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51.
Seal J Lamotte Y Donche F Bouillot A Mirguet O Gellibert F Nicodeme E Krysa G Kirilovsky J Beinke S McCleary S Rioja I Bamborough P Chung CW Gordon L Lewis T Walker AL Cutler L Lugo D Wilson DM Witherington J Lee K Prinjha RK 《Bioorganic & medicinal chemistry letters》2012,22(8):2968-2972
A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model. 相似文献
52.
Performance on perceptual tasks usually improves with training. However, too much consecutive training can be detrimental. Repeated within-day testing or overtraining demonstrates the detrimental effects this has on perceptual learning. Consolidation of learnt information during sleep has the power to prevent such deficits in learning. However, little is known regarding the role of wakeful consolidation in preventing the effects of overtraining. Here, we report that perceptual deterioration may result from the disruption of early wakeful consolidation processes. Three groups were tested on day 1 and again 24 h later, on a motion discrimination task. Participants who had a 1 h break between the two training sessions on the first day displayed improved accuracy on the second day (i.e. learning). Subjects who only completed the first training session on day 1 also exhibited learning. However, individuals who completed two blocks without a break ('overtraining') showed no improvement in accuracy on day 2. Interestingly, changes in reaction times were not susceptible to the effects of overtraining, but instead speeded up as a function of total performed trials. These data suggest that effects of overtraining might be due to disruption of wakeful consolidation processes. 相似文献
53.
Tfelt-Hansen J Hansen JL Smajilovic S Terwilliger EF Haunso S Sheikh SP 《American journal of physiology. Heart and circulatory physiology》2006,290(3):H1165-H1171
Both intra- and extracellular calcium play multiple roles in the physiology and pathophysiology of cardiomyocytes, especially in stimulus-contraction coupling. The intracellular calcium level is closely controlled through the concerted actions of calcium channels, exchangers, and pumps; however, the expression and function(s) of the so-called calcium-sensing receptor (CaR) in the heart remain less well characterized. The CaR is a seven-transmembrane receptor, which, in response to noncovalent binding of extracellular calcium, activates intracellular effectors, including G proteins and extracellular signal-regulated kinases (ERK1/2). We have shown that cultured neonatal cardiomyocytes express the CaR messenger RNA and the CaR protein. Furthermore, increasing concentrations of extracellular calcium and a type II CaR activator "calcimimetic" caused inositol phosphate (IP) accumulation, downregulated tritiated thymidine incorporation, and supported ERK1/2 phosphorylation, suggesting that the CaR protein is functionally active. Interestingly, the calcimimetic induced a more rapid ERK1/2 phosphorylation than calcium and left-shifted the IP concentration-response curve for extracellular calcium, supporting the hypothesis that CaR is functionally expressed in cardiac myocytes. This notion was underscored by studies using a virus containing a dominant-negative CaR construct, because this protein blunted the calcium-induced IP response. In conclusion, we have shown that the CaR is functionally expressed in neonatal ventricular cardiomyocytes and that the receptor activates second messenger pathways, including IP and ERK, and decreases DNA synthesis. A specific calcium-sensing receptor on cardiac myocytes could play a role in regulating cardiac development, function, and homeostasis. 相似文献
54.
Jain S Tillinger A Mopidevi B Pandey VG Chauhan CK Fiering SN Warming S Kumar A 《The Journal of biological chemistry》2010,285(52):41172-41186
Hypertension is a serious risk factor for cardiovascular disease, and the angiotensinogen (AGT) gene locus is associated with human essential hypertension. The human AGT (hAGT) gene has an A/G polymorphism at -6, and the -6A allele is associated with increased blood pressure. However, transgenic mice containing 1.2 kb of the promoter with -6A of the hAGT gene show neither increased plasma AGT level nor increased blood pressure compared with -6G. We have found that the hAGT gene has three additional SNPs (A/G at -1670, C/G at -1562, and T/G at -1561). Variants -1670A, -1562C, and -1561T almost always occur with -6A, and variants -1670G, -1562G, and -1561G almost always occur with -6G. Therefore, the hAGT gene may be subdivided into either -6A or -6G haplotypes. We show that these polymorphisms affect the binding of HNF-1α and glucocorticoid receptor to the promoter, and a reporter construct containing a 1.8-kb hAGT gene promoter with -6A haplotype has 4-fold increased glucocorticoid-induced promoter activity as compared with -6G haplotype. In order to understand the physiological significance of these haplotypes in an in vivo situation, we have generated double transgenic mice containing either the -6A or -6G haplotype of the hAGT gene and the human renin gene. Our ChIP assay shows that HNF-1α and glucocorticoid receptor have stronger affinity for the chromatin obtained from the liver of transgenic mice containing -6A haplotype. Our studies also show that transgenic mice containing -6A haplotype have increased plasma AGT level and increased blood pressure as compared with -6G haplotype. Our studies explain the molecular mechanism involved in association of the -6A allele of the hAGT gene with hypertension. 相似文献
55.
Chrisostom Ayebazibwe Frank N Mwiine Kirsten Tjørnehøj Sheila N Balinda Vincent B Muwanika Anna R Ademun Okurut Graham J Belsham Preben Normann Hans R Siegismund Soren Alexandersen 《BMC veterinary research》2010,6(1):54
Background
To study the role of African buffalos (Syncerus caffer) in the maintenance of foot-and-mouth disease in Uganda, serum samples were collected from 207 African buffalos, 21 impalas (Aepyceros melampus), 1 giraffe (Giraffa camelopardalis), 1 common eland (Taurotragus oryx), 7 hartebeests (Alcelaphus buselaphus) and 5 waterbucks (Kobus ellipsiprymnus) from four major National Parks in Uganda between 2005 and 2008. Serum samples were screened to detect antibodies against foot-and-mouth disease virus (FMDV) non-structural proteins (NSP) using the Ceditest® FMDV NS ELISA. Solid Phase Blocking ELISAs (SPBE) were used to determine the serotype-specificity of antibodies against the seven serotypes of FMDV among the positive samples. Virus isolation and sequencing were undertaken to identify circulating viruses and determine relatedness between them.Results
Among the buffalo samples tested, 85% (95% CI = 80-90%) were positive for antibodies against FMDV non-structural proteins while one hartebeest sample out of seven (14.3%; 95% CI = -11.6-40.2%) was the only positive from 35 other wildlife samples from a variety of different species. In the buffalo, high serotype-specific antibody titres (≥ 80) were found against serotypes O (7/27 samples), SAT 1 (23/29 samples), SAT 2 (18/32 samples) and SAT 3 (16/30 samples). Among the samples titrated for antibodies against the four serotypes O, SAT 1, SAT 2 and SAT 3, 17/22 (77%; CI = 59.4-94.6%) had high titres against at least two serotypes.FMDV isolates of serotypes SAT 1 (1 sample) and SAT 2 (2 samples) were obtained from buffalo probang samples collected in Queen Elizabeth National Park (QENP) in 2007. Sequence analysis and comparison of VP1 coding sequences showed that the SAT 1 isolate belonged to topotype IV while the SAT 2 isolates belonged to different lineages within the East African topotype X.Conclusions
Consistent detection of high antibody titres in buffalos supports the view that African buffalos play an important role in the maintenance of FMDV infection within National Parks in Uganda. Both SAT 1 and SAT 2 viruses were isolated, and serological data indicate that it is also likely that FMDV serotypes O and SAT 3 may be present in the buffalo population. Detailed studies should be undertaken to define further the role of wildlife in the epidemiology of FMDV in East Africa.56.
57.
Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications 总被引:1,自引:0,他引:1
58.
PSD-95 and Lin-7b interact with acid-sensing ion channel-3 and have opposite effects on H+- gated current 总被引:4,自引:0,他引:4
Hruska-Hageman AM Benson CJ Leonard AS Price MP Welsh MJ 《The Journal of biological chemistry》2004,279(45):46962-46968
The acid-sensing ion channel-3 (ASIC3) is a degenerin/epithelial sodium channel expressed in the peripheral nervous system. Previous studies indicate that it participates in the response to mechanical and painful stimuli, perhaps contributing to mechanoreceptor and/or H+ -gated nociceptor function. ASIC3 subunits contain intracellular N and C termini that may control channel localization and function. We found that a PDZ-binding motif at the ASIC3 C terminus interacts with four different proteins that contain PDZ domains: PSD-95, Lin-7b, MAGI-1b, and PIST. ASIC3 and these interacting proteins were expressed in dorsal root ganglia and spinal cord, and PSD-95 co-precipitated ASIC3 from spinal cord. When expressed in heterologous cells, PSD-95 reduced the amplitude of ASIC3 acid-evoked currents, whereas Lin-7b increased current amplitude. PSD-95 and Lin-7b altered current density by decreasing or increasing, respectively, the amount of ASIC3 on the cell surface. The finding that multiple PDZ-containing proteins bind ASIC3 and can influence its presence in the plasma membrane suggests that they may play an important role in the contribution of ASIC3 to nociception and mechanosensation. 相似文献
59.
Chou CL Christensen BM Frische S Vorum H Desai RA Hoffert JD de Lanerolle P Nielsen S Knepper MA 《The Journal of biological chemistry》2004,279(47):49026-49035
We have previously demonstrated that vasopressin increases the water permeability of the inner medullary collecting duct (IMCD) by inducing trafficking of aquaporin-2 to the apical plasma membrane and that this response is dependent on intracellular calcium mobilization and calmodulin activation. Here, we address the hypothesis that this water permeability response is mediated in part through activation of the calcium/calmodulin-dependent myosin light chain kinase (MLCK) and regulation of non-muscle myosin II. Immunoblotting and immunocytochemistry demonstrated the presence of MLCK, the myosin regulatory light chain (MLC), and the IIA and IIB isoforms of the non-muscle myosin heavy chain in rat IMCD cells. Two-dimensional electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry identified two isoforms of MLC, both of which also exist in phosphorylated and non-phosphorylated forms. 32P incubation of the inner medulla followed by autoradiography of two-dimensional gels demonstrated increased 32P labeling of both isoforms in response to the V2 receptor agonist [deamino-Cys1,D-Arg8]vasopressin (DDAVP). Time course studies of MLC phosphorylation in IMCD suspensions (using immunoblotting with anti-phospho-MLC antibodies) showed that the increase in phosphorylation could be detected as early as 30 s after exposure to vasopressin. The MLCK inhibitor ML-7 blocked the DDAVP-induced MLC phosphorylation and substantially reduced [Arg8]vasopressin (AVP)-stimulated water permeability. AVP-induced MLC phosphorylation was associated with a rearrangement of actin filaments (Alexa Fluor 568-phalloidin) in primary cultures of IMCD cells. These results demonstrate that MLC phosphorylation by MLCK represents a downstream effect of AVP-activated calcium/calmodulin signaling in IMCD cells and point to a role for non-muscle myosin II in regulation of water permeability by vasopressin. 相似文献
60.
Bruun JM Lihn AS Verdich C Pedersen SB Toubro S Astrup A Richelsen B 《American journal of physiology. Endocrinology and metabolism》2003,285(3):E527-E533
Adiponectin is an adipose tissue-specific protein that is abundantly present in the circulation and suggested to be involved in insulin sensitivity and development of atherosclerosis. Because cytokines are suggested to regulate adiponectin, the aim of the present study was to investigate the interaction between adiponectin and three adipose tissue-derived cytokines (IL-6, IL-8, and TNF-alpha). The study was divided into three substudies as follows: 1) plasma adiponectin and mRNA levels in adipose tissue biopsies from obese subjects [mean body mass index (BMI): 39.7 kg/m2, n = 6] before and after weight loss; 2) plasma adiponectin in obese men (mean BMI: 38.7 kg/m2, n = 19) compared with lean men (mean BMI: 23.4 kg/m2, n = 10) before and after weight loss; and 3) in vitro direct effects of IL-6, IL-8, and TNF-alpha on adiponectin mRNA levels in adipose tissue cultures. The results were that 1) weight loss resulted in a 51% (P < 0.05) increase in plasma adiponectin and a 45% (P < 0.05) increase in adipose tissue mRNA levels; 2) plasma adiponectin was 53% (P < 0.01) higher in lean compared with obese men, and plasma adiponectin was inversely correlated with adiposity, insulin sensitivity, and IL-6; and 3) TNF-alpha (P < 0.01) and IL-6 plus its soluble receptor (P < 0.05) decreased adiponectin mRNA levels in vitro. The inverse relationship between plasma adiponectin and cytokines in vivo and the cytokine-induced reduction in adiponectin mRNA in vitro suggests that endogenous cytokines may inhibit adiponectin. This could be of importance for the association between cytokines (e.g., IL-6) and insulin resistance and atherosclerosis. 相似文献