👤 Kai Yazaki

Apolipoprotein (apo) E is the major cholesterol carrier in the central nervous system (CNS); however, the clinical relevance of its cysteine-thiol redox status in cerebrospinal fluid (CSF) remains unclear. We investigated whether CSF apoE redox indices (redox-IDX-apoE) reflect cholesterol transport efficiency and disease-specific pathologies. We quantified reduced (red), reversibly oxidized (roxi), and irreversibly oxidized (oxi) apoE in CSF and serum using a maleimide-based band-shift assay. We analyzed relationships between redox-IDX-apoE, CSF cholesterol (TC) level, and the TC/apoE ratio (inverse transport efficiency) in patients with apoE3/E3 and identified transport determinants using isometric log-ratio (ILR) regression. Significant but only moderate correlations between CSF and serum indices suggested distinct redox behavior in the two compartments. ApoE3/E4 carriers exhibited higher oxi-apoE, reflecting reduced buffering capacity. In apoE3/E3 CSF, aging increased roxi/total and decreased red/roxi, suggesting a shift toward oxidized forms. CSF TC level positively correlated with roxi-related indices. Conversely, the TC/apoE ratio negatively correlated with red/roxi, indicating that red-apoE supports higher efficiency. ILR analysis confirmed that maintaining the reduced monomeric state, rather than the reversibly oxidized form, was independently associated with improved transport efficiency. Diagnostic groups exhibited distinct signatures: neurodegenerative disorders showed elevated irreversible oxidation, whereas neuroimmunological and infectious conditions exhibited profiles suggestive of reversible and acute oxidation, respectively. The CSF apoE redox status links local redox balance to cholesterol handling and reflects CNS pathophysiology. Maintaining reduced cysteine-thiol appears important for functional capacity, whereas a shift toward oxidation reflects a trade-off between buffering ability and transport efficiency. These indices may serve as potential biomarkers. Show less

Being overweight exacerbates various metabolic diseases, necessitating the identification of target molecules for obesity control. In the current study, we investigated common physiological features related to metabolism in mice with low weight gain: (1) G protein-coupled receptor, family C, group 5, member B-knockout; (2) gastric inhibitory polypeptide receptor-knockout; and (3) Iroquois-related homeobox 3-knockout. Moreover, we explored genes involved in metabolism by analyzing differentially expressed genes (DEGs) between low-weight gain mice and the respective wild-type control mice. The common characteristics of the low-weight gain mice were low inguinal white adipose tissue (iWAT) and liver weight despite similar food intake along with lower blood leptin levels and high energy expenditure. The DEGs of iWAT, epididymal (gonadal) WAT, brown adipose tissue, muscle, liver, hypothalamus, and hippocampus common to these low-weight gain mice were designated as candidate genes associated with metabolism. One such gene tetraspanin 7 (Tspan7) from the iWAT was validated using knockout and overexpressing mouse models. Mice with low Tspan7 expression gained more weight, while those with high Tspan7 expression gained less weight, confirming the involvement of the Tspan7 gene in weight regulation. Collectively, these findings suggest that the candidate gene list generated in this study contains potential target molecules for obesity regulation. Further validation and additional data from low-weight gain mice will aid in understanding the molecular mechanisms associated with obesity. Show less

Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells transform to acquire mesenchymal phenotypes. Accumulating evidence indicate the involvement of EMT in the progression of malignant diseases. Notch signaling mediates TGF-β1-induced EMT through direct transcriptional activation of Snai1. The molecular mechanism how TGF-β1 activates Notch signaling, however, remains unknown. In this study, we show a pivotal role for reactive oxygen species (ROS)-Nrf2 pathway in TGF-β1-induced Notch signaling activation and EMT development. TGF-β1 induces Nrf2 activation through ROS production. Inhibiting Nrf2 activation either by reducing ROS levels by N-acetylcysteine or by knocking down of Nrf2 by small interfering RNA attenuated both Notch signaling activation and EMT development. TGF-β1 induced the transcription of Notch4 via Nrf2-dependent promoter activation. In conclusion, our study indicates the ROS-Nrf2 pathway mediates the development of TGF-β1-induced EMT through the activation of Notch signaling. Show less

Many gene variants are involved in the susceptibility to schizophrenia and some of them are expected to be associated with other human characters. Recently reported meta-analysis of genetic associations revealed nucleotide variants in synaptic vesicular transport/Golgi apparatus genes with schizophrenia. In this study, we selected the dymeclin gene (DYM) as a candidate gene for schizophrenia. The DYM gene encodes dymeclin that has been identified to be associated with the Golgi apparatus and with transitional vesicles of the reticulum-Golgi interface. A three-step case-control study of total of 2105 Japanese cases of schizophrenia and 2087 Japanese control subjects was carried out for tag single-nucleotide polymorphisms (SNPs) in the DYM gene and an association between an SNP, rs833497, and schizophrenia was identified (allelic P=2 × 10(-5), in the total sample). DYM is the causal gene for Dyggve-Melchior-Clausen syndrome and this study shows the second neuropsychiatric disorder in which the DYM gene is involved. The present data support the involvement of Golgi function and vesicular transport in the presynapse in schizophrenia. Show less