Peripheral biomarkers to diagnose obstructive sleep apnea in adults: A systematic review and meta-analysis.

BACKGROUND: Obstructive Sleep Apnea (OSA) has been recognized as a major health concern worldwide, given its increasing prevalence, difficulties in diagnosis and treatment, and impact on health, economy, and society. Clinical guidelines highlight the need of biomarkers to guide OSA clinical decision-making, but so far, without success. In this systematic review and meta-analysis, registered on the International Prospective Register of Systematic Reviews database (ID CRD42020132556), we proposed to gather and further explore candidates identified in the literature as potential OSA biomarkers. METHODS: Search strategies for eight different databases (PubMed/Medline, Cochrane Library, Biblioteca Virtual da Saúde, Web of Science, EMBASE, World Intellectual Property Organization database, and bioRxiV and medRxiV Preprint Servers) were developed. We identified studies exploring potential biomarkers of OSA, in peripheral samples of adults, with and without OSA, with no comorbidities defined in study inclusion criteria, published after the last systematic review and meta-analysis conducted on OSA biomarkers, until May 31st, 2020. Risk of bias was assessed through the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies. Demographic, clinical, and candidate biomarkers' data were collected and analyzed via random effects meta-analyses. FINDINGS: Among the 1512 unique studies screened, 120 met the inclusion criteria and 16 studies with low risk of bias were selected for meta-analyses. The selected 16 studies enrolled a total of 2156 participants, from which 1369 were diagnosed with OSA and 787 were disease-free controls. The assessed variables showed high heterogeneity. From the 38 biomarker candidates evaluated, only two were evaluated in more than one study. Most studies pinpointed candidates with more potential for OSA prognosis. ADAM29, FLRT2 and SLC18A3 mRNA levels in PBMCs, Endocan and YKL-40 levels in serum, and IL-6 and Vimentin levels in plasma revealed the most promising candidates for OSA diagnosis. INTERPRETATION: Although the current systematic review and meta-analysis allowed us to identify candidates to further explore as potential biomarkers in future studies, it is evident that OSA biomarkers research is still at an early stage. Most findings derive from small-size single-center study cohorts and single-candidate studies. We point several gaps in current OSA biomarker research that may guide into new directions and approaches towards the identification of OSA biomarkers.

Neuropeptide Y system in the retina: From localization to function.

The retina is a highly complex structure where several types of cells communicate through countless different molecules to codify visual information. Each type of cells plays unique roles in the retina, presenting a singular expression of neurotransmitters. Some neurotransmitter systems in the retina are well understood, while others need to be better explored to unravel the intricate signaling system involved. Neuropeptide Y (NPY), a 36 amino acid peptide, is one of the most common peptide neurotransmitter in the CNS and a highly conserved peptide among species. We review the localization of NPY and NPY receptors (mainly NPY Y1, Y2, Y4 and Y5) in retinal cells. Common features of the expression of NPY and NPY receptors in mammalian and non-mammalian species indicate universal roles of this system in the retina. In the present review, we highlight the putative roles of NPY receptor activation in the retina, discussing, in particular, their involvement in retinal development, neurotransmitter release modulation, neuroprotection, microglia and Muller cells function, retinal pigmented epithelium changes, retinal endothelial physiology and proliferation of retinal progenitor cells. Further studies are needed to confirm that targeting the NPY system might be a potential therapeutic strategy for retinal degenerative diseases.

Emerging novel roles of neuropeptide Y in the retina: from neuromodulation to neuroprotection.

Neuropeptide Y (NPY) and NPY receptors are widely expressed in the central nervous system, including the retina. Retinal cells, in particular neurons, astrocytes, and Müller, microglial and endothelial cells express this peptide and its receptors (Y1, Y2, Y4 and/or Y5). Several studies have shown that NPY is expressed in the retina of various mammalian and non-mammalian species. However, studies analyzing the distribution of NPY receptors in the retina are still scarce. Although the physiological roles of NPY in the retina have not been completely elucidated, its early expression strongly suggests that NPY may be involved in the development of retinal circuitry. NPY inhibits the increase in [Ca(2+)]i triggered by elevated KCl in retinal neurons, protects retinal neural cells against toxic insults and induces the proliferation of retinal progenitor cells. In this review, we will focus on the roles of NPY in the retina, specifically proliferation, neuromodulation and neuroprotection. Alterations in the NPY system in the retina might contribute to the pathogenesis of retinal degenerative diseases, such as diabetic retinopathy and glaucoma, and NPY and its receptors might be viewed as potentially novel therapeutic targets.

Neuropeptide Y receptors Y1 and Y2 are present in neurons and glial cells in rat retinal cells in culture.

PURPOSE: Neuropeptide Y (NPY) is one of the most abundant peptides in the central nervous system (CNS), including the retina. This peptide activates various different G-coupled receptors (NPY Y(1), Y(2), Y(4), and Y(5)) that are also present in the retina. However, the localization of NPY receptors in the several types of retinal cells is not completely known. In this study, we have looked at the distribution of NPY Y(1) and Y(2) receptors in rat retinal cells to reveal new perspectives on the role of NPY receptors in retina physiology. METHODS: Rat retinal neural cell cultures were prepared from newborn Wistar rats (P3-P5) and pure rat Müller cell culture was obtained after treatment of these cells with ascorbic acid. The presence of NPY Y(1) and Y(2) in retinal cell types was studied by immunocytochemistry. RESULTS: We show that NPY Y(1) and Y(2) receptors are present on every cell type of rat retinal cell cultures. Neurons, as photoreceptors, bipolar, horizontal, amacrine, and ganglion cells, express these two types of NPY receptors. NPY Y(1) and Y(2) receptors are also located in macroglial cells (Müller cells and astrocytes) and microglial cells. CONCLUSIONS: We have clarified the presence of the NPY Y(1) and Y(2) receptors in all different cell types that constitute the retina, which we believe will help open new perspectives for studying the physiology and the potential pathophysiologic function of NPY and its receptors in the retina.

Moderate long-term modulation of neuropeptide Y in hypothalamic arcuate nucleus induces energy balance alterations in adult rats.

Neuropeptide Y (NPY) produced by arcuate nucleus (ARC) neurons has a strong orexigenic effect on target neurons. Hypothalamic NPY levels undergo wide-ranging oscillations during the circadian cycle and in response to fasting and peripheral hormones (from 0.25 to 10-fold change). The aim of the present study was to evaluate the impact of a moderate long-term modulation of NPY within the ARC neurons on food consumption, body weight gain and hypothalamic neuropeptides. We achieved a physiological overexpression (3.6-fold increase) and down-regulation (0.5-fold decrease) of NPY in the rat ARC by injection of AAV vectors expressing NPY and synthetic microRNA that target the NPY, respectively. Our work shows that a moderate overexpression of NPY was sufficient to induce diurnal over-feeding, sustained body weight gain and severe obesity in adult rats. Additionally, the circulating levels of leptin were elevated but the immunoreactivity (ir) of ARC neuropeptides was not in accordance (POMC-ir was unchanged and AGRP-ir increased), suggesting a disruption in the ability of ARC neurons to response to peripheral metabolic alterations. Furthermore, a dysfunction in adipocytes phenotype was observed in these obese rats. In addition, moderate down-regulation of NPY did not affect basal feeding or normal body weight gain but the response to food deprivation was compromised since fasting-induced hyperphagia was inhibited and fasting-induced decrease in locomotor activity was absent.These results highlight the importance of the physiological ARC NPY levels oscillations on feeding regulation, fasting response and body weight preservation, and are important for the design of therapeutic interventions for obesity that include the NPY.