This study aimed to estimate overreporting (the false positive) and underreporting (false negative) rates in self-reported IGD assessment compared with clinical diagnosed IGD. The study population ...consisted of 45 with IGD and 228 without IGD based on clinical diagnosis from the Internet User Cohort for Unbiased Recognition of Gaming Disorder in Early Adolescence (iCURE) study. All participants completed self-reported IGD assessments. Clinical interviews were conducted blindly by trained mental health professionals based on DSM-5 IGD criteria. Self-assessed average daily amount of gaming time and game genre were measured. Psychological characteristics, including anxiety, suicidality, aggression, self-control, self-esteem, and family support, were obtained from the baseline survey. The false-negative rate for self-reported IGD assessment was 44%. The false-negative group reported less time playing online games than the IGD group, though their psychological characteristics were similar to those of the IGD group. The false-positive rate was 9.6%. They reported more time playing online games than non-IGD group, though their psychological characteristics were similar to those of non-IGD group except self-control. The discrepancy of IGD diagnoses between self-reports and clinical diagnosis revealed limitations of self-measurements. Various strategies are required to overcome the methodological shortfalls of self-reports for the assessment of IGD.
•Obesity induces oxidative stress causing various pathological phenomena.•Obesity-induced pathological phenomena are modelled in rats fed a high fat diet.•Treadmill exercise rescued obesity-induced ...pathological phenomena in rats.
Obesity induces oxidative stress by causing hyperglycemia and insulin resistance, while contributing to cognitive and memory decline by inducing insulin resistance in the brain and hyperphosphorylation of Tau proteins. We aimed to investigate the effects of treadmill exercise in improving these obesity-induced pathological phenomena. Sprague-Dawley rats aged 20 weeks were fed a high-fat diet (HFD) for 20 weeks to induce obesity. The rats were subsequently subjected to treadmill exercise (progressively increasing load intensity) for 8 weeks. The rats were divided into three groups: normal diet-control (n = 15), HFD-control (n = 15), and HFD-treadmill exercise (n = 15). We performed water maze and passive avoidance tests and assessed weight, area under the curve, homeostatic model assessment of insulin resistance, and abdominal visceral fat/body weight. Western blot was used to examine protein expression related to brain insulin signaling, tau hyperphosphorylation, and NADPH oxidase, and immunohistochemistry was performed to examine the immunoreactivity of p-Tau (Ser 202/Thr 205) and p22-phox. Treadmill exercise effectively rescued brain insulin signaling, hyperphosphorylation and aggregation of Tau protein, and NADPH oxidase activation in the high fat diet group. Furthermore, it improved insulin resistance inhibitors, decreased abdominal fat mass, inhibited weight gain, and rescued learning and memory. Obesity-induced insulin resistance contributes to cognitive decline, such as reduced learning and memory, but physical activity, such as treadmill exercise, was found to have a positive effect on brain function by improving thesepathological phenomena. Therefore, we suggest that treadmill exercise must be considered in the prevention and treatment of metabolic and neurodegenerative diseases.
Dysregulation of Ca
/calmodulin-dependent protein kinase (CaMK)II is closely linked with myocardial hypertrophy and heart failure. However, the mechanisms that regulate CaMKII activity are ...incompletely understood. Here we show that protein arginine methyltransferase 1 (PRMT1) is essential for preventing cardiac CaMKII hyperactivation. Mice null for cardiac PRMT1 exhibit a rapid progression to dilated cardiomyopathy and heart failure within 2 months, accompanied by cardiomyocyte hypertrophy and fibrosis. Consistently, PRMT1 is downregulated in heart failure patients. PRMT1 depletion in isolated cardiomyocytes evokes hypertrophic responses with elevated remodeling gene expression, while PRMT1 overexpression protects against pathological responses to neurohormones. The level of active CaMKII is significantly elevated in PRMT1-deficient hearts or cardiomyocytes. PRMT1 interacts with and methylates CaMKII at arginine residues 9 and 275, leading to its inhibition. Accordingly, pharmacological inhibition of CaMKII restores contractile function in PRMT1-deficient mice. Thus, our data suggest that PRMT1 is a critical regulator of CaMKII to maintain cardiac function.
In the present study, we investigated the effects of type 2 diabetes-induced hyperglycemia on the integrity of the blood–brain barrier and tight junction markers in the rat hippocampus. ...Forty-week-old diabetic (Zucker diabetic fatty, ZDF) rats and littermate control (Zucker lean control, ZLC) rats were used in this study. We evaluated the integrity of the blood–brain barrier by measuring sodium fluorescein extravasation and blood vessel ultrastructure. In addition, tight junction markers, such as zona occludens-1, occludin and claudin-5, were quantified by western blot analysis. ZDF rats showed significantly increased sodium fluorescein leakage in the hippocampus. Tight junction markers, such as occludin and claudin-5, were significantly decreased in the hippocampi of ZDF rats compared to those of ZLC rats. In addition, ZDF rats showed ultrastructural changes with phagocytic findings in the blood vessels. These results suggest that chronic untreated diabetes impairs the permeability of the hippocampal blood–brain barrier by down-regulating occludin and claudin-5, indicating that chronic untreated diabetes may cause hippocampus-dependent dysfunction.
AMP-activated protein kinase (AMPK) plays a key role in controlling energy metabolism in response to physiological and nutritional status. Although AMPK activation has been proposed as a promising ...molecular target for treating obesity and its related comorbidities, the use of pharmacological AMPK activators has been met with contradictory therapeutic challenges. Here we show a regulatory mechanism for AMPK through its ubiquitination and degradation by the E3 ubiquitin ligase makorin ring finger protein 1 (MKRN1). MKRN1 depletion promotes glucose consumption and suppresses lipid accumulation due to AMPK stabilisation and activation. Accordingly, MKRN1-null mice show chronic AMPK activation in both liver and adipose tissue, resulting in significant suppression of diet-induced metabolic syndrome. We demonstrate also its therapeutic effect by administering shRNA targeting MKRN1 into obese mice that reverses non-alcoholic fatty liver disease. We suggest that ubiquitin-dependent AMPK degradation represents a target therapeutic strategy for metabolic disorders.
▶ Treadmill exercise ameliorates cognitive deficits in Tg mice. ▶ Treadmill exercise reduces Aβ-42 and tau deposition in Tg mice. ▶ Treadmill exercise reduces the number of TUNEL-positive cells in Tg ...mice. ▶ Treadmill exercise reduces TC, insulin, glucose, and corticosterone levels in Tg mice. ▶ Treadmill exercise may be beneficial in prevention or treatment in AD.
The present study was undertaken to further investigate the protective effect of treadmill exercise on the hippocampal proteins associated with neuronal cell death in an aged transgenic (Tg) mice with Alzheimer's disease (AD). To address this, Tg mouse model of AD, Tg-NSE/PS2m, which expresses human mutant PS2 in the brain, was chosen. Animals were subjected to treadmill exercise for 12 weeks from 24 months of age. The exercised mice were treadmill run at speed of 12
m/min, 60
min/day, 5 days/week on a 0% gradient for 3 months. Treadmill exercised mice improved cognitive function in water maze test. Treadmill exercised mice significantly reduced the expression of Aβ-42, Cox-2, and caspase-3 in the hippocampus. In parallel, treadmill exercised Tg mice decreased the phosphorylation levels of JNK, p38MAPK and tau (Ser404, Ser202, Thr231), and increased the phosphorylation levels of ERK, PI3K, Akt and GSK-3α/β. In addition, treadmill exercised Tg mice up-regulated the expressions of NGF, BDNF and phospho-CREB, and the expressions of SOD-1, SOD-2 and HSP-70. Treadmill exercised Tg mice up-regulated the expression of Bcl-2, and down-regulated the expressions of cytochrome c and Bax in the hippocampus. The number of TUNEL-positive cells in the hippocampus in mice was significantly decreased after treadmill exercise. Finally, serum TC, insulin, glucose, and corticosterone levels were significantly decreased in the Tg mice after treadmill exercise. As a consequence of such change, Aβ-dependent neuronal cell death in the hippocampus of Tg mice was markedly suppressed following treadmill exercise. These results strongly suggest that treadmill exercise provides a therapeutic potential to inhibit both Aβ-42 and neuronal death pathways. Therefore, treadmill exercise may be beneficial in prevention or treatment of AD.
Accumulation of amyloid-β (Aβ) correlates significantly with progressive cognitive deficits, a main symptom of Alzheimer's disease (AD). Although treadmill exercise reduces Aβ levels, the molecular ...mechanisms underlying the effects are not fully understood. We hypothesize that treadmill exercise decreases Aβ production and alleviates cognitive deficits by activating the non-amyloidogenic pathway via SIRT-1 signaling. Treadmill exercise improved cognitive deficits and alleviated neurotoxicity. Most importantly, treadmill exercise increased SIRT-1 level, which subsequently resulted in increased ADAM-10 level by down-regulation of ROCK-1 and upregulation of RARβ, ultimately facilitating the non-amyloidogenic pathway. Treadmill exercise-induced activation in SIRT-1 level also elevated PGC-1α level and reduced BACE-1 and C-99 level, resulting in inhibition of the amyloidogenic pathway. Treadmill exercise may thus inhibit Aβ production via upregulation of SIRT-1, which biases amyloid precursor protein processing toward the non-amyloidogenic pathway. This study provides novel and valuable insight into the molecular mechanisms possibly by which treadmill exercise reduces Aβ production.
•Treadmill exercise increased SIRT-1 levels, resulting in increased ADAM-10 by downregulating ROCK-1 and upregulating RARβ.•Treadmill exercise increased PGC-1α levels, which reduced BACE-1 and C-99 expression.•Treadmill exercise inhibits Aβ production possibly by activating non-amyloidogenic pathway via SIRT-1/PGC-1α signaling.
Brain iron increases with age and abnormal brain iron metabolism is proving increasingly likely to be involved in the pathology of Alzheimer’s disease (AD). The iron-regulatory effect of furin, a ...ubiquitously expressed proconvertase, might play an important role in AD. Therefore, there is an urgent need to study the effect of furin on iron regulation in AD. For that purpose, we aimed to determine the role of physical exercise in AD associated with brain iron dyshomeostasis. Treadmill exercise attenuated the AD-related abnormal brain iron regulation by furin in vivo, as demonstrated via experiments in aged APP-C105 mice. Next, we examined whether treadmill exercise decreases excessive iron, directly affecting amyloid-β (Aβ) production through the regulation of α-secretase-dependent processing of amyloid protein precursor (APP) involved in the modulation of furin activity. We first observed that cognitive decline and Aβ-induced neuronal cell death were induced by disruption of APP processing via excess iron-induced disruption of furin activity in aged APP-C105 mice. The induced cognitive decline and cell death were attenuated by treadmill exercise. This result suggests that treadmill exercise alleviated cognitive decline and Aβ-induced neuronal cell death by promoting α-secretase-dependent processing of APP through low iron-induced enhancement of furin activity. This is concomitant with decreasing levels of lipid peroxidation products and promoting antioxidant defense enzyme capacities. Therefore, iron-targeted therapeutic strategies involving treadmill exercise might be useful for patients with AD.
Background
Pancreatic neuroendocrine tumors (PNET) include heterogeneous tumors with a variable degree of inherent biologic aggressiveness represented by the histopathologic grade. Although several ...studies investigated the computed tomography (CT) characteristics which can predict the histopathologic grade of PNET, accurate prediction of the PNET grade by CT examination alone is still limited.
Purpose
To investigate the important CT findings and CT texture variables for prediction of grade of PNET.
Material and Methods
Sixty-six patients with pathologically confirmed PNETs (grade 1 = 45, grades 2/3 = 21) underwent preoperative contrast-enhanced CT. Two reviewers determined the presence of predefined CT findings. CT texture was also analyzed on arterial and portal phase using both two-dimensional (2D) and three-dimensional (3D) analysis. Multivariate logistic regression analysis was performed in order to identify significant predictors for tumor grade.
Results
Among CT findings and CT texture variables, the significant predictors for grade 2/3 tumors were an ill-defined margin (odds ratio OR = 7.273), lower sphericity (OR = 0.409) on arterial 2D analysis, higher skewness (OR = 1.972) and lower sphericity (OR = 0.408) on arterial 3D analysis, lower kurtosis (OR = 0.436) and lower sphericity (OR = 0.420) on portal 2D analysis, and a larger surface area (OR = 2.007) and lower sphericity (OR = 0.503) on portal 3D analysis (P < 0.05). Diagnostic performance of texture analysis was superior to CT findings (AUC = 0.774 vs. 0.683).
Conclusion
CT is useful for predicting grade 2/3 PNET using not only the imaging findings including an ill-defined margin, but also the CT texture variables such as lower sphericity, higher skewness, and lower kurtosis.
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