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91.
92.
Geraniol Averts Methotrexate-Induced Acute Kidney Injury via Keap1/Nrf2/HO-1 and MAPK/NF-κB Pathways
Nancy S. Younis Heba S. Elsewedy Tamer M. Shehata Maged E. Mohamed 《Current issues in molecular biology》2021,43(3):1741
Objectives: Geraniol, a natural monoterpene, is an essential oil component of many plants. Methotrexate is an anti-metabolite drug, used for cancer and autoimmune conditions; however, clinical uses of methotrexate are limited by its concomitant renal injury. This study investigated the efficacy of geraniol to prevent methotrexate-induced acute kidney injury and via scrutinizing the Keap1/Nrf2/HO-1, P38MAPK/NF-κB and Bax/Bcl2/caspase-3 and -9 pathways. Methods: Male Wister rats were allocated into five groups: control, geraniol (orally), methotrexate (IP), methotrexate and geraniol (100 and 200 mg/kg). Results: Geraniol effectively reduced the serum levels of creatinine, urea and Kim-1 with an increase in the serum level of albumin when compared to the methotrexate-treated group. Geraniol reduced Keap1, escalated Nrf2 and HO-1, enhanced the antioxidant parameters GSH, SOD, CAT and GSHPx and reduced MDA and NO. Geraniol decreased renal P38 MAPK and NF-κB and ameliorated the inflammatory mediators TNF-α, IL-1β, IL-6 and IL-10. Geraniol negatively regulated the apoptotic mediators Bax and caspase-3 and -9 and increased Bcl2. All the biochemical findings were supported by the alleviation of histopathological changes in kidney tissues. Conclusion: The current findings support that co-administration of geraniol with methotrexate may attenuate methotrexate-induced acute kidney injury. 相似文献
93.
94.
Mucins have been implicated in tumor-associated immunosuppression. The possibility that colon cancer mucin (CCM) may modulate
T-helper 1 (TH1) activity was evaluated by investigating its effect on the production of interleukin-2 (IL-2) by CD4+ cells, a process that requires antigen-specific and costimulatory signals. Methods: CCM was purified from human colorectal cancer cells by gel-exclusion fast-pressure liquid chromatography. Cytokine production
of purified CD4+ cells was evaluated at the protein and gene level in the presence of a phorbol ester or an anti-CD3 monoclonal antibody (mAb)
plus mAb against the CD28 costimulatory receptor to mimic two-signal activation. Results: Soluble CCM, which contains mucins MUC2 as well as MUC1, inhibited IL-2 mRNA expression and secretion of CD4+ stimulated with a phorbol ester or an anti-CD3 mAb plus anti-CD28 mAb. Pretreatment of CD4+ cells with anti-CD28 mAb abrogated the suppressive effects of CCM on IL-2 production, and flow cytometry showed decreased
binding of anti-CD28 mAb to its receptor in the presence of mucin. In addition, Ca2+ mobilization after T cell receptor cross-linking with anti-CD3 mAb was maintained in the presence of CCM. Although interferon
γ production was also diminished, CCM did not induce a general inhibition of cytokine production, nor did it decrease cell
viability. Macrophage inflammatory protein 1α production was up-regulated; the production of IL-10 and transforming growth
factor β was unchanged. Conclusions: The results indicate that CCM can alter TH1 activity and suggest that the modulation of costimulatory interactions is involved.
They provide another mechanism of immunosuppression mediated by these highly expressed tumor products.
Received: 23 March 1999 / Accepted: 3 August 1999 相似文献
95.
The CCL4 chemokine is secreted by a variety of cells following stimulation. CCL4 affects several different types of cells that are important for acute inflammatory responses and are critical for the development of specific immune responses to foreign antigens. The human genome contains two genes for the CCL4 chemokine. Although highly homologous, the two genes encode slightly different proteins. We analyzed the mRNA expressed in monocytes and B lymphocytes and found that while monocytes express predominantly one CCL4 gene, known as ACT-2, peripheral blood B lymphocytes express a mixture of ACT-2 and the second CCL4 gene, lymphocyte activating gene-1 (LAG-1). Although peripheral blood B cells, CD27– B cells, and CD27+ B cells all express a mixture of LAG-1 and ACT-2, the B-cell lines that were studied regulate the two genes independently. RL, SU-DHL-6, and REH cells predominantly express LAG-1. These studies demonstrate that monocytes and B cells utilize different mechanisms to regulate expression of the two CCL4 genes and suggest that the two genes may not have identical activities. 相似文献
96.
Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice 总被引:6,自引:0,他引:6
Cyclooxygenase-2 (COX-2), the rate-limiting enzyme for prostanoid biosynthesis, plays a key role in gastrointestinal carcinogenesis. Among various prostanoids, prostaglandin E2 (PGE2) appears to be most responsible for cancer development. To investigate the role of PGE2 in gastric tumorigenesis, we constructed transgenic mice simultaneously expressing COX-2 and microsomal prostaglandin E synthase (mPGES)-1 in the gastric epithelial cells. The transgenic mice developed metaplasia, hyperplasia and tumorous growths in the glandular stomach with heavy macrophage infiltrations. Although gastric bacterial counts in the transgenic mice were within the normal range, treatment with antibiotics significantly suppressed activation of the macrophages and tumorous hyperplasia. Importantly, the antibiotics treatment did not affect the macrophage accumulation. Notably, treatment of the transgenic mice with lipopolysaccharides induced proinflammatory cytokines through Toll-like receptor 4 in the gastric epithelial cells. These results indicate that an increased level of PGE2 enhances macrophage infiltration, and that they are activated through epithelial cells by the gastric flora, resulting in gastric metaplasia and tumorous growth. Furthermore, Helicobacter infection upregulated epithelial PGE2 production, suggesting that the COX-2/mPGES-1 pathway contributes to the Helicobacter-associated gastric tumorigenesis. 相似文献
97.
Luo Z Palasis M Yamakawa M Liu LX Vincent KA Trudell L Akita GA Koch WJ Cheng SH Gregory RJ Jiang C 《The journal of gene medicine》2004,6(10):1061-1068
BACKGROUND: Previous studies have shown that incubation of balloon-injured rat carotid arteries with adenoviral vectors encoding the carboxyl terminus of the beta-adrenergic receptor kinase (Ad2/betaARKct) for 30 min reduces neointima formation. However, it is unclear whether this beneficial effect of betaARKct could be achieved using a catheter-based vector delivery system and whether the observed inhibition of neointima formation translated into a reduction of vessel stenosis. METHODS: In this study, Ad2/betaARKct was infused into the balloon-injured site of rabbit iliac arteries using a porous infusion catheter over 2 min. Twenty-eight days after gene transfer, angiographic and histological assessments were performed. RESULTS: Angiographic and histological assessments indicate significant (p < 0.05) inhibition of iliac artery neointima formation and lumen stenosis by Ad2/betaARKct. Our studies demonstrate that an inhibitory effect of Ad2/betaARKct on neointima formation is achievable using a catheter-based vector delivery system and that the inhibition of neointima formation translates into a gain in the vessel minimal luminal diameter. The extent of inhibition (35%) was comparable to that observed with adenoviral-mediated expression of thymidine kinase plus ganciclovir treatment, a cytotoxic gene therapy approach for restenosis. CONCLUSIONS: These results suggest that adenoviral-mediated gene transfer of betaARKct is a clinically viable cytostatic gene therapy strategy for the treatment of restenosis. 相似文献
98.
Etiopathogenesis of mucosal inflammation in inflammatory bowel disease remains a complex and enigmatic field; various factors (genetic, environmental and microbial) trigger an event that activates intestinal immune and nonimmune systems culminating in inflammation and tissue injury. Specifically, both innate and adaptive immune systems seem to play important roles in the pathophysiology of this disease. Cyclosporine A represents a macrolide immune modulator with primary inhibitory effects on T helper lymphocyte production of interleukin-2, and other cytokines leading to altered T-lymphocyte and B-lymphocyte function. The diversity of its therapeutic outcome reported in inflammatory bowel disease may be due to the intricate immuno-pathogenic profile of the disease and the variety of the applied dose-dependent courses of therapy. Cyclosporine A exerts additional actions on other components of the inflammatory infiltrate, including neutrophils and mast cells, thereby appearing to be a multi-dynamic therapeutic approach, although with potential drawbacks, that may be applied alone or combined with other immunomodulatory agents in inflammatory bowel disease patients. Because cyclosporine A induces apoptosis of T-lymphocytes responsible for perpetuation of the chronic inflammatory process in the disease with potential tumorigenic effect, it may exert a further inhibitory effect on cancer development in inflammatory bowel disease patients, and can be combined with other relative agents, such as rapamycin, which also promotes T-lymphocyte apoptosis. Therefore, recently established multifactorial action of cyclosporine A in relation to the pathogenesis of the disease can open new horizons for prospective, controlled trials in large cohorts, aiming to emphasize cyclosporine A's potential. 相似文献
99.
Chakrabarti S Kobayashi KS Flavell RA Marks CB Miyake K Liston DR Fowler KT Gorelick FS Andrews NW 《The Journal of cell biology》2003,162(4):543-549
Members of the synaptotagmin family have been proposed to function as Ca2+ sensors in membrane fusion. Syt VII is a ubiquitously expressed synaptotagmin previously implicated in plasma membrane repair and Trypanosoma cruzi invasion, events which are mediated by the Ca2+-regulated exocytosis of lysosomes. Here, we show that embryonic fibroblasts from Syt VII-deficient mice are less susceptible to trypanosome invasion, and defective in lysosomal exocytosis and resealing after wounding. Examination of mutant mouse tissues revealed extensive fibrosis in the skin and skeletal muscle. Inflammatory myopathy, with muscle fiber invasion by leukocytes and endomysial collagen deposition, was associated with elevated creatine kinase release and progressive muscle weakness. Interestingly, similar to what is observed in human polymyositis/dermatomyositis, the mice developed a strong antinuclear antibody response, characteristic of autoimmune disorders. Thus, defective plasma membrane repair in tissues under mechanical stress may favor the development of inflammatory autoimmune disease. 相似文献
100.
低氧对培养的不同内径的肺动脉平滑肌细胞增殖的影响 总被引:4,自引:0,他引:4
目的和方法:分离培养三种不同内径的肺动脉平滑肌细胞(PASMCs),用^3H-TdR掺入速率和细胞计数作为细胞增殖的指标,观察低氧对其增殖作用的影响。结果:低氧对三种不同内径的PASMCs(内径分别为>1000μm、500-800μm、300-400μm)增殖促进作用显著不同,其^3H-TdR掺入速率和细胞计数分别增加23.5%和11.1%、60.0%和33.8%、141.4%和52.0%,选择对低氧最敏感的PASMCs(内径为300-400μm),进一步探讨低氧促PASMCs增殖作用的细胞机制:钙拮抗剂verapail、蛋白激酶C抑制剂staurosporine(Stau)和细胞Na-H交换抑制剂amiloride可显著降低低氧情况下PASMCs^3H-TdR掺入速率和细胞计数。结论:低氧对三种不同内径的PASMCs增殖促进作用显著不同; Ca^2 、蛋白激酶C和Na^2 -H^ 交换的激活,可能是低氧促PASMCs增殖的重要胞内信息转导机制。 相似文献