DOCK8 interference alleviates Aß­induced damage of BV2 cells by inhibiting STAT3/NLRP3/NF­κB signaling.

Dementia is defined as memory loss and other cognitive decline and it severely influences daily life. Alzheimer's disease (AD) is the most common cause of dementia. Dedicator of cytokinesis 8 (DOCK8) is reported to be involved in neurological diseases. The present study focused on investigating the role that DOCK8 serves in AD and addressing its hidden regulatory mechanism. Initially, Aß1-42 (Aß) was applied for the administration of BV2 cells. Subsequently, the mRNA and protein expression levels of DOCK8 were evaluated utilizing reverse transcription-quantitative PCR (RT-qPCR) and western blotting. After the DOCK8 silencing, immunofluorescence staining (IF), ELISA, wound healing and Transwell assays were applied to assess ionized calcium binding adapter molecule-1 (IBA-1) expression, release of inflammatory factors, migration and invasion in Aß-induced BV2 cells. IF was used to evaluate cluster of differentiation (CD)11b expression. RT-qPCR and western blotting were to analyze the levels of M1 cell markers inducible nitric oxide synthase (iNOS) and CD86. The expression of STAT3/NLR family pyrin domain containing 3 (NLRP3)/NF-κB signaling-related proteins were determined by western blotting. Finally, the viability and apoptosis in hippocampal HT22 cells with DOCK8 depletion were estimated. Results revealed that Aß induction greatly stimulated the expression levels of IBA-1 and DOCK8. DOCK8 silencing suppressed Aß-induced inflammation, migration and invasion of BV2 cells. Additionally, DOCK8 deficiency conspicuously decreased the expression levels of CD11b, iNOS and CD86. The expression of phosphorylated (p-)STAT3, NLRP3, ASC, caspase1 and p-p65 was downregulated in Aß-induced BV2 cells after DOCK8 depletion. STAT3 activator Colivelin reversed the effects of DOCK8 knockdown on IBA-1 expression, inflammation, migration, invasion and M1 cell polarization. In addition, the viability and apoptosis in hippocampal HT22 cells stimulated by neuroinflammatory release of BV2 cells were repressed following DOCK8 deletion. Collectively, DOCK8 interference alleviated Aß-induced damage of BV2 cells by inhibiting STAT3/NLRP3/NF-κB signaling.

Two Novel Functional Mutations in Promoter Region of SCN3B Gene Associated with Atrial Fibrillation.

The sodium voltage-gated channel beta subunit 3 (SCN3B) plays a crucial role in electrically excitable cells and conduction tissue in the heart. Some previous studies have established that genetic modification in sodium voltage-channel genes encoding for the cardiac ß-subunits, such as SCN1B, SCN2B, SCN3B and SCN4B, can result in atrial fibrillation (AF). In the current study, we identified two rare variants in 5'UTR (NM_018400.4: c.-324C>A, rs976125894 and NM_018400.4: c.-303C>T, rs1284768362) of SCN3B in two unrelated lone AF patients. Our further functional studies discovered that one of them, the A allele of c.-324C>A (rs976125894), can improve transcriptional activity and may raise SCN3B expression levels. The A allele of c.-324C>A (rs976125894) has higher transcriptional activity when it interacts with GATA4, as we confirmed transcription factor GATA4 is a regulator of SCN3B. To the best of our knowledge, the current study is the first to demonstrate that the gain-of-function mutation of SCN3B can produce AF and the first to link a mutation occurring in the non-coding 5'UTR region of SCN3B to lone AF. The work also offers empirical proof that GATA4 is a critical regulator of SCN3B gene regulation. Our findings may serve as an encyclopedia for AF susceptibility variants and can also provide insight into the investigation of the functional mechanisms behind AF variants discovered by genetic methods.

Bifunctional covalent bromine: an advanced redox mediator for rechargeable lithium-oxygen batteries.

In this work, we introduce trimethylbromosilane (C3H9SiBr), which can protect lithium metal anodes via an in situ formed SEI layer while catalyzing the decomposition of Li2O2. As a result, lithium-oxygen batteries with C3H9SiBr offer a long cycle life of 110 cycles with a significantly reduced charging/discharging overpotential.

Health services for non-communicable diseases have been severely disrupted by COVID-19 based on an analysis of MicroBlog rescue data in Wuhan, China.

Diagnostic and treatment services for non-communicable diseases (NCDs) face significant challenges in the context of the COVID-19 pandemic. We used the Python programing language to extract and classify messages for help posted on the social networking platform microblog by NCD patients in the early stage of the COVID-19 epidemic in Wuhan, China. We found of all NCD patients, the most frequently recorded conditions were basic chronic diseases (42.50%), acute critical diseases (35.53%), malignant tumours (15.10%), and patients requiring haemodialysis (6.79%). Regarding COVID-19, 54.70% of patients reported suspected symptoms of infection, 32.01% were diagnosed with comorbidities, and 13.29% were non-COVID-19 patients. According to the analysis of the needs of the patients, 82.46% of the patients reported "No beds were available in the hospital", 25.31% of patients needed nucleic acid tests. Our results confirmed it is difficult to meet the regular needs in the diagnosis and treatment of patients with NCDs. Effective prevention and management of NCDs in public health emergencies has become an urgent issue to be addressed. During the COVID-19 epidemic, it is necessary to pay particular attention to the prevention and control of NCD patients, especially those with chronic disease. Governments and medical and health institutions at all levels should improve treatment mechanisms during major epidemics and ensure the uninterrupted treatment of patients with NCDs.

Toll­like receptor 4 contributes to acute kidney injury after cardiopulmonary resuscitation in mice.

Toll-like receptor 4 (TLR4) activation mediates renal injury in regional ischemia and reperfusion (I/R) models generated by clamping renal pedicles. However, it remains unclear whether TLR4 is causal in the kidney injury following global I/R induced by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The present study used wild­type (C3H/HeN) and TLR4­mutant (C3H/HeJ) mice to produce the CA/CPR model. CA was induced by injection of cold KCl and left untreated for different time periods. After resuscitation (72 h), the level of blood urea nitrogen (BUN) and serum creatinine (Scr), as well as histological changes in renal tissue were assessed to evaluate the severity of acute kidney injury (AKI). The expression of TLR4, intercellular adhesion molecule­1 (ICAM­1), myeloperoxidase (MPO) and growth­regulated oncogene­ß (GRO­ß) in kidney tissues was detected. The results demonstrated that the levels of Scr and BUN increased significantly in C3H/HeN and C3H/HeJ mice after CPR. CPR also resulted in increased expression of TLR4, ICAM­1, GRO­ß and MPO in a CA­duration dependent manner. However, there was decreased expression of ICAM­1, GRO­ß and MPO in C3H/HeJ mice compared with that in C3H/HeN mice. C3H/HeJ mice were resistant to AKI as demonstrated by the minor changes in renal histology and function following CPR. In conclusion, mice suffered from AKI after successful CPR and severe AKI occurred in mice with prolonged CA duration. TLR4 and its downstream signaling events that promote neutrophil infiltration via ICAM­1 and GRO­ß may be important in mediating inflammatory responses to renal injury after CPR.

Minocycline attenuates microglial response and reduces neuronal death after cardiac arrest and cardiopulmonary resuscitation in mice.

The possible role of minocycline in microglial activation and neuronal death after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in mice was investigated in this study. The mice were given potassium chloride to stop the heart beating for 8 min to achieve CA, and they were subsequently resuscitated with epinephrine and chest compressions. Forty adult C57BL/6 male mice were divided into 4 groups (n=10 each): sham-operated group, CA/CPR group, CA/CPR+minocycline group, and CA/CPR+vehicle group. Animals in the latter two groups were intraperitoneally injected with minocycline (50 mg/kg) or vehicle (normal saline) 30 min after recovery of spontaneous circulation (ROSC). Twenty-four h after CA/CPR, the brains were removed for histological evaluation of the hippocampus. Microglial activation was evaluated by detecting the expression of ionized calcium-binding adapter molecule-1 (Iba1) by immunohistochemistry. Neuronal death was analyzed by hematoxylin and eosin (H&E) staining and the levels of tumor necrosis factor-alpha (TNF-α) in the hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that the neuronal death was aggravated, most microglia were activated and TNF-α levels were enhanced in the hippocampus CA1 region of mice subjected to CA/CPR as compared with those in the sham-operated group (P<0.05). Administration with minocycline 30 min after ROSC could significantly decrease the microglial response, TNF-α levels and neuronal death (P<0.05). It was concluded that early administration with minocycline has a strong therapeutic potential for CA/CPR-induced brain injury.