全文获取类型
收费全文 | 1226篇 |
免费 | 74篇 |
出版年
2023年 | 8篇 |
2022年 | 10篇 |
2021年 | 50篇 |
2020年 | 16篇 |
2019年 | 33篇 |
2018年 | 43篇 |
2017年 | 22篇 |
2016年 | 44篇 |
2015年 | 74篇 |
2014年 | 85篇 |
2013年 | 117篇 |
2012年 | 121篇 |
2011年 | 112篇 |
2010年 | 52篇 |
2009年 | 59篇 |
2008年 | 75篇 |
2007年 | 80篇 |
2006年 | 58篇 |
2005年 | 43篇 |
2004年 | 32篇 |
2003年 | 30篇 |
2002年 | 24篇 |
2001年 | 10篇 |
2000年 | 6篇 |
1999年 | 5篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 8篇 |
1995年 | 2篇 |
1994年 | 5篇 |
1993年 | 4篇 |
1992年 | 3篇 |
1989年 | 7篇 |
1988年 | 3篇 |
1987年 | 7篇 |
1986年 | 3篇 |
1985年 | 5篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 3篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 5篇 |
1974年 | 5篇 |
1973年 | 3篇 |
1972年 | 2篇 |
1968年 | 1篇 |
排序方式: 共有1300条查询结果,搜索用时 15 毫秒
61.
Carolina Serena Enrique Calvo Mari Paz Clares María Luisa Diaz Javier U. Chicote Raúl Beltrán-Debon Ramón Fontova Alejandro Rodriguez Enrique García-Espa?a Antonio García-Espa?a 《PloS one》2015,10(3)
Background
The clinical use of purified SOD enzymes has strong limitations due to their large molecular size, high production cost and immunogenicity. These limitations could be compensated by using instead synthetic SOD mimetic compounds of low molecular weight.Background/Methodology
We have recently reported that two SOD mimetic compounds, the MnII complexes of the polyamines Pytren2Q and Pytren4Q, displayed high antioxidant activity in bacteria and yeast. Since frequently molecules with antioxidant properties or free-radical scavengers also have anti-inflammatory properties we have assessed the anti-inflammatory potential of Pytren2Q and Pytren4Q MnII complexes, in cultured macrophages and in a murine model of inflammation, by measuring the degree of protection they could provide against the cellular injury produced by lipopolisacharide, a bacterial endotoxin.Principal Findings
In this report we show that the MnII complex of Pytren4Q but not that of Pytren2Q effectively protected human cultured THP-1 macrophages and whole mice from the inflammatory effects produced by LPS. These results obtained with two molecules that are isomers highlight the importance of gathering experimental data from animal models of disease in assessing the potential of candidate molecules.Conclusion/Significance
The effective anti-inflammatory activity of the MnII complex of Pytren4Q in addition to its low toxicity, water solubility and ease of production would suggest it is worth taking into consideration for future pharmacological studies. 相似文献62.
Elena Turola Salvatore Petta Ester Vanni Fabiola Milosa Luca Valenti Rosina Critelli Luca Miele Livia Maccio Vincenza Calvaruso Anna L. Fracanzani Marcello Bianchini Nazarena Raos Elisabetta Bugianesi Serena Mercorella Marisa Di Giovanni Antonio Craxì Silvia Fargion Antonio Grieco Calogero Cammà Franco Cotelli Erica Villa 《Disease models & mechanisms》2015,8(9):1037-1046
63.
Cinzia Scambi Sara Ugolini T. Sakari Jokiranta Lucia De Franceschi Oscar Bortolami Valentina La Verde Patrizia Guarini Paola Caramaschi Viviana Ravagnani Guido Martignoni Chiara Colato Serena Pedron Fabio Benedetti Marco Sorio Fabio Poli Domenico Biasi 《PloS one》2015,10(2)
ObjectiveThe role of complement system in the pathogenesis of systemic sclerosis (SSc) has been debated during the last decade but an evident implication in this disease has never been found. We carried out an explorative study on SSc patients to evaluate the expression of soluble and local C5b-9 complement complex and its relation with a complement regulator, the Membrane Cofactor Protein (MCP, CD46) on skin vascular bed as target distinctive of SSc disease. We also analyzed two polymorphic variants in the complement activation gene cluster involving the MCP region.MethodsC5b-9 plasma levels of SSc patients and healthy subjects were analyzed by ELISA assay. Archival skin biopsies of SSc patients and controls were subjected to immunofluorescence analysis to detect C5b-9 and MCP on vascular endothelial cells. The expression of MCP was validated by immunoblot analysis with specific antibody. Polymorphic variants in the MCP gene promoter were tested by a quantitative PCR technique-based allelic discrimination method.ResultsEven though circulating levels of C5b-9 did not differ between SSc and controls, C5b-9 deposition was detected in skin biopsies of SSc patients but not in healthy subjects. MCP was significantly lower in skin vessels of SSc patients than in healthy controls and was associated with the over-expression of two polymorphic variants in the MCP gene promoter, which has been related to more aggressive phenotypes in other immune-mediated diseases.ConclusionsOur results firsty document the local complement activation with an abnormal expression of MCP in skin vessels of SSc patients, suggesting that a subset of SSc patients might be exposed to more severe organ complications and clinical evolution due to abnormal local complement activation. 相似文献
64.
65.
66.
Elena Grossini Kevin Bellofatto Serena Farruggio Lorenzo Sigaudo Patrizia Marotta Giulia Raina Veronica De Giuli David Mary Piero Pollesello Rosalba Minisini Mario Pirisi Giovanni Vacca 《PloS one》2015,10(4)
Background
Levosimendan protects rat liver against peroxidative injuries through mechanisms related to nitric oxide (NO) production and mitochondrial ATP-dependent K (mitoKATP) channels opening. However, whether levosimendan could modulate the cross-talk between apoptosis and autophagy in the liver is still a matter of debate. Thus, the aim of this study was to examine the role of levosimendan as a modulator of the apoptosis/autophagy interplay in liver cells subjected to peroxidation and the related involvement of NO and mitoKATP.Methods and Findings
In primary rat hepatocytes that have been subjected to oxidative stress, Western blot was performed to examine endothelial and inducible NO synthase isoforms (eNOS, iNOS) activation, apoptosis/autophagy and survival signalling detection in response to levosimendan. In addition, NO release, cell viability, mitochondrial membrane potential and mitochondrial permeability transition pore opening (MPTP) were examined through specific dyes. Some of those evaluations were also performed in human hepatic stellate cells (HSC). Pre-treatment of hepatocytes with levosimendan dose-dependently counteracted the injuries caused by oxidative stress and reduced NO release by modulating eNOS/iNOS activation. In hepatocytes, while the autophagic inhibition reduced the effects of levosimendan, after the pan-caspases inhibition, cell survival and autophagy in response to levosimendan were increased. Finally, all protective effects were prevented by both mitoKATP channels inhibition and NOS blocking. In HSC, levosimendan was able to modulate the oxidative balance and inhibit autophagy without improving cell viability and apoptosis.Conclusions
Levosimendan protects hepatocytes against oxidative injuries by autophagic-dependent inhibition of apoptosis and the activation of survival signalling. Such effects would involve mitoKATP channels opening and the modulation of NO release by the different NOS isoforms. In HSC, levosimendan would also play a role in cell activation and possible evolution toward fibrosis. These findings highlight the potential of levosimendan as a therapeutic agent for the treatment or prevention of liver ischemia/reperfusion injuries. 相似文献67.
Serena P. Koenig Alexandra Bornstein Karine Severe Elizabeth Fox Jessy G. Dévieux Patrice Severe Patrice Joseph Adias Marcelin Dgndy Alexandre Bright Ngoc Pham Pierre Cremieux Jean William Pape 《PloS one》2015,10(11)
Objective
We assessed the association between gender and mortality on antiretroviral therapy (ART) using identical models with and without sex-specific categories for weight and hemoglobin.Design
Cohort study of adult patients on ART.Setting
GHESKIO Clinic in Port-au-Prince, Haiti.Participants
4,717 ART-naïve adult patients consecutively enrolled on ART at GHESKIO from 2003 to 2008.Main Outcome Measure
Mortality on ART; multivariable analyses were conducted with and without sex-specific categories for weight and hemoglobin.Results
In Haiti, male gender was associated with mortality (OR 1.61; 95% CI: 1.30–2.00) in multivariable analyses with hemoglobin and weight included as control variables, but not when sex-specific interactions with hemoglobin and weight were used.Conclusions
If sex-specific categories are omitted, multivariable analyses indicate a higher risk of mortality for males vs. females of the same weight and hemoglobin. However, because males have higher normal values for weight and hemoglobin, the males in this comparison would generally have poorer health status than the females. This may explain why gender differences in mortality are sometimes observed after controlling for differences in baseline variables when gender-specific interactions with weight and hemoglobin are omitted. 相似文献68.
Alessandra Silvestri Francesco Palumbo Ignazio Rasi Daniela Posca Theodora Pavlidou Serena Paoluzi Luisa Castagnoli Giovanni Cesareni 《PloS one》2015,10(8)
Introduction
Metformin is proposed as adjuvant therapy in cancer treatment because of its ability to limit cancer incidence by negatively modulating the PI3K/AKT/mTOR pathway. In vitro, in addition to inhibiting cancer cell proliferation, metformin can also induce apoptosis. The molecular mechanism underlying this second effect is still poorly characterized and published data are often contrasting. We investigated how nutrient availability can modulate metformin-induced apoptosis in three breast cancer cell lines.Material and Methods
MCF7, SKBR3 and MDA-MB-231 cells were plated in MEM medium supplemented with increasing glucose concentrations or in DMEM medium and treated with 10 mM metformin. Cell viability was monitored by Trypan Blue assay and treatment effects on Akt/mTOR pathway and on apoptosis were analysed by Western Blot. Moreover, we determined the level of expression of pyruvate kinase M2 (PKM2), a well-known glycolytic enzyme expressed in cancer cells.Results
Our results showed that metformin can induce apoptosis in breast cancer cells when cultured at physiological glucose concentrations and that the pro-apoptotic effect was completely abolished when cells were grown in high glucose/high amino acid medium. Induction of apoptosis was found to be dependent on AMPK activation but, at least partially, independent of TORC1 inactivation. Finally, we showed that, in nutrient-poor conditions, metformin was able to modulate the intracellular glycolytic equilibrium by downregulating PKM2 expression and that this mechanism was mediated by AMPK activation.Conclusion
We demonstrated that metformin induces breast cancer cell apoptosis and PKM2 downregulation only in nutrient-poor conditions. Not only glucose levels but also amino acid concentration can influence the observed metformin inhibitory effect on the mTOR pathway as well as its pro-apoptotic effect. These data demonstrate that the reduction of nutrient supply in tumors can increase metformin efficacy and that modulation of PKM2 expression/activity could be a promising strategy to boost metformin anti-cancer effect. 相似文献69.
Serena Rinaldo Giorgio GiardinaFrancesca Cutruzzolà 《Biochemical and biophysical research communications》2014
The reduction of nitrite into nitric oxide (NO) in denitrifying bacteria is catalyzed by nitrite reductase. In several species, this enzyme is a heme-containing protein with one c heme and one d1 heme per monomer (cd1NiR), encoded by the nirS gene. 相似文献
70.
Trincavelli ML Cuboni S Catena Dell'osso M Maggio R Klotz KN Novi F Panighini A Daniele S Martini C 《Purinergic signalling》2010,6(4):373-381
A(2A) adenosine receptors are considered an excellent target for drug development in several neurological and psychiatric disorders. It is noteworthy that the responses evoked by A(2A) adenosine receptors are regulated by D(2) dopamine receptor ligands. These two receptors are co-expressed at the level of the basal ganglia and interact to form functional heterodimers. In this context, possible changes in A(2A) adenosine receptor functional responses caused by the chronic blockade/activation of D(2) dopamine receptors should be considered to optimise the therapeutic effectiveness of dopaminergic agents and to reduce any possible side effects. In the present paper, we investigated the regulation of A(2A) adenosine receptors induced by antipsychotic drugs, commonly acting as D(2) dopamine receptor antagonists, in a cellular model co-expressing both A(2A) and D(2) receptors. Our data suggest that the treatment of cells with the classical antipsychotic haloperidol increased both the affinity and responsiveness of the A(2A) receptor and also affected the degree of A(2A)-D(2) receptor heterodimerisation. In contrast, an atypical antipsychotic, clozapine, had no effect on A(2A) adenosine receptor parameters, suggesting that the two classes of drugs have different effects on adenosine-dopamine receptor interaction. Modifications to A(2A) adenosine receptors may play a significant role in determining cerebral adenosine effects during the chronic administration of antipsychotics in psychiatric diseases and may account for the efficacy of A(2A) adenosine receptor ligands in pathologies associated with dopaminergic system dysfunction. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11302-010-9201-z) contains supplementary material, which is available to authorized users. 相似文献