Objective-To investigate the role of endogenous apelin in pathological retinal angiogenesis. Methods and Results-The progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis, mainly induced by vascular endothelial growth factor (VEGF) and erythropoietin. Although antiangiogenic therapies using anti-VEGF drugs are effective in treating retinal neovascularization, they show a transient efficacy and cause general adverse effects. New therapeutic target molecules are needed to resolve these issues. It was recently demonstrated that the apelin/APJ system, a newly deorphanized G protein-coupled receptor system, is involved in physiological retinal vascularization. Retinal angiography and mRNA expression were examined during hypoxia-induced retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Compared with age-matched control mice, retinal apelin expression was dramatically increased during the hypoxic phase in oxygen-induced retinopathy model mice. APJ was colocalized in proliferative cells, which were probably endothelial cells of the ectopic vessels in the vitreous body. Apelin deficiency hardly induced hypoxia-induced retinal angiogenesis despite the upregulation of VEGF and erythropoietin mRNA in oxygen-induced retinopathy model mice. Apelin small and interfering RNA suppressed the proliferation of endothelial cells independent of the VEGF/VEGF receptor 2 signaling pathway. Conclusion-These results suggest that apelin is a prerequisite factor for hypoxia-induced retinal angiogenesis. Key Words: angiogenesis Ⅲ VEGF Ⅲ apelin Ⅲ retinopathy T he progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis, which is mainly induced by vascular endothelial growth factor (VEGF) 1 and erythropoietin (Epo). 2 Antiangiogenic therapies targeting these factors are effective in treating proliferative diabetic retinopathy. 3,4 However, these therapies show a transient efficacy and cause the general adverse effects. 5 Furthermore, elevated VEGF levels do not necessarily correlate with pathological retinal angiogenesis in patients with diabetic maculopathy. 6 This suggests that the entire process of pathological retinal angiogenesis includes more than just upregulation of VEGF expression. Therefore, finding other factors involved in pathological retinal angiogenesis is important.The apelin/apelin receptor (APJ) system is a newly deorphanized G protein-coupled receptor system. 7 Recently, much attention has been focused on the possible roles of the apelin/APJ system in vascular pathophysiology. 8,9 APJ is expressed in endothelial cells at the leading edge of vessels during early embryogenesis; and apelin, in combination with VEGF, induces the proliferation and assembly of endothelial cells. 10 Moreover, we demonstrated a retardation of physiological retinal vascular development during the early postnatal period and a reduced angiogenic response to VEGF in apelin-knockout...

Acetals are the most useful protecting groups for carbonyl functional groups. In addition to the role of protection, they can also be used as synthons of carbonyl functions. Previously, we developed a chemoselective deprotection and nucleophilic substitution of acetals from aldehydes in the presence of ketals. This article describes the highly discriminative and chemoselective transformations of acetals bearing different substitution patterns, different types of acetals, as well as mixed acetals. These reactions can achieve the transformations that cannot be attained by conventional methods, and their results strongly suggest the combination of RSiOTf/2,4,6-collidine to promote such unprecedented phenomena.

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The intermediates formed during the Beckmann fragmentation of α-alkoxy and α-alkoxy-α-alkyl oxime acetates have been successfully trapped as phosphonium salts, which were subsequently reacted with a variety of Grignard reagents to give the corresponding substituted products in good yields. Notably, this reaction proceeded smoothly even from α-alkoxy-α-alkyl oxime acetates.Key words Beckmann fragmentation; phosphonium salt intermediate; Grignard reagent; carbon-carbon bond formationWe recently found that the treatment of acetals with a combination of trifluoromethanesulfonic acid trialkylsilyl ester (R 3 SiOTf) and base (e.g., pyridinium-type bases or triarylphosphines) gave the corresponding electrophilic pyridinium or phosphonium salts as stable intermediates. We subsequently showed that these salts can be used as stable synthetic equivalents of oxonium ions from acetals, and went on to develop a series of acetal substitution reactions using a variety of different nucleophiles (Eq. 1).1-10) One of the main advantages of our new methods is that the nucleophiles can be added to the reaction mixture long after the formation of the intermediate salts. Furthermore, these methods are compatible with a wide variety of nucleophiles, including acid and base labile nucleophiles. It is noteworthy that acid labile nucleophiles cannot normally be used in the reactions of oxonium ions, because oxonium ions are usually formed under Lewis acidic conditions in the presence of a nucleophile, which would preclude the use of an acid labile nucleophile. 11) We subsequently investigated the application of this salt chemistry to another reaction involving sequential Beckmann fragmentation/carbon-carbon (C-C) bond forming reactions, which has been previously reported by our group using organoaluminum reagents.12-15) The treatment of α-alkoxy oxime acetates with trifluoromethanesulfonic acid trimethylsilyl ester (TMSOTf) and 2,4,6-collidine produced the corresponding collidinium salt intermediates, which were successfully subjected to a C-C bond forming reaction with a variety of different Gilman reagents (Eq. 2).16) Gilman reagents were found to be the best type of organometallic carbon nucleophile for this reaction, with several other more popular organometallic reagents, including organolithium and Grignard reagents, failing to provide good results. However, we previously found that the phosphonium salts derived from O,O-acetals and (o-tol) 3 P reacted smoothly with Grignard reagents. [8][9][10] We therefore envisioned that the formation of a phosphonium salt instead of a collidinium salt would make it possible to use Grignard reagents in this reaction, which would represent a significant improvement over our previous method in terms of its scope and convenience.