Abnormal visual experience during the critical period can cause deficits in visual function,such as amblyopia.High magnesium(Mg^(2+))supplementary can restore ocular dominance(OD)plasticity,which promotes the recovery...Abnormal visual experience during the critical period can cause deficits in visual function,such as amblyopia.High magnesium(Mg^(2+))supplementary can restore ocular dominance(OD)plasticity,which promotes the recovery of amblyopic eye acuity in adults.However,it remains unsolved whether Mg^(2+)could recover binocular vision in amblyopic adults and what the molecular mechanism is for the recovery.We found that in addition to the recovery of OD plasticity,binocular integration can be restored under the treatment of high Mg^(2+)in amblyopic mice.Behaviorally,Mg^(2+)-treated amblyopic mice showed better depth perception.Moreover,the effect of high Mg^(2+)can be suppressed with transient receptor potential melastatin-like 7(TRPM7)knockdown.Collectively,our results demonstrate that high Mg^(2+)could restore binocular visual functions from amblyopia.TRPM7 is required for the restoration of plasticity in the visual cortex after high Mg^(2+)treatment,which can provide possible clinical applications for future research and treatment of amblyopia.展开更多
Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from o...Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 mu mol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.展开更多
基金National Natural Science Foundation of China(31872764 and 82171090)Shanghai Science and Technology Committee Rising-Star Program(19QA1401600)+1 种基金Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJLab,Shanghai Center for Brain Science and Brain-Inspired Technology.
文摘Abnormal visual experience during the critical period can cause deficits in visual function,such as amblyopia.High magnesium(Mg^(2+))supplementary can restore ocular dominance(OD)plasticity,which promotes the recovery of amblyopic eye acuity in adults.However,it remains unsolved whether Mg^(2+)could recover binocular vision in amblyopic adults and what the molecular mechanism is for the recovery.We found that in addition to the recovery of OD plasticity,binocular integration can be restored under the treatment of high Mg^(2+)in amblyopic mice.Behaviorally,Mg^(2+)-treated amblyopic mice showed better depth perception.Moreover,the effect of high Mg^(2+)can be suppressed with transient receptor potential melastatin-like 7(TRPM7)knockdown.Collectively,our results demonstrate that high Mg^(2+)could restore binocular visual functions from amblyopia.TRPM7 is required for the restoration of plasticity in the visual cortex after high Mg^(2+)treatment,which can provide possible clinical applications for future research and treatment of amblyopia.
基金financial support from the National Natural Science Foundation of China(Grants Nos.91229204 and 81220108025)Major Project of Chinese National Programs for Fundamental Research and Development(No.2015CB910304)+2 种基金National High Technology Research and Development Program of China(No.2012AA020302)National Basic Research Program of China(No.2012CB518005)National S&T Major Projects(Nos.2012ZX09103101-072,2014ZX09507002-001,and 2013ZX09507-001)
文摘Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 mu mol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
