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Yay F, Ayan D. Bioinformatic analysis of neuropeptide related genes in patients diagnosed with invasive breast carcinoma. Comput Biol Med 2024; 183:109304. [PMID: 39437604 DOI: 10.1016/j.compbiomed.2024.109304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/28/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024]
Abstract
PURPOSE Neuropeptide receptors are expressed in many malignancies. Effectors involved in the action mechanisms of HCRTR1, HCRTR2, NPY4R (PPYR1) may be related to breast cancer (BC). Genes encoding these receptors and PPY and PTPN11 genes were aimed to examine via bioinformatics tools in the BRCA cohort. To our knowledge, this is the first study in which these receptor genes and PP, which have not found much research in BC, are examined together with PTPN11 and analyzed comprehensively in large patient cohorts from public databases. METHODS cBioPortal was used for gene alteration analyses, GeneMania for association analyses with other genes, Kaplan-Meier Plotter for Overall Survival (OS) and Relapse Free Survival (RFS) analyses, UALCAN for methylation analyses, TIMER2.0 for expression analyses, The Human Protein Atlas database for expression validations, TIMER for immune infiltration analyses, WEKA 3.8.6 for diagnostic classification performances of the genes based on Random Forest Classifier and Enrichr-KG for Gene Ontology (GO) Biological Process (BP) and KEGG analysis. RESULTS 19 (1.9 %) nucleotide changes were found in 996 cases. Missense mutation is most common. Decreased expression levels of the HCRTR1 gene were associated with shorter OS and RFS, but decreased expression levels of the PTPN11 gene were associated with longer OS and RFS. Decreased expression levels NPY4R (PPYR1) gene were associated with shorter RFS. Increased expression levels of HCRTR2 and PPY genes were associated with longer RFS. HCRTR1 and NPY4R (PPYR1) genes were statistically hypermethylated; conversely HCRTR2 and PPY genes were hypomethylated. There was no significant change in PTPN11 gene promoter methylation level. HCRTR1, NPY4R (PPYR1) and PTPN11 gene expressions were downregulated; conversely, HCRTR2 and PPY gene expressions upregulated. Weak correlations were observed between NPY4R (PPYR1) gene expression and CD4+ T Cell, Neutrophil, Dendritic Cell and between PTPN11 gene expression and CD8+ T Cell, Macrophage, Neutrophil, Dendritic Cell infiltrations. Area under the receiver operating characteristics curve values of the 10-fold cross-validation and by splitting the dataset in a ratio of 80:20 models were 0.930 and 0.963 respectively. HCRTR2 and HCRTR1 belong to regulation of cytosolic calcium ion concentration, cellular calcium ion homeostasis GO BPs. CONCLUSION In BC patients, increases in HCRTR2 and PPY gene expressions could be considered as positive prognostic factors. Decreases in HCRTR1 and NPY4R (PPYR1) gene expressions could be considered as negative prognostic factors. Decreased expression of PTPN11 gene may have a positive prognostic factor. Changes in existing genes are likely to be both a biomarker and therapeutic target for BC. However, experimental and clinical studies are needed to elucidate the mechanisms underlying these neuropeptide receptors in terms of breast carcinogenesis.
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Affiliation(s)
- Fatih Yay
- Nigde Omer Halisdemir University Training and Research Hospital, Clinical Biochemistry Laboratory, Nigde, Turkey.
| | - Durmus Ayan
- Nigde Omer Halisdemir University Training and Research Hospital, Clinical Biochemistry Laboratory, Nigde, Turkey; Nigde Omer Halisdemir University, Faculty of Medicine, Medical Biochemistry, Nigde, Turkey.
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Leysen H, Walter D, Clauwaert L, Hellemans L, van Gastel J, Vasudevan L, Martin B, Maudsley S. The Relaxin-3 Receptor, RXFP3, Is a Modulator of Aging-Related Disease. Int J Mol Sci 2022; 23:4387. [PMID: 35457203 PMCID: PMC9027355 DOI: 10.3390/ijms23084387] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/08/2022] [Accepted: 04/12/2022] [Indexed: 12/12/2022] Open
Abstract
During the aging process our body becomes less well equipped to deal with cellular stress, resulting in an increase in unrepaired damage. This causes varying degrees of impaired functionality and an increased risk of mortality. One of the most effective anti-aging strategies involves interventions that combine simultaneous glucometabolic support with augmented DNA damage protection/repair. Thus, it seems prudent to develop therapeutic strategies that target this combinatorial approach. Studies have shown that the ADP-ribosylation factor (ARF) GTPase activating protein GIT2 (GIT2) acts as a keystone protein in the aging process. GIT2 can control both DNA repair and glucose metabolism. Through in vivo co-regulation analyses it was found that GIT2 forms a close coexpression-based relationship with the relaxin-3 receptor (RXFP3). Cellular RXFP3 expression is directly affected by DNA damage and oxidative stress. Overexpression or stimulation of this receptor, by its endogenous ligand relaxin 3 (RLN3), can regulate the DNA damage response and repair processes. Interestingly, RLN3 is an insulin-like peptide and has been shown to control multiple disease processes linked to aging mechanisms, e.g., anxiety, depression, memory dysfunction, appetite, and anti-apoptotic mechanisms. Here we discuss the molecular mechanisms underlying the various roles of RXFP3/RLN3 signaling in aging and age-related disorders.
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Affiliation(s)
- Hanne Leysen
- Receptor Biology Laboratory, University of Antwerp, 2610 Wilrijk, Belgium; (H.L.); (D.W.); (L.C.); (L.H.); (J.v.G.)
| | - Deborah Walter
- Receptor Biology Laboratory, University of Antwerp, 2610 Wilrijk, Belgium; (H.L.); (D.W.); (L.C.); (L.H.); (J.v.G.)
| | - Lore Clauwaert
- Receptor Biology Laboratory, University of Antwerp, 2610 Wilrijk, Belgium; (H.L.); (D.W.); (L.C.); (L.H.); (J.v.G.)
| | - Lieselot Hellemans
- Receptor Biology Laboratory, University of Antwerp, 2610 Wilrijk, Belgium; (H.L.); (D.W.); (L.C.); (L.H.); (J.v.G.)
| | - Jaana van Gastel
- Receptor Biology Laboratory, University of Antwerp, 2610 Wilrijk, Belgium; (H.L.); (D.W.); (L.C.); (L.H.); (J.v.G.)
- SGS Belgium, Intercity Business Park, Generaal De Wittelaan 19-A5, 2800 Mechelen, Belgium
| | | | - Bronwen Martin
- Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium;
| | - Stuart Maudsley
- Receptor Biology Laboratory, University of Antwerp, 2610 Wilrijk, Belgium; (H.L.); (D.W.); (L.C.); (L.H.); (J.v.G.)
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Mlyczyńska E, Kieżun M, Kurowska P, Dawid M, Pich K, Respekta N, Daudon M, Rytelewska E, Dobrzyń K, Kamińska B, Kamiński T, Smolińska N, Dupont J, Rak A. New Aspects of Corpus Luteum Regulation in Physiological and Pathological Conditions: Involvement of Adipokines and Neuropeptides. Cells 2022; 11:957. [PMID: 35326408 PMCID: PMC8946127 DOI: 10.3390/cells11060957] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 02/28/2022] [Accepted: 03/08/2022] [Indexed: 11/17/2022] Open
Abstract
The corpus luteum is a small gland of great importance because its proper functioning determines not only the appropriate course of the estrous/menstrual cycle and embryo implantation, but also the subsequent maintenance of pregnancy. Among the well-known regulators of luteal tissue functions, increasing attention is focused on the role of neuropeptides and adipose tissue hormones-adipokines. Growing evidence points to the expression of these factors in the corpus luteum of women and different animal species, and their involvement in corpus luteum formation, endocrine function, angiogenesis, cells proliferation, apoptosis, and finally, regression. In the present review, we summarize the current knowledge about the expression and role of adipokines, such as adiponectin, leptin, apelin, vaspin, visfatin, chemerin, and neuropeptides like ghrelin, orexins, kisspeptin, and phoenixin in the physiological regulation of the corpus luteum function, as well as their potential involvement in pathologies affecting the luteal cells that disrupt the estrous cycle.
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Affiliation(s)
- Ewa Mlyczyńska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (M.D.); (K.P.); (N.R.)
| | - Marta Kieżun
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (M.K.); (E.R.); (B.K.); (T.K.); (N.S.)
| | - Patrycja Kurowska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (M.D.); (K.P.); (N.R.)
| | - Monika Dawid
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (M.D.); (K.P.); (N.R.)
| | - Karolina Pich
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (M.D.); (K.P.); (N.R.)
| | - Natalia Respekta
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (M.D.); (K.P.); (N.R.)
| | - Mathilde Daudon
- Unité Physiologie de la Reproduction et des Comportements, French National Institute for Agriculture, Food, and Environment, 37380 Nouzilly, France; (M.D.); (J.D.)
| | - Edyta Rytelewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (M.K.); (E.R.); (B.K.); (T.K.); (N.S.)
| | - Kamil Dobrzyń
- Department of Zoology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland;
| | - Barbara Kamińska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (M.K.); (E.R.); (B.K.); (T.K.); (N.S.)
| | - Tadeusz Kamiński
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (M.K.); (E.R.); (B.K.); (T.K.); (N.S.)
| | - Nina Smolińska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (M.K.); (E.R.); (B.K.); (T.K.); (N.S.)
| | - Joelle Dupont
- Unité Physiologie de la Reproduction et des Comportements, French National Institute for Agriculture, Food, and Environment, 37380 Nouzilly, France; (M.D.); (J.D.)
| | - Agnieszka Rak
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (M.D.); (K.P.); (N.R.)
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Couvineau A, Nicole P, Gratio V, Voisin T. The Orexin receptors: Structural and anti-tumoral properties. Front Endocrinol (Lausanne) 2022; 13:931970. [PMID: 35966051 PMCID: PMC9365956 DOI: 10.3389/fendo.2022.931970] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/11/2022] [Indexed: 12/12/2022] Open
Abstract
At the end of the 20th century, two new neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) expressed in hypothalamus as a prepro-orexins precursor, were discovered. These two neuropeptides interacted with two G protein-coupled receptor isoforms named OX1R and OX2R. The orexins/OX receptors system play an important role in the central and peripheral nervous system where it controls wakefulness, addiction, reward seeking, stress, motivation, memory, energy homeostasis, food intake, blood pressure, hormone secretions, reproduction, gut motility and lipolysis. Orexins and their receptors are involved in pathologies including narcolepsy type I, neuro- and chronic inflammation, neurodegenerative diseases, metabolic syndrome, and cancers. Associated with these physiopathological roles, the extensive development of pharmacological molecules including OXR antagonists, has emerged in association with the determination of the structural properties of orexins and their receptors. Moreover, the identification of OX1R expression in digestive cancers encompassing colon, pancreas and liver cancers and its ability to trigger mitochondrial apoptosis in tumoral cells, indicate a new putative therapeutical action of orexins and paradoxically OXR antagonists. The present review focuses on structural and anti-tumoral aspects of orexins and their receptors.
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Couvineau A, Voisin T, Nicole P, Gratio V, Blais A. Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions. World J Gastroenterol 2021; 27:7582-7596. [PMID: 34908800 PMCID: PMC8641057 DOI: 10.3748/wjg.v27.i44.7582] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/22/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system. These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation, intestinal motility, hormone secretion, lipolyze and reproduction functions. Associated to these peripheral functions, it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation, metabolic syndrome and cancers. The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease, multiple sclerosis and septic shock, obesity and digestive cancers.
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Affiliation(s)
- Alain Couvineau
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Thierry Voisin
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Pascal Nicole
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Valerie Gratio
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Anne Blais
- UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris 75005, France
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Saad L, Zwiller J, Kalsbeek A, Anglard P. Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction. Genes (Basel) 2021; 12:1263. [PMID: 34440437 PMCID: PMC8394526 DOI: 10.3390/genes12081263] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/04/2021] [Accepted: 08/11/2021] [Indexed: 12/19/2022] Open
Abstract
Based on studies describing an increased prevalence of addictive behaviours in several rare sleep disorders and shift workers, a relationship between circadian rhythms and addiction has been hinted for more than a decade. Although circadian rhythm alterations and molecular mechanisms associated with neuropsychiatric conditions are an area of active investigation, success is limited so far, and further investigations are required. Thus, even though compelling evidence connects the circadian clock to addictive behaviour and vice-versa, yet the functional mechanism behind this interaction remains largely unknown. At the molecular level, multiple mechanisms have been proposed to link the circadian timing system to addiction. The molecular mechanism of the circadian clock consists of a transcriptional/translational feedback system, with several regulatory loops, that are also intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape shows profound changes in the addictive brain, with significant alterations in histone modification, DNA methylation, and small regulatory RNAs. The combination of these two observations raises the possibility that epigenetic regulation is a common plot linking the circadian clocks with addiction, though very little evidence has been reported to date. This review provides an elaborate overview of the circadian system and its involvement in addiction, and we hypothesise a possible connection at the epigenetic level that could further link them. Therefore, we think this review may further improve our understanding of the etiology or/and pathology of psychiatric disorders related to drug addiction.
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Affiliation(s)
- Lamis Saad
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands;
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Jean Zwiller
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- Centre National de la Recherche Scientifique (CNRS), 75016 Paris, France
| | - Andries Kalsbeek
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands;
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Patrick Anglard
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- Institut National de la Santé et de la Recherche Médicale (INSERM), 75013 Paris, France
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Alain C, Pascal N, Valérie G, Thierry V. Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target. Molecules 2021; 26:4849. [PMID: 34443437 PMCID: PMC8398691 DOI: 10.3390/molecules26164849] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/03/2021] [Accepted: 08/06/2021] [Indexed: 02/05/2023] Open
Abstract
Over 20 years ago, orexin neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) produced from the same precursor in hypothalamus were identified. These two neurotransmitters and their receptors (OX1R and OX1R), present in the central and peripheral nervous system, play a major role in wakefulness but also in drug addiction, food consumption, homeostasis, hormone secretion, reproductive function, lipolysis and blood pressure regulation. With respect to these biological functions, orexins were involved in various pathologies encompassing narcolepsy, neurodegenerative diseases, chronic inflammations, metabolic syndrome and cancers. The expression of OX1R in various cancers including colon, pancreas and prostate cancers associated with its ability to induce a proapoptotic activity in tumor cells, suggested that the orexins/OX1R system could have a promising therapeutic role. The present review summarizes the relationship between cancers and orexins/OX1R system as an emerging target.
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Affiliation(s)
- Couvineau Alain
- INSERM UMR1149/Inflammation Research Center (CRI), Team “From Inflammation to Cancer in Digestive Diseases” Labeled by “la Ligue Nationale Contre le Cancer”, University of Paris, DHU UNITY, 75018 Paris, France; (N.P.); (G.V.); (V.T.)
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Saad L, Kalsbeek A, Zwiller J, Anglard P. Rhythmic Regulation of DNA Methylation Factors and Core-Clock Genes in Brain Structures Activated by Cocaine or Sucrose: Potential Role of Chromatin Remodeling. Genes (Basel) 2021; 12:genes12081195. [PMID: 34440369 PMCID: PMC8392220 DOI: 10.3390/genes12081195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/25/2022] Open
Abstract
The circadian system interacts with the mesocorticolimbic reward system to modulate reward and memory in a time-of-day dependent manner. The circadian discrimination of reward, however, remains difficult to address between natural reinforcers and drugs of abuse. Circadian rhythms control cocaine sensitization and conversely cocaine causes long-term alteration in circadian periodicity in part through the serotonergic neurotransmission. Since neural circuits activated by cocaine and natural reinforcers do not completely overlap, we compared the effect of cocaine with that of sucrose, a strong reinforcer in rodents, by using passive chronic administration. The expression of fifteen genes playing a major role in DNA methylation (Dnmts, Tets), circadian rhythms (Clock, Bmal1, Per1/2, Cry1/2, Rev-Erbβ, Dbp1), appetite, and satiety (Orexin, Npy) was analyzed in dopamine projection areas like the prefrontal cortex, the caudate putamen, and the hypothalamus interconnected with the reward system. The corresponding proteins of two genes (Orexin, Per2) were examined by IHC. For many factors controlling biological and cognitive functions, striking opposite responses were found between the two reinforcers, notably for genes controlling DNA methylation/demethylation processes and in global DNA methylation involved in chromatin remodeling. The data are consistent with a repression of critical core-clock genes by cocaine, suggesting that, consequently, both agents differentially modulate day/night cycles. Whether observed cocaine and sucrose-induced changes in DNA methylation in a time dependent manner are long lasting or contribute to the establishment of addiction requires further neuroepigenetic investigation. Understanding the mechanisms dissociating drugs of abuse from natural reinforcers remains a prerequisite for the design of selective therapeutic tools for compulsive behaviors.
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Affiliation(s)
- Lamis Saad
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, 1066 EA Amsterdam, The Netherlands
| | - Andries Kalsbeek
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, 1066 EA Amsterdam, The Netherlands
- Correspondence: (A.K.); or (P.A.)
| | - Jean Zwiller
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- CNRS, Centre National de la Recherche Scientifique, 75016 Paris, France
| | - Patrick Anglard
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- INSERM, Institut National de la Santé et de la Recherche Médicale, 75013 Paris, France
- Correspondence: (A.K.); or (P.A.)
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Saad L, Sartori M, Pol Bodetto S, Romieu P, Kalsbeek A, Zwiller J, Anglard P. Regulation of Brain DNA Methylation Factors and of the Orexinergic System by Cocaine and Food Self-Administration. Mol Neurobiol 2019; 56:5315-5331. [PMID: 30603957 DOI: 10.1007/s12035-018-1453-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 12/07/2018] [Indexed: 12/22/2022]
Abstract
Inhibitors of DNA methylation and orexin type-1 receptor antagonists modulate the neurobiological effects driving drugs of abuse and natural reinforcers by activating common brain structures of the mesolimbic reward system. In this study, we applied a self-administration paradigm to assess the involvement of factors regulating DNA methylation processes and satiety or appetite signals. These factors include Dnmts and Tets, miR-212/132, orexins, and orx-R1 genes. The study focused on dopamine projection areas such as the prefrontal cortex (PFCx) and caudate putamen (CPu) and in the hypothalamus (HP) that is interconnected with the reward system. Striking changes were observed in response to both reinforcers, but differed depending on contingent and non-contingent delivery. Expression also differed in the PFCx and the CPu. Cocaine and food induced opposite effects on Dnmt3a expression in both brain structures, whereas they repressed both miRs to a different extent, without affecting their primary transcript in the CPu. Unexpectedly, orexin mRNAs were found in the CPu, suggesting a transport from their transcription site in the HP. The orexin receptor1 gene was found to be induced by cocaine in the PFCx, consistent with a regulation by DNA methylation. Global levels of 5-methylcytosines in the PFCx were not significantly altered by cocaine, suggesting that it is rather their distribution that contributes to long-lasting behaviors. Together, our data demonstrate that DNA methylation regulating factors are differentially altered by cocaine and food. At the molecular level, they support the idea that neural circuits activated by both reinforcers do not completely overlap.
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Affiliation(s)
- Lamis Saad
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Neuropôle de Strasbourg, Université de Strasbourg, Strasbourg, France
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands
| | - Maxime Sartori
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Neuropôle de Strasbourg, Université de Strasbourg, Strasbourg, France
- IGBMC, Inserm U 964, CNRS UMR 7104, University of Strasbourg, Illkirch, France
| | - Sarah Pol Bodetto
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Neuropôle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - Pascal Romieu
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Neuropôle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - Andries Kalsbeek
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Jean Zwiller
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Neuropôle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - Patrick Anglard
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Neuropôle de Strasbourg, Université de Strasbourg, Strasbourg, France.
- INSERM, Institut National de la Santé et de la Recherche Médicale, Paris, France.
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Cai Z, Liu H, Wang L, Li X, Bai L, Gan X, Li L, Han C. Molecular Evolutionary Analysis of the HCRTR Gene Family in Vertebrates. BIOMED RESEARCH INTERNATIONAL 2018; 2018:8120263. [PMID: 29967787 PMCID: PMC6008884 DOI: 10.1155/2018/8120263] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 03/17/2018] [Accepted: 04/17/2018] [Indexed: 12/02/2022]
Abstract
Hypocretin system is composed of hypocretins (hcrts) and their receptors (hcrtrs), which has multiple vital functions. Hypocretins work via hypocretin receptors and it is reported that functional differentiation occurred in hcrtrs. It is necessary to figure out the evolution process of hypocretin receptors. In our study, we adopt a comprehensive approach and various bioinformatics tools to analyse the evolution process of HCRTR gene family. It turns out that the second round of whole genome duplication in early vertebrate ancestry and the independent round in fish ancestry may contribute to the diversity of HCRTR gene family. HCRTR1 of fishes and mammals are not the same receptor, which means that there are three members in the family. HCRTR2 is proved to be the most ancient one in HCRTR gene family. After duplication events, the structure of HCRTR1 diverged from HCRTR2 owing to relaxed selective pressure. Negative selection is the predominant evolutionary force acting on the HCRTR gene family but HCRTR1 of mammals is found to be subjected to positive selection. Our study gains insight into the molecular evolution process of HCRTR gene family, which contributes to the further study of the system.
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Affiliation(s)
- Zhen Cai
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hehe Liu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Liyun Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Xinxin Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Lili Bai
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Xinmeng Gan
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Liang Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Chunchun Han
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
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Tsuneki H, Wada T, Sasaoka T. Chronopathophysiological implications of orexin in sleep disturbances and lifestyle-related disorders. Pharmacol Ther 2018; 186:25-44. [PMID: 29289556 DOI: 10.1016/j.pharmthera.2017.12.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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12
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Effect of orexin B on CYP17A1 and CYP19A3 expression and oestradiol, oestrone and testosterone secretion in the porcine uterus during early pregnancy and the oestrous cycle. Animal 2018; 12:1921-1932. [PMID: 29366436 DOI: 10.1017/s1751731117003779] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Orexin A (OXA) and B (OXB) are hypothalamic neuropeptides identified as regulators of food intake, energy homoeostasis, sleep-wake cycle and arousal. They also create an integrative link between energy homoeostasis and reproduction. Although their functions in the ovaries and testes have been partially explored, to date, less attention has been focused on the role of the peptides in the uterus. The aim of this study was to investigate the effect of one of orexins - orexin B on oestradiol (E2), oestrone (E1) and testosterone (T) secretion by porcine endometrial and myometrial slices as well as the gene expression of key steroidogenic enzymes responsible for steroid production (CYP17A1, CYP19A3) during the luteal phase of the oestrous cycle (days 10 to 11) and early pregnancy (days 10 to 11, 12 to 13, 15 to 16, 27 to 28). Orexin B suppressed E2 secretion by endometrial slices on days 10 to 11 and 15 to 16 of pregnancy, and days 10 to 11 of the cycle. In the myometrium, OXB inhibited E2 production on days 10 to 11 of pregnancy, whereas on days 12 to 13 it enhanced steroid output. Endometrial E1 release was potentiated by the peptide during all studied periods of the cycle and pregnancy, with the exception of days 12 to 13, when an inhibitory effect was observed. Myometrial secretion of E1 was increased, except on days 27 to 28. Testosterone secretion by endometrial slices was increased on days 12 to 13 and 27 to 28 of pregnancy. On days 10 to 11 of the cycle, T release was stimulated in response to the lowest and decreased under the influence of the highest dose of OXB. In the myometrium, T production was inhibited by OXB on days 10 to 11 of pregnancy and during the corresponding period of the cycle. On days 27 to 28 of pregnancy, T release was potentiated by the lowest dose of OXB. Expression of both genes was modified by OXB depending on the period of pregnancy and the type of examined uterine tissues. Our findings suggest that OXB, through modulation of uterine steroidogenesis, may have a regulatory role in the uterus.
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13
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Couvineau A, Dayot S, Nicole P, Gratio V, Rebours V, Couvelard A, Voisin T. The Anti-tumoral Properties of Orexin/Hypocretin Hypothalamic Neuropeptides: An Unexpected Therapeutic Role. Front Endocrinol (Lausanne) 2018; 9:573. [PMID: 30319552 PMCID: PMC6170602 DOI: 10.3389/fendo.2018.00573] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 09/10/2018] [Indexed: 02/05/2023] Open
Abstract
Orexins (OxA and OxB) also termed hypocretins are hypothalamic neuropeptides involved in central nervous system (CNS) to control the sleep/wake process which is mediated by two G protein-coupled receptor subtypes, OX1R, and OX2R. Beside these central effects, orexins also play a role in various peripheral organs such as the intestine, pancreas, adrenal glands, kidney, adipose tissue and reproductive tract.In the past few years, an unexpected anti-tumoral role of orexins mediated by a new signaling pathway involving the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in both orexin receptors subtypes, the recruitment of the phosphotyrosine phosphatase SHP2 and the induction of mitochondrial apoptosis has been elucidated. In the present review, we will discuss the anti-tumoral effect of orexin/OXR system in colon, pancreas, prostate and other cancers, and its interest as a possible therapeutic target.
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14
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Graybill NL, Weissig V. A review of orexin's unprecedented potential as a novel, highly-specific treatment for various localized and metastatic cancers. SAGE Open Med 2017; 5:2050312117735774. [PMID: 29147564 PMCID: PMC5673000 DOI: 10.1177/2050312117735774] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 09/14/2017] [Indexed: 01/12/2023] Open
Abstract
A systematic review was conducted to categorize the types of cancerous tissues that express orexin receptors and also to examine the effect of in vitro administration of orexin A or B to corresponding cell samples. Comprehensive literature analyses of primary experimental studies were performed. The results of the review included an increased frequency of orexin receptor expression in many colon and prostate cancer tissues and an upward trend of pro-apoptotic activity in these aggressive cell types.
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Affiliation(s)
- Nicole L Graybill
- Department of Pharmaceutical Sciences, Nanomedicine Center of Excellence in Translational Cancer Research, College of Pharmacy-Glendale, Midwestern University, Glendale, AZ, USA
| | - Volkmar Weissig
- Department of Pharmaceutical Sciences, Nanomedicine Center of Excellence in Translational Cancer Research, College of Pharmacy-Glendale, Midwestern University, Glendale, AZ, USA
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15
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Genes encoding neuropeptide receptors are epigenetic markers in patients with head and neck cancer: a site-specific analysis. Oncotarget 2017; 8:76318-76328. [PMID: 29100314 PMCID: PMC5652708 DOI: 10.18632/oncotarget.19356] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 06/29/2017] [Indexed: 02/07/2023] Open
Abstract
Staging and pathological grading systems are useful but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). To identify potential prognostic markers, we examined the methylation status of eight neuropeptide receptor gene promoters in 231 head and neck squamous cell carcinomas. The NPFFR1, NPFFR2, HCRTR1, HCRTR2, NPY1R, NPY2R, NPY4R, and NPY5R promoters were methylated in 80.5%, 79.2%, 67.1%, 73.2%, 35.1%, 36.4%, 38.5%, and 35.9% of the samples, respectively. In a multivariate Cox proportional hazards analysis, the odds ratio for recurrence was 2.044 (95% confidence interval [CI], 1.323–3.156; P = 0.001) when the NPY2R promoter was methylated. In patients without lymph node metastasis (n = 100), methylation of NPY2R (compared with methylation of the other seven genes) best correlated with poor disease-free survival (DFS) (odds ratio, 2.492; 95% CI, 1.190–5.215; P = 0.015). In patients with oral cancer (n = 69), methylated NPY1R and NPY2R were independent prognostic factors for poor DFS, both individually and, even more so, in combination (odds ratio, 3.90; 95% CI, 1.523–9.991; P = 0.005). Similar findings were observed for NPY2R and NPY4R in patients with oropharyngeal cancer (n = 162) (odds ratio, 5.663; 95% CI, 1.507–21.28; P = 0.010).
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16
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Liguori G, Pavone LM, Assisi L, Langella E, Tafuri S, Mirabella N, Costagliola A, Vittoria A. Expression of orexin B and its receptor 2 in rat testis. Gen Comp Endocrinol 2017; 242:66-73. [PMID: 26631456 DOI: 10.1016/j.ygcen.2015.11.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 11/23/2015] [Accepted: 11/25/2015] [Indexed: 11/18/2022]
Abstract
The peptides orexin A (OxA) and orexin B (OxB) deriving from a common precursor molecule, prepro-orexin, by proteolytic cleavage, bind the two G-coupled OX1 and OX2 receptors. While OX1 selectively binds OxA, OX2 shows similar affinity for both orexins. Firstly discovered in the hypothalamus, orexins and their receptors have been found in other brain regions as well as in peripheral tissues of mammals, thus resulting involved in the regulation of a broad variety of physiological functions. While the functional localization of OxA and OX1 in the mammalian genital tract has been already described, the expression of OxB and OX2 and their potential role in the reproductive functions remain to be explored. Here, we investigated the presence of OxB and OX2 in the rat testis by immunohistochemical and biochemical analyses. The results definitely demonstrated the localization of OxB and OX2 in pachytene and second spermatocytes as well as in spermatids at all stages of the cycle of the seminiferous epithelium. The expression of both OX2 mRNA and protein in the rat testis was also established by RT-PCR and Western blotting, respectively. The analysis of the molecular mechanism of action of OxB in the rat testis showed that OxB, in contrast with OxA, is unable to promote steroidogenesis. These results translate into the regulation of diverse biological actions by OxA and OxB in the male gonad.
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Affiliation(s)
- Giovanna Liguori
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy
| | - Luigi Michele Pavone
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Loredana Assisi
- Department of Biology, University of Naples Federico II, Via Mezzocannone 6, 80134 Naples, Italy
| | - Emilia Langella
- School of Agricultural, Forestry, Food and Environmental Sciences, University of Basilicata, Viale dell'Ateneo Lucano 10, 85100 Potenza, Italy
| | - Simona Tafuri
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy
| | - Nicola Mirabella
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy
| | - Anna Costagliola
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy
| | - Alfredo Vittoria
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy.
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Smolinska N, Kiezun M, Dobrzyn K, Szeszko K, Maleszka A, Kaminski T. Adiponectin, orexin A and orexin B concentrations in the serum and uterine luminal fluid during early pregnancy of pigs. Anim Reprod Sci 2017; 178:1-8. [PMID: 28089263 DOI: 10.1016/j.anireprosci.2017.01.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 12/22/2016] [Accepted: 01/06/2017] [Indexed: 01/09/2023]
Abstract
Adiponectin is the most abundant adipose-released protein that circulates in human plasma at high concentrations. The neuropeptides orexin A (OXA, hypocretin-1) and orexin B (OXB, hypocretin-2) are derived from a common precursor peptide, prepro-orexin and are produced mainly by neurons located in the lateral hypothalamus. It has been demonstrated that the peptides such as adiponectin and orexins have an important role in the regulation of energy metabolism and neuroendocrine functions. These hormones appear to be implicated in both normal and disturbed pregnancy. The objectives of this study were to determine adiponectin and orexin concentrations in the plasma and uterine luminal fluid (ULF) of pigs during early gestation and to explore the relationships between hormone concentrations and stages of pregnancy. The greatest plasma concentrations of adiponectin were observed on days 15-16 and 27-28 of pregnancy, and the least concentrations were on days 30-32 of gestation and on days 10-11 of the oestrous cycle. In ULF, adiponectin concentrations were greater on days 15-16 of pregnancy and on days 10-11 of the oestrous cycle than on days 10-11 and days 12-13 of pregnancy. The greatest OXA concentrations in the blood plasma were noted on days 10-16 of gestation, and the least OXA concentrations were on days 27-32 of pregnancy and on days 10-11 of the oestrous cycle. Orexin A concentrations in ULF were greater on days 10-11 of the cycle than throughout pregnancy. Serum OXB concentrations were greatest on days 10-11 and 30-32 of pregnancy, and least on days 12-28 of gestation. The greatest OXB concentrations in ULF were on days 10-13 of gestation, and the least OXB concentrations were on days 15-16 of pregnancy. This is first study to demonstrate the presence of adiponectin and orexins in the serum and ULF during early pregnancy of pigs as well as the relationships between adiponectin and orexin concentrations and the stage of pregnancy. The fluctuations in adiponectin and orexin concentrations in the plasma and ULF suggest that the hormones present in ULF are mostly of local origin and that these hormones participate in the processes that accompany early pregnancy.
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Affiliation(s)
- Nina Smolinska
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowski Street 1A, 10-719 Olsztyn, Poland.
| | - Marta Kiezun
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowski Street 1A, 10-719 Olsztyn, Poland.
| | - Kamil Dobrzyn
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowski Street 1A, 10-719 Olsztyn, Poland.
| | - Karol Szeszko
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowski Street 1A, 10-719 Olsztyn, Poland.
| | - Anna Maleszka
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowski Street 1A, 10-719 Olsztyn, Poland.
| | - Tadeusz Kaminski
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowski Street 1A, 10-719 Olsztyn, Poland.
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Taximaimaiti R, Abuliken X, Maihemuti M, Abudujilile D, Abudulimu H. Elevated Expression of Ox2R in Cervical Cancers and Placentas of Uyghur Women in Xinjiang, China. Asian Pac J Cancer Prev 2016; 17:4959-4963. [PMID: 28032723 PMCID: PMC5454703 DOI: 10.22034/apjcp.2016.17.11.4959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Objective: Cervical cancer is one of the major causes of mortality of Uyghur women in Xinjiang, China. Although increased expression of orexin receptor (OxR), known to be strongly expressed in human placenta, has a proven relation to some cancers, there have been few studies of cervical cancer. Thus, we explored this question by evaluating the expression of orexin receptor as a biomarker for screening early stage of cervical cancer in Uyghur women with highest occurrence rate of cervical cancer in China. Study Design: We used polymerase chain reaction (PCR) and immunohistochemical staining to determine the expression of both Ox1R and Ox2R in cervical cancer and cervicitis biopsies collected from Uyghur women infected with human papilloma virus (HPV)16. The expression rate was compared between cervical cancers of low, intermediate and high differentiation and cervicitis. Results: Although there was no significant difference in the expression rate of Ox1R between groups, Ox2R was significantly overexpressed in cervical cancer patients when compared to the cervicitis group. Ox1R was negative in normal human placenta while Ox2R was positive. Conclusions: While expression of Ox1R had no correlation with invasion or metastatic potential, Ox2R demonstrated elevation in cervical cancer with heterogeneity in groups with different metastatic potential, in the human placenta as well, implying that it might serve as an indicator of invasive capacity along with other indices.
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Affiliation(s)
- Reyisha Taximaimaiti
- Seven-year Clinical Medicine of Class 2, year 2011,Xinjiang Medical University, Urumqi, PR China.
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19
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Expression of the orexin system in the porcine uterus, conceptus and trophoblast during early pregnancy. Animal 2015; 9:1820-31. [DOI: 10.1017/s1751731115001020] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
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Liu Y, Zhao Y, Ju S, Guo L. Orexin A upregulates the protein expression of OX1R and enhances the proliferation of SGC-7901 gastric cancer cells through the ERK signaling pathway. Int J Mol Med 2014; 35:539-45. [PMID: 25515760 DOI: 10.3892/ijmm.2014.2038] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Accepted: 11/25/2014] [Indexed: 11/06/2022] Open
Abstract
Orexins are hypothalamic peptides that regulate food intake, wakefulness, the reward system and energy metabolism. Recent studies have demonstrated the ability of orexins to promote a robust apoptosis and subsequent inhibition of cell growth in various types of cancer cells. The present study was conducted to investigate the effects of orexin A on the survival of human gastric cancer cells, SGC‑7901, and the possible mechanisms. SGC‑7901 cells were exposed to various concentrations of orexin A in vitro in the presence or absence of the orexin receptor 1 (OX1R) antagonist (SB334867), extracellular signal‑regulated kinases 1 and 2 (ERK1/2) antagonist (U0126) or a combination of the two antagonists. The amount of cell proliferation, viability and apoptosis, caspase‑8 and caspases‑9 activities, OX1R protein expression and ERK1/2 protein levels were determined. The expression of OX1R in SGC‑7901 cells was observed. Orexin A (10-10 to 10-6 M) stimulated SGC‑7901 cell proliferation and viability, reduced the pro‑apoptotic activity of caspase‑9 and protected the cells from apoptosis in a dose‑dependent manner. Additionally, ERK1/2 phosphorylation was stimulated by orexin A (10-10 to 10-6 M). However, the OX1R antagonist SB334867 (10-6 M), ERK1/2 antagonist U0126 (30 µM) or the combination of antagonists blocked the effects of orexin A to a certain extent. These results suggest that stimulation of OX1R induces the growth of SGC‑7901 gastric cancer cells through activation of ERK1/2 signaling pathway. These findings add a new dimension to the biological activities of orexin, which may have important implications in health and disease, in particular gastric cancer.
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Affiliation(s)
- Yuanyuan Liu
- Department of Endocrinology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yuyan Zhao
- Department of Endocrinology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Shujing Ju
- Department of Endocrinology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Lei Guo
- Department of Orthopedic Surgery, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
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Crujeiras AB, Casanueva FF. Obesity and the reproductive system disorders: epigenetics as a potential bridge. Hum Reprod Update 2014; 21:249-61. [DOI: 10.1093/humupd/dmu060] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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22
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Xu TR, Yang Y, Ward R, Gao L, Liu Y. Orexin receptors: Multi-functional therapeutic targets for sleeping disorders, eating disorders, drug addiction, cancers and other physiological disorders. Cell Signal 2013; 25:2413-23. [DOI: 10.1016/j.cellsig.2013.07.025] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 07/26/2013] [Indexed: 12/29/2022]
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