Search Results (5)

Orexins A (OXA) and B (OXB) and their specific receptors, receptor 1 (OX1R) and 2 (OX2R) for orexins, are hypothalamic peptides involved in orchestrating several functions in the central nervous system and peripheral organs, including sleep, excitement, nutrition, reward, circadian rhythm, anxiety, cognition, and reproduction. The aim of this narrative review is, in particular, to speculate the role of orexins in the male genital tract of animal species and human beings. The experimental evidence collected in recent years assumed that in the testes of the animal species here described, orexins are directly involved in steroidogenesis and spermatogenesis regulation. In the epididymis, these peptides are locally synthesized, thus suggesting their role governing the fertilizing capability of the immature male gamete. In addition to playing a physiological role, orexins are involved in numerous inflammatory and/or neoplastic pathologies too. The expression of the orexinergic system in prostate cancer suggests that they might play a potential therapeutic function. Overall, the future directions of this literature review allow us to hypothesize a role of the orexinergic complex not only as a marker for the diagnosis of certain tumors affecting the male genital tract but also for the treatment of hypo/infertility condition. Full article

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. Full article

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. Full article

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. Full article

Orexins/hypocretins are neuropeptides formed by proteolytic cleavage of a precursor peptide, which are produced by neurons found in the lateral hypothalamus. The G protein-coupled receptors (GPCRs) for these ligands, the OX₁ and OX₂ orexin receptors, are more widely expressed throughout the central nervous system. The orexin/hypocretin system has been implicated in many pathways, and its dysregulation is under investigation in a number of diseases. Disorders in which orexinergic mechanisms are being investigated include narcolepsy, idiopathic sleep disorders, cluster headache and migraine. Human narcolepsy has been associated with orexin deficiency; however, it has only rarely been attributed to mutations in the gene encoding the precursor peptide. While gene variations within the canine OX₂ gene hcrtr2 have been directly linked with narcolepsy, the majority of human orexin receptor variants are weakly associated with diseases (the idiopathic sleep disorders, cluster headache and polydipsia-hyponatremia in schizophrenia) or are of potential pharmacogenetic significance. Evidence for functional and/or heterodimerization between wild-type variant orexin receptors and opioid and cannabinoid receptors is discussed in the context of its relevance to depression and epilepsy. Full article