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Polychlorinated biphenyls (PCBs) can severely interfere with multiple animals and human systems. To explore the molecular mechanisms underlying 2, 3′, 4, 4′, 5- pentachlorobiphenyl (PCB118)-induced thyroid dysfunction, Fischer rat thyroid cell line-5(FRTL-5) cells were treated with either different concentrations of PCB118 or dimethyl sulfoxide (DMSO). The effects of PCB118 on FRTL-5 cells viability and apoptosis were assessed by using a Cell Counting Kit-8 assay and apoptosis assays, respectively. Quantitative real-time polymerase chain reaction was used to quantify protein kinase B (Akt), Forkhead box protein O3a (FoxO3a), and sodium/iodide symporter (NIS) mRNA expression levels. Western blotting was used to detect Akt, phospho-Akt (p-Akt), FoxO3a, phospho-FoxO3a (p-FoxO3a), and NIS protein levels. Luciferase reporter gene technology was used to detect the transcriptional activities of FoxO3a and NIS promoters. The effects of the constitutively active Akt (CA-Akt) and dominant-negative Akt (DN-Akt) plasmids on p-Akt, p-FoxO3a, and NIS levels were examined in PCB118-treated FRTL-5 cells. The effects of FoxO3a siRNA on FoxO3a, p-FoxO3a, and NIS protein levels were examined in the PCB118-treated FRTL-5 cells. The effects of pcDNA3 (plsmid vectors designed for high-level stable and transient expression in mammalian host)-FoxO3a on NIS promoter activity were examined in the PCB118-treated FRTL-5 cells. Our results indicated that relatively higher PCB118 concentrations can inhibit cell viability in a concentration- and time-dependent manner. Akt, p-Akt, and p-FoxO3a protein or mRNA levels increased significantly in PCB118-treated groups and NIS protein and mRNA levels decreased considerably compared with the control groups. FoxO3a promoter activity increased significantly, whereas NIS promoter activity decreased. These effects on p-FoxO3a and NIS could be decreased by the DN-Akt plasmid, enhanced by the CA-Akt plasmid, and blocked by FoxO3a siRNA. The overexpressed FoxO3a could reduce NIS promoter activity. Our results suggested that PCB118 induces thyroid cell dysfunction through the Akt/FoxO3a/NIS signaling pathway. [ABSTRACT FROM AUTHOR]

A meta-analysis was performed to assess the association between the PAI-1 -675 4G/5G polymorphism and susceptibility to diabetes mellitus (DM), diabetic nephropathy (DN), diabetic retinopathy (DR) and diabetic coronary artery disease (CAD). A literature-based search was conducted to identify all relevant studies. The fixed or random effect pooled measure was calculated mainly at the allele level to determine heterogeneity bias among studies. Further stratified analyses and sensitivity analyses were also performed. Publication bias was examined by the modified Begg’s and Egger’s test. Twenty published articles with twenty-seven outcomes were included in the meta-analysis: 6 studies with a total of 1,333 cases and 3,011 controls were analyzed for the PAI-1 -675 4G/5G polymorphism with diabetes risk, 7 studies with 1,060 cases and 1,139 controls for DN risk, 10 studies with 1,327 cases and 1,557 controls for DR and 4 studies with 610 cases and 1,042 controls for diabetic CAD risk respectively. Using allelic comparison (4G vs. 5G), the PAI-1 -675 4G/5G polymorphism was observed to have no significant association with diabetes (REM OR 1.07, 95% CI 0.96, 1.20), DN (REM OR 1.10, 95% CI 0.98, 1.25), DR (REM OR 1.09, 95% CI 0.97, 1.22) or diabetic CAD risk (REM OR 1.07, 95% CI 0.81, 1.42), and similar results were obtained in the dominant, recessive and co-dominant models. Our meta-analyses suggest that the PAI-1 -675 4G/5G polymorphism might not be a risk factor for DM, DN, DR or diabetic CAD risk in the populations investigated. This conclusion warrants confirmation by further studies. [ABSTRACT FROM AUTHOR]

A meta-analysis was performed to assess the association between the PAI-1 -675 4G/5G polymorphism and susceptibility to diabetes mellitus (DM), diabetic nephropathy (DN), diabetic retinopathy (DR) and diabetic coronary artery disease (CAD). A literature-based search was conducted to identify all relevant studies. The fixed or random effect pooled measure was calculated mainly at the allele level to determine heterogeneity bias among studies. Further stratified analyses and sensitivity analyses were also performed. Publication bias was examined by the modified Begg's and Egger's test. Twenty published articles with twenty-seven outcomes were included in the meta-analysis: 6 studies with a total of 1,333 cases and 3,011 controls were analyzed for the PAI-1 -675 4G/5G polymorphism with diabetes risk, 7 studies with 1,060 cases and 1,139 controls for DN risk, 10 studies with 1,327 cases and 1,557 controls for DR and 4 studies with 610 cases and 1,042 controls for diabetic CAD risk respectively. Using allelic comparison (4G vs. 5G), the PAI-1 -675 4G/5G polymorphism was observed to have no significant association with diabetes (REM OR 1.07, 95% CI 0.96, 1.20), DN (REM OR 1.10, 95% CI 0.98, 1.25), DR (REM OR 1.09, 95% CI 0.97, 1.22) or diabetic CAD risk (REM OR 1.07, 95% CI 0.81, 1.42), and similar results were obtained in the dominant, recessive and co-dominant models. Our meta-analyses suggest that the PAI-1 -675 4G/5G polymorphism might not be a risk factor for DM, DN, DR or diabetic CAD risk in the populations investigated. This conclusion warrants confirmation by further studies.