The SUMO-specific protease SENP2 plays an essential role in the regulation of Kv7.2 and Kv7.3 potassium channels.

Sentrin/small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2)-deficient mice develop spontaneous seizures in early life because of a marked reduction in M currents, which regulate neuronal membrane excitability. We have previously shown that hyper-SUMOylation of the Kv7.2 and Kv7.3 channels is critically involved in the regulation of the M currents conducted by these potassium voltage-gated channels. Here, we show that hyper-SUMOylation of the Kv7.2 and Kv7.3 proteins reduced binding to the lipid secondary messenger PIP2. CaM1 has been shown to be tethered to the Kv7 subunits via hydrophobic motifs in its C termini and implicated in the channel assembly. Mutation of the SUMOylation sites on Kv7.2 and Kv7.3 specifically resulted in decreased binding to CaM1 and enhanced CaM1-mediated assembly of Kv7.2 and Kv7.3, whereas hyper-SUMOylation of Kv7.2 and Kv7.3 inhibited channel assembly. SENP2-deficient mice exhibited increased acetylcholine levels in the brain and the heart tissue because of increases in the vagal tone induced by recurrent seizures. The SENP2-deficient mice develop seizures followed by a period of sinus pauses or atrioventricular conduction blocks. Chronic administration of the parasympathetic blocker atropine or unilateral vagotomy significantly prolonged the life of the SENP2-deficient mice. Furthermore, we showed that retigabine, an M-current opener, reduced the transcription of SUMO-activating enzyme SAE1 and inhibited SUMOylation of the Kv7.2 and Kv7.3 channels, and also prolonged the life of SENP2-deficient mice. Taken together, the previously demonstrated roles of PIP2, CaM1, and retigabine on the regulation of Kv7.2 and Kv7.3 channel function can be explained by their roles in regulating SUMOylation of this critical potassium channel.

Irisin attenuates lipopolysaccharide-induced acute lung injury by downregulating inflammatory cytokine expression through miR-199a-mediated Rad23b overexpression.

AIMS: Acute lung injury (ALI) is a leading cause of mortality as a result of inflammatory cytokine overexpression and increased rates of apoptosis. Therapies for ALI are yet to be thoroughly investigated. Recent evidence has shown that irisin exerts protective effects against many types of pathologies. The present study aimed to determine the function of irisin in an ALI mouse model induced by lipopolysaccharide (LPS) and the corresponding underlying mechanisms at the tissue, cellular, and molecular levels. MAIN METHODS: We assessed irisin function in A549 cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays. The cell apoptosis was evaluated by flow cytometry. Western blotting and RT-PCR were used to test expression level. Animal models of ALI was established. KEY FINDINGS: We found that irisin treatment maintained lung weight, significantly reduced inflammatory cytokine expression, and alleviated lung injury by downregulating miR-199a. In LPS-stimulated cells, forced miR-199a expression downregulated Rad23b expression by targeting its 3' untranslated region, indicating that Rad23b is a direct target of miR-199a. SIGNIFICANCE: These findings reveal that irisin can alleviate ALI by inhibiting miR-199a and upregulating Rad23b expression, suggesting that irisin has clinical potential for the treatment of ALI.

Expression of Paxillin is Correlated with Clinical Prognosis in Colorectal Cancer Patients.

BACKGROUND: The aim of this study was to investigate the expression of Paxillin in colorectal carcinoma and its significance in clinical prognosis. MATERIAL AND METHODS: Tissue specimens from 242 colorectal cancer patients who underwent radical resection were collected in Shaanxi Provincial People's Hospital from 2010 to 2014. The mRNA levels of Paxillin in colorectal cancer tissue and tissue adjacent to carcinoma of 62 patients were measured by quantitative real-time PCR. Immunohistochemistry staining was used to detect the expression of Paxillin in 242 samples of paraffin-embedded tissues. RESULTS: The mRNA and protein level of Paxillin in colorectal cancer tissues were significantly higher than those in the tissue adjacent to carcinoma (P<0.001 and P=0.003, respectively). The expression of Paxillin was significantly correlated to tumor histological grade (P<0.001), tumor size (P=0.01), serum CA199 level (P<0.001), the clinical TNM stage (P<0.001), and distant metastasis (P<0.001). Survival analysis showed that the prognosis of the patients with high expression of Paxillin was poorer than those with low expression of Paxillin (P=0.03). Cox proportional hazards model with stepwise selection showed that age, Paxillin expression level, and the clinical TNM stage were independent prognostic factors influencing survival for patients (P=0.01, P=0.004 and P<0.001, respectively). CONCLUSIONS: Paxillin was expressed at significantly higher levels in colorectal cancer tissues and might serve as a potential prognostic indicator in patients with colorectal cancer.

Epidemiology of Suicide and Associated Socio-Demographic Factors in Emergency Department Patients in 7 General Hospitals in Northwestern China.

BACKGROUND: This study aimed to illustrate the characteristics of suicide attempters treated in the Emergency Departments of 7 general hospitals in Xi'an and to provide relevant data for early psychological treatment. MATERIAL AND METHODS: Between October 2010 and September 2014, 155 suicide attempters were treated in the Emergency Departments. Data were collected using a semi-structured questionnaire. Descriptive statistics, chi-square tests, and multivariate analyses were used to identify the factors associated with suicidal behaviors. RESULTS: Females outnumbered males at a ratio of 3.7 to 1. The greatest proportion of cases was in the age group of 21 to 30 years (52.9%). Patients who finished middle school or high school accounted for most of the suicide attempters (50.3%). The most common method used for attempted suicide was drug ingestion (86.5%). The majority of cases attempted suicide at home (74.8%) during the night. Marriage frustration, work and study problems, family fanaticism and conflict, somatic disease, and history of mental disorders were all significantly associated with suicide attempts. The ratio of patients to be discharged or to die were similar in occupation, marital status, and the place of suicide attempt; however, the results were different in gender, age, educational level, methods used for suicide, time of day, and reason. CONCLUSIONS: Suicide is an important public health problem and is multidimensional in nature. Future studies with larger samples are expected to provide more specific knowledge of the effect of each social factor on the suicide risk in Chinese in order to improve the prevention of suicides.

The association between diabetes and nocturia: A systematic review and meta-analysis.

Background: Many studies have explored the association between diabetes and nocturia, but it remains unclear. This article systematically analyses existing evidence of the relationship between diabetes and nocturia, including subgroup analysis based on the number of voids, gender, and continent, in the hope of reaching more reliable clinical conclusions relating to diabetes and nocturia. Methods: PubMed, Web of Science, and Cochrane Library were searched for identifying studies relating to diabetes and nocturia prior to July 2021. Literature quality evaluation was performed using the Newcastle Ottawa Scale. A random effect meta-analysis was used for pooled odds ratios (ORs) and confidence intervals (CIs) as a means of evaluating the relationship between diabetes and nocturia. Results: In total, 29 of 781 potentially relevant studies were proven to be eligible. The overall pooled OR demonstrated that diabetes increases the risk of nocturia (OR: 1.49; 95% CI: 1.38, 1.61; P < 0.00001). The association was found to be more robust among subjects ≥ 1 void than ≥ 2 void (OR: 1.74; 95% CI: 1.41, 2.14; P < 0.00001 vs. OR: 1.45; 95% CI: 1.33, 1.59; P < 0.00001), in males than females (OR: 1.59; 95% CI: 1.41, 1.79; P < 0.00001 vs. OR: 1.41; 95% CI: 1.20, 1.66; P < 0.0001) and in Asia than Europe or North America (OR: 1.54; 95% CI: 1.36, 1.75; P < 0.00001 vs. OR: 1.43; 95% CI: 1.19, 1.72; P = 0.0001 vs. OR: 1.45; 95% CI: 1.22, 1.73; P < 0.0001). Conclusions: Diabetes has an association with a 1.49-fold higher risk of nocturia. This association is more robust for Asian and male subjects or those at a lower nocturia cut-off.

Classification for Memory Activities: Experiments and EEG Analysis Based on Networks Constructed via Phase-Locking Value.

Electroencephalogram (EEG) plays a crucial role in the study of working memory, which involves the complex coordination of brain regions. In this research, we designed and conducted series of experiments of memory with various memory loads or target forms and collected behavioral data as well as 32-lead EEG simultaneously. Combined with behavioral data analysis, we segmented EEG into slices; then, we calculated phase-locking value (PLV) of Gamma rhythms between every two leads, conducted binarization, constructed brain function network, and extracted three network characteristics of node degree, local clustering coefficient, and betweenness centrality. Finally, we inputted these network characteristics of all leads into support vector machines (SVM) for classification and obtained decent performances; i.e., all classification accuracies are greater than 0.78 on an independent test set. Particularly, PLV application was restricted to the narrow-band signals, and rare successful application to EEG Gamma rhythm, defined as wide as 30-100 Hz, had been reported. In order to address this limitation, we adopted simulation on band-pass filtered noise with the same frequency band as Gamma to help determine the PLV binarizing threshold. It turns out that network characteristics based on binarized PLV have the ability to distinguish the presence or absence of memory, as well as the intensity of the mental workload at the moment of memory. This work sheds a light upon phase-locking investigation between relatively wide-band signals, as well as memory research via EEG.

Spatial Difference and Equity Analysis for Accessibility to Three-Level Medical Services Based on Actual Medical Behavior in Shaanxi, China.

The contradiction between the supply and demand of public medical resources in China is serious. On the basis of the "graded diagnosis and treatment" model, the Chinese government divides the medical grade and adjusts the allocation of medical facilities so as to alleviate the adverse impact of these issues on residents' health. Although the government tries to guide residents' medical treatment according to the level of medical facilities, there are differences between residents' medical treatment mode and policy rules in reality. Therefore, it is of great significance to explore spatial differences in accessibility to medical services for residents on the basis of the actual medical behavior. This article takes Shaanxi province as the research area, and uses the improved node cost network analysis method with the space-time distance model and the two-step floating catchment area method, respectively, to analyze the spatial differences of accessibility to three-level medical services and evaluate the equity of accessibility in different areas and groups in Shaanxi. Results showed that the overall level of accessibility to primary medical services in the province is good, and spatial distribution is balanced; the polarization of accessibility to secondary and tertiary medical services is a serious issue, and within the research area, a band-shaped multicore spatial structure was formed with the built-up areas of various cities as high-level centers of accessibility. Provincial residents have poor equity to access three-level medical services, and the equity of accessibility to primary medical services is better than that to highly specialized medical services. There is no obvious gap between accessibility to three-level medical services for the aging and the nonaging populations in Shaanxi, but the unfair phenomenon between agricultural and the nonagricultural populations is prominent. In addition, this article found that the improvement in traffic conditions can produce space-time convergence and effectively weaken spatial deprivation. Therefore, developing public transportation is an effective approach to improve the equity of accessibility to medical services.

Peroxiredoxin-3 attenuates traumatic neuronal injury through preservation of mitochondrial function.

Peroxiredoxins (PRDXs) are a highly conserved family of thiol peroxidases that scavenge peroxides in cells. PRDX3 is one member of PRDXs localized in the mitochondria, and has been shown to be involved in antioxidant defense and redox signaling. In this study, we investigated the role of PRDX3 in neuronal trauma using a traumatic neuronal injury (TNI) model in primary cultured cortical neurons. We found that TNI significantly decreased the expression of PRDX3 at both mRNA and protein levels. Overexpression of PRDX3 by lentivirus (LV-PRDX3) transfection attenuated lactate dehydrogenase (LDH) release and neuronal apoptosis after TNI. The results of immunostaining showed that LV-PRDX3 transfection markedly reduced TNI-induced intracellular ROS production, protein radical formation and lipid peroxidation. In addition, overexpression of PRDX3 preserved mitochondrial membrane potential (MMP) levels and ATP generation, and inhibited mitochondrial cytochrome c release in TNI-injured neurons. The results of polymerase chain reaction (PCR) showed that PRDX3 overexpression also increased mitochondrial DNA (mtDNA) content and upregulated the expression of mitochondrial biogenesis-related factors. Taken together, our data demonstrate that PRDX3 protects against TNI insult by preserving mitochondrial function and mitochondrial biogenesis, and may have potential therapeutic value for traumatic brain injury (TBI).

[RH Factor and Clinical Transfusion Effectiveness for ß-Thalassemia Children with Long-Term Blood Transfusion].

OBJECTIVE: To investigate the irregular antibody production and its relationship with Rh factor genotypes and the loci of thalassemia gene mutations for the ß-thalassemic children with long-term transfusion, so as provide experimental basis for clinical safe and effective transfusions for thalassemic children. METHODS: The peripheral blood from 246 children with ß-thalassemia was collected in our hospital; the extraction of genomic DNA and Rh factor (C/c, E/e) genotypes were assayed by PCR-SSP method, the irregular antibodies were screened and identified by serological method, the genotypes for thalassemia and gene mutations were analysed by PCR-RD method. RESULTS: The genotypes of Rh factors classified by PCR- SSP in the 246 cases of ß-thalassemia children were as follws: Ce/Ce (143/246, 58.1%), CE/ce (59/246, 24%), cE/cE (14/24, 5.7%), Ce/ce (12/246, 4.9%); The positive rate of irregular antibody was 7.7% (19/246), including anti-E (7/19), anti-c (5/19), anti-C (2/19), anti-E and anti-c (2/19), anti-e (1/19), anti-D (2/19); Of the 19 cases with positive irregular antibody, the genotypings of Rh factor were: Ce/Ce (11/19), CE/ce (2/19), cE/cE (2/19), Ce/ce (2/19), cE/ce (2/19); the gene mutations location of thalassemia for 19 cases with positive irregular antibody: CD41-42M (13/19), CD71-72M (2/19), IVS-II-654M (3/19), -28M (1/19). CONCLUSION: The irregular antibody production for ß-thalassemic children with long-term transfusion may have some relevance with Rh factor genotypes and thalassemia genetic mutations. This study possesses a certain significance for effective prevention of RBC alloimmune response of ß-thalassemia children and improvement of efficacy and safety of clinical transfasion blood.

The mitochondrial division inhibitor mdivi-1 attenuates spinal cord ischemia-reperfusion injury both in vitro and in vivo: Involvement of BK channels.

Mitochondrial division inhibitor (mdivi-1), a selective inhibitor of a mitochondrial fission protein dynamin-related protein 1 (Drp1), has been shown to exert protective effects in heart and cerebral ischemia-reperfusion models. The present study was designed to investigate the beneficial effects of mdivi-1 against spinal cord ischemia-reperfusion (SCIR) injury and its associated mechanisms. SCIR injury was induced by glutamate treatment in cultured spinal cord neurons and by descending thoracic aorta occlusion for 20 min in rats. We found that mdivi-1 (10 µM) significantly attenuated glutamate induced neuronal injury and apoptosis in spinal cord neurons. This neuroprotective effect was accompanied by decreased expression of oxidative stress markers, inhibited mitochondrial dysfunction and preserved activities of antioxidant enzymes. In addition, mdivi-1 significantly increased the expression of the large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels, and blocking BK channels by paxilline partly ablated mdivi-1 induced protection. The in vivo experiments showed that mdivi-1 treatment (1 mg/kg) overtly mitigated SCIR injury induced spinal cord edema and neurological dysfunction with no organ-related toxicity in rats. Moreover, mdivi-1 increased the expression of BK channels in spinal cord tissues, and paxilline pretreatment nullified mdivi-1 induced protection after SCIR injury in rats. Thus, mdivi-1 may be an effective therapeutic agent for SCIR injury via activation of BK channels as well as reduction of oxidative stress, mitochondrial dysfunction and neuronal apoptosis. This article is part of a Special Issue entitled SI: Spinal cord injury.

Small-molecule inhibitors at the PSD-95/nNOS interface attenuate MPP+-induced neuronal injury through Sirt3 mediated inhibition of mitochondrial dysfunction.

Post-synaptic density protein 95 (PSD-95) links neuronal nitric oxide synthase (nNOS) with the N-methyl-D-aspartic acid (NMDA) receptor in the central nervous system, and this molecular complex has been implicated in regulating neuronal excitability in several neurological disorders. Here, small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 and ZL006 were tested for neuroprotective effects in an in vitro Parkinson's disease (PD) model. We now report that IC87201 and ZL006 reduced MPP(+)-induced neuronal injury and apoptotic cell death in a dose-dependent manner in cultured cortical neurons. These protective effects were associated with suppressed mitochondrial dysfunction, as evidenced by decreased reactive oxygen species (ROS) generation, cytochrome c release, mitochondrial membrane potential (MMP) collapse, and the preserved mitochondrial complex I activity and ATP synthesis. IC87201 and ZL006 also preserved intracellular homeostasis through mitigating mitochondrial Ca(2+) uptake and promoting mitochondrial Ca(2+) buffering capacity. Moreover, treatment with IC87201 and ZL006 significantly increased the expression of Sirt3 after MPP(+) exposure, and knockdown of Sirt3 using specific targeted small interfere RNA (siRNA) partially nullified the protective effects induced by these two inhibitors. These data strongly support the hypothesis that targeting the PSD-95/nNOS interaction produces neuroprotective effects and may represent a novel class of therapeutics for PD as well as other neurological diseases where detrimental NMDA receptor signaling plays a major role.