Vitamin D is involved in the effects of the intestinal flora and its related metabolite TMAO on perirenal fat and kidneys in mice with DKD.

BACKGROUND: Vitamin D was shown to directly exert a protective effect on diabetic kidney disease (DKD) in our previous study. However, whether it has an effect on perirenal adipose tissue (PRAT) or the intestinal flora and its metabolites (trimethylamine N-oxide, TMAO) is unclear. METHODS: DKD mice were received different concentrations of 1,25-(OH)2D3 for 2 weeks. Serum TNF-α levels and TMAO levels were detected. 16S rRNA sequencing was used to analyze gut microbiota. qPCR was used to detect the expression of TLR4, NF-Κb, PGC1α, and UCP-1 in kidney and adipose tissue. Histological changes in kidney and perirenal adipose tissue were observed using HE, PAS, Masson and oil red staining. Immunofluorescence and immunohistochemistry were used to detect the expression of VDR, PGC1α, podocin, and UCP-1 in kidney and adipose tissue. Electron microscopy was used to observe the pathological changes in the kidney. VDR knockout mice were constructed to observe the changes in the gut and adipose tissue, and immunofluorescence and immunohistochemistry were used to detect the expression of UCP-1 and collagen IV in the kidney. RESULTS: 1,25-(OH)2D3 could improve the dysbiosis of the intestinal flora of mice with DKD, increase the abundance of beneficial bacteria, decrease the abundance of harmful bacteria, reduce the pathological changes in the kidney, reduce fat infiltration, and downregulate the expression of TLR4 and NF-κB in kidneys. The serum TMAO concentration in mice with DKD was significantly higher than that of the control group, and was significantly positively correlated with the urine ACR. In addition, vitamin D stimulated the expression of the surface markers PGC1α, UCP-1 and VDR in the PRAT in DKD mice, and TMAO downregulated the expression of PRAT and renal VDR. CONCLUSIONS: The protective effect of 1,25-(OH)2D3 in DKD mice may affect the intestinal flora and its related metabolite TMAO on perirenal fat and kidneys.

Is thyroid function associated with polycystic ovary syndrome? A bidirectional Mendelian randomization study.

OBJECTIVE: Some observational studies have suggested the association between thyroid function and polycystic ovary syndrome (PCOS). However, it remains to be determined whether these associations are causal or not. The aim of this study was to investigate the underlying causal association between different thyroid function status and PCOS. METHODS: Bidirectional Mendelian randomization (MR) analysis was conducted to explore the impact of different thyroid function statuses on PCOS. The study included 10,074 individuals with PCOS and 103,164 controls for the primary analysis, with validation analysis repeated in the FinnGen R9 and EstBB PCOS cohorts. Female-specific thyroid function GWAS data were obtained from European population, including Hyperthyroidism (22,383 cases and 54,288 controls) and Hypothyroidism (27,383 cases and 54,288 controls) from the UK Biobank, and TSH (54,288 cases and 72,167 controls) and FT4 (49,269 cases and 72,167 controls) within the reference range from the ThyroidOmics Consortium. Inverse variance weighting (IVW) was chosen as the principal method, and sensitivity analysis was conducted to test for the presence of horizontal pleiotropy or heterogeneity. RESULTS: The IVW analysis indicated nominal significance between normal TSH levels and PCOS after adjusted for age and BMI [OR (95% CI) = 0.78(0.62,0.97), P = 0.029], suggesting that maintaining normal TSH levels might act as a protective factor against the pathogenesis of PCOS. Besides, in order to increase the statistical power, we pooled PCOS GWAS above together by meta-analysis and found PCOS contributed to the occurrence of hyperthyroidism [OR(95%CI) = 1.37(0.73,2.57), P = 0.012]. However, no causal relationship was found after Bonferroni correction (P-value < 0.0031). CONCLUSION: Although the MR analysis didn't indicate genetic causal association between thyroid function and PCOS after Bonferroni correction. Further efforts are needed to interpret the potential causal relationship between thyroid function and PCOS in different age and BMI subgroup.

Elevated plasma myoglobin level is closely associated with type 2 diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD) is the most frequent complication in patients with type 2 diabetes mellitus (T2DM). It causes a chronic and progressive decline in kidney function, and ultimately patients require renal replacement therapy. To date, an increasing number of clinical studies have been conducted to explore the potential and novel biomarkers, which can advance the diagnosis, estimate the prognosis, and optimize the therapeutic strategies at the early stage of DKD. In the current study, we sought to investigate the association of plasma myoglobin with DKD. METHODS: A total of 355 T2DM patients with DKD and 710 T2DM patients without DKD were enrolled in this study. Laboratory parameters including blood cell count, hemoglobin A1c, biochemical parameters, and plasma myoglobin were recorded. Patients were classified on admission according to the tertile of myoglobin and clinical parameters were compared between the groups. Pearson correlation analysis, linear regression, logistic regression, receiver operating characteristics (ROC) analysis, and spline regression were performed. RESULTS: Plasma myoglobin significantly increased in patients with DKD and was associated with renal function and inflammatory parameters. Plasma myoglobin was an independent risk factor for the development of DKD. The area under ROC curve of myoglobin was 0.831. Spline regression showed that there was a significant linear association between DKD incidence and a high level of plasma myoglobin when it exceeded 36.4 mg/mL. CONCLUSIONS: This study shows that elevated plasma myoglobin level is closely associated with the development of kidney injury in patients with T2DM.

Clinical value of noninvasive lens advanced glycation end product detection in early screening and severity evaluation of patients with diabetic kidney disease.

BACKGROUND: Advanced glycation end products (AGEs) deposited in the lens are correlated with those in the kidneys, indicating a possible value in evaluating diabetic kidney disease (DKD). This study explored the value of noninvasively measuring lens AGEs to diagnose and evaluate the severity of diabetic nephropathy in patients with type 2 diabetes mellitus (T2DM). METHODOLOGY: A total of 134 T2DM patients admitted to the Fifth People's Hospital of Shanghai from March 2020 to May 2021 were selected randomly. Patients were divided into low-, medium-and high-risk groups according to the risk assessment criteria for DKD progression and into DKD and non-DKD (non-DKD) groups according to the Guidelines for the Prevention and Treatment of Diabetic Nephropathy in China. The concentrations of noninvasive AGEs in the lens in all the groups were retrospectively analyzed. RESULTS: The concentration of noninvasive lens AGEs in the high-risk patients, according to the 2012 guidelines of the Global Organization for Improving the Prognosis of Kidney Diseases, was significantly higher than that in the remaining groups. Regression analysis suggested the value of lens AGEs in diagnosing DKD and evaluating DKD severity. Cox regression analysis indicated that the noninvasive lens AGE concentration was positive correlated with the course of disease. CONCLUSION: The receiver operating characteristic (ROC) curve suggested that using noninvasive lens AGE measurements has clinical value in the diagnosis of DKD (area under the curve 62.4%,95% confidence interval (CI) 52.4%-73.9%, p = 0.014) and in assessing the severity of DKD (area under the curve 83.2%, 95% CI 74.1%-92.3%, P < 0.001). Noninvasive lens AGE testing helps screen T2DM patients for DKD and evaluate the severity of DKD.

Association between radioactive iodine uptake and neutropenia in untreated Graves' disease.

Objective: Neutropenia is a complication of Graves' disease (GD), but there is currently no means by which to predict its occurrence. This study aimed to investigate the risk factors for the development of neutropenia in untreated GD. Methods: This was a retrospective cohort study. Between January 1, 2010, and July 31, 2020, 1000 patients with new-onset or relapsing GD without treatment were enrolled in the study and divided into two groups: neutropenia group (neutrophil count < 2 × 109/L) and non-neutropenia group (neutrophil count ≥ 2 × 109/L). Clinical characteristics of subjects were compared between the two groups, and logistic regression analysis was applied to determine risk factors for neutropenia. To further explore the correlation of radioactive iodine uptake (RAIU) with neutropenia, subjects were first classified according to quartile of 3 h RAIU and 24 h RAIU prior to logistic regression analysis. Results: Of all patients recruited, 293 (29.6%) were diagnosed with neutropenia. Compared with non-neutropenic patients, those with neutropenia had a higher level of free thyroxine (FT4) (56.64 ± 31.80 vs 47.64 ± 39.64, P = 0.001), 3 h RAIU (55.64 ± 17.04 vs 49.80 ± 17.21, P < 0.001) and 24 h RAIU (67.38 ± 12.54 vs 64.38 ± 13.58, P < 0.001). Univariate logistic regression analysis revealed that FT4, 3 h RAIU, 24 h RAIU, creatinine, and low-density lipoprotein were risk factors for development of neutropenia in GD. After adjusting for confounding factors of age, BMI, and sex, we determined that 3 h RAIU and 24 h RAIU (Model 1: OR = 1.021, 95% CI: 1.008-1.033, P = 0.001; Model 2: OR = 1.023, 95% CI: 1.007-1.039, P = 0.004), but not FT4, were associated with the development of neutropenia. Conclusions: RAIU is associated with neutropenia in patients with untreated GD.

High concentration of estradiol has a negative correlation with free thyroxine during the second trimester of pregnancy.

Objective: To explore the relationship between estradiol (E2) and thyroid function during the second trimester of pregnancy and the effect of E2 on sodium iodide transporter (NIS) expression in cultured thyroid cells. Materials and methods: We analyzed relationships between E2 and thyroid function in 196 pregnant women during the second trimester. Multiple linear regression analysis was performed between E2 and thyroid function. The human thyroid Nthy-ori3-1 cells were cultured in different E2 concentrations, and the mRNA levels of NIS, estrogen receptor (ER)-α, and ER-ß were measured by quantitative real-time PCR. Their protein levels were assessed by western blot. Results: E2 was positively correlated with thyroid-stimulating hormone (TSH) and negatively correlated with free thyroxine (FT4) (P < 0.05). When we corrected for age, BMI, alanine aminotransferase, and serum creatinine, E2 was still negatively correlated with FT4 (P < 0.5) during the second trimester. In Nthy-ori3-1 cells treated with 10 nM E2, NIS and ER-ß mRNA levels were significantly reduced, while ER-α mRNA level was not altered (P > 0.5). Moreover, 10 nM E2 significantly decreased protein levels of ER-ß, phosphorylated versions of protein kinase A (p-PKA), phosphorylated versions of cAMP response element-binding protein (p-CREB), and NIS, while treatment with the ER-ß inhibitor restored the expression of p-PKA, p-CREB, and NIS (P < 0.05). Conclusion: High concentration of E2 has a negative correlation with FT4. High concentration of E2 can inhibit the NIS expression through the ER-ß-mediated pathway, which may cause thyroid hormone fluctuations during pregnancy.

Increased neutrophil count Is associated with the development of chronic kidney disease in patients with diabetes.

BACKGROUND: This study aims to investigate the potential association of peripheral inflammatory blood cell parameters with the incidence and progression of chronic kidney disease (CKD) in patients with diabetes. METHODS: The cross-sectional study included 1192 subjects with diabetes derived from one center. The cohort study included 2060 subjects with diabetes derived from another two centers followed up for 4 years. Logistic regression and Cox proportional hazards models were used to evaluate the association of peripheral inflammatory blood cell with CKD. RESULTS: In the cross-sectional study, neutrophil count performed best as an independent risk factor for CKD (odds ratio 2.556 [95% confidence interval 1.111, 5.879]) even after 1:1 case-control matching for age, gender, history of high blood pressure and duration of diabetes. Spline regression revealed a significant linear association of CKD incidence with continuous neutrophil count in excess of 3.6 × 109 /L. In the cohort study, subjects were grouped based on tertile of neutrophil count and neutrophil-to-lymphocyte ratio. Cox regression analysis results showed that only neutrophil count was independently associated with CKD progression (the highest group vs. the lowest group, hazard ratio 2.293 [95% confidence interval 1.260, 4.171]) after fully adjusting for potential confounders. The cumulative incidence of CKD progression in patients with diabetes gradually increased with increasing neutrophil count (53 (7.7%) subjects in the lowest group vs. 60 (8.2%) in the middle group vs. 78 (12.2%) in the highest group). CONCLUSIONS: This study suggested that neutrophil count is an independent risk factor for progression of CKD in patients with diabetes.

Exploration of Noninvasive Detection of Advanced Glycation End Products in the Lens to Screen for Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a complication of diabetes, which is the most common cause of end-stage renal disease (dialysis). DKD has a high mortality rate, and only early detection can nip this disease in the bud. Advanced glycation end products (AGEs)are generally believed to be involved in the occurrence of DKD. Studies have shown that the lens AGEs fluorescence for noninvasive detection has high consistency with the gold standard OGTT, has high sensitivity and specificity, and could be used as a practical tool for the early screening of type 2 diabetes mellitus (T2DM).Therefore, we speculated that the noninvasive lens AGEs fluorescence detection method can be used to predict the occurrence of DKD. This study detected levels of AGEs in multiple cellular and tissues and analyzed the relationships between AGEs and lens, eyeballs, peripheral blood mononuclear cell (PBMC), serum, and kidney. Additionally, we examined the possible role of lens AGEs fluorescence in DKD screening. Our preexperimental study found that lens AGE levels in patients with T2DM were positively correlated with PBM and serum AGE levels. Lens AGE levels in patients with T2DM were negatively correlated with eGFR and positively correlated with urinary ACR. The animal and cell experiments showed that the AGE levels in the eyeballs of DM mice were also positively correlated with those in the serum and kidney. To increase the reliability of the experiment, we increased the sample size. In our results, lens AGEs levels were positively correlated with the occurrence of DKD, and the incidence of DKD in the high lens AGEs group was 2.739 times that in the low lens AGEs group. The receiver operating characteristic (ROC) curves showed that patients with T2DM with a lens AGEs value ≥ 0.306 were likely to have DKD. The area under the ROC curve of the noninvasive technique for identifying DKD was 0.757 (95% Cl: 0.677-0.838, p<0.001), and the sensitivity and specificity were 70.0% and 78.7%, respectively. These results suggest that noninvasive lens AGEs detection technology has certain clinical value in diagnosing whether patients with T2DM have DKD.

Serum Trimethylamine N-oxide and the Diversity of the Intestinal Microbial Flora in Type 2 Diabetes Complicated by Diabetic Kidney Disease.

BACKGROUND: Trimethylamine N-oxide (TMAO) serves as a metabolite of intestinal bacteria as well as a urotoxin influencing the prognosis of chronic kidney disease (CKD), which has become a research hotspot in the field of kidney disease. This study preliminarily explored the alternations of the microbial flora and serum TMAO in patients with type 2 diabetes mellitus (T2DM) complicated with diabetic kidney disease (DKD). METHODS: Seventeen T2DM patients at the Affiliated Hospital of Zunyi Medical University between September 2018 and February 2019 were included. Among these patients, 8 patients had T2DM complicated with DKD. Eight healthy volunteers constituted the control group. Fresh stool was collected for Illumina sequencing. Based on the sequencing outcomes, the flora diversity and species differences were analyzed. Serum TMAO, cystatin C, urinary albumin/urine creatinine ratios (ACRs), and routine biochemical outcomes were also compared. RESULTS: The DKD group exhibited a significantly higher TMAO level than the remaining groups. The high-TMAO group had a significantly increased ACR level compared with the low-TMAO group. TMAO positively correlated with the ACR. Compared with the control group, the DKD group exhibited a decreased flora diversity. At the genus level, both the T2DM group and the DKD group showed decreased numbers of Alloprevotella and Megasphaera compared with the control group. The difference in Megasphaera between the DKD group and the control group was significant. CONCLUSIONS: The alternation of the intestinal microbial flora may participate in the development of DKD, and TMAO and chronic inflammation might be important factors for DKD development.

Preliminary Observation of the Changes in the Intestinal Flora of Patients With Graves' Disease Before and After Methimazole Treatment.

Immune dysfunction caused by environmental factors plays an important role in the development of Graves' disease (GD), and environmental factors are closely related to the intestinal flora. Our previous study showed significant changes in the intestinal flora in GD patients compared with healthy volunteers. This study analyzed the relationships between changes in the intestinal flora, thyroid function and relevant thyroid antibodies in GD patients before and after methimazole treatment. The subjects were divided into the UGD group (18 newly diagnosed GD patients), the TGD group (10 GD patients with normal or approximately normal thyroid function after methimazole treatment) and the NC group (11 healthy volunteers). Their fresh stool samples were sent for 16S rRNA gene amplification and Illumina platform sequencing. The correlations of the relative abundance of Bifidobacterium with the levels of TRAb, TgAb and TPOAb in the NC group and the UGD group were analyzed. A total of 1,562,445 high-quality sequences were obtained. In the UGD group, the abundances of Bifidobacterium and Collinsella were higher than that in the NC group; Bacteroides abundance in the TGD group was higher than that in the NC group, while Prevotella and Dialister abundances were lower than that in the NC group; Prevotella and Collinsella abundances in the UGD group were higher than that in the TGD group. The predominant abundance distribution of Bifidobacteriaceae in the UGD group at the family level was superior to that in the NC group. The abundance of Bifidobacterium was positively correlated with the levels of TRAb, TgAb, and TPOAb. The biological diversity of the intestinal flora was reduced in GD patients. After methimazole treatment, the composition of the intestinal flora was significantly altered. The change in Bifidobacterium abundance was positively correlated with TRAb, TgAb and TPOAb, suggesting that it might be related to the immune mechanism of GD. The results of this study may deepen our understanding of the pathogenesis of GD and provide a new idea for the treatment of GD.

Decreased Monocyte Count Is Associated With Gestational Diabetes Mellitus Development, Macrosomia, and Inflammation.

CONTEXT: The immune system plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). Monocytes, the main innate immune cells, are especially important in the maintenance of a normal pregnancy. OBJECTIVE: Here, we investigated the potential effect of monocytes in GDM. METHODS: Monocyte count was monitored throughout pregnancy in 214 women with GDM and 926 women without in a case-control and cohort study. Circulating levels of inflammatory cytokines, placenta-derived macrophages, and their products were measured. RESULTS: Throughout pregnancy, monocyte count was significantly decreased in women with GDM, and was closely associated with glucose level, insulin resistance, and newborn weight. First-trimester monocyte count outperformed that of the second and third trimester as a risk factor and diagnostic predictor of GDM and macrosomia both in the case-control and cohort study. In addition, our cohort study showed that as first-trimester monocyte count decreased, GDM and macrosomia incidence, glucose level, and newborn weight increased in a stepwise manner. Risk of GDM started to decrease rapidly when first-trimester monocyte count exceeded 0.48 × 109/L. Notably, CD206 and interleukin 10 (IL-10) were significantly lower, whereas CD80, CD86, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) were higher both in GDM placental tissue and peripheral blood. First-trimester monocyte count was positively related to IL-10 and CD206, but negatively related to CD80, CD86, TNF-α, and IL-6. CONCLUSION: Decreased monocyte count throughout pregnancy was closely associated with the development of GDM, macrosomia, and the chronic inflammatory state of GDM. First-trimester monocyte count has great potential as an early diagnostic marker of GDM.

Serum ferritin as a risk factor for type 2 diabetes mellitus, regulated by liver transferrin receptor 2.

OBJECTIVE: The aim of this study was to evaluate the effect of TFR2 on iron storage in type 2 diabetes. METHODS: A cross-sectional study was conducted among 1938 participants from the Jiangchuan Community of Shanghai. A total of 784 participants with T2DM and 1154 normal participants (non-T2DM) were enrolled in this study. Serum ferritin, fasting blood glucose, postprandial blood glucose, and HbA1C (glycated hemoglobin A1c) levels were determined. Eighteen Wistar male rats were randomly assigned into three groups (n = 6/group): rats in a high-fat diet streptozotocin (HFD+STZ) group were fed with HFD for 4 weeks and intraperitoneally injected with streptozotocin (STZ); rats in a control group were fed with a standard diet for 4 weeks and intraperitoneally injected with buffer; rats in an STZ group were fed with a standard diet for 4 weeks and intraperitoneally injected with streptozotocin. Glucose tolerance test was performed at the end of the study. Blood samples and liver tissues were assessed for liver TFR2, blood glucose, serum ferritin, and iron levels. RESULTS: The mean serum ferritin level of T2DM participants was significantly higher than that of the control group (227 (140-352) vs 203.5 (130.5-312) ng/mL, P < 0.05). Serum ferritin level was an independent risk factor for T2DM (high ferritin group vs low ferritin group, 1.304 (1.03-1.651), P < 0.05). Diabetic rats showed reduced liver TFR2 levels, with increased serum ferritin levels. CONCLUSION: T2DM participants exhibited iron disorder with elevated serum ferritin levels. Elevated serum ferritin levels in diabetic rats were accompanied by reduced liver TFR2 levels.

Fibrinogen to Albumin Ratio as an Independent Risk Factor for Type 2 Diabetic Kidney Disease.

PURPOSE: Diabetic kidney disease (DKD) is an inflammatory disease. This study aimed to investigate the association of fibrinogen to albumin ratio (FAR) with DKD. PATIENTS AND METHODS: A total of 1022 type 2 diabetes mellitus (T2DM) patients with DKD and 1203 T2DM patients without DKD were enrolled in this study. Laboratory values including blood cell count, hemoglobin A1c, biochemical parameters, and fibrinogen and albumin creatinine ratio were recorded. Patients were classified according to tertile of admission FAR. Clinical parameters were compared between groups. Logistic regression, linear regression, ROC analysis and spline regression were carried out. RESULTS: FAR in the DKD group was significantly higher than that in the non-DKD group. FAR had the highest odds ratio as an independent risk factor for the development of DKD and the highest area under ROC curve for predicting DKD compared with albumin (ALB) or fibrinogen (FIB) alone. Simple linear regression analyses revealed a significant and linear correlation of FAR with neutrophil and neutrophil-to-lymphocyte ratio. FAR was an independent risk factor for development of DKD. Spline regression showed that there was a significant linear association between DKD incidence and continuous FAR value when it exceeded 67.3mg/g. CONCLUSION: FAR is a stronger independent predictor of DKD than FIB and ALB. FAR is an independent risk factor for DKD development when it exceeded 67.3mg/g. FAR might be one of novel diagnostic biomarkers to predict and prevent DKD progression. However, a prospective study to validate the prognostic model is still needed.

Monocyte to high-density lipoprotein cholesterol ratio as an independent risk factor for papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is considered to be an inflammatory disease. This study aimed to investigate the association of monocyte to high-density lipoprotein cholesterol ratio (MHR) with PTC. METHODS: Clinical parameters from 300 patients with PTC and 552 patients with benign thyroid nodule were compared. Serum renal function and liver enzymes, fasting plasma glucose, lipid profile, and blood cell count were measured. RESULTS: Patients with PTC had a higher MONO (p < 0.001) and MHR (p < 0.001). There was a step-wise increase in the prevalence of PTC (p = 0.003) with the tertile of MHR. Logistic regression analysis revealed that MHR could be considered an independent risk factor (p < 0.001) in the case-control study and the cohort study. Pearson correlation analysis and simple linear regression analysis indicated that MHR was positively associated with neutrophil (NEU) and lymphocyte (LYM) count as well as neutrophil-to-lymphocyte ratio (NLR). Area under the curve (AUC) was 0.711. The optimal cutoff of MHR was 0.33 × 109 /mmol. CONCLUSION: This study identifies novel evidence that patients with PTC have a higher MHR. MHR is an independent risk factor for PTC. These findings support the application of MHR to predict, diagnose, and evaluate the occurrence of PTC.

Alterations in CD8+ Tregs, CD56+ Natural Killer Cells and IL-10 Are Associated With Invasiveness of Nonfunctioning Pituitary Adenomas (NFPAs).

Invasive nonfunctioning pituitary adenomas (NFPAs) grow rapidly and the mechanisms are unclear. Among many complex mechanisms, the role of immunity in the development of NFPAs has not been fully explored. Here, we analyzed the clinical features 146 NFPA patients who underwent trans-sphenoidal surgery or craniotomy and examined the effects of immune tolerance in invasiveness of NFPA patients using fluorescence-activated cell sorting and immunohistochemical methods. We found patients with invasive NFPAs had more visual deficits and defective fields, higher tumor size, and lower white blood cell count compared with patients with noninvasive NFPAs. Additionally, compared with patients with noninvasive NFPAs, patients with invasive NFPAs had conspicuously lower CD3-CD56+ natural killer (NK) cells and significantly higher levels of CD3+CD8+CD28-T cells (CD8+ Tregs) and interleukin-10 (IL-10) in peripheral blood. Moreover, patients with invasive NFPAs had lower infiltrated CD56+ cells, less infiltrated CD28+ cells, and significantly greater IL-10 expression. These results demonstrated that low CD56+ cells infiltration and CD28+ cells infiltration, as well as high IL-10 expression in pituitary tumor tissues, were related with increased invasiveness of NFPAs. Levels of CD3-CD56+ NK cells, CD8+ Tregs and IL-10 in the peripheral blood could be feasible diagnostic markers for invasive NFPAs.

The roles of STAT6 in regulating B cell fate, activation, and function.

Signal transducers and activators of transcription (STATs) family of proteins are the key signal molecules in the JAK-STAT classical activation pathway of cell biology. STAT6, as a member of the STATs family, is principally activated by IL-4 and IL-13. In addition to Th2 cell differentiation, it plays a crucial role in promoting the development, differentiation, and class switching of B cells. STAT6 deficiency leads to impaired immune function, decreased glycolysis, and morphological changes in B cells, which will help develop various diseases. In this review, we will systematically summarize the major findings of how STAT6 regulates B cells to reveal the potential of STAT6 in treating human diseases.

Thresholds of Glycemia and the Outcomes of COVID-19 Complicated With Diabetes: A Retrospective Exploratory Study Using Continuous Glucose Monitoring.

OBJECTIVE: Although elevated glucose levels are reported to be associated with adverse outcomes of coronavirus disease 2019 (COVID-19), the optimal range of glucose in patients with COVID-19 and diabetes remains unknown. This study aimed to investigate the threshold of glycemia and its association with the outcomes of COVID-19. RESEARCH DESIGN AND METHODS: Glucose levels were assessed through intermittently scanned continuous glucose monitoring in 35 patients for an average period of 10.2 days. The percentages of time above range (TAR), time below range (TBR), time in range (TIR), and coefficient of variation (CV) were calculated. Composite adverse outcomes were defined as either the need for admission to the intensive care unit, need for mechanical ventilation, or morbidity with critical illness. RESULTS: TARs using thresholds from 160 to 200 mg/dL were significantly associated with composite adverse outcomes after adjustment of covariates. Both TBR (<70 mg/dL) and TIR (70-160 mg/dL), but not mean sensor glucose level, were significantly associated with composite adverse outcomes and prolonged hospitalization. The multivariate-adjusted odds ratios of the CV of sensor glucose across tertiles for composite adverse outcomes of COVID-19 were 1.00, 1.18, and 25.2, respectively. CONCLUSIONS: Patients with diabetes and COVID-19 have an increased risk of adverse outcomes with glucose levels >160 mg/dL and <70 mg/dL and a high CV. Therapies that improve these metrics of glycemic control may result in better prognoses for these patients.

HSP70, a Novel Regulatory Molecule in B Cell-Mediated Suppression of Autoimmune Diseases.

B cells have recently emerged as playing regulatory role in autoimmune diseases. We have previously demonstrated that human peripheral blood CD19+CD24hiCD27+ B cells have regulatory function both in healthy donors and in patients with autoimmune disease. However, the mechanism of this regulation is still not fully understood. In this study, microarrays were utilized to compare gene expression of CD19+CD24hiCD27+ B cells (regulatory B cells, Bregs) with CD19+CD24loCD27- B cells (non-Bregs) in human peripheral blood. We found that heat shock protein 70 (HSP70) expression was significantly upregulated in Bregs. In vitro studies explored that HSP70 inhibition impaired the regulatory function of peripheral blood Bregs. In mouse models of autoimmune disease, using HSP70-deficient mice or HSP70 inhibitors, Bregs suppressed effector cells and rescued disease-associated phenotypes that were dependent on HSP70. Mechanistically, Bregs secreted HSP70, directly suppressing effector cells, such as T effect cells. These findings reveal that HSP70 is a novel factor that modulates Breg function and suggest that enhancing Breg-mediated production of HSP70 could be a viable therapy for autoimmune disease.

Low Serum IL-17A in Pregnancy During Second Trimester Is Associated With an Increased Risk of Subclinical Hypothyroidism.

Problem: Interleukin-17A (IL-17A) has a role in sustaining normal pregnancy. IL-17A is also associated with thyroid autoimmunity during pregnancy. This study sought to investigate whether IL-17A is a risk factor for thyroid dysfunction during pregnancy in women negative for thyroid autoantibodies. Methods of Study: The study comprised 216 pregnant women with negative thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) during the second trimester who provided blood samples for serum IL-17A, thyroid autoantibodies and thyroid function tests. To further evaluate the ratio of CD4+IL-17A+ Th17 cells, we collected peripheral blood from 26 women with thyroid-stimulating hormone (TSH) levels ≤ 2.5 mIU/L and 26 pregnancy-week matched women with TSH levels >2.5 mIU/L, along with samples from 20 women with TSH levels ≤ 4 mIU/L and 20 pregnancy-week matched women with TSH levels >4 mIU/L. Results: The serum IL-17A levels and ratios of CD4+IL-17A+ cells were significantly lower in women with TSH > 2.5 mIU/L than in those with TSH ≤ 2.5 mIU/L (both P < 0.01). Similar lower differences were noted in women with TSH > 4 mIU/L than in those with TSH ≤ 4 mIU/L (both P < 0.01). Moreover, serum TSH correlated negatively with IL-17A levels (ß = -0.195, P = 0.004), but positively with the week of gestation (ß = 0.284, P < 0.001). Logistic regression indicated that a lower serum IL-17A level was a risk factor for TSH > 2.5 mIU/L [OR = 0.453 (0.298-0.689), P = 0.000] and TSH > 4.0 mIU/L [OR = 0.588 (0.385-0.899), P = 0.013]. Conclusion: A low serum IL-17A level during the second trimester is associated with an increased risk of TSH > 2.5 mIU/L and subclinical hypothyroidism.

Microarray profile of B cells from Graves' disease patients reveals biomarkers of proliferation.

B lymphocytes are the source of autoantibodies against the thyroid-stimulating hormone receptor (TSHR) in Graves' disease (GD). Characterization of autoimmune B-cell expression profiles might enable a better understanding of GD pathogenesis. To reveal this, the expression levels of long noncoding RNAs (lncRNAs) and mRNAs (genes) in purified B cells from patients with newly diagnosed GD and healthy individuals were compared using microarrays, which elucidated 604 differentially expressed lncRNAs (DE-lncRNAs) and 410 differentially expressed genes (DEGs). GO and pathway analyses revealed that the DEGs are mainly involved in immune response. A protein-protein interaction network presented experimentally validated interactions among the DEGs. Two independent algorithms were used to identify the DE-lncRNAs that regulate the DEGs. Functional annotation of the deregulated lncRNA-mRNA pairs identified 14 pairs with mRNAs involved in cell proliferation. The lncRNAs TCONS_00022357-XLOC_010919 and n335641 were predicted to regulate TCL1 family AKT coactivator A (TCL1A), and the lncRNA n337845 was predicted to regulate SH2 domain containing 1A (SH2D1A). TCL1A and SH2D1A are highly involved in B-cell proliferation. The differential expression of both genes was validated by qRT-PCR. In conclusion, lncRNA and mRNA expression profiles of B cells from patients with GD indicated that the lncRNA-mRNA pairs n335641-TCL1A, TCONS_00022357-XLOC_010919-TCL1A, and n337845-SH2D1A may participate in GD pathogenesis by modulating B-cell proliferation and survival. Therefore, the identified lncRNA and mRNA may represent novel biomarkers and therapeutic targets for GD.