scholarly journals Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5582
Author(s):  
Ariadni Spyroglou ◽  
George P. Piaditis ◽  
Gregory Kaltsas ◽  
Krystallenia I. Alexandraki
Keyword(s):  
Primary Aldosteronism ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Treatment Strategies ◽  
Micro Rna ◽  
The Past ◽  
Mutational Status ◽  
Endocrine Hypertension ◽  
Protein Receptors ◽  
Aldosterone Production

Introduction: Primary aldosteronism (PA) is the most common cause of endocrine hypertension, mainly caused by aldosterone-producing adenomas or hyperplasia; understanding its pathophysiological background is important in order to provide ameliorative treatment strategies. Over the past several years, significant progress has been documented in this field, in particular in the clarification of the genetic and molecular mechanisms responsible for the pathogenesis of aldosterone-producing adenomas (APAs). Methods: Systematic searches of the PubMed and Cochrane databases were performed for all human studies applying transcriptomic, epigenetic or metabolomic analyses to PA subjects. Studies involving serial analysis of gene expression and microarray, epigenetic studies with methylome analyses and micro-RNA expression profiles, and metabolomic studies focused on improving understanding of the regulation of autonomous aldosterone production in PA were all included. Results: In this review we summarize the main findings in this area and analyze the interplay between primary aldosteronism and several signaling pathways with differential regulation of the RNA and protein expression of several factors involved in, among others, steroidogenesis, calcium signaling, and nuclear, membrane and G-coupled protein receptors. Distinct transcriptomic and metabolomic patterns are also presented herein, depending on the mutational status of APAs. In particular, two partially opposite transcriptional and steroidogenic profiles appear to distinguish APAs carrying a KCNJ5 mutation from all other APAs, which carry different mutations. Conclusions: These findings can substantially contribute to the development of personalized treatment in patients with PA.

scholarly journals TRANSCRIPTOMICS RESEARCH IN THE CLINICAL AND EXPERIMENTAL INVESTIGATION OF PATHOGENETIC MECHANISMS OF ALIMENTARY OBESITY

2018 ◽  
Vol 73 (3) ◽  
pp. 172-180
Author(s):  
I. V. Gmoshinski ◽  
S. A. Apryatin ◽  
Kh. Kh. Sharafetdinov ◽  
D. B. Nikitjuk ◽  
V. A. Tutelyan
Keyword(s):  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Micro Rna ◽  
New Drugs ◽  
Rt Pcr ◽  
Clinical Predictors ◽  
In Vivo Models ◽  
Transcriptomic Studies

The review considers the significant role of changes in the transcriptome of organs and tissues for studying the molecular mechanisms of obesity development. Modern methods of transcriptomics including technologies for quantitative RT-PCR and DNA microarrays provided a new approach to the search for sensitive molecular markers as obesity predictors Differential gene expression profiles are mostly organo- and tissue-specific for adipose tissue, liver, brain, and other organs and tissues; can significantly differ in animal in vivo models with genetically determined and dietary induced obesity. At the same time, coordinated regulation is registered in the organs and tissues of expression of extensive groups of genes associated with lipid, cholesterol, and carbohydrate metabolism, the synthesis and circulation of neurotransmitters of dopamine and serotonin, peptide hormones, cytokines which induce systemic inflammation. For systemic regulation mechanisms causing a concerted change in the transcription of tens and hundreds of genes in obesity, the adipokines effects should be pointed out, primarily leptin, as well as pro-inflammatory cytokines, the micro-RNA (miRs) system and central effects developing at NPY/AgRP+ and POMC/CART+ neurons of the arcuate nucleus of the hypothalamus. Results of transcriptomic studies can be used in preclinical trials of new drugs and methods of dietary correction of obesity in animal’s in vivo models, as well as in the search for clinical predictors and markers of metabolic abnormalities in patients with obesity receiving personalized therapy. The main problem of transcriptomic studies in in vivo models is incomplete consistency between the data obtained with full-transcriptional profiling and the results of quantitative RT-PCR expression of individual candidate genes, as well as metabolic and proteomic studies. The identification and elimination of the causes of such discrepancies can be one of the promising areas for improving transcriptomical research.

scholarly journals A Transcriptomic Approach Reveals Selective Ribosomal Remodelling in the Tumour Versus the Stromal Compartment of Metastatic Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4188
Author(s):  
Elena Lastraioli ◽  
Federico Alessandro Ruffinatti ◽  
Francesco Di Costanzo ◽  
Cesare Sala ◽  
Luca Munaron ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Ribosomal Proteins ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene List ◽  
Treatment Strategies ◽  
Gene Set Enrichment Analysis ◽  
Stromal Compartment ◽  
Tissue Samples ◽  
Mitochondrial Ribosome

Because of its high incidence and poor prognosis, colorectal cancer (CRC) represents an important health issue in several countries. As with other carcinomas, the so-called tumour microenvironment (TME) has been shown to play key roles in CRC progression and related therapeutical outcomes, even though a deeper understanding of the underlying molecular mechanisms is needed to devise new treatment strategies. For some years now, omics technologies and consolidated bioinformatics pipelines have allowed scientists to access large amounts of biologically relevant information, even when starting from small tissue samples; thus, in order to shed new light upon the role of the TME in CRC, we compared the gene expression profiles of 6 independent tumour tissues (all progressed towards metastatic disease) to the expression profile of the surrounding stromata. To do this, paraffin-embedded whole tissues were first microdissected to obtain samples enriched with tumour and stromal cells, respectively. Afterwards, RNA was extracted and analysed using a microarray-based approach. A thorough bioinformatics analysis was then carried out to identify transcripts differentially expressed between the two groups and possibly enriched functional terms. Overall, 193 genes were found to be significantly downregulated in tumours compared to the paired stromata. The functional analysis of the downregulated gene list revealed three principal macro areas of interest: the extracellular matrix, cell migration, and angiogenesis. Conversely, among the upregulated genes, the main alterations detected by the functional annotation were related to the ribosomal proteins (rProteins) of both the large (60S) and small (40S) subunits of the cytosolic ribosomes. Subsequent gene set enrichment analysis (GSEA) confirmed the massive overexpression of most cytosolic—but not mitochondrial—ribosome rProteins.

scholarly journals Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways

2018 ◽  
Vol 11 (557) ◽  
pp. eaar5680 ◽  
Author(s):  
Jimmy Van den Eynden ◽  
Ganesh Umapathy ◽  
Arghavan Ashouri ◽  
Diana Cervantes-Madrid ◽  
Joanna Szydzik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Expression Profiles ◽  
Neuroblastoma Cell ◽  
Treatment Strategies ◽  
Tyrosine Kinase Receptor ◽  
Anaplastic Lymphoma ◽  
Major Interest

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is a clinical target of major interest in cancer. Mutations and rearrangements inALKtrigger the activation of the encoded receptor and its downstream signaling pathways.ALKmutations have been identified in both familial and sporadic neuroblastoma cases as well as in 30 to 40% of relapses, which makes ALK a bona fide target in neuroblastoma therapy. Tyrosine kinase inhibitors (TKIs) that target ALK are currently in clinical use for the treatment of patients with ALK-positive non–small cell lung cancer. However, monotherapy with the ALK inhibitor crizotinib has been less encouraging in neuroblastoma patients withALKalterations, raising the question of whether combinatorial therapy would be more effective. In this study, we established both phosphoproteomic and gene expression profiles of ALK activity in neuroblastoma cells exposed to first- and third-generation ALK TKIs, to identify the underlying molecular mechanisms and identify relevant biomarkers, signaling networks, and new therapeutic targets. This analysis has unveiled various important leads for novel combinatorial treatment strategies for patients with neuroblastoma and an increased understanding of ALK signaling involved in this disease.

scholarly journals Gene expression profiles in aldosterone-producing adenomas and adjacent adrenal glands

2011 ◽  
Vol 164 (4) ◽  
pp. 613-619 ◽  
Author(s):  
Tao Wang ◽  
Fumitoshi Satoh ◽  
Ryo Morimoto ◽  
Yasuhiro Nakamura ◽  
Hironobu Sasano ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Cytochrome B5 ◽  
Gene List ◽  
Gene Expression Profiles ◽  
Transcript Level ◽  
Calmodulin Binding ◽  
Aldosterone Production ◽  
Transcript Profiles

BackgroundPrimary aldosteronism (PA) is the most common form of endocrine hypertension affecting ∼8–10% of hypertensive subjects. Aldosterone production in PA occurs under low-renin conditions, and the mechanisms that maintain the production of aldosterone in PA remain unknown.ObjectiveThis study was designed to compare the transcript profiles between aldosterone-producing adenoma (APA) and their adjacent adrenal gland (AAG) from the same adrenal.MethodsTotal RNA was extracted from ten APA and ten AAG; and subsequently analyzed by microarray and real-time quantitative RT-PCR (qPCR). The microarray data were paired for each APA–AAG, and analyzed by GeneSpring GX 11 with paired t-test and fold change calculations for each transcript. Changes identified by microarray analysis were confirmed by qPCR.ResultsMicroarray analysis indicated that 14 genes had significantly up-regulated expression in APA compared to AAG. Among the elevated genes were aldosterone synthase (CYP11B2) as well as novel transcription factors, calmodulin-binding proteins, and other genes that have not been previously studied in APA. Selective analysis of 11 steroidogenic enzymes using microarray demonstrated that only CYP11B2 showed a significantly higher transcript level in APA compared to AAG (P<0.001). In contrast, AKR1C3 (17β-hydroxysteroid dehydrogenase type 5), CYP17 (17α-hydroxylase/17,20 lyase), and CYB5 (cytochrome b5) showed significantly lower transcript level in APA (P<0.05).ConclusionThe transcriptome analysis of APA compared with AAG showed several novel genes that are associated with APA phenotype. This gene list provides new candidates for the elucidation of the molecular mechanisms leading to PA.

scholarly journals SAT-543 Human Hair Aldosterone Measurements for Evaluation of Primary Aldosteronism

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Andrew Paul Demidowich ◽  
Jancarlos Camacho ◽  
Maria de la Luz Sierra ◽  
Elena Belyavskaya ◽  
Charalampos Lysikatos ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Human Hair ◽  
Serum Cortisol ◽  
Diagnostic Techniques ◽  
Endocrine Hypertension ◽  
Serum Aldosterone ◽  
Hair Samples ◽  
Aldosterone Production ◽  
Student’S T ◽  
Aldosterone To Renin Ratio

Abstract Background: Primary Aldosteronism (PA) is the most common cause of endocrine hypertension in US. Diagnostic techniques such as a 24 hour urine collection or saline suppression test (SST) can be laborious for both patients and staff. Our group previously showed that human hair cortisol measurements correlated with urine and serum cortisol levels in patients with endogenous cortisol excess. In this study, we explored whether human hair aldosterone correlated with other measures of aldosterone production. Methods: 41 adult subjects were evaluated at the NIH Clinical Center for adrenal disorders. A pencil-width of hair near the occiput was removed, and the 1cm segment closest to the scalp was analyzed by enzyme immunoassay for aldosterone, reported as pg aldosterone/mg dry hair. Not all subjects underwent complete workup for PA. Data were transformed as necessary to maintain assumptions of normality. Student’s t-test and Pearson correlations were used for statistical analysis. Results: Of the evaluated subjects, 18 were diagnosed with PA, 22 subjects did not have PA, and 1 subject was indeterminate. The mean hair weight was 33.0±13.7mg. For hair samples weighing greater than 10mg, hair weight was not correlated with hair aldosterone concentration (p=0.40). There was no difference in measured hair aldosterone between the subjects with and without PA (2.01±1.09 vs. 2.52±2.45 pg/mg; p=0.82). Among all subjects, hair aldosterone did not correlate with serum aldosterone (p=0.92), aldosterone-to-renin ratio (ARR; p=0.94), 24 hour urine aldosterone (Ualdo; p=0.85), or the serum aldosterone at the 4 hour time point of a SST (4hrAldo; p=0.98). Serum aldosterone, ARR, Ualdo, and 4hrAldo all correlated highly amongst each other (all p’s&lt;0.001). Conclusions: Hair aldosterone levels do not correlate with other markers of PA. Further work is needed to understand whether optimization of study conditions could improve the usefulness of hair aldosterone measurements in the evaluation of PA.

scholarly journals Molecular mechanisms in primary aldosteronism

2019 ◽  
Vol 242 (3) ◽  
pp. R67-R79 ◽  
Author(s):  
Kelly De Sousa ◽  
Alaa B Abdellatif ◽  
Rami M El Zein ◽  
Maria-Christina Zennaro
Keyword(s):  
Arterial Hypertension ◽  
Adrenal Cortex ◽  
Primary Aldosteronism ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Type I ◽  
Adrenal Hyperplasia ◽  
New Genes ◽  
Aldosterone Production ◽  
Bilateral Adrenal Hyperplasia

Primary aldosteronism (PA) is the most common form and an under-diagnosed cause of secondary arterial hypertension, accounting for up to 10% of hypertensive cases and associated to increased cardiovascular risk. PA is caused by autonomous overproduction of aldosterone by the adrenal cortex. It is mainly caused by a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Excess aldosterone leads to arterial hypertension with suppressed renin, frequently associated to hypokalemia. Mutations in genes coding for ion channels and ATPases have been identified in APA, explaining the pathophysiology of increased aldosterone production. Different inherited genetic abnormalities led to the distinction of four forms of familial hyperaldosteronism (type I to IV) and other genetic defects very likely remain to be identified. Somatic mutations are identified in APA, but also in aldosterone-producing cell clusters (APCCs) in normal adrenals, in image-negative unilateral hyperplasia, in transitional lesions and in APCC from adrenals with bilateral adrenal hyperplasia (BAH). Whether these structures are precursors of APA or whether somatic mutations occur in a proliferative adrenal cortex, is still a matter of debate. This review will summarize our knowledge on the molecular mechanisms responsible for PA and the recent discovery of new genes related to early-onset and familial forms of the disease. We will also address new issues concerning genomic and proteomic changes in adrenals with APA and discuss adrenal pathophysiology in relation to aldosterone-producing structures in the adrenal cortex.

scholarly journals The role of micro-RNA in the regulation of signal pathways in gliomas

2017 ◽  
Vol 63 (6) ◽  
pp. 481-498
Author(s):  
O.I. Kit ◽  
D.I. Vodolazhsky ◽  
E.E. Rostorguev ◽  
D.H. Porksheyan ◽  
S.B. Panina
Keyword(s):  
Target Genes ◽  
Expression Profiles ◽  
Treatment Strategies ◽  
Micro Rna ◽  
Present Review ◽  
Signal Pathways ◽  
Aberrant Expression ◽  
Micro Rnas ◽  
Non Coding Rnas

Gliomas are invasive brain tumors with high rates of recurrence and mortality. Glioblastoma multiforme (GBM) is the most deadly form of glioma with nearly 100% rate of recurrence and unfavorable prognosis in patients. Micro-RNAs (miR) are the class of wide-spread short non-coding RNAs that inhibit translation via binding to the mRNA of target genes. The aim of the present review is to analyze recent studies and experimental results concerning aberrant expression profiles of miR, which target components of the signaling pathways Hedgehog, Notch, Wnt, EGFR, TGFb, HIF1a in glioma/glioblastoma. Particularly, the interactions of miR with targets of 2-hydroxyglutarate (the product of mutant isocytrate dehydrogenase, R132H IDH1, which is specific for the glioma pathogenesis) have been considered in the present review. Detecting specific miRNAs in tissue and serum may serve as a diagnostic and prognostic tool for glioma, as well as for predicting treatment response of an individual patient, and potentially serving as a mechanism for creating personalized treatment strategies

scholarly journals Approach to the Patient with Primary Aldosteronism: Utility and Limitations of Adrenal Vein Sampling

2020 ◽  
Author(s):  
Adina F Turcu ◽  
Richard Auchus
Keyword(s):  
Primary Aldosteronism ◽  
Mineralocorticoid Receptor ◽  
Interventional Procedures ◽  
Adrenal Vein ◽  
Mineralocorticoid Receptor Antagonists ◽  
Adrenal Vein Sampling ◽  
Hypertensive Patients ◽  
Case Identification ◽  
The Past ◽  
Aldosterone Production

Abstract Several studies over the past 3 decades document a higher prevalence of primary aldosteronism (PA) among hypertensive patients than generally presumed. PA exists as a spectrum from mild to severe aldosterone excess. Although a variety of PA subtypes exist, the two most common are aldosterone-producing adenomas (APAs) and bilateral hyperaldosteronism (BHA). The distinction is important, because APA – and other subtypes with aldosterone production mostly from one adrenal – can be cured surgically, and BHA should be treated medically with mineralocorticoid-receptor antagonists (MRAs). The major shortcomings in the tailored management of patients with possible PA are the low rates of screening for case identification and the expensive and technically challenging imaging and interventional procedures required to distinguish APA from BHA, especially adrenal vein sampling (AVS). When AVS identifies an APA and allows the patient to be cured surgically, the procedure is of great value. In contrast, the patient with BHA is treated with MRA whether AVS is performed or not. Consequently, it is prudent to gauge how likely it is to benefit from imaging and AVS in each case prior to embarking on these studies. The explosion of information about PA in the last decade, including predictors of APA and of surgical benefit, are useful in limiting the evaluation for some patients with a positive PA screening test. This article will review our suggestions for approaching these patients in a pragmatic style, recognizing the limitations to even the best resources and facilities.

scholarly journals SUN-210 Differentially Expressed Mirnas in Zona Reticularis (ZR) Cells of the Human Adrenal Cortex

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Francisco Garcia ◽  
Diego Colman ◽  
Luciana Zoff ◽  
Nora Isabel Saraco ◽  
Alicia Belgorosky ◽  
...  
Keyword(s):  
Adrenal Cortex ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Expression Profiles ◽  
Life Time ◽  
Micro Rna ◽  
Differentially Expressed ◽  
Zona Fasciculata ◽  
Adaptive Responses ◽  
Time Specific

Abstract The human adrenal cortex, involved in adaptive responses to stress, fluid homeostasis, and secondary sexual characteristics, arises from a tightly regulated development of a zone and cell type-specific secretory pattern. However, the molecular mechanisms governing adrenal zonation, particularly postnatal ZR development, which produces adrenal androgens in a life-time-specific manner, remain poorly understood. The hallmark of ZR is the low expression of type 2 3β-hydroxysteroid dehydrogenase (HSD3B2). However, the mechanisms underlying HSD3B2 downregulation in the ZR remain unknown. MiRNAs are seen as regulators of cell phenotypes. The objective of the study was to compare miRNA expression profiles in human adrenal ZR and zona fasciculata (ZF). ZF and ZR were microdissected from human adrenals tissues (n=5, from boys aged 16, 17 and 19 yr and girls aged 12 and 16 yr) by laser capture microdissection (LCM). Total RNA was extracted from 5 ZF/ZR pairs and next-generation sequencing (NGS) was used to perform the microRNA expression profiling. 281 mature microRNAs were identified in human adrenal cortex. Among them, 7 microRNAs were significantly differentially expressed between ZF and ZR. The expression of miR-375-3p, miR-483-3p and miR-7-5p was higher in ZR compared with its paired ZF by 2-fold or greater. Multiple available bioinformatic algorithms (TargetScan, miRanda, DianaLab and PicTar) were employed to search for its target genes. Among predicted target genes, several genes (GATA-6, GATA-4, SF1, NR4A2, and IGF-1) are known to be involved in HSD3B2 regulation. In summary, LCM combined with NGS provided a robust approach to explore the adrenal zone-specific micro-RNA profiling. Our data gave first hints that miRNAs might be novel regulatory modules associated with human adrenal ZR cell-specific transcript regulation underlying developmental androgen production.

scholarly journals Somatic mutations in adrenocortical carcinoma with primary aldosteronism or hyperreninemic hyperaldosteronism

2019 ◽  
Vol 26 (2) ◽  
pp. 217-225 ◽  
Author(s):  
Isobel C Mouat ◽  
Kei Omata ◽  
Andrew S McDaniel ◽  
Namita G Hattangady ◽  
Debnita Talapatra ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Chart Review ◽  
Somatic Mutations ◽  
Retrospective Chart Review ◽  
Tissue Microarrays ◽  
Positive Staining ◽  
Alternative Mechanism ◽  
Genetic Changes ◽  
Mutational Status ◽  
Aldosterone Production

Several somatic mutations specific to aldosterone-producing adenomas (APAs) have been described. A small proportion of adrenocortical carcinomas (ACCs) are associated with hyperaldosteronism, either primary aldosteronism or hyperreninemic hyperaldosteronism. However, it is unknown whether they harbor mutations of the same spectrum as APAs. The objective of this study is to describe the clinical phenotype and molecular genotype of ACCs with hyperaldosteronism, particularly the analysis for common APA-associated genetic changes. Patients were identified by retrospective chart review at a specialized referral center and by positive staining for CYP11B2 of tissue microarrays. Twenty-five patients with ACC and hyperaldosteronism were initially identified by retrospective chart review, and tissue for further analysis was available on 13 tumors. Seven patients were identified by positive staining for CYP11B2 in a tissue microarray, of which two were already identified in the initial chart review. Therefore, a total number of 18 patients with a diagnosis of ACC and features of either primary aldosteronism or hyperreninemic hyperaldosteronism were therefore included in the final study. Mutational status for a select list of oncogenes, tumor suppressor genes and genes known to carry mutations in APAs were analyzed by next-generation sequencing. Review of clinical data suggested autonomous aldosterone production in the majority of cases, while for some cases, hyperreninemic hyperaldosteronism was the more likely mechanism. The mutational landscape of ACCs associated with hyperaldosteronism was not different from ACCs with a different hormonal phenotype. None of the ACCs harbored mutations of known APA-associated genes, suggesting an alternative mechanism conferring aldosterone production.

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