![]() Gene ontology/pathway analysis of expression variant genes KUS121 NMDA: analysis of genes that were downregulated in NMDA-injected mice retina and upregulated by KUS121 treatment, KUS187 > NMDA: analysis of genes that were downregulated in NMDA-injected mice retina and upregulated by KUS187 treatment. GO terms that were common between KUS121 and KUS187 included excretion (GO: 0007588). ![]() ( c) GO terms and pathways that were significantly related to genes upregulated by NMDA injection and downregulated by KUS treatment. There were no GO terms or pathways which were common between KUS121 and KUS187. ( b) GO terms and pathways that were significantly related to genes downregulated by NMDA injection and upregulated by KUS treatment. ( a) Chemical structures of KUS121 and KUS187. Gene ontology (GO)/pathway analysis of gene clusters. Thus, KUSs are expected to have several possibilities for treatment of various neurodegenerative diseases in the future. #Www ns nlo trialMoreover, a first-in-human clinical trial (phase 1/2) has shown that KUS121, one of the KUSs, improved the visual outcome in patients with central retinal artery occlusion 9. ![]() KUSs have been shown to protect neuronal cells in animal models of glaucoma 5, retinitis pigmentosa 4, 6, macular degeneration 7 and retinal artery occlusion 8. Several types of KUSs have a common naphthalene-derived structure and exhibit similar physiological activities (Fig. We have previously shown that the novel synthesized Kyoto University Substances (KUSs), which modulate ATPase activity of the valosin-containing protein (VCP), the most abundant soluble ATPase in the cell, protect cells under stress conditions 4. ![]() The possible treatment of ocular diseases, including glaucoma and macular degeneration, might protect retinal nerve cells. Moreover, there are cases where visual impairment progresses even with the currently established treatments, such as intraocular pressure reduction in glaucoma 2 or vitreous injection of anti-VEGF drugs in age-related macular degeneration 3. In the aging society, visual impairment due to glaucoma and age-related macular degeneration is expected to continually increase worldwide 1. These results suggest that KUSs protect cells partially by suppressing the upregulated endothelin signaling under stress conditions. This protective effect was partially attenuated in the presence of an endothelin antagonist or agonist under glucose-free conditions. ![]() KUS showed a significant protective effect under glucose-free conditions and tunicamycin-induced stress. Next, to clarify the influence of KUSs on cell viability in relation to the endothelin signaling, cell viability was examined with or without antagonists or agonists of endothelin and with or without KUS in 661W retinal cells under stress conditions. First, we confirmed that the expression of Edn1 and Ednrb was upregulated by NMDA and suppressed by KUS administration in mice retinae. In this study, among the genes whose expression in retinal ganglion cells was altered by KUS treatment in the N-methyl- d-aspartic acid (NMDA) injury model, we focused on two genes, endothelin-1 ( Edn1) and endothelin receptor type B ( Ednrb), whose expression was up-regulated by NMDA and down-regulated by KUS treatment. We have previously shown that Kyoto University Substances (KUSs), valosin-containing protein (VCP) modulators, suppress cell death in retinal ganglion cells of glaucoma mouse models through alterations of various genes expressions. ![]()
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