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1.
J. I. Macdonald S. M. Wallace V. Mahachai R. K. Verbeeck 《European journal of clinical pharmacology》1992,42(5):471-474
Summary The pharmacokinetics of diflunisal, a salicylate derivative that undergoes phenolic and acyl glucuronidation as well as sulphate conjugation, has been studied after a single oral dose (250 mg) in patients with cirrhosis (n=5) and in healthy controls (n=5).The plasma clearance of total (bound + unbound) diflunisal was 10.2 ml · min–1 in the control subjects and it was not affected by cirrhosis (10.9 ml · min–1). The plasma protein binding of diflunisal was significantly reduced in cirrhosis; the percentage of unbound diflunisal in plasma was 0.089 in the controls and 0.147 in the patients with cirrhosis. Plasma clearance of unbound diflunisal was significantly impaired in cirrhosis: 11.51 · min–1 in control subjects vs 7.41 · min–1 in cirrhotics.In cirrhotic patients, the unbound partial clearances to the phenolic and acyl glucuronides were both significantly reduced, by approximately 38%. The unbound partial clearance to the sulphate conjugate was not significantly affected by cirrhosis.The results show that both the phenolic and acyl glucuronidation pathways of diflunisal are equally susceptible to the effects of liver cirrhosis. 相似文献
2.
大黄化学成分的药动学及其代谢的研究进展 总被引:1,自引:0,他引:1
大黄是临床常用中药之一,当前关于其药动学和代谢研究主要关注游离蒽醌类成分。本文综述近年来关于大黄药动学与代谢的文献,梳理大黄化学成分的药动学研究(应用的分析技术、药味配伍对大黄蒽醌药动学影响、在不同机体状态下对大黄蒽醌药动学影响、大黄复方中蒽醌药动学研究),大黄化学成分在体内的代谢研究(应用的分析手段、借助的信息技术、体内的代谢途径)和大黄化学成分在体外的代谢研究。总结其吸收和代谢的特征,为该药物的后期研究奠定基础和提供参考。研究发现大黄蒽醌吸收快而消除慢,而药味配伍和机体状态都会影响其吸收和代谢。大黄化学成分的体内和体外代谢途径主要是葡萄糖醛酸化、硫酸酯化、甲基化等,其代谢物主要来源于蒽醌类成分。 相似文献
3.
目的 利用星点设计-效应面法优化白鲜皮多糖(Dictamnus dasycarpus polysaccharide,DDP)硫酸酯化工艺,考察DDP修饰前后结构特征及抗氧化活性。方法 采用氯磺酸-吡啶法,以酯化试剂比例、酯化试剂与多糖溶液比例、反应温度、反应时间为自变量,硫酸根取代度(degree of substitution,DS)为因变量,对自变量各水平进行多元回归拟合,利用效应面法筛选最佳工艺并进行预测分析;采用红外光谱及扫描电镜观察其结构特点。测定硫酸酯化白鲜皮多糖(sulfated polysaccharides from Dictamnus dasycarpus,SDDP)对DPPH、OH·、O2-·清除能力,考察其抗氧化活性。结果 最佳工艺条件为酯化试剂比例1:4,酯化试剂与多糖溶液比例1:1,反应温度73℃,反应时间5 h。红外光谱显示SDDP在820 cm-1和1 254 cm-1附近出现C-O-S和S=O硫酸基特征吸收峰,表明DDP修饰成功;扫描电镜显示SDDP表面粗糙,排列紧密,且块状体积明显小于DDP;DDP和SDDP都有清除DPPH、OH·和O2-·能力,且SDDP对DPPH、OH·和O2-·清除率强于DDP。结论 星点设计-效应面法优化DDP硫酸酯化工艺方法简便且预测性良好,DDP经硫酸酯化后,抗氧化活性有所提高。 相似文献
4.
Fate of goblet cells in experimental colitis 总被引:3,自引:0,他引:3
Makkink MK Schwerbrock NM Mähler M Boshuizen JA Renes IB Cornberg M Hedrich HJ Einerhand AW Büller HA Wagner S Enss ML Dekker J 《Digestive diseases and sciences》2002,47(10):2286-2297
We sought to correlate the characteristic changes in goblet cell morphology in the chronically inflamed large intestine of IL10
–/– mice to specific changes in goblet cell gene expression. In healthy as well as IL10
–/– mice, marked differences were found among the large intestinal regions in goblet cell morphology and gene expression. The mucin Muc2, which is a major determinant of goblet cell morphology, was expressed in most goblet cells, yet only in cells staining positive for both Alcian blue and high iron diamine. TFF3 was expressed in only a small subset of goblet cells. Inflamed colon of IL10
–/– mice still contained high numbers of small, hypotrophic goblet cells with similar histochemical staining and Muc2 and TFF3 expression patterns, contradicting the often reported goblet cell depletion in colitis. Quantitatively, the Muc2 and TFF3 levels remained relatively stabile in IL10
–/– mice. Muc2 in distal IL10
–/– colon contained significantly less sulfate residues than in controls, which may compromise its protective properties. 相似文献
5.
Zachary E. Tibbs Amber L. Guidry Josie L. Falany Susan A. Kadlubar 《Xenobiotica; the fate of foreign compounds in biological systems》2018,48(1):79-88
1.?Human cytosolic sulfotransferase 1B1 (SULT1B1) sulfates small phenolic compounds and bioactivates polycyclic aromatic hydrocarbons. To date, no SULT1B1 allelic variants have been well-characterized.2.?While cloning SULT1B1 from human endometrial specimens, an allelic variant resulting in valine instead of leucine at the 145th amino acid position (L145V) was detected. NCBI reported this alteration as the highest frequency SULT1B1 allelic variant.3.?L145V frequency comprised 9% of 37 mixed-population human patients and was specific to African Americans with an allelic frequency of 25%. Structurally, replacement of leucine with valine potentially destabilizes a conserved helix (α8) that forms the “floor” of both the substrate and PAPS binding domains. This destabilization results in altered kinetic properties including a four-fold decrease in affinity for PAP (3′, 5′-diphosphoadenosine). Kms for 3′-phosphoadenosine- 5′-phosphosulfate (PAPS) are similar; however, maximal turnover rate of the variant isoform (0.86?pmol/(min*μg)) is slower than wild-type (WT) SULT1B1 (1.26?pmol/(min*μg)). The L145V variant also displays altered kinetics toward small phenolic substrates, including a diminished p-nitrophenol Km and increased susceptibility to 1-naphthol substrate inhibition.4.?No significant correlation between genotype and prostate or colorectal cancer was observed in patients; however, the variant isoform could underlie specific pathologies in sub-Saharan African carriers. 相似文献
6.
马尾松花粉硫酸酯化多糖调控脾细胞[Ca~(2+)]_i的研究 总被引:1,自引:0,他引:1
目的探讨马尾松花粉多糖硫酸酯化物(SPPM60-A)对小鼠脾细胞内游离钙离子浓度([Ca2+]i)调控的机制。方法热水浸提醇沉淀法提取马尾松花粉粗多糖,SephacrylS-400HR分离纯化,氯磺酸-吡啶法进行硫酸酯化,荧光分光光度计测定脾淋巴细胞[Ca2+]i。结果 LPS与SPPM60-A都能促进脾淋巴细胞[Ca2+]i升高,与对照相比升高率分别为11.7%和15.4%(P<0.01)。TAK-242、LY294002、U73122、低分子肝素与维拉帕米均可以抑制[Ca2+]i的升高。结论推测硫酸酯化马尾松花粉多糖可通过TLR4-PI3K-PLC-IP3R信号通路促进脾淋巴细胞内[Ca2+]i升高。 相似文献
7.
Estrogen stimulation is an important factor in human breast cancer cell growth and development. Metabolism of -estradiol (E2), the major endogenous human estrogen, is important in regulating both the level and activity of the hormone in breast tissues. Conjugation of E2 with a sulfonate moiety is an inactivation process since the sulfate ester formed by this reaction can not bind and activate the estrogen receptor. In human tissues including the breast, estrogen sulfotransferase (EST, SULT1E1) is responsible for high affinity E2 sulfation activity. EST is expressed in human mammary epithelial (HME) cells but not in most cultured breast cancer cell lines, including estrogen responsive MCF-7 cells. Stable expression of EST in MCF-7 cells at levels similar to those detected in HME cells significantly inhibits cell growth at physiologically relevant E2 concentrations. The mechanism of cell growth inhibition involves the abrogation of responses observed in growth factor expression in MCF-7 cells following E2 stimulation. MCF-7 cells expressing EST activity did not show a decrease in estrogen receptor- levels, nor a characteristic increase in progesterone receptor or decrease in transforming growth factor- expression upon exposure to 100 pM or 1 nM E2. The lack of response in these MCF-7 cells is apparently due to the rapid sulfation and inactivation of free E2 by EST. These results suggest that loss of EST expression in the transformation of normal breast tissues to breast cancer may be an important factor in increasing the growth responsiveness of preneoplastic or tumor cells to estrogen stimulation. 相似文献
8.
The posttranslational sulfation of tyrosine has been though to be initiated by the recognition of specific consensus features
by the sulfating enzyme tyrosylprotein sulfotransferase (TPST). However, using these recognition features to identify new
tyrosine sulfation sites misses recently characterized sites that lack these features. Rigorous analysis of the amino acids
surrounding the target tyrosin using the position-specific scoring matrix (PSSM) demonstrates that a consensus sequence does
not contain all the information necessary to predict tyrosine sulfation. Instead, accurate prediction requires consideration
of all residues within five amino acids on either side of the target tyrosine. These results support the notion that secondary
structure is the major determinant of sulfation and that other residues within the sulfation site can compensate for deviations
from commonly observed features. This view implies that specific consensus features are not critical for TPST substrate recognition
but that TPST may instead broadly recognize any sufficiently exposed tyrosine residue. 相似文献
9.
Sherry DM Murray AR Kanan Y Arbogast KL Hamilton RA Fliesler SJ Burns ME Moore KL Al-Ubaidi MR 《The European journal of neuroscience》2010,32(9):1461-1472
To investigate the role(s) of protein‐tyrosine sulfation in the retina, we examined retinal function and structure in mice lacking tyrosylprotein sulfotransferases (TPST) 1 and 2. Tpst double knockout (DKO; Tpst1?/?/Tpst2 ?/?) retinas had drastically reduced electroretinographic responses, although their photoreceptors exhibited normal responses in single cell recordings. These retinas appeared normal histologically; however, the rod photoreceptors had ultrastructurally abnormal outer segments, with membrane evulsions into the extracellular space, irregular disc membrane spacing and expanded intradiscal space. Photoreceptor synaptic terminals were disorganized in Tpst DKO retinas, but established ultrastructurally normal synapses, as did bipolar and amacrine cells; however, the morphology and organization of neuronal processes in the inner retina were abnormal. These results indicate that protein‐tyrosine sulfation is essential for proper outer segment morphogenesis and synaptic function, but is not critical for overall retinal structure or synapse formation, and may serve broader functions in neuronal development and maintenance. 相似文献
10.
PapA1 and PapA2 are acyltransferases essential for the biosynthesis of the Mycobacterium tuberculosis virulence factor sulfolipid-1 总被引:1,自引:0,他引:1
Kumar P Schelle MW Jain M Lin FL Petzold CJ Leavell MD Leary JA Cox JS Bertozzi CR 《Proceedings of the National Academy of Sciences of the United States of America》2007,104(27):11221-11226
Mycobacterium tuberculosis produces numerous exotic lipids that have been implicated as virulence determinants. One such glycolipid, Sulfolipid-1 (SL-1), consists of a trehalose-2-sulfate (T2S) core acylated with four lipid moieties. A diacylated intermediate in SL-1 biosynthesis, SL(1278), has been shown to activate the adaptive immune response in human patients. Although several proteins involved in SL-1 biosynthesis have been identified, the enzymes that acylate the T2S core to form SL(1278) and SL-1, and the biosynthetic order of these acylation reactions, are unknown. Here we demonstrate that PapA2 and PapA1 are responsible for the sequential acylation of T2S to form SL(1278) and are essential for SL-1 biosynthesis. In vitro, recombinant PapA2 converts T2S to 2'-palmitoyl T2S, and PapA1 further elaborates this newly identified SL-1 intermediate to an analog of SL(1278). Disruption of papA2 and papA1 in M. tuberculosis confirmed their essential role in SL-1 biosynthesis and their order of action. Finally, the Delta papA2 and Delta papA1 mutants were screened for virulence defects in a mouse model of infection. The loss of SL-1 (and SL(1278)) did not appear to affect bacterial replication or trafficking, suggesting that the functions of SL-1 are specific to human infection. 相似文献