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21.
Computer simulations of signal transduction mechanism in {alpha}1B-adrenergic and m3-muscarinic receptors 总被引:2,自引:0,他引:2
Fanelli Franceses; Menziani M.Cristina; de Benedetti Pier G. 《Protein engineering, design & selection : PEDS》1995,8(6):557-564
Molecular dynamices simulations of the hamster 1Badrenergicand the rat m3-muscarinic seven-helix bundle receptor modelshave been carried out. The free, agonist-bound and antagonist-boundforms have been considered. Moreover, three mutant forms ofthe m3-muscarinic recep-tor (N507A, N507D and N507S) have alsobeen simulated; among these, the N507S mutant shows a constitutiveactivity. A comparative structural/dynamics analysis has beenperformed to elucidate (i) the perturbations induced by thefunctionally different ligands upon binding to their targetreceptor, (ii) the features of the three single-point mutantswith respect to the receptor wild type and (iii) the propertiesshared by the agonist-boundforms of the 1B-adrenergic receptorand the m3-muscarinic receptor and by the constitutively activemutant N507S. The consistency obtained between the structuralrearrangement of the transmembrane seven-helix bundle modelsconsidered, and the experimental pharmacological efficaciesof the ligands and of the mutants, constitute an important validationof the 3-D models obtained and allow the inference of the mechanismof ligand- or mutation-induced receptor activation at the molecularlevel. 相似文献
22.
Immobilization of Photo‐Immunoconjugates on Nanoparticles Leads to Enhanced Light‐Activated Biological Effects 下载免费PDF全文
Huang‐Chiao Huang Michael Pigula Yanyan Fang Tayyaba Hasan 《Small (Weinheim an der Bergstrasse, Germany)》2018,14(31)
The past three decades have witnessed notable advances in establishing photosensitizer–antibody photo‐immunoconjugates for photo‐immunotherapy and imaging of tumors. Photo‐immunotherapy minimizes damage to surrounding healthy tissue when using a cancer‐selective photo‐immunoconjugate, but requires a threshold intracellular photosensitizer concentration to be effective. Delivery of immunoconjugates to the target cells is often hindered by I) the low photosensitizer‐to‐antibody ratio of photo‐immunoconjugates and II) the limited amount of target molecule presented on the cell surface. Here, a nanoengineering approach is introduced to overcome these obstacles and improve the effectiveness of photo‐immunotherapy and imaging. Click chemistry coupling of benzoporphyrin derivative (BPD)–Cetuximab photo‐immunoconjugates onto FKR560 dye‐containing poly(lactic‐co‐glycolic acid) nanoparticles markedly enhances intracellular photo‐immunoconjugate accumulation and potentiates light‐activated photo‐immunotoxicity in ovarian cancer and glioblastoma. It is further demonstrated that co‐delivery and light activation of BPD and FKR560 allow longitudinal fluorescence tracking of photoimmunoconjugate and nanoparticle in cells. Using xenograft mouse models of epithelial ovarian cancer, intravenous injection of photo‐immunoconjugated nanoparticles doubles intratumoral accumulation of photo‐immunoconjugates, resulting in an enhanced photoimmunotherapy‐mediated tumor volume reduction, compared to “standard” immunoconjugates. This generalizable “carrier effect” phenomenon is attributed to the successful incorporation of photo‐immunoconjugates onto a nanoplatform, which modulates immunoconjugate delivery and improves treatment outcomes. 相似文献
23.
嵌合蛋白sTNFRⅡ-IgG Fc纯化与生物学活性研究 总被引:1,自引:0,他引:1
目的 建立嵌合蛋白sTNFR IgGFc的纯化工艺 ,并对该蛋白的理化和生物活性进行研究。方法 嵌合蛋白sTNFRⅡ IgGFc经变性、复性后 ,用金属螯合层析进行纯化 ,纯化的蛋白进行配基结合实验和拮抗TNF活性检测。结果 该嵌合蛋白的纯度大于 95 % ,在体外能够二聚化 ,保留了sTNFRⅡ对hTNFα的结合特性 ,同单体sTNFRⅡ相比 ,对hTNFα的拮抗活性明显提高。结论 为进一步研究奠定了基础 相似文献
24.
蛙皮素受体亚型-3(BRS-3)属G蛋白偶联受体,至今未发现天然配体。BRS-3具有广泛的生物学作用,可调控神经内分泌功能、能量代谢及细胞生长增殖。在啮齿类动物及哺乳动物体内都有分布,大多数组织表达水平很低(包括正常肺组织),但在某些肺部疾病及胎肺中表达增加。就BRS-3受体特点、激活后信号转导机制及其与肺肿瘤、肺发育、慢性炎症性肺病的联系作一综述。 相似文献
25.
为研究更有效的γ-氨基丁酸受体激动剂,以海兔烟碱乙酰胆碱结合蛋白(PDB登记号2XYS,0.194 nm)作为模板,运用同源模建的方法构建人γ-氨基丁酸A型受体模型,并利用拉氏图和分子动力学分析验证其模型的合理性.将41个黄酮类化合物与模建的人γ-氨基丁酸A型受体进行对接研究,对接打分与实测活性值相吻合.黄酮类化合物与人γ-氨基丁酸A型受体对接结果显示,黄酮类化合物的母环分别与190位酪氨酸和140位酪氨酸形成共轭,降低体系能量并使体系稳定,验证了模型的合理性.此外,3'位对黄酮类化合物活性的影响至关重要,尤其引入硝基时活性明显提高.38号化合物的对接打分最高,也说明相应的增加取代基个数有利于提高该类化合物活性. 相似文献
26.
生长抑素-葡聚糖的99Tcm标记及体外结合分析 总被引:2,自引:2,他引:2
采用还原氨化方法,将天然生长抑素(SMS)与葡聚糖(Dx20)偶联,并以125I-奥曲肽(125I-Tyr3-Octreotide)为放射配基,进行受体竞争结合实验,测定了SMS-Dx50的IC50;以SnCl2为还原剂对SMS-Dx50进行99Tcm标记,并进行99Tcm- SMS-Dx50受体结合分析,考察其对生长抑素受体的亲合能力。结果表明:SMS-Dx50保持了对SMS 2型受体的高亲和力;其IC50与奥曲肽的IC50(0.79 nmol/L)相近,为5.95 nmol/L;99Tcm- SMS-Dx50标记率>85%, 经PD-10柱分离纯化,其放化纯度>98%;99Tcm- SMS-Dx50对生长抑素2型受体特异性结合为25%~40%,保持了较高的亲和力;SMS-Dx50适合于99Tcm标记,可用于生长抑素受体阳性肿瘤诊断的进一步研究 相似文献
27.
Repeated high dose (5.0 mg/kg) anabolic-androgenic steroid (AAS) exposure during adolescence stimulates offensive aggression in male Syrian hamsters. These studies examined whether AAS-induced aggression was regulated by the activity of serotonin (5HT) type-1B receptors and correlated with altered 5HT1B expression. AAS-treated hamsters were tested for offensive aggression following the administration of the 5HT1B agonist anpirtoline (0.125-0.5 mg/kg). Anpirtoline dose-dependently reduced select components of the AAS-induced aggressive response, with significant reductions observed at 0.25 mg/kg. Aggressive, AAS-treated hamsters showed significant decreases in the area covered by 5HT1B-containing neuronal puncta and increases in the number of 5HT1B-containing neuronal somata in select brain regions implicated in aggression control. Together, these data support a role for site-specific alterations in 5HT1B signaling and expression in adolescent AAS-induced aggression. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
28.
D'Anna Kimberly L.; Stevenson Sharon A.; Gammie Stephen C. 《Canadian Metallurgical Quarterly》2005,119(4):1061
Lactating female mice fiercely defend offspring while exhibiting decreased fear and anxiety. Recent work (J. S. Lonstein & S. C. Gammie, 2002) found that intracerebroventricular (icv) injections of corticotropin releasing factor (CRF), a putative anxiogenic peptide, inhibit maternal defense behavior. This study examines effects of CRF-related peptides, urocortin (Ucn) 1 and Ucn 3, on maternal aggression in mice. Intracerebroventricular injections of both Ucn 1 (0.2 μg) and Ucn 3 (0.5 μg) reduced aggression but not pup retrieval. c-Fos levels were elevated by intracerebroventricular injections of Ucn 1 (0.2 μg) and Ucn 3 (0.5 μg) in 2 and 6 brain regions, respectively; however, both triggered increases in bed nucleus of the stria terminalis dorsal (BNSTd) and lateral septum (LS). These findings suggest that CRF-related peptides similarly modulate maternal aggression and that BNSTd/LS may be critical sites for negative regulation of maternal aggression. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
29.
Recent studies have shown that both systemic and intra-nucleus accumbens (NAc) or intra-amygdala administration of dopamine D? receptor ligands modulate reward-related learning. A previous study (H. Aujla, H. Sokoloff, & R. J. Beninger. 2002) showed that systemic administration of the partial dopamine D? receptor agonist BP 897 selectively blocked the expression, but not the acquisition, of amphetamine-conditioned activity. This suggested the hypothesis that intra-NAc or intra-basolateral amygdala (BLA) BP 897 would attenuate the expression, but not the acquisition, of amphetamine-conditioned activity. Rats were habituated to activity-monitoring chambers for 5 days, for 1 hr each day. Conditioning occurred on the next 3 days, followed by a single 1-hr test session. Intra-NAc or intra-BLA infusions of BP 897 during test, but not during conditioning, attenuated intra-NAc amphetamine conditioned activity. Results indicate that the ability of BP 897 to attenuate the expression of conditioned activity is mediated in part by the NAc and BLA. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
30.
Beardsley Patrick M.; Aceto Mario D.; Cook Charles D.; Bowman Edward R.; Newman Jennifer L.; Harris Louis S. 《Canadian Metallurgical Quarterly》2004,12(3):163
Despite oxycodone's (4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one) history of clinical use and the attention it has received as a drug of abuse, few reports have documented its pharmacology's relevance to its abuse or its mechanism of action. The purposes of the present study were to further characterize the analgesic effects of oxycodone, its mechanism of action, and its effects in terms of its relevance to its abuse liability. The results indicate that oxycodone had potent antinociceptive effects in the mouse paraphenylquinone writhing, hot-plate, and tail-flick assays, in which it appeared to be acting as a μ-opioid receptor agonist. It generalized to the heroin discriminative stimulus and served as a positive reinforcer in rats and completely suppressed withdrawal signs in morphinedependent rhesus monkeys. These results suggest that the analgesic and abuse liability effects of oxycodone are likely mediated through μ-opioid receptors and provide the first laboratory report of its discriminative stimulus, reinforcing, and morphine cross-dependency effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献