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Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy characterized by progressive muscle degeneration. This disease is caused by the mutation or deletion of the dystrophin gene. Currently, there are no effective treatments and glucocorticoid administration is a standard care for DMD. However, the mechanism underlying prednisolone effects, which leads to increased walking, as well as decreased muscle wastage, is poorly understood. Our purpose in this study is to investigate the mechanisms of the efficacy of prednisolone for this disease. We converted fibroblasts of normal human cell line and a DMD patient sample to myotubes by MyoD transduction using a retroviral vector. In myotubes from the MyoD-transduced fibroblasts of the DMD patient, the myotube area was decreased and its apoptosis was increased. Furthermore, we confirmed that prednisolone could rescue these pathologies. Prednisolone increased the expression of not utrophin but laminin by down-regulation of MMP-2 mRNA. These results suggest that the up-regulation of laminin may be one of the mechanisms of the efficacy of prednisolone for DMD.

Drug repositioning (DR) is the process of identifying new indications for existing drugs. DR usually focuses on drugs that have cleared phase-I safety trials but has yet to show efficacy for the intended indication. Therefore, DR can probably skip the preclinical and phase-I study, which can reduce the cost throughout drug development. However, the expensive phase-II/III trials are required to establish efficacy. The obstacles to DR include identification of new indications with a high success rate in clinical studies, obtaining funding for clinical studies, patent protection, and approval systems. To tackle these obstacles, various approaches have been applied to DR worldwide. In this perspective, we provide representative examples of DR and discuss the ongoing efforts to overcome obstacles to DR in Japan.

The C-C chemokine receptor type 3 (CCR3) is the receptor for eotaxins (CCL-11, 24, 26), RANTES (CCL-5) and MCP-3 (CCL-7). It was reported that an inhibition of CCR3 by antagonists or antibodies reduces the degree of laser-induced choroidal neovascularization in mice, a model for wet age-related macular degeneration (AMD). Although several chemokine receptors have the potential of reducing the degree of the chronic inflammation in experimental dry AMD, the association of CCR3 remains unknown. The purpose of this study was to determine the role played by CCR3 in the death of 661W cells which are cells of a murine photoreceptor-derived cell line as an in vitro model of dry AMD. The expression of CCR3 was increased in the 661W cells after light exposure. Inhibition of CCR3 reduced the rate of cell death induced by light exposure. A blockade of CCR3 signaling by CCR3 silencing and two kinds of CCR3 antagonists, SB 328437 and SB 297006, reduced the rate of light-induced cell death. In addition, CCR3 inhibition decreased the level of reactive oxygen species and the activation of caspase-3/7 induced by light exposure. These findings indicated that the CCR3 blockade should be considered for the treatment of the dry AMD. [ABSTRACT FROM AUTHOR]

Exposure of rhodopsin to bright white light can induce photoreceptor cell damage and degeneration. However, a comprehensive understanding of the mechanisms underlying light-induced retinopathy remains elusive. In this study, we performed comparative transcriptome analysis of three rodent models of light-induced retinopathy, and we identified 37 genes that are dysregulated in all three models. Gene ontology analysis revealed that this gene set is significantly associated with a cytokine signaling axis composed of signal transducer and activator of transcription 1 and 3 (STAT1/3), interleukin 6 signal transducer (IL6ST), and oncostatinM receptor (OSMR). Furthermore, the analysis suggested that the histone acetyltransferase EP300 may be a key upstream regulator of the STAT1/3-IL6ST/OSMR axis. To examine the role of EP300 directly, we developed a larval zebrafish model of light-induced retinopathy. Using this model, we demonstrated that pharmacological inhibition of EP300 significantly increased retinal cell apoptosis, decreased photoreceptor cell outer segments, and increased proliferation of putative Müller cells upon exposure to intense light. These results suggest that EP300 may protect photoreceptor cells from light-induced damage and that activation of EP300 may be a novel therapeutic approach for the treatment of retinal degenerative diseases. [ABSTRACT FROM AUTHOR]