المؤلفون: Pilar Marcos, Rafael Coveñas

المصدر: Applied Sciences; Volume 13; Issue 13; Pages: 7596

مصطلحات موضوعية: orexin A, orexin B, orexin receptor, hypocretin, adrenocortical adenoma, breast cancer, colon cancer, gastric cancer, neuroblastoma, prostate cancer

جغرافية الموضوع: agris

الوصف: Peptides promote the mitogenesis and migration of tumor cells, and cancer cells overexpress peptide receptors. The involvement of the orexinergic system in cancer is reviewed here, including thirteen cancer types (e.g., adrenocortical adenoma, breast, colon, gastric, liver, neuroblastoma, pancreas, prostate). An upregulation of the orexinergic system has been reported in many tumors, and orexin receptors (OXRs) mediate a dual effect: apoptosis in some tumors and a proliferative action in others. OXR antagonists or agonists are potential antitumor agents against tumors expressing OXRs. The complexities of the biological processes associated with the orexigenic system are also described in the review, as they may provide the basis for the development of new therapies: OXR dimerization/oligomerization, epigenetic mechanisms controlling the orexinergic system, possible biomarkers of this system for tumor risk/prognosis, protective effects mediated by orexins against chemotherapeutic drugs, the combination therapy of OXR antagonists/agonists with radiotherapy or chemotherapy, and the anti-inflammatory effects mediated by orexins. Taking these data into account, future therapeutic applications as well as research lines to be developed are also mentioned and discussed. This knowledge will allow for the development of antitumor strategies in the future.

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العلاقة: Applied Biosciences and Bioengineering; https://dx.doi.org/10.3390/app13137596Test

الإتاحة: https://doi.org/10.3390/app13137596Test

المؤلفون: Pignatelli Garrigos, Jaime, Mayoral, Irene, Fernandez de Sevilla, M.E., Torres Alemán, Ignacio

المساهمون: Instituto de Salud Carlos III, Comunidad de Madrid, European Commission, Ministerio de Ciencia e Innovación (España), Fulbright Commission

مصطلحات موضوعية: IGF-I, central control of metabolism, circadian activity, feeding entrainment, orexin

الوصف: Uncoupling of metabolism and circadian activity is associated with an increased risk of a wide spectrum of pathologies. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain less defined. We recently showed that IGF-I targets orexin neurons in the lateral hypothalamus, and now we evaluated whether IGF-I modulates orexin neurons to align circadian rhythms with metabolism. Mice with disrupted IGF-IR activity in orexin neurons (Firoc mice) showed sexually dimorphic alterations in daily glucose rhythms and feeding activity patterns which preceded the appearance of metabolic disturbances. Thus, Firoc males developed hyperglycemia and glucose intolerance, while females developed obesity. Since IGF-I directly modulates orexin levels and hepatic expression of KLF genes involved in circadian and metabolic entrainment in an orexin-dependent manner, it seems that IGF-I entrains metabolism and circadian rhythms by modulating the activity of orexin neurons. ; This research was funded by a grant from Ciberned (Instituto de Salud Carlos III, Spain), an Inter-CIBER project (PIE14/00061), part of the projects PID2019-104376RB-I00 funded by MCIN/AEI/10.13039/ 501100011033; and a grant by Comunidad de Madrid through the European Social Fund (ESF)-financed program NEUROMETAB-CM (B2017/BMD-3700) to ITA. Sperber, Jacob was funded by a Fulbright grant.

العلاقة: #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104376RB-I00/ES/PLASTICIDAD AFECTIVA: MODULACION DEL ESTADO DE ANIMO POSITIVO POR PEPTIDOS INSULINICOS/; Publisher's version; https://www.mdpi.com/1422-0067/23/9/4679Test; Sí; International Journal of Molecular Sciences; http://hdl.handle.net/10261/351862Test

الإتاحة: https://doi.org/10.3390/ijms23094679Test
http://hdl.handle.net/10261/351862Test

المؤلفون: Yoshiaki Soejima, Nahoko Iwata, Ran Nishioka, Mako Honda, Yasuhiro Nakano, Koichiro Yamamoto, Atsuhito Suyama, Fumio Otsuka

المصدر: International Journal of Molecular Sciences; Volume 24; Issue 16; Pages: 12559

مصطلحات موضوعية: bone morphogenetic protein (BMP), orexin, steroidogenesis and adrenal

جغرافية الموضوع: agris

الوصف: Orexins are neuropeptides that play important roles in sleep-wake regulation and food intake in the central nervous system, but their receptors are also expressed in peripheral tissues, including the endocrine system. In the present study, we investigated the functions of orexin in adrenal steroidogenesis using human adrenocortical H295R cells by focusing on its interaction with adrenocortical bone morphogenetic proteins (BMPs) that induce adrenocortical steroidogenesis. Treatment with orexin A increased the mRNA levels of steroidogenic enzymes including StAR, CYP11B2, CYP17, and HSD3B1, and these effects of orexin A were further enhanced in the presence of forskolin. Interestingly, orexin A treatment suppressed the BMP-receptor signaling detected by Smad1/5/9 phosphorylation and Id-1 expression through upregulation of inhibitory Smad7. Orexin A also suppressed endogenous BMP-6 expression but increased the expression of the type-II receptor of ActRII in H295R cells. Moreover, treatment with BMP-6 downregulated the mRNA level of OX1R, but not that of OX2R, expressed in H295R cells. In conclusion, the results indicate that both orexin and BMP-6 accelerate adrenocortical steroidogenesis in human adrenocortical cells; both pathways mutually inhibit each other, thereby leading to a fine-tuning of adrenocortical steroidogenesis.

وصف الملف: application/pdf

العلاقة: Molecular Endocrinology and Metabolism; https://dx.doi.org/10.3390/ijms241612559Test

الإتاحة: https://doi.org/10.3390/ijms241612559Test

المؤلفون: Maria P. Mogavero, Justyna Godos, Giuseppe Grosso, Filippo Caraci, Raffaele Ferri

المصدر: Nutrients; Volume 15; Issue 17; Pages: 3679

مصطلحات موضوعية: orexin, hypocretin, REM sleep, feeding, appetite, sleep, wakefulness, eating disorders

جغرافية الموضوع: agris

الوصف: Orexin plays a significant role in the modulation of REM sleep, as well as in the regulation of appetite and feeding. This review explores, first, the current evidence on the role of orexin in the modulation of sleep and wakefulness and highlights that orexin should be considered essentially as a neurotransmitter inhibiting REM sleep and, to a much lesser extent, a wake promoting agent. Subsequently, the relationship between orexin, REM sleep, and appetite regulation is examined in detail, shedding light on their interconnected nature in both physiological conditions and diseases (such as narcolepsy, sleep-related eating disorder, idiopathic hypersomnia, and night eating syndrome). Understanding the intricate relationship between orexin, REM sleep, and appetite regulation is vital for unraveling the complex mechanisms underlying sleep-wake patterns and metabolic control. Further research in this field is encouraged in order to pave the way for novel therapeutic approaches to sleep disorders and metabolic conditions associated with orexin dysregulation.

وصف الملف: application/pdf

العلاقة: Nutrition and Public Health; https://dx.doi.org/10.3390/nu15173679Test

الإتاحة: https://doi.org/10.3390/nu15173679Test

المؤلفون: Nushrat Yasmin, Adam D. Collier, Abdul R. Abdulai, Olga Karatayev, Boyi Yu, Milisia Fam, Sarah F. Leibowitz

المصدر: Cells; Volume 12; Issue 10; Pages: 1399

مصطلحات موضوعية: chemokine, Cxcl12, hypocretin, orexin, ethanol, prenatal alcohol exposure, zebrafish

الوصف: Studies in zebrafish and rats show that embryonic ethanol exposure at low-moderate concentrations stimulates hypothalamic neurons expressing hypocretin/orexin (Hcrt) that promote alcohol consumption, effects possibly involving the chemokine Cxcl12 and its receptor Cxcr4. Our recent studies in zebrafish of Hcrt neurons in the anterior hypothalamus (AH) demonstrate that ethanol exposure has anatomically specific effects on Hcrt subpopulations, increasing their number in the anterior AH (aAH) but not posterior AH (pAH), and causes the most anterior aAH neurons to become ectopically expressed further anterior in the preoptic area (POA). Using tools of genetic overexpression and knockdown, our goal here was to determine whether Cxcl12a has an important function in mediating the specific effects of ethanol on these Hcrt subpopulations and their projections. The results demonstrate that the overexpression of Cxcl12a has stimulatory effects similar to ethanol on the number of aAH and ectopic POA Hcrt neurons and the long anterior projections from ectopic POA neurons and posterior projections from pAH neurons. They also demonstrate that knockdown of Cxcl12a blocks these effects of ethanol on the Hcrt subpopulations and projections, providing evidence supporting a direct role of this specific chemokine in mediating ethanol’s stimulatory effects on embryonic development of the Hcrt system.

وصف الملف: application/pdf

العلاقة: Cells of the Nervous System; https://dx.doi.org/10.3390/cells12101399Test

الإتاحة: https://doi.org/10.3390/cells12101399Test

المؤلفون: Wojciech Ziemichód, Antonina Kurowska, Karolina Grabowska, Michalina Kurowska, Grażyna Biała

المصدر: Molecules; Volume 28; Issue 8; Pages: 3575

مصطلحات موضوعية: orexin system, depression, anxiety, seltorexant

جغرافية الموضوع: agris

الوصف: Twenty-five years have passed since the discovery of the orexin system, during which time we have learned more and more about it. A number of studies have been conducted showing the role of the orexin system in insomnia, as well as its potential use in the treatment of obesity and depression. In this review, we present the role of the orexin system in the development of depressive illness and show the characteristics of seltorexant, a potential drug for the treatment of depression. This review describes the structure and synthesis of the compound as well as its pharmacodynamics and pharmacokinetics. Pre-clinical and clinical studies are also described, including side effects. There is evidence that the use of seltorexant is considered safe, with no clear or major clinically significant side effects, which makes it a promising candidate for the treatment of depression and anxiety disorders.

وصف الملف: application/pdf

العلاقة: https://dx.doi.org/10.3390/molecules28083575Test

الإتاحة: https://doi.org/10.3390/molecules28083575Test

المؤلفون: Jia He, Jing Fang, Yuxin Wang, Chengyu Ge, Shao Liu, Yueping Jiang

المصدر: Pharmaceuticals; Volume 16; Issue 4; Pages: 542

مصطلحات موضوعية: traditional Chinese medicine (TCM), orexin receptors, in-home ligand library, neferine, screening and verification

الوصف: Insomnia is an important public health problem. The currently available treatments for insomnia can cause some adverse effects. Orexin receptors 1 (OX1R) and 2 (OX2R) are burgeoning targets for insomnia treatment. It is an effective approach to screening OX1R and OX2R antagonists from traditional Chinese medicine, which contains abundant and diverse chemical components. This study established an in-home ligand library of small-molecule compounds from medicinal plants with a definite hypnotic effect, as described in the Chinese Pharmacopoeia. Molecular docking was applied to virtually screen potential orexin receptor antagonists using molecular operating environment software, and surface plasmon resonance (SPR) technology was used to detect the binding affinity between potential active compounds and orexin receptors. Finally, the results of virtual screening and SPR analysis were verified through in vitro assays. We successfully screened one potential lead compound (neferine) as an orexin receptor antagonist from the in-home ligand library, which contained more than 1000 compounds. The screened compound was validated as a potential agent for insomnia treatment through comprehensive biological assays. This research enabled the discovery of a potential small-molecule antagonist of orexin receptors for the treatment of insomnia, providing a novel screening approach for the detection of potential candidate compounds for corresponding targets.

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العلاقة: Medicinal Chemistry; https://dx.doi.org/10.3390/ph16040542Test

الإتاحة: https://doi.org/10.3390/ph16040542Test

المؤلفون: Akeem Sanni, Mona Goli, Jingfu Zhao, Junyao Wang, Chloe Barsa, Samer El Hayek, Farid Talih, Bartolo Lanuzza, Firas Kobeissy, Giuseppe Plazzi, Monica Moresco, Stefania Mondello, Raffaele Ferri, Yehia Mechref

المصدر: Biomolecules; Volume 13; Issue 3; Pages: 420

مصطلحات موضوعية: autoimmunity, NT1, pathophysiology, serum-protein biomarkers, orexin/hypocretin

جغرافية الموضوع: agris

الوصف: Narcolepsy type 1 (NT1) is the most common type of narcolepsy known to be caused by the loss of specific neurons responsible for producing peptide neurotransmitters (orexins/hypocretins), resulting in a sleep-wake cycle disorder. It is characterized by its association with cataplexy and abnormalities in rapid eye movement. To date, no cure has been established for this life-threatening condition. Misdiagnosis of NT1 is also quite common, although it is not exceedingly rare. Therefore, successfully identifying candidate serum biomarkers for NT1 would be a head start for accurate diagnosis and development of therapeutics for this disorder. This study aims to identify such potential serum biomarkers. A depletion protocol was employed for 27 human serum samples (16 NT1 and 11 healthy controls), followed by applying LC-MS/MS bottom-up proteomics analysis, then LC-PRM-MS for validation. The comparison of the proteome profiles of the low-abundant proteins in the samples was then investigated based on age, sex, sample groups, and the presence of the Human Leukocyte Antigen (HLA) DQB1*0602 allele. The results were tracked to gene expression studies as well as system biology to identify key proteins and understand their relationship in the pathogenesis of NT1. Our results revealed 36 proteins significantly and differentially expressed. Among the impaired pathways and bioprocesses, the complement activation pathway is impaired by six of the differentially expressed proteins (DEPs). They are coded by the genes C2, CFB, C5, C1R, C1S, and MASP1, while 11 DEPs are involved in Acute Phase Response Signaling (APRS), which are coded by the genes FN1, AMBP, APOH, CFB, CP, ITIH2, C5, C2, F2, C1, and ITIH4. The combined AUCs of the downregulated and upregulated DEPs are 0.95 and 0.76, respectively. Overall, this study reveals potential serum-protein biomarkers of NT1 and explains the possible correlation between the biomarkers and pathophysiological effects, as well as important biochemical pathways involved in NT1.

وصف الملف: application/pdf

العلاقة: https://dx.doi.org/10.3390/biom13030420Test

الإتاحة: https://doi.org/10.3390/biom13030420Test

المؤلفون: Hye Ji J. Kim, Ayat Zagzoog, Costanza Ceni, Rebecca Ferrisi, Nicola Janz, Robert B. Laprairie

المصدر: Brain Sciences; Volume 13; Issue 2; Pages: 314

مصطلحات موضوعية: anhedonia, restraint stress, endocannabinoid system, cannabinoid, orexin

الوصف: The endocannabinoid and orexin systems share many biological functions, including wakefulness, stress response, reward processing, and mood. While these systems work against one another with respect to arousal, chronic stress-induced downregulation of both systems often leads to anhedonia or the inability to experience pleasure from natural rewards. In the current study, a 24 h restraint stress test (24 h RST) reduced sucrose preference in adult male and female C57BL/6 mice. Prior to the stressor, subsets of mice were intraperitoneally administered cannabinoid and orexin receptor agonists, antagonists, and combinations of these drugs. Restraint mice that received the cannabinoid receptor type 1 (CB1R) antagonist SR141716A, orexin receptor type 2 (OX2R) agonist YNT-185, and the combination of SR141716A and YNT-185, exhibited less anhedonia compared to vehicle/control mice. Thus, the 24 h RST likely decreased orexin signaling, which was then restored by YNT-185. Receptor colocalization analysis throughout mesocorticolimbic brain regions revealed increased CB1R-OX1R colocalization from SR141716A and YNT-185 treatments. Although a previous study from our group showed additive cataleptic effects between CP55,940 and the dual orexin receptor antagonist (TCS-1102), the opposite combination of pharmacological agents proved additive for sucrose preference. Taken together, these results reveal more of the complex interactions between the endocannabinoid and orexin systems.

وصف الملف: application/pdf

العلاقة: Psychiatric Diseases; https://dx.doi.org/10.3390/brainsci13020314Test

الإتاحة: https://doi.org/10.3390/brainsci13020314Test

المؤلفون: Martina Rotondo, Claudia Honisch, Stefano Tartaggia, Paolo Ruzza

المصدر: Molecules; Volume 28; Issue 2; Pages: 484

مصطلحات موضوعية: orexin B, oxidative stress, peptide synthesis, peptide conformation, membrane mimetic environment, circular dichroism, MALDI-TOF

جغرافية الموضوع: agris

الوصف: The neuropeptides orexin A and B regulate various vital functions of the body, such as sleep/wake states, metabolism, and energy homeostasis. A loss of their physiological activity, with reduced ability to recognize their receptors, is suspected to be associated with oxidative stress conditions. These are related to excessive presence of reactive oxygen and nitrogen species, as well as of reactive lipoxidation byproducts. With the aim of evaluating the effects of oxidative stress on the secondary structure of orexin peptides, orexin B was synthesized and characterized by circular dichroism spectroscopy under different conditions. In aqueous solution it presents an unordered conformation, while in a membrane mimetic environment it assumes a helical structure. The effects of oxidative stress were evaluated exposing it to both oxygen and nitrogen radicals as well as to lipoxidation byproducts. The results showed that ROS, but not NRS, induced appreciable conformational changes, and only in the membrane mimetic environment. Lipoxidation byproducts, instead, led to secondary structure modifications much more evident than those induced by the direct action of ROS and RNS, and in both analyzed media. Additionally, MALDI-TOF analyses detected mass variations in the peptide attributable to oxidation of the C-terminal Met residue and deamination of asparagine in the Asn–His sequence. Taken together, all these data seem to confirm the involvement of oxidative processes in dysfunctions of the orexinergic system.

وصف الملف: application/pdf

العلاقة: Medicinal Chemistry; https://dx.doi.org/10.3390/molecules28020484Test

الإتاحة: https://doi.org/10.3390/molecules28020484Test