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91.
92.
Linking phospholipase C isoforms with differentiation function in human vascular smooth muscle cells
Louise S. Mackenzie Joanne S. Lymn Alun D. Hughes 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2013,1833(12):3006-3012
The phosphoinositol-phospholipase C (PLC) family of enzymes consists of a number of isoforms, each of which has different cellular functions. PLCγ1 is primarily linked to tyrosine kinase transduction pathways, whereas PLCδ1 has been associated with a number of regulatory proteins, including those controlling the cell cycle. Recent studies have shown a central role of PLC in cell organisation and in regulating a wide array of cellular responses. It is of importance to define the precise role of each isoform, and how this changes the functional outcome of the cell. Here we investigated differences in PLC isoform levels and activity in relation to differentiation of human and rat vascular smooth muscle cells. Using Western blotting and PLC activity assay, we show that PLCδ1 and PLCγ1 are the predominant isoforms in randomly cycling human vascular smooth muscle cells (HVSMCs). Growth arrest of HVSMCs for seven days of serum deprivation was consistently associated with increases in PLCδ1 and SM α-actin, whereas there were no changes in PLCγ1 immuno-reactivity. Organ culture of rat mesenteric arteries in serum free media (SFM), a model of de-differentiation, led to a loss of contractility as well as a loss of contractile proteins (SM α-actin and calponin) and PLCδ1, and no change in PLCγ1 immuno-reactivity. Taken together, these data indicate that PLCδ1 is the predominant PLC isoform in vascular smooth muscle, and confirm that PLCδ1 expression is affected by conditions that affect the cell cycle, differentiation status and contractile function. 相似文献
93.
Alcoholism has complex etiology and there is evidence for both genetic and environmental factors in its pathophysiology. Chronic, long-term alcohol abuse and alcohol dependence are associated with neuronal loss with the prefrontal cortex being particularly susceptible to neurotoxic damage. This brain region is involved in the development and persistence of alcohol addiction and neurotoxic damage is likely to exacerbate the reinforcing effects of alcohol and may hinder treatment. Understanding the mechanism of alcohol’s neurotoxic effects on the brain and the genetic risk factors associated with alcohol abuse are the focus of current research. Because of its well-established role in neurodegenerative and neuropsychological disorders, and its emerging role in the pathophysiology of addiction, here we review the genetic and epigenetic factors involved in regulating α-synuclein expression and its potential role in the pathophysiology of chronic alcohol abuse. Elucidation of the mechanisms of α-synuclein regulation may prove beneficial in understanding the role of this key synaptic protein in disease and its potential for therapeutic modulation in the treatment of substance use disorders as well as other neurodegenerative diseases. 相似文献
94.
Capsule Skylarks breeding in Ireland prefer extensive grassland habitats and almost completely avoid tillage habitats.Aims To describe the distribution and habitat use of breeding Skylarks in Ireland, particularly in lowland agricultural habitats, and to use this information to inform conservation measures for this species.Methods Countryside Bird Survey (CBS) and Farmland Bird Project (FBP) data were examined to determine large-scale (national) distribution and habitat selection, in addition to smaller-scale (farm- and field-level) habitat use. The CBS is a national breeding bird monitoring scheme involving 397 1-km squares. The FBP collected detailed bird and habitat data from 122 farms.Results CBS and FBP data both showed significant regional differences in breeding Skylark densities, with the highest relative abundances in the northwest and west. Dry grassland/grass moor habitats supported the highest densities of breeding Skylarks in the CBS, which were significantly higher than in improved grassland or tillage. At the farm-level, Skylark numbers were positively related to wetland habitats but negatively associated with trees in field boundaries, dense ground vegetation and overall density of farm boundaries. At the field-scale, larger fields and unimproved grasslands were preferred.Conclusion Agri-environment measures tailored to region-specific requirements and to the relatively local habitat preferences of target species are required if population declines of species of conservation concern, including Skylarks, are to be reversed. 相似文献
95.
David M. Wilson James Apps Nicholas Bailey Mark J. Bamford Isabel J. Beresford Michael A. Briggs Andrew R. Calver Barry Crook Robert P. Davis Susannah Davis David K. Dean Leanne Harris Tom D. Heightman Terry Panchal Christopher A. Parr Nigel Quashie Jon G.A. Steadman Joanne Schogger Andrew D. Medhurst 《Bioorganic & medicinal chemistry letters》2013,23(24):6897-6901
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties. 相似文献
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97.
Willem F. Wolkers Sheri A. Looper Ariane E. McKiernan Nelly M. Tsvetkova Fern Tablin John H. Crowe 《Molecular membrane biology》2013,30(3):201-210
Membrane properties and the overall protein secondary structure of freeze-dried trehalose-loaded mouse platelets were studied using steady state fluorescence anisotropy and Fourier transform infrared spectroscopy (FTIR). FTIR results showed that fresh control mouse platelets have a main phase transition at ~14°C, whereas, freeze-dried platelets exhibited a main phase transition ~12°C. However, the cooperativity of the transition of the rehydrated platelets was greatly enhanced compared to that of control platelets. Anisotropy experiments performed with 1,6 diphenyl-1,3,5 hexatriene (DPH) complemented FTIR results and showed that the lipid order in the core of the membrane was affected by freeze-drying procedures. Similar experiments with trimethyl ammonium 1,6 diphenyl-1,3,5 hexatriene (TMA-DPH), a membrane surface probe, indicated that membrane properties at the membrane/water interface were less affected by freeze-drying procedures than the core of the membrane. Lyophilization did not result in massive protein denaturation, but the overall protein secondary structure was altered, based on in situ assessment of the amide-I and amide-II band profiles. Lyophilization-induced changes to endogenous platelet proteins were further investigated by studying the protein's heat stability. In fresh control platelets, proteins denatured at 42°C, whereas proteins in the rehydrated platelets denatured at 48°C. 相似文献
98.
Yong-Jin Wu Huan He Robert Bertekap Ryan Westphal Snjezana Lelas Amy Newton Tanya Wallace Matthew Taber Carl Davis John E. Macor Joanne Bronson 《Bioorganic & medicinal chemistry》2013,21(8):2217-2228
This report describes the synthesis, structure–activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders. 相似文献
99.
100.
M. Joanne Lemieux 《Protein science : a publication of the Protein Society》2013,22(4):425-433
The overexpression of milligram quantities of protein remains a key bottleneck in membrane protein structural biology. A challenge of particular difficulty has been the overproduction of eukaryotic membrane proteins. In order to cope with the frequently poor expression levels associated with these challenging proteins, it is often necessary to screen a large number of homologues to find a well expressing clone. To facilitate this process using the heterologous, eukaryotic expression host Pichia pastoris, we have developed a simple fluorescent induction plate‐screening assay that allows for the rapid detection of well expressing clones of eukaryotic membrane proteins that have been fused to GFP. Using a eukaryotic membrane protein known to express well in P. pastoris (human aquaporin 4) and homologues of the ER associated membrane protein phosphatidylethanolamine N‐methyltransferase (PEMT), we demonstrate that when a large number of clones are screened, a small number of highly expressing “jackpot” clones can be isolated. A jackpot PEMT clone resulted in 5 mg/L yield after purification. The method allows for the facile simultaneous screening of hundreds of clones providing an alternate to in‐culture screening and will greatly accelerate the search for overexpressing eukaryotic membrane proteins. 相似文献