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1
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Tillinger A, Mravec B. Vagotomy Affects Lipopolysaccharide-Induced Changes of Urocortin 2 Gene Expression in the Brain and on the Periphery. Neurochem Res 2021; 46:159-164. [PMID: 33170479 DOI: 10.1007/s11064-020-03165-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/28/2020] [Accepted: 10/31/2020] [Indexed: 11/29/2022]
Abstract
The corticotropin-releasing hormone family of peptides is involved in regulating the neuroendocrine stress response. Also, the vagus nerve plays an important role in the transmission of immune system-related signals to brain structures, thereby orchestrating the neuroendocrine stress response. Therefore, we investigated gene expression of urocortin 2 (Ucn2) and c-fos, a markers of neuronal activity, within the hypothalamic paraventricular nucleus (PVN), a brain structure involved in neuroendocrine and neuroimmune responses, as well as in the adrenal medulla and spleen in vagotomized rats exposed to immune challenge. In addition, markers of neuroendocrine stress response activity were investigated in the adrenal medulla, spleen, and plasma. Intraperitoneal administration of lipopolysaccharide (LPS) induced a significant increase of c-fos and Ucn2 gene expression in the PVN, and adrenal medulla as well as increases of plasma corticosterone levels. In addition, LPS administration induced a significant increase in the gene expression of tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) in the adrenal medulla. In the spleen, LPS administration increased gene expression of c-fos, while gene expression of TH and PNMT was significantly reduced, and gene expression of Ucn2 was not affected. Subdiaphragmatic vagotomy significantly attenuated the LPS-induced increases of gene expression of c-fos and Ucn2 in the PVN and Ucn2 in the adrenal medulla. Our data has shown that Ucn2 may be involved in regulation of the HPA axis in response to immune challenge. In addition, our findings indicate that the effect of immune challenge on gene expression of Ucn2 is mediated by vagal pathways.
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Affiliation(s)
- Andrej Tillinger
- Institute of Experimental Endocrinology, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia.
| | - Boris Mravec
- Institute of Experimental Endocrinology, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
- Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
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2
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Wang Q, Liu Y, Zhang J, Wang W. Corticotropin-Releasing Factor Receptors in the Locus Coeruleus Modulate the Enhancement of Active Coping Behaviors Induced by Chronic Predator Odor Inoculation in Mice. Front Psychol 2020; 10:3028. [PMID: 31998206 PMCID: PMC6965494 DOI: 10.3389/fpsyg.2019.03028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 12/20/2019] [Indexed: 01/09/2023] Open
Abstract
Stress inoculation has been proved to induce active coping behaviors to subsequent stress. However, the specific neural mechanisms underlying this effect remain unclear. In this study, a chronic and mild predator odor exposure model was established to investigate the effect of predator odor stress inoculation on behaviors in novel predator odor exposure, open field test and forced swimming test (FST), and on the expression of CRF receptors in locus coeruleus (LC) and dorsal raphe nuclei (DRN). The results showed that predator odor stress inoculation increased the active coping of mice under the severe stress environment without changing the stress response to a new predator odor. Meanwhile, in LC, the CRFR1 expression was increased by predator odor stress inoculation. These results suggested that predator odor stress inoculation can be used as an effective training method to improve active response to later severe stress and the function of CRFR1 in LC might be a potential underlying biological mechanism.
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Affiliation(s)
- Qiong Wang
- School of Education, Zhengzhou University, Zhengzhou, China
| | - Yingjuan Liu
- School of Life Sciences and Technology, Nanyang Normal University, Nanyang, China
| | - Jianxu Zhang
- State Key Laboratory of Integrated Management of Pest Insects and Rodents in Agriculture, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Weiwen Wang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China.,Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
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3
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Short treatment with antalarmin alters adrenal gland receptors in the rat model of endometriosis. PLoS One 2020; 15:e0227456. [PMID: 31935235 PMCID: PMC6959558 DOI: 10.1371/journal.pone.0227456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/18/2019] [Indexed: 11/19/2022] Open
Abstract
Endometriosis is a chronic inflammatory disorder in which endometrial tissue is found outside the uterine cavity. Previous reports suggest that there is a dysregulation of the hypothalamic pituitary adrenal axis during the progression of endometriosis. Our previous report showed that a short-term treatment with antalarmin, a corticotrophin releasing hormone receptor type 1 (CRHR1) antagonist decreases the number and size of endometriotic vesicles in the auto-transplantation rat model of endometriosis. Our current goal was to examine the mRNA expression of intra-adrenal receptors to better understand the mechanisms of the hypothalamic pituitary adrenal (HPA) axis involvement in endometriosis. We used two groups of female rats. The first received sham surgery or endometriosis surgery before collecting the adrenals after 7 days of the disease progression. The second group of animals received endometriosis surgery and a treatment of either vehicle or antalarmin (20 mg/kg, i.p.) during the first 7 days after endometriosis induction and then the disease was allowed to progress until day 60. Rats with sham surgery served as controls. Results showed that the mRNA expression of the mineralocorticoid (MRC2) receptor was lower in the rats after 7 days of endometriosis surgery and in rats with endometriosis that received antalarmin. In addition, the CRHR1 was significantly elevated in animals that received antalarmin and this was counteracted by a non-significant elevation in CRHR2 mRNA. The glucocorticoid receptor mRNA within the adrenals was not affected by endometriosis or antalarmin treatment. This report is one of the first to explore intra-adrenal mRNA for receptors involved in the HPA axis signaling as well as in the sympatho-adrenal signaling, calling for additional research towards understanding the role of the adrenal glands in chronic inflammatory diseases such as endometriosis.
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4
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Evaluation of Serum Urocortin 2 Levels in Patients with Hypertension. High Blood Press Cardiovasc Prev 2020; 27:35-42. [DOI: 10.1007/s40292-019-00357-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 12/26/2019] [Indexed: 01/19/2023] Open
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Baritaki S, de Bree E, Chatzaki E, Pothoulakis C. Chronic Stress, Inflammation, and Colon Cancer: A CRH System-Driven Molecular Crosstalk. J Clin Med 2019; 8:E1669. [PMID: 31614860 PMCID: PMC6833069 DOI: 10.3390/jcm8101669] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/08/2019] [Accepted: 10/11/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic stress is thought to be involved in the occurrence and progression of multiple diseases, via mechanisms that still remain largely unknown. Interestingly, key regulators of the stress response, such as members of the corticotropin-releasing-hormone (CRH) family of neuropeptides and receptors, are now known to be implicated in the regulation of chronic inflammation, one of the predisposing factors for oncogenesis and disease progression. However, an interrelationship between stress, inflammation, and malignancy, at least at the molecular level, still remains unclear. Here, we attempt to summarize the current knowledge that supports the inseparable link between chronic stress, inflammation, and colorectal cancer (CRC), by modulation of a cascade of molecular signaling pathways, which are under the regulation of CRH-family members expressed in the brain and periphery. The understanding of the molecular basis of the link among these processes may provide a step forward towards personalized medicine in terms of CRC diagnosis, prognosis and therapeutic targeting.
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Affiliation(s)
- Stavroula Baritaki
- Division of Surgery, School of Medicine, University of Crete, Heraklion, 71500 Crete, Greece.
| | - Eelco de Bree
- Division of Surgery, School of Medicine, University of Crete, Heraklion, 71500 Crete, Greece.
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | - Charalabos Pothoulakis
- IBD Center, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 10833, USA.
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6
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Squillacioti C, Pelagalli A, Liguori G, Mirabella N. Urocortins in the mammalian endocrine system. Acta Vet Scand 2019; 61:46. [PMID: 31585551 PMCID: PMC6778379 DOI: 10.1186/s13028-019-0480-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Accepted: 09/21/2019] [Indexed: 12/13/2022] Open
Abstract
Urocortins (Ucns), peptides belonging to the corticotropin-releasing hormone (CRH) family, are classified into Ucn1, Ucn2, and Ucn3. They are involved in regulating several body functions by binding to two G protein-coupled receptors: receptor type 1 (CRHR1) and type 2 (CRHR2). In this review, we provide a historical overview of research on Ucns and their receptors in the mammalian endocrine system. Although the literature on the topic is limited, we focused our attention particularly on the main role of Ucns and their receptors in regulating the hypothalamic-pituitary-adrenal and thyroid axes, reproductive organs, pancreas, gastrointestinal tract, and other tissues characterized by "diffuse" endocrine cells in mammals. The prominent function of these peptides in health conditions led us to also hypothesize an action of Ucn agonists/antagonists in stress and in various diseases with its critical consequences on behavior and physiology. The potential role of the urocortinergic system is an intriguing topic that deserves further in-depth investigations to develop novel strategies for preventing stress-related conditions and treating endocrine diseases.
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Affiliation(s)
- Caterina Squillacioti
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via Veterinaria 1, 80137 Naples, Italy
| | - Alessandra Pelagalli
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
- Institute of Biostructures and Bioimages, National Research Council, Via De Amicis 95, 80131 Naples, Italy
| | - Giovanna Liguori
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via Veterinaria 1, 80137 Naples, Italy
| | - Nicola Mirabella
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via Veterinaria 1, 80137 Naples, Italy
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Wang Z, Gai Y, Zhou J, Liu J, Cui S. miR-375 mediates the CRF signaling pathway to regulate catecholamine biosynthesis by targeting Sp1 in porcine adrenal gland. Stress 2019; 22:332-346. [PMID: 30714474 DOI: 10.1080/10253890.2018.1561845] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Corticotropin-releasing-factor (CRF) is a key regulator of catecholamines (CATs) biosynthesis in the adrenal gland. Furthermore, miR-375 has been confirmed to be localized in the mouse adrenal gland. However, the relationships between miR-375 and CRF in regulating CATs biosynthesis remain to be established. This study was designed to investigate the relationship between CRF and miR-375 in the regulation of CATs biosynthesis in the porcine adrenal gland. Eight adult female pigs (four controls; four injected intracerebroventricularly with 50 μg of CRF) were used for the in vivo experiments in this study. The results showed that miR-375 was exclusively localized in porcine adrenal medullary cells. Functional studies showed that miR-375 negatively regulated CATs synthesis in primary cells by affecting the expression of the CATs synthetases tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine-N-methyltransferase (PNMT). CRF up-regulated the expression of CATs synthetase in primary adrenal medullary cells under basal conditions and upon endogenous miR-375 inhibition; the enhanced effects vanished when cellular miR-375 was overexpressed by transfecting miR-375-mic. CRF decreased the expression of miR-375 both in vivo and in vitro. Our in vitro results showed that CRF significantly decreased the expression of miR-375, perhaps by binding to CRFR1. miR-375 functions by directly binding to the 3'-UTR region of specificity protein 1 (Sp1), which is involved in regulating Th and Dbh expression. These data collectively indicate that miR-375 plays an important role in regulating CATs synthesis and mediates the CRF signaling pathway in porcine adrenal medullary cells.
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Affiliation(s)
- Zhijuan Wang
- a State Key Laboratory of Agrobiotechnology, College of Biological Sciences , China Agricultural University , Beijing , PR China
| | - Yedan Gai
- a State Key Laboratory of Agrobiotechnology, College of Biological Sciences , China Agricultural University , Beijing , PR China
| | - Jinlian Zhou
- b The 306th Hospital of People's Liberation Army , Beijing , PR China
| | - Jiali Liu
- a State Key Laboratory of Agrobiotechnology, College of Biological Sciences , China Agricultural University , Beijing , PR China
| | - Sheng Cui
- a State Key Laboratory of Agrobiotechnology, College of Biological Sciences , China Agricultural University , Beijing , PR China
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8
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Do urocortins have a role in treating cardiovascular disease? Drug Discov Today 2019; 24:279-284. [DOI: 10.1016/j.drudis.2018.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 08/20/2018] [Accepted: 09/05/2018] [Indexed: 02/02/2023]
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True C, Arik A, Lindsley S, Kirigiti M, Sullivan E, Kievit P. Early High-Fat Diet Exposure Causes Dysregulation of the Orexin and Dopamine Neuronal Populations in Nonhuman Primates. Front Endocrinol (Lausanne) 2018; 9:508. [PMID: 30258403 PMCID: PMC6143816 DOI: 10.3389/fendo.2018.00508] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 08/14/2018] [Indexed: 01/01/2023] Open
Abstract
Maternal obesity and consumption of a high-fat diet (HFD) during pregnancy has a negative impact on offspring, including an increased risk for the development of obesity in adolescence. The mechanism for this transferred metabolic risk is unclear, but many studies have focused on the brain due to its important role in appetite and body-weight regulation. Two main pathways regulate appetite in the brain; homeostatic regulation that occurs predominantly in hypothalamic circuits and hedonic regulation of feeding that occurs via dopaminergic pathways. The current proposal examined the impact of early HFD exposure on the dopaminergic control of hedonic feeding pathways in a translational nonhuman primate model. Japanese macaque offspring from mothers consuming a control (CTR) or HFD were weaned onto control or HFD at an average 8 months of age yielding four groups: maternal and post-weaning control diet (mCTRpCTR), maternal control diet and post-weaning HFD (mCTRpHFD), maternal HFD and post-weaning control diet (mHFDpCTR) and maternal and post-weaning HFD (mHFDpHFD). Brains from 13-month-old offspring were evaluated for expression of neuropeptides that regulate dopaminergic pathways including orexin, melanin-concentrating hormone (MCH) in the lateral hypothalamus (LH), and tyrosine hydroxylase expression in the ventral tegmental area (VTA). Orexin cell numbers in the LH were significantly increased in animals exposed to a post-weaning HFD, while no difference was observed for orexin mRNA content or MCH cell numbers. Orexin fiber projections to the rostral VTA were significantly reduced in mCTRpHFD, mHFDpCTR, and mHFDpHFD groups, but these differences were not significant in the caudal VTA. There was no difference in the percentage of dopamine neurons receiving close appositions from orexin fibers in either the rostral or caudal VTA, nor was there any difference between groups in the number of orexin contacts per TH cell. In conclusion, the current study finds that prolonged early exposure to HFD during the in utero and postnatal period causes alterations at several levels in the dopaminergic circuits regulating reward.
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Affiliation(s)
- Cadence True
- Cardiometabolic Health Division, Oregon National Primate Research Center, Beaverton, OR, United States
| | - Anam Arik
- Cardiometabolic Health Division, Oregon National Primate Research Center, Beaverton, OR, United States
| | - Sarah Lindsley
- Cardiometabolic Health Division, Oregon National Primate Research Center, Beaverton, OR, United States
| | - Melissa Kirigiti
- Cardiometabolic Health Division, Oregon National Primate Research Center, Beaverton, OR, United States
| | - Elinor Sullivan
- Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, United States
- Department of Human Physiology, University of Oregon, Eugene, OR, United States
| | - Paul Kievit
- Cardiometabolic Health Division, Oregon National Primate Research Center, Beaverton, OR, United States
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10
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Tillinger A, Horváthová Ľ, Nostramo R, Serova LI, Kvetňanský R, Sabban EL, Mravec B. Glucocorticoid withdrawal affects stress-induced changes of urocortin 2 gene expression in rat adrenal medulla and brain. J Neuroendocrinol 2018; 30:e12595. [PMID: 29604138 DOI: 10.1111/jne.12595] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 03/24/2018] [Indexed: 12/24/2022]
Abstract
Corticotropin-releasing factor is well known activator of the hypothalamic-pituitary-adrenocortical axis, that represents crucial system participating on stress response of the organism. Urocortins are members of the corticotropin-releasing factor family of peptides with proposed effects on neuroendocrine and behavioral stress response mechanisms. Urocortin 2, one of three known urocortins, is present in central and peripheral stress response system and its expression can be augmented by glucocorticoids. In the present study we have examined how glucocorticoid withdrawal affects urocortin 2 gene expression after acute immobilization in the adrenal medulla and selected brain areas in rats. We used pharmacological adrenalectomy to block synthesis of corticosterone. Our results show that the immobilization-induced rise in urocortin 2 mRNA levels in rat adrenal medulla was not inhibited by glucocorticoid withdrawal. On the other hand, observed changes in the brain indicate that the effect of stress and pharmacological adrenalectomy on urocortin 2 gene expression is site-specific. While in the paraventricular nucleus and locus coeruleus the immobilization induced rise of urocortin 2 was not inhibited by pharmacological adrenalectomy in the arcuate nucleus and central amygdala it was. Moreover, we have seen a significant depletion of urocortin 2 plasma levels after immobilization. The immobilization induced rise of urocortin 2 gene expression in rat adrenal medulla and brain areas regulating stress response pathways and preservation of its induction after adrenalectomy suggests a role of urocortin 2 in the neuroendocrine stress response of an organism. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Andrej Tillinger
- Institute of Experimental Endocrinology, Biomedical Research Center Slovak Academy of Sciences, Bratislava, Slovakia
| | - Ľubica Horváthová
- Institute of Experimental Endocrinology, Biomedical Research Center Slovak Academy of Sciences, Bratislava, Slovakia
| | - Regina Nostramo
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, USA
- Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA
| | - Lidia I Serova
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, USA
| | - Richard Kvetňanský
- Institute of Experimental Endocrinology, Biomedical Research Center Slovak Academy of Sciences, Bratislava, Slovakia
| | - Esther L Sabban
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, USA
| | - Boris Mravec
- Institute of Experimental Endocrinology, Biomedical Research Center Slovak Academy of Sciences, Bratislava, Slovakia
- Institute of Physiology, Faculty of Medicine Comenius University in Bratislava, Bratislava, Slovakia
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11
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Gai Y, Zhang J, Wei C, Cao W, Cui Y, Cui S. miR-375 negatively regulates the synthesis and secretion of catecholamines by targeting Sp1 in rat adrenal medulla. Am J Physiol Cell Physiol 2017; 312:C663-C672. [PMID: 28356269 DOI: 10.1152/ajpcell.00345.2016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 03/13/2017] [Accepted: 03/13/2017] [Indexed: 02/08/2023]
Abstract
The adrenal gland is an important endocrine gland in balancing homeostasis and the response to stress by synthesizing and secreting catecholamines (CATs), and it has been confirmed that microRNA-375 (miR-375) is highly expressed in adrenal medulla. However, up to now there are few reports about the functions and related mechanisms in adrenal medulla. The present study was thus designed to study the roles and related mechanisms in rat adrenal medulla. Our results showed that miR-375 was specifically expressed in rat adrenal medulla chromaffin cells, and its expression was downregulated when rats were exposed to stress. The further functional studies demonstrated that the inhibition of endogenous miR-375 induced the secretion of CATs in primary rat medulla chromaffin cells and PC12 cells, whereas miR-375 overexpression resulted in a decline of CAT secretion. In addition, our results showed that miR-375 negatively regulated tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH) and mediated adrenomedullary CAT biosynthesis. These functions of miR-375 were accomplished by its binding to the 3'-untranslated region of Sp1, which was involved in the regulation of TH and DBH expressions. These novel findings suggest that miR-375 acts as a potent negative mediator in regulating the synthesis and secretion of CATs in the adrenal medulla during the maintenance of homeostasis under stress.
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Affiliation(s)
- Yedan Gai
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China; and
| | - Jinglin Zhang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China; and
| | - Chao Wei
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China; and
| | - Wei Cao
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China; and
| | - Yan Cui
- The 306th Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Sheng Cui
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China; and
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12
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Rivera HM, Kievit P, Kirigiti MA, Bauman LA, Baquero K, Blundell P, Dean TA, Valleau JC, Takahashi DL, Frazee T, Douville L, Majer J, Smith MS, Grove KL, Sullivan EL. Maternal high-fat diet and obesity impact palatable food intake and dopamine signaling in nonhuman primate offspring. Obesity (Silver Spring) 2015; 23:2157-64. [PMID: 26530932 PMCID: PMC4636015 DOI: 10.1002/oby.21306] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 07/15/2015] [Accepted: 07/31/2015] [Indexed: 01/31/2023]
Abstract
OBJECTIVE To utilize a nonhuman primate model to examine the impact of maternal high-fat diet (HFD) consumption and pre-pregnancy obesity on offspring intake of palatable food and to examine whether maternal HFD consumption impaired development of the dopamine system, critical for the regulation of hedonic feeding. METHODS The impact of exposure to maternal HFD and obesity on offspring consumption of diets of varying composition was assessed after weaning. The influence of maternal HFD consumption on the development of the prefrontal cortex-dopaminergic system at 13 months of age was also examined. RESULTS During a preference test, offspring exposed to maternal HFD consumption and obesity displayed increased intake of food high in fat and sugar content relative to offspring from lean control mothers. Maternal HFD consumption suppressed offspring dopamine signaling (as assessed by immunohistochemistry) relative to control offspring. Specifically, there was decreased abundance of dopamine fibers and of dopamine receptor 1 and 2 proteins. CONCLUSIONS This study reveals that offspring exposed to both maternal HFD consumption and maternal obesity during early development are at increased risk for obesity due to overconsumption of palatable energy-dense food, a behavior that may be related to reduced central dopamine signaling.
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Affiliation(s)
- Heidi M. Rivera
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Paul Kievit
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Melissa A. Kirigiti
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Leigh Ann Bauman
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Karalee Baquero
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Peter Blundell
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Tyler A. Dean
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Jeanette C. Valleau
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Diana L. Takahashi
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Tim Frazee
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Luke Douville
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
- Department of Biology, University of Portland, Portland, OR, 97203, United States
| | - Jordan Majer
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - M. Susan Smith
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Kevin L. Grove
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
| | - Elinor L. Sullivan
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center Beaverton, OR 97006, United States
- Department of Biology, University of Portland, Portland, OR, 97203, United States
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13
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Chan WYW, Charles CJ, Frampton CM, Richards AM, Crozier IG, Troughton RW, Jardine DL. Human muscle sympathetic nerve responses to urocortin-2 in health and stable heart failure. Clin Exp Pharmacol Physiol 2015; 42:888-895. [DOI: 10.1111/1440-1681.12449] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Revised: 06/11/2015] [Accepted: 06/19/2015] [Indexed: 11/28/2022]
Affiliation(s)
- W Y Wandy Chan
- Department of Medicine; Christchurch Heart Institute; University of Otago; Christchurch New Zealand
- Advanced Heart Failure and Cardiac Transplant Unit; The Prince Charles Hospital; Brisbane QLD Australia
| | - Christopher J Charles
- Department of Medicine; Christchurch Heart Institute; University of Otago; Christchurch New Zealand
| | - Christopher M Frampton
- Department of Medicine; Christchurch Heart Institute; University of Otago; Christchurch New Zealand
| | - A Mark Richards
- Department of Medicine; Christchurch Heart Institute; University of Otago; Christchurch New Zealand
| | - Ian G Crozier
- Department of Medicine; Christchurch Heart Institute; University of Otago; Christchurch New Zealand
| | - Richard W Troughton
- Department of Medicine; Christchurch Heart Institute; University of Otago; Christchurch New Zealand
| | - David L Jardine
- Department of Medicine; Christchurch Heart Institute; University of Otago; Christchurch New Zealand
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Rodriguez JA, Huerta-Yepez S, Law IKM, Baay-Guzman GJ, Tirado-Rodriguez B, Hoffman JM, Iliopoulos D, Hommes DW, Verspaget HW, Chang L, Pothoulakis C, Baritaki S. Diminished expression of CRHR2 in human colon cancer promotes tumor growth and EMT via persistent IL-6/Stat3 signaling. Cell Mol Gastroenterol Hepatol 2015; 1:610-630. [PMID: 26495412 PMCID: PMC4610032 DOI: 10.1016/j.jcmgh.2015.08.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Chronic inflammation promotes development and progression of colorectal cancer (CRC). We explored the distribution of Corticotropin-Releasing-Hormone (CRH)-family of receptors and ligands in CRC and their contribution in tumor growth and oncogenic EMT. METHODS mRNA expression of CRH-family members was analyzed in CRC (N=56) and control (N=46) samples, 7 CRC cell lines and normal NCM460 cells. Immunohistochemical detection of CRHR2 was performed in 20 CRC and 5 normal tissues. Cell proliferation, migration and invasion were compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing (CRHR2+) cells in absence or presence of IL-6. CRHR2/Ucn2-targeted effects on tumor growth and EMT were validated in SW620-xenograft mouse models. RESULTS CRC tissues and cell lines showed decreased mRNA and protein CRHR2 expression compared to controls and NCM460, respectively. The opposite trend was shown for Ucn2. CRHR2/Ucn2 signaling inhibited cell proliferation, migration, invasion and colony formation in CRC-CRHR2+ cells. In vivo, SW620-CRHR2+ xenografts showed decreased growth, reduced expression of EMT-inducers and elevated levels of EMT-suppressors. IL-1b, IL-6 and IL-6R mRNAs where diminished in CRC-CRHR2+ cells, while CRHR2/Ucn2 signaling inhibited IL-6-mediated Stat3 activation, invasion, migration and expression of downstream targets acting as cell cycle- and EMT-inducers. Expression of cell cycle- and EMT-suppressors was augmented in IL-6/Ucn2-stimulated CRHR2+ cells. In patients, CRHR2 mRNA expression was inversely correlated with IL-6R and vimentin levels and metastasis occurrence, while positively associated with E-cadherin expression and overall survival. CONCLUSIONS CRHR2 downregulation in CRC supports tumor expansion and spread through maintaining persistent inflammation and constitutive Stat3 activation. CRHR2low CRC phenotypes are associated with higher risk for distant metastases and poor clinical outcomes.
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Affiliation(s)
- Jorge A. Rodriguez
- IBD Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles (UCLA), Los Angeles, California
| | - Sara Huerta-Yepez
- Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de México Federico Gomez, Mexico City, Mexico
| | - Ivy Ka Man Law
- IBD Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles (UCLA), Los Angeles, California
| | - Guillermina J. Baay-Guzman
- Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de México Federico Gomez, Mexico City, Mexico
| | - Belen Tirado-Rodriguez
- Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de México Federico Gomez, Mexico City, Mexico
| | - Jill M. Hoffman
- IBD Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles (UCLA), Los Angeles, California
| | - Dimitrios Iliopoulos
- Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Daniel W. Hommes
- IBD Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles (UCLA), Los Angeles, California,Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Hein W. Verspaget
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Lin Chang
- Gail and Gerard Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Charalabos Pothoulakis
- IBD Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles (UCLA), Los Angeles, California
| | - Stavroula Baritaki
- IBD Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles (UCLA), Los Angeles, California,Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de México Federico Gomez, Mexico City, Mexico,Division of Surgery, School of Medicine, University of Crete, Heraklion, Crete, Greece,Correspondence Address correspondence to: Stavroula Baritaki, PhD, IBD Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, 675 Charles E. Young Drive, South MRL Building 1240, Los Angeles, California 90095.IBD CenterDivision of Digestive DiseasesDavid Geffen School of MedicineUCLA, 675 Charles E. Young Drive, South MRL Building 1240Los AngelesCalifornia 90095
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15
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Huang J, Tufan T, Deng M, Wright G, Zhu MY. Corticotropin releasing factor up-regulates the expression and function of norepinephrine transporter in SK-N-BE (2) M17 cells. J Neurochem 2015. [PMID: 26212818 DOI: 10.1111/jnc.13268] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Corticotropin releasing factor (CRF) has been implicated to act as a neurotransmitter or modulator in central nervous activation during stress. In this study, we examined the regulatory effect of CRF on the expression and function of the norepinephrine transporter (NET) in vitro. SK-N-BE (2) M17 cells were exposed to different concentrations of CRF for different periods. Results showed that exposure of cells to CRF significantly increased mRNA and protein levels of NET in a concentration- and time-dependent manner. The CRF-induced increase in NET expression was mimicked by agonists of either CRF receptor 1 or 2. Furthermore, similar CRF treatments induced a parallel increase in the uptake of [(3) H] norepinephrine. Both increased expression and function of NET caused by CRF were abolished by simultaneous administration of CRF receptor antagonists, indicating a mediation by CRF receptors. However, there was no additive effect for the combination of both receptor antagonists. Chromatin immunoprecipitation assays confirm an increased acetylation of histone H3 on the NET promoter following treatment with CRF. Taken together, this study demonstrates that CRF up-regulates the expression and function of NET in vitro. This regulation is mediated through CRF receptors and an epigenetic mechanism related to histone acetylation may be involved. This CRF-induced regulation on NET expression and function may play a role in development of stress-related depression and anxiety. This study demonstrated that corticotropin release factor (CRF) up-regulated the expression and function of norepinephrine transporter (NET) in a concentration- and time-dependent manner, through activation of CRF receptors and possible histone acetylation in NET promoter. The results indicate that their interaction may play an important role in stress-related physiological and pathological status.
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Affiliation(s)
- Jingjing Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Turan Tufan
- Departments of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Maoxian Deng
- Departments of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Jiangsu Polytechnic College of A&F, Jurong, Jiangsu, China
| | - Gary Wright
- Departments of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Meng-Yang Zhu
- Departments of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
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16
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Sladek CD, Michelini LC, Stachenfeld NS, Stern JE, Urban JH. Endocrine‐Autonomic Linkages. Compr Physiol 2015; 5:1281-323. [DOI: 10.1002/cphy.c140028] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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17
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Abstract
The human adult adrenal cortex is composed of the zona glomerulosa (zG), zona fasciculata (zF), and zona reticularis (zR), which are responsible for production of mineralocorticoids, glucocorticoids, and adrenal androgens, respectively. The final completion of cortical zonation in humans does not occur until puberty with the establishment of the zR and its production of adrenal androgens; a process called adrenarche. The maintenance of the adrenal cortex involves the centripetal displacement and differentiation of peripheral Sonic hedgehog-positive progenitors cells into zG cells that later transition to zF cells and subsequently zR cells.
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Affiliation(s)
- Yewei Xing
- Internal Medicine, Medical School, University of Michigan, 109 Zina Pitcher Place, 1860 BSRB, Ann Arbor, MI 48109, USA
| | - Antonio M Lerario
- Internal Medicine, Medical School, University of Michigan, 109 Zina Pitcher Place, 1860 BSRB, Ann Arbor, MI 48109, USA
| | - William Rainey
- Internal Medicine, Medical School, University of Michigan, 109 Zina Pitcher Place, 1860 BSRB, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, 2560D MSRB II, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5622, USA
| | - Gary D Hammer
- Endocrine Oncology Program, Center for Organogenesis, University of Michigan, 109 Zina Pitcher Place, 1528 BSRB, Ann Arbor, MI 48109-2200, USA.
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18
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Maternal exposure to low levels of corticosterone during lactation protects against experimental inflammatory colitis-induced damage in adult rat offspring. PLoS One 2014; 9:e113389. [PMID: 25405993 PMCID: PMC4236199 DOI: 10.1371/journal.pone.0113389] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Accepted: 10/25/2014] [Indexed: 12/24/2022] Open
Abstract
Opposing emotional events (negative/trauma or positive/maternal care) during the postnatal period may differentially influence vulnerability to the effects of stress later in life. The development and course of intestinal disorders such as inflammatory bowel disease are negatively affected by persistent stress, but to date the role of positive life events on these pathologies has been entirely unknown. In the present study, the effect of early life beneficial experiences in the development of intestinal dysfunctions, where inflammation and stress stimuli play a primary role, was investigated. As a “positive” experimental model we used adult male rat progeny nursed by mothers whose drinking water was supplemented with moderate doses of corticosterone (CORT) (0.2 mg/ml) during the lactation period. Such animals have been generally shown to cope better with different environmental situations during life. The susceptibility to inflammatory experimental colitis induced by intracolonic infusion of TNBS (2,4,6-trinitrobenzenesulphonic acid) was investigated in CORT-nursed rats in comparison with control rats. This mild increase in maternal corticosterone during lactation induced, in CORT-nursed rats, a long lasting protective effect on TNBS-colitis, characterized by improvements in some indices of the disease (increased colonic myeloperoxidase activity, loss of body weight and food intake) and by the involvement of endogenous peripheral pathways known to participate in intestinal disorder development (lower plasma corticosterone levels and colonic mast cell degranulation, alterations in the colonic expression of both corticotrophin releasing factor/CRF and its receptor/CRH-1R). All these findings contribute to suggesting that the reduced vulnerability to TNBS-colitis in CORT-nursed rats is due to recovery from the colonic mucosal barrier dysfunction. Such long lasting changes induced by mild hormonal manipulation during lactation, making the adult also better adapted to colonic inflammatory stress, constitute a useful experimental model to investigate the etiopathogenetic mechanisms and therapeutic treatments of some gastrointestinal diseases.
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19
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Navarro-Zaragoza J, Martínez-Laorden E, Mora L, Hidalgo J, Milanés M, Laorden M. Cardiac adverse effects of naloxone-precipitated morphine withdrawal on right ventricle: Role of corticotropin-releasing factor (CRF) 1 receptor. Toxicol Appl Pharmacol 2014; 275:28-35. [DOI: 10.1016/j.taap.2013.12.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 11/29/2013] [Accepted: 12/28/2013] [Indexed: 01/14/2023]
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20
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Immunohistochemical demonstration of urocortin 1 in Edinger–Westphal nucleus of the human neonate: Colocalization with tyrosine hydroxylase under acute perinatal hypoxia. Neurosci Lett 2013; 554:47-52. [DOI: 10.1016/j.neulet.2013.08.054] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 08/12/2013] [Accepted: 08/25/2013] [Indexed: 11/23/2022]
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21
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Chatzaki E, Anton PA, Million M, Lambropoulou M, Constantinidis T, Kolios G, Taché Y, Grigoriadis DE. Corticotropin-releasing factor receptor subtype 2 in human colonic mucosa: Down-regulation in ulcerative colitis. World J Gastroenterol 2013; 19:1416-1423. [PMID: 23539366 PMCID: PMC3602501 DOI: 10.3748/wjg.v19.i9.1416] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 12/05/2012] [Accepted: 12/20/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess corticotropin-releasing factor receptor 2 (CRF2) expression in the colon of healthy subjects and patients with ulcerative colitis (UC).
METHODS: We examined CRF2 gene and protein expression in the distal/sigmoid colonic mucosal biopsies from healthy subjects and patients with UC (active or disease in remission), human immunodeficiency virus (HIV) and functional bowel disease (FBD) by reverse transcription-polymerase chain reaction and immunofluorescence.
RESULTS: Gene expression of CRF2 was demonstrated in the normal human colonic biopsies, but not in the human colorectal adenocarcinoma cell line Caco2. Receptor protein localization showed immunoreactive CRF2 receptors in the lamina propria and in the epithelial cells of the distal/sigmoid biopsy samples. Interestingly, CRF2 immunoreactivity was no longer observed in epithelial cells of patients with mild-moderately active UC and disease in remission, while receptor protein expression did not change in the lamina propria. No differences in CRF2 expression profile were observed in distal/sigmoid intestinal biopsies from HIV infection and FBD patients, showing no signs of inflammation.
CONCLUSION: The down-regulation of the CRF2 receptor in the distal/sigmoid biopsies of UC patients is indicative of change in CRF2 signalling associated with the process of inflammation.
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22
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Tillinger A, Nostramo R, Kvetnansky R, Serova L, Sabban EL. Stress-induced changes in gene expression of urocortin 2 and other CRH peptides in rat adrenal medulla: involvement of glucocorticoids. J Neurochem 2013; 125:185-92. [DOI: 10.1111/jnc.12152] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Revised: 12/31/2012] [Accepted: 01/02/2013] [Indexed: 11/29/2022]
Affiliation(s)
- Andrej Tillinger
- Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla New York USA
| | - Regina Nostramo
- Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla New York USA
| | - Richard Kvetnansky
- Institute of Experimental Endocrinology; Slovak Academy of Sciences; Bratislava Slovakia
| | - Lidia Serova
- Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla New York USA
| | - Esther L. Sabban
- Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla New York USA
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23
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Squillacioti C, De Luca A, Alì S, Paino S, Liguori G, Mirabella N. Expression of urocortin and corticotropin-releasing hormone receptors in the horse thyroid gland. Cell Tissue Res 2012; 350:45-53. [DOI: 10.1007/s00441-012-1450-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Accepted: 05/03/2012] [Indexed: 10/28/2022]
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24
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Jin L, Chen C, Guo R, Wan R, Li S. Role of corticotropin-releasing hormone family peptides in androgen receptor and vitamin D receptor expression and translocation in human breast cancer MCF-7 cells. Eur J Pharmacol 2012; 684:27-35. [DOI: 10.1016/j.ejphar.2012.03.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 03/09/2012] [Accepted: 03/22/2012] [Indexed: 01/30/2023]
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25
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Dermitzaki E, Tsatsanis C, Gravanis A, Margioris AN. The calcineurin-nuclear factor of activated T cells signaling pathway mediates the effect of corticotropin releasing factor and urocortins on catecholamine synthesis. J Cell Physiol 2012; 227:1861-72. [DOI: 10.1002/jcp.22914] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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26
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Takahashi K. Distribution of urocortins and corticotropin-releasing factor receptors in the cardiovascular system. Int J Endocrinol 2012; 2012:395284. [PMID: 22675352 PMCID: PMC3362921 DOI: 10.1155/2012/395284] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2011] [Revised: 03/10/2012] [Accepted: 03/15/2012] [Indexed: 12/27/2022] Open
Abstract
Urocortins are human homologues of urotensin I, a fish corticotropin-releasing-factor- (CRF-) like peptide secreted from the urophysis. There are three urocortins: urocortin 1, urocortin 2, and urocortin 3 in mammals. We have shown that urocortin 1 and urocortin 3 are endogenously synthesized in the myocardial cells of human heart and may act on CRF type 2 receptor (CRFR2) expressed in the heart. Expression levels of urocortin 1 in the heart and plasma urocortin 1 levels are elevated in patients with heart failure. Recent studies have shown that urocortins have various biological actions in the cardiovascular system, such as a vasodilator action, a positive inotropic action, a cardioprotective action against ischemia/reperfusion injury, and suppressive actions against the renin angiotensin system and the sympathetic nervous system. Urocortins and CRFR2 may therefore be a potential therapeutic target for cardiovascular diseases, such as congestive heart failure, hypertension, and myocardial infarction.
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Affiliation(s)
- Kazuhiro Takahashi
- Departments of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
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27
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Pérez-García S, Juarranz Y, Carrión M, Gutiérrez-Cañas I, Margioris A, Pablos JL, Tsatsanis C, Gomariz RP. Mapping the CRF-urocortins system in human osteoarthritic and rheumatoid synovial fibroblasts: effect of vasoactive intestinal peptide. J Cell Physiol 2011; 226:3261-9. [PMID: 21360527 DOI: 10.1002/jcp.22687] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
In addition to the brain and pituitary gland, the corticotrophin-releasing factor (CRF) system is expressed in peripheral tissues. In this study we characterize the expression of CRF, urocortins (UCN1, UCN2, and UCN3), and their receptors (CRFR1 and CRFR2) in osteoarthritis (OA) and rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). Moreover, we analyze the vasoactive intestinal peptide (VIP) effect on the CRF system, as well as its physiological consequences on mediators of inflammatory/destructive processes. CRF and UCNs exhibit differential pattern in OA and RA-FLS. By real-time PCR we detected more expression of CRF and UCN1 in RA, and UCN2 and UCN3 in OA, while the CRFR2 expression was similar. In RA-FLS VIP treatment resulted in a significant decrease of the proinflammatory peptides, CRF and UCN1, and a significant increase of the potential anti-inflammatory agents, UCN3 and CRFR2. Using Western blot assays, we showed that the ratio between phospho-CREB (p-CREB) and c-AMP response element-binding (CREB) is higher in OA and significantly lower in RA-FLS after VIP treatment, with consequences upon cAMP response element in CRF and UCN1 genes. Real-time PCR and EIA proved that VIP significantly inhibits cycloxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in RA-FLS. In all cases, we consider significant data when P < 0.05. These data indicate a role of endogenous CRF, UCNs, and CRFR2 in the OA and RA joint microenvironment. We confirm the anti-inflammatory function of VIP, through the modulation of the expression of CRF system that impacts in a reduction of mediators with inflammatory/destructive functions, supporting its therapeutic potential in rheumatic diseases.
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Affiliation(s)
- Selene Pérez-García
- Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain
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Squillacioti C, De Luca A, Liguori G, Paino S, Mirabella N. Expression of urocortin and corticotropin-releasing hormone receptors in the bovine adrenal gland. Gen Comp Endocrinol 2011; 172:416-22. [PMID: 21504748 DOI: 10.1016/j.ygcen.2011.04.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2010] [Revised: 03/24/2011] [Accepted: 04/04/2011] [Indexed: 11/26/2022]
Abstract
Urocortin (UCN), a 40 amino acid peptide, is a corticotrophin-releasing hormone (CRH)-related peptide. The biological actions of CRH family peptides are mediated via two types of G protein-coupled receptors, CRH type 1 receptor (CRHR1) and CRH type 2 receptor (CRHR2). The aim of the present study was to investigate the expression of UCN, CRHR1 and CRHR2 by immunohistochemistry, western blot and real-time RT-PCR in the bovine adrenal gland to clarify the mechanisms of the intra-adrenal CRH-based regulatory system. The results showed that UCN, CRHR1 and CRHR2 were expressed in both the cortex and medulla. Specifically, UCN-immunoreactivity (IR) was distributed in the outer part of the zona fasciculata and in the zona reticularis of the cortex and in the medulla. UCN and CRHR2 mRNA expression levels were higher in the cortex than in the medulla, while CRHR1 mRNA levels were undetectable in the cortex. These results suggest that UCN, CRHR1 and CRHR2 are expressed in the bovine adrenal gland and that UCN might play a role in the intra-adrenal CRH-based regulatory system through an autocrine mechanism.
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Affiliation(s)
- Caterina Squillacioti
- Department of Structure, Functions and Biological Technologies, University of Naples Federico II, Naples, Italy.
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29
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Gu Y, Zhang K, Biswas N, Friese RS, Lin DH, Mahata SK, Hoshijima M, O'Connor DT, Peterson KL, Brar BK. Urocortin 2 lowers blood pressure and reduces plasma catecholamine levels in mice with hyperadrenergic activity. Endocrinology 2010; 151:4820-9. [PMID: 20668031 PMCID: PMC2946150 DOI: 10.1210/en.2009-1454] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Exaggerated adrenergic activity is associated with human hypertension. The peptide urocortin 2 (Ucn 2) inhibits catecholamine synthesis and secretion from adrenal chromaffin cells in vitro and administration to mammals lowers blood pressure (BP). The chromogranin A-null mouse (Chga-/-) manifests systemic hypertension because of excessive catecholamine secretion from the adrenal and decreased catecholamine storage. In the present study, we investigated whether systemic administration of Ucn 2 could reduce BP and adrenal and plasma levels of catecholamines in vivo. Ucn 2 peptide was administered to freely moving, conscious Chga-/- and wild-type control mice. Telemetry and HPLC measured changes in BP and catecholamine levels, respectively. In both groups of mice, Ucn 2 dose-dependently decreased BP, and this effect was mediated by corticotropin factor-receptor type 2. However, in Chga-/- mice, the maximal percentage decrease of systolic BP from basal systolic BP was 37% compared with only a 23% reduction in wild-type mice (P=0.04). In Chga-/- mice only, Ucn 2 decreased adrenal and plasma levels of catecholamines as well as adrenal levels of tyrosine hydroxylase protein and phosphorylation. In vitro mechanistic studies demonstrated that Ucn 2 reduces both catecholamine secretion and tyrosine hydroxylase promoter activity, suggesting that the exaggerated action of Ucn 2 to reduce BP in the Chga-/- mouse is mediated through inhibition of both catecholamine synthesis and secretion. The data suggest that Ucn 2 may be therapeutically useful in regulating the exaggerated sympathoadrenal function of hyperadrenergic hypertension.
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Affiliation(s)
- Yusu Gu
- Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0838, USA
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30
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Paschos KA, Charsou C, Constantinidis TC, Anagnostoulis S, Lambropoulou M, Papachristou F, Simopoulos K, Chatzaki E. Corticotropin-releasing hormone receptors mediate opposing effects in cholestasis-induced liver cell apoptosis. Endocrinology 2010; 151:1704-12. [PMID: 20189999 DOI: 10.1210/en.2009-1208] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
CRH receptors are expressed in human and rat liver. The current study investigated the biological role of the CRH system in the hepatocellular apoptotic process and aimed to reveal the responsible molecular mechanisms. Using a rat experimental model of common bile duct surgical ligation leading to obstructive jaundice and cholestasis, liver apoptosis was induced in the hepatic parenchyma as confirmed by the elevated expression of the early apoptotic neoepitope M30. This effect was reversed by administration of the nonselective CRH antagonist astressin but not by the selective CRH(2) antagonist astressin2B, suggesting that antagonism of the endogenous CRH(1) blocked the cholestasis-induced apoptotic mechanism. No effect was observed in the noncholestasis controls. In our experimental model, early and late apoptosis-preventing markers were induced in parallel to apoptosis; elevated gene transcript levels of the anti-apoptotic bcl-2 were found by real-time PCR in the first postoperative day and increased serum hepatocyte growth factor levels were measured by ELISA in the third postoperative day. Selective CRH(2) antagonism reversed the elevated expression of bcl-2 and hepatocyte growth factor, suggesting that this receptor type mediated antiapoptotic actions of the endogenous CRH system, opposing the preapoptotic ones mediated by CRH(1). In conclusion, the present study indicated that the CRH neuroendocrine system regulates cholestasis-induced apoptosis in the hepatic parenchyma via receptor-specific pathways. These data may contribute to better understanding of the CRH biology and its pathophysiological significance in the periphery.
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Affiliation(s)
- Konstantinos A Paschos
- Department of Pharmacology, Democritus University of Thrace, Dragana, 68100 Alexandroupolis, Thrace, Greece
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31
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Valego NK, Rose JC. A specific CRH antagonist attenuates ACTH-stimulated cortisol secretion in ovine adrenocortical cells. Reprod Sci 2010; 17:477-86. [PMID: 20220106 DOI: 10.1177/1933719110361959] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Corticotropin releasing hormone (CRH) has been detected in the adrenal gland of many species and may be involved in regulation of glucocorticoid secretion. In cultured human fetal adrenal definitive/transitional zone cells, CRH upregulates the adrenocorticotropic hormone (ACTH) receptor and steroidogenic enzymes and is blocked by the selective CRH type 1 receptor (CRH(1)) antagonist, antalarmin. Based on these findings and evidence that antalarmin infusion into sheep suppressed prepartum increases in cortisol, we hypothesized that antalarmin would influence adrenal cortisol secretion. Antalarmin strongly attenuated ACTH and forskolin (FSK)-stimulated cortisol and cyclic adenosine monophosphate (cAMP) release from cultured ovine adrenocortical cells but did not prevent ACTH binding to cells or ACTH-induced proliferation in adult cells. Corticotropin releasing hormone was minimally effective as a secretagogue but increased the cortisol response to subsequent ACTH. These results suggest that antalarmin attenuates ACTH-induced cortisol secretion from cultured ovine adrenal cortical cells at a site distal to the ACTH receptor. Although CRH may modulate the secretory response to ACTH, it is probably not a direct cortisol secretagogue in the sheep.
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Affiliation(s)
- Nancy K Valego
- Center of Research for Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
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Paschos KA, Kolios G, Chatzaki E. The corticotropin-releasing factor system in inflammatory bowel disease: prospects for new therapeutic approaches. Drug Discov Today 2009; 14:713-20. [PMID: 19379831 DOI: 10.1016/j.drudis.2009.04.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2008] [Revised: 04/01/2009] [Accepted: 04/06/2009] [Indexed: 12/16/2022]
Abstract
Mounting evidence suggests that stress is implicated in the development of inflammatory bowel disease (IBD), via initial nervous disturbance and subsequent immune dysfunction through brain-gut interactions. The corticotropin-releasing factor (CRF) system, being the principal neuroendocrine coordinator of stress responses, is involved in the inflammatory process within the gastrointestinal tract, via vagal and peripheral pathways, as implied by multiple reports reviewed here. Blocking of CRF receptors could theoretically exert beneficial anti-inflammatory effects in colonic tissues. The recently synthesised small-molecule CRF(1) antagonists or alternatively non-peptide CRF(2) antagonists when available, may become new reliable options in the treatment of IBD.
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Affiliation(s)
- Konstantinos A Paschos
- Laboratory of Pharmacology, Faculty of Medicine, Laboratory of Pharmacology, Democritus University of Thrace (DUTH), DUTH, Dragana, Alexandroupolis 68100, Thrace, Greece
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Gutknecht E, Hauger RL, Van der Linden I, Vauquelin G, Dautzenberg FM. Expression, binding, and signaling properties of CRF2(a) receptors endogenously expressed in human retinoblastoma Y79 cells: passage-dependent regulation of functional receptors. J Neurochem 2007; 104:926-36. [PMID: 17976162 DOI: 10.1111/j.1471-4159.2007.05052.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Endogenous expression of the corticotropin-releasing factor type 2a receptor [CRF2(a)] but not CRF2(b) and CRF2(c) was observed in higher passage cultures of human Y79 retinoblastoma cells. Functional studies further demonstrated an increase in CRF2(a) mRNA and protein levels with higher passage numbers (> 20 passages). Although the CRF1 receptor was expressed at higher levels than the CRF2(a) receptor, both receptors were easily distinguishable from one another by selective receptor ligands. CRF(1)-preferring or non-selective agonists such as CRF, urocortin 1 (UCN1), and sauvagine stimulated cAMP production in Y79 to maximal responses of approximately 100 pmoles/10(5) cells, whereas the exclusive CRF2 receptor-selective agonists UCN2 and 3 stimulated cAMP production to maximal responses of approximately 25-30 pmoles/10(5) cells. UCN2 and 3-mediated cAMP stimulation was potently blocked by the approximately 300-fold selective CRF2 antagonist antisauvagine (IC50 = 6.5 +/- 1.6 nmol/L), whereas the CRF(1)-selective antagonist NBI27914 only blocked cAMP responses at concentrations > 10 microL. When the CRF(1)-preferring agonist ovine CRF was used to activate cAMP signaling, NBI27914 (IC50 = 38.4 +/- 3.6 nmol/L) was a more potent inhibitor than antisauvagine (IC50 = 2.04 +/- 0.2 microL). Finally, UCN2 and 3 treatment potently and rapidly desensitized the CRF2 receptor responses in Y79 cells. These data demonstrate that Y79 cells express functional CRF1 and CRF2a receptors and that the CRF2(a) receptor protein is up-regulated during prolonged culture.
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Affiliation(s)
- Eric Gutknecht
- CNS Research, Johnson & Johnson Research & Development, Beerse, Belgium
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