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chromaffin tissue [keywords]
- Impairment of vesicular ATP release affects glucose metabolism and increases insulin sensitivity. [Journal Article]
- Sci Rep 2014.:6689.
Neuroendocrine cells store ATP in secretory granules and release it along with hormones that may trigger a variety of cellular responses in a process called purinergic chemical transmission. Although the vesicular nucleotide transporter (VNUT) has been shown to be involved in vesicular storage and release of ATP, its physiological relevance in vivo is far less well understood. In Vnut knockout (Vnut(-/-)) mice, we found that the loss of functional VNUT in adrenal chromaffin granules and insulin granules in the islets of Langerhans led to several significant effects. Vesicular ATP accumulation and depolarization-dependent ATP release were absent in the chromaffin granules of Vnut(-/-) mice. Glucose-responsive ATP release was also absent in pancreatic β-cells in Vnut(-/-) mice, while glucose-responsive insulin secretion was enhanced to a greater extent than that in wild-type tissue. Vnut(-/-) mice exhibited improved glucose tolerance and low blood glucose upon fasting due to increased insulin sensitivity. These results demonstrated an essential role of VNUT in vesicular storage and release of ATP in neuroendocrine cells in vivo and suggest that vesicular ATP and/or its degradation products act as feedback regulators in catecholamine and insulin secretion, thereby regulating blood glucose homeostasis.
- Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma. [Journal Article]
- Int J Endocrinol 2014.:546347.
Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation.
- Rare extra-adrenal paraganglioma mimicking a painful Schwannoma Case report. [Journal Article]
- Ann Ital Chir 2014.
Paragangliomas originate from chromaffin tissue primarily found in the Zuckerkandl body. A 53 years old man, was investigated with abdominal MRI for chronic backache, that had lasted for 2 years.MRI revealed an incidental mass in para-aortic region, at the adrenal lodge, with characteristics of a solid nodular mass, which did not seem to arise from the adrenal gland. An abdominal CT showed a mass localized prior to left adrenal gland; the radiologist reported this mass as a malignant peripheral nerve sheath tumor (Schwannoma). During his stay in hospital, tumoral markers chromogranin and neuron-specific enolase were dosed, with a concentration of 187.00 ng/mL and 7.7 ng/mL. Patient's back pain was treated first with ketorolac, without any resolution of the problem, then with ketorolac plus tramadol in elastomeric pump, again with no relief, and finally with a continuous infusion of morphine. Since the exact nature of the neoplasm was not known and a CT guided biopsy was not technically feasible to do, a laparoscopic excision of the mass, with transperitoneal anterior submesocolic approach, as well as for the left adrenalectomy, was planned. After surgery, the patient no longer needed morphine. The postoperative course was uneventful.Histopathological findings consisted of periadrenal paraganglioma. Extra-adrenal paragangliomas are rarely recognized during preoperative study. This is often due to its capacity of mimicking other type of tumors.Paragangliomas could be successfully resected by laparoscopy, they are difficult to distinguish from other tumor and they should be investigated even if preoperative findings argue for something else.Laparoscopic adrenalectomy, Paraganglioma, Schwannoma.
- Knockout of the BK β2 subunit abolishes inactivation of BK currents in mouse adrenal chromaffin cells and results in slow-wave burst activity. [Journal Article]
- J Gen Physiol 2014 Oct; 144(4):275-95.
Rat and mouse adrenal medullary chromaffin cells (CCs) express an inactivating BK current. This inactivation is thought to arise from the assembly of up to four β2 auxiliary subunits (encoded by the kcnmb2 gene) with a tetramer of pore-forming Slo1 α subunits. Although the physiological consequences of inactivation remain unclear, differences in depolarization-evoked firing among CCs have been proposed to arise from the ability of β2 subunits to shift the range of BK channel activation. To investigate the role of BK channels containing β2 subunits, we generated mice in which the gene encoding β2 was deleted (β2 knockout [KO]). Comparison of proteins from wild-type (WT) and β2 KO mice allowed unambiguous demonstration of the presence of β2 subunit in various tissues and its coassembly with the Slo1 α subunit. We compared current properties and cell firing properties of WT and β2 KO CCs in slices and found that β2 KO abolished inactivation, slowed action potential (AP) repolarization, and, during constant current injection, decreased AP firing. These results support the idea that the β2-mediated shift of the BK channel activation range affects repetitive firing and AP properties. Unexpectedly, CCs from β2 KO mice show an increased tendency toward spontaneous burst firing, suggesting that the particular properties of BK channels in the absence of β2 subunits may predispose to burst firing.
- The Hemodynamically-Regulated Vascular Microenvironment Promotes Migration of the Steroidogenic Tissue during Its Interaction with Chromaffin Cells in the Zebrafish Embryo. [Journal Article]
- PLoS One 2014; 9(9):e107997.
While the endothelium-organ interaction is critical for regulating cellular behaviors during development and disease, the role of blood flow in these processes is only partially understood. The dorsal aorta performs paracrine functions for the timely migration and differentiation of the sympatho-adrenal system. However, it is unclear how the adrenal cortex and medulla achieve and maintain specific integration and whether hemodynamic forces play a role.In this study, the possible modulation of steroidogenic and chromaffin cell integration by blood flow was investigated in the teleostean counterpart of the adrenal gland, the interrenal gland, in the zebrafish (Danio rerio). Steroidogenic tissue migration and angiogenesis were suppressed by genetic or pharmacologic inhibition of blood flow, and enhanced by acceleration of blood flow upon norepinephrine treatment. Repressed steroidogenic tissue migration and angiogenesis due to flow deficiency were recoverable following restoration of flow. The regulation of interrenal morphogenesis by blood flow was found to be mediated through the vascular microenvironment and the Fibronectin-phosphorylated Focal Adhesion Kinase (Fn-pFak) signaling. Moreover, the knockdown of krüppel-like factor 2a (klf2a) or matrix metalloproteinase 2 (mmp2), two genes regulated by the hemodynamic force, phenocopied the defects in migration, angiogenesis, the vascular microenvironment, and pFak signaling of the steroidogenic tissue observed in flow-deficient embryos, indicating a direct requirement of mechanotransduction in these processes. Interestingly, epithelial-type steroidogenic cells assumed a mesenchymal-like character and downregulated β-Catenin at cell-cell junctions during interaction with chromaffin cells, which was reversed by inhibiting blood flow or Fn-pFak signaling. Blood flow obstruction also affected the migration of chromaffin cells, but not through mechanosensitive or Fn-pFak dependent mechanisms.These results demonstrate that hemodynamically regulated Fn-pFak signaling promotes the migration of steroidogenic cells, ensuring their interaction with chromaffin cells along both sides of the midline during interrenal gland development.
- Immunocytochemical markers of neuronal maturation in human diagnostic neuropathology. [JOURNAL ARTICLE]
- Cell Tissue Res 2014 Sep 17.
Histological descriptions of morphogenesis in human fetal brain and in malformations and tumours can now be supplemented by the timing and sequence of the maturation of individual neurons. In human neuropathology, this is principally achieved by immunocytochemical reactivities used as maturational markers of neuronal properties denoted by molecules and cell products. Cytological markers can appear early and then regress, often being replaced by more mature molecules, or might not exhibit the onset of immunoreactivity until a certain stage of neuronal differentiation is achieved, some early, others intermediate and some late during the maturational process. Inter-specific differences occur in some structures of the brain. The classification of markers of neuronal maturation can be based, in addition to those mentioned above, on several criteria: cytological localisation, water solubility, biochemical nature of the antigen, specificity and various technical factors. The most useful immunocytochemical markers of neuronal maturation in human neuropathology are NeuN, synaptophysin, calretinin and other calcium-binding molecules, various microtubule-associated proteins and chromogranins. Non-antibody histochemical stains that denote maturational processes include luxol fast blue for myelination, acridine orange fluorochrome for nucleic acids, mitochondrial respiratory chain enzymes and argentophilic impregnations. Neural crest derivatives of the peripheral nervous system, including chromaffin and neuroendocrine cells, have special features that are shared and others that differ greatly between lineages. Other techniques used in human diagnostic neuropathology, particularly as applied to tumours, include chromosomal and genetic analyses, the mTOR signalling pathway, BRAF V600E and other tumour-suppressor gene products, transcription products of developmental genes and the proliferation index of the tumour cells and of mitotic neuroepithelial cells.
- Low-intensity aerobic exercise mitigates exercise-induced bronchoconstriction by improving the function of adrenal medullary chromaffin cells in asthmatic rats. [Journal Article]
- Tohoku J Exp Med 2014; 234(2):99-110.
Exercise is one of the most common triggers of bronchoconstriction in patients with asthma. The low levels of circulating epinephrine produced by the adrenal medullary chromaffin cells (AMCCs) are associated with exercise-induced bronchoconstriction (EIB) in asthmatics. In the present study, we tested the hypothesis that low-intensity aerobic exercise may ameliorate EIB using a rat model of asthma. Male Sprague-Dawley rats at 7 weeks of age, sensitized with ovalbumin or treated with saline, were subjected to low or moderate exercise training (50 or 75% of maximum velocity) for one hour in a treadmill 30 min after ovalbumin or saline inhalation. The exercise capacity, airway responsiveness, lung morphology, the morphological changes and endocrine function of AMCCs were measured in both groups of rats after exercise training for 6 weeks. Either low-intensity or moderate-intensity exercise mitigated EIB and increased exercise capacity in ovalbumin-sensitized (asthmatic) rats. Low-intensity aerobic exercise reduced the vacuolar degeneration degrees, lipid contents, neuronal peripherin and neurofilament-68 expression, demolished neurites, but increased the chromaffin granule density, endocrine chromogranin A and phenylethanolamine N-methyltransferase expression in the adrenal medullary tissues, accompanied by increased levels of circulating epinephrine and corticosterone, but decreased nerve growth factor in asthmatic rats. Finally, low-intensity aerobic exercise significantly reduced the relative levels of phosphorylated extracellular signal-regulated kinase and phosphorylated cAMP responsive element-binding protein and the relative mRNA expression levels of downstream molecules, including c-FOS and c-JUN in the adrenal medullary of asthmatic rats. We suggest that low-intensity aerobic exercise improves the endocrine dysfunction of AMCCs and mitigates EIB.
- Nuclear imaging to characterize adrenal tumors: Comparison with MRI. [Journal Article]
- World J Radiol 2014 Jul 28; 6(7):493-501.
To describe the role of nuclear imaging modalities using nor-cholesterol, metaiodobenzylguanidine (MIBG) and fluorine-deoxy-glucose (FDG) in adrenal tumors for lesion characterization in comparison with magnetic resonance (MR).Population was classified in group 1 consisting of 30 patients with non-hypersecreting unilateral adrenal masses, in group 2 consisting of 34 patients with hypersecreting (n = 19) or non-hypersecreting (n = 15) adrenal adenomas and in group 3 consisting of 18 patients with chromaffin-tissue tumors (CTT), of which 14 were pheochromocytomas while 4 were paragangliomas (n = 4). All patients underwent MR and nuclear studies (nor-cholesterol, MIBG and FDG). Pathology samples (n = 63) or follow-up data in adenomas (n = 19) were used as standard of reference for imaging studies interpretation.In group 1, MR findings were not highly accurate for lesion characterization, while the results of nuclear scans showed abnormal nor-cholesterol, MIBG and FDG concentration in all cases of adenomas, pheos and malignant tumors, respectively. In group 2, no differences in MR parameters were found between hyperfunctioning and non-hyperfunctioning adenomas, while nor-cholesterol uptake was significantly higher in hyperfunctioning compared to non-hyperfunctioning lesions. In group 3, no differences in MR parameters were found between benign and malignant CCT, while MIBG uptake was significantly higher in malignant compared to benign tumors.On the basis of our findings, nuclear imaging modalities using specific target agents are able to better characterize adrenal tumors, compared with MR. In particular, radionuclide techniques are able to identify the nature of adrenal incidentalomas and to differentiate between hypersecreting and non-hypersecreting adenomas as well as between benign and malignant CTT.
- Adrenal adrenoceptors in heart failure. [Journal Article, Review]
- Front Physiol 2014.:246.
Heart failure (HF) is a chronic clinical syndrome characterized by the reduction in left ventricular (LV) function and it represents one of the most important causes of morbidity and mortality worldwide. Despite considerable advances in pharmacological treatment, HF represents a severe clinical and social burden. Sympathetic outflow, characterized by increased circulating catecholamines (CA) biosynthesis and secretion, is peculiar in HF and sympatholytic treatments (as β-blockers) are presently being used for the treatment of this disease. Adrenal gland secretes Epinephrine (80%) and Norepinephrine (20%) in response to acetylcholine stimulation of nicotinic cholinergic receptors on the chromaffin cell membranes. This process is regulated by adrenergic receptors (ARs): α2ARs inhibit CA release through coupling to inhibitory Gi-proteins, and β ARs (mainly β2ARs) stimulate CA release through coupling to stimulatory Gs-proteins. All ARs are G-protein-coupled receptors (GPCRs) and GPCR kinases (GRKs) regulate their signaling and function. Adrenal GRK2-mediated α2AR desensitization and downregulation are increased in HF and seem to be a fundamental regulator of CA secretion from the adrenal gland. Consequently, restoration of adrenal α2AR signaling through the inhibition of GRK2 is a fascinating sympatholytic therapeutic strategy for chronic HF. This strategy could have several significant advantages over existing HF pharmacotherapies minimizing side-effects on extra-cardiac tissues and reducing the chronic activation of the renin-angiotensin-aldosterone and endothelin systems. The role of adrenal ARs in regulation of sympathetic hyperactivity opens interesting perspectives in understanding HF pathophysiology and in the identification of new therapeutic targets.
- Pre-operative (68)Ga-DOTANOC somatostatin receptor PET/CT imaging demonstrating multiple synchronous lesions in a patient with head and neck paraganglioma. [JOURNAL ARTICLE]
- Rev Esp Med Nucl Imagen Mol 2014 Jul 17.
Paragangliomas, or glomus tumors, are neoplasms arising from extra-adrenal chromaffin tissue. They frequently cause symptoms by over-production of catecholamines with known predilection to multicentricity. We describe the case of a patient with bilateral carotid body tumor who underwent a preoperative (68)Gallium labeled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI3-Octreotide ((68)Ga-DOTANOC) positron emission tomography/computed tomography (PET/CT) imaging for staging. This is a unique case in which multiple paraganglioma and pheochromocytoma were demonstrated in a single patient using (68)Ga-DOTANOC PET/CT.