Disrupting glycolysis and DNA repair in anaplastic thyroid cancer with nucleus-targeting platinum nanoclusters.

Cancer cells rely on aerobic glycolysis and DNA repair signals to drive tumor growth and develop drug resistance. Yet, fine-tuning aerobic glycolysis with the assist of nanotechnology, for example, dampening lactate dehydrogenase (LDH) for cancer cell metabolic reprograming remains to be investigated. Here we focus on anaplastic thyroid cancer (ATC) as an extremely malignant cancer with the high expression of LDH, and develop a pH-responsive and nucleus-targeting platinum nanocluster (Pt@TAT/sPEG) to simultaneously targets LDH and exacerbates DNA damage. Pt@TAT/sPEG effectively disrupts LDH activity, reducing lactate production and ATP levels, and meanwhile induces ROS production, DNA damage, and apoptosis in ATC tumor cells. We found Pt@TAT/sPEG also blocks nucleotide excision repair pathway and achieves effective tumor cell killing. In an orthotopic ATC xenograft model, Pt@TAT/sPEG demonstrates superior tumor growth suppression compared to Pt@sPEG and cisplatin. This nanostrategy offers a feasible approach to simultaneously inhibit glycolysis and DNA repair for metabolic reprogramming and enhanced tumor chemotherapy.

Epigenetic inhibition of CTCF by HN1 promotes dedifferentiation and stemness of anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is one of the deadliest cancers, whose important malignant feature is dedifferentiation. Chromatin remodeling is critical for tumorigenesis and progression, while its roles and regulator in facilitating dedifferentiation of ATC had been poorly understood. In our study, an emerging function of hematological and neurological expressed 1 (HN1) in promoting dedifferentiation of ATC cells was uncovered. HN1 expression was negatively correlated with the thyroid differentiation markers both at mRNA and protein level. Knockdown of HN1 in ATC cells effectively upregulated the thyroid differentiation markers and impeded the sphere formation capacity, accompanying with the loss of cancer stemness. In contrast, overexpression of HN1 drove the gain of stemness and the loss of thyroid differentiation markers. Nude mouse and zebrafish xenograft models showed that inhibition of HN1 in ATC cells effectively hindered tumor growth due to the loss of cancer stemness. Further study showed that HN1 was negatively correlated with CTCF in an independent thyroid-cancer cohort, and inhibition of HN1 enhanced the expression of CTCF in ATC cells. Overexpression of CTCF significantly reversed the dedifferentiation phenotypes of ATC cells, whereas simultaneously inhibiting HN1 and CTCF was unable to recover the level of thyroid differentiation markers. The combination of ATAC-seq and ChIP-seq analysis confirmed that CTCF regulated genes relating with thyroid gland development through influencing their chromatin accessibility. HN1 inhibited the acetylation of H3K27 at the promoter of CTCF by recruiting HDAC2, thereby inhibiting the transcriptional activation of CTCF. These findings demonstrated an essential role of HN1 in regulating the chromatin accessibility of thyroid differentiation genes during ATC dedifferentiation.

Rab11-FIP4 interacts with ARF5 to promote cancer stemness in hepatocellular carcinoma

Recent studies suggest that Rab11-family interacting proteins (Rab11-FIPs) play an important role in tumorigenesis and progression. Among the Rab11-FIPs, Rab11-FIP4 has been reported to be significantly upregulated in various cancers, including hepatocellular carcinoma (HCC). However, the possible effect on HCC stemness and the underlying mechanism has never been characterized. Here, we found that Rab11-FIP4 was dramatically increased in HCC cell lines and tissues, and had a positive correlation with cancer stemness. Functional studies revealed that elevated expression of Rab11-FIP4 in HCC cells significantly promoted sphere formation, and enhanced the mRNA and protein levels of stemness-associated markers, ALDH1A1, CD133, NANOG, and OCT4. Conversely, the knockdown of Rab11-FIP4 suppressed the cancer stem cell (CSC)-like characteristics of HCC cells. Moreover, silencing of Rab11-FIP4 obviously increased the sensitivity of HCC cells to sorafenib. Mechanistically, Rab11-FIP4 was shown to interact with ADP-ribosylation factor 5 (ARF5) to influence cell cycle-related proteins, CDK1/cyclin B, thereby promoting HCC stemness. Taken together, our results uncovered an essential role for Rab11-FIP4 in regulating CSC-like features of HCC cells and identified Rab11-FIP4 as a potential target for HCC therapy. (AU)

Rab11-FIP4 interacts with ARF5 to promote cancer stemness in hepatocellular carcinoma.

Recent studies suggest that Rab11-family interacting proteins (Rab11-FIPs) play an important role in tumorigenesis and progression. Among the Rab11-FIPs, Rab11-FIP4 has been reported to be significantly upregulated in various cancers, including hepatocellular carcinoma (HCC). However, the possible effect on HCC stemness and the underlying mechanism has never been characterized. Here, we found that Rab11-FIP4 was dramatically increased in HCC cell lines and tissues, and had a positive correlation with cancer stemness. Functional studies revealed that elevated expression of Rab11-FIP4 in HCC cells significantly promoted sphere formation, and enhanced the mRNA and protein levels of stemness-associated markers, ALDH1A1, CD133, NANOG, and OCT4. Conversely, the knockdown of Rab11-FIP4 suppressed the cancer stem cell (CSC)-like characteristics of HCC cells. Moreover, silencing of Rab11-FIP4 obviously increased the sensitivity of HCC cells to sorafenib. Mechanistically, Rab11-FIP4 was shown to interact with ADP-ribosylation factor 5 (ARF5) to influence cell cycle-related proteins, CDK1/cyclin B, thereby promoting HCC stemness. Taken together, our results uncovered an essential role for Rab11-FIP4 in regulating CSC-like features of HCC cells and identified Rab11-FIP4 as a potential target for HCC therapy.

Gender variations in the impact of hyperuricemia on thyroid disorders.

This study aimed to examine the impact of hyperuricemia on various thyroid disorders with emphasized focus on differences resulting from different genders. 16094 adults aged ≥18 years were enrolled in this cross-sectional study using a randomized stratified sampling strategy. Clinical data including thyroid function and antibodies, uric acid, and anthropometric measurements were measured. Multivariable logistic regression was used to determine the association between hyperuricemia and thyroid disorders. Women who have hyperuricemia are at a significantly increased risk of developing hyperthyroidism. Women's risk of overt hyperthyroidism and Graves' disease may be markedly increased by hyperuricemia. Men with hyperuricemia did not differ significantly in their chance of acquiring any thyroid disorders.

Exploration of novel dihydroquinoxalinone derivatives as EGFRL858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer.

To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFRL858R/T790M with an IC50 value of 0.55 ± 0.02 nM and potent anti-proliferative activity against H1975 cells with an IC50 value of 5.88 ± 0.07 nM. Moreover, the strong down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent antitumor activities. Compound 29 was also demonstrated with good ADME profile in various in vitro assays. Further in vivo studies confirmed that compound 29 could suppress the growth of xenograft tumors. These results verified that compound 29 would be a promising lead compound for targeting drug-resistant EGFR mutations.

Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto's thyroiditis.

Hashimoto's thyroiditis (HT) is an autoimmune illness caused by a combination of genetic, epigenetic, and environmental factors. The pathogenesis of HT is not fully elucidated, especially in epigenetics. The epigenetic regulator Jumonji domain-containing protein D3 (JMJD3) has been extensively investigated in immunological disorders. This study has been performed to explore the roles and potential mechanisms of JMJD3 in HT. Thyroid samples from patients and healthy subjects were collected. We first analyzed the expression of JMJD3 and chemokines in the thyroid gland using real-time PCR and immunohistochemistry. In vitro, the apoptosis effect of the JMJD3-specific inhibitor GSK-J4 on the thyroid epithelial cell line Nthy-ori 3-1 was evaluated using FITC Annexin V Detection kit. Reverse transcription-polymerase chain reaction and Western blotting were applied to examine the inhibitory effect of GSK-J4 on the inflammation of thyrocytes. In the thyroid tissue of HT patients, JMJD3 messenger RNA and protein levels were substantially greater than in controls (P < 0.05). Chemokines C-X-C motif chemokine ligand 10 (CXCL10) and C-C motif chemokine ligand 2 (CCL2) were elevated in HT patients, and thyroid cells with stimulation of tumor necrosis factor α (TNF-α). GSK-J4 could suppress TNF-α-induced synthesis of chemokines CXCL10 and CCL2 and prohibit thyrocyte apoptosis. Our results shed light on the potential role of JMJD3 in HT and indicate that JMJD3 may become a novel therapeutic target in HT treatment and prevention.

IL2RA+VSIG4+ tumor-associated macrophage is a key subpopulation of the immunosuppressive microenvironment in anaplastic thyroid cancer.

Extensive infiltration of tumor-associated macrophages was correlated poor prognosis in anaplastic thyroid cancer (ATC). However, the heterogeneity and characteristics of the ATC-associated macrophages (ATAMs) in ATC remain far from clear. We combined single-cell RNA-sequencing analysis and gene expression microarray datasets to assess the molecular signature of ATAMs. Compared with normal thyroid-associated macrophages (NTAMs), 778 differentially expressed genes (DEGs) significantly changed in ATAMs compared with NTAMs. These DEGs were correlated with oxidative phosphorylation (M2 phenotype) and phagocytosis (M1 phenotype). Moreover, ATAMs highly expressed pro-tumor genes associated with angiogenesis, fibrosis, metalloprotease activity, and metastasis. Notably, we identified one ATC-specific subset, IL2RA+ VSIG4+ ATAMs, co-expressed M1 and M2 markers. The infiltration of IL2RA+ VSIG4+ ATAMs showed strong correlation with BRAF and RAS signaling, and its high infiltration was associated with favorable prognosis in thyroid-cancer patients. IL2RA+ VSIG4+ ATAMs were associated with increased tumor-infiltrating lymphocytes (B cells, CD8+ T cells, Tregs). IL2RA+ VSIG4+ ATAMs interacted with CD8+ T cells and Tregs through immune checkpoints (such as LGALS9_HAVCR2), cytokines (such as CXCL10_CXCR3), and receptors (such as CSF1R_CSF1), thereby forming an immunosuppressive microenvironment. Multiplex immunohistochemistry staining and coculture experiment confirmed that ATC cancer cells were able to induce the polarization of IL2RA+ VSIG4+ ATAMs. Besides, we identified several novel ATC-specific immune checkpoint genes including the immunosuppressive molecule VSIG4, LAIR1, and LILRB2. Expression of VSIG4 was also significantly correlated with tumor-infiltrating lymphocytes (B cells, CD8+ T cells, Tregs). In conclusion, our study revealed an ATC-specific ATAM subset with bifunctional phenotype, which provided a comprehensive insight to delineate the molecular characteristics of ATC-associated macrophages.

CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment.

Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC.

A signature of circadian rhythm genes in driving anaplastic thyroid carcinoma malignant progression.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) was a rare and extremely malignant endocrine cancer. Recently, dysregulation of circadian rhythm genes was demonstrated to play an essential role in tumor progression, while its exact role and mechanism in ATC remained poorly clear. METHODS: 4 ATC-related datasets were integrated to screen for differentially expressed circadian rhythm genes (DE-CRGs). Thereafter, Multiscale Embedded Gene Co-expression Network Analysis (MEGENA) and network enrichment analysis were conducted to investigate the dynamic characteristics of circadian rhythm genes. Next, Lasso-logistic model and immunohistochemistry were applied for determining the candidates. Finally, cell biological experiments and gene set enrichment analysis (GSEA) were used to confirm the roles of NPAS2 in ATC. RESULTS: 25 DE-CRGs were firstly identified in ATC. These DE-CRGs mainly regulated mitotic nuclear division, cytokinesis and DNA replication signals. Notably, NPAS2, CSNK1E, NAMPT, TYMS, SERPINE1, TOP2A, JUN, EGR3 and HEBP1 were identified as the dynamic signature in the malignant progression of ATC, which were confirmed by prognostic analysis. Furthermore, NPAS2 was found to be significantly up-regulated in ATC through clinical samples and cell experiments. Silencing NPAS2 effectively inhibited the proliferation, migration and invasion of ATC cells. GSEA showed that high expression of NPAS2 was mainly associated with cell cycle and focal adhesion, and silencing of NPAS2 suppressed these signals in our experiments. CONCLUSIONS: In summary, we found a dynamic 9-DE-CRGs signature in ATC. And the aberrant expression of NPAS2 drove the malignant phenotypes of ATC, which facilitated to deepen our understanding of the roles of circadian rhythm genes in ATC.

Changes in histone H3 lysine 4 trimethylation in Hashimoto's thyroiditis.

INTRODUCTION: The precise pathogenesis of Hashimoto's thyroiditis (HT) is yet to be fully elucidated. The role of epigenetics in the pathogenesis of HT has scarcely been addressed. Tri-methylated histone H3 lysine 4 (H3K4me3) is generally regarded as a marker of gene activation. The aim of this study was to explore genome-wide H3K4me3 patterns and global protein levels in primary thyrocytes and thyroids from HT patients. MATERIAL AND METHODS: Chromatin immunoprecipitation sequencing (ChIP-seq) was used to analyze genome-wide H3K4me3 patterns in primary cultured thyrocytes from three HT females and three age-matched female control subjects. Western blotting was used to analyze global H3K4me3 levels in thyrocytes and thyroid tissues. Gene expression was determined using RT-PCR. Mixed-lineage leukemia 1 (MLL1) protein levels were measured by western blotting and immunohistochemistry. RESULTS: Nine genes - TG, CXCL8, CCL2, CXCL10, FASLG, ICAM1, ITGA4, IL18 and TRAIL - showed increased H3K4me3 enrichment in promoter regions around the transcriptional start sites, and gene expression of ICAM1, CCL2 and CXCL8 was consistently increased (p < 0.05). KEGG pathway analysis suggested that differential peak-related genes were markedly associated with autoimmune thyroid disease< 0.05). CONCLUSIONS: This first investigation of genome-wide H3K4me3 distribution in thyroid follicular cells suggested that genes associated with autoimmune thyroiditis showed differential H3K4me3 enrichment, which was partly related to gene expression. Global H3K4me3 changes and increased MLL1 expression were found in thyroid tissues from HT patients.

Metabolic Reprogramming of Thyroid Cancer Cells and Crosstalk in Their Microenvironment.

Metabolism differs significantly between tumor and normal cells. Metabolic reprogramming in cancer cells and metabolic interplay in the tumor microenvironment (TME) are important for tumor formation and progression. Tumor cells show changes in both catabolism and anabolism. Altered aerobic glycolysis, known as the Warburg effect, is a well-recognized characteristic of tumor cell energy metabolism. Compared with normal cells, tumor cells consume more glucose and glutamine. The enhanced anabolism in tumor cells includes de novo lipid synthesis as well as protein and nucleic acid synthesis. Although these forms of energy supply are uneconomical, they are required for the functioning of cancer cells, including those in thyroid cancer (TC). Increasing attention has recently focused on alterations of the TME. Understanding the metabolic changes governing the intricate relationship between TC cells and the TME may provide novel ideas for the treatment of TC.

Contribution of Different Phenotypes of Obesity to Metabolic Abnormalities from a Cross-Sectional Study in the Northwest China.

BACKGROUND: This study has been conducted to explore the correlation between phenotypes of obesity and metabolic comorbidities. METHODS: This cross-sectional study recruited 14,724 adults aged ≥18 years with a randomized stratified sampling strategy. Obesity was classified into four types according to body mass index (BMI) and waist-to-height ratio (WHtR): normal weight with central obesity (NWCO) and without (NW) CO, and obese or overweight with (OBCO) and without (OB) central obesity. Uric acid (UA), fasting blood glucose (FBG), and lipid profile were measured. RESULTS: The prevalence of hyperuricemia in the 4 groups (NW, NWCO, OB and OBCO) was 3.7%, 5.6%, 8.7% and 12.4%, whilst the prevalence of hypertriglyceridemia was 13.4%, 27.4%, 30.3% and 43.7%, separately. The prevalence of hypo-high-density lipoprotein cholesterolemia (hypo-HDL emia) was 20.1%, 21.4%, 30.8% and 27.9%, while the prevalence of hyper-low-density lipoprotein cholesterolemia (hyper-LDL emia) was 9.8%, 24.4%, 12.3% and 27.9%. The prevalence of hypercholesterolemia was 11.2%, 23.5%, 14.7%, 28.5% and the prevalence of hyperglycemia was 9.7%, 22.6%, 18.5%, and 27.0%, respectively. The prevalence of hypertension was 6.9%, 13.1%, 14.7%, and 20.6%. For various metabolic abnormalities, OBCO have the highest risks compared with NW (hyperuricemia: adjusted OR (aOR)= 2.60; hypertriglyceridemia: aOR= 3.19; hypercholesterolemia: aOR= 1.48; hyper LDLemia: aOR= 2.21; hypo HDLemia: aOR= 1.42; hyperglycemia: aOR= 1.95; hypertension: aOR= 2.16). The risk of hyper LDLemia, hypercholesterolemia and hyperglycemia in the NWCO group was higher than that in the OB group (hyperLDLemia: aOR: 1.69 vs 0.97; hypercholesterolemia: aOR: 1.27 vs 1.24; hyperglycemia: aOR: 1.62 vs 1.28). CONCLUSION: Different phenotypes of obesity are significantly associated with metabolic abnormalities. NWCO is more closely associated with hypercholesterolemia, hyperglycemia and hyper LDLemia. General obesity and central obesity have a synergistic effect on the diseases.

Serum hsa_circ_0054633 Is Elevated and Correlated with Clinical Features in Type 2 Diabetes Mellitus.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a chronic disease that seriously threatens human health with high incidence and various complications. Circular RNA has become a research hotspot in recent years due to its high stability and wide expression, and has been found to be related to many diseases. The main purpose of this study was to investigate the expression of serum hsa_circ_0054633 in T2DM patients and explore the potential role of serum hsa_circ_0054633 in T2DM diagnosis and its association with clinical characteristics. METHODS: This retrospective case-control study enrolled 88 participants including 44 patients with T2DM and 44 age- and sex-matched controls between January 2018 and March 2019 at Ningxia Medical University General Hospital. Serum hsa_circ_0054633 levels were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) with absolute quantification. Baseline information including clinical background, glucose control and biochemical variables were collected. Receiver operating characteristic (ROC) curves were used to evaluate diagnostic effect. RESULTS: We found that serum expression of hsa_circ_0054633 was dramatically increased in patients with T2DM. Serum hsa_circ_0054633 levels had high sensitivity (75.0%) and specificity (95.5%) for differentiating T2DM. Besides, serum expression of circ_0054633 was significantly correlated with fasting blood glucose (r=0.698), hemoglobin A1c (r=0.503) and low-density lipoprotein (r=0.399). CONCLUSION: Serum hsa_circ_0054633 is a potential noninvasive biomarker in discerning T2DM and is associated with changes in blood glucose and lipid.

Resveratrol inhibits the migration, invasion and epithelial-mesenchymal transition in liver cancer cells through up- miR-186-5p expression.

To investigate the molecular mechanism of resveratrol inhibiting the metastasis of liver cancer . HepG2 and Huh7 cells were treated with different concentrations of resveratrol, and the cell viability was determined by CCK-8 assay to determine the optimal concentration of resveratrol for subsequent experiments. The expressions of miR-186-5p in liver cancer tissues and liver cancer cells were determined by quantitative real-time RT-PCR. The migration and invasion of HepG2 and Huh7 cells were detected by wound healing assay and Transwell assay, and the expression levels of epithelial-mesenchymal transition (EMT) related proteins were determined by Western blotting. Resveratrol with concentration of had no effect on the viability of HepG2 and Huh7 cells, so the concentration of resveratrol in subsequent experiments was 6.25 µmol/L. Resveratrol inhibited the wound healing and invasion of liver cancer cells; increased the expression of E-cadherin, and decreased the expression of vimentin and Twist1. The expression of miR-186-5p was significantly down-regulated in liver cancer tissues and cells compared with the adjacent tissues and normal liver cells (both <0.05). Furthermore, resveratrol induced the expression of miR-186-5p in liver cancer cells (both <0.01). Overexpression of miR-186-5p suppressed the migration, invasion and EMT of liver cancer cells. Knockdown of miR-186-5p blocked the inhibition effects of resveratrol on the migration, invasion and EMT of liver cancer cells. Resveratrol could inhibit the metastasis of liver cancer , which might be associated with up-regulating miR-186-5p.

Immunotherapy for anaplastic thyroid carcinoma: the present and future.

Anaplastic thyroid carcinoma (ATC) is the most malignant tumor of endocrine system, which is an urgent medical problem to be solved. At present, immunotherapy studies on ATC mainly include cutting off the recruitment of tumor-associated macrophage (TAM), inducing the reprogramming of TAM and restoring its phagocytic function, targeting related immune checkpoints on T cells and natural killer cells, tumor vaccines based on oncolytic viruses and dendritic cells, and adoptive immunotherapy. Among them, immunotherapy strategies represented by targeted blocking of programmed death-1/programmed death ligand-1 at immune checkpoint have been preliminarily confirmed to benefit ATC patients, especially the combination of molecular targeted inhibitors and immunotherapy has shown excellent therapeutic effects. Due to the great heterogeneity of ATC, it is expected to provide more therapeutic strategies for patients of ATC by carrying out various immunotherapy studies including biological, immune and cellular therapies and exploring the therapeutic potential of the next generation of immune checkpoint inhibitors. This article reviews the potential immunotherapeutic targets of ATC and the progress of immunotherapy.

A negative association between urinary iodine concentration and the prevalence of hyperuricemia and gout: a cross-sectional and population-based study in Mainland China.

BACKGROUND AND AIMS: Iodine is one of the most important trace elements in the human body. It is not only the main component of thyroid hormones but also has extrathyroid biological functions. To date, there have been no large-scale epidemiological studies on the relationship between hyperuricemia and iodine intake, although both are closely related to health. A population-based epidemiological survey in China offers such an opportunity. METHODS: This population-based cross-sectional study recruited 75,653 adults aged ≥ 18 years from 2015 to 2017 with a randomized, multistage, stratified sampling strategy. Serum uric acid levels and urinary iodine concentrations (UICs) were measured. RESULTS: Stratified by UIC, the prevalence of hyperuricemia was 17.8%, 18.8%, 16.0% and 13.7% in the UIC < 100, 100-199, 200-299, and ≥ 300 µg/L groups, respectively; the prevalence of gout was 4.0%, 3.4%, 2.4% and 1.7%, respectively. The prevalence of gout decreased significantly as the UIC increased. The prevalence of hyperuricemia and gout were markedly higher in postmenopausal females than in the premenopausal population (hyperuricemia: 15.9% vs. 8.3%, X2 = 520.072, p < 0.001; gout: 3.6% vs. 1.3%, X2 = 219.889, p < 0.001), and the prevalence decreased as the UIC increased. Subjects in the more than adequate and excessive iodine groups had lower likelihoods of having hyperuricemia [aOR = 0.81 (95% CI 0.77-0.85), aOR = 0.68 (95% CI 0.64-0.72)] and lower odds of having gout than subjects in the adequate iodine (AI) group [aOR = 0.77 (95% CI 0.68-0.86), aOR = 0.59 (95% CI 0.51-0.68)]. CONCLUSIONS: UIC was inversely associated with the occurrence of hyperuricemia and gout. More in-depth research and prospective studies are needed to explore the molecular mechanisms and confirm the observed association.

Divergence of Iodine and Thyroid Hormones in the Fetal and Maternal Parts of Human-Term Placenta.

The human placenta is an important organ that forms a barrier where maternal and fetal exchange takes place. The placenta transport iodine to the fetal circulation by transfer of maternal iodine and deiodination of thyroid hormones (THs). The aim of the study was to examine the distribution of iodine and thyroid hormone transporters in the maternal and fetal sides of human-term placenta. A cross-sectional study was performed at the First Affiliated Hospital of China Medical University. Placental samples (maternal and fetal surfaces) were collected from 113 healthy-term pregnant women. The iodine content; the concentration of thyroxine (T4), triiodothyronine (T3), and reverse T3 (rT3); and the enzyme activity of placental type 2 iodothyronine deiodinase (D2) and D3 were examined. The mRNA and protein localization/expression of iodine and thyroid hormone transporters in the placenta were also studied. We also analyzed the association between expression level of Na+/I- symporter (NIS), thyroid hormone transporter protein, D3 activity in maternal and fetal surfaces of placenta with iodine content, and thyroid hormone levels. Iodine levels in placental samples from the maternal side were significantly higher than those in samples from the fetal side. T3 and T4 expression in fetal placenta was significantly lower than in maternal placenta. D3 activity in the fetal side of the placentas was significantly higher than that in the maternal side. The mRNA and protein expression of monocarboxylate transporters 8 (MCT8), L-amino acid transporters 1 (LAT1), organic anion transporting polypeptides 4A1 (OATP4A1), and TH binding protein transthyretin (TTR) were significantly increased in maternal side, while the NIS expression was higher in fetal side of human-term placenta. In conclusion, the enzymatic deiodination of thyroid hormones forms a barrier which reduces transplacental passage of the hormones and that the maternal part of the placenta is the primary factor in the mechanism regulating the hormonal transfer.

Decreased expression of FcγRII in active Graves' disease patients.

BACKGROUND: Graves' disease (GD) is a common autoimmune disease characterized by genetic and environmental factors. Fcγ receptors (FcγRs) are involved in several autoimmune disorders through recognizing immunoglobulin (Ig) G antibodies and mediating immune response. The study on the expression of FcγRs in GD patients is scarce. The purpose of this study was to evaluate the expression of three different types of FcγRs in patients with active and remissive GD. METHODS: Blood samples of patients and healthy subjects were collected to analyze the percentage of FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16) on peripheral blood mononuclear cells (PBMCs) and monocytes by flow cytometry and Western blotting. CD32 isotypes were also examined in cases and controls by real-time PCR. RESULTS: The cell percentages expressed CD32 and protein expressions of CD32 on PBMCs, and monocytes from patients with active GD were significantly reduced compared to controls and patients with remissive GD. In particular, the expression of CD32B on PBMC was also decreased in active GD patients. However, the cell percentages expressed CD16 and CD64 from PBMCs and monocytes were comparable between three groups. Besides, the percentages of CD14+ CD32+ cells were negatively correlated with TRAb titers in active GD patients (r = -0.5825, P ï¼œ 0.001). CONCLUSION: These results suggested that CD32 may act as a novel marker for active GDs. The expression of monocytic CD32, in particular CD32B, in GD patients might play a crucial role in maintaining FcγRs function and be a therapeutic target in GD patients.

TGF-ß signalling prevents pancreatic beta cell death after proliferation.

OBJECTIVES: Maintenance of functional beta cell mass is critical for prevention of diabetes. The transforming growth factor-beta (TGF-ß) receptor signalling pathway plays an essential role in pancreatic development. However, its involvement in control of post-natal beta cell growth has only been recently reported. MATERIALS AND METHODS: Here, we studied the role of TGF-ß receptor signalling in beta cell proliferation after 50% partial pancreatectomy (PPx), using beta cell-specific TGF-ß receptor II (TBR2)-mutated mice. RESULTS: Consistent with previous reports, we found that inhibition of TGF-ß receptor signalling in beta cells resulted in slightly higher beta cell mass 1 week after PPx, due to greater beta cell proliferation. However, beta cell mass in these beta cell-specific TBR2-mutated mice significantly decreased by 12 weeks after PPx, resulting from increase in beta cell apoptosis. CONCLUSIONS: Our data thus suggest that TGF-ß receptor signalling may be required for prevention of beta cell death after proliferation, and highlight this pathway as an essential regulator during post-natal beta cell homoeostasis.