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Small GTPases Apr 2017Altered Rho GTPase signaling has been linked to many types of cancer. As many small G proteins, Rho GTPases cycle between an active and inactive state thanks to specific... (Review)
Review
Altered Rho GTPase signaling has been linked to many types of cancer. As many small G proteins, Rho GTPases cycle between an active and inactive state thanks to specific regulators that catalyze exchange of GDP into GTP (Rho-GEF) or hydrolysis of GTP into GDP (Rho-GAP). Recent studies have shown that alteration takes place either at the level of Rho proteins themselves (expression levels, point mutations) or at the level of their regulators, mostly RhoGEFs and RhoGAPs. Most reports describe Rho GTPases gain of function that may participate to the tumorigenesis processes. In contrast, we have recently reported that decreased activities of Cdc42 and Rac1 as well as decreased expression of 2 Rho-GEFs, FARP1 and ARHGEF1, correlate with pheochromocytomas, a tumor developing in the medulla of the adrenal gland (Croisé et al., Endocrine Related Cancer, 2016). Here we highlight the major evidence and further study the correlation between Rho GTPases activities and expression levels of ARHGEF1 and FARP1. Finally we also discuss how the decrease of Cdc42 and Rac1 activities may help human pheochromocytomas to develop and comment the possible relationship between FARP1, ARHGEF1 and the 2 Rho GTPases Cdc42 and Rac1 in tumorigenesis.
Topics: Adrenal Gland Neoplasms; Adrenal Medulla; Animals; Carcinogenesis; Down-Regulation; Gene Silencing; Humans; PC12 Cells; Pheochromocytoma; Rats; cdc42 GTP-Binding Protein; rac1 GTP-Binding Protein
PubMed: 27355516
DOI: 10.1080/21541248.2016.1202634 -
International Journal of Molecular... May 2023The homeostasis of the adrenal gland plays a decisive role in its proper functioning, both in non-stressful conditions and under the influence of various types of...
The homeostasis of the adrenal gland plays a decisive role in its proper functioning, both in non-stressful conditions and under the influence of various types of stress. This consists of interactions between all types of cells that make up the organ, including parenchymal and interstitial cells. The amount of available information on this subject in the rat adrenal glands under non-stressful conditions is insufficient; the aim of the research was to determine the expression of marker genes for rat adrenal cells depending on their location. The material for the study consisted of adrenal glands taken from intact adult male rats that were separated into appropriate zones. Transcriptome analysis by means of Affymetrix Rat Gene 2.1 ST Array was used in the study, followed by real-time PCR validation. Expression analysis of interstitial cell marker genes revealed both the amount of expression of these genes and the zone in which they were expressed. The expression of marker genes for fibroblasts was particularly high in the cells of the ZG zone, while the highest expression of specific macrophage genes was observed in the adrenal medulla. The results of this study, especially with regard to interstitial cells, provide a so far undescribed model of marker gene expression of various cells, both in the cortex and medulla of the sexually mature rat adrenal gland. The interdependence between parenchymal and interstitial cells creates a specific microenvironment that is highly heterogeneous within the gland with respect to some of the interstitial cells. This phenomenon most likely depends on the interaction with the differentiated parenchymal cells of the cortex, as well as the medulla of the gland.
Topics: Rats; Male; Animals; Transcriptome; Adrenal Glands; Adrenal Medulla; Gene Expression Profiling
PubMed: 37298112
DOI: 10.3390/ijms24119159 -
Journal of Clinical Medicine Aug 2018Pheochromocytoma (PCC) and sympathetic paraganglioma (PGL) are rare neuroendocrine tumors characterized by catecholamine production in the adrenal medulla and... (Review)
Review
Pheochromocytoma (PCC) and sympathetic paraganglioma (PGL) are rare neuroendocrine tumors characterized by catecholamine production in the adrenal medulla and extra-adrenal paraganglia. PCC and PGL (PPGL) with metastasis was termed malignant PPGL. However, the distinction between "benign" and "malignant" PPGLs has been debated. Currently, all PPGLs are believed to have some metastatic potential and are assigned malignant tumors (ICD-O/3) by the WHO Classification of Endocrine Organs (2017, 4th edition). Therefore, the previous categories benign and malignant PPGL have been eliminated in favor of risk stratification approach. The Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) is a tool for risk stratification for predicting metastasis and the prognosis of patients. At least 30% of PPGLs are hereditary, with 20 genes identified and genotype-phenotype correlations clarified. Of these genes, and have been well investigated and are the primary cause of bilateral PCC. In addition, mutation of succinate dehydrogenase gene subunits and are strongly correlated with extra-adrenal location, younger age, multiple tumors, metastasis and poor prognosis. Disease stratification by catecholamine phenotype and molecular profiling correlates with histological grading by GAPP. PPGLs should be understood comprehensively based on clinical, biochemical, molecular and pathological data for patient care. A flow chart for pathological diagnosis is included.
PubMed: 30150569
DOI: 10.3390/jcm7090242 -
International Journal of Molecular... Apr 2022Epinephrine is the most abundant catecholamine hormone, produced by the nervous system and adrenal glands. Endocrine disruption of epinephrine synthesis, secretion and...
Epinephrine is the most abundant catecholamine hormone, produced by the nervous system and adrenal glands. Endocrine disruption of epinephrine synthesis, secretion and signaling is less studied than steroid and thyroid hormones. Dichlorodiphenyltrichloroethane (DDT) is recognized as one of the most prominent environmental contaminants with a long half-life. It is a potent endocrine disrupter affecting sex steroid, mineralocorticoid, glucocorticoid and thyroid hormone production. Exposure to low doses of DDT is universal and begins in utero. Therefore, we studied adrenal medulla growth and function in male Wistar rats exposed to low doses of DDT during prenatal and postnatal development until puberty and adulthood, as well as rats exposed to DDT since the first day of postnatal development. All the exposed rats demonstrated lowered epinephrine blood levels, gradually reducing with age. DDT was found to inhibit the synthesis of tyrosine hydroxylase and affect the mitochondrial apparatus of epinephrine-producing cells during puberty and even after maturation. Low-dose exposure to DDT from birth resulted in more pronounced changes in adrenomedullary cells and a more profound decrease (up to 50%) in epinephrine secretion in adult rats. Prenatal onset of exposure demonstrated a mild effect on epinephrine-producing function (30% reduction), but was associated with lower rate of adrenal medulla growth during maturation and 25% smaller adrenal medullar size in adult rats. All subjects exposed to low doses of DDT failed to develop adaptive changes and restore proper epinephrine production. These results indicate a dysmorphogenetic effect of prenatal exposure and disruption of secretory function of adrenal chromaffin cells by postnatal exposure to DDT.
Topics: Adrenal Medulla; Adult; Animals; DDT; Endocrine Disruptors; Epinephrine; Female; Humans; Male; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar
PubMed: 35563302
DOI: 10.3390/ijms23094912 -
International Journal of Molecular... Sep 2023Chronic stress is known to perturb serotonergic regulation in the brain, leading to mood, learning and memory impairments and increasing the risk of developing mood...
Chronic stress is known to perturb serotonergic regulation in the brain, leading to mood, learning and memory impairments and increasing the risk of developing mood disorders. The influence of the gut microbiota on serotonergic regulation in the brain has received increased attention recently, justifying the investigation of the role of diet on the gut and the brain in mood disorders. Here, using a 4-week chronic unpredictable mild stress (CUMS) model in mice, we aimed to investigate the effects of a high-fat high-glycaemic index (HFD) and high-fibre fruit & vegetable "superfood" (SUP) modifications of a semi-pure AIN93M diet on behaviour, serotonin synthesis and metabolism pathway regulation in the brain and the gut, as well as the gut microbiota and the peripheral adrenal medullary system. CUMS induced anxiety-like behaviour, dysregulated the tryptophan and serotonin metabolic pathways in the hippocampus, prefrontal cortex, and colon, and altered the composition of the gut microbiota. CUMS reduced the catecholamine synthetic capacity of the adrenal glands. Differential effects were found in these parameters in the HFD and SUP diet. Thus, dietary modifications may profoundly affect the multiple dynamic systems involved in mood disorders.
Topics: Mice; Animals; Serotonin; Mice, Inbred C57BL; Brain; Diet; Adrenal Medulla; Stress, Psychological; Depression
PubMed: 37834073
DOI: 10.3390/ijms241914618 -
Endocrine Pathology Sep 2017The fourth edition of the World Health Organization (WHO) classification of endocrine tumours contains substantial new findings for the adrenal tumours. The tumours are... (Review)
Review
The fourth edition of the World Health Organization (WHO) classification of endocrine tumours contains substantial new findings for the adrenal tumours. The tumours are presented in two chapters labelled as "Tumours of the adrenal cortex" and "Tumours of the adrenal medulla and extra-adrenal paraganglia." Tumours of the adrenal cortex are classified as cortical carcinoma, cortical adenoma, sex cord stromal tumours, adenomatoid tumour, mesenchymal and stromal tumours (myelolipoma and schwannoma), haematological tumours, and secondary tumours. Amongst them, schwannoma and haematological tumours are newly documented. The major updates in adrenal cortical lesions are noted in the genetics of the cortical carcinoma and cortical adenoma based on the data from The Cancer Genome Atlas (TCGA). Also, a system for differentiation of oncocytoma from oncocytic cortical carcinoma is adopted. Tumours of the adrenal medulla and extra-adrenal paraganglia comprise pheochromocytoma, paraganglioma (head and neck paraganglioma and sympathetic paraganglioma), neuroblastic tumours (neuroblastoma, nodular ganglioneuroblastoma, intermixed ganglioneuroblastoma, and ganglioneuroma), composite pheochromocytoma, and composite paraganglioma. In this group, neuroblastic tumours are newly included in the classification. The clinical features, histology, associated pathologies, genetics, and predictive factors of pheochromocytoma and paraganglioma are the main changes introduced in this chapter of WHO classification of endocrine tumours. The term "metastatic pheochromocytoma/paraganglioma" is used to replace "malignant pheochromocytoma/paraganglioma." Also, composite pheochromocytoma and composite paraganglioma are now documented in separate sections instead of one. Overall, the new classification incorporated new data on pathology, clinical behaviour, and genetics of the adrenal tumours that are important for current management of patients with these tumours.
Topics: Adrenal Gland Neoplasms; Humans; World Health Organization
PubMed: 28477311
DOI: 10.1007/s12022-017-9484-5 -
Molecular and Cellular Endocrinology Feb 2017The adrenal gland is a highly plastic organ with the capacity to adapt the body homeostasis to different physiological needs. The existence of stem-like cells in the... (Review)
Review
The adrenal gland is a highly plastic organ with the capacity to adapt the body homeostasis to different physiological needs. The existence of stem-like cells in the adrenal cortex has been revealed in many studies. Recently, we identified and characterized in mice a pool of glia-like multipotent Nestin-expressing progenitor cells, which contributes to the plasticity of the adrenal medulla. In addition, we found that these Nestin progenitors are actively involved in the stress response by giving rise to chromaffin cells. Interestingly, we also observed a Nestin-GFP-positive cell population located under the adrenal capsule and scattered through the cortex. In this article, we discuss the possibility of a common progenitor giving rise to subpopulations of cells both in the adrenal cortex and medulla, the isolation and characterization of this progenitor as well as its clinical potential in transplantation therapies and in pathophysiology.
Topics: Adaptation, Physiological; Adrenal Cortex; Animals; Chromaffin Cells; Humans; Neurodegenerative Diseases; Stem Cells; Stress, Physiological
PubMed: 27637345
DOI: 10.1016/j.mce.2016.09.011 -
American Journal of Physiology.... Sep 2015Pendrin (Slc26a4) is a Cl(-)/HCO3 (-) exchanger expressed in renal intercalated cells and mediates renal Cl(-) absorption. With pendrin gene ablation, blood pressure and...
Pendrin (Slc26a4) is a Cl(-)/HCO3 (-) exchanger expressed in renal intercalated cells and mediates renal Cl(-) absorption. With pendrin gene ablation, blood pressure and vascular volume fall, which increases plasma renin concentration. However, serum aldosterone does not significantly increase in pendrin-null mice, suggesting that pendrin regulates adrenal zona glomerulosa aldosterone production. Therefore, we examined pendrin expression in the adrenal gland using PCR, immunoblots, and immunohistochemistry. Pendrin protein was detected in adrenal lysates from wild-type but not pendrin-null mice. However, immunohistochemistry and qPCR of microdissected adrenal zones showed that pendrin was expressed in the adrenal medulla, rather than in cortex. Within the adrenal medulla, pendrin localizes to both epinephrine- and norepinephrine-producing chromaffin cells. Therefore, we examined plasma catecholamine concentration and blood pressure in wild-type and pendrin-null mice under basal conditions and then after 5 and 20 min of immobilization stress. Under basal conditions, blood pressure was lower in the mutant than in the wild-type mice, although epinephrine and norepinephrine concentrations were similar. Catecholamine concentration and blood pressure increased markedly in both groups with stress. With 20 min of immobilization stress, epinephrine and norepinephrine concentrations increased more in pendrin-null than in wild-type mice, although stress produced a similar increase in blood pressure in both groups. We conclude that pendrin is expressed in the adrenal medulla, where it blunts stress-induced catecholamine release.
Topics: Adrenal Glands; Adrenal Medulla; Animals; Anion Transport Proteins; Blood Pressure; Chloride-Bicarbonate Antiporters; Epinephrine; Gene Expression Profiling; Immunoblotting; Immunohistochemistry; Kidney; Mice; Mice, Knockout; Norepinephrine; RNA, Messenger; Rats; Restraint, Physical; Reverse Transcriptase Polymerase Chain Reaction; Stress, Psychological; Sulfate Transporters
PubMed: 26173457
DOI: 10.1152/ajpendo.00035.2015 -
Frontiers in Cellular Neuroscience 2016Gamma-aminobutyric acid (GABA) is produced not only in the brain, but also in endocrine cells by the two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67.... (Review)
Review
Gamma-aminobutyric acid (GABA) is produced not only in the brain, but also in endocrine cells by the two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. In rat adrenal medullary chromaffin cells only GAD67 is expressed, and GABA is stored in large dense core vesicles (LDCVs), but not synaptic-like microvesicles (SLMVs). The α3β2/3γ2 complex represents the majority of GABAA receptors expressed in rat and guinea pig chromaffin cells, whereas PC12 cells, an immortalized rat chromaffin cell line, express the α1 subunit as well as the α3. The expression of α3, but not α1, in PC12 cells is enhanced by glucocorticoid activity, which may be mediated by both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). GABA has two actions mediated by GABAA receptors in chromaffin cells: it induces catecholamine secretion by itself and produces an inhibition of synaptically evoked secretion by a shunt effect. Allopregnanolone, a neuroactive steroid which is secreted from the adrenal cortex, produces a marked facilitation of GABAA receptor channel activity. Since there are no GABAergic nerve fibers in the adrenal medulla, GABA may function as a para/autocrine factor in the chromaffin cells. This function of GABA may be facilitated by expression of the immature isoforms of GAD and GABAA receptors and the lack of expression of plasma membrane GABA transporters (GATs). In this review, we will consider how the para/autocrine function of GABA is achieved, focusing on the structural and molecular mechanisms for GABA signaling.
PubMed: 27147972
DOI: 10.3389/fncel.2016.00100 -
Molecular Aspects of Medicine 2016Acute O2 sensing is necessary for the activation of cardiorespiratory reflexes (hyperventilation and sympathetic activation), which permit the survival of individuals... (Review)
Review
Acute O2 sensing is necessary for the activation of cardiorespiratory reflexes (hyperventilation and sympathetic activation), which permit the survival of individuals under hypoxic environments (e.g. high altitude) or medical conditions presenting with reduced capacity for gas exchange between the lung alveoli and the blood. Changes in blood O2 tension are detected by the arterial chemoreceptors, in particular the carotid body (CB), which act in concert with the adrenal medulla (AM) to facilitate rapid adaptations to hypoxia. The field of arterial chemoreception has undergone a considerable expansion in recent years, with many of the fundamental observations made at the molecular and cellular levels serving to improve our understanding of the pathogenesis of numerous medical disorders, and even to propose advances in the treatment strategies. In this review, after a short historical preface, we describe the current model of chemosensory transduction based on the modulation of membrane K(+) channels by O2 in specialized chemoreceptor cells. Recent progress in elucidating the molecular mechanisms underlying the modulation of ion channels by O2 tension, which involves mitochondrial complex I, is also discussed. The discovery in the last few years of a specific population of neural crest-derived stem cells in the CB explains the reversible growth of this organ, an intriguing and unusual property of this type of neuronal tissue that contributes to acclimatization under chronic hypoxia. The essential homeostatic role of the CB-AM axis is clearly evident in newly generated mouse models that reach adulthood, albeit with CB and AM atrophy. These animals exhibit a marked intolerance to even mild hypoxia. CB inhibition or over-activation can have important medical consequences. Respiratory depression by general anesthetics or by opioid use is a common clinical condition that frequently causes death in susceptible individuals. An exaggerated sympathetic outflow due to over-activation of the CB-AM axis may contribute to the pathogenesis of several highly prevalent medical conditions, such as chronic heart failure, obstructive sleep apnea, obesity, metabolic syndrome, and diabetes. A detailed understanding of the molecular mechanisms underlying acute O2 sensing may help in the design of more efficient therapeutic approaches to combat these disorders.
Topics: Adrenal Medulla; Animals; Carotid Body; Chemoreceptor Cells; Homeostasis; Humans; Hypoxia; Models, Animal; Oxygen; Potassium Channels
PubMed: 26709054
DOI: 10.1016/j.mam.2015.12.002