Silica nanoparticles as an enhancer in the IL-1ß-induced inflammation cycle of A549 cells.

Objective: The industrial production and combustion of coal can produce silica nanoparticles (nano-SiO2). It enters the human body mainly through the respiratory tract and exerts a toxic effect. However, whether nano-SiO2 can increase the IL-1ß-induced inflammatory expression in A549 cells has not been tested. Therefore, the synergistic toxicity of nano-SiO2 and IL-1ß to A549 was observed in our study. Materials and methods: We exposed A549 cells to nano-SiO2 (0, 100, 500, and 1000 µg/ml) for 12 and 24 h. The effect of nano-SiO2 on the viability of A549 cells was observed by the CCK-8 method. The A549 cells were exposed to nano-SiO2 (1 mg/mL) and cytokine IL-1ß (10 ng/mL) for 4 h, and we detected the expression of IL-1ß and IL-6 cytokines by real time quantitative polymerase chain (RT-qPCR) and enzyme linked immunosorbent assay (ELISA). The expression of ß-Actin, I-κB, phospho-ERK1/2 (P-ERK1/2), total-ERK1/2 (T-ERK1/2), phospho-JNK (P-JNK), total-JNK (T-JNK), phospho-P38 (P-P38), and total-P38 (T-P38) in A549 cells was detected by the Western Blot method. Results: The nano-SiO2 treatment resulted in a time-dependent decrease in the viability of A549 cells. The synergistic effect of nano-SiO2 and IL-1ß was observed on the new production of IL-1ß and IL-6 in A549 cells. The Western blot results showed that nano-SiO2 can increase the expression of IL-1ß and IL-6 by promoting the phosphorylation of ERK1/2 and elevating the phosphorylation of I-κB by IL-1ß. IL-1ß and IL-6 were induced by nano-SiO2, and the IL-1ß treatment with 20 µM of I-κBα phosphorylation inhibitor (PD98059) and 20 µM of ERK1/2 inhibitor (BAY11-7082) for 1 h was significantly lower than that of the control group in A549 cells. Discussion and conclusion: These results indicated that nano-SiO2 had a toxic effect on A549 cells, and this effect could increase IL-1ß on the A549 cell-induced inflammatory response. The results suggested that the release of IL-1ß and IL-6 in A549 was enhanced by the synergistic IL-1ß-induced phosphorylation of ERK1/2 and I-κB. This process is similar to a snowball, and it is possible that IL-1ß is continuously produced and repeatedly superimposed in A549 cells to produce an inflammatory effect; then, a vicious circle occurs, and an inflammatory storm is accelerated.

The association between Toxoplasma gondii infection and hypertensive disorders in T2DM patients: a case-control study in the Han Chinese population.

Type 2 diabetes mellitus (T2DM) is a major global health problem. The rate of infection with Toxoplasma gondii (T. gondii) is more than one-third of the total world population. The effects of T. gondii infection on the risk of diabetic complications and comorbidities are unclear. This study aims to determine the relationship between T. gondii infection and complications of T2DM in the Han Chinese population. We collected 1580 blood samples from T2DM patients and measured the levels of specific IgG antibodies against T. gondii in the sera of these patients using an ELISA assay. A logistic regression analysis was performed to estimate the effect of T. gondii infection on the complications of T2DM, while adjusting for age, gender, and triglyceride level (TG). We applied the multifactor dimensionality reduction (MDR) method to detect the interactions between T. gondii infections, demographic indexes and biochemical indicators among the different complications. Gender (the odds ratio (OR) = 0.63, 95%CI =0.45-0.89, P = 0.008) and TG level (OR = 0.64, 95%CI =0.45-0.89, P = 0.009) were influencing factors in T. gondii infections. T2DM patients who were infected with T. gondii had a 2.34 times risk of developing hypertension than those patients without T. gondii infection (OR = 2.34, 95%CI = 1.12-4.88, P = 0.024). The multiplicative interaction analysis and the additive interaction analysis did not reveal any evidence of interactive effects on diabetic complications and comorbidities. T. gondii might be a factor associated with hypertension in T2DM patients.

Association of pre-pregnancy body mass index with adverse pregnancy outcome among first-time mothers.

BACKGROUND: Studies have reported an increased risk of adverse pregnancy outcome associated with pre-pregnancy body mass index (BMI). However, the data on such associations in urban areas of southern Chinese women is limited, which drive us to clarify the associations of pre-pregnancy BMI and the risks of adverse pregnancy outcomes (preterm birth (PTB) and low birth weight (LBW)) and maternal health outcomes (gestational hypertension and cesarean delivery). METHODS: We performed a hospital-based case-control study including 3,864 Southern Chinese women who gave first birth to a live singleton infant from January 2015 to December 2015. PTB was stratified into three subgroups according to gestational age (extremely PTB, very PTB and moderate PTB). Besides, we combined birth weight and gestational age to dichotomise as being small for gestational age (SGA, less than the tenth percentile of weight for gestation) and non-small for gestational age (NSGA, large than the tenth percentile of weight for gestation), gestational week was also classified into categories of term, 34-36 week and below 34 week.. We then divided newborns into six groups: (1) term and NSGA; (2) 34-36 week gestation and NSGA; (3) below 34 week gestation and NSGA; (4) term and SAG; (5) 34-36 week gestation and SAG; (6) below 34 week gestation and SAG. Adjusted logistic regression models was used to estimate the odds ratios of adverse outcomes. RESULTS: Underweight women were more likely to give LBW (AOR = 1.44, 95% CI [1.11-1.89]), the similar result was seen in term and SAG as compared with term and NSAG (AOR = 1.78, 95% CI [1.45-2.17]), whereas underweight was significantly associated with a lower risk of gestational hypertension (AOR = 0.45, 95% CI [0.25-0.82) and caesarean delivery (AOR = 0.74, 95% CI [0.62-0.90]). The risk of extremely PTB is relatively higher among overweight and obese mothers in a subgroup analysis of PTB (AOR = 8.12, 95% CI [1.11-59.44]; AOR = 15.06, 95% CI [1.32-172.13], respectively). Both maternal overweight and obesity were associated with a greater risk of gestational hypertension (AOR = 1.71, 95% CI [1.06-2.77]; AOR = 5.54, 95% CI [3.02-10.17], respectively) and caesarean delivery (AOR = 1.91, 95% CI [1.53-2.38]; AOR = 1.85, 95% CI [1.21-2.82], respectively). CONCLUSIONS: Our study suggested that maternal overweight and obesity were associated with a significantly higher risk of gestational hypertension, caesarean delivery and extremely PTB. Underweight was correlated with an increased risk of LBW and conferred a protective effect regarding the risk for gestational hypertension and caesarean delivery for the first-time mothers among Southern Chinese.

Interaction Between Susceptibility Loci in MAVS and TRAF3 Genes, and High-risk HPV Infection on the Risk of Cervical Precancerous Lesions in Chinese Population.

Persistent high-risk HPV infection is considered as a major cause of cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The RIG-I pathway in innate immunity plays an important role in antivirus response. Here, we hypothesized that altered function of mitochondrial antiviral signaling protein (MAVS) and mitochondrial TNF receptor-associated factor 3(TRAF3), key molecules downstream of the viral sensors RIG-I, may impair their ability of clearing HPV and thereby influence the risk for cervical precancerous lesions. To investigate the effects of MAVS and TRAF3 polymorphisms on susceptibility to cervical precancerous lesions, 8 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls. Gene-environment interactions were also calculated. We found that CA genotype of rs6052130 in MAVS gene were at 1.48 times higher risk of developing cervical precancerous lesion than individuals with CC genotype (CA vs. CC: ORadjusted = 1.48, 95% CI, 1.02-2.16). In addition, a significant synergetic interaction between high-risk HPV infection and rs6052130 was found on an additive scale. A significantly decreased risk of cervical precancerous lesions for the TC genotype of rs12435483 in the TRAF3 gene (ORadjusted = 0.67, 95% CI, 0.45-0.98) was also found. Moreover, MDR analysis identified a significant three-locus interaction model, involving high-risk HPV infection, TRAF3 rs12435483 and number of full-term pregnancies. Our results indicate that the MAVS rs6052130 and TRAF3 rs12435483 confer genetic susceptibility to cervical precancerous lesions. Moreover, MAVS rs6052130-mutant individuals have an increased vulnerability to high-risk HPV-induced cervical precancerous lesions.

Association Study Between Methylation in the Promoter Regions of cGAS, MAVS, and TRAF3 Genes and the Risk of Cervical Precancerous Lesions and Cervical Cancer in a Southern Chinese Population.

A case-control study was used to explore the association between the methylation status in the promoter regions of the cGAS, MAVS, and TRAF3 genes and the diseases of cervical precancerous lesions (CPL) and cervical cancer (CC) in a Southern Chinese population, and to further explore their interaction effects with high-risk human papillomavirus (hrHPV) infection and environmental factors in these diseases. The study protocol was approved by the ethics committee of The First Affiliated Hospital of Jinan University, and this study was performed in 97 healthy controls, 75 patients with CPL and 33 patients with CC, while each participant has read and signed the informed consent forms before enrolment. The promoter methylation status genes were detected from the bisulfite-treated DNA by the bisulfite sequencing PCR (BSP) technique, which was carried out using MethPrimer. The cGAS, MAVS, and TRAF3 promoter methylation levels in CPL (CPL cGAS = 35.40%, CPL MAVS = 24.26%, and CPL TRAF3 = 96.76%) were significantly higher than those in the control (Control cGAS = 31.87%, Control MAVS = 21.16%, and Control TRAF3 = 96.26%, PcGAS < 0.001, PMAVS < 0.001, and PTRAF3 = 0.001); however, there was no significant differences between the CC and control. In the logistic regression model with adjusted covariates, compared with the individuals whose cGAS methylation levels were less than or equal to 31.87%, the women with the levels more than 31.87% increased the risk of CPL by 2.49 times (ORa = 2.49, 95% CI = 1.31-4.75, P a = 0.006). The women with MAVS methylation levels above 21.16% were 1.97 times more likely to have CPL than the those with the levels less than 21.16% (ORa = 1.97, 95% CI = 1.06-3.69, P a = 0.033). A synergistic interaction was found between hrHPV and gene promoter methylation levels of cGAS and MAVS in CPL; however, no potential interaction was observed in CC. The promoter methylation levels in cGAS, MAVS, and TRAF3 genes are higher in CPL than in control, indicating that hypermethylation might be an early event in the progression of cervical intraepithelial neoplasia (CIN). The interaction between the promoter methylation levels in cGAS and MAVS genes and hrHPV infection might play a role in the development of CPL.

Association Between MALAT1 and THRIL Polymorphisms and Precancerous Cervical Lesions.

BACKGROUND: The occurrence of cervical cancer is a complex process, for which human papillomavirus (HPV) infection is a risk factor, although not all women infected with HPV will develop the disease. Knockout of mammalian lung metastasis associated transcript 1 (MALAT1) is associated with increased risk for several cancer types, whereas the long non-coding RNA (lncRNA) THRIL is essential for induction of tumor necrosis factor-α expression, which plays important roles in HPV infection. MATERIALS AND METHODS: To investigate the effects of polymorphisms in the lncRNAs MALAT1 and THRIL on the susceptibility to precancerous cervical lesions, 12 single nucleotide polymorphisms (SNPs) were analyzed from 164 cervical precancerous lesion cases and 428 controls. Gene-gene and gene-environment interactions and haplotype associations were also evaluated. RESULTS: We found a significantly decreased risk of precancerous cervical lesions for the THRIL rs7133268 AG genotype (odds ratio adjusted = 0.63, 95% confidence interval: 0.42-0.94, p = 0.025). Multifactor dimensionality reduction analysis identified a significant two-locus interaction model involved in HPV infection and THRIL rs7133268 (training balanced accuracy = 0.6957, testing balanced accuracy = 0.6948, cross-validation consistency = 10/10, p = 0.0046). Other SNPs, including the two identified for MALAT1, were not significantly related to the risk of precancerous cervical lesions. CONCLUSION: Our results suggest that the rs7133268 polymorphism of the lncRNA THRIL gene can reduce the genetic susceptibility of precancerous cervical lesions and in turn reduce the risk of HPV infection.

Association Analysis of NLRP3 Inflammation-Related Gene Promotor Methylation as Well as Mediating Effects on T2DM and Vascular Complications in a Southern Han Chinese Population.

Objective: To explore the association between the methylation levels in the promoter regions of the NLRP3, AIM2, and ASC genes and T2DM and its vascular complications in a Southern Han Chinese population and further analyze their interaction and mediating effects with environmental factors in T2DM. Methods: A case-control study was used to determine the association between population characteristics, the methylation level in the promoter region of the NLRP3, AIM2, and ASC genes and T2DM and vascular complications. A mediating effect among genes-environment-T2DM and the interaction of gene-gene or gene-environment factors was explored. Results: In the logistic regression model with adjusted covariants, healthy people with lower total methylation levels in the AIM2 promoter region exhibited a 2.29-fold [OR: 2.29 (1.28~6.66), P = 0.011] increased risk of developing T2DM compared with higher-methylation individuals. T2DM patients without any vascular complications who had lower methylation levels (

Association of variants of miRNA processing genes with cervical precancerous lesion risk in a southern Chinese population.

The miRNA processing genes play essential roles in the biosynthesis of mammalian miRNAs, and their genetic variants are involved in the development of various cancers. Our study aimed to determine the potential association between miRNA processing gene polymorphisms and cervical precancerous lesions. Five single nucleotide polymorphisms (SNPs), including Ran-GTP (RAN) rs14035, exportin-5 (XPO5) rs11077, DICER1 rs3742330, DICER1 rs13078, and TARBP2 rs784567, were genotyped in a case-control study to estimate risk factors of cervical precancerous lesions. The gene-environment interactions and haplotype association were estimated. We identified a 27% decreased risk of cervical precancerous lesions for individuals with minor G allele in DICER1 rs3742330 (odds ratio (OR) = 0.73, 95% confidence interval (95% CI) = 0.58-0.92, P = 0.009). The AG and AG/GG genotypes in DICER1 rs3742330 were also found to decrease the risk of cervical precancerous lesions (AG compared with AA: OR = 0.51, 95% CI = 0.35-0.73, P <0.001; AG/GG compared with AA: OR = 0.54, 95% CI = 0.39-0.77, P = 0.001). The GT haplotype in DICER1 had a risk effect on cervical precancerous lesions compared with the AT haplotype (OR = 1.36, 95% CI = 1.08-1.73, P = 0.010). A two-factor (DICER1 rs3742330 and human papillomavirus (HPV) infection) and two three-factor (model 1: rs3742330, passive smoking, and HPV infection; model 2: rs3742330, abortion history, and HPV infection) interaction models for cervical precancerous lesions were identified. In conclusion, the genetic variants in the miRNA processing genes and interactions with certain environmental factors might contribute to the risk of cervical precancerous lesions in southern Chinese women.

Interactions of TRAF6 and NLRX1 gene polymorphisms with environmental factors on the susceptibility of type 2 diabetes mellitus vascular complications in a southern Han Chinese population.

AIMS: To evaluate the effects of TRAF6 and NLRX1 polymorphisms and their interactions with environmental factors on the susceptibility of type 2 diabetes mellitus (T2DM) vascular complications in a southern Han Chinese population. METHODS: Five single nucleotide polymorphisms (SNPs) were genotyped in a case-control study to estimate risk factors of T2DM vascular complications. Gene-gene and gene-environment interactions and haplotype associations were also estimated. RESULTS: The CA genotype of the NLRX1 rs4245191 was identified as a risk factor for T2DM macrovascular complications and diabetic cerebral infarction (OR=2.88, 95% CI=1.15-7.22, P=0.024; OR=4.00, 95% CI=1.04-15.38, P=0.043, respectively). A significantly lower T allele frequency in the TRAF6 rs16928973 was observed in T2DM patients with both microvascular and macrovascular complications compared with patients without any complication under the allelic model (T vs. C: OR=0.36, 95% CI=0.14-0.98, P=0.038). No significant differences in haplotypes, gene-gene interactions and gene-environment interactions were observed among T2DM vascular subgroup patients. CONCLUSIONS: Our study provides evidence that the NLRX1 rs4245191 polymorphisms influence the risk of T2DM macrovascular complications and diabetic cerebral infarction.

The effects of TLR3, TRIF and TRAF3 SNPs and interactions with environmental factors on type 2 diabetes mellitus and vascular complications in a Han Chinese population.

Toll-like receptor 3 (TLR3) is involved in type I interferon-ß (IFN-ß) via TIR-domain-containing adapter-inducing interferon-ß (TRIF) and Tumor necrosis factor receptor-associated factor 3 (TRAF3), culminating in inflammation and immunity reactions. TLR3 is implicated in insulin resistance and type 2 diabetes mellitus (T2DM). Eight SNPs of these genes were detected in 552 T2DM patients and 552 matched healthy control subjects. Gene-gene and gene-environment interactions and haplotype associations were also evaluated. We identified a 21% increased risk of T2DM for the T allele of rs12435483 in the TRAF3 gene (OR: 1.21; 95% CI: 1.01-1.44; P=0.036). The GA genotype and GA+AA genotype of TRAF3 rs12147254 were found to increase the risk of coronary heart disease (CHD) among T2DM patients (GA vs. GG: OR=4.17, 95% CI: 1.04-16.79, P=0.045; GA+AA vs. GG: OR=3.97, 95% CI: 1.02-15.48, P=0.047). However, the GACGAC haplotype in TRAF3 had a protective effect on T2DM micro-macrovascular complications (OR=0.33, 95% CI: 0.13-0.85, P=0.017). Two-factor (TRAF3 rs12435483 and LDL) and three-factor (TRAF3 rs12435483, BMI and HDL) interactions of the risk of T2DM were identified. In conclusion, the genetic variants in the TLR3-TRIF-TRAF3-INF-ß signaling pathway and interactions with some particular environmental factors (LDL, BMI and HDL) may contribute to susceptibility to T2DM and vascular complications in the Han Chinese population.

Global Epidemiology of Dengue Outbreaks in 1990-2015: A Systematic Review and Meta-Analysis.

Dengue is an arthropod-borne infectious disease caused by dengue virus (DENV) infection and transmitted by Aedes mosquitoes. Approximately 50-100 million people are infected with DENV each year, resulting in a high economic burden on both governments and individuals. Here, we conducted a systematic review and meta-analysis to summarize information regarding the epidemiology, clinical characteristics, and serotype distribution and risk factors for global dengue outbreaks occurring from 1990 to 2015. We searched the PubMed, Embase and Web of Science databases through December 2016 using the term "dengue outbreak." In total, 3,853 studies were identified, of which 243 studies describing 262 dengue outbreaks met our inclusion criteria. The majority of outbreak-associated dengue cases were reported in the Western Pacific Region, particularly after the year 2010; these cases were primarily identified in China, Singapore and Malaysia. The pooled mean age of dengue-infected individuals was 30.1 years; of the included patients, 54.5% were male, 23.2% had DHF, 62.0% had secondary infections, and 1.3% died. The mean age of dengue patients reported after 2010 was older than that of patients reported before 2010 (34.0 vs. 27.2 years); however, the proportions of patients who had DHF, had secondary infections and died significantly decreased after 2010. Fever, malaise, headache, and asthenia were the most frequently reported clinical symptoms and signs among dengue patients. In addition, among the identified clinical symptoms and signs, positive tourniquet test (OR = 4.86), ascites (OR = 13.91) and shock (OR = 308.09) were identified as the best predictors of dengue infection, DHF and mortality, respectively (both P < 0.05). The main risk factors for dengue infection, DHF and mortality were living with uncovered water container (OR = 1.65), suffering from hypotension (OR = 6.18) and suffering from diabetes mellitus (OR = 2.53), respectively (all P < 0.05). The serotype distribution varied with time and across WHO regions. Overall, co-infections were reported in 47.7% of the evaluated outbreaks, and the highest pooled mortality rate (2.0%) was identified in DENV-2 dominated outbreaks. Our study emphasizes the necessity of implementing programs focused on targeted prevention, early identification, and effective treatment.

Association of LPP and TAGAP Polymorphisms with Celiac Disease Risk: A Meta-Analysis.

Background: Lipoma preferred partner (LPP) and T-cell activation Rho GTPase activating protein (TAGAP) polymorphisms might influence the susceptibility to celiac disease. Therefore, we performed a meta-analysis by identifying relevant studies to estimate the risks of these polymorphisms on celiac disease. Methods: The PubMed, Web of Science and Embase databases were searched (up to October 2016) for LPP rs1464510 and TAGAP rs1738074 polymorphisms. Results: This meta-analysis included the same 7 studies for LPP rs1464510 and TAGAP rs1738074. The minor risk A allele at both rs1464510 and rs1738074 carried risks (odds ratios) of 1.26 (95% CI: 1.22-1.30) and 1.17 (95% CI: 1.14-1.21), respectively, which contributed to increased risks in all celiac disease patients by 10.72% and 6.59%, respectively. The estimated lambdas were 0.512 and 0.496, respectively, suggesting that a co-dominant model would be suitable for both gene effects. Conclusions: This meta-analysis provides robust estimates that polymorphisms in LPP and TAGAP genes are potential risk factors for celiac disease in European and American. Prospective studies and more genome-wide association studies (GWAS) are needed to confirm these findings, and some corresponding molecular biology experiments should be carried out to clarify the pathogenic mechanisms of celiac disease.

Interaction between susceptibility loci in cGAS-STING pathway, MHC gene and HPV infection on the risk of cervical precancerous lesions in Chinese population.

Human papillomavirus (HPV) infection is a definite risk factor for cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The cGAS-STING pathway in innate immunity plays an important role in protecting against HPV infection. Chen et al. described that the rs2516448 SNP in the MHC locus may affect susceptibility to cervical cancer, a finding that we attempted to replicate in a Chinese population. To investigate the effects of cGAS, STING and MHC polymorphisms on susceptibility to cervical precancerous lesions, 9 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls. Gene-gene and gene-environment interactions were also evaluated. We found a significantly decreased risk of cervical precancerous lesions for the GG genotype of rs311678 in the cGAS gene (ORadjusted = 0.40, 95% CI: 0.16-0.98). Moreover, MDR analysis identified a significant three-locus interaction model, involving HPV infection, age at menarche and rs311678 in cGAS. Additionally, a significant antagonistic interaction between HPV infection and rs311678 was found on an additive scale. In conclusion, our results indicate that the rs311678 polymorphism in the cGAS gene confers genetic susceptibility to cervical precancerous lesions. Moreover, the three-way gene-environment interactions further demonstrate that the rs311678 polymorphism in cGAS can significantly decrease the risk of HPV infection and the elder at menarche.