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91.
Dick H J Thijssen Gerard A Rongen Arie van Dijk Paul Smits Maria T E Hopman 《Journal of applied physiology》2007,103(3):852-857
Advanced age is associated with a decreased leg blood flow and reduced physical activity. Endothelin (ET-1), a powerful vasoconstrictor, may play a role in the increased leg vascular tone in older men. objectives: to assess the ET-1-mediated vascular tone in the legs of healthy sedentary older men, both before and after 8 wk of exercise training. methods: in 8 younger subjects (19-50 yr) and 8 older men (67-76 yr), bilateral leg blood flow was measured using venous occlusion plethysmography before and after antagonizing ET-1 (using selective ET(A/B)-receptor antagonists). In older men, reversibility of the observations was assessed after 8 wk of cycling. results: ET-receptor inhibition increased leg blood flow significantly more in older men compared with younger individuals (29 +/- 9% and 10 +/- 4%, respectively, P < 0.05). Eight-week cycling training increased baseline blood flow in older men. The blood flow response to ET-receptor inhibition in older men was not affected by the training program (25 +/- 8%, P > 0.05 for comparison with pretraining). The flow ratio (blood flows infused leg/noninfused leg) decreased significantly by training from 26 +/- 8% to 7+3% (P < 0.05). CONCLUSION: the increased baseline vascular tone in aging is at least in part mediated by the endothelin. Eight-weeks cycling training in older sedentary men decreased leg vascular tone and seems to partly decrease the ET-1-mediated vascular tone. 相似文献
92.
Jeroen C. Verheijen Ker Yu Lourdes Toral-Barza Irwin Hollander Arie Zask 《Bioorganic & medicinal chemistry letters》2010,20(1):375-379
2-Aryl-4-morpholinothieno[3,2-d]pyrimidines are known PI3K inhibitors. This class of compounds also potently inhibited the homologous enzyme mTOR. Replacement of the morpholine group in these compounds with an 8-oxa-3-azabicyclo[3.2.1]octane group led to mTOR inhibitors with selectivity over PI3K. Optimization of the 2-aryl substituent led to the discovery of 2-(4-ureidophenyl)-thienopyrimidines as highly potent (IC50 <1 nM) mTOR inhibitors with excellent selectivity (up to >1000-fold) over PI3K and good potency in a cellular proliferation assay (IC50 <50 nM). 相似文献
93.
Sandra Bouwhuis Arie J. Van Noordwijk Ben C. Sheldon Simon Verhulst Marcel E. Visser 《Journal of avian biology》2010,41(6):615-620
The process of ageing was long thought to be too infrequent to affect life‐histories in natural populations. Long‐term studies have, however, recently demonstrated ageing to be ubiquitous even in the wild, although confounding factors, such as emigration instead of mortality, or inter‐population variation in rates of ageing have seldom been addressed. Here, we present analyses of female age‐specific reproductive performance in a Dutch island population of great tits Parus major. For this population with limited connectivity to surrounding areas, we show that, between individuals, reproductive lifespan positively co‐varies with recruit production, while within individuals performance improves up to 3 years of age, after which it gradually declines. We also show these patterns to be strikingly similar to those recently found in a less isolated British mainland population of great tits, characterised by different environmental conditions and life‐history strategies, in particular the frequency of multiple breeding. Our results therefore suggest patterns of age‐specific reproductive performance to be robust to both environmental and life‐history variation. 相似文献
94.
Helmerhorst EJ van't Hof W Breeuwer P Veerman EC Abee T Troxler RF Amerongen AV Oppenheim FG 《The Journal of biological chemistry》2001,276(8):5643-5649
Histatin 5 is a 24-residue peptide from human saliva with antifungal properties. We recently demonstrated that histatin 5 translocates across the yeast membrane and targets to the mitochondria, suggesting an unusual antifungal mechanism (Helmerhorst, E. J., Breeuwer, P., van't Hof, W., Walgreen-Weterings, E., Oomen, L. C. J. M., Veerman, E. C. I., Nieuw Amerongen, A. V., and Abee, T. (1999) J. Biol. Chem. 274, 7286-7291). The present study used specifically designed synthetic analogs of histatin 5 to elucidate the role of peptide amphipathicity, hydrophobicity, and the propensity to adopt alpha-helical structures in relation to membrane permeabilization and fungicidal activity. Studies included circular dichroism measurements, evaluation of the effects on the cytoplasmic transmembrane potential and on the respiration of isolated mitochondria, and analysis of the peptide hydrophobicity/amphipathicity relationship (Eisenberg, D. (1984) Annu. Rev. Biochem. 53, 595-623). The 14-residue synthetic peptides used were dh-5, comprising the functional domain of histatin 5, and dhvar1 and dhvar4, both designed to maximize amphipathic characteristics. The results obtained show that the amphipathic analogs exhibited a high fungicidal activity, a high propensity to form an alpha-helix, dissipated the cytoplasmic transmembrane potential, and uncoupled the respiration of isolated mitochondria, similar to the pore-forming peptide PGLa (Peptide with N-terminal Glycine and C-terminal Leucine-amide). In contrast, histatin 5 and dh-5 showed fewer or none of these features. The difference in these functional characteristics between histatin 5 and dh-5 on the one hand and dhvar1, dhvar4, and PGLa on the other hand correlated well with their predicted affinity for membranes based on hydrophobicity/amphipathicity analysis. These data indicate that the salivary protein histatin 5 exerts its antifungal function through a mechanism other than pore formation. 相似文献
95.
Metal binding has been suggested to be relevant in the antifungal and antibacterial mechanism of histatin 5, a human salivary protein. Proton nuclear magnetic resonance (NMR) spectra were obtained to investigate the specificity of metal binding to the seven histidyl, one aspartyl and one glutamyl amino acid side-chains of histatin 5 in aqueous solutions. Three C(epsilon1)-H histidyl and the C(gamma)-H glutamyl resonances of histatin 5 were selectively altered in spectra of solutions containing three equivalents of zinc. Copper binding to histatin 5 resulted in a reduced intensity of C(beta)-H aspartyl resonances, while no evidence for calcium binding was found. These results indicate that zinc binding to histatin 5 involves His-15 present within the -H-E-X-X-H- zinc binding motif, and copper binding occurs within the N-terminal D-S-H-, ATCUN motif. 相似文献
96.
Histatin 5 is a low molecular weight salivary protein which is known to exhibit inhibitory activity against several proteinases, including the cysteine proteinases gingipains. The purpose of this study was to characterize the effect of salivary histatin on the proteolytic activity of the cysteine proteinase clostripain derived from the pathogen Clostridium histolyticum. Using a synthetic nitroanilide substrate, we studied in detail the inhibition of clostripain by histatin 5 and compared the effect of this peptide to that of leupeptin, a known competitive inhibitor of clostripain. It was found that the concentration of histatin 5 required to inhibit 50% of clostripain activity was 23.6+/-1.6 nM. Kinetic analysis revealed that histatin 5 is a competitive inhibitor of clostripain with an inhibition constant (K(i)) of 10 nM. The K(i) for the inhibition of clostripain activity against nitroanilide substrate by leupeptin was found to be 60 nM, significantly higher than that of histatin 5. Thus, histatin 5 inhibits clostripain more effectively than leupeptin and other cysteine protease inhibitors studied here. No significant proteolysis of histatin 5 was observed when histatin 5 was incubated at physiologic concentrations with clostripain. The potent inhibition of clostripain by histatin 5 points towards the possibility that this protein may prevent establishment of clostridial infections and therefore may have significant potential for the treatment of diseases associated with this enzyme. 相似文献
97.
Differential regulation of formyl peptide receptor-like 1 expression during the differentiation of monocytes to dendritic cells and macrophages 总被引:6,自引:0,他引:6
Yang D Chen Q Le Y Wang JM Oppenheim JJ 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(6):4092-4098
Monocytes are the common precursors for myeloid dendritic cells (DC) and macrophages. Identification of chemotactic receptors expressed by myeloid DC, macrophages, and their precursors in the course of differentiation and maturation is important not only for elucidation of their in vivo trafficking, but also for understanding of the functional distinction between DC and macrophages. We chose to study formyl peptide receptor like-1 (FPRL1), a chemotactic receptor known to interact with several endogenous agonists that are involved in inflammatory and host defense responses. Here we show that FPRL1 is down-regulated as monocytes differentiate into DC. This down-regulation occurs at both mRNA and functional levels. Therefore, the interaction of FPRL1 with its agonists is more likely to regulate the in vivo trafficking of DC precursors than DC. In contrast, FPRL1 expression is maintained at both mRNA and functional levels as monocytes differentiate into macrophages. Thus, our results demonstrate further distinctions between myeloid DC and macrophages, albeit they share a common precursor. The fact that macrophages rather than myeloid DC express functional FPRL1 suggests that this chemotactic receptor may be more involved in inflammatory reactions and innate host defense than in adaptive immune responses. 相似文献
98.
Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells 总被引:8,自引:0,他引:8
Salcedo R Young HA Ponce ML Ward JM Kleinman HK Murphy WJ Oppenheim JJ 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(12):7571-7578
Chemokines are attractants and regulators of cell activation. Several CXC family chemokine members induce angiogenesis and promote tumor growth. In contrast, the only CC chemokine, reported to play a direct role in angiogenesis is monocyte-chemotactic protein-1. Here we report that another CC chemokine, eotaxin (also known as CCL11), also induced chemotaxis of human microvascular endothelial cells. CCL11-induced chemotactic responses were comparable with those induced by monocyte-chemotactic protein-1 (CCL2), but lower than those induced by stroma-derived factor-1alpha (CXCL12) and IL-8 (CXCL8). The chemotactic activity was consistent with the expression of CCR3, the receptor for CCL11, on human microvascular endothelial cells and was inhibited by mAbs to either human CCL11 or human CCR3. CCL11 also induced the formation of blood vessels in vivo as assessed by the chick chorioallantoic membrane and Matrigel plug assays. The angiogenic response induced by CCL11 was about one-half of that induced by basic fibroblast factor, and it was accompanied by an inflammatory infiltrate, which consisted predominantly of eosinophils. Because the rat aortic sprouting assay, which is not infiltrated by eosinophils, yielded a positive response to CCL11, this angiogenic response appears to be direct and is not mediated by eosinophil products. This suggests that CCL11 may contribute to angiogenesis in conditions characterized by increased CCL11 production and eosinophil infiltration such as Hodgkin's lymphoma, nasal polyposis, endometriosis, and allergic diathesis. 相似文献
99.
A quantitative in silico analysis calculates the angiotensin I converting enzyme (ACE) inhibitory activity in pea and whey protein digests 总被引:5,自引:0,他引:5
Angiotensin I converting enzyme (ACE) inhibitory peptides can induce antihypertensive effects after oral administration. By means of an ACE inhibitory peptide database, containing about 500 reported sequences and their IC(50) values, the different proteins in pea and whey were quantitatively evaluated as precursors for ACE inhibitory peptides. This analysis was combined with experimental data from the evolution in ACE inhibitory activity and protein degradation during in vitro gastrointestinal digestion. Pea proteins produced similar in silico scores and were degraded early in the in vitro digestion. High ACE inhibitory activity was observed after the simulated stomach phase and augmented slightly in the simulated small intestine phase. The major whey protein beta-lactoglobulin obtained the highest in silico scores, which corresponded with the fact that degradation of this protein in vitro only occurred from the simulated small intestine phase on and resulted in a 10-fold increase in the ACE inhibitory activity. Whey protein obtained total in silico scores of about 124 ml/mg, compared to 46 ml/mg for pea protein, indicating that whey protein would be a richer source of ACE inhibitory peptides than pea protein. Although beta-lactoglobulin is only partially digested, a higher ACE inhibitory activity was indeed found in the whey (IC(50) = 0.048 mg/ml) compared to the pea digest (IC(50) = 0.076 mg/ml). In silico gastrointestinal digestion of the highest scoring proteins in pea and whey, vicilin and albumin PA2, and beta-lactoglobulin, respectively, directly released a number of potent ACE inhibitory peptides. Several other ACE inhibitory sequences resisted in silico digestion by gastrointestinal proteases. Briefly, the quantitative in silico analysis will facilitate the study of precursor proteins on a large scale and the specific release of bioactive peptides. 相似文献
100.
Virulent and avirulent strains of Aerococcus viridans (var.) homari were used to extend previous studies to determine and confirm differences between the 2 types. Virulent strains possessed polysaccharide capsules and were not agglutinated by lobster hemolymph serum; avirulent strains did not have capsules, were agglutinated by the lobster hemolymph serum, and most did not grow well in lobster hemolymph serum. Growth of the avirulent strains in sterile lobster hemolymph serum induced the production of capsules (which reached a maximum after 5 to 7 d incubation), eliminated susceptibility of the strains to the lobster serum agglutinin, and restored their virulence against lobsters. The factor(s) in lobster hemolymph serum inducing the long-lasting phenotypic response of virulence was (were) heat labile. 相似文献