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.

وصف الملف: application/pdf

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

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

المؤلفون: Dexin Zhang, Ying Cui, Manman Zhao, Xuecheng Zheng, Chunyan Li, Jingbo Wei, Kaijie Wang, Jianzhong Cui

المصدر: Frontiers in Cellular Neuroscience, Vol 16 (2022)

مصطلحات موضوعية: orexin A, autophagy, intracerebral hemorrhage, neuroprotection, orexin receptor, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: BackgroundOrexin-A (OXA) is a polypeptide produced in the hypothalamus, which binds to specific receptors and exerts multiple physiological effects. Autophagy plays a vital role in early brain injury (EBI) after intracerebral hemorrhage (ICH). However, the relationship between OXA and autophagy after ICH has not been confirmed.MethodsIn this study, the protective role of OXA was investigated in a model of hemin-induced injury in PC12 cells and blood-injection ICH model in rats, and its potential molecular mechanism was clarified. Neurobehavioral tests, brain water content, and pathologic morphology were assessed after ICH. Cell survival rate was determined using Cell Counting Kit-8 (CCK-8), while apoptosis was detected using flow cytometry. The autophagy protein LC3 that was originally identified as microtubule-associated protein 1 light 3 was evaluated by immunohistochemistry. The ultrastructural changes of cells following ICH were observed by transmission electron microscopy. Western blotting was performed to determine the expression levels of LC3, p62/SQSTM1 (p62), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), total extracellular signal-regulated kinase 1/2 (t-ERK1/2), mammalian target of rapamycin (mTOR), and phosphorylated mammalian target of rapamycin (p-mTOR).ResultsOXA treatment significantly improved neurofunctional outcomes, reduced brain edema, and alleviated neuronal apoptosis. OXA administration upregulated p-mTOR and p62, while it downregulated p-ERK1/2 and LC3; this effect was reversed by the orexin receptor 1 (OXR1) antagonist SB-334867.ConclusionsThis study demonstrates that OXA suppresses autophagy via the OXR1-mediated ERK/mTOR signaling pathway to exert neuroprotective effects, and it might provide a novel therapeutic approach in patients suffering from ICH.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fncel.2022.1045034/fullTest; https://doaj.org/toc/1662-5102Test

الوصول الحر: https://doaj.org/article/3485fbf3306d4041954ac06859291f3dTest

المؤلفون: 知花 和行

المصدر: アレルギー / Japanese Journal of Allergology. 2023, 72(9):1176

المؤلفون: Leino, Teppo O., Turku, Ainoleena, Urvas, Lauri, Adhikari, Karuna, Oksanen, Jouni, Steynen, Yana, Yli-Kauhaluoma, Jari, Xhaard, Henri, Kukkonen, Jyrki P., Wallén, Erik A. A.

المساهمون: Divisions of Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Pharmaceutical Design and Discovery group, Veterinary Biosciences, Faculty of Veterinary Medicine, Faculty of Pharmacy, Department of Pharmacology, Jari Yli-Kauhaluoma / Principal Investigator, Computational Adme, Henri Xhaard / Principal Investigator, Division of Pharmaceutical Biosciences, Erik Wallen / Principal Investigator, Medicinal Chemistry research group

مصطلحات موضوعية: Agonist, Azulene, Medicinal chemistry, Orexin receptor, Sulfonamides, 3111 Biomedicine, 1182 Biochemistry, cell and molecular biology, 317 Pharmacy

الوصف: Azulene is a rare ring structure in drugs, and we investigated whether it could be used as a biphenyl mimetic in known orexin receptor agonist Nag 26, which is binding to both orexin receptors OX1 and OX2 with preference towards OX2. The most potent azulene-based compound was identified as an OX1 orexin receptor agonist (pEC50 = 5.79 +/- 0.07, maximum response = 81 +/- 8% (s.e.m. of five independent experiments) of the maximum response to orexin-A in Ca2+ elevation assay). However, the azulene ring and the biphenyl scaffold are not identical in their spatial shape and electron distribution, and their derivatives may adopt different binding modes in the binding site. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: Leino , T O , Turku , A , Urvas , L , Adhikari , K , Oksanen , J , Steynen , Y , Yli-Kauhaluoma , J , Xhaard , H , Kukkonen , J P & Wallén , E A A 2023 , ' Azulene as a biphenyl mimetic in orexin/hypocretin receptor agonists ' , Bioorganic & Medicinal Chemistry , vol. 88-89 , 117325 . https://doi.org/10.1016/j.bmc.2023.117325Test; ORCID: /0000-0002-6989-1564/work/137437590; ORCID: /0000-0003-0370-7653/work/137437764; ORCID: /0000-0003-0959-7221/work/137438818; ORCID: /0000-0003-2582-7971/work/137440251; http://hdl.handle.net/10138/359559Test; c9572f10-7a1b-42fd-9f32-fe162591a425; 001001557400001

الإتاحة: http://hdl.handle.net/10138/359559Test

المؤلفون: Masami Yamaguchi, Manabu Ishikawa, Yuri Aono, Tadashi Saigusa

المصدر: Neuropsychopharmacology Reports, Vol 40, Iss 1, Pp 30-38 (2020)

مصطلحات موضوعية: chronic pain, intracellular calcium ion levels, orexin receptor, orexin‐A, rat, Therapeutics. Pharmacology, RM1-950, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Abstract Aims Orexin‐A is known to induce anti‐nociceptive effects in animal models of chronic pain. We have found that orexin‐A inhibits KCl loading‐induced increases in the intracellular calcium ion levels ([Ca2+]i) in C‐fiber‐like neurons of rats showing inflammatory nociceptive behavior. Here, we examined the effects of orexin‐A on the depolarization of C‐fiber‐like neurons derived from a rat model for another type of chronic pain, namely neuropathic pain. Thus, we analyzed the effects of orexin‐A on KCl‐induced increases in [Ca2+]i in C‐fiber‐like neurons of rats with sciatic nerve ligation. Methods Paw withdrawal and threshold force in response to tactile stimuli were evaluated using von Frey filaments. Sham‐operated rats served as controls. [Ca2+]i in neurons were visualized by calcium fluorescent probe. Changes in [Ca2+]i were assessed using relative fluorescence intensity. Results Seven days after sciatic nerve ligation, paw withdrawal and threshold force for tactile stimuli were increased and reduced, respectively. KCl loading to neurons from either sciatic nerve‐ligated or control rats increased relative fluorescence intensity. The KCl‐induced increase in relative fluorescence intensity in sciatic nerve‐ligated, but not that of control, rats was inhibited by orexin‐A. The OX1 and OX2 receptor antagonist MK‐4305 and OX2 receptor antagonist EMPA, but not the OX1 receptor antagonist SB 334867, each counteracted orexin‐A‐induced inhibition of KCl‐provoked increases in relative fluorescence intensity. Conclusion The present findings constitute neuropharmacological evidence that OX2 but not OX1 receptors mediate the inhibitory effects of orexin‐A on KCl‐induced increases in [Ca2+]i in C‐fiber‐like neurons of rats showing hyperalgesia provoked by sciatic nerve ligation.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2574-173XTest

الوصول الحر: https://doaj.org/article/5c7128a7a5d747e4adfb6610db139eb9Test

المؤلفون: Hye Ji J. Kim, Ayat Zagzoog, Anna Maria Smolyakova, Udoka C. Ezeaka, Michael J. Benko, Teagan Holt, Robert B. Laprairie

المصدر: Frontiers in Neuroscience, Vol 15 (2021)

مصطلحات موضوعية: cannabinoid, cannabinoid receptor, receptor antagonist, orexin receptor, heterodimerization, colocalization, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: The endocannabinoid and orexin neuromodulatory systems serve key roles in many of the same biological functions such as sleep, appetite, pain processing, and emotional behaviors related to reward. The type 1 cannabinoid receptor (CB1R) and both subtypes of the orexin receptor, orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R) are not only expressed in the same brain regions modulating these functions, but physically interact as heterodimers in recombinant and neuronal cell cultures. In the current study, male and female C57BL/6 mice were co-treated with the cannabinoid receptor agonist CP55,940 and either the OX2R antagonist TCS-OX2-29 or the dual orexin receptor antagonist (DORA) TCS-1102. Mice were then evaluated for catalepsy, body temperature, thermal anti-nociception, and locomotion, after which their brains were collected for receptor colocalization analysis. Combined treatment with the DORA TCS-1102 and CP55,940 potentiated catalepsy more than CP55,940 alone, but this effect was not observed for changes in body temperature, nociception, locomotion, or via selective OX2R antagonism. Co-treatment with CP55,940 and TCS-1102 also led to increased CB1R-OX1R colocalization in the ventral striatum. This was not seen following co-treatment with TCS-OX2-29, nor in CB1R-OX2R colocalization. The magnitude of effects following co-treatment with CP55,940 and either the DORA or OX2R-selective antagonist was greater in males than females. These data show that CB1R-OX1R colocalization in the ventral striatum underlies cataleptic additivity between CP55,940 and the DORA TCS-1102. Moreover, cannabinoid-orexin receptor interactions are sex-specific with regards to brain region and functionality. Physical or molecular interactions between these two systems may provide valuable insight into drug-drug interactions between cannabinoid and orexin drugs for the treatment of insomnia, pain, and other disorders.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fnins.2021.790546/fullTest; https://doaj.org/toc/1662-453XTest

الوصول الحر: https://doaj.org/article/4b6877ca895647578248337cf8d05398Test

المؤلفون: Pilar Marcos, Rafael Coveñas

المصدر: Applied Sciences; Volume 12; Issue 1; Pages: 86

مصطلحات موضوعية: feeding, obesity, orexin A, orexin B, orexin receptor, orexinergic peptide, prepro-orexin

جغرافية الموضوع: agris

الوصف: To know the processes involved in feeding, the dysregulation of hypothalamic neuropeptides promoting anorexigenic/orexigenic mechanisms must be investigated. Many neuropeptides are involved in this behavior and in overweight/obesity. Current pharmacological strategies for the treatment of obesity are unfortunately not very effective and, hence, new therapeutic strategies must be investigated and developed. Due to the crucial role played by orexins in feeding behavior, the aim of this review is to update the involvement of the orexinergic system in this behavior. The studies performed in experimental animal models and humans and the relationships between the orexinergic system and other substances are mentioned and discussed. Promising research lines on the orexinergic system are highlighted (signaling pathways, heterogeneity of the hypothalamic orexinergic neurons, receptor-receptor interaction, and sex differences). Each of the orexin 1 and 2 receptors plays a unique role in energy metabolism, exerting a differential function in obesity. Additional preclinical/clinical studies must be carried out to demonstrate the beneficial effects mediated by orexin receptor antagonists. Because therapies applied are in general ineffective when they are directed against a single target, the best option for successful anti-obesity treatments is the development of combination therapies as well as the development of new and more specific orexin receptor antagonists.

وصف الملف: application/pdf

العلاقة: Applied Biosciences and Bioengineering; https://dx.doi.org/10.3390/app12010086Test

الإتاحة: https://doi.org/10.3390/app12010086Test

المؤلفون: Aki Fujiwara, Mana Tsukada, Hideshi Ikemoto, Takuji Izuno, Satoshi Hattori, Takayuki Okumo, Tadashi Hisamitsu, Masataka Sunagawa

المصدر: Healthcare; Volume 9; Issue 5; Pages: 503

مصطلحات موضوعية: orexin, acupuncture, press tack needle, antistress effect, orexin receptor, aggressive behavior

الوصف: The aim of this research was to investigate the antistress effect of press tack needle (PTN) acupuncture treatment using rats with social isolation stress (SIS). Rats were divided into non-stress group (Grouped+sham), stress group (SIS+sham), and PTN-treated SIS group (SIS+PTN). Rats in the SIS+PTN and SIS+sham groups were housed alone for eight days. For the SIS+PTN group, a PTN (length, 0.3 or 1.2 mm) was fixed on the GV20 acupoint on day 7. We measured stress behavior based on the time the rats showed aggressive behavior and the levels of plasma corticosterone and orexin A on day 8. In addition, the orexin-1 receptor or orexin-2 receptor antagonist was administered to rats that were exposed to SIS. The duration of aggressive behavior was significantly prolonged in the SIS+sham group, and the prolonged duration was inhibited in the SIS+PTN (1.2 mm) group. The levels of plasma corticosterone and orexin A were significantly increased in the SIS+sham group; however, these increases were inhibited in the SIS+PTN group. The aggressive behavior was significantly reduced after the orexin-2 receptor antagonist was administered. These findings suggest that PTN treatment at GV20 may have an antistress effect, and the control of orexin is a mechanism underlying this phenomenon.

وصف الملف: application/pdf

العلاقة: https://dx.doi.org/10.3390/healthcare9050503Test

الإتاحة: https://doi.org/10.3390/healthcare9050503Test

المؤلفون: Mingxin Lyu, Xiaolong Gao, Mo Zhang, Shihui Lin, Xuan Luo, Weiwei You, Caihuan Ke

المصدر: Frontiers in Marine Science, Vol 8 (2021)

مصطلحات موضوعية: abalone, digestive enzyme, feeding behavior, neuropeptide F, orexin receptor, Science, General. Including nature conservation, geographical distribution, QH1-199.5

الوصف: Abalone (Haliotis spp.) are typical nocturnal creatures but Haliotis discus hannai is bold and active in the nighttime whereas H. gigantea tends to be timid and inactive. In this study, we quantified and compared differences in movement, feeding, and digestive physiology between H. discus hannai and H. gigantea as well as the potential molecular mechanisms on the basis of video observations and expression levels of genes related to feeding regulation. The feeding behaviors of both species were characterized by significant circadian rhythms (P < 0.05). However, the distance moved and the cumulative duration of movement were 2.61 and 1.94 times higher, respectively, in H. discus hannai than in H. gigantea over the 24-h cycle. The cumulative duration of feeding by H. discus hannai was only 1.15 times that by H. gigantea, but the feeding time as a percentage of the cumulative duration of movement (FTP) was up to 94.6% for H. gigantea and only 56.0% for H. discus hannai. The peaks for α-amylase activity and NPF expression levels in both species as well as the peak OX2R expression level in H. gigantea occurred during 20:00–00:00 h. By contrast, the peaks for alginate lyase activity and NPYR expression levels in H. discus hannai occurred at 16:00 h, when the FTP was significantly higher for H. discus hannai than for H. gigantea. These initial findings quantify specific behavior parameters and thus provide a reference for the selection of appropriate feeding strategies and the proliferation of abalone via bottom sowing.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fmars.2021.751401/fullTest; https://doaj.org/toc/2296-7745Test

الوصول الحر: https://doaj.org/article/9f271ac784404b32a4f2e0e1078d07b2Test

المؤلفون: Teppo O. Leino, Ainoleena Turku, Lauri Urvas, Karuna Adhikari, Jouni Oksanen, Yana Steynen, Jari Yli-Kauhaluoma, Henri Xhaard, Jyrki P. Kukkonen, Erik A.A. Wallén

المساهمون: Divisions of Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Pharmaceutical Design and Discovery group, Veterinary Biosciences, Faculty of Veterinary Medicine, Faculty of Pharmacy, Department of Pharmacology, Jari Yli-Kauhaluoma / Principal Investigator, Computational Adme, Henri Xhaard / Principal Investigator, Division of Pharmaceutical Biosciences, Erik Wallen / Principal Investigator

مصطلحات موضوعية: Orexin receptor, Sulfonamides, azulene, Organic Chemistry, Clinical Biochemistry, Agonist, Pharmaceutical Science, Medicinal chemistry, Biochemistry, lääkekemia, 317 Pharmacy, medicinal chemistry, sulfonamides, Drug Discovery, atsuleeni, Molecular Medicine, 1182 Biochemistry, cell and molecular biology, Azulene, 3111 Biomedicine, agonist, Molecular Biology, orexin receptor

الوصف: Azulene is a rare ring structure in drugs, and we investigated whether it could be used as a biphenyl mimetic in known orexin receptor agonist Nag 26, which is binding to both orexin receptors OX1 and OX2 with preference towards OX2. The most potent azulene-based compound was identified as an OX1 orexin receptor agonist (pEC50 = 5.79 +/- 0.07, maximum response = 81 +/- 8% (s.e.m. of five independent experiments) of the maximum response to orexin-A in Ca2+ elevation assay). However, the azulene ring and the biphenyl scaffold are not identical in their spatial shape and electron distribution, and their derivatives may adopt different binding modes in the binding site.

وصف الملف: application/pdf; fulltext

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d7df09711b7611d8344b9ac76de0bc4cTest
http://hdl.handle.net/10138/359559Test