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51.
Seana O'Regan Marie-Françoise Diebler François-Marie Meunier Sheela Vyas 《Journal of neurochemistry》1995,64(1):69-76
Abstract: The Ewing's sarcoma cell line ICB 112 was examined in detail for a cholinergic phenotype. Choline acetyltransferase activity (12.3 ± 2.9 nmol/h/mg of protein) was associated with the presence of multiple mRNA species labeled with a human choline acetyltransferase riboprobe. Choline was taken up by the cells by a high-affinity, hemicholinium-3-sensitive transporter that was partially inhibited when lithium replaced sodium in the incubation medium; the choline taken up was quickly incorporated into both acetylcholine and phosphorylcholine. High-affinity binding sites for vesamicol, an inhibitor of vesicular acetylcholine transport, were also present. The mRNAs for synaptotagmin (p65) and the 15-kDa proteolipid were readily detected and were identical in size to those observed in cholinergic regions of the human brain. Cumulative acetylcholine efflux was increased by raising the extracellular potassium level or the addition of a calcium ionophore, but the time course of stimulated efflux was slow and persistent. These results show that this morphologically undifferentiated cell line is capable of acetylcholine synthesis and expresses markers for synaptic vesicles as well as proteins implicated in calcium-dependent release but lacks an organized release mechanism. 相似文献
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53.
Megha Dubey Sheela Nagarkoti Deepika Awasthi Abhishek K Singh Tulika Chandra J Kumaravelu Manoj K Barthwal Madhu Dikshit 《Cell death & disease》2016,7(9):e2348
Neutrophils play an indispensable role in killing of invading pathogens by enhancing reactive oxygen species (ROS) and NO generation, and subsequently undergoing apoptosis. Unlike ROS/NOX2, role of NO/NOS still remains undefined in the apoptosis of neutrophils (PMNs) and the present study attempts to decipher the importance of NO/NOS in the neutrophil apoptosis. Prolonged treatment of human PMNs or mice bone marrow derived neutrophils (BMDN) with NO led to enhanced ROS generation, caspase-8/caspase-3 cleavage, reduced mitochondrial membrane potential and finally cellular apoptosis. NO-induced ROS generation led to caspase-8 deglutathionylation and activation, which subsequently activated mitochondrial death pathway via BID (Bcl-2 family protein) cleavage. NO-mediated augmentation of caspase-8 and BID cleavage was significantly prevented in BMDN from neutrophil cytosolic factor-1 (NCF-1) knockout (KO) mice, implying the involvement of NOX2 in NO-induced apoptosis of PMNs. Furthermore, ROS, NO generation and inducible nitric oxide synthase (iNOS) expression were enhanced in a time-dependent manner in human PMNs and mice BMDN undergoing spontaneous apoptosis. Pharmacological and genetic ablation of iNOS in human PMNs and mice BMDN significantly reduced the levels of apoptosis. Impaired apoptosis of BMDN from iNOS KO mice was due to reduced caspase-8 activity which subsequently prevented caspase-3 and -9 activation. Altogether, our results suggest a crucial role of NO/iNOS in neutrophil apoptosis via enhanced ROS generation and caspase-8 mediated activation of mitochondrial death pathway.Neutrophils are the most abundant terminally differentiated white blood cells. Although in a normal healthy human, 1–2 × 1011 neutrophils are produced daily but hardly a few survive for more than 10 h in circulation.1, 2 Neutrophil phagocytose invading pathogens and kill them by producing reactive oxygen intermediates and/or by proteolytic enzymes. Besides pathogen clearance, neutrophils are also detrimental in a number of inflammatory diseases.3 Spontaneous apoptosis is thus crucial for neutrophil homeostasis and resolution of inflammation. Neutrophil apoptosis is controlled by apoptotic and survival pathways, which are modulated by pro- and anti-inflammatory cytokines, caspases and calpains. Moreover, a critical balance between reactive oxygen species (ROS) and anti-oxidants is required for cell survival. In neutrophils, ROS is largely produced by the enzyme NADPH oxidase (NOX) which adversely affects their survival.4, 5, 6 Yan et al.7 have recently demonstrated that NOX4 derived ROS following TGF-β stimulation induced apoptosis in endothelial cells.Nitric oxide (NO), a gaseous signalling molecule synthesized by NO synthase (NOS) from l-arginine, regulates several cellular functions such as vasodilation, migration, proliferation, differentiation and apoptosis. Cell death is induced following enhanced levels of NO from inducible nitric oxide synthase (iNOS) during inflammation, ischaemia/reperfusion or by NO donors such as DETA-NO, sodium nitroprusside and S-nitroso-N-acetyl-penicillamine.8, 9, 10 Our previous work has demonstrated a dose-dependent pro- and anti-apoptotic effect of NO on promyelocytic cell line HL-60.11 Two isoforms of NOS-iNOS and nNOS are constitutively expressed in human and mice PMNs12 but their regulation and interplay in neutrophil apoptosis is still enigmatic.Caspases having a crucial role in the modulation of apoptosis and apoptotic pathways have two components; caspase-8, an initiator caspase13 which mediates Fas induced death pathway, and caspase-9, which is vital for the mitochondrial mediated death. Opening of the mitochondrial membrane transition pore leads to cytochrome c release into the cytosol-forming apoptosis protease activating factor-1 (Apaf-1), a multimeric complex known as apoptosome which then activate pro-caspase-9. On the other hand, caspase-8 cleaves BID to tBID which translocate to mitochondria and release cytochrome c.5 Caspase-3, the effector caspase, is important for both extrinsic and intrinsic pathway with well documented role in the regulation of neutrophil apoptosis.14 It was shown that the anti-apoptotic effect of NO was related to the inhibition of caspase-3 activation through cGMP-dependent and independent mechanisms.15 S-glutathionylation is a redox-based regulatory mechanism which regulates caspase cleavage and its activation. Caspase-3 undergoes glutathionylation at Cys (163, 184 and 220) which prevents its cleavage and activation.16 In endothelial cells, TNF-α induced caspase-3 cleavage and apoptosis are regulated by caspase-3 glutathionylation/deglutathionylation cycles.17The present study demonstrates the crucial role of NO/iNOS in neutrophil survival. NO-induced ROS generation in human PMNs and mice bone marrow derived neutrophils (BMDN) led to caspase-8 cleavage, activation of BID and initiation of the mitochondrial death pathway. Augmented ROS production and apoptosis in NO pre-treated cells were attenuated in neutrophil cytosolic factor-1 (NCF-1) knockout (KO) mice BMDN or VAS-2870 treated human PMNs suggesting role of NOX in NO mediated initiation of apoptosis. NO-induced deglutathionylation of caspase-3 and -8 suggest redox mediated modulation of neutrophil apoptosis. Moreover, spontaneous apoptosis of BMDN was reduced in iNOS KO mice, iNOS silenced or iNOS inhibitor treated human PMNs, implying the importance of iNOS in neutrophil apoptosis. Altogether, these findings demonstrate the role of caspase-3, -8 and -9 in NO/iNOS induced neutrophil apoptosis. 相似文献
54.
Narbada Thapa Krishna Kumar Aryal Rupendra Puri Saraswoti Shrestha Sheela Shrestha Pukar Thapa Suresh Mehata Pushpa Thapa Megha Raj Banjara Babill Stray-Pedersen 《PloS one》2016,11(4)
BackgroundAlcohol chemically known as ethanol, causes several health, economic and social consequences across the world. Literatures suggest potential harm of alcohol drinking by pregnant women especially to the fetus and the mother. Despite anumber of significant public health problems related to alcohol consumption, this area has been ignored in Nepal and information at the national level is limited. Thus this study aimed at finding the prevalence of alcohol consumption among married women of reproductive age.MethodsA nationally representative household survey was carried out from April to August 2013 by taking 16 districts across all 15 eco administrative regions. From the selected districts, 86 village development committees and 14 municipalities were selected as primary sampling units using probability proportionate to size, followed by random selection of 3 wards from each primary sampling unit. Finally, 30 households within each ward were selected using systematic random sampling, and one married women of reproductive age from each household. A total of 9000 married women of reproductive age were interviewed using a semi-structured questionnaire, on alcohol consumption practices including environmental factors and socio demographic characteristics and were included in the analysis.ResultsNational prevalence of alcohol consumption ever among married women of reproductive age was 24.7% (95% CI:21.7–28.0), last 12 months 17.9% (95% CI:15.3–20.7) and last 30 days (current drinking) 11.8% (95% CI:9.8–14.1). There was substantial variation among the districts ranging from 2% to 60%. Multivariable analysis suggests women with no education or within formal education, dalit and janajatis ethnicity, whose husbands drink alcohol, who brew alcohol at home and women from mountains were significantly at higher risk of consuming alcohol. Among the women who drank alcohol in last 12 months, a substantial proportion of them drank home brewed alcoholic beverages (95.9%, 95% CI:94.3–97.4).ConclusionAlcohol consumption was common practice among married women of reproductive age in Nepal with variation among the subgroups of population. Thus, further investigation and behavior change communication interventions to reduce alcohol consumption especially among the women with higher risk of drinking is essential. 相似文献
55.
Gregory Lacraz Volatiana Rakotoarivelo Sebastien M. Labbé Mathieu Vernier Christophe Noll Marian Mayhue Jana Stankova Adel Schwertani Guillaume Grenier André Carpentier Denis Richard Gerardo Ferbeyre Julie Fradette Marek Rola-Pleszczynski Alfredo Menendez Marie-France Langlois Subburaj Ilangumaran Sheela Ramanathan 《PloS one》2016,11(11)
56.
Fensulfothion (O,O-diethyl O-[4-(methylsulfinyl)phenyl]phosphorothioate), an organophosphorus pesticide used to control the golden nematode Heterodera rostochiensis, is used as a source of carbon by microorganisms isolated from soils treated with the pesticide. Two of the microbial isolates, Pseudomonas alcaligenes C1 and Alcaligenes sp. strain NC3, used more than 80% of the pesticide in 120 h in culture when supplemented as a source of carbon. P. alcaligenes C1, which showed maximal growth on fensulfothion, degraded the compound to p-methylsulfinyl phenol and diethyl phosphorothioic acid. The phenolic metabolite could be identified by conventional spectral analysis, whereas the spectral patterns of the phosphorus-containing metabolite suggested that the compound was complexed with some cellular molecules. However, utilization of the phosphoric acid ester and ethanol by P. alcaligenes C1 suggested that the microbe attacks fensulfothion by an initial hydrolysis of the compound and subsequent utilization of the phosphoric acid ester. The pathway of degradation of fensulfothion by P. alcaligenes is of great value in the detoxification of the pesticide residues and also in the environmentally stable phosphoric acid esters. 相似文献
57.
Recent technological advances have expanded and increased the resolution of studies in evolutionary biology, creating a need for a modern textbook that highlights the latest developments in the field. Evolutionary Genetics: Concepts, Analysis, and Practice, by Glenn‐Peter Sætre and Mark Ravinet (2019), as well as the book's accompanying online tutorials, provide a clear, up‐to‐date, and enjoyable introduction to evolutionary biology and genetics that explains fundamental evolutionary concepts, illustrates recent exciting findings, and offers hands‐on experience in analysing and interpreting genomic data. The book's accessible nature and emphasis on developing practical skills make it a valuable resource for undergraduate courses on evolutionary biology. 相似文献
58.
Thomas SA Li T Woods KW Song X Packard G Fischer JP Diebold RB Liu X Shi Y Klinghofer V Johnson EF Bouska JJ Olson A Guan R Magnone SR Marsh K Luo Y Rosenberg SH Giranda VL Li Q 《Bioorganic & medicinal chemistry letters》2006,16(14):3740-3744
Based on lead compounds 2 and 3 a series of 3,5-disubstituted pyridines have been designed and evaluated for inhibition of AKT/PKB. Modifications at the 3 position of the pyridine ring led to a number of potent compounds with improved physical properties, resulting in the identification of 11g as a promising, orally active Akt inhibitor. The synthesis, structure-activity relationship studies, and pharmacokinetic data are presented in this paper. 相似文献
59.
Li Q Woods KW Thomas S Zhu GD Packard G Fisher J Li T Gong J Dinges J Song X Abrams J Luo Y Johnson EF Shi Y Liu X Klinghofer V Des Jong R Oltersdorf T Stoll VS Jakob CG Rosenberg SH Giranda VL 《Bioorganic & medicinal chemistry letters》2006,16(7):2000-2007
Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC(50) values of 0.42 and 0.59microM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC(50) of 1.5microM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined. 相似文献
60.
J. Priscilla Salome R. Amutha P. Jagannathan J.J.M. Josiah Sheela Berchmans V. Yegnaraman 《Biosensors & bioelectronics》2009,24(12):3487-3491
This work describes an electrochemical method for the determination of the nitrate and nitrite reductase activities of Rhizobium japonicum. The advantage of the method lies in the use of whole cells for the analysis and we earlier developed this protocol for the assay of NO. The results obtained are comparable to the spectrophotometric Griess assay. As the method is based on electrochemical reduction, the commonly interfering biological components like ascorbic acid, uric acid, dopamine, etc., will not interfere with the analysis. This method can be extended to the fabrication of biosensors for nitrate and nitrite using the same principle. 相似文献