Enhancement of phospholipase A2 activation by phosphatidic acid endogenously formed through phospholipase D action in rat peritoneal mast cell

AbstractContribution of phosphatidic acid (PA) generated by activated phospholipase (PL) D to PLA2 activation was studied in rat peritoneal mast cells. Exogenous didecanoyl PA induced arachidonate liberation in the permeabilized cells which was inhibited by p-bromophenacyl bromide. Upon exposure of the cells to ethanol in a high enough concentration to prevent PA formation, A23187-induced arachidonate liberation was suppressed by 50% and the rest was completely inhibited by p-bromophenacyl bromide. In contrast, propranolol, which enhanced PA accumulation, significantly increased the arachidonate liberation. These results suggest that A23187-induced PLA2 activation may be potentiated, at least in part, by PA generated through PLD action

Prevalence of somatic diseases in adults with attention deficit hyperactivity disorder in Japan is highest in people aged ≥40 years with mental disorders: a cross-sectional study of a Japanese health insurance claims database

IntroductionStudies have reported an association between attention deficit hyperactivity disorder (ADHD) and somatic diseases; however, the correlation of mental disorders with the association between ADHD and somatic diseases remains uninvestigated. This study investigated and compared the prevalence of somatic diseases among adults with/without ADHD, stratified by the presence or absence of mental disorders.MethodsThis cross-sectional study (October 2020–September 2021), using data (June 2013–September 2021) from a Japanese health insurance claims database, included adult participants with a medical record of and receiving medication for ADHD (ADHD group); the control group (matched 1:5 by age/sex) comprised participants without ADHD. The prevalence and odds ratio (OR; ADHD versus control) of type 2 diabetes mellitus (T2DM), diabetes complications, hypertension, cardiovascular disease (CVD), dyslipidemia, gout and hyperuricemia, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), and atopic dermatitis were investigated. Pooled ORs for stratified analysis were calculated using the Mantel-Haenszel method.ResultsIn the matched analysis sets, the ORs for all somatic diseases were significantly higher for the ADHD group (n=15,028) versus the control group (n=74,796). On stratified analysis, the Mantel-Haenszel ORs were significant for NAFLD/NASH (1.53; 95% confidence interval [CI]: 1.34, 1.73), diabetes complications (1.39; 95% CI: 1.09, 1.77), and gout and hyperuricemia (1.34; 95% CI: 1.19, 1.51). Furthermore, the stratum-specific ORs for T2DM, hypertension, and dyslipidemia were >1 and <1 in the presence and absence of mental disorders, respectively. The prevalence of all somatic diseases except atopic dermatitis increased with age. For participants aged ≥40 years, the Mantel-Haenszel ORs were significant for all somatic diseases except CVD, COPD, and atopic dermatitis.ConclusionsThe prevalence of several somatic diseases, including chronic disorders, was high among adults with ADHD, particularly in those aged ≥40 years and those with mental disorders

DataSheet_1_Prevalence of somatic diseases in adults with attention deficit hyperactivity disorder in Japan is highest in people aged ≥40 years with mental disorders: a cross-sectional study of a Japanese health insurance claims database.docx

IntroductionStudies have reported an association between attention deficit hyperactivity disorder (ADHD) and somatic diseases; however, the correlation of mental disorders with the association between ADHD and somatic diseases remains uninvestigated. This study investigated and compared the prevalence of somatic diseases among adults with/without ADHD, stratified by the presence or absence of mental disorders.MethodsThis cross-sectional study (October 2020–September 2021), using data (June 2013–September 2021) from a Japanese health insurance claims database, included adult participants with a medical record of and receiving medication for ADHD (ADHD group); the control group (matched 1:5 by age/sex) comprised participants without ADHD. The prevalence and odds ratio (OR; ADHD versus control) of type 2 diabetes mellitus (T2DM), diabetes complications, hypertension, cardiovascular disease (CVD), dyslipidemia, gout and hyperuricemia, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), and atopic dermatitis were investigated. Pooled ORs for stratified analysis were calculated using the Mantel-Haenszel method.ResultsIn the matched analysis sets, the ORs for all somatic diseases were significantly higher for the ADHD group (n=15,028) versus the control group (n=74,796). On stratified analysis, the Mantel-Haenszel ORs were significant for NAFLD/NASH (1.53; 95% confidence interval [CI]: 1.34, 1.73), diabetes complications (1.39; 95% CI: 1.09, 1.77), and gout and hyperuricemia (1.34; 95% CI: 1.19, 1.51). Furthermore, the stratum-specific ORs for T2DM, hypertension, and dyslipidemia were >1 and ConclusionsThe prevalence of several somatic diseases, including chronic disorders, was high among adults with ADHD, particularly in those aged ≥40 years and those with mental disorders.</p

Essential role of Gas6 for glomerular injury in nephrotoxic nephritis

Growth-arrest specific gene 6 (Gas6) is a vitamin K–dependent growth factor for mesangial and epithelial cells. To investigate whether Gas6 is essential for progressive glomerular injury, we constructed Gas6(–/–) mice and examined the role of Gas6 in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis. We found less mortality and proteinuria in Gas6(–/–) mice than in wild-type mice following injection of nephrotoxic serum. Glomerular cell proliferation, glomerular sclerosis, crescent formation, and deposition of fibrin/fibrinogen in glomeruli were also reduced in Gas6(–/–) mice. Furthermore, administering Gas6(–/–) mice recombinant wild-type Gas6, but not Gas6 lacking a previously characterized N-terminal γ-carboxyl group, induced massive proteinuria, glomerular cell proliferation, and glomerulosclerosis, comparable to responses seen in wild-type mice. These data indicate that Gas6 induces glomerular cell proliferation in NTN and suggest that this factor contributes to glomerular injury and the progression of chronic nephritis

Ubiquitination of Lysine 867 of the Human SETDB1 Protein Upregulates Its Histone H3 Lysine 9 (H3K9) Methyltransferase Activity

<div><p>Posttranslational modifications (PTMs) of proteins play a crucial role in regulating protein-protein interactions, enzyme activity, subcellular localization, and stability of the protein. SET domain, bifurcated 1 (SETDB1) is a histone methyltransferase that regulates the methylation of histone H3 on lysine 9 (H3K9), gene silencing, and transcriptional repression. The C-terminal region of SETDB1 is a key site for PTMs, and is essential for its enzyme activity in mammalian and insect cells. In this study, we aimed to evaluate more precisely the effect of PTMs on the H3K9 methyltransferase activity of SETDB1. Using mass spectrometry analysis, we show that the C-terminal region of human SETDB1 purified from insect cells is ubiquitinated. We also demonstrate that the ubiquitination of lysine 867 of the human SETDB1 is necessary for full H3K9 methyltransferase activity in mammalian cells. Finally, we show that SETDB1 ubiquitination regulates the expression of its target gene, serpin peptidase inhibitor, clade E, member 1 (<i>SERPINE1</i>) by methylating H3K9. These results suggest that the ubiquitination of SETDB1 at lysine 867 controls the expression of its target gene by activating its H3K9 methyltransferase activity.</p></div

Ubiquitination of K867 of GST-SETDB1 (570–1291) upregulates its H3K9 methyltransferase activity in HeLa cells.

<p>(A) SETDB1 proteins were expressed as GST fusion proteins in HeLa cells and purified on glutathione-sepharose beads. The purified SETDB1 proteins were resolved on 5% SDS-PAGE, and electroblotted onto PVDF membranes. Western blot analyses of GST-SETDB1 proteins were probed with anti-SETDB1 antibody or anti-ubiquitin antibody. (B) H3K9 methyltransferase activity of the GST affinity-purified SETDB1 proteins in HeLa cells was measured. The values represent means±SEM (n = 3). **<i>P</i><0.01 compared with the value of DEL570.</p

GST-SETDB1 (570–1291) protein expressed in Sf9 cells was prepared using various types of chromatography for mass spectrometry analysis.

<p>(A) Schematic representation of the construction of GST-SETDB1 (570–1291) (top) and the flow chart for SETDB1 (570–1291) purification (bottom). (B) SETDB1 (570–1291) purified using chromatography was separated by SDS-PAGE and analyzed by Coomassie blue staining. (C) Summary of the mass spectrometry analysis data, showing the comparison between the upper and lower band of SETDB1 (570–1291).</p