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排序方式: 共有115条查询结果,搜索用时 15 毫秒
91.
Julia M. Assini Erin E. Mulvihill Brian G. Sutherland Dawn E. Telford Cynthia G. Sawyez Sarah L. Felder Sanjiv Chhoker Jane Y. Edwards Robert Gros Murray W. Huff 《Journal of lipid research》2013,54(3):711-724
Obesity-associated chronic inflammation contributes to metabolic dysfunction and propagates atherosclerosis. Recent evidence suggests that increased dietary cholesterol exacerbates inflammation in adipose tissue and liver, contributing to the proatherogenic milieu. The ability of the citrus flavonoid naringenin to prevent these cholesterol-induced perturbations is unknown. To assess the ability of naringenin to prevent the amplified inflammatory response and atherosclerosis induced by dietary cholesterol, male Ldlr−/− mice were fed either a cholesterol-enriched high-fat or low-fat diet supplemented with 3% naringenin for 12 weeks. Naringenin, through induction of hepatic fatty acid (FA) oxidation and attenuation of FA synthesis, prevented hepatic steatosis, hepatic VLDL overproduction, and hyperlipidemia induced by both cholesterol-rich diets. Naringenin attenuated hepatic macrophage infiltration and inflammation stimulated by dietary cholesterol. Insulin resistance, adipose tissue expansion, and inflammation were alleviated by naringenin. Naringenin attenuated the cholesterol-induced formation of both foam cells and expression of inflammatory markers in peritoneal macrophages. Naringenin significantly decreased atherosclerosis and inhibited the formation of complex lesions, which was associated with normalized aortic lipids and a reversal of aortic inflammation. We demonstrate that in mice fed cholesterol-enriched diets, naringenin attenuates peripheral and systemic inflammation, leading to protection from atherosclerosis. These studies offer a therapeutically relevant alternative for the prevention of cholesterol-induced metabolic dysregulation. 相似文献
92.
Keith R. Hornberger Dan M. Berger Andrew P. Crew Hanqing Dong Andrew Kleinberg An-Hu Li Matthew R. Medeiros Mark J. Mulvihill Kam Siu James Tarrant Jing Wang Felix Weng Victoria L. Wilde Mark Albertella Mark Bittner Andrew Cooke Michael J. Gray Paul Maresca Brianna Tokar 《Bioorganic & medicinal chemistry letters》2013,23(16):4517-4522
The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ~10 nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization. 相似文献
93.
M. Muenke K. W. Gripp D. M. McDonald-McGinn K. Gaudenz L. A. Whitaker S. P. Bartlett R. I. Markowitz N. H. Robin N. Nwokoro J. J. Mulvihill H. W. Losken J. B. Mulliken A. E. Guttmacher R. S. Wilroy L. A. Clarke G. Hollway L. C. Adès E. A. Haan J. C. Mulley M. M. Cohen G. A. Bellus C. A. Francomano D. M. Moloney S. A. Wall A. O. M. Wilkie E. H. Zackai 《American journal of human genetics》1997,60(3):555
The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis. 相似文献
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95.
Keith R. Hornberger Xin Chen Andrew P. Crew Andrew Kleinberg Lifu Ma Mark J. Mulvihill Jing Wang Victoria L. Wilde Mark Albertella Mark Bittner Andrew Cooke Salam Kadhim Jennifer Kahler Paul Maresca Earl May Peter Meyn Darlene Romashko Brianna Tokar Roy Turton 《Bioorganic & medicinal chemistry letters》2013,23(16):4511-4516
The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer. 相似文献
96.
Murphy RT Foley JB Tome MT Mulvihill NT Murphy A McCarroll N Crean P Walsh MJ 《Free radical biology & medicine》2004,36(8):959-965
Acute coronary syndromes are characterized by the expression of proinflammatory cytokines such as C-reactive protein (CRP). Sustained upregulation of inflammatory markers is associated with an adverse prognosis. Vitamin E is known to have significant anti-inflammatory properties and has been associated with a reduction in cardiovascular events in some studies of high-risk patients. The mechanism of benefit remains controversial. We conducted a randomized, double-blind placebo controlled trial of vitamin E 400 IU daily for 6 months in 110 patients with acute coronary syndromes. Serum samples were collected at enrollment and at 2, 4, and 6 months. CRP, interleukin-6 and the soluble cell adhesion molecules were measured. Vitamin E levels increased significantly in the treatment group (from 31 micromol/l at baseline to 51 micromol/l, p <.0001) and were unchanged in the placebo group (32 micromol/l at baseline to 34 micromol/l, p = NS). CRP levels fell in both the vitamin E group and the placebo group over the treatment period (from 17.2 +/- 2.9 to 6.1 +/- 0.8 mg/l and from 21.5 +/- 4.9 to 5.9 +/- 0.9 mg/l, p = NS for the difference between active and placebo groups). However, vitamin E treatment was associated with significantly lower 6 month CRP levels in smokers versus smokers on placebo (4.7 +/- 0.71 mg/l vs. 8.26 +/- 1.5 mg/l, p =.02). Vitamin E reduces CRP levels in smokers with acute coronary syndromes for up to 6 months after hospitalization. 相似文献
97.
98.
Annette Ehrhardt W. Joon Chung Louise C. Pyle Wei Wang Krzysztof Nowotarski Cory M. Mulvihill Mohabir Ramjeesingh Jeong Hong Sadanandan E. Velu Hal A. Lewis Shane Atwell Steve Aller Christine E. Bear Gergely L. Lukacs Kevin L. Kirk Eric J. Sorscher 《The Journal of biological chemistry》2016,291(4):1854-1865
In this study, we present data indicating a robust and specific domain interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) first cytosolic loop (CL1) and nucleotide binding domain 1 (NBD1) that allows ion transport to proceed in a regulated fashion. We used co-precipitation and ELISA to establish the molecular contact and showed that binding kinetics were not altered by the common clinical mutation F508del. Both intrinsic ATPase activity and CFTR channel gating were inhibited severely by CL1 peptide, suggesting that NBD1/CL1 binding is a crucial requirement for ATP hydrolysis and channel function. In addition to cystic fibrosis, CFTR dysregulation has been implicated in the pathogenesis of prevalent diseases such as chronic obstructive pulmonary disease, acquired rhinosinusitis, pancreatitis, and lethal secretory diarrhea (e.g. cholera). On the basis of clinical relevance of the CFTR as a therapeutic target, a cell-free drug screen was established to identify modulators of NBD1/CL1 channel activity independent of F508del CFTR and pharmacologic rescue. Our findings support a targetable mechanism of CFTR regulation in which conformational changes in the NBDs cause reorientation of transmembrane domains via interactions with CL1 and result in channel gating. 相似文献
99.
The Metabotropic Glutamate Receptor mGluR4, but Not mGluR1α, Is Palmitoylated when Expressed in BHK Cells 总被引:1,自引:1,他引:0
Simon Alaluf Eileen R. Mulvihill Robert A. J. McIlhinney 《Journal of neurochemistry》1995,64(4):1548-1555
Abstract: Several G protein-coupled receptors have been shown to be palmitoylated, and for some of these receptors the covalent attachment of palmitate has been implicated in the regulation of receptor-G protein coupling. The metabotropic glutamate receptor (mGluR) family forms a distinct group of G protein-coupled receptors, and the possibility that these may also be palmitoylated has been examined. Clonal baby hamster kidney (BHK) cells permanently transfected with the mGluR4 and mGluR1α subtypes were labelled with [3 H]palmitic acid. The cells were lysed, the receptors were immuno-precipitated with specific antipeptide antibodies, and the immunoprecipitates were analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and autoradiography. The palmitoylated, endogenously expressed G protein α-subunit αq could be immunoprecipitated from [3 H]palmitate-labelled BHK cells expressing mGluR1α using a specific antipeptide antibody, but in the same cell lysates no detectable [3 H]palmitate-labelled mGluR1α was found. This suggests that this mGluR subtype, associated with stimulation of phospholipase C, is not palmitoylated. In contrast, mGluR4, which is coupled to inhibition of adenylyl cyclase, was found to be labelled with [3 H]palmitic acid, and the palmitate was quantitatively removed by treatment with 1 M hydroxylamine, suggesting attachment of the palmitate through a thioester bond. Stimulation with maximal doses of the neurotransmitter glutamate for 1, 5, or 10 min appeared to have no effect on the level of receptor palmitoylation. 相似文献
100.
Inheritance of acute appendicitis: familial aggregation and evidence of polygenic transmission. 总被引:2,自引:1,他引:1 下载免费PDF全文
M Basta N E Morton J J Mulvihill Z Radovanovi C Radojici D Marinkovi 《American journal of human genetics》1990,46(2):377-382
We explored familiality as well as the heritability and possible mode(s) of inheritance of acute appendicitis in childhood and early adolescence. Our case-control study showed that a positive family history for reported appendectomy was significantly more frequent in families of 80 consecutive patients eventually proved to have histopathologic acute appendicitis than in families of surgical controls matched for sex, age, and number of siblings. The relative risk was 10.0 (95% confidence limits 4.7-21.4). The pattern of familial aggregation was further supported by the fact that the age-standardized morbidity ratio was four times greater among family members of cases than among controls. We then applied the unified mixed model of segregation analysis, as implemented in the computer program POINTER, to a new set of 100 multigenerational pedigrees of children with histopathologically confirmed acute appendicitis that were broken down into 674 nuclear families. Age-specific morbidity risk and lifetime incidence of acute appendicitis were estimated from relatives of controls matched for age and sex to probands. Complex segregation analysis supported a polygenic or multifactorial model with a total heritability of 56%. There was no evidence to support a major gene, although a rare gene could not be ruled out as the cause of a small proportion of cases. Specific studies to address genetic and environmental factors in this serious disease seem worthwhile; but, for now, a positive family history of appendicitis might join other evidence leading to improved clinical recognition of acute appendicitis. 相似文献