全文获取类型
收费全文 | 795篇 |
免费 | 51篇 |
国内免费 | 29篇 |
出版年
2023年 | 11篇 |
2022年 | 8篇 |
2021年 | 22篇 |
2020年 | 30篇 |
2019年 | 38篇 |
2018年 | 44篇 |
2017年 | 26篇 |
2016年 | 28篇 |
2015年 | 42篇 |
2014年 | 93篇 |
2013年 | 88篇 |
2012年 | 43篇 |
2011年 | 63篇 |
2010年 | 44篇 |
2009年 | 53篇 |
2008年 | 48篇 |
2007年 | 47篇 |
2006年 | 31篇 |
2005年 | 37篇 |
2004年 | 30篇 |
2003年 | 22篇 |
2002年 | 10篇 |
2001年 | 2篇 |
2000年 | 5篇 |
1999年 | 2篇 |
1998年 | 2篇 |
1997年 | 1篇 |
1995年 | 1篇 |
1993年 | 1篇 |
1991年 | 1篇 |
1986年 | 1篇 |
1985年 | 1篇 |
排序方式: 共有875条查询结果,搜索用时 15 毫秒
51.
甲壳素脱乙酰酶(chitin deacetylase,CDA,E.C.3.5.1.41)是一种能催化脱去甲壳素分子中N-乙酰葡糖胺链上的乙酰基,使之变成壳聚糖的酶。而壳聚糖因其独特的性质被广泛应用于医药、食品、化工、化妆品等行业。对CDA的来源、分离纯化和酶学性质、结构和催化机制、基因的克隆表达及应用前景等方面的研究进行了综述,并分析出今后的主要研究方向应在CDA基因的克隆表达、CDA底物的改造及CDA的结构和催化机制等方面。 相似文献
52.
Epigenetic and posttranslational modifications of the expression of cell cycle-relevant genes or proteins like p21, e.g., by miRNAs are crucial mechanisms in the development or prevention of colon cancer. The present study investigated the influence of butyrate and trichostatin A (TSA) as histone deacetylase inhibitors on the expression of colon cancer-relevant miRNA (miR-135a, miR-135b, miR-24, miR-106b, miR-let-7a) in LT97 colon adenoma cells as a model of an early stage of colon carcinogenesis. The impact of distinct miRNAs (miR-106b, miR-135a) on butyrate-mediated regulation of p21 and Cyclin D2 gene and protein expression as well as the effect on LT97 cell proliferation (non-transfected, miR-106b and miR-135a mimic transfected) was analyzed. Butyrate and partial TSA reduced the expression of miR-135a, miR-135b, miR-24 and miR-let-7a (~0.5-fold, 24 h) and miR-24, miR-106b and miR-let-7a (~0.5–0.7-fold, 48 h) in LT97 cells. Levels of p21 mRNA and protein were significantly increased by butyrate and TSA (~threefold and 4.5-fold, respectively, 24 h) in non-transfected but not in miR-106b transfected LT97 cells. Levels of Cyclin D2 mRNA were significantly reduced by butyrate and TSA (~0.3-fold, 24 h) in non-transfected and miR-135a-transfected LT97 cells, whereas protein levels were predominantly not influenced. MiR-106b and miR-135a significantly reduced butyrate-/TSA-mediated inhibition of LT97 cell proliferation (72 h). These results indicate that butyrate is able to modify colon cancer-relevant miRNAs like miR-106b and miR-135a which are involved in the regulation of cell cycle-relevant genes like p21 and might influence inhibition of adenoma cell proliferation.
Electronic supplementary material
The online version of this article (doi:10.1007/s12263-015-0500-4) contains supplementary material, which is available to authorized users. 相似文献53.
The biochemical events surrounding ischemia reperfusion injury in the acute setting are of great importance to furthering novel treatment options for myocardial infarction and cardiac complications of thoracic surgery. The ability of certain drugs to precondition the myocardium against ischemia reperfusion injury has led to multiple clinical trials, with little success. The isolated heart model allows acute observation of the functional effects of ischemia reperfusion injury in real time, including the effects of various pharmacological interventions administered at any time-point before or within the ischemia-reperfusion injury window. Since brief periods of ischemia can precondition the heart against ischemic injury, in situ aortic cannulation is performed to allow for functional assessment of non-preconditioned myocardium. A saline filled balloon is placed into the left ventricle to allow for real-time measurement of pressure generation. Ischemic injury is simulated by the cessation of perfusion buffer flow, followed by reperfusion. The duration of both ischemia and reperfusion can be modulated to examine biochemical events at any given time-point. Although the Langendorff isolated heart model does not allow for the consideration of systemic events affecting ischemia and reperfusion, it is an excellent model for the examination of acute functional and biochemical events within the window of ischemia reperfusion injury as well as the effect of pharmacological intervention on cardiac pre- and postconditioning. The goal of this protocol is to demonstrate how to perform in situ aortic cannulation and heart excision followed by ischemia/reperfusion injury in the Langendorff model. 相似文献
54.
Cardiac hypertrophy is a form of global remodeling, although the initial step
seems to be an adaptation to increased hemodynamic demands. The characteristics
of cardiac hypertrophy include the functional reactivation of the arrested fetal
gene program, where histone deacetylases (HDACs) are closely linked in the
development of the process. To date, mammalian HDACs are divided into four
classes: I, II, III, and IV. By structural similarities, class II HDACs are then
subdivided into IIa and IIb. Among class I and II HDACs, HDAC2, 4, 5, and 9 have
been reported to be involved in hypertrophic responses; HDAC4, 5, and 9 are
negative regulators, whereas HDAC2 is a pro-hypertrophic mediator. The molecular
function and regulation of class IIa HDACs depend largely on the
phosphorylation-mediated cytosolic redistribution, whereas those of HDAC2 take
place primarily in the nucleus. In response to stresses, posttranslational
modification (PTM) processes, dynamic modifications after the translation of
proteins, are involved in the regulation of the activities of those
hypertrophy-related HDACs. In this article, we briefly review 1) the activation
of HDAC2 in the development of cardiac hypertrophy and 2) the PTM of HDAC2 and
its implications in the regulation of HDAC2 activity. [BMB Reports 2015; 48(3):
131-138] 相似文献
55.
Amornrat Naranuntarat Jensen Worathad Chindaudomsate Kanate Thitiananpakorn Skorn Mongkolsuk Laran T. Jensen 《FEBS letters》2014
Lysine deacetylases (KDACs) inhibitors may have therapeutic value in anti-malarial combination therapies with artemisinin. To evaluate connections between KDACs and artemisinin, Saccharomyces cerevisiae deletion mutants in KDAC genes were assayed. Deletion of RPD3, but not other KDAC genes, resulted in strong sensitivity to artemisinin, which was also observed in sit4Δ mutants with impaired endoplasmic reticulum (ER) to Golgi protein trafficking. Decreased accumulation of the transporters Pdr5p, Fur4p, and Tat2p was observed in rpd3Δ and sit4Δ cells. The unfolded protein response is induced in rpd3Δ cells consistent with retention of proteins in the ER. Disruption of protein trafficking appears to sensitize cells to artemisinin and targeting these pathways may be useful as part of artemisinin based anti-malarial therapy. 相似文献
56.
Haejin Yoon Seung-Hyun ShinDong Hoon Shin Yang-Sook ChunJong-Wan Park 《Biochemical and biophysical research communications》2014
Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) determine cancer cell fate under hypoxia. Despite the similarities of their structures, HIF-1α and HIF-2α have distinct roles in cancer growth under hypoxia, that is, HIF-1α induces growth arrest whereas HIF-2α promotes cell growth. Recently, sirtuin 1 (Sirt1) was reported to fine-tune cellular responses to hypoxia by deacetylating HIF-1α and HIF-2α. Yet, the roles of Sirt1 in HIF-1α and HIF-2α functions have been controversial. We here investigated the precise roles of Sirt1 in HIF-1α and HIF-2α regulations. Immunological analyses revealed that HIF-1α K674 and HIF-2α K741 are acetylated by PCAF and CBP, respectively, but are deacetylated commonly by Sirt1. In the Gal4 reporter systems, Sirt1 was found to repress HIF-1α activity constantly in ten cancer cell-lines but to regulate HIF-2α activity cell type-dependently. Moreover, Sirt1 determined cell growth under hypoxia depending on HIF-1α and HIF-2α. Under hypoxia, Sirt1 promoted cell proliferation of HepG2, in which Sirt1 differentially regulates HIF-1α and HIF-2α. In contrast, such an effect of Sirt1 was not shown in HCT116, in which Sirt1 inactivates both HIF-1α and HIF-2α because conflicting actions of HIF-1α and HIF-2α on cell growth may be offset. Our results provide a better understanding of the roles of Sirt1 in HIF-mediated hypoxic responses and also a basic concept for developing anticancer strategy targeting Sirt1. 相似文献
57.
58.
Courtney R. LaValle Kara M. George Elizabeth R. Sharlow John S. Lazo Peter Wipf Q. Jane Wang 《生物化学与生物物理学报:癌评论》2010
Protein kinase D is a novel family of serine/threonine kinases and diacylglycerol receptors that belongs to the calcium/calmodulin-dependent kinase superfamily. Evidence has established that specific PKD isoforms are dysregulated in several cancer types, and PKD involvement has been documented in a variety of cellular processes important to cancer development, including cell growth, apoptosis, motility, and angiogenesis. In light of this, there has been a recent surge in the development of novel chemical inhibitors of PKD. This review focuses on the potential of PKD as a chemotherapeutic target in cancer treatment and highlights important recent advances in the development of PKD inhibitors. 相似文献
59.
Pei-Ming Yang Wen-Yu Huang Shu-Hao Yeh 《Biochemical and biophysical research communications》2010,391(3):1396-79
Methotrexate (MTX) is a dihydrofolate reductase (DHFR) inhibitor widely used for treating human cancers, and overexpression of histone deacetylase (HDAC) is usually found in tumors. HDAC inhibitors (HDACi) can reactivate tumor suppressor genes and serve as potential anti-cancer drugs. In this study, we found that MTX shared structural similarity with some HDACi and molecular modeling showed that MTX indeed docks into the active site of HDLP, a bacterial homologue of HDAC. Subsequent in vitro assay demonstrated MTX’s inhibition on HDAC activity in human cancer cells. The global acetylation of histone H3 was also induced by MTX. Moreover, MTX inhibited immunoprecipitated HDAC1/2 activity but not their protein levels. This study provides evidence that MTX inhibits HDAC activity. 相似文献
60.