全文获取类型
收费全文 | 172篇 |
免费 | 3篇 |
出版年
2023年 | 2篇 |
2021年 | 6篇 |
2020年 | 6篇 |
2019年 | 6篇 |
2018年 | 4篇 |
2017年 | 2篇 |
2016年 | 7篇 |
2015年 | 8篇 |
2014年 | 12篇 |
2013年 | 15篇 |
2012年 | 13篇 |
2011年 | 13篇 |
2010年 | 7篇 |
2009年 | 6篇 |
2008年 | 11篇 |
2007年 | 6篇 |
2006年 | 7篇 |
2005年 | 4篇 |
2004年 | 8篇 |
2003年 | 6篇 |
2002年 | 8篇 |
2001年 | 4篇 |
2000年 | 2篇 |
1998年 | 1篇 |
1997年 | 2篇 |
1990年 | 1篇 |
1989年 | 2篇 |
1985年 | 1篇 |
1982年 | 1篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有175条查询结果,搜索用时 46 毫秒
1.
Iron(III)-adriamycin and Iron(III)-daunorubicin complexes: physicochemical characteristics, interaction with DNA, and antitumor activity 总被引:1,自引:0,他引:1
Fe(III) complexes of two anthracyclines, adriamycin and daunorubicin, have been studied. Using potentiometric and spectroscopic measurements, we have shown that adriamycin and daunorubicin form two well-defined species with Fe(III), which can be formulated as respectively Fe(HAd)3 and Fe(HDr)3. In these formulas, HAd and HDr stand for adriamycin and daunorubicin in which the 1,4-dihydroxy-anthraquinone moiety is half-deprotonated. Both complexes are six-membered chelates. The stability constant is beta = (2.5 +/- 0.5) X 10(28) for both complexes. Interaction with DNA has been studied showing that, despite strong coordination to Fe(III), anthracyclines are able to intercalate between DNA bases pairs, releasing the metal. These complexes display antitumor activity against P 388 leukemia that compares with that of the free drug. Fe(HAd)3, unlike adriamycin, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase. Moreover, it is shown that the triferric adriamycin compound so called "quelamycin" is in fact a mixture of Fe(HAd)3 and polymeric ferric hydroxide. 相似文献
2.
3.
Heloisa P. Soares Yang Ni Krisztina Kisfalvi James Sinnett-Smith Enrique Rozengurt 《PloS one》2013,8(2)
The mTOR pathway is aberrantly stimulated in many cancer cells, including pancreatic ductal adenocarcinoma (PDAC), and thus it is a potential target for therapy. However, the mTORC1/S6K axis also mediates negative feedback loops that attenuate signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feed-back loops unleashes over-activation of upstream pathways that potentially counterbalance the antiproliferative effects of mTOR inhibitors. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic cancer cells with either rapamycin or active-site mTOR inhibitors suppressed S6K and S6 phosphorylation induced by insulin and the GPCR agonist neurotensin. Rapamycin caused a striking increase in Akt phosphorylation at Ser473 while the active-site inhibitors of mTOR (KU63794 and PP242) completely abrogated Akt phosphorylation at this site. Conversely, active-site inhibitors of mTOR cause a marked increase in ERK activation whereas rapamycin did not have any stimulatory effect on ERK activation. The results imply that first and second generation of mTOR inhibitors promote over-activation of different pro-oncogenic pathways in PDAC cells, suggesting that suppression of feed-back loops should be a major consideration in the use of these inhibitors for PDAC therapy. In contrast, metformin abolished mTORC1 activation without over-stimulating Akt phosphorylation on Ser473 and prevented mitogen-stimulated ERK activation in PDAC cells. Metformin induced a more pronounced inhibition of proliferation than either KU63794 or rapamycin while, the active-site mTOR inhibitor was more effective than rapamycin. Thus, the effects of metformin on Akt and ERK activation are strikingly different from allosteric or active-site mTOR inhibitors in PDAC cells, though all these agents potently inhibited the mTORC1/S6K axis. 相似文献
4.
Kelli Cristina Micocci Ana Carolina Baptista Moreno Martin Cyntia de Freitas Montenegro Araceli Cristina Durante Normand Pouliot Márcia Regina Cominetti Heloisa Sobreiro Selistre-de-Araujo 《Biochimie》2013
ADAM9 (A Disintegrin And Metalloproteinase 9) is a member of the ADAM protein family which contains a disintegrin domain. This protein family plays key roles in many physiological processes, including fertilization, migration, and cell survival. The ADAM proteins have also been implicated in various diseases, including cancer. Specifically, ADAM9 has been suggested to be involved in metastasis. To address this question, we generated ADAM9 knockdown clones of MDA-MB-231 breast tumor cells using silencing RNAs that were tested for cell adhesion, proliferation, migration and invasion assays. In RNAi-mediated ADAM9 silenced MDA-MB-231 cells, the expression of ADAM9 was lower from the third to the sixth day after silencing and inhibited tumor cell invasion in matrigel by approximately 72% when compared to control cells, without affecting cell adhesion, proliferation or migration. In conclusion, the generation of MDA-MB-231 knockdown clones lacking ADAM9 expression inhibited tumor cell invasion in vitro, suggesting that ADAM9 is an important molecule in the processes of invasion and metastasis. 相似文献
5.
Tiago G. Santos Flavio H. Beraldo Glaucia N. M. Hajj Marilene H. Lopes Martin Roffe Fernanda C. S. Lupinacci Valeriy G. Ostapchenko Vania F. Prado Marco A. M. Prado Vilma R. Martins 《Journal of neurochemistry》2013,124(2):210-223
Prion protein (PrPC) is a cell surface glycoprotein that is abundantly expressed in nervous system. The elucidation of the PrPC interactome network and its significance on neural physiology is crucial to understanding neurodegenerative events associated with prion and Alzheimer's diseases. PrPC co‐opts stress inducible protein 1/alpha7 nicotinic acetylcholine receptor (STI1/α7nAChR) or laminin/Type I metabotropic glutamate receptors (mGluR1/5) to modulate hippocampal neuronal survival and differentiation. However, potential cross‐talk between these protein complexes and their role in peripheral neurons has never been addressed. To explore this issue, we investigated PrPC‐mediated axonogenesis in peripheral neurons in response to STI1 and laminin‐γ1 chain‐derived peptide (Ln‐γ1). STI1 and Ln‐γ1 promoted robust axonogenesis in wild‐type neurons, whereas no effect was observed in neurons from PrPC‐null mice. PrPC binding to Ln‐γ1 or STI1 led to an increase in intracellular Ca2+ levels via distinct mechanisms: STI1 promoted extracellular Ca2+ influx, and Ln‐γ1 released calcium from intracellular stores. Both effects depend on phospholipase C activation, which is modulated by mGluR1/5 for Ln‐γ1, but depends on, C‐type transient receptor potential (TRPC) channels rather than α7nAChR for STI1. Treatment of neurons with suboptimal concentrations of both ligands led to synergistic actions on PrPC‐mediated calcium response and axonogenesis. This effect was likely mediated by simultaneous binding of the two ligands to PrPC. These results suggest a role for PrPC as an organizer of diverse multiprotein complexes, triggering specific signaling pathways and promoting axonogenesis in the peripheral nervous system. 相似文献
6.
Marina Azevêdo Souza Susana Johann Luciana Alves Rodrigues dos Santos Lima Fernanda Fraga Campos Isolda Castro Mendes Heloisa Beraldo Elaine Maria de Souza-Fagundes Patrícia Silva Cisalpino Carlos Augusto Rosa Tania Maria de Almeida Alves Nívea Pereira de Sá Carlos Leomar Zani 《Memórias do Instituto Oswaldo Cruz》2013,108(3):342-351
Lapachol was chemically modified to obtain its thiosemicarbazone and semicarbazone derivatives. These compounds were tested for antimicrobial activity against several bacteria and fungi by the broth microdilution method. The thiosemicarbazone and semicarbazone derivatives of lapachol exhibited antimicrobial activity against the bacteria Enterococcus faecalis and Staphylococcus aureus with minimal inhibitory concentrations (MICs) of 0.05 and 0.10 µmol/mL, respectively. The thiosemicarbazone and semicarbazone derivatives were also active against the pathogenic yeast Cryptococcus gattii (MICs of 0.10 and 0.20 µmol/mL, respectively). In addition, the lapachol thiosemicarbazone derivative was active against 11 clinical isolates of Paracoccidioides brasiliensis, with MICs ranging from 0.01-0.10 µmol/mL. The lapachol-derived thiosemicarbazone was not cytotoxic to normal cells at the concentrations that were active against fungi and bacteria. We synthesised, for the first time, thiosemicarbazone and semicarbazone derivatives of lapachol. The MICs for the lapachol-derived thiosemicarbazone against S. aureus, E. faecalis, C. gattii and several isolates of P. brasiliensis indicated that this compound has the potential to be developed into novel drugs to treat infections caused these microbes. 相似文献
7.
8.
Danielly Beraldo dos Santos Silva Luana Mireli Carbonera Rodrigues Adriana Araújo de Almeida Kelly Mari Pires de Oliveira Alexéia Barufatti Grisolia/ 《Memórias do Instituto Oswaldo Cruz》2016,111(3):192-199
The azoles are the class of medications most commonly used to fight infections caused
by Candida sp. Typically, resistance can be attributed to mutations
in ERG11 gene (CYP51) which encodes the cytochrome P450
14α-demethylase, the primary target for the activity of azoles. The objective of this
study was to identify mutations in the coding region of theERG11
gene in clinical isolates of Candidaspecies known to be resistant to
azoles. We identified three new synonymous mutations in the ERG11
gene in the isolates of Candida glabrata (C108G, C423T and A1581G)
and two new nonsynonymous mutations in the isolates of Candida
krusei - A497C (Y166S) and G1570A (G524R). The functional consequence of
these nonsynonymous mutations was predicted using evolutionary conservation scores.
The G524R mutation did not have effect on 14α-demethylase functionality, while the
Y166S mutation was found to affect the enzyme. This observation suggests a possible
link between the mutation and dose-dependent sensitivity to voriconazole in the
clinical isolate of C. krusei. Although the presence of the Y166S in
phenotype of reduced azole sensitivity observed in isolate C.
kruseidemands investigation, it might contribute to the search of new
therapeutic agents against resistant Candida isolates. 相似文献
9.
10.
We have previously reported that lizard red blood cells control their cytosolic calcium concentration by sequestering calcium ions in pools, which could be discharged by thapsigargin, by the Na+/H+ ionophore, monensin, by the K+/H+ ionophore, nigericin and by the proton pump inhibitor, bafilomycin A1 [1]. We have now demonstrated, with the aid of confocal microscopy, the presence in these cells of organelles, which accumulate the dye acridine orange and are thus by inference the sites of proton pools. We have found, moreover, that monensin, nigericin and bafilomycin all act to discharge these pools. We further show that calcium release ensues when the calcium ionophore, ionomycin, is added after thapsigargin and monensin; this implies the existence of a third pool, besides the acidic pool and the Endoplasmic Reticulum (ER), which participates in calcium homeostasis. The ER calcium pool can de discharged by the addition of the second messenger, IP3, and we present evidence, based on confocal microscopy, that the IP3 receptors are located in or close to the nucleus. 相似文献