Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

Nuclear dysfunction in motor neurons has been hypothesized to be a principal cause of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we investigated the mechanism by which the nuclear pore complex (NPC) is disrupted in dying motor neurons in a mechanistic ALS mouse model (adenosine deaminase acting on RNA 2 (ADAR2) conditional knockout (AR2) mice) and in ALS patients. We showed that nucleoporins (Nups) that constituted the NPC were cleaved by activated calpain via a Ca2+-permeable AMPA receptor-mediated mechanism in dying motor neurons lacking ADAR2 expression in AR2 mice. In these neurons, nucleo-cytoplasmic transport was disrupted, and the level of the transcript elongation enzyme RNA polymerase II phosphorylated at Ser2 was significantly decreased. Analogous changes were observed in motor neurons lacking ADAR2 immunoreactivity in sporadic ALS patients. Therefore, calpain-dependent NPC disruption may participate in ALS pathogenesis, and inhibiting Ca2+-mediated cell death signals may be a therapeutic strategy for ALS.UTokyo Research掲載「核と細胞質間の分子輸送経路の破綻が筋萎縮性側索硬化症に関与」 URI: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/disruption-of-molecule-transport-pathway-between-nucleus-and-cytoplasm-involved-in-als.htmlUTokyo Research "Disruption of molecule transport pathway between nucleus and cytoplasm involved in ALS" URI: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/disruption-of-molecule-transport-pathway-between-nucleus-and-cytoplasm-involved-in-als.htm

Identification of Marker Gene of Pars Tuberalis Morphogenesis in Chicken Embryo. The expression of Cytokine-like 1 and Gap junction protein alpha 5 in the pars tuberalis

Adenohypophysis delivered from oral ectoderm consists of pars distalis (PD), pars intermedia and pars tuberalis (PT). The mechanisms of development of PD has been well studied, and the cell differentiation of PD has been well understood. However, the morphogenesis and the differentiation of PT are still unclear, and the gene expression during the PT development remains largely unknown. In this study, we explored the specifically expressing genes in PT during development and analyzed its spatiotemporal expressions pattern. Microarray analysis on laser-captured PT and PD tissues obtained from chicken embryos on embryonic day 10 (E10.0) showed high expressing genes, Cytokine-like 1 (CYTL1) and Gap junction protein alpha 5 (GJA5) in PT. A detail analysis of spatiotemporal expressions pattern during chick embryo development by in situ hybridization revealed that CYTL1 mRNA was first detected in lateral head ectoderm and ventral head ectoderm in E1.5. The CYTL1 expressions moved into Rathke’s pouch at E2.5, then it was localized in PT primordium and continuously expressed in PT primordium until E12.0. On the other hand, GJA5 mRNA was transiently detected in PT primordium from E6 to E14.0, while the expression was not detected in PD during development. These results suggested that these genes may be involved in the regulation mechanism of PT development and could be a useful marker in the PT development

Diagnostic imaging in patients with retinitis pigmentosa

Retinitis pigmentosa (RP) is a progressive inherited retinal disease, and patients with RP have reduced visual function caused by a degeneration of the photoreceptors and retinal pigment epithelium (RPE). At the end stage of RP, the degeneration of the photoreceptors in the fovea reduces central vision, and RP is one of the main causes of acquired blindness in developed countries. Therefore, morphological and functional assessments of the photoreceptors in the macula area can be useful in estimating the residual retinal function in RP patients. Optical coherence tomography (OCT) is a wellestablished method of examining the retinal architecture in situ. The photoreceptor inner/outer segment (IS/OS) junction is observed as a distinct, highly reflective line by OCT. The presence of the IS/OS junction in the OCT images is essential for normal visual function. Fundus autofluorescence (FAF) results from the accumulation of lipofuscin in the RPE cells and has been used to investigate RPE and retinal function. More than one-half of RP patients have an abnormally high density parafoveal FAF ring (AF ring). The AF ring represents the border between functional and dysfunctional retina. In this review, we shall summarize recent progress on diagnostic imaging in eyes with RP

Neuromedin U-deficient rats do not lose body weight or food intake

Studies in genetically modified mice establish that essential roles of endogenous neuromedin U (NMU) are anorexigenic function and metabolic regulation, indicating that NMU is expected to be a potential target for anti-obesity agents. However, in central administration experiments in rats, inconsistent results have been obtained, and the essential role of NMU energy metabolism in rats remain unclear. This study aims to elucidate the role of endogenous NMU in rats. We generated NMU knockout (KO) rats that unexpectedly showed no difference in body weight, adiposity, circulating metabolic markers, body temperature, locomotor activity, and food consumption in both normal and high fat chow feeding. Furthermore, unlike reported in mice, expressions of Nmu and NMU receptor type 2 (Nmur2) mRNA were hardly detectable in the rat hypothalamic nuclei regulating feeding and energy metabolism, including the arcuate nucleus and paraventricular nucleus, while Nmu was expressed in pars tuberalis and Nmur2 was expressed in the ependymal cell layer of the third ventricle. These results indicate that the species-specific expression pattern of Nmu and Nmur2 may allow NMU to have distinct functions across species, and that endogenous NMU does not function as an anorexigenic hormone in rats

Role of Differential Signaling Pathways and Oxidative Stress in Diabetic Cardiomyopathy

Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Hyperglycemia-induced oxidative stress is a major risk factor for the development of micro-vascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis and endothelial dysfunction. Diabetes-mediated biochemical changes show cross-interaction and complex interplay culminating in the activation of several intracellular signaling molecules. Diabetic cardiomyopathy is characterized by morphologic and structural changes in the myocardium and coronary vasculature mediated by the activation of various signaling pathways. This review focuses on the oxidative stress and signaling pathways in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic cardiomyopathy

Anti-Inflammatory Effects of Rebamipide Eyedrop Administration on Ocular Lesions in a Murine Model of Primary Sjögren’s Syndrome

Background: Topical therapy is effective for dry eye, and its prolonged effects should help in maintaining the quality of life of patients with dry eye. We previously reported that the oral administration of rebamipide (Reb), a mucosal protective agent, had a potent therapeutic effect on autoimmune lesions in a murine model of Sjögren’s syndrome (SS). However, the effects of topical treatment with Reb eyedrops on the ocular lesions in the murine model of SS are unknown. 　 　Methods and Finding: Reb eyedrops were administered to the murine model of SS aged 4–8 weeks four times daily. Inflammatory lesions of the extraorbital and intraorbital lacrimal glands and Harderian gland tissues were histologically evaluated. The direct effects of Reb on the lacrimal glands were analyzed using cultured lacrimal gland cells. Tear secretions of Reb-treated mice were significantly increased compared with those of untreated mice. In addition to the therapeutic effect of Reb treatment on keratoconjunctivitis, severe inflammatory lesions of intraorbital lacrimal gland tissues in this model of SS were resolved. The mRNA expression levels of IL-10 and mucin 5Ac in conjunctival tissues from Reb-treated mice was significantly increased compared with those of control mice. Moreover, lactoferrin production from lacrimal gland cells was restored by Reb treatment. 　Conclusion: Topical Reb administration had an anti-inflammatory effect on the ocular autoimmune lesions in the murine model of SS and a protective effect on the ocular surfaces

思春期女性の踵骨骨評価値に対する利き足の影響に関する検討

When I perform bone evaluation by supersonic wave measurement，I only evaluate the right foot without considering the subject’s laterality，or potential differences between right and left foot bone density. Puberty is the period during which bone density rises，and during which the influence of mechanical stress is considered great，and evaluation of the right foot has been considered sufficient to clarify this effect. From the viewpoint of general health and prevention of osteoporosis we must measure one’s bone density in puberty， raise the peak bone mass，and maintain it. The present experiment was performed to clarify what kind of influence laterality of foot and exercise habits had on the bone density of the right calcaneus. Exercise habits did not have much influence on the bone density rise if the right foot was non-dominant. However，a meaningful connection was recognized between exercise habits and bone density rise if the right foot was dominant. From these results，it was thought that the measurement of calcaneus bone density by a supersonic wave method in puberty is more effective if the dominant foot is used

体組成と脈波伝播速度からみた思春期女性の生活習慣病危険因子の検討

We reviewed what kind of factors became lifestyle-related diseases risk factors in girls at puberty. The purpose of this study was to gather data for the primary prevention of lifestyle-related diseases. Subjects were 57 basically healthy girls at the age of puberty，from seventh grade to twelfth grade. We measured body composition including bone density of the whole body using Dual Energy X-ray Absorptiometry. We used form PWV/ABI（Omron Colin Co.，Ltd.，Japan）for the measurement of Pulse Wave Velocity. It became clear that there was a danger of elevated baPWV values in girls whose percentage of body fat and soft tissue fat rate were low. On the other hand，it became clear that bone mineral density（BMD）was likely high in subjects whose percentage of body fat and soft tissue fat rate were high. It is thought that a higher-than-standard percent of body fat becomes an advantage for elevated bone density. From these results，it was concluded that lifestyle-related disease risk factors for girls at puberty with a high rate of body fat are low

若年女性の生活習慣と脂質代謝の関連に関する検討

The purpose of this study is to review the factors influencing lipid metabolism of young women in terms of both exercise and nutrition. From the side of nutrition，we reviewed how lipid metabolism is influenced by taking a commercial fish oil supplement（LIQUAMEN）. Total cholesterol deteriorated significantly by taking LIQUAMEN. Improvement of lipid metabolism by LIQUAMEN was suggested. The value of HDL-cholesterol，adiponectin，and leptin were significantly lower in the group of living activity strength Ⅱ while the values of TG and TNF-α increased significantly. This result suggested the possibility that lipid metabolism deteriorated in subjects whose activity was below a certain amount. It also suggested the possibility that lipid metabolism improved in those whose activity was above a certain amount. In the body fat-to-weight ratio， the living activity strengthⅢ・ Ⅳ group showed a significantly lower tendency compared to the group of living activity strength Ⅱ and the group of living activity strengthⅢ・ Ⅳ . This finding suggested that if activity was greater than a certain amount，the body fat-to-weight ratio tended to be comparatively low