The role of ZC3H12D-regulated TLR4-NF-κB pathway in LPS-induced pro-inflammatory microglial activation.

Lipopolysaccharide (LPS) is an important neurotoxin that can cause inflammatory activation of microglia. ZC3H12D is a novel immunomodulator, which plays a remarkable role in neurological pathologies. It has not been characterized whether ZC3H12D is involved in the regulation of microglial activation. The aim of this study was to investigate the role of ZC3H12D in LPS-induced pro-inflammatory microglial activation and its potential mechanism. To elucidate this, we established animal models of inflammatory injury by intraperitoneal injection of LPS (10 mg/kg). The results of the open-field test showed that LPS caused impaired motor function in mice. Meanwhile, LPS caused pro-inflammatory activation of microglia in the mice cerebral cortex and inhibited the expression of ZC3H12D. We also constructed in vitro inflammatory injury models by treating BV-2 microglia with LPS (0.5 µg/mL). The results showed that down-regulated ZC3H12D expression was associated with LPS-induced pro-inflammatory microglial activation, and further intervention of ZC3H12D expression could inhibited LPS-induced pro-inflammatory activation of microglia. In addition, LPS activated the TLR4-NF-κB signaling pathway, and this process can also be reversed by promoting ZC3H12D expression. At the same time, the addition of resveratrol, a nutrient previously proven to inhibit pro-inflammatory microglial activation, can also reverse this process by increasing the expression of ZC3H12D. Summarized, our data elucidated that ZC3H12D in LPS-induced pro-inflammatory activation of brain microglia via restraining the TLR4-NF-κB pathway. This study may provide a valuable clue for potential therapeutic targets for neuroinflammation-related injuries.

The association between intermediate-term sulfur dioxide exposure and outpatient visits for Parkinson's disease: a time-series study in southwestern China.

Parkinson's disease (PD) is the second most common human neurodegenerative disorder, and the pathogenesis of it remains poorly understood. Limited studies have shown that both long- and short-term exposure to air pollutants may be associated with increased risk of PD while lacking evidence on the effects of intermediate-term exposure. In this study, over-dispersed Poisson generalized additive models (GAMs) were applied to explore the association between intermediate-term sulfur dioxide (SO2) exposure and outpatient visits for PD in Chongqing, China, and further stratified analyses were performed by age and gender. A total of 39,984 PD cases from January 1, 2014, to December 31, 2019 (2191 days) were included. The association of intermediate-term SO2 exposure with outpatient visits for PD was statistically significant: per 1 µg/m3 increase of SO2 corresponded to 2.34% (95% CI: 0.88%, 3.80%) elevation in monthly PD outpatient visits at lag 0 (the concurrent month). Stratified analyses showed that the associations between SO2 and PD outpatient visits were stronger in younger (≤ 60 years) and female patients. In conclusion, intermediate-term SO2 exposure can be associated with an increased risk of PD outpatient visits. Our results highlight the importance of recognizing the role of intermediate-term SO2 exposure in the development of PD. In addition to focusing on the effects of long-term or short-term air pollutants, it is necessary to pay more attention to the health effects of intermediate-term exposure time windows of air pollutants, which will facilitate policy formulation and public health interventions for health risks.

The role of MAPK/NF-κB-associated microglial activation in T-2 toxin-induced mouse learning and memory impairment.

T-2 toxin is a mycotoxin with multiple toxic effects and has emerged as an important food pollutant. Microglia play a significant role in the toxicity of various neurotoxins. However, whether they participate in the neurotoxicity of T-2 toxin has not been reported. To clarify this point, an in vivo mouse model of T-2 toxin (4 mg/kg) poisoning was established. The results of Morris water maze and open-field showed that T-2 toxin induced learning and memory impairment and locomotor inhibition. Meanwhile, T-2 toxin induced microglial activation, while inhibiting microglia activation by minocycline (50 mg/kg) suppressed the toxic effect of the T-2 toxin. To further unveil the potential mechanisms involved in T-2 toxin-induced microglial activation, an in vitro model of T-2 toxin (0, 2.5, 5, 10 ng/mL) poisoning was established using BV-2 cells. Transcriptomic sequencing revealed lots of differentially expressed genes related to MAPK/NF-κB pathway. Western blotting results further confirmed that T-2 toxin (5 ng/mL) induced the activation of MAPKs and their downstream NF-κB. Moreover, the addition of inhibitors of NF-κB and MAPKs reversed the microglial activation induced by T-2 toxin. Overall, microglial activation may contribute a considerable role in T-2 toxin-induced behavioral abnormalities, which could be MAPK/NF-κB pathway dependent.

Genome-wide association study of serum tumor markers in Southern Chinese Han population.

BACKGROUND: Serum indicators AFP, CA50, CA125, CA153, CA19-9, CEA, f-PSA, SCC-Ag have been confirmed as tumor markers (TMs). We conducted a genome-wide association study on 8 tumor markers of our 427 Han population in southern China, in order to identify genetic loci that are significantly associated with the level of 8 tumor markers. METHODS: We use Gene Titan multi-channel instrument and Axiom Analysis Suite 6.0 software for genotyping. We used IMPUTE2 software for imputation, and 1000 Genomes Project (Phase 3) was used as haplotype reference. After necessary quality control and statistical analysis, genetic loci genome-wide associated with TMs (p < 5E-8) will be identified. Finally, we selected Top SNPs (p < 5E-7) from the GWAS results for replication test. We used SPSS software to draw the distribution box plots of serum TMs under different genotypes of significant loci. RESULTS: The results showed that there were only MUC1 (mucin 1)-rs4072037 significantly genome-wide associated with CA153 (p = 1.28E-18). However, we found that a total of 30 genetic loci have a suggestively significant genome-wide association with the level of 8 serum tumor markers (p < 5E-6). Then 3 Top SNPs (p < 5E-7) were selected for replication verification. The results showed that MUC1-rs4072037 was still significantly associated with CA153 in another population (p = 3.73E-08). Comparing with the TT genotype of rs4072037, the CA153 level was higher under CC or CT genotype of rs4072037. CONCLUSION: MUC1-rs4072037 is significantly genome-wide associated with CA153 level. There are 30 genetic loci suggestively genome-wide associated with level of tumor markers among the Han population from Southern China.

IL6R gene polymorphisms and their relation to chronic obstructive pulmonary disease susceptibility in the Chinese population.

Background: This work was designed to explore the correlation between IL6R polymorphisms and chronic obstructive pulmonary disease (COPD) susceptibility. Methods: Agena MassARRAY was used to genotype five SNPs of IL6R in 498 patients with COPD and 498 controls. Genetic models and haplotype analysis were used to assess the associations between SNPs and COPD risk. Results: Rs6689306 and rs4845625 increase the risk of COPD. Rs4537545, rs4129267 and rs2228145 were related to a decreased risk of COPD in different subgroups. Haplotype analysis revealed that GTCTC, GCCCA and GCTCA contributed to a reduced risk of COPD after adjustment. Conclusion: IL6R polymorphisms are significantly associated with COPD susceptibility.