全文获取类型
收费全文 | 1356篇 |
免费 | 71篇 |
国内免费 | 67篇 |
出版年
2024年 | 5篇 |
2023年 | 27篇 |
2022年 | 39篇 |
2021年 | 66篇 |
2020年 | 58篇 |
2019年 | 70篇 |
2018年 | 66篇 |
2017年 | 36篇 |
2016年 | 51篇 |
2015年 | 48篇 |
2014年 | 75篇 |
2013年 | 126篇 |
2012年 | 43篇 |
2011年 | 60篇 |
2010年 | 45篇 |
2009年 | 56篇 |
2008年 | 58篇 |
2007年 | 61篇 |
2006年 | 55篇 |
2005年 | 47篇 |
2004年 | 56篇 |
2003年 | 35篇 |
2002年 | 36篇 |
2001年 | 17篇 |
2000年 | 22篇 |
1999年 | 24篇 |
1998年 | 15篇 |
1997年 | 25篇 |
1996年 | 13篇 |
1995年 | 19篇 |
1994年 | 10篇 |
1993年 | 18篇 |
1992年 | 19篇 |
1991年 | 8篇 |
1990年 | 5篇 |
1989年 | 14篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 14篇 |
1985年 | 7篇 |
1984年 | 11篇 |
1983年 | 4篇 |
1982年 | 4篇 |
1981年 | 5篇 |
1980年 | 4篇 |
1979年 | 2篇 |
1977年 | 1篇 |
1976年 | 3篇 |
1974年 | 2篇 |
1972年 | 1篇 |
排序方式: 共有1494条查询结果,搜索用时 328 毫秒
171.
172.
173.
Luigi Messori Francesca Piccioli Anna Rita Bilia Marco Allegrozzi 《Inorganica chimica acta》2004,357(15):4602-4606
The mechanism of action of trioxane antimalarial drugs is still largely controversial and warrants further investigation. We report here on the direct reaction of artemisinin with hemin, carried out in DMSO, in the absence of reducing agents. The reaction was analysed, independently, by visible spectroscopy, HPLC-ESI/MS and 1H NMR. Two isomeric artemisinin-hemin long-lived adducts are unambiguously detected. Eventual degradation of the porphyrin ring and loss of the Soret band are observed as well. Implications of the present results for the mechanism of action of artemisinin-based antimalarials are discussed. 相似文献
174.
利用在体注射实验和放射免疫测定法,研究了多巴胺能药物对性腺处于再发育期虎纹蛙的促性腺激素释放激素(GnRH)及促黄体激素(LH)分泌活动的影响。结果是:多巴胺(DA)及其激素剂阿扑吗啡(APO)可显著降低血浆LH水平;而多巴胺的拮抗剂-地欧酮(DOM)可显著增加垂体LH含量。DA对脑中cGnRH-Ⅱ的合成有抑制作用,而OM对其mGnRH的释放有一定的刺激作用。结果表明:DA可在脑及垂体水平分别抑制虎纹蛙GnRH和LH的释放,DA对LH释放的抑制作用很可能是通过D2受体实现的。 相似文献
175.
RNA干扰作用(RNAi)研究进展 总被引:25,自引:4,他引:21
RNA干扰作用 (RNAi)是生物界一种古老而且进化上高度保守的现象 ,是基因转录后沉默作用 (PTGS)的重要机制之一 .RNAi主要通过dsRNA被核酸酶切割成 2 1~ 2 5nt的干扰性小RNA即siRNA ,由siRNA介导识别并靶向切割同源性靶mRNA分子而实现 .RNAi要有多种蛋白因子以及ATP参与 ,而且具有生物催化反应特征 .RNAi是新发现的一种通过dsRNA介导的特异性高效抑制基因表达途径 ,在后基因组时代的基因功能研究和药物开发中具有广阔应用前景 相似文献
176.
So Jeong Park Doo Ri Park Deepak Bhattarai Kyeong Lee Jaesang Kim Yun Soo Bae Soo Young Lee 《Molecules and cells》2014,37(8):628-635
2-(Trimethylammonium) ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate [(R)-TEMOSPho], a derivative of an organic chemical identified from a natural product library, promotes highly efficient megakaryopoiesis. Here, we show that (R)-TEMOSPho blocks osteoclast maturation from progenitor cells of hematopoietic origin, as well as blocking the resorptive function of mature osteoclasts. The inhibitory effect of (R)-TEMOSPho on osteoclasts was due to a disruption of the actin cytoskeleton, resulting from impaired downstream signaling of c-Fms, a receptor for macrophage-colony stimulating factor linked to c-Cbl, phosphoinositol-3-kinase (PI3K), Vav3, and Rac1. In addition, (R)-TEMOSPho blocked inflammation-induced bone destruction by reducing the numbers of osteoclasts produced in mice. Thus, (R)-TEMOSPho may represent a promising new class of antiresorptive drugs for the treatment of bone loss associated with increased osteoclast maturation and activity. 相似文献
177.
《Bioorganic & medicinal chemistry》2016,24(7):1419-1430
Parkinson’s disease (PD) is a common chronic degenerative disease of the central nervous system. Due to a rapidly aging society worldwide, PD morbidity is on the rise; however, the treatment of PD with conventional drugs carries serious adverse reactions and cannot fix the root cause of PD, the degeneration of dopaminergic neurons, which limits conventional drug usage in clinical practice. In recent years, research on the pathogenesis of PD and its clinical manifestations has led to the discovery of an increasing number of novel targets in PD, including several small molecule targeted compounds. In this paper, we analyze and summarize the most recently published PD literature and review several recently discovered novel targets in PD and their small molecule targeted pharmacologically active agents based on their mechanisms of action and pharmacodynamic profiles. 相似文献
178.
Elaine R. Reynolds Eric A. Stauffer Laura Feeney Elizabeth Rojahn Benjamin Jacobs Carol McKeever 《Developmental neurobiology》2004,58(4):503-513
Drosophila bang‐sensitive (bs) mutants exhibit a stereotypic seizure and paralysis following exposure to mechanical shock. In a physiological preparation, seizures and failures corresponding to the defective behavior are observed in response to high frequency stimulation. The amplitude of the stimulus necessary to produce bs behavior, or seizure threshold, varies with bs mutant and its gene dosage. In many respects, the bs defects are similar to those observed in mammalian seizure disorders. Antiepileptic drugs (AEDs) were administered by feeding to easily shocked2 (eas2), a representative bs mutant. The mean recovery times of treated flies were examined in comparison to control cultures. Some of the drugs administered, including carbamazeprine, ethosuximide, and vigabactrin, had little or no effect on the bs behavior of eas2. Gabapentin, however, showed a reduction in mean recovery time with chronic drug exposure. Phenytoin also had a significant effect on the bs behavior of treated flies. There was a reduction of both mean recovery time and the percentage of flies that displayed bang‐sensitive behavior with both acute and chronic treatment. The adult giant fiber preparation was used to examine the effects of phenytoin physiologically. Treated eas2 flies showed changes in their response to normal stimulation as well as alterations in seizure threshold in response to high frequency stimulation. Gabapentin was also effective against two other bs mutants, bangsenseless1 and slamdanceiso7.8, at strain‐specific concentrations, while phenytoin also reduced bang‐sensitive behaviors in bangsenseless1 in a dose dependent manner. AEDs, therefore, can be used to dissect aspects of bs behavior and this model may be useful in understanding the underlying basis of seizure disorders. © 2003 Wiley Periodicals, Inc. J Neurobiol 58: 503–513, 2004 相似文献
179.
The Oxidative Inactivation of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) by Hypochlorous Acid (HOCl) is Suppressed by Anti-Rheumatic Drugs 总被引:2,自引:0,他引:2
Tissue inhibitors of metalloproteinases (TIMPs) prevent uncontrolled connective tissue destruction by limiting the activity of matrix metalloproteinases (MMPs). That TIMPs should be susceptible to oxidative inactivation is suggested by their complex tertiary structure which is dependent upon 6 disulphide bonds. We examined the oxidative inactivation of human recombinant TIMP-1 (hr TIMP-1) by HOCl and the inhibition of this process by anti-rheumatic agents.
TIMP-1 was exposed to HOCl in the presence of a variety of disease modifying anti-rheumatic drugs. TIMP-1 activity was measured by its ability to inhibit BC1 collagenase activity as measured by a fluorimetric assay using the synthetic pEptide substrate (DNP-Pro-Leu-Ala-Leu-Trp-Ala-Arg), best cleaved by MMP-1.
The neutrophil derived oxidant HOCl, but not the derived oxidant N-chlorotaurine, can inactivate TIMP-1 at concentrations achieved at sites of inflammation. Anti-rheumatic drugs have the ability to protect hrTIMP-1 from inactivation by HOCl. For D-penicil-lamine, this effect occurs at plasma levels achieved with patients taking the drug but for other anti-rheumatic drugs tested this occurs at relatively high concentrations that are unlikely to be achieved in vivo, except possibly in a microenvironment. These results are in keeping with the concept that biologically derived oxidants can potentiate tissue damage by inactivating key but susceptible protein inhibitors such as TIMP-1 which form the major local defence against MMP induced tissue breakdown. 相似文献
TIMP-1 was exposed to HOCl in the presence of a variety of disease modifying anti-rheumatic drugs. TIMP-1 activity was measured by its ability to inhibit BC1 collagenase activity as measured by a fluorimetric assay using the synthetic pEptide substrate (DNP-Pro-Leu-Ala-Leu-Trp-Ala-Arg), best cleaved by MMP-1.
The neutrophil derived oxidant HOCl, but not the derived oxidant N-chlorotaurine, can inactivate TIMP-1 at concentrations achieved at sites of inflammation. Anti-rheumatic drugs have the ability to protect hrTIMP-1 from inactivation by HOCl. For D-penicil-lamine, this effect occurs at plasma levels achieved with patients taking the drug but for other anti-rheumatic drugs tested this occurs at relatively high concentrations that are unlikely to be achieved in vivo, except possibly in a microenvironment. These results are in keeping with the concept that biologically derived oxidants can potentiate tissue damage by inactivating key but susceptible protein inhibitors such as TIMP-1 which form the major local defence against MMP induced tissue breakdown. 相似文献
180.
The anticancer drug mitomycin C produces cytotoxic effects after being converted to a highly reactive bis-electrophile by a reductive activation, a reaction that a number of 1-electron or 2-electron oxidoreductase enzymes can perform in cells. Several reports in the literature indicate that ascorbic acid can modulate the cytotoxic effects of mitomycin C, either potentiating or inhibiting its effects. As ascorbic acid is a reducing agent that is known to be able to reduce quinones, it could be possible that the observed modulatory effects are a consequence of a direct redox reduction between mitomycin C and ascorbate. To determine if this is the case, the reaction between mitomycin C and ascorbate was studied using UV/Vis spectroscopy and LC/MS. We also studied the reaction of ascorbate with mitomycin A, a highly toxic member of the mitomycin family with a higher redox potential than mitomycin C. We found that ascorbate is capable to reduce mitomycin A efficiently, but it reduces mitomycin C rather inefficiently. The mechanisms of activation have been elucidated based on the kinetics of the reduction and on the analysis of the mitosene derivatives formed after the reaction. We found that the activation occurs by the interplay of three different mechanisms that contribute differently, depending on the pH of the reaction. As the reduction of mitomycin C by ascorbate is rather inefficiently at physiologically relevant pH values we conclude that the modulatory effect of ascorbate on the cytotoxicity of mitomycin C is not the result of a direct redox reaction and therefore this modulation must be the consequence of other biochemical mechanisms. 相似文献