排序方式: 共有202条查询结果,搜索用时 15 毫秒
41.
Sangita Choudhury Soochan Bae Qingen Ke Ji Yoo Lee Sylvia S. Singh René St-Arnaud Federica del Monte Peter M. Kang 《PloS one》2014,9(9)
Aim
Altered vitamin D signaling is associated with cardiac dysfunction, but the pathogenic mechanism is not clearly understood. We examine the mechanism and the role of vitamin D signaling in the development of cardiac dysfunction.Methods and Results
We analyzed 1α-hydroxylase (1α-OHase) knockout (1α-OHase−/−) mice, which lack 1α-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1α-OHase−/− mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1α-OHase−/− mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca2+) transient demonstrated profound Ca2+ handling abnormalities in 1α-OHase−/− mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D3 analog, significantly attenuated defective Ca2+ handling in 1α-OHase−/− CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1α-OHase−/− mice, followed then by either a daily maintenance dose of vitamin D or vehicle (to achieve vitamin D deficiency) at the time of sham or TAC. In mice treated with vitamin D, there was a significant attenuation of TAC-induced cardiac hypertrophy, interstitial fibrosis, inflammatory markers, Ca2+ handling abnormalities and cardiac function compared to the vehicle treated animals.Conclusions
Our results provide insight into the mechanism of cardiac dysfunction, which is associated with severely defective Ca2+ handling and defective vitamin D signaling in 1α-OHase−/− mice. 相似文献42.
Mariner family transposons are perhaps the most widespread transposable elements of eukaryotes. While we are beginning to understand
the precise mechanism of transposition of these elements, the structure of their transposases are still poorly understood.
We undertook an extensive mutagenesis of the N-terminal third of the transposase of the Himar1 mariner transposon to begin the process of determining the structure and evolution of mariner transposases. N and C-terminal deletion analyses localized the DNA binding domain of Himar1 transposase to the first 115 amino acids. Alanine scanning of 23 selected sites within this region uncovered mutations that
not only affected DNA binding but DNA cleavage as well. The behavior of other mutations strongly suggested that the N-terminus
is also involved in multimerization of the transposase on a single inverted terminal repeat and in paired ends complex formation
which brings together the two ends of the transposon. Finally, two hyperactive mutations at conserved sites suggest that mariner transposases are under a pattern of stabilizing selection in nature with regard to how efficiently they mediate transposition,
resulting in a population of “average” transposons. 相似文献
43.
Taurai Chiku Dominique Padovani Weidong Zhu Sangita Singh Victor Vitvitsky Ruma Banerjee 《The Journal of biological chemistry》2009,284(17):11601-11612
44.
Sharma Richa Roopak Sangita Pathak Nilesh kumar Uma R. Sharma R. P. 《Plasmonics (Norwell, Mass.)》2018,13(1):335-343
Plasmonics - In the present work, we report our observations drawn from the numerical simulation of absorption and scattering efficiencies of spheroid shape nanostructures using discrete dipole... 相似文献
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46.
Solverson P Murali SG Brinkman AS Nelson DW Clayton MK Yen CL Ney DM 《American journal of physiology. Endocrinology and metabolism》2012,302(7):E885-E895
Phenylketonuria (PKU) is caused by a mutation in the phenylalanine (phe) hydroxylase gene and requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to AA formula. Our objective was to compare growth, body composition, and energy balance in Pah(enu2) (PKU) and wild-type mice fed low-phe GMP, low-phe AA, or high-phe casein diets from 3-23 wk of age. The 2 × 2 × 3 design included main effects of genotype, sex, and diet. Fat and lean mass were assessed by dual-energy X-ray absorptiometry, and acute energy balance was assessed by indirect calorimetry. PKU mice showed growth and lean mass similar to wild-type littermates fed the GMP or AA diets; however, they exhibited a 3-15% increase in energy expenditure, as reflected in oxygen consumption, and a 3-30% increase in food intake. The GMP diet significantly reduced energy expenditure, food intake, and plasma phe concentration in PKU mice compared with the casein diet. The high-phe casein diet or the low-phe AA diet induced metabolic stress in PKU mice, as reflected in increased energy expenditure and intake of food and water, increased renal and spleen mass, and elevated plasma cytokine concentrations consistent with systemic inflammation. The low-phe GMP diet significantly attenuated these adverse effects. Moreover, total fat mass, %body fat, and the respiratory exchange ratio (CO(2) produced/O(2) consumed) were significantly lower in PKU mice fed GMP compared with AA diets. In summary, GMP provides a physiological source of low-phe dietary protein that promotes growth and attenuates the metabolic stress induced by a high-phe casein or low-phe AA diet in PKU mice. 相似文献
47.
Natarajan SR Heller ST Nam K Singh SB Scapin G Patel S Thompson JE Fitzgerald CE O'Keefe SJ 《Bioorganic & medicinal chemistry letters》2006,16(22):5809-5813
p38 inhibitors based on 3,4-dihydropyrido[4,3-d]pyrimidazin-2-one template were synthesized and their SAR explored. Benchmark compounds 30, 35, and 36 were found to be potent against the enzyme. Crystal structure of p38 in complex with 30 indicated a key pi-stacking interaction with the pendant tyrosine residue-35 in the glycine-rich loop. 相似文献
48.
Scott D. Edmondson Anthony Mastracchio Jason M. Cox George J. Eiermann Huaibing He Kathryn A. Lyons Reshma A. Patel Sangita B. Patel Aleksandr Petrov Giovanna Scapin Joseph K. Wu Shiyao Xu Bing Zhu Nancy A. Thornberry Ranabir Sinha Roy Ann E. Weber 《Bioorganic & medicinal chemistry letters》2009,19(15):4097-4101
A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported. 相似文献
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Scapin G Patel SB Becker JW Wang Q Desponts C Waddleton D Skorey K Cromlish W Bayly C Therien M Gauthier JY Li CS Lau CK Ramachandran C Kennedy BP Asante-Appiah E 《Biochemistry》2003,42(39):11451-11459
Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors. 相似文献