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Receptors, Transmitters and Signaling Pathways in Thyroid Disorders and Diabetes

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 52072

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Special Issue Editors

Prof. Dr. Andrzej Lewinski

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Guest Editor

Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Lodz, Poland
Interests: growth processes of the thyroid gland; preoperative diagnostics of thyroid cancer (fine-needle aspiration biopsy); genetics of differentiated thyroid cancers; molecular background of subacute thyroiditis; role of dendritic cells in the thyroid

Dr. Magdalena Stasiak

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Guest Editor

Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
Interests: molecular background of endocrine diseases; adult and pediatric endocrinology; especially genetic background of thyroiditis

Special Issue Information

Dear Colleagues,

The incidence of thyroid disease and diabetes has been rapidly increasing in recent decades. The cause of this phenomenon is not clearly established, and many aspects of the pathogenesis of these diseases remain unexplained. The need for an accurate explanation of the molecular basis of diseases such as thyroid cancer, autoimmune thyroid diseases, subacute thyroiditis, and type 1 diabetes mellitus is particularly significant. The abnormal structure or function of receptors, and disturbances in signaling pathways and transmitters involved in pathogenesis of the above-mentioned diseases, is of great importance. Knowledge of these issues can be exceptionally useful in the management of thyroid diseases and diabetes, because it can increase the accuracy of diagnosis and may be used to select patients at risk of the disease or at risk of its unfavorable, more severe course. Complex molecular studies provide important results that enable one to better understand the pathogenesis of thyroid diseases and diabetes and allow for the wider use of individualized potential target molecules to develop novel diagnostic methods and new treatment strategies. Target therapies have appeared to be beneficial in the management of several diseases, mainly in cancer and autoimmunological disorders. The aim of this Special Issue is to provide new findings regarding the molecular background of thyroid disorders and diabetes, with special regard to receptors, transmitters, and signaling pathways, which are of key importance in pathogenesis and could improve the diagnosis and/or treatment options.

Prof. Dr. Andrzej Lewinski
Dr. Magdalena Stasiak
Guest Editors

Manuscript Submission Information

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Keywords

Thyroid disorders
Diabetes mellitus type 1
Pathogenesis
Receptors
Transmitters
Signaling pathways
Molucular genetics
HLA
Diagnostic markers
Prognostic markers.

Published Papers (6 papers)

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Research

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13 pages, 5776 KiB

Open AccessArticle

The Precursor for Nerve Growth Factor (proNGF) in Thyroid Cancer Lymph Node Metastases: Correlation with Primary Tumour and Pathological Variables

by Christopher W. Rowe, Tony Dill, Sam Faulkner, Craig Gedye, Jonathan W. Paul, Jorge M. Tolosa, Mark Jones, Simon King, Roger Smith and Hubert Hondermarck

Int. J. Mol. Sci. 2019, 20(23), 5924; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235924 - 25 Nov 2019

Cited by 4 | Viewed by 2608

Abstract

Metastases in thyroid cancer are associated with aggressive disease and increased patient morbidity, but the factors driving metastatic progression are unclear. The precursor for nerve growth factor (proNGF) is increased in primary thyroid cancers, but its expression or significance in metastases is not known. In this study, we analysed the expression of proNGF in a retrospective cohort of thyroid cancer lymph node metastases (n = 56), linked with corresponding primary tumours, by automated immunohistochemistry and digital quantification. Potential associations of proNGF immunostaining with clinical and pathological parameters were investigated. ProNGF staining intensity (defined by the median h-score) was significantly higher in lymph node metastases (h-score 94, interquartile range (IQR) 50–147) than in corresponding primary tumours (57, IQR 42–84) (p = 0.002). There was a correlation between proNGF expression in primary tumours and corresponding metastases, where there was a 0.68 (95% CI 0 to 1.2) increase in metastatic tumour h-score for each unit increase in the primary tumour h-score. However, larger tumours (both primary and metastatic) had lower proNGF expression. In a multivariate model, proNGF expression in nodal metastases was negatively correlated with lateral neck disease and being male. In conclusion, ProNGF is expressed in locoregional metastases of thyroid cancer and is higher in lymph node metastases than in primary tumours, but is not associated with high-risk clinical features. Full article

(This article belongs to the Special Issue Receptors, Transmitters and Signaling Pathways in Thyroid Disorders and Diabetes)

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19 pages, 8524 KiB

Open AccessArticle

Cardiac Cx43 and ECM Responses to Altered Thyroid Status Are Blunted in Spontaneously Hypertensive versus Normotensive Rats

by Matus Sykora, Barbara Szeiffova Bacova, Tamara Egan Benova, Miroslav Barancik, Jitka Zurmanova, Hana Rauchova, Peter Weismann, Stanislav Pavelka, Lin Hai Kurahara, Jan Slezak, Tomas Soukup and Narcis Tribulova

Int. J. Mol. Sci. 2019, 20(15), 3758; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20153758 - 01 Aug 2019

Cited by 9 | Viewed by 3241

Abstract

Heart function and its susceptibility to arrhythmias are modulated by thyroid hormones (THs) but the responsiveness of hypertensive individuals to thyroid dysfunction is elusive. We aimed to explore the effect of altered thyroid status on crucial factors affecting synchronized heart function, i.e., connexin-43 (Cx43) and extracellular matrix proteins (ECM), in spontaneously hypertensive rats (SHRs) compared to normotensive Wistar Kyoto rats (WKRs). Basal levels of circulating THs were similar in both strains. Hyperthyroid state (HT) was induced by injection of T3 (0.15 mg/kg b.w. for eight weeks) and hypothyroid state (HY) by the administration of methimazol (0.05% for eight weeks). The possible benefit of omega-3 polyunsaturated fatty acids (Omacor, 200 mg/kg for eight weeks) intake was examined as well. Reduced levels of Cx43 in SHRs were unaffected by alterations in THs, unlike WKRs, in which levels of Cx43 and its phosphorylated form at serine368 were decreased in the HT state and increased in the HY state. This specific Cx43 phosphorylation, attributed to enhanced protein kinase C-epsilon signaling, was also increased in HY SHRs. Altered thyroid status did not show significant differences in markers of ECM or collagen deposition in SHRs. WKRs exhibited a decrease in levels of profibrotic transforming growth factor β1 and SMAD2/3 in HT and an increase in HY, along with enhanced interstitial collagen. Short-term intake of omega-3 polyunsaturated fatty acids did not affect any targeted proteins significantly. Key findings suggest that myocardial Cx43 and ECM responses to altered thyroid status are blunted in SHRs compared to WKRs. However, enhanced phosphorylation of Cx43 at serine368 in hypothyroid SHRs might be associated with preservation of intercellular coupling and alleviation of the propensity of the heart to malignant arrhythmias. Full article

(This article belongs to the Special Issue Receptors, Transmitters and Signaling Pathways in Thyroid Disorders and Diabetes)

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14 pages, 1182 KiB

Open AccessArticle

Differences in Mutational Profile between Follicular Thyroid Carcinoma and Follicular Thyroid Adenoma Identified Using Next Generation Sequencing

by Martyna Borowczyk, Ewelina Szczepanek-Parulska, Szymon Dębicki, Bartłomiej Budny, Frederik A. Verburg, Dorota Filipowicz, Barbara Więckowska, Małgorzata Janicka-Jedyńska, Lidia Gil, Katarzyna Ziemnicka and Marek Ruchała

Int. J. Mol. Sci. 2019, 20(13), 3126; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133126 - 26 Jun 2019

Cited by 26 | Viewed by 3723

Abstract

We aimed to identify differences in mutational status between follicular thyroid adenoma (FTA) and follicular thyroid cancer (FTC). The study included 35 patients with FTA and 35 with FTC. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) samples from thyroidectomy. Next-generation sequencing (NGS) was performed with the 50-gene Ion AmpliSeq Cancer Hotspot Panel v2. Potentially pathogenic mutations were found in 14 (40%) FTA and 24 (69%) FTC patients (OR (95%CI) = 3.27 (1.22−8.75)). The number of mutations was higher in patients with FTC than FTA (p-value = 0.03). SMAD4 and STK11 mutations were present only in patients with FTA, while defects in FBXW7, JAK3, KIT, NRAS, PIK3CA, SMARCB1, and TP53 were detected exclusively in FTC patients. TP53 mutations increased the risk of FTC; OR (95%CI) = 29.24 (1.64–522.00); p-value = 0.001. FLT3-positivity was higher in FTC than in the FTA group (51.4% vs. 28.6%; p-value = 0.051). The presence of FLT3 and TP53 with no RET mutations increased FTC detectability by 17.1%, whereas the absence of FLT3 and TP53 with a presence of RET mutations increased FTA detectability by 5.7%. TP53 and FLT3 are candidate markers for detecting malignancy in follicular lesions. The best model to predict FTA and FTC may consist of FLT3, TP53, and RET mutations considered together. Full article

(This article belongs to the Special Issue Receptors, Transmitters and Signaling Pathways in Thyroid Disorders and Diabetes)

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9 pages, 451 KiB

Open AccessArticle

The Risk of Recurrence of Subacute Thyroiditis Is HLA-Dependent

by Magdalena Stasiak, Bogusław Tymoniuk, Bartłomiej Stasiak and Andrzej Lewiński

Int. J. Mol. Sci. 2019, 20(5), 1089; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051089 - 03 Mar 2019

Cited by 50 | Viewed by 4243

Abstract

The frequency of recurrence of subacute thyroiditis (SAT) is rather high, reaching 20–30%. The reason for SAT relapse is still unknown. Recently, we have demonstrated the association between SAT and the presence of HLA-B*18:01, DRB1*01, and C*04:01, apart from the previously known HLA-B*35. The aim of the present study was to evaluate the correlation between SAT-associated HLA haplotypes and the risk of SAT recurrence. HLA-A, -B, -C, -DQB1 and -DRB1 were genotyped using a next-generation sequencing method in 49 SAT patients. The patients were divided into the following HLA groups: 1. HLA-B*35 and/or HLA-C*04, but without any other of the analyzed antigens; 2. HLA-DRB1*01, regardless of the co-presence of HLA-B*35 or -C*04:01, but without HLA-B*18:01; 3. HLA-B18 only, without any other antigen; 4. HLA-B*18:01 plus -B*35, regardless of the presence of any other analyzed antigens. The recurrence rate was compared between the groups. The recurrence rate was significantly increased in patients with HLA-B*18:01 plus HLA-B*35. In conclusion, the risk of SAT recurrence was HLA-dependent and the determining factor was the co-presence of HLA-B*18:01 and -B*35. In such high-risk patients, the steroid treatment regimen should be intensified with a slower dose reduction. Full article

(This article belongs to the Special Issue Receptors, Transmitters and Signaling Pathways in Thyroid Disorders and Diabetes)

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21 pages, 8569 KiB

Open AccessArticle

Differences of the Structure of Immune Regulatory Cell Populations between Cellular Material from Sonographically Detected Focal Thyroid Lesions and Peripheral Blood in Humans

by Mariusz Stasiołek, Przemysław W. Śliwka, Magdalena Stasiak, Kinga Krawczyk-Rusiecka, Elżbieta Skowrońska-Jóźwiak, Zbigniew Adamczewski and Andrzej Lewiński

Int. J. Mol. Sci. 2019, 20(4), 918; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040918 - 20 Feb 2019

Cited by 1 | Viewed by 2625

Abstract

Focal thyroid lesions are common ultrasound findings with the estimated prevalence up to 67% of the population. They form characteristically enveloped regions with individual encapsulated microenvironment that may involve the specific distribution of immune system compounds—especially antigen presenting cells (APC). We analyzed and compared the most potent APC—plasmacytoid and conventional dendritic cells (DCs) subpopulations and three monocyte subpopulations as well as other immune cells—in peripheral blood and local blood of thyroid gland obtained parallelly in patients with focal thyroid lesions using flow cytometry. The analysis revealed significant differences in the distribution of main subsets of assessed cells between peripheral blood and biopsy material. The results support the existence of local, organ-specific immune reaction control networks within thyroid nodules. Full article

(This article belongs to the Special Issue Receptors, Transmitters and Signaling Pathways in Thyroid Disorders and Diabetes)

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Review

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15 pages, 1092 KiB

Open AccessReview

Effects of Magnesium Deficiency on Mechanisms of Insulin Resistance in Type 2 Diabetes: Focusing on the Processes of Insulin Secretion and Signaling

by Krasimir Kostov

Int. J. Mol. Sci. 2019, 20(6), 1351; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061351 - 18 Mar 2019

Cited by 127 | Viewed by 35049

Abstract

Magnesium (Mg²⁺) is an essential mineral for human health and plays an important role in the regulation of glucose homeostasis and insulin actions. Despite the widespread clinical evidences for the association of Mg²⁺ deficiency (MgD) and type 2 diabetes mellitus (T2D), molecular mechanisms by which Mg²⁺ contributes to insulin resistance (IR) are still under discussion. Mg²⁺ regulates electrical activity and insulin secretion in pancreatic beta-cells. Intracellular Mg²⁺ concentrations are critical for the phosphorylation of the insulin receptor and other downstream signal kinases of the target cells. Low Mg²⁺ levels result in a defective tyrosine kinase activity, post-receptor impairment in insulin action, altered cellular glucose transport, and decreased cellular glucose utilization, which promotes peripheral IR in T2D. MgD triggers chronic systemic inflammation that also potentiates IR. People with T2D may end up in a vicious circle in which MgD increases IR and IR causes MgD, that requires periodic monitoring of serum Mg²⁺ levels. Full article

(This article belongs to the Special Issue Receptors, Transmitters and Signaling Pathways in Thyroid Disorders and Diabetes)

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