全文获取类型
收费全文 | 378篇 |
免费 | 13篇 |
专业分类
391篇 |
出版年
2023年 | 5篇 |
2022年 | 20篇 |
2021年 | 30篇 |
2020年 | 11篇 |
2019年 | 10篇 |
2018年 | 19篇 |
2017年 | 14篇 |
2016年 | 9篇 |
2015年 | 19篇 |
2014年 | 29篇 |
2013年 | 14篇 |
2012年 | 35篇 |
2011年 | 30篇 |
2010年 | 20篇 |
2009年 | 14篇 |
2008年 | 19篇 |
2007年 | 22篇 |
2006年 | 18篇 |
2005年 | 14篇 |
2004年 | 6篇 |
2003年 | 8篇 |
2002年 | 9篇 |
2001年 | 2篇 |
2000年 | 5篇 |
1998年 | 1篇 |
1997年 | 2篇 |
1995年 | 1篇 |
1993年 | 1篇 |
1991年 | 1篇 |
1989年 | 1篇 |
1980年 | 1篇 |
1975年 | 1篇 |
排序方式: 共有391条查询结果,搜索用时 0 毫秒
81.
The everted rat intestinal‐sac model was utilized to assess the effect of post‐prandial conditions on the stereoselective intestinal metabolism of halofantrine to its active metabolite desbutylhalofantrine. Everted intestinal sacs were incubated with (±)‐halofantrine HCl in the presence of simulated bile solution (containing lecithin, lipase and cholesterol) and lipids to mimic post‐prandial conditions in the small intestine. The halofantrine enantiomer concentrations in intestinal sacs were relatively constant in the presence of bile, but decreased significantly on addition of lipids to the incubation media. Formation of desbutylhalofantrine enantiomers was inversely proportional to bile concentration whereas addition of lipids in the presence of bile caused a significant decrease in desbutylhalofantrine:halofantrine ratio of (?) enantiomers. Pre‐treatment of rats with peanut oil had no significant effect on desbutylhalofantrine formation in the incubated sacs or microsomal preparations, nor did it affect the expression of intestinal cytochrome P450. Addition of extra cholesterol to the bile incubations caused a significant increase in tissue halofantrine and desbutylhalofantrine concentrations, which as for lower cholesterol, were diminished on addition of other lipids. The results were consistent with previous in vivo evaluations showing that the desbutylhalofantrine to halofantrine ratio was decreased by the ingestion of a high fat meal. Chirality, 2010. © 2009 Wiley‐Liss, Inc. 相似文献
82.
Yousri M. Hussein Sally M. Shalaby Amani Nassar Saad S. Alzahrani Ayman S. Alharbi Maha Nouh 《Gene》2014
Objective
To determine whether IL-4, IL-4Rα and STAT6 polymorphisms are associated with susceptibility to dermatitis in Egyptian children.Methods
We genotyped three groups of children, consisting of 106 atopic dermatitis (AD) children, 95 non-AD children, and 100 of healthy controls, for IL-4 (− 590 C/T), (− 33 C/T), IL-4Rα (I50V), (Q576R) and STAT6 (2964 G/A), (2892 C/T) gene polymorphisms using PCR-RFLP assay. Total serum IgE and serum IL-4 levels were detected by ELISA.Results
There was a non-significant association of IL-4 − 590 C/T, − 33 C/T polymorphisms in the children with non-AD or those with AD when compared with the controls. We identified a significant association between IL-4Rα I50V, Q576R polymorphisms and dermatitis susceptibility in AD (p = 0.002, < 0.001 respectively), whereas no such association was observed in non-AD group (p = 0.52, 0.99 respectively). A significant association between STAT6 polymorphisms and both types of dermatitis was found. Patients who were carriers of IL4 − 590C, IL-4Rα I50V G, STAT6 2964 A and STAT6 2892 T had an increased risk of AD [OR and 95% CI: 3.2 (2.5–4.2), p = 0.005]. Furthermore, there was no relation between each polymorphism and serum IL-4 level (p > 0.05 for each) while homozygosity for the risk alleles of IL-4, IL-4Rα and STAT6 SNPs were significantly associated with increased total IgE levels in all subjects.Conclusion
In Egyptian children, the IL-4Rα and the STAT6 polymorphism may play a role in susceptibility to AD. In addition, gene–gene interaction between the IL-4, the IL-4Rα and the STAT6 significantly increases an individual's susceptibility to AD. 相似文献83.
84.
We have shown that gastrin-releasing peptide-29 (GRP-29), the large molecular form of GRP in rats, reduces meal size (MS, intake of 10% sucrose solution) and prolongs the intermeal interval (IMI). In these studies, we first investigated possible pathways for these responses in rats undergoing total subdiaphragmatic vagotomy (VGX, removal of vagal afferent and efferent innervation of the gut), celiaco-mesenteric ganglionectomy (CMGX, removal of splanchnic afferent and efferent innervation of the gut) and combined VGX and CMGX. Second, we examined if the duodenum communicates the feeding signals (MS and IMI) of GRP-29 (0, 0.3, 1.0, 2.1, 4.1, 10.3 and 17.2 nmol/kg) with the feeding control areas of the hindbrain by performing duodenal myotomy (MYO), a procedure that severs some layers of the duodenal wall including the vagal, splanchnic and enteric neurons. We found that GRP-29 (2.1, 4.1, 10.3, 17.2 nmol/kg) reduced the size of the first meal (10% sucrose) and (1, 4.1, 10.3 nmol/kg) prolongs the first IMI but did not affect the subsequent meals or IMIs. In addition, CMGX and combined VGX/CMGX attenuated reduction of MS by GRP-29 and all surgeries attenuated the prolongation of the IMI. Therefore, reduction of MS and prolongation of IMI by GRP-29 require vagal and splanchnic nerves, and the duodenum is the major conduit that communicates prolongation of IMI by GRP-29 with the brain. 相似文献
85.
Glutathione transferase (GST) is a phase II detoxifying enzyme that plays a protective mechanism against oxidizing substances and toxic contaminants. Among these contaminants, heavy metals and polycyclic and halogenated aromatic hydrocarbons (PHAHs) have been shown to exert their toxic effects through the modulation of detoxifying enzymes, including the GSTs. Recently, we showed that heavy metals particularly Hg2+, Pb2+, and Cu2+ modulate the expression of phase II detoxifying enzymes such as NAD(P)H:quinone oxidoreductase 1 and Gsta1 in a concentration- and time-dependent manner. However, the effect of heavy metals and their potential interactions with aryl hydrocarbon receptor (AhR) ligands, PHAHs, on total Gst activity is still unknown. In the current study, we have investigated the effects of Hg2+, Pb2+, and Cu2+ in the absence and presence of four AhR ligands on the total Gst activity and reactive oxygen species (ROS) production in wild-type and AhR-deficient Hepa 1c1c7 cells. Our results showed that Hg2+ and Cu2+, but not Pb2+, significantly induced Gst activity in wild-type cells, whereas all metals induced the Gst activity in AhR-deficient cells. The induction of Gst activity by heavy metals was strongly correlated with an increase in the ROS production in wild-type, but not in AhR-deficient cells. Co-administration of heavy metals with AhR ligands differentially modulated Gst activity, in that co-exposure to Hg2+ plus AhR ligands could be beneficial in protecting against cytotoxicity as demonstrated by the increase in Gst activity with a proportional decrease in ROS production. Whereas co-exposure to Cu2+ plus AhR ligands was more toxic in that a decrease in Gst activity and an increase in oxidative stress of the cell were observed. We concluded that heavy metals differentially modulate the Gst activity through oxidative stress- and AhR-mediated mechanisms. 相似文献
86.
D. Jabborova R.Z. Sayyed A. Azimov Z. Jabbarov A. Matchanov Y. Enakiev Alaa Baazeem Ayman EL Sabagh Subhan Danish Rahul Datta 《Saudi Journal of Biological Sciences》2021,28(9):5268-5274
Ginger is used as one of the important ingredients in traditional as well as modern medicine besides as a spice. It boosts immunity and is a rich source of many biologically active substances and minerals. Although it is a medicinally important crop, its productivity is, however, affected due to poor nutrient management and therefore it requires an adequate supply of nutrients in the form of inorganic fertilizers or organic manuring, or a mixture of both. In this context, the present study was aimed to investigate the effect of mineral fertilizers on the content of mineral elements in the ginger rhizome, on soil enzyme activity, and soil properties. Lysimeter experiments were conducted at the Institute of Genetics and Plant Experimental Biology, Kibray, Tashkent region, Uzbekistan. The experiment comprised of four treatments T1 – Control, T2 - N75P50K50 kg/ha, T3 - and T4 - N100P75K75 + B3Zn6Fe6 kg/ha. The results showed that the application of N125P100K100 kg/ha increased rhizome K content by 49%, P content by 20%, and Na content by 58% as compared to control without fertilizer. While the application of N100P75K75 + B3Zn6Fe6 kg/ha showed a significant enhancement in rhizome K, Ca, P, Mg, Na, Fe, Mn, Zn, Cu, Cr, Mo, and Si contents over the control. This treatment also improved active P content by 29%, total P content by 80%, total K content 16%, and N content by 33% content, and the activities of urease, invertase, and catalase activities as compared to control of without mineral fertilizer and control respectively. Thus the application of NPK + BZnFe at the rate of 100:75:75:3:6:6 kg/ha helps in improving macroelements and microelements in the ginger rhizome and activities of soil enzymes that helps in mineral nutrition of the rhizome. 相似文献
87.
88.
Vinodkumar B. Pillai Nagalingam R. Sundaresan Gene Kim Madhu Gupta Senthilkumar B. Rajamohan Jyothish B. Pillai Sadhana Samant P. V. Ravindra Ayman Isbatan Mahesh P. Gupta 《The Journal of biological chemistry》2010,285(5):3133-3144
Since the discovery of NAD-dependent deacetylases, sirtuins, it has been recognized that maintaining intracellular levels of NAD is crucial for the management of stress response of cells. Here we show that agonist-induced cardiac hypertrophy is associated with loss of intracellular levels of NAD, but not exercise-induced physiologic hypertrophy. Exogenous addition of NAD was capable of maintaining intracellular levels of NAD and blocking the agonist-induced cardiac hypertrophic response in vitro as well as in vivo. NAD treatment blocked the activation of pro-hypertrophic Akt1 signaling, and augmented the activity of anti-hypertrophic LKB1-AMPK signaling in the heart, which prevented subsequent induction of mTOR-mediated protein synthesis. By using gene knock-out and transgenic mouse models of SIRT3 and SIRT1, we showed that the anti-hypertrophic effects of exogenous NAD are mediated through activation of SIRT3, but not SIRT1. SIRT3 deacetylates and activates LKB1, thus augmenting the activity of the LKB1-AMPK pathway. These results reveal a novel role of NAD as an inhibitor of cardiac hypertrophic signaling, and suggest that prevention of NAD depletion may be critical in the treatment of cardiac hypertrophy and heart failure. 相似文献
89.
Elsheikh A Lavergne SN Castrejon JL Farrell J Wang H Sathish J Pichler WJ Park BK Naisbitt DJ 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(11):6448-6460
Recognition of drugs by immune cells is usually explained by the hapten model, which states that endogenous metabolites bind irreversibly to protein to stimulate immune cells. Synthetic metabolites interact directly with protein-generating antigenic determinants for T cells; however, experimental evidence relating intracellular metabolism in immune cells and the generation of physiologically relevant Ags to functional immune responses is lacking. The aim of this study was to develop an integrated approach using animal and human experimental systems to characterize sulfamethoxazole (SMX) metabolism-derived antigenic protein adduct formation in immune cells and define the relationship among adduct formation, cell death, costimulatory signaling, and stimulation of a T cell response. Formation of SMX-derived adducts in APCs was dose and time dependent, detectable at nontoxic concentrations, and dependent on drug-metabolizing enzyme activity. Adduct formation above a threshold induced necrotic cell death, dendritic cell costimulatory molecule expression, and cytokine secretion. APCs cultured with SMX for 16 h, the time needed for drug metabolism, stimulated T cells from sensitized mice and lymphocytes and T cell clones from allergic patients. Enzyme inhibition decreased SMX-derived protein adduct formation and the T cell response. Dendritic cells cultured with SMX and adoptively transferred to recipient mice initiated an immune response; however, T cells were stimulated with adducts derived from SMX metabolism in APCs, not the parent drug. This study shows that APCs metabolize SMX; subsequent protein binding generates a functional T cell Ag. Adduct formation above a threshold stimulates cell death, which provides a maturation signal for dendritic cells. 相似文献
90.
Nguyen LT Yen PH Nie J Liadis N Ghazarian D Al-Habeeb A Easson A Leong W Lipa J McCready D Reedijk M Hogg D Joshua AM Quirt I Messner H Shaw P Crump M Sharon E Ohashi PS 《PloS one》2010,5(11):e13940