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Vance L Trudeau - One of the best experts on this subject based on the ideXlab platform.
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Secretoneurin A Directly Regulates the Proteome of Goldfish Radial Glial Cells In Vitro
Frontiers Media S.A., 2018Co-Authors: Dillon F. Da Fonte, Chris J. Martyniuk, Lei Xing, Vance L TrudeauAbstract:Radial glial cells (RGCs) are the main macroglia in the teleost brain and have established roles in neurogenesis and neurosteroidogenesis. They are the only brain cell type expressing aromatase B (cyp19a1b), the enzyme that synthesizes estrogens from androgen precursors. There are few studies on the regulation of RGC functions, but our previous investigations demonstrated that dopamine stimulates cyp19a1b expression in goldfish RGCs, while Secretoneurin A (SNa) inhibits the expression of this enzyme. Here, we determine the range of proteins and cellular processes responsive to SNa treatments in these steroidogenic cells. The focus here is on SNa, because this peptide is derived from selective processing of secretogranin II in magnocellular cells embedded within the RGC-rich preoptic nucleus. Primary cultures of RGCs were treated (24 h) with 10, 100, or 1,000 nM SNa. By using isobaric tagging for relative and absolute quantitation and a Hybrid Quadrupole Obritrap Mass Spectrometry system, a total of 1,363 unique proteins were identified in RGCs, and 609 proteins were significantly regulated by SNa at one or more concentrations. Proteins that showed differential expression with all three concentrations of SNa included H1 histone, glutamyl-prolyl-tRNA synthetase, Rho GDP dissociation inhibitor γ, vimentin A2, and small nuclear ribonucleoprotein-associated protein. At 10, 100, and 1,000 nM SNa, there were 5, 195, and 489 proteins that were downregulated, respectively, whereas the number of upregulated proteins were 72, 44, and 51, respectively. Subnetwork enrichment analysis of differentially regulated proteins revealed that processes such as actin organization, cytoskeleton organization and biogenesis, apoptosis, mRNA processing, RNA splicing, translation, cell growth, and proliferation are regulated by SNa based on the proteomic response. Moreover, we observed that, at the low concentration of SNa, there was an increase in the abundance of proteins involved in cell growth, proliferation, and migration, whereas higher concentration of SNa appeared to downregulate proteins involved in these processes, indicating a dose-dependent proteome response. At the highest concentration of SNa, proteins linked to the etiology of diseases of the central nervous system (brain injuries, Alzheimer disease, Parkinson’s disease, cerebral infraction, brain ischemia) were also differentially regulated. These data implicate SNa in the control of cell proliferation and neurogenesis
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data_sheet_1.XLSX
2018Co-Authors: Dillon F. Da Fonte, Chris J. Martyniuk, Lei Xing, Vance L TrudeauAbstract:Radial glial cells (RGCs) are the main macroglia in the teleost brain and have established roles in neurogenesis and neurosteroidogenesis. They are the only brain cell type expressing aromatase B (cyp19a1b), the enzyme that synthesizes estrogens from androgen precursors. There are few studies on the regulation of RGC functions, but our previous investigations demonstrated that dopamine stimulates cyp19a1b expression in goldfish RGCs, while Secretoneurin A (SNa) inhibits the expression of this enzyme. Here, we determine the range of proteins and cellular processes responsive to SNa treatments in these steroidogenic cells. The focus here is on SNa, because this peptide is derived from selective processing of secretogranin II in magnocellular cells embedded within the RGC-rich preoptic nucleus. Primary cultures of RGCs were treated (24 h) with 10, 100, or 1,000 nM SNa. By using isobaric tagging for relative and absolute quantitation and a Hybrid Quadrupole Obritrap Mass Spectrometry system, a total of 1,363 unique proteins were identified in RGCs, and 609 proteins were significantly regulated by SNa at one or more concentrations. Proteins that showed differential expression with all three concentrations of SNa included H1 histone, glutamyl-prolyl-tRNA synthetase, Rho GDP dissociation inhibitor γ, vimentin A2, and small nuclear ribonucleoprotein-associated protein. At 10, 100, and 1,000 nM SNa, there were 5, 195, and 489 proteins that were downregulated, respectively, whereas the number of upregulated proteins were 72, 44, and 51, respectively. Subnetwork enrichment analysis of differentially regulated proteins revealed that processes such as actin organization, cytoskeleton organization and biogenesis, apoptosis, mRNA processing, RNA splicing, translation, cell growth, and proliferation are regulated by SNa based on the proteomic response. Moreover, we observed that, at the low concentration of SNa, there was an increase in the abundance of proteins involved in cell growth, proliferation, and migration, whereas higher concentration of SNa appeared to downregulate proteins involved in these processes, indicating a dose-dependent proteome response. At the highest concentration of SNa, proteins linked to the etiology of diseases of the central nervous system (brain injuries, Alzheimer disease, Parkinson’s disease, cerebral infraction, brain ischemia) were also differentially regulated. These data implicate SNa in the control of cell proliferation and neurogenesis.
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Secretoneurin a regulates neurogenic and inflammatory transcriptional networks in goldfish carassius auratus radial glia
Scientific Reports, 2017Co-Authors: Dillon F. Da Fonte, Lei Xing, Christopher J Martyniuk, Adrian Pelin, Nicolas Corradi, Vance L TrudeauAbstract:Radial glial cells (RGCs) are the most abundant macroglia in the teleost brain and have established roles in neurogenesis and neurosteroidogenesis; however, their transcriptome remains uncharacterized, which limits functional understanding of this important cell type. Using cultured goldfish RGCs, RNA sequencing and de novo transcriptome assembly were performed, generating the first reference transcriptome for fish RGCs with 17,620 unique genes identified. These data revealed that RGCs express a diverse repertoire of receptors and signaling molecules, suggesting that RGCs may respond to and synthesize an array of hormones, peptides, cytokines, and growth factors. Building upon neuroanatomical data and studies investigating direct neuronal regulation of RGC physiology, differential gene expression analysis was conducted to identify transcriptional networks that are responsive to the conserved secretogranin II-derived neuropeptide Secretoneurin A (SNa). Pathway analysis of the transcriptome indicated that cellular processes related to the central nervous system (e.g., neurogenesis, synaptic plasticity, glial cell development) and immune functions (e.g., immune system activation, leukocyte function, macrophage response) were preferentially modulated by SNa. These data reveal an array of new functions that are proposed to be critical to neuronal-glial interactions through the mediator SNa.
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secretogranin ii plays a critical role in zebrafish neurovascular modeling
bioRxiv, 2017Co-Authors: Binbin Tao, Kimberly Mitchell, Ji Chen, Haibo Jia, Zuoyan Zhu, Vance L TrudeauAbstract:Secretoneurin (SN) is a neuropeptide derived from specific proteolytic processing of the precursor secretogranin II (SgII). In zebrafish and other teleosts there are 2 paralogs we previously named sgIIa and sgIIb. Our results showed that neurons expressing sgIIb were aligned with central arteries in hindbrain, demonstrating a close neurovascular association. Both sgIIb-/- and sgIIa-/-/sgIIb-/- mutant embryos were defective in hindbrain central artery development, while artery development in sgIIa-/- mutant embryos was not affected. Hindbrain arterial and venous network identities were not affected in sgIIb-/- mutant embryos, and the mRNA levels of Notch and VEGF pathway-related genes were not altered. However, the activation of MAPK and PI3K/AKT pathways were inhibited in sgIIb-/- mutant embryos. Injection of a synthetic SNb mRNA or delivery of the protein kinase activator N-arachidonoyl-L-serine could partially rescue the central artery developmental defects in the sgIIb mutants. This study provides the first in vivo evidence that sgIIb plays a critical role in neurovascular modeling the hindbrain.
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the secretogranin ii derived peptide Secretoneurin modulates electric behavior in the weakly pulse type electric fish brachyhypopomus gauderio
General and Comparative Endocrinology, 2015Co-Authors: Paula Pouso, Laura Quintana, Gabriela Lopez, Gustavo M Somoza, Ana Silva, Vance L TrudeauAbstract:Secretoneurin (SN) in the preoptic area and pituitary of mammals and fish has a conserved close association with the vasopressin and oxytocin systems, members of a peptide family that are key in the modulation of sexual and social behaviors. Here we show the presence of SN-immunoreactive cells and projections in the brain of the electric fish, Brachyhypopomus gauderio. Secretoneurin colocalized with vasotocin (AVT) and isotocin in cells and fibers of the preoptic area. In the rostral pars distalis of the pituitary, many cells were both SN and prolactin-positive. In the hindbrain, at the level of the command nucleus of the electric behavior (pacemaker nucleus; PN), some of SN-positive fibers colocalized with AVT. We also explored the potential neuromodulatory role of SN on electric behavior, specifically on the rate of the electric organ discharge (EOD) that signals arousal, dominance and subordinate status. Each EOD is triggered by the command discharge of the PN, ultimately responsible for the basal EOD rate. SN modulated diurnal basal EOD rate in freely swimming fish in a context-dependent manner; determined by the initial value of EOD rate. In brainstem slices, SN partially mimicked the in vivo behavioral effects acting on PN firing rate. Taken together, our results suggest that SN may regulate electric behavior, and that its effect on EOD rate may be explained by direct action of SN at the PN level through either neuroendocrine and/or endocrine mechanisms.
Youssef Anouar - One of the best experts on this subject based on the ideXlab platform.
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The Proinflammatory Cytokines Tumor Necrosis Factor- � and Interleukin-1 Stimulate Neuropeptide Gene Transcription and Secretion in Adrenochromaffin Cells via Activation of Extracellularly Regulated Kinase 1/2 and p38 Protein Kinases, and Activator Protei
2013Co-Authors: Djida Ait-ali, Hubert Vaudry, Valerie Turquier, Luca Grumolato, Laurent Yon, Matthieu Jourdain, David Alexandre, Lee E. Eiden, Youssef AnouarAbstract:Immune-autonomic interactions are known to occur at the level of the adrenal medulla, and to be important in immune and stress responses, but the molecular signaling pathways through which cytokines actually affect adrenal chromaffin cell function are unknown. Here, we studied the effects of the proinflammatory cytokines, TNF- � and IL-1, on gene transcription and secretion of bioactive neuropeptides, in primary bovine adrenochromaffin cells. TNF- � and IL-1 induced a time- and dosedependent increase in galanin, vasoactive intestinal polypeptide, and secretogranin II mRNA levels. The two cytokines also stimulated the basal as well as depolarization-provoked release of enkephalin and Secretoneurin from chromaffin cells. Stimulatory effects of TNF- � on neuropeptide gene expression and release appeared to be mediated through the type 2 TNF- � receptor, and required activation of ERK 1/2 and p38, but not Janus kinase, MAPKs. In addition, TNF- � increased the Abbreviations: AP-1, Activator protein-1; ATF, activating transcription factors; C/EBP, CCAAT enhancer-binding protein
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chromogranins a and b and secretogranin ii evolutionary and functional aspects
Acta Physiologica, 2007Co-Authors: Maite Monterohadjadje, Sucheta M Vaingankar, Salah Elias, Herve Tostivint, Youssef AnouarAbstract:Chromogranins/secretogranins or granins are a class of acidic, secretory proteins that occur in endocrine, neuroendocrine, and neuronal cells. Granins are the precursors of several bioactive peptides and may be involved in secretory granule formation and neurotransmitter/hormone release. Characterization and analysis of chromogranin A (CgA), chromogranin B (CgB), and secretogranin II (SgII) in distant vertebrate species confirmed that CgA and CgB belong to related monophyletic groups, probably evolving from a common ancestral precursor, while SgII sequences constitute a distinct monophyletic group. In particular, selective sequences within these proteins, bounded by potential processing sites, have been remarkably conserved during evolution. Peptides named vasostatin, secretolytin and Secretoneurin, which occur in these regions, have been shown to exert various biological activities. These conserved domains may also be involved in the formation of secretory granules in different vertebrates. Other peptides such as catestatin and pancreastatin may have appeared late during evolution. The function of granins as propeptide precursors and granulogenic factors is discussed in the light of recent data obtained in various model species and using knockout mice strains.
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the proinflammatory cytokines tumor necrosis factor α and interleukin 1 stimulate neuropeptide gene transcription and secretion in adrenochromaffin cells via activation of extracellularly regulated kinase 1 2 and p38 protein kinases and activator protein 1 transcription factors
Molecular Endocrinology, 2004Co-Authors: Djida Aitali, Hubert Vaudry, Valerie Turquier, Luca Grumolato, Laurent Yon, Matthieu Jourdain, David Alexandre, Lee E. Eiden, Youssef AnouarAbstract:Immune-autonomic interactions are known to occur at the level of the adrenal medulla, and to be important in immune and stress responses, but the molecular signaling pathways through which cytokines actually affect adrenal chromaffin cell function are unknown. Here, we studied the effects of the proinflammatory cytokines, TNF-alpha and IL-1, on gene transcription and secretion of bioactive neuropeptides, in primary bovine adrenochromaffin cells. TNF-alpha and IL-1 induced a time- and dose-dependent increase in galanin, vasoactive intestinal polypeptide, and secretogranin II mRNA levels. The two cytokines also stimulated the basal as well as depolarization-provoked release of enkephalin and Secretoneurin from chromaffin cells. Stimulatory effects of TNF-alpha on neuropeptide gene expression and release appeared to be mediated through the type 2 TNF-alpha receptor, and required activation of ERK 1/2 and p38, but not Janus kinase, MAPKs. In addition, TNF-alpha increased the binding activity of activator protein-1 (AP-1) and stimulated transcription of a reporter gene containing AP-1-responsive elements in chromaffin cells. The AP-1-responsive reporter gene could also be activated through the ERK pathway. These results suggest that neuropeptide biosynthesis in chromaffin cells is regulated by TNF-alpha via an ERK-dependent activation of AP-1-responsive gene elements. Either locally produced or systemic cytokines might regulate biosynthesis and release of neuropeptides in chromaffin cells, integrating the adrenal medulla in the physiological response to inflammation. This study describes, for the first time, a signal transduction pathway activated by TNF-alpha in a major class of neuroendocrine cells that, unlike TNF-alpha signaling in lymphoid cells, employs ERK and p38 rather than Janus kinase and p38 to transmit gene-regulatory signals to the cell nucleus.
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Biochemical Characterization and Immunocytochemical Localization of EM66, a Novel Peptide Derived from Secretogranin II, in the Rat Pituitary and Adrenal Glands
Journal of Histochemistry and Cytochemistry, 2003Co-Authors: Maite Montero-hadjadje, Songyun Li, Johann Guillemot, Rabia Magoul, Hubert Vaudry, Georges Pelletier, Yves Tillet, Youssef AnouarAbstract:Characterization of secretogranin II (SgII) mRNA in various vertebrates has revealed selective conservation of the amino acid sequences of two regions of the protein, i.e., the bioactive peptide Secretoneurin and a flanking novel peptide that we named EM66. To help elucidate the possible role of EM66, we examined the occurrence as well as the cellular and subcellular distribution of EM66 in rat pituitary and adrenal glands by using a polyclonal antibody raised against the recombinant human EM66 peptide. High-performance liquid chromatography (HPLC) analysis of rat pituitary and adrenal extracts combined with a radioimmu-noassay resolved EM66-immunoreactive material exhibiting the same retention time as recom-binant EM66. In the rat pituitary, double-labeling immunohistochemical (IHC) studies showed that EM66 immunoreactivity (IR) was present in gonadotrophs, lactotrophs, thyrotrophs, and melanotrophs, whereas corticotrophs were devoid of labeling. EM66-IR was also observed in nerve endings in the neural lobe. Immunocytochemical staining at the electron microscopic level revealed that EM66-IR is sequestered in the secretory granules within gonadotrophs and lactotrophs. In the adrenal medulla, double IHC labeling showed that EM66-IR occurs exclusively in epinephrine-synthesizing cells. At the ultrastructural level, EM66-IR was seen in chro-maffin vesicles of adrenomedullary cells. These results demonstrate that post-translational processing of SgII generates a novel peptide that exhibits a cell-specific distribution in the rat pituitary and adrenal glands where it is stored in secretory granules, supporting the notion that EM66 may play a role in the endocrine system. (J Histochem Cytochem 51:1083–1095, 2003)
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Pituitary Adenylate Cyclase-Activating Polypeptide Stimulates Secretoneurin Release and Secretogranin II Gene Transcription in Bovine Adrenochromaffin Cells through Multiple Signaling Pathways and Increased Binding of Pre-Existing Activator Protein-1-Like Transcription Factors
Molecular Pharmacology, 2001Co-Authors: Valerie Turquier, Hubert Vaudry, Luca Grumolato, Laurent Yon, David Alexandre, Alain Fournier, Youssef AnouarAbstract:Secretoneurin (SN) is a novel bioactive peptide that derives from the neuroendocrine protein secretogranin II (SgII) by pro-teolytic processing and participates in neuro-immune communication. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP-38) dose-dependently stimulates (EC 50 ϳ 3 nM) SN release (up to 4-fold) and SgII gene expression (up to 60-fold) in cultured bovine adrenochromaffin cells. The effect of PACAP on both SN secretion and SgII mRNA levels is rapid and long lasting. We analyzed in this neuroen-docrine cell model the transduction pathways involved in both SN secretion and SgII gene transcription in response to PACAP. The cytosolic calcium chelator BAPTA-AM and the nonselective calcium channel antagonist NiCl 2 equally inhibited both secretion of the peptide and transcription of the SgII gene, indicating a major contribution of calcium influx in PACAP-induced SN biosynthesis and release in chromaffin cells. Inhibition of protein kinase A (PKA) or C (PKC) also reduced PACAP-evoked SN release but did not alter the stimulatory effect of PACAP on SgII mRNA levels. Conversely, application of mitogen-activated protein kinase inhibitors suppressed PACAP-induced SgII gene expression. The effect of PACAP on SgII mRNA levels, like the effect of the PKC stimulator 12-O-tetradecanoylphorbol-13-acetate (TPA), was not affected by cycloheximide, whereas the effects of the PKA stimulator for-skolin or cell-depolarization by high K ϩ were significantly reduced by the protein synthesis inhibitor. PACAP and TPA both increased the binding activity of the SgII cAMP response element to transacting factors present in chromaffin cell nuclear extracts, which are recognized by antibodies to activator protein -1-related proteins. These data indicate that SN biosynthe-sis is regulated by PACAP in chromaffin cells through complex signaling cascades, suggesting that SN may play a function during trans-synaptic stimulation of the adrenal medulla.
Reiner Fischercolbrie - One of the best experts on this subject based on the ideXlab platform.
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secretogranin ii novel insights into expression and function of the precursor of the neuropeptide Secretoneurin
2017Co-Authors: Reiner Fischercolbrie, Markus Theurl, Rudolf KirchmairAbstract:SgII is an acidic secretory which belongs to the family of chromogranins. It is present in the large-dense cored vesicles of the regulated secretory pathway of many neurons and endocrine cells and it is well conserved during evolution. Like chromogranin A, SgII can induce granulogenesis in endocrine cells but also in cells typically lacking secretory vesicles like fibroblasts. In the secretory vesicles SgII is processed to smaller peptides, e.g. secretoeneurin, EM66 and manserin. For Secretoneurin several biological effects like induction of neurotransmitter release, chemotactic activity towards immune-, endothelial- and muscle cells, and potent angiogenic and vasculogenic properties have been established. Thus, SN displays potent hormonal and paracrine effects, which help to orchestrate development, maintenance, physiologic activity and repair of the surrounding tissue. In addition, SgII has been established as valuable biomarker for endocrine tumours and cardiovascular diseases.
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Secretoneurin stimulates the production and release of luteinizing hormone in mouse lβt2 gonadotropin cells
American Journal of Physiology-endocrinology and Metabolism, 2011Co-Authors: E Zhao, Reiner Fischercolbrie, Ajoy Basak, Judy R Mcneilly, A S Mcneilly, Jae Young Seong, Vance L TrudeauAbstract:Secretoneurin (SN) is a functional secretogranin II (SgII)-derived peptide that stimulates luteinizing hormone (LH) production and its release in the goldfish. However, the effects of SN on the pit...
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conditional knockout of the secretogranin ii gene to reveal biological functions of Secretoneurin
BMC Pharmacology, 2008Co-Authors: Johannes Leierer, Rudolf Kirchmair, Sushil K Mahata, Christoph Schwarzer, Reiner FischercolbrieAbstract:Secretogranin II (SgII) belongs to the family of chromogranins, which are widely expressed in large dense-core vesicles (LDV) of nerves and neuroendocrine tissues. In LDV SgII is processed to smaller peptides, like Secretoneurin (SN). SN was initially described in our lab [1] and has been established as a novel biologically active neuropeptide linking nerves, blood vessels and the immune system. SN releases dopamine and dynorphin from rat striatal slices, potently and specifically attracts monocytes, eosinophils, dendritic and endothelial cells towards a concentration gradient and acts as an angiogenic and vasculogenic cytokine comparable in potency to VEGF. SN contributes to neurogenic inflammation and might play a role in the irritative response in the eye, as it innervates a wide range of ocular tissues. The role of SN in hypoxiadriven induction of neo-vascularization in ischemic diseases like cerebral ischemia or in solid tumours will be subject of studies with a conditional knockout mouse for the secretogranin II gene. For these studies, a targeting vector was generated in our lab. In classical knockout animals the target gene is disrupted by either deleting parts of the gene, or by insertion of foreign DNA sequences into the target gene by site-specific homologous recombination. This genetic rearrangement is present in each cell of the animal right from the start. In conditional knockout animals, the structure and function of the gene of interest is only minimally altered. The gene of interest gets flanked by loxP sites, which serve as cleavage site for the Cre recombinase. In the presence of this enzyme, the gene will be excised precisely while other cells without Cre recombinase remain unaffected. The advantages of the conditional knockout system are: (i) It circumvents problems of simple knockouts such as compensation during development. (ii) Spatial knockout allows the study of gene functions in defined regions or tissues, without complications due to whole-body gene deletion. The generation of a conditional SgII knockout mouse will contribute to a better understanding of the physiological relevance of SN. Alterations of these mice in physiological and pathological conditions central to angiogenesis like wound healing; tissue ischemia following cardiovascular diseases; tumour growth and metastasis will be investigated. Due to the involvement of chromogranins in LDV biogenesis the ablation of SgII might also impair LDV generation.
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secretogranin ii relative amounts and processing to Secretoneurin in various rat tissues
Journal of Neurochemistry, 2002Co-Authors: Bernd Leitner, Reiner Fischercolbrie, Gerhard Scherzer, H WinklerAbstract:Secretoneurin is a 33-amino-acid peptide produced in vivo from secretogranin II. An antiserum raised against this peptide recognizes both the free peptide and its precursors. By HPLC and radioimmunoassay we characterized the immunoreactive molecules and determined the levels of immunoreactivity in various rat organs. In adrenal medulla and to a lesser degree in the anterior pituitary processing of secretogranin II to Secretoneurin was very limited, whereas in all other organs studied (brain, intestine, endocrine pancreas, thyroid gland, and posterior pituitary) a high degree of processing was apparent. Thus, practically all of the immunoreactivity was present as free Secretoneurin. This was also true for serum. When the total amount of Secretoneurin immunoreactivity was calculated for the various organs, the largest pools in descending order were in the intestine, CNS, anterior pituitary, pancreas, and adrenal gland. This makes it likely that Secretoneurin in serum is mainly derived from the intestine. The high degree of processing of secretogranin II in most organs is consistent with the concept that this protein acts as a precursor of a functional peptide, i.e., Secretoneurin.
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Secretoneurin in carcinoids of the appendix immunohistochemical comparison with chromogranins a b and secretogranin ii
Anticancer Research, 1998Co-Authors: Rupert Prommegger, Reiner Fischercolbrie, Peter Obrist, Christian Ensinger, H G Schwelberger, C Wolf, Gregor Mikuz, E BodnerAbstract:Background: The aim of the present study was to investigate immunohistochemically the distribution of Secretoneurin, a novel 33 amino acid peptide, in comparison to chromogranin A, chromogranin B, and secretogranin II in carcinoids of the appendix Materials and Methods: Paraffin-embedded tissues from 47 carcinoids were incubated with antibodies specific for chromogranin A, chromogranin B, the secretogranin II derived peptide LF- 19, and Secretoneurin. Results: 44 tumors (94%) were positive for Secretoneurin, whereas only 39 tumors (83%) were immunoreactive for chromogranin A. There was no significant correlation between neuropeptide expression and type of carcinoid, tumor size, vascular infiltration, serosal involvement or mesoappendiceal infiltration. Conclusions: Our investigations revealed that Secretoneurin is detected more frequently than chromogranin A in carcinoids of the appendix. This supports the theory that tumor cells of appendiceal carcinoids are of a different origin than other midgut carcinoids. No special tumor entity with a characteristic Secretoneurin-chromogranin pattern could be identified.
E Zhao - One of the best experts on this subject based on the ideXlab platform.
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The Secretogranin II-Derived Peptide Secretoneurin Stimulates Luteinizing Hormone Secretion from
2015Co-Authors: E Zhao, C. L. Grey, A. Basak, A. O. L. Wong, A. Chen, G. C. López, L. F. Canosa, G. M. Somoza, J. P. ChangAbstract:Secretoneurin (SN) is a 33- to 34-aminoacidneuropeptidederived from secretogranin-II, amember of the chromogranin family. We previously synthesized a putative goldfish (gf) SN and demon-strated its ability to stimulate LH release in vivo. However, it was not known whether goldfish actually produced the free SN peptide or whether SN directly stimulates LH release from isolated pituitary cells. Using a combination of reverse-phase HPLC and mass spectrometry analysis, we isolated for the first time a 34-amino acid free gfSN peptide from the whole brain. Moreover, Western blot analysis indicated the existence of this peptide in goldfish pituitary. Immunocyto-chemical localization studies revealed the presence of SN immunoreactivity in prolactin cells of rostral pars distalis of the anterior pituitary. Additionally, we found thatmagnocellular cells of the goldfish preoptic region are highly immunoreactive for SN. These neurons send heavily labeled projections thatpass through thepituitary stalk and innervate theneurointermediateandanterior lobes. In static 12-h incubation of dispersed pituitary cells, application of SN antiserum reduced LH levels, whereas 1 and 10 nM gfSN, respectively, induced 2.5-fold (P 0.001) and 1.9-fold (P 0.01) increments of LH release into the medium, increases similar to those elicited by 100 nM concen-trationsofGnRH. LikeGnRH,gfSNelevated intracellularCa2 in identifiedgonadotrophs.Wherea
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Secretoneurin stimulates the production and release of luteinizing hormone in mouse lβt2 gonadotropin cells
American Journal of Physiology-endocrinology and Metabolism, 2011Co-Authors: E Zhao, Reiner Fischercolbrie, Ajoy Basak, Judy R Mcneilly, A S Mcneilly, Jae Young Seong, Vance L TrudeauAbstract:Secretoneurin (SN) is a functional secretogranin II (SgII)-derived peptide that stimulates luteinizing hormone (LH) production and its release in the goldfish. However, the effects of SN on the pit...
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Secretoneurin is a potential paracrine factor from lactotrophs stimulating gonadotropin release in the goldfish pituitary
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2010Co-Authors: E Zhao, Ajoy Basak, Dapeng Zhang, Jan A Mennigen, C. L. Grey, J. P. Chang, Vance L TrudeauAbstract:Secretoneurin (SN) is a functional neuropeptide derived from the evolutionarily conserved part of precursor protein secretogranin II (SgII). In the time course study, SN (10 nM) stimulates luteiniz...
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the secretogranin ii derived peptide Secretoneurin stimulates luteinizing hormone secretion from gonadotrophs
Endocrinology, 2009Co-Authors: E Zhao, Luis Fabián Canosa, G. C. Lopez, Ajoy Basak, C. L. Grey, J. P. Chang, A. O. L. Wong, A. Chen, G. M. Somoza, Vance L TrudeauAbstract:Secretoneurin (SN) is a 33- to 34-amino acid neuropeptide derived from secretogranin-II, a member of the chromogranin family. We previously synthesized a putative goldfish (gf) SN and demonstrated its ability to stimulate LH release in vivo. However, it was not known whether goldfish actually produced the free SN peptide or whether SN directly stimulates LH release from isolated pituitary cells. Using a combination of reverse-phase HPLC and mass spectrometry analysis, we isolated for the first time a 34-amino acid free gfSN peptide from the whole brain. Moreover, Western blot analysis indicated the existence of this peptide in goldfish pituitary. Immunocytochemical localization studies revealed the presence of SN immunoreactivity in prolactin cells of rostral pars distalis of the anterior pituitary. Additionally, we found that magnocellular cells of the goldfish preoptic region are highly immunoreactive for SN. These neurons send heavily labeled projections that pass through the pituitary stalk and innervate the neurointermediate and anterior lobes. In static 12-h incubation of dispersed pituitary cells, application of SN antiserum reduced LH levels, whereas 1 and 10 nM gfSN, respectively, induced 2.5-fold (P < 0.001) and 1.9-fold (P < 0.01) increments of LH release into the medium, increases similar to those elicited by 100 nM concentrations of GnRH. Like GnRH, gfSN elevated intracellular Ca(2+) in identified gonadotrophs. Whereas we do not yet know the relative contribution of neural SN or pituitary SN to LH release, we propose that SN could act as a neuroendocrine and/or paracrine factor to regulate LH release from the anterior pituitary.
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proteolytic processing and differential distribution of secretogranin ii in goldfish
General and Comparative Endocrinology, 2006Co-Authors: E Zhao, Ajoy Basak, Kate Crump, Vance L TrudeauAbstract:Abstract Secretoneurin (SN) is a 33–34 amino acid neuropeptide derived by endoproteolysis of secretogranin-II (SgII), a chromogranin. A multi-antigenic strategy was used to generate a rabbit polyclonal goldfish SN antiserum that was characterized for Western blot analysis. In the goldfish pituitary two intermediate proteins containing SN and likely processed from the 69.6-kDa SgII precursor were detected. No immunoreactive proteins were observed in the goldfish interrenal, ovary, cerebellum, and telencephalon whereas SgII mRNA was expressed in all these tissues. Immunoreactive levels of the ∼57 kDa product were higher in the pars distalis (PD) than in the neurointermediate lobe (NIL). The abundance of the ∼57 kDa protein indicates that this SgII-product containing the SN sequence is a major stored form in secretory granules of the goldfish pituitary. High expression and processing of SN in the hypothalamus and pituitary suggest important roles for SgII-derived peptides in neuroendocrine tissues.
Rudolf Kirchmair - One of the best experts on this subject based on the ideXlab platform.
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secretogranin ii novel insights into expression and function of the precursor of the neuropeptide Secretoneurin
2017Co-Authors: Reiner Fischercolbrie, Markus Theurl, Rudolf KirchmairAbstract:SgII is an acidic secretory which belongs to the family of chromogranins. It is present in the large-dense cored vesicles of the regulated secretory pathway of many neurons and endocrine cells and it is well conserved during evolution. Like chromogranin A, SgII can induce granulogenesis in endocrine cells but also in cells typically lacking secretory vesicles like fibroblasts. In the secretory vesicles SgII is processed to smaller peptides, e.g. secretoeneurin, EM66 and manserin. For Secretoneurin several biological effects like induction of neurotransmitter release, chemotactic activity towards immune-, endothelial- and muscle cells, and potent angiogenic and vasculogenic properties have been established. Thus, SN displays potent hormonal and paracrine effects, which help to orchestrate development, maintenance, physiologic activity and repair of the surrounding tissue. In addition, SgII has been established as valuable biomarker for endocrine tumours and cardiovascular diseases.
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Secretoneurin gene therapy improves blood flow in an ischemia model in type 1 diabetic mice by enhancing therapeutic neovascularization. PLoS One 8:e74029. doi: 10.1371/journal.pone.0074029 PMID: 24086307
2013Co-Authors: Wilfried Schgoer, Markus Theurl, Karin Albrecht-schgoer, Verena Jonach, Bernhard Koller, Daniela Lener, Wolfgang M. Franz, Rudolf KirchmairAbstract:Deficient angiogenesis after ischemia may contribute to worse outcome of peripheral arterial disease in patients with diabetes mellitus. Based on our previous work where we demonstrated that Secretoneurin (SN) is up-regulated under hypoxic conditions and enhances angiogenesis, we analyzed the therapeutic potential of SN gene therapy using a model of severe hind limb ischemia in streptozotocin-induced diabetic mice (STZ-DM). After induction of hind limb ischemia, blood flow was assessed by means of laser Doppler perfusion imaging (LDPI) and increased blood perfusion in the SN-treated animal group was observed. These results were complemented by the clinical observation of reduced necrosis and by an increased number of capillaries and arterioles in the SN-treated animal group. In vitro, we found that SN is capable of promoting proliferation and chemotaxis and reduces apoptosis in HUVECs cultured under hyperglycemic conditions. Additionally, SN activated ERK, eNOS and especially AKT as well as EGF-receptor in hyperglycemic HUVECs. In conclusion, we show that SN gene therapy improves post-ischemic neovascularization in diabetic mice through stimulation of angiogenesis and arteriogenesis indicating a possible therapeutic role of this factor in ischemia-related diseases in diabetic patients
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Secretoneurin Gene Therapy Improves Blood Flow in an Ischemia Model in Type 1 Diabetic Mice by Enhancing Therapeutic Neovascularization
2013Co-Authors: Wilfried Schgoer, Markus Theurl, Karin Albrecht-schgoer, Verena Jonach, Bernhard Koller, Daniela Lener, Wolfgang M. Franz, Rudolf KirchmairAbstract:Deficient angiogenesis after ischemia may contribute to worse outcome of peripheral arterial disease in patients with diabetes mellitus. Based on our previous work where we demonstrated that Secretoneurin (SN) is up-regulated under hypoxic conditions and enhances angiogenesis, we analyzed the therapeutic potential of SN gene therapy using a model of severe hind limb ischemia in streptozotocin-induced diabetic mice (STZ-DM). After induction of hind limb ischemia, blood flow was assessed by means of laser Doppler perfusion imaging (LDPI) and increased blood perfusion in the SN-treated animal group was observed. These results were complemented by the clinical observation of reduced necrosis and by an increased number of capillaries and arterioles in the SN-treated animal group. In vitro, we found that SN is capable of promoting proliferation and chemotaxis and reduces apoptosis in HUVECs cultured under hyperglycemic conditions. Additionally, SN activated ERK, eNOS and especially AKT as well as EGF-receptor in hyperglycemic HUVECs. In conclusion, we show that SN gene therapy improves post-ischemic neovascularization in diabetic mice through stimulation of angiogenesis and arteriogenesis indicating a possible therapeutic role of this factor in ischemia-related diseases in diabetic patients.
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conditional knockout of the secretogranin ii gene to reveal biological functions of Secretoneurin
BMC Pharmacology, 2008Co-Authors: Johannes Leierer, Rudolf Kirchmair, Sushil K Mahata, Christoph Schwarzer, Reiner FischercolbrieAbstract:Secretogranin II (SgII) belongs to the family of chromogranins, which are widely expressed in large dense-core vesicles (LDV) of nerves and neuroendocrine tissues. In LDV SgII is processed to smaller peptides, like Secretoneurin (SN). SN was initially described in our lab [1] and has been established as a novel biologically active neuropeptide linking nerves, blood vessels and the immune system. SN releases dopamine and dynorphin from rat striatal slices, potently and specifically attracts monocytes, eosinophils, dendritic and endothelial cells towards a concentration gradient and acts as an angiogenic and vasculogenic cytokine comparable in potency to VEGF. SN contributes to neurogenic inflammation and might play a role in the irritative response in the eye, as it innervates a wide range of ocular tissues. The role of SN in hypoxiadriven induction of neo-vascularization in ischemic diseases like cerebral ischemia or in solid tumours will be subject of studies with a conditional knockout mouse for the secretogranin II gene. For these studies, a targeting vector was generated in our lab. In classical knockout animals the target gene is disrupted by either deleting parts of the gene, or by insertion of foreign DNA sequences into the target gene by site-specific homologous recombination. This genetic rearrangement is present in each cell of the animal right from the start. In conditional knockout animals, the structure and function of the gene of interest is only minimally altered. The gene of interest gets flanked by loxP sites, which serve as cleavage site for the Cre recombinase. In the presence of this enzyme, the gene will be excised precisely while other cells without Cre recombinase remain unaffected. The advantages of the conditional knockout system are: (i) It circumvents problems of simple knockouts such as compensation during development. (ii) Spatial knockout allows the study of gene functions in defined regions or tissues, without complications due to whole-body gene deletion. The generation of a conditional SgII knockout mouse will contribute to a better understanding of the physiological relevance of SN. Alterations of these mice in physiological and pathological conditions central to angiogenesis like wound healing; tissue ischemia following cardiovascular diseases; tumour growth and metastasis will be investigated. Due to the involvement of chromogranins in LDV biogenesis the ablation of SgII might also impair LDV generation.
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csf of neuroleptic naive first episode schizophrenic patients levels of biogenic amines substance p and peptides derived from chromogranin a ge 25 and secretogranin ii Secretoneurin
Biological Psychiatry, 1996Co-Authors: C H Miller, Reiner Fischercolbrie, Rudolf Kirchmair, Alois Saria, A Benzer, Josef Troger, Wolfgang W Fleischhacker, H WinklerAbstract:Lumbar cerebrospinal fluid (CSF) was collected from controls and neuroleptic-naive patients with their first acute schizophrenic episode. The CSF was analyzed for several biogenic amines and their metabolites [dopamine, dihydroxyphenylacetic acid (DOPAC), noradrenaline, 5-hydroxytryptamine (5-HT), 5-hydroxyindolacetic acid (5-HIAA)]. For these transmitters, which are stored and secreted from synaptic vesicles, there was no significant difference between controls and schizophrenic patients. As constituents of large dense-core vesicles substance P (SP) and GE-25 (derived from chromogranin A)—and Secretoneurin (derived from secretogranin II)—immunoreactivities were determined. SP-like immunoreactivity levels did not differ between controls and patients; however, GE-25 was elevated and especially the GE-25/Secretoneurin ratio was significantly (p
