全文获取类型
收费全文 | 60篇 |
免费 | 5篇 |
专业分类
耳鼻咽喉 | 1篇 |
妇产科学 | 1篇 |
基础医学 | 5篇 |
口腔科学 | 1篇 |
临床医学 | 8篇 |
内科学 | 7篇 |
神经病学 | 3篇 |
外科学 | 9篇 |
综合类 | 1篇 |
预防医学 | 20篇 |
药学 | 9篇 |
出版年
2020年 | 1篇 |
2018年 | 1篇 |
2015年 | 1篇 |
2014年 | 1篇 |
2013年 | 1篇 |
2012年 | 2篇 |
2011年 | 8篇 |
2010年 | 3篇 |
2009年 | 2篇 |
2008年 | 6篇 |
2007年 | 3篇 |
2006年 | 2篇 |
2005年 | 3篇 |
2004年 | 4篇 |
2003年 | 1篇 |
2002年 | 2篇 |
2001年 | 7篇 |
2000年 | 2篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1984年 | 2篇 |
1982年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1968年 | 1篇 |
1954年 | 1篇 |
排序方式: 共有65条查询结果,搜索用时 15 毫秒
1.
2.
Nancy A. Thornberry Douglas K. Miller Donald W. Nicholson 《Perspectives in Drug Discovery and Design》1995,2(3):389-399
Summary Interleukin-1-converting enzyme (ICE, EC 3.4.22.36) is the cysteine protease responsible for the production of interleukin-1 in monocytes. Since its discovery in 1989, this enzyme has been the subject of enthusiastic investigation because of the suspected role of this cytokine in the pathogenesis of inflammatory diseases such as rheumatoid arthritis. These studies have culminated in the purification and cloning of the enzyme, development of potent inhibitors, determination of its structure by X-ray crystallography and the development of knockout mice, which have confirmed an important role for this protease in inflammation. Late in 1993, the protease became the subject of further interest because of its homology to CED-3, the product of a gene required for programmed cell death in the nematodeC. elegans. It is now clear that ICE is the first identified member of a new cysteine protease family that includes CED-3 and at least four other human homologues. Although the extent to which ICE itself plays a role in mammalian apoptosis remains controversial, it is clear that at least one of these homologues, CPP32, is an important player. The recognition that members of this family play key biological roles in both inflammation and apoptosis, two extremely attractive targets for therapeutic intervention, has led to intense interest in these proteases. 相似文献
3.
Mufaddal S. Soni Mary E. Rabaglia Sushant Bhatnagar Jin Shang Olga Ilkayeva Randall Mynatt Yun-Ping Zhou Eric E. Schadt Nancy A. Thornberry Deborah M. Muoio Mark P. Keller Alan D. Attie 《Diabetes》2014,63(11):3805-3814
We previously demonstrated that micro-RNAs (miRNAs) 132 and 212 are differentially upregulated in response to obesity in two mouse strains that differ in their susceptibility to obesity-induced diabetes. Here we show the overexpression of miRNAs 132 and 212 enhances insulin secretion (IS) in response to glucose and other secretagogues including nonfuel stimuli. We determined that carnitine acyl-carnitine translocase (CACT; Slc25a20) is a direct target of these miRNAs. CACT is responsible for transporting long-chain acyl-carnitines into the mitochondria for β-oxidation. Small interfering RNA–mediated knockdown of CACT in β-cells led to the accumulation of fatty acyl-carnitines and enhanced IS. The addition of long-chain fatty acyl-carnitines promoted IS from rat insulinoma β-cells (INS-1) as well as primary mouse islets. The effect on INS-1 cells was augmented in response to suppression of CACT. A nonhydrolyzable ether analog of palmitoyl-carnitine stimulated IS, showing that β-oxidation of palmitoyl-carnitine is not required for its stimulation of IS. These studies establish a link between miRNA-dependent regulation of CACT and fatty acyl-carnitine–mediated regulation of IS. 相似文献
4.
5.
Cosgrove CM Thornberry DJ Wilkins DC Ashley S 《Annals of the Royal College of Surgeons of England》2002,84(5):344-347
AIM: Only half of those patients undergoing major lower limb amputations for peripheral vascular disease (PVD) are likely to mobilise on a prosthesis. This study aimed to determine whether a surgeon's experience influenced the quality of the residual limb and thus the likelihood of the stump being suitable for a prosthesis. METHODS: All patients undergoing major lower limb amputations for PVD were recruited prospectively, between August 1992 and July 1996. Following surgery, patients were categorised, by a consultant in rehabilitation medicine, as potentially suitable (group 1) or unsuitable (group II) for rehabilitation. Patients in group I were further assessed by prosthetists for limb fitting. RESULTS: A total of 217 patients underwent 260 amputations for PVD between 1992 and 1996: transfemoral (TFA) 131, trans-tibial (TTA) 127, and through-knee (TKA) in 2. The 30-day mortality was 12% (n = 27). Following surgery, 109 patients were assigned to group I (51%), and 81 patients to group II (37%). The proportion of junior surgeons performing surgery was similar for patients in both groups. Twenty-three amputation stumps (9%) required revision or conversion to a higher level within 30 days. Revisions or conversions were significantly more frequent where the original operation had been performed by an unsupervised junior surgeon rather than a senior surgeon (P = 0.009). The rate of defective amputations compromising limb fitting also reached significance when unsupervised junior and senior surgeons were compared (P = 0.04). CONCLUSIONS: Rehabilitation of the relatively few amputees who reach the stage of limb fitting is hindered by poor surgical technique in a large proportion of cases. Patients operated on by a more experienced surgeon had a better chance of mobilising without revision or conversion surgery. 相似文献
6.
7.
Alessandro Pocai Paul E. Carrington Jennifer R. Adams Michael Wright George Eiermann Lan Zhu Xiaobing Du Aleksandr Petrov Michael E. Lassman Guoqiang Jiang Franklin Liu Corey Miller Laurie M. Tota Gaochao Zhou Xiaoping Zhang Michael M. Sountis Alessia Santoprete Elena Capito' Gary G. Chicchi Nancy Thornberry Elisabetta Bianchi Antonello Pessi Donald J. Marsh Ranabir SinhaRoy 《Diabetes》2009,58(10):2258-2266
OBJECTIVE
Oxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist.RESEARCH DESIGN AND METHODS
We developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in diet-induced obese (DIO) mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r−/− and Gcgr−/− mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG.RESULTS
Peptide DualAG exhibits superior weight loss, lipid-lowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The antiobesity effects of DualAG require activation of both GLP1R and GCGR.CONCLUSIONS
Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.Obesity is an important risk factor for type 2 diabetes, and ∼90% of patients with type 2 diabetes are overweight or obese (1). Among new therapies for type 2 diabetes, peptidyl mimetics of the gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) stimulate insulin biosynthesis and secretion in a glucose-dependent manner (2,3) and cause modest weight loss in type 2 diabetic patients. The glucose-lowering and antiobesity effects of incretin-based therapies for type 2 diabetes have prompted evaluation of the therapeutic potential of other glucagon-family peptides, in particular oxyntomodulin (OXM). The OXM peptide is generated by post-translational processing of preproglucagon in the gut and is secreted postprandially from l-cells of the jejuno-ileum together with other preproglucagon-derived peptides including GLP-1 (4,5). In rodents, OXM reduces food intake and body weight, increases energy expenditure, and improves glucose metabolism (6–8). A 4-week clinical study in obese subjects demonstrated that repeated subcutaneous administration of OXM was well tolerated and caused significant weight loss with a concomitant reduction in food intake (9). An increase in activity-related energy expenditure was also noted in a separate study involving short-term treatment with the peptide (10).OXM activates both, the GLP-1 receptor (GLP1R) and glucagon receptor (GCGR) in vitro, albeit with 10- to 100-fold reduced potency compared with the cognate ligands GLP-1 and glucagon, respectively (11–13). It has been proposed that OXM modulates glucose and energy homeostasis solely by GLP1R agonism, because its acute metabolic effects in rodents are abolished by coadministration of the GLP1R antagonist exendin(9–39) and are not observed in Glp1r−/− mice (7,8,14,15). Other aspects of OXM pharmacology, however, such as protective effects on murine islets and inhibition of gastric acid secretion appear to be independent of GLP1R signaling (14). In addition, pharmacological activation of GCGR by glucagon, a master regulator of fasting metabolism (16), decreases food intake in rodents and humans (17–19), suggesting a potential role for GCGR signaling in the pharmacology of OXM. Because both OXM and GLP-1 are labile in vivo (T1/2 ∼12 min and 2–3 min, respectively) (20,21) and are substrates for the cell surface protease dipeptidyl peptidase 4 (DPP-4) (22), we developed two long-acting DPP-4–resistant OXM analogs as pharmacological agents to better investigate the differential pharmacology and therapeutic potential of dual GLP1R/GCGR agonism versus GLP1R-selective agonism. Peptide DualAG exhibits in vitro GLP1R and GCGR agonist potency comparable to that of native OXM and is conjugated to cholesterol via a Cys sidechain at the C-terminus for improved pharmacokinetics. Peptide GLPAG differs from DualAG by only one residue (Gln3→Glu) and is an equipotent GLP1R agonist, but has no significant GCGR agonist or antagonist activity in vitro. The objective of this study was to leverage the matched GLP1R agonist potencies and pharmacokinetics of peptides DualAG and GLPAG in comparing the metabolic effects and therapeutic potential of a dual GLP1R/GCGR agonist with a GLP1R-selective agonist in a mouse model of obesity. 相似文献8.
Garcia-Calvo M Lisnock J Bull HG Hawes BE Burnett DA Braun MP Crona JH Davis HR Dean DC Detmers PA Graziano MP Hughes M Macintyre DE Ogawa A O'neill KA Iyer SP Shevell DE Smith MM Tang YS Makarewicz AM Ujjainwalla F Altmann SW Chapman KT Thornberry NA 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(23):8132-8137
Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia, but its molecular target has been elusive. Using a genetic approach, we recently identified Niemann-Pick C1-Like 1 (NPC1L1) as a critical mediator of cholesterol absorption and an essential component of the ezetimibe-sensitive pathway. To determine whether NPC1L1 is the direct molecular target of ezetimibe, we have developed a binding assay and shown that labeled ezetimibe glucuronide binds specifically to a single site in brush border membranes and to human embryonic kidney 293 cells expressing NPC1L1. Moreover, the binding affinities of ezetimibe and several key analogs to recombinant NPC1L1 are virtually identical to those observed for native enterocyte membranes. KD values of ezetimibe glucuronide for mouse, rat, rhesus monkey, and human NPC1L1 are 12,000, 540, 40, and 220 nM, respectively. Last, ezetimibe no longer binds to membranes from NPC1L1 knockout mice. These results unequivocally establish NPC1L1 as the direct target of ezetimibe and should facilitate efforts to identify the molecular mechanism of cholesterol transport. 相似文献
9.
Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes 总被引:11,自引:0,他引:11
Mu J Woods J Zhou YP Roy RS Li Z Zycband E Feng Y Zhu L Li C Howard AD Moller DE Thornberry NA Zhang BB 《Diabetes》2006,55(6):1695-1704
Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic beta-cell mass and function. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic beta-cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA(1c), and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2-3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive beta-cells in islets, leading to the normalization of beta-cell mass and beta-cell-to-alpha-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease. 相似文献
10.