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Komagane, Japan

Delaurier A.,University of Oregon | Nakamura Y.,Showa Inan General Hospital | Braasch I.,University of Oregon | Khanna V.,University of Oregon | And 4 more authors.
BMC Developmental Biology | Year: 2012

Background: Histone deacetylase-4 (Hdac4) is a class II histone deacetylase that inhibits the activity of transcription factors. In humans, HDAC4 deficiency is associated with non-syndromic oral clefts and brachydactyly mental retardation syndrome (BDMR) with craniofacial abnormalities. Results: We identify hdac4 in zebrafish and characterize its function in craniofacial morphogenesis. The gene is present as a single copy, and the deduced Hdac4 protein sequence shares all known functional domains with human HDAC4. The zebrafish hdac4 transcript is widely present in migratory cranial neural crest (CNC) cells of the embryo, including populations migrating around the eye, which previously have been shown to contribute to the formation of the palatal skeleton of the early larva. Embryos injected with hdac4 morpholinos (MO) have reduced or absent CNC populations that normally migrate medial to the eye. CNC-derived palatal precursor cells do not recover at the post-migratory stage, and subsequently we found that defects in the developing cartilaginous palatal skeleton correlate with reduction or absence of early CNC cells. Palatal skeletal defects prominently include a shortened, clefted, or missing ethmoid plate, and are associated with a shortening of the face of young larvae. Conclusions: Our results demonstrate that Hdac4 is a regulator of CNC-derived palatal skeletal precursors during early embryogenesis. Cleft palate resulting from HDAC4 mutations in human patients may result from defects in a homologous CNC progenitor cell population. © 2012 DeLaurier et al.; licensee BioMed Central Ltd.

Yuan Q.,University of Houston | Chiquet B.T.,University of Houston | Chiquet B.T.,University of Texas Health Science Center at Houston | Devault L.,University of Houston | And 4 more authors.
Genesis | Year: 2012

Nonsyndromic cleft lip and palate (NSCLP), a common birth defect, affects 4,000 newborns in the US each year. Previously, we described an association between CRISPLD2 and NSCLP and showed Crispld2 expression in the murine palate. These results suggested that a perturbation in CRISPLD2 activity affects craniofacial development. Here, we describe crispld2 expression and the phenotypic consequence of its loss of function in zebrafish. crispld2 was expressed at all stages of zebrafish morphogenesis examined and localized to the rostral end by 1-day postfertilization. Morpholino knockdown of crispld2 resulted in significant jaw and palatal abnormalities in a dose-dependent manner. Loss of crispld2 caused aberrant patterning of neural crest cells (NCC) suggesting that crispld2 is necessary for normal NCC formation. Altogether, we show that crispld2 plays a significant role in the development of the zebrafish craniofacies and alteration of normal protein levels disturbs palate and jaw formation. These data provide support for a role of CRISPLD2 in NSCLP. © 2012 Wiley Periodicals, Inc.

Nagaya T.,Shinshu University | Tanaka N.,Shinshu University | Suzuki T.,Shinshu University | Sano K.,Shinshu University | And 12 more authors.
Journal of Hepatology | Year: 2010

Background & Aims: It is well-known that hepatic triglycerides (TG) diminish with the progression of non-alcoholic steatohepatitis (NASH), which has been designated as burned-out NASH, but its mechanism remains unclear. We aimed to explore the changes in hepatic fatty acid (FA) and TG metabolism with disease progression. Methods: Hepatic expression of key genes in healthy individuals (n = 6) and patients with simple steatosis (SS, n = 10), mild NASH (fibrosis stage 1-2, n = 20), and advanced NASH (fibrosis stage 3-4, n = 20) were assessed by quantitative polymerase chain reaction. Results: Hepatic expression of genes related to FA uptake and oxidation and very-low-density lipoprotein synthesis/export did not differ among the groups. However, the mRNA levels of sterol regulatory element-binding protein (SREBP)-1c and its downstream genes FA synthase, acetyl-coenzyme A carboxylase 1, and diacylglycerol acyltransferase 1 were inversely correlated with fibrosis stage. Immunoblot analysis revealed a remarkable reduction in mature SREBP-1c levels in advanced NASH. Furthermore, hepatic expression of tumor necrosis factor-α increased in accordance with fibrosis progression, which was possibly related to the decrease in hepatic SREBP-1c expression. Conclusions: Down-regulation of SREBP-1c and lipogenic enzymes may be associated with the development of burned-out NASH. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Nakagawa M.,Shinshu University | Tojo K.,Shinshu University | Sekijima Y.,Shinshu University | Yamazaki K.-H.,Showa Inan General Hospital | Ikeda S.-I.,Shinshu University
Amyloid | Year: 2012

We describe a rare complication, systemic arterial thromboembolism, seen in two patients with senile systemic amyloidosis (SSA). Case 1 was a 73-year-old man who was tentatively diagnosed as having cardiac amyloidosis. Five months later, he was afflicted by severe left flank pain. CT disclosed renal infarction and then he received endomyocardial biopsy and the transthyretin (TTR) gene analysis, leading to the final diagnosis of SSA. Case 2 was an 88-year-old woman who had been definitively diagnosed as having SSA-related heart failure with atrial fibrillation two years before. She was transferred to the emergency room in our hospital and enhanced CT revealed complete occlusions of the left internal carotid and left vertebral arteries, both subclavian arteries, and the left renal and left internal iliac arteries. Paying much attention to intracardiac thrombosis might be necessary in taking care of SSA patients. © 2012 Informa UK, Ltd.

Tsuruta G.,Shinshu University | Tanaka N.,Shinshu University | Hongo M.,Shinshu University | Komatsu M.,Shinshu University | And 8 more authors.
Journal of Gastroenterology | Year: 2010

Background Despite the increase in nonalcoholic fatty liver disease (NAFLD) in Japanese adults, its prevalence in adolescents remains unclear. This prompted us to evaluate the incidence and clinical characteristics of NAFLD among junior high school students. Methods A population-based cross-sectional study was conducted among students in a single junior high school in Nagano prefecture. Serum alanine aminotransferase (ALT) and γ-glutamyltransferase (γGT) measurements and abdominal ultrasonography were performed in 249 and 288 students in 2004 and 2007, respectively. In the latter survey, student lifestyle habits were also assessed, using questionnaires. Results The prevalence of NAFLD was 4.4% and 4.5% in 2004 and 2007, respectively, which was lower than that of obesity (10.0% and 5.9%). Body mass index and ALT and γGT levels increased significantly with hepatic steatosis severity. Multivariate logistic regression analysis demonstrated that the presence of obesity and an ALT level of 30 U/L or more were independent predictors of NAFLD (odds ratio 16.9, P<0.001 and odds ratio 16.6, P = 0.001, respectively). The ratios of students commuting to and from school by car and not doing sports outside of school were higher in NAFLD students compared with non- NAFLD ones. Such tendencies were observed independently of the presence of obesity. Additionally, one obese student with severe steatosis and liver dysfunction was diagnosed as having nonalcoholic steatohepatitis (NASH). Conclusions Approximately 4% of junior high school students had NAFLD that was primarily associated with obesity and reduced daily physical activity. Serum ALT measurement during school check-ups is recommended for the early detection of young adolescent NAFLD/NASH. © Springer 2010.

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