全文获取类型
收费全文 | 382篇 |
免费 | 27篇 |
国内免费 | 2篇 |
专业分类
411篇 |
出版年
2023年 | 7篇 |
2022年 | 5篇 |
2021年 | 11篇 |
2020年 | 3篇 |
2019年 | 12篇 |
2018年 | 11篇 |
2017年 | 10篇 |
2016年 | 7篇 |
2015年 | 7篇 |
2014年 | 19篇 |
2013年 | 40篇 |
2012年 | 15篇 |
2011年 | 15篇 |
2010年 | 12篇 |
2009年 | 10篇 |
2008年 | 20篇 |
2007年 | 18篇 |
2006年 | 7篇 |
2005年 | 14篇 |
2004年 | 16篇 |
2003年 | 10篇 |
2002年 | 10篇 |
2001年 | 7篇 |
2000年 | 4篇 |
1999年 | 5篇 |
1998年 | 4篇 |
1997年 | 2篇 |
1996年 | 2篇 |
1995年 | 4篇 |
1994年 | 5篇 |
1993年 | 2篇 |
1991年 | 2篇 |
1989年 | 5篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 11篇 |
1983年 | 8篇 |
1982年 | 10篇 |
1981年 | 8篇 |
1980年 | 7篇 |
1979年 | 6篇 |
1978年 | 7篇 |
1977年 | 8篇 |
1976年 | 6篇 |
1975年 | 4篇 |
1974年 | 1篇 |
1973年 | 2篇 |
1972年 | 2篇 |
排序方式: 共有411条查询结果,搜索用时 15 毫秒
351.
Hamasaki N Ishii E Tominaga K Tezuka Y Nagaoka T Kadota S Kuroki T Yano I 《Microbiology and immunology》2000,44(1):9-15
To elucidate the antibacterial activity of Gosyuyu, the crude extract from the fruit of Evodia rutaecarpa, a Chinese herbal medicine, has been fractionated chromatographically, and each fraction was assayed for antibacterial activity against Helicobacterpylori (H. pylori) in vitro. As the result, a single spot having marked antibacterial activity against H. pylori was obtained and the chemical structure was analyzed. The isolated compound was revealed to be a novel alkyl quinolone alkaloid based on the solubility, IR spectra, NMR analysis and mass spectrometric data after purification by TLC of silica. We compared the antimicrobial activity of this compound with that of other antimicrobial agents and examined susceptibility of various intestinal pathogens. As the result, the new quinolone compounds obtained from Gosyuyu extracts were found to be a mixture of two quinolone alkaloids, 1-methyl-2-[(Z)-8-tridecenyl]-4-(1H)-quinolone and 1-methyl-2-[(Z)-7-tridecenyl]-4-(1H)-quinolone (MW: 339), reported previously. The minimum inhibitory concentration (MIC) of these compounds against reference strains and clinically isolated H. pylori strains were less than 0.05 microg/ml, which was similar to the MIC of amoxicillin and clarithromycin that are used worldwide for the eradication of H. pylori, clinically. Furthermore, it was noted that the antimicrobial activity of these compounds was highly selective against H. pylori and almost non-active against other intestinal pathogens. The above results showed that these alkyl methyl quinolone (AM quinolones) alkaloids were useful for the eradication of H. pylori without affecting other intestinal flora. 相似文献
352.
Genistein as a potential inducer of the anti-atherogenic enzyme paraoxonase-1: studies in cultured hepatocytes in vitro and in rat liver in vivo 总被引:1,自引:0,他引:1
Schrader C Ernst IM Sinnecker H T Soukup S Kulling SE Rimbach G 《Journal of cellular and molecular medicine》2012,16(10):2331-2341
A number of cardioprotective effects, including the reduced oxidation of the low‐density lipoprotein (LDL) particles, have been attributed to dietary soy isoflavones. Paraoxonase 1 (PON1), an enzyme mainly synthesized in the liver, may exhibit anti‐atherogenic activity by protecting LDL from oxidation. Thus, dietary and pharmacological inducers of PON1 may decrease cardiovascular disease risk. Using a luciferase reporter gene assay we screened different flavonoids for their ability to induce PON1 in Huh7 hepatocytes in culture. Genistein was the most potent flavonoid with regard to its PON1‐inducing activity, followed by daidzein, luteolin, isorhamnetin and quercetin. Other flavonoids such as naringenin, cyanidin, malvidin and catechin showed only little or no PON1‐inducing activity. Genistein‐mediated PON1 transactivation was partly inhibited by the oestrogen‐receptor antagonist fulvestrant as well as by the aryl hydrocarbon receptor antagonist 7‐ketocholesterol. In contrast to genistein, the conjugated genistein metabolites genistein‐7‐glucuronide, genistein‐7‐sulfate and genistein‐7,4′‐disulfate were only weak inducers of PON1 transactivation. Accordingly, dietary genistein supplementation (2 g/kg diet over three weeks) in growing rats did not increase hepatic PON1 mRNA and protein levels as well as plasma PON1 activity. Thus, genistein may be a PON1 inducer in cultured hepatocytes in vitro, but not in rats in vivo. 相似文献
353.
K Stolpmann J Brinkmann S Salzmann D Genkinger E Fritsche C Hutzler H Wajant A Luch F Henkler 《Cell death & disease》2012,3(9):e388
In this study, we have analysed the apoptotic effects of the ubiquitous environmental toxin benzo[a]pyrene (BP) in HaCaT cells and human keratinocytes. Although prolonged exposure to BP was not cytotoxic on its own, a strong enhancement of CD95 (Fas)-mediated apoptosis was observed with BP at concentrations activating the aryl hydrocarbon receptor (AhR). Importantly, the ultimately mutagenic BP-metabolite, that is, (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE), failed to enhance CD95-mediated cell death, suggesting that the observed pro-apoptotic effect of BP is neither associated with DNA adducts nor DNA-damage related signalling. CD95-induced apoptosis was also enhanced by β-naphtoflavone, a well-known agonist of the AhR that does not induce DNA damage, thus suggesting a crucial role for AhR activation. Consistently, BP failed to sensitise for CD95L-induced apoptosis in AhR knockdown HaCaT cells. Furthermore, inhibition of CYP1A1 and/or 1B1 expression did not affect the pro-apoptotic crosstalk. Exposure to BP did not increase expression of CD95, but led to augmented activation of caspase-8. Enhancement of apoptosis was also observed with the TRAIL death receptors that activate caspase-8 and apoptosis by similar mechanisms as CD95. Together, these observations indicate an interference of AhR signalling with the activity of receptor-associated signalling intermediates that are shared by CD95 and TRAIL receptors. Our data thus suggest that AhR agonists can enhance cytokine-mediated adversity upon dermal exposure. 相似文献
354.
355.
Bloksgaard M Bek S Marcher AB Neess D Brewer J Hannibal-Bach HK Helledie T Fenger C Due M Berzina Z Neubert R Chemnitz J Finsen B Clemmensen A Wilbertz J Saxtorph H Knudsen J Bagatolli L Mandrup S 《Journal of lipid research》2012,53(10):2162-2174
The acyl-CoA binding protein (ACBP) is a 10 kDa intracellular protein expressed in all eukaryotic species. Mice with targeted disruption of Acbp (ACBP(-/-) mice) are viable and fertile but present a visible skin and fur phenotype characterized by greasy fur and development of alopecia and scaling with age. Morphology and development of skin and appendages are normal in ACBP(-/-) mice; however, the stratum corneum display altered biophysical properties with reduced proton activity and decreased water content. Mass spectrometry analyses of lipids from epidermis and stratum corneum of ACBP(+/+) and ACBP(-/-) mice showed very similar composition, except for a significant and specific decrease in the very long chain free fatty acids (VLC-FFA) in stratum corneum of ACBP(-/-) mice. This finding indicates that ACBP is critically involved in the processes that lead to production of stratum corneum VLC-FFAs via complex phospholipids in the lamellar bodies. Importantly, we show that ACBP(-/-) mice display a ~50% increased transepidermal water loss compared with ACBP(+/+) mice. Furthermore, skin and fur sebum monoalkyl diacylglycerol (MADAG) levels are significantly increased, suggesting that ACBP limits MADAG synthesis in sebaceous glands. In summary, our study shows that ACBP is required for production of VLC-FFA for stratum corneum and for maintaining normal epidermal barrier function. 相似文献
356.
357.
Imaoka S Muraguchi T Kinoshita T 《Biochemical and biophysical research communications》2007,355(2):419-425
Hypoxia is an important physiological condition during embryonic development. Hypoxia-inducible factor (HIF) is the mediator of hypoxic response of cells. The prolyl hydroxylase (PHD) of HIF plays a key role in stabilizing of HIF and the oxygen homeostasis of organisms. In this study, we isolated two PHD proteins, PHD45 and PHD28, and characterized them during the embryonic development of Xenopus laevis, which is an excellent model for embryonic development because of the ease of embryonic manipulation and the feasibility of transgenesis. Based on amino acid sequences, Xenopus PHD45 and PHD28 were homologous with human PHD2 and PHD3, respectively. In embryonic development, PHD45 expression was complementary to that of PHD28. xHIF-1alpha protein level was at a maximum around stage 20 when expression of PHD45 disappeared, while expression of PHD28 reached a maximum at stage 20, suggesting that PHD28 is inducible by HIF-1alpha. Recently, Siah2 was found to be an ubiquitin ligase of PHD proteins and to regulate degradation of PHD proteins. Over-expression of xSiah2 decreased PHD45 but not PHD28 and caused the small-eye phenotype of Xenopus. Additional over-expression of PHD47 rescued the abnormality caused by xSiah2, suggesting that the level of expression or activity of PHD proteins is important to the maintenance of homeostasis in embryonic development. 相似文献
358.
Guillouzo A Corlu A Aninat C Glaise D Morel F Guguen-Guillouzo C 《Chemico-biological interactions》2007,168(1):66-73
Although they have several important limitations primary human hepatocytes still represent the in vitro gold standard model for xenobiotic metabolism and toxicity studies. The large use of human liver cell lines either from tumoral origin or obtained by oncogenic immortalisation is prevented by the loss of various liver-specific functions, especially many cytochrome P450 (CYP)-related enzyme activities. We review here recent results obtained with a new human hepatoma cell line, named HepaRG, derived from a human hepatocellular carcinoma. These cells exhibit unique features: when seeded at low density they acquire an elongated undifferentiated morphology, actively divided and after having reached confluency formed typical hepatocyte-like colonies surrounded by biliary epithelial-like cells. Moreover contrary to other human hepatoma cell lines including HepG2 cells, HepaRG cells express various CYPs (CYP1A2, 2B6, 2C9, 2E1, 3A4) and the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) at levels comparable to those found in cultured primary human hepatocytes. They also express various other functions such phase 2 enzymes, apical and canalicular ABC transporters and basolateral solute carrier transporters, albumin, haptoglobin as well as aldolase B that is a specific marker of adult hepatocytes. HepaRG cells could represent a surrogate to primary human hepatocytes for xenobiotic metabolism and toxicity studies and even more, a unique model system for analysing genotoxic compounds. 相似文献
359.
Design,Synthesis, Lipophilic Properties,and Binding Affinities of Potential Ligands in Positron Emission Tomography (PET) for Visualization of Brain Dopamine D4 Receptors 下载免费PDF全文
Enza Lacivita Paola De Giorgio Nicola A. Colabufo Francesco Berardi Roberto Perrone Mauro Niso Marcello Leopoldo 《化学与生物多样性》2014,11(2):299-310
We report the synthesis of compounds structurally related to the high‐affinity dopamine D4 receptor ligand N‐{2‐[4‐(3‐cyanopyridin‐2‐yl)piperazin‐1‐yl]ethyl}‐3‐methoxybenzamide ( 1e ). All compounds were specifically designed as potential PET radioligands for brain D4 receptor visualization, having lipophilicity within a range for brain uptake and weak non‐specific binding (0.75<cLogP<3.15) and bearing a substituent for easy access to labeling with the positron emitter isotope 11C or 18F. The best compound of the series, N‐{2‐[4‐(4‐chlorophenyl)piperazin‐1‐yl]ethyl}‐6‐fluoropyridine‐3‐carboxamide ( 7a ), displayed excellent selectivity over D2 and D3 receptors (>100‐fold), but its D4 receptor affinity was suboptimal for imaging of brain D4 receptors (Ki=30 nM ). 相似文献
360.