PARP-1 modulates the expression of miR-223 through histone acetylation to involve in the hydroquinone-induced carcinogenesis of TK6 cells.

The upstream regulators of microRNAs were rarely reported. Hydroquinone (HQ) is the main metabolite of benzene, one of the important environmental factors contributing to leukemia and lymphoma. In HQ-induced malignant transformed TK6 (TK6-HT) cells, the expression of PARP-1 and miR-223 were upregulated. When in PARP-1 silencing TK6-HT cells, miR-223 was downregulated and the apoptotic cell number correspondingly increased. In TK6 cells treated with HQ for different terms, the expression of miR-223 and PARP-1 were dynamically observed and found to be decreased and increased, respectively. Trichostatin A could increase the expression of miR-223, then the expression of HDAC1-2 and nuclear factor kappa B were found to be increased, but that of mH2A was decreased. PARP-1 silencing inhibited the protein expression of H3Ac, mH2A, and H3K27ac. By co-immunoprecipitation experiment, PARP-1 and HDAC2 were found to form a regulatory complex. In conclusion, we demonstrated that the upregulation of PARP-1 mediated activation of acetylation to promote the transcription of miR-223 possibly via coregulating with HDAC2, an epigenetic regulation mechanism involved in cell malignant transformation resulting from long-term exposure to HQ, in which course, H3K27ac might be a specific marker for the activation of histone H3, which also gives hints for benzene exposure research.

Obesity is negatively associated with dental caries among children and adolescents in Huizhou: a cross-sectional study.

BACKGROUND: Obesity and dental caries among children and adolescents are growing worldwide public health problems. They share some common and modifiable influences. The objective of this study was to evaluate the prevalence of obesity and dental caries among children and adolescents in Huizhou and explore the association between Body Mass Index (BMI) category and dental caries. METHODS: This cross-sectional study enrolled 105,181 students (55,500 males and 49,681 females) from 87 schools in Huizhou. Height and weight were measured, and BMI was calculated. Based on Chinese BMI standards, students were classified into underweight, normal weight, overweight, and obesity groups. Dental caries was diagnosed according to criteria recommended by World Health Organization (WHO). We used the Chi-square test to compare proportions of groups and performed Association Rules Mining to identify patterns and combinations of BMI categories and dental caries. Finally, a multilevel logistic regression model was applied to analyze the association between BMI category and dental caries when confounders were considered. RESULTS: The prevalence of underweight, overweight, and obesity among children and adolescents was 7.56%, 8.85%, and 2.95%, respectively. The overall prevalence of dental caries was 58.10%, with a lower prevalence among boys than girls. Students from primary schools and remote towns more easily suffer from dental caries. Caries prevalence of students belonged to underweight, normal, overweight, and obesity was 65.6%, 58.8%, 49.6%, and 46.1% individually. With increasing BMI levels, the prevalence of dental caries decreased. Further, this trend still exists in each subgroup of gender, educational stage, school type, and area. Association rules indicate underweight has a positive effect on the occurrence of dental caries, while overweight or obesity has a negative impact on the occurrence of dental caries. The three-level logistic regression model results show that BMI category is inversely associated with dental caries after adjusting confounders. CONCLUSION: Obesity is negatively associated with dental caries among children and adolescents in Huizhou. Further research is required to investigate how dietary habits, oral hygiene habits, and parental socioeconomic status mediate the association between BMI and dental caries.

The expression and clinical significance of CLIC1 and HSP27 in lung adenocarcinoma.

The purpose of this research was to study the roles of chloride intracellular channel protein 1 (CLIC1) and heat shock protein 27 (HSP27) in the clinical pathology of lung adenocarcinoma and to explore whether the expression of CLIC1 and HSP27 can be used as independent factors for the prediction of recurrence and prognosis after radical resection of lung adenocarcinoma. One hundred and three paraffin sections of lung adenocarcinoma tissues were collected, and the expression of CLIC1 and HSP27 was detected in these tumors using immunohistochemistry. The correlation of the expression of these two proteins with clinicopathological parameters and prognosis was statistically analyzed. In the 103 samples, the expression of HSP27 and CLIC1 was strongly positive in 61 (59.2%) and 49 cases (47.6%), respectively. Statistical analysis showed that the expression level of HSP27 did not significantly correlate with the patient's age, sex, degree of tumor differentiation, T staging of tumors, and TNM staging of tumors (p > 0.05), whereas the expression of CLIC1 did significantly correlate with T staging of tumors (p = 0.029). Univariate analysis indicated that the patient's ECOG score, T staging, N staging, TNM staging, and CLIC1 expression correlated with prognosis (p = 0.031, 0.001, 0.011, 0.013, and <0.001, respectively). Multivariate statistical analysis showed that age, T staging, and CLIC1 expression were independent associated factors for predicting the 5-year survival rate of patients (p = 0.026, 0.004, and <0.001, respectively). Age, T staging, and CLIC1 expression significantly correlated with the overall survival of post-operative lung adenocarcinoma patients. CLIC1 may be closely associated with the occurrence and development of lung adenocarcinoma and may be used as an effective marker for predicting the prognosis of this disease.

Free Triiodothyronine Is Independently Associated with Nonalcoholic Fatty Liver Disease in Hospitalized Type 2 Diabetes Mellitus Patients.

OBJECTIVE: Free triiodothyronine (FT3) is an independent risk factor for nonalcoholic fatty liver disease (NAFLD) in patients with euthyroid. However, whether FT3 has an independent effect on NAFLD in a population of type 2 diabetes remains unknown. The purpose of this study was to identify the potential role of FT3 in NAFLD with T2DM. DESIGN: A cross-sectional study. Patient. A total of 859 T2DM patients who met the inclusion criteria were included. There were 506 T2DM patients without NAFLD and 353 T2DM patients with NAFLD. METHODS: The independent samples t-test or Wilcoxon rank sum test were used for continuous variables of different distribution types, while the chi-square test was used for categorical variables. Pearson correlation analysis and linear regression were used to analyze the correlation between FT3 and clinical measurements and biochemical indicators. Multivariate logistic regression analysis was used to determine independent predictors. RESULTS: Patients with NAFLD had higher BMI, SBP, and DBP, longer duration of T2DM, and higher islet function index, blood glucose index, liver function index, renal function index, blood lipid index, and FT3. We also found that FT3 was affected by other five indicators, including ALT, CR, GGT, TC, and LDL-C only in the NAFLD group but not in the non-NAFLD group. FT3 was significantly associated with NAFLD in T2DM patients, and the prevalence of NAFLD increased gradually from the lowest FT3 tertile to the highest FT3 tertile (P for trend < 0.001). CONCLUSION: FT3 is independently associated with NAFLD in hospitalized T2DM patients after rigorous adjustment for various metabolic parameters.

Research Status of Differentially Expressed Noncoding RNAs in Type 2 Diabetes Patients.

AIMS: Noncoding RNAs (ncRNAs) play an important role in the occurrence and development of type 2 diabetes mellitus (T2DM). This paper summarized the current evidences of the involvement microRNAs, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in the differential expressions and their interaction with each other in T2DM. METHODS: The differentially expressed miRNAs, lncRNAs, and circRNAs in the blood circulation (plasma, serum, whole blood, and peripheral blood mononuclear cells) of patients with T2DM were found in PubMed, GCBI, and other databases. The interactions between ncRNAs were predicted based on the MiRWalk and the DIANA Tools databases. The indirect and direct target genes of lncRNAs and circRNAs were predicted based on the starBase V2.0, DIANA Tools, and LncRNA-Target databases. Then, GO and KEGG analysis on all miRNA, lncRNA, and circRNA target genes was performed using the mirPath and Cluster Profile software package in R language. The lncRNA-miRNA and circRNA-miRNA interaction diagram was constructed with Cytoscape. The aim of this investigation was to construct a mechanism diagram of lncRNA involved in the regulation of target genes on insulin signaling pathways and AGE-RAGE signaling pathways of diabetic complications. RESULTS: A total of 317 RNAs, 283 miRNAs, and 20 lncRNAs and circRNAs were found in the circulation of T2DM. Dysregulated microRNAs and lncRNAs were found to be involved in signals related to metabolic disturbances, insulin signaling, and AGE-RAGE signaling in T2DM. In addition, lncRNAs participate in the regulation of key genes in the insulin signaling and AGE-RAGE signaling pathways through microRNAs, which leads to insulin resistance and diabetic vascular complications. CONCLUSION: Noncoding RNAs participate in the occurrence and development of type 2 diabetes and lead to its vascular complications by regulating different signaling pathways.

Regulatory loop between lncRNA FAS-AS1 and DNMT3b controls FAS expression in hydroquinone-treated TK6 cells and benzene-exposed workers.

Hydroquinone (HQ), one of the main metabolites of benzene, is a well-known human leukemogen. However, the specific mechanism of how benzene or HQ contributes to the development of leukemia is unknown. In a previous study, we demonstrated the upregulation of DNA methyltransferase (DNMT) expression in HQ-induced malignant transformed TK6 (HQ-TK6) cells. Here, we investigated whether a regulatory loop between the long noncoding RNA FAS-AS1 and DNMT3b exists in HQ-TK6 cells and benzene-exposed workers. We found that the expression of FAS-AS1 was downregulated in HQ-TK6 cells and workers exposed to benzene longer than 1.5 years via histone acetylation, and FAS-AS1 expression was negatively correlated with the time of benzene exposure. Restoration of FAS-AS1 in HQ-TK6 cells promoted apoptosis and inhibited tumorigenicity in female nude mice. Interestingly, treatment with a DNMT inhibitor (5-aza-2-deoxycytidine), histone deacetylase inhibitor (trichostatin A), or DNMT3b knockout led to increased FAS-AS1 through increased H3K27ac protein expression in HQ-TK6 cells, and DNMT3b knockout decreased H3K27ac and DNMT3b enrichment to the FAS-AS1 promoter region, which suggested that DNMT3b and/or histone acetylation involve FAS-AS1 expression. Importantly, restoration of FAS-AS1 resulted in reduced expression of DNMT3b and SIRT1 and increased expression of FAS in both HQ-TK6 cells and xenograft tissues. Moreover, the average DNMT3b expression in 17 paired workers exposed to benzene within 1.5 years was decreased, but that of the remaining 103 paired workers with longer exposure times was increased. Conversely, DNMT3b was negatively correlated with FAS-AS1 expression. Both FAS-AS1 and DNMT3b influenced the enrichment of H3K27ac in the FAS promoter region by regulating the expression of SIRT1, consequently upregulating FAS expression. Taken together, these observations demonstrate crosstalk between FAS-AS1 and DNMT3b via a mutual inhibition loop and indicate a new mechanism by which FAS-AS1 regulates the expression of FAS in benzene-related carcinogenesis.

Tfh cell subset biomarkers and inflammatory markers are associated with frailty status and frailty subtypes in the community-dwelling older population: a cross-sectional study.

We conducted a cross-sectional study investigating community-dwelling older population to determine association between immunoscenescence marker, inflammatory cytokines and frailty. Frailty status was classified with 33-item modified frailty index and latent class analysis was applied to explore the latent classes (subtypes) of frailty. In multivariable analysis, higher Tfh2 cells were associated with a higher risk of frailty [1.13(1.03-1.25)] in females, but a lower risk of cognitive and functional frail [0.92(0.86-0.99)] and physiological frail [0.92(0.87-0.98)]. Additionally, a greater risk of multi-frail and physiological frail correlated with low Tfh1 [0.77(0.60-0.99); 0.87(0.79-0.96)] and Tfh17 cells [0.79(0.65-0.96); 0.86(0.78-0.94)], respectively. Higher B cells were associated with decreased frailty/pre-frailty both in females [0.89(0.81-0.98)] and males [0.82(0.71-0.96)], but did not correlate with frailty subtypes. Regarding inflammatory markers, participants in the TGF-ß 2nd quartile showed a decreased risk of pre-frailty/frailty in females [0.39(0.17-0.89)] and psychological frail [0.37(0.16-0.88)], compared with those in the top tertile. Moreover, we found participants in the 2nd tertile for IL-12 levels showed a decreased risk of physiological frail [0.40 (0.17-0.97)]. Our study highlights the importance of Tfh cell subsets and inflammatory markers in frailty in a sex-specific manner, particularly in terms of frailty subtype.

Development of frailty subtypes and their associated risk factors among the community-dwelling elderly population.

In order to explore frailty subtypes and find their associated risk factors, we conducted cross-sectional surveys of 5,341 seniors aged 60 and over in China using the Frailty Index (FI) scale. We identified four frailty subtypes, namely multi-frail, cognitive and functionally frail, psychologically frail and physiologically frail. Old age and low education level were the common risk factors among the four subtypes. Being widowed, divorced or unmarried was a risk factor for multi-frail, cognitive and functionally frail and psychologically frail, and male sex was a protective factor against cognitive and functionally frail and psychologically frail subtypes. Having a harmonious relationship with family was a protective factor against multi-frail, and fewer visits to the elderly by their children was a risk factor for psychologically frail. Dissatisfaction with their housing was a risk factor for cognitive and functionally frail, psychologically frail and physiologically frail, and a pension being the main source of income was a risk factor for cognitive and functionally frail and psychologically frail. Exercising every day was a protective factor against multi-frail and cognitive and functionally frail, and a lower level of physical activity was a risk factor for all four frailty subtypes. Our findings confirm the heterogeneity of frailty and suggest that different frail elderly individuals need more targeted care interventions.

The Level of Vitamin D in Children and Adolescents with Nonalcoholic Fatty Liver Disease: A Meta-Analysis.

BACKGROUND: The relationship between vitamin D level and NAFLD has not been investigated in children and adolescents. We performed a meta-analysis of published observational studies to assess this association between vitamin D levels (measured as serum 25-hydroxy vitamin D [25(OH)D]) and NAFLD in this age group. METHODS: Relevant studies conducted before May 20, 2018, were identified from the following electronic databases: PubMed, the Cochrane Library, Embase, and the Chinese CNKI databases. The quality of the included studies was evaluated using the Newcastle Ottawa Scale, and associations between vitamin D levels and NAFLD were estimated using standardised mean differences (SMD) and 95% confidence interval (CI). Subgroup and sensitivity analysis were used to identify sources of heterogeneity, and publication bias was evaluated using funnel plots. RESULTS: Eight articles were included in this meta-analysis. A significant difference was observed between low 25(OH)D levels and NAFLD in children and adolescents (SMD = -0.59, 95%CI = -0.98, -0.20, P <  0.01). Subgroup analysis revealed no differences in the study type, geographic location, BMI, and age subgroups. CONCLUSIONS: Low vitamin D levels were associated with NAFLD in children and adolescents.

Free Fatty Acids Activate Renin-Angiotensin System in 3T3-L1 Adipocytes through Nuclear Factor-kappa B Pathway.

The activity of a local renin-angiotensin system (RAS) in the adipose tissue is closely associated with obesity-related diseases. However, the mechanism of RAS activation in adipose tissue is still unknown. In the current study, we found that palmitic acid (PA), one kind of free fatty acid, induced the activity of RAS in 3T3-L1 adipocytes. In the presence of fetuin A (Fet A), PA upregulated the expression of angiotensinogen (AGT) and angiotensin type 1 receptor (AT1R) and stimulated the secretion of angiotensin II (ANG II) in 3T3-L1 adipocytes. Moreover, the activation of RAS in 3T3-L1 adipocytes was blocked when we blocked Toll-like receptor 4 (TLR4) signaling pathway using TAK242 or NF-κB signaling pathway using BAY117082. Together, our results have identified critical molecular mechanisms linking PA/TLR4/NF-κB signaling pathway to the activity of the local renin-angiotensin system in adipose tissue.

Sparstolonin B inhibits lipopolysaccharide-induced inflammation in 3T3-L1 adipocytes.

Sparstolonin B (SsnB), an isocoumarin compound isolated from the tubers of both Sparganium stoloniferum and Scirpus yagara, has been reported to have anti-inflammatory effects. However, whether SsnB has anti-inflammatory effects on LPS-stimulated 3T3-L1 adipocytes remains unclear. In this study, we investigated the effects of SsnB on adipocyte inflammation in 3T3-L1 adipocytes and anti-obesity properties in high fat diet (HFD)-induced obese rats. 3T3-L1 adipocytes were pretreated with SsnB 1h before LPS treatment. The expression of MCP-1, IL-6, TNF-α, and IL-10 were measured by qRT-PCR and ELISA. The expression of PPAR-γ, TLR4 and NF-κB were detected by western blotting. SsnB was administered to HFD-induced obese rats to confirm its effects in vivo. Our results showed that SsnB dose-dependently inhibited LPS-induced MCP-1, IL-6, and TNF-α production. SsnB was found to inhibit LPS-induced TLR4 expression and NF-κB activition. Furthermore, SsnB was found to activate PPAR-γ and the inhibitory effects of SsnB on MCP-1, IL-6, and TNF-α production can be reversed by PPAR-γ antagonist GW9662. In vivo, SsnB was found to reduce the body weight of rats fed with HFD. SsnB also inhibited the levels of serum triglyceride (TG) and cholesterol (TC) induced by HFD. In conclusion, the results suggested that SsnB could reduce HFD-induced obesity in rats and inhibited LPS-induced cytokines production in 3T3-L1 adipocytes by activating PPAR-γ.

Association of DRD3, COMT, and SLC6A4 Gene Polymorphisms with Type 2 Diabetes in Southern Chinese: A Hospital-Based Case-Control Study.

AIM: The aim of this study was to assess the associations of six single nucleotide polymorphisms (SNPs) of three genes (DRD3, COMT, and SCL6A4) with type 2 diabetes mellitus (T2DM) in Southern Chinese. SUBJECTS AND METHODS: Five hundred ninety-five cases with T2DM and 725 healthy controls of Han origin were recruited from six hospitals in Guangdong Province, Southern China. Fasting serum concentrations of markers of interest (total cholesterol, triglyceride, plasma glucose, etc.) were measured in hospitals. SNP genotyping was performed using a custom-by-design 2-×48-Plex SNPscan™ kit (Genesky Biotechnologies Inc., Shanghai, China). Single-point SNP analysis, haplotype analysis, and SNP-SNP interactions were carried out. RESULTS: SNP rs4646312 in COMT achieved statistical significance in both allelic association and genotypic association and even after adjusting covariates (odds ratio [OR]=1.26; 95% confidence interval [CI], 1.04-1.53; P=0.021). Two haplotypes consisting of rs4646312 and rs4680 were also significantly associated with T2DM, of which C-G was a protective haplotype for T2DM (OR=0.83; 95% CI, 0.70-0.98; P=0.029), whereas T-A was a risk one (OR=1.23, 95% CI, 1.03-1.46; P=0.022). Interaction analysis identified a significant epistatic effect between rs4680 in COMT and rs2066713 in SCL6A4 after adjusting for covariates (OR=3.59, 95% CI, 1.72-7.48; P=0.001 for dominant-dominant model). However, only the interaction between rs4680 and rs2066713 was significant, and haplotype T-A showed a marginally increased risk after Bonferroni correction. CONCLUSIONS: The genetic polymorphisms in COMT and SCL6A4 confer significant effects in joint actions to T2DM in Southern Chinese.

[Study on the association between catechol-O-methyltransferase gene polymorphisms and type 2 diabetes mellitus].

OBJECTIVE: To evaluate the association between the two single nucleotide polymorphisms located in catechol-O-methyltransferase (COMT) gene and type 2 diabetes mellitus (T2DM)in Han population in Guangdong province. METHODS: Two tagSNPs (rs4646312 and rs4680) were picked out from COMT gene. Using the SNPscan(TM) Kit, SNP genotyping was then performed, in two cohorts, including 595 cases and 725 controls. Finally, Chi-square test, logistic regression model and other methods were employed for statistical analysis. RESULTS: The frequencies of TT, CT and CC of rs4646312 appeared to be 304(51.1%), 234(39.3%)and 57 (8.6%) in cases, 323 (44.6%), 319 (44.0%) and 83(11.4%)in controls, respectively. The frequencies of GG,GA and AA of rs4680 were 311(52.4%), 236 (39.8%) and 46(7.8%)in cases, 417(57.7%), 265 (36.6%) and 41 (5.7%) in controls, respectively. RESULTS: showed that SNP rs4646312 was significantly associated with T2DM both in allelic association analysis (P = 0.020,OR = 1.26, 95%CI:1.04-1.53)and in recessive model (P = 0.022, OR = 1.35, 95% CI:1.05-1.74)after adjustment for sex,BMI and TG. The association between rs4680 and T2DM was not significant, but BMI was remarkably different among the three genotypes of rs4680 after controlling for other factors. CONCLUSION: SNP rs4646312 of COMT gene was associated with the increased risk of T2DM in Han population in Guangdong province. However, rs4680 was not significantly associated with T2DM.

A meta-analysis of the association between TNF-α -308G>A polymorphism and type 2 diabetes mellitus in Han Chinese population.

OBJECTIVE: A meta-analysis was applied to evaluate the associations between tumor necrosis factor-α (TNF-α) -308G>A (rs1800629) polymorphism and type 2 diabetes mellitus (T2DM). METHODS: Hardy-Weinberg equilibrium (HWE) was employed to test genetic equilibrium among the genotypes of the selected literature. Power analysis was performed with the Power and Sample Size Calculation (PS) program. A fixed or random effect model was used on the basis of heterogeneity. Publication bias was quantified and examined with the Begg's funnel plot test and Egger's linear regression test. The meta-analysis was performed with Review Manager 5.1 and Stata 11.0. RESULTS: There were 10 studies including 1425 T2DM patients and 1116 healthy control subjects involved in this meta-analysis. No significant publication bias was found in the studies. The pooled ORs (95% CIs) for TNF-α -308G>A of A vs. G allele and GA+AA vs. GG genotype were 1.63 (1.17-2.25) and 1.47 (1.17-1.85), respectively. CONCLUSION: This meta-analysis result suggested that TNF-α -308G>A polymorphism was strongly associated with T2DM risk, and A allele at this locus might be a susceptibility allele for the development of T2DM in Han Chinese population.

Adaptation of the Audit of Diabetes-Dependent Quality of Life questionnaire to people with diabetes in China.

AIM: This study was intended to cross-culturally adapt and evaluate the Chinese version of the Audit of Diabetes Dependent Quality of Life (ADDQoL)--the Chinese Normal Audit of Diabetes-Dependent Quality of Life (CN-ADDQoL) in Mainland, China. METHODS: The standard procedure for cross-culture adaptation was used to develop the Chinese version CN-ADDQoL. After the linguistic validation, the validity and reliability of CN-ADDQoL questionnaire were evaluated based on a sample of 697 Type 2 diabetes patients. The Cronbach's α coefficient, correlation analysis and the structural equation model (SEM) were applied, respectively. RESULTS: We developed 19 items for the CN-ADDQoL questionnaire. The estimated Cronbach's α coefficient was 0.941, indicating an excellent internal consistency of the scale. All items had high performance in the structural validity evaluation, with most factor loading values being larger than 0.40 (varied from 0.44 to 0.88). CONCLUSIONS: The Chinese version CN-ADDQoL has maintained its original psychometric properties and achieved adequate reliability and validity. Therefore, it could be efficiently used to evaluate the current trend of diabetes self-management education programs and multinational clinical research trials.