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71.
A new class of bradykinin 1 receptor antagonists containing the piperidine acetic acid tetralin core
Fotsch C Biddlecome G Biswas K Chen JJ D'Amico DC Groneberg RD Han NB Hsieh FY Kamassah A Kumar G Lester-Zeiner D Liu Q Mareska DA Riahi BB Wang YJ Yang K Zhan J Zhu J Johnson E Ng G Askew BC 《Bioorganic & medicinal chemistry letters》2006,16(8):2071-2075
The bradykinin 1 (B1) receptor is upregulated during times of inflammation and is important for maintaining inflamed and chronic pain states. Blocking this receptor has been shown to reverse and/or ameliorate pain and inflammation in animal models. In this report, we describe a new class of B1 receptor antagonists that contain the piperidine acetic acid tetralin core. A structure-activity relationship for these analogs is described in this paper. The most potent compounds from this class have IC50s<20 nM in a B1 receptor functional assay. One of these compounds, 13g, shows modest oral bioavailability in rats. 相似文献
72.
BACKGROUND: Simple stimuli can evoke complex behavioral responses coordinated by multiple neural circuits. O(2) is an important environmental variable for most animals. The nematode C. elegans avoids high O(2), and O(2) levels regulate its foraging and aggregation. RESULTS: Here, we dissect aggregation and responses to O(2) gradients into behavioral motifs and show how O(2) responses can promote aggregation. To remain in a group, C. elegans continually modify their movement. Animals whose heads emerge from a group will reverse or turn, thereby returning to the group. Re-entry inhibits further reversal, aiding retention in the group. If an animal's tail exits a group during a reversal, it switches to forward movement, returning to the group. Aggregating C. elegans locally deplete O(2). The rise in O(2) levels experienced by animals leaving a group induces both reversal and turning. Conversely, the fall in O(2) encountered when entering a clump suppresses reversal, turning, and high locomotory activity. The soluble guanylate cyclases GCY-35 and GCY-36, which are expressed in head and tail neurons, promote reversal and turning when O(2) rises. Avoidance of high O(2) is also promoted by the TRP-related channel subunits OCR-2 and OSM-9, and the transmembrane protein ODR-4, acting in the nociceptive neurons ASH and ADL. Both O(2) responsiveness and aggregation can be modified by starvation, but this is regulated by natural variation in the npr-1 neuropeptide receptor. CONCLUSIONS: Our work provides insights into how a complex behavior emerges from simpler behavioral motifs coordinated by a distributed circuit. 相似文献
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76.
Robin F. A. Moritz Nizar Haddad Ahmed Bataieneh Benny Shalmon Abraham Hefetz 《Biological invasions》2010,12(5):1093-1099
The dwarf honeybee, Apis florae, is an open nesting honeybee typical to Southern Asia. In the past decades it has been accidentally introduced by man to East Africa and the Arabian Peninsula where the species established sustainable and expanding populations. Recently it has also been introduced to Aqaba and Eilat, where it has also established expanding populations. We here study the genetic structure of this invasive population with nine microsatellite DNA markers to reconstruct the invasion history. The population shows indications of an extreme bottleneck suggesting that it established itself very recently and may have originated from a single introduced colony only. The impact of the species for both apiculture and conservation of biodiversity is discussed. 相似文献
77.
The diets of the mangrove crabs, Metopograpsus frontalis Miers and Perisesarma bidens de Haan, were investigated monthly for 13 months at two Hong Kong mangroves, to examine possible spatial and temporal influences
on their feeding ecology. In both species, a higher degree of gut fullness was observed in summer (May–September) than in
winter, suggesting a reduction in winter foraging activity. M. frontalis was omnivorous, with animal and plant materials and inorganic sediments being the major food items. P. bidens was detritivorous, with plant materials and inorganic sediment dominating the gut contents. M. frontalis is, therefore, an opportunistic feeder, whilst P. bidens, like many other members of the Sesarmidae, is a detritivore. Some degree of seasonal variation was shown in the diet of
M. frontalis (with more algal material in winter) and P. bidens (with more sediments in summer), but diets were similar between sexes in both species. The dietary pattern of M. frontalis also varied between sites. The diets of the crabs, therefore, appear to be a result of the interplay between the seasonal,
physical climate and biological factors, especially food availability and the crabs’ ecology. Results suggest that the predatory
role of Metopograpsus, which has been poorly studied, is potentially important to estuarine food webs; whilst the trophic importance of sesarmid
crabs, such as Perisesarma, especially in mangrove outwelling, should be critically re-evaluated. 相似文献
78.
Benny Hung-Junn Chang Lan Li Pradip Saha Lawrence Chan 《Journal of lipid research》2010,51(8):2132-2142
We previously showed that adipose differentiation related protein (Adfp)-deficient mice display a 60% reduction in hepatic triglyceride (TG) content. In this study, we investigated the role of ADFP in lipid and glucose homeostasis in a genetic obesity model, Lepob/ob mice. We bred Adfp−/− mice with Lepob/ob mice to create Lepob/ob/Adfp−/− and Lepob/ob/Adfp+/+ mice and analyzed the hepatic lipids, lipid droplet (LD) morphology, LD protein composition and distribution, lipogenic gene expression, and VLDL secretion, as well as insulin sensitivity of the two groups of mice. Compared with Lepob/ob/Adfp+/+ mice, Lepob/ob/Adfp−/− mice displayed an increased VLDL secretion rate, a 25% reduction in hepatic TG associated with improvement in fatty liver grossly and microscopically with a change of the size of LDs in a proportion of the hepatocytes and a redistribution of major LD-associated proteins from the cytoplasmic compartment to the LD surface. There was no detectable change in lipogenic gene expression. Lepob/ob/Adfp−/− mice also had improved glucose tolerance and insulin sensitivity in both liver and muscle. The alteration of LD size in the liver of Lepob/ob/Adfp−/− mice despite the relocation of other LDPs to the LD indicates a nonredundant role for ADFP in determining the size and distribution of hepatic LDs. 相似文献
79.
The interaction between stromal cell-derived factor-1 (SDF-1) with CXCR4 chemokine receptors plays an important role in hematopoiesis following hematopoietic stem cell transplantation. We examined the efficacy of post transplant administration of a specific CXCR4 antagonist (AMD3100) in improving animal survival and in enhancing donor hematopoietic cell engraftment using a congeneic mouse transplantation model. AMD3100 was administered subcutaneously at 5 mg/kg body weight 3 times a week beginning at day +2 post-transplant. Post-transplant administration of AMD3100 significantly improves animal survival. AMD3100 reduces pro-inflammatory cytokine/chemokine production. Furthermore, post transplant administration of AMD3100 selectively enhances donor cell engraftment and promotes recovery of all donor cell lineages (myeloid cells, T and B lymphocytes, erythrocytes and platelets). This enhancement results from a combined effect of increased marrow niche availability and greater cell division induced by AMD3100. Our studies shed new lights into the biological roles of SDF-1/CXCR4 interaction in hematopoietic stem cell engraftment following transplantation and in transplant-related mortality. Our results indicate that AMD3100 provides a novel approach for enhancing hematological recovery following transplantation, and will likely benefit patients undergoing transplantation. 相似文献
80.
Intracellular glutathione depletion and reactive oxygen species generation are important in α-hederin-induced apoptosis of P388 cells 总被引:2,自引:0,他引:2
alpha-Hederin, a pentacyclic triterpene saponin isolated from the seeds of Nigella sativa, was recently reported to have potent in vivo antitumor activity against LL/2 (Lewis Lung carcinoma) in BDF1 mice. In this study we observed that alpha-hederin caused a dose- and time-dependent increase in apoptosis of murine leukemia P388 cells. In order to evaluate the possible mechanisms for apoptosis, the effects of alpha-hederin on intracellular thiol concentration, including reduced glutathione (GSH), and protein thiols, and the effects of pretreatment with N-acetlycysteine (NAC), a precursor of intracellular GSH synthesis, or buthionine sulfoxime (BSO), a specific inhibitor of intracellular GSH synthesis, on alpha-hederin-induced apoptosis were investigated. It was found that alpha-hederin rapidly depleted intracellular GSH and protein thiols prior to the occurrence of apoptosis. NAC significantly alleviated alpha-hederin-induced apoptosis, while BSO augmented alpha-hederin-induced apoptosis significantly. The depletion of cellular thiols observed after alpha-hederin treatment caused disruption of mitochondrial membrane potential (deltapsi(m)) and subsequently increased the production of reactive oxygen species (ROS) in P388 cells at an early time point. Bongkrekic acid (BA), a ligand of the mitochondrial adenine nucleotide translocator, and cyclosporin (CsA) attenuated the alpha-hederin-induced loss of deltapsi(m), and ROS production. Thus, oxidative stress after alpha-hederin treatment is an important event in alpha-hederin-induced apoptosis. As observed in this study, permeability transition of mitochondrial membrane occurs after depletion of GSH and precedes a state of reactive oxygen species (ROS) generation. Further, we observed that alpha-hederin caused the release of cytochrome c from the mitochondria to cytosol, leading to caspase-3 activation. Our findings thus demonstrate that changes in intracellular thiols and redox status leading to perturbance of mitochondrial functions are important components in the mechanism of alpha-hederin-induced cell death. 相似文献