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The mammalian skin is a heterogeneous organ/tissue covering our body, showing regional variations and endowed with neuroendocrine activities. The latter is represented by its ability to produce and respond to neurotransmitters, neuropeptides, hormones and neurohormones, of which expression and phenotypic activities can be modified by ultraviolet radiation, chemical and physical factors, as well as by cytokines. The neuroendocrine contribution to the responses of skin to stress is served, in part, by local synthesis of all elements of the hypothalamo-pituitary–adrenal axis. Skin with subcutis can also be classified as a steroidogenic tissue because it expresses the enzyme, CYP11A1, which initiates steroid synthesis by converting cholesterol to pregnenolone, as in other steroidogenic tissues. Pregnenolone, or steroidal precursors from the circulation, are further transformed in the skin to corticosteroids or sex hormones. Furthermore, in the skin CYP11A1 acts on 7-dehydrocholesterol with production of 7-dehydropregnolone, which can be further metabolized to other Δ7steroids, which after exposure to UVB undergo photochemical transformation to vitamin D like compounds with a short side chain. Vitamin D and lumisterol, produced in the skin after exposure to UVB, are also metabolized by CYP11A1 to several hydroxyderivatives. Vitamin D hydroxyderivatives generated by action of CYP11A1 are biologically active and are subject to further hydroxylations by CYP27B1, CYP27A1 and CP24A. Establishment of which intermediates are produced in the epidermis in vivo and whether they circulate on the systemic level represent a future research challenge. In summary, skin is a neuroendocrine organ endowed with steroid/secosteroidogenic activities [ABSTRACT FROM AUTHOR]

Arginine vasotocin (AVT) and the mammalian homologue, arginine vasopressin (AVP), modulate vertebrate social behaviors, including vocalizations in male anurans. To study the impact of AVT and social stimuli on calling in male Xenopus tropicalis , we injected males with vehicle, 1 μg, or 10 μg AVT and recorded vocalizations under four social contexts (no stimulus, with male call playback, with a female, and with call playback and a female). More males called when injected with 10 μg AVT. Furthermore, calling males called only when paired with a female. We identified four call types: long fast trill; short fast trill; slow trill; or click. Next, we injected males with vehicle, 10 μg, or 20 μg AVT and recorded vocalizations with or without a female. AVT treatment did not affect calling in this experiment, but we confirmed that more males, regardless of AVT treatment, called when a female was present. Then we evaluated the effect of human chorionic gonadotropin (hCG) on male sexual behavior. 20 IU hCG elevated behavior compared to controls while the 10 IU hCG treatment group was not different from either treatment. Last, we examined the effect of AVT on hCG-induced reproductive behavior. Males were injected with 10 IU hCG or with 10 IU hCG and 20 μg AVT. Males receiving hCG and AVT clasped and called significantly more than males receiving hCG only. Our results suggest that AVT and a female stimulus induce vocalizations in a male pipid anuran, X. tropicalis , and the interaction between gonadotropins and neurohormones influences reproductive behaviors in this anuran amphibian. [ABSTRACT FROM AUTHOR]

Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT 2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT 2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5–40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20 mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT 2 partial agonists were blocked by the pre-treatment with the MT 2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT 2 melatonin receptor may be a novel target for analgesic drug development. [ABSTRACT FROM AUTHOR]

The impact of dietary factors on brain health and vulnerability to disease is increasingly appreciated. The results of epidemiological studies, and intervention trials in animal models suggest that diets rich in phytochemicals can enhance neuroplasticity and resistance to neurodegeneration. Here we describe how interactions of plants and animals during their co-evolution, and resulting reciprocal adaptations, have shaped the remarkable characteristics of phytochemicals and their effects on the physiology of animal cells in general, and neurons in particular. Survival advantages were conferred upon plants capable of producing noxious bitter-tasting chemicals, and on animals able to tolerate the phytochemicals and consume the plants as an energy source. The remarkably diverse array of phytochemicals present in modern fruits, vegetables spices, tea and coffee may have arisen, in part, from the acquisition of adaptive cellular stress responses and detoxification enzymes in animals that enabled them to consume plants containing potentially toxic chemicals. Interestingly, some of the same adaptive stress response mechanisms that protect neurons against noxious phytochemicals are also activated by dietary energy restriction and vigorous physical exertion, two environmental challenges that shaped brain evolution. In this perspective article, we describe some of the signaling pathways relevant to cellular energy metabolism that are modulated by ‘neurohormetic phytochemicals’ (potentially toxic chemicals produced by plants that have beneficial effects on animals when consumed in moderate amounts). We highlight the cellular bioenergetics-related sirtuin, adenosine monophosphate activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 (IGF-1) pathways. The inclusion of dietary neurohormetic phytochemicals in an overall program for brain health that also includes exercise and energy restriction may find applications in the prevention and treatment of a range of neurological disorders. [ABSTRACT FROM AUTHOR]

Earthworm decerebration causes temporary inhibition of reproduction which is mediated by certain brain-derived neurohormones; thus, cocoon production is an apposite supravital marker of neurosecretory center functional recovery during brain regeneration. The core aim of the present study was to investigate aspects of the interactions of nervous and immune systems during brain regeneration in adult Dendrobaena veneta (Annelida; Oligochaeta). Surgical brain extirpation was combined, either with (i) maintenance of immune-competent coelomic cells (coelomocytes) achieved by surgery on prilocaine-anesthetized worms or (ii) prior extrusion of fluid-suspended coelomocytes by electrostimulation. Both brain renewal and cocoon output recovery were significantly faster in earthworms with relatively undisturbed coelomocyte counts compared with individuals where coelomocyte counts had been experimentally depleted. These observations provide empirical evidence that coelomocytes and/or coelomocyte-derived factors (e.g. riboflavin) participate in brain regeneration and, by implication, that there is close functional synergy between earthworm neural and immune systems. [ABSTRACT FROM AUTHOR]

In this study, we examined differences among the gonadotropin-inhibitory hormone (GnIH), kisspeptin 1 (Kiss1), Kiss 1 receptor (G-protein-coupled receptor 54; GPR54), melatonin receptor 1 (MT1), and melatonin levels in brain cells of goldfishCarassius auratusexposed to white fluorescent light and three light-emitting diode (LED) wavelength and melatonin treatments in the culture medium. In the green and blue LED treatment groups, GnIH and MT1 mRNA expression levels were significantly lower than in the other groups; conversely, levels significantly increased in the melatonin treatment groups. Additionally, expression levels of Kiss1 and its receptor, GPR54, in the white fluorescent and red LED light groups were significantly lower than the other groups, but levels also significantly decreased in the melatonin treatment groups. These results suggest that white fluorescent and red wavelengths downregulate the production of neurohormones in the brains ofC. auratusand thus may inhibit sexual maturation in goldfish. [ABSTRACT FROM PUBLISHER]

Systemic inflammation leads to a variety of physiological (e.g. fever) and behavioral (e.g. anorexia, immobility, social withdrawal, depressed mood, disturbed sleep) responses that are collectively known as sickness. While these phenomena have been studied for the past few decades, the neurobiological mechanisms by which sickness occurs remain unclear. In this review, we first revisit how the body senses and responds to infections and injuries by eliciting systemic inflammation. Next, we focus on how peripheral inflammatory molecules such as cytokines, prostaglandins, and activated complement factors communicate with the brain to trigger neuroinflammation and sickness. Since depression also involves inflammation, we further elaborate on the interrelationship between sickness and depression. Finally, we discuss how immune activation can modulate neurons in the brain, and suggest future perspectives to help unravel how changes in neuronal functions relate to sickness responses. [ABSTRACT FROM AUTHOR]

There is strong evidence that brain nonapeptides are implicated as modulators of a wide array of social and reproductive behaviors in fishes. However, the question remains, as to whether there is a link between the distribution of active nonapeptides across brain regions and fishes specific behavioral phenotypes. To explore this link we compared the nonapeptides’ profile across the brains of fishes representing different degrees of mutualistic behavior (here: cleaning behavior). Herein we studied the quantitative distribution of both nonapeptides, arginine vasotocin (AVT) and isotocin (IT), in the brains of four species of fish belonging to the family Labridae : two are obligatory cleaners throughout their entire life ( Labroides dimidiatus and Labroides bicolor ), one species is a facultative cleaner ( Labropsis australis ; juveniles are cleaners and adults are corallivorous), and one is a non-cleaner species, corallivorous throughout its entire life ( Labrichthys unilineatus ). The biologically available AVT and IT concentrations were measured simultaneously in distinct brain macro-areas: forebrain, optic tectum, cerebellum and brain stem, using liquid chromatography–tandem mass spectrometry (LC–MS/MS). We showed that the levels of both AVT and IT varied significantly across species, as measured in the whole brain or in the specific macro-areas. Significantly higher AVT concentrations in the cerebellum which were found in the obligate cleaners seemed to be related to expression of mutualistic behavior. On the other hand, the higher levels of brain IT in the non-cleaner L. unilineatus suggested that these might be linked to the development of sexual dimorphism, which occurs only in this non-cleaner species. [ABSTRACT FROM AUTHOR]

To evaluate the dose-effects of Androctonus australis hector (Aah) venom injected subcutaneously on hemodynamics and neurohormonal secretions, 10 anesthetized and ventilated mongrel dogs, were split in two groups (n = 5/group). Subcutaneous injection was done with either 0.2 mg/kg or 0.125 mg/kg of the purified G50 scorpion toxic fraction. Hemodynamic parameters using right heart catheter were recorded and plasma concentrations of catecholamine, troponin, and serum toxic fraction were measured sequentially from baseline to 120 min. We identified the dose of toxic fraction evoking characteristic hemodynamic perturbation of severe envenomation, the time-lapse to envenomation, and the associated plasma level. The injection of 0.125 mg/kg toxic fraction was not associated with significant variations in hemodynamic parameters, whereas the 0.2 mg/kg dose caused envenomation characterized by significant increase in plasma catecholamines, increased pulmonary artery occluded pressure, mean arterial pressure, and systemic vascular resistance (p < 0.05), in association with sustained decline in cardiac output (p < 0.001). Envenomation occurred by the 30th minute, and the corresponding concentration of toxic fraction was 1.14 ng/ml. The current experiment allowed the identification of the sub-lethal dose (0.2 mg/kg) of the toxic fraction of Aah administered by the subcutaneous route. Two parameters with potential clinical relevance were also uncovered: the time-lapse to envenomation and the corresponding concentration of toxic fraction. [ABSTRACT FROM AUTHOR]

STUDY QUESTION: Do patients with congenital combined pituitary hormone deficiency(CCPHD)have different responses to gonadotrophin- induced spermatogenesis compared with those with idiopathic hypogonadotropic hypogonadism (IHH)? SUMMARY ANSWER: CCPHD patients have a better response to gonadotrophin therapy than IHH patients. WHAT IS KNOWN ALREADY: Gonadotrophins are effective in inducing spermatogenesis in patients with hypogonadotropic hypogonadism. DESIGN, SIZE AND DURATION: This retrospective cohort study included 75 patients, 53 of whom had IHH and 22 CCPHD. They were diagnosed, treated and followed up between January 2008 and December 2013. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Combined gonadotrophin therapy, consisting of human chorionic gonadotrophin and human menopausal gonadotrophin, was administered for 24 months. The success rate of spermatogenesis (≥1 sperm in ejaculate), serum total testosterone level, testicle size and sperm concentration during the treatment, as well as the first time sperm were detected in the ejaculate, were compared between the two diagnostic groups. All patients were treated in Peking Union Medical College Hospital. MAIN RESULTS AND THE ROLE OF CHANCE: Spermatogenesis was successfully induced in 85% of IHH patients and 100% of CCPHD patients after 24-month combined gonadotrophin treatment (P = 0.03). In comparison with IHH, CCPHD patients had larger mean testicle sizes during the gonadotrophin treatment at 6, 12, 18 and 24 months (all P<0.05). The initial time for sperm appearance in IHH group (n = 45) and CCPHD group (n = 22) was 13.2±5.9 versus 10.4 ±3.8 months (P = 0.045). Generally, CCPHD patients had higher sperm counts [median (quartiles)] than IHH patients during the treatment, but the difference was only statistically significant at 12 months of treatment, 3.3 (1.8, 12.0) versus 1.0 (0.0, 4.6) million/ml, P = 0.001. There was a higher level of serum total testosterone [mean (SD)] in the CCPHD group than the IHH group (676 ± 245 versus 555 ± 209 ng/dl, P = 0.035). LIMITATIONS, REASONS FOR CAUTION: First, the inherent nature of a retrospective designed study was a main shortcoming. Secondly, pathological gene mutations in IHH and CCPHD patients should be further investigated. Clarification of the underlying mechanisms between cryptorchidism and mutated genes may provide more information for the divergent therapeutic responses between two groups. Only a minority of patients were actively seeking to have children so information about fertility is limited. WIDER IMPLICATIONS OF THE FINDINGS: CCPHD patients had a lower incidence of cryptorchidism and a better response to gonadotrophin therapy than IHH patients, reflecting multiple defects on the different levels of reproduction axis in IHH. Furthermore, growth hormone is not indispensable for spermatogenesis in CCPHD patients. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by Natural Science Foundation of China (No: 81100416). None of the authors has any conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

The neurohormone Oxytocin (OT) has been one of the most studied peptides in behavioral sciences over the past two decades. Many studies have suggested that OT could increase trusting behaviors. A previous study, based on the “Envelope Task” paradigm, where trust is assessed by the degree of openness of an envelope containing participant’s confidential information, showed that OT increases trusting behavior and reported one of the most powerful effects of OT on a behavioral variable. In this paper we present two failed replications of this effect, despite sufficient power to replicate the original large effect. The non-significant results of these two failed replications clearly exclude a large effect of OT on trust in this paradigm but are compatible with either a null effect of OT on trust, or a small effect, undetectable with small sample size (N = 95 and 61 in Study 1 and 2, respectively). Taken together, our results question the purported size of OT’s effect on trust and emphasize the need for replications. [ABSTRACT FROM AUTHOR]

A simple, specific, high-throughput enzyme-linked immunosorbent assay (ELISA) for quantitative determination of melatonin was developed for directly measuring melatonin in cell culture medium with 10% FBS. This assay adopts a commercial monoclonal melatonin antibody and melatonin–HRP conjugate, so it can be applied in multiple labs rapidly with low cost compared with commercial RIA and ELISA kits. In addition, the procedure is much simpler with only four steps: 1) sample/conjugate incubation, 2) plate washing, 3) TMB color reaction and 4) reading of results. The standards of the assay cover a wide working range from 100 pg/mL to 10 ng/mL. The sensitivity was 68 pg/mL in cell culture medium with 10% FBS and 26 pg/mL in PBS with as little as 25 μL sample volume. The recovery of melatonin from cell culture medium was 101.0%. The principal cross-reacting compound was 5-methoxytryptophol (0.1%). The variation coefficients of the assay, within and between runs, ranged between 6.68% and 15.76% in cell culture medium. The mean linearity of a series diluted cell culture medium sample was 105% (CV = 5%), ranging between 98% and 111%, y = 5.5263x + 0.0646, R 2 = 0.99. The assay enables small research and teaching labs to reliably measure this important neurohormone. [ABSTRACT FROM AUTHOR]

There has been a 10-year hiatus in the approval of a new pharmacotherapy for patients with chronic heart failure with a reduced ejection fraction ( HFr EF). Combining an angiotensin receptor blocker, valsartan, with sacubitril, an inhibitor of neprilysin, results in increasing levels of natriuretic peptides that counterbalance high circulating levels of neurohormones in HFr EF. This has resulted in the development of a new agent, LCZ696. A comprehensive overview of LCZ696, its pharmacology, its role in the pathophysiology of HFr EF, completed and future clinical trial information, specific critical issues, and the place of LCZ696 in HFr EF therapy are presented. [ABSTRACT FROM AUTHOR]

The definition of a hormone has been in part delineated by its journey to distant receptor targets. Following activation of a receptor, a subsequent reaction facilitates the regulation of physiology and, ultimately, behavior. However, a growing number of studies report that hormones can influence these events at a previously underappreciated high speed. With the potential to act as neurotransmitters, the definition of a hormone and its mechanisms of action are evolving. In this symposium, we united scientists who use contemporary molecular, electrophysiological, and biochemical approaches to study aspects of rapid hormone action in a broad array of systems across different levels of biological organization. What emerged was an overwhelming consensus that the use of integrative and comparative approaches fuels discovery and increases our understanding of de novo hormone synthesis, local actions of neurohormones, and subsequent effects on neuroplasticity and behavior. [ABSTRACT FROM AUTHOR]

The discovery of steroid hormone receptors in brain regions that mediate every aspect of brain function has broadened the definition of 'neuroendocrinology' to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. This imbalance, in turn, affects systemic physiology via neuroendocrine, autonomic, immune and metabolic mediators. In the short term, as for increased fearful vigilance and anxiety in a threatening environment, these changes may be adaptive. But, if the danger passes and the behavioral state persists along with the changes in neural circuitry, such maladaptation may need intervention with a combination of pharmacological and behavioral therapies, as is the case for chronic anxiety and depression. There are important sex differences in the brain responses to stressors that are in urgent need of further exploration. Moreover, adverse early-life experience, interacting with alleles of certain genes, produce lasting effects on brain and body over the life-course via epigenetic mechanisms. While prevention is most important, the plasticity of the brain gives hope for therapies that take into consideration brain-body interactions. [ABSTRACT FROM AUTHOR]

Geoffrey Harris, while still a medical student at Cambridge, was the first researcher (1937) to provide experimental proof for the then tentative view that the anterior pituitary gland was controlled by the CNS. The elegant studies carried out by Harris in the 1940s and early 1950s, alone and in collaboration with John Green and Dora Jacobsohn, established that this control was mediated by a neurohumoral mechanism that involved the transport by hypophysial portal vessel blood of chemical substances from the hypothalamus to the anterior pituitary gland. The neurohumoral control of anterior pituitary secretion was proved by the isolation and characterisation of the 'chemical substances' (mainly neuropeptides) and the finding that these substances were released into hypophysial portal blood in a manner consistent with their physiological functions. The new discipline of neuroendocrinology - the way that the brain controls endocrine glands and vice versa - revolutionised the treatment of endocrine disorders such as growth and pubertal abnormalities, infertility and hormone-dependent tumours, and it underpins our understanding of the sexual differentiation of the brain and key aspects of behaviour and mental disorder. Neuroendocrine principles are illustrated in this Thematic Review by way of Harris' major interest: hypothalamic-pituitary-gonadal control. Attention is focussed on the measurement of GnRH in hypophysial portal blood and the role played by the self-priming effect of GnRH in promoting the onset of puberty and enabling the oestrogen-induced surge or pulses of GnRH to trigger the ovulatory gonadotrophin surge in humans and other spontaneously ovulating mammals. [ABSTRACT FROM AUTHOR]

The brain's unimaginably complex operations are expressed in just two types of output: muscle activity and hormone release. These are the means by which the brain acts beyond its bony casing. Muscle-mediated actions (such as speaking, writing, pupillary reflexes) send signals to the outside world that may convey thoughts, emotions or evidence of neurological disorder. The outputs of the brain as a hormone secreting gland are usually less evident. Their discovery required several paradigm shifts in our understanding of anatomy. The first occurred in 1655. Exactly 300 years later, Geoffrey Harris' monograph Neural control of the pituitary gland launched the scientific discipline that is now known as neuroendocrinology. His hypotheses have stood the test of time to a remarkable degree. A key part of his vision concerned the two-way 'interplay between the central nervous system and endocrine glands'. Over the past 60 years, the importance of this reciprocity and the degree to which cerebral functions are influenced by the endocrine environment have become increasingly clear. [ABSTRACT FROM AUTHOR]

Investigating the proximate mechanism underlying behavior has long been a primary goal of ethologists. With the recent focus on behavioral correlations (e.g., behavioral syndromes), a fundamental question arises regarding what mechanisms may drive positive relationships between functionally distinct behaviors. Understanding these mechanisms can inform critical questions, such as why distinct behaviors are often correlated, and can also lend insights into how behavioral similarities are conserved across species. Arthropods provide an idea system to study these questions as the biogenic amines, such as octopamine and serotonin, have long been known to mediate a large number of behaviors such as aggression, dominance, escape behavior, and others. Behaviorists have several ways in which they can manipulate these biogenic amines in vivo, including injection, feeding, and topical application. Topical application is potentially an optimal method for manipulating amine concentrations, given that it is minimally invasive and relatively precise. Here, we investigate the role of biogenic amines, octopamine, and serotonin, in mediating a range of similar and often correlated behaviors in two distantly related species of spiders, the western black widow, Latrodectus hesperus, and the funnel-web spider, Agelenopsis pennsylvanica. Additionally, we investigate the behavioral effects associated with three commonly used carrier solvents: dimethylformamide ( DMF), dimethyl sulfoxide ( DMSO), and acetone. We demonstrate that biogenic amines are involved both in mediating several behaviors, and also potentially the links between different behaviors. We also show that the same behaviors in different species are not affected by biogenic amines in the same manner, suggesting differences in the underlying neurophysiological mechanisms governing behavior. Furthermore, we discovered large and pervasive effects associated with both carrier solvents, thus calling into question the potential usefulness and interpretability of topical application methods in behavioral research. [ABSTRACT FROM AUTHOR]

Gonadotropin-releasing hormone (GnRH) controls mammalian reproduction via the hypothalamic-pituitary-gonadal (hpg) axis, acting on gonadotrope cells in the pituitary gland that express the GnRH receptor (GnRHR). Cells expressing the GnRHR have also been identified in the brain. However, the mechanism by which GnRH acts on these potential target cells remains poorly understood due to the difficulty of visualizing and identifying living GnRHR neurons in the central nervous system. We have developed a mouse strain in which GnRHR neurons express a fluorescent marker, enabling the reliable identification of these cells independent of the hormonal status of the animal. In this study, we analyze the GnRHR neurons of the periventricular hypothalamic nucleus in acute brain slices prepared from adult female mice. Strikingly, we find that the action potential firing pattern of these neurons alternates in synchrony with the estrous cycle, with pronounced burst firing during the preovulatory period. We demonstrate that GnRH stimulation is sufficient to trigger the conversion from tonic to burst firing in GnRHR neurons. Furthermore, we show that this switch in the firing pattern is reversed by a potent GnRHR antagonist. These data suggest that endogenous GnRH acts on Gn- RHR neurons and triggers burst firing in these cells during late proestrus and estrus. Our data have important clinical implications in that they indicate a novel mode of action for GnRHR agonists and antagonists in neurons of the central nervous system that are not part of the classical hpg axis. [ABSTRACT FROM AUTHOR]

Orexins (OX) have been recently implicated in ethanol seeking and self-administration. A few recent studies have provided additional evidence that OX receptor antagonists effectively reduce voluntary ethanol consumption in subjects spontaneously showing high levels of ethanol intake. The present study further evaluates the contribution of OXR1 to excessive binge-like drinking of ethanol in ad libitum-fed C57BL/6J mice from a pharmacological and molecular approach. The main findings in the study are: (1) Icv administration of SB-334867 (3 μg/μl) blunted ethanol (20% v/v), but not saccharin (0.15% w/v) binge-like drinking in a drinking in the dark procedure, without any alteration of chow consumption or total calories ingested; (2) Icv administration of SB-334867 (3 μg/μl) increased the latency to recover the righting reflex after a sedative dose of ethanol without any significant alteration in ethanol peripheral metabolism; (3) four repetitive, 2-h daily episodes of saccharin, but not ethanol binge-like drinking blunted OXR1 mRNA expression in the lateral hypothalamus. Present findings extend the current knowledge pointing to a role for OX signaling in ethanol sedation, which might partially explain the inhibitory effect of OXR1 antagonists on ethanol consumption. Combined pharmacological and molecular data suggesting the contribution of OXR1 in ethanol binge-drinking leading us to propose the idea that targeting OXR1 could represent a novel pharmacological approach to control binge-consumption episodes of ethanol in vulnerable organisms failing to spontaneously reduce OX activity. [ABSTRACT FROM AUTHOR]

Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) in the brain plays an important role in the progression of hypertension and hydrogen peroxide (H 2 O 2 ) is a major component of ROS. The aim of this study is to explore whether endogenous H 2 O 2 changed by polyethylene glycol-catalase (PEG-CAT) and aminotriazole (ATZ) in the hypothalamic paraventricular nucleus (PVN) regulates neurotransmitters, renin-angiotensin system (RAS), and cytokines, and whether subsequently affects the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in high salt-induced hypertension. Male Sprague–Dawley rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 10 weeks. Then rats were treated with bilateral PVN microinjection of PEG-CAT (0.2 i.u./50 nl), an analog of endogenous catalase, the catalase inhibitor ATZ (10 nmol/50 nl) or vehicle. High salt-fed rats had significantly increased MAP, RSNA, plasma norepinephrine (NE) and pro-inflammatory cytokines (PICs). In addition, rats with high-salt diet had higher levels of NOX-2, NOX-4 (subunits of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), interleukin-1beta (IL-1β), glutamate and NE, and lower levels of gamma-aminobutyric acid (GABA) and interleukin-10 (IL-10) in the PVN than normal diet rats. Bilateral PVN microinjection of PEG-CAT attenuated the levels of RAS and restored the balance of neurotransmitters and cytokines, while microinjection of ATZ into the PVN augmented those changes occurring in hypertensive rats. Our findings demonstrate that ROS component H 2 O 2 in the PVN regulating MAP and RSNA are partly due to modulate neurotransmitters, renin-angiotensin system, and cytokines within the PVN in salt-induced hypertension. [ABSTRACT FROM AUTHOR]

Over the past decade, science has greatly advanced our understanding of interdependent feedback mechanisms involving the heart, lung, and kidney. Organ injury is the consequence of maladaptive neurohormonal activation, oxidative stress, abnormal immune cell signaling, and a host of other mechanisms that precipitate adverse functional and structural changes. The presentation of interorgan crosstalk may include an acute, chronic, or acute on chronic timeframe. We review the current, state-of-the-art understanding of cardio-pulmonary-renal interactions and their related pathophysiology, perpetuating nature, and cycles of increased susceptibility and reciprocal progression. To this end, we present a multidisciplinary approach to frame the diverse spectrum of published observations on the topic. Assessment of organ functional reserve and use of biomarkers are valuable clinical strategies to screen and detect disease, assist in diagnosis, assess prognosis, and predict recovery or progression to chronic disease. [ABSTRACT FROM AUTHOR]

Tako-Tsubo cardiomyopathy (TTC) is characterized by apical ballooning of the left ventricle and symptoms and signs mimicking acute myocardial infarction. The high catecholamine levels in the acute phase of TTC and common emotional triggers suggest a dysregulated stress response system. This study examined whether patients with TTC show exaggerated emotional, neurohormonal, and hemodynamic responses to mental stress. Patients with TTC (n = 18; mean age 68.3 ± 11.7,78% women) and 2 comparison groups (healthy controls, n = 19; mean age 60.0 ± 7.6,68% women; chronic heart failure, n = 19; mean age 68.8 ± 10.1,68% women) performed a structured mental stress task (anger recall and mental arithmetic) and low-grade exercise with repeated assessments of negative emotions, neurohormones (catecholamines: norepinephrine, epinephrine, dopamine, hypothalamic-pituitary-adrenal axis hormones: adrenocorticotropic hormone [ACTH], cortisol), echocardiography, blood pressure, and heart rate. TTC was associated with higher norepinephrine (520.7 ± 125.5 vs 407.9 ± 155.3 pg/ml, p = 0.021) and dopamine (16.2 ± 10.3 vs 10.3 ± 3.9 pg/ml, p = 0.027) levels during mental stress and relatively low emotional arousal (p <0.05) compared with healthy controls. During exercise, norepinephrine (511.3 ± 167.1 vs 394.4 ± 124.3 pg/ml, p = 0.037) and dopamine (17.3 ± 10.0 vs 10.8 ± 4.1 pg/ml, p = 0.017) levels were also significantly higher in patients with TTC compared with healthy controls. In conclusion, catecholamine levels during mental stress and exercise were elevated in TTC compared with healthy controls. No evidence was found for a dysregulated hypothalamic-pituitary-adrenal axis or hemodynamic responses. Patients with TTC showed blunted emotional arousal to mental stress. This study suggests that catecholamine hyper-reactivity and not emotional hyper-reactivity to stress is likely to play a role in myocardial vulnerability in TTC. [ABSTRACT FROM AUTHOR]

Objective: To determine the effects of Ramadan fasting on serum levels of stress neurohormones in Iranian women with polycystic ovary syndrome (PCOS). Materials and methods: This study was a clinical trial and was performed during July 2011 (month of Ramadan) in Royan institute, Tehran. A total of 40 women who were aged 20-40 years and known cases of PCOS and had no other medical diseases were included in the study. They were divided into two groups as follows: (i) study group (n = 20) who participated in Ramadan fasting and (ii) control group (n = 20) who did not participate in fasting. For evaluating Ramadan's effect on the level of neurohormones serum level of the following variables were evaluated before and after Ramadan: cortisol, adrenaline (A), noradrenalin (NA), beta-endorphin (ß-End), insulin, as well as sex hormones including follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Results: In the study group after Ramadan serum cortisol and nor-adrenaline levels were significantly lower than the initial levels obtained at beginning of Ramadan (p < 0.05) as compared to control group. Conclusion: This study indicates that Ramadan fasting decreases stress neurohormones in women with PCOS. [ABSTRACT FROM AUTHOR]

Background In elderly patients with chronic heart failure (CHF), a gap exists between widespread use of lower doses of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs) and β-blockers (BBs) and guideline recommendations. Therefore, the aim of the present study was to investigate whether patients receiving ≥ 50% target dose outperform those receiving < 50% target dose, despite maximum up-titration, and whether the target dose outperforms all other doses. Methods and Results Patients (n = 185) aged ≥ 80 years with CHF and left ventricular ejection fraction ≤ 40% referred (between January 2000 and January 2008) to two CHF outpatient clinics at two university hospitals, were included and retrospectively studied. Of the study population, 53% received the target dose of ACEIs/ARBs, whereas 26% received < 50% of the target dose. Half received < 50% of the target dose of BBs and 21% received the target dose. After ≥ 5 years of follow-up, all-cause mortality was 76.8%. Patients who received the target dose of ACEIs/ARBs had higher survival rates from all-cause mortality than those receiving < 50% of target dose (HR = 0.6, 95%CI 0.4-0.9, P = 0.033), but those receiving ≥ 50% of target dose did not statistically differ from those who achieved target dose. This dose-survival relationship was not the case for BBs. Conclusions Target dose of ACEIs/ARBs is associated with reduced all-cause five-year mortality in very old patients with systolic heart failure, despite that this was achievable in only about half of the patients. However, the clinical outcome of BB therapy is independent of BB dose when the target heart rate is achieved. [ABSTRACT FROM AUTHOR]

Structural myocardial remodeling is an important concept in understanding chronic heart failure disease. Its recognition leads to important treatments of heart failure, mainly to blocking of the activation of neurohormonal systems in these patients. The authors try to summarize known experience about structural remodeling, focusing mainly on cardiovascular inflammation, on collagen matrix alteration and on cardiomyocyte damage during the progression of heart failure. They also try to look for possible treatments. Fig. 2, Lit. 54, Online full text (Free, PDF) www. cardiology.sk [ABSTRACT FROM AUTHOR]

Neurohormonal excitation and dyspnea are the hallmarks of heart failure (HF) and have long been associated with poor prognosis in HF patients. Sympathetic nerve activity (SNA) and ventilatory equivalent of carbon dioxide (VE/VO2) are elevated in moderate HF patients, and increased even further in severe HF patients. The increase in SNA in HF patients is present regardless of age, gender, and etiology of systolic dysfunction. Neurohormonal activation is the major mediator of the peripheral vasoconstriction characteristic of HF patients. In addition, reduction in peripheral blood flow increases muscle inflammation, oxidative stress and protein degradation, which is the essence of the skeletal myopathy and exercise intolerance in HF. Here we discuss the beneficial effects of exercise training on resting SNA in patients with systolic HF and its central and peripheral mechanisms of control. Further, we discuss the exercise-mediated improvement in peripheral vasoconstriction in patients with HF. We will also focus on the effects of exercise training on ventilatory responses. Finally, we review the effects of exercise training on features of the skeletal myopathy in HF. In summary, exercise training plays an important role in HF, working synergistically with pharmacological therapies to ameliorate these abnormalities in clinical practice. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is associated with a loss of renal and vascular protection in women compared with men, but the responsible mechanisms are unclear. Recent experimental work implicated humanin (HN) as a novel cytoprotective hormone in DM. Our goal was to measure sex-related differences in HN levels in uncomplicated type 1 DM patients (T1D) and healthy controls (HC), as well as the interaction between HN, circulating neurohormones, and vascular function. Plasma HN, cGMP and aldosterone, blood pressure (BP), glomerular filtration rate, and effective renal plasma flow (inulin and para-aminohippurate) were measured in HC (11 men, 10 women) and T1D (23 men and 18 women) during clamped euglycemia (4-6 mmol·L-1). Plasma HN levels were generally lower in HC men by comparison with the women, but the differences were not statistically significant. In contrast, levels in the T1D men were higher compared with the T1D women ( p = 0.026) and HC men ( p < 0.0001). In the HC men, but not the women, HN correlated negatively with BP, but not with renal function, cGMP, or aldosterone. In the T1D men, HN negatively correlated with plasma cGMP. In the T1D women, HN did not correlate with neurohormones or vascular function. Future work should determine the role of HN in the pathogenesis of sex-related vascular function differences in DM. [ABSTRACT FROM AUTHOR]

We analyze a four-dimensional slow-fast piecewise linear system consisting of two coupled McKean caricatures of the FitzHugh-Nagumo system. Each oscillator is a continuous slow-fast piecewise linear system with three zones of linearity. The coupling is one-way, that is, one subsystem evolves independently and is forcing the other subsystem. In contrast to the original FitzHugh-Nagumo system, we consider a negative slope of the linear nullcline in both the forcing and the forced system. In the forcing system, this lets us, by just changing one parameter, pass from a system having one equilibrium and a relaxation cycle to a system with three equilibria keeping the relaxation cycle. Thus, we can easily control the changes in the oscillation frequency of the forced system. The case with three equilibria and a linear slow nullcline is a new configuration of the McKean caricature, where the existence of the relaxation cycle was not studied previously. We also consider a negative slope of the y-nullcline in the forced system that enables us to reproduce a quasi-steady state called the surge. We analyze not only the qualitative behavior of the four-dimensional system, but also quantitative aspects such as the period, frequency, and amplitude of the oscillations. The system is used to reproduce all the features endowed in a former smooth model and reproduce the secretion pattern of the hypothalamic neurohormone GnRH along the ovarian cycle in different species. [ABSTRACT FROM AUTHOR]

Arthropod molt is coordinated through the interplay between ecdysteroids and neuropeptide hormones. In crustaceans, changes in the activity of Y-organs during the molt cycle have been regulated by molt-inhibiting hormone (MIH) and crustacean hyperglycemic hormone (CHH). Little has been known of the mode of direct effects of ecdysteroids on the levels of MIH and CHH in the eyestalk ganglia during the molt cycle. This study focused on a putative feedback of ecdysteroids on the expression levels of MIH transcripts using in vitro incubation study with ecdysteroids and in vivo RNAi in the blue crab, Callinectes sapidus. Our results show a specific expression of ecdysone receptor (EcR) in which EcR1 is the major isoform in eyestalk ganglia. The initial elevation of MIH expression at the early premolt stages is replicated by in vitro incubations of eyestalk ganglia with ecdysteroids that mimic the intrinsic conditions of D0 stage: the concentration (75 ng/ml) and composition (ponasterone A and 20-hydroxyecdysone at a 3:1 (w:w) ratio). Additionally, multiple injections of EcR1-dsRNA reduce MIH expression by 67%, compared to the controls. Our data provide evidence on a putative feedback mechanism of hormonal regulation during molting cycle, specifically how the molt cycle is repeated during the life cycle of crustaceans. The elevated concentrations of ecdysteroids at early premolt stage may act positively on the levels of MIH expression in the eyestalk ganglia. Subsequently, the increased MIH titers in the hemolymph at postmolt would inhibit the synthesis and release of ecdysteroids by Y-organs, resulting in re-setting the subsequent molt cycle. [ABSTRACT FROM AUTHOR]

Background Brain natriuretic peptide (BNP) levels are elevated in patients with repaired Tetralogy of Fallot (rTOF), the clinical significance of which remains uncertain. Methods and results Ninety consecutive adults (=16 years) with rTOF (mean age 32.7±11.3 years, 64% men) were prospectively recruited from a single tertiary centre, together with 15 age-matched and gendermatched controls. Patients with rTOF had elevated BNP (8.9 (5.9-14.6) vs 5.4 (2.2-7.5) pmol/L; p<0.01), and BNP activation was common even in asymptomatic patients. Also, atrial natriuretic peptide (6.9 (4.0-9.9) vs 3.3 (1.0-4.0) pmol/L; p<0.01), endothelin-1 (1.14 (0.94-1.48) vs 0.75 (0.44-0.93) pmol/L; p<0.01) and renin (55.0 (45.5-66.5) vs 18.6 (12.0-22.7) pmol/L; p<0.01) were elevated at baseline compared with controls. Interactions between BNP with endothelin-1, cardiothoracic ratio and right atrial area were evident. Eight deaths occurred over a median follow-up of 10 years. On Cox regression analysis, BNP emerged as a strong predictor of death (HR 1.16 per 10 pmol/L, 95% CI 1.05 to 1.29; p<0.01). Survival receiver operating curve analysis revealed an optimum cut-off of BNP =15 pmol/L (=52 pg/mL), above which BNP was related to significantly increased mortality (HR 5.40, 95% CI 1.29 to 22.6; p<0.01); absolute mortality at 5 years 19% vs 3% in patients with BNP =15 pmol/L. BNP was also a predictor of sustained arrhythmia (HR 2.06 per 10 pmol/L, 95% CI 1.32 to 3.21; p<0.05). Conclusions Neurohormonal activation is present in adults with rTOF including asymptomatic patients. BNP level =15 pmol/L is associated with a fivefold increased risk of death. These data suggest that BNP measurement in patients with rTOF should be incorporated in the periodic risk stratification assessment of these patients under lifelong follow-up. [ABSTRACT FROM AUTHOR]

Because of resetting, a role for baroreflexes in long-term control of arterial pressure has been commonly dismissed in the past. However, in recent years, this perspective has changed. Novel approaches for determining chronic neurohormonal and cardiovascular responses to natural variations in baroreceptor activity and to electrical stimulation of the carotid baroreflex indicate incomplete resetting and sustained responses that lead to long-term alterations in sympathetic activity and arterial pressure. [ABSTRACT FROM AUTHOR]