DEHP Down-Regulates Tshr Gene Expression in Rat Thyroid Tissues and FRTL-5 Rat Thyrocytes: A Potential Mechanism of Thyroid Disruption

Background@#Di-2-ethylhexyl phthalate (DEHP) is known to disrupt thyroid hormonal status. However, the underlying molecular mechanism of this disruption is unclear. Therefore, we investigated the direct effects of DEHP on the thyroid gland. @*Methods@#DEHP (vehicle, 50 mg/kg, and 500 mg/kg) was administered to Sprague-Dawley rats for 2 weeks. The expression of the thyroid hormone synthesis pathway in rat thyroid tissues was analyzed through RNA sequencing analysis, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and immunohistochemical (IHC) staining. DEHP was treated to FRTL-5 rat thyroid cells, and an RT-PCR analysis was performed. A reporter gene assay containing the promoter of thyroid stimulating hormone receptor (TSHR) in Nthy-ori 3-1 human thyroid cells was constructed, and luciferase activity was determined. @*Results@#After DEHP treatment, the free thyroxine (T4) and total T4 levels in rats significantly decreased. RNA sequencing analysis of rat thyroid tissues showed little difference between vehicle and DEHP groups. In the RT-PCR analysis, Tshr expression was significantly lower in both DEHP groups (50 and 500 mg/kg) compared to that in the vehicle group, and IHC staining showed that TSHR expression in the 50 mg/kg DEHP group significantly decreased. DEHP treatment to FRTL-5 cells significantly down-regulated Tshr expression. DEHP treatment also reduced luciferase activity in a reporter gene assay for TSHR. @*Conclusion@#Although overall genetic changes in the thyroid hormone synthesis pathway are not clear, DEHP exposure could significantly down-regulate Tshr expression in thyroid glands. Down-regulation of Tshr gene appears to be one of potential mechanisms of thyroid disruption by DEHP exposure.

DEHP Down-Regulates Tshr Gene Expression in Rat Thyroid Tissues and FRTL-5 Rat Thyrocytes: A Potential Mechanism of Thyroid Disruption

Background@#Di-2-ethylhexyl phthalate (DEHP) is known to disrupt thyroid hormonal status. However, the underlying molecular mechanism of this disruption is unclear. Therefore, we investigated the direct effects of DEHP on the thyroid gland. @*Methods@#DEHP (vehicle, 50 mg/kg, and 500 mg/kg) was administered to Sprague-Dawley rats for 2 weeks. The expression of the thyroid hormone synthesis pathway in rat thyroid tissues was analyzed through RNA sequencing analysis, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and immunohistochemical (IHC) staining. DEHP was treated to FRTL-5 rat thyroid cells, and an RT-PCR analysis was performed. A reporter gene assay containing the promoter of thyroid stimulating hormone receptor (TSHR) in Nthy-ori 3-1 human thyroid cells was constructed, and luciferase activity was determined. @*Results@#After DEHP treatment, the free thyroxine (T4) and total T4 levels in rats significantly decreased. RNA sequencing analysis of rat thyroid tissues showed little difference between vehicle and DEHP groups. In the RT-PCR analysis, Tshr expression was significantly lower in both DEHP groups (50 and 500 mg/kg) compared to that in the vehicle group, and IHC staining showed that TSHR expression in the 50 mg/kg DEHP group significantly decreased. DEHP treatment to FRTL-5 cells significantly down-regulated Tshr expression. DEHP treatment also reduced luciferase activity in a reporter gene assay for TSHR. @*Conclusion@#Although overall genetic changes in the thyroid hormone synthesis pathway are not clear, DEHP exposure could significantly down-regulate Tshr expression in thyroid glands. Down-regulation of Tshr gene appears to be one of potential mechanisms of thyroid disruption by DEHP exposure.

Sodium butyrate has context-dependent actions on dipeptidyl peptidase-4 and other metabolic parameters

Sodium butyrate (SB) has various metabolic actions. However, its effect on dipeptidyl peptidase 4 (DPP-4) needs to be studied further. We aimed to evaluate the metabolic actions of SB, considering its physiologically relevant concentration. We evaluated the effect of SB on regulation of DPP-4 and its other metabolic actions, both in vitro (HepG2 cells and mouse mesangial cells) and in vivo (high fat diet [HFD]-induced obese mice). Ten-week HFD-induced obese C57BL/6J mice were subjected to SB treatment by adding SB to HFD which was maintained for an additional 16 weeks. In HepG2 cells, SB suppressed DPP-4 activity and expression at sub-molar concentrations, whereas it increased DPP-4 activity at a concentration of 1,000 µM. In HFD-induced obese mice, SB decreased blood glucose, serum levels of insulin and IL-1β, and DPP-4 activity, and suppressed the increase in body weight. On the contrary, various tissues including liver, kidney, and peripheral blood cells showed variable responses of DPP-4 to SB. Especially in the kidney, although DPP-4 activity was decreased by SB in HFD-induced obese mice, it caused an increase in mRNA expression of TNF-α, IL-6, and IL-1β. The pro-inflammatory actions of SB in the kidney of HFD-induced obese mice were recapitulated by cultured mesangial cell experiments, in which SB stimulated the secretion of several cytokines from cells. Our results showed that SB has differential actions according to its treatment dose and the type of cells and tissues. Thus, further studies are required to evaluate its therapeutic relevance in metabolic diseases including diabetes and obesity.

Cancers with Higher Density of Tumor-Associated Macrophages Were Associated with Poor Survival Rates

BACKGROUND: Macrophages are a component of a tumor's microenvironment and have various roles in tumor progression and metastasis. This study evaluated the relationships between tumor-associated macrophage (TAM) density and clinical outcomes in 14 different types of human cancers. METHODS: We investigated TAM density in human tissue microarray sections from 14 different types of human cancers (n = 266) and normal thyroid, lung, and breast tissues (n = 22). The five-year survival rates of each cancer were obtained from the 2011 Korea Central Cancer Registry. RESULTS: Among 13 human cancers, excluding thyroid cancer, pancreas, lung, and gallbladder cancers had the highest density of CD163-positive macrophages (7.0+/-3.5%, 6.9+/-7.4%, and 6.9 +/- 5.5%, respectively). The five-year relative survival rates of these cancers (pancreas, 8.7%; lung, 20.7%; gallbladder, 27.5%) were lower than those of other cancers. The histological subtypes in thyroid cancer exhibited significantly different CD163-positive macrophages densities (papillary, 1.8 +/- 1.6% vs anaplastic, 22.9 +/- 17.1%; p < .001), but no significant difference between histological subtypes was detected in lung and breast cancers. Moreover, there was no significant difference in CD163-positive macrophages densities among the TNM stages in lung, breast, and thyroid cancers. CONCLUSIONS: Cancers with higher TAM densities (pancreas, lung, anaplastic thyroid, and gallbladder) were associated with poor survival rate.

Effect of Green Tea Extract/Poly-gamma-Glutamic Acid Complex in Obese Type 2 Diabetic Mice

BACKGROUND: The increasing prevalence of type 2 diabetes mellitus (T2DM) is associated with the rapid spread of obesity. Obesity induces insulin resistance, resulting in beta-cell dysfunction and thus T2DM. Green tea extract (GTE) has been known to prevent obesity and T2DM, but this effect is still being debated. Our previous results suggested that circulating green tea gallated catechins (GCs) hinders postprandial blood glucose lowering, regardless of reducing glucose and cholesterol absorption when GCs are present in the intestinal lumen. This study aimed to compare the effect of GTE with that of GTE coadministered with poly-gamma-glutamic acid (gamma-PGA), which is likely to inhibit the intestinal absorption of GCs. METHODS: The db/db mice and age-matched nondiabetic mice were provided with normal chow diet containing GTE (1%), gamma-PGA (0.1%), or GTE+gamma-PGA (1%:0.1%) for 4 weeks. RESULTS: In nondiabetic mice, none of the drugs showed any effects after 4 weeks. In db/db mice, however, weight gain and body fat gain were significantly reduced in the GTE+gamma-PGA group compared to nondrug-treated db/db control mice without the corresponding changes in food intake and appetite. Glucose intolerance was also ameliorated in the GTE+gamma-PGA group. Histopathological analyses showed that GTE+gamma-PGA-treated db/db mice had a significantly reduced incidence of fatty liver and decreased pancreatic islet size. Neither GTE nor gamma-PGA treatment showed any significant results. CONCLUSION: These results suggest that GTE+gamma-PGA treatment than GTE or gamma-PGA alone may be a useful tool for preventing both obesity and obesity-induced T2DM.