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排序方式: 共有597条查询结果,搜索用时 15 毫秒
81.
Hitzman CJ Elmquist WF Wattenberg LW Wiedmann TS 《Journal of pharmaceutical sciences》2006,95(5):1114-1126
The release rate of 5-fluorouracil (5-FU) from liposomes, microspheres, and lipid-coated nanoparticles (LNPs) was determined by microdialysis to investigate their use as a respirable delivery system for adjuvant (postsurgery) therapy of lung cancer. 5-FU was incorporated into liposomes using thin film hydration and into microspheres and LNPs by spray drying. Primary particle size distributions were measured by dynamic light scattering. Liposomes released 5-FU in 4-10 h (k(1) = 0.44-2.31/h, first-order release model). Extruded vesicles with diameters less than one micron released 5-FU more quickly than nonextruded vesicles. With poly-(lactide) (PLA) and Poly-(lactide-co-glycolide) (PLGA) microspheres, slower release rates were observed (k(1) = 0.067-0.202/h). Increasing the lactide:glycolide ratio (50:50-100:0) resulted in a progressive decrease in the release rate of 5-FU. poly-(lactide-co-caprolactone) (PLCL) microspheres released 5-FU more rapidly compared to PLGA systems (k(1) = 0.254-0.259/h). LNPs formulated with polymeric core excipients had lower release rates compared to monomeric excipients (k(1) = 0.043-0.105/h vs. k(1) = 0.192-0.345/h). Changing the lipid chain length of the shell lipid components had a relatively minor effect (k(1) = 0.043-0.129/h). Overall, these systems yielded a wide range of delivery durations that may be suitable for use as an inhalation delivery system for adjuvant therapy of lung cancer. 相似文献
82.
Two cases of intracerebral pneumatocele following trauma are presented. One to two months after initial treatment both patients had deteriorating neurologic status. The diagnosis was made by radiography. When a pneumatocele is suspected clinically, computed tomography can play a vital role in determining the precise location of the gas collection, its relationship to the fracture site, and the amount of mass effect on the brain. 相似文献
83.
84.
2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a highly mutagenic heterocyclic amine found in cooked meats. The major DNA adduct of IQ is at the C8-position of dGuo. We have previously reported the incorporation of the C8-IQ adduct into oligonucleotides, namely, the G1-position of codon 12 of the N-ras oncogene sequence (G1G2T) and the G3-position of the NarI recognition sequence (G1G2CG3CC) (Elmquist et al. (2004) J. Am. Chem. Soc. 126, 11189-11201). Ultraviolet spectroscopy and circular dichroism studies indicated that the conformation of the adduct in the two oligonucleotides was different, and they were assigned as groove-bound and base-displaced intercalated, respectively. The conformation of the latter was subsequently confirmed through NMR and restrained molecular dynamics studies (Wang et al. (2006) J. Am. Chem. Soc. 128, 10085-10095). We report here the incorporation of the C8-IQ adduct into the G1- and G2-positions of the NarI sequence. A complete analysis of the UV, CD, and NMR chemical shift data for the IQ protons are consistent with the IQ adduct adopting a minor groove-bound conformation at the G1- and G2-positions of the NarI sequence. To further correlate the spectroscopic data with the adduct conformation, the C8-aminofluorene (AF) adduct of dGuo was also incorporated into the NarI sequence; previous NMR studies demonstrated that the AF-modified oligonucleotides were in a sequence-dependent conformational exchange between major groove-bound and base-displaced intercalated conformations. The spectroscopic data for the IQ- and AF-modified oligonucleotides are compared. The sequence-dependent conformational preferences are likely to play a key role in the repair and mutagenicity of C8-arylamine adducts. 相似文献
85.
RJ Mann NE Nasr JK Sinfield E Paci D Donnelly 《British journal of pharmacology》2010,160(8):1973-1984
BACKGROUND AND PURPOSE
Exendin-4 (exenatide, Ex4) is a high-affinity peptide agonist at the glucagon-like peptide-1 receptor (GLP-1R), which has been approved as a treatment for type 2 diabetes. Part of the drug/hormone binding site was described in the crystal structures of both GLP-1 and Ex4 bound to the isolated N-terminal domain (NTD) of GLP-1R. However, these structures do not account for the large difference in affinity between GLP-1 and Ex4 at this isolated domain, or for the published role of the C-terminal extension of Ex4. Our aim was to clarify the pharmacology of GLP-1R in the context of these new structural data.EXPERIMENTAL APPROACH
The affinities of GLP-1, Ex4 and various analogues were measured at human and rat GLP-1R (hGLP-1R and rGLP-1R, respectively) and various receptor variants. Molecular dynamics coupled with in silico mutagenesis were used to model and interpret the data.KEY RESULTS
The membrane-tethered NTD of hGLP-1R displayed similar affinity for GLP-1 and Ex4 in sharp contrast to previous studies using the soluble isolated domain. The selectivity at rGLP-1R for Ex4(9–39) over Ex4(9–30) was due to Ser-32 in the ligand. While this selectivity was not observed at hGLP-1R, it was regained when Glu-68 of hGLP-1R was mutated to Asp.CONCLUSIONS AND IMPLICATIONS
GLP-1 and Ex4 bind to the NTD of hGLP-1R with similar affinity. A hydrogen bond between Ser32 of Ex4 and Asp-68 of rGLP-1R, which is not formed with Glu-68 of hGLP-1R, is responsible for the improved affinity of Ex4 at the rat receptor. 相似文献86.
Obesity has reached epidemic proportions in the United States, and obesity-related illnesses have become a leading preventable cause of death. Childhood obesity is also growing in frequency, and the impact of a lifetime spent in the overweight state is only beginning to emerge in the literature. In this issue of the JCI, Bumaschny et al. used a genetic mouse model to investigate the self-perpetuating nature of obesity and shed some light on why it can become increasingly difficult to lose weight over time.
The global pandemic of obesity affects the health of more than 500 million people. Obesity poses a major risk for other comorbid diseases and has become a leading preventable cause of death in the United States. For morbidly obese patients, a modest (5%–10%) reduction in body weight can bring significant health benefits such as improvements in blood pressure and glycemic control, which may ultimately contribute to decreased mortality (1). Nevertheless, despite lifestyle interventions and numerous efforts in developing effective anti-obesity therapies, sustained weight management remains a challenge for most obese patients.
Limited efficacy and weight rebound are two common problems, yet the mechanisms underlying treatment refractoriness remain to be identified. It is generally believed that chronic obesity may trigger maladaptive responses that help retain a state of sustained positive energy balance. However, given the complex genetic, environmental, and social factors involved in the etiology of obesity, it has been very difficult to evaluate the impact of chronic obesity itself on the effectiveness of anti-obesity therapies.In this issue of the JCI, Bumaschny and colleagues generated a novel mouse obesity model in which severe and early-onset obesity is induced by the loss of a single gene, proopiomelanocortin (Pomc), in a small population of neurons in the brain (2). Notably, the model allowed the authors to “treat” the obesity by restoring Pomc expression at different ages and directly test the efficacy of gene therapy after different durations of the obese state. 相似文献
87.
Rajneet K. Oberoi Karen E. Parrish Terence T. Sio Rajendar K. Mittapalli William F. Elmquist Jann N. Sarkaria 《Neuro-oncology》2016,18(1):27-36
Glioblastoma (GBM) is a lethal and aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. Molecularly targeted agents hold great promise in treating these genetically heterogeneous tumors, yet have produced disappointing results. One reason for the clinical failure of these novel therapies can be the inability of the drugs to achieve effective concentrations in the invasive regions beyond the bulk tumor. In this review, we describe the influence of the blood–brain barrier on the distribution of anticancer drugs to both the tumor core and infiltrative regions of GBM. We further describe potential strategies to overcome these drug delivery limitations. Understanding the key factors that limit drug delivery into brain tumors will guide future development of approaches for enhanced delivery of effective drugs to GBM. 相似文献
88.
89.
Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area
Carol F. Elias Clifford B. Saper Eleftheria Maratos-Flier Nicholas A. Tritos Charlotte Lee Joseph Kelly Jeffrey B. Tatro Gloria E. Hoffman Michael M. Ollmann Gregory S. Barsh Takeshi Sakurai Masashi Yanagisawa Joel K. Elmquist 《The Journal of comparative neurology》1998,402(4):442-459
Recent studies have identified several neuropeptide systems in the hypothalamus that are critical in the regulation of body weight. The lateral hypothalamic area (LHA) has long been considered essential in regulating food intake and body weight. Two neuropeptides, melanin-concentrating hormone (MCH) and the orexins (ORX), are localized in the LHA and provide diffuse innervation of the neuraxis, including monosynaptic projections to the cerebral cortex and autonomic preganglionic neurons. Therefore, MCH and ORX neurons may regulate both cognitive and autonomic aspects of food intake and body weight regulation. The arcuate nucleus also is critical in the regulation of body weight, because it contains neurons that express leptin receptors, neuropeptide Y (NPY), α-melanin-stimulating hormone (α-MSH), and agouti-related peptide (AgRP). In this study, we examined the relationships of these peptidergic systems by using dual-label immunohistochemistry or in situ hybridization in rat, mouse, and human brains. In the normal rat, mouse, and human brain, ORX and MCH neurons make up segregated populations. In addition, we found that AgRP- and NPY-immunoreactive neurons are present in the medial division of the human arcuate nucleus, whereas α-MSH-immunoreactive neurons are found in the lateral arcuate nucleus. In humans, AgRP projections were widespread in the hypothalamus, but they were especially dense in the paraventricular nucleus and the perifornical area. Moreover, in both rat and human, MCH and ORX neurons receive innervation from NPY-, AgRP-, and α-MSH-immunoreactive fibers. Projections from populations of leptin-responsive neurons in the mediobasal hypothalamus to MCH and ORX cells in the LHA may link peripheral metabolic cues with the cortical mantle and may play a critical role in the regulation of feeding behavior and body weight. J. Comp. Neurol. 402:442–459, 1998. © 1998 Wiley-Liss, Inc. 相似文献
90.
Joel K. Elmquist Christopher D. Breder Jonathan E. Sherin Thomas E. Scammell William F. Hickey David Dewitt Clifford B. Saper 《The Journal of comparative neurology》1997,381(2):119-129
Production of prostaglandins is a critical step in transducing immune stimuli into central nervous system (CNS) responses, but the cellular source of prostaglandins responsible for CNS signalling is unknown. Cyclooxygenase catalyzes the rate-limiting step in the synthesis of prostaglandins and exists in two isoforms. Regulation of the inducible isoform, cyclooxygenase 2, is thought to play a key role in the brain's response to acute inflammatory stimuli. In this paper, we report that intravenous lipopolysaccharide (LPS or endotoxin) induces cyclooxygenase 2-like immunoreactivity in cells closely associated with brain blood vessels and in cells in the meninges. Neuronal staining was not noticeably altered or induced in any brain region by endotoxin challenge. Furthermore, many of the cells also were stained with a perivascular microglial/macrophage-specific antibody, indicating that intravenous LPS induces cyclooxygenase in perivascular microglia along blood vessels and in meningeal macrophages at the edge of the brain. These findings suggest that perivascular microglia and meningeal macrophages throughout the brain may be the cellular source of prostaglandins following systemic immune challenge. We hypothesize that distinct components of the CNS response to immune system activation may be mediated by prostaglandins produced at specific intracranial sites such as the preoptic area (altered sleep and thermoregulation), medulla (adrenal corticosteroid response), and cerebral cortex (headache and encephalopathy). J. Comp. Neurol. 381:119-129, 1997. © 1997 Wiley-Liss, Inc. 相似文献