3,3′,4′-Trihydroxyflavone and 3′,4′-dihydroxyflavone inhibited A

3,3′,4′-Trihydroxyflavone and 3′,4′-dihydroxyflavone inhibited A beta fibril formation more potently than fisetin or

3′,4′,7-trihydroxyflavone, suggesting that the 7-hydroxy group is not necessary for anti-amyloidogenic activity. 3,3′,4′,5′-Tetrahydroxyflavone and 3′,4′,5′-trihydroxyflavone inhibited A beta fibril formation far more potently than 3,3′,4′-trihydroxyflavone and 3′,4′-dihydroxyflavone, suggesting that 3′,4′,5′-trihydroxyl group of the B ring is crucial for the anti-amyloidogenic activity of flavonoids. Based on the structure-activity relationship, we synthesized 3,3′,4′,5,5′-pentahydroxyflavone, and confirmed that this compound is the most potent inhibitor of A beta fibril formation among fisetin analogues that have been tested. Cytotoxicity Quizartinib chemical structure assay using rat hippocampal neuron cultures demonstrated that A beta preincubated with 3,3′,4′,5,5′-pentahydroxyflavone GSK2118436 in vitro was significantly less toxic than A beta preincubated with vehicle. 3,3′,4′,5,5′-Pentahydroxyflavone could be a new therapeutic drug candidate for the treatment of Alzheimer’s disease. (c) 2012 Elsevier Ireland Ltd. All rights reserved.”

inherited polyglutamine disorders are chronic neurodegenerative diseases therapeutically amenable to gene-specific silencing strategies. Several compelling nucleic acid-based approaches have recently been developed to block the expression of mutant proteins and prevent toxic LCL161 mouse neurodegenerative sequelae. With such approaches, avoiding potential side effects caused by the concomitant ablation of the normal protein is an important objective. Therefore, allele-specific gene silencing is highly desirable; however, retaining wild type function is complex given that the common CAG mutation cannot be directly targeted, and might not be necessary or justifiable in all cases. Insights from polyglutamine gene function studies and the further development of allele-specific and other gene silencing methodologies will be important to determine

the optimal therapeutic strategy for each polyglutamine disorder.”
“Childhood trauma is a potent risk factor for developing depression in adulthood, particularly in response to additional stress. We here summarize results from a series of. clinical studies suggesting that childhood trauma in humans is associated with sensitization of the neuroendocrine stress response, glucocorticoid resistance, increased central corticotropin-releasing factor (CRF) activity, immune activation, and reduced hippocampal volume, closely paralleling several of the neuroendocrine features of depression. Neuroendocrine changes secondary to early-life stress likely reflect risk to develop depression in response to stress, potentially due to failure of a connected neural circuitry implicated in emotional, neuroendocrine and autonomic control to compensate in response to challenge.

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