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1.
Internalization of sst2, sst3, and sst5 receptors: effects of somatostatin agonists and antagonists. 总被引:4,自引:0,他引:4
Renzo Cescato Stefan Schulz Beatrice Waser Véronique Eltschinger Jean E Rivier Hans-Jürgen Wester Michael Culler Mihaela Ginj Qisheng Liu Agnes Schonbrunn Jean Claude Reubi 《Journal of nuclear medicine》2006,47(3):502-511
The uptake of radiolabeled somatostatin analogs by tumor cells through receptor-mediated internalization is a critical process for the in vivo targeting of tumoral somatostatin receptors. In the present study, the somatostatin receptor internalization induced by a variety of somatostatin analogs was measured with new immunocytochemical methods that allow characterization of trafficking of the somatostatin receptor subtype 2 (sst2), somatostatin receptor subtype 3 (sst3), and somatostatin receptor subtype 5 (sst5) in vitro at the protein level. METHODS: Human embryonic kidney 293 (HEK293) cells expressing the sst2, sst3, or the sst5 were used in a morphologic immunocytochemical internalization assay using specific sst2, sst3 and sst5 antibodies to qualitatively and quantitatively determine the capability of somatostatin agonists or antagonists to induce somatostatin receptor internalization. In addition, the internalization properties of a selection of these agonists have been compared and quantified in sst2-expressing CHO-K1 cells using an ELISA. RESULTS: Agonists with a high sst2-binding affinity were able to induce sst2 internalization in the HEK293 and CHO-K1 cell lines. New sst2 agonists, such as Y-DOTA-TATE, Y-DOTA-NOC, Lu-DOTA-BOC-ATE (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; TATE is [Tyr3, Thr8]-octreotide; NOC is [1-NaI3]-octreotide; and BOC-ATE is [BzThi3, Thr8]-octreotide), iodinated sugar-containing octreotide analogs, or BIM-23244 were considerably more potent in internalizing sst2 than was DTPA-octreotide (where DTPA is diethylenetriaminepentaacetic acid). Similarly, compounds with high sst3 affinity such as KE108 were able to induce sst3 internalization. In sst2- or sst3-expressing cell lines, agonist-induced receptor internalization was efficiently abolished by sst2- or sst3-selective antagonists, respectively. Antagonists alone had no effect on sst2 or sst3 internalization. We also showed that somatostatin-28 and somatostatin-14 can induce sst5 internalization. Unexpectedly, however, potent sst5 agonists such as KE108, BIM-23244, and L-817,818 were not able to induce sst5 internalization under the same conditions. CONCLUSION: Using sensitive and reproducible immunocytochemical methods, the ability of various somatostatin analogs to induce sst2, sst3, and sst5 internalization has been qualitatively and quantitatively determined. Whereas all agonists triggered sst2 and sst3 internalization, sst5 internalization was induced by natural somatostatin peptides but not by synthetic high-affinity sst5 agonists. Such assays will be of considerable help for the future characterization of ligands foreseen for nuclear medicine applications. 相似文献
2.
Johnson JG Cohen P Kotler L Kasen S Brook JS 《Journal of consulting and clinical psychology》2002,70(5):1119-1128
Longitudinal data were used to investigate whether anxiety, depressive, disruptive, personality, or substance use disorders are associated with risk for the development of eating disorders during adolescence or early adulthood. Psychiatric disorders were assessed among 726 youths from a random community sample during adolescence and early adulthood. Depressive disorders during early adolescence were associated with elevated risk for the onset of eating disorders, dietary restriction, purging behavior, and recurrent weight fluctuations after preexisting eating problems and other psychiatric disorders were controlled statistically. Disruptive and personality disorders were independently associated with elevated risk for specific eating or weight problems. The present findings suggest that depressive disorders during early adolescence may contribute to the development of eating disorders during middle adolescence or early adulthood. 相似文献
3.
Correlation of penicillin Binding protein 2a detection with oxacillin resistance in Staphylococcus aureus and discovery of a novel penicillin binding protein 2a mutation 总被引:2,自引:0,他引:2
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Bressler AM Williams T Culler EE Zhu W Lonsway D Patel JB Nolte FS 《Journal of clinical microbiology》2005,43(9):4541-4544
We compared a rapid slide latex agglutination test (LAT; Oxoid, Basingstoke, United Kingdom) that detects penicillin binding protein 2a (PBP2a) with MicroScan conventional panels (Dade Behring, West Sacramento, CA) for detection of oxacillin resistance in Staphylococcus aureus. The PBP2a LAT demonstrated 99% agreement with MicroScan oxacillin MIC results for 388 isolates of S. aureus. All 249 oxacillin-resistant isolates gave strong positive reactions in the LAT (100% sensitivity). Three of the 139 oxacillin-susceptible isolates were also strongly positive and one was weakly positive in the LAT (97.1% specificity). The three oxacillin-susceptible isolates with strongly positive reactions were further characterized. The mecA gene was detected in all three by PCR; one isolate was determined to be resistant to oxacillin by reference broth microdilution testing (MIC, 8 microg/ml), one isolate was inducibly resistant to oxacillin (MIC of 16 microg/ml after overnight induction), and one isolate remained susceptible regardless of the method used for testing. Sequence analysis of a 2.1-kb gene fragment of the mecA gene from the susceptible isolate revealed a one-base substitution at nucleotide position 1449 which results in a Met-to-Ile change for amino acid residue 483. This amino acid substitution has not been previously reported and may be associated with a change in the function of PBP2a resulting in oxacillin susceptibility. An additional 487 isolates were tested in parallel with the both the LAT and MicroScan panels using criteria in which only strong (3 to 4+) or repeatedly weak (1 to 2+) LAT reactions were considered positive, and the results showed 99.4% agreement. The PBP2a LAT provided rapid and reliable detection of oxacillin resistance and proved a useful adjunct to the phenotypic method. Both methods provided reliable detection of oxacillin-resistant S. aureus and facilitated the discovery of a novel, functionally impaired form of PBP2a. 相似文献
4.
Johnson JG Cohen P Skodol AE Oldham JM Kasen S Brook JS 《Archives of general psychiatry》1999,56(9):805-811
BACKGROUND: A community-based longitudinal study was conducted to investigate whether personality disorders (PDs) during adolescence increase the risk for Axis I psychiatric disorders and suicidality during early adulthood. METHOD: Psychosocial and psychiatric interviews were administered to a representative community sample of 717 youths and their mothers from 2 counties in the state of New York in 1975, 1983, 1985-1986, and 1991-1993. Anxiety, disruptive, eating, mood, personality, and substance use disorders and suicidal ideation and behavior were assessed in 1983 and 1985-1986, when the participants were adolescents, and in 1991-1993, when they were young adults. RESULTS: Adolescents with PDs were more than twice as likely as those without PDs to have anxiety, disruptive, mood, and substance use disorders during early adulthood. These associations remained statistically significant after co-occurring Axis I disorders during adolescence were controlled statistically. Cluster A, B, and C PDs and DSM-IV Appendix B PDs during adolescence were all associated with elevated risk for Axis I disorders during early adulthood after co-occurring Axis I and Axis II disorders during adolescence were controlled statistically. Cluster C PDs during adolescence were associated with elevated risk for suicidal ideation or behavior during early adulthood after co-occurring psychiatric disorders and suicidality during adolescence were controlled statistically. CONCLUSIONS: Adolescents in the community with personality disorders are at elevated risk for major mental disorders and suicidal ideation or behavior during early adulthood. This increase in risk is not accounted for by co-occurring Axis I disorders or suicidality during adolescence. 相似文献
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6.
Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease 总被引:5,自引:0,他引:5
Sakugawa H Nakayoshi T Kobashigawa K Yamashiro T Maeshiro T Miyagi S Shiroma J Toyama A Nakayoshi T Kinjo F Saito A 《World journal of gastroenterology : WJG》2005,11(2):255-259
AIM: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), and progresses to the end stage of liver disease. Biochemical markers of liver fibrosis are strongly associated with the degree of histological liver fibrosis in patients with chronic liver disease. However, data are few on the usefulness of markers in NAFLD patients. The aim of this study was to identify better noninvasive predictors of hepatic fibrosis, with special focus on markers of liver fibrosis, type VI collagen 7S domain and hyaluronic acid. METHODS: One hundred and twelve patients with histologically proven NAFLD were studied. RESULTS: The histological stage of NAFLD correlated with several clinical and biochemical variables, the extent of hepatic fibrosis and the markers of liver fibrosis were relatively strong associated. The best cutoff values to detect NASH were assessed by using receiver operating characteristic analysis: type VI collagen 75 domain ≥5.0 ng/mL, hyaluronic acid ≥43 ng/mL. Both markers had a high positive predictive value: type VI collagen 7S domain, 86% and hyaluronic acid, 92%. Diagnostic accuracies of these markers were evaluated to detect severe fibrosis. Both markers showed high negative predictive values: type VI collagen 7S domain (≥5.0 ng/mL), 84% and hyaluronic acid (≥50 ng/mL), 78%, and were significantly and independently associated with the presence of NASH or severe fibrosis by logistic regression analysis. CONCLUSION: Both markers of liver fibrosis are useful in discriminating NASH from fatty liver alone or patients with severe fibrosis from patients with non-severe fibrosis. 相似文献
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8.
B Bloch R C Gaillard M D Culler A Negro-Vilar 《The Journal of clinical endocrinology and metabolism》1992,74(1):135-138
To determine the presence of LHRH prohormone products in the human hypothalamus, antisera raised against LHRH and GnRH-associated peptide (GAP) were used to search for the presence of the corresponding antigens in the human adult and fetal hypothalamus by an immunohistochemical approach. The comparison of immunostaining on adjacent sections shows that all of the cells labeled with LHRH antiserum are also labeled with GAP antiserum and vice versa. Labeled cells are detectable during the 9th week of fetal life, this being the earliest time evaluated. At this time, the LHRH/GAP-positive cells frequently have a neuroblastic appearance. The first detectable fibers appear during the 11th week, and these were observed in the lamina terminalis cinerea and median eminence. In the adult brain, fibers and endings labeled with LHRH or GAP antiserum in the median eminence demonstrate the same topography and morphological characteristics, which are distinct from fibers labeled with other neuropeptide antisera. These results show that the LHRH precursor molecule is produced throughout life in the human hypothalamus, including the earliest stages of development of the peptidergic neurons. Moreover, the detection of LHRH- and GAP-positive fibers in the median eminence by the 11th week of fetal life suggests the possibility of an early role of LHRH and, possibly, other LHRH prohormone-derived peptides in the development of anterior pituitary function during the fetal period. 相似文献
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10.
Paul Kievit Heather Halem Daniel L. Marks Jesse Z. Dong Maria M. Glavas Puspha Sinnayah Lindsay Pranger Michael A. Cowley Kevin L. Grove Michael D. Culler 《Diabetes》2013,62(2):490-497
The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for pharmacological therapy for the treatment of obesity. However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure. We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model. Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance. Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment. In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake. These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects.Maintenance of body weight and energy homeostasis requires balance between energy intake and expenditure and is achieved via the interaction between central and peripheral signals. The central melanocortin system is one of the key neural circuits involved in mediating the integration of information from both sites. Proopiomelanocortin is a prohormone that is processed into multiple bioactive peptides, including α-melanocyte–stimulating hormone (MSH), β-MSH, γ-MSH, and the endogenous opioid β-endorphin (1). α-MSH, or its analogs, are potent inhibitors of food intake and increase energy expenditure to promote weight loss in rodent and rhesus macaque models (2–5). Central melanocortins are involved in many physiological functions, including stress responses; however, their actions on the regulation of food intake and energy expenditure have been a focus.Melanocortin-4 receptor (MC4R) is the main melanocortin receptor involved in the regulation of food intake and energy expenditure, primarily through modulation of sympathetic outflow (6–8). MC4R has a broad distribution, including expression in several peripheral tissues, such as muscle, kidney, and lung (9). The importance of MC4R in the maintenance of body weight homeostasis is highlighted by genetic studies in humans and mice. MC4R−/− mice are hyperphagic, have increased adipose and lean mass, and develop insulin resistance (10). In humans, mutations in the proopiomelanocortin gene (11) and the MC4R gene have a similar phenotype (12–14).Although the effects of MC4R agonists on energy/glucose homeostasis (15,16) make it an attractive target for a therapeutic agent, the potential side effects of increasing heart rate and blood pressure have been a major limitation (17). Indeed, recent studies reported by Greenfield et al. (18) showed that acute peripheral administration with a centrally acting MC4R selective agonist increased blood pressure and heart rate in moderately obese humans. There is an obvious concern in treating obese individuals with a high risk of hypertension and cardiovascular disease with a weight loss therapy that is exacerbating these same risks. In the current study, we use a diet-induced obesity (DIO) nonhuman primate model (NHP) to determine if long-term treatment with the MC4R-specific agonist BIM-22493 can reduce food intake and adiposity without adversely affecting cardiovascular function. 相似文献