Exploring the Effects of Repetitive Transcranial Magnetic Stimulation on Comorbid Sleep Disorders in Preschool Children with Attention-Deficit Hyperactivity Disorder.

Background: Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurological developmental disorders in children, and sleep disorders (SDs) are a common comorbidity in children with ADHD. There are currently no pharmacological treatment options for SD in children with ADHD of preschool age (4-6 years). Repetitive transcranial magnetic stimulation (rTMS) is a novel, non-invasive neuromodulation technique. This study explores the effectiveness of rTMS for comorbid SDs in preschool-aged children with ADHD. Methods: Thirty-five children of preschool age with ADHD and comorbid SDs were recruited for this study. The children were divided into a parent behavior management training (PBMT) group (n = 19) and a repetitive transcranial magnetic stimulation combined with parent behavior management training group (n = 16). Both groups underwent 8 weeks of treatment. The children's SD scores were assessed using the Chinese Children's Sleep Habits Questionnaire, were measured before the start, at the end, and 4 weeks after the end of the intervention, and were used to measure the effects. Within-group differences were compared using a repeated-measures analysis of variance, and between-group differences were compared using an independent samples t-test and Mann-Whitney U-test. Results: Both the PBMT group and the rTMS combined with the PBMT group significantly improved the SDs of preschool-aged children with ADHD (P < .001), but the effect of the intervention was more pronounced in the rTMS combined with the PBMT group (P < .001) and lasted longer than the PBMT group (P = .004). Conclusion: Repetitive transcranial magnetic stimulation is a promising non-pharmacological therapy to improve SD in preschool-aged children with ADHD.

The Role of TAK1 in RANKL-Induced Osteoclastogenesis.

Bone remodelling is generally a dynamic process orchestrated by bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts are the only cell type capable of bone resorption to maintain bone homeostasis in the human body. However, excessive osteoclastogenesis can lead to osteolytic diseases. The receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) has been widely considered to be an important modulator of osteoclastogenesis thereby participating in the pathogenesis of osteolytic diseases. Transforming growth factor ß-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, is an important intracellular molecule that regulates multiple signalling pathways, such as NF-κB and mitogen-activated protein kinase to mediate multiple physiological processes, including cell survival, inflammation, and tumourigenesis. Furthermore, increasing evidence has demonstrated that TAK1 is intimately involved in RANKL-induced osteoclastogenesis. Moreover, several detailed mechanisms by which TAK1 regulates RANKL-induced osteoclastogenesis have been clarified, and some potential approaches targeting TAK1 for the treatment of osteolytic diseases have emerged. In this review, we discuss how TAK1 functions in RANKL-mediated signalling pathways and highlight the significant role of TAK1 in RANKL-induced osteoclastogenesis. In addition, we discuss the potential clinical implications of TAK1 inhibitors for the treatment of osteolytic diseases.

Methylmercury induces lysosomal membrane permeabilization through JNK-activated Bax lysosomal translocation in neuronal cells.

MeHg, an environmental toxicant, is highly toxic to the central nervous system. Recent studies have reported that LMP is an important way in the lysosomal damage. However, the role and molecular mechanism of LMP in MeHg-induced neurotoxicity remain unknown. To study MeHg-induced LMP, we used 10µM MeHg to treat SH-SY5Y cells and 2µM MeHg to treat rat cerebral cortical neurons. Acridine orange (AO) staining and analysis of cathepsin B (CTSB) release were used to determine LMP. We found that MeHg reduced red AO fluorescence and induced CTSB release from lysosomes to the cytoplasm in a time-dependent manner. Moreover, pretreatment with the CTSB inhibitor alleviated cytotoxicity in neuronal cells. These results indicate MeHg induces LMP and subsequent CTSB-dependent cytotoxicity in neuronal cells. Bax is a pore-forming protein, which is involved in mitochondrial outer membrane permeabilization. Intriguingly, we demonstrated that MeHg induced Bax to translocate to lysosomes by using immunofluorescence and Western blot analysis of subcellular fractions. Furthermore, downregulating Bax expression suppressed MeHg-induced LMP. Bax subcellular localization is regulated by protein interaction with the cytoplasmic 14-3-3. Our previous study demonstrated that JNK participated in neurotoxicity through regulating protein interaction. In the current study, we showed that JNK dissociated Bax-14-3-3 complex to facilitate Bax lysosomal translocation. Finally, inhibition of the JNK/Bax pathway could alleviate MeHg-induced cytotoxicity in neuronal cells. The present study implies that inhibiting lysosomal damage (LMP)-related signaling might alleviate MeHg neurotoxicity.

Increased heat shock protein 70 levels in induced sputum and plasma correlate with severity of asthma patients.

Damage-associated molecular pattern molecules such as high-mobility group box 1 protein (HMGB1) and heat shock protein 70 (HSP70) have been implicated in the pathogenesis of asthma. The aim of our study was to examine the induced sputum and plasma concentrations of HSP70 in asthmatic patients to determine their relationship with airway obstruction. Thirty-four healthy controls and 56 patients with persistent bronchial asthma matched for gender and age were enrolled in this study. Spirometry measurements were performed before sputum induction. HSP70 levels in induced sputum and plasma were measured using the ELISA Kit. Sputum and plasma concentrations of HSP70 in asthmatics patients were significantly higher than that in control subjects (sputum, (0.88 ng/ml (0.27-1.88 ng/ml) versus 0.42 ng/ml (0.18-0.85 ng/ml), p < 0.001); plasma, (0.46 ng/ml (0.20-0.98 ng/ml) versus 0.14 ng/ml (0.11-0.37 ng/ml), p < 0.001) and were significantly negatively correlated with forced expiratory volume in 1 s (FEV1), FEV1 (percent predicted), and FEV1/FVC in all 90 participants and 56 patients with asthma. There were no significant differences in HSP70 levels between patients with eosinophilic and non-eosinophilic asthma. HSP70 levels in plasma were positively correlated with neutrophil count, and HSP70 levels in induced sputum were positively correlated with lymphocyte count. In multivariate analysis, independent predictors of sputum HSP70 were diseases and disease severity but not smoking, age, or gender, and independent predictors of plasma HSP70 were also diseases and disease severity. In conclusion, this study indicates that induced sputum and plasma HSP70 could serve as a useful marker for assessing the degree of airway obstruction in patients with asthma. However, further investigation is needed to establish the role of circulating and sputum HSP70 in the pathogenesis of asthma.