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1.
The galanin peptide family and its three receptors have with compelling evidence been implicated in several high-order physiological disorders. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. In the current study we present data on receptor binding and functional response for a novel galanin receptor type 2 (GalR2) selective chimeric peptide, M1145 [(RG)2-N-galanin(2-13)-VL-(P)3-(AL)2-A-amide]. The M1145 peptide shows more than 90-fold higher affinity for GalR2 over GalR1 and a 76-fold higher affinity over GalR3. Furthermore, the peptide yields an agonistic effect in vitro, seen as an increase in inositol phosphate (IP) accumulation, both in the absence or the presence of galanin. The peptide design with a N-terminal extension of galanin(2-13), prevails new insights in the assembly of novel subtype specific ligands for the galanin receptor family and opens new possibilities to apply the galanin system as a putative drug target. 相似文献
2.
Katrin Trummal Külli T?nism?gi Ene Siigur Anu Aasp?llu Annika Lopp Tarvo Sillat Riste Saat Lagle Kasak Indrek Tammiste Priit Kogerman Nisse Kalkkinen Jüri Siigur 《Toxicon》2005,46(1):46-61
A novel endothelial cell apoptosis inducing metalloprotease (VLAIP) was found in the snake venom of Vipera lebetina. This metalloprotease is a heterodimeric glycoprotein with molecular mass of about 106 kDa. The protease hydrolyzes azocasein, fibrinogen and oxidized insulin B-chain. The enzyme readily hydrolyzes the Aalpha-chain and more slowly Bbeta-chain of fibrinogen. VLAIP does not cleave fibrin. The complete amino acid sequences of the two different monomers of VLAIP are deduced from the nucleotide sequences of cDNAs encoding these proteins. The full-length cDNA sequences of the VLAIP-A and VLAIP-B encode open reading frames of 616 and 614 amino acids that include signal peptide, propeptide and mature metalloproteinase with disintegrin-like and cysteine-rich domains. VLAIP belongs to the metalloprotease/disintegrin family of reprolysins and has high identity with the proteins that induce apoptosis of endothelial cells. Treatment of HUVEC cells with VLAIP induces changes in the attachment of cells to the substrate and causes cell death. We demonstrated that VLAIP inhibits endothelial cell adhesion to extracellular matrix proteins: fibrinogen, fibronectin, vitronectin, collagen I, and collagen IV. The induction of apoptosis by VLAIP was shown by means of a typical DNA fragmentation pattern of apoptotic cells as well as by monitoring phosphatidylserine externalization using annexin V-FITC staining and flow cytometric analysis. 相似文献
3.
Prospecting the full biodiversity of nature to find leads for new drugs is not necessary. Because finding leads is aimed at identifying biological activity, structure is of secondary importance. Furthermore, although natural chemical diversity might be unrivalled, functional diversity is bound to be considerably less. It is likely that many millions of chemically distinct molecules exist in nature but it is inconceivable that the number of different biological functions is near this number. This is corroborated by knowledge obtained from the genome sequences of an increasing number of species. It is unlikely that ligands for specific molecular targets are restricted to one species and even individual compounds are often found in more than one species. Important molecular mechanisms are likely to be ubiquitous and there are no a priori reasons to assume that some are restricted to, for example, tropical rainforests. Thus, there are no obvious advantages of "biodiversity prospecting", which will, possibly, endanger fragile ecosystems in the search for rare species. 相似文献
4.
Goosen JH Verheyen CC Tulp NJ 《The Journal of bone and joint surgery. British volume》2005,87(11):1475-1479
We investigated the rate of polyethylene wear of a cementless acetabular component at different periods of follow-up in order to test the hypothesis than an irrecoverable deformation process (creep) was followed by an initially low, but gradually increasing wear rate. We studied prospectively 93 uncemented total hip arthroplasties in 83 patients (mean age 50 years (22 to 63)) with a mean follow-up of 8.2 years (3 to 12). We measured the penetration of the femoral head from radiographs taken immediately after surgery at three, six and nine years, or at the latest follow-up. The median wear rate was 0.17 mm per year in the first three years, a finding which we considered to be caused by creep. Thereafter, the rate of wear declined to 0.07 mm per year (four- to six-year period) and then increased to 0.17 mm per year (seven to nine years) and 0.27 mm per year (more than nine years), which we considered to be a reflection of genuine polyethylene wear. After the nine-year follow-up the wear rates were higher in patients with marked osteolysis. We found no relationship between the inclination angle of the acetabular component or femoral head orientation and the rate of wear. No acetabular component required revision. 相似文献
5.
In this study, the affinity profile of idaverine for the M1- (neuronal tissue), M2- (heart) and M3- (glandular tissue/nonvascular smooth muscle) muscarinic receptors was examined by means of radioligand binding and in vitro organ bath experiments in order to use the compound for the investigation of the muscarinic receptor subtype involved in motion sickness. In the profile study a comparison was made with the muscarinic antagonists atropine, pirenzepine (M1-selective) AF-DX 116 (M2-selective) and 4-DAMP (high affinity for M1- and M3-binding sites). The affinity of idaverine appeared to be equally high for the M1- and M2-binding sites. However, the affinity for the M1-binding sites should be interpreted cautiously since the Hill slope deviated from unity. Idaverine showed a 20-fold selectivity for the M2-binding sites over the M3-binding sites, whereas it showed a small selectivity (less than 5-fold) for the M2-receptors compared to the ileal and tracheal smooth muscle receptors. Thus idaverine appears to be M2 over M3 selective. However, in contrast to AF-DX 116, it is not clear whether idaverine is also M2 over M1 selective. In experiments with cats, idaverine failed to prevent motion sickness at doses from 0.03 to 3 mg/kg. These results are interpreted to implicate M3-receptors in the motion sickness suppressant effect of antimuscarinic drugs. 相似文献
6.
Deborah O Yarnell David S Knight Kathryn Hamilton Orien Tulp Patrick Tso 《Brain research》1998,785(1):2798
Leptin, a product of the obese (ob) gene, is secreted by adipocytes and appears to act as a hormone to regulate food intake, metabolism and body weight. Subcutaneous administration of leptin causes reductions in food intake and body and fat-depot weights in both lean and genetically obese (ob/ob) mice, and leptin infusion into the lateral cerebral ventricles decreases feeding with short latency, suggesting a central site of action. A gene defect in the Zucker obese rat causes an amino acid substitution in the leptin receptor and reduced leptin binding at the cell surface. An antiserum to a portion of the mouse leptin receptor (AA 877–894) located within the intracellular domain was used to label Zucker lean (Fa/?) and obese (fa/fa) rat brain sections. At optimal dilution (1:8000), only cells in the basal forebrain, preoptic area, hypothalamus and brainstem were moderately or intensely labeled. The most intensely-labeled nuclei, the anterior commissural, magnocellular paraventricular, supraoptic, circularis in the anterior hypothalamus and fornical in the lateral hypothalamus contain large neurons that synthesize and secrete vasopressin or oxytocin and their respective neurophysins. Diminished leptin transport into the central nervous system or defective signal transduction in Zucker obese rats may sufficiently compromise leptin regulation of the HPA axis, NPY-immunoreactive neurons or other hypothalamic elements to cause obesity. 相似文献
7.
Neurochemical profile of eltoprazine 总被引:1,自引:0,他引:1
In this paper we present the neurochemical profile of eltoprazine, a drug that specifically inhibits offensive aggression. Eltoprazine interacts selectively with serotonin (5-HT) receptor subtypes (Ki-values for 5-HT1A, 5-HT1B and 5-HT1C receptors are 40, 52 and 81 nM respectively). Affinity for other neurotransmitter receptors is much lower (Ki-values greater than 400 nM) than for 5-HT1 receptors. The selective interaction with 5-HT1 receptor subtypes is confirmed by in vitro autoradiographic studies using radiolabelled eltoprazine. The overall distribution of [3H]eltoprazine bears a strong resemblance to the localization of 5-HT1 binding sites labelled by [3H]5-HT, although some differences are observed. Eltoprazine (1 microM) inhibits the forskolin stimulated c-AMP production in hippocampus slices of the rat, indicating an agonistic action on the 5-HT1A receptor. The K+ stimulated release of 5-HT from rat cortex slices is inhibited by eltoprazine (pD2 = 7.8). The maximal response, however, was clearly less than that of the full agonist 5-HT, indicating partial agonistic activity on the 5-HT1B receptor (alpha = 0.5). Eltoprazine has a weak antagonistic action (IC50 = 7 microM) on the 5-HT1C receptor as revealed by inhibition of the 5-HT-induced accumulation of inositol phosphates in the choroid plexus of the pig. In vivo, eltoprazine reduces 5-HIAA levels in the striatum, without affecting the 5-HT levels. Eltoprazine also reduces the 5-HT synthesis rate as shown by 5-HTP accumulation after decarboxylase inhibition. These data indicate that eltoprazine acts as a 5-HT agonist in vivo in a dose range that affects aggressive behaviour (0.3-3 mg/kg p.o.). Taken together from a variety of neurochemical studies there is strong evidence both in vitro and in vivo that the pharmacological actions of eltoprazine can be attributed to an interaction with the 5-HT system, most probably via a (partial) agonistic action on 5-HT1A and 5-HT1B receptors. 相似文献
8.
9.
David C. Robbins Edward S. Horton Orien Tulp Ethan A.H. Sims 《Metabolism: clinical and experimental》1982,31(5):445-452
The increased frequency of metabolic perturbations in overweight individuals whose fat is predominantly central, as compared with those whose fat is more generalized in distribution suggests that characteristics of fat other than an excess promote the morbidity of the obese. In this report we describe the location and quantity of body fat together with the status of carbohydrate and lipid metabolism in 8 females affected with familial partial lipodystrophy, a rare condition in which peripheral subcutaneous fat is mostly absent while there is retention or an increase in central adiposity. The 8 subjects had normal or reduced amounts of body fat as determined by body density measurements. Computerized axial tomograms in two subjects showed that there was normal to increased amounts of intra-abdominal fat and irregular pockets of subcutaneous fat overlying the abdomen. Plasma triglycerides varied but were elevated in all subjects ranging from 171 to 3720 mg/dl (normal = 103 ± 36). Mild sustained elevations in mean systolic blood pressure (> 135 mm Hg) occurred in 4. Two of the 8 had fasting hyperglycemia (>140 mg/dL) and a third was intolerant to oral, but not to intravenous glucose. Fasting serum insulin concentrations were uniformly elevated (22 to 51 uU/ml) and, in most instances, responded to both glucose and arginine with exaggerated increments, but there was no delay in insulin release. Mild insulin resistance was documented by the failure to respond to standard insulin injections, and there were decreased insulin receptors on erythrocytes. Basal plasma glucagon concentrations were generally elevated, did not suppress during oral glucose administrations and rose 2 to 5 times basal levels during intravenous infusion of arginine.These studies emphasize that the various complications of the obese, especially those with centralized obesity, are seen in a non-obese condition characterized by an increase in the ratio of central to peripheral fat. 相似文献
10.