Potential role of group X secretory phospholipase A2 in cyclooxygenase-2-dependent PGE2 formation during colon tumorigenesis

AbstractAlthough the cyclooxygenase-2 (COX-2) pathway of the arachidonic acid cascade has been suggested to play an important role in colon carcinogenesis, there is little information concerning the identity of phospholipase A2 (PLA2) involved in the arachidonic acid release in colon tumors. Here, we compared the potencies of three types of secretory PLA2s (group IB, IIA and X sPLA2s) for the arachidonic acid release from cultured human colon adenocarcinoma cells, and found that group X sPLA2 has the most powerful potency in the release of arachidonic acid leading to COX-2-dependent prostaglandin E2 (PGE2) formation. Furthermore, immunohistological analysis revealed the elevated expression of group X sPLA2 in human colon adenocarcinoma neoplastic cells in concert with augmented expression of COX-2. These findings suggest a critical role of group X sPLA2 in the PGE2 biosynthesis during colon tumorigenesis

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

Hair Follicular Expression and Function of Group X Secreted Phospholipase A2 in Mouse Skin*

Although perturbed lipid metabolism can often lead to skin abnormality, the role of phospholipase A2 (PLA2) in skin homeostasis is poorly understood. In the present study we found that group X-secreted PLA2 (sPLA2-X) was expressed in the outermost epithelium of hair follicles in synchrony with the anagen phase of hair cycling. Transgenic mice overexpressing sPLA2-X (PLA2G10-Tg) displayed alopecia, which was accompanied by hair follicle distortion with reduced expression of genes related to hair development, during a postnatal hair cycle. Additionally, the epidermis and sebaceous glands of PLA2G10-Tg skin were hyperplasic. Proteolytic activation of sPLA2-X in PLA2G10-Tg skin was accompanied by preferential hydrolysis of phosphatidylethanolamine species with polyunsaturated fatty acids as well as elevated production of some if not all eicosanoids. Importantly, the skin of Pla2g10-deficient mice had abnormal hair follicles with noticeable reduction in a subset of hair genes, a hypoplasic outer root sheath, a reduced number of melanin granules, and unexpected up-regulation of prostanoid synthesis. Collectively, our study highlights the spatiotemporal expression of sPLA2-X in hair follicles, the presence of skin-specific machinery leading to sPLA2-X activation, a functional link of sPLA2-X with hair follicle homeostasis, and compartmentalization of the prostanoid pathway in hair follicles and epidermis

Assessment Report of Doctoral Theses

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