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951.
Xing‐Zhu Lu Xue‐Yuan Bi Xi He Ming Zhao Man Xu Xiao‐Jiang Yu Zheng‐Hang Zhao Wei‐Jin Zang 《British journal of pharmacology》2015,172(23):5619-5633
Background and Purpose
The activation of M 3 cholinoceptors (M 3 receptors) by choline reduces cardiovascular risk, but it is unclear whether these receptors can regulate ischaemia/reperfusion (I/R)‐induced vascular injury. Thus, the primary goal of the present study was to explore the effects of choline on the function of mesenteric arteries following I/R, with a major focus on Ca2+/calmodulin‐dependent protein kinase II (CaMKII) regulation.Experimental Approach
Rats were given choline (10 mg·kg−1, i.v.) and then the superior mesenteric artery was occluded for 60 min (ischaemia), followed by 90 min of reperfusion. The M 3 receptor antagonist, 4‐diphenylacetoxy‐N‐methylpiperidine methiodide (4‐DAMP), was injected (0.12 μg·kg−1, i.v.) 5 min prior to choline treatment. Vascular function was examined in rings of mesenteric arteries isolated after the reperfusion procedure. Vascular superoxide anion production, CaMKII and the levels of Ca2+‐cycling proteins were also assessed.Key Results
Choline treatment attenuated I/R‐induced vascular dysfunction, blocked elevations in the levels of reactive oxygen species (ROS) and decreased the up‐regulated expression of oxidised CaMKII and phosphorylated CaMKII. In addition, choline reversed the abnormal expression of Ca2+‐cycling proteins, including Na+/Ca2+ exchanger, inositol 1,4,5‐trisphosphate receptor, sarcoplasmic reticulum Ca2+‐ATPase and phospholamban. All of these cholinergic effects of choline were abolished by 4‐DAMP.Conclusions and Implications
Our data suggest that inhibition of the ROS‐mediated CaMKII pathway and modulation of Ca2+‐cycling proteins may be novel mechanisms underlying choline‐induced vascular protection. These results represent a significant addition to the understanding of the pharmacological roles of M 3 receptors in the vasculature, providing a new therapeutic strategy for I/R‐induced vascular injury.Linked Articles
This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23Abbreviations
- 4‐DAMP
- 4‐diphenylacetoxy‐N‐methylpiperidine methiodide
- CaMKII
- Ca2+/calmodulin‐dependent protein kinase II
- DHE
- dihydroethidium
- I/R
- ischaemia/reperfusion
- IP3R
- inositol 1,4,5‐trisphosphate receptor
- NAC
- N‐acetyl‐L‐cysteine
- NCX
- Na+/Ca2+ exchanger
- PLB
- phospholamban
- ROS
- reactive oxygen species
- SERCA
- sarcoplasmic reticulum Ca2+‐ATPase
- SNP
- sodium nitroprusside
TARGETS |
---|
GPCRs a |
M3 receptors |
Enzymes b |
SERCA 2, sarcoplasmic reticulum Ca2+‐ATPase |
Ion channels c |
NCX1, Na+/Ca2+ exchanger |
Ligand‐gated ion channels d |
IP3R, inositol 1,4,5‐trisphosphate receptor |
LIGANDS |
---|
4‐DAMP, 4‐diphenylacetoxy‐N‐methylpiperidine methiodide |
5‐HT |
ACh |
Caffeine |
Choline |
Darifenacin |
KN‐93 |
L‐NAME, NG‐nitro‐L‐arginine methyl ester |
Phenylephrine |
952.
Wen‐Lin Cheng Pi‐Xiao Wang Tao Wang Yan Zhang Cheng Du Hongliang Li Yong Ji 《British journal of pharmacology》2015,172(23):5676-5689
Background and Purpose
Atherosclerosis is a chronic inflammatory disease, in which ‘vulnerable plaques’ have been recognized as the underlying risk factor for coronary disease. Regulator of G‐protein signalling (RGS) 5 controls endothelial cell function and inflammation. In this study, we explored the effect of RGS5 on atherosclerosis and the potential underlying mechanisms.Experimental Approach
RGS5−/− apolipoprotein E (ApoE)−/− and ApoE −/− littermates were fed a high‐fat diet for 28 weeks. Total aorta surface and lipid accumulation were measured by Oil Red O staining and haematoxylin–eosin staining was used to analyse the morphology of atherosclerotic lesions. Inflammatory cell infiltration and general inflammatory mediators were examined by immunofluorescence staining. Apoptotic endothelial cells and macrophages were assayed with TUNEL. Expression of RGS5and adhesion molecules, and ERK1/2 phosphorylation were evaluated by co‐staining with CD31. Expression of mRNA and protein were determined by quantitative real‐time PCR and Western blotting respectively.Key Results
Atherosclerotic phenotypes were significantly accelerated in RGS5−/− ApoE −/− mice, as indicated by increased inflammatory mediator expression and apoptosis of endothelial cells and macrophages. RGS5 deficiency enhanced instability of vulnerable plaques by increasing infiltration of macrophages in parallel with the accumulation of lipids, and decreased smooth muscle cell and collagen content. Mechanistically, increased activation of NF‐κB and MAPK/ERK 1/2 could be responsible for the accelerated development of atherosclerosis in RGS5‐deficient mice.Conclusions and Implications
RGS5 deletion accelerated development of atherosclerosis and decreased the stability of atherosclerotic plaques partly through activating NF‐κB and the MEK‐ERK1/2 signalling pathways.Linked Articles
This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23Abbreviations
- ApoE
- apolipoprotein E
- CHD
- coronary heart disease
- H&E
- haematoxylin‐eosin
- ICAM‐1
- intercellular adhesion molecue‐1
- LDL
- low‐density lipoprotein
- MEK
- MAPK/ERK kinase
- RGS
- regulator of G‐protein signalling
- SMC
- smooth muscle cell
- VCAM‐1
- vascular cell adhesion molecule‐1
TARGETS |
---|
Enzymes |
Caspase 3 |
ERK1/2 |
JNK1/2 |
MEK 1 |
MEK 2 |
p38 (kinase) |
LIGANDS |
---|
ICAM‐1 |
IL‐10 |
IL‐1β |
IL‐6 |
RGS5 |
TNFα |
VCAM‐1 |
953.
954.
Sun Ya Nan Li Wei Kim Jang Hoon Yan Xi Tao Kim Ji Eun Yang Seo Young Kim Young Ho 《Archives of pharmacal research》2015,38(6):998-1004
Archives of Pharmacal Research - Fourteen compounds were isolated from a methanol extract of Polygonum multiflorum roots, and their structures were elucidated by comparing spectroscopic data to... 相似文献
955.
Dimethylarsinic acid (DMAV) changed the expressions of proliferative related factors and secretion of inflammatory cytokines in rat bladder 下载免费PDF全文
Zhang Lin Liu Shengnan Wang Fei Song Yingli Sun Qingshan Sheng Wei Xi. Shuhua Sun Guifan 《Journal of applied toxicology : JAT》2015,35(2):133-141
Dimethylarsinic acid (DMAV), the major urinary metabolite of inorganic arsenic, is a urinary bladder carcinogen and bladder tumor promoter in adult rats. Increased urothelial cellular proliferation has been considered as an earlier phenotype in DMAV‐induced bladder carcinogenesis. The present study examined the ultrastructural changes of bladder epithelial cells and expressions of proliferation factors, as well as the secretion of inflammatory cytokines in rats exposed to DMAV for 10 weeks by transmission electron microscopy (TEM), qRT‐PCR, immunohistochemical staining and ELISA methods. The results showed that DMAV administered in the drinking water produced urothelial cytotoxicity and ultrastructural changes in rats. PCNA, cyclin D1 and COX‐2 mRNA expressions and immunoreactivities were elevated in bladder urothelium. In addition, 200 ppm DMAV treatment increased the transforming growth factor‐beta 1 (TGF‐β1) secretion and decreased tumor necrosis factor‐alpha (TNF)‐α level in the urine of rats. These data suggest that chronic inflammation, bladder epithelium lesions and proliferation might be the basic process of the chronic toxicity effects in DMAV‐treated rats. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
956.
Biological effect of food additive titanium dioxide nanoparticles on intestine: an in vitro study 下载免费PDF全文
Zheng‐Mei Song Ni Chen Jia‐Hui Liu Huan Tang Xiaoyong Deng Wen‐Song Xi Kai Han Aoneng Cao Yuanfang Liu Haifang Wang 《Journal of applied toxicology : JAT》2015,35(10):1169-1178
Titanium dioxide nanoparticles (TiO2 NPs) are widely found in food‐related consumer products. Understanding the effect of TiO2 NPs on the intestinal barrier and absorption is essential and vital for the safety assessment of orally administrated TiO2 NPs. In this study, the cytotoxicity and translocation of two native TiO2 NPs, and these two TiO2 NPs pretreated with the digestion simulation fluid or bovine serum albumin were investigated in undifferentiated Caco‐2 cells, differentiated Caco‐2 cells and Caco‐2 monolayer. TiO2 NPs with a concentration less than 200 µg ml–1 did not induce any toxicity in differentiated cells and Caco‐2 monolayer after 24 h exposure. However, TiO2 NPs pretreated with digestion simulation fluids at 200 µg ml–1 inhibited the growth of undifferentiated Caco‐2 cells. Undifferentiated Caco‐2 cells swallowed native TiO2 NPs easily, but not pretreated NPs, implying the protein coating on NPs impeded the cellular uptake. Compared with undifferentiated cells, differentiated ones possessed much lower uptake ability of these TiO2 NPs. Similarly, the traverse of TiO2 NPs through the Caco‐2 monolayer was also negligible. Therefore, we infer the possibility of TiO2 NPs traversing through the intestine of animal or human after oral intake is quite low. This study provides valuable information for the risk assessment of TiO2 NPs in food. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
957.
Vitamin D3 potentiates the growth inhibitory effects of metformin in DU145 human prostate cancer cells mediated by AMPK/mTOR signalling pathway 下载免费PDF全文
Hong‐Xia Li Jing‐Miao Gao Jia‐Qi Liang Jun‐Min Xi Meng Fu Yong‐Jie Wu 《Clinical and experimental pharmacology & physiology》2015,42(6):711-717
Metformin and vitamin D3 both exhibit a strong antiproliferative action in numerous cancer cell lines, including in human prostate cancer cells. Here we showed that the combination of the two drugs had a much stronger effect on DU145 human prostate cancer cell growth than either drug alone. In this research, cell proliferation was measured by methylthiazol tetrazolium (MTT) assay. Cell apoptosis was determined with Hoechst 33342 staining. Western blotting and cell cycle analyses were used to elucidate potential mechanisms of interaction between the drugs. It is shown that in cultured DU145 cells, vitamin D3 combined with metformin exhibits synergistic effects on cell proliferation and apoptosis. The underlying antitumor mechanisms may involve altered cycle distribution with a G1/S cell cycle arrest, activation of phospho‐AMPK with subsequent inhibition of downstream mTOR signalling pathway, down‐regulate c‐Myc expression, and reducing the level of anti‐apoptotic protein p‐Bcl‐2. In conclusion, metformin and vitamin D3 synergistically inhibit DU145 cell growth, indicating a promising clinical therapeutic strategy for the treatment of androgen‐independent prostate cancer. 相似文献
958.
Correlation between osteocalcin‐positive endothelial progenitor cells and spotty calcification in patients with coronary artery disease 下载免费PDF全文
He Zhang Li‐jun Wang Dong‐lei Si Chuan Wang Jing‐ci Yang Ping Jiang Chao Du Jian‐jun Wang 《Clinical and experimental pharmacology & physiology》2015,42(7):734-739
Immature endothelial progenitor cells (EPC) carrying osteocalcin (OCN) might mediate vascUlar calcification in coronary artery disease (CAD). Spotty calcification within atherosclerotic plaque is associated with cardiovascular events. The aim of the present study was to assess the correlation between immature EPC levels and spotty calcification in CAD patients. In the 224 CAD patients studied, 76 had acute myocardial infarction (AMI), 102 had unstable angina pectoris (UAP), and 46 had stable angina pectoris (SAP). The levels of OCN‐positive (OCN+) EPC were analysed by flow cytometry. The status of spotty calcification was determined by cardiac computed tomography angiography. OCN+ EPC and calcium deposits were significantly increased in acute coronary artery syndrome (ACS) when compared with those in SAP patients. Positive correlation was also revealed between the number of OCN+ EPC and the frequency of spotty calcification and levels of serum high‐sensitivity C‐reactive protein (hs‐CRP) and serum alkaline phosphatase in AMI and UAP patients. In summary, the number of OCN+ EPC is positively related to the frequency of spotty calcification in ACS patients. Serum hs‐CRP and serum alkaline levels are thought to contribute to the elevation of OCN+ EPC. 相似文献
959.
960.
Bingqing Zhu Zheng Xu Pengcheng Du Li Xu Xiaofang Sun Yuan Gao Zhujun Shao 《Emerging infectious diseases》2015,21(6):925-932
Serogroup B Neisseria meningitidis strains belonging to sequence type 4821 clonal complex (CC4821), a hyperinvasive lineage first identified for serogroup C in 2003, have been increasingly isolated in China. We characterized the outer membrane protein genes of 48 serogroup B and 214 serogroup C strains belonging to CC4821 and analyzed the genomic sequences of 22 strains. Four serogroup B strains had porin A (i.e., PorA), PorB, and ferric enterobactin transport (i.e., FetA) genotypes identical to those for serogroup C. Phylogenetic analysis of the genomic sequences showed that the 22 CC4821 strains from patients and healthy carriers were unevenly clustered into 2 closely related groups; each group contained serogroup B and C strains. Serogroup B strains appeared variable at the capsule locus, and several recombination events had occurred at uncertain breakpoints. These findings suggest that CC4821 serogroup C N. meningitidis is the probable origin of highly pathogenic CC4821 serogroup B strains. 相似文献