Inhibition of the Dead Box RNA Helicase 3 Prevents HIV-1 Tat and Cocaine-Induced Neurotoxicity by Targeting Microglia Activation.

HIV-1 Associated Neurocognitive Disorder (HAND) is a common and clinically detrimental complication of HIV infection. Viral proteins, including Tat, released from infected cells, cause neuronal toxicity. Substance abuse in HIV-infected patients greatly influences the severity of neuronal damage. To repurpose small molecule inhibitors for anti-HAND therapy, we employed MOLIERE, an AI-based literature mining system that we developed. All human genes were analyzed and prioritized by MOLIERE to find previously unknown targets connected to HAND. From the identified high priority genes, we narrowed the list to those with known small molecule ligands developed for other applications and lacking systemic toxicity in animal models. To validate the AI-based process, the selective small molecule inhibitor of DDX3 helicase activity, RK-33, was chosen and tested for neuroprotective activity. The compound, previously developed for cancer treatment, was tested for the prevention of combined neurotoxicity of HIV Tat and cocaine. Rodent cortical cultures were treated with 6 or 60 ng/ml of HIV Tat and 10 or 25 µM of cocaine, which caused substantial toxicity. RK-33 at doses as low as 1 µM greatly reduced the neurotoxicity of Tat and cocaine. Transcriptome analysis showed that most Tat-activated transcripts are microglia-specific genes and that RK-33 blocks their activation. Treatment with RK-33 inhibits the Tat and cocaine-dependent increase in the number and size of microglia and the proinflammatory cytokines IL-6, TNF-α, MCP-1/CCL2, MIP-2, IL-1α and IL-1ß. These findings reveal that inhibition of DDX3 may have the potential to treat not only HAND but other neurodegenerative diseases. Graphical Abstract RK-33, selective inhibitor of Dead Box RNA helicase 3 (DDX3) protects neurons from combined Tat and cocaine neurotoxicity by inhibition of microglia activation and production of proinflammatory cytokines.

[Epidemiological survey of asthma among children aged 0-14 years in 2010 in urban Zhongshan, China].

OBJECTIVE: To investigate the prevalence, current treatment, and clinical characteristics of asthma, as well as the risk factors for this disease, among children aged 0-14 years in 2010 in urban Zhongshan, China. METHODS: A total of 10 336 children aged 0-14 years were selected from urban Zhongshan by cluster random sampling. The Third National Childhood Asthma Epidemiological Questionnaire 2010 was used to analyze the prevalence, current treatment, and clinical characteristics of childhood asthma, as well as the risk factors for this disease. RESULTS: Asthma was diagnosed in 179 cases (1.73%). The prevalence of asthma in male children was significantly higher than that in female children (2.25% vs 1.16%; P<0.01). Of the 179 patients, severe attacks were common in 104 cases (58.1%), 110 cases (61.5%) had slow onset, 102 cases (57.0%) had gradually relieved conditions, 61 cases (34.1%) suffered from asthma during seasonal transition, and 150 cases (83.8%) developed asthma due to respiratory tract infection. Among all asthmatic children, 71.5% had been treated with inhaled corticosteroids, and 71.5% had been treated with bronchodilator. The multivariate logistic regression analysis showed that a history of penicillin allergy, a family history of allergy, food allergy, eczema, allergic rhinitis, cesarean delivery, family mould, and perinatal passive smoking were independent risk factors for childhood asthma. CONCLUSIONS: The prevalence of childhood asthma in urban Zhongshan is on a high level, and is associated with gender. The treatment of asthma has been standardized, but still needs further improvement. The onset of asthma attack is influenced by various factors.

[Incidence of wheezing and chronic cough in children aged 3-14 years in rural and urban areas of Zhongshan, China: a questionnaire survey].

OBJECTIVE: To investigate the incidence of wheezing and chronic cough in children aged 3-14 years in different living areas of Zhongshan, China. METHODS: According to the unified program of the 2010 national epidemiological survey of asthmatic children aged 0-14 years, a questionnaire survey of the children aged 3-14 years in rural and urban areas of Zhongshan was conducted. RESULTS: A total of 15 763 children were included in the survey. Among all participants, 8 248 were from the urban area, and 7 515 from the rual area; 8 306 were boys, and 7 457 were girls. The percentage of children with a history of wheezing was significantly higher in the urban group than in the rural group (6.6% vs 3.2%; P<0.05), and it was significantly higher in boys than in girls for each group (P<0.05). The urban group had a significantly higher percentage of individuals who had wheezing in the past one year than the rural group (2.8% vs 1.5%; P<0.05), and this percentage was significantly higher in boys than in girls for each group (P<0.05). Compared with the rural group, the urban group had a significantly higher percentage of individuals who had chronic cough (duration 1 year) (7.9% vs 3.1%; P<0.05). The above indices were relatively high in children under 6 years of age, and all but the percentage of girls who had wheezing in the past one year in both rural and urban areas showed significant differences between all age groups. CONCLUSIONS: The incidence of wheezing and chronic cough varies with age, sex, and living area for children aged 3-14 years in Zhongshan, and it is relatively high under 6 years of age, in the urban area, and among boys.

[Risk factors for bronchial asthma in school children].

OBJECTIVE: To investigate the roles of the residential environment and eating habits in the pathogenesis of bronchial asthma in school children. METHODS: One hundred and twenty-nine children between 6-12 years who were diagnosed with asthma were enrolled. Two hundred and fifty-eight healthy age- and gender-matched children were used as the control group. A questionaire which included 23 factors related to respiratory tract anaphylactic diseases such as residential environment and eating habits were completed by the children's parents. RESULTS: Logistic regression analysis showed that 6 variances out of 16 agents of the residential environment, the experience of raising pets, the type of floor, the type of pillow, the type of quilts, the heating equipments and the house area, were entered into the regression equation; none of the 7 variances of eating inhabits was entered into it. CONCLUSIONS: The residential environment plays an impotent role in the pathogenesis of bronchial asthma in children. The incidence of bronchial asthma in children can be reduced by the improvement of the residential environment.