全文获取类型
收费全文 | 432篇 |
免费 | 25篇 |
国内免费 | 5篇 |
专业分类
耳鼻咽喉 | 1篇 |
儿科学 | 11篇 |
妇产科学 | 4篇 |
基础医学 | 199篇 |
口腔科学 | 10篇 |
临床医学 | 11篇 |
内科学 | 45篇 |
皮肤病学 | 29篇 |
神经病学 | 19篇 |
特种医学 | 4篇 |
外科学 | 37篇 |
综合类 | 16篇 |
预防医学 | 10篇 |
眼科学 | 2篇 |
药学 | 43篇 |
中国医学 | 5篇 |
肿瘤学 | 16篇 |
出版年
2023年 | 2篇 |
2022年 | 2篇 |
2021年 | 4篇 |
2020年 | 4篇 |
2019年 | 2篇 |
2018年 | 1篇 |
2017年 | 8篇 |
2016年 | 8篇 |
2015年 | 12篇 |
2014年 | 12篇 |
2013年 | 29篇 |
2012年 | 13篇 |
2011年 | 20篇 |
2010年 | 13篇 |
2009年 | 25篇 |
2008年 | 26篇 |
2007年 | 20篇 |
2006年 | 23篇 |
2005年 | 22篇 |
2004年 | 13篇 |
2003年 | 13篇 |
2002年 | 14篇 |
2001年 | 9篇 |
2000年 | 9篇 |
1999年 | 6篇 |
1998年 | 18篇 |
1997年 | 4篇 |
1996年 | 10篇 |
1995年 | 8篇 |
1994年 | 13篇 |
1993年 | 10篇 |
1992年 | 6篇 |
1991年 | 7篇 |
1990年 | 4篇 |
1989年 | 9篇 |
1988年 | 9篇 |
1987年 | 6篇 |
1986年 | 7篇 |
1985年 | 7篇 |
1984年 | 5篇 |
1983年 | 6篇 |
1982年 | 7篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1979年 | 1篇 |
1978年 | 3篇 |
1977年 | 1篇 |
1976年 | 3篇 |
排序方式: 共有462条查询结果,搜索用时 171 毫秒
1.
Blockade of LTB4-induced chemotaxis by bioactive molecules interfering with the BLT2-Gαi interaction
BLT2, a low-affinity leukotriene B4 (LTB4) receptor, is a member of the G-protein coupled receptor (GPCR) family and is involved in the pathogenesis of inflammatory diseases such as asthma. Despite its clinical implications, however, no pharmacological inhibitors are available. In the present study, we screened for small molecules that interfere with the interaction between the third intracellular loop region of BLT2 (BLT2iL3) and the Gαi3 protein subunit (Gαi3), using a high-throughput screening (HTS) assay with a library of 1040 FDA-approved drugs and bioactive compounds. We identified two small molecules—purpurin [1,2,4-trihydroxy-9,10-anthraquinone; IC50 = 1.6 μM for BLT2] and chloranil [tetrachloro-1,4-benzoquinone; IC50 = 0.42 μM for BLT2]—as specific BLT2-blocking agents. We found that blockade of the BLT2iL3-Gαi3 interaction by these small molecules inhibited the BLT2-downstream signaling cascade. For example, BLT2-signaling to phosphoinositide-3 kinase (PI3K)/Akt phosphorylation was completely abolished by these molecules. Furthermore, we observed that these small molecules blocked LTB4-induced chemotaxis by inhibiting the BLT2-PI3K/Akt-downstream, Rac1-reactive oxygen species-dependent pathway. Taken together, our results show that purpurin and chloranil interfere with the interaction between BLT2iL3 and Gαi3 and thus block the biological functions of BLT2 (e.g., chemotaxis). The present findings suggest a potential application of purpurin and chloranil as pharmacological therapeutic agents against BLT2-associated inflammatory human diseases. 相似文献
2.
Seishiro Hirano Takako Asami Naomi Kodama Kazuo T. Suzuki 《Archives of toxicology》1994,68(7):444-449
In a preceding study, we reported that the numbers of macrophages and polymorphonuclear leukocytes (PMN) were increased in
bronchoalveolar lavage fluid (BALF) following the intratracheal instillation of nickel sulfate (NiSO4) in rats. In the present study, BALF chemotactic activities for both macrophages and PMN were measured to investigate if
the increases of these inflammatory cells in BALF depend on increases in chemotactic activities in epithelial lining fluid
(ELF) of the lung. Both the number of PMN and the PMN chemotactic activity peaked at 2 days post-instillation and they were
significantly correlated. However, the PMN chemotactic activity was inversely correlated with concentration of leukotriene
B4 (LTB4), a well-known chemotaxin. Although PMN were not observed in control BALF, LTB4 concentration in the control ELF (ca. 5×10–7 M) was estimated to have a potential to attract PMN chemotactically through a membrane in in vitro migration assay. These
results suggest that the presence of LTB4 in ELF itself does not trigger transpulmonary PMN infiltration. The rat BALF were fractionated by high performance liquid
chromatography (HPLC), and PMN chemotactic activity of each fraction was measured. The elution profiles of PMN chemotactic
activity showed that there were at least two different chemotaxins in BALF obtained from the NiSO4-exposed rats. Macrophage chemotactic activity in BALF also peaked at 2 days post-instillation. However, the number of macrophages
was not significantly correlated with the chemotactic activity for macrophage in BALF. The HPLC study showed that the macrophage
chemotactic substance in the BALF obtained from NiSO4-exposed rats was different from complement fragment (C5a) and its MW was estimated to be 10 – 12 kD.
Received: 1 December 1993/Accepted: 16 March 1994 相似文献
3.
Substance P (SP) is a tachykinin involved in the regulation of inflammatory processes. To investigate a modulatory role of the neuropeptide SP in allergic inflammation, we studied its priming effect on human eosinophil chemotaxis and kinetic responses towards platelet activating factor (PAF) and recombinant human interleukin 5 (rhlL-5). Blood was obtained from normal subjects and eosinophils were separated by Percoll discontinuous density gradient centrifugation. High purification was obtained by negative selection procedure (CD16-beads) and the experiments were performed in a 48-well microchemotaxis Boyden chamber. In the present study we demonstrate a potent synergistic effect of 100nM dose of SP on the migratory function of human eosinophils stimulated by PAF and rhIL-5. This synergism was chemotaxis specific and was abolished by NK-1 receptor antagonist (FK888). The results suggest that neurogenic stimuli may play a significant role in eosinophil infiltration via its priming effect on the cell. 相似文献
4.
We have investigated the effects of the bioactive lipid lysophosphatidic acid (LPA) on several functions of activated human natural killer (NK) cells. Flow cytometric and immunoblot analyses show that these cells express LPA(1, )LPA(2) and LPA(3). LPA but not its precursor phosphatidic acid (PA) induces the chemotaxis of NK cells, an activity that is inhibited by prior treatment of the cells with pertussis toxin (PTX). In addition, LPA induces the mobilization of intracellular calcium, an effect that is markedly inhibited by PTX, but is not inhibited by the addition of EGTA. PA also induces calcium flux in NK cells, but with much lower efficacy than LPA. Cross-desensitization experiments demonstrate that LPA and PA utilize different receptors. Moreover, LPA or PA but not sphingosine 1-phosphate, enhances IFN-gamma secretion by activated NK cells. Our results may shed some light on the findings that activated NK cells are found at the sites of tumor growth. 相似文献
5.
Multiple molecular species of the eosinophil chemoattractant platelet activating factor (PAF) are produced as a result of inflammatory processes. We therefore compared the ability of three naturally occurring PAF species (C160, C180, and C181), which only varied at carbon 1, to induce eosinophil chemotaxis through naked 3-m pore polycarbonate filters. Timecourse experiments indicated that all species of PAF tested induced significant and equivalent eosinophil migration at 1 h which peaked at 2 h. Overall, the rank order of chemotactic potency for the PAF species was relatively equivalent. The specific PAF antagonist WEB 2086 inhibited eosinophil migration induced by all three PAF species equally. We conclude that the degree of PAF-induced eosinophil migration is not dependent upon the molecular species of PAF.accepted by G. W. CarterThis work was supported in part by a Veterans Administration Merit Review Award. 相似文献
6.
Lin F Nguyen CM Wang SJ Saadi W Gross SP Jeon NL 《Annals of biomedical engineering》2005,33(4):475-482
Neutrophils migrating in tissue respond to complex overlapping signals generated by a variety of chemotactic factors (CFs). Previous studies suggested a hierarchy between bacteria-derived CFs and host-derived CFs but could not differentiate neutrophil response to potentially equal host-derived CFs (IL-8 and LTB4). This paper reports neutrophil migration in conflicting gradients of IL-8 and LTB4 using a microfluidic chemotaxis device that can generate stable and well-defined gradients. We quantitatively characterized the movement of cells from time-lapse images. Neutrophils migrate more efficiently toward single IL-8 gradients than single LTB4 gradients as measured by the effective chemotactic index (ECI). In opposing gradients of IL-8 and LTB4, neutrophils show obvious chemotaxis toward a distant gradient, consistent with previous reports. When an opposing gradient of LTB4 is present, neutrophils show less effective chemotaxis toward IL-8 than when they are in a gradient of IL-8 alone. In contrast, the chemotactic response of neutrophils to LTB4 is not reduced in opposing gradients as compared to that in a single LTB4 gradient. These results indicate that the presence of one host-derived CF modifies the response of neutrophils to a second CF suggesting a subtle hierarchy between them.This revised version was published online in May 2005 with corrected author affiliations 相似文献
7.
Marion Dorsch Hanno Hock Ulrich Kunzendorf Tibor Diamantstein Thomas Blankenstein 《European journal of immunology》1993,23(1):186-190
In order to analyze the effect of a high local concentration of macrophage colony-stimulating factor (M-CSF; CSF-1) on tumor growth, the plasmacytoma cell line J558L was transfected with the human M-CSF gene and injected into syngeneic BALB/c mice. In contrast to the parental tumors, M-CSF transfectants were heavily infiltrated by macrophages as evidenced by immunohistochemistry with antibodies to Mac-1 and Mac-3 and by isolation of the macrophages from the tumor. Nevertheless, tumor growth was only slightly affected by M-CSF and M-CSF-producing cells grew as tumor in all cases. The growth retardation of M-CSF-producing cells varied depending on the experiment and seemed to be due to an indirect effect because the growth rate of the cells in vitro had not changed upon gene transfer. Attempts to activate the tumor-infiltrating macrophages for tumor suppression by systemic application of interferon-γ and/or lipopolysaccharide were not successful. Altogether, our results suggest that M-CSF is a potent chemoattractant for macrophages in vivo but alone is not sufficient to activate these macrophages for tumoricidal activity. 相似文献
8.
Several age-related alterations occur at the cellular level in the immune system leading to a decrease in the immune response. The present study was designed to determine the effect of L-carnitine on impaired neutrophil functions of aged rats. For this reason, superoxide anion radical production, chemotaxis and phagocytic activity were studied in the neutrophils obtained from the peripheral blood of young and old rats. We orally gavaged L-carnitine (50 mg/kg b.w. per day) or control vehicle into young (2 months) and aged (24 months) rats for 30 consecutive days. The neutrophils of aged rats exhibited an increase in superoxide anion production and decline in phagocytosis and chemotaxis when compared with that in young rat neutrophils. Superoxide anion production in aged rats was significantly decreased by L-carnitine treatment which was accompanied with a significant enhancement of chemotactic and phagocytic activity being restored to control levels. These findings demonstrated that L-carnitine is capable of restoring the age-related changes of neutrophil functions. 相似文献
9.
Cytokines induce selective granulocyte chemotactic responses 总被引:1,自引:0,他引:1
Neutrophils, eosinophils and cytokines are important in allergic airway inflammatory responses. However, it is unclear how cytokines selectively influence neutrophils versus eosinophils to migrate to an inflammatory site. The cytokines, transforming growth factor-1 (TGF-1), interleukin (IL)-1, IL-5, IL-8, granulocyte macrophage-colony stimulating factor (GM-CSF) and tumor necrosis factor- (TNF-), are released subsequent to allergic reactions and affect both neutrophil and eosinophil functions. We studied whether these cytokines differed in capacity to induce human neutrophil versus eosinophil migration through naked filters and human umbilical vein endothelial cell (HUVEC) and human pulmonary type II-like epithelial (A549) cell monolayers grown on filters. Dose-response experiments using all barriers were performed for each granulocyte and cytokine. TGF-1 did not induce granulocyte migration. IL-5 induced eosinophil migration only through naked filters. IL-1 stimulated neutrophil migration through cellular barriers, but not through naked filters. TNF- and GMCSF induced neutrophil and eosinophil migration through filters, but only neutrophil migration through cellular monolayers. Only IL-8 induced significant neutrophil and eosinophil migration; however, there were clear-cut differences between the neutrophilotactic and eosinophilotactic responses through all barriers emploved. Thus, our data show that these cytokines induce distinct chemotactic responses for neutrophils versus eosinophils. Moreover, by using relevant cellular barriers versus naked filters, our data better examines the capability of these cytokines to induce selective granulocyte migration to an inflammatory site in lung diseases such as asthma.accepted by G. W. Carter 相似文献
10.
Allergic diseases are characterized by the presence of eosinophils, which are recruited to the affected tissues by chemoattractants produced by T cells, mast cells and epithelium. Our objective was to evaluate if allergens can directly activate human eosinophils. The capacity of purified allergen extracts to elicit eosinophil chemotaxis, respiratory burst, degranulation and up-regulation of the adhesion molecule complement receptor 3 (CR3) was determined in eosinophils isolated from healthy blood donors. Eosinophils stimulated with an extract from house dust mite (HDM) released the granule protein major basic protein (MBP) and up-regulated the surface expression of CR3. Cat allergen extracts also induced the up-regulation of CR3, but not the release of MBP; instead cat, as well as birch and grass allergens, elicited the release of eosinophil peroxidase (EPO). In addition, grass pollen extract caused the secretion of MBP. None of the allergens stimulated eosinophilic cationic protein release, nor production of free oxygen radicals. Both HDM and birch extracts were chemotactic for eosinophils. These findings establish that common aeroallergens can directly activate eosinophils in vitro. We propose that eosinophil activation in vivo is not exclusively mediated by cytokines and chemokines of the allergic inflammatory reaction, but could partly be the result of direct interaction between allergens and eosinophils. 相似文献