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The environment plays a critical role in shaping development and function of the brain. Stress, especially when experienced early in life, can interfere with these processes. In the context of respiratory control, perinatal stress can therefore alter the ability to achieve the “fine-tuning” necessary for proper detection of chemosensory stimuli and production of an adequate motor (respiratory) command. Depending on the timing, intensity, and duration, the detrimental consequences of perinatal exposure to adverse conditions on the respiratory network become manifest at various life stages and can persist into adulthood. During early life, respiratory diseases commonly associated with dysfunction of neural networks include apnea of prematurity (AOP) and cardio-respiratory failure leading to sudden infant death syndrome (SIDS). Sleep disordered breathing (SDB) can occur at various life stages, including adulthood. Regardless of age, a common element of these disorders is their greater prevalence in males. While this sexual dimorphism points to a potential role of sex hormones, our understanding of the neuroendocrine mechanisms remain poorly understood. In addition to their modulatory influence on breathing, gonadal hormones regulate sexual differentiation of the brain. Stress alters these effects, and over the years our laboratory has used various perinatal stress protocols to gain insight into the origins of sex-based differences in respiratory disorders. This review discusses our recent advances with a focus on the sex-specific impact of early life stress on O 2 -chemoreflex function both in newborn and adult rats. We conclude by discussing the basic principles emerging from this work, potential mechanisms, and clinical relevance. [ABSTRACT FROM AUTHOR]

As part of the study of the resilience of Antarctic crustaceans to global warming, the shrimp Chorismus antarcticus was subjected to an analysis of global approach using the Next Generation Sequencing Illumina Hi-Seq platform. With this data a detailed study into the principal neuropeptides and neurohormones of this species have been undertaken. Total RNAs from whole animals were enriched with eyestalk extracts to ensure maximum sequencing depth of the different neurohormones and neuropeptides mainly expressed into the X organ-sinus gland complex, which is a major endocrine organ of their synthesis. Apart from the information that can provide the availability of the transcriptome of a polar crustacean, the study of neuropeptides of a caridean shrimp will partially fill the limited data available for this taxon. Illumina sequencing was used to produce a transcriptome of the polar shrimp. Analysis of the Trinity assembled contigs produced 55 pre-pro-peptides, coding for 111 neuropeptides belonging to the following families: adipokinetic-corazonin-like peptide, Allatostatins (A, B et C), Bursicon (α), CCHamide, Crustacean Hyperglycemic Hormones (CHH), Crustacean Cardioactive Peptide (CCAP), Corazonin, Crustacean Female Sex Hormone (CSFH), Diuretic Hormones 31 and 45 (DH), Eclosion Hormone (EH), FLRFamide, GSEFLamide, Intocin, Ion Transport Peptide-like (ITP-like), Leucokinin, Molt-inhibiting Hormone, Myosuppresin, Neuroparsin, Neuropeptide F (NPF), Orcokinin, Orcomyotropin, Pigment Dispersing Hormone (PDH), Pyrokinin, Red Pigment Concentrating Hormone (RPCH), SIFamide, small Neuropeptide F (sNPF), Sulfakinin and finally Tachykinin Related peptides. Among the new peptides highlighted in this study, the focus was placed on the peptides of the CHH family and more particularly on a new ITP-like in order to confirm its belonging to a new group of peptides of the family. A phylogeny made from more than 200 sequences of peptides, included new sequences from new species besides Chorismus antarcticus , confirms the peculiarity of this new set of peptides gathered under the name ITP-like. [ABSTRACT FROM AUTHOR]

Background Untreated and preclinical heart failure patients with reduced ejection fraction (HFrEF) have an impaired ability to alleviate excess intravascular volume. Objectives To investigate 1) the renal response to intravascular volume expansion in euvolemic and optimally treated HFrEF patients and 2) loop diuretic efficiency. Methods 14 healthy and 28 HFrEF patients underwent intravascular volume expansion with 1 l hydroxyl ethyl starch 6% during 3 h after which a loop diuretic was administered. Clinical parameters, neurohormones and urine were hourly measured. Results In response to intravascular volume expansion (+ 0.6 ± 0.2 L; p < 0.001 vs baseline) HFrEF patients demonstrated significantly lower natriuresis compared to healthy subjects (0.9 ± 0.5 versus 1.7 ± 0.6 g/3 h; p < 0.001). However, natriuresis varied substantially with half of HFrEF patients exhibiting a response within the range of healthy and the other half demonstrating a significantly decreased response (1.4 ± 0.4 vs 0.5 ± 0.2 g/3 h; p < 0.001). Natriuresis was associated with glomerular filtration function (eGFR), NT-proBNP and tubular fractional sodium excretion (FE Na ). Loop diuretic efficiency was significantly lower in HFrEF patients compared to healthy subjects (3.4 ± 0.7 vs 2.6 ± 1.1 g/2 h; p = 0.044) but was only related to eGFR (R 2 = 0.47; p < 0.001) and independent of FE Na (R 2 = 0.07; p = 0.20). Loop diuretics increased FE Na similarly in healthy subjects and HFrEF patients (9.1 ± 2.4 vs 9.3 ± 3.3%; p = 0.64). Conclusion The ability of the kidneys to remove excess intravascular volume is decreased in a substantial amount of euvolemic and optimally treated HFrEF patients. Renal response relates to filtration function and tubular sodium handling. In contrast, loop diuretics can surmount decreased renal tubular sodium excretion but remain dependent on eGFR. [ABSTRACT FROM AUTHOR]

The chemical signalling molecule nitric oxide (NO), which freely diffuses through aqueous and lipid environments, subserves an array of functions in the mammalian central nervous system, such as the regulation of synaptic plasticity, blood flow and neurohormone secretion. In this Review, we consider the cellular and molecular mechanisms by which NO evokes short-term and long-term changes in neuronal activity. We also highlight recent studies showing that discrete populations of neurons that synthesize NO in the hypothalamus constitute integrative systems that support life by relaying metabolic and gonadal signals to the neuroendocrine brain, and thus gate the onset of puberty and adult fertility. The putative involvement and therapeutic potential of NO in the pathophysiology of brain diseases, for which hormonal imbalances during postnatal development could be risk factors, is also discussed. [ABSTRACT FROM AUTHOR]

A new cryochemical strategy of producing nanoparticles and polymorphous nanostructures of drugs is used, which is based on the dynamic combination of high and low temperatures, gas and solid phases, and inert carrier gases. This technology is applied to the synthesis of nanoparticles of steroid neurohormone dehydroepiandrosterone (DHEA). We have optimized the conditions of synthesis of the new polymorphous DHEA structure, FVII. The molecules of DHEA in FVII structure are bound by hydrogen bonds via oxygen atoms. The grain size is 100 nm. It is shown that the yield and ratio of the resulting nanoforms of this hormone are determined by the nature and properties of the inert carrier gas. The highest yield and selectivity of FVII are observed when carbon dioxide is used as the carrier gas. In the case of helium, the FVII content decreases from 85 to 30% and other structures are formed. In experiments without carrier gas, nanoparticles are formed but no FVII is produced. The selectivity and the effect of carrier gas are considered on the basis of homogeneous and heterogeneous formation of nanoparticles and the relationship between particle selectivity and its activity. The synthesis of various polymorphous structures on the nanoscale is assumed to be the manifestation of the size effect in the synthesis of drugs. [ABSTRACT FROM AUTHOR]

Melatonin is a neurohormone that is linked to the aetiopathogenesis of schizophrenia. The aim of this study was to assess the potentials of oral melatonin supplement in the management of induced schizophrenia-like behavioural and brain oxidative status changes, using an animal model. The relative degrees of modulation of ketamine-induced behaviours by haloperidol, olanzapine or melatonin were assessed in the open-field, Y-maze, elevated plus maze and the social interaction tests. 12-week old, male mice were assigned to six groups of ten each (n = 10). They were pretreated with daily intraperitoneal ketamine at 15 mg/kg (except vehicle) for 10 days, before commencement of 14 day treatment with standard drug (haloperidol or olanzapine) or melatonin. Ketamine injection also continued alongside melatonin or standard drugs administration for the duration of treatment. Melatonin, haloperidol and olanzapine were administered by gavage. Treatments were given daily, and behaviours assessed on days 11 and 24. On day 24, animals were sacrificed and whole brain homogenates used for the estimation of glutathione, nitric oxide and malondialdehyde levels. Ketamine injection increased open-field behaviours; while it decreased working-memory, social-interaction and glutathione activity. Nitric oxide and malondialdehyde levels also increased after ketamine injection. Administration of melatonin was associated with variable degrees of reversal of these effects. In conclusion, melatonin may have the potential of a possible therapeutic agent and/or adjunct in the management of schizophrenia. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a widely prevalent syndrome imposing a significant burden of morbidity and mortality world-wide. Differential circulating microRNA profiles observed in HF cohorts suggest the diagnostic utility of microRNAs as biomarkers. Given their function in fine tuning gene expression, alternations in microRNA landscape could reflecting the underlying mechanisms of disease and present potential therapeutic targets. Using multiple computational target predicting algorithms together with the luciferase-based reporting platform, the interactions between HF-related microRNAs and the 3′ untranslated regions (3′UTRs) of neurohormone associated genes were examined and compared. Our results indicate that although in silico prediction provides an overview of possible microRNA-mRNA target pairs, less than half of the predicted interactions were experimentally confirmed by reporter assays in HeLa cells. Thus, the establishment of microRNA/3′UTR reporters is essential to systemically evaluate the roles of microRNAs for signaling cascades of interest, including cardiovascular neurohormonal signaling. The physiological relevance of HF-related microRNAs on the expression of putative gene targets was further established by using gain-of-function assays in two human cardiac-derived cells. Our findings, for the first time, provide direct evidence of the regulatory effects of HF-related microRNAs on the neurohormonal signaling in cardiac cells. More importantly, our study presents a rational approach to further exploring microRNA profiling data in deciphering the role of microRNA in complex syndromes such as HF. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang. [ABSTRACT FROM AUTHOR]

Glucose homeostasis is finely regulated by a number of hormones and peptides released mainly from the brain, gastrointestinal tract, and muscle, regulating pancreatic secretion through cellular receptors and their signal transduction cascades. The endocrine function of the pancreas is controlled by islets within the exocrine pancreatic tissue that release hormones like insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin. Moreover, both exocrine and endocrine pancreatic functions are regulated by a variety of hormonal and neural mechanisms, such as ghrelin, glucagon-like peptide, glucose-dependent insulinotropic polypeptide, or the inhibitory peptide somatostatin. In this review, we describe the role of neurohormones that have been less characterized compared to others, on the regulation of insulin secretion. In particular, we will focus on melatonin, galanin, and RFamide neuropeptides QRFP26 and QRFP43, which display either insulinotropic or insulinostatic effects. In fact, in addition to other hormones, amino acids, cytokines, and a variety of proteins, brain-derived hormones are now considered as key regulators of glucose homeostasis, representing potential therapeutic targets for the treatment of diabetes and obesity. [ABSTRACT FROM AUTHOR]

Background/Methods: Melatonin, the neurohormone for darkness, mediates photoperiod-dependent changes in physiology and behavior by targeting specific membrane- bound receptors (MT1 and MT2). In the present study, we investigated the impact of MT1 receptor deficiency on feeding behavior, locomotor activity and mRNA expression levels encoding for the polypeptide pro-opiomelanocortin (Pomc) and neuropeptide Y (Npy) in the hypothalamic arcuate nucleus (ARC) and the adenohypophysis [pars distalis (PD) and pars intermedia (PI)] in a comparison between wild-type (WT) and MT1-deficient (MT1-/-) mice. Results: The MT1-/- mice spent significantly more time feeding than the WT mice, while the general locomotor behavior, body weight and the total amount of food consumed did not differ between both genotypes. The nocturnal expression levels of Pomc in the ARC and PD were significantly higher in WT as compared to MT1-/- mice and exogenous melatonin administered during the light phase stimulated Pomc expression in WT mice only. No differences were found between WT and MT1-/- mice with regard to Pomc expression levels in the PI. Conclusion: Thus, the MT1-mediated signaling stimulates Pomc expression in a region-specific pattern. Since the MT1-mediated changes in Pomc expression do not elicit direct orexigenic or anorexigenic effects, such effects are obviously mediated by regulatory systems downstream of the Pomc mRNA (e.g. cleavage and release of POMC derivatives), which are independent of MT1 signaling. [ABSTRACT FROM AUTHOR]

The non-consumptive effects of predation contribute to reduce preys' fitness. In this way, predation imposes a cost to animals, not only through direct consumption, but also as an energetic cost. One way used to estimate this cost in the past has been to measure the production of CO 2 to estimate the change in metabolic rate because of predation. It has been proposed that this change is mediated by the insect stress neurohormone octopamine. Here we study the change in metabolic rate of the black field cricket ( Teleogryllus commodus ), and how the production of CO 2 varies when a chemical cue from a sympatric predator is added. We hypothesised that after the addition of a predatory cue, the metabolic rate will increase. Moreover, since the pressure of predation is stronger on females, we propose that females will have a greater increase in the CO 2 produce as consequence of the added cues from the predator. Our results confirmed our first hypothesis, showing an almost two-fold increase in CO 2 when the predatory cue was added. However, males were the ones that showed a greater increase, in opposition to our second hypothesis. We put these results in the context of the escape theory and, in particular, the “landscape of fear” hypothesis. Also, because the timing between the increase of metabolic rate we measure here and the release of octopamine reported in previous studies do not match, we reject the idea that octopamine causes the increase in metabolism. [ABSTRACT FROM AUTHOR]

The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic-pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment. [ABSTRACT FROM AUTHOR]

The aim of this study was to detect the effect of immunization against gonadotropin-releasing hormone (GnRH) on cell-meditated immunity. Three-week-old male Sprague-Dawley rats (n = 32) were randomly and equally assigned to two groups: 1) GnRH-tandem-ovalbumin immunized group; and 2) the control group (injected with an equivalent Al(OH) 3 adjuvant). Blood samples were collected at two-week intervals to assess the level of GnRH-specific antibodies and testosterone. Moreover, blood and thymus samples were also collected to analyze the T lymphocyte subpopulations one and two months after the last booster immunization. T lymphocyte immunity against GnRH was activated during the first month post-immunization as exhibited by increased numbers of CD3+ (P < 0.05) and CD4+ (P < 0.05) T lymphocytes following testosterone suppression (P < 0.01), which was then restored and maintained at appropriate levels in the second month. In contrast, the differentiation of T lymphocytes in the thymus was reduced during the first month after immunization as exhibited by the significant decreased number of CD3+ (P < 0.05) cells, followed by the restoration and heightened numbers at later time points for both the number of CD3+ (P < 0.05) and CD4+ (P < 0.01) T lymphocytes. These results suggest that immunization against GnRH interferes with the number of lymphocytes during the early time points following immunization. The number of T lymphocytes initially decreased in the peripheral blood following immunization, but was replenished by newly exported cells from the thymus which eventually restored the T lymphocytes to normal levels. [ABSTRACT FROM AUTHOR]

The hypothalamic-pituitary-gonadal axis controls reproduction via a series of hormones regulating gonadal function through interconnected feedback loops. Secretion of hypothalamic-derived gonadotropin-releasing hormone (GnRH) integrates inputs from higher brain centers to coordinate the activity of the pituitary gonadotrope and the biosynthesis and secretion of the gonadotropins which ultimately regulate gonadal function. Failure of GnRH to serve as the central integrator of this system has been associated with hypogonadotropic-hypogonadism and clinical infertility, while pharmacological application of GnRH analogs and gonadotropins have important implications of the treatment of such infertility. Furthermore, the GnRH-GnRH receptor system has been characterized in several types of cancer and may offer therapeutic possibilities in their treatment. Given the central role of GnRH action in the control of fertility, it is of paramount importance to understand the molecular basis of control of GnRH action in the pituitary gonadotrope, including new and novel alternate ways to modulate GnRH action and gonadotropin secretion. The goal of this review is to discuss several new findings in this field focusing on novel regulators of GnRH action. [ABSTRACT FROM AUTHOR]

Aims Chronic heart failure (HF) is associated with activation of blood coagulation but there is a lack of prospective studies on the association between coagulation markers and incident HF in general populations. We have examined the association between the coagulation markers fibrinogen, von Willebrand Factor (VWF), Factors VII, VIII and IX, D-dimer, activated protein C (APC) and activated partial thromboplastin time (aPPT) with NT-proBNP and incident HF. Methods and results Prospective study of 3366 men aged 60–79 years with no prevalent HF, myocardial infarction or venous thrombosis and who were not on warfarin, followed up for a mean period of 13 years, in whom there were 203 incident HF cases. D-dimer and vWF were significantly and positively associated with NT-proBNP (a marker of neurohormonal activation and left ventricular wall stress) even after adjustment for age, lifestyle characteristics, renal dysfunction, atrial fibrillation (AF) and inflammation (C-reactive protein). By contrast Factor VII related inversely to AF and NT-proBNP even after adjustment. No association was seen however between the coagulation markers VWF, Factor VII, Factor VIII, Factor IX, D-dimer, APC resistance or aPPT with incident HF in age-adjusted analyses. Fibrinogen was associated with incident HF but this was abolished after adjustment for HF risk factors. Conclusion Coagulation activity is not associated with the development of HF. However D-dimer and vWF were significantly associated with NT-proBNP, suggesting that increased coagulation activity is related to cardiac stress; and the increased coagulation seen in HF patients may in part be a consequence of neurohormonal activation. [ABSTRACT FROM AUTHOR]

The process of alcohol dependence has been conceptualized as a progress from controlled alcohol intake to compulsive alcohol consumption or a shift from alcohol intake for pleasure to compulsory alcohol seeking behavior. Hereditary and physical factors and the interaction of individuals with their environment, as well as permanent changes in the neurotransmitter and neurohormonal systems in the brain due to alcohol use, have an important role in the etiology of alcohol dependence. The effects of ethanol on the neurotransmitter, neuropeptide, and neuroendocrine systems not only account for its acute physiological and euphoric/reinforcing effects but also seem to be responsible for the development of dependence. While the motivation for alcohol use is mainly positive reinforcement in the earlier phases of alcohol consumption, both positive and negative reinforcements are involved in the process once dependence has developed. This event, termed allostasis, is caused by a neuroadaptive process due to chronic alcohol consumption. It seems that the most important neuroadaptive changes in progression from occasional alcohol intake to dependence are the: (1) down-regulation of the dopamine and gamma aminobutyric acid systems; (2) permanent upregulation in the glutamate system; and (3) dysregulation in the stress systems (corticotropin-releasing hormone and serotonin) of the brain. In this paper, we will review the adaptive changes caused by chronic alcohol consumption, which are important in the development of dependence, and address the potential therapeutic contributions of interventions to these changes in alcohol dependence. [ABSTRACT FROM AUTHOR]

Carbaryl (1-naphthyl methylcarbamate) and carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate) are among the most toxic insecticides, implicated in a variety of diseases including diabetes and cancer among others. Using an integrated pharmacoinformatics based screening approach, we have identified these insecticides to be structural mimics of the neurohormone melatonin and were able to bind to the putative melatonin binding sites in MT1 and MT2 melatonin receptors in silico. Carbaryl and carbofuran then were tested for competition with 2-[125I]-iodomelatonin (300 pM) binding to hMT1 or hMT2 receptors stably expressed in CHO cells. Carbaryl and carbofuran showed higher affinity for competition with 2-[125I]-iodomelatonin binding to the hMT2 compared to the hMT1 melatonin receptor (33 and 35-fold difference, respectively) as predicted by the molecular modeling. In the presence of GTP (100 μM), which decouples the G-protein linked receptors to modulate signaling, the apparent efficacy of carbaryl and carbofuran for 2-[125I]-iodomelatonin binding for the hMT1 melatonin receptor was not affected but significantly decreased for the hMT2 melatonin receptor compatible with receptor antagonist/inverse agonist and agonist efficacy, respectively. Altogether, our data points to a potentially new mechanism through which carbamate insecticides carbaryl and carbofuran could impact human health by altering the homeostatic balance of key regulatory processes by directly binding to melatonin receptors. [ABSTRACT FROM AUTHOR]

Melatonin, a naturally occurring neurohormone in the pineal gland, has been shown to exert antioxidant and anti-inflammatory effects. This study examined the effects of melatonin on manganese (Mn) and/or lipopolysaccharide (LPS)-induced microglial activation. Melatonin (10 μM) inhibited Mn (100 μM) and/or LPS (0.5 μg/ml)-induced phagocytotic activity of activated BV2 microglia. It also inhibited the lipid peroxidation and intracellular reduced glutathione (GSH) depletion induced by Mn and/or LPS. Melatonin effectively suppressed the upregulation of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) at both mRNA and protein levels in Mn and/or LPS-stimulated BV2 microglia. In addition, melatonin pretreatment attenuated Mn and/or LPS-induced degradation of IκB-α, nuclear translocation of nuclear factor-κB (NF-κB) and its activation, and the expressions of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in BV2 microglial cells. These results suggest that melatonin can effectively modulate phagocytosis and expression of proinflammatory mediators, and can prevent neuroinflammatory disorders accompanied by microglial activation. [ABSTRACT FROM AUTHOR]

Introduction: Early clinical diagnosis of heart failure (HF) is challenging because the signs and symptoms are neither sensitive nor specific for diagnosis. B-type natriuretic peptide (BNP), a cardiac neurohormone is a useful biomarker for patients with HF. Objectives: The purpose of this review is to evaluate the role of BNP in HF as a diagnostic, prognostic, and therapeutic marker in both outpatient care and urgent care settings. Methodology: An extensive literature review was conducted for this study. Findings: Determination of BNP is particularly useful as a rule-out test for suspected cases of HF in patients with dyspnoea. HF is very unlikely in patients with levels of BNP < 100 pg/mL whereas BNP levels > 400 pg/mL strongly support the diagnosis of HF. Elevated level of BNP indicates a worse prognosis in patients with HF. Conclusion: Although, it is recommended in the diagnostic pathways of guidelines for HF, it is not well established to recommend measurement of BNP to titrate HF medications because of lack of enough evidence. It requires further in-depth research. [ABSTRACT FROM AUTHOR]

The insulin signal system of the brain plays a key role in regulating fundamental cellular process in neurons, and it controls metabolic processes in the CNS and the periphery. In hypothalamic neurons, the insulin signaling system interacts closely with other signal systems controlled by leptin, melanocortin peptides, dopamine, and serotonin, and is a key component of the signal network of the hypothalamus, integrating and transforming central and peripheral signals. Impairments to the insulin system of the brain lead to the development of central insulin resistance, which is one of the prime causes of type 2 diabetes mellitus (DM), metabolic syndrome, and Alzheimer's disease. Timely restoration of the insulin system of the brain is an effective approach for the prophylaxis and treatment of type 2 DM and associated neurodegenerative diseases. This review analyzes and assesses published data and our own results on the structural-functional organization of the insulin signal system of the brain, impairments to insulin signaling in the CNS, and approaches to its restoration in type 2 DM. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a disabling condition involving complex vascular, neurohormonal and immune systems' interactions. Osteoprotegerin (OPG), a bone-regulatory cytokine, has been suggested to play a key role in skeletal, vascular, and immune biology, with elevated levels observed in both experimental and clinical HF. In the present study we aimed to identify clinical OPG correlates and investigated whether elevated OPG, as a marker of HF vascular and immune activation, may interact with N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of HF neurohormonal activation, thus synergistically increasing HF risk. We used a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition-Potsdam, comprising 2647 participants including 252 incident HF cases identified during a mean follow-up of 8.2 ± 1.6 years. In both men and women significant positive associations were observed between OPG and age, smoking, prevalent diabetes, C-reactive protein, sex hormone-binding globulin, and additionally prevalent coronary heart disease and uric acid in men only. In women, OPG was furthermore positively related to hypertension and fetuin-A. After multivariable adjustment each doubling of OPG was associated with a 3.01-fold increased HF risk (95 % CI 1.49-6.06) in men. A significant interaction was observed between OPG and NT-proBNP. In men, a combination of high levels of both OPG and NT-proBNP, compared to a combination of low levels, was associated with an approximately fivefold increased HF risk. In women, no associations were observed. These findings suggest that, in men, the activation of different immune, neurohormonal, and vascular pathophysiological pathways may confer increased HF risk. [ABSTRACT FROM AUTHOR]

Introduction: Atrial (ANP) and B-type (BNP) natriuretic peptides are hormones secreted by the heart as a response to volume expansion and pressure overload. Aim: To assess the changes of ANP and BNP after percutaneous balloon mitral valvuloplasty (PBMV) and to investigate factors associated with endpoints. Material and methods: The study included 96 patients (90.7% females, age 51.6 ±12.2 years) with rheumatic mitral valve stenosis (mitral valve area (MVA) 1.18 (1.01-1.33) cm2, mean mitral gradient (MMG) 8.2 (7.1-9.2) mm Hg, NYHA 2.09 (1.9-2.5)). Patients were followed up for 29.1 months for the search of endpoints. Results: The PBMV was successful in all cases. After the procedure MVA increased (1.18-1.78 cm2, p < 0.01) and pulmonary capillary wedge pressure (PCWP) decreased (29.8-21.8 mm Hg, p < 0.01). Concentration of ANP significantly rose 30 min after the PBMV (79.2 vs. 134.2 pg/ml, p = 0.012) and dropped significantly after 24 h (134.2 vs. 70.4 pg/ml, p = 0.01). Furthermore, after 36 months concentration of ANP did not differ from the baseline value (p = NS). BNP concentration at day 1 was lower than at baseline (94.5 vs. 80.2 pg/ml, p = 0.032). Moreover, during the follow-up period BNP continued to fall at all time points. In univariate analysis parameters associated with endpoint occurrence were baseline PAP (p = 0.023), baseline PCWP (p = 0.022), baseline NYHA (p = 0.041) and increase in 6-minute walk test (6MWT) (p = 0.043). In multivariate analysis the only factor associated with endpoint occurrence was baseline NYHA (HR = 1.52, 95% CI: -1.3-1.91, p = 0.022). Conclusions: Patients with MS had increased levels of both BNP and ANP. Baseline NYHA class was found to be associated with outcomes after the procedure. [ABSTRACT FROM AUTHOR]

Heart failure with reduced ejection fraction (HFrEF) develops when cardiac output falls as a result of cardiac injury. The most well-recognized of the compensatory homeostatic responses to a fall in cardiac output are activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS). In the short term, these 'neurohormonal' systems induce a number of changes in the heart, kidneys, and vasculature that are designed to maintain cardiovascular homeostasis. However, with chronic activation, these responses result in haemodynamic stress and exert deleterious effects on the heart and the circulation. Neurohormonal activation is now known to be one of the most important mechanisms underlying the progression of heart failure, and therapeutic antagonism of neurohormonal systems has become the cornerstone of contemporary pharmacotherapy for heart failure. In this Review, we discuss the effects of neurohormonal activation in HFrEF and highlight the mechanisms by which these systems contribute to disease progression. [ABSTRACT FROM AUTHOR]

Melatonin is a neurohormone with multiple and different actions, such as chronobiotic or antioxidant. Melatonin is usually orally administered, but dermal administration is also useful in dermatological diseases or as adjuvant to certain skin treatments. Here, we studied the variability of the pharmacokinetics of melatonin and its metabolite AFMK, when melatonin is transdermally administered to Hairless rat at two different times of day (Zeitgeber Time 4 (ZT4) and ZT16). Moreover, in order to obtain the bioavailability, kinetics after intravenous administration was also studied. In addition, a permeation study was carried out, at both ZTs, to test the amount of melatonin retained in the skin after transdermal administration. Results showed that pharmacokinetic parameters of melatonin administered exogenously depended on the time of the day. When intravenous data were fitted to a compartmental model, the extrapolated plasma concentration at time 0 and the area under the curve were higher at ZT4, while clearance, volumes of central and peripheral compartments and volume of distribution at the steady state were higher at ZT16. Transdermal administration was best fitted to a one-compartment model and t max , half-life of absorption and area under the curve showed higher values at ZT4, while the absorption rate and constant of absorption were higher at ZT16. AFMK was detected in all cases, but no differences between the two ZTs were observed. Transdermal administration showed better bioavailability also at ZT4. Results indicate that time of day is a variable that should be taken into account when melatonin is transdermally administered. [ABSTRACT FROM AUTHOR]

Kisspeptin (Kiss1) is an amidated neurohormone that belongs to the RF-amide peptide family, which has a key role in the control of reproduction. Specifically, kisspeptin regulates reproductive events, including puberty and ovulation, primarily by activating the surface receptor Kiss1r (aka GPR54), at hypothalamic gonadotropin-releasing hormone (GnRH) neurons. More recently, it has been found that kisspeptin peptide is present in the hypophyseal portal circulation and that the Kiss1/Kiss1r system is expressed in pituitary cells, which suggest that kisspeptin could exert an endocrine, paracrine or even autocrine role at the pituitary gland level. Indeed, mounting evidence is pointing towards a direct role of kisspeptin in the control of not only gonadotropins but also other pituitary secretions such as growth hormone or prolactin. In this review, we summarize the most recent advances in the study of the role that the Kiss/Kiss1r system plays in the control of pituitary gland function, paying special attention to the direct role of this neuropeptide on pituitary cells and its interactions with other relevant regulators. [ABSTRACT FROM AUTHOR]

Inhaled pollutants produce effects in virtually all organ systems in our body and have been linked to chronic diseases including hypertension, atherosclerosis, Alzheimer's and diabetes. A neurohormonal stress response (referred to here as a systemic response produced by activation of the sympathetic nervous system and hypothalamus–pituitary–adrenal (HPA)-axis) has been implicated in a variety of psychological and physical stresses, which involves immune and metabolic homeostatic mechanisms affecting all organs in the body. In this review, we provide new evidence for the involvement of this well-characterized neurohormonal stress response in mediating systemic and pulmonary effects of a prototypic air pollutant — ozone. A plethora of systemic metabolic and immune effects are induced in animals exposed to inhaled pollutants, which could result from increased circulating stress hormones. The release of adrenal-derived stress hormones in response to ozone exposure not only mediates systemic immune and metabolic responses, but by doing so, also modulates pulmonary injury and inflammation. With recurring pollutant exposures, these effects can contribute to multi-organ chronic conditions associated with air pollution. This review will cover, 1) the potential mechanisms by which air pollutants can initiate the relay of signals from respiratory tract to brain through trigeminal and vagus nerves, and activate stress responsive regions including hypothalamus; and 2) the contribution of sympathetic and HPA-axis activation in mediating systemic homeostatic metabolic and immune effects of ozone in various organs. The potential contribution of chronic environmental stress in cardiovascular, neurological, reproductive and metabolic diseases, and the knowledge gaps are also discussed. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. [ABSTRACT FROM AUTHOR]

Shortly after emergence the exoskeleton (cuticle) of adult insects is rapidly expanded, hardened (sclerotized), and pigmented (melanized). In parallel with this process, the oenocytes, which are large polyploid cells located below the abdominal epidermis, secrete onto the cuticle a cocktail of cuticular hydrocarbons (CHs) and waxes. These improve the waterproofing of the cuticle, and also provide important chemosensory and pheromonal cues linked with gender, age, and species differentiation. The hardening and pigmentation of the new cuticle are controlled by the neurohormone, bursicon, and its receptor, encoded by the DLGR2 receptor, rickets ( rk ); by contrast, little is known about the timecourse of changes in CH profile and about the role of bursicon in this process. Here we show in Drosophila that rk function is also required for the normal maturation of the fly's CH profile, with flies mutant for rk function showing dramatically elevated levels of CHs. Interestingly, this effect is mostly abrogated by mutations in the Δ9 desaturase encoded by the desaturase1 gene, which introduces a first double bond into elongated fatty-acid chains, suggesting that desaturase1 acts downstream of rk . In addition, flies mutant for rk showed changes in the absolute and relative levels of specific 7-monoenes (in males) and 7,11-dienes (in females). The fact that these differences in CH amounts were obtained using extractions of very different durations suggests that the particular CH profile of flies mutant for rk is not simply due to their unsclerotized cuticle but that bursicon may be involved in the process of CH biosynthesis itself. [ABSTRACT FROM AUTHOR]

Bursicon is a heterodimeric neurohormone that acts through a G protein-coupled receptor named rickets (rk), thus inducing an increase in cAMP and the activation of tyrosine hydroxylase, the rate-limiting enzyme in the cuticular tanning pathway. In insects, the role of bursicon in the post-ecdysial tanning of the adult cuticle and wing expansion is well characterized. Here we investigated the roles of the genes encoding the bursicon subunits during the adult cuticle development in the honeybee, Apis mellifera. RNAi-mediated knockdown of AmBurs α and AmBurs β bursicon genes prevented the complete formation and tanning (melanization/sclerotization) of the adult cuticle. A thinner, much less tanned cuticle was produced, and ecdysis toward adult stage was impaired. Consistent with these results, the knockdown of bursicon transcripts also interfered in the expression of genes encoding its receptor, AmRk, structural cuticular proteins, and enzymes in the melanization/sclerotization pathway, thus evidencing roles for bursicon in adult cuticle formation and tanning. Moreover, the expression of AmBurs α, AmBurs β and AmRk is contingent on the declining ecdysteroid titer that triggers the onset of adult cuticle synthesis and deposition. The search for transcripts of AmBurs α, AmBurs β and candidate targets in RNA-seq libraries prepared with brains and integuments strengthened our data on transcript quantification through RT-qPCR. Together, our results support our premise that bursicon has roles in adult cuticle formation and tanning, and are in agreement with other recent studies pointing for roles during the pharate-adult stage, in addition to the classical post-ecdysial ones. [ABSTRACT FROM AUTHOR]

Aim. To compare the effects of renin-angiotensin-aldosterone system (RAAS) modulators in patients with severe chronic heart failure (CHF). Material and methods. In total, 148 patients (57,4±0,4 years), with severe systolic left ventricular (LV) dysfunction (ejection fraction (EF)

A fundamental goal of animal behavior research is to discover the proximate mechanisms driving individual behavioral differences. Biogenic amines are known to mediate various aspects of behavior across many species, including aggression, one of the most commonly measured behavioral traits in animals. Arthropods provide an excellent system to manipulate biogenic amines and quantify subsequent behavioral changes. Here, we investigated the role of dopamine (DA) and serotonin (5-HT) on foraging aggression in western black widow spiders (Latrodectus hesperus), as measured by the number of attacks on a simulated prey animal in the web. We injected spiders with DA or 5-HT and then quantified subsequent changes in behavior over 48 h. Based on previous work on insects and spiders, we hypothesized that increasing DA levels would increase aggression, while increasing 5-HT would decrease aggression. We found that injection of 5-HT did decrease black widow foraging aggression, but DA had no effect. This could indicate that the relationship between DA and aggression is complex, or that DA may not play as important a role in driving aggressive behavior as previously thought, at least in black widow spiders. Aggressive behavior is likely also influenced by other factors, such as inter-individual differences in genetics, metabolic rates, environment, and other neurohormonal controls. • Biogenic amines like dopamine and serotonin mediate aggressive behavior in animals • We manipulated dopamine and serotonin in spiders and measured behavioral changes. • Serotonin led to lower aggression, while dopamine had no effect. [ABSTRACT FROM AUTHOR]

Heart failure is the consequence of sustained, abnormal neurohormonal and mechanical stress and remains a leading cause of death worldwide. The aim of this work was to identify whether blockade of receptor for advanced glycation end products (RAGE) protected against systolic overload-induced heart failure and investigate the possible underlying mechanism. It was found that RAGE mRNA and protein expression was up-regulated in cardiac tissues from mice subjected to pressure overload by transverse aortic constriction (TAC). Importantly, inhibition of RAGE by treatment with soluble RAGE (sRAGE) or FPS-ZM1 (a high-affinity RAGE-specific inhibitor) for 8 weeks attenuated cardiac remodeling (including cardiac hypertrophy and fibrosis), and dysfunction in mice exposed to TAC. Furthermore, treatment of TAC mice with sRAGE or FPS-ZM1 enhanced phosphorylation of AMPK and reduced phosphorylation of mTOR and protein expression of NFκB p65 in cardiac tissues. In addition, treatment of TAC mice with sRAGE or FPS-ZM1 abated oxidative stress, attenuated endoplasmic reticulum stress, and suppressed inflammation in cardiac tissues. These data demonstrated the benefits of blocking RAGE on the progression of systolic overload-induced heart failure in mice, which was possibly through modulating AMPK/mTOR and NFκB pathways. [ABSTRACT FROM AUTHOR]

The mechanism of weight gain through application of olanzapine, a serotonin and dopamine receptor antagonist has not been fully understood. Weight gain and food intake are under the control of various neurohormones; POMC (proopiomelanocortin), CART (cocaine and amphetamine regulated transcript), AgRP (Agouti-related peptide) and NPY (neuropeptide Y) that are majorly synthesized and secreted from the arcuate nucleus (ARC) of hypothalamus. In this study, the alteration of the ARC neurohormone levels in rats were determined as one of the weight gain mechanisms. To understand the underlying mechanism of olanzapine-induced weight gain, the drug was orally administrated to healthy male Wistar rats for analysis of both the hypothalamic gene expression and peripheral levels of those candidate neuropeptides. In rats hypothalamic mRNA levels of NPY , AgRP and POMC decreased while CART levels did not show any alteration. Consistently, circulating levels of NPY, AgRP and α-MSH decreased significantly yet CART levels were also reduced. In conclusion, it may be presumed that the antagonistic effect of olanzapine on the ARC neurons might be the onset for a dysregulation of the neurohormones secretion which may cause weight gain during treatment. [ABSTRACT FROM AUTHOR]

The insect neuropeptide prothoracicotropic hormone (PTTH) is a critical regulator of larval development. We recently demonstrated that PTTH is also present in adult Rhodnius prolixus and is released by adult brains in vitro with a clear daily rhythm during egg development. Here, we employ a well-established in vitro bioassay, to show that the daily rhythm of PTTH release by brains in vitro is under circadian control since it persists in aperiodic conditions with a free running period of around 24 h that is temperature compensated. Prolonged exposure (3 weeks) of insects to continuous constant light (LL) completely eliminated PTTH release. Subsequent transfer of such insects from LL to constant darkness (DD) rapidly induced rhythmic PTTH release, indicating that the circadian rhythm of PTTH release is induced by photic cues. Western analysis identified PTTH in the adult hemolymph, suggesting that PTTH acts as a functional neurohormone in the adult insect. Dot blot analysis revealed that PTTH levels in the hemolymph also cycled with a daily rhythm that persisted in DD and was synchronous with the rhythm of PTTH release by brains in vitro . We conclude that the previously documented photosensitive clock in the brain regulates rhythmic PTTH release and thus generates the rhythm seen in the hemolymph. These results emphasize the importance of rhythmic PTTH release in the adult insect and support a role for PTTH in adult physiology and possibly within the adult circadian system. [ABSTRACT FROM AUTHOR]

Although there are many biomarkers for heart failure, limited data are available regarding their prognostic value in adult congenital heart disease (ACHD). We investigated the potential of various biomarkers to predict ACHD mortality in a single-center, retrospective cohort study. Blood levels of neurohormones [angiotensin II, endothelin-1 (ET-1), norepinephrine (NE), aldosterone, and plasma renin activity]; inflammatory biomarkers [high-sensitivity C-reactive protein (hs-CRP), high-sensitivity tumor necrosis factor, soluble TNF receptor type I and II (sTNF-RI and sTNF-RII), and interleukin-6 (IL-6)]; and brain natriuretic peptide (BNP) were measured in 103 ACHD patients (median age 28 years). Subjects were divided into patients with single-ventricle physiology (SV group, n = 61) and those with two-ventricle physiology (TV group, n = 42); and into patients with a systemic right ventricle (SRV group, n = 25) and those with a systemic left ventricle (SLV group, n = 78). During a median follow-up period of 6.5 years, 12 patients (11 %) died of acute decompensated heart failure (ADHF). Predictive biomarkers, which are related to the New York Heart Association class and cardiothoracic ratio, were as follows: elevated levels of BNP, ET-1, sTNF-RI, NE, and IL-6 in the overall patient group; IL-6, NE, hs-CRP, BNP, and ET-1 in the TV group; BNP and ET-1 in the SV group; BNP, NE, hs-CRP, sTNF-RI, IL-6, and ET-1 in the SLV group. Elevated levels of ET-1 in SRV groups were slightly although not significantly associated with these. Various clinical biomarkers are associated with ADHF mortality in ACHD patients. The most prominent mortality predictors in biomarker profiles may vary according to differences in ventricular physiology and systemic ventricle morphology. [ABSTRACT FROM AUTHOR]

Background Neurohormones play a key role in regulating hemodynamics in heart failure (HF) both at rest and during exercise. In contrast, little is known about the importance of neurohormonal regulation for exercise capacity in continuous-flow left ventricular assist device (CF-LVAD) patients. The aim of this study was to assess the relation between neurohormonal activation patterns in CF-LVAD patients and exercise capacity. Methods Plasma concentrations of the C-terminal portion of pro-arginine vasopressin precursor (copeptin), pro-adrenomedullin (proADM), pro-B-type (proBNP) and pro-atrial (proANP) natriuretic peptides were measured in 25 CF-LVAD patients (HeartMate II) in the morning prior to maximal cardiopulmonary exercise testing determining peak oxygen uptake (peak VO 2 ). Quality of life (QOL) was determined by questionnaires. Results Peak VO 2 was severely reduced averaging 13.0 ± 5.3 ml/kg/min and exhibited strong negative correlations with copeptin, r = − 0.61 (p = 0.001) and proADM, r = − 0.56 (p = 0.005). Additionally comparing patients with peak VO 2 < 14 vs ≥ 14 ml/kg/min demonstrated significant differences in copeptin and proADM concentrations, 2.8 ± 0.8 vs 2.1 ± 0.7 pmol/l (p = 0.03) and 1.0 ± 0.5 vs 0.7 ± 0.2 nmol/l (p = 0.01), respectively. In contrast natriuretic peptides were not associated with maximal exercise capacity. Lower QOL correlated with increasing proBNP. Conclusion Resting plasma levels of proADM and copeptin are significantly correlated with peak VO 2 in CF-LVAD patients. Future studies should address if interventions to lower the levels of these markers are associated with restoration of exercise tolerance. [ABSTRACT FROM AUTHOR]

The present review focuses on the brain structure of male-to-female (MtF) and female-to-male (FtM) homosexual transsexuals before and after cross-sex hormone treatment as shown by in vivo neuroimaging techniques. Cortical thickness and diffusion tensor imaging studies suggest that the brain of MtFs presents complex mixtures of masculine, feminine, and demasculinized regions, while FtMs show feminine, masculine, and defeminized regions. Consequently, the specific brain phenotypes proposed for MtFs and FtMs differ from those of both heterosexual males and females. These phenotypes have theoretical implications for brain intersexuality, asymmetry, and body perception in transsexuals as well as for Blanchard's hypothesis on sexual orientation in homosexual MtFs. Falling within the aegis of the neurohormonal theory of sex differences, we hypothesize that cortical differences between homosexual MtFs and FtMs and male and female controls are due to differently timed cortical thinning in different regions for each group. Cross-sex hormone studies have reported marked effects of the treatment on MtF and FtM brains. Their results are used to discuss the early postmortem histological studies of the MtF brain. [ABSTRACT FROM AUTHOR]

A large body of data suggests that body weight influences puberty onset and adult reproduction. However, the underlying mechanism of how body weight influences puberty onset and fertility is not completely understood. The hypothalamic neuronal circuit regulating reproduction is restrained by inhibitory signals during childhood. At the time of puberty, these inhibitory signals are weakened and supplanted by stimulatory signals that, in turn, stimulate the release of gonadotropin-releasing hormone (GnRH) - a hypothalamic neuropeptide governing reproduction. A number of studies, however, suggest that puberty commencement occurs when body (fat) weight reaches a certain threshold, which is critical for the initiation of puberty and for support of the adult reproductive function. Previously, various signals have been studied which might link body (fat) weight-related information to the hypothalamic neuronal network regulating reproduction. However, the nature of the signal(s) that may link body fat and/or muscle mass with the hypothalamic neuronal network governing reproduction is still unclear. It has been intuitively speculated that augmentation of such signal(s) will cause a restriction of inhibitory input and activation of stimulatory input to GnRH secreting neurons at the time of puberty onset. Therefore, the unveiling of such signal(s) will greatly help in understanding the mechanism of puberty onset. Recently, it has been shown that expression of fibronectin type III domain containing-5 (FNDC5) mRNA in central and peripheral tissues upsurges during postnatal development, especially around the time of puberty onset. Moreover, the systemic level of irisin - one of the protein products of the FNDC5 gene that is secreted as myokine and adipokine - also rises during postnatal development and correlates with the timing of puberty onset. Therefore, we propose here that irisin might serve as a possible signal for linking body fat/muscle mass with the hypothalamic center governing reproductive function. We hypothesize that irisin acts as a trigger for the activation of the hypothalamic neuronal network monitoring the onset of puberty. [ABSTRACT FROM AUTHOR]

Hypothalamic peptide neurohormones such as gonadotropin-releasing hormones (GnRHs) and gonadotropin-inhibitory hormone (GnIH) play pivotal roles in the control of reproduction and gonadal maturation in teleost fish. To study the effects of GnIH on fish reproduction, we investigated the influence of seabream GnRH (sbGnRH) and GnIH (both alone and in combination) on levels of reproductive genes (GnIH, GnIH-receptor [GnIH-R], melatonin receptor [MT 3 ], sbGnRH, and gonadotropic hormones [GTHs]) during different stages of gonadal maturation in male, female, and immature cinnamon clownfish, Amphiprion melanopus. The results showed that the expression levels of GnIH, GnIH-R, and MT 3 genes increased after the GnIH injection, but decreased after the sbGnRH injection. In addition, these gene expression levels gradually lowered after GnIH3 and sbGnRH combination treatment, as compared to the MT 3 mRNA levels of GnIH treatment alone. However, the expression levels of the HPG (hypothalamus–pituitary–gonad) axis genes (sbGnRH and GTHs) decreased after the GnIH injection, but increased after the sbGnRH injection. In all cinnamon clownfish groups, HPG axis gene mRNA levels gradually decreased after mixed GnIH3 and sbGnRH treatment, compared to GnIH treatment alone. The present study provides novel information on the effects of GnIH and strongly supports the hypothesis that GnIH plays an important role in the negative regulation of the HPG axis in the protandrous cinnamon clownfish. [ABSTRACT FROM AUTHOR]