👤 Kenji Ono

Bodin et al. (2025) provide valuable insights into neurodevelopmental vulnerability by examining radiofrequency electromagnetic fields (RF‑EMF) exposure during early life. Their integrative design, combining whole-body exposure with endpoints such as neonatal brain proteomics, BDNF expression, synaptogenesis, and oxidative stress, offers a comprehensive framework for developmental neurotoxicology. However, interpretation of proteomic clustering relies heavily on principal component analysis (PCA), a linear technique ill-suited for high-dimensional datasets dominated by non-linear dependencies and strong inter-feature correlations. PCA plots (Figure 3) illustrate group separation, yet variance explained (55%) and clustering stability remain underreported, raising concerns about robustness and biological interpretability, particularly given only ten differentially expressed proteins. To enhance inference, future studies should adopt biologically meaningful feature selection and advanced frameworks such as Feature Agglomeration and Highly Variable Feature Selection, alongside non-parametric correlation measures such as Spearman's rho and Kendall's tau. These strategies will improve reproducibility, uncover mechanistic patterns, and strengthen translational relevance for neurodevelopmental research. Show less

We report the case of a 47-year-old woman with severe hypertriglyceridemia due to a homozygous APOA5 c.553G>T (p.Gly185Cys) mutation. She presented with markedly elevated triglyceride levels (TG, 1,047 mg/dL) that were unresponsive to lifestyle modifications. Lipoprotein fractionation revealed increased chylomicrons (CMs, 21%) and very-low-density lipoprotein (35%), consistent with type V hyperlipoproteinemia. Secondary causes, such as diabetes, alcohol intake, and hypothyroidism, were excluded. The post-heparinization lipoprotein lipase (PH-LPL) level was reduced (104 ng/mL), indicating impaired lipolysis. Genetic testing revealed no pathogenic variants in LPL or other major genes related to triglyceride metabolism. A homozygous APOA5 c.553G>T variant was identified. Pemafibrate (0.2 mg/day), a selective PPARα modulator (SPPARMα), was initiated. After 2 months, the blood lipid levels had markedly improved, with the complete disappearance of CMs, and the PH-LPL level had normalized to 173 ng/mL. This case highlights the potential pathogenic role of APOA5 mutations in LPL-related hypertriglyceridemia. Furthermore, it demonstrates the multifaceted therapeutic effects of pemafibrate, suggesting a potential role for SPPARMα therapy in the management of hereditary hypertriglyceridemia. Homozygous APOA5 mutations can cause reduced LPL protein levels, leading to severe hypertriglyceridemia with elevated CMs and VLDL. Pemafibrate may improve both LPL levels and lipid profiles, even in cases with reduced LPL protein and chylomicronemia. ApoA5-related chylomicronemia can resemble familial chylomicronemia syndrome but may respond to therapies such as pemafibrate, highlighting the importance of accurate genetic diagnosis. Show less

Apolipoprotein C-III (ApoC-III) amyloidosis is an extremely rare systemic amyloidosis previously reported only in humans and white lions. This report describes the first case of ApoC-III amyloidosis in an Asiatic lion (16-year-old male) that died with clinical manifestations of renal failure. Histopathological and ultrastructural examinations identified amyloid deposits predominantly at the renal corticomedullary junction. Mass spectrometry and immunohistochemistry identified ApoC-III as an amyloid precursor protein. Sequencing of the lion's APOC3 gene found no pathogenic mutations, although lion species have a unique M30V substitution compared with other Panthera species, which may predispose them to Apo-CIII amyloidosis. This first case of a non-white lion indicates that ApoC-III amyloidosis is not restricted to white lions. Show less

We demonstrated that low-intensity pulsed ultrasound (LIPUS) therapy tended to ameliorate cognitive declines in patients with early Alzheimer's disease (AD) in the pilot trial. Thus, we have started the pivotal trial in a randomized, double-blind, placebo-controlled manner (LIPUS-AD). We here report the clinical characteristics of AD patients enrolled in the trial. The major inclusion criteria included age 50-90 years of both sex, Clinical Dementia Rating (CDR) global score of 0.5∼1.0 and Japanese version of the Mini-Mental State Examination (MMSE-J) score greater than 20 at screening, positive brain Aβ-PET, and no symptomatic brain hemorrhage, infarction, or edema on brain MRI. A total of 231 subjects were finally enrolled. As compared with the pilot trial, they were characterized by older age and higher prevalence of dyslipidemia. They had lower scores of ADAS-J-cog and Modified Hachinski Ischemic Scale (MHIS), while other cognitive scores were comparable with the pilot trial. Use of cholinesterase inhibitors was less as compared with the pilot trial. Clinical characteristics of subjects in the LIPUS-AD trial largely mimic those in the pilot trial, addressing efficacy and safety of the LIPUS therapy in early AD.Clinical Trial Gov. No.: NCT05983575, jRCT No.: jRCT2032230125. Show less

Cardiac fibrosis drives dysfunction in dilated cardiomyopathy (DCM); yet, effective therapies are limited. This study identifies FGFR1 as a critical target in cardiac fibrosis using transcriptomic and histological analyses of 58 human DCM biopsies. FGFR1 expression correlated with fibrosis severity, and inhibition by AZD4547 reduced fibrosis and improved cardiac function in organoid and murine models. These findings validate FGFR1 inhibition as a promising therapeutic strategy for mitigating fibrosis and improving outcomes in heart failure associated with DCM. Show less

Orthodontic treatment enables tooth movement through bone remodeling. The effects of fibroblast growth factor 2 (FGF2) on human periodontal ligament fibroblasts (HPdLFs) in response to mechanical stimulation that occurs during orthodontic treatment remain unexplained. We investigated the effects of FGF2 and mechanical stress on HPdLF differentiation, focusing on cementoblast differentiation. The effects of FGF2 and mechanical stress (applied for 24 hours using a centrifuge) on HPdLFs were evaluated. Changes in marker levels were assessed using real-time reverse transcriptase-polymerase chain reaction and western blotting. Furthermore, the effect of FGF2 treatment on HPdLF mineralization was assessed after 3 and 5 weeks using Alizarin red S staining (BMK-R009: Bio Future Technologies, Tokyo, Japan). Treatment of HPdLFs with 20 ng/mL FGF2 increased the expression of CEMP1 and RUNX2 but did not significantly alter the expression of FGF2, FGFR1, and FGFR2. In HPdLFs exposed to mechanical stress, expression of FGFR1 and OCN was increased, whereas that of FGF2, CEMP1, CAP, GLUT1, ALP, and OPN was reduced considerably. Treatment of mechanically-stressed HPdLFs with FGF2 did not change FGF2 expression, but expression of FGFR1, CEMP1, CAP, and GLUT1 increased significantly. In addition, FGFR1 was significantly upregulated at the protein level, whereas cementoblast differentiation markers showed an upward trend. Mineralization showed no changes at 3 weeks. However, at 5 weeks, considerable mineralization was observed in mechanically-stressed cells continuously exposed to FGF2. Mechanical stress increases FGFR1 expression in HPdLFs. FGF2 promotes the differentiation of mechanical-stressed HPdLFs into cementoblasts and their mineralization. Show less

Endometriosis is hypothesized to result from retrograde menstruation where cell debris including endometrial stromal cells (ESCs) travel through the fallopian tubes. This chronic inflammatory disease is characterized by inflammatory and fibrotic endometrial tissue. We have previously observed reduced expression of the anti-inflammatory factor SERPINA1 in endometriosis-like lesions in a mouse model implanted with human ESCs. Additionally, pro-inflammatory factors present in peritoneal hemorrhage exacerbated inflammation in these grafts, partly through prostaglandin (PG) E2 and thrombin. However, it remains unclear whether the reduction of SERPINA1, in combination with PGE2 and thrombin, synergistically influences the expression of inflammatory factors in endometriosis lesions and the underlying mechanisms. We analyzed RNA sequencing data from ESCs treated with SERPINA1 siRNA and PGE2/thrombin, comparing them to data sets derived from ESCs subjected to either SERPINA1 knockdown or PGE2/thrombin treatment. Comparative analysis identified 49 transcripts that were upregulated under both conditions and enriched for transcription regulatory genes, including SNAI1, HDAC5, PBX1, SOX4, EPAS1, LHX9, and MAFK. Silencing SNAI1, HDAC5, SOX4, EPAS1, or LHX9 suppressed IL6, CXCL8, and IL1B expression, which had been upregulated by SERPINA1 siRNA and PGE2/thrombin. Among these genes, LHX9 expression was significantly elevated in ectopic lesions, predominantly localized to stromal and glandular epithelial cells, with more pronounced expression during the secretory phase. LHX9 levels were also increased in endometriotic lesions compared to the normal endometrium. In conclusion, reduced SERPINA1 expression in ectopic ESCs, combined with PGE2/thrombin, induces inflammatory cytokine expression linked to LHX9. Pharmacological targeting of LHX9 may present a promising therapeutic strategy for mitigating chronic inflammation in endometriotic lesions. Show less

Imeglimin and metformin act in metabolic organs, including β-cells, via different mechanisms. In the present study, we investigated the impacts of imeglimin, metformin, or their combination (Imeg + Met) on β-cells, the liver, and adipose tissues in db/db mice. Imeglimin, metformin, or Imeg + Met treatment had no significant effects on glucose tolerance, insulin sensitivity, respiratory exchange ratio, or locomotor activity in db/db mice. The responsiveness of insulin secretion to glucose was recovered by Imeg + Met treatment. Furthermore, Imeg + Met treatment increased β-cell mass by enhancing β-cell proliferation and ameliorating β-cell apoptosis in db/db mice. Hepatic steatosis, the morphology of adipocytes, adiposity assessed by computed tomography, and the expression of genes related to glucose or lipid metabolism and inflammation in the liver and fat tissues showed no notable differences in db/db mice. Global gene expression analysis of isolated islets indicated that the genes related to regulation of cell population proliferation and negative regulation of cell death were enriched by Imeg + Met treatment in db/db islets. In vitro culture experiments confirmed the protective effects of Imeg + Met against β-cell apoptosis. The expression of Snai1, Tnfrsf18, Pdcd1, Mmp9, Ccr7, Egr3, and Cxcl12, some of which have been linked to apoptosis, in db/db islets was attenuated by Imeg + Met. Treatment of a β-cell line with Imeg + Met prevented apoptosis induced by hydrogen peroxide or palmitate. Thus, the combination of imeglimin and metformin is beneficial for the maintenance of β-cell mass in db/db mice, probably through direct action on β-cells, suggesting a potential strategy for protecting β-cells in the treatment of type 2 diabetes. Show less

The cytoplasmic phosphatase DUSP6 and its nuclear counterpart DUSP5 are negative regulators of RAS/ERK signalling. Here we use deletion of either Dusp5 or Dusp6 to explore the roles of these phosphatases in a murine model of KRAS Show less

Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC. Show less

Amyloidosis is induced by extracellular deposition of certain proteins. Thirty-six proteins have so far been identified as amyloidogenic proteins in humans. Although it is very important to determine the specific amyloid protein type for the choice of therapy for amyloidosis patient, it might be difficult to identify specific proteins from amyloid-deposited tissue. Apolipoprotein A-IV is known as an amyloid-associated protein, but there have been few reports of apolipoprotein A-IV amyloidosis. Here we report a case of systemic apolipoprotein A-IV-associated amyloidosis that was confirmed by proteome analysis using formalin-fixed paraffin-embedded tissue and an immunohistochemical technique. Show less

Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene are responsible for several severe forms of craniosynostotic disorders, such as Apert and Crouzon syndromes. Patients with craniosynostotic disorders caused by a mutation in Fgfr2 present with several clinical symptoms, including hypersalivation. Here we used a transgenic mouse model of Apert syndrome (Fgfr2 Fgfr2 The number of ducts and acini in Fgfr2 These results suggested that increased FGFR1 signaling and apoptosis in the submandibular glands of Fgfr2 Show less

Transient ischemic attack (TIA) is a predictor for cerebral infarction (CI), and early diagnosis of TIA is extremely important for the prevention of CI. We set out to identify novel antibody biomarkers for TIA and CI, and detected matrix metalloproteinase 1 (MMP1), chromobox homolog 1 (CBX1), and chromobox homolog 5 (CBX5) as candidate antigens using serological identification of antigens by recombinant cDNA expression cloning (SEREX) and Western blotting to confirm the presence of serum antibodies against the antigens. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) revealed that serum antibody levels were significantly higher in patients with TIA or acute-phase CI (aCI) compared with healthy donors ( Show less

Apert syndrome is characterized by craniosynostosis and bony syndactyly of the hands and feet. The cause of Apert syndrome is a single nucleotide substitution mutation (S252W or P253R) in fibroblast growth factor receptor 2 (FGFR2). Clinical experience suggests increased production of saliva by Apert syndrome patients, but this has not been formally investigated. FGFR2 signaling is known to regulate branching morphogenesis of the submandibular glands (SMGs). With the Apert syndrome mouse model (Ap mouse), we investigated the role of FGFR2 in SMGs and analyzed the SMG pathology of Apert syndrome. Ap mice demonstrated significantly greater SMG and sublingual gland (SMG/SLG complex) mass/body weight and percentage of parenchyma per unit area of the SMG compared with control mice. Furthermore, gene expression of Fgf1, Fgf2, Fgf3, Pdgfra, Pdgfrb, Mmp2, Bmp4, Lama5, Etv5, and Dusp6 was significantly higher in the SMG/SLG complex of Ap mice. FGF3 and BMP4 exhibited altered detection patterns. The numbers of macrophages were significantly greater in SMGs of Ap mice than in controls. Regarding functional evaluations of the salivary glands, no significant differences were observed. These results suggest that the gain-of-function mutation in FGFR2 in the SMGs of Ap mice enhances branching morphogenesis. Developmental Dynamics 247:1175-1185, 2018. © 2018 Wiley Periodicals, Inc. Show less

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically heterogeneous. Cardiac function is improved after treatment in some cardiomyopathy patients, but little is known about genetic predictors of long-term outcomes and myocardial recovery following medical treatment. To elucidate the genetic basis of cardiomyopathy in Japan and the genotypes involved in prognosis and left ventricular reverse remodeling (LVRR), we performed targeted sequencing on 120 DCM (70 sporadic and 50 familial) and 52 HCM (15 sporadic and 37 familial) patients and integrated their genotypes with clinical phenotypes. Among the 120 DCM patients, 20 (16.7%) had TTN truncating variants and 13 (10.8%) had LMNA variants. TTN truncating variants were the major cause of sporadic DCM (21.4% of sporadic cases) as with Caucasians, whereas LMNA variants, which include a novel recurrent LMNA E115M variant, were the most frequent in familial DCM (24.0% of familial cases) unlike Caucasians. Of the 52 HCM patients, MYH7 and MYBPC3 variants were the most common (12 (23.1%) had MYH7 variants and 11 (21.2%) had MYBPC3 variants) as with Caucasians. DCM patients harboring TTN truncating variants had better prognosis than those with LMNA variants. Most patients with TTN truncating variants achieved LVRR, unlike most patients with LMNA variants. Show less

Association between gastric inhibitory polypeptide receptor polymorphism, rs10423928, and body mass index in olanzapine-treated schizophrenia was examined. Body mass index change for the A/T+A/A genotypes was significantly higher than that for the T/T genotype. rs10423928 may predict weight gain in schizophrenia. Show less

Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP‑1R) are incretin receptors that play important roles in regulating insulin secretion from pancreatic β cells. Incretin receptors are also thought to play a potential role in bone metabolism. Osteoblasts in animals and humans express GIPR; however, the presence of GLP-1R in these cells has not been reported to date. Thus, the aim of this study was to determine whether GLP-1R and GIPR are expressed in osteoblastic cells, and whether their expression levels are regulated by the extracellular glucose concentration. Mouse osteoblastic MC3T3-E1 cells were cultured in medium containing normal (5.6 mM) or high (10, 20 or 30 mM) glucose concentrations, with or without bone morphogenetic protein-2 (BMP-2). RT-PCR, western blot analysis and immunofluorescence were carried out to determine GIPR and GLP-1R mRNA and protein expression levels. Cell proliferation was also assessed. The GLP-1R and GIPR mRNA expression levels were higher in the MC3T3-E1 cells cultured in medium containing high glucose concentrations with BMP-2 compared with the cells cultured in medium containing normal glucose concentrations with or without BMP-2. GLP-1R protein expression increased following culture in high-glucose medium with BMP-2 compared with culture under normal glucose conditions. However, the cellular localization of GLP-1R was not affected by either glucose or BMP-2. In conclusion, our data demonstrate that the expression of GLP-1R and GIPR is regulated by glucose concentrations in MC3T3-E1 cells undergoing differentiation induced by BMP-2. Our results reveal the potential role of incretins in bone metabolism. Show less

Glucose-dependent insulinotropic polypeptide receptors (GIPR) are expressed throughout the body. The expression of its ligand, glucose-dependent insulinotropic polypeptide (GIP) however, has only been reported in a limited numbers of organs. Although the rat submandibular salivary gland (SMG) has been found to express GIP, its biological role is still not understood. Moreover, nothing is known about the expression of GIP in other types of salivary glands, i.e. the parotid (PG) and sublingual (SLG) glands. We detected the expression of GIP mRNA in the rat PG, SMG and SLG. Immunohistochemical analyses revealed that GIP and GIPR were expressed only in the ductal area of all types of major salivary glands, and no immunostaining was found in the acini area. We also found GIP expression in the rat SMG to be age dependent, with 8-week-old rats showing 2-3-fold higher than those of 9- and 11-week-old rats, respectively. This is the first study to indicate both GIP and GIPR expression in the rat major salivary glands, as well as its variation in the rat SMG during the growth period. These findings are crucial for a better understanding of the physiological function of GIP in rat major salivary gland. Show less

Apolipoprotein B (ApoB) and ApoE have been shown to participate in the particle formation and the tissue tropism of hepatitis C virus (HCV), but their precise roles remain uncertain. Here we show that amphipathic α-helices in the apolipoproteins participate in the HCV particle formation by using zinc finger nucleases-mediated apolipoprotein B (ApoB) and/or ApoE gene knockout Huh7 cells. Although Huh7 cells deficient in either ApoB or ApoE gene exhibited slight reduction of particles formation, knockout of both ApoB and ApoE genes in Huh7 (DKO) cells severely impaired the formation of infectious HCV particles, suggesting that ApoB and ApoE have redundant roles in the formation of infectious HCV particles. cDNA microarray analyses revealed that ApoB and ApoE are dominantly expressed in Huh7 cells, in contrast to the high level expression of all of the exchangeable apolipoproteins, including ApoA1, ApoA2, ApoC1, ApoC2 and ApoC3 in human liver tissues. The exogenous expression of not only ApoE, but also other exchangeable apolipoproteins rescued the infectious particle formation of HCV in DKO cells. In addition, expression of these apolipoproteins facilitated the formation of infectious particles of genotype 1b and 3a chimeric viruses. Furthermore, expression of amphipathic α-helices in the exchangeable apolipoproteins facilitated the particle formation in DKO cells through an interaction with viral particles. These results suggest that amphipathic α-helices in the exchangeable apolipoproteins play crucial roles in the infectious particle formation of HCV and provide clues to the understanding of life cycle of HCV and the development of novel anti-HCV therapeutics targeting for viral assembly. Show less

Inner ear mechanosensory hair cells transduce sound and balance information. Auditory hair cells emerge from a Sox2-positive sensory patch in the inner ear epithelium, which is progressively restricted during development. This restriction depends on the action of signaling molecules. Fibroblast growth factor (FGF) signalling is important during sensory specification: attenuation of Fgfr1 disrupts cochlear hair cell formation; however, the underlying mechanisms remain unknown. Here we report that in the absence of FGFR1 signaling, the expression of Sox2 within the sensory patch is not maintained. Despite the down-regulation of the prosensory domain markers, p27(Kip1), Hey2, and Hes5, progenitors can still exit the cell cycle to form the zone of non-proliferating cells (ZNPC), however the number of cells that form sensory cells is reduced. Analysis of a mutant Fgfr1 allele, unable to bind to the adaptor protein, Frs2/3, indicates that Sox2 maintenance can be regulated by MAP kinase. We suggest that FGF signaling, through the activation of MAP kinase, is necessary for the maintenance of sensory progenitors and commits precursors to sensory cell differentiation in the mammalian cochlea. Show less

Several studies have shown increased rates of hyperglycemia and diabetes in schizophrenic patients treated with olanzapine. However, the underlying mechanism is poorly understood. Glucose-dependent insulinotropic polypeptide (GIP) is known to affect insulin secretion by pancreatic β cells. Recently, a meta-analysis study reported an association between a GIP receptor (GIPR) gene polymorphism (rs10423928) and insulin secretion measured by an oral glucose tolerance test (OGTT). We assessed the influence of this GIPR gene polymorphism on glucose metabolism in 60 schizophrenic patients treated with olanzapine and 103 healthy controls. The GIPR gene polymorphism was determined using TaqMan methods. We performed repeated-measures analysis of variance (ANOVA) and one-way ANOVA for the glucose and insulin levels during OGTTs in four groups divided by the GIPR gene polymorphism and cohort (schizophrenia or control). We found significant effects of the GIPR gene and cohort on the insulin levels at 30 min. Our findings suggest that schizophrenic patients with the A allele of GIPR rs10423928 are at risk of developing hyperinsulinemia when treated with antipsychotics. Show less

Sesamin is a major lignan in sesame seed. We confirmed that ingestion of sesamin and α-tocopherol synergistically reduced the concentration of blood cholesterol in rats given a high-cholesterol diet. To elucidate the molecular mechanism behind this effect, we analyzed the gene-expression profiles in rat liver after co-ingestion of sesamin and α-tocopherol. Six-week-old male Sprague-Dawley rats were fed a 1% cholesterol diet (HC) or HC containing 0.2% sesamin, 1% α-tocopherol or sesamin + α-tocopherol for 10 days. Blood samples were collected on days 1, 3, 7, and 10 and livers were excised on day 10. The gene expressions of ATP-binding cassette, sub-family G (WHITE), members 5 (ABCG5) and 8 (ABCG8) were significantly increased, while the gene expression of apolipoprotein (Apo) A4 was significantly decreased. ABCG5 and ABCG8 form a functional heterodimer that acts as a cholesterol efflux transporter, which contributes to the excretion of cholesterol from the liver. ApoA4 controls the secretion of ApoB, which is a component of low-density-lipoprotein cholesterol. These studies indicate that the cholesterol-lowering mechanism underlying the effects of co-ingestion of sesamin and α-tocopherol might be attributable to increased biliary excretion of cholesterol and reduced ApoB secretion into the bloodstream. Show less

Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is an autosomal recessive disorder of the urea cycle which causes hyperammonemia. Two forms of CPS1D are recognized: a lethal neonatal type and a less severe, delayed onset type. Neonatal CPS1D cases often present their symptoms within the first days of life. Delayed onset type were adolescents or adults, and infantile cases were rare. We report a case of CPS1D in a boy who developed symptoms at one month of age. He showed excellent response to treatments including continuous hemodialysis, drugs and a low-protein diet. His development and weight gain were good at the last follow-up at 1 year and three months of age. Molecular assay of the CPS1 gene demonstrated that the patient was heterozygous for c.2407C>G (R803G: maternal) in exon 20 and c.3784C>T (R1262X: paternal) in exon 32. Our clinical experience suggests that CPS1D could be one of the causes of hyperammonemia in early infantile cases. Show less

Neuronal differentiation is regulated by many basic-helix-loop-helix (bHLH) family transcriptional activators and repressors, and the balance of activity between these factors is important for the differentiation process. Here, we report the identification of a novel transcriptional repressor, designated Helt. Helt encoded a Hey-related bHLH protein containing the bHLH and Orange domains. Helt could homodimerize, and heterodimerize with Hes5 or Hey2. Both the bHLH and Orange domains were involved in the homodimerization. In contrast, only the bHLH domain was required for the heterodimerization with Hey2, whereas only the Orange domain mediated the interaction between Helt and Hes5. Thus, Helt has two dimerization domains, and these domains independently select a partner. Identification of preferred recognition sequences by CASTing experiments revealed that Helt bound to the E box, which was distinct from the Hes1 optimal sequence around the E box core. Not only the core sequence but also sequences flanking the E box were essential for the recognition by Helt and Hes1. Furthermore, Helt repressed transcription from an artificial promoter through binding to the optimal E box elements, as well as transcription from its own promoter. Using in situ hybridization and immunohistochemistry, Helt expression in embryos was investigated. Helt was mainly expressed in undifferentiated neural progenitors in some of the developing brain regions, including the mesencephalon and diencephalon, at the neurogenesis stage. These results suggest that Helt acts as a transcriptional repressor to regulate neuronal differentiation and/or identity. Show less

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA beta-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA beta-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen. Show less