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1.

Aim

The purpose of this study was to investigate whether the flavonoid quercetin can prevent alterations in the behavioral tests and of cholinergic neurotransmission in rats submitted to the ethidium bromide (EB) experimental demyelination model during events of demyelination and remyelination.

Main methods

Wistar rats were randomly distributed into four groups (20 animals per group): Control (pontine saline injection and treatment with ethanol), Querc (pontine saline injection and treatment with quercetin), EB (pontine 0.1% EB injection and treatment with ethanol), and EB + Querc (pontine 0.1% EB injection and treatment with quercetin). The groups Querc and Querc + EB were treated once daily with quercetin (50 mg/kg) diluted in 25% ethanol solution (1 ml/kg) and the animals of the control and EB groups were treated once daily with 25% ethanol solution (1 ml/kg). Two stages were observed: phase of demyelination (peak on day 7) and phase of remyelination (peak on day 21 post-injection). Behavioral tests (beam walking, foot fault and inclined plane test), acetylcholinesterase (AChE) activity and lipid peroxidation in pons, cerebellum, hippocampus, hypothalamus, striatum and cerebral cortex were measured.

Key findings

The quercetin promoted earlier locomotor recovery, suggesting that there was demyelination prevention or further remyelination velocity as well as it was able to prevent the inhibition of AChE activity and the increase of lipidic peroxidation, suggesting that this compound can protect cholinergic neurotransmission.

Significance

These results may contribute to a better understanding of the neuroprotective role of quercetin and the importance of an antioxidant diet in humans to provide benefits in neurodegenerative diseases such as MS.  相似文献   
2.
Alzheimer’s disease (AD) is a genetically complex, progressive and irreversible neurodegenerative disorder of the brain which involves multiple associated etiological targets. The complex pathogenesis of AD gave rise to multi-target-directed ligands (MTDLs) principle to combat this dreaded disease. Within this approach, the design and synthesis of hybrids prevailed greatly because of their capability to simultaneously target the intertwined pathogenesis components of the disease. The hybrids include pharmacophoric hybridization of two or more established chemical scaffolds endowed with the desired pharmacological properties into a single moiety. In AD, the primary foundation of medication therapy and drug design strategies includes the inhibition of cholinesterase (ChE) enzymes. Hence the development of ChE inhibition based hybrids is the central choice of AD medicinal chemistry research. To illustrate the progress of ChE inhibition based hybrids and novel targets, we reviewed the medicinal chemistry and pharmacological properties of the multi-target molecules published since 1998-December 2018. We hope that this article will allow the readers to easily follow the evolution of this prominent medicinal chemistry approach to develop a more efficient inhibitor.  相似文献   
3.
The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC50: 0.68 ± 0.13 μM) with strong DPPH and ABTS radical scavenging activity (IC50: 13.77 ± 0.25 μM and IC50: 12.59 ± 0.21 μM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC50: 0.74 ± 0.09 μM) and with DPPH and ABTS radical scavenging activity (IC50: 13.52 ± 0.62 μM and IC50: 13.13 ± 0.85 μM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents.  相似文献   
4.
In order to study the structure–activity relationship of Flavokawain B Mannich-based derivatives as acetylcholinesterase (AChE) inhibitors in our recent investigation, 20 new nitrogen-containing chalcone derivatives (4?a–8d) were designed, synthesized, and evaluated for AChE inhibitory activity in vitro. The results suggested that amino alkyl side chain of chalcone dramatically influenced the inhibitory activity against AChE. Among them, compound 6c revealed the strongest AChE inhibitory activity (IC50 value: 0.85?μmol/L) and the highest selectivity against AChE over BuChE (ratio: 35.79). Enzyme kinetic study showed that the inhibition mechanism of compound 6c against AChE was a mixed-type inhibition. The molecular docking assay showed that this compound can both bind with the catalytic site and the peripheral site of AChE.  相似文献   
5.
Zusammenfassung In der Epiphyse von Bombina kommen durch synaptic ribbons gekennzeichnete Synapsen und konventionelle Synapsen vor. Bei den ribbon-Synapsen handelt es sich um axodendritische und axosomatische Formen. Die axodendritischen ribbon-Synapsen lassen sich aufgrund der Zahl der Dendriten und der synaptic ribbons in 2 Typen gliedern. Es kommen Dendriten vor, die nacheinander in ribbon-Synapsen und konventionelle Synapsen einbezogen sind. Neben konventionellen und durch ribbons gekennzeichneten synaptischen Verbindungen finden sich weitere Kontakte zwischen Sinnes- und Nervenzellen und Interrezeptorkontakte, die jedoch beide nicht als echte Synapsen angesprochen werden können. Anhand der Befunde zur Synaptologie werden Probleme der neuronalen Schaltung der Epiphyse diskutiert.Beim Acetylcholinesterase-Nachweis findet sich das Reaktionsprodukt vor allem in den Neuropilzonen der Epiphyse. Eine eindeutige Zuordnung zu Fortsätzen bestimmter Zelltypen ist nicht möglich. Das Ergebnis des Acetylcholinesterase-Nachweises in der Epiphyse wird mit entsprechenden Befunden in anderen Bereichen des ZNS und in der Netzhaut verglichen.
The forms of synapses and the occurrence of acetylcholinesterase in the Pineal Organ of Bombina variegata (L.), (Anura)
Summary Both conventional and ribbon synapses occur in the pineal organ of Bombina. Ribbon synapses are both axodendritic and axosomatic. Two axodendritic types can be distinguished on the basis of the number of dendrites and synaptic ribbons. Both conventional and ribbon synapses can be formed with the same dendrite. Other contacts, which cannot be classified as true synapses, are also found between sensory cells and nerve cells and likewise between sensory cells. The synaptology of the pineal organ permits a discussion of the problems of its neurocircuitry.Products of the acetylcholinesterase reaction occur mainly in the plexiform layer of the pineal organ. It is not possible to correlate the reaction products with definite cell types. The results of the acetylcholinesterase reaction in the pineal is compared with corresponding findings in other parts of the CNS and in the retina of the lateral eyes.
Herrn Prof. Dr. H. Altner danke ich für die Förderung der Arbeit und die kritische Durchsicht des Manuskripts.  相似文献   
6.
It has been proposed that amplification of genes for esterase that provide resistance to insecticides may originate from transposition events. To test this hypothesis, we have constructed a minigene coding for a soluble acetylcholinesterase under the control of a nontissue-specific promoter (hsp70). When introduced into Drosophila, the gene is expressed in all tissues and the extra acetylcholinesterase produced confers a low level of insecticide resistance (twofold). The minigene was mobilized by crossing the initial transformant with a strain providing a source of P-element transposase. After 34 generations of exposure to the organophosphate parathion, we obtained a strain with a higher resistance (fivefold). This strain had only one extra Ace gene, which overexpressed acetylcholinesterase. Thus, following transposition, resistance resulted from the overexpression of a single copy of the gene and not from gene amplification. Received: 9 August 1996 / Accepted: 27 May 1997  相似文献   
7.
Antiparaoxon immune sera were employed in a new immunoassay based on competition between acetylcholinesterase and antibodies for the binding ofparaoxon. Unlike radioimmunoassay, the new assay described herein can be extended to predict the feasibility of antibodies to confer in vivo protection of acetylcholinesterase against organophosphate poisoning. The toxicity of paraoxon was reduced in mice which were pre-injected with the immune sera.  相似文献   
8.
无脊椎动物乙酰胆碱酯酶研究进展   总被引:1,自引:0,他引:1  
乙酰胆碱酯酶(AChE)是生物体中一种十分重要的神经递质水解酶,也是有机磷和氨基甲酸酯类杀虫剂的作用靶标。AChE在不同生物中的性质显著不同,如编码基因个数、序列保守性、表达分布及生理功能等。作为杀虫剂的主要作用靶标之一,AChE不但可以通过单个点突变引起昆虫抗药性,还能够通过多个点突变联合作用、靶标表达量变化及基因复制等方式引起抗药性并且改变昆虫的适合度代价。本文主要从AChE的基因类型、分子进化、蛋白结构、生理功能、与昆虫的抗药性关系、同一物种中不同AChE的性质等6个方面对昆虫纲、蛛形纲和线虫等无脊椎动物AChE的研究进展作一综述。  相似文献   
9.
The effects of tertiary amine local anesthetics (procaine, lidocaine, tetracaine and dibucaine) and chlorpromazine were investigated for three enzyme activities associated with rat brain synaptosomal membranes, i.e., (Na+ + K+)-ATPase (ouabain-sensitive), Mg2+-ATPase (ouabain-insensitive) and acetylcholinesterase. Approximately the same concentrations of each agent gave 50% inhibition of both ATPase, for example 7.9 and 10 mM tetracaine for Mg2+-ATPase and (Na+ + K+)-ATPase, respectively; these concentrations are 10-fold higher than required for inhibition of mitochondrial F1-ATPase. The relative inhibitory potency of the several agents was proportional to their octanol/water partition coefficients. Acetylcholinesterase was inhibited by all agents tested, but the ester anesthetics (procaine and tetracaine) were considerably more potent than the others after correction for partition coefficient differences. For tetracaine, 0.18 mM gave 50% inhibition and showed competitive inhibition on a Lineweaver-Burk plot, but for dibucaine a mixed type of inhibition was observed, and 0.63 mM was required for 50% inhibition. Tetracaine evidently binds at the active site, and dibucaine at the peripheral or modulator site, on this enzyme.  相似文献   
10.
Abstract: A soluble fraction from rat brain neuronal perikarya was shown to contain both the specific and nonspecific forms of the enzyme acetylcholines-terase (EC's 3.1.1.7. and 3.1.1.8., respectively). The ratio of the enzyme activities varied along the course of brain development: the nonspecific form being predominant from 1 to 15 days of age and the specific one showing the pattern of rising activity from day 15 onward. We suggest a possible relationship between this changing in cholinesterase activities and the establishment of synapses within the rat cerebral cortex.  相似文献   
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