentally validated in the Large Helical Device for the electron heat transport channel. Electron cyclotron resonance heating with different modulation frequencies by

  1. Impacts of urbanization on national transport and road energy use: Evidence from low, middle and high income countries

    International Nuclear Information System (INIS)

    Poumanyvong, Phetkeo; Kaneko, Shinji; Dhakal, Shobhakar

    2012-01-01

    Few attempts have been made to investigate quantitatively and systematically the impact of urbanization on transport energy use for countries of different stages of economic development. This paper examines the influence of urbanization on national transport and road energy use for low, middle and high income countries during 1975–2005, using the Stochastic Impacts by Regression on Population, Affluence and Technology (STIRPAT) model. After controlling for population size, income per capita and the share of services in the economy, the main results suggest that urbanization influences national transport and road energy use positively. However, the magnitude of its influence varies among the three income groups. Changes in urbanization appear to have a greater impact on transport and road energy use in the high income group than in the other groups. Surprisingly, the urbanization elasticities of transport and road energy use in the middle income group are smaller than those of the low income group. This study not only sheds further light on the existing literature, but also provides policy makers with insightful information on the link between urbanization and transport energy use at the three different stages of development. - Highlights: ► Overall, urbanization increases national transport and road energy use. ► Urbanization elasticities of transport energy use differ across development stages. ► Urbanization elasticities in high-income group are higher than in other groups.

  2. Selective serotonin reuptake inhibitors and risk for gastrointestinal bleeding

    Directory of Open Access Journals (Sweden)

    Batić-Mujanović Olivera

    2014-01-01

    Full Text Available The most of the known effects of selective serotonin reuptake inhibitors, beneficial or harmful, are associated with the inhibitory action of the serotonin reuptake transporter. This mechanism is present not only in neurons, but also in other cells such as platelets. Serotoninergic mechanism seems to have an important role in hemostasis, which has long been underestimated. Abnormal activation may lead to a prothrombotic state in patients treated with selective serotonin reuptake inhibitors. On one hand there may be an increased risk of bleeding, and on the other hand reduction in thrombotic risk may be possible. Serotonin is critical to maintain a platelet haemostatic function, such as platelet aggregation. Evidences from the studies support the hypothesis that antidepressants with a relevant blockade of action of serotonin reuptake mechanism may increase the risk of bleeding, which can occur anywhere in the body. Epidemiological evidences are, however, the most robust for upper gastrointestinal bleeding. It is estimated that this bleeding can occur in 1 in 100 to 1 in 1.000 patient-years of exposure to the high-affinity selective serotonin reuptake inhibitors, with very old patients at the highest risk. The increased risk may be of particular relevance when selective serotonin reuptake inhibitors are taken simultaneously with nonsteroidal anti-inflammatory drugs, low dose of aspirin or warfarin.

  3. Dissolved iron anomaly in the deep tropical-subtropical Pacific: Evidence for long-range transport of hydrothermal iron

    Science.gov (United States)

    Wu, Jingfeng; Wells, Mark L.; Rember, Robert

    2011-01-01

    Dissolved iron profiles along a north-south transect along 158°W in the tropical Pacific show evidence of two deepwater anomalies. The first extends from Station ALOHA (22.78°N) to the equator at ˜1000-1500 m and lies below the maximum apparent oxygen utilization and nutrient (N, P) concentrations. The feature is not supported by vertical export processes, but instead corresponds with the lateral dilution field of δ 3He derived from the Loihi seamount, Hawaii, though a sediment source associated with the Hawaiian Island Chain cannot be entirely ruled out. The second, deeper (2000-3000 m) anomaly occurs in tropical South Pacific waters (7°S) and also does not correlate with the depths of maximum nutrient concentrations or apparent oxygen utilization, but it does coincide closely with δ 3He emanating from the East Pacific Rise, more than 5000 km to the east. We hypothesize that these anomalies represent the long-range (>2000 km) transport of hydrothermal iron residuals, stabilized against scavenging by complexation with excess organic ligands in the plume source regions. Such trace leakage of hydrothermal iron to distal plume regions would have been difficult to identify in most hydrothermal vent mapping studies because low analytical detection limits were not needed for the proximal plume regions. These findings suggest that hydrothermal activity may represent a major source of dissolved iron throughout the South Pacific deep basin today, as well as other regions having high mid-ocean spreading rates in the geologic past. In particular, we hypothesize that high spreading rates along the South Atlantic and Southern Ocean mid-oceanic ridges, combined with the upwelling ventilation of these distal hydrothermal plumes, may have increased ocean productivity and carbon export in the Southern Ocean. Assessing the magnitude and persistence of dissolved hydrothermal iron in basin scale deep waters will be important for understanding the marine biogeochemistry of iron

  4. Sodium-glucose co-transporter 2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus: A meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Tang, Huilin; Cui, Wei; Li, Dandan; Wang, Tiansheng; Zhang, Jingjing; Zhai, Suodi; Song, Yiqing

    2017-01-01

    Given inconsistent trial results of sodium-glucose cotransporter 2 (SGLT2) inhibitors in addition to insulin therapy for treating type 2 diabetes mellitus (T2DM), a meta-analysis was performed to evaluate the efficacy and safety of this combination for T2DM by searching available randomized trials from PubMed, Embase, CENTRAL and ClinicalTrials.gov. Our meta-analysis included seven eligible placebo-controlled trials involving 4235 patients. Compared with placebo, SGLT2 inhibitor treatment was significantly associated with a mean reduction in HbA1c of -0.56%, fasting plasma glucose of -0.95 mmol/L, body weight of -2.63 kg and insulin dose of -8.79 IU, but an increased risk of drug-related adverse events by 36%, urinary tract infections by 29% and genital infections by 357%. No significant increase was observed in risk of overall adverse events [risk ratio (RR), 1.00], serious adverse events (RR, 0.90), adverse events leading to discontinuation (RR, 1.16), hypoglycaemia events (RR, 1.07) and severe hypoglycaemia events (RR, 1.24). No diabetic ketoacidosis events were reported. Further studies are needed to establish optimal combination type and dose. © 2016 John Wiley & Sons Ltd.

  5. A qualitative systematic review of the evidence base for non-cross-resistance between steroidal and non-steroidal aromatase inhibitors in metastatic breast cancer.

    Science.gov (United States)

    Beresford, M; Tumur, I; Chakrabarti, J; Barden, J; Rao, N; Makris, A

    2011-04-01

    The most effective sequence of tamoxifen and both steroidal (SAIs) and non-steroidal aromatase inhibitors (NSAIs) has been extensively studied in the adjuvant setting. However, treatments for women who have failed initial aromatase inhibitor therapy in the metastatic setting have received relatively little attention. A systematic review was undertaken to assess the use of SAIs and NSAIs in metastatic breast cancer. Medline, Embase and the Cochrane library were searched using free text and MeSH terms. Studies assessing the cross-resistance, efficacy and safety of SAIs and NSAIs for postmenopausal women with advanced metastatic breast cancer confirmed by histology/cytology were included. Patients had progressed/relapsed from previous adjuvant, first- or second-line aromatase inhibitor treatment and had undergone treatment with at least two regimens consisting of aminoglutethimide, anastrozole, letrozole and/or exemestane. Nine studies reported results for patients treated with an SAI after treatment failure with an NSAI. For SAI after NSAI, clinical benefit was the most frequently reported outcome. The clinical benefit for exemestane (SAI) after any NSAI failure or before treatment ranged from 12% (complete response not recorded, partial response 2%, stable disease 10%) to 55% (complete response 6%, partial response 13%, stable disease 35%) Survival outcomes were infrequently reported; four studies reported disease progression. The time to progression ranged from 3.7 to 5.2 months. Only one study reported a median overall survival with exemestane at 15.2 months. Only one study reported information for an NSAI after SAI and an NSAI followed by another NSAI. This review suggests that switching from an NSAI to an SAI is a reasonable option. This would be particularly important for patients who would probably respond to further endocrine manoeuvres; strongly oestrogen receptor-positive disease, non-visceral disease, a good prior response or a long duration of response

  6. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence.

    Science.gov (United States)

    Segovia-Mendoza, Mariana; González-González, María E; Barrera, David; Díaz, Lorenza; García-Becerra, Rocío

    2015-01-01

    An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents.

  7. Subnanomolar indazole-5-carboxamide inhibitors of monoamine oxidase B (MAO-B) continued: indications of iron binding, experimental evidence for optimised solubility and brain penetration.

    Science.gov (United States)

    Tzvetkov, Nikolay T; Antonov, Liudmil

    2017-12-01

    Pharmacological and physicochemical studies of N-unsubstituted indazole-5-carboxamides (subclass I) and their structurally optimised N1-methylated analogues (subclass II), initially developed as drug and radioligand candidates for the treatment and diagnosis of Parkinson's disease (PD), are presented. The compounds are highly brain permeable, selective, reversible, and competitive monoamine oxidase B (MAO-B) inhibitors with improved water-solubility and subnanomolar potency (pIC 50  >8.8). Using a well-validated, combined X-ray/modelling technology platform, we performed a semi-quantitative analysis of the binding modes of all compounds and investigated the role of the indazole N1 position for their MAO-B inhibitory activity. Moreover, compounds NTZ-1006, 1032, and 1441 were investigated for their ability to bind Fe 2+ and Fe 3+ ions using UV-visible spectroscopy.

  8. Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system

    Science.gov (United States)

    Okine, Bright N; Norris, Leonie M; Woodhams, Stephen; Burston, James; Patel, Annie; Alexander, Stephen PH; Barrett, David A; Kendall, David A; Bennett, Andrew J; Chapman, Victoria

    2012-01-01

    BACKGROUND AND PURPOSE Elevating levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is a major focus of pain research, purported to be a safer approach devoid of cannabinoid receptor-mediated side effects. Here, we have determined the effects of sustained pharmacological inhibition of FAAH on inflammatory pain behaviour and if pharmacological inhibition of FAAH was as effective as genetic deletion of FAAH on pain behaviour. EXPERIMENTAL APPROACH Effects of pre-treatment with a single dose, versus 4 day repeated dosing with the selective FAAH inhibitor, URB597 (i.p. 0.3 mg·kg−1), on carrageenan-induced inflammatory pain behaviour and spinal pro-inflammatory gene induction were determined in rats. Effects of pain induction and of the drug treatments on levels of arachidonoyl ethanolamide (AEA), palmitoyl ethanolamide (PEA) and oleolyl ethanolamide (OEA) in the spinal cord were determined. KEY RESULTS Single, but not repeated, URB597 treatment significantly attenuated the development of inflammatory hyperalgesia (P < 0.001, vs. vehicle-treated animals). Neither mode of URB597 treatment altered levels of AEA, PEA and OEA in the hind paw, or carrageenan-induced paw oedema. Single URB597 treatment produced larger increases in AEA, PEA and OEA in the spinal cord, compared with those after repeated administration. Single and repeated URB597 treatment decreased levels of immunoreactive N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) in the spinal cord and attenuated carrageenan-induced spinal pro-inflammatory gene induction. CONCLUSION AND IMPLICATIONS Changes in the endocannabinoid system may contribute to the loss of analgesic effects following repeated administration of low dose URB597 in this model of inflammatory pain. PMID:22595021

  9. Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol

    DEFF Research Database (Denmark)

    Madsen, Karsten Kirkegaard; Ebert, Bjarke; Clausen, Rasmus Prætorius

    2011-01-01

    seizures. Even though less is known about the therapeutic potential of other GABA transport inhibitors, previous investigations have demonstrated that N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502), which, like tiagabine, is inactive...... of gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), which, at the doses used in this study (i.e., 1-5 mg/kg) selectively activates extrasynaptic a4-containing GABA(A) receptors, was determined alone and in combination with either tiagabine or EF1502 using Frings audiogenic seizure-susceptible and CF...

  10. Beta-Sulfonamido Functionalized Aspartate Analogs as Excitatory Amino Acid Transporter Inhibitors: Distinct Subtype-Selectivity Profiles Arising from Subtle Structural Differences

    DEFF Research Database (Denmark)

    Hansen, Jacob Christian; Bjørn-Yoshimoto, Walden Emil; Bisballe, Niels

    2016-01-01

    In this study inspired by previous work on 3-substituted Asp analogues, we designed and synthesized a total of 32 β-sulfonamide Asp analogues and characterized their pharmacological properties at the excitatory amino acid transporter subtypes EAAT1, EAAT2, and EAAT3. In addition to several potent...

  11. [Syk inhibitors].

    Science.gov (United States)

    Kimura, Yukihiro; Chihara, Kazuyasu; Takeuchi, Kenji; Sada, Kiyonao

    2013-07-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in the University of Fukui in 1991. Syk is known to be essential for the various physiological functions, especially in hematopoietic lineage cells. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Recently, novel Syk inhibitors were developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure, and function of Syk, and then describe the novel Syk inhibitors and their current status. Furthermore, we will introduce our findings of the adaptor protein 3BP2 (c-Abl SH3 domain-binding protein-2), as a novel target of Syk.

  12. On the Causal Nexus of Road Transport CO2 Emissions and Macroeconomic Variables in Tunisia: Evidence from Combined Cointegration Tests

    OpenAIRE

    Shahbaz, Muhammad; Khraief, Naceur; Dhaoui, Abderrazak

    2015-01-01

    This paper investigates the causal relationship between road transportation energy consumption, fuel prices, transport sector value added and CO2 emissions in Tunisia for the period 1980-2012. We apply the newly developed combined cointegration test proposed by Bayer and Hanck (2013) and the ARDL bounds testing approach to cointegration to establish the existence of long-run relationship in presence of structural breaks. The direction of causality between these variables is determined via vec...

  13. How scientific evidence is used in Australia to inform public policy on the long distance transportation of animals.

    Science.gov (United States)

    Thornber, Peter M; Adams, David B

    2008-01-01

    Most Australian livestock are transported at some stage in their lives and the attendant risks must be managed. Like other countries, Australia has location-specific challenges for the land transport of animals that derive from general geography and history, quality of the road and rail systems, design of vehicles and handling facilities, competency and experience of drivers and livestock handlers, and pre- and post-journey management of animals. Australia is a large and sparsely populated country and requires a risk-based approach which builds on equivalent outcomes and performance criteria to ensure good welfare for animals during long distance transport. There are shared responsibilities by owners and service providers along the transport chain. Governments work closely with livestock industries, transporters, stock agents, sale yard operators, abattoir owners, feedlot owners and animal welfare organisations to develop and then apply sustainable animal welfare standards and appropriate regulations. The Australian Animal Welfare Strategy sets out a broad and inclusive forum for this to occur in a consultative and cooperative manner and with the necessary input from science. Animal welfare is protected through a combination of codes of practice, appropriate transport standards, industry quality assurance programmes and the enforcement of laws and regulations.

  14. How scientific evidence is used in Australia to inform public policy on the long distance transportation of animals

    Directory of Open Access Journals (Sweden)

    Peter M. Thornber

    2008-03-01

    Full Text Available Most Australian livestock are transported at some stage in their lives and the attendant risks must be managed. Like other countries, Australia has location-specific challenges for the land transport of animals that derive from general geography and history, quality of the road and rail systems, design of vehicles and handling facilities, competency and experience of drivers and livestock handlers, and pre- and post-journey management of animals. Australia is a large and sparsely populated country and requires a risk-based approach which builds on equivalent outcomes and performance criteria to ensure good welfare for animals during long distance transport. There are shared responsibilities by owners and service providers along the transport chain. Governments work closely with livestock industries, transporters, stock agents, sale yard operators, abattoir owners, feedlot owners and animal welfare organisations to develop and then apply sustainable animal welfare standards and appropriate regulations. The Australian Animal Welfare Strategy sets out a broad and inclusive forum for this to occur in a consultative and cooperative manner and with the necessary input from science. Animal welfare is protected through a combination of codes of practice, appropriate transport standards, industry quality assurance programmes and the enforcement of laws and regulations.

  15. Syk inhibitors.

    Science.gov (United States)

    Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

    2013-01-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

  16. North to Alaska: Evidence for conveyor belt transport of Dungeness crab larvae along the west coast of the United States and Canada

    Science.gov (United States)

    Park, W.; Douglas, David C.; Shirley, Thomas C.

    2007-01-01

    We propose and evaluate the hypothesis that Dungeness crab (Cancer magister) larvae from the northwestern coast of the United States and Canada can be transported northward to southeastern Alaska. Larvae collected in southeastern Alaska during May and June 1997–2004 had abundances and stages that varied seasonally, interannually, and spatially. An unexpected presence of late-stage larvae in spring raises a question regarding their origin, and the most plausible explanation is that they hatched off the northern Washington and British Columbia coasts and were transported to southeastern Alaska. Buoy drift tracks support the hypothesis that larvae released off the northern Washington and British Columbia coasts during the peak hatching season can be physically transported to southeastern Alaska, arriving as late-stage larvae in May and June, when local larvae are only beginning to hatch. A northward spring progression of monthly mean 7°C SST isotherms and phytoplankton blooms provide further evidence that environmental conditions are conducive for larval growth and metabolism during the transport period. The proposed larval transport suggests possible unidirectional gene flow between southern and northern populations of Dungeness crabs in southeastern Alaska.

  17. Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2.

    Science.gov (United States)

    Hankosky, Emily R; Joolakanti, Shyam R; Nickell, Justin R; Janganati, Venumadhav; Dwoskin, Linda P; Crooks, Peter A

    2017-12-15

    A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [ 3 H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [ 3 H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [ 3 H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [ 3 H]DA uptake at VMAT2, Ki changes in the nanomolar range (K i  = 0.014-0.073 µM). Compound 15d exhibited the highest affinity (K i  = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (K i  = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Dronerarone acts as a selective inhibitor of 3,5,3'-triiodothyronine binding to thyroid hormone receptor-alpha1: in vitro and in vivo evidence.

    Science.gov (United States)

    Van Beeren, H C; Jong, W M C; Kaptein, E; Visser, T J; Bakker, O; Wiersinga, W M

    2003-02-01

    Dronedarone (Dron), without iodine, was developed as an alternative to the iodine-containing antiarrhythmic drug amiodarone (AM). AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor alpha(1) (TRalpha(1)) and TRbeta(1) antagonist. Here we investigate whether Dron and/or its metabolite debutyldronedarone inhibit T(3) binding to TRalpha(1) and TRbeta(1) in vitro and whether dronedarone behaves similarly to amiodarone in vivo. In vitro, Dron had a inhibitory effect of 14% on the binding of T(3) to TRalpha(1), but not on TRbeta(1). Desethylamiodarone inhibited T(3) binding to TRalpha(1) and TRbeta(1) equally. Debutyldronedarone inhibited T(3) binding to TRalpha(1) by 77%, but to TRbeta(1) by only 25%. In vivo, AM increased plasma TSH and rT(3), and decreased T(3). Dron decreased T(4) and T(3), rT(3) did not change, and TSH fell slightly. Plasma total cholesterol was increased by AM, but remained unchanged in Dron-treated animals. TRbeta(1)-dependent liver low density lipoprotein receptor protein and type 1 deiodinase activities decreased in AM-treated, but not in Dron-treated, animals. TRalpha(1)-mediated lengthening of the QTc interval was present in both AM- and Dron-treated animals. The in vitro and in vivo findings suggest that dronedarone via its metabolite debutyldronedarone acts as a TRalpha(1)-selective inhibitor.

  19. Maternal Use of Selective Serotonin Reuptake Inhibitors and Lengthening of the Umbilical Cord: Indirect Evidence of Increased Foetal Activity-A Retrospective Cohort Study.

    Directory of Open Access Journals (Sweden)

    Julia Kivistö

    Full Text Available Antenatal depression affects up to 19% of pregnant women. Some of these women are also in need of antidepressant treatment. Nevertheless, the impact of maternal antidepressant treatment and prenatal depression on the course of pregnancy, foetal development and delivery outcomes is not fully understood.We analysed data from 24 818 women who gave birth at Kuopio University Hospital between 2002-2012. Logistic regression analysis was used to estimate associations between the use of selective serotonin reuptake inhibitors (SSRIs during pregnancy and the progression of pregnancy, development of the foetus and delivery outcomes.Altogether, 369 (1.5% women used SSRIs. A regression model adjusted for age, overweight, nulliparity, prior termination, miscarriages, smoking, maternal alcohol consumption, chronic illness and polyhydramnion showed that pregnant women exposed to SSRI medication had significantly lower Apgar scores at 1 minute (p < 0.0001 and 5 minutes (p < 0.0001 and more admissions to the neonatal intensive care unit (p < 0.0001 than unexposed pregnant women. In addition, exposed newborns had longer umbilical cords (p < 0.0001 than non-exposed newborns.In addition to the previously known associates with maternal SSRI exposure, such as lowered Apgar scores, SSRI exposure appeared to be associated with increased umbilical cord length. The observation related to increased umbilical cord length may be explained by an SSRI-induced increase in the movements of the developing foetus.

  20. Determination of free and conjugated catecholamines and L-3,4-dihydroxyphenylalanine in plasma and urine: evidence for a catechol-O-methyltransferase inhibitor in uraemia

    International Nuclear Information System (INIS)

    Demassieux, S.; Corneille, L.; Lachance, S.; Carriere, S.

    1981-01-01

    A sensitive, accurate and reproducible method has been developed for the determination of free and conjugated catecholamines and L-3,4-dihydroxyphenylalanine in plasma and urine. The assay involves the enzymatic conversion of these compounds to their radio-labelled O-methylated derivatives using catechol-O-methyltransferase and S-adenosyl-L-[methyl- 3 H]methionine. Recoveries of 75 +- 5% for dopamine, 70 +- 5% for adrenaline and 65 +- 5% for noradrenaline were obtained. The sensitivities were 0.5 pg for adrenaline and noradrenaline and 5-7 pg for dopamine and dihydroxyphenylalanine. Measurements of conjugated catecholamines were performed after mild acid hydrolysis for 20 min at 95 0 C. During this procedure no degradation of the catecholamines was observed. This assay led to the discovery of a dialyzable factor in the plasma of chronic uraemic patients which inhibits catechol-O-methyltransferase activity in vitro. The mean 22% inhibition observed for unhydrolyzed plasma increased to 42% after hydrolysis. The identity of this inhibitor which exists as an inactive conjugated form, probably a sulphate ester, and its implication in physiopathological disorders remain to be established. (Auth.)

  1. Evidence for the involvement of Ala 166 in coupling Na(+) to sugar transport through the human Na(+)/glucose cotransporter

    DEFF Research Database (Denmark)

    Meinild, A K; Loo, D D; Hirayama, B A

    2001-01-01

    . The affinity for Na(+) was unchanged compared to that of hSGLT1, whereas the sugar affinity was reduced and sugar specificity was altered. There was a reduction in the turnover rate of the transporter, and in contrast to that of hSGLT1, the turnover rate depended on the sugar molecule. Exposure of A166C......We mutated residue 166, located in the putative Na(+) transport pathway between transmembrane segments 4 and 5 of human Na(+)/glucose cotransporter (hSGLT1), from alanine to cysteine (A166C). A166C was expressed in Xenopus laevis oocytes, and electrophysiological methods were used to assay function...... to MTSEA and MTSET, but not MTSES, abolished sugar transport. Accessibility of A166C to alkylating reagents was independent of protein conformation, indicating that the residue is always accessible from the extracellular surface. Sugar and phlorizin did not protect the residue from being alkylated...

  2. A γ-secretase inhibitor, but not a γ-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP.

    Directory of Open Access Journals (Sweden)

    April M Weissmiller

    Full Text Available Clues to Alzheimer disease (AD pathogenesis come from a variety of different sources including studies of clinical and neuropathological features, biomarkers, genomics and animal and cellular models. An important role for amyloid precursor protein (APP and its processing has emerged and considerable interest has been directed at the hypothesis that Aβ peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of Aβ peptides have been discovered such as γ-secretase inhibitors (GSIs and modulators (GSMs. GSIs and GSMs reduce Aβ levels through very different mechanisms. However, GSIs, but not GSMs, markedly increase the levels of APP CTFs that are increasingly viewed as disrupting neuronal function. Here, we evaluated the effects of GSIs and GSMs on a number of neuronal phenotypes possibly relevant to their use in treatment of AD. We report that GSI disrupted retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF, suppressed BDNF-induced downstream signaling pathways and induced changes in the distribution within neuronal processes of mitochondria and synaptic vesicles. In contrast, treatment with a novel class of GSMs had no significant effect on these measures. Since knockdown of APP by specific siRNA prevented GSI-induced changes in BDNF axonal trafficking and signaling, we concluded that GSI effects on APP processing were responsible, at least in part, for BDNF trafficking and signaling deficits. Our findings argue that with respect to anti-amyloid treatments, even an APP-specific GSI may have deleterious effects and GSMs may serve as a better alternative.

  3. Advective transport of CO2 in permeable media induced by atmospheric pressure fluctuations: 2. Observational evidence under snowpacks

    Science.gov (United States)

    W. J. Massman; J. M. Frank

    2006-01-01

    Meadow and forest CO2 amounts sampled beneath an approximately meter deep (steady state) snowpack at a subalpine site in southern Rocky Mountains of Wyoming are observed to vary by nearly 200 ppm over periods ranging from 4 to 15 days. This work employs the model of periodic, pressure-induced, advective transport in permeable media developed in...

  4. Experimental evidence for the suitability of ELMing H-mode operation in ITER with regard to core transport of helium

    International Nuclear Information System (INIS)

    Wade, M.R.; Hillis, D.L.; Burrell, K.H.

    1996-09-01

    Studies have been conducted in DIII-D to assess the viability of the ITER design with regard to helium ash removal, including both global helium exhaust studies and detailed helium transport studies. With respect to helium ash accumulation, the results are encouraging for successful operation of ITER in ELMing H-mode plasmas with conventional high-recycling divertor operation. Helium can be removed from the plasma core with a characteristic time constant of ∼ 8 energy confinement times, even with a central source of helium. Furthermore, the exhaust rate is limited by the pumping efficiency of the system and not by transport of helium within the plasma core. Helium transport studies have shown that D He /X eff ∼ 1 in all confinement regimes studied to date and there is little dependence of D He /X eff on normalized gyroradius in dimensionless scaling studies, suggesting that D He /X eff will be ∼ 1 in ITER. These observations suggest that helium transport within the plasma core should be sufficient to prevent unacceptable fuel dilution in ITER. However, helium exhaust is also strongly dependent on many factors (e.g., divertor plasma conditions, plasma and baffling geometry, flux amplification, pumping speed, etc.) that are difficult to extrapolate. Studies have revealed the helium diffusivity decreases as the plasma density increases, which is unfavorable to ITER's extremely high density operation

  5. Metabolic evidence that serosal sodium does not recycle through the active transepithelial transport pathway of toad bladder.

    Science.gov (United States)

    Canessa, M; Labarca, P; Leaf, A

    1976-12-25

    The possibility that sodium from the serosal bathing medium "back diffuses" into the active sodium transport pool within the mucosal epithelial cell of the isolated toad bladder was examined by determining the effect on the metabolism of the tissue of removing sodium from the serosal medium. It was expected that if recycling of serosal sodium did occur through the active transepithelial transport pathway of the isolated toad bladder, removal of sodium from the serosal medium would reduce the rate of CO2 production by the tissue and enhance of stoichiometric ratio of sodium ions transported across the bladder per molecula of sodium transport dependent CO2 produced simultaneously by the bladder (JNa/JCO2). The data revealed no significant change in this ratio (17.19 with serosal sodium and 16.13 after replacing serosal sodium with choline). Further, when transepithelial sodium transport was inhibited (a) by adding amiloride to the mucosal medium, or (b) by removing sodium from the mucosal medium, subsequent removal of sodium from the serosal medium, or (c) addition of ouabain failed to depress the basal rate of CO2 production by the bladder [(a)rate of basal, nontransport related, CO2 production (JbCO2) equals 1.54 +/- 0.52 with serosal sodium and 1.54 +/- 0.37 without serosal sodium; (b) Jb CO2 equals 2.18 +/- 0.21 with serosal sodium and 2.09 +/- 0.21 without serosal sodium; (c) 1.14 +/- 0.26 without ouabain and 1.13 +/- 0.25 with ouabain; unite of JbCO2 are nmoles mg d.w.-1 min-1]. The results support the hypothesis that little, if any, recycling of serosal sodium occurs in the total bladder.

  6. Air pollution over the North China Plain and its implication of regional transport: A new sight from the observed evidences.

    Science.gov (United States)

    Ge, Baozhu; Wang, Zifa; Lin, Weili; Xu, Xiaobin; Li, Jie; Ji, Dongshen; Ma, Zhiqiang

    2018-03-01

    High concentrations of the fine particles (PM 2.5 ) are frequently observed during all seasons over the North China Plain (NCP) region in recent years. In NCP, the contributions of regional transports to certain area, e.g. Beijing city, are often discussed and estimated by models when considering an effective air pollution controlling strategy. In this study, we selected three sites from southwest to northeast in NCP, in which the concentrations of air pollutants displayed a multi-step decreasing trend in space. An approach based on the measurement results at these sites has been developed to calculate the relative contributions of the minimal local emission (MinLEC) and the maximum regional transport (MaxRTC) to the air pollutants (e.g., SO 2 , NO 2 , CO, PM 2.5 ) in Beijing. The minimal influence of local emission is estimated by the difference of the air pollutants' concentrations between urban and rural areas under the assumption of a similar influence of regional transport. Therefore, it's convenient to estimate the contributions of local emission from regional transport based on the selective measurement results instead of the complex numerical model simulation. For the whole year of 2013, the averaged contributions of MinLEC (MaxRTC) for NO 2 , SO 2 , PM 2.5 and CO are 61.7% (30.7%), 46.6% (48%), 52.1% (40.2%) and 35.8% (45.5%), respectively. The diurnal variation of MaxRTC for SO 2 , PM 2.5 and CO shows an increased pattern during the afternoon and reached a peak (more than 50%) around 18:00, which indicates that the regional transport is the important role for the daytime air pollution in Beijing. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Gram-scale solution-phase synthesis of selective sodium bicarbonate co-transport inhibitor S0859: in vitro efficacy studies in breast cancer cells.

    Science.gov (United States)

    Larsen, Ann M; Krogsgaard-Larsen, Niels; Lauritzen, Gitte; Olesen, Christina W; Honoré Hansen, Steen; Boedtkjer, Ebbe; Pedersen, Stine F; Bunch, Lennart

    2012-10-01

    Na(+)-coupled HCO(3)(-) transporters (NBCs) mediate the transport of bicarbonate ions across cell membranes and are thus ubiquitous regulators of intracellular pH. NBC dysregulation is associated with a range of diseases; for instance, NBCn1 is strongly up-regulated in a model of ErbB2-dependent breast cancer, a malignant and widespread cancer with no targeted treatment options, and single-nucleotide polymorphisms in NBCn1 genetically link to breast cancer development and hypertension. The N-cyanosulfonamide S0859 has been shown to selectively inhibit NBCs, and its availability on the gram scale is therefore of significant interest to the scientific community. Herein we describe a short and efficient synthesis of S0859 with an overall yield of 45 % from commercially available starting materials. The inhibitory effect of S0859 on recovery of intracellular pH after an acid load was verified in human and murine cancer cell lines in Ringer solutions. However, S0859 binds very strongly to components in plasma, and accordingly, measurements on isolated murine tissues showed no effect of S0859 at concentrations up to 50 μM. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. 5'-azido-N-1-naphthylphthalamic acid, a photolabile analog of the auxin transport inhibitor, N-1-naphthylphthalamic acid: synthesis and binding properties

    International Nuclear Information System (INIS)

    Voet, J.G.; Howley, K.; Shumsky, J.S.

    1987-01-01

    The polar transport of the plant growth regulator, auxin (indole-3-acetic acid, IAAH), is thought to involve the participation of several proteins in the plasma membrane, including a specific, saturable, voltage independent H + /IAA - efflux carrier located preferentially at the basal end of each cell. Auxin transport is specifically inhibited by the herbicide, N-1-naphthylphthalamic acid (NPA), which binds specifically to a protein in the plasma membrane, thought to be either the IAA - efflux carrier or an allosteric effector protein. They have synthesized and characterized a photolabile analog of NPA, 5'-azido-N-1-naphthylphthalamic acid (Az-NPA). This potential photoaffinity label for the NPA binding protein competes with 3 H-NPA for binding sites on Curcurbita pepo L. (zucchini) stem cell membranes with K/sub j/ = 1.5 x 10 -7 M. The K/sub i/ for NPA under these conditions is 2 x 10 -8 M, indicating that the affinity of Az-NPA for the membranes is only 7.5 fold lower than NPA. While the binding of 4.6 x 10 -6 M Az-NPA to NPA binding sites is reversible in the dark, exposure to light results in a 30% loss in 3 H-NPA binding ability. Pretreatment with 10 -4 M NPA protects the membranes against photodestruction of 3 H-NPA binding sites by Az-NPA, supporting the conclusion that Az-NPA destroys these sites by specific covalent attachment

  9. The glutamate transport inhibitor DL-Threo-β-Benzyloxyaspartic acid (DL-TBOA) differentially affects SN38- and oxaliplatin-induced death of drug-resistant colorectal cancer cells

    International Nuclear Information System (INIS)

    Pedraz-Cuesta, Elena; Christensen, Sandra; Jensen, Anders A.; Jensen, Niels Frank; Bunch, Lennart; Romer, Maria Unni; Brünner, Nils; Stenvang, Jan; Pedersen, Stine Falsig

    2015-01-01

    Colorectal cancer (CRC) is a leading cause of cancer death globally and new biomarkers and treatments are severely needed. Here, we employed HCT116 and LoVo human CRC cells made resistant to either SN38 or oxaliplatin, to investigate whether altered expression of the high affinity glutamate transporters Solute Carrier (SLC)-1A1 and -1A3 (EAAT3, EAAT1) is associated with the resistant phenotypes. Analyses included real-time quantitative PCR, immunoblotting and immunofluorescence analyses, radioactive tracer flux measurements, and biochemical analyses of cell viability and glutathione content. Results were evaluated using one- and two-way ANOVA and Students two-tailed t-test, as relevant. In SN38-resistant HCT116 and LoVo cells, SLC1A1 expression was down-regulated ~60 % and up-regulated ~4-fold, respectively, at both mRNA and protein level, whereas SLC1A3 protein was undetectable. The changes in SLC1A1 expression were accompanied by parallel changes in DL-Threo-β-Benzyloxyaspartic acid (TBOA)-sensitive, UCPH101-insensitive [ 3 H]-D-Aspartate uptake, consistent with increased activity of SLC1A1 (or other family members), yet not of SLC1A3. DL-TBOA co-treatment concentration-dependently augmented loss of cell viability induced by SN38, while strongly counteracting that induced by oxaliplatin, in both HCT116 and LoVo cells. This reflected neither altered expression of the oxaliplatin transporter Cu 2+ -transporter-1 (CTR1), nor changes in cellular reduced glutathione (GSH), although HCT116 cell resistance per se correlated with increased cellular GSH. DL-TBOA did not significantly alter cellular levels of p21, cleaved PARP-1, or phospho-Retinoblastoma protein, yet altered SLC1A1 subcellular localization, and reduced chemotherapy-induced p53 induction. SLC1A1 expression and glutamate transporter activity are altered in SN38-resistant CRC cells. Importantly, the non-selective glutamate transporter inhibitor DL-TBOA reduces chemotherapy-induced p53 induction and augments

  10. B7-H3 is a potent inhibitor of human T cell activation: No evidence for B7-H3 and TREML2 interaction

    Science.gov (United States)

    Leitner, Judith; Klauser, Christoph; Pickl, Winfried F.; Stöckl, Johannes; Majdic, Otto; Bardet, Anaïs F.; Kreil, David P.; Dong, Chen; Yamazaki, Tomohide; Zlabinger, Gerhard; Pfistershammer, Katharina; Steinberger, Peter

    2010-01-01

    B7-H3 belongs to the B7 superfamily, a group of molecules that costimulate or down-modulate T cell responses. Although it was shown that B7-H3 can inhibit T cell responses, several studies - most of them performed in murine systems - found B7-H3 to act in a costimulatory manner. In this study we have specifically addressed a potential functional dualism of human B7-H3 by assessing the effect of this molecule under varying experimental conditions as well as on different T cell subsets. We show that B7-H3 does not costimulate human T cells. In presence of strong activating signals, B7-H3 potently and consistently down-modulated human T cell responses. This inhibitory effect was evident when analyzing proliferation and cytokine production and affected naïve as well as pre-activated T cells. We furthermore demonstrate that B7-H3 - T cell interaction is characterized by an early suppression of IL-2 and that T cell inhibition can be reverted by exogenous IL-2. Since TREML2 has been recently described as costimulatory receptor of murine B7-H3 we have extensively analysed interaction of human B7-H3 with TREML2 (TLT2). In these experiments we found no evidence for such an interaction. Furthermore our data do not point to a role for murine TREML2 as a receptor for murine B7-H3. PMID:19544488

  11. New evidence and impact of electron transport non-linearities based on new perturbative inter-modulation analysis

    Science.gov (United States)

    van Berkel, M.; Kobayashi, T.; Igami, H.; Vandersteen, G.; Hogeweij, G. M. D.; Tanaka, K.; Tamura, N.; Zwart, H. J.; Kubo, S.; Ito, S.; Tsuchiya, H.; de Baar, M. R.; LHD Experiment Group

    2017-12-01

    A new methodology to analyze non-linear components in perturbative transport experiments is introduced. The methodology has been experimentally validated in the Large Helical Device for the electron heat transport channel. Electron cyclotron resonance heating with different modulation frequencies by two gyrotrons has been used to directly quantify the amplitude of the non-linear component at the inter-modulation frequencies. The measurements show significant quadratic non-linear contributions and also the absence of cubic and higher order components. The non-linear component is analyzed using the Volterra series, which is the non-linear generalization of transfer functions. This allows us to study the radial distribution of the non-linearity of the plasma and to reconstruct linear profiles where the measurements were not distorted by non-linearities. The reconstructed linear profiles are significantly different from the measured profiles, demonstrating the significant impact that non-linearity can have.

  12. Transport Improvements and Impacts on Land Use Dynamics and Economic Development: Evidence for the Dublin-Belfast Corridor

    DEFF Research Database (Denmark)

    Williams, Brendan; Foley, Walter; Shahumyan, Harutyun

    2016-01-01

    Transport infrastructure improvements are frequently dealt without adequate consideration of land use management issues. Theoretically this would not appear to be consistent with urban economic theory which prioritises the critical role that transportation plays in all urban economic spatial land...... and planning systems need to be better aligned. In this paper we examine policy evolution and recent policy outcomes and trends in the Belfast-Dublin corridor in light of the major infrastructure investment which occurred based upon official data within the time period mid 1990s (when many investments...... commenced) to 2012 (completion and use of those investments). It will investigate recent trends in terms of emerging economic development patterns since the creation of the M1 motorway and improved rail links. The research will incorporate spatial analytic modelling of current and future development trends...

  13. In vitro characterization of luseogliflozin, a potent and competitive sodium glucose co-transporter 2 inhibitor: Inhibition kinetics and binding studies

    Directory of Open Access Journals (Sweden)

    Saeko Uchida

    2015-05-01

    Full Text Available In this study, we evaluated an inhibition model of luseogliflozin on sodium glucose co-transporter 2 (SGLT2. We also analyzed the binding kinetics of the drug to SGLT2 protein using [3H]-luseogliflozin. Luseogliflozin competitively inhibited human SGLT2 (hSGLT2-mediated glucose uptake with a Ki value of 1.10 nM. In the absence of glucose, [3H]-luseogliflozin exhibited a high affinity for hSGLT2 with a Kd value of 1.3 nM. The dissociation half-time was 7 h, suggesting that luseogliflozin dissociates rather slowly from hSGLT2. These profiles of luseogliflozin might contribute to the long duration of action of this drug.

  14. Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport

    International Nuclear Information System (INIS)

    Rebouche, C.J.; Engel, A.G.

    1984-01-01

    The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine was administered intravenously to six normal subjects, one patient with primary muscle carnitine deficiency (MCD), and four patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 d. A three-compartment model (extracellular fluid, muscle, and ''other tissues'') was adopted. Rate constants, fluxes, pool sizes, and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. However, in SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD, the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these are unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine intake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. However, we found no radioactive metabolites of L-[methyl-3H]carnitine in urine. These observations suggest that dietary carnitine was metabolized in the gastrointestinal tract

  15. Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport.

    OpenAIRE

    Rebouche, C J; Engel, A G

    1984-01-01

    The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine wa...

  16. Evidence for a poloidally localized enhancement of radial transport in the scrape-off layer of the Tore Supra tokamak

    Czech Academy of Sciences Publication Activity Database

    Gunn, J. P.; Boucher, C.; Dionne, M.; Ďuran, Ivan; Fuchs, Vladimír; Loarer, T.; Nanobashvili, I.; Pánek, Radomír; Pascal, J.-Y.; Saint-Laurent, F.; Stöckel, Jan; Van Rompuy, T.; Zagórski, R.; Adámek, Jiří; Bucalossi, J.; Dejarnac, Renaud; Devynck, P.; Hertout, P.; Hron, Martin; Lebrun, G.; Moreau, P.; Rimini, F.; Sarkissian, A.; Van Oost, G.

    363-365, - (2007), s. 484-490 ISSN 0022-3115. [International Conference on Plasma-Surface Interactions in Controlled Fusion Devices/17th./. Hefei, 22.05.2006-26.05. 2006] R&D Projects: GA ČR GP202/03/P062 Institutional research plan: CEZ:AV0Z20430508 Keywords : Cross-field transport * Edge plasma * Plasma flow * Tore Supra Subject RIV: BG - Nuclear, Atomic and Molecular Physics, Colliders Impact factor: 1.643, year: 2007

  17. Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans.

    Science.gov (United States)

    Heni, Martin; Schöpfer, Patricia; Peter, Andreas; Sartorius, Tina; Fritsche, Andreas; Synofzik, Matthis; Häring, Hans-Ulrich; Maetzler, Walter; Hennige, Anita M

    2014-08-01

    Eating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity. Healthy human subjects participated in an oral glucose tolerance test to determine whole-body insulin sensitivity and underwent lumbar puncture. Blood and CSF concentrations of insulin were significantly correlated. The CSF/serum ratio for insulin was significantly associated with whole body insulin sensitivity with reduced insulin transported into the CSF in insulin-resistant subjects. Together, our data suggest that transport of insulin into the CSF relates to peripheral insulin sensitivity and impairs insulin action in the brain. This underlines the need for sensitizing measures in insulin-resistant subjects.

  18. In vitro evidence for the brain glutamate efflux hypothesis: brain endothelial cells cocultured with astrocytes display a polarized brain-to-blood transport of glutamate.

    Science.gov (United States)

    Helms, Hans Christian; Madelung, Rasmus; Waagepetersen, Helle Sønderby; Nielsen, Carsten Uhd; Brodin, Birger

    2012-05-01

    The concentration of the excitotoxic amino acid, L-glutamate, in brain interstitial fluid is tightly regulated by uptake transporters and metabolism in astrocytes and neurons. The aim of this study was to investigate the possible role of the blood-brain barrier endothelium in brain L-glutamate homeostasis. Transendothelial transport- and accumulation studies of (3) H-L-glutamate, (3) H-L-aspartate, and (3) H-D-aspartate in an electrically tight bovine endothelial/rat astrocyte blood-brain barrier coculture model were performed. After 6 days in culture, the endothelium displayed transendothelial resistance values of 1014 ± 70 Ω cm(2) , and (14) C-D-mannitol permeability values of 0.88 ± 0.13 × 10(-6) cm s(-1) . Unidirectional flux studies showed that L-aspartate and L-glutamate, but not D-aspartate, displayed polarized transport in the brain-to-blood direction, however, all three amino acids accumulated in the cocultures when applied from the abluminal side. The transcellular transport kinetics were characterized with a K(m) of 69 ± 15 μM and a J(max) of 44 ± 3.1 pmol min(-1) cm(-2) for L-aspartate and a K(m) of 138 ± 49 μM and J(max) of 28 ± 3.1 pmol min(-1) cm(-2) for L-glutamate. The EAAT inhibitor, DL-threo-ß-Benzyloxyaspartate, inhibited transendothelial brain-to-blood fluxes of L-glutamate and L-aspartate. Expression of EAAT-1 (Slc1a3), -2 (Slc1a2), and -3 (Slc1a1) mRNA in the endothelial cells was confirmed by conventional PCR and localization of EAAT-1 and -3 in endothelial cells was shown with immunofluorescence. Overall, the findings suggest that the blood-brain barrier itself may participate in regulating brain L-glutamate concentrations. Copyright © 2012 Wiley Periodicals, Inc.

  19. Walking School Buses as a Form of Active Transportation for Children--A Review of the Evidence

    Science.gov (United States)

    Smith, Liz; Norgate, Sarah H.; Cherrett, Tom; Davies, Nigel; Winstanley, Christopher; Harding, Mike

    2015-01-01

    Background: Walking school buses (WSBs) offer a potentially healthier way for children to get to school while reducing traffic congestion. A number of pressing societal challenges make it timely to evaluate evidence of their value. Methods: Studies that focused solely on WSBs were identified through online and manual literature searches. Twelve…

  20. Polymorphisms in ABC transporter genes and concentrations of mercury in newborns--evidence from two Mediterranean birth cohorts.

    Directory of Open Access Journals (Sweden)

    Sabrina Llop

    Full Text Available The genetic background may influence methylmercury (MeHg metabolism and neurotoxicity. ATP binding cassette (ABC transporters actively transport various xenobiotics across biological membranes.To investigate the role of ABC polymorphisms as modifiers of prenatal exposure to MeHg.The study population consisted of participants (n = 1651 in two birth cohorts, one in Italy and Greece (PHIME and the other in Spain (INMA. Women were recruited during pregnancy in Italy and Spain, and during the perinatal period in Greece. Total mercury concentrations were measured in cord blood samples by atomic absorption spectrometry. Maternal fish intake during pregnancy was determined from questionnaires. Polymorphisms (n = 5 in the ABC genes ABCA1, ABCB1, ABCC1 and ABCC2 were analysed in both cohorts.ABCB1 rs2032582, ABCC1 rs11075290, and ABCC2 rs2273697 modified the associations between maternal fish intake and cord blood mercury concentrations. The overall interaction coefficient between rs2032582 and log2-transformed fish intake was negative for carriers of GT (β = -0.29, 95%CI -0.47, -0.12 and TT (β = -0.49, 95%CI -0.71, -0.26 versus GG, meaning that for a doubling in fish intake of the mothers, children with the rs2032582 GG genotype accumulated 35% more mercury than children with TT. For rs11075290, the interaction coefficient was negative for carriers of TC (β = -0.12, 95%CI -0.33, 0.09, and TT (β = -0.28, 95%CI -0.51, -0.06 versus CC. For rs2273697, the interaction coefficient was positive when combining GA+AA (β = 0.16, 95%CI 0.01, 0.32 versus GG.The ABC transporters appear to play a role in accumulation of MeHg during early development.

  1. In vitro and in vivo evidence for active brain uptake of the GHB analogue HOCPCA by the monocarboxylate transporter subtype 1

    DEFF Research Database (Denmark)

    Thiesen, Louise; Kehler, Jan; Clausen, Rasmus P

    2015-01-01

    and in vivo, and to investigate the hypothesis that HOCPCA, like GHB, is a substrate for the monocarboxylate transporters (MCTs). For in vitro uptake studies, MCT1, 2 and 4 were recombinantly expressed in Xenopus laevis oocytes and the previously reported radioligand [(3)H]HOCPCA was used (as substrate......). HOCPCA inhibited the uptake of the endogenous MCT substrate L-[(14)C]lactate, and [(3)H]HOCPCA was shown to act as substrate for MCT1 and 2 (Km values in the low millimolar range). Introducing single point amino acid mutations into positions essential for MCT function supported that HOCPCA binds...... to the endogenous substrate pocket of MCTs. MCT1-mediated brain entry of HOCPCA (10 mg/kg s.c.) was further confirmed in vivo in mice by co-administration of increasing doses of the MCT inhibitor [(R)-5-(3-hydroxypyrrolidine-1-carbonyl)-1-isobutyl-3-methyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H...

  2. A quantile regression analysis of the rebound effect: Evidence from the 2009 National Household Transportation Survey in the United States

    International Nuclear Information System (INIS)

    Su Qing

    2012-01-01

    This paper applies quantile regression method to measure the rebound effect and differentiate it with respect to demand for mobility using the 2009 National Household Transportation Survey (NHTS). The quantile regression results indicate that the rebound effect varies with the distribution of vehicle miles traveled (VMT), ranging between 0.11 and 0.19. Road network density and population density also play an important role in determining travel demand. Regression results indicate that travelers living in areas with higher road network density travel more miles although this positive impact consistently declines along the VMT distribution. Travelers living in areas with population density of at most 3000 persons per square miles travel more miles than those living in higher density areas. The quantile regression results also indicate that the impact of income is positive but declines consistently along the VMT distribution. - Highlights: ► This paper examines the magnitude of rebound effect using the 2009 National Household Transportation Survey data. ► Quantile regression method is applied to capture the variation of the rebound effect given the heterogeneous travelers. ► The regression results indicate that the rebound effect varies with VMT distribution. ► The estimated rebound effect fluctuates between 0.11 and 0.19.

  3. Evidence for a poloidally localized enhancement of radial transport in the scrape-off layer of the Tore Supra tokamak

    International Nuclear Information System (INIS)

    Gunn, J.P.; Boucher, C.; Dionne, M.; Duran, I.; Fuchs, V.; Loarer, T.; Nanobashvili, I.; Panek, R.; Pascal, J.-Y.; Saint-Laurent, F.; Stoeckel, J.; Rompuy, T. van; Zagorski, R.; Adamek, J.; Bucalossi, J.; Dejarnac, R.; Devynck, P.; Hertout, P.; Hron, M.; Lebrun, G.; Moreau, P.; Rimini, F.; Sarkissian, A.; Oost, G. van

    2007-01-01

    Near-sonic parallel flows are systematically observed in the far scrape-off layer (SOL) of the limiter tokamak Tore Supra, as in many L-mode X-point divertor tokamak plasmas. The poloidal variation of the parallel flow has been measured by moving the contact point of a small circular plasma onto limiters at different poloidal angles. The resulting variations of flow are consistent with the existence of a poloidally localized enhancement of radial transport concentrated in a 30 deg. sector near the outboard midplane. If the plasma contact point is placed on the inboard limiters, then the SOL expands to fill all the space between the plasma and the outboard limiters, with density decay lengths between 10 and 20 cm. On the other hand, if the contact point lies on the outboard limiters, the localized plasma outflux is scraped off and the SOL is very thin with decay lengths around 2-3 cm. The outboard radial transport would have to be about two orders of magnitude stronger than inboard to explain these results

  4. The earliest long-distance obsidian transport: Evidence from the ∼200 ka Middle Stone Age Sibilo School Road Site, Baringo, Kenya.

    Science.gov (United States)

    Blegen, Nick

    2017-02-01

    This study presents the earliest evidence of long-distance obsidian transport at the ∼200 ka Sibilo School Road Site (SSRS), an early Middle Stone Age site in the Kapthurin Formation, Kenya. The later Middle Pleistocene of East Africa (130-400 ka) spans significant and interrelated behavioral and biological changes in human evolution including the first appearance of Homo sapiens. Despite the importance of the later Middle Pleistocene, there are relatively few archaeological sites in well-dated contexts (n obsidian transport, important for investigating expansion of intergroup interactions in hominin evolution, is rare from the Middle Pleistocene record of Africa. The SSRS offers a unique contribution to this small but growing dataset. Tephrostratigraphic analysis of tuffs encasing the SSRS provides a minimum age of ∼200 ka for the site. Levallois points and methods of core preparation demonstrate characteristic Middle Stone Age lithic technologies present at the SSRS. A significant portion (43%) of the lithic assemblage is obsidian. The SSRS obsidian comes from three different sources located at distances of 25 km, 140 km and 166 km from the site. The majority of obsidian derives from the farthest source, 166 km to the south of the site. The SSRS thus provides important new evidence that long-distance raw material transport, and the expansion of hominin intergroup interactions that this entails, was a significant feature of hominin behavior ∼200 ka, the time of the first appearance of H. sapiens, and ∼150,000 years before similar behaviors were previously documented in the region. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Magmatic Vapor Phase Transport of Copper in Reduced Porphyry Copper-Gold Deposits: Evidence From PIXE Microanalysis of Fluid Inclusions

    Science.gov (United States)

    Rowins, S. M.; Yeats, C. J.; Ryan, C. G.

    2002-05-01

    Nondestructive proton-induced X-ray emission (PIXE) studies of magmatic fluid inclusions in granite-related Sn-W deposits [1] reveal that copper transport out of reduced felsic magmas is favored by low-salinity vapor and not co-existing high-salinity liquid (halite-saturated brine). Copper transport by magmatic vapor also has been documented in oxidized porphyry Cu-Au deposits, but the magnitude of Cu partitioning into the vapor compared to the brine generally is less pronounced than in the reduced magmatic Sn-W systems [2]. Consideration of these microanalytical data leads to the hypothesis that Cu and, by inference, Au in the recently established "reduced porphyry copper-gold" (RPCG) subclass should partition preferentially into vapor and not high-salinity liquid exsolving directly from fluid-saturated magmas [3-4]. To test this hypothesis, PIXE microanalysis of primary fluid inclusions in quartz-sulfide (pyrite, pyrrhotite & chalcopyrite) veins from two RPCG deposits was undertaken using the CSIRO-GEMOC nuclear microprobe. PIXE microanalysis for the ~30 Ma San Anton deposit (Mexico) was done on halite-saturated aqueous brine (deposit (W. Australia) was done on halite-saturated "aqueous" inclusions, which contain a small (deposits of the new RPCG subclass demonstrate the greater potential of these systems, compared to the classically oxidized porphyry Cu-Au systems, to transport Cu and probably precious metals in a magmatic aqueous vapor phase. These PIXE data also support the possibility that Cu partitions preferentially into an immiscible CO2-rich magmatic fluid. References: [1] Heinrich, C.A. et al. (1992) Econ. Geol., 87, 1566-1583. [2] Heinrich, C.A. et al. (1999) Geology, 27, 755-758. [3] Rowins, S.M. (2000) Geology, 28, 491-494. [4] Rowins, S.M. (2000) The Gangue, GAC-MDD Newsletter, 67, 1-7 (www.gac.ca). [5] Rowins, S.M. et al. (1993) Geol. Soc. Australia Abs., 34, 68-70.

  6. Observational evidence of competing source, loss, and transport processes for relativistic electrons in Earth's outer radiation belt

    Science.gov (United States)

    Turner, Drew; Mann, Ian; Usanova, Maria; Rodriguez, Juan; Henderson, Mike; Angelopoulos, Vassilis; Morley, Steven; Claudepierre, Seth; Li, Wen; Kellerman, Adam; Boyd, Alexander; Kim, Kyung-Chan

    Earth’s outer electron radiation belt is a region of extreme variability, with relativistic electron intensities changing by orders of magnitude over time scales ranging from minutes to years. Extreme variations of outer belt electrons ultimately result from the relative impacts of various competing source (and acceleration), loss, and transport processes. Most of these processes involve wave-particle interactions between outer belt electrons and different types of plasma waves in the inner magnetosphere, and in turn, the activity of these waves depends on different solar wind and magnetospheric driving conditions and thus can vary drastically from event to event. Using multipoint analysis with data from NASA’s Van Allen Probes, THEMIS, and SAMPEX missions, NOAA’s GOES and POES constellations, and ground-based observatories, we present results from case studies revealing how different source/acceleration and loss mechanisms compete during active periods to result in drastically different distributions of outer belt electrons. By using a combination of low-Earth orbiting and high-altitude-equatorial orbiting satellites, we briefly review how it is possible to get a much more complete picture of certain wave activity and electron losses over the full range of MLTs and L-shells throughout the radiation belt. We then show example cases highlighting the importance of particular mechanisms, including: substorm injections and whistler-mode chorus waves for the source and acceleration of relativistic electrons; magnetopause shadowing and wave-particle interactions with EMIC waves for sudden losses; and ULF wave activity for driving radial transport, a process which is important for redistributing relativistic electrons, contributing both to acceleration and loss processes. We show how relativistic electron enhancement events involve local acceleration that is consistent with wave-particle interactions between a seed population of 10s to 100s of keV electrons, with a

  7. Road Transport Infrastructure and Manufacturing Location: An Empirical Evidence and Comparative Study between Tijuana and Nuevo Laredo, Mexico

    Directory of Open Access Journals (Sweden)

    Saúl OBREGÓN-BIOSCA

    2014-01-01

    Full Text Available La infraestructura de transporte influye en la localización de empresas manufactureras, por ello el presente trabajo compara la influencia de la accesibilidad al puerto fronterizo y la localización de empresas manufactureras en dos municipios de la frontera norte de México. Las herramientas utilizadas incluyen el manejo de un sistema de información geográfica y datos a nivel micro de empresas. El análisis estadístico se basa en modelos de Poisson, esti- mando los conjuntos de opciones de ubicación. Los resultados muestran que la accesibilidad y el tamaño del mercado presentan mayor significación en la localización de las empresas en ambas ciudades.

  8. PDE5 Inhibitors As Potential Tools In The Treatment Of Cystic Fibrosis

    Directory of Open Access Journals (Sweden)

    Sabrina eNoel

    2012-09-01

    Full Text Available Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF, there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5 inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF.

  9. Internal mobility of reactive-site-hydrolyzed recombinant Cucurbita maxima trypsin inhibitor-V characterized by NMR spectroscopy: evidence for differential stabilization of newly formed C- and N-termini.

    Science.gov (United States)

    Liu, J; Prakash, O; Huang, Y; Wen, L; Wen, J J; Huang, J K; Krishnamoorthi, R

    1996-09-24

    The solution structure and internal dynamics of the reactive-site (Lys44-Asp45 peptide bond) hydrolyzed form of recombinant Cucurbita maxima trypsin inhibitor-V (rCMTI-V*) were characterized by the application of two-dimensional 1H-15N NMR methods to the uniformly 15N-labeled protein. The 1H-15N chemical shift correlation spectra of rCMTI-V* were assigned, and the chemical shift data were compared with those available for rCMTI-V [Liu, J., Prakash, O., Cai, M., Gong, Y., Huang, Y., Wen, L., Wen, J. J., Huang, J.-K., & Krishnamoorthi, R. (1996) Biochemistry 35, 1516-1524] and CMTI-V* [Cai, M., Gong, Y., Prakash, O., & Krishnamoorthi, R. (1995) Biochemistry 34, 12087-12094] for which three-dimensional solution structures have been determined. It was deduced that the solution structure of rCMTI-V* was almost the same as that of CMTI-V*. 15N spin-lattice and spin-spin relaxation rate constants (R1 and R2, respectively) and ¿1H¿-15N steady-state heteronuclear Overhauser effects were measured for the peptide NH units and arginine and tryptophan N epsilon H groups in rCMTI-V*, and the model-free parameters [Lipari, G., & Szabo, A. (1982) J. Am. Chem. Soc. 104, 4546-4559, 4559-4570] were computed. Most of the backbone of rCMTI-V* is found to be highly constrained (S2 = 0.85), including the N-terminal residues 3-6 (S2 = 0.77). Residues 39-44, forming the C-terminal fragment of the binding loop, exhibit increased mobility (S2 = 0.51); however, the N-terminal segment (residues 46-48) retains rigidity as in the intact form (S2 = 0.83). The S2 values, 0.78 and 0.59, respectively, of Arg50 and Arg52 side chain NHs provide evidence not only for the conservation of the Arg hydrogen-bonds with the binding loop segments but also for the difference in strength between them. This is consistent with the earlier observation made from a study of rCMTI-V at two different pHs and its R50 and R52 mutants [Cai, M., Huang, Y., Prakash, O., Wen, L., Dunkelbarger, S. P., Huang, J.-K., Liu, J

  10. Walking school buses as a form of active transportation for children-a review of the evidence.

    Science.gov (United States)

    Smith, Liz; Norgate, Sarah H; Cherrett, Tom; Davies, Nigel; Winstanley, Christopher; Harding, Mike

    2015-03-01

    Walking school buses (WSBs) offer a potentially healthier way for children to get to school while reducing traffic congestion. A number of pressing societal challenges make it timely to evaluate evidence of their value. Studies that focused solely on WSBs were identified through online and manual literature searches. Twelve WSB studies involving a total of 9169 children were reviewed. Study aims, designs, methods, outcomes, and barriers and facilitators were examined. WSBs were found to be associated with increased prevalence of walking to school and general activity levels although not always significantly. Time constraints emerged as barriers to WSBs, impacting on recruitment of volunteers and children to the WSBs. Facilitators of WSBs included children enjoying socializing and interacting with the environment. Preliminary evidence of the health value of WSBs was demonstrated, along with recommendations for the design of future studies. By tackling barriers of time constraints, volunteer recruitment, and parents' safety concerns while at the same time, increasing convenience and time savings for families, future WSBs are likely to be more sustainable and taken up by more schools. Implications for future innovation in school health were identified. © 2015, American School Health Association.

  11. Charge Transport in 4 nm Molecular Wires with Interrupted Conjugation: Combined Experimental and Computational Evidence for Thermally Assisted Polaron Tunneling.

    Science.gov (United States)

    Taherinia, Davood; Smith, Christopher E; Ghosh, Soumen; Odoh, Samuel O; Balhorn, Luke; Gagliardi, Laura; Cramer, Christopher J; Frisbie, C Daniel

    2016-04-26

    We report the synthesis, transport measurements, and electronic structure of conjugation-broken oligophenyleneimine (CB-OPI 6) molecular wires with lengths of ∼4 nm. The wires were grown from Au surfaces using stepwise aryl imine condensation reactions between 1,4-diaminobenzene and terephthalaldehyde (1,4-benzenedicarbaldehyde). Saturated spacers (conjugation breakers) were introduced into the molecular backbone by replacing the aromatic diamine with trans-1,4-diaminocyclohexane at specific steps during the growth processes. FT-IR and ellipsometry were used to follow the imination reactions on Au surfaces. Surface coverages (∼4 molecules/nm(2)) and electronic structures of the wires were determined by cyclic voltammetry and UV-vis spectroscopy, respectively. The current-voltage (I-V) characteristics of the wires were acquired using conducting probe atomic force microscopy (CP-AFM) in which an Au-coated AFM probe was brought into contact with the wires to form metal-molecule-metal junctions with contact areas of ∼50 nm(2). The low bias resistance increased with the number of saturated spacers, but was not sensitive to the position of the spacer within the wire. Temperature dependent measurements of resistance were consistent with a localized charge (polaron) hopping mechanism in all of the wires. Activation energies were in the range of 0.18-0.26 eV (4.2-6.0 kcal/mol) with the highest belonging to the fully conjugated OPI 6 wire and the lowest to the CB3,5-OPI 6 wire (the wire with two saturated spacers). For the two other wires with a single conjugation breaker, CB3-OPI 6 and CB5-OPI 6, activation energies of 0.20 eV (4.6 kcal/mol) and 0.21 eV (4.8 kcal/mol) were found, respectively. Computational studies using density functional theory confirmed the polaronic nature of charge carriers but predicted that the semiclassical activation energy of hopping should be higher for CB-OPI molecular wires than for the OPI 6 wire. To reconcile the experimental and

  12. Direct evidence of the feedback between climate and nutrient, major, and trace element transport to the oceans

    Science.gov (United States)

    Eiriksdottir, Eydis Salome; Gislason, Sigurður Reynir; Oelkers, Eric H.

    2015-10-01

    transport from the glacial rivers is far higher than all other measured fluxes. This observation, together with the finding that the flux to the oceans of biolimiting elements such as P and Fe is dominated by particulates, suggests that particulate transport by melting glaciers have a relatively strong effect on the feedback between continental weathering, atmospheric chemistry, and climate regulation over geologic time.

  13. Effects in the network topology due to node aggregation: Empirical evidence from the domestic maritime transportation in Greece

    Science.gov (United States)

    Tsiotas, Dimitrios; Polyzos, Serafeim

    2018-02-01

    This article studies the topological consistency of spatial networks due to node aggregation, examining the changes captured between different network representations that result from nodes' grouping and they refer to the same socioeconomic system. The main purpose of this study is to evaluate what kind of topological information remains unalterable due to node aggregation and, further, to develop a framework for linking the data of an empirical network with data of its socioeconomic environment, when the latter are available for hierarchically higher levels of aggregation, in an effort to promote the interdisciplinary research in the field of complex network analysis. The research question is empirically tested on topological and socioeconomic data extracted from the Greek Maritime Network (GMN) that is modeled as a non-directed multilayer (bilayer) graph consisting of a port-layer, where nodes represent ports, and a prefecture-layer, where nodes represent coastal and insular prefectural groups of ports. The analysis highlights that the connectivity (degree) of the GMN is the most consistent aspect of this multilayer network, which preserves both the topological and the socioeconomic information through node aggregation. In terms of spatial analysis and regional science, such effects illustrate the effectiveness of the prefectural administrative division for the functionality of the Greek maritime transportation system. Overall, this approach proposes a methodological framework that can enjoy further applications about the grouping effects induced on the network topology, providing physical, technical, socioeconomic, strategic or political insights.

  14. Evidence-based guidelines for the use of tyrosine kinase inhibitors in adults with Philadelphia chromosome–positive or BCR-ABL–positive acute lymphoblastic leukemia: a Canadian consensus

    Science.gov (United States)

    Couban, S.; Savoie, L.; Mourad, Y. Abou; Leber, B.; Minden, M.; Turner, R.; Palada, V.; Shehata, N.; Christofides, A.; Lachance, S.

    2014-01-01

    Adult Philadelphia chromosome–positive (Ph+) or BCR-ABL–positive (BCR-ABL+) acute lymphoblastic leukemia (all) is an acute leukemia previously associated with a high relapse rate, short disease-free survival, and poor overall survival. In adults, allogeneic hematopoietic cell transplant in first remission remains the only proven curative strategy for transplant-eligible patients. The introduction of tyrosine kinase inhibitors (tkis) in the treatment of patients with Ph+ or BCR-ABL+ all has significantly improved the depth and duration of complete remission, allowing more patients to proceed to transplantation. Although tkis are now considered a standard of care in this setting, few randomized trials have examined the optimal use of tkis in patients with Ph+ all. Questions of major importance remain, including the best way to administer these medications, the choice of tki to administer, and the schedule and the duration to use. We present the results of a systematic review of the literature with consensus recommendations based on the available evidence. PMID:24764712

  15. Evidence of horizontal and vertical transport of water in the Southern Hemisphere tropical tropopause layer (TTL from high-resolution balloon observations

    Directory of Open Access Journals (Sweden)

    S. M. Khaykin

    2016-09-01

    Full Text Available High-resolution in situ balloon measurements of water vapour, aerosol, methane and temperature in the upper tropical tropopause layer (TTL and lower stratosphere are used to evaluate the processes affecting the stratospheric water budget: horizontal transport (in-mixing and hydration by cross-tropopause overshooting updrafts. The obtained in situ evidence of these phenomena are analysed using satellite observations by Aura MLS (Microwave Limb Sounder and CALIPSO (Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation together with trajectory and transport modelling performed using CLaMS (Chemical Lagrangian Model of the Stratosphere and HYSPLIT (Hybrid Single-Particle Lagrangian Integrated Trajectory model. Balloon soundings were conducted during March 2012 in Bauru, Brazil (22.3° S in the frame of the TRO-Pico campaign for studying the impact of convective overshooting on the stratospheric water budget. The balloon payloads included two stratospheric hygrometers: FLASH-B (Fluorescence Lyman-Alpha Stratospheric Hygrometer for Balloon and Pico-SDLA instrument as well as COBALD (Compact Optical Backscatter Aerosol Detector sondes, complemented by Vaisala RS92 radiosondes. Water vapour vertical profiles obtained independently by the two stratospheric hygrometers are in excellent agreement, ensuring credibility of the vertical structures observed. A signature of in-mixing is inferred from a series of vertical profiles, showing coincident enhancements in water vapour (of up to 0.5 ppmv and aerosol at the 425 K (18.5 km level. Trajectory analysis unambiguously links these features to intrusions from the Southern Hemisphere extratropical stratosphere, containing more water and aerosol, as demonstrated by MLS and CALIPSO global observations. The in-mixing is successfully reproduced by CLaMS simulations, showing a relatively moist filament extending to 20° S. A signature of local cross-tropopause transport of water is observed in

  16. Long-term measurements of carbonaceous aerosols in the Eastern Mediterranean: evidence of long-range transport of biomass burning

    Directory of Open Access Journals (Sweden)

    J. Sciare

    2008-09-01

    Full Text Available Long-term (5-year measurements of Elemental Carbon (EC and Organic Carbon (OC in bulk aerosols are presented here for the first time in the Mediterranean Basin (Crete Island. A multi-analytical approach (including thermal, optical, and thermo-optical techniques was applied for these EC and OC measurements. Light absorbing dust aerosols were shown to poorly contribute (+12% on a yearly average to light absorption coefficient (babs measurements performed by an optical method (aethalometer. Long-range transport of agricultural waste burning from European countries surrounding the Black Sea was shown for each year during two periods (March–April and July–September. The contribution of biomass burning to the concentrations of EC and OC was shown to be rather small (20 and 14%, respectively, on a yearly basis, although this contribution could be much higher on a monthly basis and showed important seasonal and interannual variability. By removing the biomass burning influence, our data revealed an important seasonal variation of OC, with an increase by almost a factor of two for the spring months of May and June, whereas BC was found to be quite stable throughout the year. Preliminary measurements of Water Soluble Organic Carbon (WSOC have shown that the monthly mean WSOC/OC ratio remains stable throughout the year (0.45±0.12, suggesting that the partitioning between water soluble and water insoluble organic matter is not significantly affected by biomass burning and secondary organic aerosol (SOA formation. A chemical mass closure performed in the fine mode (Aerodynamic Diameter, A.D.<1.5μm showed that the mass contribution of organic matter (POM was found to be essentially invariable during the year (monthly average of 26±5%.

  17. Long-term measurements of carbonaceous aerosols in the Eastern Mediterranean: evidence of long-range transport of biomass burning

    International Nuclear Information System (INIS)

    Sciare, J.; Oikonomou, K.; Favez, O.; Cachier, H.; Liakakou, E.; Markaki, Z.; Mihalopoulos, N.

    2008-01-01

    Long-term (5-year) measurements of Elemental Carbon (EC) and Organic Carbon (OC) in bulk aerosols are presented here for the first time in the Mediterranean Basin (Crete Island). A multi-analytical approach (including thermal, optical, and thermo-optical techniques) was applied for these EC and OC measurements. Light absorbing dust aerosols were shown to poorly contribute (+12% on a yearly average) to light absorption coefficient (b(abs)) measurements performed by an optical method (aethalometer). Long-range transport of agricultural waste burning from European countries surrounding the Black Sea was shown for each year during two periods (March-April and July-September). The contribution of biomass burning to the concentrations of EC and OC was shown to be rather small (20 and 14%, respectively, on a yearly basis), although this contribution could be much higher on a monthly basis and showed important seasonal and inter annual variability. By removing the biomass burning influence, our data revealed an important seasonal variation of OC, with an increase by almost a factor of two for the spring months of May and June, whereas BC was found to be quite stable throughout the year. Preliminary measurements of Water Soluble Organic Carbon (WSOC) have shown that the monthly mean WSOC/ OC ratio remains stable throughout the year (0.45 ± 0.12), suggesting that the partitioning between water soluble and water insoluble organic matter is not significantly affected by biomass burning and secondary organic aerosol (SOA) formation. A chemical mass closure performed in the fine mode (Aerodynamic Diameter, A. D.≤ 1.5 μm) showed that the mass contribution of organic matter (POM) was found to be essentially invariable during the year (monthly average of 26 ± 5%). (authors)

  18. Forced transport of thermal energy in magmatic and phreatomagmatic large volume ignimbrites: Paleomagnetic evidence from the Colli Albani volcano, Italy

    Science.gov (United States)

    Trolese, Matteo; Giordano, Guido; Cifelli, Francesca; Winkler, Aldo; Mattei, Massimo

    2017-11-01

    Few studies have detailed the thermal architecture of large-volume pyroclastic density current deposits, although such work has a clear importance for understanding the dynamics of eruptions of this magnitude. Here we examine the temperature of emplacement of large-volume caldera-forming ignimbrites related to magmatic and phreatomagmatic eruptions at the Colli Albani volcano, Italy, by using thermal remanent magnetization analysis on both lithic and juvenile clasts. Results show that all the magmatic ignimbrites were deposited at high temperature, between the maximum blocking temperature of the magnetic carrier (600-630 °C) and the glass transition temperature (about 710 °C). Temperature estimations for the phreatomagmatic ignimbrite range between 200 and 400 °C, with most of the clasts emplaced between 200 and 320 °C. Because all the investigated ignimbrites, magmatic and phreatomagmatic, share similar magma composition, volume and mobility, we attribute the temperature difference to magma-water interaction, highlighting its pronounced impact on thermal dissipation, even in large-volume eruptions. The homogeneity of the deposit temperature of each ignimbrite across its areal extent, which is maintained across topographic barriers, suggests that these systems are thermodynamically isolated from the external environment for several tens of kilometers. Based on these findings, we propose that these large-volume ignimbrites are dominated by the mass flux, which forces the lateral transport of mass, momentum, and thermal energy for distances up to tens of kilometers away from the vent. We conclude that spatial variation of the emplacement temperature can be used as a proxy for determining the degree of forced-convection flow.

  19. Assessing the rebound effect using a natural experiment setting: Evidence from the private transportation sector in Israel

    International Nuclear Information System (INIS)

    Steren, Aviv; Rubin, Ofir D.; Rosenzweig, Stav

    2016-01-01

    Subsidizing energy-efficient technologies is considered by energy and environmental organizations to be one of the most effective policies for decreasing energy consumption. In the transportation sector such policies are becoming ever more popular, and have been implemented in a considerable number of countries in recent years. Because these policies promote energy-efficient cars with lower usage costs, they may rebound and increase the distances traveled by households that have switched to energy-efficient cars. From an econometric perspective, a subsidization policy can be used as a valid instrument to identify the households’ choice of energy efficiency levels of the cars they own. This identification, in turn, can be utilized to account for endogeneity in the estimation of a rebound effect. The present study uses a natural experiment setting of such a policy implemented in Israel in 2009. The empirical results indicate a fairly large average rebound effect of 40%. The results also indicate that while the policy indeed encouraged the purchase of energy-efficient cars, households that bought a new or used car during the surveyed period did not generate a rebound effect of a different magnitude compared with other households that did not. We discuss the implications of our findings. - Highlights: •Subsidizing energy-efficient cars has become a popular policy in many countries. •We are unaware of studies identifying rebound via cars’ subsidization policy. •We explored a rebound in light of such a policy in Israel. •Household expenditure survey data, fuel prices and car characteristics were employed. •We found an average rebound effect of 40%.

  20. The Putative Role of the Non-Gastric H+/K+-ATPase ATP12A (ATP1AL1 as Anti-Apoptotic Ion Transporter: Effect of the H+/K+ ATPase Inhibitor SCH28080 on Butyrate-Stimulated Myelomonocytic HL-60 Cells

    Directory of Open Access Journals (Sweden)

    Martin Jakab

    2014-10-01

    Full Text Available Background/Aims: The ATP12A gene codes for a non-gastric H+/K+ ATPase, which is expressed in a wide variety of tissues. The aim of this study was to test for the molecular and functional expression of the non-gastric H+/K+ ATPase ATP12A/ATP1AL1 in unstimulated and butyrate-stimulated (1 and 10 mM human myelomonocytic HL-60 cells, to unravel its potential role as putative apoptosis-counteracting ion transporter as well as to test for the effect of the H+/K+ ATPase inhibitor SCH28080 in apoptosis. Methods: Real-time reverse-transcription PCR (qRT-PCR was used for amplification and cloning of ATP12A transcripts and to assess transcriptional regulation. BCECF microfluorimetry was used to assess changes of intracellular pH (pHi after acute intracellular acid load (NH4Cl prepulsing. Mean cell volumes (MCV and MCV-recovery after osmotic cell shrinkage (Regulatory Volume Increase, RVI were assessed by Coulter counting. Flow-cytometry was used to measure MCV (Coulter principle, to assess apoptosis (phosphatidylserine exposure to the outer leaflet of the cell membrane, caspase activity, 7AAD staining and differentiation (CD86 expression. Results: We found by RT-PCR, intracellular pH measurements, MCV measurements and flow cytometry that ATP12A is expressed in human myelomonocytic HL-60 cells. Treatment of HL-60 cells with 1 mM butyrate leads to monocyte-directed differentiation whereas higher concentrations (10 mM induce apoptosis as assessed by flow-cytometric determination of CD86 expression, caspase activity, phosphatidylserine exposure on the outer leaflet of the cell membrane and MCV measurements. Transcriptional up-regulation of ATP12A and CD86 is evident in 1 mM butyrate-treated HL-60 cells. The H+/K+ ATPase inhibitor SCH28080 (100 µM diminishes K+-dependent pHi recovery after intracellular acid load and blocks RVI after osmotic cell shrinkage. After seeding, HL-60 cells increase their MCV within the first 24 h in culture, and subsequently

  1. Radon as a geophysical tracer on Mars: study of its transport, first evidence and development of an instrument for its measurement

    International Nuclear Information System (INIS)

    Meslin, Pierre-Yves

    2008-01-01

    Radon-222, an inert and radioactive gas stemming from the uranium decay series, and its progeny are often used as tracers to study transfers in soils and in the atmosphere. They have also been studied on the surface of the Moon in connection with lunar outgassing. On Mars, where radon has never been studied nor measured so far, we show that their measurement could provide new insight and constraints on the chemical nature of the hydrogen measured in the Martian soil, in surface-atmosphere exchange processes, in atmospheric transport and, finally, in the dust cycle. Our approach is based on a coupled soil-atmosphere transport model implemented into the Global Circulation Model LMDZ. It includes the source term, the diffusion and adsorption of radon within the soil, and its atmospheric transport. The model input parameters are derived either experimentally (emanation factor and adsorption coefficient extrapolated to low temperatures) or by realistic models of porous media (diffusion coefficient at low pressure and as a function of the water saturation level). The model yields predictive maps of the radon exhalation rate as well as 3D fields of concentration in the soil and atmosphere, which will allow direct comparison with bismuth-214 measurements made by the GRS onboard the Mars Odyssey orbiter. We present preliminary results on this subject. An analysis of alpha spectra acquired by the APXS of the rover Opportunity is also presented, which shows evidence of a polonium-210 deposit on atmospheric dust, providing the first indirect proof of the presence of radon in the Martian atmosphere. We propose a simplified dust cycle model that enables us to infer an estimate of the global average radon exhalation rate on Mars. Lastly, we simulate the performance of an alpha spectrometer aimed at measuring radon and its progeny on the surface of the planet. (author)

  2. Electric transport of a single-crystal iron chalcogenide FeSe superconductor: Evidence of symmetry-breakdown nematicity and additional ultrafast Dirac cone-like carriers

    Science.gov (United States)

    Huynh, K. K.; Tanabe, Y.; Urata, T.; Oguro, H.; Heguri, S.; Watanabe, K.; Tanigaki, K.

    2014-10-01

    An SDW antiferromagnetic (SDW-AF) low-temperature phase transition is generally observed and the AF spin fluctuations are considered to play an important role for the superconductivity pairing mechanism in FeAs superconductors. However, a similar magnetic phase transition is not observed in FeSe superconductors, which has caused considerable discussion. We report on the intrinsic electronic states of FeSe as elucidated by electric transport measurements under magnetic fields using a high quality single crystal. A mobility spectrum analysis, an ab initio method that does not make assumptions on the transport parameters in a multicarrier system, provides very important and clear evidence that another hidden order, most likely the symmetry broken from the tetragonal C4 symmetry to the C2 symmetry nematicity associated with the selective d -orbital splitting, exists in the case of superconducting FeSe other than the AF magnetic order spin fluctuations. The intrinsic low-temperature phase in FeSe is in the almost compensated semimetallic states but is additionally accompanied by Dirac cone-like ultrafast electrons ˜104cm2(VS) -1 as minority carriers.

  3. Crucial role of Asp408 in the proton translocation pathway of multidrug transporter AcrB: evidence from site-directed mutagenesis and carbodiimide labeling.

    Science.gov (United States)

    Seeger, Markus A; von Ballmoos, Christoph; Verrey, François; Pos, Klaas M

    2009-06-30

    The three-component AcrA/AcrB/TolC efflux system of Escherichia coli catalyzes the proton motive force-driven extrusion of a variety of cytotoxic compounds. The inner membrane pump component AcrB belongs to the resistance nodulation and cell division (RND) superfamily and is responsible for drug specificity and energy transduction of the entire tripartite efflux system. Systematic mutational analysis of titratable and polar membrane-located amino acids revealed four residues, D407, D408, K940, and, R971, to be of prime importance for AcrB function. Using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry, D408 was shown to specifically react with dicyclohexylcarbodiimide (DCCD) in a pH-dependent manner. The apparent pK(a) of D408 of 7.4 would enable binding and release of protons under physiological conditions. In contrast to other secondary transporters, D408 was not protected from carbodiimide modification in the presence of drugs, which supports the notion of spatially separated transport pathways for drugs and protons. This study provides evidence for a substantial role of membrane-located carboxylates as a central element of the proton translocation pathway in AcrB and other members of the RND superfamily.

  4. Accumulation and transport of microbial-size particles in a pressure protected model burn unit: CFD simulations and experimental evidence

    Directory of Open Access Journals (Sweden)

    Mimoun Maurice

    2011-03-01

    Full Text Available Abstract Background Controlling airborne contamination is of major importance in burn units because of the high susceptibility of burned patients to infections and the unique environmental conditions that can accentuate the infection risk. In particular the required elevated temperatures in the patient room can create thermal convection flows which can transport airborne contaminates throughout the unit. In order to estimate this risk and optimize the design of an intensive care room intended to host severely burned patients, we have relied on a computational fluid dynamic methodology (CFD. Methods The study was carried out in 4 steps: i patient room design, ii CFD simulations of patient room design to model air flows throughout the patient room, adjacent anterooms and the corridor, iii construction of a prototype room and subsequent experimental studies to characterize its performance iv qualitative comparison of the tendencies between CFD prediction and experimental results. The Electricité De France (EDF open-source software Code_Saturne® (http://www.code-saturne.org was used and CFD simulations were conducted with an hexahedral mesh containing about 300 000 computational cells. The computational domain included the treatment room and two anterooms including equipment, staff and patient. Experiments with inert aerosol particles followed by time-resolved particle counting were conducted in the prototype room for comparison with the CFD observations. Results We found that thermal convection can create contaminated zones near the ceiling of the room, which can subsequently lead to contaminate transfer in adjacent rooms. Experimental confirmation of these phenomena agreed well with CFD predictions and showed that particles greater than one micron (i.e. bacterial or fungal spore sizes can be influenced by these thermally induced flows. When the temperature difference between rooms was 7°C, a significant contamination transfer was observed to

  5. Efficacy and safety of the glycine transporter-1 inhibitor org 25935 for the prevention of relapse in alcohol-dependent patients: a randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    de Bejczy, Andrea; Nations, Kari R; Szegedi, Armin; Schoemaker, Joep; Ruwe, Frank; Söderpalm, Bo

    2014-09-01

    Org 25935 is a glycine transporter inhibitor that increases extracellular glycine levels and attenuates alcohol-induced dopaminergic activity in the nucleus accumbens. In animal models, Org 25935 has dose-dependent effects on ethanol intake, preference, and relapse-like behavior without tolerance. The current study aimed to translate these animal findings to humans by examining whether Org 25935 prevents relapse in detoxified alcohol-dependent patients. This was a multicenter, randomized, double-blind, placebo-controlled clinical trial. Adult patients diagnosed with alcohol dependence were randomly assigned to receive Org 25935 12 mg twice a day or placebo for 84 days. The primary end point was percentage heavy drinking days (defined as ≥ 5 standard drinks per day for men and ≥ 4 for women). Secondary end points included other measures of relapse-related drinking behavior (e.g., drinks per day, time to relapse), as well as measures of global functioning, alcohol-related thoughts and cravings, and motivation. A total of 140 subjects were included in the intent-to-treat analysis. The trial was stopped approximately midway after a futility analysis showing that the likelihood of detecting a signal at study term was Org 25935 and placebo on percentage heavy drinking days or any other measure of relapse-related drinking behavior. Org 25935 showed no safety issues and was fairly well tolerated, with fatigue, dizziness, and transient visual events as the most commonly occurring side effects. Org 25935 demonstrated no benefit over placebo in preventing alcohol relapse. Study limitations and implications are discussed. Copyright © 2014 by the Research Society on Alcoholism.

  6. Using scientific evidence to inform public policy on the long distance transportation of animals: role of the European Food Safety Authority.

    Science.gov (United States)

    Ribò, Oriol; Candiani, Denise; Aiassa, Elisa; Correia, Sandra; Afonso, Ana; De Massis, Fabrizio; Serratosa, Jordi

    2008-01-01

    The authors review the work of the previous Scientific Committee on Animal Health and Animal Welfare and the current European Food Safety Authority (EFSA) in providing scientific advice on the welfare aspects of animal transport and the impact of this advice on the European Union (EU) regulatory framework. Through its Protocol on the Protection and Welfare of Animals, the Treaty of Amsterdam obliges European institutions to pay full regard to the welfare requirements of animals when formulating and implementing EU legislation. Regulation 1/2005 states that EU legislation should be amended to take into account new scientific evidence. Provisions for poultry, cats and dogs take into account the recommendations included in EFSA's Scientific Opinion which considers different species (poultry, deer, rabbits, dogs and cats, fish and exotic animals). Examples of the effect of the scientifically based conclusions and recommendations from the Scientific Opinion on the measures in Regulation 1/2005 are summarised and show the impact of scientific evidence on EU legislation.

  7. Using scientific evidence to inform public policy on the long distance transportation of animals: role of the European Food Safety Authority

    Directory of Open Access Journals (Sweden)

    Oriol Ribò

    2008-03-01

    Full Text Available The authors review the work of the previous Scientific Committee on Animal Health and Animal Welfare and the current European Food Safety Authority (EFSA in providing scientific advice on the welfare aspects of animal transport and the impact of this advice on the European Union (EU regulatory framework. Through its Protocol on the Protection and Welfare of Animals, the Treaty of Amsterdam obliges European institutions to pay full regard to the welfare requirements of animals when formulating and implementing EU legislation. Regulation 1/2005 states that EU legislation should be amended to take into account new scientific evidence. Provisions for poultry, cats and dogs take into account the recommendations included in EFSA's Scientific Opinion which considers different species (poultry, deer, rabbits, dogs and cats, fish and exotic animals. Examples of the effect of the scientifically based conclusions and recommendations from the Scientific Opinion on the measures in Regulation 1/2005 are summarised and show the impact of scientific evidence on EU legislation.

  8. Intranasal dopamine reduces in vivo [123I]FP-CIT binding to striatal dopamine transporter: correlation with behavioral changes and evidence for Pavlovian conditioned dopamine response

    Directory of Open Access Journals (Sweden)

    Maria A de Souza Silva

    2016-04-01

    drugs. Conclusions: The results (a demonstrate a direct central action of intranasally applied dopamine on the dopamine transporter in the dorsal striatum, indicating enhanced DA availability and (b provide first evidence of a Pavlovian conditioned DA response at the DA transporter. The latter results have relevance to understanding neurochemical mechanisms the underlie placebo action in the treatment of

  9. The renal effects of SGLT2 inhibitors and a mini-review of the literature.

    Science.gov (United States)

    Andrianesis, Vasileios; Glykofridi, Spyridoula; Doupis, John

    2016-12-01

    Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new and promising class of antidiabetic agents which target renal tubular glucose reabsorption. Their action is based on the blockage of SGLT2 sodium-glucose cotransporters that are located at the luminal membrane of tubular cells of the proximal convoluted tubule, inducing glucosuria. It has been proven that they significantly reduce glycated hemoglobin (HbA1c), along with fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus (T2DM). The glucosuria-induced caloric loss as well as the osmotic diuresis significantly decrease body weight and blood pressure, respectively. Given that SGLT2 inhibitors do not interfere with insulin action and secretion, their efficacy is sustained despite the progressive β-cell failure in T2DM. They are well tolerated, with a low risk of hypoglycemia. Their most frequent adverse events are minor: genital and urinal tract infections. Recently, it was demonstrated that empagliflozin presents a significant cardioprotective effect. Although the SGLT2 inhibitors' efficacy is affected by renal function, new data have been presented that some SGLT2 inhibitors, even in mild and moderate renal impairment, induce significant HbA1c reduction. Moreover, recent data indicate that SGLT2 inhibition has a beneficial renoprotective effect. The role of this review paper is to explore the current evidence on the renal effects of SGLT2 inhibitors.

  10. [SGLT2 inhibitors: a new therapeutic class for the treatment of type 2 diabetes mellitus].

    Science.gov (United States)

    Dagan, Amir; Dagan, Bracha; SegaL, Gad

    2015-03-01

    SGLT2 (Sodium Glucose co-Transporter 2 Inhibitors) inhibitors are a new group of oral medications for the treatment of type 2 diabetes mellitus patients. These medications interfere with the process of glucose reabsorption in the proximal convoluted tubules in the kidneys, therefore increasing both glucose and water diuresis. SGLT2 inhibitors were found to be effective in lowering HbA1c levels in double-blinded studies, both as monotherapy and in combination with other oral hypoglycemic medications of various other mechanisms of action. SGLT2 Inhibitors are not a risk factor for hypoglycemia and are suitable for combination with insulin therapy. Their unique mode of action, relying on glomerular filtration, make these medication unsuitable for usage as treatment for type 2 diabetes patients who are also suffering from moderate to severe renal failure. Their main adverse effects are increased risk for urinary and genital tract infections. The following review describes the relevant pathophysiology addressed by these novel medications, evidence for efficacy and the safety profile of SGLT2 Inhibitors.

  11. Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: An Evidence-Based Analysis.

    Science.gov (United States)

    2010-01-01

    In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenetics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT: http://www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST CANCER: An Evidence-Based AnalysisEpidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based AnalysisK-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based Analysis The Medical Advisory Secretariat undertook a systematic review of the evidence on the clinical effectiveness and cost-effectiveness of epidermal growth factor receptor (EGFR) mutation testing compared with no EGFR mutation testing to predict response to tyrosine kinase inhibitors (TKIs), gefitinib (Iressa(®)) or erlotinib (Tarceva(®)) in patients with advanced non-small cell lung cancer (NSCLC). TARGET POPULATION AND CONDITION With an estimated 7,800 new cases and 7,000 deaths last year, lung cancer is the leading cause of cancer

  12. Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons.

    Science.gov (United States)

    Eastwood, S L; Harrison, P J

    2005-03-01

    Synaptic protein gene expression is altered in schizophrenia. In the hippocampal formation there may be particular involvement of glutamatergic neurons and their synapses, but overall the profile remains unclear. In this in situ hybridization histochemistry (ISHH) study, we examined four informative synaptic protein transcripts: vesicular glutamate transporter (VGLUT) 1, VGLUT2, complexin I, and complexin II, in dorsolateral prefrontal cortex (DPFC), superior temporal cortex (STC), and hippocampal formation, in 13 subjects with schizophrenia and 18 controls. In these areas, VGLUT1 and complexin II are expressed primarily by excitatory neurons, whereas complexin I is mainly expressed by inhibitory neurons. In schizophrenia, VGLUT1 mRNA was decreased in hippocampal formation and DPFC, complexin II mRNA was reduced in DPFC and STC, and complexin I mRNA decreased in STC. Hippocampal VGLUT1 mRNA declined with age selectively in the schizophrenia group. VGLUT2 mRNA was not quantifiable due to its low level. The data provide additional evidence for a synaptic pathology in schizophrenia, in terms of a reduced expression of three synaptic protein genes. In the hippocampus, the loss of VGLUT1 mRNA supports data indicating that glutamatergic presynaptic deficits are prominent, whereas the pattern of results in temporal and frontal cortex suggests broadly similar changes may affect inhibitory and excitatory neurons. The impairment of synaptic transmission implied by the synaptic protein reductions may contribute to the dysfunction of cortical neural circuits that characterises the disorder.

  13. Transport Statistics - Transport - UNECE

    Science.gov (United States)

    Sustainable Energy Statistics Trade Transport Themes UNECE and the SDGs Climate Change Gender Ideas 4 Change UNECE Weekly Videos UNECE Transport Areas of Work Transport Statistics Transport Transport Statistics About us Terms of Reference Meetings and Events Meetings Working Party on Transport Statistics (WP.6

  14. Combinations of ERK and p38 MAPK inhibitors ablate tumor necrosis factor-alpha (TNF-alpha ) mRNA induction. Evidence for selective destabilization of TNF-alpha transcripts.

    Science.gov (United States)

    Rutault, K; Hazzalin, C A; Mahadevan, L C

    2001-03-02

    Tumor necrosis factor-alpha (TNF-alpha) is a potent proinflammatory cytokine whose synthesis and secretion are implicated in diverse pathologies. Hence, inhibition of TNF-alpha transcription or translation and neutralization of its protein product represent major pharmaceutical strategies to control inflammation. We have studied the role of ERK and p38 mitogen-activated protein (MAP) kinase in controlling TNF-alpha mRNA levels in differentiated THP-1 cells and in freshly purified human monocytes. We show here that it is possible to produce virtually complete inhibition of lipopolysaccharide-stimulated TNF-alpha mRNA accumulation by using a combination of ERK and p38 MAP kinase inhibitors. Furthermore, substantial inhibition is achievable using combinations of 1 microm of each inhibitor, whereas inhibitors used individually are incapable of producing complete inhibition even at high concentrations. Finally, addressing mechanisms involved, we show that inhibition of p38 MAP kinase selectively destabilizes TNF-alpha transcripts but does not affect degradation of c-jun transcripts. These results impinge on the controversy in the literature surrounding the mode of action of MAP kinase inhibitors on TNF-alpha mRNA and suggest the use of combinations of MAP kinase inhibitors as an effective anti-inflammatory strategy.

  15. Intranasal Dopamine Reduces In Vivo [(123)I]FP-CIT Binding to Striatal Dopamine Transporter: Correlation with Behavioral Changes and Evidence for Pavlovian Conditioned Dopamine Response.

    Science.gov (United States)

    de Souza Silva, Maria A; Mattern, Claudia; Decheva, Cvetana; Huston, Joseph P; Sadile, Adolfo G; Beu, Markus; Müller, H-W; Nikolaus, Susanne

    2016-01-01

    Dopamine (DA), which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA), nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT) binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We hypothesized that, based on the finding of increased extracellular DA in the striatum induced by application of IN-DA, binding of [(123)I]FP-CIT to the DAT should be decreased due to competition at the receptor. Rats were administered 3 mg/kg IN-DA and vehicle (VEH), with IN-DA injection either preceding or following VEH. Then motor and exploratory behaviors (traveled distance, velocity, center time, sitting, rearing, head-shoulder motility, grooming) were assessed for 30 min in an open field prior to administration of [(123)I]FP-CIT. DAT binding after IN-DA and VEH was measured with small animal SPECT 2 h following administration of the radioligand. (1) After IN-DA application, striatal DAT binding was significantly lower as compared to VEH, indicating that the nasally delivered DA had central action and increased DA levels comparable to that found previously with L-DOPA administration; and (2) DAT binding in response to intranasal VEH was lower when IN-DA application preceded VEH treatment. This finding is suggestive of Pavlovian conditioning of DA at the level of the DAT, since the DA treatment modified (decreased) the binding in response to the subsequent VEH treatment. VEH treatment also reduced motor and exploratory behaviors more when applied before, as compared to when it followed IN-DA application, also indicative of behavioral Pavlovian conditioning akin to that found upon application of various psychostimulant drugs. (a) demonstrate a direct central action of intranasally

  16. SGLT2 Inhibitors May Predispose to Ketoacidosis.

    Science.gov (United States)

    Taylor, Simeon I; Blau, Jenny E; Rother, Kristina I

    2015-08-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

  17. Biosynthesis of sesquiterpenes in grape berry exocarp of Vitis vinifera L.: evidence for a transport of farnesyl diphosphate precursors from plastids to the cytosol.

    Science.gov (United States)

    May, Bianca; Lange, B Markus; Wüst, Matthias

    2013-11-01

    The participation of the mevalonic acid (MVA) and 1-deoxy-d-xylulose 5-phosphate/2-C-methyl-d-erythritol-4-phosphate (DOXP/MEP) pathways in sesquiterpene biosynthesis of grape berries was investigated. There is an increasing interest in this class of terpenoids, since the oxygenated sesquiterpene rotundone was identified as the peppery aroma impact compound in Australian Shiraz wines. To investigate precursor supply pathway utilization, in vivo feeding experiments were performed with the deuterium labeled, pathway specific, precursors [5,5-(2)H2]-1-deoxy-d-xylulose and [5,5-(2)H2]-mevalonic acid lactone. Head Space-Solid Phase Micro Extraction-Gas Chromatography-Mass Spectrometry (HS-SPME-GC-MS) analysis of the generated volatile metabolites demonstrated that de novo sesquiterpene biosynthesis is mainly located in the grape berry exocarp (skin), with no detectable activity in the mesocarp (flesh) of the Lemberger variety. Interestingly, precursors from both the (primarily) cytosolic MVA and plastidial DOXP/MEP pathways were incorporated into grape sesquiterpenes in the varieties Lemberger, Gewürztraminer and Syrah. Our labeling data provide evidence for a homogenous, cytosolic pool of precursors for sesquiterpene biosynthesis, indicating that a transport of precursors occurs mostly from plastids to the cytosol. The labeling patterns of the sesquiterpene germacrene D were in agreement with a cyclization mechanism analogous to that of a previously cloned enantioselective (R)-germacrene D synthase from Solidago canadensis. This observation was subsequently confirmed by enantioselective GC-MS analysis demonstrating the exclusive presence of (R)-germacrene D, and not the (S)-enantiomer, in grape berries. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Benefits of SGLT2 Inhibitors beyond glycemic control - A focus on metabolic, cardiovascular, and renal outcomes.

    Science.gov (United States)

    Minze, Molly G; Will, Kayley; Terrell, Brian T; Black, Robin L; Irons, Brian K

    2017-08-16

    Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new pharmacotherapeutic class for the treatment of type 2 diabetes mellitus (T2DM). To evaluate beneficial effects of the SGLT2 inhibitors on metabolic, cardiovascular, and renal outcomes. A Pub-Med search (1966 to July 2017) was performed of published English articles using keywords sodium-glucose co-transporter 2 inhibitors, canagliflozin, dapagliflozin, and empagliflozin. A review of literature citations provided further references. The search identified 17clinical trials and 2 meta-analysis with outcomes of weight loss and blood pressure reduction with dapagliflozin, canagliflozin, or empagliflozin. Three randomized trials focused on either empagliflozin or canagliflozin and reduction of cardiovascular disease and progression of renal disease. SGLT2 inhibitors have a beneficial profile in the treatment of T2DM. They have evidence of reducing weight between 2.9 kilograms when used as monotherapy to 4.7 kilograms when used in combination with metformin, and reduce systolic blood pressure between 3 to 5 mmHg and reduce diastolic blood pressure approximately 2 mmHg. To date, reduction of cardiovascular events was seen specifically with empagliflozin in patients with T2DM and a history of cardiovascular disease. In the same population, empagliflozin was associated with slowing the progression of kidney disease. Moreover, patients with increased risk of cardiovascular disease treated with canagliflozin has decreased risk of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. Data regarding these outcomes with dapagliflozin are underway. SGLT2 inhibitors demonstrate some positive metabolic effects. In addition, empagliflozin specifically has demonstrated reduction in cardiovascular events and delay in the progression of kidney disease in patients with T2DM and a history of cardiovascular disease. Further data is needed to assess if this is a class effect. Copyright© Bentham Science Publishers

  19. Urea transporter proteins as targets for small-molecule diuretics.

    Science.gov (United States)

    Esteva-Font, Cristina; Anderson, Marc O; Verkman, Alan S

    2015-02-01

    Conventional diuretics such as furosemide and thiazides target salt transporters in kidney tubules, but urea transporters (UTs) have emerged as alternative targets. UTs are a family of transmembrane channels expressed in a variety of mammalian tissues, in particular the kidney. UT knockout mice and humans with UT mutations exhibit reduced maximal urinary osmolality, demonstrating that UTs are necessary for the concentration of urine. Small-molecule screening has identified potent and selective inhibitors of UT-A, the UT protein expressed in renal tubule epithelial cells, and UT-B, the UT protein expressed in vasa recta endothelial cells. Data from UT knockout mice and from rodents administered UT inhibitors support the diuretic action of UT inhibition. The kidney-specific expression of UT-A1, together with high selectivity of the small-molecule inhibitors, means that off-target effects of such small-molecule drugs should be minimal. This Review summarizes the structure, expression and function of UTs, and looks at the evidence supporting the validity of UTs as targets for the development of salt-sparing diuretics with a unique mechanism of action. UT-targeted inhibitors may be useful alone or in combination with conventional diuretics for therapy of various oedemas and hyponatraemias, potentially including those refractory to treatment with current diuretics.

  20. Impact of ubiquitous inhibitors on the GUS gene reporter system: evidence from the model plants Arabidopsis, tobacco and rice and correction methods for quantitative assays of transgenic and endogenous GUS

    Directory of Open Access Journals (Sweden)

    Gerola Paolo D

    2009-12-01

    Full Text Available Abstract Background The β-glucuronidase (GUS gene reporter system is one of the most effective and employed techniques in the study of gene regulation in plant molecular biology. Improving protocols for GUS assays have rendered the original method described by Jefferson amenable to various requirements and conditions, but the serious limitation caused by inhibitors of the enzyme activity in plant tissues has thus far been underestimated. Results We report that inhibitors of GUS activity are ubiquitous in organ tissues of Arabidopsis, tobacco and rice, and significantly bias quantitative assessment of GUS activity in plant transformation experiments. Combined with previous literature reports on non-model species, our findings suggest that inhibitors may be common components of plant cells, with variable affinity towards the E. coli enzyme. The reduced inhibitory capacity towards the plant endogenous GUS discredits the hypothesis of a regulatory role of these compounds in plant cells, and their effect on the bacterial enzyme is better interpreted as a side effect due to their interaction with GUS during the assay. This is likely to have a bearing also on histochemical analyses, leading to inaccurate evaluations of GUS expression. Conclusions In order to achieve reliable results, inhibitor activity should be routinely tested during quantitative GUS assays. Two separate methods to correct the measured activity of the transgenic and endogenous GUS are presented.

  1. Proton pump inhibitors and osteoporosis

    DEFF Research Database (Denmark)

    Andersen, Bjarne Nesgaard; Johansen, Per Birger; Abrahamsen, Bo

    2016-01-01

    PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a di......PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months...... and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology. RECENT FINDINGS: New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower...... risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism. SUMMARY: The use of PPIs is a risk factor for development of osteoporosis...

  2. Reaching carbon neutral transport sector in Denmark - Evidence from the incorporation of modal shift into the TIMES energy system modeling framework

    DEFF Research Database (Denmark)

    Tattini, Jacopo; Gargiulo, Maurizio; Karlsson, Kenneth Bernard

    2018-01-01

    Energy/Economy/Environment/Engineering (E4) models have been rarely apt to represent human behaviour in transportation mode adoption. This paper contributes to the scientific literature by using an E4 model to analyse the long-term decarbonisation of the Danish transport sector. The study...

  3. Transport of D-xylose in Lactobacillus pentosus, Lactobacillus casei, and Lactobacillus plantarum: Evidence for a mechanism of facilitated diffusion via the phosphoenolpyruvate:mannose phosphotransferase system

    NARCIS (Netherlands)

    Chaillou, S.; Pouwels, P.H.; Postma, P.W.

    1999-01-01

    We have identified and characterized the D-xylose transport system of Lactobacillus pentosus. Uptake of D-xylose was not driven by the proton motive force generated by malolactic fermentation and required D-xylose metabolism. The kinetics of D-xylose transport were indicative of a low- affinity

  4. Evidence that maturation of the N-linked glycans of the respiratory syncytial virus (RSV) glycoproteins is required for virus-mediated cell fusion: The effect of α-mannosidase inhibitors on RSV infectivity

    International Nuclear Information System (INIS)

    McDonald, Terence P.; Jeffree, Chris E.; Li, Ping; Rixon, Helen W. McL.; Brown, Gaie; Aitken, James D.; MacLellan, Kirsty; Sugrue, Richard J.

    2006-01-01

    Glycan heterogeneity of the respiratory syncytial virus (RSV) fusion (F) protein was demonstrated by proteomics. The effect of maturation of the virus glycoproteins-associated glycans on virus infectivity was therefore examined using the α-mannosidase inhibitors deoxymannojirimycin (DMJ) and swainsonine (SW). In the presence of SW the N-linked glycans on the F protein appeared in a partially mature form, whereas in the presence of DMJ no maturation of the glycans was observed. Neither inhibitor had a significant effect on G protein processing or on the formation of progeny virus. Although the level of infectious virus and syncytia formation was not significantly affected by SW-treatment, DMJ-treatment correlated with a one hundred-fold reduction in virus infectivity. Our data suggest that glycan maturation of the RSV glycoproteins, in particular those on the F protein, is an important step in virus maturation and is required for virus infectivity

  5. Geochemical evidence of groundwater flow paths and the fate and transport of constituents of concern in the alluvial aquifer at Fort Wingate Depot Activity, New Mexico, 2009

    Science.gov (United States)

    Robertson, Andrew J.; Henry, David W.; Langman, Jeffery B.

    2013-01-01

    As part of an environmental investigation at Fort Wingate Depot Activity, New Mexico, the U.S. Geological Survey, in cooperation with the U.S. Army Corps of Engineers, interpreted aqueous geochemical concentrations to better understand the groundwater flow paths and the fate and transport of constituents of concern in the alluvial aquifer underlying the study area. The fine-grained nature of the alluvial matrix creates a highly heterogeneous environment, which adds to the difficulty of characterizing the flow of groundwater and the fate of aqueous constituents of concern. The analysis of the groundwater geochemical data collected in October 2009 provides evidence that is used to identify four groundwater flow paths and their extent in the aquifer and indicates the dominant attenuation processes for the constituents of concern. The extent and interaction of groundwater flow paths were delineated by the major ion concentrations and their relations to each other. Four areas of groundwater recharge to the study area were identified based on groundwater elevations, hydrogeologic characteristics, and geochemical and isotopic evidence. One source of recharge enters the study area from the saturated alluvial deposits underlying the South Fork of the Puerco River to the north of the study area. A second source of recharge is shown to originate from a leaky cistern containing production water from the San Andres-Glorieta aquifer. The other two sources of recharge are shown to enter the study area from the south: one from an arroyo valley draining an area to the south and one from hill-front recharge that passes under the reported release of perchlorate and explosive constituents. The spatial extent and interaction of groundwater originating from these various sources along identified flow paths affect the persistence and attenuation of constituents of concern. It was determined that groundwater originating in the area of a former explosives’ wash-out operation and an

  6. Astrocytic GABA Transporters

    DEFF Research Database (Denmark)

    Schousboe, Arne; Wellendorph, Petrine; Frølund, Bente

    2017-01-01

    , and several of these compounds have been shown to exhibit pronounced anticonvulsant activity in a variety of animal seizure models. As proof of concept of the validity of this drug development approach, one GABA-transport inhibitor, tiagabine, has been developed as a clinically active antiepileptic drug......Inactivation of GABA-mediated neurotransmission is achieved by high-affinity transporters located at both GABAergic neurons and the surrounding astrocytes. Early studies of the pharmacological properties of neuronal and glial GABA transporters suggested that different types of transporters might...... be expressed in the two cell types, and such a scenario was confirmed by the cloning of four distinctly different GABA transporters from a number of different species. These GABA-transport entities have been extensively characterized using a large number of GABA analogues of restricted conformation...

  7. The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays

    NARCIS (Netherlands)

    M. Pieters (Marlien); S.A. Barnard (Sunelle A.); D.T. Loots (Du Toit); D.C. Rijken (Dingeman)

    2017-01-01

    textabstractDue to controversial evidence in the literature pertaining to the activity of plasminogen activator inhibitor-1 in platelets, we examined the effects of residual platelets present in plasma (a potential pre-analytical variable) on various plasminogen activator inhibitor-1 and plasminogen

  8. Synthesis of poly[N-(2-hydroxypropyl)methacrylamide] conjugates of inhibitors of the ABC transporter that overcome multidrug resistance in doxorubicin-resistant P388 cells in vitro

    Czech Academy of Sciences Publication Activity Database

    Šubr, Vladimír; Sivák, Ladislav; Koziolová, Eva; Braunová, Alena; Pechar, Michal; Strohalm, Jiří; Kabešová, Martina; Říhová, Blanka; Ulbrich, Karel; Kovář, Marek

    2014-01-01

    Roč. 15, č. 8 (2014), s. 3030-3043 ISSN 1525-7797 R&D Projects: GA ČR GAP301/12/1254; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : N-(2-hydroxypropyl)methacrylamide copolymers * multidrug resistance * P-glycoprotein inhibitors Subject RIV: CD - Macromolecular Chemistry; FD - Oncology ; Hematology (MBU-M) Impact factor: 5.750, year: 2014

  9. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic)

    DEFF Research Database (Denmark)

    Birkeland, Kåre I.; Jørgensen, Marit E.; Carstensen, Bendix

    2017-01-01

    , and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. Findings Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0·9 (SD 4·1) years (80 669 patient-years) and mean age of 61 (12·0) years; 40...... with the results of clinical trials in patients at high cardiovascular risk. Funding AstraZeneca....

  10. Intranasal dopamine reduces in vivo [123I]FP-CIT binding to striatal dopamine transporter: correlation with behavioral changes and evidence for Pavlovian conditioned dopamine response

    OpenAIRE

    Maria A de Souza Silva; C. eMattern; C. eMattern; C.I. eDecheva; Joseph P. Huston; A. eSadile; M. eBeu; H.W. eMüller; Susanne eNikolaus

    2016-01-01

    Purpose: Dopamine (DA), which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA), nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT) binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We ...

  11. Monoamine Oxidase Inhibitors (MAOIs)

    Science.gov (United States)

    ... health-medications/index.shtml. Accessed May 16, 2016. Hirsch M, et al. Monoamine oxidase inhibitors (MAOIs) for ... www.uptodate.com/home. Accessed May 16, 2016. Hirsch M, et al. Discontinuing antidepressant medications in adults. ...

  12. Transport pathways in the malaria-infected erythrocyte: characterization and their use as potential targets for chemotherapy

    Directory of Open Access Journals (Sweden)

    Hagai Ginsburg

    1994-01-01

    Full Text Available The intraerythrocytic malarial parasite is involved in an extremely intensive anabolic activity while it resides in its metabolically quiescent host cell. The necessary fast uptake of nutrients and the discharge of waste product, are guaranteed by parasite-induced alterations of the constitutive transporters of the host cell and the production of new parallel pathways. The membrane of the host cell thus becomes permeable to phospholipids, purine bases and nucleosides, small non-electrolytes, anions and cations. When the new pathways are quantitatively unimportant, classical inhibitors of native transporters can be used to inhibit parasite growth. Several compounds were found to effectively inhibit the new pathways and consequently, parasite growth. The pathways have also been used to introduce cytotoxic agents. The parasitophorous membrane consists of channels which are highly permeable to small solutes and display no ion selectivity. Transport of some cations and anions across the parasite membrane is rapid and insensitive to classical inhibitors, and in some cases it is mediated by specific antiporters which respond to their respective inhibitors. Macromolecules have been shown to reach the parasitophorous space through a duct contiguous with the host cell membrane, and subsequently to be endocytosed at the parasite membrane. The simultaneous presence of the parasitophorous membrane channels and the duct, however, is incompatible with experimental evidences. No specific inhibitors were found as yet that would efficiently inhibit transport through the channels or the duct.

  13. Zymosan-induced immune challenge modifies the stress response of hypoxic air-breathing fish (Anabas testudineus Bloch): Evidence for reversed patterns of cortisol and thyroid hormone interaction, differential ion transporter functions and non-specific immune response.

    Science.gov (United States)

    Simi, S; Peter, Valsa S; Peter, M C Subhash

    2017-09-15

    Fishes have evolved physiological mechanisms to exhibit stress response, where hormonal signals interact with an array of ion transporters and regulate homeostasis. As major ion transport regulators in fish, cortisol and thyroid hormones have been shown to interact and fine-tune the stress response. Likewise, in fishes many interactions have been identified between stress and immune components, but the physiological basis of such interaction has not yet delineated particularly in air-breathing fish. We, therefore, investigated the responses of thyroid hormones and cortisol, ion transporter functions and non-specific immune response of an obligate air-breathing fish Anabas testudineus Bloch to zymosan treatment or hypoxia stress or both, to understand how immune challenge modifies the pattern of stress response in this fish. Induction of experimental peritonitis in these fish by zymosan treatment (200ngg -1 ) for 24h produced rise in respiratory burst and lysozomal activities in head kidney phagocytes. In contrast, hypoxia stress for 30min in immune-challenged fish reversed these non-specific responses of head kidney phagocytes. The decline in plasma cortisol in zymosan-treated fish and its further suppression by hypoxia stress indicate that immune challenge suppresses the cortisol-driven stress response of this fish. Likewise, the decline in plasma T 3 and T 4 after zymosan-treatment and the rise in plasma T 4 after hypoxia stress in immune-challenged fish indicate a critical role for thyroid hormone in immune-stress response due to its differential sensitivity to both immune and stress challenges. Further, analysis of the activity pattern of ion-dependent ATPases viz. Na + /K + -ATPase, H + /K + -ATPase and Na + /NH 4 + -ATPase indicates a functional interaction of ion transport system with the immune response as evident in its differential and spatial modifications after hypoxia stress in immune-challenged fish. The immune-challenge that produced differential

  14. On the possibility of high-velocity tidal sterams as dynamic barriers to longshore sediment transport: evidence from the continental shelf off the Gulf of Kutch, India

    Digital Repository Service at National Institute of Oceanography (India)

    Nair, R.R.; Hashimi, N.H.; Rao, V.P

    and clay minerals. The distinct differences have resulted because the high-velocity (2 to 2.5 knots) tidal stream at the gulf mouth acts as a dynamic barrier inhibiting sediment transport across the month. Differences in the distribution of sand size...

  15. The impact of transport- and transaction-cost reductions on food markets in developing countries: evidence for tempered expectations for Burkina Faso

    NARCIS (Netherlands)

    Ruijs, A.J.W.; Schweigman, C.; Lutz, C.

    2004-01-01

    Reductions in transport and transaction costs are expected to have a major effect on the functioning of food markets in developing countries. For Burkina Faso, this is a relevant issue as it may have important consequences for the food markets in urban and rural deficit areas. A partial equilibrium

  16. The impact of transport- and transaction-cost reductions on food markets in developing countries : evidence for tempered expectations for Burkina Faso

    NARCIS (Netherlands)

    Ruijs, A.J.W.; Schweigman, C.; Lutz, C.H.M.

    2004-01-01

    Reductions in transport and transaction costs are expected to have a major effect on the functioning of food markets in developing countries. For Burkina Faso, this is a relevant issue as it may have important consequences for the food markets in urban and rural deficit areas. A partial equilibrium

  17. The Potential of Online Respondent Data for Choice Modeling in Transportation Research: Evidence from Stated Preference Experiments using Web-based Samples: Evidence from Stated Preference Experiments using Web-based Samples

    OpenAIRE

    Hoffer, Brice

    2015-01-01

    The aim of this thesis is to analyze the potential of online survey services for conducting stated preference experiments in the field of transportation planning. Several web-products for hosting questionnaires are evaluated considering important features required when conducting a stated preference survey. Based on this evaluation, the open-source platform LimeSurvey is the most appropriated for this kind of research. A stated preference questionnaire about pedestrians’ route choice in a Sin...

  18. Blood Sample Transportation by Pneumatic Transportation Systems

    DEFF Research Database (Denmark)

    Nybo, Mads; Lund, Merete E; Titlestad, Kjell

    2018-01-01

    BACKGROUND: Pneumatic transportation systems (PTSs) are increasingly used for transportation of blood samples to the core laboratory. Many studies have investigated the impact of these systems on different types of analyses, but to elucidate whether PTSs in general are safe for transportation...... analysis, and the hemolysis index). CONCLUSIONS: Owing to their high degree of heterogeneity, the retrieved studies were unable to supply evidence for the safety of using PTSs for blood sample transportation. In consequence, laboratories need to measure and document the actual acceleration forces...

  19. Effect of DNA polymerase inhibitors on DNA repair in intact and permeable human fibroblasts: Evidence that DNA polymerases δ and β are involved in DNA repair synthesis induced by N-methyl-N'-nitro-N-nitrosoguanidine

    International Nuclear Information System (INIS)

    Hammond, R.A.; Miller, M.R.; McClung, J.K.

    1990-01-01

    The involvement of DNA polymerases α, β, and δ in DNA repair synthesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in human fibroblasts (HF). The effects of anti-(DNA polymerase α) monoclonal antibody, (p-n-butylphenyl)deoxyguanosine triphosphate (BuPdGTP), dideoxythymidine triphosphate (ddTTP), and aphidicolin on MNNG-induced DNA repair synthesis were investigated to dissect the roles of the different DNA polymerases. A subcellular system (permeable cells), in which DNA repair synthesis and DNA replication were differentiated by CsCl gradient centrifugation of BrdUMP density-labeled DNA, was used to examine the effects of the polymerase inhibitors. Another approach investigated the effects of several of these inhibitors of MNNG-induced DNA repair synthesis in intact cells by measuring the amount of [ 3 H]thymidine incorporated into repair DNA as determined by autoradiography and quantitation with an automated video image analysis system. In permeable cells, MNNG-induced DNA repair synthesis was inhibited 56% by 50 μg of aphidicolin/mL, 6% by 10 μM BuPdGTP, 13% by anti-(DNA polymerse α) monoclonal antibodies, and 29% by ddTTP. In intact cells, MNNG-induced DNA repair synthesis was inhibited 57% by 50 μg of aphidicolin/mL and was not significantly inhibited by microinjecting anti-(DNA polymerase α) antibodies into HF nuclei. These results indicate that both DNA polymerase δ and β are involved in repairing DNA damage caused by MNNG

  20. Janus kinase inhibitors: jackpot or potluck?

    Directory of Open Access Journals (Sweden)

    Pavithran Keechilat

    2012-06-01

    Full Text Available The reports of a unique mutation in the Janus kinase-2 gene (JAK2 in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN: primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

  1. Aromatase inhibitors in pediatrics.

    Science.gov (United States)

    Wit, Jan M; Hero, Matti; Nunez, Susan B

    2011-10-25

    Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole--currently approved as adjuvant therapy for breast cancer--have stimulated off-label use of aromatase inhibitors in pediatrics for the following conditions: hyperestrogenism, such as aromatase excess syndrome, Peutz-Jeghers syndrome, McCune-Albright syndrome and functional follicular ovarian cysts; hyperandrogenism, for example, testotoxicosis (also known as familial male-limited precocious puberty) and congenital adrenal hyperplasia; pubertal gynecomastia; and short stature and/or pubertal delay in boys. Current data suggest that aromatase inhibitors are probably effective in the treatment of patients with aromatase excess syndrome or testotoxicosis, partially effective in Peutz-Jeghers and McCune-Albright syndrome, but probably ineffective in gynecomastia. Insufficient data are available in patients with congenital adrenal hyperplasia or functional ovarian cysts. Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution.

  2. Localization effects in the disordered Ta interlayer of multilayer Ta–FeNi films: Evidence from dc transport and spectroscopic ellipsometry study

    Czech Academy of Sciences Publication Activity Database

    Kovaleva, Natalia; Chvostová, Dagmar; Pacherová, Oliva; Fekete, Ladislav; Kugel, K.I.; Pudonin, F.A.; Dejneka, Alexandr

    2017-01-01

    Roč. 111, č. 18 (2017), s. 1-5, č. článku 183104. ISSN 0003-6951 R&D Projects: GA ČR GA15-13778S Institutional support: RVO:68378271 Keywords : dc transport * wide-band * spectroscopic ellipsometry techniques * disordered metallic Subject RIV: BM - Solid Matter Physics ; Magnetism OBOR OECD: Condensed matter physics (including formerly solid state physics, supercond.) Impact factor: 3.411, year: 2016

  3. Isotopic evidence for the influence of typhoons and submarine canyons on the sourcing and transport behavior of biospheric organic carbon to the deep sea

    Science.gov (United States)

    Zheng, Li-Wei; Ding, Xiaodong; Liu, James T.; Li, Dawei; Lee, Tsung-Yu; Zheng, Xufeng; Zheng, Zhenzhen; Xu, Min Nina; Dai, Minhan; Kao, Shuh-Ji

    2017-05-01

    Export of biospheric organic carbon from land masses to the ocean plays an important role in regulating the global carbon cycle. High-relief islands in the western Pacific are hotspots for such land-to-ocean carbon transport due to frequent floods and active tectonics. Submarine canyon systems serve as a major conduit to convey terrestrial organics into the deep sea, particularly during episodic floods, though the nature of ephemeral sediment transportation through such canyons remains unclear. In this study, we deployed a sediment trap in southwestern Taiwan's Gaoping submarine canyon during summer 2008, during which Typhoon Kalmaegi impacted the study area. We investigated sources of particulate organic carbon and quantified the content of fossil organic carbon (OCf) and biospheric non-fossil carbon (OCnf) during typhoon and non-typhoon periods, based on relations between total organic carbon (TOC), isotopic composition (δ13 C, 14C), and nitrogen to carbon ratios (N/C) of newly and previously reported source materials. During typhoons, flooding connected terrestrial rivers to the submarine canyon. Fresh plant debris was not found in the trap except in the hyperpycnal layer, suggesting that only hyperpycnal flow is capable of entraining plant debris, while segregation had occurred during non-hyperpycnal periods. The OCnf components in typhoon flood and trapped samples were likely sourced from aged organics buried in ancient landslides. During non-typhoon periods, the canyon is more connected to the shelf, where waves and tides cause reworking, thus allowing abiotic and biotic processes to generate isotopically uniform and similarly aged OCnf for transport into the canyon. Therefore, extreme events coupled with the submarine canyon system created an efficient method for deep-sea burial of freshly produced organic-rich material. Our results shed light on the ephemeral transport of organics within a submarine canyon system on an active tectonic margin.

  4. Nd isotopic structure of the Pacific Ocean 70-30 Ma and numerical evidence for vigorous ocean circulation and ocean heat transport in a greenhouse world

    Science.gov (United States)

    Thomas, Deborah J.; Korty, Robert; Huber, Matthew; Schubert, Jessica A.; Haines, Brian

    2014-05-01

    The oceanic meridional overturning circulation (MOC) is a crucial component of the climate system, impacting heat and nutrient transport, and global carbon cycling. Past greenhouse climate intervals present a paradox because their weak equator-to-pole temperature gradients imply a weaker MOC, yet increased poleward oceanic heat transport appears to be required to maintain these weak gradients. To investigate the mode of MOC that operated during the early Cenozoic, we compare new Nd isotope data with Nd tracer-enabled numerical ocean circulation and coupled climate model simulations. Assimilation of new Nd isotope data from South Pacific Deep Sea Drilling Project and Ocean Drilling Program Sites 323, 463, 596, 865, and 869 with previously published data confirm the hypothesized MOC characterized by vigorous sinking in the South and North Pacific 70 to 30 Ma. Compilation of all Pacific Nd isotope data indicates vigorous, distinct, and separate overturning circulations in each basin until 40 Ma. Simulations consistently reproduce South Pacific and North Pacific deep convection over a broad range of conditions, but cases using strong deep ocean vertical mixing produced the best data-model match. Strong mixing, potentially resulting from enhanced abyssal tidal dissipation, greater interaction of wind-driven internal wave activity with submarine plateaus, or higher than modern values of the geothermal heat flux enable models to achieve enhanced MOC circulation rates with resulting Nd isotope distributions consistent with the proxy data. The consequent poleward heat transport may resolve the paradox of warmer worlds with reduced temperature gradients.

  5. JAK inhibitors in autoinflammation.

    Science.gov (United States)

    Hoffman, Hal M; Broderick, Lori

    2018-06-11

    Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.

  6. Cathepsin D inhibitors

    Directory of Open Access Journals (Sweden)

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  7. gamma-Glutamyl amino acids. Transport and conversion to 5-oxoproline in the kidney

    International Nuclear Information System (INIS)

    Bridges, R.J.; Meister, A.

    1985-01-01

    Transport of gamma-glutamyl amino acids, a step in the proposed glutathione-gamma-glutamyl transpeptidase-mediated amino acid transport pathway, was examined in mouse kidney. The transport of gamma-glutamyl amino acids was demonstrated in vitro in studies on kidney slices. Transport was followed by measuring uptake of 35 S after incubation of the slices in media containing gamma-glutamyl methionine [ 35 S]sulfone. The experimental complication associated with extracellular conversion of the gamma-glutamyl amino acid to amino acid and uptake of the latter by slices was overcome by using 5-oxoproline formation (catalyzed by intracellular gamma-glutamyl-cyclotransferase) as an indicator of gamma-glutamyl amino acid transport. This method was also successfully applied to studies on transport of gamma-glutamyl amino acids in vivo. Transport of gamma-glutamyl amino acids in vitro and in vivo is inhibited by several inhibitors of gamma-glutamyl transpeptidase and also by high extracellular levels of glutathione. This seems to explain urinary excretion of gamma-glutamylcystine by humans with gamma-glutamyl transpeptidase deficiency and by mice treated with inhibitors of this enzyme. Mice depleted of glutathione by treatment with buthionine sulfoximine (which inhibits glutathione synthesis) or by treatment with 2,6-dimethyl-2,5-heptadiene-4-one (which effectively interacts with tissue glutathione) exhibited significantly less transport of gamma-glutamyl amino acids than did untreated controls. The findings suggest that intracellular glutathione functions in transport of gamma-glutamyl amino acids. Evidence was also obtained for transport of gamma-glutamyl gamma-glutamylphenylalanine into kidney slices

  8. Custos de transporte e urbanização: evidências a partir da criação de cidades

    Directory of Open Access Journals (Sweden)

    Flávia Chein

    2009-09-01

    Full Text Available Este artigo investiga a relação entre urbanização e rendimentos individuais em cidades emergentes (pouco urbanizadas, a partir da relação entre custo de transporte e urbanização. Para tanto, considera as cidades criadas a partir da construção da rodovia Belém-Teresina e da pavimentação da rodovia Cuiabá-Porto Velho. Os resultados mostram que existe uma relação positiva entre urbanização e rendimento em cidades de pequeno porte, mas essa relação não é, necessariamente, direta. Características individuais e a estrutura produtiva e do mercado de trabalho local aparecem como importantes canais dessa relação. Ao contrário do que ocorre em cidades médias e grandes, o acúmulo de capital humano nos pequenos aglomerados urbanos não parece ter efeito sobre os rendimentos individuais.This paper investigates the relationship between urbanization and individual incomes by exploring the role of transport costs in the process of urbanization. Our empirical framework is built on the importance of the transport networks, especially roads, in creating urban agglomerations and new towns. We find that, although this relationship exists, it is not, necessarily, direct. Productive structure and local labor market are important channels that link urbanization and individual income in emerging towns around the roads. There is no statistically significant relationship between the accumulation of human capital in those towns and the individual incomes differently from the findings for large and medium-sized cities.

  9. Evidence that the rabbit proton-peptide co-transporter PepT1 is a multimer when expressed in Xenopus laevis oocytes.

    Science.gov (United States)

    Panitsas, Konstantinos-E; Boyd, C A R; Meredith, David

    2006-04-01

    To test whether the rabbit proton-coupled peptide transporter PepT1 is a multimer, we have employed a combination of transport assays, luminometry and site-directed mutagenesis. A functional epitope-tagged PepT1 construct (PepT1-FLAG) was co-expressed in Xenopus laevis oocytes with a non-functional but normally trafficked mutant form of the same transporter (W294F-PepT1). The amount of PepT1-FLAG cRNA injected into the oocytes was kept constant, while the amount of W294F-PepT1 cRNA was increased over the mole fraction range of 0 to 1. The uptake of [(3)H]-D: -Phe-L: -Gln into the oocytes was measured at pH(out) 5.5, and the surface expression of PepT1-FLAG was quantified by luminometry. As the mole fraction of injected W294F-PepT1 increased, the uptake of D: -Phe-L: -Gln decreased. This occurred despite the surface expression of PepT1-FLAG remaining constant, and so we can conclude that PepT1 must be a multimer. Assuming that PepT1 acts as a homomultimer, the best fit for the modelling suggests that PepT1 could be a tetramer, with a minimum requirement of two functional subunits in each protein complex. Western blotting also showed the presence of higher-order complexes of PepT1-FLAG in oocyte membranes. It should be noted that we cannot formally exclude the possibility that PepT1 interacts with unidentified Xenopus protein(s). The finding that PepT1 is a multimer has important implications for the molecular modelling of this protein.

  10. [Mechanisms and efficacy of SGLT2 inhibitors].

    Science.gov (United States)

    Shiba, Teruo

    2015-03-01

    SGLT2 is a low affinity, high capacity glucose co-transporter, almost exclusively expressed in the kidney cortex. Inhibition of SGLT2 has been shown to increase the daily 50g or more urinary glucose excretion, as compared to placebo, leading to a reduction in blood glucose levels and indicated only for the treatment of type 2 diabetes. In Japan 6 species of SGLT2 inhibitors have already been sold and reported to results in a decrease of FPG by 14.4 to 45.8 (mg/dL), in a reduction of HbA1c by 0.35 to 1.24% and in loss of body weight by 1.29 to 2.50(kg). There is less effect of the SGLT2 inhibitor in diabetic subjects with renal impairment and the reduction in HbA1c and FPG will be approximately half of the average in those with 30 ≤ eGFR ≤ 59. The position of SGLT2 inhibitors would be considered as the drug administered in combination or add-on therapy when the young obese type 2 diabetics without renal impairment has not yet reached to the glycemic target with other drugs although in AACE consensus statement of 2013, it has been shelved for inexperienced use with respect to the positioning of the SGLT2 inhibitors.

  11. Tyrosine Phosphorylation of the Human Serotonin Transporter: A Role in the Transporter Stability and Function

    Science.gov (United States)

    Annamalai, Balasubramaniam; Mannangatti, Padmanabhan; Arapulisamy, Obulakshmi; Shippenberg, Toni S.; Jayanthi, Lankupalle D.

    2012-01-01

    The serotonin (5-HT) transporter (SERT) regulates serotoninergic neurotransmission by clearing 5-HT released into the synaptic space. Phosphorylation of SERT on serine and threonine mediates SERT regulation. Whether tyrosine phosphorylation regulates SERT is unknown. Here, we tested the hypothesis that tyrosine-phosphorylation of SERT regulates 5-HT transport. In support of this, alkali-resistant 32P-labeled SERT was found in rat platelets, and Src-tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4,d]pyrimidine (PP2) decreased platelet SERT function and expression. In human placental trophoblast cells expressing SERT, PP2 reduced transporter function, expression, and stability. Although siRNA silencing of Src expression decreased SERT function and expression, coexpression of Src resulted in PP2-sensitive increases in SERT function and expression. PP2 treatment markedly decreased SERT protein stability. Compared with WT-SERT, SERT tyrosine mutants Y47F and Y142F exhibited reduced 5-HT transport despite their higher total and cell surface expression levels. Moreover, Src-coexpression increased total and cell surface expression of Y47F and Y142F SERT mutants without affecting their 5-HT transport capacity. It is noteworthy that Y47F and Y142F mutants exhibited higher protein stability compared with WT-SERT. However, similar to WT-SERT, PP2 treatment decreased the stability of Y47F and Y142F mutants. Furthermore, compared with WT-SERT, Y47F and Y142F mutants exhibited lower basal tyrosine phosphorylation and no further enhancement of tyrosine phosphorylation in response to Src coexpression. These results provide the first evidence that SERT tyrosine phosphorylation supports transporter protein stability and 5HT transport. PMID:21992875

  12. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

    Jong, G.A.H. de; Wijngaards, G.; Koppelman, S.J.

    2003-01-01

    Cross-linking experiments of skimmed bovine milk with bacterial transglutaminase isolated from Streptoverticillium mobaraense showed only some degree of formation of high-molecular-weight casein polymers. Studies on the nature of this phenomenon revealed that bovine milk contains an inhibitor of

  13. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

    Lohse, Brian; Kristensen, Jesper L; Kristensen, Line H

    2011-01-01

    Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the i...

  14. Atmospheric transport of urban-derived NHx: Evidence from nitrogen concentration and δ15N in epilithic mosses at Guiyang, SW China

    International Nuclear Information System (INIS)

    Liu Xueyan; Xiao Huayun; Liu Congqiang; Li Youyi; Xiao Hongwei

    2008-01-01

    Nitrogen concentration and δ 15 N in 175 epilithic moss samples were investigated along four directions from urban to rural sites in Guiyang, SW China. The spatial variations of moss N concentration and δ 15 N revealed that atmospheric N deposition is dominated by NH x -N from two major sources (urban sewage NH 3 and agricultural NH 3 ), the deposition of urban-derived NH x followed a point source pattern characterized by an exponential decline with distance from the urban center, while the agricultural-derived NH x was shown to be a non-point source. The relationship between moss N concentration and distance (y = 1.5e -0.13x + 1.26) indicated that the maximum transporting distance of urban-derived NH x averaged 41 km from the urban center, and it could be determined from the relationship between moss δ 15 N and distance [y = 2.54 ln(x) - 12.227] that urban-derived NH x was proportionally lower than agricultural-derived NH x in N deposition at sites beyond 17.2 km from the urban center. Consequently, the variation of urban-derived NH x with distance from the urban center could be modeled as y = 56.272e -0.116x - 0.481 in the Guiyang area. - Tissue N concentration and δ 15 N in epilithic mosses may be indicators for atmospheric transport of urban-derived NH x

  15. Acute exposure to space flight results in evidence of reduced lymph Transport, tissue fluid Shifts, and immune alterations in the rat gastrointestinal system

    Science.gov (United States)

    Cromer, W. E.; Zawieja, D. C.

    2018-05-01

    Space flight causes a number of alterations in physiological systems, changes in the immunological status of subjects, and altered interactions of the host to environmental stimuli. We studied the effect of space flight on the lymphatic system of the gastrointestinal tract which is responsible for lipid transport and immune surveillance which includes the host interaction with the gut microbiome. We found that there were signs of tissue damage present in the space flown animals that was lacking in ground controls (epithelial damage, crypt morphological changes, etc.). Additionally, morphology of the lymphatic vessels in the tissue suggested a collapsed state at time of harvest and there was a profound change in the retention of lipid in the villi of the ileum. Contrary to our assumptions there was a reduction in tissue fluid volume likely associated with other fluid shifts described. The reduction of tissue fluid volume in the colon and ileum is a likely contributing factor to the state of the lymphatic vessels and lipid transport issues observed. There were also associated changes in the number of MHC-II+ immune cells in the colon tissue, which along with reduced lymphatic competence would favor immune dysfunction in the tissue. These findings help expand our understanding of the effects of space flight on various organ systems. It also points out potential issues that have not been closely examined and have to potential for the need of countermeasure development.

  16. Role of multiple phosphorylation sites in the COOH-terminal tail of aquaporin-2 for water transport: evidence against channel gating

    DEFF Research Database (Denmark)

    Moeller, Hanne B; Macaulay, Nanna; Knepper, Mark A

    2009-01-01

    demonstrated that lack of phosphorylation at S256, S261, S264, or S269 had no effect on AQP2 unit water transport. Similarly, no effect on AQP2 unit water transport was observed for the 264D and 269D forms, indicating that phosphorylation of the COOH-terminal tail of AQP2 is not involved in gating......Arginine vasopressin (AVP)-regulated phosphorylation of the water channel aquaporin-2 (AQP2) at serine 256 (S256) is essential for its accumulation in the apical plasma membrane of collecting duct principal cells. In this study, we examined the role of additional AVP-regulated phosphorylation sites...... in the COOH-terminal tail of AQP2 on protein function. When expressed in Xenopus laevis oocytes, prevention of AQP2 phosphorylation at S256A (S256A-AQP2) reduced osmotic water permeability threefold compared with wild-type (WT) AQP2-injected oocytes. In contrast, prevention of AQP2 single phosphorylation at S...

  17. ST-segment resolution with bivalirudin versus heparin and routine glycoprotein IIb/IIIa inhibitors started in the ambulance in ST-segment elevation myocardial infarction patients transported for primary percutaneous coronary intervention: The EUROMAX ST-segment resolution substudy.

    Science.gov (United States)

    Van't Hof, Arnoud; Giannini, Francesco; Ten Berg, Jurrien; Tolsma, Rudolf; Clemmensen, Peter; Bernstein, Debra; Coste, Pierre; Goldstein, Patrick; Zeymer, Uwe; Hamm, Christian; Deliargyris, Efthymios; Steg, Philippe G

    2017-08-01

    Myocardial reperfusion after primary percutaneous coronary intervention (PCI) can be assessed by the extent of post-procedural ST-segment resolution. The European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) trial compared pre-hospital bivalirudin and pre-hospital heparin or enoxaparin with or without GPIIb/IIIa inhibitors (GPIs) in primary PCI. This nested substudy was performed in centres routinely using pre-hospital GPI in order to compare the impact of randomized treatments on ST-resolution after primary PCI. Residual cumulative ST-segment deviation on the single one hour post-procedure electrocardiogram (ECG) was assessed by an independent core laboratory and was the primary endpoint. It was calculated that 762 evaluable patients were needed to show non-inferiority (85% power, alpha 2.5%) between randomized treatments. A total of 871 participated with electrocardiographic data available in 824 patients (95%). Residual ST-segment deviation one hour after PCI was 3.8±4.9 mm versus 3.9±5.2 mm for bivalirudin and heparin+GPI, respectively ( p=0.0019 for non-inferiority). Overall, there were no differences between randomized treatments in any measures of ST-segment resolution either before or after the index procedure. Pre-hospital treatment with bivalirudin is non-inferior to pre-hospital heparin + GPI with regard to residual ST-segment deviation or ST-segment resolution, reflecting comparable myocardial reperfusion with the two strategies.

  18. Functional expression of sodium-glucose transporters in cancer

    Science.gov (United States)

    Scafoglio, Claudio; Hirayama, Bruce A.; Kepe, Vladimir; Liu, Jie; Ghezzi, Chiara; Satyamurthy, Nagichettiar; Moatamed, Neda A.; Huang, Jiaoti; Koepsell, Hermann; Barrio, Jorge R.; Wright, Ernest M.

    2015-01-01

    Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside (Me4FDG), which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy. PMID:26170283

  19. Stimulation of Na{sup +} transport by stress protein and by its inhibitors by sheep maw epithelium; Stimulacia transportu Na{sup +} stresovym proteinom a jeho inhibitormi cez epitel bachora oviec

    Energy Technology Data Exchange (ETDEWEB)

    Dano, M; Galambos, M; Rosskopfova, O [Univerzita Komenskeho v Bratislave, Prirodovedecka fakulta, Katedra jadrovej chemie, 84215 Bratislava (Slovakia)

    2012-04-25

    Stress proteins - 'Heat shock proteins' (Hsp) are formed during sublethal stress and other impulses, and can play an important role in protecting the functions of sheep maw epithelium, such as transport of minerals and development of the epithelium itself. The paper is aimed at assessing the protective mechanism of Hsp originated during returning to the original state from temporary acidosis of sheep maw epithelium. The aim was to determine the activity of the Na{sup +}/H{sup +} exchanger, which was affected by the expression of Hsp70 in ruminal acidosis by the method of radioactive indication. (authors)

  20. Directly transport of suspended matter from the Yangtze River to the Okinawa trough post-major flood '98: evidence from stable isotopes and C/N ratios

    International Nuclear Information System (INIS)

    Cai Deling; Shi Xuefa; Song Xiaohong

    2007-01-01

    Water column concentrations of total suspended matter (TSM), particulate organic carbon (POC), particulate nitrogen (PN) and their stable isotopic compositions (δ 13 C and δ 15 N) are measured at two to five different depths in the Yellow Sea and East China Seas and Yangtze Estuary to clarify the effect of '98 Yangtze great flood on the transport of suspended matter in the Yellow Sea and East China Sea. Suspended matters are collected to analyze the distributions of TSM, POC, PN and salinity throughout the Yellow Sea and East China Sea in the autumn of 1998. There are marked positive correlations (r=0.89-0.98) among TSM, POC and PN, but negative relationships (r=-0.29 - -0.59) between TSM and salinity. These results conclude that the POC and PN were controlled primarily by the concentrations of TSM. The C/N ratios of particulate organic matter have a negative linear correlation with PN% (r=-0.44 - -0.71), but no correlation with POC%, which suggests C/N ratios are mainly controlled by PN%. There are distinct positive correlations between δ 15 N and POC% or PN% in surface water (r=0.36 and 0.24, p<0.01, respectively), however, the correlation do not exist in more deeper depths. In indicates that δ 15 N PN could be changed by a lot of factors, such as nutrient availability, nitrification, denitrification, different material sources and so on, except decomposition of organic matter. The distributions of C/N ratios and δ 13 C values of the particulate organic matter suggest that suspended matters from Yangtze River could be transported directly into the Okinawa Trough under the condition of '98 Yangtze major flood, which break through the foregone knowledge obtained under the normal hydrological condition. (authors)

  1. Different transport mechanisms for cadmium and mercury in Caco-2 cells: inhibition of Cd uptake by Hg without evidence for reciprocal effects

    International Nuclear Information System (INIS)

    Aduayom, Ismaeel; Campbell, Peter G.C.; Denizeau, Francine; Jumarie, Catherine

    2003-01-01

    Cadmium/Hg interactions have been studied in the TC7 clone of the enterocytic-like Caco-2 cells to test the hypothesis that these metals may compete for intestinal transport. Comparison of the kinetic parameter values for 203 Hg(II) and 109 Cd(II) uptake in a serum-free medium revealed that Hg is accumulated much more rapidly and to higher concentrations. The very rapid uptake/binding step and the initial uptake rate of 109 Cd were both significantly inhibited by an excess of unlabeled Cd or Hg (apparent K i for Hg of 9.3 ± 1.2 μM) without reciprocal effects. 109 Cadmium uptake was highly sensitive to temperature and a significant fraction of accumulation (12%) was EDTA extractable. 203 Hg uptake remained insensitive to temperature or the EDTA washing procedure. However, the uptake of both tracers was half-decreased when an excess of the respective unlabeled metal was added in the stop solution, suggesting an exchange mechanism for adsorption. Cell pretreatment with N-ethylmaleimide (NEM) led to a 30% decrease or a 73% increase in the 3-min specific transport of 109 Cd when NEM was still present in or removed from the uptake medium, respectively. NEM had no effect on 203 Hg uptake. Overall our results suggest the involvement of a saturable specific mechanism for Cd, which is highly sensitive to inhibition by Hg and NEM under some conditions, and a nonspecific passive diffusion for Hg. The Hg- or NEM-induced inhibition of Cd uptake likely involves a thiol-mediated reaction, but our results suggest that NEM pretreatment may activate other cellular mechanisms leading to a stimulatory effect

  2. Studies of axon-glial cell interactions and periaxonal K+ homeostasis--II. The effect of axonal stimulation, cholinergic agents and transport inhibitors on the resistance in series with the axon membrane.

    Science.gov (United States)

    Hassan, S; Lieberman, E M

    1988-06-01

    The small electrical resistance in series with the axon membrane is generally modeled as the intercellular pathway for current flow through the periaxonal glial (Schwann cell) sheath. The series resistance of the medial giant axon of the crayfish, Procambarus clarkii, was found to vary with conditions known to affect the electrical properties of the periaxonal glia. Series resistance was estimated from computer analysed voltage waveforms generated by axial wire-constant current and space clamp techniques. The average series resistance for all axons was 6.2 +/- 0.5 omega cm2 (n = 128). Values ranged between 1 and 30 omega cm2. The series resistance of axons with low resting membrane resistance (less than 1500 omega cm2) increased an average of 30% when stimulated for 45 s to 7 min (50 Hz) whereas the series resistance of high membrane resistance (greater than 1500 omega cm2) axons decreased an average of 10%. Carbachol (10(-7) M) caused the series resistance of low membrane resistance axons to decrease during stimulation but had no effect on high membrane resistance axons. d-Tubocurare (10(-8) M) caused the series resistance of high membrane resistance axons to increase during stimulation but had no effect on low membrane resistance axons. Bumetanide, a Na-K-Cl cotransport inhibitor and low [K+]o, prevented the stimulation-induced increase in series resistance of low membrane resistance axons but had no effect on the high membrane resistance axons. The results suggest that the series resistance of axons varies in response to the activity of the glial K+ uptake mechanisms stimulated by the appearance of K+ in the periaxonal space during action potential generation.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Patterning of leaf vein networks by convergent auxin transport pathways.

    Science.gov (United States)

    Sawchuk, Megan G; Edgar, Alexander; Scarpella, Enrico

    2013-01-01

    The formation of leaf vein patterns has fascinated biologists for centuries. Transport of the plant signal auxin has long been implicated in vein patterning, but molecular details have remained unclear. Varied evidence suggests a central role for the plasma-membrane (PM)-localized PIN-FORMED1 (PIN1) intercellular auxin transporter of Arabidopsis thaliana in auxin-transport-dependent vein patterning. However, in contrast to the severe vein-pattern defects induced by auxin transport inhibitors, pin1 mutant leaves have only mild vein-pattern defects. These defects have been interpreted as evidence of redundancy between PIN1 and the other four PM-localized PIN proteins in vein patterning, redundancy that underlies many developmental processes. By contrast, we show here that vein patterning in the Arabidopsis leaf is controlled by two distinct and convergent auxin-transport pathways: intercellular auxin transport mediated by PM-localized PIN1 and intracellular auxin transport mediated by the evolutionarily older, endoplasmic-reticulum-localized PIN6, PIN8, and PIN5. PIN6 and PIN8 are expressed, as PIN1 and PIN5, at sites of vein formation. pin6 synthetically enhances pin1 vein-pattern defects, and pin8 quantitatively enhances pin1pin6 vein-pattern defects. Function of PIN6 is necessary, redundantly with that of PIN8, and sufficient to control auxin response levels, PIN1 expression, and vein network formation; and the vein pattern defects induced by ectopic PIN6 expression are mimicked by ectopic PIN8 expression. Finally, vein patterning functions of PIN6 and PIN8 are antagonized by PIN5 function. Our data define a new level of control of vein patterning, one with repercussions on other patterning processes in the plant, and suggest a mechanism to select cell files specialized for vascular function that predates evolution of PM-localized PIN proteins.

  4. Patterning of leaf vein networks by convergent auxin transport pathways.

    Directory of Open Access Journals (Sweden)

    Megan G Sawchuk

    Full Text Available The formation of leaf vein patterns has fascinated biologists for centuries. Transport of the plant signal auxin has long been implicated in vein patterning, but molecular details have remained unclear. Varied evidence suggests a central role for the plasma-membrane (PM-localized PIN-FORMED1 (PIN1 intercellular auxin transporter of Arabidopsis thaliana in auxin-transport-dependent vein patterning. However, in contrast to the severe vein-pattern defects induced by auxin transport inhibitors, pin1 mutant leaves have only mild vein-pattern defects. These defects have been interpreted as evidence of redundancy between PIN1 and the other four PM-localized PIN proteins in vein patterning, redundancy that underlies many developmental processes. By contrast, we show here that vein patterning in the Arabidopsis leaf is controlled by two distinct and convergent auxin-transport pathways: intercellular auxin transport mediated by PM-localized PIN1 and intracellular auxin transport mediated by the evolutionarily older, endoplasmic-reticulum-localized PIN6, PIN8, and PIN5. PIN6 and PIN8 are expressed, as PIN1 and PIN5, at sites of vein formation. pin6 synthetically enhances pin1 vein-pattern defects, and pin8 quantitatively enhances pin1pin6 vein-pattern defects. Function of PIN6 is necessary, redundantly with that of PIN8, and sufficient to control auxin response levels, PIN1 expression, and vein network formation; and the vein pattern defects induced by ectopic PIN6 expression are mimicked by ectopic PIN8 expression. Finally, vein patterning functions of PIN6 and PIN8 are antagonized by PIN5 function. Our data define a new level of control of vein patterning, one with repercussions on other patterning processes in the plant, and suggest a mechanism to select cell files specialized for vascular function that predates evolution of PM-localized PIN proteins.

  5. The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays.

    Directory of Open Access Journals (Sweden)

    Marlien Pieters

    Full Text Available Due to controversial evidence in the literature pertaining to the activity of plasminogen activator inhibitor-1 in platelets, we examined the effects of residual platelets present in plasma (a potential pre-analytical variable on various plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays. Blood samples were collected from 151 individuals and centrifuged at 352 and 1500 g to obtain plasma with varying numbers of platelet. In a follow-up study, blood samples were collected from an additional 23 individuals, from whom platelet-poor (2000 g, platelet-containing (352 g and platelet-rich plasma (200 g were prepared and analysed as fresh-frozen and after five defrost-refreeze cycles (to determine the contribution of in vitro platelet degradation. Plasminogen activator inhibitor-1 activity, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasma clot lysis time, β-thromboglobulin and plasma platelet count were analysed. Platelet α-granule release (plasma β-thromboglobulin showed a significant association with plasminogen activator inhibitor-1 antigen levels but weak associations with plasminogen activator inhibitor-1 activity and a functional marker of fibrinolysis, clot lysis time. Upon dividing the study population into quartiles based on β-thromboglobulin levels, plasminogen activator inhibitor-1 antigen increased significantly across the quartiles while plasminogen activator inhibitor-1 activity and clot lysis time tended to increase in the 4th quartile only. In the follow-up study, plasma plasminogen activator inhibitor-1 antigen was also significantly influenced by platelet count in a concentration-dependent manner. Plasma plasminogen activator inhibitor-1 antigen levels increased further after complete platelet degradation. Residual platelets in plasma significantly influence plasma plasminogen activator inhibitor-1 antigen levels mainly

  6. Acid corrosion inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Chen, N G

    1964-04-28

    An acid corrosion inhibitor is prepared by a 2-stage vacuum evaporation of effluents obtained from the ammonia columns of the coking oven plant. The effluent, leaving a scrubber in which the phenols are removed at a temperature of 98$C, passes through a quartz filter and flows into a heated chamber in which it is used for preheating a solution circulating through a vacuum unit, maintaining the temperature of the solution at 55$ to 60$C. The effluent enters a large tank in which it is boiled at 55$ to 60$C under 635 to 640 mm Hg pressure. Double evaporation of this solution yields a very effective acid corrosion inhibitor. Its corrosion-preventing effect is 97.9% compared with 90.1% for thiourea and 88.5% for urotropin under identical conditions.

  7. Benzoylurea Chitin Synthesis Inhibitors.

    Science.gov (United States)

    Sun, Ranfeng; Liu, Chunjuan; Zhang, Hao; Wang, Qingmin

    2015-08-12

    Benzoylurea chitin synthesis inhibitors are widely used in integrated pest management (IPM) and insecticide resistance management (IRM) programs due to their low toxicity to mammals and predatory insects. In the past decades, a large number of benzoylurea derivatives have been synthesized, and 15 benzoylurea chitin synthesis inhibitors have been commercialized. This review focuses on the history of commercial benzolyphenylureas (BPUs), synthetic methods, structure-activity relationships (SAR), action mechanism research, environmental behaviors, and ecotoxicology. Furthermore, their disadvantages of high risk to aquatic invertebrates and crustaceans are pointed out. Finally, we propose that the para-substituents at anilide of benzoylphenylureas should be the functional groups, and bipartite model BPU analogues are discussed in an attempt to provide new insight for future development of BPUs.

  8. Cyanide as a copper and quinone-directed inhibitor of amine oxidases from pea seedlings ( Pisum sativum) and Arthrobacter globiformis: evidence for both copper coordination and cyanohydrin derivatization of the quinone cofactor.

    Science.gov (United States)

    Shepard, Eric M; Juda, Gregory A; Ling, Ke-Qing; Sayre, Lawrence M; Dooley, David M

    2004-04-01

    The interactions of cyanide with two copper-containing amine oxidases (CuAOs) from pea seedlings (PSAO) and the soil bacterium Arthrobacter globiformis (AGAO) have been investigated by spectroscopic and kinetic techniques. Previously, we rationalized the effects of azide and cyanide for several CuAOs in terms of copper coordination by these exogenous ligands and their effects on the internal redox equilibrium TPQ(amr)-Cu(II) right harpoon over left harpoon TPQ(sq)-Cu(I). The mechanism of cyanide inhibition was proposed to occur through complexation to Cu(I), thereby directly competing with O(2) for reoxidation of TPQ. Although cyanide readily and reversibly reacts with quinones, no direct spectroscopic evidence for cyanohydrin derivatization of TPQ has been previously documented for CuAOs. This work describes the first direct spectroscopic evidence, using both model and enzyme systems, for cyanohydrin derivatization of TPQ. K(d) values for Cu(II)-CN(-) and Cu(I)-CN(-), as well as the K(i) for cyanide inhibition versus substrate amine, are reported for PSAO and AGAO. In spite of cyanohydrin derivatization of the TPQ cofactor in these enzymes, the uncompetitive inhibition of amine oxidation is determined to arise almost exclusively through CN(-) complexation of Cu(I).

  9. [A history and review of cholesterol ester transfer protein inhibitors and their contribution to the understanding of the physiology and pathophysiology of high density lipoprotein].

    Science.gov (United States)

    Corral, Pablo; Schreier, Laura

    2014-01-01

    There is irrefutable evidence that statins reduce the risk of cardiovascular events in a magnitude proportional to the intensity of the decrease in cholesterol transport by the low density lipoproteins. Despite this great advance there is still a residual risk of cardiovascular events. For this reason, an increase in the levels of high density lipoprotein is considered in order to boost the main action of this lipoprotein, which is reverse cholesterol transport. Distinct classes of evidence (epidemiological, genetic, and pathophysiological) show that the inhibition and/or modulation of cholesterol ester transfer protein increases plasma high density lipoprotein-cholesterol levels. The main reason for presenting this review is to look at the physiology of cholesterol ester transfer protein, its interrelationship with high density lipoproteins, and to give an update on the development of different cholesterol ester transfer protein inhibitor/modulator molecules. Copyright © 2013 Elsevier España, S.L. y SEA. All rights reserved.

  10. Understanding the determinants of active transportation to school among children: evidence of environmental injustice from the Quebec Longitudinal Study of Child Development.

    Science.gov (United States)

    Pabayo, Roman A; Gauvin, Lise; Barnett, Tracie A; Morency, Patrick; Nikiéma, Béatrice; Séguin, Louise

    2012-03-01

    To examine the combined influence of poverty and dangerousness of the neighborhood on active transportation (AT) to school among a cohort of children followed throughout the early school years. Growth curve modeling was used to identify determinants of AT to school among 710 children participating in the Quebec Longitudinal Study of Child Development from 2003 through 2006. Parent-reported dangerousness and pedestrian-vehicle collision data were merged with travel mode and health data. At age 6 years, insufficient household income, having an older sibling, and living in a neighborhood that is not excellent for raising children, or characterized with high decay were predictive of greater likelihood of using AT and remained unchanged as children progressed from kindergarten through grade 2. A public health concern is children experiencing environmental injustice. Since AT is most likely to be adopted by those living in poverty and because it is also associated with unsafe environments, some children are experiencing environmental injustice in relation to AT. Interventions may be implemented to reduce environmental injustice through improvements in road safety. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Constitutive expression of a putative high-affinity nitrate transporter in Nicotiana plumbaginifolia: evidence for post-transcriptional regulation by a reduced nitrogen source.

    Science.gov (United States)

    Fraisier, V; Gojon, A; Tillard, P; Daniel-Vedele, F

    2000-08-01

    The NpNRT2.1 gene encodes a putative inducible component of the high-affinity nitrate (NO3-) uptake system in Nicotiana plumbaginifolia. Here we report functional and physiological analyses of transgenic plants expressing the NpNRT2.1 coding sequence fused to the CaMV 35S or rolD promoters. Irrespective of the level of NO3- supplied, NO3- contents were found to be remarkably similar in wild-type and transgenic plants. Under specific conditions (growth on 10 mM NO3-), the steady-state NpNRT2. 1 mRNA level resulting from the deregulated transgene expression was accompanied by an increase in 15NO3- influx measured in the low concentration range. This demonstrates for the first time that the NRT2.1 sequence codes a limiting element of the inducible high-affinity transport system. Both 15NO3- influx and mRNA levels decreased in the wild type after exposure to ammonium, in agreement with previous results from many species. Surprisingly, however, influx was also markedly decreased in transgenic plants, despite stable levels of transgene expression in independent transformants after ammonium addition. We conclude that the conditions associated with the supply of a reduced nitrogen source such as ammonium, or with the generation of a further downstream metabolite, probably exert a repressive effect on NO3- influx at both transcriptional and post-transcriptional levels.

  12. ACCRETION AND PRESERVATION OF D-RICH ORGANIC PARTICLES IN CARBONACEOUS CHONDRITES: EVIDENCE FOR IMPORTANT TRANSPORT IN THE EARLY SOLAR SYSTEM NEBULA

    International Nuclear Information System (INIS)

    Remusat, L.; Guan, Y.; Wang, Y.; Eiler, J. M.

    2010-01-01

    We have acquired NanoSIMS images of the matrices of CI, CM, and CR carbonaceous chondrites to study, in situ, the organic matter trapped during the formation of their parent bodies. D/H ratio images reveal the occurrence of D-rich hot spots, constituting isolated organic particles. Not all the organic particles are D-rich hot spots, indicating that at least two kinds of organic particles have been accreted in the parent bodies. Ratio profiles through D-rich hot spots indicate that no significant self-diffusion of deuterium occurs between the D-rich organic matter and the depleted hydrous minerals that are surrounding them. This is not the result of a physical shielding by any constituent of the chondrites. Ab initio calculations indicate that it cannot be explained by isotopic equilibrium. Then it appears that the organic matter that is extremely enriched in D does not exchange with the hydrous minerals, or this exchange is so slow that it is not significant over the 4.5 billion year history on the parent body. If we consider that the D-rich hot spots are the result of an exposure to intense irradiation, then it appears that carbonaceous chondrites accreted organic particles that have been brought to different regions of the solar nebula. This is likely the result of important radial and vertical transport in the early solar system.

  13. Negative self-referential processing is associated with genetic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR): Evidence from two independent studies.

    Science.gov (United States)

    Dainer-Best, Justin; Disner, Seth G; McGeary, John E; Hamilton, Bethany J; Beevers, Christopher G

    2018-01-01

    The current research examined whether carriers of the short 5-HTTLPR allele (in SLC6A4), who have been shown to selectively attend to negative information, exhibit a bias towards negative self-referent processing. The self-referent encoding task (SRET) was used to measure self-referential processing of positive and negative adjectives. Ratcliff's diffusion model isolated and extracted decision-making components from SRET responses and reaction times. Across the initial (N = 183) and replication (N = 137) studies, results indicated that short 5-HTTLPR allele carriers more easily categorized negative adjectives as self-referential (i.e., higher drift rate). Further, drift rate was associated with recall of negative self-referential stimuli. Findings across both studies provide further evidence that genetic variation may contribute to the etiology of negatively biased processing of self-referent information. Large scale studies examining the genetic contributions to negative self-referent processing may be warranted.

  14. Transportability of an Evidence-Based Early Childhood Intervention in a Low-Income African Country: Results of a Cluster Randomized Controlled Study.

    Science.gov (United States)

    Huang, Keng-Yen; Nakigudde, Janet; Rhule, Dana; Gumikiriza-Onoria, Joy Louise; Abura, Gloria; Kolawole, Bukky; Ndyanabangi, Sheila; Kim, Sharon; Seidman, Edward; Ogedegbe, Gbenga; Brotman, Laurie Miller

    2017-11-01

    Children in Sub-Saharan Africa (SSA) are burdened by significant unmet mental health needs. Despite the successes of numerous school-based interventions for promoting child mental health, most evidence-based interventions (EBIs) are not available in SSA. This study investigated the implementation quality and effectiveness of one component of an EBI from a developed country (USA) in a SSA country (Uganda). The EBI component, Professional Development, was provided by trained Ugandan mental health professionals to Ugandan primary school teachers. It included large-group experiential training and small-group coaching to introduce and support a range of evidence-based practices (EBPs) to create nurturing and predictable classroom experiences. The study was guided by the Consolidated Framework for Implementation Research, the Teacher Training Implementation Model, and the RE-AIM evaluation framework. Effectiveness outcomes were studied using a cluster randomized design, in which 10 schools were randomized to intervention and wait-list control conditions. A total of 79 early childhood teachers participated. Teacher knowledge and the use of EBPs were assessed at baseline and immediately post-intervention (4-5 months later). A sample of 154 parents was randomly selected to report on child behavior at baseline and post-intervention. Linear mixed effect modeling was applied to examine effectiveness outcomes. Findings support the feasibility of training Ugandan mental health professionals to provide Professional Development for Ugandan teachers. Professional Development was delivered with high levels of fidelity and resulted in improved teacher EBP knowledge and the use of EBPs in the classroom, and child social competence.

  15. A novel class of small molecule inhibitors of HDAC6.

    Science.gov (United States)

    Inks, Elizabeth S; Josey, Benjamin J; Jesinkey, Sean R; Chou, C James

    2012-02-17

    Histone deacetylases (HDACs) are a family of enzymes that play significant roles in numerous biological processes and diseases. HDACs are best known for their repressive influence on gene transcription through histone deacetylation. Mapping of nonhistone acetylated proteins and acetylation-modifying enzymes involved in various cellular pathways has shown protein acetylation/deacetylation also plays key roles in a variety of cellular processes including RNA splicing, nuclear transport, and cytoskeletal remodeling. Studies of HDACs have accelerated due to the availability of small molecule HDAC inhibitors, most of which contain a canonical hydroxamic acid or benzamide that chelates the metal catalytic site. To increase the pool of unique and novel HDAC inhibitor pharmacophores, a pharmacological active compound screen was performed. Several unique HDAC inhibitor pharmacophores were identified in vitro. One class of novel HDAC inhibitors, with a central naphthoquinone structure, displayed a selective inhibition profile against HDAC6. Here we present the results of a unique class of HDAC6 inhibitors identified using this compound library screen. In addition, we demonstrated that treatment of human acute myeloid leukemia cell line MV4-11 with the selective HDAC6 inhibitors decreases levels of mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation, all of which are associated with the inhibitor's selective toxicity against leukemia.

  16. Effects of the EGFR Inhibitor Erlotinib on Magnesium Handling

    NARCIS (Netherlands)

    Dimke, Henrik; van der Wijst, Jenny; Alexander, Todd R.; Meijer, Inez M. J.; Mulder, Gemma M.; van Goor, Harry; Tejpar, Sabine; Hoenderop, Joost G.; Bindels, Rene J.

    A mutation in pro-EGF causes isolated hypomagnesemia, and monoclonal antibodies targeting the extracellular domain of the EGF receptor (EGFR) affect epithelial Mg2+ transport. The effect of the EGFR tyrosine kinase inhibitor erlotinib on Mg2+ homeostasis, however, remains unknown. Here, we injected

  17. Histochemical evidence for the differential surface labeling, uptake, and intracellular transport of a colloidal gold-labeled insulin complex by normal human blood cells.

    Science.gov (United States)

    Ackerman, G A; Wolken, K W

    1981-10-01

    A colloidal gold-labeled insulin-bovine serum albumin (GIA) reagent has been developed for the ultrastructural visualization of insulin binding sites on the cell surface and for tracing the pathway of intracellular insulin translocation. When applied to normal human blood cells, it was demonstrated by both visual inspection and quantitative analysis that the extent of surface labeling, as well as the rate and degree of internalization of the insulin complex, was directly related to cell type. Further, the pathway of insulin (GIA) transport via round vesicles and by tubulo-vesicles and saccules and its subsequent fate in the hemic cells was also related to cell variety. Monocytes followed by neutrophils bound the greatest amount of labeled insulin. The majority of lymphocytes bound and internalized little GIA, however, between 5-10% of the lymphocytes were found to bind considerable quantities of GIA. Erythrocytes rarely bound the labeled insulin complex, while platelets were noted to sequester large quantities of the GIA within their extracellular canalicular system. GIA uptake by the various types of leukocytic cells appeared to occur primarily by micropinocytosis and by the direct opening of cytoplasmic tubulo-vesicles and saccules onto the cell surface in regions directly underlying surface-bound GIA. Control procedures, viz., competitive inhibition of GIA labeling using an excess of unlabeled insulin in the incubation medium, preincubation of the GIA reagent with an antibody directed toward porcine insulin, and the incorporation of 125I-insulin into the GIA reagent, indicated the specificity and selectivity of the GIA histochemical procedure for the localization of insulin binding sites.

  18. Histochemical evidence for the differential surface labeling, uptake, and intracellular transport of a colloidal gold-labeled insulin complex by normal human blood cells

    International Nuclear Information System (INIS)

    Ackerman, G.A.; Wolken, K.W.

    1981-01-01

    A colloidal gold-labeled insulin-bovine serum albumin (GIA) reagent has been developed for the ultrastructural visualization of insulin binding sites on the cell surface and for tracing the pathway of intracellular insulin translocation. When applied to normal human blood cells, it was demonstrated by both visual inspection and quantitative analysis that the extent of surface labeling, as well as the rate and degree of internalization of the insulin complex, was directly related to cell type. Further, the pathway of insulin (GIA) transport via round vesicles and by tubulo-vesicles and saccules and its subsequent fate in the hemic cells was also related to cell variety. Monocytes followed by neutrophils bound the greatest amount of labeled insulin. The majority of lymphocytes bound and internalized little GIA, however, between 5-10% of the lymphocytes were found to bind considerable quantities of GIA. Erythrocytes rarely bound the labeled insulin complex, while platelets were noted to sequester large quantities of the GIA within their extracellular canalicular system. GIA uptake by the various types of leukocytic cells appeared to occur primarily by micropinocytosis and by the direct opening of cytoplasmic tubulo-vesicles and saccules onto the cell surface in regions directly underlying surface-bound GIA. Control procedures, viz., competitive inhibition of GIA labeling using an excess of unlabeled insulin in the incubation medium, preincubation of the GIA reagent with an antibody directed toward porcine insulin, and the incorporation of 125I-insulin into the GIA reagent, indicated the specificity and selectivity of the GIA histochemical procedure for the localization of insulin binding sites

  19. Effectiveness of a dynein team in a tug of war helped by reduced load sensitivity of detachment: evidence from the study of bidirectional endosome transport in D. discoideum.

    Science.gov (United States)

    Bhat, Deepak; Gopalakrishnan, Manoj

    2012-08-01

    Bidirectional cargo transport by molecular motors in cells is a complex phenomenon in which the cargo (usually a vesicle) alternately moves in retrograde and anterograde directions. In this case, teams of oppositely pulling motors (e.g., kinesin and dynein) bind to the cargo, simultaneously, and 'coordinate' their activity such that the motion consists of spells of positively and negatively directed segments, separated by pauses of varying duration. A set of recent experiments have analyzed the bidirectional motion of endosomes in the amoeba D. discoideum in detail. It was found that in between directional switches, a team of five to six dyneins stall a cargo against a stronger kinesin in a tug of war, which lasts for almost a second. As the mean detachment time of a kinesin under its stall load was also observed to be ∼1 s, we infer that the collective detachment time of the dynein assembly must also be similar. Here, we analyze this inference from a modeling perspective, using experimentally measured single-molecule parameters as inputs. We find that the commonly assumed exponential load-dependent detachment rate is inconsistent with observations, as it predicts that a five-dynein assembly will detach under its combined stall load in less than a hundredth of a second. A modified model where the load-dependent unbinding rate is assumed to saturate at stall-force level for super-stall loads gives results which are in agreement with experimental data. Our analysis suggests that the load-dependent detachment of a dynein in a team is qualitatively different at sub-stall and super-stall loads, a conclusion which is likely to have implications in other situations involving collective effects of many motors.

  20. Inhibitin: a specific inhibitor of sodium/sodium exchange in erythrocytes.

    OpenAIRE

    Morgan, K; Brown, R C; Spurlock, G; Southgate, K; Mir, M A

    1986-01-01

    An inhibitor of ouabain-insensitive sodium/sodium exchange in erythrocytes has been isolated from leukemic promyelocytes. To explore the specific effects of this inhibitor, named inhibitin, sodium transport experiments were carried out in human erythrocytes. Inhibitin reduced ouabain-insensitive bidirectional sodium transport. It did not change net sodium fluxes, had no significant effect on rubidium influx, and did not inhibit sodium-potassium-ATPase activity. The inhibitory effect of inhibi...

  1. Possibility of Predicting Serotonin Transporter Occupancy From the In Vitro Inhibition Constant for Serotonin Transporter, the Clinically Relevant Plasma Concentration of Unbound Drugs, and Their Profiles for Substrates of Transporters.

    Science.gov (United States)

    Yahata, Masahiro; Chiba, Koji; Watanabe, Takao; Sugiyama, Yuichi

    2017-09-01

    Accurate prediction of target occupancy facilitates central nervous system drug development. In this review, we discuss the predictability of serotonin transporter (SERT) occupancy in human brain estimated from in vitro K i values for human SERT and plasma concentrations of unbound drug (C u,plasma ), as well as the impact of drug transporters in the blood-brain barrier. First, the geometric means of in vitro K i values were compared with the means of in vivo K i values (K i,u,plasma ) which were calculated as C u,plasma values at 50% occupancy of SERT obtained from previous clinical positron emission tomography/single photon emission computed tomography imaging studies for 6 selective serotonin transporter reuptake inhibitors and 3 serotonin norepinephrine reuptake inhibitors. The in vitro K i values for 7 drugs were comparable to their in vivo K i,u,plasma values within 3-fold difference. SERT occupancy was overestimated for 5 drugs (P-glycoprotein substrates) and underestimated for 2 drugs (presumably uptake transporter substrates, although no evidence exists as yet). In conclusion, prediction of human SERT occupancy from in vitro K i values and C u,plasma was successful for drugs that are not transporter substrates and will become possible in future even for transporter substrates, once the transporter activities will be accurately estimated from in vitro experiments. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  2. Raltegravir: first in class HIV integrase inhibitor

    Directory of Open Access Journals (Sweden)

    Zelalem Temesgen

    2008-06-01

    Full Text Available Zelalem Temesgen1, Dawd S Siraj21Mayo Clinic, Rochester, MN, USA; 2East Carolina University Greenville, NC, USAAbstract: On October 16, 2007, the US Food and Drug Administration (FDA approved raltegravir for treatment of human immunodeficiency virus (HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.Keywords: raltegravir, HIV, antiretroviral agents, integrase inhibitors

  3. Petrophysical, Geochemical, and Hydrological Evidence for Extensive Fracture-Mediated Fluid and Heat Transport in the Alpine Fault's Hanging-Wall Damage Zone

    Science.gov (United States)

    Townend, John; Sutherland, Rupert; Toy, Virginia G.; Doan, Mai-Linh; Célérier, Bernard; Massiot, Cécile; Coussens, Jamie; Jeppson, Tamara; Janku-Capova, Lucie; Remaud, Léa.; Upton, Phaedra; Schmitt, Douglas R.; Pezard, Philippe; Williams, Jack; Allen, Michael John; Baratin, Laura-May; Barth, Nicolas; Becroft, Leeza; Boese, Carolin M.; Boulton, Carolyn; Broderick, Neil; Carpenter, Brett; Chamberlain, Calum J.; Cooper, Alan; Coutts, Ashley; Cox, Simon C.; Craw, Lisa; Eccles, Jennifer D.; Faulkner, Dan; Grieve, Jason; Grochowski, Julia; Gulley, Anton; Hartog, Arthur; Henry, Gilles; Howarth, Jamie; Jacobs, Katrina; Kato, Naoki; Keys, Steven; Kirilova, Martina; Kometani, Yusuke; Langridge, Rob; Lin, Weiren; Little, Tim; Lukacs, Adrienn; Mallyon, Deirdre; Mariani, Elisabetta; Mathewson, Loren; Melosh, Ben; Menzies, Catriona; Moore, Jo; Morales, Luis; Mori, Hiroshi; Niemeijer, André; Nishikawa, Osamu; Nitsch, Olivier; Paris, Jehanne; Prior, David J.; Sauer, Katrina; Savage, Martha K.; Schleicher, Anja; Shigematsu, Norio; Taylor-Offord, Sam; Teagle, Damon; Tobin, Harold; Valdez, Robert; Weaver, Konrad; Wiersberg, Thomas; Zimmer, Martin

    2017-12-01

    Fault rock assemblages reflect interaction between deformation, stress, temperature, fluid, and chemical regimes on distinct spatial and temporal scales at various positions in the crust. Here we interpret measurements made in the hanging-wall of the Alpine Fault during the second stage of the Deep Fault Drilling Project (DFDP-2). We present observational evidence for extensive fracturing and high hanging-wall hydraulic conductivity (˜10-9 to 10-7 m/s, corresponding to permeability of ˜10-16 to 10-14 m2) extending several hundred meters from the fault's principal slip zone. Mud losses, gas chemistry anomalies, and petrophysical data indicate that a subset of fractures intersected by the borehole are capable of transmitting fluid volumes of several cubic meters on time scales of hours. DFDP-2 observations and other data suggest that this hydrogeologically active portion of the fault zone in the hanging-wall is several kilometers wide in the uppermost crust. This finding is consistent with numerical models of earthquake rupture and off-fault damage. We conclude that the mechanically and hydrogeologically active part of the Alpine Fault is a more dynamic and extensive feature than commonly described in models based on exhumed faults. We propose that the hydrogeologically active damage zone of the Alpine Fault and other large active faults in areas of high topographic relief can be subdivided into an inner zone in which damage is controlled principally by earthquake rupture processes and an outer zone in which damage reflects coseismic shaking, strain accumulation and release on interseismic timescales, and inherited fracturing related to exhumation.

  4. DGAT inhibitors for obesity.

    Science.gov (United States)

    Matsuda, Daisuke; Tomoda, Hiroshi

    2007-10-01

    Obesity is characterized by the accumulation of triacylglycerol in adipocytes. Diacylglycerol acyltransferase (DGAT) catalyzes the final reaction of triacylgycerol synthesis. Two isozymes of DGAT, DGAT1 and DGAT2, have been reported. Increased DGAT2 activity has a role in steatosis, while DGAT1 plays a role in very (V)LDL synthesis; increased plasma VLDL concentrations may promote obesity and thus DGAT1 is considered a potential therapeutic target of inhibition for obesity control. Several DGAT inhibitors of natural and synthetic origin have been reported, and their future prospect as anti-obesity drugs is discussed in this review.

  5. Radiation Transport

    Energy Technology Data Exchange (ETDEWEB)

    Urbatsch, Todd James [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-06-15

    We present an overview of radiation transport, covering terminology, blackbody raditation, opacities, Boltzmann transport theory, approximations to the transport equation. Next we introduce several transport methods. We present a section on Caseology, observing transport boundary layers. We briefly broach topics of software development, including verification and validation, and we close with a section on high energy-density experiments that highlight and support radiation transport.

  6. Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells.

    Science.gov (United States)

    Federici, Cristina; Lugini, Luana; Marino, Maria Lucia; Carta, Fabrizio; Iessi, Elisabetta; Azzarito, Tommaso; Supuran, Claudiu T; Fais, Stefano

    2016-01-01

    Proton Pump Inhibitors (PPIs) reduce tumor acidity and therefore resistance of tumors to drugs. Carbonic Anhydrase IX (CA IX) inhibitors have proven to be effective against tumors, while tumor acidity might impair their full effectiveness. To analyze the effect of PPI/CA IX inhibitors combined treatment against human melanoma cells. The combination of Lansoprazole (LAN) and CA IX inhibitors (FC9-399A and S4) has been investigated in terms of cell proliferation inhibition and cell death in human melanoma cells. The combination of these inhibitors was more effective than the single treatments in both inhibiting cell proliferation and in inducing cell death in human melanoma cells. These results represent the first successful attempt in combining two different proton exchanger inhibitors. This is the first evidence on the effectiveness of a new approach against tumors based on the combination of PPI and CA IX inhibitors, thus providing an alternative strategy against tumors.

  7. Neuroprotective effects of the novel glutamate transporter inhibitor (-)-3-hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]-isoxazole-4-carboxylic acid, which preferentially inhibits reverse transport (glutamate release) compared with glutamate reuptake

    DEFF Research Database (Denmark)

    Colleoni, Simona; Jensen, Anders Asbjørn; Landucci, Elisa

    2008-01-01

    on the three hEAAT subtypes. (-)-HIP-A maintained the remarkable property, previously reported with the racemates, of inhibiting synaptosomal glutamate-induced [3H]D-aspartate release (reverse transport) at concentrations significantly lower than those inhibiting [3H]L-glutamate uptake. New data suggest...

  8. Pulmonary Toxicity of Cholinesterase Inhibitors

    National Research Council Canada - National Science Library

    Hilmas, Corey; Adler, Michael; Baskin, Steven I; Gupta, Ramesh C

    2006-01-01

    .... Whereas nerve agents were produced primarily for military deployment, other cholinesterase inhibitors were used for treating conditions such as myasthenia gravis and as pretreaunents for nerve agent exposure...

  9. Proton Pump Inhibitors and Risk of Rhabdomyolysis.

    Science.gov (United States)

    Duncan, Scott J; Howden, Colin W

    2017-01-01

    Proton pump inhibitors (PPIs) have been associated with a variety of adverse events, although the level of evidence for many of these is weak at best. Recently, one national regulatory authority has mandated a change to the labeling of one PPI based on reports of possible associated rhabdomyolysis. Thus, in this review we summarize the available evidence linking PPI use with rhabdomyolysis. The level of evidence is insufficient to establish a causal relationship and is largely based on sporadic case reports. In general, patients with suspected PPI-associated rhabdomyolysis have not been re-challenged with a PPI after recovery. The mechanism whereby PPIs might have been associated with rhabdomyolysis is unclear but possibly related to interaction with concomitantly administered drugs such as HMG-CoA reductase inhibitors (statins). For patients with rhabdomyolysis, a careful search must be made for possible etiological factors. In patients who recover from an episode of possible PPI-related rhabdomyolysis but do not have a genuine requirement for PPI treatment, the PPI should not be re-introduced. For those with a definite indication for ongoing PPI treatment, the PPI can be re-introduced but should preferably not be administered with a statin.

  10. Cellular growth kinetics distinguish a cyclophilin inhibitor from an HSP90 inhibitor as a selective inhibitor of hepatitis C virus.

    Directory of Open Access Journals (Sweden)

    Rudolf K F Beran

    Full Text Available During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA and heat-shock protein 90 (HSP90 which have each been reported to inhibit replication of hepatitis C virus (HCV. By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino-17-demethoxygeldanamycin (17-AAG to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA, exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth.

  11. KCl stimulation increases norepinephrine transporter function in PC12 cells.

    Science.gov (United States)

    Mandela, Prashant; Ordway, Gregory A

    2006-09-01

    The norepinephrine transporter (NET) plays a pivotal role in terminating noradrenergic signaling and conserving norepinephrine (NE) through the process of re-uptake. Recent evidence suggests a close association between NE release and regulation of NET function. The present study evaluated the relationship between release and uptake, and the cellular mechanisms that govern these processes. KCl stimulation of PC12 cells robustly increased [3H]NE uptake via the NET and simultaneously increased [3H]NE release. KCl-stimulated increases in uptake and release were dependent on Ca2+. Treatment of cells with phorbol-12-myristate-13-acetate (PMA) or okadaic acid decreased [3H]NE uptake but did not block KCl-stimulated increases in [3H]NE uptake. In contrast, PMA increased [3H]NE release and augmented KCl-stimulated release, while okadaic acid had no effects on release. Inhibition of Ca2+-activated signaling cascades with KN93 (a Ca2+ calmodulin-dependent kinase inhibitor), or ML7 and ML9 (myosin light chain kinase inhibitors), reduced [3H]NE uptake and blocked KCl-stimulated increases in uptake. In contrast, KN93, ML7 and ML9 had no effect on KCl-stimulated [3H]NE release. KCl-stimulated increases in [3H]NE uptake were independent of transporter trafficking to the plasma membrane. While increases in both NE release and uptake mediated by KCl stimulation require Ca2+, different intracellular mechanisms mediate these two events.

  12. Chamber transport

    International Nuclear Information System (INIS)

    Olson, Craig L.

    2001-01-01

    Heavy ion beam transport through the containment chamber plays a crucial role in all heavy ion fusion (HIF) scenarios. Here, several parameters are used to characterize the operating space for HIF beams; transport modes are assessed in relation to evolving target/accelerator requirements; results of recent relevant experiments and simulations of HIF transport are summarized; and relevant instabilities are reviewed. All transport options still exist, including (1) vacuum ballistic transport, (2) neutralized ballistic transport, and (3) channel-like transport. Presently, the European HIF program favors vacuum ballistic transport, while the US HIF program favors neutralized ballistic transport with channel-like transport as an alternate approach. Further transport research is needed to clearly guide selection of the most attractive, integrated HIF system

  13. Interaction of antidepressants with the serotonin and norepinephrine transporters

    DEFF Research Database (Denmark)

    Sørensen, Lena; Andersen, Jacob; Thomsen, Mette

    2012-01-01

    The serotonin transporter (SERT) and the norepinephrine transporter (NET) are sodium-dependent neurotransmitter transporters responsible for reuptake of released serotonin and norepinephrine, respectively, into nerve terminals in the brain. A wide range of inhibitors of SERT and NET are used...

  14. Multiple nucleobase transporters contribute to boscalid sensitivity in Aspergillus nidulans.

    Science.gov (United States)

    Kalampokis, Ioannis F; Kapetanakis, George C; Aliferis, Konstantinos A; Diallinas, George

    2018-03-01

    The development of fungicide-resistant fungal populations represents a major challenge for the agrochemical and agri-food sectors, which threatens food supply and security. The issue becomes complex for fungi that cause quantitative and qualitative losses due to mycotoxin biosynthesis. Nonetheless, currently, the molecular details underlying fungicide action and fungal resistance mechanisms are partially known. Here, we have investigated whether plasma membrane transporters contribute to specific fungicide uptake in the model fungus Aspergillus nidulans. Independent physiological tests and toxicity screening of selected fungicides provided evidence that the antifungal activity of Succinate Dehydrogenase Inhibitors (SDHIs) is associated with the expression of several nucleobase-related transporters. In particular, it was shown that a strain genetically inactivated in all seven nucleobase-related transporters is resistant to the fungicide boscalid, whereas none of the single null mutants exhibited significant resistance level. By constructing and testing isogenic strains that over-express each one of the seven transporters, we confirmed that five of them, namely, UapC, AzgA, FycB, CntA, and FurA, contribute to boscalid uptake. Additionally, by employing metabolomics we have examined the effect of boscalid on the metabolism of isogenic strains expressing or genetically lacking boscalid-related nucleobase transporters. The results confirmed the involvement of specific nucleobase transporters in fungicide uptake, leading to the discovery of corresponding metabolites-biomarkers. This work is the first report on the involvement of specific transporters in fungicide uptake and toxicity and their impact on fungal metabolism regulation and results might be further exploited towards the deeper understanding of fungal resistance to fungicides. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Inhibitors of polyamine metabolism: review article.

    Science.gov (United States)

    Wallace, H M; Fraser, A V

    2004-07-01

    The identification of increased polyamine concentrations in a variety of diseases from cancer and psoriasis to parasitic infections has led to the hypothesis that manipulation of polyamine metabolism is a realistic target for therapeutic or preventative intervention in the treatment of certain diseases. The early development of polyamine biosynthetic single enzyme inhibitors such as alpha-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) showed some interesting early promise as anticancer drugs, but ultimately failed in vivo. Despite this, DFMO is currently in use as an effective anti-parasitic agent and has recently also been shown to have further potential as a chemopreventative agent in colorectal cancer. The initial promise in vitro led to the development and testing of other potential inhibitors of the pathway namely the polyamine analogues. The analogues have met with greater success than the single enzyme inhibitors possibly due to their multiple targets. These include down regulation of polyamine biosynthesis through inhibition of ornithine decarboxylase and S-adenosylmethionine decarboxylase and decreased polyamine uptake. This coupled with increased activity of the catabolic enzymes, polyamine oxidase and spermidine/spermine N1-acetyltransferase, and increased polyamine export has made the analogues more effective in depleting polyamine pools. Recently, the identification of a new oxidase (PAO-h1/SMO) in polyamine catabolism and evidence of induction of both PAO and PAO-h1/SMO in response to polyamine analogue treatment, suggests the analogues may become an important part of future chemotherapeutic and/or chemopreventative regimens.

  16. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms.

    Directory of Open Access Journals (Sweden)

    Costanza Bogani

    Full Text Available BACKGROUND: Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN, usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells. FINDINGS: Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001 and an ATP-competitive (PP242 mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib. mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with

  17. Planning Public Transport

    DEFF Research Database (Denmark)

    Andersen, Jonas Lohmann Elkjær; Landex, Alex

    2009-01-01

    This good practice guide is composed for the master course 13120 Public Transport Planning held at the Department of Transport, Technical University of Denmark. It is intended to use as guide in the different planning aspects and assignments of the course. Since the course is about the planning...... of new public transport infrastructure this guide also focuses on the planning of new infrastructure. Furthermore, the new infrastructure in the course is expected to be a light rail and even though this guide aims at being general for public transport some of the issues evidently become more relevant...... will enable a capability for planning both bus and rail. The guide is build as a full sketch investigation of a new public transport project ranging chronological from project clarification to physical and timetable planning to traffic modeling and project appraisal. The same steps that are expected...

  18. Biological abatement of cellulase inhibitors

    Science.gov (United States)

    Bio-abatement uses a fungus to metabolize and remove fermentation inhibitors. To determine whether bio-abatement could alleviate enzyme inhibitor effects observed in biomass liquors after pretreatment, corn stover at 10% (w/v) solids was pretreated with either dilute acid or liquid hot water. The ...

  19. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.

    2004-01-01

    -amylase inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha...

  20. Corrosion inhibitors. Manufacture and technology

    International Nuclear Information System (INIS)

    Ranney, M.W.

    1976-01-01

    Detailed information is presented relating to corrosion inhibitors. Areas covered include: cooling water, boilers and water supply plants; oil well and refinery operations; fuel and lubricant additives for automotive use; hydraulic fluids and machine tool lubes; grease compositions; metal surface treatments and coatings; and general processes for corrosion inhibitors

  1. Carbohydrate as covalent crosslink in human inter-alpha-trypsin inhibitor

    DEFF Research Database (Denmark)

    Jessen, T E; Faarvang, K L; Ploug, M

    1988-01-01

    The primary structure of inter-alpha-trypsin inhibitor is partially elucidated, but controversy about the construction of the polypeptide backbone still exists. We present evidence suggesting that inter-alpha-trypsin inhibitor represents a novel plasma protein structure with two separate polypept...... polypeptide chains covalently crosslinked only by carbohydrate (chondroitin sulphate)....

  2. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials

    OpenAIRE

    Kaduszkiewicz, Hanna; Zimmermann, Thomas; Beck-Bornholdt, Hans-Peter; van den Bussche, Hendrik

    2005-01-01

    Objectives Pharmacological treatment of Alzheimer's disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents.

  3. GSK-3 inhibitors induce chromosome instability

    Directory of Open Access Journals (Sweden)

    Staples Oliver D

    2007-08-01

    Full Text Available Abstract Background Several mechanisms operate during mitosis to ensure accurate chromosome segregation. However, during tumour evolution these mechanisms go awry resulting in chromosome instability. While several lines of evidence suggest that mutations in adenomatous polyposis coli (APC may promote chromosome instability, at least in colon cancer, the underlying mechanisms remain unclear. Here, we turn our attention to GSK-3 – a protein kinase, which in concert with APC, targets β-catenin for proteolysis – and ask whether GSK-3 is required for accurate chromosome segregation. Results To probe the role of GSK-3 in mitosis, we inhibited GSK-3 kinase activity in cells using a panel of small molecule inhibitors, including SB-415286, AR-A014418, 1-Azakenpaullone and CHIR99021. Analysis of synchronised HeLa cells shows that GSK-3 inhibitors do not prevent G1/S progression or cell division. They do, however, significantly delay mitotic exit, largely because inhibitor-treated cells have difficulty aligning all their chromosomes. Although bipolar spindles form and the majority of chromosomes biorient, one or more chromosomes often remain mono-oriented near the spindle poles. Despite a prolonged mitotic delay, anaphase frequently initiates without the last chromosome aligning, resulting in chromosome non-disjunction. To rule out the possibility of "off-target" effects, we also used RNA interference to selectively repress GSK-3β. Cells deficient for GSK-3β exhibit a similar chromosome alignment defect, with chromosomes clustered near the spindle poles. GSK-3β repression also results in cells accumulating micronuclei, a hallmark of chromosome missegregation. Conclusion Thus, not only do our observations indicate a role for GSK-3 in accurate chromosome segregation, but they also raise the possibility that, if used as therapeutic agents, GSK-3 inhibitors may induce unwanted side effects by inducing chromosome instability.

  4. SGLT2 inhibitors: their potential reduction in blood pressure.

    Science.gov (United States)

    Maliha, George; Townsend, Raymond R

    2015-01-01

    The sodium glucose co-transporter 2 (SGLT2) inhibitors represent a promising treatment option for diabetes and its common comorbidity, hypertension. Emerging data suggests that the SGLT2 inhibitors provide a meaningful reduction in blood pressure, although the precise mechanism of the blood pressure drop remains incompletely elucidated. Based on current data, the blood pressure reduction is partially due to a combination of diuresis, nephron remodeling, reduction in arterial stiffness, and weight loss. While current trials are underway focusing on cardiovascular endpoints, the SGLT2 inhibitors present a novel treatment modality for diabetes and its associated hypertension as well as an opportunity to elucidate the pathophysiology of hypertension in diabetes. Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  5. Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2.

    Science.gov (United States)

    Mostyn, Shannon N; Carland, Jane E; Shimmon, Susan; Ryan, Renae M; Rawling, Tristan; Vandenberg, Robert J

    2017-09-20

    It has been demonstrated previously that the endogenous compound N-arachidonyl-glycine inhibits the glycine transporter GlyT2, stimulates glycinergic neurotransmission, and provides analgesia in animal models of neuropathic and inflammatory pain. However, it is a relatively weak inhibitor with an IC 50 of 9 μM and is subject to oxidation via cyclooxygenase, limiting its therapeutic value. In this paper we describe the synthesis and testing of a novel series of monounsaturated C18 and C16 acyl-glycine molecules as inhibitors of the glycine transporter GlyT2. We demonstrate that they are up to 28 fold more potent that N-arachidonyl-glycine with no activity at the closely related GlyT1 transporter at concentrations up to 30 μM. This novel class of compounds show considerable promise as a first generation of GlyT2 transport inhibitors.

  6. Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors.

    Science.gov (United States)

    Liu, Shuang; Zha, Congxiang; Nacro, Kassoum; Hu, Min; Cui, Wenge; Yang, Yuh-Lin; Bhatt, Ulhas; Sambandam, Aruna; Isherwood, Matthew; Yet, Larry; Herr, Michael T; Ebeltoft, Sarah; Hassler, Carla; Fleming, Linda; Pechulis, Anthony D; Payen-Fornicola, Anne; Holman, Nicholas; Milanowski, Dennis; Cotterill, Ian; Mozhaev, Vadim; Khmelnitsky, Yuri; Guzzo, Peter R; Sargent, Bruce J; Molino, Bruce F; Olson, Richard; King, Dalton; Lelas, Snjezana; Li, Yu-Wen; Johnson, Kim; Molski, Thaddeus; Orie, Anitra; Ng, Alicia; Haskell, Roy; Clarke, Wendy; Bertekap, Robert; O'Connell, Jonathan; Lodge, Nicholas; Sinz, Michael; Adams, Stephen; Zaczek, Robert; Macor, John E

    2014-07-10

    A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

  7. Melatonin as an angiogenesis inhibitor to combat cancer: Mechanistic evidence.

    Science.gov (United States)

    Goradel, Nasser Hashemi; Asghari, Mohammad Hossein; Moloudizargari, Milad; Negahdari, Babak; Haghi-Aminjan, Hamed; Abdollahi, Mohammad

    2017-11-15

    Melatonin, a pineal indolamine, participates in different body functions and is shown to possess diverse biological activities such as anti-tumor action. Angiogenesis inhibition is one of the mechanisms by which melatonin exerts its oncostatic effects. Increased angiogenesis is a major feature of tumor progression, thus angiogenesis inhibition is a critical step in cancer therapy. Melatonin employs a variety of mechanisms to target nutrients and oxygen supply to cancer cells. At the transcriptional level, hypoxia induced factor-1α (HIF-1α) and the genes under its control, such as vascular endothelial growth factor (VEGF) are the main targets of melatonin for inhibition of angiogenesis. Melatonin prevents translocation of HIF-1α into the nucleus thereby hindering VEGF expression and also prevents the formation of HIF-1α, phospho-STAT3 and CBP/p300 complex which is involved in the expression of angiogenesis-related genes. Angiostatic properties of melatonin could be also due to its ability to inhibit VEGFR2's activation and expression. Other angiostatic mechanisms of melatonin include the inhibition of endothelial cell migration, invasion, and tube formation. In the present study, we have reviewed the molecular anti-angiogenesis pathways mediated by melatonin and the responsible mechanisms in various types of cancers both in vitro and in vivo. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. PD-1 Checkpoint Inhibitor Associated Autoimmune Encephalitis

    Directory of Open Access Journals (Sweden)

    Stephanie Schneider

    2017-05-01

    Full Text Available Objective: To report first-hand narrative experience of autoimmune encephalitis and to briefly review currently available evidence of autoimmune encephalitis in cancer patients treated with immune checkpoint inhibitors. Setting: A case study is presented on the management of a patient who developed autoimmune encephalitis during nivolumab monotherapy occurring after 28 weeks on anti-PD-1 monotherapy (nivolumab 3 mg/kg every 2 weeks for non-small cell lung cancer. Results: No substantial improvement was observed by antiepileptic treatment. After administration of 80 mg methylprednisolone, neurologic symptoms disappeared within 24 h and the patient fully recovered. Conclusions: Immune checkpoint inhibitor treatment can lead to autoimmune encephalitis. Clinical trial data indicate a frequency of autoimmune encephalitis of ≥0.1 to <1% with a higher probability during combined or sequential anti-CTLA-4/anti-PD-1 therapy than during anti-PD-1 or anti-PD-L1 monotherapy. Further collection of evidence and translational research is warranted.

  9. Transport phenomena

    International Nuclear Information System (INIS)

    Kirczenow, G.; Marro, J.

    1974-01-01

    Some simple remarks on the basis of transport theory. - Entropy, dynamics and scattering theory. - Response, relaxation and fluctuation. - Fluctuating hydrodynamics and renormalization of susceptibilities and transport coefficients. - Irreversibility of the transport equations. - Ergodic theory and statistical mechanics. - Correlation functions in Heisenberg magnets. - On the Enskog hard-sphere kinetic eqquation and the transport phenomena of dense simple gases. - What can one learn from Lorentz models. - Conductivity in a magnetic field. - Transport properties in gases in presence of external fields. - Transport properties of dilute gases with internal structure. (orig.) [de

  10. Serotonin transporter gene promoter polymorphisms modify the association between paroxetine serotonin transporter occupancy and clinical response in major depressive disorder

    NARCIS (Netherlands)

    Ruhé, Henricus G.; Ooteman, Wendy; Booij, Jan; Michel, Martin C.; Moeton, Martina; Baas, Frank; Schene, Aart H.

    2009-01-01

    BACKGROUND: In major depressive disorder, selective serotonin reuptake inhibitors target the serotonin transporter (SERT). Their response rates (30-50%) are modified by SERT promotor polymorphisms (5-HTTLPR). OBJECTIVES: To quantify the relationship between SERT occupancy and response, and whether

  11. Auxin transport inhibitor induced low complexity petiolated leaves ...

    Indian Academy of Sciences (India)

    2013-04-15

    Apr 15, 2013 ... 2SKA Institution for Research, Education and Development (SKAIRED), 4/11 Sarv Priya Vihar, ... ing plants (angiosperms), born orderly on their stem nodes. ..... First-strand cDNAs were generated by using the oligo.

  12. Classification of Breast Cancer Resistant Protein (BCRP) Inhibitors and Non-Inhibitors Using Machine Learning Approaches.

    Science.gov (United States)

    Belekar, Vilas; Lingineni, Karthik; Garg, Prabha

    2015-01-01

    The breast cancer resistant protein (BCRP) is an important transporter and its inhibitors play an important role in cancer treatment by improving the oral bioavailability as well as blood brain barrier (BBB) permeability of anticancer drugs. In this work, a computational model was developed to predict the compounds as BCRP inhibitors or non-inhibitors. Various machine learning approaches like, support vector machine (SVM), k-nearest neighbor (k-NN) and artificial neural network (ANN) were used to develop the models. The Matthews correlation coefficients (MCC) of developed models using ANN, k-NN and SVM are 0.67, 0.71 and 0.77, and prediction accuracies are 85.2%, 88.3% and 90.8% respectively. The developed models were tested with a test set of 99 compounds and further validated with external set of 98 compounds. Distribution plot analysis and various machine learning models were also developed based on druglikeness descriptors. Applicability domain is used to check the prediction reliability of the new molecules.

  13. Multi-Drug Resistance Transporters and a Mechanism-Based Strategy for Assessing Risks of Pesticide Combinations to Honey Bees.

    Science.gov (United States)

    Guseman, Alex J; Miller, Kaliah; Kunkle, Grace; Dively, Galen P; Pettis, Jeffrey S; Evans, Jay D; vanEngelsdorp, Dennis; Hawthorne, David J

    2016-01-01

    Annual losses of honey bee colonies remain high and pesticide exposure is one possible cause. Dangerous combinations of pesticides, plant-produced compounds and antibiotics added to hives may cause or contribute to losses, but it is very difficult to test the many combinations of those compounds that bees encounter. We propose a mechanism-based strategy for simplifying the assessment of combinations of compounds, focusing here on compounds that interact with xenobiotic handling ABC transporters. We evaluate the use of ivermectin as a model substrate for these transporters. Compounds that increase sensitivity of bees to ivermectin may be inhibiting key transporters. We show that several compounds commonly encountered by honey bees (fumagillin, Pristine, quercetin) significantly increased honey bee mortality due to ivermectin and significantly reduced the LC50 of ivermectin suggesting that they may interfere with transporter function. These inhibitors also significantly increased honey bees sensitivity to the neonicotinoid insecticide acetamiprid. This mechanism-based strategy may dramatically reduce the number of tests needed to assess the possibility of adverse combinations among pesticides. We also demonstrate an in vivo transporter assay that provides physical evidence of transporter inhibition by tracking the dynamics of a fluorescent substrate of these transporters (Rhodamine B) in bee tissues. Significantly more Rhodamine B remains in the head and hemolymph of bees pretreated with higher concentrations of the transporter inhibitor verapamil. Mechanism-based strategies for simplifying the assessment of adverse chemical interactions such as described here could improve our ability to identify those combinations that pose significantly greater risk to bees and perhaps improve the risk assessment protocols for honey bees and similar sensitive species.

  14. Neurotransmitter transporters

    DEFF Research Database (Denmark)

    Gether, Ulrik; Andersen, Peter H; Larsson, Orla M

    2006-01-01

    The concentration of neurotransmitters in the extracellular space is tightly controlled by distinct classes of membrane transport proteins. This review focuses on the molecular function of two major classes of neurotransmitter transporter that are present in the cell membrane of neurons and....... Recent research has provided substantial insight into the structure and function of these transporters. In particular, the recent crystallizations of bacterial homologs are of the utmost importance, enabling the first reliable structural models of the mammalian neurotransmitter transporters...

  15. [ACE inhibitors and the kidney].

    Science.gov (United States)

    Hörl, W H

    1996-01-01

    Treatment with ACE inhibitors results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes melitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients. In patients with renal insufficiency dose reduction of ACE inhibitors is necessary (exception: fosinopril) but more important is the risk for development of hyperkalemia. Patients at risk for renal artery stenosis and patients pretreated with diuretics should receive a low ACE inhibitor dosage initially ("start low - go slow"). For compliance reasons once daily ACE inhibitor dosage is recommended.

  16. Proton pump inhibitors inhibit pancreatic secretion

    DEFF Research Database (Denmark)

    Wang, Jing; Barbuskaite, Dagne; Tozzi, Marco

    2015-01-01

    +/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar...... of major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3-, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3- secretion. We propose that proton transport is driving secretion, and that in addition...

  17. Selective mGAT2 (BGT-1) GABA Uptake Inhibitor

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Jørgensen, Lars; Madsen, Karsten Kirkegaard

    2013-01-01

    β-Amino acids sharing a lipophilic diaromatic side chain were synthesized and characterized pharmacologically on mouse GABA transporter subtypes mGAT1−4. The parent amino acids were also characterized. Compounds 13a, 13b, and 17b displayed more than 6-fold selectivity for mGAT2 over mGAT1. Compou...... 17b displayed anticonvulsive properties inferring a role of mGAT2 in epileptic disorders. These results provide new neuropharmacological tools and a strategy for designing subtype selective GABA transport inhibitors....

  18. Evidence connecting old, new and neglected glucose-lowering drugs to bile acid-induced GLP-1 secretion

    DEFF Research Database (Denmark)

    Kårhus, Martin L; Brønden, Andreas; Sonne, David P

    2017-01-01

    Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have...... current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid...... sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism....

  19. Inhibitors of glutamate dehydrogenase block sodium-dependent glutamate uptake in rat brain membranes

    Directory of Open Access Journals (Sweden)

    Brendan S Whitelaw

    2013-09-01

    Full Text Available We recently found evidence for anatomic and physical linkages between the astroglial Na+-dependent glutamate transporters (GLT-1/EAAT2 and GLAST/EAAT1 and mitochondria. In these same studies, we found that the glutamate dehydrogenase (GDH inhibitor, epigallocatechin-monogallate (EGCG, inhibits both glutamate oxidation and Na+-dependent glutamate uptake in astrocytes. In the present study, we extend this finding by exploring the effects of EGCG on Na+-dependent L-[3H]-glutamate (Glu uptake in crude membranes (P2 prepared from rat brain cortex. In this preparation, uptake is almost exclusively mediated by GLT-1. EGCG inhibited L-[3H]-Glu uptake in cortical membranes with an IC50 value of 230 µM. We also studied the effects of two additional inhibitors of GDH, hexachlorophene (HCP and bithionol (BTH. Both of these compounds also caused concentration-dependent inhibition of glutamate uptake in cortical membranes. Pre-incubating with HCP for up to 15 min had no greater effect than that observed with no pre-incubation, showing that the effects occur rapidly. HCP decreased the Vmax for glutamate uptake without changing the Km, consistent with a non-competitive mechanism of action. EGCG, HCP, and BTH also inhibited Na+-dependent transport of D-[3H]-aspartate (Asp, a non-metabolizable substrate, and [3H]-γ-aminobutyric acid (GABA. In contrast to the forebrain, glutamate uptake in crude cerebellar membranes (P2 is likely mediated by GLAST (EAAT1. Therefore, the effects of these compounds were examined in cerebellar membranes. In this region, none of these compounds had any effect on uptake of either L-[3H]-Glu or D-[3H]-Asp, but they all inhibited [3H]-GABA uptake. Together these studies suggest that GDH is preferentially required for glutamate uptake in forebrain as compared to cerebellum, and GDH may be required for GABA uptake as well. They also provide further evidence for a functional linkage between glutamate transport and mitochondria.

  20. Energy policy in transport and transport policy

    International Nuclear Information System (INIS)

    Van Dender, Kurt

    2009-01-01

    Explanations for, and indirect evidence of, imperfections in the market for private passenger vehicle fuel economy suggest there is a reasonable case for combining fuel economy standards and fuel or carbon taxes to contribute to an energy policy that aims to reduce greenhouse gas emissions and improve energy security. Estimates of key elasticities, including the rebound effect, indicate that the positive and negative side-effects of fuel economy measures on transport activities and external costs are limited. However, an energy policy for transport does not replace a transport policy that aims to manage the main transport externalities including congestion and local pollution. Conventional marginal cost estimates and standard cost-benefit reasoning suggest that policies that address congestion and local pollution likely bring benefits at least as large as those from fuel economy measures. But the large uncertainty on the possible effects of greenhouse gas emissions constitutes a strong challenge for standard cost-benefit reasoning. Emerging results from methods to cope with this uncertainty suggest that policies to stimulate the widespread adoption of low-carbon technologies in transport are justified.

  1. Energy policy in transport and transport policy

    Energy Technology Data Exchange (ETDEWEB)

    Van Dender, Kurt [Joint Transport Research Centre of the International Transport Forum and the OECD, 2 rue Andre Pascale, F-75775 Paris Cedex 16 (France)

    2009-10-15

    Explanations for, and indirect evidence of, imperfections in the market for private passenger vehicle fuel economy suggest there is a reasonable case for combining fuel economy standards and fuel or carbon taxes to contribute to an energy policy that aims to reduce greenhouse gas emissions and improve energy security. Estimates of key elasticities, including the rebound effect, indicate that the positive and negative side-effects of fuel economy measures on transport activities and external costs are limited. However, an energy policy for transport does not replace a transport policy that aims to manage the main transport externalities including congestion and local pollution. Conventional marginal cost estimates and standard cost-benefit reasoning suggest that policies that address congestion and local pollution likely bring benefits at least as large as those from fuel economy measures. But the large uncertainty on the possible effects of greenhouse gas emissions constitutes a strong challenge for standard cost-benefit reasoning. Emerging results from methods to cope with this uncertainty suggest that policies to stimulate the widespread adoption of low-carbon technologies in transport are justified. (author)

  2. Sustainable Transportation

    DEFF Research Database (Denmark)

    Hall, Ralph P.; Gudmundsson, Henrik; Marsden, Greg

    2014-01-01

    The transportation system is the backbone of economic and social progress and the means by which humans access goods and services and connect with one another. Yet, as the scale of transportation activities has grown worldwide, so too have the negative environmental, social, and economic impacts...... that relate to the construction and maintenance of transportation infrastructure and the operation or use of the different transportation modes. The concept of sustainable transportation emerged in response to these concerns as part of the broader notion of sustainable development. Given the transportation...... sector’s significant contribution to global challenges such as climate change, it is often said that sustainable development cannot be achieved without sustainable transportation....

  3. Corrosion control of carbon steel using inhibitor of banana peel extract in acid diluted solutions

    Science.gov (United States)

    Komalasari; Utami, S. P.; Fermi, M. I.; Aziz, Y.; Irianti, R. S.

    2018-04-01

    Issues of corrosion happened in pipes, it was used as fluid transportation in the chemical industry. Corrosion cannot be preventing, however it could be controlled or blocked. Inhibitor addition is one of the method to control the corrosion inside the pipe. Corrosion inhibitors consisted of inorganic and organic compound inhibitors. Organic inhibitor is composed from synthetic and natural material. This study focused to evaluate the inhibition’s efficiency from banana peel to carbon steel in different concentration of inhibitor and immersing time in acid solution variation. The research employed inhibitor concentration of 0 gram/liter, 2 gram/liter, 4 gram/liter and 6 gram/liter, immersed time of carbon steel for 2, 4, 6, 8 and 10 hours. It was immersed in chloride acid solution of 0.5 M and 1.5 M. Carbon Steel AISI 4041 was used as specimen steel. Results were analyzed using corrosion rate evaluation for each specimens and inhibitor efficiencies determination. It was found that the specimen without inhibitor yielded fast corrosion rate in long immersing time and high concentration of HCl. However, the specimens with inhibitor gave lowest corrosion rate which was 78.59% for 6 gram/litre and 10 hours in 0.5 M HCl.

  4. Use of SGLT2 inhibitors for diabetes and risk of infection: Analysis using general practice records from the NPS MedicineWise MedicineInsight program.

    Science.gov (United States)

    Gadzhanova, Svetla; Pratt, Nicole; Roughead, Elizabet

    2017-08-01

    To explore the feasibility of MedicineInsight data to support risk management plan evaluation, focusing on sodium glucose co-transporter 2 (SGLT2) inhibitors for type 2 diabetes. A retrospective study using de-identified electronic general practitioner records. Patients who initiated SGLT2 inhibitor between 1 Jan 2012 to 1 Sep 2015 were compared to patients who initiated dipeptidyl peptidase 4 (DPP-4) inhibitors. The two cohorts were followed-up for six months. Risk of urinary-tract (UT) and genital infections was evaluated. The indication for use of SGLT2 inhibitors, recommended prior diabetes therapies and recommended monitoring were investigates. There were 1977 people in the SGLT2 cohort (with 93% initiated on dapagliflozin) and 1964 people in the DPP-4 cohort. Of the SGLT2 initiators, 54% had a documented indication for use as type 2 diabetes; 86% had used metformin and/or a sulfonylurea in the prior 12months. Renal function monitoring was documented for only 25% in the 6months initiation. The frequency of UTI in the 6months post SGLT2 initiation was not significantly increased compared to the DPP-4 cohort (3.6%vs 4.9%; aHR=0.90, 95% CI 0.66-1.24). Genital infection were more frequent in the SGLT2 than in the DPP-4 cohort (2.9% vs 0.9%, aHR=3.50, 95% CI 1.95-5.89). Similar to existing evidence, we found a higher risk of genital infection associated with SGLT2 inhibitors (primarily dapagliflozin) but no increased risk of UTIs compared to DPP-4 use. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  5. Identification of novel targets for PGC-1α and histone deacetylase inhibitors in neuroblastoma cells

    International Nuclear Information System (INIS)

    Cowell, Rita M.; Talati, Pratik; Blake, Kathryn R.; Meador-Woodruff, James H.; Russell, James W.

    2009-01-01

    Recent evidence suggests that the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) is involved in the pathology of Huntington's Disease (HD). While animals lacking PGC-1α express lower levels of genes involved in antioxidant defense and oxidative phosphorylation in the brain, little is known about other targets for PGC-1α in neuronal cells and whether there are ways to pharmacologically target PGC-1α in neurons. Here, PGC-1α overexpression in SH-SY5Y neuroblastoma cells upregulated expression of genes involved in mitochondrial function, glucose transport, fatty acid metabolism, and synaptic function. Overexpression also decreased vulnerability to hydrogen peroxide-induced cell death and caspase 3 activation. Treatment of cells with the histone deacetylase inhibitors (HDACi's) trichostatin A and valproic acid upregulated PGC-1α and glucose transporter 4 (GLUT4). These results suggest that PGC-1α regulates multiple pathways in neurons and that HDACi's may be good candidates to target PGC-1α and GLUT4 in HD and other neurological disorders.

  6. Mechanism of ochratoxin A transport in kidney

    International Nuclear Information System (INIS)

    Sokol, P.P.; Ripich, G.; Holohan, P.D.; Ross, C.R.

    1988-01-01

    The effect of the fungal metabolite (mycotoxin) Ochratoxin A (OTA) on the transport of p-amino[ 3 H]hippurate (PAH), a prototypic organic anion, was examined in renal brush border (BBMV) and basolateral membrane vesicles (BLMV). OTA was as effective an inhibitor of PAH uptake in both membranes as probenecid. The dose response curves for OTA in BBMV and BLMV gave IC50 values of 20 +/- 6 and 32 +/- 7 microM, respectively. The effect was specific since the transport of the organic cation N1-methylnicotinamide was not affected. The phenomenon of counterflow was studied to establish that OTA is translocated. OTA produced trans stimulation of PAH transport in both BBMV and BLMV, demonstrating that OTA is transported across both these membranes. The data suggest that OTA interacts with the PAH transport system in both BBMV and BLMV. We conclude that OTA transport in the kidney is mediated via the renal organic anion transport system

  7. The association study between the interaction of serotonin and norepinephrine transporter gene polymorphisms and the effects of selective serotonin reuptake inhibitors%5-羟色胺和去甲肾上腺素转运体基因多态性的交互作用与重性抑郁障碍临床疗效的关联研究

    Institute of Scientific and Technical Information of China (English)

    孟亚琴; 孙宁; 王彦芳; 段慧君; 李素萍; 彭菊意; 杜巧荣; 张克让

    2013-01-01

    Objective To explore the relevance of the interaction of serotonin and norepinephrine transporter gene polymorphisms and the effects of selective serotonin reuptake inhibitors.Methods The subjects comprised 246 patients according to the diagnostic and statistical manual of mental disorders in the fourth edition (DSM-Ⅳ) criterion for major depressive disorder(MDD).The clinical efficacy were assessed by using 17 Hamilton depression quantity (HAMD) scale after selective serotonin reuptake inhibitors(SSRIs) citalopram (20 to 60 mg/d) or paroxetine (20 to 60 mg/d) were used randomly for 1,2,4,6 weeks.Polymerase chain reaction(PCR),sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE)and DNA sequencing analysis were used to detect the genotype of 5-HTT gene single nucleotide polymorphisms (SNP) of VNTR and LPR and SNPs at rs2242446 and rs5569 of NET.SPSS13.0 software were used for statistical analysis.Results (1) An association between 5-HTT LPR and the efficacy of SSRIs was found after 6 weeks in these samples (P =0.023).The clinical efficiency of LL genotype was higher than SS + LS genotype(OR =2.225,OR 95% CI=1.118,4.427).(2) The interaction of 5-HTT LPR and NET rs5569 and the SSRIs antidepressant effects was statistical significance (P =0.01).Conclusion Preliminary study found that the interaction of 5-HTT LPR and NET rs5569 may be related to SSRIs antidepressant effects in China' s patients with MDD.%目的 探讨5-羟色胺和去甲肾上腺素转运体基因多态性的交互作用与选择性5-羟色胺再摄取抑制剂临床疗效的关联研究.方法 收集符合美国精神障碍诊断与统计手册第四版(DSM-Ⅳ)重性抑郁障碍(MDD)诊断标准的患者246例,给予选择性5-羟色胺再摄取抑制剂(SSRIs)西酞普兰(20~ 60mg/d)或帕罗西汀(20 ~ 60 mg/d),在治疗后1,2,4,6周运用17项汉密尔顿抑郁量表(HAMD)评定临床疗效;应用聚合酶链反应技术(PCR)、聚丙烯酰胺凝胶电

  8. Seizure following the Use of the COX-2 Inhibitor Etoricoxib

    Directory of Open Access Journals (Sweden)

    Valentina Arnao

    2017-01-01

    Full Text Available We describe a case of epileptic seizures occurring after the use of a COX-2 inhibitor. A 61-year-old man was admitted to our department because of a generalized tonic-clonic seizure. EEG showed generalized slowdown of the activity. Neuroimaging and blood samples studies did not evidence alterations, but a careful pharmacological history revealed that the patient had taken the COX-2 inhibitor etoricoxib to treat lumbago few days before the onset of clinical symptoms. No seizures were reported after etoricoxib discontinuation and an EEG resulted to be normal two months after this. Conclusion. Knowing the pharmacological history of a patient is important for understanding the clinical presentation and selecting appropriate treatment. This is, to the best of our knowledge, the first reported case of generalized seizures associated with the use of COX-2 inhibitors.

  9. The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors.

    Science.gov (United States)

    Secrest, Matthew H; Udell, Jacob A; Filion, Kristian B

    2017-04-01

    In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. What Are The Benefits In The Association Of SGLT2 Inhibitors And Other Drugs?

    Directory of Open Access Journals (Sweden)

    Deici Aparecida Gomes Rodrigues

    2017-11-01

    Full Text Available The SGLT2 inhibitors are a class of drugs that blocks the sodium-glucose co-transport, which is responsible for 90% of the nephron glucose. Objective: To show the benefits of the SGLT2 inhibitors in monotherapy and in association with other drugs. Results: The association of SGLT2 inhibitors and other drugs has shown several additional benefits after their interaction, including weight loss, reduction of body fat, reduction of triglycerides level, decrease of glycated hemoglobin, decrease in postprandial glucose level, reduction of arterial pressure, decrease of hypoglycemia risk and improvement of glucose metabolism. Therefore, this is a promising interaction for type 2 diabetes.

  11. l-Arginine Uptake by Cationic Amino Acid Transporter Promotes Intra-Macrophage Survival of Leishmania donovani by Enhancing Arginase-Mediated Polyamine Synthesis

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    Abhishek Mandal

    2017-07-01

    Full Text Available The survival of intracellular protozoan parasite, Leishmania donovani, the causative agent of Indian visceral leishmaniasis (VL, depends on the activation status of macrophages. l-Arginine, a semi-essential amino acid plays a crucial regulatory role for activation of macrophages. However, the role of l-arginine transport in VL still remains elusive. In this study, we demonstrated that intra-macrophage survival of L. donovani depends on the availability of extracellular l-arginine. Infection of THP-1-derived macrophage/human monocyte-derived macrophage (hMDM with Leishmania, resulted in upregulation of l-arginine transport. While investigating the involvement of the transporters, we observed that Leishmania survival was greatly impaired when the transporters were blocked either using inhibitor or siRNA-mediated downregulation. CAT-2 was found to be the main isoform associated with l-arginine transport in L. donovani-infected macrophages. l-arginine availability and its transport regulated the host arginase in Leishmania infection. Arginase and inducible nitric oxide synthase (iNOS expression were reciprocally regulated when assayed using specific inhibitors and siRNA-mediated downregulation. Interestingly, induction of iNOS expression and nitric oxide production were observed in case of inhibition of arginase in infected macrophages. Furthermore, inhibition of l-arginine transport as well as arginase resulted in decreased polyamine production, limiting parasite survival inside macrophages. l-arginine availability and transport regulated Th1/Th2 cytokine levels in case of Leishmania infection. Upregulation of l-arginine transport, induction of host arginase, and enhanced polyamine production were correlated with increased level of IL-10 and decreased level of IL-12 and TNF-α in L. donovani-infected macrophages. Our findings provide clear evidence for targeting the metabolism of l-arginine and l-arginine-metabolizing enzymes as an important

  12. Metal corrosion inhibitors and ecology

    International Nuclear Information System (INIS)

    Krasts, H.; Svarce, J.; Berge, B.

    1999-01-01

    The use of metal corrosion inhibitors in water is one of the cheapest method to protect metals against corrosion. However, the used inhibitors can come to surface water in the course of time and can become as source of environmental pollution. It is important to co-ordinate amount of substances in the elaborated inhibitors not only with demands for metal protection, but also with demands for quality of surface water and drinking water according to normative statements: 3.5 mg/l (as PO 4 ) for hexametaphosphate, tripolyphosphate and phosphonate; 40 mg/l (as SiO 2 for silicate, up to 1 mg/l for CU 2+ ; up to 5 mg/l for Zn 2+ ; up to 1 mg/l for B; up to 0.5 mg/l for Mo 2+ . The examples of the elaborated inhibitors are given. Many organic substances can be used as corrosion inhibitors, but there is shortage of standard methods for their analysis in water in Latvia. Removing of salt's deposits from boilers needs elaboration of a separate normative statement for dispersing waste water which content chloride at high concentration and heavy metals. (authors)

  13. Lonafarnib is a potential inhibitor for neovascularization.

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    Linlin Sun

    Full Text Available Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

  14. Hedgehog Pathway Inhibitor HhAntag691 Is a Potent Inhibitor of ABCG2/BCRP and ABCB1/Pgp

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    Yimao Zhang

    2009-01-01

    Full Text Available HhAntag691 (GDC-0449, a low-molecular weight inhibitor of the tumor-promoting hedgehog (Hh signaling pathway, has been used to treat medulloblastoma in animal models and has recently entered clinical trials for a variety of solid tumors. Here, we show that HhAntag691 inhibits multiple ATP-binding cassette (ABC transporters. ATP-binding cassette transporters are within a family of membrane proteins, the overexpression of which is associated with multidrug resistance, a major impediment to successful cancer treatment. HhAntag691 is a potent inhibitor of two ABC transporters, ABCG2/BCRP and ABCB1/Pgp, and is a mild inhibitor of ABCC1/MRP1. In ABCG2-overexpressing HEK293 cells, HhAntag691 increased retention of the fluorescent ABCG2 substrate BODIPY-prazosin and resensitized these cells to mitoxantrone, an antineoplastic ABCG2 substrate. In Madin-Darby canine kidney II cells engineered to overexpress Pgp or MRP1, HhAntag691 increased the retention of calcein-AM and resensitized them to colchicine. HhAntag691 also resensitized human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to mitoxantrone, to mitoxantrone, and to topotecan or SN-38. The IC50 values of HhAntag691 for inhibition of ABCG2 and Pgp were ∼1.4 and ∼3.0 µM, respectively. Because ABC transporters are highly expressed at the blood-brain barrier and on many tumor cells, they contribute significantly to treatment failure of many types of cancer, particularly of those within the neuraxis. In addition to its effect on Hh signaling, the ability of HhAntag691 and related compounds to inhibit two key ABC transporters could contribute to their effectiveness in treating malignancies.

  15. Nuclear transport

    International Nuclear Information System (INIS)

    Anon.

    2003-01-01

    During january and february 2003, a unique event concerning nuclear transport was reported and rated 1 on the INES scale. This event concerns the absence of a maintenance operation on a shipping cask. This shipping cask was used for several years for nuclear transport inside La-hague site before being re-assigned to transport on public thoroughfare. The re-assignment of the cask should have been preceded and conditioned by a maintenance operation whose purpose is to check the efficiency of its radiation shield. During this period 2 on-site inspections concerning the transport of nuclear materials were performed. (A.C.)