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71.
R D Krell R Osborn L Vickery K Falcone M O'Donnell J Gleason C Kinzig D Bryan 《Prostaglandins》1981,22(3):387-409
The pharmacology of leukotrienes (LT) C4 and D4 in isolated airway smooth muscle was investigated. In rat trachea, neither LTC4 or D4 elicited a response. In contrast, LTC4 was a potent contractile agonist in guinea-pig trachea, bronchus and parenchymal lung strip. Similar effects were obtained with LTD4 in trachea and parenchyma. In trachea and bronchus, the concentration-response curve to LTC4 was biphasic: indomethacin converted the biphasic response curve to a simple sigmoidal shape and enhanced the maximum contractile response. The SRS-A antagonist FPL 55712 antagonized the effect of LTD4 in both trachea and parenchyma. As regards LTC4-induced contraction of trachea and bronchus, FPL 55712, depending on concentration, either antagonized, or antagonized and enhanced the maximum contractile response. The enhancement of the maximum contractile response by FPL 55712 was not apparent when indomethacin was present. FPL 55712 failed to antagonize the effect of LTC4 in parenchyma. 相似文献
72.
We determined regional (Vr) and overall lung volumes in six head-up anesthetized dogs before and after the stepwise introduction of saline into the right pleural space. Functional residual capacity (FRC), as determined by He dilution, and total lung capacity (TLC) decreased by one-third and chest wall volume increased by two-thirds the saline volume added. Pressure-volume curves showed an apparent increase in lung elastic recoil and a decrease in chest wall elastic recoil with added saline, but the validity of esophageal pressure measurements in these head-up dogs is questionable. Vr was determined from the positions of intraparenchymal markers. Lower lobe TLC and FRC decreased with added saline. The decrease in upper lobe volume was less than that of lower lobe volume at FRC and was minimal at TLC. Saline increased the normal Vr gradient at FRC and created a gradient at TLC. During deflation from TLC to FRC before saline was added, the decrease in lung volume was accompanied by a shape change of the lung, with greatest distortion in the transverse (ribs to mediastinum) direction. After saline additions, deflation was associated with deformation of the lung in the cephalocaudal and transverse directions. The deformation with saline may be a result of upward displacement of the lungs into a smaller cross-sectional area of the thoracic cavity. 相似文献
73.
David Marcoux Lan-Ying Qin Zheming Ruan Qing Shi Qian Ruan Carolyn Weigelt Hongchen Qiu Gary Schieven John Hynes Rajeev Bhide Michael Poss Joseph Tino 《Bioorganic & medicinal chemistry letters》2017,27(13):2849-2853
Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined. 相似文献
74.
Viktor Hartung Tino Prell Christian Gaser Martin R. Turner Florian Tietz Benjamin Ilse Martin Bokemeyer Otto W. Witte Julian Grosskreutz 《PloS one》2014,9(8)
Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons. Advanced MRI techniques such as diffusion tensor imaging have shown great potential in capturing a common white matter pathology. However the sensitivity is variable and diffusion tensor imaging is not yet applicable to the routine clinical environment. Voxel-based morphometry (VBM) has revealed grey matter changes in ALS, but the bias-reducing algorithms inherent to traditional VBM are not optimized for the assessment of the white matter changes. We have developed a novel approach to white matter analysis, namely voxel-based intensitometry (VBI). High resolution T1-weighted MRI was acquired at 1.5 Tesla in 30 ALS patients and 37 age-matched healthy controls. VBI analysis at the group level revealed widespread white matter intensity increases in the corticospinal tracts, corpus callosum, sub-central, frontal and occipital white matter tracts and cerebellum. VBI results correlated with disease severity (ALSFRS-R) and patterns of cerebral involvement differed between bulbar- and limb-onset. VBI would be easily translatable to the routine clinical environment, and once optimized for individual analysis offers significant biomarker potential in ALS. 相似文献
75.
Xiang-Yang Ye Stephanie Chen Hao Zhang Kenneth T. Locke Kevin O’Malley Litao Zhang Raijit Srivastava Bowman Miao Daniel Meyers Hossain Monshizadegan Debra Search Denise Grimm Rongan Zhang Jonathan Lippy Celeste Twamley Jodi K. Muckelbauer Chiehying Chang Yongmi An Vinayak Hosagrahara Lisa Zhang Joseph A. Tino 《Bioorganic & medicinal chemistry letters》2010,20(9):2933-2937
The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARα/γ dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARα versus PPARγ. Potent, highly selective PPARα activators 2a and 2l, as well as PPARα activators with significant PPARγ activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed. 相似文献
76.
Roszak AW Robinson DA Krell T Hunter IS Fredrickson M Abell C Coggins JR Lapthorn AJ 《Structure (London, England : 1993)》2002,10(4):493-503
The structure of the type II DHQase from Streptomyces coelicolor has been solved and refined to high resolution in complexes with a number of ligands, including dehydroshikimate and a rationally designed transition state analogue, 2,3-anhydro-quinic acid. These structures define the active site of the enzyme and the role of key amino acid residues and provide snap shots of the catalytic cycle. The resolution of the flexible lid domain (residues 21-31) shows that the invariant residues Arg23 and Tyr28 close over the active site cleft. The tyrosine acts as the base in the initial proton abstraction, and evidence is provided that the reaction proceeds via an enol intermediate. The active site of the structure of DHQase in complex with the transition state analog also includes molecules of tartrate and glycerol, which provide a basis for further inhibitor design. 相似文献
77.
78.
For trophic interactions to generate population cycles and complex spatio-temporal patterns, like travelling waves, the spatial dynamics must be matched across trophic levels. Here, we propose a spatial methodological approach for detecting such spatial match–mismatch and apply it to geometrid moths and their larval parasitoids in northern Norway, where outbreak cycles and travelling waves occur. We found clear evidence of spatial mismatch, suggesting that the spatially patterned moth cycles in this system are probably ruled by trophic interactions involving other agents than larval parasitoids. 相似文献
79.
80.