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排序方式: 共有10000条查询结果,搜索用时 62 毫秒
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Jeanine Jochems Janette Boulden Bridgin G Lee Julie A Blendy Matthew Jarpe Ralph Mazitschek John H Van Duzer Simon Jones Olivier Berton 《Neuropsychopharmacology》2014,39(2):389-400
HDAC inhibitors have been reported to produce antidepressant and pro-cognitive effects in animal models, however, poor brain bioavailability or lack of isoform selectivity of current probes has limited our understanding of their mode of action. We report the characterization of novel pyrimidine hydroxyl amide small molecule inhibitors of HDAC6, brain bioavailable upon systemic administration. We show that two compounds in this family, ACY-738 and ACY-775, inhibit HDAC6 with low nanomolar potency and a selectivity of 60- to 1500-fold over class I HDACs. In contrast to tubastatin A, a reference HDAC6 inhibitor with similar potency and peripheral activity, but more limited brain bioavailability, ACY-738 and ACY-775 induce dramatic increases in α-tubulin acetylation in brain and stimulate mouse exploratory behaviors in novel, but not familiar environments. Interestingly, despite a lack of detectable effect on histone acetylation, we show that ACY-738 and ACY-775 share the antidepressant-like properties of other HDAC inhibitors, such as SAHA and MS-275, in the tail suspension test and social defeat paradigm. These effects of ACY-738 and ACY-775 are directly attributable to the inhibition of HDAC6 expressed centrally, as they are fully abrogated in mice with a neural-specific loss of function of HDAC6. Furthermore, administered in combination, a behaviorally inactive dose of ACY-738 markedly potentiates the anti-immobility activity of a subactive dose of the selective serotonin reuptake inhibitor citalopram. Our results validate new isoform-selective probes for in vivo pharmacological studies of HDAC6 in the CNS and reinforce the viability of this HDAC isoform as a potential target for antidepressant development. 相似文献
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Geoffrey N. Gobert Hong You Malcolm K. Jones Russell McInnes Donald P. McManus 《Molecular and cellular probes》2013,27(1):19-27
The Chinese (SjC) and Philippine (SjP) strains of the blood fluke Schistosoma japonicum have been shown to present clearly different phenotypes in fecundity, pathology, drug sensitivity and immunology. We used microarray based comparative genomic hybridisation (aCGH) to investigate structural differences in the genomes of the two strains and identified seven distinct regions of the S. japonicum genome that present differential aCGH representing either deletion or duplication regions in SjP. Within these regions, genes predicted to be associated with the recognised phenotypic differences were identified and that may provide new insights into the biology and evolution of the two strains, with implications for the epidemiology and control of schistosomiasis japonica in China and the Philippines. 相似文献
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Anthony K. P. Jones Nathan T. M. Huneke Donna M. Lloyd Chris A. Brown Alison Watson 《Current rheumatology reports》2012,14(6):557-567
Rheumatic pain and, in particular, rheumatoid arthritis, osteoarthritis and fibromyalgia, are common and debilitating chronic pain syndromes. Recently, human functional neuroimaging, for example EEG, fMRI, and PET has begun to reveal some of the crucial central nervous system mechanisms underlying these diseases. The purpose of this review is to summarise current knowledge on the brain mechanisms of rheumatic pain revealed by functional neuroimaging techniques. The evidence suggests that two mechanisms may be largely responsible for the clinical pain associated with these rheumatic diseases: abnormalities in the medial pain system and/or central nervous system sensitisation and inhibition. If we can understand how functioning of the central nociceptive system becomes altered, even in the absence of peripheral nociceptive input, by using functional neuroimaging techniques, in the future we may be able to develop improved, more effective treatments for patients with chronic rheumatic pain. 相似文献