Long-Term Outcomes of Thermal Ablation for Benign Thyroid Nodules: The Issue of RegrowthRead the full article
International Journal of Endocrinology publishes original research articles, review articles, and clinical studies that provide insights into the endocrine system and its associated diseases at a genomic, molecular, biochemical and cellular level.
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Classic and Novel Sex Hormone Binding Globulin Effects on the Cardiovascular System in Men
In men, 70% of circulating testosterone binds with high affinity to plasma sex hormone binding globulin (SHBG), which determines its bioavailability in their target cells. In recent years, a growing body of evidence has shown that circulating SHBG not only is a passive carrier for steroid hormones but also actively regulates testosterone signaling through putative plasma membrane receptors and by local expression of androgen-binding proteins apparently to reach local elevated testosterone concentrations in specific androgen target tissues. Circulating SHBG levels are influenced by metabolic and hormonal factors, and they are reduced in obesity and insulin resistance, suggesting that SHBG may have a broader clinical utility in assessing the risk for cardiovascular diseases. Importantly, plasma SHBG levels are strongly correlated with testosterone concentrations, and in men, low testosterone levels are associated with an adverse cardiometabolic profile. Although obesity and insulin resistance are associated with an increased incidence of cardiovascular disease, whether they lead to abnormal expression of circulating SHBG or its interaction with androgen signaling remains to be elucidated. SHBG is produced mainly in the liver, but it can also be expressed in several tissues including the brain, fat tissue, and myocardium. Expression of SHBG is controlled by peroxisome proliferator-activated receptor γ (PPARγ) and AMP-activated protein kinase (AMPK). AMPK/PPAR interaction is critical to regulate hepatocyte nuclear factor-4 (HNF4), a prerequisite for SHBG upregulation. In cardiomyocytes, testosterone activates AMPK and PPARs. Therefore, the description of local expression of cardiac SHBG and its circulating levels may shed new light to explain physiological and adverse cardiometabolic roles of androgens in different tissues. According to emerging clinical evidence, here, we will discuss the potential mechanisms with cardioprotective effects and SHBG levels to be used as an early metabolic and cardiovascular biomarker in men.
Identification of Potential lncRNAs and miRNAs as Diagnostic Biomarkers for Papillary Thyroid Carcinoma Based on Machine Learning
Background. Papillary thyroid carcinoma (PTC) accounts for most of the proportion of thyroid cancer (TC). The objective of this study was to identify diagnostic, differentially expressed long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), contributing to understanding the epigenetics mechanism of PTC. Methods. The data of lncRNA, miRNA, and mRNA were downloaded from the Cancer Genome Atlas (TCGA) dataset, followed by functional analysis of differentially expressed mRNAs. Optimal diagnostic lncRNA and miRNA biomarkers were identified via random forest. The regulatory network between optimal diagnostic lncRNA and mRNAs and optimal diagnostic miRNA and mRNAs was identified, followed by the construction of ceRNA network of lncRNA-mRNA-miRNA. Expression validation and diagnostic analysis of lncRNAs, miRNAs, and mRNAs were performed. Overexpression of ADD3-AS1 was performed in PTC-UC3 cell lines, and cell proliferation and invasion assay were used for investigating the role of ADD3-AS1 in PTC. Results. A total of 107 differentially expressed lncRNAs, 81 differentially expressed miRNAs, and 515 differentially expressed mRNAs were identified. 11 lncRNAs and 6 miRNAs were regarded as the optimal diagnostic biomarkers for PTC. The epigenetic modifications via the above diagnostic lncRNAs and miRNAs were identified, including MIR181A2HG-FOXP2-hsa-miR-146b-3p, BLACAT1/ST7-AS1-RPS6KA5-hsa-miR-34a-5p, LBX2-AS1/MIR100HG-CDHR3-hsa-miR-34a-5p, ADD3-AS1-PTPRE-hsa-miR-9-5p, ADD3-AS1-TGFBR1-hsa-miR-214-3p, LINC00506-MMRN1-hsa-miR-4709-3p, and LOC339059-STK32A-hsa-miR-199b-5p. In the functional analysis, MMRN1 and TGFBR1 were involved in cell adhesion and endothelial cell migration, respectively. Overexpression of ADD3-AS1 inhibited cell growth and invasion in PTC cell lines. Conclusion. The identified lncRNAs/miRNAs/mRNA were differentially expressed between normal and cancerous tissues. In addition, identified altered lncRNAs and miRNAs may be potential diagnostic biomarkers for PTC. Additionally, epigenetic modifications via the above lncRNAs and miRNAs may be involved in tumorigenesis of PTC.
Healthy Eating Index-2015 and Dietary Total Antioxidant Capacity as Predictors of Prediabetes: A Case-Control Study
Background. The overall dietary quality, as well as the dietary total antioxidant capacity (DTAC), deserves central attention in the management of borderline high glucose levels since nonpharmacological strategies are imperative in this regard. Thus, we aimed to investigate the association between prediabetes with dietary quality and DTAC. Methods. A case-control study was conducted on 49 patients with prediabetes and 98 controls. Demographics, anthropometric measures, and fasting blood glucose levels of all participants were obtained. Participants completed a validated 80-item food frequency questionnaire (FFQ). DTAC scores were generated using FFQ data, and Healthy Eating Index-2015 (HEI-2015) was used as a diet quality index. The lowest tertile of HEI-2015 and DTAC was considered as the reference category, and logistic regression was used to estimate the relationship between prediabetes with HEI-215 and DTAC. Results. Mean age and body mass index of participants were 47.42 ± 15.98 years and 27.90 ± 4.96 kg/m2. Patients with prediabetes had lower DTAC scores when compared to controls (11.86 ± 5.77 and 17.81 ± 12.08, = 0.01). There was a significant inverse association between the highest tertile of the DTAC score when compared with the lowest tertile in crude (OR = 0.11; 95% CI: 0.03–0.43), age-adjusted (OR = 0.13; 95% CI: 0.03–0.48), and fully adjusted (OR = 0.09; 95% CI: 0.02–0.53) models. In contrast, there was no difference between HEI-2015 in patients with prediabetes when compared to controls (74.41 ± 8.91 and 74.41 ± 9.35, respectively; = 0.85). Correspondingly, no difference was observed between the highest tertile of the HEI-2015 score when compared with the lowest tertile in crude (OR = 1.23; 95% CI: 0.53–2.86), age-adjusted (OR = 1.17; 95% CI: 0.48–2.82), and fully adjusted (OR = 1.53; 95% CI: 0.56–4.16) models. Conclusion. This study demonstrates a clear association between prediabetes with less DTAC, but not with HEI-2015.
Identification of a Ferroptosis-Related Signature Associated with Prognosis and Immune Infiltration in Adrenocortical Carcinoma
Adrenocortical carcinoma (ACC) is a rare malignant tumor with poor prognosis. Ferroptosis, a new form of cell death, differs from other forms of cell death and plays a vital role in tumor progress. Our study aimed to establish a ferroptosis-related signature with prognostic value in ACC. RNA-seq data and corresponding clinical characteristics for ACC were downloaded from TCGA and GEO databases. Genes included in ferroptosis risk signature were assessed by univariable and multivariable Cox regression analysis as well as lasso regression analysis. The prognostic value of the ferroptosis risk signature was assessed using K-M and ROC curves. Furthermore, we performed GSEA to discover the enriched gene sets in high-risk group. Additionally, TIMER website was applied to detect a possible connection between the signature and immune cells infiltration. ssGSEA was performed to evaluate scores of immune cells and immune-related pathways in two groups. A ferroptosis signature comprised of six genes (SLC7A11, TP53, HELLS, ACSL4, PCBP2, and HMGB1) was constructed to predict prognosis and reflect the immune infiltration in ACC. Patients in high-risk group were inclined to have worse prognosis. The ferroptosis model performed well in predicting prognosis and could be served as an independent indicator in ACC. GSEA revealed that gene sets correlated with biological processes including cell cycle, DNA replication, base excision repair, and P53 signaling pathway were highly enriched in high-risk group. In addition, we discovered that the expressional levels of hub genes were linked to six immune cells’ infiltration in ACC tumor. ssGSEA revealed that contents of most immune cells significantly decreased in the high-risk group. In conclusion, the novel ferroptosis risk signature could be useful in predicting prognosis and reflecting immune infiltration in ACC. It also brings us new insights into the possible value of targeting ferroptosis during the therapy of ACC.
PERK-Dependent Activation of the JAK2/STAT3 Pathway Contributes to High Glucose-Induced Extracellular Matrix Deposition in Renal Tubular Epithelial Cells
Background. Although the deposition of extracellular matrix (ECM) is critical leading to tubular damage in diabetic kidney disease (DKD), the mechanism still remains unclear. The purpose of this study was to demonstrate a role for protein kinase R-like endoplasmic reticulum kinase (PERK) (a protein located in the endoplasmic reticulum membrane) in this pathologic process. Methods. NRK-52E cells were grown in the media containing different concentrations of glucose or thapsigargin for different durations. Cells were subsequently incubated with or without AG490, a selective inhibitor of Janus kinase 2 (JAK2) or GSK2606414 (a selective PERK inhibitor). We evaluated the production of TGF-β1, fibronectin, and collagen I proteins by ELISA. The levels of 78 kD-glucose-regulated protein (GRP78) and PERK, as well as the phosphorylation statues of PERK and JAK2/signal transducer and activator of transcription (STAT3), were determined by western blotting analysis. Results. We showed that the increased phosphorylation of JAK2 and STAT3 was accompanied by overexpression of TGF-β1 and ECM deposition in high glucose medium. Disruption of the JAK2/STAT3 pathway with AG490 significantly prevents the high glucose-induced increase in TGF-β1, fibronectin, and collagen I. High glucose induced the overproduction of GRP78 and phosphorylation of PERK, which indicated that endoplasmic reticulum stress (ERS) was triggered in NRK-52E cells cultured under high glucose condition. Inhibition of PERK phosphorylation with GSK2606414, however, blocked the effect of JAK2/STAT3 on the production of TGF-β1 and ECM components in NRK-52E cells. Conclusion. Our data indicated that the ECM accumulation induced by high glucose arouse via the PERK-dependent JAK2/STAT3-signaling pathway in renal tubular epithelial cells.
Association between Metabolic Syndrome and Osteoporosis: A Systematic Review and Meta-Analysis
Background. Previous studies have reached mixed conclusions regarding the association between metabolic syndrome (MS) and osteoporosis. We aimed to perform a meta-analysis based on published studies that explored the association between osteoporosis and MS. Methods. To identify related literature, a systematic search of PubMed, Cochrane Library, and EMBASE databases from inception to June 2020 was performed. Original studies that reported the risk estimates of osteoporosis morbidity for two or three categories of bone mineral density (BMD) in patients with MS were selected. Two independent investigators screened and selected the articles. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models. Results. Of 2632 identified studies, nine cross-sectional studies with 14 datasets were eligible for our meta-analysis. In seven studies (10 datasets), the summarized ORs of osteoporosis for MS were 0.72 (95% CI: 0.52–0.99). Subgroup analyses by gender showed that significant inverse associations were observed only in men (OR = 0.72, 95% CI: 0.55–0.96) but not in women (OR = 0.70, 95% CI: 0.41–1.22). The definition of MS, the source of the study population, and the adjustment of covariates affected the estimates. In two studies (4 datasets), there was no evidence for an association between MS and decreased BMD. Conclusions. Our findings demonstrated that MS was significantly associated with a lower osteoporosis risk. There might be gender differences in the association between MS and osteoporosis. In addition, the association was likely to relate to the definition of MS, the source of the study population, and the adjustment of covariates.