Identification of lipid-modifying drug targets for autoimmune diseases: insights from drug target mendelian randomization.

BACKGROUNDS: A growing body of evidence has highlighted the interactions of lipids metabolism and immune regulation. Nevertheless, there is still a lack of evidence regarding the causality between lipids and autoimmune diseases (ADs), as well as their possibility as drug targets for ADs. OBJECTIVES: This study was conducted to comprehensively understand the casual associations between lipid traits and ADs, and evaluate the therapeutic possibility of lipid-lowering drug targets on ADs. METHODS: Genetic variants for lipid traits and variants encoding targets of various lipid-lowering drugs were derived from Global Lipid Genetics Consortium (GLGC) and verified in Drug Bank. Summary data of ADs were obtained from MRC Integrative Epidemiology Unit (MER-IEU) database and FinnGen consortium, respectively. The causal inferences between lipid traits/genetic agents of lipid-lowering targets and ADs were evaluated by Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses. Enrichment analysis and protein interaction network were employed to reveal the functional characteristics and biological relevance of potential therapeutic lipid-lowering targets. RESULTS: There was no evidence of causal effects regarding 5 lipid traits and 9 lipid-lowering drug targets on ADs. Genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with a reduced risk of rheumatoid arthritis (RA) in both discovery (OR [odds ratio] = 0.45, 95%CI: 0.32, 0.63, P = 6.79 × 10- 06) and replicate datasets (OR = 0.37, 95%CI: 0.23, 0.61, P = 7.81 × 10- 05). SMR analyses supported that genetically proxied HMGCR inhibition had causal effects on RA in whole blood (OR = 0.48, 95%CI: 0.29, 0.82, P = 6.86 × 10- 03) and skeletal muscle sites (OR = 0.75, 95%CI: 0.56, 0.99, P = 4.48 × 10- 02). After controlling for blood pressure, body mass index (BMI), smoking and drinking alchohol, HMGCR suppression showed a direct causal effect on a lower risk of RA (OR = 0.33, 95%CI: 0.40, 0.96, P = 0.042). CONCLUSIONS: Our study reveals causal links of genetically proxied HMGCR inhibition (lipid-lowering drug targets) and HMGCR expression inhibition with a decreased risk of RA, suggesting that HMGCR may serve as candidate drug targets for the treatment and prevention of RA.

[Formation Potential of Secondary Organic Aerosols and Sources of Volatile Organic Compounds During an Air Pollution Episode in Autumn, Langfang].

A typical particulate matter pollution process occurred from October 9 to 17,2018,in Langfang,and 99 types of volatile organic compounds (VOCs) were monitored by using ZF-KU-1007. The characteristics of VOCs,formation potential of secondary organic aerosol (SOA),and source of VOCs were systematically analyzed. The results showed that the maximum concentration of PM2.5 was 198 µg·m-3 during the pollution process and was 2.64 times the National Ambient Air Quality Standard (GB 3095-2012). The average concentration of VOCs was 56.8×10-9,127.8×10-9,and 72.5×10-9 in the early,middle,and late stages of the pollution process,respectively,and the concentration of VOCs increased significantly in the middle stage. The formation potential of SOA was significantly positively correlated with PM2.5,and the contribution of aromatic hydrocarbon for SOA was larger and significantly correlated with the concentration of PM2.5. In the middle pollution stage,SOA increased,and the contribution ratio of aromatic hydrocarbon increased significantly. Conversely,the contribution of alkanes and olefin decreased significantly,which showed that aromatic hydrocarbons,namely benzene series,were the dominant species of SOA generation and had a great influence on the pollution process. Benzene,toluene,m-/p-xylene,o-xylene,and ethylbenzene and nonane,n-undecane,and methylcyclohexane were the priority control species in this pollution process. Solvent use source and motor vehicle emission source (gasoline and diesel vehicles) were the main sources affecting the concentration of VOCs during the autumn pollution process of Langfang,among which the contribution of gasoline vehicle emissions increased significantly in the middle pollution contribution and was the key control source.

Dopamine receptor-mediated roles on retinal ganglion cell hyperexcitability and injury in experimental glaucoma.

Extraordinary excitability (hyperexcitability) is closely related to retinal ganglion cell (RGC) injury in glaucoma. Dopamine (DA) and its receptors are involved in modulating RGC excitability. We investigated how DA system affects RGC injury in chronic ocular hypertension (COH) experimental glaucoma model. Western blotting and immunohistochemistry results revealed that expression of DA D2-like receptor (D2R) in RGCs was increased in COH retinas. Patch-clamp recordings showed that outward K+ currents were downregulated, while Na+ currents and NaV1.6 expression were upregulated in RGCs of COH retinas, which could be reversed by intravitreal pre-injection of the D2R antagonist sulpiride, but not by the D1-like receptor (D1R) antagonist SCH23390. However, pre-injection of the D1R agonist SKF81297 could partially reverse the increased expression of NaV1.6 proteins. Consistently, the numbers of evoked action potentials induced by current injections were increased in RGCs of COH retinas, indicating that RGCs may be in a condition of hyperexcitability. The increased frequency of evoked action potentials could be partially block by pre-injection of sulpiride, SKF81297 or DA, respectively. Furthermore, the increased number of TUNEL-positive RGCs in COH retinas could be partially reduced by intravitreal pre-injection of sulpiride, but not by pre-injection of SCH23390. Moreover, pre-injection of SKF81297 or DA could reduce the number of TUNEL-positive RGCs in COH retinas. All these results indicate that in COH retina, activation of D2R enhances RGC hyperexcitability and injury, while activation of D1R results in the opposite effects. Selective inhibition of D2R or activation of D1R may be an effective strategy for treatment of glaucoma.

Down-expression of Foxj1 on airway epithelium with impaired cilia architecture in non-cystic fibrosis bronchiectasis implies disease severity.

INTRODUCTION: The pathogenesis of non-cystic fibrosis bronchiectasis has not been clearly clarified. This study aimed to investigate the expression of ciliary regulating protein forkhead box protein j1 (Foxj1) on airway epithelium in non-cystic fibrosis bronchiectasis and its association with airway cilia structure disorder and disease severity. METHODS: Lung tissue sections excised from 47 patients with non-cystic fibrosis bronchiectasis were included between January 2018 and June 2021. Specimens from 26 subjects who underwent a lobectomy due to lung nodule were chosen as controls. Clinical information was collected, and pathologic analysis was performed to assess the epithelial structure and expression of ciliary regulating Foxj1. RESULTS: Of the 47 patients with non-cystic fibrosis bronchiectasis, 25 were considered as mild, 12 were moderate whereas the remaining 10 cases were severe according to the bronchiectasis severity index score evaluation. Epithelial hyperplasia, hyperplasia of goblet cells and inflammatory cell infiltration were observed in non-cystic fibrosis bronchiectasis, compared with control subjects. Cilia length in non-cystic fibrosis bronchiectasis patients were shorter than that in the control group, (5.34 ± 0.89) µm versus (7.34 ± 0.71) µm, respectively (P = 0.002). The expression of Foxj1 was (2.69 ± 1.09) × 106 in non-cystic fibrosis bronchiectasis, compared with (6.67 ± 1.15) × 106 in the control group (P = 0.001). Moreover, patients with lower expression of Foxj1 showed shorter airway cilia and worse in disease severity. CONCLUSION: Foxj1 declined in the airway epithelium of patients with non-cystic fibrosis bronchiectasis, positively correlated to cilia length and might imply worse disease severity.

[Characteristics and Source of VOCs During O3 Pollution Between August to September, Langfang Development Zones].

A total of 99 volatile organic compound(VOC) species were detected the Langfang development zones based on continuous monitoring using a ZF-PKU-1007 between August 25 and September 30, 2018. The concentrations, reactivity, and sources of VOCs were studied under different O3 concentrations using compositional analysis. The results showed that the average VOCs concentration during the research period was(75.17±38.67)×10-9, and was(112.33±30.96)×10-9, (66.25±34.84)×10-9 on pollution days and cleaning days, respectively(VOCs concentrations were 69.6% higher on pollution days). The contribution of VOCs species to the ozone formation potential(OFP) were ranked in the order aldehydes > aromatics > alkenes > alkanes. In the case of L·OH, the main contributions were from aromatics(30.0%) and alkenes(25.8%) on pollution days, while the contribution from aromatic alkenes(29.8%) was a slightly higher than aromatics(28.0%) on cleaning days. By applying the positive matrix factorization(PMF) model, five major VOCs sources were extracted, namely vehicle emissions(34.4%), solvent usage and evaporation(31.7%), the petrochemical industry(15.7%), combustion(11.1%), and plant emissions(7.9%). The contributions of solvent usage and evaporation and plant emission sources on pollution days were 13.1% and 1.2% higher than on cleaning days, respectively, which was likely due to relatively higher temperatures on these days. Therefore, vehicle emissions and solvent usage and evaporation should be priorities in VOCs control strategies for the Langfang development zones between August to September.

[Impact of transition readiness on quality of life in children with chronic diseases].

OBJECTIVE: To investigate the current quality of life in children with chronic diseases, and to explore the impact of transition readiness on quality of life. METHODS: A total of 332 children with chronic diseases from two children's hospitals in Shanghai, China were enrolled. A self-designed demographic questionnaire, Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQLTM 4.0), and Self-Management and Transition to Adulthood with Rx=Treatment (STARx) Questionnaire were used to evaluate transition readiness and quality of life. RESULTS: The children with chronic diseases had a significantly lower total quality of life score than the national norm (74.66±15.85 vs 81.81±12.03; P<0.001). Doctor-patient communication and health care responsibilities (the child's abilities to take care of himself/herself and adaptation to the process of diagnosis and treatment from childhood to adulthood) were positively correlated with the scores on each dimension of quality of life (P<0.05). Duration of disease, time of absence from school within six months, and the number of types of drugs taken orally were negatively correlated with the total quality of life score (rs=-0.172, -0.236, and -0.280; P<0.05). The residence (urban or rural area), monthly family income, parents' educational level, and father's occupation had significant influence on children's quality of life (P<0.05). The hierarchical multiple regression analysis revealed that doctor-patient communication and health care responsibilities led to a 14.3% increase in the explanation of the total variation in quality of life (P<0.001). CONCLUSIONS: Quality of life is not satisfactory in children with chronic diseases. Two domains of transition readiness, namely the abilities to communicate with health providers and health care responsibilities, are major factors influencing quality of life in these children.