Corticostriatal causality analysis in children and adolescents with attention-deficit/hyperactivity disorder.

AIM: The effective connectivity between the striatum and cerebral cortex has not been fully investigated in attention-deficit/hyperactivity disorder (ADHD). Our objective was to explore the interaction effects between diagnosis and age on disrupted corticostriatal effective connectivity and to represent the modulation function of altered connectivity pathways in children and adolescents with ADHD. METHODS: We performed Granger causality analysis on 300 participants from a publicly available Attention-Deficit/Hyperactivity Disorder-200 dataset. By computing the correlation coefficients between causal connections between striatal subregions and other cortical regions, we estimated the striatal inflow and outflow connection to represent intermodulation mechanisms in corticostriatal pathways. RESULTS: Interactions between diagnosis and age were detected in the superior occipital gyrus within the visual network, medial prefrontal cortex, posterior cingulate gyrus, and inferior parietal lobule within the default mode network, which is positively correlated with hyperactivity/impulsivity severity in ADHD. Main effect of diagnosis exhibited a general higher cortico-striatal causal connectivity involving default mode network, frontoparietal network and somatomotor network in ADHD compared with comparisons. Results from high-order effective connectivity exhibited a disrupted information pathway involving the default mode-striatum-somatomotor-striatum-frontoparietal networks in ADHD. CONCLUSION: The interactions detected in the visual-striatum-default mode networks pathway appears to be related to the potential distraction caused by long-term abnormal information input from the retina in ADHD. Higher causal connectivity and weakened intermodulation may indicate the pathophysiological process that distractions lead to the impairment of motion planning function and the inhibition/control of this unplanned motion signals in ADHD.

Metformin regulates the effects of IR and IGF-1R methylation on mast cell activation and airway reactivity in diabetic rats with asthma through miR-152-3p/DNMT1 axis.

BACKGROUND/AIM: Metformin is a drug for treating type 2 diabetes mellitus (T2DM). Recently, metformin has been shown to reduce the risks of asthma-associated outcomes and asthma deterioration, thereby holding promise as a superior medicine for diabetic patients with asthma. However, the mechanism by which metformin reduces diabetic asthma is yet to be clarified. This study aimed at ascertaining the downstream molecules underlying the effect of metformin on the activation of mast cells (MCs) and airway reactivity in a concomitant diabetic and asthmatic rat model. METHODS: A T2DM model was induced utilizing a high-fat diet and streptozotocin. Then, 10% ovalbumin was utilized to stimulate asthma-like pathology in the T2DM rats. RBL-2H3 cells were induced by anti-dinitrophenyl-specific immunoglobulin E for constructing an in vitro model. Luciferase assay and RNA immunoprecipitation (IP) assay were conducted to identify the interaction between microRNA-152-3p (miR-152-3p) and DNA methyltransferase 1 (DNMT1), while chromatin IP to identify the binding of DNMT1 to insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) promoters. The effects of metformin on both pathological changes in vivo and biological behaviors of cells were evaluated. Using gain- and loss-of-function approaches, we assessed the role of the two interactions in the metformin-induced effect. RESULTS: It was suggested that metformin could impede the MC activation and airway resistance in the concomitant diabetic and asthmatic rats. Additionally, metformin downregulated IR and IGF-1R through DNMT1-dependent methylation to repress MC activation and airway resistance. DNMT1 was testified to be a target gene of miR-152-3p. Furthermore, miR-152-3p-induced silencing of DNMT1 was blocked by metformin, hence restraining MC activation and airway resistance. CONCLUSION: The findings cumulatively demonstrate that metformin downregulates IR/IGF-1R to block MC activation and airway resistance via impairing the binding affinity between miR-152-3p and DNMT1.