MIF promotes Th17 cell differentiation in Hashimoto's thyroiditis by binding HVEM and activating NF-κB signaling pathway.

Hashimoto's thyroiditis is a typical thyroid autoimmune disease and Th17 cells are crucial in its development. In recent years, MIF (Macrophage Migration Inhibitory Factor) has been found to promote the secretion of IL-17A and the production and differentiation of Th17 cells. However, the specific mechanism of it remains unclear. Here, we found that the expression of MIF, IL-17A and HVEM (Herpes Virus Entry Mediator) were up-regulated in HT patients. The proportion of Th17 cells in peripheral blood mononuclear cells was positively correlated with the serum MIF protein level. We further found that the expression of HVEM and the phosphorylation level of NF-κB in peripheral blood mononuclear cells of HT patients were significantly increased. Therefore, we speculated that MIF promotes Th17 cell differentiation through HVEM and NF-κB signaling pathways. Further mechanism studies showed that MIF could directly bind to HVEM, and the stimulation of rhMIF in vitro could increase the expression of HVEM and activate NF-κB signaling pathways to promote Th17 cell differentiation. After blocking HVEM with HVEM antibody, the effect of MIF on Th17 cell differentiation disappeared. The results above show that the differentiation of Th17 cells is promoted by MIF combined with HVEM through NF-κB signaling pathways. Our research provides a new theory to the regulation mechanism of Th17 cell differentiation and gives hint to new potential therapeutic targets for HT.

Association of multiple blood metals with thyroid function in general adults: A cross-sectional study.

Introduction: Thyroid function has a large impact on humans' metabolism and is affected by iodine levels, but there is a scarcity of studies that elucidate the association between thyroid function and other elements. Methods: We performed a cross-sectional study on 1,067 adults to evaluate the associations of the common essential metals with thyroid function in adults living in an iodine-adequate area of China. Serum free thyroxine (FT4), free triiodothyronine (FT3), thyroid stimulating hormone (TSH), and blood metals (zinc, iron, copper, magnesium, manganese, and calcium) were measured. Further, the thyroid hormone sensitivity indexes, FT3:FT4 ratio, and thyrotropin T4 resistance index (TT4RI) were calculated. Linear regression, quantile g-computation, and Bayesian kernel machine regression methods were used to explore the association of metals with thyroid function. Results: We found that the TSH levels correlated with copper (negative) and zinc (positive). Iron and copper were positively associated with FT3 and FT4 levels, respectively. Iron (positive) and copper (negative) were correlated with the FT3:FT4 ratio. Furthermore, we found that manganese was inversely correlated with TT4RI, while zinc was positively correlated. Discussion: Our findings suggest that manganese, iron, copper, and zinc levels were strongly correlated with thyroid function, and patients with thyroid disorders are recommended to measure those metals levels.

Associations of metal profiles in blood with thyroiditis: a cross-sectional study.

Autoimmune thyroiditis (AIT) is increasingly common, and serological markers include thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb). To determine if selected metals influence thyroiditis antibody positivity, this cross-sectional study investigated associations between metals and thyroiditis antibody status. Healthy individuals (n = 1104) completed a questionnaire and underwent checkups of anthropometric parameters, thyroid function status, and levels of seven metals in blood (magnesium, iron, calcium, copper, zinc, manganese, and lead). Associated profiles of glyco- and lipid metabolism were also established. Logistic regression and restricted cubic spline (RCS) regression analysis were applied to adjudge associations between metals and TPOAb and TgAb status. It was found that, after adjusting for likely cofounding factors, participants with antibody positivity had significantly lower serum concentrations of magnesium and iron. When serum magnesium levels were analyzed in quartiles, the odds ratios of quartile 4 were 0.329-fold (95% confidence interval (CI): 0.167-0647) and 0.259-fold (95% CI 0.177-0.574) that of quartile 1 regarding TPOAb and TgAb positivity (P = 0.004, 0.003). After adjustment, the RCS analysis detected nonlinear associations between iron and TPOAb and TgAb positivity (P < 0.01, both). In stratified analyses, these associations regarding magnesium and iron remained for women of reproductive age, but not for postmenopausal women and men. We conclude that lower serum levels of magnesium and iron are associated with incremental positivity of thyroiditis antibodies and may be among the most important metals contributing to AIT in women of reproductive age.

The Association of Thyroid Nodules With Blood Trace Elements Identified in a Cross-Section Study.

Background: The association between occurrence of thyroid nodules (TNs) and trace elements detectable in blood are still inconclusive. The present study sought to determine the relationship between selected trace elements and TNs in the iodine-adequate area of Guangdong, China. Methods: A total of 1,048 participants from four communities were enrolled. A number of medical checkups were conducted to collect relevant data on anthropometric parameters, blood pressure, glucose blood levels and lipid profiles, as well as data on thyroid function, presence of thyroid autoantibodies, and trace elements. Presence of TN was diagnosed by ultrasonography. Results: Of the 1048 participants (49.5 ± 14.4 years old), 543 participants (51.8%) had TNs. Serum copper, magnesium and zinc levels are associated with the presence of TNs among healthy subjects. Subjects with higher levels of zinc, magnesium and copper had 1.23-fold, 1.04-fold, and 1.007-fold increased risks of the prevalence of TNs (P = 0.013, 0.017, and < 0.001, resp). Compared with the first quartile of copper content in serum, participants in the fourth quartile had the highest prevalence of TNs with an odds ratio of 8.90 (95% confidence interval (CI) 5.41, 14.94) among all participants. Women in the third quartile of magnesium level had a 1.86-fold (95%CI 1.05, 3.31) risk of the prevalence of TNs. Subjects in the highest quartile of zinc level had a 1.82-fold (95%CI 1.06, 3.16) risk of the prevalence of TNs in females. Conclusion: TNs were found highly prevalent in females in the investigated population from an iodine-adequate area of Guangdong, China. The imbalance of selected trace elements (copper, magnesium and zinc) in the body is related to the presence of TNs among healthy subjects. The observed correlation of copper on TNs warrants further studies.

SPTBN1 Prevents Primary Osteoporosis by Modulating Osteoblasts Proliferation and Differentiation and Blood Vessels Formation in Bone.

Osteoporosis is a common systemic skeletal disorder that leads to increased bone fragility and increased risk of fracture. Although ßII-Spectrin (SPTBN1) has been reported to be involved in the development of various human cancers, the function and underlying molecular mechanisms of SPTBN1 in primary osteoporosis remain unclear. In this study, we first established a primary osteoporosis mouse model of senile osteoporosis and postmenopausal osteoporosis. The results showed that the expression of SPTBN1 was significantly downregulated in primary osteoporosis mice model compared with the control group. Furthermore, silencing of SPTBN1 led to a decrease in bone density, a small number of trabecular bones, wider gap, decreased blood volume fraction and number of blood vessels, as well as downregulation of runt-related transcription factor 2 (Runx2), Osterix (Osx), Osteocalcin (Ocn), and vascular endothelial growth factor (VEGF) in primary osteoporosis mice model compared with the control group. Besides, the silencing of SPTBN1 inhibited the growth and induced apoptosis of mouse pre-osteoblast MC3T3-E1 cells compared with the negative control group. Moreover, the silencing of SPTBN1 significantly increased the expression of TGF-ß, Cxcl9, and the phosphorylation level STAT1 and Smad3 in MC3T3-E1 cells compared with the control group. As expected, overexpression of SPTBN1 reversed the effect of SPTBN1 silencing in the progression of primary osteoporosis both in vitro and in vivo. Taken together, these results suggested that SPTBN1 suppressed primary osteoporosis by facilitating the proliferation, differentiation, and inhibition of apoptosis in osteoblasts via the TGF-ß/Smad3 and STAT1/Cxcl9 pathways. Besides, overexpression of SPTBN1 promoted the formation of blood vessels in bone by regulating the expression of VEGF. This study, therefore, provided SPTBN1 as a novel therapeutic target for osteoporosis.

Conditional knockout of pyruvate dehydrogenase in mouse pancreatic ß­cells causes morphological and functional changes.

Diabetes mellitus is a metabolic disorder predominantly caused by the dysfunction of pancreatic ß­cells. This dysfunction is partly caused by the dysregulation of pyruvate dehydrogenase (PDH), which acts as an important mediator of pyruvate oxidation after glycolysis and fuels the tricarboxylic acid cycle. Previous studies have reported decreased PDH expression in rodent models and humans with type 2 diabetes mellitus (T2DM), suggesting that PDH may play an important role in the development of T2DM. However, the mechanism by which PDH affects insulin secretion and ß­cell development is poorly understood. Using immunofluorescence staining, the present study found that the expression of pyruvate dehydrogenase E1­α subunit (PDHA1; encoded by the PDHA1 gene) in the islets of type 2 diabetic mice (db/db mice) was lower than in wild­type mice, which indicated the possible association between PDHA1and diabetes. To further understand this mechanism, an inducible, islet­specific PDHA1 knockout mouse (ßKO) model was established. The phenotype was authenticated, and the blood glucose levels and islet function between the ßKO and control mice were compared. Though no changes were found in food intake, development status, fasting blood glucose or weight between the groups, the level of insulin secretion at 30 min after glucose injection in the ßKO group was significantly lower compared with the control group. Furthermore, the performed of the ßKO mice on the intraperitoneal glucose tolerance test was visibly impaired when compared with the control mice. Pancreatic tissues were collected for hematoxylin and eosin staining, immunohistochemical and confocal laser­scanning microscopy analysis. Examination of the islets from the ßKO mouse model indicated that abolishing the expression of PDH caused a compensatory islet enlargement and impaired insulin secretion.