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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.

Orexins are hypothalamic neuropeptides primarily involved in regulating the sleep/wakefulness cycle and circadian rhythm. They bind to the orexin receptor type 1 (OX 1 ) and type 2 (OX 2 ), well-known drug targets in the treatment of sleep disorders, that have recently been shown to play a significant role in different cancers. Lemborexant is one of a few orexin receptor antagonists that have been approved for the treatment of insomnia. Despite being classified as an antagonist, lemborexant may display agonist-like behavior in the non-canonical signaling pathway of the orexin receptors, as confirmed recently in cancer cell models. Here, we generated a model of OX 2 in complex with the full-length G q protein and used it in the molecular dynamics (MD) study. We compared the impact of lemborexant and the OX 2 -selective, potent agonist compound 1 on OX 2 activation and subsequent guanosine diphosphate (GDP) to guanosine triphosphate (GTP) exchange in the Gα q subunit. These 2 µs MD simulations showed that both ligands evoke similar, activation-like conformational changes in OX 2 and explained the observed lemborexant-mediated apoptosis of cancer cells. In addition, MD simulations of the active-state OX 2 -G q complexes allowed us to uncover a sequence of micro- and macroscale events during the activation of G q  and to detect important micro- and macroswitches in the Gα subunit.

Homeostasis of the human immune system is regulated by many cellular components, including two neuropeptides, VIP and PACAP, primary stimuli for three class B G protein-coupled receptors, VPAC1, VPAC2, and PAC1. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) regulate intestinal motility and secretion and influence the functioning of the endocrine and immune systems. Inhibition of VIP and PACAP receptors is an emerging concept for new pharmacotherapies for chronic inflammation and cancer, while activation of their receptors provides neuroprotection. A small number of known active compounds for these receptors still impose limitations on their use in therapeutics. Recent cryo-EM structures of VPAC1 and PAC1 receptors in their agonist-bound active state have provided insights regarding their mechanism of activation. Here, we describe major molecular switches of VPAC1, VPAC2, and PAC1 that may act as triggers for receptor activation and compare them with similar non-covalent interactions changing upon activation that were observed for other GPCRs. Interhelical interactions in VIP and PACAP receptors that are important for agonist binding and/or activation provide a molecular basis for the design of novel selective drugs demonstrating anti-inflammatory, anti-cancer, and neuroprotective effects. The impact of genetic variants of VIP, PACAP, and their receptors on signalling mediated by endogenous agonists is also described. This sequence diversity resulting from gene splicing has a significant impact on agonist selectivity and potency as well as on the signalling properties of VIP and PACAP receptors.

The authors describe a germ-line mutation in the gene for PRKAR1A in three unrelated patients with acrodysostosis and resistance to multiple hormones. The mutated protein subunit impairs the response of protein kinase A to cyclic-AMP stimulation. Numerous hormones activate heterotrimeric G-protein–coupled receptors, which then activate G protein and adenylyl cyclase, generating intracellular cAMP. 1 In turn, cAMP activates protein kinase A, resulting in the phosphorylation of specific proteins that mediate the physiological effects of these hormones. 2 – 4 Loss-of-function mutations in the gene encoding GNAS cause pseudohypoparathyroidism type 1a, a disease with characteristic developmental and skeletal abnormalities (collectively called Albright's hereditary osteodystrophy, i.e., short stature, brachydactyly most frequently affecting the fourth and fifth metacarpals, rounded facies, obesity, and heterotopic subcutaneous ossification) that are associated with hormone resistance. 1 , 5 Acrodysostosis (Online Mendelian Inheritance in Man number 101800) is a . . .

Background Orexins (hypocretins, Hcrt ) A and B are GPCR-binding hypothalamic neuropeptides known to regulate sleep/wake states and feeding behavior. A few studies have shown that orexin A exhibits anti-inflammatory and neuroprotective properties, suggesting that it might provide therapeutic effects in inflammatory and neurodegenerative diseases like multiple sclerosis (MS). In MS, encephalitogenic Th1 and Th17 cells trigger an inflammatory response in the CNS destroying the myelin sheath. Here, we investigated the effects of peripheral orexin A administration to mice undergoing experimental autoimmune encephalomyelitis (EAE), a widely used model of MS. Methods Mice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG) 35–55 in CFA. Mice were treated intraperitoneally for five consecutive days with either PBS or 300 μg of orexin A starting at a moderate EAE score. Molecular, cellular, and histological analysis were performed by real-time PCR, ELISA, flow cytometry, and immunofluorescence. Results Orexin A strongly ameliorated ongoing EAE, limiting the infiltration of pathogenic CD4 + T lymphocytes, and diminishing chemokine (MCP-1/CCL2 and IP-10/CXCL10) and cytokine (IFN-γ (Th1), IL-17 (Th17), TNF-α, IL-10, and TGF-β) expressions in the CNS. Moreover, orexin A treatment was neuroprotective, decreasing demyelination, astrogliosis, and microglial activation. Despite its strong local therapeutic effects, orexin A did not impair peripheral draining lymph node cell proliferation and Th1/Th17 cytokine production in response to MOG 35–55 in vitro. Conclusions Peripherally-administered orexin A ameliorated EAE by reducing CNS neuroinflammation. These results suggest that orexins may represent new therapeutic candidates that should be further investigated for MS treatment.

Orexin-A and -B are hypothalamic neuropeptides of 33 and 28-amino acids, which regulate many homeostatic systems including sleep/wakefulness states, energy balance, energy homeostasis, reward seeking and drug addiction. Orexin-A treatment was also shown to reduce tumor development in xenografted nude mice and is thus a potential treatment for carcinogenesis. The aim of this work was to explore in healthy mice the consequences on energy expenditure components of an orexin-A treatment at a dose previously shown to be efficient to reduce tumor development. Physiological approaches were used to evaluate the effect of orexin-A on food intake pattern, energy metabolism body weight and body adiposity. Modulation of the expression of brain neuropeptides and receptors including NPY, POMC, AgRP, cocaine- and amphetamine related transcript (CART), corticotropin-releasing hormone (CRH) and prepro-orexin (HCRT), and Y2 and Y5 neuropeptide Y, MC4 (melanocortin), OX1 and OX2 orexin receptors (Y2R, Y5R, MC4R, OX1R and OX2R, respectively) was also explored. Our results show that orexin-A treatment does not significantly affect the components of energy expenditure, and glucose metabolism but reduces intraperitoneal fat deposit, adiposity and the expression of several brain neuropeptide receptors suggesting that peripheral orexin-A was able to reach the central nervous system. These findings establish that orexin-A treatment which is known for its activity as an inducer of tumor cell death, do have minor parallel consequence on energy homeostasis control.

Inflammatory diseases commonly associated with humans are chronic inflammatory gastrointestinal diseases (CIGDs) [...].Inflammatory diseases commonly associated with humans are chronic inflammatory gastrointestinal diseases (CIGDs) [...].

Orexins are hypothalamic neuropeptides primarily involved in regulating the sleep/wakefulness cycle and circadian rhythm. They bind to the orexin receptor type 1 (OX ) and type 2 (OX ), well-known drug targets in the treatment of sleep disorders, that have recently been shown to play a significant role in different cancers. Lemborexant is one of a few orexin receptor antagonists that have been approved for the treatment of insomnia. Despite being classified as an antagonist, lemborexant may display agonist-like behavior in the non-canonical signaling pathway of the orexin receptors, as confirmed recently in cancer cell models. Here, we generated a model of OX in complex with the full-length G protein and used it in the molecular dynamics (MD) study. We compared the impact of lemborexant and the OX -selective, potent agonist compound 1 on OX activation and subsequent guanosine diphosphate (GDP) to guanosine triphosphate (GTP) exchange in the Gα subunit. These 2 µs MD simulations showed that both ligands evoke similar, activation-like conformational changes in OX and explained the observed lemborexant-mediated apoptosis of cancer cells. In addition, MD simulations of the active-state OX -G complexes allowed us to uncover a sequence of micro- and macroscale events during the activation of G  and to detect important micro- and macroswitches in the Gα subunit.

Inflammatory bowel diseases are chronic inflammation of the intestinal mucosa characterized by relapsing–remitting cycle periods of variable duration. Infliximab (IFX) was the first monoclonal antibody used for the treatment of Crohn’s disease and ulcerative colitis (UC). High variability between treated patients and loss of IFX efficiency over time support the further development of drug therapy. An innovative approach has been suggested based on the presence of orexin receptor (OX1R) in the inflamed human epithelium of UC patients. In that context, the aim of this study was to compare, in a mouse model of chemically induced colitis, the efficacy of IFX compared to the hypothalamic peptide orexin-A (OxA). C57BL/6 mice received 3.5% dextran sodium sulfate (DSS) in drinking water for 5 days. Since the inflammatory flare was maximal at day 7, IFX or OxA was administered based on a curative perspective at that time for 4 days using intraperitoneal injection. Treatment with OxA promoted mucosal healing and decreased colonic myeloperoxidase activity, circulating concentrations of lipopolysaccharide-binding protein, IL-6 and tumor necrosis factor alpha (TNFα) and decreased expression of genes encoding cytokines in colonic tissues with better efficacy than IFX allowing for more rapid re-epithelization. This study demonstrates the comparable anti-inflammatory properties of OxA and IFX and shows that OxA is efficient in promoting mucosal healing, suggesting that OxA treatment is a promising new biotherapy.