Lipidomic studies revealing serological markers associated with the occurrence of retinopathy in type 2 diabetes.

PURPOSE: The duration of type 2 diabetes mellitus (T2DM) and blood glucose levels have a significant impact on the development of T2DM complications. However, currently known risk factors are not good predictors of the onset or progression of diabetic retinopathy (DR). Therefore, we aimed to investigate the differences in the serum lipid composition in patients with T2DM, without and with DR, and search for potential serological indicators associated with the development of DR. METHODS: A total of 622 patients with T2DM hospitalized in the Department of Endocrinology of the First Affiliated Hospital of Xi'an JiaoTong University were selected as the discovery set. One-to-one case-control matching was performed according to the traditional risk factors for DR (i.e., age, duration of diabetes, HbA1c level, and hypertension). All cases with comorbid chronic kidney disease were excluded to eliminate confounding factors. A total of 42 pairs were successfully matched. T2DM patients with DR (DR group) were the case group, and T2DM patients without DR (NDR group) served as control subjects. Ultra-performance liquid chromatography-mass spectrometry (LC-MS/MS) was used for untargeted lipidomics analysis on serum, and a partial least squares discriminant analysis (PLS-DA) model was established to screen differential lipid molecules based on variable importance in the projection (VIP) > 1. An additional 531 T2DM patients were selected as the validation set. Next, 1:1 propensity score matching (PSM) was performed for the traditional risk factors for DR, and a combined 95 pairings in the NDR and DR groups were successfully matched. The screened differential lipid molecules were validated by multiple reaction monitoring (MRM) quantification based on mass spectrometry. RESULTS: The discovery set showed no differences in traditional risk factors associated with the development of DR (i.e., age, disease duration, HbA1c, blood pressure, and glomerular filtration rate). In the DR group compared with the NDR group, the levels of three ceramides (Cer) and seven sphingomyelins (SM) were significantly lower, and one phosphatidylcholine (PC), two lysophosphatidylcholines (LPC), and two SMs were significantly higher. Furthermore, evaluation of these 15 differential lipid molecules in the validation sample set showed that three Cer and SM(d18:1/24:1) molecules were substantially lower in the DR group. After excluding other confounding factors (e.g., sex, BMI, lipid-lowering drug therapy, and lipid levels), multifactorial logistic regression analysis revealed that a lower abundance of two ceramides, i.e., Cer(d18:0/22:0) and Cer(d18:0/24:0), was an independent risk factor for the occurrence of DR in T2DM patients. CONCLUSION: Disturbances in lipid metabolism are closely associated with the occurrence of DR in patients with T2DM, especially in ceramides. Our study revealed for the first time that Cer(d18:0/22:0) and Cer(d18:0/24:0) might be potential serological markers for the diagnosis of DR occurrence in T2DM patients, providing new ideas for the early diagnosis of DR.

Study on interface engineering and chemical bonding of the ReS2@ZnO heterointerface for efficient charge transfer and nonlinear optical conversion efficiency.

Rhenium sulfide (ReS2) has emerged as a promising two-dimensional material, demonstrating broad-spectrum visible absorption properties that make it highly relevant for diverse optoelectronic applications. Manipulating and optimizing the pathway of photogenerated carriers play a pivotal role in enhancing the efficiency of charge separation and transfer in novel semiconductor composites. This study focuses on the strategic construction of a semiconductor heterostructure by synthesizing ZnO on vacancy-containing ReS2 (VRe-ReS2) through chemical bonding processes. The ingeniously engineered built-in electric field within the heterostructure effectively suppresses the recombination of photogenerated electron-hole pairs. A direct and well-established interfacial connection between VRe-ReS2 and ZnO is achieved through a robust Zn-S bond. This distinctive bond configuration leads to enhanced nonlinear optical conversion efficiency, attributed to shortened carrier migration distances and accelerated charge transfer rates. Furthermore, theoretical calculations unveil the superior chemical interactions between Re vacancies and sulfide moieties, facilitating the formation of Zn-S bonds. The photoluminescence (PL) intensity is increased by the formation of VRe-ReS2 and ZnO heterostructure and the PL quantum yield of VRe-ReS2 is improved. The intricate impact of the Zn-S bond on the nonlinear absorption behavior of the VRe-ReS2@ZnO heterostructure is systematically investigated using femtosecond Z-scan techniques. The charge transfer from ZnO to ReS2 defect levels induces a transition from saturable absorption to reverse saturable absorption in the VRe-ReS2@ZnO heterostructure. Transient absorption measurements further confirm the presence of the Zn-S bond between the interfaces, as evidenced by the prolonged relaxation time (τ3) in the VRe-ReS2@ZnO heterostructure. This study offers valuable insights into the rational construction of heterojunctions through tailored interfacial bonding and surface/interface charge transfer pathways. These endeavors facilitate the modulation of electron transfer dynamics, ultimately yielding superior nonlinear optical conversion efficiency and effective charge regulation in optoelectronic functional materials.

A follow-up study on factors affecting the recovery of patients with hypothyroidism in different selenium environments.

BACKGROUND: Hypothyroidism is a major manifestation of autoimmune thyroid diseases (AITD). We previously reported that a low selenium (Se) status was linked to an elevated prevalence of thyroid diseases. We hypothesized that Se status may also influence the restoration of thyroid function. Thus, this study aimed to investigate the factors affecting the recovery of thyroid function in patients with (sub-)clinical hypothyroidism, with a specific focus on Se status. METHODS: We conducted a 6-year prospective cohort study comparing two counties with different Se concentrations. Demographic and disease data were collected from 1,190 individuals (549 Se-adequate and 641 Se-deficient) who completed a follow-up study in 2019. In addition, urinary iodine (I) levels, thyroid function, and serum and nail Se levels were measured. Logistic regression was used to investigate the relationship between Se deficiency and recovery of thyroid function. RESULTS: Sex and smoking status was similar between the two counties studied. Thyroid function recovery rate was significantly higher in Se-deficient counties (46.0% vs. 30.6%, P = 0.008). In the multivariate analysis, our results show that female sex (odds ratio [OR] (95% confidence interval [CI]) = 1.875 (1.080-3.257), P = 0.026] and increasing age [OR (95%CI) = 1.028(1.007-1.049), P = 0.009] were associated with the recovery rate. Additionally, our study revealed that while Se status was significant in the univariate analysis, this association appeared to disappear in the multivariate analysis. CONCLUSIONS: Female sex and increasing age have unfavorable effects on the recovery of thyroid function in patients over 30 years of age with (sub-) clinical hypothyroidism.

VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway.

BACKGROUND: CD4+ cytotoxic T cells (CD4 CTLs) are CD4+ T cells with major histocompatibility complex-II-restricted cytotoxic function. Under pathologic conditions, CD4 CTLs hasten the development of autoimmune disease or viral infection by enhancing cytotoxicity. However, the regulators of the cytotoxicity of CD4 CTLs are not fully understood. METHODS: To explore the potential regulators of the cytotoxicity of CD4 CTLs, bulk RNA and single-cell RNA sequencing (scRNA-seq), enzyme-linked immunosorbent assay, flow cytometry, quantitative PCR, and in-vitro stimulation and inhibition assays were performed. RESULTS: In this study, we found that VEGF-A promoted the cytotoxicity of CD4 CTLs through scRNA-seq and flow cytometry. Regarding the specific VEGF receptor (R) involved, VEGF-R1/R2 signaling was activated in CD4 CTLs with increased cytotoxicity, and the VEGF-A effects were inhibited when anti-VEGF-R1/R2 neutralizing antibodies were applied. Mechanistically, VEGF-A treatment activated the AKT/mTOR pathway in CD4 CTLs, and the increases of cytotoxic molecules induced by VEGF-A were significantly reduced when the AKT/mTOR pathway was inhibited. CONCLUSION: In conclusion, VEGF-A enhances the cytotoxicity of CD4 CTLs through the VEGF-R1/VEGF-R2/AKT/mTOR pathway, providing insights for the development of novel treatments for disorders associated with CD4 CTLs.

Cellular heterogeneity and transcriptomic profiles during intrahepatic cholangiocarcinoma initiation and progression.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is not fully investigated, and how stromal cells contribute to ICC formation is poorly understood. We aimed to uncover ICC origin, cellular heterogeneity, and critical modulators during ICC initiation/progression, and to decipher how fibroblast and endothelial cells in the stromal compartment favor ICC progression. APPROACH AND RESULTS: We performed single-cell RNA sequencing (scRNA-seq) using AKT/Notch intracellular domain-induced mouse ICC tissues at early, middle, and late stages. We analyzed the transcriptomic landscape, cellular classification and evolution, and intercellular communication during ICC initiation/progression. We confirmed the findings using quantitative real-time PCR, western blotting, immunohistochemistry or immunofluorescence, and gene knockout/knockdown analysis. We identified stress-responding and proliferating subpopulations in late-stage mouse ICC tissues and validated them using human scRNA-seq data sets. By integrating weighted correlation network analysis and protein-protein interaction through least absolute shrinkage and selection operator regression, we identified zinc finger, MIZ-type containing 1 (Zmiz1) and Y box protein 1 (Ybx1) as core transcription factors required by stress-responding and proliferating ICC cells, respectively. Knockout of either one led to the blockade of ICC initiation/progression. Using two other ICC mouse models (YAP/AKT, KRAS/p19) and human ICC scRNA-seq data sets, we confirmed the orchestrating roles of Zmiz1 and Ybx1 in ICC occurrence and development. In addition, hes family bHLH transcription factor 1, cofilin 1, and inhibitor of DNA binding 1 were identified as driver genes for ICC. Moreover, periportal liver sinusoidal endothelial cells could differentiate into tip endothelial cells to promote ICC development, and this was Dll4-Notch4-Efnb2 signaling-dependent. CONCLUSIONS: Stress-responding and ICC proliferating subtypes were identified, and Zmiz1 and Ybx1 were revealed as core transcription factors in these subtypes. Fibroblast-endothelial cell interaction promotes ICC development.

Graves' Orbitopathy Models: Valuable Tools for Exploring Pathogenesis and Treatment.

Graves' orbitopathy (GO) is the most common extrathyroidal complication of Graves' disease (GD) and severely affects quality of life. However, its pathogenesis is still poorly understood, and therapeutic options are limited. Animal models are important tools for preclinical research. The animals in some previous models only exhibited symptoms of hyperthyroidism without ocular lesions. With the improvements achieved in modeling methods, some progressive animal models have been established. Immunization of mice with A subunit of the human thyroid stimulating hormone receptor (TSHR) by either adenovirus or plasmid (with electroporation) is widely used and convincing. These models are successful to identify that the gut microbiota influences the occurrence and severity of GD and GO, and sex-related risk factors may be key contributors to the female bias in the occurrence of GO rather than sex itself. Some data provide insight that macrophages and CD8+ T cells may play an important pathogenic role in the early stage of GO. Our team also replicated the time window from GD onset to GO onset and identified a group of CD4+ cytotoxic T cells. In therapeutic exploration, TSHR derived peptides, fingolimod, and rapamycin offer new potential options. Further clinical trials are needed to investigate these drugs. With the increasing use of these animal models and more in-depth studies of the new findings, scientists will gain a clearer understanding of the pathogenesis of GO and identify more treatments for patients.

Identification of TCR repertoires in asymptomatic COVID-19 patients by single-cell T-cell receptor sequencing.

The T cell-mediated immune responses associated with asymptomatic infection (AS) of SARS-CoV-2 remain largely unknown. The diversity of T-cell receptor (TCR) repertoire is essential for generating effective immunity against viral infections in T cell response. Here, we performed the single-cell TCR sequencing of the PBMC samples from five AS subjects, 33 symptomatic COVID-19 patients and eleven healthy controls to investigate the size and the diversity of TCR repertoire. We subsequently analyzed the TCR repertoire diversity, the V and J gene segment deference, and the dominant combination of αß VJ gene pairing among these three study groups. Notably, we revealed significant TCR preference in the AS group, including the skewed usage of TRAV1-2-J33-TRBV6-4-J2-2 and TRAV1-2-J33-TRBV6-1-J2-3. Our findings may shed new light on understanding the immunopathogenesis of COVID-19 and help identify optimal TCRs for development of novel therapeutic strategies against SARS-CoV-2 infection.

Leptin receptor is a key gene involved in the immunopathogenesis of thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO), the most common and severe manifestation of Graves' disease (GD), is a disfiguring and potentially blinding autoimmune disease. The high relapse rate (up to 20%) and substantial side effects of glucocorticoid treatment further decrease the life quality of TAO patients. To develop novel therapies, we amid to explore the immunopathogenesis of TAO. To identify the key immune-related genes (IRGs) in TAO, we integrated the IRG expression profiles in thyrocytes from a GD patient set (GD vs healthy control) and a TAO patient set (TAO vs GD). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) and receiver operating characteristic (ROC) curve analyses identified the leptin receptor (LEPR) gene as the key IRG in TAO immunopathogenesis. Gene set enrichment analysis (GSEA) suggested enrichment of the antigen presentation pathway in TAO patients with higher LEPR. Increased LEPR expression was validated in TAO orbital tissues, and weighted gene co-expression network analysis (WGCNA) showed that cell adhesion processes were positively correlated with LEPR. Our study revealed that LEPR is a key gene in TAO immunopathogenesis and plays different roles in thyrocytes and orbital tissues. Our findings provide new insights into diagnostic and therapeutic biomarkers for TAO.

Dickkopf (Dkk)-2 is a beige fat-enriched adipokine to regulate adipogenesis.

In the past decades, remarkable efforts have been made to unravel the regulation of adipose tissue metabolism, given the increasing prevalence of obesity and its huge impact on human health. Wnt signaling pathway is closely involved in this entity. As extracellular inhibitors to Wnt signaling, secreted protein Dickkopfs (Dkks) may be potential targets to combat obesity and related metabolic disorders. In this study, we showed that Dkk2 was a beige fat-enriched adipokine to regulate adipogenesis. Dkk2 was strikingly expressed in beige fat depot compared to classic white, brown, and subcutaneous fat. Dkk2 treatment inhibited adipogenesis in 3T3-L1 pre-adipocytes, C3H10T1/2 mesenchymal stem cells, and primary bone marrow mesenchymal stromal cells. Activation of the master adipogenic factor PPARγ by the synthetic Thiazolidinedione ligand rosiglitazone largely rescued the inhibition of adipogenesis by Dkk2. Furthermore, adenoviral overexpression of Dkk2 in the liver to mimic its gain-of-function showed minimal effect on whole-body metabolism. These results collectively suggest that Dkk2 is a first-in-class beige fat adipokine and functions mainly through a paracrine manner to inhibit adipogenesis rather than as an endocrine factor. Our findings aid a better understanding of beige fat function and regulation and further, provide a potential therapeutic target for treating obesity.

Lower normal free thyroxine is associated with a higher risk of metabolic syndrome: a retrospective cohort on Chinese population.

BACKGROUND: Recently, the relationship between thyroid hormones (THs) across the euthyroid ranges and metabolic syndrome (MetS) has been widely discussed. This study aimed to present specific cutoff values of THs to assess the association between THs and MetS in a euthyroid cohort. METHODS: Data of 2694 subjects, aged 18-80 years, who attended health examination in Xi'an Electric Power Central Hospital from April 2011 to December 2015 were collected and analyzed. The first cohort enrolled 929 participants (followed up by 2221 person-years totally) to assess correlations between serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4) levels and MetS. The second cohort included 698 participants (followed up by 1709 person-years totally) to evaluate relationships between serum free triiodothyronine (FT3), free thyroxine (FT4) levels and MetS. MetS was defined according to the criteria of the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) scientific statements of 2009. Euthyroidism was defined as serum TSH, FT3 and FT4 levels within the reference ranges without taking any thyroid medication. RESULTS: The cutoff values for TSH, T3, T4, FT3 and FT4 were 2.0mIU/L, 1.9 nmol/L, 117 nmol/L, 4.3 pmol/L and 16 pmol/L, respectively. Participants were categorized into two groups according to cutoff values: the lower-THs group and the higher-THs group. There was no significant difference in the risk of MetS between two groups in TSH, T3, T4 and FT3. The incidence of MetS was significantly higher in lower-FT4 group than higher-FT4 group (1.00 vs 0.622 (0.458, 0.846), P = 0.002). The lower-FT4/higher-TSH group had the highest hazard ratios of MetS. (2.131vs 1.0 (1.380,3.291), P = 0.006). CONCLUSIONS: Lower normal FT4 (FT4 ≤ 16.0 pmol/L) is an independent risk factor for MetS, and lower normal thyroid function (TSH > 2.0 mIU/L and FT4 ≤ 16.0 pmol/L) is associated with a higher risk of developing MetS.

The association between subclinical hypothyroidism and metabolic syndrome: an update meta-analysis of observational studies.

The association between subclinical hypothyroidism (SCH) and metabolic syndrome (MetS) has been widely discussed. This study aimed to conduct an update and comprehensive meta-analysis to reveal the risk of MetS and its components in SCH. PubMed, Embase and ISI Web of Knowledge were searched to identify relevant studies through February 20th, 2020. Review Manager 5.3 and Stata 14.0 were used to conduct the meta-analysis. Both fixed-effects and random-effects models were used. In total, 18 articles (19 studies) incorporating 79,727 participants were included. The pooled OR for MetS comparing subjects with SCH with euthyroid subjects was 1.28 (95% CI: 1.19 to 1.39, p = 0.04, I2 = 40%). Subgroup analysis results showed significant associations of SCH and MetS in the adult subgroup (OR = 1.28, 95% CI: 1.18-1.40), Asian population subgroup (OR = 1.30, 95% CI: 1.19-1.42) and cross-sectional study design subgroup (OR = 1.31, 95% CI: 1.16-1.47). Significant associations of SCH and MetS also existed in all MetS definition criteria subgroups except the Chinese Diabetes Society (CDS) subgroup. SCH was correlated with MetS and was not affected by the subgroup analysis stratified by the proportion of females in the total population, the TSH cutoff value in SCH diagnostic criteria, or the adjustment for confounding factors. SCH was identified to be associated with an increased risk of obesity, hypertension, high triglyceride (TG) levels and low high-density lipoprotein cholesterol (HDL-C) levels. In conclusion, SCH is significantly associated with an increased risk of MetS and four out of five components of MetS.

Impact on decision making framework for medicine purchasing in Chinese public hospital decision-making: determining the value of five dipeptidyl peptidase 4 (DPP-4) inhibitors.

BACKGROUND: Medicine purchasing in Chinese public hospitals is decided by the hospital Pharmacy Management Committee (PMC), that is complex, subjective and requires efficient approaches to ensure transparency and consistency for the factors being considered. This study aimed to use the Evidence and Value: Impact on Decision Making (EVIDEM) framework to assess medicine in these hospitals. In this study anti-diabetic drugs DPP-4 inhibitors, which work by inhibiting the activation of the Dipeptidyl Peptidase 4 (DPP-4) inhibitors, were appraised. METHODS: Following EVIDEM methodology (EVIDEM-10th), we convened an appraisal group and asked each individual to express their perspectives by assigning weights to each criterion. A systematic literature search for information of each criterion of five DPP-4 inhibitors was completed. Then the appraisal group scored for each criterion of the five DPP-4 inhibitors. The estimated value of the five DPP-4 inhibitors was obtained by Multi-Criteria Decision Analysis (MCDA) which combined individual weighting of each criterion with individual scoring for each intervention in each criterion. RESULTS: By assigning weights, the most important criterion was the quality of evidence (4.01±0.52), and that the comparative cost consequences-non-medical cost was the least important criterion (2.87±1.03). Criteria included disease severity, size of the affected population, comparative effectiveness, type of therapeutic/preventive benefit and cost of intervention, all of which were assigned the same weight of 3.58. After MCDA, the overall value orders for each DPP-4 inhibitor included Sitagliptin (0.45), Linagliptin (0.44), Vildagliptin (0.43), Alogliptin (0.42) and Saxagliptin (0.40). CONCLUSIONS: Based on EVIDEM framework and MCDA, we found that overall value of five DPP-4 inhibitors was similar. It is feasible to use the EVIDEM framework and MCDA in purchasing medicine for Chinese public hospitals.

Diagnostic significance of DNA methylation of PTEN and DAPK in thyroid tumors.

OBJECTIVE: DNA Methylation of the tumour suppressor gene leading to gene silencing plays an important role in thyroid tumour development. The purpose was to determine the DNA methylation status of phosphatase and tensin homolog (PTEN) and death-associated protein kinase (DAPK) in patients with thyroid nodules and to explore whether they can be used as molecular diagnostic tools to differentiate benign and malignant thyroid nodules. DESIGN, PATIENTS AND MEASUREMENTS: Thyroid tissue and blood samples were obtained from normal healthy individuals (controls) and patients suffering from clinically diagnosed thyroid nodular disease [papillary thyroid carcinoma (PTC), adenoma and nodular goitre]. DNA methylation level, mRNA expression and protein expression of PTEN and DAPK in the thyroid tissues and peripheral blood were detected using methylation-specific PCR, semi-quantitative reverse transcription PCR and Western blot, respectively. Diagnostic sensitivity, specific and accuracy of detection were evaluated between blood and thyroid tissue. RESULTS: There was a significant increase in the level of DNA methylation of PTEN and DAPK in PTC (P < .05) compared with controls and other types of thyroid nodules. Levels of the mRNA of both PTEN and DAPK were lower in PTC in both peripheral blood and tissue samples compared with controls, while there was concomitant decrease of both PTEN and DAPK protein expression in PTC tissues (P < .05). There was no significant difference in diagnostic specificity, sensitivity and accuracy between blood sample and thyroid tissues. CONCLUSIONS: Hypermethylated status of both PTEN and DAPK in peripheral blood and tissue samples can be useful biomarkers for clinical diagnosis and, distinguishing of benign and malignant thyroid nodules.

The potential markers involved in newly diagnosed graves' disease and the development of active graves' orbitopathy.

BACKGROUND: Graves' disease (GD) patients experience two major issues: one is the severe hyperthyroidism associated with newly diagnosed GD, and the other involves the disfiguring and dysfunctional features of active Graves' orbitopathy (GO). Therefore, the aim of our study was to identify potential markers involved in the initial phase of GD dysfunction and the development of active GO. METHODS: Seventy-eight subjects were recruited: 40 with newly diagnosed GD, 20 with inactive GO and 18 with active GO. GO activity was evaluated by the clinical activity score (CAS, active GO = CAS ≥ 3), and severity was assessed according to the NOSPECS classification. Plasma selenium concentrations were determined by dual channel hydride generation atomic fluorescence photometry. A liquid chip assay was used to measure plasma Th1 cytokines IFN-γ and TNF-α; Th2 cytokines IL4, IL5 and IL6; Th17 cytokine IL23; Treg cytokines IL10 and TGF-ß; and two chemokines, CCL2 (Th2 chemokine) and CXCL10 (Th1 chemokine). RESULTS: Among the three groups, newly diagnosed GD patients showed significantly elevated plasma levels of CXCL10 and IL-23 (all p < 0.05). Both CXCL10 and IL23 were significantly correlated with hyperthyroidism severity, specifically, increasing FT3 and FT4 and decreasing TSH. Notably, a very strong positive relationship between IL23 and CXCL10 was revealed (adjusted R square = 0.795; p < 0.001). Moreover, the selenium level was lower, while that of CCL2 was higher, in active GO than in inactive GO (p = 0.007, p < 0.001, respectively). Likewise, we also discovered that increasing CCL2 levels and decreasing selenium levels were associated with high CAS. Remarkably, after adjusting for potential confounding factors, selenium (OR, 0.919) and CCL2 (OR, 1.042) were still independent predictors for the diagnosis of active GO, and similar conclusions were drawn by receiver operating characteristic (ROC) curve analysis. CONCLUSION: Pro-inflammatory cytokines, especially Th17-associated cytokines (e.g., IL23) and Th1 chemokines (e.g., CXCL10), appear to be involved in the initial phase of GD dysfunction. Moreover, we revealed for the first time that decreased plasma selenium levels and increased concentrations of Th2 chemokines (e.g., CCL2) may reflect GO disease activity, shedding light on the diagnosis and evaluation of active GO.

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.

The Correlation Between Metabolic Disorders And Tpoab/Tgab: A Cross-Sectional Population-Based Study.

OBJECTIVE: Studies have shown that metabolic abnormalities influence the immune system. Because the prevalence of metabolic and autoimmune thyroid diseases has increased synchronously, the correlation between them was worth exploring. The study objective was to investigate the relationship between metabolic disorders and thyroid auto-antibodies in euthyroid subjects. METHODS: Data were obtained from the Thyroid Diseases and Diabetes Mellitus project survey of 55,891 subjects from 31 provinces in China. The body mass index (BMI), waist circumference (WC), blood pressure, thyroid peroxidase antibodies (TPOAbs), thyroglobulin antibodies (TgAbs), thyroid-stimulating hormone (TSH), urinary iodine concentration, blood glucose, lipid profile, and uric acid levels were evaluated. Free thyroxine and free triiodothyronine levels were measured in patients with abnormal serum TSH levels. RESULTS: In males, the BMI, WC, systolic blood pressure (SBP), diastolic blood pressure (DBP), and 2-hour post-glucose oral glucose tolerance test results of the TPOAb-/TgAb-positive group were significantly higher than those of the TPOAb-/TgAb-negative group. In females, the BMI, WC, SBP, DBP, total cholesterol, and low-density-lipoprotein cholesterol (LDL-C) in the TPOAb-/TgAb-positive group were significantly increased compared to the TPOAb-/TgAb-negative group. Multivariate analysis showed that in males, the odds ratio (OR) of positive TgAbs in the abdominal obesity group was 1.175 (95% confidence interval [CI], 1.016 to 1.359; P = .03), and the OR of positive TPOAbs in the hyperuricemia group was 1.195 (95% CI, 1.041 to 1.372; P = .011). In females, the OR of positive TgAbs was 1.19 (95% CI, 1.068 to 1.326; P = .002) in the high LDL-C group. CONCLUSION: Obesity, high LDL-C, and hyperuricemia were positively correlated with the prevalence of positive thyroid autoantibodies in euthyroid subjects in a gender-dependent manner. This cross-sectional survey showed that metabolic disorders are associated with increased positive thyroid autoantibody levels in euthyroid subjects in a gender-dependent manner. ABBREVIATIONS: AIT = autoimmune thyroiditis; BMI = body mass index; CI = confidence interval; DBP = diastolic blood pressure; FPG = fasting plasma glucose; FT3 = free triiodothyronine; FT4 = free thyroxine; HbA1c = glycated hemoglobin; HDL-C = high-density-lipoprotein cholesterol; LDL-C = low-density-lipoprotein cholesterol; OGTT2hPG = oral glucose tolerance test 2-hours post-glucose; OR = odds ratio; SBP = systolic blood pressure; TC = total cholesterol; TG = triglycerides; TgAb = thyroglobulin antibody; TPOAb = thyroid peroxidase antibody; TSH = thyroid-stimulating hormone; UA = uric acid; WC = waist circumference.

The proportion of peripheral blood Tregs among the CD4+ T cells of autoimmune thyroid disease patients: a meta-analysis.

Autoimmune thyroid disease (AITD) is characterized by a loss of self-tolerance to thyroid antigen. Tregs, whose proportions are controversial among CD4+ T cell from AITD patients (AITDs), are crucial in immune tolerance. Considering that drugs might affect Treg levels, we assumed that the differences originated from different treatment statuses. Thus, we performed a meta-analysis to explore proportions of Tregs in untreated and treated AITDs. PubMed, Embase and ISI Web of Knowledge were searched for relevant studies. Review Manager 5.3 and Stata 14.0 were used to conduct the meta-analysis. Subgroup analysis based on different diseases and cell surface markers was performed. Egger linear regression analysis was used to assess publication bias. Approximately 1,100 AITDs and healthy controls (HCs) from fourteen studies were included. Proportions of Tregs among CD4+ T cells of untreated AITDs were significantly lower than those in HCs (p = 0.002), but were not in treated patients (p = 0.40). Subgroup analysis revealed lower proportions of Tregs in untreated Graves' disease patients (GDs) (p = 0.001) but did not show obvious differences in untreated Hashimoto's thyroiditis patients (HTs) (p = 0.62). Furthermore, proportions of circulating FoxP3+ Tregs were reduced in untreated GDs (p < 0.00001) and HTs (p = 0.04). No publication bias was found. In this first meta-analysis exploring proportions of circulating Tregs among CD4+ T cells of AITDs with different treatment statuses, we found that Tregs potentially contribute to the pathogenesis of AITD but function differently in GD and HT. Remarkably, FoxP3+ Tregs, which were decreased in both diseases, might be promising targets for novel therapies.

Factors associated with the efficacy of intravenous methylprednisolone in moderate-to-severe and active thyroid-associated ophthalmopathy: A single-centre retrospective study.

OBJECTIVE: Intravenous methylprednisolone (IVMP) is recommended as the first-line treatment for moderate-to-severe and active thyroid-associated ophthalmopathy (TAO). This study aimed to identify potential predictors and establish a multivariable prediction model for the efficacy of IVMP therapy. DESIGN: A single-centre retrospective study. PATIENTS: A total of 302 consecutive patients diagnosed with moderate-to-severe and active TAO who underwent the full course of IVMP therapy were included. METHODS: Participants were sequentially divided into the training set (n = 200) and the validation set (n = 102). Multivariate logistic regression analysis was used to identify the independent predictors and establish the predictive model. RESULTS: In addition to the pretreatment clinical activity score (OR = 3.506, P < 0.001), elevated thyroid-stimulating hormone (TSH) levels during treatment (OR = 0.145, P = 0.005), pretreatment anti-TSH receptor antibody levels (OR = 0.061, P < 0.001) and duration of eye symptoms (OR = 0.878, P = 0.017), a significant relationship was found between therapeutic efficacy and the pretreatment triglyceride levels (OR = 0.090, P = 0.001). The prediction model showed good calibration and excellent discrimination, with an area under curve of 0.915 (P < 0.001) and 0.885 (P < 0.001) in the training and validation sets, respectively. CONCLUSIONS: This study provides some novel insights into the factors associated with the efficacy of IVMP therapy. A multivariable prediction model has been established and validated to help determine the indication and prognosis of IVMP therapy. Moreover, several suggestions have been made in the management of TAO patients: early diagnosis and treatment (within 15 months); prompt restoration and maintenance of euthyroidism, especially meticulous control of TSH levels (≤5 µIU/mL); and regular monitoring of triglyceride levels.

URINARY IODINE CONCENTRATION IS INVERSELY ASSOCIATED WITH THYROGLOBULIN ANTIBODIES.

Objective: Epidemiologic studies on the relationship between iodine and thyroid antibodies are inconsistent. Iodine nutrition, genetic, and environmental factors have been shown to modify the effects of iodine on thyroid autoimmunity. We investigated the relationship between urinary iodine concentration (UIC) and thyroglobulin antibodies (TgAbs) in individuals living in iodine-sufficient areas in this cross-sectional study. Methods: A total of 15,008 participants were recruited according to the age range of the population of China in our study. An oral questionnaire was administered to collect basic demographic information. Serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAbs), TgAbs, and UIC were measured, and thyroid ultrasonography was performed in all subjects. Participants were further divided according to the level of UIC and the status of TgAb, and logistic regression was applied to determine the relationship between UIC and TgAbs. Results: The median UIC of the study population was 205.23 (95% confidence interval [CI], 65.7 to 537.67) µg/L. A total of 17.6% of participants had UIC <100 µg/L. With the increase in UIC, the prevalence of positive TgAbs decreased gradually. UIC level was lowest in subjects with high TgAb titer (median, 182.36 µg/L; 95% CI, 52.88 µg/L to 506.71 µg/L) and highest in the TgAb-negative group (median, 207.16 µg/L; 95% CI, 66.94 µg/L to 538.72 µg/L). Multilinear correlation analysis showed that gender (ß = 37.632; P<.001), age (ß = 0.467; P = .038), TSH (ß = 13.107; P<.001), TPOAb (ß = 1.150; P<.001), thyroid volume (ß = 2.883; P<.001), and UIC (ß = -0.047; P = .032) were independent predictors of TgAb variations. Low UIC (<100 µg/L) was associated with increased risk of positive TgAbs (adjusted odds ratio = 1.255 [1.004 to 1.568]). Conclusion: Low UIC is an independent risk factor for positive TgAb in individuals living in iodine-sufficient areas. Abbreviations: CI = confidence interval; CV = coefficient of variation; FT3 = free triiodothyronine; FT4 = free thyroxine; OR = odds ratio; TgAb = thyroglobulin antibody; TPOAb = thyroid peroxidase antibody; TSH = thyrotropin; UIC = urinary iodine concentration; USI = universal salt iodization.

PKCα promotes insulin secretion via TRPC1 phosphorylation in INS-1E cells.

Protein kinase C (PKC) is a class of phospholipid-dependent serine/threonine kinases that contribute to cell survival, migration, and invasion. Previous studies demonstrated that PKC participates in insulin secretion. However, the role of PKC in glucose-stimulated insulin secretion (GSIS) remains unclear. Herein, we demonstrated that PKC is an important mediator of insulin secretion and revealed a close relationship between PKC activation and insulin secretion in INS-1E cells. Meanwhile, the presence of PKCα was found to induce TRPC1 phosphorylation in INS-1E cells. TRPC1 phosphorylation levels increased by activating PKCα activity. Inhibition of PKCα activity reduced TRPC1 phosphorylation. Finally, we showed that TRPC1 could reverse the decrease in intracellular Ca2+ levels and reduced insulin secretion induced by treatment with PKCα inhibitor under high glucose conditions. In conclusion, our findings indicated that TRPC1 and PKCα are involved in promoting insulin secretion and that PKCα promotes insulin secretion via TRPC1 phosphorylation in INS-1E cells.