全文获取类型
收费全文 | 684篇 |
免费 | 94篇 |
国内免费 | 1篇 |
专业分类
779篇 |
出版年
2021年 | 15篇 |
2020年 | 5篇 |
2019年 | 10篇 |
2018年 | 17篇 |
2017年 | 15篇 |
2016年 | 8篇 |
2015年 | 24篇 |
2014年 | 24篇 |
2013年 | 33篇 |
2012年 | 33篇 |
2011年 | 29篇 |
2010年 | 29篇 |
2009年 | 11篇 |
2008年 | 27篇 |
2007年 | 32篇 |
2006年 | 26篇 |
2005年 | 36篇 |
2004年 | 22篇 |
2003年 | 22篇 |
2002年 | 26篇 |
2001年 | 24篇 |
2000年 | 26篇 |
1999年 | 30篇 |
1998年 | 9篇 |
1997年 | 7篇 |
1996年 | 9篇 |
1995年 | 9篇 |
1994年 | 6篇 |
1993年 | 9篇 |
1992年 | 15篇 |
1991年 | 12篇 |
1990年 | 17篇 |
1989年 | 18篇 |
1988年 | 11篇 |
1987年 | 11篇 |
1986年 | 12篇 |
1985年 | 7篇 |
1982年 | 5篇 |
1981年 | 6篇 |
1980年 | 5篇 |
1979年 | 6篇 |
1978年 | 10篇 |
1977年 | 5篇 |
1976年 | 8篇 |
1975年 | 6篇 |
1974年 | 7篇 |
1973年 | 7篇 |
1972年 | 7篇 |
1971年 | 8篇 |
1969年 | 5篇 |
排序方式: 共有779条查询结果,搜索用时 15 毫秒
101.
Allicin inhibits cell growth and induces apoptosis through the mitochondrial pathway in HL60 and U937 cells 总被引:2,自引:0,他引:2
Miron T Wilchek M Sharp A Nakagawa Y Naoi M Nozawa Y Akao Y 《The Journal of nutritional biochemistry》2008,19(8):524-535
In this article, the effects of allicin, a biological active compound of garlic, on HL60 and U937 cell lines were examined. Allicin induced growth inhibition and elicited apoptotic events such as blebbing, mitochondrial membrane depolarization, cytochrome c release into the cytosol, activation of caspase 9 and caspase 3 and DNA fragmentation. Pretreatment of HL60 cells with cyclosporine A, an inhibitor of the mitochondrial permeability transition pore (mPTP), inhibited allicin-treated cell death. HL60 cell survival after 1 h pretreatment with cyclosporine A, followed by 16 h in presence of allicin (5 microM) was approximately 80% compared to allicin treatment alone (approximately 50%). Also N-acetyl cysteine, a reduced glutathione (GSH) precursor, prevented cell death. The effects of cyclosporine A and N-acetyl cysteine suggest the involvement of mPTP and intracellular GSH level in the cytotoxicity. Indeed, allicin depleted GSH in the cytosol and mitochondria, and buthionine sulfoximine, a specific inhibitor of GSH synthesis, significantly augmented allicin-induced apoptosis. In HL60 cells treated with allicin (5 microM, 30 min) the redox state for 2GSH/oxidized glutathione shifted from EGSH -240 to -170 mV. The same shift was observed in U937 cells treated with allicin at a higher concentration for a longer period of incubation (20 microM, 2 h). The apoptotic events induced by various concentrations of allicin correlate to intracellular GSH levels in the two cell types tested (HL60: 3.7 nmol/10(6) cells; U937: 7.7 nmol/10(6) cells). The emerging mechanistic basis for the antiproliferative function of allicin, therefore, involves the activation of the mitochondrial apoptotic pathway by GSH depletion and by changes in the intracellular redox status. 相似文献
102.
Pasternak A Goble SD Vicario PP Di Salvo J Ayala JM Struthers M DeMartino JA Mills SG Yang L 《Bioorganic & medicinal chemistry letters》2008,18(3):994-998
This report describes replacement of the 4-(4-fluorophenyl)piperidine moiety in our CCR2 antagonists with 4-heteroaryl piperidine and 4-(carboxyphenyl)-piperidine subunits. Some of the resulting analogs retained potency in our CCR2 binding assay and had improved selectivity versus the I(Kr) channel; poor selectivity against I(Kr) had been a liability of earlier analogs in this series. 相似文献
103.
Pasternak A Goble SD Doss GA Tsou NN Butora G Vicario PP Ayala JM Struthers M Demartino JA Mills SG Yang L 《Bioorganic & medicinal chemistry letters》2008,18(4):1374-1377
In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold. 相似文献
104.
The presence of ATP in the genital tract fluid of mammals provokes questions regarding its function in the fertilization process. We investigated the effect of extracellular ATP (ATPe) on the activation of bovine spermatozoa. A signal transduction mechanism for ATP involving the receptor-mediated release of second messengers is described. Treatment of spermatozoa with ATP, uridine triphosphate (UTP), or 2-methylthio-ATP resulted in a concentration-dependent increase of acrosomal exocytosis, whereas treatment with either AMP or adenosine induced little exocytosis. This suggested that the receptor involved is of the P2 and not the P1 type. Several lines of evidence also suggest that the ATP purinoceptor is of the P2y and not the P2x type. First, the acrosome reaction was induced by the P2y-agonists ATP, UTP, or 2-methylthio-ATP, but no effects were shown by the P2x-agonists alpha,beta-methylene-ATP or beta,gamma-methylene-ATP. Second, ATP-induced acrosomal exocytosis was inhibited by the P2y antagonists, but not by the P2x antagonists. Third, enhanced Ca2+ uptake into the cells was observed with ATP and 2-methylthio-ATP, but not with beta,gamma-methylene-ATP. Additionally, ATP induced elevation of intracellular Ca2+ and cAMP, and the effect on cAMP was predominantly enhanced by including Ca2+ and the Ca2+-ionophore A23187 in the incubation medium. Extracellular ATP also activates protein kinase Calpha (PKCalpha), and the acrosome reaction, stimulated by ATPe, is inhibited by a PKC-specific inhibitor. In summary, we suggest that ATPe activates the P2 purinoceptor that elevates [Ca2+]i, which leads to PKCalpha activation and culminates in acrosomal exocytosis. 相似文献
105.
D Ayala P Lissoni C Archili S Barni G Roveda M Giacomelli A Bissi 《Journal of biological regulators and homeostatic agents》1990,4(4):150-152
The endocrine effects of ovariectomy need to be further investigated. The present study was carried out to evaluate the influence of the adjuvant ovariectomy on the mastectomy-induced changes in PRL response to TRH in breast cancer. The study included 34 patients with locally limited breast carcinoma, 18 of whom were treated with radical mastectomy, whereas the other 16 underwent mastectomy plus adjuvant ovariectomy. PRL secretion in response to TRH (200 mcg I.V. as bolus) was evaluated one day before and 7 days after surgery. In patients treated with mastectomy only, PRL increase after TRH was significantly higher after surgery than before. On the contrary, no difference was seen in patients treated with mastectomy plus ovariectomy. This study shows that the adjuvant ovariectomy may block the increase in PRL response to TRH induced by mastectomy in breast cancer. 相似文献
106.
Changiz Geula Sara R. Dunlop Ivan Ayala Allegra S. Kawles Margaret E. Flanagan Tamar Gefen Marek-Marsel Mesulam 《Journal of neurochemistry》2021,158(6):1394-1411
107.
Naphthalene is an environmental toxicant to which humans are exposed. Naphthalene causes dose-dependent cytotoxicity to murine airway epithelial cells but a link between exposure and human pulmonary disease has not been established. Naphthalene toxicity in rodents depends on P450 metabolism. Subsequent biotransformation results in urinary elimination of several conjugated metabolites. Glucuronide and sulfate conjugates of naphthols have been used as markers of naphthalene exposure but, as the current studies demonstrate, these assays provide a limited view of the range of metabolites generated from the parent hydrocarbon. Here, we present a liquid chromatography tandem mass spectrometry method for measurement of the glucuronide and sulfate conjugates of 1-naphthol as well as the mercapturic acids and N-acetyl glutathione conjugates from naphthalene epoxide. Standard curves were linear over 2 log orders. On column detection limits varied from 0.91 to 3.4 ng; limits of quantitation from 1.8 to 6.4 ng. The accuracy of measurement of spiked urine standards was -13.1 to + 5.2% of target and intra-day and inter-day variability averaged 7.2 (± 4.5) and 6.8 (± 5.0) %, respectively. Application of the method to urine collected from mice exposed to naphthalene at 15 ppm (4 hrs) showed that glutathione-derived metabolites accounted for 60-70% of the total measured metabolites and sulfate and glucuronide conjugates were eliminated in equal amounts. The method is robust and directly measures several major naphthalene metabolites including those derived from glutathione conjugation of naphthalene epoxide. The assays do not require enzymatic deconjugation, extraction or derivatization thus simplifying sample work up. 相似文献
108.
109.
Florentino Carral San Laureano José Vicente Gutiérrez Manzanedo Carmen Ayala Ortega Concepción García Calzado Juan José Silva Rodríguez Manuel Aguilar Diosdado 《Endocrinología y nutrición》2010,57(6):268-276
Together with a balanced diet, regular physical activity is one of the pillars of diabetes mellitus (DM) management. Physical activity theoretically provides the same advantages in people with DM as in the general population and also has some beneficial effects in controlling metabolic factors, such as improving blood glucose levels and insulin sensitivity. In this article, we analyze the main clinical studies published to date that evaluate the impact of physical activity on metabolic control or the development of chronic complications in patients with type 1 diabetes mellitus. In conclusion, most of the evaluated studies show that regular physical activity favorably affects metabolic control in DM (or at least does not have adverse effects). However, there is insufficient information about the impact of physical activity on the development and progression of chronic complications. 相似文献
110.